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Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease.,To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients.,Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA).,The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor.,We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity.,A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%.,After validation in another independent cohort, sensitivity was maintained at 85%.,Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage.,The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis.,Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis.,However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood.,Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation.,While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability.,Peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1β) is a transcriptional coactivator that plays important roles in regulating multiple aspects of energy metabolism and cytokine signaling pathways.,PGC-1β overexpression leads to the attenuation of macrophage-mediated inflammation.,In this study, we aimed to determine the expression of PGC-1β in RA synovium and fibroblast-like synoviocytes (FLS), and explore the mechanisms of PGC-1β on both the proinflammatory effects and apoptosis in RA-FLS.,Synovium was obtained from 31 patients with active RA, as well as 13 osteoarthritis (OA) and 10 orthopedic arthropathies (Orth.A) as “less inflamed” disease controls.,FLS were then isolated and cultured.,Synovial PGC-1β expression was determined by immunohistochemistry staining, while FLS PGC-1β expression was detected by immunofluorescence staining, quantitative real-time PCR (qPCR) assay and western blot.,PGC-1β was depleted by lentivirus sh-RNA, and up-regulated by pcDNA3.1- PGC-1β.,The expression of proinflammatory cytokines, matrix metalloproteinases and receptor activator of nuclear factor-kappaB ligand was analyzed by qPCR, cytometric bead array and western blot.,The expression of mitogen-activated protein kinases and nuclear factor-kappaB (NF-κB) was determined by qPCR and western blot.,Besides, cell apoptosis was examined using flow cytometry.,The interaction between PGC-1β and NF-κB was performed by dual-luciferase reporter gene assays.,(A) Synovial PGC-1β was over-expressed in RA patients compared with OA or Orth.A patients.,(B) PGC-1β expression significantly increased in RA-FLS compared with OA-FLS.,(C) PGC-1β mediated the expression of proinflammatory cytokines and apoptosis through extracellular signal-regulated kinase (ERK), p38 and NF-κB in RA-FLS.,(D) PGC-1β mediated NF-κB transcription in RA-FLS, but did not affect ERK and p38.,The results indicate that PGC-1β may play important roles in the proinflammatory effects and apoptosis of RA-FLS.

On the basis of extensive studies in Joslin Clinic patients over 25 years, we propose a new model of diabetic nephropathy in type 1 diabetes.,In this model, the predominant clinical feature of both early and late stages of diabetic nephropathy is progressive renal decline, not albuminuria.,Progressive renal decline (estimated glomerular filtration rate loss >3.5 mL/min/year) is a unidirectional process that develops while patients have normal renal function.,It progresses at an almost steady rate until end-stage renal disease is reached, albeit at widely differing rates among individuals.,Progressive renal decline precedes the onset of microalbuminuria, and as it continues, it increases the risk of proteinuria.,Therefore, study groups ascertained for microalbuminuria/proteinuria are enriched for patients with renal decline (decliners).,We found prevalences of decliners in 10%, 32%, and 50% of patients with normoalbuminuria, microalbuminuria, and proteinuria, respectively.,Whether the initial lesion of progressive renal decline is in the glomerulus, tubule, interstitium, or vasculature is unknown.,Similarly unclear are the initiating mechanism and the driver of progression.,No animal model mimics progressive renal decline, so etiological studies must be conducted in humans with diabetes.,Prospective studies searching for biomarkers predictive of the onset and rate of progression of renal decline have already yielded positive findings that will help to develop not only accurate methods for early diagnosis but also new therapeutic approaches.,Detecting in advance which patients will have rapid, moderate, or minimal rates of progression to end-stage renal disease will be the foundation for developing personalized methods of prevention and treatment of progressive renal decline in type 1 diabetes.

This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).,Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study.,GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.,A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%).,Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease.,Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs.,1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.,Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2.,However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

Disease activity, severity and comorbidity contribute to increased mortality in patients with rheumatoid arthritis (RA).,We evaluated the impact of age at disease onset on prognostic risk factors and treatment in patients with early disease.,In this study, 950 RA patients were followed regularly from the time of inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender and/or swollen joints, Visual Analogue Scale pain and global scores, and Disease Activity Score in 28 joints (DAS28)) and function (Health Assessment Questionnaire (HAQ)).,Disease severity, measured on the basis of radiographs of the hands and feet (erosions based on Larsen score), extraarticular disease, nodules, and comorbidities and treatment (disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biologics and nonsteroidal anti-inflammatory drugs) were recorded at the time of inclusion and at 5 years.,Autoantibodies (rheumatoid factor, antinuclear antibodies and antibodies against cyclic citrullinated peptides (ACPAs)) and genetic markers (human leucocyte antibody (HLA) shared epitope and protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analysed at the time of inclusion.,Data were stratified as young-onset RA (YORA) and late-onset RA (LORA), which were defined as being below or above the median age at the time of onset of RA (58 years).,LORA was associated with lower frequency of ACPA (P < 0.05) and carriage of PTPN22-T variant (P < 0.01), but with greater disease activity at the time of inclusion measured on the basis of ESR (P < 0.001), CRP (P < 0.01) and accumulated disease activity (area under the curve for DAS28 score) at 6 months (P < 0.01), 12 months (P < 0.01) and 24 months (P < 0.05), as well as a higher HAQ score (P < 0.01) compared with YORA patients.,At baseline and 24 months, LORA was more often associated with erosions (P < 0.01 for both) and higher Larsen scores (P < 0.001 for both).,LORA was more often treated with corticosteroids (P < 0.01) and less often with methotrexate (P < 0.001) and biologics (P < 0.001).,YORA was more often associated with early DMARD treatment (P < 0.001).,The results of multiple regression analyses supported our findings regarding the impact of age on chosen treatment.,YORA patients were more frequently ACPA-positive than LORA patients.,LORA was more often associated with erosions, higher Larsen scores, higher disease activity and higher HAQ scores at baseline.,Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and less often with DMARDs in early-stage disease.,These findings could have implications for the development of comorbidities.

The aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice since the introduction of RTX therapy.,This was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany.,Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI).,Safety was assessed by recording adverse drug reactions (ADRs).,Physician and patient global efficacy and tolerability assessments were also evaluated.,Overall, 2,484 patients (76.7% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7% monotherapy).,The total observation period was approximately six-years (median follow-up 14.7 months).,RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses.,DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml.,Response and tolerability were rated good/very good by the majority of physicians and patients.,Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively.,Infections were the most frequently reported ADRs (9.1%; 11.39/100 patient-years); approximately 1% of patients per course discontinued therapy due to ADRs.,Prolonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians’ and patients’ global assessments.,Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness.,With growing experience, physicians repeated treatments earlier in patients with less severe disease activity.

‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity.,Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.,To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’),We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%).,At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001).,Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001).,NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001).,NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.

Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.,The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.,Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV).,We assessed patient disability using the Expanded Disability Status Scale (EDSS).,We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).,In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid.,In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.,Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy.,Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE).,Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations.,Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A).,Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative.,When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results).,False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies.,Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA.,Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies.,Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis.,If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is accepted as an autoimmune disorder of the central nervous system (CNS).,NLR family pyrin domain containing 3 (NLRP3) inflammasome, a potent innate inflammatory mediator, can activate IL-1β and induce the migration of T helper cell into CNS.,However, the possible role of NLRP3 inflammasome in the pathogenesis of anti-NMDAR encephalitis remains unclear.,This study aims to determine the levels of NLRP3 and related cytokines (IL-1β, IL-6, and IL-17) in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients and to assess whether NLRP3 influences the clinical outcomes of this disease.,Twenty-five patients with anti-NMDAR encephalitis, 12 viral meningoencephalitis patients and 26 controls with non-inflammatory neurological diseases were recruited.,CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 were measured by enzyme-linked immunosorbent assay.,Thirteen out of 25 patients were re-examed for the concentrations of NLRP3 and cytokines 6 months later.,Our results showed significant increases of CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 in anti-NMDAR encephalitis patients.,There were positive correlations between CSF NLRP3 inflammasome and cytokines in anti-NMDAR encephalitis patients.,There was also a positive correlation between maximum modified Rankin Scale (mRS) scores and CSF NLRP3 inflammasome in anti-NMDAR encephalitis patients.,During follow-up, the decrease of mRS was positively correlated with the decrease of CSF NLRP3 inflammasomes.,These results suggested that the level of CSF NLRP3 inflammasome could represent the severity of anti-NMDAR encephalitis and the reduction of CSF NLRP3 inflammasome could act as an indicator for the prognosis of this disease.

A novel member of human RNA coronavirus, which is an enveloped betacoronavirus, has been termed severe acute respiratory syndrome coronavirus-2 (SARS COV-2).,The illness caused by SARS COV-2 is referred to as the coronavirus disease 2019 (COVID-19).,It is a highly contagious disease that has resulted in a global pandemic.,The clinical spectrum of COVID-19 ranges from asymptomatic illness to acute respiratory distress syndrome, septic shock, multi-organ dysfunction, and death.,The most common symptoms include fever, fatigue, dry cough, dyspnea, and diarrhea.,Neurological manifestations have also been reported.,However, the data on the association of Guillain-Barré syndrome (GBS) with COVID-19 are scarce.,We report a rare case of a COVID-19-positive 36-year-old immunocompromised male who presented with clinical features of GBS.,His clinical examination showed generalized weakness and hyporeflexia.,The cerebrospinal fluid (CSF) analysis showed albuminocytological dissociation.,Intravenous immunoglobulin (IVIG) was administered based on the high clinical suspicion of GBS.,The patient’s neurological condition worsened with progression to bulbar weakness and ultimately neuromuscular respiratory failure requiring mechanical ventilation.,His nerve conduction studies were consistent with demyelinating polyneuropathy.,He received five plasma exchange treatments and was successfully weaned from mechanical ventilation.,A brain and cervical spine magnetic resonance imaging was obtained to rule out other causes, which was normal.,COVID-19 is believed to cause a dysregulated immune system, which likely plays an important role in the neuropathogenesis of GBS.

Presented herein is a severe case of SARS-CoV-2 associated Guillain-Barré syndrome (GBS), showing only slight improvement despite adequate therapy.,To date, only few cases of GBS associated with this infection have been described.,This case report summarizes the insights gain so far to GBS with this antecedent trigger.,So far, attention has mostly focused on complications of the CNS involvement.,Taking into account that GBS can cause a considerable impairment of the respiratory system, clinicians dealing with SARS-CoV-2 positive-tested patients should pay attention to symptoms of the peripheral nervous system.,As far as we know from this reported case and the review of the current literature, there seems to be no association with antiganglioside antibodies or a positive SARS-CoV-2 RT-PCR in CSF.,An obvious frequent occurrence of a bilateral facial weakness or bilateral peripheral facial diplegia should be emphasized.

Severe coronavirus disease 2019 (COVID -19) has led to a rapid increase in mortality worldwide.,Rheumatoid arthritis (RA) was a high-risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas the molecular mechanisms underlying RA and CVOID-19 are not well understood.,The objectives of this study were to analyze potential molecular mechanisms and identify potential drugs for the treatment of COVID-19 and RA using bioinformatics and a systems biology approach.,Two Differentially expressed genes (DEGs) sets extracted from GSE171110 and GSE1775544 datasets were intersected to generate common DEGs, which were used for functional enrichment, pathway analysis, and candidate drugs analysis.,A total of 103 common DEGs were identified in the two datasets between RA and COVID-19.,A protein-protein interaction (PPI) was constructed using various combinatorial statistical methods and bioinformatics tools.,Subsequently, hub genes and essential modules were identified from the PPI network.,In addition, we performed functional analysis and pathway analysis under ontological conditions and found that there was common association between RA and progression of COVID-19 infection.,Finally, transcription factor-gene interactions, protein-drug interactions, and DEGs-miRNAs coregulatory networks with common DEGs were also identified in the datasets.,We successfully identified the top 10 hub genes that could serve as novel targeted therapy for COVID-19 and screened out some potential drugs useful for COVID-19 patients with RA.

To investigate outcomes of Coronavirus Disease-2019 (COVID-19) in patients with rheumatoid arthritis (RA) as compared to the general population.,Additionally, outcomes were explored among RA patients stratified by sex, race, and medications use through sub-cohort analyses.,This comparative cohort study used a US multicenter research network (TriNetX) to extract data on all adult RA patients who were diagnosed with COVID-19, and adults without RA who were diagnosed with COVID-19 (comparative cohort) anytime from January 20, 2020 to April 11, 2021.,COVID-19 outcomes were assessed within 30 days after its diagnosis.,Baseline characteristics that included demographics and comorbidities were controlled in propensity score matching.,A total of 9730 RA patients with COVID-19 and 656,979 non-RA with COVID-19 were identified.,Before matching, the risk of all outcomes including mortality (RR: 2.11, 95%CI: 1.90 to 2.34), hospitalization (RR: 1.60, 1.55 to 1.66), intensive care unit-ICU admission (RR: 1.86, 1.71 to 2.05), mechanical ventilation (RR: 1.62, 1.44 to 1.82), severe COVID-19 (RR: 1.89, 1.74 to 2.06), acute kidney injury (RR: 2.13, 1.99 to 2.29), kidney replacement therapy/hemodialysis (RR: 1.40, 1.03 to 1.89), acute respiratory distress syndrome-ARDS (RR: 1.76, 1.53 to 2.02), ischemic stroke (RR: 2.62, 2.24 to 3.07), venous thromboembolism-VTE (RR: 2.30, 2.07 to 2.56), and sepsis (RR: 1.97, 1.81 to 2.13) was higher in RA compared to non-RA.,After matching, the risks did not differ in both cohorts except for VTE (RR: 1.18, 1.01 to 1.38) and sepsis (RR: 1.27, 1.12 to 1.43), which were higher in the RA cohort.,Male sex, black race, and glucocorticoid use increased the risk of adverse outcomes.,The risk of hospitalization was higher in rituximab or interleukin 6 inhibitors (IL-6i) users compared to tumor necrosis factor inhibitors (TNFi) users, with no significant difference between Janus kinase inhibitors (JAKi) or abatacept users and TNFi users.,This large cohort study of RA-COVID-19 found that the risk of all outcomes was higher in the RA compared to the non-RA cohort before matching, with no difference in the majority of outcomes after matching, implying the risk being attributed to adjusted factors.,However, the risk of VTE and sepsis was higher in RA cohort even after matching, indicating RA as an independent risk factor.,Male sex, black race, and glucocorticoid use were associated with adverse outcomes in RA with COVID-19.,Rituximab or IL-6i users were associated with an increased risk of hospitalization compared to TNFi users.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are liver-specific autoimmune conditions that are characterized by chronic hepatic damage and often lead to cirrhosis and hepatic failure.,Specifically, the protein tyrosine phosphatase N22 (PTPN22) gene encodes the lymphoid protein tyrosine phosphatase, which acts as a negative regulator of T-cell receptor signaling.,A missense single nucleotide polymorphism (SNP) (rs2476601) in PTPN22 has been linked to numerous autoimmune diseases in Caucasians.,In the present series, nine SNPs in the PTPN22 gene were analyzed in 166 patients with AIH, 262 patients with PBC, and 322 healthy controls in the Japanese population using TaqMan assays.,Although the functional rs3996649 and rs2476601 were non-polymorphic in all subject groups, the frequencies of the minor alleles at rs1217412, rs1217388, rs1217407, and rs2488458 were significantly decreased in AIH patients as compared with controls (all Pc < 0.05).,There were no significant relationships with PTPN22 SNPs in PBC patients.,Interestingly, the AAGTCCC haplotype was significantly associated with resistance to both AIH (odds ratio [OR] = 0.58, P = 0.0067) and PBC (OR = 0.58, P = 0.0048).,SNPs in the PTPN22 gene may therefore play key roles in the genetic resistance to autoimmune liver disease in the Japanese.

Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases.,More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH).,In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects.,Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene.,We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing.,The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model.,Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH.,In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH.,Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population.,This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population.

In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities.,We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls.,In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed.,MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration.,Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages.,Lesions developed on the background of inflammation.,Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions.,Demyelination and neurodegeneration were associated with oxidative injury.,Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination.,In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration.,This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons.,Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron.,Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease.,Cardiovascular disease (CVD) is common and a major cause of mortality.,Studies on cardiovascular morbidity are abundant, whereas mortality studies focusing on cardiovascular outcomes are scarce.,The aim of this study was to investigate causes of death and baseline predictors of overall (OM), non-vascular (N-VM), and specifically cardiovascular (CVM) mortality in SLE, and to evaluate systematic coronary risk evaluation (SCORE).,208 SLE patients were included 1995-1999 and followed up after 12 years.,Clinical evaluation, CVD risk factors, and biomarkers were recorded at inclusion.,Death certificates and autopsy protocols were collected.,Causes of death were divided into CVM (ischemic vascular and general atherosclerotic diseases), N-VM and death due to pulmonary hypertension.,Predictors of mortality were investigated using multivariable Cox regression.,SCORE and standardized mortality ratio (SMR) were calculated.,During follow-up 42 patients died at mean age of 62 years.,SMR 2.4 (CI 1.7-3.0). 48% of deaths were caused by CVM.,SCORE underestimated CVM but not to a significant level.,Age, high cystatin C levels and established arterial disease were the strongest predictors for all- cause mortality.,After adjusting for these in multivariable analyses, only smoking among traditional risk factors, and high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), anti-beta2 glycoprotein-1 (abeta2GP1) and any antiphospholipid antibody (aPL) among biomarkers, remained predictive of CVM.,With the exception of smoking, traditional risk factors do not capture the main underlying risk factors for CVM in SLE.,Rather, cystatin C levels, inflammatory and endothelial markers, and antiphospholipid antibodies (aPL) differentiate patients with favorable versus severe cardiovascular prognosis.,Our results suggest that these new biomarkers are useful in evaluating the future risk of cardiovascular mortality in SLE patients.

Systemic lupus erythematosus (SLE) patients have a striking increase in cardiovascular (CV) comorbidity not fully explained by the Framingham risk score.,Recent evidence from in vitro studies suggests that type I interferons (IFN) could promote premature CV disease (CVD) in SLE.,We assessed the association of type I IFN signatures with functional and anatomical evidence of vascular damage, and with biomarkers of CV risk in a cohort of lupus patients without overt CVD.,Serum type I IFN activity (induction of five IFN-inducible genes; IFIGs) from 95 SLE patient and 38 controls was quantified by real-time PCR.,Flow mediated dilatation (FMD) of the brachial artery and carotid intima media thickness (CIMT) were quantified by ultrasound, and coronary calcification by computed tomography.,Serum vascular biomarkers were measured by ELISA.,We evaluated the effect of type I IFNs on FMD, CIMT and coronary calcification by first applying principal components analysis to combine data from five IFIGs into summary components that could be simultaneously modeled.,Three components were derived explaining 97.1% of the total IFIG variation.,Multivariable linear regression was utilized to investigate the association between the three components and other covariates, with the outcomes of FMD and CIMT; zero-inflated Poisson regression was used for modeling of coronary calcification.,After controlling for traditional CV risk factors, enhanced serum IFN activity was significantly associated with decreased endothelial function in SLE patients and controls (p<0.05 for component 3), increased CIMT among SLE patients (p<0.01 for components 1 and 2), and severity of coronary calcification among SLE patients (p<0.001 for component 3).,Type I IFNs are independently associated with atherosclerosis development in lupus patients without history of overt CVD and after controlling for Framingham risk factors.,This study further supports the hypothesis that type I IFNs promote premature vascular damage in SLE.

To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes.,Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.,Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017.,Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks.,45 eligible trials were identified.,Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate.,These analyses showed few statistically significant differences between the combination treatments.,For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections.,Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections.,Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included.,For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate.,However, the analysis was hampered by a lack of long term direct comparisons.,The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.

Investigate whether the efficacy and safety of intravenous tocilizumab (TCZ) demonstrated at week 52 in patients with early rheumatoid arthritis (RA) are maintained to week 104.,Methotrexate (MTX)-naive patients with early progressive RA were randomly assigned to double-blind 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo or placebo+MTX for 104 weeks.,Patients not receiving 8 mg/kg TCZ and not achieving Disease Activity Score-28 joints (DAS28-erythrocyte sedimentation rate (ESR)) ≤3.2 at week 52 switched to escape therapy (8 mg/kg TCZ+MTX).,Analyses were exploratory.,Intent-to-treat and safety populations included 1157 and 1153 patients, respectively.,DAS28-ESR remission (<2.6) rates were maintained from weeks 52 to 104 (eg, 8 mg/kg TCZ+MTX, 49.3% to 47.6%).,Placebo+MTX and 4 mg/kg TCZ+MTX escape patients' week 104 response rates were 51.4% and 30.5%, respectively.,Inhibition of radiographic progression was maintained with 8 mg/kg TCZ (eg, 8 mg/kg TCZ+MTX mean (SD) change from baseline in modified total Sharp score: 0.13 (1.28), week 52; 0.19 (2.08), week 104).,The safety profile of TCZ was consistent with that of previous reports.,Patients with early RA treated with TCZ monotherapy or TCZ+MTX maintained clinical benefits during their second year of treatment with no new safety signals.,NCT01007435; Results.

We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients.,The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually.,We assessed relative rates of transition using maximum likelihood estimation in a multistate model.,The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality.,We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry.,Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001).,Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage.,Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)).,Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)).,Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point).,Damage in SLE predicts future damage accrual and mortality.,We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.

Objectives.,To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score.,Methods.,Data from two multi-centre studies were used in the analysis: in a cross-sectional and a longitudinal fashion.,At every assessment, data were collected on SLEDAI-2000 and treatment.,The cross-sectional analysis with receiver operating characteristic (ROC) curves was used to examine the appropriate SLEDAI-2000 score to define active disease and increase in therapy was the reference standard.,In the longitudinal analysis, sensitivity to change of SLEDAI-2000 was assessed with multinomial logistic regression.,ROC curves analysis was used to examine possible cut-points in score changes associated with change in therapy, and mean changes were estimated.,Results.,In the cross-sectional analysis, the most appropriate cut-off scores for active disease were 3 or 4.,In the longitudinal analysis, the best model for predicting treatment increase was with the change in SLEDAI-2000 score and the score from the previous visit as continuous variables.,The use of cut-points was less predictive of treatment change than the use of continuous score.,The mean difference in the change in SLEDAI-2000 scores, adjusted for prior score, between patients with treatment increase and those without was 2.64 (95% CI 2.16, 3.14).,Conclusions.,An appropriate SLEDAI-2000 score to define active disease is 3 or 4.,SLEDAI-2000 index is sensitive to change.,The use of SLEDAI-2000 as a continuous outcome is recommended for comparative purposes.

To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA).,In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant disease-modifying antirheumatic drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg.,The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12.,Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy.,Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response.,The total incidence of treatment-emergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively).,TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea.,No cases of serious infections were reported.,Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg).,Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile.,These findings support further developments of peficitinib for RA treatment.,NCT01649999; Results.

