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Transcriptome imputation has become a popular method for integrating genotype data with publicly available expression data to investigate the potentially causal role of genes in complex traits.,Here, we compare three approaches (PrediXcan, MetaXcan and FUSION) via application to genome-wide association study (GWAS) data for Crohn’s disease and type 1 diabetes from the Wellcome Trust Case Control Consortium.,We investigate: (i) how the results of each approach compare with each other and with those of standard GWAS analysis; and (ii) how variants in the models used by the prediction tools compare with variants previously reported as eQTLs.,We find that all approaches produce highly correlated results when applied to the same GWAS data, although for a subset of genes, mostly in the major histocompatibility complex, the approaches strongly disagree.,We also observe that most associations detected by these methods occur near known GWAS risk loci.,Application of these transcriptome imputation approaches to summary statistics from meta-analyses in Crohn’s disease and type 1 diabetes detects 53 significant expression-Crohn’s disease associations and 154 significant expression-type 1 diabetes associations, providing insight into biology underlying these diseases.,We conclude that while current implementations of transcriptome imputation typically detect fewer associations than GWAS, they nonetheless provide an interesting way of interpreting association signals to identify potentially causal genes.

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.

To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).,Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.,Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days).,For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ.,A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031).,During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD).,Disability follow-up indicated stabilization.,MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord).,Chronic pain was unchanged.,Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28).,Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD.,No severe or unexpected safety signals were observed.,Add-on therapy showed no advantage compared with TCZ monotherapy.,This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association.,However, some severe cases are refractory to systemic immunotherapy.,This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy.,Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks.,Cerebrospinal fluid (CSF) was collected at baseline and each time of intrathecal injection for identification of anti-NMDAR antibody titers.,Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers (maximum: 1/320 to minimum: 1/10).,After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people (modified Rankin scale [mRS] of 0-2).,At 12 months of follow-up, they all had returned to most activities of daily life (mRS of 0), and no relapses were reported.,One patient showed no clinical improvement and died of neurologic complications.,Intrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis.,Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Galactose‐deficient IgA1 (Gd‐IgA1) plays a crucial role in the development of Immunoglobulin A nephropathy (IgAN), however, the underlying pathogenic mechanisms driving Gd‐IgA1 production in B cells are not well understood.,In this study, RNA‐seq analysis identified 337 down‐regulated and 405 up‐regulated genes in B cells from 17 patients with IgAN and 6 healthy controls.,Among them, ST6Gal1, which was associated with IgAN in a previous genome‐wide association study (GWAS), was up‐regulated in IgAN and significantly positive correlated with elevated Gd‐IgA1.,In addition, we identified increased plasma ST6Gal1 levels in 100 patients with IgAN, which were associated with higher levels of proteinuria, plasma IgA, Gd‐IgA1 levels, greater degrees of systemic complement activation including C3a, Bb, C4d, MAC and a lower proportion classified as C2 grade (crescent proportion ≥25%).,Interesting, in vitro, recombinant ST6Gal1 (rST6Gal1) exposure reduced the production of Gd‐IgA1 in cultured peripheral blood mononuclear cells from IgAN patients. rST6Gal1 stimuli also increased expression of C1GALT1, which were well‐known proportional to the decrease in galactose deficiency of IgA1.,In conclusions, we identified increased plasma ST6Gal1 levels and the association of ST6Gal1 with disease severity of IgAN.,Additionally, rST6Gal1 administration in vitro increased expression of C1GALT1 and reduced the production of Gd‐IgA1.

Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions.,Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases.,IKZF1, HLA-DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE.,We undertook this large multicenter case-control study to determine whether SLE is associated with altered IgG glycosylation.,Using ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).,Multiple statistically significant differences in IgG glycome composition were observed between patients and controls.,The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).,The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins.,The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL.,Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included.,Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine.,Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models.,Age was not associated with the rate of BVL (β = −0.003; Cohen f2 = 0.0005; adjusted p = 0.39).,Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = −0.012; Cohen f2 = 0.004; adjusted p = 4 × 10−5).,Analysis of association between tissue-specific brain volume changes and age (β = −0.019 to −0.011; adjusted p = 0.028-1.00) or disease duration (β = −0.028 to −0.008; adjusted p = 0.16-0.96) confirmed these results.,Although increase in the relapse rate (β = 0.10; adjusted p = 9 × 10−9), Expanded Disability Status Scale (EDSS; β = 0.17; adjusted p = 8 × 10−5), and EDSS change (β = 0.15; adjusted p = 2 × 10−5) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007).,In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = −0.29; Cohen f2 = 0.133; p = 5.5 × 10−8).,The rate of BVL is relatively stable throughout the course of RRMS.,The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.

Chronic active and slowly expanding/evolving lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis.,Elliott et al. report that T1-weighted measures of chronic lesion activity predict clinically progressive multiple sclerosis, may represent a longitudinal neuroimaging correlate of smouldering demyelination and axonal loss, and are reduced by ocrelizumab.,Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology.,T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation.,Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570).,We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test.,We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation.,There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions.,Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite.,In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level.,Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions.,Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

Coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Physicians in China reported what is believed to be the first adult case of a SARS-CoV-2 infection associated with acute Guillain-Barré syndrome (GBS), followed by 5 adult Italian patients and another case in the United States.,In the current report, we present one of the first descriptions of an association of GBS and SARS-CoV-2 infection in a child.,In our facility, an 11-year-old boy presented with typical features of GBS and, after 5 days, a morbilliform skin rash over the palms of both hands.,Three weeks before the start of the neurological symptoms, the boy had experienced an episode of mild febrile illness with mild respiratory manifestations and a persistent cough.,The diagnosis of SARS-CoV-2 infection was confirmed by oropharyngeal swab on reverse-transcription polymerase chain reaction assay.,The disease course of our patient strongly suggests a possible relationship between the development of GBS and SARS-CoV-2 infection.,The case is discussed in view of previous case reports regarding the association of GBS and COVID-19.

•A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,•SARS-CoV-2 has also been shown to affect the peripheral nervous system.,•Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,•Some GBS have led to hypothesize a possible parainfectious pathogenesis.,A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,SARS-CoV-2 has also been shown to affect the peripheral nervous system.,Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,Some GBS have led to hypothesize a possible parainfectious pathogenesis.,In recent months, the new beta-coronavirus has caused a pandemic with symptoms affecting mainly the respiratory system.,It is established that the virus may play a neurotropic role and in recent months several cases of Guillain-Barré-Strohl syndrome (GBS) have been reported in patients infected with COVID-19.,We report the case of a 54-year-old patient with acute demyelinating polyneuropathy during infection by SARS-CoV-2 who progressed clinically to require assisted ventilation.,After several weeks of specific symptomatic treatment, the patient had a favorable outcome.,In conclusion, despite being a rare complication, we think it is important to consider the possibility of diffuse involvement of the peripheral nervous system in patients with COVID-19 to adjust clinical monitoring and treatment in these cases.

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability.,The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA.,This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015.,Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years.,Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor).,PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5.,Taste acceptability of the oral solution was evaluated.,Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively.,The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment.,Geometric mean AUC at steady state (AUCtau) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively.,Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1.,Median time to Cmax (Tmax) was similar between cohorts.,Apparent clearance and volume of distribution decreased with decreasing age.,Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported.,Taste acceptability was confirmed.,PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program.,ClinicalTrials.gov: NCT01513902.,The online version of this article (10.1186/s12969-017-0212-y) contains supplementary material, which is available to authorized users.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).,We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.,Data were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015).,Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.,6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years.,IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0).,IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4).,IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis.,IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7).,IR for gastrointestinal perforations was 0.1 (0.1 to 0.2).,Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.,This analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports.,AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.,NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration.,While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many multiple sclerosis patients.,Although it is currently unknown why remyelination fails, recurrent demyelination of previously demyelinated white matter areas is one contributing factor.,In this study, we investigated whether laquinimod, which has demonstrated protective effects in active multiple sclerosis patients, protects against recurrent demyelination.,To address this, male mice were intoxicated with cuprizone for up to eight weeks and treated with either a vehicle solution or laquinimod at the beginning of week 5, where remyelination was ongoing.,The brains were harvested and analyzed by immunohistochemistry.,At the time-point of laquinimod treatment initiation, oligodendrocyte progenitor cells proliferated and maturated despite ongoing demyelination activity.,In the following weeks, myelination recovered in the laquinimod- but not vehicle-treated mice, despite continued cuprizone intoxication.,Myelin recovery was paralleled by less severe microgliosis and acute axonal injury.,In this study, we were able to demonstrate that laquinimod, which has previously been shown to protect against cuprizone-induced oligodendrocyte degeneration, exerts protective effects during oligodendrocyte progenitor differentiation as well.,By this mechanism, laquinimod allows remyelination in non-supportive environments.,These results should encourage further clinical studies in progressive multiple sclerosis patients.

Primary loss and dysfunction of astrocytes may trigger demyelination, as seen in neuromyelitis optica, an inflammatory disease of the central nervous system.,In most patients affected by this disease, injury to astrocytes is initiated by the action of autoantibodies targeting aquaporin 4 (AQP-4), a water channel on astrocytes.,We show here that damage of astrocytes and subsequent demyelination can also occur in the absence of autoantibody-mediated mechanisms.,Following injection of lipopolysaccharide into the white matter initial microglia activation is followed by a functional disturbance of astrocytes, mainly reflected by retraction of astrocytic foot processes at the glia limitans and loss of AQP-4 and connexins, which are involved in the formation of gap junctions between astrocytes and oligodendrocytes.,Demyelination and oligodendrocyte degeneration in this model follows astrocyte pathology.,Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis.,Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation.

Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs).,However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown.,The expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot.,Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays.,The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay.,The level of phosphorylated-p65 was examined by Western blot.,The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays.,Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot.,HAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway.,Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p.,Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown.,HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs.,MSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.

The purpose of this study was to investigate the profile of histone deacetylase (HDAC) expression in the synovial tissue of rheumatoid arthritis (RA) compared with that of normal control and osteoarthritis (OA), and to examine whether there is a link between HDAC activity and synovial inflammation.,HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of total synovial tissue surgically obtained from normal, OA and RA joints.,The level of cytoplasmic tumor necrosis factor a (TNFα) fraction was measured by ELISA.,Total RNA of synovial tissue was used for RT-PCR of HDAC1-8.,In synovial fibroblasts from RA (RASFs), the effects of TNFα on nuclear HDAC activity and class I HDACs (1, 2, 3, 8) mRNA expressions were examined by quantitative real-time PCR.,The protein expression and distribution of class I HDACs were examined by Western blotting.,Nuclear HDAC activity was significantly higher in RA than in OA and normal controls and correlated with the amount of cytoplasmic TNFα.,The mRNA expression of HDAC1 in RA synovial tissue was higher than in OA and normal controls, and showed positive correlation with TNFα mRNA expression.,The protein level of nuclear HDAC1 was higher in RA synovial tissue compared with OA synovial tissue.,Stimulation with TNFα significantly increased the nuclear HDAC activity and HDAC1 mRNA expression at 24 hours and HDAC1 protein expression at 48 hours in RASFs.,Our results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα stimulation in RASFs.,These data might provide important clues for the development of specific small molecule HDAC inhibitors.

Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood.,Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs).,IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg.,We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs.,During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity.,Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity.,•IDO expression by LN pDCs is closely dependent on MHCII-mediated, antigen-dependent, interactions with Tregs.•pDCs are the predominant source of IDO in both steady-state and inflamed lymph nodes.,•IDO production by pDCs is necessary to confer suppressive function to Tregs in EAE.,IDO expression by LN pDCs is closely dependent on MHCII-mediated, antigen-dependent, interactions with Tregs.,pDCs are the predominant source of IDO in both steady-state and inflamed lymph nodes.,IDO production by pDCs is necessary to confer suppressive function to Tregs in EAE.

Galectin-1 (Gal-1), a proto-type member of galectin family, is highly expressed in immune privileged sites, including the testis.,However, in spite of considerable progress the relevance of endogenous and exogenous Gal-1 in testis pathophysiology have not yet been explored.,Here we evaluated the in vivo roles of Gal-1 in experimental autoimmune orchitis (EAO), a well-established model of autoimmune testicular inflammation associated with subfertility and infertility.,A significant reduction in the incidence and severity of EAO was observed in mice genetically deficient in Gal-1 (Lgals1−/−) versus wild-type (WT) mice.,Testicular histopathology revealed the presence of multifocal testicular damage in WT mice characterized by an interstitial mononuclear cell infiltrate and different degrees of germ cell sloughing of seminiferous tubules.,TUNEL assay and assessment of active caspase-3 expression, revealed the prevalence of apoptotic spermatocytes mainly localized in the adluminal compartment of seminiferous tubules in EAO mice.,A significant increased number of TUNEL-positive germ cells was detected in EAO testis from WT compared with Lgals1−/− mice.,In contrast, exogenous administration of recombinant Gal-1 to WT mice undergoing EAO attenuated the severity of the disease.,Our results unveil a dual role of endogenous versus exogenous Gal-1 in the control of autoimmune testis inflammation.

The important role of microRNAs as major modulators of various physiological processes, including immune regulation and homeostasis, has been increasingly recognized.,Consequently, aberrant miRNA expression contributes to the defective regulation of T cell development, differentiation, and function.,This can result in immune activation and impaired tolerance mechanisms, which exert a cardinal function for the onset of islet autoimmunity and the progression to T1D.,The specific impact of miRNAs for immune regulation and how miRNAs and their downstream targets are involved in the pathogenesis of islet autoimmunity and T1D has been investigated recently.,These studies revealed that increased expression of individual miRNAs is involved in several layers of tolerance impairments, such as inefficient Treg induction and Treg instability.,The targeted modulation of miRNAs using specific inhibitors, resulting in improved immune homeostasis, as well as improved methods for the targeting of miRNAs, suggest that miRNAs, especially in T cells, are a promising target for the reestablishment of immune tolerance.

Regulatory T cells (Tregs) are critical contributors to immune homeostasis and their dysregulation can lead to the loss of immune tolerance and autoimmune diseases like type 1 diabetes (T1D).,Recent studies have highlighted microRNAs (miRNAs) as important regulators of the immune system, by fine-tuning relevant genes in various immune cell types.,In this review article, we discuss recent insights into miRNA regulation of immune tolerance and activation.,Specifically, we discuss how the dysregulation of miRNAs in T cells contributes to their aberrant function and the onset of islet autoimmunity, as well as their potential as targets of novel intervention strategies to interfere with autoimmune activation.,Several studies have shown that the dysregulation of individual miRNAs in T cells can contribute to impaired immune tolerance, contributing to onset and progression of islet autoimmunity.,Importantly, the targeting of these miRNAs, including miR-92a, miR-142-3p and miR-181a, resulted in relevant effects on downstream pathways, improved Treg function and reduced islet autoimmunity in murine models.,miRNAs are critical regulators of immune homeostasis and the dysregulation of individual miRNAs in T cells contributes to aberrant T cell function and autoimmunity.,The specific targeting of individual miRNAs could improve Treg homeostasis and therefore limit overshooting T cell activation and islet autoimmunity.

We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D).,Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect.,Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years.,The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo.,Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months.,C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046).,The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept.,Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group.,The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.,Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D.,The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes.,Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis.,We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset.,HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate decarboxylase (GADA), IA-2, IA-2β, and ZnT8 were analyzed in samples collected from patients with recent-onset type 1 diabetes.,After correction for age, sex, and HLA class II genotype, HLA-A*24 was shown to be a negative determinant of IA-2A and ZnT8A.,These effects were epitope specific.,Antibodies targeting the protein tyrosine phosphatase domains of IA-2 and IA-2β, but not the IA-2 juxtamembrane region, were less common in patients carrying HLA-A*24 alleles.,The prevalence of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those specific to arginine-325, was reduced in HLA-A*24-positive patients.,No associations were found between HLA-A*24 and IAA or GADA.,Association of an HLA class I susceptibility allele with altered islet autoantibody phenotype at diagnosis suggests CD8 T-cell and/or natural killer cell-mediated killing modulates humoral autoimmune responses.

Epigenetic mechanisms can integrate gene-environment interactions that mediate disease transition from preclinical to clinically overt rheumatoid arthritis (RA).,To better understand their role, we evaluated microRNA (miRNA, miR) expression profile in indigenous North American patients with RA who were positive for anticitrullinated protein antibodies; their autoantibody-positive, asymptomatic first-degree relatives (FDRs); and disease-free healthy control subjects (HCs).,Total RNA was isolated from whole blood samples obtained from HC (n = 12), patients with RA (n = 18), and FDRs (n = 12).,Expression of 35 selected relevant miRNAs, as well as associated downstream messenger RNA (mRNA) targets of miR-103a-3p, was determined by qRT-PCR.,Whole blood expression profiling identified significantly differential miRNA expression in patients with RA (13 miRNAs) and FDRs (10 miRNAs) compared with HCs.,Among these, expression of miR-103a-3p, miR-155, miR-146a-5p, and miR-26b-3p was significantly upregulated, whereas miR-346 was significantly downregulated, in both study groups.,Expression of miR-103a-3p was consistently elevated in FDRs at two time points 1 year apart.,We also confirmed increased miR-103a-3p expression in peripheral blood mononuclear cells from patients with RA compared with HCs.,Predicted target analyses of differentially expressed miRNAs in patients with RA and FDRs showed overlapping biological networks.,Consistent with these curated networks, mRNA expression of DICER1, AGO1, CREB1, DAPK1, and TP53 was downregulated significantly with miR-103a-3p expression in FDRs.,We highlight systematically altered circulating miRNA expression in at-risk FDRs prior to RA onset, a profile they shared with patients with RA.,Prominently consistent miR-103a-3p expression indicates its utility as a prognostic biomarker for preclinical RA while highlighting biological pathways important for transition to clinically detectable disease.,The online version of this article (doi:10.1186/s13075-017-1459-x) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA) is a chronic systemic auto- immune disease characterized by joint synovitis.,Recent evidence suggests that rheumatoid arthritis synovial fibroblasts (RASFs) promote joint destruction.,In this study, we investigated the role of microRNA-26b (miR-26b) in cell proliferation and inflammatory cytokine secretion using patient-derived Rheumatoid arthritis fibroblast-like synoviocyte (RAFLS) to understand pathways influencing rheumatoid arthritis.,RAFLS were cultured in vitro and transfected with miR-26b mimics (experimental group) and negative sequence (control group).,The protein levels of Wnt4, Wnt5ɑ, GSK-3β, CyclinD1, Ser9-GSK-3β and β-catenin were detected by western blot analysis.,Tumor Necrosis Factor-ɑ (TNF-ɑ), IL- 1β, and IL-6 levels were quantified by Enzyme-linked Immunosorbent Assay (ELISA).,RAFLS proliferation and apoptosis were measured by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry, respectively.,GSK-3β and CyclinD1 expression levels were lower in miR-26b mimic group compared to Mock group and negative control (NC) group.,Conversely, GSK-3β and CyclinD1 expression levels were markedly higher in the miR-26b inhibitor group compared to Mock and NC group (P < 0.05).,Transfection of miR-26b mimics significantly increased the, levels of Ser9-GSK-3β and β-catenin in comparison to Mock and NC groups, while transfection of miR-26b inhibitors showed the opposite effect.,In miR-26b mimic group, TNF-α, IL- 1β and IL-6 levels were lower than the Mock and NC groups, while in miR-26b inhibitor group, these cytokine levels were higher than the Mock and NC groups (P < 0.05).,Transfection of miR-26b mimics significantly reduced the cell proliferation of RAFLS, compared to the Mock and NC groups, and miR-26b inhibitors increased the proliferative capacity of RAFLS compared to Mock and NC groups (P < 0.05).,The miR-26b mimic group exhibited higher RAFLS apoptosis rate compared to Mock and NC group and miR-26b inhibitor group showed significantly lower RAFLS apoptosis rate compared to Mock and NC groups (P < 0.05).,MiR-26b regulates β-catenin and CyclinD1 levels by inhibiting GSK-3β expression, which in-turn alters the Wnt/GSK-3β/β-catenin pathway to lower RAFLS proliferation and elevate cell apoptosis and the secretion of TNF-α,IL-1β and IL-6 cytokines.,Therefore, our results show that miR-26B plays a central role in inhibiting the inflammation associated with rheumatoid arthritis.,The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9063056861547150

C-C chemokine receptor 6 (CCR6) is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN).,In this study, we aimed to identify the functional variants.,First, we analyzed the associations of CCR6 common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region.,Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15, P = 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P = 1.45 × 10−3).,It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10−7).,Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP, the alleles of rs3093023 (G>A) rather than of CCR6DNP were shown differential nuclear protein binding effect by electrophoretic mobility shift assay.,The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated with CCR6 mRNA (r = −0.60, P = 3.94 × 10−9).,At the mRNA level, the eQTL effect of CCR6 was validated (P = 4.39 × 10−2), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG.,At the protein level, a higher CCR6+ cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P = 3.57 × 10−2), CD3+ T cells (P = 4.54 × 10−2), and CD4+ T cells (P = 1.32 × 10−2), but not in CD8+ T cells.,Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis.,Overall, the rs3093023 was prioritized as the function variant in CCR6, which may contribute to IgAN susceptibility by regulating Th17 cells.

Infections have been considered to play a critical role in the pathogenesis of IgA nephropathy (IgAN) because synpharyngitic hematuria is a common feature in IgAN.,However, how infections participate in this process is still debated.,More recent studies have also revealed that the alteration of the gut microbiome exerts a profound effect on host immune responses, contributing to the etiology or progression of autoimmunity.,Considering IgA as the first line of defense against bacterial and viral antigens, this review evaluates the relationships among intestinal infections, gut microbiome, and IgA for a better understanding of the pathogenesis of IgAN.,Moreover, as a prototype of IgA immunity, we provide detailed clarification of IgAN pathogenesis to shed light on other diseases in which IgA plays a role.,Finally, we discuss potential therapies focusing on microbes and mucosal immune responses in IgAN.

Graves‘ disease (GD) is a clinical syndrome with an enlarged and overactive thyroid gland, an accelerated heart rate, Graves’ orbitopathy (GO), and pretibial myxedema (PTM).,GO is the most common extrathyroidal complication of GD.,GD/GO has a significant negative impact on the quality of life.,GD is the most common systemic autoimmune disorder, mediated by autoantibodies to the thyroid-stimulating hormone receptor (TSHR).,It is generally accepted that GD/GO results from complex interactions between genetic and environmental factors that lead to the loss of immune tolerance to thyroid antigens.,However, the exact mechanism is still elusive.,Systematic investigations into GD/GO animal models and clinical patients have provided important new insight into these disorders during the past 4 years.,These studies suggested that gut microbiota may play an essential role in the pathogenesis of GD/GO.,Antibiotic vancomycin can reduce disease severity, but fecal material transfer (FMT) from GD/GO patients exaggerates the disease in GD/GO mouse models.,There are significant differences in microbiota composition between GD/GO patients and healthy controls.,Lactobacillus, Prevotella, and Veillonella often increase in GD patients.,The commonly used therapeutic agents for GD/GO can also affect the gut microbiota.,Antigenic mimicry and the imbalance of T helper 17 cells (Th17)/regulatory T cells (Tregs) are the primary mechanisms proposed for dysbiosis in GD/GO.,Interventions including antibiotics, probiotics, and diet modification that modulate the gut microbiota have been actively investigated in preclinical models and, to some extent, in clinical settings, such as probiotics (Bifidobacterium longum) and selenium supplements.,Future studies will reveal molecular pathways linking gut and thyroid functions and how they impact orbital autoimmunity.,Microbiota-targeting therapeutics will likely be an essential strategy in managing GD/GO in the coming years.

Dysbiosis of the intestinal microbiota affecting the gut barrier could be triggering Type 1 Diabetes (T1D), the second most frequent autoimmune disease in childhood.,This study compared the structure of the fecal microbiota in 29 mestizo children aged 7-18 years, including 8 T1D at onset, 13 T1D after 2 years treatment, and 8 healthy controls.,Clinical information was collected, predisposing haplotypes were determined; the fecal DNA was extracted, the V4 region of the 16S rRNA gene amplified and 454-pyrosequenced.,The newly diagnosed T1D cases had high levels of the genus Bacteroides (p < 0.004), whereas the control group had a gut microbiota dominated by Prevotella.,Children with T1D treated for ≥2 years had levels of Bacteroides and Prevotella compared to those of the control group.,The gut microbiota of newly diagnosed T1D cases is altered, but whether it is involved in disease causation or is a consequence of host selection remains unclear.

Rheumatoid arthritis (RA) is a common autoimmune disease with characteristics of synovial inflammation, pannus formation, cartilage destruction, and bone erosion.,Further, the inflammation is linked to increased oxygen consumption, resulting in hypoxia within the inflammatory area.,Hypoxia-inducible factor (HIF) was reported to be associated with adaptation to the hypoxic microenvironment in the RA synovium.,Here, we have briefly summarized the structure and expression of HIF.,Moreover, the function of HIF in inflammation, angiogenesis, cartilage damage, and immune cells of RA has been discussed.