Patients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles).,The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA.,HZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long-term extension (LTE) clinical trials in the Tofacitinib RA Development Program.,Crude incidence rates (IRs) of HZ per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated by exposure group.,Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use).,Among 4,789 participants, 239 were identified as having tofacitinib-associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21-75 years).,One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death.,Twenty-four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs.,The crude HZ IR across the development program was 4.4 per 100 patient-years (95% CI 3.8-4.9), but the IR was substantially higher within Asia (7.7 per 100 patient-years, 95% CI 6.4-9.3).,Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5-2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient-years, 95% CI 3.2-6.0) and those receiving 10 mg twice daily (4.2 per 100 patient-years, 95% CI 3.1-5.8).,In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient-years (95% CI 0.5-4.6).,In the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia.,Complicated HZ among tofacitinib-treated patients was rare.

The underlying mechanism of fatigue in multiple sclerosis (MS) remains poorly understood.,Our study investigates the involvement of the ascending reticular activating system (ARAS), originating in the pontine brainstem, in MS patients with symptoms of fatigue.,Female relapsing-remitting MS patients (n = 17) and controls (n = 15) underwent a magnetic resonance spectroscopic imaging protocol at 1.5T.,Fatigue was assessed in every subject using the Fatigue Severity Scale (FSS).,Using an FSS cut-off of 36, patients were categorized into a low (n = 9, 22 ± 10) or high (n = 10, 52 ± 6) fatigue group.,The brain metabolites N-acetylaspartate (NAA) and total creatine (tCr) were measured from sixteen 5x5x10 mm3 spectroscopic imaging voxels in the rostral pons.,MS patients with high fatigue had lower NAA/tCr concentration in the tegmental pons compared to control subjects.,By using NAA and Cr values in the cerebellum for comparison, these NAA/tCr changes in the pons were driven by higher tCr concentration, and that these changes were focused in the WM regions.,Since there were no changes in NAA concentration, the increase in tCr may be suggestive of gliosis, or an imbalanced equilibrium of the creatine and phosphocreatine ratio in the pons of relapsing-remitting MS patients with fatigue.

Introduction: Magnetic Resonance Imaging is a sensitive technique for detecting white matter (WM) MS lesions, but the relation with clinical disability is low.,Because of this, changes in both ‘normal appearing white matter’ (NAWM) and ‘diffusely abnormal white matter’ (DAWM) have been of interest in recent years.,MR techniques, including quantitative magnetic resonance imaging (qMRI) and quantitative magnetic resonance spectroscopy (qMRS), have been developed in order to detect and quantify such changes.,In this study, qMRI and qMRS were used to investigate NAWM and DAWM in typical MS patients and in MS patients with low number of WM lesions.,Patient data were compared to ‘normal white matter’ (NWM) in healthy controls.,Methods: QMRI and qMRS measurements were performed on a 1.5 T Philips MR-scanner. 35 patients with clinically definite MS and 20 healthy controls were included.,Twenty of the patients fulfilled the ‘Barkhof-Tintoré criteria’ for MS, (‘MRIpos’), whereas 15 showed radiologically atypical findings with few WM lesions (‘MRIneg’).,QMRI properties were determined in ROIs of NAWM, DAWM and lesions in the MS groups and of NWM in controls.,Descriptive statistical analysis and comparisons were performed.,Correlations were calculated between qMRI measurements and (1) clinical parameters and (2) WM metabolite concentrations.,Regression analyses were performed with brain parenchyma fraction and MSSS.,Results: NAWM in the MRIneg group was significantly different from NAWM in the MRIpos group and NWM.,In addition, R1 and R2 of NAWM in the MRIpos group correlated negatively with EDSS and MSSS.,DAWM was significantly different from NWM, but similar in the MS groups.,N-acetyl aspartate correlated negatively with R1 and R2 in MRIneg.,R2 of DAWM was associated with BPF.,Conclusions: Changes in NAWM and DAWM are independent pathological entities in the disease.,The correlation between qMRI and clinical status may shed new light on the clinicoradiological paradox.

Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases.,Due to its cost‐effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis.,Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood.,By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll‐like receptor activation and calcium signalling.,These effects alter several aspects of the immune system with the synergistic consequence of reducing pro‐inflammatory cytokine production and release, one of the most marked symptoms of RADs.,Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects.,This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs.,Hydroxychloroquine has been heavily discussed in the context of COVID19, but this anti‐malarial drug is primarily used in rheumatic autoimmune disorders (RADs).,This comprehensive review recapitulates our knowledge on the mode of action of this drug in RADs, and on its potential applications and side effects.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation.,The presence of autoantibodies in the sera of RA patients has provided many clues to the underlying disease pathophysiology.,Based on the presence of several autoantibodies like rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), anti-carbamylated protein antibodies (anti-CarP), and more recently anti-acetylated protein antibodies RA can be subdivided into seropositive and seronegative disease.,The formation of these autoantibodies is associated with both genetic and environmental risk factors for RA, like specific human leukocyte antigen (HLA) alleles and smoking.,Autoantibodies can be detected many years before disease onset in a subset of patients, suggesting a sequence of events in which the first autoantibodies develop in predisposed hosts, before an inflammatory response ensues leading to clinically apparent arthritis.,Research on the characteristics and effector functions of these autoantibodies might provide more insight in pathophysiological processes underlying arthritis in RA.,Recent data suggests that ACPA might play a role in perpetuating inflammation once it has developed.,Furthermore, pathophysiological mechanisms have been discovered supporting a direct link between the presence of ACPA and both bone erosions and pain in RA patients.,In conclusion, investigating the possible pathogenic potential of autoantibodies might lead to improved understanding of the underlying pathophysiological processes in rheumatoid arthritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease of diverse manifestations, with onset usually in young women in the third to fourth decade of life.,The chronic nature of this relapsing remitting disease leads to organ damage accrual over time.,Mortality and morbidity are increased in patients with SLE compared with the general population.,Therapeutic advances over the last few decades have led to significant improvements in patient outcomes.,Five-year survival has improved to over 90% from a low of 50% in the 1950s.,However, multiple aspects of the management of SLE patients are still far from optimal.,Early diagnosis remains a challenge; diagnostic delays leading to delay in definitive treatment are common.,Monitoring treatment remains problematic due to the paucity of sensitive biomarkers.,Current treatment regimens rely heavily on corticosteroids, even though corticosteroids are well known to cause organ damage.,Treatment of refractory disease manifestations such as nephritis, recalcitrant cutaneous lesions and neurological involvement require new approaches with greater efficacy.,Cognitive dysfunction is common in SLE patients, but early recognition and adequate treatment are yet to be established.,Premature accelerated atherosclerosis remains a leading cause of morbidity and mortality.,Fatigue is one of the most disabling symptoms, and contributes to the poor quality of life in patients with SLE.,Ongoing research in SLE faces many challenges, including enrollment of homogeneous patient populations, use of reliable outcome measures and a standard control arm.,The current review will highlight some of the outstanding unmet challenges in the management of this complex disease.

To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.,Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies.,The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm.,The performance of the scores was evaluated relative to clinical disease activity assessments.,Change in MBDA score over time was assessed by paired Wilcoxon rank sum test.,Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.,The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7.,In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures.,Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001).,Neither MBDA score nor clinical variables were predictive of radiographic progression.,This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study.,Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.

Multiple sclerosis (MS) is an inflammatory-neurodegenerative disease of the central nervous system presenting with significant inter- and intraindividual heterogeneity.,However, the application of clinical and imaging biomarkers is currently not able to allow individual characterization and prediction.,Complementary, molecular biomarkers which are easily quantifiable come from the areas of immunology and neurobiology due to the causal pathomechanisms and can excellently complement other disease characteristics.,Only a few molecular biomarkers have so far been routinely used in clinical practice as their validation and transfer take a long time.,This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers.,In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.

To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).,NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs).,In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months.,The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay.,The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.,In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001).,Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively).,Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (p < 0.001).,Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).,Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker.,Disease activity and DMT had similar effects on serum and CSF NFL concentrations.,Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors.,How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear.,Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype.,Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner.,Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation.,T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.,Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells.,These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.,•Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis•The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation•Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells•Autoproliferating T cells recognize antigens expressed in B cells and brain lesions,Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis,The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation,Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells,Autoproliferating T cells recognize antigens expressed in B cells and brain lesions,Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.

It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk.,This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated.,This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging.,Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively.,In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase.,Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS.,Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients.,Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges.,We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.

A small proportion of intraductal papillary mucinous neoplasms (IPMNs) are accompanied by type 1 autoimmune pancreatitis (AIP); however their clinical courses and image characteristics have not been fully reported.,A 65-year-old woman was referred to our hospital for the examination of a pancreatic head cyst that had shown exacerbation for two years.,Several images demonstrated a multilocular cyst with a symmetrically thickened, enhanced, cyst wall.,Cancerization of IPMN was suspected, and pancreatoduodenectomy was performed.,The resected specimens showed a multilocular cyst with solid areas.,The solid areas demonstrated pathological findings that corresponded with type 1 AIP.,Papillary epithelia suggestive of IPMN was recognized in some parts of the cystic wall.

Differentially diagnosing focal-type autoimmune pancreatitis (f-AIP) and pancreatic cancer (PC) is challenging.,Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) may provide information for differentiating pancreatic masses.,In this study, we evaluated the usefulness of CEH-EUS in differentiating f-AIP from PC.,Data were collected prospectively and analyzed on patients who underwent CEH-EUS between May 2014 and May 2015.,Eighty consecutive patients were diagnosed with f-AIP or PC.,PC and f-AIP were compared for enhancement intensity, contrast agent distribution, and internal vasculature.,The study group comprised 53 PC patients and 27 f-AIP patients (17 with type-1 AIP [15 definite and two probable], two with probable type-2 AIP, and eight with AIP, not otherwise specified).,Hyper- to iso-enhancement in the arterial phase (f-AIP, 89% vs PC, 13%; p<0.05), homogeneous contrast agent distribution (f-AIP, 81% vs PC, 17%; p<0.05), and absent irregular internal vessels (f-AIP, 85% vs PC, 30%; p<0.05) were observed more frequently in the f-AIP group.,The combination of CEH-EUS and enhancement intensity, absent irregular internal vessels improved the specificity (94%) in differentiating f-AIP from PC.,CEH-EUS may be a useful noninvasive modality for differentially diagnosing f-AIP and PC.,Combined CEH-EUS findings could improve the specificity of CEH-EUS in differentiating f-AIP from PC.

To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome.,Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non-rituximab-treated patients were analyzed retrospectively.,Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%).,Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days).,Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment.,Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%).,In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly.,No improvement was observed in patients with GAD65 disease.,A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%).,Detection of NMDAR antibodies was significantly associated with mRS score improvement.,A favorable outcome was also observed with early treatment initiation.,We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany.,We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE.,This study provides Class IV evidence that rituximab is an effective treatment for some types of AE.

Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG.,MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction.,The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass.,MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles.,MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life.,Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors.,Therefore, current treatment involves immunosuppression, primarily by corticosteroids.,In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions.,Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.

Exposure to respirable crystalline silica is suggested to increase the risk of autoimmune rheumatic diseases.,We examined the association between respirable crystalline silica exposure and systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis.,In a cohort study of the total Danish working population, we included 1 541 505 male and 1 470 769 female workers followed since entering the labour market 1979-2015.,Each worker was annually assigned a level of respirable crystalline silica exposure estimated with a quantitative job exposure matrix.,We identified cases of autoimmune rheumatic diseases in a national patient register and examined sex-specific exposure-response relations by cumulative exposure and other exposure metrics.,We identified 4673 male and 12 268 female cases.,Adjusted for age and calendar year, men exposed to high levels of respirable crystalline silica compared with non-exposed showed increased incidence rate ratio (IRR) for the four diseases combined of 1.53 [95% confidence interval (CI): 1.39-1.69], for systemic sclerosis of 1.62 (1.08-2.44) and rheumatoid arthritis of 1.57 (1.41-1.75).,The overall risk increased with increasing cumulative exposure attained since entering the workforce [IRR: 1.07 (1.05-1.09) per 50 µg/m3-years].,Female workers were less exposed to respirable crystalline silica, but showed comparable risk patterns with overall increased risk with increasing cumulative exposure [IRR: 1.04 (0.99-1.10) per 50 µg/m3-years].,This study shows an exposure-dependent association between occupational exposure to respirable crystalline silica and autoimmune rheumatic diseases and thus suggests causal effects, most evident for systemic sclerosis and rheumatoid arthritis.

Neutrophil extracellular traps (NETs) are web-like DNA decorated with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils.,Although NETs are essential in innate immunity, an excessive formation of NETs has adverse effects, e.g., induction of anti-neutrophil cytoplasmic antibody (ANCA), to the hosts.,Since ANCA can induce NET formation in the primed neutrophils, a positive feedback loop can be formed between NETs and ANCA, which is called “ANCA-NETs vicious cycle.”,A 79-year-old Japanese woman developed hydralazine-induced pauci-immune necrotizing crescentic glomerulonephritis with MPO-ANCA.,Although the illness improved after cessation of hydralazine, MPO-ANCA-associated vasculitis relapsed 16 months later.,Remission was achieved 5 months after beginning of administration of prednisone.,In order to determine the involvement of ANCA-NETs vicious cycle in this patient, we examined NET degradation and induction activities in sera obtained at the disease onset (Serum A; MPO-ANCA, 107 IU/ml), at relapse (Serum B; MPO-ANCA, 195 IU/ml), at 3 months after treatment (Serum C; MPO-ANCA, 4.5 IU/ml), and at remission (Serum D; MPO-ANCA, 2.4 IU/ml).,NET degradation activity was low in the all sera.,NET induction activity was high in Sera A, B, and C but not in D.,Additionally, we demonstrated the presence of anti-NET antibody (ANETA) in Sera B and C but not in A or D.,The collective findings suggest NET induction potential of ANETA in the present patient and that the ANETA could contribute to the enhancement of NETs resulting in amplification of the ANCA-NETs vicious cycle.

A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies.,Recently, a novel CD11c+ B-cell subset has been identified that is critical for the development of autoimmunity.,However, the role of CD11c+ B cells in the development of lupus is unclear.,Chronic graft-versus-host disease (cGVHD) is a lupus-like syndrome with high autoantibody production.,The purpose of this study was to explore the role of CD11c+ B cells in the pathogenesis of lupus in cGVHD mice.,cGVHD was induced by an intraperitoneal injection of 5 × 107 Bm12 splenocytes into B6 mice.,Flow cytometry was used to analyze mice splenocytes and human samples.,Magnetic beads were used to isolate mice B cells.,Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR).,Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in serum and supernatants.,The percentage and absolute number of CD11c+ B cells was increased in cGVHD-induced lupus, with elevated levels of antichromatin immunoglobulin (Ig)G and IgG2a in sera.,CD11c+ plasma cells from cGVHD mice produced large amounts of antichromatin IgG2a upon stimulation.,Depletion of CD11c+ B cells reduced antichromatin IgG and IgG2a production.,T-bet was upregulated in CD11c+ B cells.,Knockout of T-bet in B cells alleviated cGVHD-induced lupus.,Importantly, the percentage of T-bet+CD11c+ B cells increased in lupus patients and positively correlated with serum antichromatin levels.,T-bet+CD11c+ B cells promoted high antichromatin IgG production in the lupus-like disease model cGVHD.,In lupus patients, the percentage of T-bet+CD11c+ B cells was elevated and positively correlated with antichromatin antibodies.,The findings provide potential therapeutic insight into lupus disease treatment.,The online version of this article (doi:10.1186/s13075-017-1438-2) contains supplementary material, which is available to authorized users.

Jackson et al. propose a role for B cell-intrinsic IFN-γ receptor signaling in spontaneous germinal center activation and autoantibody production.,Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE).,Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed.,In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development.,In contrast, B cells functioning as antigen-presenting cells initiate CD4+ T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity.,Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development.,Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein.,Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.

To understand preferences for and estimate the likely uptake of preventive treatments currently being evaluated in randomized controlled trials with individuals at increased risk of developing rheumatoid arthritis (RA).,Focus groups were used to identify key attributes of potential preventive treatment for RA (reduction in risk of RA, how treatment is taken, chance of side effects, certainty in estimates, health care providers opinion).,A web-based discrete choice experiment (DCE) was administered to people at-risk of developing RA, asking them to first choose their preferred of two hypothetical preventive RA treatments, and then between their preferred treatment and ‘no treatment for now.’,DCE data was analyzed using conditional logit regression to estimate the significance and relative importance of attributes in influencing preferences.,Two-hundred and eighty-eight first-degree relatives (60% female; 66% aged 18-39 years) completed all tasks in the survey.,Fourteen out of fifteen attribute levels significantly influenced preferences for treatments.,How treatment is taken (oral vs. infusion β0.983, p<0.001), increasing reduction in risk of RA (β0.922, p<0.001), health care professional preference (β0.900, p<0.001), and avoiding irreversible (β0.839, p<0.001) or reversible serious side effects (β0.799, p<0.001) were most influential.,Predicted uptake was high for non-biologic drugs (e.g. 84% hydroxycholoroquine), but very low for atorvastatin (8%) and biologics (<6%).,Decisions to take preventative treatments are complex, and uptake depends on how treatments can compromise on convenience, potential risks and benefits, and recommendations/preferences of health care professionals.,This evidence contributes to understanding whether different preventative treatment strategies are likely to be acceptable to target populations.

MRI-detected subclinical joint inflammation in the hand joints of patients with undifferentiated arthritis (UA) predicts progression to rheumatoid arthritis (RA).,It is unknown if adding MRI of the foot increases predictive accuracy compared to the hand alone.,1.5-T contrast-enhanced MRI of the unilateral foot (MTP-1-5) and hand (MCP-2-5 and wrist) was performed in 123 patients presenting with UA (not fulfilling the 2010 RA criteria) and scored for bone marrow edema (BME), synovitis and tenosynovitis.,Symptom-free controls (n = 193) served as a reference for defining an abnormal MRI.,Patients were followed for RA development ≤ 1 year, defined as fulfilling the classification criteria or initiation of disease-modifying antirheumatic drugs because of the expert opinion of RA.,The added predictive value of foot MRI to hand MRI was evaluated.,Fifty-two percent developed RA.,Foot tenosynovitis was predictive (OR 2.55, 95% CI 1.01-6.43), independent of BME and synovitis (OR 3.29, 95% CI 1.03-10.53), but not independent of CRP and number of swollen joints (OR 2.14, 95% CI 0.77-5.95).,Hand tenosynovitis was also predictive independent of BME and synovitis (OR 3.99, 95% CI 1.64-9.69) and independent of CRP and swollen joints (OR 2.36, 95% CI 1.04-5.38).,Adding foot tenosynovitis to hand tenosynovitis changed the sensitivity from 72 to 73%, specificity from 59 to 54% and AUC from 0.66 to 0.64; the net reclassification index was − 3.5.,MRI-detected tenosynovitis of the foot predicts progression to RA.,However, adding MRI of the foot does not improve the predictive accuracy compared to MRI of the hand alone.,In view of cost reduction, the performance of foot MRI for prognostic purposes in UA can be omitted.,The online version of this article (10.1186/s13075-019-1845-7) contains supplementary material, which is available to authorized users.

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality.,T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown.,We find an expanded CD8CD38high T cell subset in a sub-group of patients with increased rates of infections.,CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin.,The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells.,CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1.,Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses.,We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Systemic lupus erythematosus (SLE) is a chronic and incurable autoimmune disease involving the dysfunction of lymphocytes.,Circular RNAs (circRNAs) are noncoding RNAs (ncRNAs) with a covalently closed loop structure, with abnormal expression in various human diseases may participate in the pathogenesis, while further study is needed in SLE.,In this study, we aimed to find the circRNAs abnormally expressed in SLE and explore the function of circRNAs in SLE.,CircRNA sequencing was used to find the abnormally expressed circRNA and qRT-PCR was used to detect the expression.,Correlation analysis was used to analyze the correlation between circIBTK or miR-29b and clinicopathological variables in patients with SLE.,Cell culture, nuclear-cytoplasmic fractionation, qRT-PCR, transfection, luciferase reporter assay, western blot analysis, DNA extraction and global methylation analysis were used to explain the function of circIBTK and miR-29b in the progression of SLE.,SPSS 18.0 software was used to perform statistics.,We found that the expression of circIBTK was downregulated in SLE and correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, anti-double-stranded (ds)DNA and complement C3 level in patients with SLE.,Then miR-29b expression was upregulated in SLE and correlated with SLEDAI score, anti-dsDNA and complement C3 level in patients with SLE.,Mechanistic investigations indicated that miR-29b could induce DNA demethylation and activate the AKT signaling pathway and circIBTK might reverse the DNA demethylation and activation of the AKT signaling pathway induced by miR-29b via binding to miR-29b in SLE.,CircIBTK was downregulated in SLE and might regulate DNA demethylation and the AKT signaling pathway via binding to miR-29b in SLE.,CircIBTK and miR-29 could also act as biomarkers and therapeutic targets for SLE.,The online version of this article (10.1186/s13075-018-1618-8) contains supplementary material, which is available to authorized users.

The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA).,This study aimed to elucidate gut microbiome’s role in RA pathology by a comprehensive metagenome-wide association study (MWAS).,We conducted MWAS of the RA gut microbiome in the Japanese population (n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample).,Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis).,Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome.,The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy.,Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls.,A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison.,A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results.,No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls.,Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome’s role in RA aetiology.

Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut-joint axis in animal models.,In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease.,At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis.,Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites.,RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days.,Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation.,We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention.,Furthermore, patient-related outcomes of RA improved.,Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies.

Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear.,One potentially contributing factor is hyperexpression of HLA class I antigens.,This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual.,Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes.,The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it.,Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones.,RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays.,Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels.,The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated.,Both ‘classical’ HLA class I isoforms (i.e.,HLA-ABC) as well as a ‘non-classical’ HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets.,This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5.,However, it was strongly associated with increased STAT1 expression in all three cohorts.,Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter.,Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes.,The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction.,The online version of this article (doi:10.1007/s00125-016-4067-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The studies on the risk of tuberculosis (TB) in patients with type 1 diabetes mellitus (T1DM) alone are limited.,We examined this relationship using a population-based retrospective cohort study.,From claims data of the National Health Insurance system of Taiwan, we identified 5195 patients with T1DM newly diagnosed from 2002 to 2011 and 20,780 randomly selected controls without T1DM, frequency matched by age, sex, and year of diagnosis.,Both cohorts were followed up until the end of 2011 to evaluate the risk of TB.,The overall incidence of TB was 4.07-fold higher in the T1DM cohort than in the control cohort (1.18 vs 0.29 per 1000 person-years, P < 0.001).,Compared with the controls, the Cox model estimated adjusted hazard ratios (HRs) of TB in patients with T1DM were greater in men than in women (4.62 vs 3.59) and in adults than in children (4.06 vs 3.37), but not significant.,The adjusted HR was much greater for those with comorbidities than those without comorbidities (14.6 vs 1.62, P < 0.001).,Compared with the controls, the patients with T1DM were also more likely to develop TB with multiple emergency room visits (adjusted HR: 116.1, 95% confidence interval [CI] = 43.8-307.4) or hospitalizations (adjusted HR: 86.5, 95% CI = 33.7-222.4).,Patients with T1DM are at elevated risks of developing TB with much higher HRs for those with comorbidities, within the first year of diagnosis, and with frequent emergency cares or hospitalizations.

The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.,To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells.,A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine.,The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry.,Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories.,Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia.,CD3+ T cell depletion was modest.,The mRNA expression of metabolism genes varied between lymphocyte subsets.,A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells.,Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine.,These may offer a new target, possibly with potential biomarker activity, for future drug development.,The online version of this article (10.1007/s00415-018-8830-y) contains supplementary material, which is available to authorized users.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis.,The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan.,These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.,Ann Neurol 2011

TNF-α inhibitor (TNFi) therapies have transformed the treatment of several rheumatic musculoskeletal diseases.,However, the majority of TNFi’s are immunogenic and consequent anti-drug antibodies formation can impact on both treatment efficacy and safety.,Several controversies exist in the area of immunogenicity of TNFis and drug safety.,While anti-drug antibodies to TNFis have been described in association with infusion reactions; serious adverse events (AEs) such as thromboembolic events, lupus-like syndrome, paradoxical AEs, for example, vasculitis-like events and other autoimmune manifestations have also been reported.,The expansion of the biologic armamentarium, new treatment strategies such as introduction/switching to biosimilars and cost-saving approaches such as TNFi tapering, may all have a potential impact on immunogenicity and clinical sequelae.,In this review we evaluate how evolution of biologics relates to drug safety and immunogenicity, appraise relevant evidence from trials, spontaneous pharmacovigilance and observational studies and outline the areas of uncertainty that still exist.

Adalimumab is one of the top-selling drugs worldwide.,Its imminent patent expiration has seen the emergence of numerous biosimilar agents.,In this article, we recap the evidence from bio-originator trials in rheumatoid arthritis (RA) to provide context for a critical review of biosimilar trial data.,Currently, three adalimumab biosimilars are approved in Europe and/or the USA: Amgen’s ABP 501 (AMJEVITA/Solymbic), Boehringer Ingelheim’s BI 695501 (Cyltezo) and Samsung Bioepis’s SB5 (Imraldi).,All three agents met their pre-specified equivalence criteria.,Subtle differences in adverse events and clinical responses between the reference and biosimilar products were noted.,The introduction of adalimumab biosimilars will offer exciting opportunities in improving treatment access and increasing treatment options for RA and other licensed indications.,Real-world data will further provide assurances on efficacy as well as safety.

How does the efficacy of ponesimod compare with that of teriflunomide in a phase 3, multicenter, randomized, double-blind, active-comparator superiority study based on relapse rate, fatigue, magnetic resonance imaging-defined disease activity, tissue loss, and disability accumulation in patients with relapsing multiple sclerosis, over 108 weeks?,In this randomized clinical trial, ponesimod was significantly superior to teriflunomide in reducing the annualized relapse rate (−30.5%), Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis symptom score (−3.57), and combined unique active lesions on magnetic resonance imaging (−56%).,In this study, efficacy of ponesimod was superior to teriflunomide, and ponesimod had a safety profile consistent with sphingosine-1-phosphate modulators without any new safety signals.,This superiority study compares the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with relapsing multiple sclerosis.,To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).,To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.,This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.,Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.,The primary end point was the annualized relapse rate.,The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation.,Safety and tolerability were assessed.,Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.,For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, −3.57 (−0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively.,Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001).,Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups.,Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).,In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation.,The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.,ClinicalTrials.gov Identifier: NCT02425644

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course.,We assessed these risks in patients with MS (PwMS).,The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE).,In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated.,Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies.,The IBM® Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19.,COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity).,As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen’s Global Safety Database.,30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive.,The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry.,Similar risk factors were also identified for patients with SLE.,Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001).,In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine.,Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS.,Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort.,COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.,The online version contains supplementary material available at 10.1007/s40263-021-00804-1.

To assess the effects of lockdown due to COVID-19 pandemic on glucose metrics, measured by glucose monitoring systems, in adult individuals with type 1 diabetes.,We conducted a systematic literature search for English language articles from MEDLINE, Scopus and Web of Science up to February 28, 2021, using “diabetes”, “lockdown”, and “glucose” as key search terms.,Time in range (TIR) was the main outcome; other metrics were time above range (TAR), time below range (TBR), mean blood glucose (MBG) and its variability (%CV), estimated HbA1c (eA1c) or glucose management indicator (GMI).,Seventeen studies for a total of 3,441 individuals with type 1 diabetes were included in the analysis.,In the lockdown period, TIR 70-180 mg/dl increased by 3.05% (95% CI 1.67-4.43%; p < 0.0001) while TAR (>180 mg/dL and > 250 mg/dL) declined by 3.39% (−5.14 to −1.63%) and 1.96% (−2.51 to −1.42%), respectively (p < 0.0001 for both).,Both TBR < 70 and <54 mg/dL remained unchanged.,MBG slightly decreased by 5.40 mg/dL (−7.29 to −3.51 mg/dL; p < 0.0001) along with a reduction in %CV.,Pooled eA1c and GMI decreased by 0.18% (−0.24 to −0.11%; p < 0.0001) and a similar reduction was observed when GMI alone was considered (0.15%, −0.23 to −0.07%; p < 0.0001).,Sensor use was only slightly but not significantly reduced during lockdown.,This meta-analysis shows that well-controlled people with type 1 diabetes on both MDI and CSII with continuous or flash glucose monitoring did not experience a deterioration in glucose control throughout the COVID-19 lockdown, showing a modest, though statistically significant improvement in many glucose control parameters.

Various guidelines recommend that all adults diagnosed with type 1 diabetes (T1D) should be offered an evidence based, structured education programme (SEP) to optimize self-management care.,China has a 13,000 annual increase in newly diagnosed T1D cases, of which 65% are adults.,However, there is yet no validated SEP targeted to T1D patients in China.,The purpose of this study is to establish a structured T1D self-management education programme-‘Type 1 Diabetes Education in Lifestyle and Self Adjustment’ (TELSA) that is adapted to medical and cultural practices in China.,TELSA programme was developed based on the ADDIE model, following three steps: i) Semi-structured interviews were administered to 10 healthcare professionals (HCPs) and 13 T1D patients.,Different topic guides, focusing on 4 dimensions including goals, contents, format of delivery, and quality assurance, were designed for either HCPs or patients.,The interviews were recorded and analysed with thematic analysis. ii) Extracted themes were modified according to Delphi consultation. iii) Preliminary courses were conducted as pilot study to evaluate the effects of TELSA and optimization of the curriculum was finalized accordingly.,A total of 18 themes in 4 dimensions of the programme design were identified in the final version: i) goals: ‘behaviour modification’ and ‘outcome improvement’; ii) contents: ‘living with T1D’, ‘self-monitoring of blood glucose’, ‘knowing insulin’, ‘insulin dose adjustment’, ‘carbohydrates and carbohydrate counting’, ‘hypoglycaemia’, ‘complications of diabetes’, ‘managing psychological issues’, ‘physical activity’, and ‘question-and-answer’; iii) format: ‘multidisciplinary team combined with peer support’, ‘face-to-face education followed by remote learning’, and ‘2-day programme held on weekends’; and iv) quality assurance: ‘after-class quiz’, ‘patients’ feedback’, and ‘long-term evaluation on effectiveness’.,A type 1 diabetes structured education programme in China was set up and shown to be applicable under local medical, social, and cultural environment.,NCT03610984.,Date of registration: August 2, 2018.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that primarily manifests as persistent synovitis and progressive joint destruction.,Imatinib exhibited a therapeutic effect in murine collagen-induced arthritis (CIA) via selective inhibition tyrosine kinases.,The second-generation tyrosine kinase inhibitor dasatinib exhibits more durable hematological and cytogenetic effects and more potency compared to imatinib.,However, the effect of dasatinib on CIA is poorly understood.,The present study investigated the treatment effect of dasatinib on autoimmune arthritis.,We demonstrated that dasatinib alleviated arthritis symptoms and histopathological destruction in CIA mice.,Dasatinib treatment inhibited the production of proinflammatory cytokines including IL-1β, TNF-α, and IL-6, and promoted the production of the anti-inflammatory cytokine IL-10.,Dasatinib treatment also suppressed the expression of anti-mouse CII antibodies including total IgG, IgG1, IgG2, and IgG2b, in CIA mice.,We further demonstrated that dasatinib inhibited the migration and proliferation of fibroblast-like synoviocytes (FLS) from RA patients and promoted FLS apoptosis.,The mRNA expression of MMP13, VEGF, FGF, and DKK1 was down-regulated in FLS treated with dasatinib.,Our findings suggest that dasatinib exhibited treatment effects on CIA mice and that FLS are an important target cell of dasatinib treatment in autoimmune arthritis.

The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu.,We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA).,PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy.,Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3−CD19−CD56−CD11b+CD14+) by flow cytometry.,In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay.,Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone.,Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro.,The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5.,Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints.,Patients with PsA could be distinguished by increased RANK expression rather than total OCP population.,OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4.,In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10.,The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs.,The CCR4+ subset showed a significant negative trend during anti-TNF treatment.,CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs.,In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation.,Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.,The online version of this article (doi:10.1186/s13075-017-1337-6) contains supplementary material, which is available to authorized users.

Baicalin is a flavonoid isolated from the root of Scutellaria baicalensis with anti-inflammatory, antioxidant and antiapoptotic pharmacological properties.,However, the therapeutic effect of baicalin on rheumatoid arthritis (RA) is not completely understood.,The present study aimed to explore the therapeutic potential and mechanisms underlying baicalin in collagen-induced arthritis (CIA) model rats.,CIA was induced in male SD rats.,The hind paw thickness and severity of joint injury were monitored to assess the onset of arthritis.,At 28 days after the initial immunization, different doses of baicalin were administered once daily via oral gavage for 40 days.,The radiologic and pathological alterations were examined using X-ray, and hematoxylin and eosin staining, respectively.,ELISA was employed to measure the serum levels of proinflammatory cytokines.,Reverse transcription-quantitative PCR and western blotting were conducted to determine the expression of toll-like receptor (TLR)2, myeloid differentiation factor 88 (MYD88) and NF-κB p65.,Baicalin treatment noticeably alleviated radiographic and histologic abnormalities in the hind paw joints of CIA model rats in a dose-dependent manner.,The serum levels of proinflammatory cytokines were significantly decreased in baicalin-treated CIA model rats compared with vehicle-treated CIA model rats.,The mRNA expression levels of TLR2 and MYD88, as well as the protein expression levels of TLR2, MYD88 and NF-κB p65 were significantly decreased by baicalin treatment in the synovial tissue of CIA model rats and human RA fibroblast-like synoviocytes.,The results suggested that baicalin may exert a beneficial effect on CIA, which may be mediated by inhibiting the TLR2/MYD88/NF-κB signaling pathway.

Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others.,JAKs are the key initiating players of the JAK/STAT pathway.,Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus.,A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members.,Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond.,In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability.,Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear.,To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA.,To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset.,We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines.,We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing).,We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes.,At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA.,Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ.,Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread.,Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases.,The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).,The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis.,The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis.,The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry.,A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.,miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients.,The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells.,Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis.,Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.,We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels.,Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.

It has been suggested that rheumatoid arthritis (RA) may originate at the oral mucosa.,The aim of the present study was to assess the oral microbiome and periodontal condition in patients with early RA and individuals at risk of developing RA compared to healthy controls.,Three groups were recruited (n = 50 participants per group): 1) patients with early RA (meeting the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 classification criteria), 2) individuals at risk of developing RA (those with arthralgia who were positive for RA‐associated autoantibodies), and 3) healthy controls.,A periodontal examination was conducted to assess the presence of bleeding on probing (BOP), pocket probing depth (PPD), and periodontal inflamed surface area (PISA).,The microbial composition of subgingival dental plaque, saliva, and tongue coating was assessed using 16S ribosomal DNA amplicon sequencing, and findings were compared between groups with permutational multivariate analysis of variance (PERMANOVA).,There were no significant differences in any of the 3 periodontal variables between patients with early RA, at‐risk individuals, and healthy controls (P = 0.70 for BOP, P = 0.30 for PPD, and P = 0.57 for PISA, by Kruskal‐Wallis test).,PERMANOVA analyses comparing microbial composition between the groups showed significant differences in the microbial composition of saliva (F = 2.08, P = 0.0002) and tongue coating (F = 2.04, P = 0.008), but not subgingival dental plaque (F = 0.948, P = 0.51).,However, in post hoc tests, no significant differences in microbial composition of the saliva or tongue coating were observed between the early RA group and the at‐risk group (F = 1.12, P = 0.28 for saliva; F = 0.834, P = 0.59 for tongue coating).,In assessing microbial diversity based on the number of zero‐radius operational taxonomic units per sample, Prevotella in the saliva and Veillonella in the saliva and tongue coating were each found at a higher relative abundance in samples from patients with early RA and at‐risk individuals compared to healthy controls.,The results show similarities in the oral microbiome between patients with early RA and at‐risk individuals, since in both groups, the oral microbiome was characterized by an increased relative abundance of potentially proinflammatory species when compared to that in healthy controls.,These findings suggest a possible association between the oral microbiome and the onset of RA.

The periodontal pathogen Porphyromonas gingivalis is hypothesized to be important in rheumatoid arthritis (RA) aetiology by inducing production of anti-citrullinated protein antibodies (ACPA).,We have shown that ACPA precede RA onset by years, and that anti-P. gingivalis antibody levels are elevated in RA patients.,The aim of this study was to investigate whether anti-P. gingivalis antibodies pre-date symptom onset and ACPA production.,A case-control study (251 cases, 198 controls) was performed within the Biobank of Northern Sweden.,Cases had donated blood samples (n = 422) before the onset of RA symptoms by 5.2 (6.2) years (median (interquartile range)).,Blood was also collected from 192 RA patients following diagnosis.,Antibodies against P. gingivalis virulence factor arginine gingipainB (RgpB), and a citrullinated peptide (CPP3) derived from the P. gingivalis peptidylarginine deiminase enzyme, were analysed by ELISA.,Anti-RgpB IgG levels were significantly increased in pre-symptomatic individuals (mean ± SEM; 152.7 ± 14.8 AU/ml) and in RA patients (114.4 ± 16.9 AU/ml), compared with controls (p < 0.001).,Anti-CPP3 antibodies were detected in 5 % of pre-symptomatic individuals and in 8 % of RA patients, with elevated levels in both subsets (4.33 ± 0.59 and 9.29 ± 1.81 AU/ml, respectively) compared with controls (p < 0.001).,Anti-CPP3 antibodies followed the ACPA response, with increasing concentrations over time, whilst anti-RgpB antibodies were elevated and stable in the pre-symptomatic individuals with a trend towards lower levels after RA diagnosis.,Anti-P. gingivalis antibody concentrations were significantly increased in RA patients compared with controls, and were detectable years before onset of symptoms of RA, supporting an aetiological role for P. gingivalis in the development of RA.,The online version of this article (doi:10.1186/s13075-016-1100-4) contains supplementary material, which is available to authorized users.

Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets.,Genetic and environmental factors both contribute to T1D development.,Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial.,Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB).,In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts.,Hyperglycemia was induced in mice by specific ablation of native β-cells.,Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia.,Transplanted mice were infected with CVB4 and monitored for hyperglycemia.,Forty-seven percent of CVB4-infected mice developed hyperglycemia.,Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice.,Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes.,Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes.

Human type 1 diabetes (T1D) is considered to be an autoimmune disease, with CD8+ T-cell-mediated cytotoxicity being directed against the insulin-producing beta cells, leading to a gradual decrease in beta cell mass and the development of chronic hyperglycemia.,The histopathologically defining lesion in recent-onset T1D patients is insulitis, a relatively subtle leucocytic infiltration present in approximately 10 % of the islets of Langerhans from children with recent-onset (<1 year) disease.,Due to the transient nature of the infiltrate, its heterogeneous distribution in the pancreas and the nature of the patient population, material for research is extremely rare and limited to a cumulative total of approximately 150 cases collected over the past century.,Most studies on the etiopathogenesis of T1D have therefore focused on the non-obese diabetic (NOD) mouse model, which shares many genetic and immunological disease characteristics with human T1D, although its islet histopathology is remarkably different.,In view of these differences and in view of the limited success of clinical immune interventions based on observations in the NOD mouse, there is a renewed focus on studying the pathogenetic process in patient material.

Accumulating studies have suggested that long non-coding RNAs (lncRNAs) have drawn more and more attention in rheumatoid arthritis (RA), which can function as competitive endogenous RNAs (ceRNAs) in inflammation and immune disorders.,Previously, we have found that lncRNA HIX003209 is differentially expressed in RA.,However, the precise mechanism of lncRNA HIX003209 in RA is still vague.,We aim to elucidate the role and its targeted microRNA of lncRNA HIX003209 in RA as ceRNA.,Significantly increased expression of lncRNA HIX003209 was observed in the peripheral blood mononuclear cells (PBMCs) from RA cases.,It was positively associated with TLR2 and TLR4 in RA.,Besides, peptidoglycan (PGN) and lipopolysaccharide (LPS) could enhance the expression of lncRNA HIX003209, which reversely promoted the proliferation and activation of macrophages through IκBα/NF-κB signaling pathway.,Moreover, HIX003209 was involved in TLR4-mediated inflammation via targeting miR-6089 in macrophages.,LncRNA HIX003209 functions as a ceRNA and exaggerates inflammation by sponging miR-6089 through TLR4/NF-κB pathway in macrophages, which offers promising therapeutic strategies for RA.

We investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.,Synovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined.,To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.,SF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells.,TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN.,In contrast, stimulation with TGF-β1 induced CD248 expression.,In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248.,Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage.,PDPN+ CD248- SF preceded the appearance of PDPN- CD248+ cells in contralateral implants.,We have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane.,These markers discriminate between SF subsets with distinct biological properties.,As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.

Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling.,While this approach offers the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques.,To address this, we developed a 3D-printed, low-cost droplet microfluidic control instrument and deploy it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from five rheumatoid arthritis patients.,We sequence 20,387 single cells revealing 13 transcriptomically distinct clusters.,These encompass an unsupervised draft atlas of the autoimmune infiltrate that contribute to disease biology.,Additionally, we identify previously uncharacterized fibroblast subpopulations and discern their spatial location within the synovium.,We envision that this instrument will have broad utility in both research and clinical settings, enabling low-cost and routine application of microfluidic techniques.,Droplet-based single-cell RNA-seq is a powerful tool for cellular heterogeneity profiling in disease but is limited by instrumentation required.,Here the authors develop a 3D printed microfluidic platform for massive parallel sequencing of rheumatoid arthritis tissues.

Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA).,Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS).,RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i.,Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays.,HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS.,Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing.,Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation.,HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS.,Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11.,Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS.,Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoantibodies to nuclear antigens and inflammatory responses mediated by multiple cytokines.,Although previous studies have determined clinical associations between SLE and the anti-inflammatory cytokines IL-10 and IL-37, their role in the disease, or their potential as biomarkers, remains unclear.,We examined serum levels of IL-10 and IL-37 in a large cohort of SLE patients, with detailed longitudinal clinical data.,We demonstrate a statistically significant association of serum IL-10 with disease activity, with higher levels in active compared to inactive disease.,High first visit IL-10 was predictive of high subsequent disease activity; patients with IL-10 in highest quartile at first visit were 3.6 times more likely to have active disease in subsequent visits.,Serum IL-37 was also higher in SLE patients compared to control, and was strongly associated with Asian ethnicity.,However, IL-37 was not statistically significantly associated with disease activity.,IL-37 was significantly reduced in patients with organ damage but this association was attenuated in multivariable analysis.,The data suggest that IL-10, but not IL-37, may have potential as a biomarker predictive for disease activity in SLE.

Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.,In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage.,Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype.,It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood.,In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages.,Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris.,Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset.,Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

The aim of this study was to determine the effect of bariatric surgery on the incidence of RA in participants of the Swedish Obese Subjects (SOS) study.,The SOS is a longitudinal study aiming to assess the effect of bariatric surgery on mortality and obesity-related diseases.,This report includes 2002 subjects with obesity who underwent bariatric surgery and 2034 matched controls; none of them had RA at baseline.,Cases of incident RA were identified through the Swedish National Patient Register by searching for International Classification of Diseases codes.,Both intention-to-treat analyses and per-protocol analyses are reported.,In the per-protocol analysis, participants from the control group who underwent bariatric surgery later on during follow-up were censored at the time of surgery.,During follow-up, 92 study participants developed RA.,The median follow-up was 21 years (range 0-29).,Bariatric surgery was neither associated with the incidence of RA in the intention-to-treat analysis [hazard ratio (HR) 0.92 (95% CI 0.59, 1.46), P = 0.74], nor in the per-protocol analysis [HR 0.86 (95% CI 0.54, 1.38), P = 0.53].,Weight change at the 2 year follow-up, expressed as the change in BMI compared with baseline, did not associate with the development of RA.,Higher serum CRP levels and smoking associated with the future development of RA independent of other factors.,We did not detect any association between bariatric surgery and the incidence of RA in subjects affected by obesity followed up for up to 29 years.,(http://clinicaltrials.gov): NCT01479452.

Oral microbial dysbiosis is known to increase susceptibility of an individual to develop rheumatoid arthritis (RA).,Individuals at-risk of RA may undergo different phases of disease progression.,In this study, we aim to investigate whether and whereby the oral microbiome communities alter prior to symptoms of RA.,Seventy-nine saliva samples were collected from 29 high-risk individuals, who were positive for anti-citrullinated protein antibodies (ACPA) and have no clinical arthritis, 27 RA patients and 23 healthy controls (HCs).,The salivary microbiome was examined using 16S ribosomal RNA gene sequencing.,Alpha and beta diversity analysis and the linear discriminant analysis were applied to examine the bacterial diversity, community structure and discriminatory taxa between three groups, respectively.,The correlation between salivary bacteria and autoantibodies were analyzed.,In the “pre-clinical” stages, salivary microbial diversity was significantly reduced comparing to RA patients and HCs.,In contrast to HCs, like RA patients, individuals at high-risk for RA showed a reduction in the abundance of genus Defluviitaleaceae_UCG-011 and the species Neisseria oralis, but an expansion of Prevotella_6.,Unexpectedly, the relative abundance of Porphyromonas gingivalis, reported as opportunistic pathogens for RA development, was significantly decreased in high-risk individuals.,Additionally, we identified four genera in the saliva from high-risk individuals positively correlated with serum ACPA titers, and the other two genera inversely displayed.,In summary, we observed a characteristic compositional change of salivary microbes in individuals at high-risk for RA, suggesting that oral microbiota dysbiosis occurs in the “pre-clinical” stage of RA and are correlated with systemic autoimmune features.

Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC).,APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology.,In contrast to the well-known prominent effects of sphingosine-1-phosphate (S1P) on lymphocyte trafficking, modulatory effects on APCs have not been fully characterized.,Frequencies and activation profiles of dendritic cell (DC) subtypes, monocytes, and T cell subsets in 35 multiple sclerosis (MS) patients were evaluated prior and after undergoing fingolimod treatment for up to 24 months.,Impact of fingolimod and S1P on maturation and activation profile, pro-inflammatory cytokine release, and phagocytotic capacity was assessed in vitro and ex vivo.,Modulation of DC-dependent programming of naïve CD4+ T cells, as well as CD4+ and CD8+ T cell proliferation, was also investigated in vitro and ex vivo.,Fingolimod increased peripheral slanDC count-CD1+ DC, and monocyte frequencies remained stable.,While CD4+ T cell count decreased, ratio of Treg/Th17 significantly increased in fingolimod-treated patients over time.,CD83, CD150, and HLADR were all inhibited, but CD86 was upregulated in DCs after incubation in the presence of fingolimod.,Fingolimod but not S1P was associated with reduced release of pro-inflammatory cytokines from DCs and monocytes in vitro and ex vivo.,Fingolimod also inhibited phagocytic capacity of slanDCs and monocytes.,After fingolimod, slanDCs demonstrated reduced potential to induce interferon-gamma-expressing Th1 or IL-17-expressing Th17 cells and DC-dependent T cell proliferation in vitro and in fingolimod-treated patients.,We present the first evidence that S1P-directed therapies can act additionally as immunomodulators that decrease the pro-inflammatory capabilities of APCs, which is a crucial element in DC-dependent T cell activation and programming.

Spontaneous autoimmune peripheral neuropathy including Guillain-Barré Syndrome (GBS) represents as one of the serious emergencies in neurology.,Although pathological changes have been well documented, molecular and cellular mechanisms of GBS are still under-explored, partially due to short of appropriate animal models.,The field lacks of spontaneous and translatable models for mechanistic investigations.,As GBS is preceded often by viral or bacterial infection, a condition can enhance co-stimulatory activity; we sought to investigate the critical role of T cell co-stimulation in this autoimmune disease.,Our previous study reported that transgene-derived constitutive expression of co-stimulator B7.2 on antigen presenting cells of the nervous tissues drove spontaneous neurological disorders.,Depletion of CD4+ T cells in L31 mice accelerated the onset and increased the prevalence of the disease.,In the current study, we further demonstrated that L31/CD4-/- mice exhibited both motor and sensory deficits, including weakness and paresis of limbs, numbness to mechanical stimuli and hypersensitivity to thermal stimulation.,Pathological changes were characterized by massive infiltration of macrophages and CD8+ T cells, demyelination and axonal damage in peripheral nerves, while changes in spinal cords could be secondary to the PNS damage.,In symptomatic L31/CD4-/- mice, the disruption of the blood neural barriers was observed mainly in peripheral nerves.,Interestingly, the infiltration of immune cells was initiated in pre-symptomatic L31/CD4-/- mice, prior to the disease onset, in the DRG and spinal roots where the blood nerve barrier is virtually absent.,L31/CD4-/- mice mimic most parts of clinical and pathological signatures of GBS in human; thus providing an unconventional opportunity to experimentally explore the critical events that lead to spontaneous, autoimmune demyelinating disease of the peripheral nervous system.

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease.,TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors.,Until now, therapeutic strategy for primary Sjögren’s syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation.,Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs.,Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.

Much of the original research on desmosomes and their biochemical components was through analysis of skin and mucous membranes.,The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases.,The clinical and histological similarities of staphylococcal scalded skin syndrome or bullous impetigo and pemphigus foliaceus led us to identify desmoglein 1 as the proteolytic target of staphylococcal exfoliative toxins.,Genetic analysis of striate palmoplantar keratoderma and hypotrichosis identified their responsible genes as desmogleins 1 and 4, respectively.,More recently these fundamental findings in cutaneous biology were extended beyond the skin.,Desmoglein 2, which is expressed earliest among the four isoforms of desmoglein in development and found in all desmosome-bearing epithelial cells, was found to be mutated in arrythmogenic right ventricular cardiomyopathy and has also been identified as a receptor for a subset of adenoviruses that cause respiratory and urinary tract infections.,The story of desmoglein research illuminates how dermatologic research originally focused on one skin disease, pemphigus, has contributed to understanding biology and pathophysiology of many seemingly unrelated tissues and diseases.

The study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) with 68Ga-PRGD2 as the tracer for imaging of synovial angiogenesis in patients with rheumatoid arthritis (RA).,Twenty untreated active patients with RA underwent 68Ga-PRGD2 PET/CT and 18F-FDG PET/CT before treatment; two patients with osteoarthritis served as controls.,Among the 20 patients with RA, 12 repeated the evaluations after 3-month treatment.,The image findings were correlated with core variables of disease activity, including the clinical disease activity index (cDAI).,Our findings demonstrated that 68Ga-PRGD2 specifically accumulated in the synovia with active inflammation rich in neovasculature with high-level αvβ3-integrin expression, but not in the 18F-FDG-avid inflammatory lymph nodes.,In patients with intense 18F-FDG uptake in muscles caused by arthritic pain, we observed that 68Ga-PRGD2 PET/CT was better able to evaluate disease severity than 18F-FDG PET/CT.,Both 68Ga-PRGD2 accumulation and 18F-FDG uptake changed in response to therapeutic intervention, whereas the changes of 68Ga-PRGD2, not 18F-FDG, significantly correlated with clinical measures of changes in the form of cDAI.,This is the first integrin imaging study conducted in patients with RA that preliminarily indicates the effectiveness of the novel method for evaluating synovial angiogenesis.,This study has been registered online at NIH ClinicalTrial.gov (NCT01940926).

Integrins play an important role in cell adhesion to the extracellular matrix and other cells.,Upon ligand binding, signaling is initiated and several intracellular pathways are activated.,This leads to a wide variety of effects, depending on cell type.,Integrin activation has been linked to proliferation, secretion of matrix-degrading enzymes, cytokine production, migration, and invasion.,Dysregulated integrin expression is often found in malignant disease.,Tumors use integrins to evade apoptosis or metastasize, indicating that integrin signaling has to be tightly controlled.,During the course of rheumatoid arthritis, the synovial tissue is infiltrated by immune cells that secrete large amounts of cytokines.,This pro-inflammatory milieu leads to an upregulation of integrin receptors and their ligands in the synovial tissue.,As a consequence, integrin signaling is enhanced, leading to enhanced production of matrix-degrading enzymes and cytokines.,Furthermore, in analogy to invading tumors, synovial fibroblasts start invading and degrading cartilage, thereby generating extracellular matrix debris that can further activate integrins.

The development of accurate prognoses in multiple sclerosis is difficult, as the disease is characterized by heterogeneous patterns of brain abnormalities that relate in an unclear way to future impairments.,Here, we use a statistical modeling approach to determine if the baseline pattern of connectome disruption due to T2-FLAIR lesions could predict a patient's future processing speed, as measured using the Symbol Digits Modality Test scores.,Imaging data, demographics and Symbol Digits Modality Test scores were collected from 61 early relapsing remitting multiple sclerosis patients.,The Network Modification Tool was used to estimate damage to the connectome by quantifying white matter abnormalities' effects on 1) global network properties, 2) regional connectivity and 3) connectivity between pairs of regions.,MS subjects showed significant improvement of processing speed between baseline and follow-up (t = −2.6, p = 0.0096); however, both baseline (t = −4.01, p = 0.00012) and follow-up (t = −2.10, p = 0.038) processing speed were significantly lower than age-matched healthy controls.,Partial Least Squares Regression was used to create models that predict future processing speed from between baseline imaging metrics and demographics.,The model based on region-pair disconnection and gray matter atrophy had the lowest AIC and highest prediction accuracy (R2 = 0.79) compared to models based on global (R2 = 0.41) or regional (R2 = 0.66) disconnection and gray matter atrophy, overlap with an ROI-based atlas and gray matter atrophy (R2 = 0.73) or gray matter atrophy alone (R2 = 0.71).,We found that baseline measures of connectivity disruption in various parietal, temporal, occipital and subcortical regions and atrophy in the putamen were important predictors of future processing speed.,We conclude that information about disruptions to pairwise brain connections is more informative of future processing speed than regional or global metrics or gray matter atrophy alone.,The combination of quantitative disconnectome metrics, gray matter atrophy and statistical modeling approaches could enable clinicians in developing more accurate, individualized prognoses of future cognitive status in multiple sclerosis patients.,•Atrophy and structural disconnection estimates via NeMo Tool were collected in MS.,•Future cognitive functioning in MS patients was predicted by baseline MRI measures.,•Measures of atrophy and disconnection between region-pairs had best goodness-of-fit.,•More caudate atrophy was significantly predictive of worse future cognition.,•Disconnections in parietal/temporal/occipital areas predicted worse future cognition.,Atrophy and structural disconnection estimates via NeMo Tool were collected in MS.,Future cognitive functioning in MS patients was predicted by baseline MRI measures.,Measures of atrophy and disconnection between region-pairs had best goodness-of-fit.,More caudate atrophy was significantly predictive of worse future cognition.,Disconnections in parietal/temporal/occipital areas predicted worse future cognition.

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims.,In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions.,We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims.,Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages.,Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging.,In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence.,Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques.,Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes.,Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible.,Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003).,We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003).,Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.,The online version of this article (doi:10.1007/s00401-016-1636-z) contains supplementary material, which is available to authorized users.

Clinically, associations have been observed between Sjögren’s syndrome and fibromyalgia.,Nonetheless, population-based evidence evaluating the risk of Sjögren’s syndrome in fibromyalgia patients is lacking.,The main purpose of this retrospective cohort study was to determine the association between fibromyalgia and subsequent development of Sjögren’s syndrome.,This retrospective cohort study extracted data from the Longitudinal Health Insurance Database (LHID) of the Taiwan National Health Insurance (NHI).,During 2000-2012, patients with newly-diagnosed fibromyalgia (International Classification of Diseases, Ninth Revision, Clinical Modification code 729.1) were defined as the exposure cohort.,Age- and gender-matched individuals without fibromyalgia were used as the comparison cohort.,The adjusted hazard ratios (aHR) for the occurrence of Sjögren’s syndrome in those with fibromyalgia were evaluated along with stratified analyses of different subgroups.,Of the 149,706 subjects whose data were extracted from the LHID, 74,853 subjects had coded fibromyalgia and 74,853 control subjects were without fibromyalgia.,Compared to the control group, patients with fibromyalgia had an aHR of 2.00 (95% Confidence Interval [CI], 1.52-2.61) for developing Sjögren’s syndrome.,In fibromyalgia patients aged 20-49 years, the aHR for future Sjögren’s syndrome was 3.07 (95% CI, 1.92-4.89).,Patients with fibromyalgia, both males and females, have a higher risk for developing Sjögren’s syndrome than those without fibromyalgia, especially those aged 20-49 years.,While managing patients, clinicians should be aware of the bidirectional association between the two diseases, which helps to understand the impact of the association on disease activity and diagnosis.

Sjogren’s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression.,Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles.,Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues.,Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment.,These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression.,Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses.,Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells.,Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development.,In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.

A growing body of evidence suggests that systemic lupus erythematosus (SLE) may result in reversible cognitive dysfunction.,Vitamin D is considered important for neurons.,The therapeutic effect of vitamin D was evaluated in a rat model of SLE.,There were 20 male MRL/lpr mice randomly divided into the SLE model group and the vitamin D group, in addition, 10 male C57BL 6J mice were used as the control (CON) group.,Vitamin D was administered intraperitoneally (2 μg/kg) for 4 weeks.,After 4 weeks of continuing intervention, we tested the cognitive function using the Morris water maze.,The expression of vitamin D receptor (VDR), amyloid-β, caspase-3, and Bcl-2 were detected by western blot analysis.,In the present study, we observed that vitamin D treatment alleviated neurobehavioral deficits in the mice with SLE.,At the molecular levels, administration of vitamin D activated the expression of VDR and reduced the number of dead cells in the CA1 region of the hippocampus as well as regulated caspase-3 and Bcl-2 expression.,In conclusion, our results indicated that vitamin D played a protective role by suppressing inflammatory cytokines, thereby ultimately inhibiting the progression of apoptosis in a mouse model of SLE.,Vitamin D may be promising as a protective intervention in SLE with cognitive dysfunction, and more and more experiments are warranted for its clinical testing in the near future.

A growing evidence base implicates vitamin D, sun exposure and latitude in the aetiology of multiple sclerosis (MS), however there are less data on the associations of these variables with disease outcomes.,We undertook a cross-sectional survey of over 2000 people with MS recruited through internet platforms, seeking self-reported data on geographical location, intentional sun exposure for health, and supplementation with vitamin D, among other lifestyle variables.,We also requested data on health-related quality of life (MSQOL-54), self-reported doctor-diagnosed relapse rate, and disability (Patient Determined Disease Steps).,Bivariate and multivariate analyses were used for comparisons, including multiple linear regression modeling.,Of 2301 participants, 82.3 % were female, median age was 45 years (IQR 38-53 years), with a median time since diagnosis of 6 years (IQR 3-12 years), the majority (61.6 %) having relapsing-remitting MS.,Nearly two-thirds (64.6 %) lived in the Northern hemisphere, mostly in developed countries.,Most (66.8 %) reported deliberate sun exposure to raise their vitamin D level, and the vast majority (81.8 %) took vitamin D supplements, mostly 2000-5000 IU a day on average.,Unadjusted regression modeling incorporating deliberate sun exposure, latitude and vitamin D supplementation showed strong associations of sun exposure with HRQOL which disappeared when controlling for gender, age, disability, physical activity, and fish consumption.,In contrast, associations between vitamin D supplementation and HRQOL were maintained adjusting for these variables, with a dose-response effect.,Only latitude had significant adjusted associations with disability, with an increase of latitude by one degree (further from the equator) predicting increased odds of moderate disability (OR 1.02 (95 % CI 1.01-1.04)) or high disability (OR 1.03 (95 % CI 1.01-1.05)) compared to no/mild disability.,Similarly, latitude was related to relapse rate, with increase in latitude of 1 degree associated with increased odds of having more relapses over the previous year (1.01 (1.00-1.02)).,We detected significant associations between latitude, deliberate sun exposure and vitamin D supplementation and health outcomes of this large group of people with MS.,Vitamin D is likely to have a key role in these associations and its role in the health outcomes of people with MS urgently requires further study.,The online version of this article (doi:10.1186/s12883-015-0394-1) contains supplementary material, which is available to authorized users.

Measurement of type I interferon (IFN-I) has potential to diagnose and stratify autoimmune diseases, but existing results have been inconsistent.,Interferon-stimulated-gene (ISG) based methods may be affected by the modularity of the ISG transcriptome, cell-specific expression, response to IFN-subtypes and bimodality of expression.,We developed and clinically validated a 2-score system (IFN-Score-A and -B) using Factor Analysis of 31 ISGs measured by TaqMan selected from 3-IFN-annotated modules.,We evaluated these scores using in-vitro IFN stimulation as well as in sorted cells then clinically validated in a cohort of 328 autoimmune disease patients and healthy controls.,ISGs varied in response to IFN-subtypes and both scores varied between cell subsets.,IFN-Score-A differentiated Systemic Lupus Erythematosus (SLE) from both Rheumatoid Arthritis (RA) and Healthy Controls (HC) (both p < 0.001), while IFN-Score-B differentiated SLE and RA from HC (both p < 0.001).,In SLE, both scores were associated with cutaneous and hematological (all p < 0.05) but not musculoskeletal disease activity.,Comparing with bimodal (IFN-high/low) classification, significant differences in IFN-scores were found between diagnostic groups within the IFN-high group.,Our continuous 2-score system is more clinically relevant than a simple bimodal classification of IFN status.,This system should allow improvement in diagnosis, stratification, and therapy in IFN-mediated autoimmunity.

Significant differences have been reported in disease phenotype and severity of systemic lupus erythematosus (SLE) presenting in different age groups.,Most indicate a more severe phenotype in juvenile-onset SLE (JSLE).,There have been limited studies in older patients and no large studies looking at SLE across all age groups.,We assessed the effect of age of onset of SLE on the clinical phenotype by analysing data from two large UK cohorts (the UK JSLE Cohort and the UCLH SLE cohort).,A total of 924 individuals were compared (413 JSLE, 511 adult-onset SLE).,A female preponderance was present, but less pronounced at either end of the age spectrum.,Arthritis was more common with advancing age (93% vs 72%, p < 0.001), whereas renal disease (44% vs 33%, p = 0.001), alopecia (47% vs 23%, p < 0.001) and aphthous ulcerations (39% vs 26%, p = 0.001) were more common in the young.,Neuropsychiatric lupus was less common in mature-onset SLE (p < 0.01).,JSLE was associated more commonly with thrombocytopenia (21% vs 15%, p = 0.01), haemolytic anaemia (20% vs 3%, p < 0.001), high anti-dsDNA (71% vs 63%, p = 0.009), Sm (22% vs 16%, p = 0.02) and RNP (36% vs 29%, p < 0.04) auto-antibodies.,Leucopenia increased with advancing age (p < 0.001).,Mortality has been declining over recent decades.,However, death rates were substantially higher than the general population.,The standardized mortality ratio was 18.3 in JSLE and 3.1 in adult-onset SLE.,These data from the largest-ever direct comparison of JSLE with adult-onset SLE suggest an aggressive phenotype of disease with a worse outcome in patients with JSLE and emphasizes the importance of careful follow-up in this population.

Coronavirus disease-19 (COVID-19) is a global pandemic that is caused by COVID-19 virus, which was initially identified in December 2019 in Wuhan, China.,Vaccination is one of the most effective public health interventions, and soon after the Pfizer/BioNTech (BNT162b2) vaccine became available late in 2020, it began to be actively used to fight against COVID-19.,Since then, cases of vaccine-associated immune-mediated diseases (IMDs) have been reported.,There have been few cases of IMD flare-ups or onset after COVID-19 vaccine administration, and emerging IMDs may be identified over next few years after high use of this vaccine.,To this day, few cases of newly diagnosed systemic lupus erythematosus (SLE) following COVID-19 vaccine exposure were reported.,Herein, we present the case of a patient diagnosed with SLE, acute pancreatitis, and vasculitic skin rash on the extremities 1 week after the first dose of the Pfizer-BioNTech COVID-19 vaccine.,Key Point• COVID-19 Vaccine induced Systemic Lupus Erythematosus.,Key Point,• COVID-19 Vaccine induced Systemic Lupus Erythematosus.

To summarize current knowledge of the impact of coronavirus disease 19 (COVID-19) on patients with systemic lupus erythematosus (SLE).,Several observational studies, including case series, patient surveys, and patient registries, have examined the incidence and severity of COVID-19 in patients with SLE.,Due to methodologic limitations (focus on sicker patients, exclusion of asymptomatic or mild cases, limited or inaccurate viral testing), it is difficult to determine the risk and outcomes of COVID-19 in SLE patients.,Corticosteroids might be associated with increased hospitalizations from COVID-19 in individuals with autoimmune rheumatic diseases.,Some immune suppressive treatments do not appear to significantly increase the risk of contracting COVID-19 or poor subsequent outcomes; however, data on the safety of specific drugs remain scarce.,Studies in non-autoimmune cohorts have shown more severe COVID-19 in ethnic and racial minorities, populations also more heavily impacted by SLE.,Such results have been attributed to highly prevalent socioeconomic disparities and comorbidities.,The complex interplay between SARS-CoV-2 and the host immunologic milieu may have particular implications for patients with SLE that remain to be explored.,Concerns have been raised of COVID-19 heightening the risk of thromboembolic events in the presence of an SLE-induced procoagulant state.,Limitations in epidemiologic data available to date do not allow for assessing the risk and severity of COVID-19 in patients with SLE.,Other than corticosteroids, prior use of some immune suppressive medications does not appear to increase the risk for infection with SARS-CoV-2 however, more comprehensive studies are needed.

Rheumatoid Arthritis (RA) has been increasingly associated with perturbations to the microbial communities that reside in and on the body (the microbiome), in both human and animal studies.,To date, such studies have mainly focused on the microbial communities that inhabit the gut and oral cavity.,Mounting evidence suggests that microbial DNA can be detected in the blood circulation using a range of molecular methods.,This DNA may represent an untapped pool of biomarkers that have the potential to report on changes to the microbiome of distant sites (e.g., example, the gut and oral cavity).,To this end, through amplification and sequencing of the bacterial 16S rRNA variable region four, we evaluated the presence and identity of microbial DNA in blood samples obtained from RA patients (both prior to and 3 months following the instigation of treatment) in comparison to a small number of healthy control subjects and samples obtained from patients with ankylosing spondylitis (AS) and psoriatic arthritis (PA).,Bacterial-derived DNA was identified in the majority of our patient samples.,Taxonomic classification revealed that the microbiome community in RA was distinct from AS, PA, and the healthy state.,Through analysis of paired patient samples obtained prior to and 3 months following treatment (V0 vs.,V3), we found the microbiome to be modulated by treatment, and in many cases, this shift reduced the distance between these samples and the healthy control samples, suggesting a partial normalization following treatment in some patients.,This effect was especially evident in seronegative arthritis patients.,Herein, we provide further evidence for the existence of a blood microbiome in health and identify specific taxa modulated in disease and following treatment.,These blood-derived signatures may have significant utility as disease biomarkers and suggest this area warrants further investigation.