This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation.,Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates.,Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays.,RASF metabolism was assessed by the XF24-Flux Analyzer.,Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM).,In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology.,A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging.,RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).,DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01).,This was coupled with altered mitochondrial morphology.,Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05).,In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05).,Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders.,Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation.,3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions.,Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.

Demonstrating the effectiveness of expensive new rheumatoid arthritis (RA) therapeutics is imperative to determine whether the quality of care has improved with the introduction of these agents.,Our current RA quality measures are primarily process based, but they must become outcomes based to better demonstrate quality.,New RA quality measures must be multidimensional, accounting for all of the important outcomes in RA: radiographic, functional status, and disease activity.,To fully understand the potential benefits of new therapeutics in RA, outcome measures must be integrated with routine practice.

Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to control active rheumatoid arthritis (RA); however there is little information about patients’ perspectives, their expectations, concerns and experiences of this intensive treatment.,We interviewed a quota sample of 18 patients from a single tertiary outpatient clinic, stratified by gender, ethnicity and age, based on the outpatient clinic population.,Patients with early RA (<2 years) received combined conventional DMARDs; patients with established RA (>2 years) received combined conventional DMARDs or DMARDs with biologics.,Four main themes emerged from the analytical framework: (i) patients’ expectations about the combined treatment focuses mainly on physical symptoms; (ii) the impact of the treatment on quality of life varied with the new medication in both groups (iii) concerns about new interventions concentrated mainly on potential side effects; and (iv) combination therapy can be self-managed in close collaboration with clinic staff, but this requires individualised management approaches.,These themes resonate with von Korff’s collaborative management of chronic illness model.,To our knowledge this is the first qualitative study that examined systematically in patients with early and established RA their expectations, impact on quality of life, concerns about side effects and the management of the treatment when taking combined medication with DMARDs or DMARDs and biologics.,Patients have generally positive views of combination DMARDs.,Within routine practice settings, achieving medication concordance with complex combined DMARD regimens is challenging, and the concerns vary between patients; careful individual assessments are essential to successfully deliver such intensive treatment.

In a Genome Wide Association Study (GWAS) of individuals of European ancestry afflicted with Systemic Lupus Erythematosus (SLE) the extensive utilization of imputation, stepwise multiple regression, lasso regularization, and increasing study power by utilizing False Discovery Rate (FDR) instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of 4 genes previously reported to be associated.,Novel genes associated with SLE susceptibility included two transcription factors (EHF, and MED1), two components of the NFκB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6), and two genes involved in antigen presentation (BIN1 and SEC61G).,In addition, the strongly significant association of multiple single nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals.,The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors.,To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation450 microarrays.,We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p<1×10−8) among SLE patients.,Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I).,These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels.,This interferon hypersensitivity was apparent in memory, naïve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations.,We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (>16,000 CpGs at FDR<1%) near genes involved in cell division and MAPK signaling.,These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.

Background: Guillain-Barré Syndrome (GBS) is a rapidly progressive immune-mediated polyneuropathy often associated with an antecedent infectious illness or vaccination.,The classic presentation of GBS is characterized by ascending limb weakness and numbness with loss of reflexes.,However, atypical variants involving the face and arms or with purely sensory symptoms also exist.,In up to 30% of cases, GBS progresses to respiratory failure, with patients requiring mechanical ventilation.,Case Report: We report a case of atypical GBS occurring after Coronavirus disease 2019 (COVID-19) vaccination in an otherwise healthy 38-year-old man.,The patient's clinical presentation was characterized by bilateral hand and foot paresthesias, dysarthria, bilateral facial weakness, and an absence of classic ascending limb weakness.,Albuminocytological dissociation within the cerebrospinal fluid was suggestive of GBS.,The patient received intravenous immunoglobulin therapy, with modest improvement in his symptoms at the time of his discharge from the hospital.,Why Should an Emergency PhysicianBe Aware of This?,Patients with GBS are at risk for life-threatening complications, including respiratory failure requiring mechanical ventilation.,It is critical for emergency physicians to be aware of the manifold presentations of GBS for early recognition and treatment.,This may be of particular importance in the context of a worldwide vaccination campaign in response to the COVID-19 pandemic.

The objective of this study is to assess cases of thrombocytopenia, including immune thrombocytopenia (ITP), reported to the Vaccine Adverse Event Reporting System (VAERS) following vaccination with mRNA COVID-19 vaccines.,This case-series study analyzed VAERS reports of thrombocytopenia after vaccination with Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine.,Fifteen cases of thrombocytopenia were identified among 18,841,309 doses of Pfizer-BioNTech COVID-19 Vaccine and 13 cases among 16,260,102 doses of Moderna COVID-19 Vaccine.,The reporting rate of thrombocytopenia was 0.80 per million doses for both vaccines.,Based on an annual incidence rate of 3.3 ITP cases per 100,000 adults, the observed number of all thrombocytopenia cases, which includes ITP, following administration of mRNA COVID-19 vaccines is not greater than the number of ITP cases expected.,The number of thrombocytopenia cases reported to VAERS does not suggest a safety concern attributable to mRNA COVID-19 vaccines at this time.

In 9-20% of cases, Sjögren's syndrome is associated with various respiratory symptoms.,The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease.,The most common manifestation of ILD is nonspecific interstitial pneumonia in its fibrosing variant.,Other types of ILD, such as organising pneumonia, usual interstitial pneumonia and lymphocytic interstitial pneumonitis, are rare.,Their radiological presentation is less distinctive, and definitive diagnosis may require the use of transbronchial or surgical lung biopsy.,Corticosteroid therapy is the mainstay of ILD treatment in Sjögren's syndrome, but the use of other immunosuppressive drugs needs to be determined.,ILD is a significant cause of death in Sjögren's syndrome.,Tracheobronchial disease is common in Sjögren's syndrome, characterised by diffuse lymphocytic infiltration of the airway.,It is sometimes responsible for a crippling chronic cough.,It can also present in the form of bronchial hyperresponsiveness, bronchiectasis, bronchiolitis or recurrent respiratory infections.,The management of these manifestations may require treatment for dryness and/or inflammation of the airways.,Airway disease has little effect on respiratory function and is rarely the cause of death in Sjögren's syndrome patients.,Rare respiratory complications such as amyloidosis, lymphoma or pulmonary hypertension should not be disregarded in Sjögren's syndrome patients.,We present the features, diagnostic tests and treatments of thoracic manifestations of Sjögren's syndromehttp://ow.ly/10m8vd

Interstitial lung disease associated with primary Sjögren’s syndrome (pSS-ILD) shows several patterns such as nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP).,Although UIP is a well-recognized prognostic determinant in idiopathic interstitial pneumonias, whether this is also the case in pSS-ILD is unclear.,The objectives of this study were to evaluate the prognostic effect of UIP, and to identify the prognostic factors in pSS-ILD.,A retrospective review of medical records identified 33 consecutive patients with pathologically-proven pSS-ILD.,Each patient was classified into each ILD pattern by multidisciplinary analysis.,Baseline clinical-radiologic-pathologic characteristics and survival rates were compared between the ILD patterns.,Finally, the prognostic factors in pSS-ILD were assessed by univariate and subsequent multivariate analyses using Cox’s proportional hazards regression model.,pSS-ILD patients were diagnosed with NSIP (n = 22) or UIP (n = 11).,The median follow-up period was 110 months, and five-year survival rate was 87.3% in the total patient population.,The prognosis of the UIP patients was not significantly different from that of the NSIP patients (NSIP to UIP, hazard ratio [HR]: 0.77, 95% confidence interval [CI]: 0.18-3.36, P = 0.73).,Multivariate analysis identified PaCO2 (HR: 1.68 per 1 Torr increase, 95% CI: 1.24-2.28, P < 0.01), extent of reticular abnormality on high-resolution CT (HR: 4.17 per 1-grade increment, 95% CI: 1.18-14.73, P = 0.03), and severity of fibroblastic foci (HR: 9.26 per 1-grade increment, 95% CI: 1.74-49.35, P < 0.01) as prognostic factors in pSS-ILD.,UIP in pSS-ILD was not related to poorer prognosis than NSIP.,Assessment of detailed clinical-radiologic-pathologic findings is more important than distinguishing UIP to evaluate prognosis in this disease.

Recently, along with increasing use of immune checkpoint inhibitors such as nivolumab, the incidence of immune-related adverse events, including type 1 diabetes mellitus, has become a serious problem.,We report a patient who had immune checkpoint inhibitor-associated type 1 diabetes mellitus that developed after a second mRNA-based SARS-CoV-2 vaccination.

A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL.,Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy.,His CPR levels gradually decreased and were depleted within 1 week.,We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission.,Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise.,While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood.,Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human.,Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice.,Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs.,These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.,miRNA142-3p and Tet2 are separately known to regulate Treg.,Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.

C3.,MRL-Faslpr/J mice spontaneously develop high titers of anti-dsDNA, mild glomerular nephritis, and severe lymphoproliferation symptoms.,This study aimed to compare the effects of long-term serial administration of human adipose tissue-derived mesenchymal stem cells (ASCs), and cyclophosphamide treatment in C3.,MRL-Faslpr/J mice using a murine SLE model.,C3.,MRL-Faslpr/J mice were divided into saline (C), cyclophosphamide (Y), and ASC (H) treatment groups.,Background-matched control C3H mice treated with saline (N) were also compared.,The Y group showed the greatest improvement in disease parameters, but with damaged trabecular integrity.,ASC transplantation reduced anti-dsDNA levels, glomerular C3 deposition and CD138 proportion significantly, without trabecular damage.,Furthermore, both cyclophosphamide and ASC treatment significantly decreased the ratio of Th1/Th2 compared with the saline-treatment.,The expression levels of miR-31-5p, miR-96-5p, miR-182-5p, miR-183-5p, and miR-379-5p were significantly higher, while those of miR150-5p were significantly lower in the C group than in the N group.,The expression levels of miR-96-5p, miR-182-5p in the Y and H groups were significantly lower than in the C group.,Thus, treatment with cyclophosphamide or ASC can change miRNAs and decrease miR-96-5p and miR-182-5p expression, as well as decreasing the CD138 proportion and the Th1/Th2 ratio, which might be involved in the therapeutic mechanism.

The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to HLA-DRB1 alleles.,Yet controversy persists about the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC.,Using existing genome-wide SNP data in 5,018 seropositive cases and 14,974 controls, we imputed and tested classical alleles and amino acid polymorphisms for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, and DRB1 along with 3,117 SNPs across the MHC.,Conditional and haplotype analyses reveal that three amino acid positions (11, 71 and 74) in HLA-DRβ1, and single amino acid polymorphisms in HLA-B (position 9) and HLA-DPβ1 (position 9), all located in the peptide-binding grooves, almost completely explain the MHC association to disease risk.,This study illustrates how imputation of functional variation from large reference panels can help fine-map association signals in the MHC.

Cumulative genetic profiles can help identify individuals at high-risk for developing RA.,We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.,We evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II.,We created a weighted genetic risk score (GRS) and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking) to assess the relationship between GRS group and odds of developing seronegative (RF− and CCP−), seropositive (RF+ or CCP+), erosive, and seropositive, erosive RA phenotypes.,In separate case only analyses, we assessed the relationships between GRS and age of symptom onset.,In 542 RA cases, 317 (58%) were seropositive, 163 (30%) had erosions and 105 (19%) were seropositive with erosions.,Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8-2.1) for seronegative RA, 3.0 (95% CI = 1.9-4.7) for seropositive RA, 3.2 (95% CI = 1.8-5.6) for erosive RA, and 7.6 (95% CI = 3.6-16.3) for seropositive, erosive RA.,No significant relationship was seen between GRS and age of onset.,Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.

Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care.,The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.,Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases.,The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.,A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days.,The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy.,Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus.,There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections.,Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response.,Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab.,Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).,Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world.,This analysis included 3881 patients.,Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks.,Data on baseline characteristics and adverse events (AE) were collected.,Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively.,The most frequent AE and serious AE were infections.,Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years.,Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients.,Tocilizumab is acceptably safe in the real clinical setting.,Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.

Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS).,The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far.,The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR).,A case-control (1:2) study was set up.,Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19.,Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence.,No healthy controls were included in this study.,COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates.,The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered.,A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls).,In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19.,Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk.,Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home.,This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities.,Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS.,This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19.,Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

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.

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved.,The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis.,We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).,Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT.,Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR.,Histological morphology was evaluated on light and electron microscopy images.,Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation.,Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e.,T-cells) in the optic nerve 11 days post immunisation.,Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema.,Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation.,Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL.,Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.,Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis.,Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms.,Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning.,These results add morphological substrate to our OCT findings.,The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.,The online version of this article (10.1186/s40478-019-0768-5) contains supplementary material, which is available to authorized users.

Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors.,However, the impact of microglia depletion and repopulation in the long-term state of the CNS environment has not been characterized.,Here, we report that acute and synchronous microglia depletion and subsequent repopulation induces gray matter microgliosis, neuronal death in the somatosensory cortex and ataxia-like behavior.,We find a type 1 interferon inflammatory signature in degenerating somatosensory cortex from microglia-depleted mice.,Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state.,Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type 1 interferon-driven inflammation, restore microglia homeostasis and reduce ataxic behavior.,Neither microglia depletion nor repopulation impact neuropathology or T-cell responses during experimental autoimmune encephalomyelitis.,Together, we found that acute microglia ablation induces a type 1 interferon activation state of gray matter microglia associated with acute neurodegeneration.,Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death.,Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.

Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions.,We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilamentandlongtermoutcome inMS (NaloMS) cohort.,The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204).,Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated.,During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs.,7.2 pg/ml (4.5-12.5), p<0.017).,In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine.,In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs.,0.96 (0.75-1.23), p=0.011).,This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning.,sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later.,While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion.,This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung.

To investigate the total circular RNA (circRNA) profile in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs).,Hybridization microarray was used to define the circRNA profile in peripheral blood mononuclear cells (PBMCs) from 20 untreated patients with RRMS (10 in relapse and 10 in remission) and 10 HCs.,We analyzed close to 14,000 individual circRNAs per sample.,The discovery set data were validated using quantitative reverse transcription-PCR with an independent cohort of 47 patients with RRMS (19 in relapse and 28 in remission) and 27 HCs.,Microarray analysis revealed 914 transcripts to be differentially expressed between patients with RRMS in relapse and HCs (p < 0.05).,We validated 3 circRNAs from 5 showing highest levels of differential expression in the RRMS relapse vs HC group: hsa_circRNA_101348, hsa_circRNA_102611, and hsa_circRNA_104361.,Their expression was significantly increased during relapse in RRMS (p = 0.0002, FC = 2.9; p = 0.01, FC = 1.6; and p = 0.001, FC = 1.5, respectively) and in patients showing gadolinium enhancement on brain MRI (hsa_circRNA_101348, p = 0.0039, FC = 2.4; hsa_circRNA_104361, p = 0.029, FC = 1.7).,Bioinformatic analysis revealed 15 microRNAs interacting with these circRNAs in a complementary manner and led to the discovery and validation of 3 protein-coding RNAs upregulated in patients with RRMS during relapse.,Two of these, AK2 and IKZF3, have previously been implicated in B-cell function.,circRNAs display a distinct profile in PBMCs from patients with RRMS, and our results may implicate circRNA in the known disturbed B-cell activity in RRMS and thus represent a novel biomarker for monitoring relapse activity.

Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS.,However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile.,Hence, the unmet need for safer and more selective treatments remains.,Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative.,In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.,Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials.,In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal.,The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design.,The primary objective is to assess the safety and feasibility of tolDC administration.,For safety, the number of adverse events including MRI and clinical outcomes will be assessed.,For feasibility, successful production of tolDC will be determined.,Secondary endpoints include clinical and MRI outcome measures.,The patients’ immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.,Ethics approval was obtained for the two phase I clinical trials.,The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.,NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.

Dendritic cells (DCs) play a key role not only in the initiation of primary immune responses, but also in the development and maintenance of immune tolerance.,Numerous protocols have been developed to generate tolerogenic DCs (tolDCs) ex vivo, and the therapeutic efficacy of ex vivo-generated tolDCs has been demonstrated in autoimmune disease animal models.,Based on successes in small animal models, several clinical trials have been completed or are on-going in patients with autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and Crohn's disease.,Here we describe the methods used to generate tolDCs ex vivo, and the common features shared by tolDCs.,In addition, we overview five completed clinical trials with reported outcomes and summarize the tolDC-based clinical trials that are currently registered with the U.S.,National Institutes of Health.,Although the number of tolDC-based clinical trials is much smaller than the hundreds of clinical trials using immunogenic DCs, tolDC-based treatment of autoimmune diseases is becoming a reality, and could serve as an innovative cellular therapy in the future.

In the midst of the COVID-19 pandemic, further understanding of its complications points towards dysregulated immune response as a major component.,Systemic lupus erythematosus (SLE) is also a disease of immune dysregulation leading to multisystem compromise.,We present a case of new-onset SLE concomitantly with COVID-19 and development of antiphospholipid antibodies.,An 18-year-old female that presented with hemodynamic collapse and respiratory failure, progressed to cardiac arrest, and had a pericardial tamponade drained.,She then progressed to severe acute respiratory distress syndrome, severe ventricular dysfunction, and worsening renal function with proteinuria and hematuria.,Further studies showed bilateral pleural effusions, positive antinuclear and antidouble-stranded DNA antibodies, lupus anticoagulant, and anticardiolipin B.,C3 and C4 levels were low.,SARS-Cov-2 PCR was positive after 2 negative tests.,She also developed multiple deep venous thrombosis, in the setting of positive antiphospholipid antibodies and lupus anticoagulant.,In terms of pathophysiology, COVID-19 is believed to cause a dysregulated cytokine response which could potentially be exacerbated by the shift in Th1 to Th2 response seen in SLE.,Also, it is well documented that viral infections are an environmental factor that contributes to the development of autoimmunity; however, COVID-19 is a new entity, and it is not known if it could trigger autoimmune conditions.,Additionally, it is possible that SARS-CoV-2, as it happens with other viruses, might lead to the formation of antiphospholipid antibodies, potentially contributing to the increased rates of thrombosis seen in COVID-19.

SLE is a chronic autoimmune disease caused by perturbations of the immune system.,The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression.,Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes.,We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure.,In this broad overview, we discuss the main pathways involved in SLE and highlight new findings.,We describe the immunological changes that characterize this form of autoimmunity.,The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE.

Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability.,The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption.,The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, small angle X-ray scattering experiments, trans-endothelial transport assays, vascular tension measurements, and subcutaneous blood flow imaging.,Niacinamide increased the rate of early insulin aspart absorption in pigs, and pharmacokinetic modelling revealed this effect to be most pronounced up to ~30-40 min after injection in humans.,Niacinamide increased the relative monomer fraction of insulin aspart by ~35%, and the apparent permeability of insulin aspart across an endothelial cell barrier by ~27%.,Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs.,Niacinamide mediates the acceleration of initial insulin aspart absorption, and the mechanism of action appears to be multifaceted.,Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration, and also mediates a transient, local vasodilatory effect.,The online version of this article (10.1007/s11095-019-2578-7) contains supplementary material, which is available to authorized users.

Ultra-fast-acting insulins, such as fast-acting insulin aspart (faster aspart), have pharmacokinetic properties that may be advantageous for patients using continuous subcutaneous insulin infusion (CSII), provided that they are compatible with and safe to use in CSII.,Randomized, double-blind, parallel-group, actively controlled trial evaluating compatibility, efficacy, and safety of faster aspart in adults with type 1 diabetes using their own MiniMed Paradigm pump with Quick-Set or Silhouette infusion sets.,Following run-in, subjects were randomized (2:1) to faster aspart (n = 25) or insulin aspart (n = 12) for 6 weeks.,Primary endpoint was the number of microscopically confirmed episodes of infusion-set occlusions.,No microscopically confirmed episodes of infusion-set occlusions were observed in either arm.,Seven possible infusion-set occlusions were reported by five subjects (all faster aspart); none were prompted by a plug observed by the subject (prompted by unexplained hyperglycemia [n = 6] or leakage [n = 1]) and none were confirmed.,Macroscopic and microscopic evaluation showed no color change or particle/crystal formation in the infusion sets.,Premature infusion-set changes were reported in 44% and 16.7% of subjects in the faster aspart and insulin aspart groups, respectively.,A nonsignificant trend toward better efficacy was observed with faster aspart (estimated treatment difference [ETD] [95% CI] in HbA1c change: -0.14% [-0.40, 0.11]).,No new safety issues were found in either treatment group.,Over 6 weeks of treatment, no microscopically confirmed infusion-set occlusions were observed for faster aspart or insulin aspart, indicating similar compatibility with CSII use.

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.

Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4).,In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls.,In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants.,Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex.,With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association.,This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) covers a wide spectrum of manifestations and is defined by the presence of MOG seropositivity.,However, in a proportion of patients, there may be an overlap in some of the clinical and radiological manifestations between MOGAD and multiple sclerosis (MS).,Being wary of this entity is critical to ensure appropriate therapy.,Herein, we present a case with recurrent episodes of short-segment myelitis typical for multiple sclerosis, but later diagnosed as MOGAD by MOG antibody seropositivity.,This case, along with previous reports, highlights an increasingly recognized subgroup in MOGAD with initial clinical phenotypes suggestive of MS, but later showing a disease course and therapeutic response compatible with MOGAD.,Given the potential overlap of some clinical phenotypes in patients with MS and those with MOGAD, we recommend MOG antibody testing in all patients with recurrent short-segment myelitis, conus medullaris involvement, and those who demonstrated steroid dependence.

Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is now recognised as a nosological entity with specific clinical and paraclinical features to aid early diagnosis.,Although no age group is exempt, median age of onset is within the fourth decade of life, with optic neuritis being the most frequent presenting phenotype.,Disease course can be either monophasic or relapsing, with subsequent relapses most commonly involving the optic nerve.,Residual disability develops in 50-80% of patients, with transverse myelitis at onset being the most significant predictor of long-term outcome.,Recent advances in MOG antibody testing offer improved sensitivity and specificity.,To avoid misdiagnosis, MOG antibody testing should be undertaken in selected cases presenting clinical and paraclinical features that are felt to be in keeping with MOG-AD, using a validated cell-based assay.,MRI characteristics can help in differentiating MOG-AD from other neuroinflammatory disorders, including multiple sclerosis and neuromyelitis optica.,Cerebrospinal fluid oligoclonal bands are uncommon.,Randomised control trials are limited, but observational open-label experience suggests a role for high-dose steroids and plasma exchange in the treatment of acute attacks, and for immunosuppressive therapies, such as steroids, oral immunosuppressants and rituximab as maintenance treatment.

We assessed meal timing, meal frequency, and breakfast consumption habits of adult individuals with type 1 diabetes (n = 1007) taking part in the Finnish Diabetic Nephropathy Study, and studied whether they are associated with glycaemic control.,Data on dietary intake and blood glucose measurements were retrieved from food records.,HbA1c was measured at the study visit.,In the whole sample, four peaks of energy intake emerged.,Energy intake was the greatest in the evening, followed by midday.,Altogether 7% of the participants reported no energy intake between 05:00 and 09:59 (breakfast skippers).,While breakfast skippers reported lower number of meals, no difference was observed in the total energy intake between those eating and omitting breakfast.,In a multivariable model, skipping breakfast was associated with higher mean blood glucose concentrations and lower odds of good glycaemic control.,A median of 6 daily meals was reported.,Adjusted for confounders, the number of meals was negatively associated with HbA1c, and the mean of the blood glucose measurements, but positively associated with the variability of these measurements.,Our observations support the habit of a regular meal pattern, including consumption of breakfast and multiple smaller meals for good glycaemic control in adults with type 1 diabetes.,However, an increase in the blood glucose variability may additionally be expected with an increase in the number of meals eaten.

In T1DM, delayed pubertal development and reduced final height are associated with inadequate metabolic control.,To assess whether T1DM affects pubertal growth spurt and whether metabolic control during puberty is gender-related.,Using a large multicentre database, longitudinal data from 1294 patients were analysed.,Inclusion criteria: complete records of height and HbA1c from the age of seven to 16 years.,Exclusion criteria: other significant chronic diseases and medications, T1DM duration less than three months, and initial BMI < 3rd or >97th percentile.,Growth velocity (GV) was impaired with a significant reduction of peak GV by 1.2 cm in boys.,HbA1c increase during male puberty was lower except for a period of 1.5 years.,The highest HbA1c increase in boys coincided with maximum growth spurt.,In girls, the highest HbA1c increase was observed during late puberty.,Even though there is impaired GV, both sexes reach a height at 16 years of age which corresponds to the background population height.,Worsening of metabolic control is sex-discordant and associated with gender-specific alterations of GV.,However, the vast majority of boys and girls with T1DM seems to reach normal height at the age of 16 years.

Microglia survey brain parenchyma, responding to injury and infections.,Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear.,Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature.,Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells.,During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function.,Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.,Although it is known that microglia respond to injury and systemic disease in the brain, it is unclear if they modulate blood-brain barrier (BBB) integrity, which is critical for regulating neuroinflammatory responses.,Here authors demonstrate that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB function

Brain inflammation plays a central role in multiple sclerosis (MS).,Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS.,Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes.,The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation.,Primary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats.,The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations.,After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent.,After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1β, IL-6 and TNF-α mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment.,Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis.,Pretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.,Collectively, these results suggest that the neuroprotective effects of DMF may be in part functionally attributable to the compound's ability to inhibit expression of multiple neuroinflammatory mediators in brain of MS patients.

Anti-carbamylated protein (anti-CarP) antibodies have been described in rheumatoid arthritis (RA) and arthralgia patients at risk of developing RA.,To what extent these autoantibodies are specific for RA is unknown.,Therefore, we investigated the diagnostic performance of the presence of anti-CarP antibodies for RA in a setting of early arthritis.,Anti-CarP antibodies were detected using carbamylated fetal calf serum as substrate.,Anti-CCP2 antibodies were measured using enzyme-linked immunosorbent assay and immunoglobulin M (IgM) rheumatoid factor (RF) as part of routine care.,Sera were derived from patients in the Leiden Early Arthritis Clinic cohort obtained at inclusion.,Test characteristics were determined using the fulfillment of the 2010 RA criteria after 1 year as outcome.,In total 2086 early arthritis patients were studied regarding the presence of anti-CarP antibodies.,We observed that the sensitivity and specificity of the presence of anti-CarP antibodies for RA were 44 % and 89 %, respectively.,As a reference, sensitivity and specificity of the presence of anti-CCP2 antibodies were 54 % and 96 %, respectively, and of IgM-RF 59 % and 91 %.,Patients harboring anti-CarP antibodies not classified as RA were mainly diagnosed with undifferentiated arthritis and less frequently reactive arthritis and psoriatic arthritis.,Anti-CarP antibodies are predominantly present in RA but can also be detected in other forms of arthritis.

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA).,The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2.,A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis.,All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs.,Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia).,The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P <0.001) and also increased significantly after disease onset (P <0.001).,The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA.,Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities.,Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P <0.05, all).,The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.,The online version of this article (doi:10.1186/s13075-015-0536-2) contains supplementary material, which is available to authorized users.

To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA).,A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay.,The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US).,RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm).,Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04).,The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors.,No association with other IL33-IL1RL1 genetic variants was observed.,In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA.

Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk.,Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction.,Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders.,In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients.,Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA.,Among them, 390 (18.2%) had experienced CV events.,The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression.,Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population.,Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively).,Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012).,Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.

Hu et al. demonstrate that the deubiquitinase Otud7b acts as a positive regulator of TCR-proximal signaling and T cell activation by deubiquitinating Zap70.,Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity.,How TCR signaling is regulated is incompletely understood.,In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling.,Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling.,Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses.,Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2.,These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions1,2 (www.T1DBase.org) revealing major pathways contributing to risk3, with some loci shared across immune disorders4-6.,In order to make genetic comparisons across autoimmune disorders as informative as possible a dense genotyping array, the ImmunoChip, was developed, from which four novel T1D regions were identified (P < 5 × 10−8).,A comparative analysis with 15 immune diseases (www.ImmunoBase.org) revealed that T1D is more similar genetically to other autoantibody-positive diseases, most significantly to juvenile idiopathic arthritis and least to ulcerative colitis, and provided support for three additional novel T1D loci.,Using a Bayesian approach, we defined credible sets for the T1D SNPs.,These T1D SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34+ stem cells.,Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

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.

To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).,Patients with moderate‐to‐severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks.,The primary end point was the SLE Responder Index (SRI4) at week 52.,Secondary end points were reduction in the corticosteroid dosage and time to severe flare.,Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.,Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment.,A total of 159 patients withdrew before the end of the study.,At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group.,More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P = 0.0006).,In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P = 0.0732), compared with placebo.,AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo.,A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.,In patients with moderate‐to‐severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

We have recently analyzed the profile of T-cell subtypes based on chemokine receptor expression in blood from untreated early rheumatoid arthritis (ueRA) patients compared to healthy controls (HC).,Here, we compared the levels of the respective chemokines in blood plasma of ueRA patients with those of HC.,We also studied the association of chemokine levels with the proportions of circulating T-cell subsets and the clinical disease activity.,Peripheral blood was obtained from 43 patients with ueRA satisfying the ACR 2010 criteria and who had not received any disease-modifying anti-rheumatic drugs (DMARD) or prednisolone, and from 14 sex- and age-matched HC.,Proportions of T helper cells in blood, including Th0, Th1, Th2, Th17, Th1Th17, TFh, and regulatory T cells, were defined by flow cytometry.,Fifteen chemokines, including several CXCL and CCL chemokines related to the T-cell subtypes as well as to other major immune cells, were measured in blood plasma using flow cytometry bead-based immunoassay or ELISA.,Clinical disease activity in patients was evaluated by assessing the following parameters: Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), swollen joint counts (SJC), tender joint counts (TJC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR).,The data were analyzed using multivariate factor analyses followed by univariate analyses.,Multivariate discriminant analysis showed that patients with ueRA were separated from HC based on the blood plasma chemokine profile.,The best discriminators were CXCL9, CXCL10, CXCL13, CCL4, and CCL22, which were significantly higher in ueRA compared to HC in univariate analyses.,Among the chemokines analyzed, only CXCL10 correlated with multiple disease activity measures, including DAS28-CRP, DAS28-ESR, CDAI, SJC in 66 joints, CRP, and ESR.,High circulating levels of CXCL10 in the plasma of ueRA patients and the association with the clinical disease activity suggests that CXCL10 may serve as a disease activity marker in early rheumatoid arthritis.,The online version of this article (doi:10.1186/s13075-017-1224-1) contains supplementary material, which is available to authorized users.

Objectives.,IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor-sST2.,The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest.,Methods.,Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients.,The levels of IL-33 and sST2 were measured by ELISA.,Results.,SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin.,Serum IL-33 was correlated positively with SF IL-33 in RA.,Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA.,Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33.,However, SFs from both RA and OA patients did not express sST2.,Conclusions.,This study supported that IL-33 played an important role in the local pathogenesis of RA.,Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment.

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.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway.,MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases.,We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients.,To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P meta = 2.74×10−8, odds ratio = 1.29 [1.18-1.40]).,The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls.,Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele.,Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant.,The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a.,We also observed additive effects of the risk alleles of miR-146a and ETS1.,Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE.,This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.

Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role.,Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated.,Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function.,Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response.,Similar BCR hyporesponsiveness was also noted specifically in SLE CD27− B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells.,Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo.,Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs).,The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40-CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs.,The hyporesponsiveness of AID B cells is similar to a form of functional anergy.

Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated.,Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations.,IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells.,While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.,Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear.,Here the authors show that a CD11chiT-bet+ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.

The performance of anti-NMDAR Encephalitis One-Year Functional Status (NEOS) in predicting the 1-year functional status in Chinese patients with anti-NMDAR encephalitis is unknown.,We recruited patients with anti-NMDAR encephalitis from the Multicenter and Prospective Clinical Registry Study of Anti-NMDAR Encephalitis in Beijing Area.,Patients were followed up for 1 year.,We defined the poor functional status as a modified Rankin Scale score of more than 2 and good functional status as a modified Rankin Scale score of no more than 2.,We performed a receiver-operator characteristic analysis to assess the discriminatory power of the NEOS score in predicting the 1-year functional status by using the area under the curve (AUC).,Calibration was assessed by Pearson correlation coefficient and Hosmer-Lemeshow tests.,Among the 111 patients with anti-NMDAR encephalitis recruited from 364 potentially eligible participants, 87 (78.4%) had good functional status at 1 year, whereas the remaining 24 (21.6%) had poor functional status.,The AUC of the NEOS score for 1-year poor functional status was 0.86 (95% CI 0.78-0.93, p < 0.001).,The increased NEOS was associated with higher risk of 1-year poor functional status in patients with anti-NMDAR encephalitis.,The NEOS score is considered a reliable predictor of the risk of 1-year poor functional status in Chinese patients with anti-NMDAR encephalitis.,This score could help to estimate the velocity of clinical improvement in advance.,NCT02443350.,This study provides Class III evidence that in patients with anti-NMDAR encephalitis, the NEOS score predicts 1-year functional status.

To provide detailed long-term outcome data of children and adolescents following pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL).,All Dutch children diagnosed with anti-NMDAR encephalitis were identified.,Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment.,The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue.,Primary outcome measures were z scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory.,Twenty-eight patients were included.,Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1-2, range 1-4), and 64% (18/28) of patients returned consistently to their previous school level.,Twenty-two patients were included in the cross-sectional part of the long-term follow-up study.,Median follow-up time was 31 months (interquartile range 15-49, range 5-91).,There were problems with sustained attention (z = −2.10, 95% confidence interval = −2.71 to −1.46, p < 0.0001) and fatigue (z = −0.96, 95% confidence interval = −1.64 to −0.28, p = 0.008).,Cognitive deficits were not correlated with QoL, while fatigue was strongly correlated with QoL (r = 0.82, p < 0.0001).,Although follow-up is often reported as “good” following pediatric anti-NMDAR encephalitis, many patients have cognitive problems and fatigue, even up until adolescence, resulting in academic achievement problems and lower QoL.,For physicians, it is essential to be aware of these problems, to provide valuable advice to patients and caregivers in the acute and follow-up phase, and to consider early neuropsychological counseling.

Juvenile idiopathic arthritis (JIA) has been categorized into seven different categories according to the International League of Associations for Rheumatology (ILAR) criteria.,Enthesitis-related arthritis (ERA) was found to represent the largest category in a Taiwanese cohort study.,The aim in this study was to compare the clinical characteristics, treatments, and outcomes of ERA in a single tertiary center in Taiwan, as compared to those of other categories of JIA.,Furthermore, we determined patients’ characteristics and risk factors that can help assess the outcomes in ERA.,A retrospective chart review of all patients with JIA referred to a pediatric rheumatology clinic in the National Taiwan University Hospital between 1993 and 2018 were identified according to ILAR criteria.,Outcomes were assessed based on the Wallace criteria to categorize patients into active and non-active, including inactive, remission on medication, and remission off medication, groups.,A subset of samples was further tested by DNA sequencing to identify HLA-B27 subtypes.,One-hundred and eighty-three patients were included in the study, with a mean of 8 years’ follow-up.,ERA was the single largest category of JIA (39.9%); psoriasis and undifferentiated JIA were both the least common type (0.5%).,ERA was male predominant (86%), had a late age of onset (11.0 ± 3.2 years), and the majority of ERA patients was HLA-B27-positive (97%).,Of 25 HLA-B27-positive ERA patients checked by HLA-B27 sequencing, 23 were B*27:04 and 2 were B*27:05.,ERA patients were significantly less likely to achieve non-active status compared to patients with persistent oligoarthritis (P = 0.036).,In terms of treatment response to TNF-α inhibitors in methotrexate-refractory ERA, 26 patients remained active and only 11 patients (30%) achieved a non-active status.,Sacroiliitis was a risk factor contributing to poorer treatment response in ERA (P = 0.006).,ERA represented the most common category of JIA in Taiwan.,Those ERA patients with sacroiliitis were likely to have persistent active disease and may require a more aggressive treatment strategy to improve their outcomes.

Epidemiological research reveals that the incidence of allergic diseases and that of autoimmune diseases have been increasing in parallel, raising an interest in a potential link between the two disorders.,However, the relationship between Th2-mediated allergic disease and Th1-mediated juvenile idiopathic arthritis (JIA) remains unclear.,This population-based case-control study was aimed at investigating the development of childhood-onset allergic diseases and the subsequent risks of JIA.,We included 329 children with JIA diagnosed between 2000 and 2008, and 1316 age- and sex-matched controls.,The odds ratios of developing JIA were calculated to determine an association with preexisting allergic diseases.,The incidence rate of JIA in Taiwan between 2000 and 2008 was 1.33 cases per 100,000 children/year according to the International League of Associations for Rheumatology (ILAR) criteria.,The children with a single allergic disease had an increased risk of JIA, with adjusted odds ratios of developing JIA of 1.44 for allergic conjunctivitis (95 % confidence interval [CI], 1.07-1.95), 1.50 for allergic rhinitis (1.15-1.96), and 1.44 for asthma (1.00-2.10).,The adjusted odds ratios increased with the number of concurrent allergic diseases from 1.50 (95 % CI, 1.12-2.01) for those with only one allergic disease to 1.72 (1.24-2.38) for those with at least two allergic diseases.,The adjusted odds ratios of those with at least two allergic diseases increased to 1.84 (95 % CI, 1.19-2.86) for boys and 2.54 (1.42-4.54) for those older than 12 years.,The children who made two or more medical visits for associated allergic diseases per year had an increased risk of JIA.,Children with onset of allergic diseases were at increased risk of developing JIA.,The increased risk was associated with the cumulative effect of concurrent allergic diseases and frequency of seeking medical care.,Further study to investigate the role of Th2-mediated allergic diseases that contribute to the development of Th1-mediated JIA is warranted.