A comprehensive structural portrait of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in rheumatoid arthritis.,Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens.,We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04.,Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes.,Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04.,Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals.,Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals.,In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals.,These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

To assess the safety and immunologic impact of inhibiting interferon‐γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).,Twenty‐six patients with mild‐to‐moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously.,Similar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose‐dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood.,The list of impacted genes overlapped with that identified by stimulating human whole blood with IFNγ and with those gene sets reported in the literature to be differentially expressed in SLE patients.,Serum levels of IFNγ‐induced chemokines, including IFNγ‐inducible protein 10 (IP‐10), were found to be elevated at baseline in SLE patients as compared to healthy volunteers.,In contrast to previously reported results from studies using type I IFN-blocking agents, treatment with AMG 811 led to dose‐related reductions in the serum levels of CXCL10 (IP‐10).,The scope and nature of the biomarkers impacted by AMG 811 support targeting of IFNγ as a therapeutic strategy for SLE.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens.,Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation.,Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity.,The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.,Sle1 and B6.,Sle1.,Sle3 mice.,B6.,Sle1 or B6.,Sle1.,Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days.,Following treatment, mice were examined for clinical and pathological characteristics of lupus.,The effect of PCI-32765 on specific cell types was also investigated.,In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.,Sle1 monocongenic mice.,Moreover, in B6.,Sle1.,Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.,These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

We studied the association between glycemic variability (GV) reflecting hypoglycemic stress and cardiovascular autonomic function in subjects with type 1 diabetes.,Forty-four type 1 diabetic patients (mean age 34 ± 13 years, 40% male, 86% Caucasian, mean diabetes duration 13 ± 6 years, mean hemoglobin A1c [HbA1c] 8.0 ± 1.2% [64 ± 5 mmol/mol]) without cardiovascular disease, dyslipidemia, or hypertension participated in this pilot study.,Indices of GV reflective of hypoglycemic stress (low blood glucose index [LBGI] and area under the curve [AUC] for hypoglycemia) were computed using data obtained during 5-day continuous glucose monitoring.,Cardiovascular autonomic neuropathy (CAN) was assessed using standardized cardiovascular reflex testing and measures of heart rate variability (HRV), which were analyzed as time and frequency domain measures.,Both LBGI and AUC hypoglycemia had a significant negative association with the low-frequency power of HRV (r = −0.47, P = 0.002; r = −0.43, P = 0.005, respectively) and with the high-frequency power of HRV (r = −0.37, P = 0.018; r = −0.38, P = 0.015, respectively).,These inverse associations persisted after adjusting for HbA1c, although they were attenuated in multivariable analysis after adjustment for age, diabetes duration, and several other covariates.,Increased GV promoting hypoglycemic stress was associated with reduced HRV independent of glycemic control as assessed by HbA1c.,These pilot data suggest that glucose variability may contribute to cardiovascular autonomic dysfunction among adults with type 1 diabetes.

Despite substantial evidence of the benefit of frequent self-monitoring of blood glucose (SMBG) in type 1 diabetes, certain insurers limit the number of test strips that they will provide.,The large database of the T1D Exchange clinic registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA1c levels across a wide age range of children and adults.,The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ≥1 year and not using a continuous glucose monitor (11,641 younger than age 18 years and 8,914 18 years old or older).,General linear models were used to assess the association between the number of SMBG measurements and HbA1c levels after adjusting for potential confounding variables.,A higher number of SMBG measurements per day were associated with non-Hispanic white race, insurance coverage, higher household income, and use of an insulin pump for insulin delivery (P < 0.001 for each factor).,After adjusting for these factors, a higher number of SMBG measurements per day was strongly associated with a lower HbA1c level (adjusted P < 0.001), with the association being present in all age-groups and in both insulin pump and injection users.,There is a strong association between higher SMBG frequency and lower HbA1c levels.,It is important for insurers to consider that reducing restrictions on the number of test strips provided per month may lead to improved glycemic control for some patients with type 1 diabetes.

Environmental factors may play roles in the development of rheumatoid arthritis (RA), and some studies have shown that air pollution was associated with the development of autoimmune disease.,This study was designed to investigate the effect of air pollutants on the development of adult RA.,A nested case-control cohort study was performed using the National Health Insurance Service-National Sample Cohort during 2002-2014 in Korea.,Air pollution data were collected from the National Ambient Air Monitoring System (NAMIS), and exposure levels were extrapolated using geographic information systems.,The group with RA (n = 444) was compared with a propensity score-matched control group (n = 1776), and one-year average concentrations of air pollution were predicted at each patient’s residence.,The adjusted binary logistic regression analysis showed a positive association between O3 exposure and the incidence risk of RA for the third (odds ratios (OR) = 1.45, 95% confidence intervals (CI): 1.08-1.96) and fourth (OR = 1.35, 95% CI: 1.00-1.83) quartiles in adults over 20 years of age.,The third quartile CO exposure was also associated with an increased risk of RA (OR = 1.57, 95% CI: 1.16-2.12).,The results of this nationwide population-based study showed that a one-year exposure to CO and O3 in adults was associated with an increased risk of RA.

Sodium chloride (NaCl) has been proposed as a driving factor in autoimmune diseases through the induction of pathogenic CD4+ T helper cells that produce interleukin-17 (Th17 cells).,This study investigated the effects of NaCl on inflammatory arthritis in mice and humans.,Collagen-induced arthritis (CIA) mice were fed a normal or high-salt diet ad libitum, and clinical and histologic features of arthritis were evaluated.,The proportion of Th17 cells in the spleens of CIA mice fed a normal or high-salt diet was evaluated by flow cytometry, and the expression of IL-17 in joints and intestines was determined by immunohistochemical staining.,We also analyzed the effect of NaCl on Th17 differentiation from peripheral blood monocytes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and evaluated the contents of sodium and IL-17 in the synovial fluid of RA and OA patients.,NaCl increased murine and human Th17 cell differentiation in a dose-dependent manner.,Clinical and histological arthritis was more severe in the high-salt-fed CIA mice, compared to control CIA mice.,The proportion of Th17 cells among splenocytes was higher in CIA mice fed a high-salt diet.,Expression of synovial and intestinal IL-17 was also higher in high-salt-fed CIA mice.,Comparison of synovial fluid between RA patients and OA patients revealed that Na+ and IL-17 were more abundant in RA synovial fluid.,This study suggests that NaCl can aggravate arthritis by affecting Th17 differentiation.,Accordingly, limiting salt intake may be helpful for treating inflammatory arthritis, such as RA.

Identifying whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders.,Colocalization methods disentangle shared and distinct causal variants.,However, existing approaches require independent datasets.,Here we extend two colocalization methods to allow for the shared control design commonly used in comparison of genome-wide association study results across diseases.,Our analysis of four autoimmune diseases, type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis, revealed 90 regions that were associated with at least one disease, 33 (37%) of which with two or more disorders.,Nevertheless, for 14 of these 33 shared regions there was evidence that causal variants differed.,We identified novel disease associations in 11 regions previously associated with one or more of the other three disorders.,Four of eight T1D-specific regions contained known type 2 diabetes candidate genes: COBL, GLIS3, RNLS and BCAR1, suggesting a shared cellular etiology.

Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time.,Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6).,Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis.,The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively.,Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.

In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated.,The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches.,The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process.,Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined.,Fourteen recommendations were developed (instead of 15 in 2010).,Some of the 2010 recommendations were deleted, and others were amended or split.,The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients.,The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months).,Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety.,If the first bDMARD strategy fails, any other bDMARD may be used.,The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD.,Biosimilars are also addressed.,These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs.,They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA).,AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint.,Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX.,Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2.,At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results.,The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab.,There were similar rates of adverse events (AEs) and serious adverse events (SAEs).,More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab.,There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group.,Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%).,Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes.,Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept.,NCT00929864.

Rheumatoid arthritis (RA) clinical trials often exclude patients who have low C‐reactive protein (CRP) levels, which slows enrollment into the trial.,The purpose of this study was to determine whether high Multi‐Biomarker Disease Activity (MBDA) scores (>44) in RA patients with low CRP levels (≤10 mg/liter) could be used as a complement to CRP levels >10 mg/liter to enhance patient recruitment without affecting clinical trial outcomes.,We evaluated patients from the Swedish Pharmacotherapy (SWEFOT) trial, which did not include any selection criteria for CRP levels.,Clinical outcomes were assessed after 3 months of methotrexate (MTX) monotherapy in MTX‐naive RA patients (n = 220) and after 3-10 months of add‐on therapy in patients who were incomplete responders to MTX alone (MTX‐IR) (n = 127).,Radiographic outcomes were assessed at 1 year in all patients.,Within each cohort, the outcomes were compared between patients with a CRP level of ≤10 mg/liter and an MBDA score of >44 at the start of the respective treatment interval versus those with a CRP level of >10 mg/liter.,Patients with both a CRP level of ≤10 mg/liter and an MBDA score of >44 at baseline had clinical and radiographic outcomes that were comparable to those in patients with a CRP level of >10 mg/liter at baseline.,This broadened definition of the inclusion criteria identified an additional 24% of patients in the MTX‐naive cohort and 47% in the MTX‐IR cohort.,Patient recruitment into RA clinical trials may be substantially enhanced, without any decrease in clinical and radiographic outcomes, by using as an inclusion criterion “a CRP level of >10 mg/liter and/or an MBDA score of >44.”

Objectives.,To examine the association between a multibiomarker disease activity (MBDA) score, CRP and clinical disease activity measures among RA patients with and without concomitant FM.,Methods.,In an observational cohort of patients with established RA, we performed a cross-sectional analysis comparing MBDA scores with CRP by rank correlation and cross-classification.,MBDA scores, CRP and clinical measures of disease activity were compared between patients with RA alone and RA with concomitant FM (RA and FM) by univariate and multivariate analyses.,Results.,CRP was ⩽1.0 mg/dl for 184 of 198 patients (93%).,MBDA scores correlated with CRP (r = 0.755, P < 0.001), but were often discordant, being moderate or high for 19%, 55% and 87% of patients with CRP ⩽0.1, 0.1 to ⩽0.3, or 0.3 to ⩽1.0 mg/dl, respectively.,Among patients with CRP ⩽1.0 mg/dl, swollen joint count (SJC) increased linearly across levels of MBDA score, both with (P = 0.021) and without (P = 0.004) adjustment for CRP, whereas CRP was not associated with SJC.,The 28-joint-DAS-CRP, other composite measures, and their non-joint-count component measures were significantly greater for patients with RA and FM (n = 25) versus RA alone (n = 173) (all P ⩽ 0.005).,MBDA scores and CRP were similar between groups.,Conclusion.,MBDA scores frequently indicated RA disease activity when CRP did not.,Neither one was significantly greater among patients with RA and FM versus RA alone.,Thus, MBDA score may be a useful objective measure for identifying RA patients with active inflammation when CRP is low (⩽1.0 mg/dl), including RA patients with concomitant FM.

The mechanisms underlying immunoglobulin A nephropathy (IgAN), the most common chronic form of primary glomerulonephritis, remain poorly understood.,Streptococcus mutans, a Gram-positive facultatively anaerobic oral bacterium, is a common cause of dental caries.,In previous studies, S. mutans isolates that express Cnm protein on their cell surface were frequently detected in IgAN patients.,In the present study, inoculation of Cnm-positive S. mutans in the oral cavities of 2-week-old specific-pathogen free Sprague-Dawley rats fed a high-sucrose diet for 32 weeks produced severe dental caries in all rats.,Immunohistochemical analyses of the kidneys using IgA- and complement C3-specific antibodies revealed positive staining in the mesangial region.,Scanning electron microscopy revealed a wide distribution of electron dense deposits in the mesangial region and periodic acid-Schiff staining demonstrated prominent proliferation of mesangial cells and mesangial matrix.,These results suggest that IgAN-like glomerulonephritis was induced in rats with severe dental caries by Cnm-positive S. mutans.

IgA nephropathy is an inflammatory renal disease characterised by the deposition of IgA in the glomerular mesangium and is the most commonly reported primary glomerulonephritis worldwide.,Thirty to forty percent of patients with the disease develop progressive renal function decline, requiring renal replacement therapy within two decades of diagnosis.,Despite this, accurate individual risk stratification at diagnosis and predicting treatment response remains a challenge.,Furthermore, there are currently no disease specific treatments currently licensed to treat the condition due to long standing challenges in the nature and prevalence of the disease.,Despite this, there have been exciting recent advances in the field that may represent paradigm shifts in the way IgA nephropathy is managed in the near future.,In this review, we explore the evidence base informing current approaches to management and explore new strategies and future directions in the diagnosis and management of IgA nephropathy.

To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting.,Clinical data for all adult patients with multiple sclerosis (MS) treated with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts.,The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity.,A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS).,Patients were treated with 1000 or 2000 mg rituximab IV every 6-12 months for a mean duration of 22.2 ± 24.8 months.,The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years.,During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p < 0.0001) and from 0.25 to 0.16 in PMS patients (p = 0.593).,The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients.,Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group.,No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment.,A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature.,Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma.,No case of progressive multifocal leukoencephalopathy (PML) was detected.,In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.

The nature of the inflammatory response in the MS brain is poorly defined.,Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.,Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain.,However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations.,In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls.,In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse.,A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen’s encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest.,Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis.,Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells.,The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions.,Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen’s encephalitis.,Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions.,Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.

To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data.,Regions of association were defined based on the significance of linkage disequilibrium blocks.,Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins.,Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery.,The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively).,Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages.,A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells.,This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

Compared with influenza-specific T cells, self-reactive T cells from patients with multiple sclerosis or type 1 diabetes fail to slow down and do not form normal immunological synapses upon encounter with cognate self-peptide presented by MHC.,Recognition of self-peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases.,We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes.,All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling.,However, they showed little or no visible pMHC accumulation or transport of TCR-pMHC complexes into a central supramolecular activation cluster (cSMAC).,In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities.,The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells.,2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC.,These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus.,However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.

Jackson et al. propose a role for B cell-intrinsic IFN-γ receptor signaling in spontaneous germinal center activation and autoantibody production.,Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE).,Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed.,In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development.,In contrast, B cells functioning as antigen-presenting cells initiate CD4+ T cell activation and IFN-γ production, and strikingly, B cell-intrinsic deletion of the IFN-γ receptor (IFN-γR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity.,Mechanistically, although IFN-γR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development.,Rather, in both mouse and human B cells, IFN-γ synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein.,Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE.

Neutrophil extracellular traps (NETs) are implicated in autoimmunity but how they are generated and their roles in sterile inflammation remain unclear.,Ribonucleoprotein immune complexes, inducers of NETosis, require mitochondrial ROS for maximal NET stimulation.,During this process, mitochondria become hypopolarized and translocate to the cell surface.,Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro and, when injected into mice, stimulates type-I interferon (IFN) signaling through a pathway dependent on the DNA sensor, STING.,Mitochondrial ROS is also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus (SLE).,This was also observed in individuals with chronic granulomatous disease (CGD), which lack NADPH-oxidase activity, but still develop autoimmunity and type I-IFN signatures.,Mitochondrial ROS inhibition in vivo reduces disease severity and type-I IFN responses in a mouse model of lupus.,These findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.

Interleukin 6 (IL-6) plays an important role in the initiation and acceleration of chronic inflammation and could contribute to development of microvascular complications in patients with type 1 diabetes (DM1).,Therefore, this study was aimed to investigate the association between concentration of IL-6 in relation to glucose control, lipid profile, and body mass index (BMI) in 69 DM1 patients subdivided according to the absence or presence of microvascular complications.,BMI, level of fasting plasma glucose (FPG), and concentrations of total cholesterol (TCH), LDL cholesterol (LDL-C), and IL-6 were higher in DM1 patients compared to the control group.,In DM1 patients, IL-6 concentration was positively correlated with level of FPG, LDL-C, TCH concentrations, and BMI.,These correlations were stronger in the subgroup of patients with microvascular complications.,In addition, BMI independently influences IL-6 concentration in DM1 patients.,In conclusion, elevated IL-6 concentration is associated with diabetes-related variables which could accelerate progression of microvascular complications in DM1 patients.

Previous studies have noted a specific association between type 1 diabetes and insufficient levels of vitamin D, as well as polymorphisms within genes related to vitamin D pathways.,Here, we examined whether serum levels or genotypes of the vitamin D-binding protein (VDBP), a molecule key to the biologic actions of vitamin D, specifically associate with the disorder.,A retrospective, cross-sectional analysis of VDBP levels used samples from 472 individuals of similar age and sex distribution, including 153 control subjects, 203 patients with type 1 diabetes, and 116 first-degree relatives of type 1 diabetic patients.,Single nucleotide polymorphism (SNP) typing for VDBP polymorphisms (SNP rs4588 and rs7041) was performed on this cohort to determine potential genetic correlations.,In addition, SNP analysis of a second sample set of banked DNA samples from 1,502 type 1 diabetic patients and 1,880 control subjects also was used to determine genotype frequencies.,Serum VDBP levels were highest in healthy control subjects (median 423.5 µg/mL [range 193.5-4,345.0; interquartile range 354.1-]586), intermediate in first-degree relatives (402.9 µg/mL [204.7-4,850.0; 329.6-492.4]), and lowest in type 1 diabetic patients (385.3 µg/mL [99.3-1,305.0; 328.3-473.0]; P = 0.003 vs. control subjects).,VDBP levels did not associate with serum vitamin D levels, age, or disease duration.,However, VDBP levels were, overall, lower in male subjects (374.7 µg/mL [188.9-1,602.0; 326.9-449.9]) than female subjects (433.4 µg/mL [99.3-4,850.0; 359.4-567.8]; P < 0.0001).,It is noteworthy that no differences in genotype frequencies of the VDBP polymorphisms were associated with serum VDBP levels or between type 1 diabetic patients and control subjects.,Serum VDBP levels are decreased in those with type 1 diabetes.,These studies suggest that multiple components in the metabolic pathway of vitamin D may be altered in type 1 diabetes and, collectively, have the potential to influence disease pathogenesis.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can lead to unfavorable pregnancy complications in women.,This study aimed to evaluate the factors associated with pregnancy outcomes in patients with SLE.,Fifty-nine pregnant women with SLE (121 pregnancies) participated in this retrospective cohort study.,The mean age of the patients was 33.74 ± 3.80 years (range 21 to 48 years).,Fetal loss occurred in 43.8% of pregnancies.,The most common laboratory findings in SLE patients were antinuclear antibody (81.4%) and anti-ds DNA positivity (54.2%).,High levels of C-reactive protein (CRP) during pregnancy, renal involvement, anti-double-stranded DNA positivity, anti-phospholipid antibody (APA) positivity and younger age at disease onset were significantly correlated with unfavourable pregnancy outcomes.,A significant difference was observed between duration of SLE and low birth weight (P = 0.003), pre-eclampsia (P = 0.012) and still birth (P = 0.036).,High CRP, APA positivity, anti-dsDNA positivity and kidney involvement were predictors of adverse pregnancy outcomes in SLE patients.,Renal involvement increased risk of pregnancy with complication 8.5 times (OR = 8.5, 95% CI 1.396-63.373, P = 0.017).,Antiphospholipid syndrome (APS) also was associated with an odds ratio of 5.18 (95% CI 1.681-13.647, P = 0.001).

Intravenous belimumab plus standard of care (SoC) is approved in the USA and Europe for treatment of active, autoantibody-positive systemic lupus erythematosus (SLE).,This phase III, multicentre, randomised, double-blind, placebo-controlled study (BEL113750; NCT01345253) was conducted in 49 centres across China, Japan and South Korea (May 2011-September 2015).,Patients with SLE were randomised 2:1 to intravenous belimumab 10 mg/kg or placebo, plus SoC, every 4 weeks until Week 48.,The primary endpoint was the SLE Responder Index (SRI) 4 response rate at Week 52.,Secondary endpoints were the percentage of patients with ≥4 point reduction in Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), SRI7, time to first severe flare and number of days prednisone (or equivalent) dose ≤7.5 mg/day and/or reduced by 50% from baseline.,Safety was assessed.,The modified intent-to-treat population included 677 patients (belimumab n=451, placebo n=226).,At Week 52, the SRI4 response rate was higher with belimumab versus placebo (53.8% vs 40.1%; OR: 1.99 (95% CI: 1.40, 2.82; P=0.0001)).,The percentages of patients with a ≥4 point reduction in SELENA-SLEDAI and an SRI7 response were significantly greater for belimumab versus placebo.,Patients in the belimumab group had a 50% lower risk of experiencing a severe flare than those receiving placebo (P=0.0004).,In patients with baseline prednisone dose >7.5 mg/day, there was a significant reduction in steroid use favouring belimumab (P=0.0228).,The incidence of adverse events was similar between groups.,In patients with SLE from North East Asia, belimumab significantly improved disease activity, while reducing prednisone use, with no new safety issues.

Clinical trials established the efficacy and safety of natalizumab.,Data are needed over longer periods of time and in the clinical practice setting.,To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS).,The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.,In this 5-year interim analysis, 4821 patients were enrolled.,Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals.,There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions.,Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years.,Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates.,Mean EDSS scores remained unchanged up to 5 years.,Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice.,NCT00493298.

Background: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes.,Full clinical cognitive assessment is expensive, requiring expert staff and special equipment.,Test versions and normative data are not available for all languages and cultures.,Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use.,Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened.,Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS.,Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients.,Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test - Second Edition and the Brief Visuospatial Memory Test - Revised learning trials if a further 10 minutes could be allocated for testing.,Conclusions: A brief cognitive assessment for MS has been recommended.,A validation protocol has been prepared for language groups and validation studies have commenced.

•The GBSI provided clinically meaningful measurements of spinal cord atrophy, with low sample size.,•Deriving spinal cord atrophy from brain MRI using the GBSI is easier than spinal cord MRI.,•Spinal cord atrophy on GBSI could be used as a secondary outcome measure.,The GBSI provided clinically meaningful measurements of spinal cord atrophy, with low sample size.,Deriving spinal cord atrophy from brain MRI using the GBSI is easier than spinal cord MRI.,Spinal cord atrophy on GBSI could be used as a secondary outcome measure.,We aimed to evaluate the implications for clinical trial design of the generalised boundary-shift integral (GBSI) for spinal cord atrophy measurement.,We included 220 primary-progressive multiple sclerosis patients from a phase 2 clinical trial, with baseline and week-48 3DT1-weighted MRI of the brain and spinal cord (1 × 1 × 1 mm3), acquired separately.,We obtained segmentation-based cross-sectional spinal cord area (CSA) at C1-2 (from both brain and spinal cord MRI) and C2-5 levels (from spinal cord MRI) using DeepSeg, and, then, we computed corresponding GBSI.,Depending on the spinal cord segment, we included 67.4-98.1% patients for CSA measurements, and 66.9-84.2% for GBSI.,Spinal cord atrophy measurements obtained with GBSI had lower measurement variability, than corresponding CSA.,Looking at the image noise floor, the lowest median standard deviation of the MRI signal within the cerebrospinal fluid surrounding the spinal cord was found on brain MRI at the C1-2 level.,Spinal cord atrophy derived from brain MRI was related to the corresponding measures from dedicated spinal cord MRI, more strongly for GBSI than CSA.,Spinal cord atrophy measurements using GBSI, but not CSA, were associated with upper and lower limb motor progression.,Notwithstanding the reduced measurement variability, the clinical correlates, and the possibility of using brain acquisitions, spinal cord atrophy using GBSI should remain a secondary outcome measure in MS studies, until further advancements increase the quality of acquisition and reliability of processing.