This study compares the diagnostic performance of a second generation anti-cyclic citrullinated peptide antibody (CCP2) with a third generation anti-CCP antibodies assay (CCP3), as well as the combination of both tests.,Serum samples of 127 patients were analyzed.,IgG anti-CCP 2 and IgM rheumatoid factor were determined by EliA™ technique on a Phadia 250 instrument (Thermo Fisher Scientific), anti-CCP3 by the Quanta Flash™ anti-CCP3 IgG kit, BIO-FLASH Rapid Response Chemiluminscence Analyzer (INOVA Diagnostics).,Diagnostic performance was compared using ROC-curves, sensitivity, specificity, likelihood ratios, and predictive values.,Logistic regressions were used to investigate whether using both tests (anti-CCP2 and anti-CCP3) gives a better prediction of rheumatoid arthritis.,At the manufacturer’s cut-offs sensitivity and specificity were 79.4 and 61.0% for CCP3 and 80.9 and 69.5% for CCP2.,No significant differences could be observed regarding the areas under the curve (AUC) of both ROC-curves.,The optimal cut-off point for CCP2 was 10.5 U/ml (sensitivity of 75.0% and specificity of 80.0%) and 5.6 U/ml for CCP3 (sensitivity of 86.9% and specificity of 61.0%).,Binary logistic regressions indicated that the likelihood of having rheumatoid arthritis (RA) is significantly higher when testing positive on both CCP2 and CCP3 compared to CCP2 or CCP3 alone.,In our cohort, comparable performance was found between the two CCP assays.,Positivity for both CCP2 and CCP3 resulted in the most specific identification of RA patients.,In patients with joint complaints suspected of having RA and with a weakly positive CCP 2 (≥7 and ≤16 U/ml) CCP3 testing could be of additive value for diagnosing RA.

Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction.,We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process.,Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA.,Monoclonal ACPAs were isolated from single SF B-cells of patients with RA.,OCs were developed from blood cell precursors with or without ACPAs.,We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array.,The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures.,Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin.,Protein citrullination by PADs is essential for OC differentiation.,Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation.,Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures.,Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin.,We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation.,Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.

A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod.,We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020.,As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients.,The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women.,Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization.,At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome.,Information was not available for 114 patients.,Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial.,The mean age was 54 years (from n = 45; range 31-70), and 30 were women.,Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization.,At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome.,Information was not available for 23 patients.,Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19.,However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine.,The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-β-1 (IFN-β-1; n = 46).,The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination.,More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups.,For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-β-1 groups, and in 77% of the 14-mg group, respectively.,A high proportion of patients already had detectable antibodies for each influenza strain at baseline.,Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3).,The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains.,However, fewer patients in the 14-mg than the 7-mg or IFN-β-1 groups exhibited seroprotection to H3N2 (61% vs 78% and 82%, respectively).,Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses.,This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination.

Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain.,This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5.,Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily.,Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus).,The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change.,Analysis was by modified intention to treat.,Other thrombin generation parameters, thrombosis, and bleeding were also assessed.,Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation.,This trial is registered with the ISRCTN registry, number ISRCTN68222801.,Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed.,At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957-1233 vs 548, 484-621, treatment effect 2·0, 95% CI 1·7-2·4, p<0·0001).,Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47-66 vs 86 nmol/L, 72-102, treatment effect 0·6, 95% CI 0·5-0·8, p=0·0006).,No thrombosis or major bleeding were seen.,Serious adverse events occurred in four patients in each group.,ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism.,Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.

Objectives.,To evaluate the frequency of seizures in primary antiphospholipid syndrome (PAPS) and their possible clinical and laboratory associations.,Methods.,Eighty-eight PAPS patients (Sydney's criteria) were analyzed by a standard interview, physical examination and review of medical charts.,Risk factors for seizures, clinical manifestations, associated comorbidities, and antiphospholipid antibodies were evaluated.,Results.,Nine (10.2%) patients with seizures were identified, 77.8% had convulsions onset after PAPS diagnosis.,Mean age, gender, and race were comparable in groups with or without seizures.,Interestingly, a higher frequency of current smoking (44.4 versus 10.1%, P = 0.019) was observed in the first group.,Stroke, Sneddon's syndrome, and livedo reticularis were more frequent in PAPS patients with seizures than those without seizures, although not statistically significant (P > 0.05).,Comparison between patients with seizures onset after PAPS diagnosis (n = 7) and those without convulsions (n = 79) demonstrated a higher frequency of current smoking (42.9 versus 10%, P = 0.042) and stroke in the first group (71.4 versus 30.4%, P = 0.041).,Regression analysis confirmed that smoking (P = 0.030) and stroke (P = 0.042) were independently associated to seizures.,Conclusion.,About 10.2% of PAPS patients had convulsions, predominantly after PAPS diagnosis, and seizures were associated to current smoking and stroke.

Some patients with IgG4-related disease (IgG4-RD) exhibit elevated serum interleukin (IL)-6 with excessive inflammatory reactions or with repeating relapse.,To date few reports pertaining to clinical implications of elevated serum IL-6 in IgG4-RD patients have been published.,The aims of the current retrospective study were to investigate the clinical implications of elevated serum IL-6 in IgG4-RD patients, and to examine whether IL-6 can predict the activity and/or relapse of the disease.,We examined the clinical picture at the onset of 43 patients who were diagnosed with IgG4-RD in our hospital and were able to measure serum IL-6 before steroid treatment.,The median level of serum IL-6 was 2.2 pg/mL.,There was a significant correlation between IL-6 and C-reactive protein (CRP) level (r = 0.397, p = 0.008), hemoglobin level (r = -0.390, p = 0.010) and albumin level (r = -0.556, p < 0.001).,When 43 patients were divided into two groups by using a cut-off IL-6 of 4 pg/mL, the high IL-6 group showed higher age, lower albumin, higher CRP and higher aspartate aminotransferase (AST) (age p = 0.014, albumin p = 0.006, CRP p <0.001, AST p = 0.009).,Hepatic swelling and splenomegaly were significantly more prevalent in the high IL-6 group than it was in the low IL-6 group (liver p < 0.001, spleen p = 0.020).,Biliary tract involvement tended to admit more in the high IL-6 group (p = 0.060).,Serum IL-6 level at the onset of IgG4-RD may be significantly correlated with clinical inflammatory parameters and it may also be associated with involvement of the bile duct, liver, and spleen.

To explore the clinical patterns of patients with IgG4-related disease (IgG4-RD) based on laboratory tests and the number of organs involved.,Twenty-two baseline variables were obtained from 154 patients with IgG4-RD.,Based on principal component analysis (PCA), patients with IgG4-RD were classified into different subgroups using cluster analysis.,Additionally, IgG4-RD composite score (IgG4-RD CS) as a comprehensive score was calculated for each patient by principal component evaluation.,Multiple linear regression was used to establish the “IgG4-RD CS” prediction model for the comprehensive assessment of IgG4-RD.,To evaluate the value of the IgG4-RD CS in the assessment of disease severity, patients in different IgG4-RD CS groups and in different IgG4-RD responder index (RI) groups were compared.,PCA indicated that the 22 baseline variables of IgG4-RD patients mainly consisted of inflammation, high serum IgG4, multi-organ involvement, and allergy-related phenotypes.,Cluster analysis classified patients into three groups: cluster 1, inflammation and immunoglobulin-dominant group; cluster 2, internal organs-dominant group; and cluster 3, inflammation and immunoglobulin-low with superficial organs-dominant group.,Moreover, there were significant differences in serum and clinical characteristics among subgroups based on the CS and RI scores.,IgG4-RD CS had a similar ability to assess disease severity as RI.,The “IgG4-RD CS” prediction model was established using four independent variables including lymphocyte count, eosinophil count, IgG levels, and the total number of involved organs.,Our study indicated that newly diagnosed IgG4-RD patients could be divided into three subgroups.,We also showed that the IgG4-RD CS had the potential to be complementary to the RI score, which can help assess disease severity.

Zrzavy et al. analyse the phenotype of microglia in evolving lesions from patients with multiple sclerosis.,Microglia lose their homeostatic phenotype in active lesions and express activation markers functionally related to tissue injury.,Macrophages in the lesions are derived in part from resident microglia and in part from recruited myeloid cells.,Microglia and macrophages accumulate at the sites of active demyelination and neurodegeneration in the multiple sclerosis brain and are thought to play a central role in the disease process.,We used recently described markers to characterize the origin and functional states of microglia/macrophages in acute, relapsing and progressive multiple sclerosis.,We found microglia activation in normal white matter of controls and that the degree of activation increased with age.,This microglia activation was more pronounced in the normal-appearing white matter of patients in comparison to controls and increased with disease duration.,In contrast to controls, the normal-appearing white matter of patients with multiple sclerosis showed a significant reduction of P2RY12, a marker expressed in homeostatic microglia in rodents, which was completely lost in active and slowly expanding lesions.,Early stages of demyelination and neurodegeneration in active lesions contained microglia with a pro-inflammatory phenotype, which expressed molecules involved in phagocytosis, oxidative injury, antigen presentation and T cell co-stimulation.,In later stages, the microglia and macrophages in active lesions changed to a phenotype that was intermediate between pro- and anti-inflammatory activation.,In inactive lesions, the density of microglia/macrophages was significantly reduced and microglia in part converted to a P2RY12+ phenotype.,Analysis of TMEM119, which is expressed on microglia but not on recruited macrophages, demonstrated that on average 45% of the macrophage-like cells in active lesions were derived from the resident microglia pool.,Our study demonstrates the loss of the homeostatic microglial signature in active multiple sclerosis with restoration associated with disease inactivity.

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.

This study examined the outcomes of children with chronic immune thrombocytopenia (ITP).,We retrospectively analyzed the medical records of all patients diagnosed with ITP from January 1992 to December 2011 at our institution.,A total of 128 patients (64%) satisfied the criteria for newly diagnosed ITP, 31 (15%) for persistent ITP, and 41 (21%) for chronic ITP.,The median age at diagnosis was 4.5 years (range, 1 month to 18 years).,The median platelet count at diagnosis was 32×109/L.,A comparison of the initial treatment data from 2001 to 2011 with those from 1992 to 2000 showed that the number of bone marrow examinations decreased, whereas observation increased.,Chronic ITP presented at an older age than newly diagnosed and persistent ITP (6.6 years vs.,3.8 years vs.,4.1 years, respectively); however, the difference did not reach statistical significance (p=0.17).,The probability of complete remission of chronic ITP was 50% and 76% at 2 and 5 years after diagnosis, respectively.,Patients aged <1 year at diagnosis had a significantly better prognosis than did older patients (hazard ratio, 3.86; p=0.02).,Children with chronic ITP showed a high remission rate after long-term follow-up.,This study suggests that invasive treatments such as splenectomy in children with chronic ITP can be delayed for 4 to 5 years if thrombocytopenia and therapeutic medication do not affect the quality of life.

Treatment of chronic severe pediatric ITP is not well studied.,In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109/L, and romiplostim treatment was well tolerated.,In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109/L.,Twelve patients continued in a second extension (≤127 weeks).,Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP.,Patients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109/L, maximum dose 10 µg/kg).,Bone marrow examinations were not required.,At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109/L; 73% were male; and 36% had prior splenectomy.,Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg).,Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy.,None withdrew because of adverse events (AEs).,After the first 12 weeks, median platelet counts remained >50 × 109/L.,Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy.,Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities.,Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity.,Pediatr Blood Cancer 2015;62:208-213.,© 2014.,The Authors.,Pediatr Blood & Cancer published by Wiley Periodicals, Inc.