Prediction of long term clinical outcome in patients with primary progressive multiple sclerosis (PPMS) using imaging has important clinical implications, but remains challenging.,We aimed to determine whether spatial location of T2 and T1 brain lesions predicts clinical progression during a 10-year follow-up in PPMS.,Lesion probability maps of the T2 and T1 brain lesions were generated using the baseline scans of 80 patients with PPMS who were clinically assessed at baseline and then after 1, 2, 5 and 10 years.,For each patient, the time (in years) taken before bilateral support was required to walk (time to event (TTE)) was used as a measure of progression rate.,The probability of each voxel being ‘lesional’ was correlated with TTE, adjusting for age, gender, disease duration, centre and spinal cord cross sectional area, using a multiple linear regression model.,To identify the best, independent predictor of progression, a Cox regression model was used.,A significant correlation between a shorter TTE and a higher probability of a voxel being lesional on T2 scans was found in the bilateral corticospinal tract and superior longitudinal fasciculus, and in the right inferior fronto-occipital fasciculus (p<0.05).,The best predictor of progression rate was the T2 lesion load measured along the right inferior fronto-occipital fasciculus (p=0.016, hazard ratio 1.00652, 95% CI 1.00121 to 1.01186).,Our results suggest that the location of T2 brain lesions in the motor and associative tracts is an important contributor to the progression of disability in PPMS, and is independent of spinal cord involvement.

We aimed to identify the plasma miRNA profile of antiphospholipid syndrome (APS) patients and to investigate the potential role of specific circulating miRNAs as non-invasive disease biomarkers.,Ninety APS patients and 42 healthy donors were recruited.,Profiling of miRNAs by PCR-array in plasma of APS patients identified a set of miRNAs differentially expressed and collectively involved in clinical features.,Logistic regression and ROC analysis identified a signature of 10 miRNA ratios as biomarkers of disease.,In addition, miRNA signature was related to fetal loss, atherosclerosis, and type of thrombosis, and correlated with parameters linked to inflammation, thrombosis, and autoimmunity.,Hard clustering analysis differentiated 3 clusters representing different thrombotic risk profile groups.,Significant differences between groups for several miRNA ratios were found.,Moreover, miRNA signature remained stable over time, demonstrated by their analysis three months after the first sample collection.,Parallel analysis in two additional cohorts of patients, including thrombosis without autoimmune disease, and systemic lupus erythematosus without antiphospholipid antibodies, each displayed specific miRNA profiles that were distinct from those of APS patients.,In vitro, antiphospholipid antibodies of IgG isotype promoted deregulation in selected miRNAs and their potential atherothrombotic protein targets in monocytes and endothelial cells.,Taken together, differentially expressed circulating miRNAs in APS patients, modulated at least partially by antiphospholipid antibodies of IgG isotype, might have the potential to serve as novel biomarkers of disease features and to typify patients’ atherothrombotic status, thus constituting a useful tool in the management of the disease.

MicroRNAs markedly affect the immune system, and have a relevant role in CVD and autoimmune diseases.,Yet, no study has analyzed their involvement in atherothrombosis related to APS and SLE patients.,This study intended to: 1) identify and characterize microRNAs linked to CVD in APS and SLE; 2) assess the effects of specific autoantibodies.,Six microRNAs, involved in atherothrombosis development, were quantified in purified leukocytes from 23 APS and 64 SLE patients, and 56 healthy donors.,Levels of microRNAs in neutrophils were lower in APS and SLE than in healthy donors.,Gene and protein expression of miRNA biogenesis-related molecules were also reduced.,Accordingly, more than 75% of identified miRNAs by miRNA profiling were underexpressed.,In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated.,Altered microRNAs’ expression was linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in both pathologies.,In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG or anti-dsDNA-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins.,Monocyte transfections with pre-miR-124a and/or -125a caused reduction in atherothrombosis-related target molecules.,In conclusion, microRNA biogenesis, significantly altered in neutrophils of APS and SLE patients, is associated to their atherothrombotic status, further modulated by specific autoantibodies.

Approximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia.,This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown.,We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia.,Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]).,In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3).,The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest.,In this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA1c <75 mmol/mol (9%) were recruited.,Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \dot{V}{\mathrm{O}}_{2\mathrm{peak}} $$\end{document}V˙O2peak assessment) or rest (control).,The following day they underwent a 90 min hyperinsulinaemic-hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test).,Each intervention and subsequent clamp study was separated by at least 2 weeks.,The participants and investigators were not blinded to the intervention or measurements during the study.,The investigators were blinded to the primary outcome and blood analysis results.,All participants (six male and six female, age 19-54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3-29.0] years, mean [SEM] HbA1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps).,In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p<0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p<0.01] during equivalent hypoglycaemia induced the following day.,These findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia.,ISRCTN15236211.,The online version of this article (10.1007/s00125-019-05076-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Hypoglycaemia remains the most common metabolic adverse effect of insulin and sulfonylurea therapy in diabetes.,Repeated exposure to hypoglycaemia leads to a change in the symptom complex that characterises hypoglycaemia, culminating in a clinical phenomenon referred to as impaired awareness of hypoglycaemia (IAH).,IAH effects approximately 20-25% of people with type 1 diabetes and increases the risk of severe hypoglycaemia.,This review focuses on the mechanisms that are responsible for the much higher frequency of hypoglycaemia in people with diabetes compared with those without, and subsequently how repeated exposure to hypoglycaemia leads to the development of IAH.,The mechanisms that result in IAH development are incompletely understood and likely to reflect changes in multiple aspects of the counterregulatory response to hypoglycaemia, from adaptations within glucose and non-glucose-sensing cells to changes in the integrative networks that govern glucose homeostasis.,Finally, we propose that the general process that incorporates many of these changes and results in IAH following recurrent hypoglycaemia is a form of adaptive memory called ‘habituation’.,The online version of this article (10.1007/s00125-018-4548-8) contains a slideset of the figures for download, which is available to authorised users.

A multilayer hydrogel nanofilm on the cell surface via enzymatic reactions provides a new platform for β cell-based therapy.,Pancreatic β cell therapy for type 1 diabetes is limited by low cell survival rate owing to physical stress and aggressive host immune response.,In this study, we demonstrate a multilayer hydrogel nanofilm caging strategy capable of protecting cells from high shear stress and reducing immune response by interfering cell-cell interaction.,Hydrogel nanofilm is fabricated by monophenol-modified glycol chitosan and hyaluronic acid that cross-link each other to form a nanothin hydrogel film on the cell surface via tyrosinase-mediated reactions.,Furthermore, hydrogel nanofilm formation was conducted on mouse β cell spheroids for the islet transplantation application.,The cytoprotective effect against physical stress and the immune protective effect were evaluated.,Last, caged mouse β cell spheroids were transplanted into the type 1 diabetes mouse model and successfully regulated its blood glucose level.,Overall, our enzymatic cross-linking-based hydrogel nanofilm caging method will provide a new platform for clinical applications of cell-based therapies.

T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists.,The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3.,In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic.,The major issue that remains to be resolved is how they mediate their suppressive functions.,In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms.,Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites.,Many of the concepts we have developed are based on in vitro studies, and it remains unclear if these concepts can readily be applied to Treg function in vivo.,Our lack of a specific cell surface marker that readily allows us to identify and target Treg in vivo, particularly in man, remains a major stumbling block.,Finally, I will review in some detail controversies regarding the origin of Treg, thymus versus periphery, and attempts to reverse Treg suppression by targeting antigens on their cell surface, particularly members of the TNF receptor superfamily.,Hopefully, these areas of controversy will be resolved by in depth studies over the next few years and manipulation of Treg function will be placed on a more solid experimental footing.

Plasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells.,Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes.,Nonetheless, the precise contribution of beta cell mass and function to the pathogenesis of diabetes as well as the underlying mechanisms are still unclear.,In the past, this was largely due to the restricted number of technologies suitable for studying the scarcely accessible human beta cells.,However, in recent years, a number of new platforms have been established to expand the available techniques and to facilitate deeper insight into the role of human beta cell mass and function as cause for diabetes and as potential treatment targets.,This review discusses the current knowledge about contribution of human beta cell mass and function to different stages of type 1 and type 2 diabetes pathogenesis.,Furthermore, it highlights standard and newly developed technological platforms for the study of human beta cell biology, which can be used to increase our understanding of beta cell mass and function in human glucose homeostasis.,In contrast to early disease models, recent studies suggest that in type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation.,This suggests that, in addition to beta cell mass replacement for late stage therapies, the development of novel strategies for protection and recovery of beta cell function could be most promising for successful diabetes treatment and prevention.,The use of today's developing and wide range of technologies and platforms for the study of human beta cells will allow for a more detailed investigation of the underlying mechanisms and will facilitate development of treatment approaches to specifically target human beta cell mass and function.

The study of endogenous insulin secretion may provide relevant insight into the comparison of the natural history of adult onset latent autoimmune diabetes (LADA) with types 1 and 2 diabetes mellitus.,The aim of this study was to compare the results of the C-peptide response to mixed-meal stimulation in LADA patients with different disease durations and subjects with type 2 and adult-onset type 1 diabetes.,Stimulated C-peptide secretion was assessed using the mixed-meal tolerance test in patients with LADA (n = 32), type 1 diabetes mellitus (n = 33) and type 2 diabetes mellitus (n = 30).,All patients were 30 to 70 years old at disease onset.,The duration of diabetes in all groups ranged from 6 months to 10 years.,The recruitment strategy was predefined to include at least 10 subjects in the following 3 disease onset categories for each group: 6 to 18 months, 19 months to 5 years and 5 to 10 years.,At all time-points of the mixed-meal tolerance test, patients with LADA had a lower stimulated C-peptide response than the type 2 diabetes group and a higher response than the type 1 diabetes group.,The same results were found when the peak or area under the C-peptide curve was measured.,When the results were stratified by time since disease onset, a similar pattern of residual insulin secretory capacity was observed.,The present study shows that the magnitude of stimulated insulin secretion in LADA is intermediate between that of type 1 and type 2 diabetes mellitus.,The online version of this article (doi:10.1186/1472-6823-15-1) contains supplementary material, which is available to authorized users.

To examine associations between dietary intake of omega‐3 (n‐3; generally antiinflammatory) and omega‐6 (n‐6; generally proinflammatory) fatty acids and patient‐reported outcomes in systemic lupus erythematosus (SLE).,This study was based on the population‐based Michigan Lupus Epidemiology and Surveillance cohort.,Estimates of n‐3 and n‐6 intake were derived from Diet History Questionnaire II items (past year with portion size version).,Patient‐reported outcomes included self‐reported lupus activity (Systemic Lupus Activity Questionnaire [SLAQ]).,Multivariable regression, adjusted for age, sex, race, and body mass index, was used to assess associations between absolute intake of n‐3 and n‐6, as well as the n‐6:n‐3 ratio, and patient‐reported outcomes.,Among 456 SLE cases, 425 (93.2%) were female, 207 (45.4%) were African American, and the mean ± SD age was 52.9 ± 12.3 years.,Controlling for potential confounders, the average SLAQ score was significantly higher by 0.3 points (95% confidence interval [95% CI] 0.1, 0.6; P = 0.013) with each unit increase of the n‐6:n‐3 ratio.,Both lupus activity and Patient‐Reported Outcomes Measurement Information System (PROMIS) sleep disturbance scores were lower with each 1‐gram/1,000 kcal increase of n‐3 fatty acids (SLAQ regression coefficient β = -0.8 [95% CI -1.6, 0.0]; P = 0.055; PROMIS sleep β = -1.1 [95% CI -2.0, -0.2]; P = 0.017).,Higher n‐3 intakes were nonsignificantly associated with lower levels of depressive symptoms and comorbid fibromyalgia, and with higher quality of life, whereas results for the n6:n3 ratio trended in the opposite direction.,This population‐based study suggests that higher dietary intake of n‐3 fatty acids and lower n‐6:n‐3 ratios are favorably associated with patient‐reported outcomes in SLE, particularly self‐reported lupus activity and sleep quality.

Roles of all-trans-retinoic acid (tRA), a metabolite of vitamin A (VA), in both tolerogenic and immunogenic responses are documented.,However, how tRA affects the development of systemic autoimmunity is poorly understood.,Here we demonstrate that tRA have paradoxical effects on the development of autoimmune lupus in the MRL/lpr mouse model.,We administered, orally, tRA or VA mixed with 10% of tRA (referred to as VARA) to female mice starting from 6 weeks of age.,At this age, the mice do not exhibit overt clinical signs of lupus.,However, the immunogenic environment preceding disease onset has been established as evidenced by an increase of total IgM/IgG in the plasma and expansion of lymphocytes and dendritic cells in secondary lymphoid organs.,After 8 weeks of tRA, but not VARA treatment, significantly higher pathological scores in the skin, brain and lung were observed.,These were accompanied by a marked increase in B-cell responses that included autoantibody production and enhanced expression of plasma cell-promoting cytokines.,Paradoxically, the number of lymphocytes in the mesenteric lymph node decreased with tRA that led to significantly reduced lymphadenopathy.,In addition, tRA differentially affected renal pathology, increasing leukocyte infiltration of renal tubulointerstitium while restoring the size of glomeruli in the kidney cortex.,In contrast, minimal induction of inflammation with tRA in the absence of an immunogenic environment in the control mice was observed.,Altogether, our results suggest that under a predisposed immunogenic environment in autoimmune lupus, tRA may decrease inflammation in some organs while generating more severe disease in others.

We aimed to investigate the regulation of circular RNAs in lipopolysaccharide (LPS)-treated chondrocytes isolated from SD rat.,In this study, we analyzed how circFADS2 was regulated in LPS-treated chondrocytes and isolates from Rheumatoid arthritis (RA) patients and found that circFADS2 and mTOR were highly expressed whereas miR-498 expression was significantly reduced.,We then silenced circFADS2 in LPS-treated chondrocytes; this resulted in a declined expression of type II collagen, but an increase in the expression of MMP-13, COX-2, and IL-6.,Overall, silencing circFADS2 caused a significant reduction in the proliferative rate of LPS-treated chondrocytes, increased apoptotic levels, miR-498 upregulation, and mTOR downregulation.,Dual-luciferase reporter assay indicated that circFADS2 directly targeted miR-498.,In contrast, miR-498 down-regulation affected circFADS2 silencing, promoting extracellular matrix (ECM) degradation and apoptosis.,The 3’ UTR of the mTOR gene is targeted by miR-498, and consequently, in cells transfected with miR-498, there was a significant reduction of mTOR expression at the protein and mRNA levels.,Silencing mTOR had a similar effect to circFADS2 silencing on type II collagen, MMP-13, COX-2, and IL-6 expression, as well as cell proliferation and apoptosis.,In conclusion, circFADS2 may affect LPS-induced chondrocytes properties by regulating the ECM catabolism, inflammation, and apoptosis in chondrocytes.

To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.,In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months.,Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy.,The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX.,Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive.,For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months.,DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18).,Both abatacept arms had a safety profile comparable with MTX alone.,Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile.,The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes.,NCT01142726.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis.,It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes.,We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase.,In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment.,We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells.,In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4+CD25- T cell targets.,Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14+ monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns.,These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes.,Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course.,These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.

To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).,Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity.,Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).,Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment.,ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15).,Over years 0-5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI.,Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5.,Median yearly BVL improved over years 2-4, remaining low in year 5 (years 1-5: −0.59%, −0.25%, −0.19%, −0.15%, and −0.20%).,Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study.,Thyroid disorder incidences peaked at year 3 and subsequently declined.,Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.,NCT00530348; NCT00930553.,This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.

To evaluate the potential role of vascular cell adhesion molecule-1 (VCAM-1), an endothelial factor, in endothelial dysfunction in rheumatoid arthritis (RA) patients, and to determine its relation to disease activity, oxidative stress, and inflammatory markers.,This study was designed as a cross-sectional case-control study.,One-hundred patients with RA were selected from out-patient clinics of Menoufia University Hospital, Menoufia, Egypt from May 2019 to May 2020.,Fifty patients previously diagnosed with RA for more than 6 months were included as Group I, and fifty patients newly diagnosed with RA were included as Group II.,Fifty healthy age- and gender-matched individuals were evaluated as the control group (Group III).,Complete blood count, random blood glucose, erythrocyte sedimentation rate (ESR), lipid profile, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, serum levels of urea, creatinine, C-reactive protein, VCAM-1, malondialdehyde, and total antioxidant capacity were determined.,Patients with RA showed significantly higher serum VCAM-1, malondialdehyde, ESR, C-reactive protein, triglycerides, total cholesterol, low-density lipoprotein, and atherogenic index levels than the control group.,Also, they showed significantly lower total antioxidant capacity and high-density lipoprotein levels than control group.,A significant positive correlation between serum VCAM-1 with disease activity, serum malondialdehyde, ESR, and C-reactive protein was observed.,Also, a significant negative correlation between serum VCAM-1 and total antioxidant capacity was present.,Serum VCAM-1 increases in RA, and it correlates with disease activity, oxidative stress, and inflammatory markers.

It is known that patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease and sudden cardiac death.,Abnormalities in cardiac geometry appear to be involved in the setting of the cardiovascular risk, but it has never been specifically investigated in RA.,We enrolled 44 patients with RA compared to 131 subjects without RA (normal, N): The RA aged between 18 and 70 years (mean 48.3 ± 2.1), 25 females, BMI 27.6 ± 0.9; N, of equal age (48.6 ± 1.2, n.s.), included 80 females (BMI 26.7 ± 0.2, ns).,Cardiac Ultrasounds showed an increase of the diameter of the left ventricle but not in the septum with reduction of relative wall thickness (RWT) in the RA population compared to N.,Relative wall thickness inversely correlates with biochemical parameters of inflammatory response (gamma globulin, p < 0.03; F = 5,660) and anti citrullinated peptides antibody (anti-CCP Ab) (p < 0.02; F = 7,1620) We conclude that unfavorable cardiac remodeling can increase cardiovascular risk in patients with RA.

Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions.,In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions.,During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels.,Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes.,Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT).,Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases.,Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis.,Here, we review the role of the Ca2+-calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.

To perform a systematic review and network meta-analysis (NMA) to compare the risk of serious infections with immunosuppressive medications and glucocorticoids in lupus nephritis.,A trained librarian performed two searches: (1) PubMed for all lupus nephritis trials from the end dates for the systematic review for the 2012 American College of Rheumatology (ACR) lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on treatments for lupus nephritis, to September 2013; and (2) PubMed and SCOPUS for all lupus trials (excluding lupus nephritis) from inception to February 2014, to obtain additional trials for harms data in any lupus patient.,The search was updated to May 2016.,Duplicate title/abstract review and duplicate data abstractions by two abstractors independently was performed for all eligible studies, including those studies abstracted for the 2012 ACR lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on lupus nephritis treatments.,We performed a systematic review and a Bayesian NMA, including randomized controlled trials (RCTs) of immunosuppressive drugs or glucocorticoids in patients with lupus nephritis assessing serious infection risk.,Markov chain Monte Carlo methods were used to model 95 % credible intervals (CrI).,Sensitivity analyses examined the robustness of estimates.,A total of 32 RCTs with 2611 patients provided data.,There were 26 two-arm, five three-arm, and one four-arm trials.,We found that tacrolimus was associated with significantly lower risk of serious infections compared to glucocorticoids, cyclophosphamide (CYC), mycophenolate mofetil (MMF), and azathioprine (AZA) with odds ratios (95 % CrI) of 0.33 (0.12-0.88), 0.37 (0.15-0.87), 0.340 (0.18-0.81), and 0.32 (0.12-0.81), respectively.,Conversely, CYC low dose (LD), CYC high dose (HD), and HD glucocorticoids were associated with higher odds of serious infections compared to tacrolimus, ranging from 4.84 to 12.83.,We also found that MMF followed by AZA (MMF-AZA) was associated with significantly lower risk of serious infections as compared to CYC LD, CYC HD, CYC-AZA, or HD glucocorticoids with odds ratios (95 % CrI) of 0.09 (0.01-0.76), 0.07 (0.01-0.54), 0.14 (0.02-0.71), and 0.03 (0.00-0.56), respectively.,Estimates were similar to pair-wise meta-analyses.,Sensitivity analyses that varied estimate (odds ratio vs.,Peto’s odds ratio), method (random vs. fixed effects model), data (sepsis vs. serious infection data; exclusion of observational studies), treatment grouping (CYC and CYC HD as a combined treatment group vs. separate), made little/no difference to these estimates.,Tacrolimus and MMF-AZA combination were associated with lower risk of serious infections compared to other immunosuppressive drugs or glucocorticoids for lupus nephritis.,In conjunction with comparative efficacy data, these data can help patients make informed decisions about treatment options for lupus nephritis.,CRD42016032965,The online version of this article (doi:10.1186/s12916-016-0673-8) contains supplementary material, which is available to authorized users.

The autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades.,While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies.,We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model.,We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease.,Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids.,Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects.,Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS.

Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases1.,IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing Th17 cells with pathogenic effector functions2, 3.,However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated.,Here, we used transcriptional profiling of developing Th17 cells to construct a model of their signaling network and nominate major nodes that regulate Th17 development.,We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase4, as an essential node downstream of IL-23 signaling.,SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression.,SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5, 6, 7, 8.,We here show that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity.,Loss of SGK1 abrogated Na+-mediated Th17 differentiation in an IL-23-dependent manner.,These data demonstrate that SGK1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.

To investigate the long‐term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody‐positive SLE.,The study was designed as a multicenter, open‐label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double‐blind study.,Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose.,Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16‐week intervals) and glucocorticoid use (assessed at 4‐week intervals).,Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study.,Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient‐years, median number of infusions 115.5 [range 7-155]).,The percentage of patients with AEs each year remained stable or decreased.,Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable.,The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12.,The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline.,This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials.,Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study.,For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long‐term disease control.

The study (206347) compared organ damage progression in patients with systemic lupus erythematosus (SLE) who received belimumab in the BLISS long-term extension (LTE) study with propensity score (PS)-matched patients treated with standard of care (SoC) from the Toronto Lupus Cohort (TLC).,A systematic literature review identified 17 known predictors of organ damage to calculate a PS for each patient.,Patients from the BLISS LTE and the TLC were PS matched posthoc 1:1 based on their PS (±calliper).,The primary endpoint was difference in change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to 5 years.,For the 5- year analysis, of 567 (BLISS LTE n=195; TLC n=372) patients, 99 from each cohort were 1:1 PS matched.,Change in SDI score at Year 5 was significantly lower for patients treated with belimumab compared with SoC (−0.434; 95% CI -0.667 to -0.201; p<0.001).,For the time to organ damage progression analysis (≥1 year follow-up), the sample included 965 (BLISS LTE n=259; TLC n=706) patients, of whom 179 from each cohort were PS-matched.,Patients receiving belimumab were 61% less likely to progress to a higher SDI score over any given year compared with patients treated with SoC (HR 0.391; 95% CI 0.253 to 0.605; p<0.001).,Among the SDI score increases, the proportion of increases ≥2 was greater in the SoC group compared with the belimumab group.,PS-matched patients receiving belimumab had significantly less organ damage progression compared with patients receiving SoC.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and the presence of serum autoantibodies.,In addition, skeletal muscle weakness is a common comorbidity that contributes to inability to work and reduced quality of life.,Loss in muscle mass cannot alone account for the muscle weakness induced by RA, but instead intramuscular dysfunction appears as a critical factor underlying the decreased force generating capacity for patients afflicted by arthritis.,Oxidative stress and associated oxidative post-translational modifications have been shown to contribute to RA-induced muscle weakness in animal models of arthritis and patients with RA.,However, it is still unclear how and which sources of reactive oxygen and nitrogen species (ROS/RNS) that are involved in the oxidative stress that drives the progression toward decreased muscle function in RA.,Nevertheless, mitochondria, NADPH oxidases (NOX), nitric oxide synthases (NOS) and phospholipases (PLA) have all been associated with increased ROS/RNS production in RA-induced muscle weakness.,In this review, we aim to cover potential ROS sources and underlying mechanisms of oxidative stress and loss of force production in RA.,We also addressed the use of antioxidants and exercise as potential tools to counteract oxidative stress and skeletal muscle weakness.