COVID-19 vaccination is recommended for multiple sclerosis patients.,Disease-modifying therapies can influence the safety and efficacy of COVID-19 vaccines.,RNA, DNA, protein, and inactivated vaccines are likely safe for multiple sclerosis patients.,A few incidences of central demyelination were reported with viral vector vaccines, but their benefits likely outweigh their risks if alternatives are unavailable.,Live-attenuated vaccines should be avoided whenever possible in treated patients.,Interferon-beta, glatiramer acetate, teriflunomide, fumarates, and natalizumab are not expected to impact vaccine efficacy, while cell-depleting agents (ocrelizumab, rituximab, ofatumumab, alemtuzumab, and cladribine) and sphingosine-1-phosphate modulators will likely attenuate vaccine responses.,Coordinating vaccine timing with dosing regimens for some therapies may optimize vaccine efficacy.,Unlabelled Image

The emergency represented by the COVID-19 pandemic represents a new challenge for clinicians who deal with autoimmune diseases because of patients undergoing immunosuppressive therapy.,Few cases of Multiple Sclerosis (MS) patients receiving ocrelizumab who contracted COVID-19 with a benign course have recently been published.,We present the case of a MS patient with mild COVID-19 who developed SARS-CoV-2 specific IgA without IgG ten weeks after infection.,Patients on B-cell depleting drugs have a reduced antibody immune response to viral neoantigens.,A relative sparing of mucosal-associated lymphoid tissues (MALT) could be responsible for IgA response in our patient.

Previous studies in experimental autoimmune encephalomyelitis (EAE) models have shown that some probiotic bacteria beneficially impact the development of this experimental disease.,Here, we tested the therapeutic effect of two commercial multispecies probiotics-Lactibiane iki and Vivomixx-on the clinical outcome of established EAE.,Lactibiane iki improves EAE clinical outcome in a dose-dependent manner and decreases central nervous system (CNS) demyelination and inflammation.,This clinical improvement is related to the inhibition of pro-inflammatory and the stimulation of immunoregulatory mechanisms in the periphery.,Moreover, both probiotics modulate the number and phenotype of dendritic cells (DCs).,Specifically, Lactibiane iki promotes an immature, tolerogenic phenotype of DCs that can directly induce immune tolerance in the periphery, while Vivomixx decreases the percentage of DCs expressing co-stimulatory molecules.,Finally, gut microbiome analysis reveals an altered microbiome composition related to clinical condition and disease progression.,This is the first preclinical assay that demonstrates that a commercial probiotic performs a beneficial and dose-dependent effect in EAE mice and one of the few that demonstrates a therapeutic effect once the experimental disease is established.,Because this probiotic is already available for clinical trials, further studies are being planned to explore its therapeutic potential in multiple sclerosis patients.

There is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial.,In this report, we compare functional differences and pathogenic potential of “monoclonal” T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-γ producing Th1-like and IL-17 producing Th17-like cytokine signature.,CD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35-55 in the context of I-Ab.,Adoptive transfer of Th1 cells into lymphopenic (Rag2−/−) recipients, predominantly induced “classic” paralytic EAE, whereas Th17 cells mediated “atypical” ataxic EAE in approximately 50% of the recipient animals.,Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively.,Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS.,While Th1 lesions contained IFN-γ, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-γ producing Th1-like cells.,Th1 and Th17 cells differed drastically by their lytic potential.,Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner.,In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-γ producing Th1 phenotype.,Our data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms.,We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-γ producing Th1 cells induce classical EAE.

Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed.,RA-related comorbidities affect disease control and lead to impairment in quality of life.,We aimed to develop consensus recommendations for managing RA-related comorbidities.,The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises.,The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement.,Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities.,Based on experts’ consensus, eleven recommendations were developed.,CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy.,Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously.,The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA.,The FRAX-based approach with intervention threshold is a useful strategy for managing OP.,RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity.,A treat-to-target strategy would limit RA-related comorbidities.,These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities.

Osteoporosis is a frequent comorbidity in rheumatoid arthritis (RA).,Due to the improved treatment options for RA, we expect a long-term decrease in osteoporosis as an accompanying disease.,Data from the German National Database (NDB) were used to investigate whether the frequency of osteoporosis has changed in the last 10 years.,From 2007 to 2017, approximately 4000 patients were documented annually with data on therapy and comorbidity.,The cross-sectional data were summarised descriptively.,Age, sex, disease duration, disease activity and glucocorticoids were considered as influencing factors.,The Cochrane-Armitage test for trend was used to test whether the frequency of osteoporosis at the first visit changed from 2007 to 2017.,Osteoporosis frequency in RA patients (mean age 63 years, 75% female) decreased from 20% in 2007 to 6% in 2017 (p < 0.001).,The decrease affected women (22% to 17%) and men (14% to 8%) in all age groups and both short-term (≤ 2-year disease duration: 9% to 3%) and long-term RA patients (> 10-year disease duration: 28% to 20%).,Patients with high disease activity and patients who took glucocorticoids (GC) were more often affected by osteoporosis than patients in remission or without GC.,Drug prophylaxis in patients without osteoporosis increased (20% to 41% without GC, 48% to 55% with GC).,Men with GC received less prophylactic treatment than women (48% vs. 57% in 2017).,In this cohort, osteoporosis in patients with RA is less frequently observed compared to former years.,RA-specific risk factors for osteoporosis such as disease activity and GC therapy have declined but long-term GC use is still present.,Assessment of osteoporosis in RA patients should be investigated more consistently by bone density measurement.,Male RA patients still need to be given greater consideration regarding osteoporosis drug prophylaxis, especially when GC therapy is needed.

Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS).,To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal.,Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016.,Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected.,Two-hundred and seventy-five participants were enrolled in the REALMS study.,Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients.,In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline.,More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod.,EDSS remained stable throughout the study.,Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE).,No new safety issues were reported.

To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS).,Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1.,Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP).,Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study.,Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population.,Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed.,In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients.,Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg).,Rates and types of adverse events were similar across groups; no new safety issues were reported.,Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching.,This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment.,In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid.,The primary endpoint was the area under the serum concentration-time curve from study drug infusion to infinity (AUC0-inf).,Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24.,The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208).,Three-way PD equivalence of B cell depletion was also demonstrated.,Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.,Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated.,Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.,NCT01274182; Results.

To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.,MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial.,Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks.,The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.,Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001).,Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037).,Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis).,Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab).,Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.,Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment.,The safety profiles of both therapies were consistent with anticipated class effects.,NCT02332590.

MicroRNA-21 (miR-21) is overexpressed in patients with rheumatoid arthritis (RA).,This study was designed to investigate the effect and mechanism of miR-21 on cell proliferation in fibroblast-like synoviocytes (FLS) of RA.,FLS were primary-cultured from a rat RA model.,RA-FLS and normal FLS were infected with lentivirus (anti-miR-21 or pro-miR-21) for overexpression or downregulation of miR-21, respectively.,The effects of miR-21 overexpression or inhibition on nucleoprotein NF-κB levels and FLS cell proliferation were evaluated by western blotting and MTT assays.,The effects of an inhibitor of NF-κB nuclear translocation (BAY 11-7082) were also evaluated.,The results showed that the levels of miR-21 and nucleoprotein NF-κB were increased in FLS of RA model rats compared to the control group.,Downregulation of miR-21 in RA FLS led to a significant decrease in nucleoprotein NF-κB levels and cell proliferation rates compared to the antinegative control (NC) group.,However, miR-21 overexpression in normal FLS resulted in a significant increase of nucleoprotein NF-κB levels and cell proliferation rates compared to the pro-NC group.,The effects of miR-21 overexpression were reversed by BAY 11-7082.,We concluded that upregulated miR-21 in FLS in RA model rats may promote cell proliferation by facilitating NF-κB nuclear translocation, thus affecting the NF-κB pathway.

Inflammatory cytokines play a key role in the pathogenesis of joint diseases such as rheumatoid arthritis (RA).,Current therapies target mainly tumor necrosis factor α (TNF-α) as this has proven benefits.,However, a large number of patients do not respond to or become resistant to anti-TNF-α therapy.,While the role of TNF-α in RA is quite evident, the role of TNF-β, also called lymphotoxin-α (LT-α), is unclear.,In this study we investigated whether TNF-β and its receptor play a role in chondrocytes in the inflammatory environment.,An in vitro model of primary human chondrocytes was used to study TNF-β-mediated inflammatory signaling.,Cytokine-induced inflammation enhances TNF-β and TNF-β-receptor expression in primary human chondrocytes accompanied by the up-regulation of inflammatory (cyclooxygenase-2), matrix degrading (matrix metalloproteinase-9 and -13) and apoptotic (p53, cleaved caspase-3) signaling pathways, all known to be regulated by NF-κB.,In contrast, anti-TNF-β, similar to the natural NF-κB inhibitor (curcumin, diferuloylmethane) or the knockdown of NF-κB by using antisense oligonucleotides (ASO), suppressed IL-1β-induced NF-κB activation and its translocation to the nucleus, and abolished the pro-inflammatory and apoptotic effects of IL-1β.,This highlights, at least in part, the crucial role of NF-κB in TNF-β-induced-inflammation in cartilage, similar to that expected for TNF-α.,Finally, the adhesiveness between TNF-β-expressing T-lymphocytes and the responding chondrocytes was significantly enhanced through a TNF-β-induced inflammatory microenvironment.,These results suggest for the first time that TNF-β is involved in microenvironment inflammation in chondrocytes during RA parallel to TNF-α, resulting in the up-regulation of NF-κB signaling and activation of pro-inflammatory activity.

Signals controlling the generation of regulatory B (Breg) cells remain ill-defined.,Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells.,In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement.,CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release.,In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells.,This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α.,Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation.,Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab.,We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.,•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction,pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner,Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism,pDCs are hyperactivated in SLE and fail to induce Breg cells,Patients responding to rituximab display a normalized pDC-Breg cell interaction,The signals required for Breg cell differentiation in humans are currently unknown.,Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.

Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied.,To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.,NZMSle1/2/3, MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice.,Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice.,The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice.,Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively.,As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice.,In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice.

The gut microbiota has been proposed to be an important environmental factor in the development of rheumatoid arthritis (RA).,Here, we review a growing body of evidence from human and animal studies that supports the hypothesis that intestinal microbiota play a role in RA.,Previous studies from we and others showed an altered composition of the microbiota in early RA patients.,A recent study demonstrated that Prevotella species are dominant in the intestine of patients in the preclinical stages of RA.,In addition, Prevotella-dominated microbiota isolated from RA patients contributes to the development of Th17 cell-dependent arthritis in SKG mice.,Moreover, it was reported that periodontal bacteria correlates with the pathogenesis of RA.,In this review, we discuss the link between oral bacteria and the development of arthritis.,However, many questions remain to be elucidated in terms of molecular mechanisms for the involvement of intestinal and oral microbiota in RA pathogenesis.,Microbes living in the gut and mouth have been implicated in the development of rheumatoid arthritis (RA) and treatments that promote the growth of healthier bacterial communities may help weaken this autoimmune disease.,Yuichi Maeda and Kiyoshi Takeda from Osaka University, Japan, review data from mice and humans linking RA to altered microbial compositions in the gut.,They focus on a particular bacterium called Prevotella copri, which is found at much higher numbers in the gastrointestinal tracts of people with newly diagnosed RA than in those without the disease.,Certain mouth-dwelling bacteria may also help exacerbate RA through the induction of antibodies directed against the host.,The exact molecular mechanism by which gut and oral microbes contribute to RA remains unclear.

Airway abnormalities and lung tissue citrullination are found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development.,This suggests the possibility that the lung could be a site of autoimmunity generation in RA, perhaps in response to microbiota changes.,We therefore sought to test whether the RA lung microbiome contains distinct taxonomic features associated with local and/or systemic autoimmunity.,16S rRNA gene high-throughput sequencing was utilized to compare the bacterial community composition of bronchoalveolar lavage fluid (BAL) in patients with early, disease-modifying anti-rheumatic drugs (DMARD)-naïve RA, patients with lung sarcoidosis, and healthy control subjects.,Samples were further assessed for the presence and levels of anti-citrullinated peptide antibodies (including fine specificities) in both BAL and serum.,The BAL microbiota of RA patients was significantly less diverse and abundant when compared to healthy controls, but similar to sarcoidosis patients.,This distal airway dysbiosis was attributed to the reduced presence of several genus (i.e., Actynomyces and Burkhordelia) as well as reported periodontopathic taxa, including Treponema, Prevotella, and Porphyromonas.,While multiple clades correlated with local and systemic levels of autoantibodies, the genus Pseudonocardia and various related OTUs were the only taxa overrepresented in RA BAL and correlated with higher disease activity and erosions.,Distal airway dysbiosis is present in untreated early RA and similar to that detected in sarcoidosis lung inflammation.,This community perturbation, which correlates with local and systemic autoimmune/inflammatory changes, may potentially drive initiation of RA in a proportion of cases.,The online version of this article (doi:10.1186/s40168-016-0206-x) contains supplementary material, which is available to authorized users.