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency.,Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease.,COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs.,However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19.,In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.

Type 1 diabetes (T1D) is a multifactorial autoimmune disease mediated by genetic, epigenetic, and environmental factors.,In recent years, the emergence of high-throughput sequencing has allowed us to investigate the role of gut microbiota in the development of T1D.,Significant changes in the composition of gut microbiome, also termed dysbiosis, have been found in subjects with clinical or preclinical T1D.,However, whether the dysbiosis is a cause or an effect of the disease remains unclear.,Currently, increasing evidence has supported a causal link between intestine microflora and T1D development.,The current review will focus on recent research regarding the associations between intestine microbiome and T1D progression with an intention to evaluate the causality.,We will also discuss the possible mechanisms by which imbalanced gut microbiota leads to the development of T1D.

Antigen-specific immune tolerance has been a long-standing goal for immunotherapy for the treatment of autoimmune diseases and allergies and for the prevention of allograft rejection and anti-drug antibodies directed against biologic therapies.,Nanoparticles have emerged as powerful tools to initiate and modulate immune responses due to their inherent capacity to target antigen-presenting cells (APCs) and deliver coordinated signals that can elicit an antigen-specific immune response.,A wide range of strategies have been described to create tolerogenic nanoparticles (tNPs) that fall into three broad categories.,One strategy includes tNPs that provide antigen alone to harness natural tolerogenic processes and environments, such as presentation of antigen in the absence of costimulatory signals, oral tolerance, the tolerogenic environment of the liver, and apoptotic cell death.,A second strategy includes tNPs that carry antigen and simultaneously target tolerogenic receptors, such as pro-tolerogenic cytokine receptors, aryl hydrocarbon receptor, FAS receptor, and the CD22 inhibitory receptor.,A third strategy includes tNPs that carry a payload of tolerogenic pharmacological agents that can “lock” APCs into a developmental or metabolic state that favors tolerogenic presentation of antigens.,These diverse strategies have led to the development of tNPs that are capable of inducing antigen-specific immunological tolerance, not just immunosuppression, in animal models.,These novel tNP technologies herald a promising approach to specifically prevent and treat unwanted immune reactions in humans.,The first tNP, SEL-212, a biodegradable synthetic vaccine particle encapsulating rapamycin, has reached the clinic and is currently in Phase 2 clinical trials.

SB2 is a biosimilar to the reference infliximab (INF).,Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported.,This report investigates such clinical similarity up to 54 weeks, including structural joint damage.,In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter.,Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30.,Efficacy, safety and immunogenicity were measured at each visit up to week 54.,Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54.,A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293).,The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year.,ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54.,The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups.,Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks.,The pattern of dose increment was also comparable between SB2 and INF.,SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA.,Radiographic progression was comparable at 1 year.,ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37)

To compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy.,This is a phase III, randomised, double-blind, multinational, multicentre parallel group study.,Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg.,The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30.,Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence.,584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293).,The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF.,The adjusted rate difference was −1.88% (95% CI −10.26% to 6.51%), which was within the predefined equivalence margin.,Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF.,The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF).,The PK profile was similar between SB2 and INF.,Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF.,SB2 was equivalent to INF in terms of ACR20 response at week 30.,SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF.,NCT01936181.

Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers.,Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D.,Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls.,Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR.,The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses.,We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency.,Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D.,In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.

Autoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect.,Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease.,We phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects.,We found upregulation of Th17 immunity and functional defects in CD4+CD25bright Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood.,In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients.,The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus.,These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D).,We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events.,CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]).,Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes.,Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE.,Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI.,HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]).,Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D.,After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained.

Type 1 diabetes (T1D) is associated with a greater occurrence of cardiovascular pathologies.,Vascular dysfunction has been shown at the level of the endothelial layers and failure to maintain a continuous pool of circulating nitric oxide (NO) has been implicated in the progression of poor vascular health.,Biochemically, NO can be produced via two distinct yet inter-related pathways that involve an upregulation in the enzymatic activity of nitric oxide synthase (NOS).,These pathways can be split into an endogenous oxygen-dependent pathway i.e., the catabolism of the amino acid L-arginine to L-citrulline concurrently yielding NO in the process, and an exogenous oxygen-independent one i.e., the conversion of exogenous inorganic nitrate to nitrite and subsequently NO in a stepwise fashion.,Although a body of research has explored the vascular responses to exercise and/or compounds known to stimulate NOS and subsequently NO production, there is little research applying these findings to individuals with T1D, for whom preventative strategies that alleviate or at least temper vascular pathologies are critical foci for long-term risk mitigation.,This review addresses the proposed mechanisms responsible for vascular dysfunction, before exploring the potential mechanisms by which exercise, and two supplementary NO donors may provide vascular benefits in T1D.

Our goal was to explore immunoserological relations between IgM and IgG isotypes of natural autoantibodies (nAAbs) and pathogen (or vaccine)‐induced or disease‐related antibodies in systemic autoimmune diseases (SAD); systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA).,The found significant associations between IgG isotype nAbs and specific humoral antibodies may underscore the immune response‐inducible nature of the diseases investigated, and may corroborate the notion that nAbs can act as a mediator between the innate‐like and the adaptive arms of the immune system .,The relationship between protective anti‐dsDNA IgM and the IgM isotype of anti‐F4 and anti‐CS may provide immuno‐serological evidence for the beneficial roles of nAAbs in SLE patients.,Infection or vaccine‐induced T cell‐dependent immune response and the subsequent high‐affinity neutralizing antibody production have been extensively studied, while the connection between natural autoantibodies (nAAbs) and disease‐specific antibodies has not been thoroughly investigated.,Our goal was to find the relationship between immunoglobulin (Ig)M and IgG isotype nAAbs and infection or vaccine‐induced and disease‐related autoantibody levels in systemic autoimmune diseases (SAD).,A previously described indirect enzyme‐linked immunosorbent assay (ELISA) test was used for detection of IgM/IgG nAAbs against citrate synthase (anti‐CS) and F4 fragment (anti‐F4) of DNA topoisomerase I in 374 SAD samples, with a special focus on systemic lupus erythematosus (SLE) (n = 92), rheumatoid arthritis (n = 73) and systemic sclerosis (n = 157) disease groups.,Anti‐measles IgG and anti‐dsDNA IgG/IgM autoantibodies were measured using commercial and in‐house indirect ELISA tests.,In all SAD groups the anti‐measles IgG‐seropositive cases showed significantly higher anti‐CS IgG titers (P = 0·011).,In anti‐dsDNA IgG‐positive SLE patients, we detected significantly higher levels of anti‐CS and anti‐F4 IgG nAAbs (P = 0·001 and < 0·001, respectively).,Additionally, we found increased levels of IgM isotypes of anti‐CS and anti‐F4 nAAbs in anti‐dsDNA IgM‐positive SLE patients (P = 0·002 and 0·016, respectively).,The association between IgG isotypes of pathogen‐ or autoimmune disease‐related antibodies and the IgG nAAbs may underscore the immune response‐inducible nature of the diseases investigated.,The relationship between protective anti‐dsDNA IgM and the IgM isotype of anti‐F4 and anti‐CS may provide immunoserological evidence for the beneficial roles of nAAbs in SLE patients.

It has been hypothesized that human cytomegalovirus (HCMV) infection, especially in monocyte and CD34 (+) myeloid cells, acts as a important regulator of immune system to promote inflammation in multiple autoimmune diseases.,The aim of this study was to elucidate the HCMV gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of SLE patients and demonstrate the effect and mechanism of viral gene associated with SLE in mono-macrophages functions.,Using two RNA-Seq techniques in combination with RT-PCR, 11 viral genes mainly associated with latent HCMV infection were identified in the PBMCs of SLE patients.,Among these viral genes, US31 with previously unknown function was highly expressed in the PBMCs of SLE patients compared to healthy controls.,Analysis of function indicated that US31 expression could induce inflammation in monocyte and macrophage and stimulate macrophage differentiation toward an M1 macrophage phenotype.,Screening via protein chips in combination with bioinformatic analysis and consequent detection of mono-macrophages function indicates that the direct interaction between US31 and NF-κB2 contributed the NF-kB2 activation.,Consequent analysis indicated US31 directly interacted with NF-κB2, contribute to the polyubiquitination of the phosphorylated p100 and consequent activation of NF-κB2.,Taken together, our data uncovered a previously unknown role of the HCMV protein US31 in inducing NF-κB-mediated mono-macrophage inflammation in the pathogenesis and development of SLE.,Our findings provide a foundation for the continued investigation of novel therapeutic targets for SLE patients.

The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis.,We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments.,It is concluded that leptin may lead to OA via some signaling pathways.,At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized.,Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person.,In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase.,Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients.,Treatment for leptin-increased obesity may be a treatment for OA.,The role of leptin in OA cannot be ignored and needs to be further studied.

Over 70 different genetic variants with a significant association with rheumatoid arthritis (RA) have been discovered.,Anti-citrullination protein antibodies (ACPA)-positive RA variants are more well-defined than their ACPA-negative counterparts.,The human leukocyte antigen, HLA-DRB1 locus remains the prime suspect in anti-citrullination protein antibodies (ACPA)-positive RA.,Different HLA-DRB1 alleles are linked to RA susceptibility across different ethnicities.,With evolving techniques, like genome-wide association studies (GWAS) and single nucleotide polymorphism (SNP) arrays, more non-HLA susceptibility loci have been identified for both types of RA.,However, the functional significance of only a handful of these variants is known.,Their roles include increasing susceptibility to RA or in determining the speed at which the disease progresses.,Additionally, a couple of variations are associated with protection from RA.,Defining such clear-cut biological functions can aid in the clinical diagnosis and treatment of RA.,Recent research has focused on the implication of microRNAs, with miR-146a widely studied.,In addition to disease susceptibility, genetic variations that influence the efficacy and toxicity of anti-RA agents have also been identified.,Polymorphisms in the MTHFR gene influence the effectiveness of methotrexate, the first line of therapy in RA.,Larger studies are, however, needed to identify potential biomarkers for early disease identification and monitoring disease progression.

Functional loss of gut barrier integrity with subsequent increased antigen trafficking and occurrence of low-grade intestinal inflammation precede the onset of type 1 diabetes (T1D) in patients and preclinical models, thus suggesting that these events are mechanistically linked to the autoimmune pathogenesis of the disease.,However, a causal relationship between increased intestinal permeability and autoimmune diabetes was never demonstrated.,Our data show that breakage of gut barrier continuity leads to activation of islet-reactive T cells in the intestine, thus triggering autoimmune diabetes.,An important implication of our findings is that restoration of a healthy gut barrier through microbiota and diet modulation in diabetes-prone individuals could reduce intestinal activation of islet-reactive T cells and prevent T1D occurrence.,Low-grade intestinal inflammation and alterations of gut barrier integrity are found in patients affected by extraintestinal autoimmune diseases such as type 1 diabetes (T1D), but a direct causal link between enteropathy and triggering of autoimmunity is yet to be established.,Here, we found that onset of autoimmunity in preclinical models of T1D is associated with alterations of the mucus layer structure and loss of gut barrier integrity.,Importantly, we showed that breakage of the gut barrier integrity in BDC2.5XNOD mice carrying a transgenic T cell receptor (TCR) specific for a beta cell autoantigen leads to activation of islet-reactive T cells within the gut mucosa and onset of T1D.,The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota by antibiotic treatment.,Our results indicate that loss of gut barrier continuity can lead to activation of islet-specific T cells within the intestinal mucosa and to autoimmune diabetes and provide a strong rationale to design innovative therapeutic interventions in “at-risk” individuals aimed at restoring gut barrier integrity to prevent T1D occurrence.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyperreactivity.,The underlying causes of the diffuse B-cell over-reactivity are unclear, but potential candidates include (a) intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells.,These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE.,Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities.,Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell-dependent B-cell responses on the other.,There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity.

The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA).,This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve).,Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229).,Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling.,A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission.,Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P < 0.001)], toxic adverse events [from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001], and remission [from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001].,Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001).,TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.

Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division.,We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA).,Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis.,Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood.,Here, we present experimental evidence connecting survivin and Flt3L signaling.,Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells.,Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow.,Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen.,Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L.,We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.

There is increasing interest in patient-centered approaches to chronic disease management and prevention.,For people with multiple sclerosis (PwMS), patient empowerment plays a role in improving a range of health-related outcomes.,This study aimed to compare health-related quality of life (HRQOL), fatigue, and depression risk between people who have and have not attended a week-long physician-led residential educational retreat or accessed other self-help resources (a book and online content) that foster patient empowerment including the adoption of healthy lifestyle behaviors.,PwMS were recruited to the study using online platforms and asked to complete a comprehensive online survey.,Data from 2,233 respondents were analysed.,Bivariate results indicated that PwMS who had attended a retreat (n = 247), read the associated book (n = 1,167) or regularly visited online sites promoting lifestyle modification (n = 795), had better HRQOL and lower rates of depression and fatigue than those who had not.,The depression risk among retreat attendees (8.6 %) was around half that of the whole sample.,Regression analysis showed that, controlling for age and gender, compared to the highest level of engagement, no engagement with the resources was associated with nearly threefold higher odds of clinically significant fatigue, tenfold higher odds of depression risk, and physical and mental HRQOL scores 19.5 and 15.6 points lower, respectively.,These results are congruent with previously reported post-retreat improvements in HRQOL, and strongly support a role for patient engagement in resources promoting lifestyle modification.,Physicians should encourage more active involvement of PwMS in their own health care.,The online version of this article (doi:10.1007/s10072-015-2089-1) contains supplementary material, which is available to authorized users.

There is a strong body of evidence that supports the use of non-drug therapies in the management of people with multiple sclerosis (MS).,A 5-day residential retreat for people with MS in Victoria, Australia, promotes lifestyle modification within a patient-centred model of care.,Analysis of the health-related quality of life (HRQOL) of the retreat participants was undertaken using the MSQOL-54, prior to attendance, 1 and 5 years after the retreat. 274 retreat participants (71%) completed baseline questionnaires.,Despite the usually progressive nature of MS, the cohort demonstrated clinically and statistically significant improvements in HRQOL.,One year after attending the retreat, median improvements of 11.3% were observed in the overall quality of life domain (p < 0.001); 18.6% in the physical health composite (p < 0.001); and 11.8% in the mental health composite (p < 0.001).,In the subset of 165 who had reached the 5-year time-point, there was a 19.5% median improvement in overall quality of life (p < 0.001); 17.8% in the physical health composite (p < 0.001) and 22.8% in the mental health composite (p < 0.001), compared to baseline.,Attendance at a retreat promoting lifestyle modification for the integrated management of MS appears to have positive effects on short and medium-term HRQOL.,Non-drug therapies should be considered as part of any comprehensive treatment plan for people with MS.

Our studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice.,In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor.,Macrophage depletion, either at the start of the autoimmune process or when diabetogenesis is active, leads to a significant reduction in diabetes incidence.,Depletion of the islet macrophages reduces the entrance of T cells into islets and results in the absence of antigen presentation.,Concordantly, a regulatory pathway develops that controls diabetes progression.,We conclude that treatments that target the islet macrophages may have important clinical relevance for the control of autoimmune type 1 diabetes.,Treatment of C57BL/6 or NOD mice with a monoclonal antibody to the CSF-1 receptor resulted in depletion of the resident macrophages of pancreatic islets of Langerhans that lasted for several weeks.,Depletion of macrophages in C57BL/6 mice did not affect multiple parameters of islet function, including glucose response, insulin content, and transcriptional profile.,In NOD mice depleted of islet-resident macrophages starting at 3 wk of age, several changes occurred: (i) the early entrance of CD4 T cells and dendritic cells into pancreatic islets was reduced, (ii) presentation of insulin epitopes by dispersed islet cells to T cells was impaired, and (iii) the development of autoimmune diabetes was significantly reduced.,Treatment of NOD mice starting at 10 wk of age, when the autoimmune process has progressed, also significantly reduced the incidence of diabetes.,Despite the absence of diabetes, NOD mice treated with anti-CSF-1 receptor starting at 3 or 10 wk of age still contained variably elevated leukocytic infiltrates in their islets when examined at 20-40 wk of age.,Diabetes occurred in the anti-CSF-1 receptor protected mice after treatment with a blocking antibody directed against PD-1.,We conclude that treatment of NOD mice with an antibody against CSF-1 receptor reduced diabetes incidence and led to the development of a regulatory pathway that controlled autoimmune progression.

We have investigated the efficacy of conditioning skin Langerhans cells (LCs) with agents to promote tolerance and reduce inflammation, with the goal of improving the outcomes of antigen-specific immunotherapy.,Topical treatments were assessed ex vivo, using excised human breast skin maintained in organ bath cultures, and in vivo in healthy volunteers by analysing skin biopsies and epidermal blister roof samples.,Following topical treatment with a corticosteroid, tumour necrosis factor-α levels were reduced in skin biopsy studies and blister fluid samples.,Blister fluid concentrations of monocyte chemoattractant protein-1, macrophage inflammatory proteins -1α and 1β and interferon-γ inducible protein-10 were also reduced, while preserving levels of interleukin-1α (IL-1α), IL-6, IL-8 and IL-10.,Steroid pre-treatment of the skin reduced the ability of LCs to induce proliferation, while supernatants showed an increase in the IL-10/interferon-γ ratio.,Phenotypic changes following topical steroid treatment were also observed, including reduced expression of CD83 and CD86 in blister-derived LCs, but preservation of the tolerogenic signalling molecules immunoglobulin-like transcript 3 and programmed death-1.,Reduced expression of HLA-DR, CD80 and CD86 were also apparent in LCs derived from excised human skin.,Topical therapy with a vitamin D analogue (calcipotriol) and steroid, calcipotriol alone or vitamin A elicited no significant changes in the parameters studied.,These experiments suggest that pre-conditioning the skin with topical corticosteroid can modulate LCs by blunting their pro-inflammatory signals and potentially enhancing tolerance.,We suggest that such modulation before antigen-specific immunotherapy might provide an inexpensive and safe adjunct to current approaches to treat autoimmune diseases.

Recent studies of cortical pathology in secondary progressive multiple sclerosis have shown that a more severe clinical course and the presence of extended subpial grey matter lesions with significant neuronal/glial loss and microglial activation are associated with meningeal inflammation, including the presence of lymphoid-like structures in the subarachnoid space in a proportion of cases.,To investigate the molecular consequences of pro-inflammatory and cytotoxic molecules diffusing from the meninges into the underlying grey matter, we carried out gene expression profiling analysis of the motor cortex from 20 post-mortem multiple sclerosis brains with and without substantial meningeal inflammation and 10 non-neurological controls.,Gene expression profiling of grey matter lesions and normal appearing grey matter not only confirmed the substantial pathological cell changes, which were greatest in multiple sclerosis cases with increased meningeal inflammation, but also demonstrated the upregulation of multiple genes/pathways associated with the inflammatory response.,In particular, genes involved in tumour necrosis factor (TNF) signalling were significantly deregulated in MS cases compared with controls.,Increased meningeal inflammation was found to be associated with a shift in the balance of TNF signalling away from TNFR1/TNFR2 and NFkB-mediated anti-apoptotic pathways towards TNFR1- and RIPK3-mediated pro-apoptotic/pro-necroptotic signalling in the grey matter, which was confirmed by RT-PCR analysis.,TNFR1 was found expressed preferentially on neurons and oligodendrocytes in MS cortical grey matter, whereas TNFR2 was predominantly expressed by astrocytes and microglia.,We suggest that the inflammatory milieu generated in the subarachnoid space of the multiple sclerosis meninges by infiltrating immune cells leads to increased demyelinating and neurodegenerative pathology in the underlying grey matter due to changes in the balance of TNF signalling.

Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward.,We assessed how early in the multiple sclerosis course a "surface‐in" process of injury suggesting progressive biology may begin.,We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface.,Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls.,Voxelwise volume changes were calculated using deformation‐based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods.,Twenty‐seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow‐up = 4.6 years, standard deviation = 1.9).,A total of 282 healthy children with serial scans were included as controls.,Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter.,However, only children with multiple sclerosis exhibited an additional surface‐in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021).,Our results suggest that a multiple sclerosis disease‐specific surface‐in process of damage can manifest at the earliest stages of the disease.,ANN NEUROL 2019;85:340-351.

To predict response to anti-tumor necrosis factor (anti‐TNF) prior to treatment in patients with rheumatoid arthritis (RA), and to comprehensively understand the mechanism of how different RA patients respond differently to anti‐TNF treatment.,Gene expression and/or DNA methylation profiling on peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells obtained from 80 RA patients before they began either adalimumab (ADA) or etanercept (ETN) therapy was studied.,After 6 months, treatment response was evaluated according to the European League Against Rheumatism criteria for disease response.,Differential expression and methylation analyses were performed to identify the response‐associated transcription and epigenetic signatures.,Using these signatures, machine learning models were built by random forest algorithm to predict response prior to anti‐TNF treatment, and were further validated by a follow‐up study.,Transcription signatures in ADA and ETN responders were divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells.,The genes up‐regulated in CD4+ T cells from ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes.,Differentially methylated positions (DMPs) were strongly hypermethylated in responders to ETN but not to ADA.,The machine learning models for the prediction of response to ADA and ETN using differential genes reached an overall accuracy of 85.9% and 79%, respectively.,The models using DMPs reached an overall accuracy of 84.7% and 88% for ADA and ETN, respectively.,A follow‐up study validated the high performance of these models.,Our findings indicate that machine learning models based on molecular signatures accurately predict response before ADA and ETN treatment, paving the path toward personalized anti‐TNF treatment.

Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained.,Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective.,The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.,This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain).,Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial.,To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich.,Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group).,To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature.,The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks.,The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline.,The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.,Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]).,In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI −11 to 33], p=0·31).,However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035).,Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups.,The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification.,Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab.,Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.,Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.

Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression.,RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence.,We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines.,We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes.,We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g.,NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs.,Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects.,Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g.,WDFY4) through asQTL mapping using the Geuvadis cohort.,We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications.,We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.

Trans-acting genetic variants play a substantial, albeit poorly characterized, role in the heritable determination of gene expression.,Using paired purified primary monocytes and B-cells we identify novel, predominantly cell-specific, cis- and trans-eQTL (expression quantitative trait loci).,These include multi-locus trans-associations to LYZ in monocytes and to KLF4 in B-cells.,Additionally, we observe B-cell specific trans-association of rs11171739 at 12q13.2, a known autoimmune disease locus, to IP6K2 (pB-cell=5.8×10−15), PRIC285 (pB-cell=3.0×10−10) and an upstream region of CDKN1A (pB-cell=2×10−52; pmonocyte=1.8×10−4), suggesting roles for cell cycle regulation and PPARγ signaling in disease pathogenesis.,We also find specific HLA alleles forming trans-association with the expression of AOAH and ARHGAP24 in monocytes but not in B-cells.,In summary, we demonstrate that mapping gene expression in defined primary cell populations identifies new cell-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS).,While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease.,Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels.,Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system.,While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion.,On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability.,The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood.,LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland.,This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS.,We also propose a new mechanistic pathway for the initiation of MS.

It is debated whether multiple sclerosis (MS) might result from an immunopathological response toward an active Epstein-Barr virus (EBV) infection brought into the central nervous system (CNS) by immigrating B cells.,Based on this model, a relationship should exist between the local immune milieu and EBV infection status in the MS brain.,To test this hypothesis, we analyzed expression of viral and cellular genes in brain-infiltrating immune cells.,Twenty-three postmortem snap-frozen brain tissue blocks from 11 patients with progressive MS were selected based on good RNA quality and prominent immune cell infiltration.,White matter perivascular and intrameningeal immune infiltrates, including B cell follicle-like structures, were isolated from brain sections using laser capture microdissection.,Enhanced PCR-based methods were used to investigate expression of 75 immune-related genes and 6 EBV genes associated with latent and lytic infection.,Data were analyzed using univariate and multivariate statistical methods.,Genes related to T cell activation, cytotoxic cell-mediated (or type 1) immunity, B cell growth and differentiation, pathogen recognition, myeloid cell function, type I interferon pathway activation, and leukocyte recruitment were found expressed at different levels in most or all MS brain immune infiltrates.,EBV genes were detected in brain samples from 9 of 11 MS patients with expression patterns suggestive of in situ activation of latent infection and, less frequently, entry into the lytic cycle.,Comparison of data obtained in meningeal and white matter infiltrates revealed higher expression of genes related to interferonγ production, B cell differentiation, cell proliferation, lipid antigen presentation, and T cell and myeloid cell recruitment, as well as more widespread EBV infection in the meningeal samples.,Multivariate analysis grouped genes expressed in meningeal and white matter immune infiltrates into artificial factors that were characterized primarily by genes involved in type 1 immunity effector mechanisms and type I interferon pathway activation.,These results confirm profound in situ EBV deregulation and suggest orchestration of local antiviral function in the MS brain, lending support to a model of MS pathogenesis that involves EBV as possible antigenic stimulus of the persistent immune response in the central nervous system.,The online version of this article (10.1186/s12974-017-1049-5) contains supplementary material, which is available to authorized users.

In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims.,In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions.,We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims.,Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages.,Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging.,In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence.,Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques.,Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes.,Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible.,Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003).,We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003).,Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.,The online version of this article (doi:10.1007/s00401-016-1636-z) contains supplementary material, which is available to authorized users.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.

•So far, the prevalence of COVID-19 in multiple sclerosis patients are unknown.,•The prevalence in an MS cohort from the Veneto region, Italy, was higher than in the general population.,The disease course was mild to moderate.,•MS-population based studies could be a good way to investigate indirectly the infection prevalence in the general population.,So far, the prevalence of COVID-19 in multiple sclerosis patients are unknown.,The prevalence in an MS cohort from the Veneto region, Italy, was higher than in the general population.,The disease course was mild to moderate.,MS-population based studies could be a good way to investigate indirectly the infection prevalence in the general population.,Neurologists are interested in understanding whether patients with multiple sclerosis (pwMS) undergoing immunomodulatory/immunosuppressive therapy are more susceptible to developing COVID-19 or have worse outcomes.,Currently, there are no conclusive data in this regard.,We report the prevalence and severity of COVID-19 (confirmed and possible) in pwMS followed at the Veneto Regional MS Center in Verona (Italy), an area most stricken by COVID-19.,In our sample size, the prevalence of COVID-19 seems to be much higher than that officially reported at the regional level on the general population, but it also characterized by a favourable course.

•A MS patient treated with ocrelizumab healed from COVID-19 without consequences•Immunosuppression might have played favorable role•This report supports the use of immunosuppressants in serious COVID-19 c,A MS patient treated with ocrelizumab healed from COVID-19 without consequences,Immunosuppression might have played favorable role,This report supports the use of immunosuppressants in serious COVID-19 c,Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world.,It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death.,Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response.,However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.,In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.,Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine.,Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.,This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing-remitting multiple sclerosis (MS).,Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME).,Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment.,By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients.,Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME.

Fingolimod is the first oral agent used for treatment of relapsing-remitting multiple sclerosis.,Macular edema, but not retinal hemorrhage, is a well-known adverse effect of fingolimod treatment.,To the best of our knowledge, this is the first case report of extensive retinal hemorrhages following fingolimod treatment.,A 31-year-old male with relapsing-remitting multiple sclerosis developed macular edema and retinal hemorrhages in his left eye, 1 month after starting fingolimod treatment; treatment was then discontinued.,The hemorrhages were flame-shaped, and were extensive along retinal arteries and veins.,The hemorrhages started to decrease at 4 weeks and disappeared completely at 24 weeks after cessation of fingolimod treatment.,Occurrence of retinal hemorrhage warrants careful follow-up for multiple sclerosis patients treated with fingolimod.

We aimed to evaluate the pooled incidence of central vein sign on T2*-weighted images from patients with multiple sclerosis (MS), and to determine the diagnostic performance of this central vein sign for differentiating MS from other white matter lesions and provide an optimal cut-off value.,A computerized systematic search of the literature in PUBMED and EMBASE was conducted up to December 14, 2018.,Original articles investigating central vein sign on T2*-weighted images of patients with MS were selected.,The pooled incidence was obtained using random-effects model.,The pooled sensitivity and specificity were obtained using a bivariate random-effects model.,An optimal cut-off value for the proportion of lesions with a central vein sign was calculated from those studies providing individual patient data.,Twenty-one eligible articles covering 501 patients with MS were included.,The pooled incidence of central vein sign at the level of individual lesion in patients with MS was 74% (95% CI, 65-82%).,The pooled sensitivity and pooled specificity for the diagnostic performance of the central vein sign were 98% (95% CI, 92-100%) and 97% (95% CI, 91-99%), respectively.,The area under the HSROC curve was 1.00 (95% CI, 0.99-1.00).,The optimal cut-off value for the proportion of lesions with a central vein sign was found to be 45%.,Although various T2*-weighted images have been used across studies, the current evidence supports the use of the central vein sign on T2*-weighted images to differentiate MS from other white matter lesions.

Multiple sclerosis (MS) is a complex, demyelinating disease with the involvement of autoimmunity and neurodegeneration.,Increasing efforts have been made towards identifying the diagnostic markers to differentiate the classes of MS from other similar neurological conditions.,Using a systems biology approach, we constructed four types of gene regulatory networks (GRNs) involved in peripheral blood mononuclear cells (PBMCs).,The regulatory strength of each GRN across primary progressive MS (PPMS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and control were evaluated by an integrity algorithm.,Among the constructed GRNs (referred as TF_gene_miRNA), POU3F2_CDK6_hsa-miR-590-3p, MEIS1_CASC3_hsa-miR-1261, STAT3_OGG1_hsa-miR-298, and TCF4_FMR1_hsa-miR-301b were top-ranked and differentially regulated in all classes of MS compared to control.,These GRNs showed potential involvement in regulating various molecular pathways such as interleukin, integrin, glypican, sphingosine phosphate, androgen, and Wnt signaling pathways.,For validation, the qPCR analysis of the GRN components (TFs, gene, and miRNAs) in PBMCs of healthy controls (n = 30), RRMS (n = 14), PPMS (n = 13) and SPMS (n = 12) were carried out.,Real-time expression analysis of GRNs showed a similar regulatory pattern as derived from our systems biology approach.,Also, our study provided several novel GRNs that regulate unique and common molecular mechanisms between MS conditions.,Hence, these regulatory components of GRNs will help to understand the disease mechanism across MS classes and further insight may though light towards diagnosis.

The efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program.,Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials.,Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported.,Cumulative safety data (as of February 6, 2009) from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study were analyzed.,Two patient populations were evaluated: an all-control population (n = 4,199), which included all patients randomly assigned in the placebo-controlled portions of the five core studies, and an all-exposed population (n = 4,009), which included patients from any of the eight studies who received at least one dose of tocilizumab.,Total exposure to tocilizumab was 8,580 patient years (PY), and total duration of observation was 9,414 PY.,Overall adverse event (AE) and serious AE (SAE) rates were 278.2/100 PY and 14.4/100 PY, respectively.,These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), gastrointestinal perforations (0.28/100 PY), malignancy (1.1/100 PY), myocardial infarction (0.25/100 PY), and stroke (0.19/100 PY).,The rates of SAEs and serious infections were stable over time; no increase with prolonged exposure was noted.,The longer-term safety profile of tocilizumab (mean treatment duration, 2.4 years) is consistent with that observed in the phase 3 studies (duration up to 1 year).

Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA.,Information has also been gathered from registries.,This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA.,Preparation of this new document involved many international experts experienced in the treatment of RA.,Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data.,Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement.,These committees also included patients with RA.,The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response.,Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk.,This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research.,New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years.,These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control.,This consensus statement is in line with these fundamental principles of management.

T cells reacting to self-components can promote tissue damage when escaping tolerogenic control mechanisms which may result in autoimmune disease.,The current treatments for these disorders are not antigen (Ag) specific and can compromise host immunity through chronic suppression.,We have previously demonstrated that co-administration of encapsulated or free Ag with tolerogenic nanoparticles (tNPs) comprised of biodegradable polymers that encapsulate rapamycin are capable of inhibiting Ag-specific transgenic T cell proliferation and inducing Ag-specific regulatory T cells (Tregs).,Here, we further show that tNPs can trigger the expansion of endogenous Tregs specific to a target Ag.,The proportion of Ag-specific Treg to total Ag-specific T cells remains constant even after subsequent Ag challenge in combination with a potent TLR7/8 agonist or complete Freund’s adjuvant. tNP-treated mice do not develop experimental autoimmune encephalomyelitis (EAE) after adoptive transfer of encephalitogenic T cells; furthermore, tNP treatment provided therapeutic protection in relapsing EAE that was transferred to naïve animals.,These findings describe a potent therapy to expand Ag-specific Tregs in vivo and suppress T cell-mediated autoimmunity.

As a traditional Chinese medicine, Cordyceps sinensis (CS) possesses a variety of immunoregulatory properties.,This study aimed to explore the therapeutic potential of CS in a mice model of multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE).,Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein35-55 to induce EAE, followed by an instant intragastric feeding with a low dosage of CS (low-CS group, n = 5), high dosage of CS (high-CS group, n = 5), or the same volume of normal saline (control group, n = 5).,All the mice were observed for clinical assessment.,Over the 30 days of CS treatment, flow cytometry was used to detect the frequency of helper T-cell (Th) subsets, Th1 and Th17, and CD4+ CD25+ regulatory T cells in the spleen and lymph nodes.,Meanwhile, pathological changes in brain were determined using both hematoxylin-eosin and luxol fast blue staining.,Data were analyzed using the one-way analysis of variance (ANOVA).,Over the 15 and 30 days of CS treatment, the clinical assessment for EAE demonstrated that both high-CS group (2.51 ± 0.31 and 2.26 ± 0.39 scores, respectively) and low-CS group (2.99 ± 0.40 and 2.69 ± 0.46, respectively) had lower disease severity scores than those of control group (3.57 ± 0.53 and 3.29 ± 0.53, all P < 0.01, respectively).,Meanwhile, after 15 and 30 days, the high-CS group (19.18 ± 1.34 g and 20.41 ± 1.56 g, respectively) and low-CS group (18.07 ± 1.18 g and 19.48 ± 1.69 g, respectively) had a lower body weight, as compared with control group (16.85 ± 1.15 g and 18.22 ± 1.63 g, all P < 0.01, respectively).,At 30 days post-CS treatment, there was a lower Th1 frequency in the lymph nodes (2.85 ± 1.54% and 2.77 ± 1.07% vs.,5.35 ± 1.34%, respectively; P < 0.05) and spleens (3.96 ± 1.09% and 3.09 ± 0.84% vs.,5.07 ± 1.50%, respectively; P < 0.05) and less inflammatory infiltration and demyelination in the brain of CS-treated mice than that of control group.,Our preliminary study demonstrated that CS efficiently alleviated EAE severity and EAE-related pathology damage and decreased the number of Th1s in the periphery, indicating its effectiveness in the treatment of murine EAE.,Thus, our findings strongly support the therapeutic potential of this agent as a new traditional Chinese medicine approach in MS treatment.

Describe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti-B cell therapies.,The IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects.,The main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder.,The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen.,In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg.,Because IVIg contains only 0.7%-2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn.,In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits.,Rituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies.,In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4.,Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND.

To determine the clinical and antibody response after therapeutic plasma exchange (TPE) in patients with severe refractory antibody‐associated autoimmune encephalitis (AE).,This single‐center prospective cohort included all patients consecutively admitted to our hospital because of severe refractory AE over the period from July 2014 to June 2019.,All patients received immunotherapy (steroids, intravenous immunoglobulin (IVIG), and/or TPE).,The primary outcome was evaluated at 1‐ and 2‐month postenrollment, and the long‐term outcome was followed up at 6 and 12 months.,AE antibody titers in the cerebrospinal fluid and plasma were evaluated before and after TPE/IVIG.,This study enrolled 57 patients with severe refractory AE, including anti‐NMDA receptor encephalitis (n = 51), anti‐GABAb receptor encephalitis (n = 3), anti‐LGI 1 encephalitis (n = 2), and anti‐AMPA receptor encephalitis (n = 1).,Of all 57 patients, 33 patients received TPE for a total of 193 procedures, and 24 patients with contraindications or refusal of TPE were in the non‐TPE group.,Compared with the non‐TPE group, the TPE group exhibited greater clinical improvement: 21 (37%) versus 8 (14%) after 1 month (P = 0.03) and 31 (54%) versus 16 (28%) after 2 months (P = 0.01), respectively.,Complications and adverse events associated with TPE occurred in 91 procedures (47%) without serious adverse events associated with the use of TPE.,TPE might be an effective rescue therapy associated with rapid functional improvement in patients with severe steroid/IVIG refractory antibody‐associated AE from this nonrandomized control trial.

Lupus nephritis (LN) is a frequent severe complication of Systemic Lupus Erythematosus (SLE), especially in patients of non-Caucasian ethnicity.,Induction treatment for LN consists in the combination of steroids plus a second agent (cyclophosphamide or mycophenolate mofetil) or, as a second-line, calcineurin inhibitors or Rituximab.,Induction treatment for LN can be complicated by a series of side effects, the most severe being serious infections.,Belimumab is a fully humanized monoclonal antibody that targets soluble B lymphocyte stimulator (BLyS), approved for treatment of serologically active SLE in addition to standard of care.,A young Hispanic woman was diagnosed with SLE at the age of 15.,After several immunosuppressive treatments for arthritic symptoms (high-dose steroids, mycophenolate mofetil, Rituximab, cyclophosphamide) leading to serious complications and scarce clinical improvement, she developed severe LN.,Induction treatment with a combination of intravenous high-dose methylprednisolone and cyclophosphamide was started but, after few days, the patient developed cryptococcal meningitis.,After institution of appropriate antifungal therapy, treatment with Tacrolimus was attempted but poorly tolerated by the patient and withdrawn.,Eventually, Belimumab was initiated off-label as a last resource to treat LN.,Belimumab was well tolerated by the patient and resulted in a rapid and marked improvement in clinical symptoms and reduction in proteinuria, serum complement levels and anti-dsDNA titer; of note, the patient developed no infectious complications.,We report the case of a severe LN in a young Hispanic woman who did not respond to conventional and second-line induction therapies, due both to intolerance and to the development of serious infectious complications.,Eventually, Belimumab was successfully added to steroids and was well tolerated by the patient, resulting in a marked improvement in clinical and biochemical parameters.,We suggest that Belimumab should be considered as a potentially efficacious treatment in patients with LN who cannot tolerate conventional therapies.

To describe the characteristics of patients receiving belimumab, overall patterns of systemic lupus erythematosus (SLE) care, clinical outcomes, and changes in glucocorticoid dose following 6 months of therapy with belimumab, and healthcare resource utilization in belimumab users in Canadian clinical practice settings.,Retrospective multicenter medical chart review study of adult patients with SLE who were prescribed belimumab as part of usual care and who received ≥8 infusions or 6 months of treatment.,Primary endpoints included physician-determined overall clinical improvement from baseline, glucocorticoid use, and physician-determined SLE disease severity at Month 6.,In total, 52 patients were included in the study.,At belimumab initiation, 5.8/76.9/17.3% of patients had mild/moderate/severe SLE, respectively.,Oral glucocorticoids were discontinued in 11.4% of patients and 59.1% received a lower dose at Month 6.,At Month 6, 80.8/57.7/17.3% of patients had a physician-determined clinical improvement of ≥20/≥50/≥80%, respectively.,Sixteen patients had a SLE Disease Activity Index-2K score at both baseline and Month 6, with a mean improvement of 2.6 ± 5.3 from 8.1 ± 3.2 at baseline.,No formal disease assessment tool was utilized for 42.3% of study patients at baseline.,This study provides the first real-world insights into belimumab use in Canada.,It demonstrates significant reduction or discontinuation of glucocorticoid dose in 70.5% of patients and clinically significant improvement following 6 months’ belimumab therapy.,The high number of patients with no formal disease activity assessments highlights a key care gap in SLE treatment in the real-world setting.

This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis (PwMS).,We retrospectively collected data of PwMS with suspected or confirmed COVID‐19.,All the patients had complete follow‐up to death or recovery.,Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death.,We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models.,Sensitivity analyses were run to confirm the results.,Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy.,Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.,After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID‐19.,Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001).,Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.,This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action.,However, some specific elements of risk emerged.,These will need to be considered while the COVID‐19 pandemic persists.,ANN NEUROL 2021;89:780-789

This cross-sectional study examines outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with multiple sclerosis.,How do patients with multiple sclerosis (MS) who have COVID-19 fare and are there patient and disease characteristics associated with worse outcome?,In this registry-based cross-sectional study of 1626 North American patients with MS and COVID-19 infection, ambulatory disability, both nonambulatory and requiring assistance to walk, was independently associated with increased odds of poor clinical severity levels after adjusting for other risk factors.,Other factors including older age, male sex, Black race, cardiovascular comorbidities, and corticosteroid use in the past 2 months were associated with increased odds of increasing clinical severity compared with those not requiring hospitalization or worse.,Identification of risk factors can improve the treatment of patients with MS and COVID-19 by alerting clinicians of patients requiring more intense treatment or monitoring.,Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections.,To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS.,This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry.,Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death.,Data collection began April 1, 2020, and is ongoing.,Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19.,Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death.,Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]).,A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx.,The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity.,The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%).,Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]).,In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19.,Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids.,Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Clusterin (Clu), an extracellular chaperone, exhibits characteristics of soluble innate immunity receptors, as assessed by its ability to bind some bacteria strains.,In this study, we report that Clu also binds specifically to late apoptotic cells but not to live, early apoptotic, or necrotic cells.,Histones, which accumulate on blebs during the apoptotic process, represent privileged Clu-binding motifs at the surface of late apoptotic cells.,As a consequence, Clu potentiates, both in vitro and in vivo, the phagocytosis of late apoptotic cells by macrophages.,Moreover, the increased phagocytosis of late apoptotic cells induced by Clu favors the presentation and cross-presentation of apoptotic cell-associated antigens.,Finally, we observed that, in a model of apoptotic cell-induced autoimmunity, and relative to control mice, Clu−/− mice develop symptoms of autoimmunity, including the generation of anti-dsDNA antibodies, deposition of immunoglobulins and complement components within kidneys, and splenomegaly.,These results identify Clu as a new molecule partner involved in apoptotic cell efferocytosis and suggest a protective role for Clu in inflammation and autoimmune diseases.

Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain.,This study aims to bring clarity to these questions.,We describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease.,Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.,Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation.,Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue.,C1q staining was present in all plaques suggesting a dominant role for the classical pathway.,Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.,The findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.,The online version of this article (doi:10.1186/2051-5960-2-53) contains supplementary material, which is available to authorized users.

Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress.,The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology.,This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes.,Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019.,We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls.,Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included.,Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: −0.61 (95% CI: −0.79, −0.44) but also of VSM SMD: −0.32 (95% CI: −0.57, −0.07).,The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity.,Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds.,The latter was particularly altered in cases of poor glycemic control [HbA1c > 67 mmol/mol (8.3%)].,Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes.,Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.

To evaluate the frequency of normalization, the persistence of remission, and the impact on normalization of glycemic control and lipid profile, we analyzed data from a retrospective observational cohort study of type 1 diabetic children and adolescents with abnormal urinary albumin excretion (UAE).,All diabetic children and adolescents (n = 41) who had persistent abnormal UAE in the period of 1984 to 2008 and followed up until 2009 (follow-up duration = 13.1 ± 6.2 years) were included in the study.,Nine patients progressed to macroalbuminuria; 24 patients were administered ACE inhibitor treatment.,The cumulative prevalence of abnormal UAE was 9%.,During follow-up, 14 of 17 untreated and 19 of 24 treated patients reverted to normoalbuminuria.,In the remission group compared with the nonremission group, A1C levels during follow-up decreased (7.5 ± 1.0 vs.,9.4 ± 1.2%, P < 0.0001) and serum HDL cholesterol increased (52.7 ± 11.3 vs.,42.7 ± 8.6 mg/dL, P < 0.05).,The micro-macroalbuminuric patients had lower HDL cholesterol (51.0 ± 11.4 vs.,62.4 ± 13.6 mg/dL, P < 0.0001) than 134 normoalbuminuric diabetic patients.,Microalbuminuria and macroalbuminuria were not permanent in most of our diabetic children and adolescents.,If abnormal UAE values are high and persist for >1 year, only long-lasting treatment with ACE inhibitors seems able to induce persistent remission, especially when associated with good metabolic control and high HDL cholesterol levels.