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear.,Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients.,We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment.,Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells.,Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis.,This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.,COVID-19 can cause severe neurological symptoms.,By deep spatial analysis of postmortem brain tissue, Schwabenland et al. identify accumulation of distinct microglial and T cell subsets in microglial nodules and the perivasculature.,They observe neuroinflammation with axonal damage, virus-associated perivascular inflammation, and compromised blood-brain barrier.,This profound neuroinflammation highlights the need for better strategies against this COVID-19 CNS manifestation.

Neurological complications of COVID-19 have been described.,We present the case of a 27-year-old woman who developed COVID-19 in April 2020.,She continued to present anosmia and ageusia eight months later.,Six months after contracting COVID-19, she developed dysesthesia, hypoesthesia and hyperreflexia.,Her magnetic resonance imaging showed demyelinating lesions, of which two were enhanced by gadolinium.,She was positive for oligoclonal bands in her spinal fluid.,This patient developed multiple sclerosis with a temporal relationship to COVID-19.,We believe that SARS-CoV-2 led to her autoimmune disease through a virus-induced neuroimmunopathological condition.

Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited.,To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19.,Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry.,Predictors of seropositivity were identified by multivariate regression models.,In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR.,Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively).,In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p < 0.001).,Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p < 0.001).,Rate of seropositivity did not change significantly over 6 months.,Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies.,This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.

Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the progression of the autoimmune assault to neural antigens.,Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells.,Here we characterized IL-17 and IFNγ producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25highCD127low regulatory T cells in MS patients before and 1 month after treatment was started.,We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments.,In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNγ alone or in combination with IL-17.,The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent.,Finally, we observed that CD4+ CD25highCD127low regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies.,All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations.

To prospectively evaluate quantitative assessment of fluorescence optical imaging (FOI) for differentiation of synovitic from non-synovitic joints in patients suffering from rheumatoid arthritis (RA).,FOI of the hands was performed in patients with active RA, and a stratified quantitative fluorescence readout (FLRO) of 3 phases (1-120 s; 121-240 s; 241-360 s) was generated for 5 individual joints of the clinical predominant hand (carpal joint, metacarpophalangeal and proximal interphalangeal joints of digits II & III).,To dissect the effect of the overall perfusion of the hand from the perfusion due to synovitis, a fluorescence ratio (FLRA) was additionally calculated, dividing each FLRO by the readout of the eponychium of digit II.,The mean FLRO and FLRA were compared between joints with absent vs. present synovitis determined by clinical examination, grayscale, color Doppler ultrasonography, or magnetic resonance imaging (MRI).,The analysis for 90 individual joints from 18 patients yielded FLRO ranging from 4.4 to 49.0 × 103, and FLRAs ranging from 0.37 to 2.27.,Overall, the analyses based on the FLRA revealed a higher discrimination than the analyses related to the FLRO, demonstrating most significant differences in phases 2 and 3.,A sensitivity of 26/39 (67%) and a specificity of 31/40 (77%) were calculated for FLRA of phase 3 using a cut-off value of more than 1.2 to detect MRI-confirmed synovitis with FOI.,FOI has a potential for visualizing synovitis in subjects with RA.,For adequate FOI interpretation, quantitative analysis should be based on the novel FLRA calculated for phases 2 and 3.

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.

We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA).,The exact mechanism of AD in promoting joint destruction remains unclear.,Osteopontin (OPN) is required for osteoclast recruitment.,We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue.,This study aimed to evaluate a novel role for AD in RA.,The serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA).,AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue.,Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively.,Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system.,Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing.,The expression levels of OPN and integrin αvβ3 in the ankle joint tissues of the mice were examined by double immunofluorescence.,Our results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum.,The AD distribution was coincident with that of OPN in the RA synovial tissue.,AD stimulation of RASFs increased OPN production in a dose-dependent manner.,AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN.,Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice.,When bound to integrin αvβ3, OPN functions as a mediator of AD and osteoclasts.,Our study provides new evidence of AD involvement in bone erosion.,AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion.,These data highlight AD as a novel target for RA treatment.,The online version of this article (10.1186/s13075-018-1526-y) contains supplementary material, which is available to authorized users.

Despite of the European League Against Rheumatism (EULAR) provided different sets of recommendations for the management of cardiovascular risk in inflammatory arthritis patients, it must be pointed out that cardiometabolic comorbidity, such as type 2 diabetes (T2D), remains still underdiagnosed and undertreated in patients affected by rheumatoid arthritis (RA).,In this work, we designed a single centre, prospective study in order to better investigate the occurrence of T2D during the course of 1 year of follow-up.,Furthermore, we evaluated the role of both traditional cardiovascular and RA-specific related risk factors to predict the occurrence of new T2D.,In this study, we evaluated 439 consecutive RA patients and we observed that 7.1% of our patients (31/439) developed T2D, after 12 month of prospective follow-up.,The regression analysis showed that the presence of high blood pressure, the impaired fasting glucose (IFG) at the first observation and the poor EULAR-DAS28 response, after 12 months of follow-up, were significantly associated with an increased likelihood of being classified as T2D.,Similarly, we observed that 7.7% of our patients (34/439) showed IFG after 12 months of prospective follow-up.,The regression analysis showed that the presence of high blood pressure and the poor EULAR-DAS28 response after 12 months of follow-up, were significantly associated with an increased likelihood of showing IFG.,Our study supports the hypothesis of a significant short-term risk of T2D in RA patients and of a close associations between uncontrolled disease activity and glucose metabolism derangement.,Further multicentre, randomised-controlled studies are surely needed in order to elucidate these findings and to better ascertain the possible contribution of different therapeutic regimens to reduce this risk.

This study aimed to determine the frequency of residual beta cell function in individuals with long-standing type 1 diabetes who were recruited at diagnosis, and relate this to baseline and current islet autoantibody profile.,Two hour post-meal urine C-peptide:creatinine ratio (UCPCR) and islet autoantibodies were measured in samples collected from 144 participants (median age at diagnosis: 11.7 years; 47% male), a median of 23 years (range 12-29 years) after diagnosis.,UCPCR thresholds equivalent to mixed meal-stimulated serum C-peptide >0.001 nmol/l, ≥0.03 nmol/l and ≥0.2 nmol/l were used to define ‘detectable’, ‘minimal’ and ‘residual/preserved’) endogenous insulin secretion, respectively.,Autoantibodies against GAD (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) were measured by radioimmunoassay.,Endogenous C-peptide secretion was detectable in 51 participants (35.4%), including residual secretion in seven individuals (4.9%) and minimal secretion in 14 individuals (9.7%).,In the 132 samples collected more than 10 years after diagnosis, 86 participants (65.2%) had at least one islet autoantibody: 42 (31.8%) were positive for GADA, 69 (52.3%) for IA-2A and 14 of 104 tested were positive for ZnT8A (13.5%).,The level of UCPCR was related to age at diagnosis (p = 0.002) and was independent of diabetes duration, and baseline or current islet autoantibody status.,There is evidence of ongoing autoimmunity in the majority of individuals with longstanding diabetes.,Endogenous insulin secretion continues for many years after diagnosis in individuals diagnosed with autoimmune-mediated type 1 diabetes above age 5.,These findings suggest that some beta cells are protected from continued autoimmune attack in longstanding type 1 diabetes.

Mycobacterium avium subspecies paratuberculosis (MAP) has been previously associated to T1D as a putative environmental agent triggering or accelerating the disease in Sardinian and Italian populations.,Our aim was to investigate the role of MAP in T1D development by evaluating levels of antibodies directed against MAP epitopes and their human homologs corresponding to ZnT8 and proinsulin (PI) in 54 T1D at-risk children from mainland Italy and 42 healthy controls (HCs).,A higher prevalence was detected for MAP/ZnT8 pairs (62,96% T1D vs.,7,14% HCs; p < 0.0001) compared to MAP/PI epitopes (22,22% T1D vs.,9,52% HCs) and decreasing trends were observed upon time-point analyses for most peptides.,Similarly, classical ZnT8 Abs and GADA decreased in a time-dependent manner, whereas IAA titers increased by 12%.,Responses in 0-9 year-old children were stronger than in 10-18 age group (75% vs. 69,1%; p < 0.04).,Younger age, female sex and concomitant autoimmune disorders contributed to a stronger seroreactivity suggesting a possible implication of MAP in multiple autoimmune syndrome.,Cross-reactivity of the homologous epitopes was reflected by a high correlation coefficient (r2 > 0.8) and a pairwise overlap of positivity (>83% for MAP/ZnT8).

Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease.,We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters.,199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0-12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging.,Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls.,Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different.,Mitral valve lateral e’ (17.6 ± 2.6 vs.,18.6 ± 2.6 cm/s; p < 0.001) and a’ (5.4 ± 1.1 vs.,5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e’ (7.3 ± 1.2 vs.,6.7 ± 1.3; p = 0.0003) increased in T1D.,Left ventricular mid circumferential strain (−20.4 ± 2.3 vs.,−19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (−19.0 ± 1.9 vs.,−19.8 ± 1.5 % p < 0.001) in T1D.,Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening.,Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.

Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.,Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM.,We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.,The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005-2007 and to provide risk factor data.,Major CVD events and deaths were obtained from the national hospital admissions database and death register.,The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression.,The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4-3.8, p<0.001) than men (2.3: 2.0-2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2-3.0, p<0.001) in men and 2.7 (2.2-3.4, p<0.001) in women.,Between 2005-2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis.,Among individuals 60-69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control.,Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin.,Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries.,Limitations included lack of information on the specific insulin therapy used.,Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population.,Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.,Please see later in the article for the Editors' Summary,Background.,People with diabetes are more likely to have cardiovascular disease such as heart attacks and strokes.,They also have a higher risk of dying prematurely from any cause.,Controlling blood sugar (glucose), blood pressure, and cholesterol can help reduce these risks.,Some people with type 1 diabetes can achieve tight blood glucose control through a strict regimen that includes a carefully calculated diet, frequent physical activity, regular blood glucose testing several times a day, and multiple daily doses of insulin.,Other drugs can reduce blood pressure and cholesterol levels.,Keeping one's weight in the normal range and not smoking are important ways in which all people, including those with type 1 diabetes can reduce their risks of heart disease and premature death.,Why Was This Study Done?,Researchers and doctors have known for almost two decades what patients with type 1 diabetes can do to minimize the complications from the disease and thereby reduce their risks for cardiovascular disease and early death.,So for some time now, patients should have been treated and counseled accordingly.,This study was done to evaluate the current risks for have cardiovascular disease and premature death amongst people living with type 1 diabetes in a high-income country (Scotland).,What Did the Researchers Do and Find?,From a national register of all people with type 1 diabetes in Scotland, the researchers selected those who were older than 20 years and alive at any time from January 2005 to May 2008.,This included about 19,000 people who had been diagnosed with type 1 diabetes before 2005.,Another 2,600 were diagnosed between 2005 and 2008.,They also obtained data on heart attacks and strokes in these patients from hospital records and on deaths from the natural death register.,To obtain a good picture of the current relative risks, they compared the patients with type 1 diabetes with the non-diabetic general Scottish population with regard to the risk of heart attacks/strokes and death from all causes.,They also collected information on how well the people with diabetes controlled their blood glucose, on their weight, and whether they smoked.,They found that the current risks compared with the general Scottish population are quite a bit lower than those of people with type 1 diabetes in earlier decades.,However, people with type 1 diabetes in Scotland still have much higher (more than twice) the risk of heart attacks, strokes, or premature death than the general population.,Moreover, the researchers found a high number of deaths in younger people with diabetes from coma-caused by either too much blood sugar (hyperglycemia) or too little (hypoglycemia).,Severe hyperglycemia and hypoglycemia happen when blood glucose control is poor.,When the scientists looked at test results for HbA1c levels (a test that is done once or twice a year to see how well patients controlled their blood sugar over the previous 3 months) for all patients, they found that the majority of them did not come close to controlling their blood glucose within the recommended range.,When the researchers compared body mass index (a measure of weight that takes height into account) and smoking between the people with type 1 diabetes and the general population, they found similar proportions of smokers and overweight or obese people.,What Do these Findings Mean?,The results represent a snapshot of the recent situation regarding complications from type 1 diabetes in the Scottish population.,The results suggest that within this population, strategies over the past two decades to reduce complications from type 1 diabetes that cause cardiovascular disease and death are working, in principle.,However, there is much need for further improvement.,This includes the urgent need to understand why so few people with type 1 diabetes achieve good control of their blood sugar, and what can be done to improve this situation.,It is also important to put more effort into keeping people with diabetes from taking up smoking or getting them to quit, as well as preventing them from getting overweight or promoting weight reduction, because this could further reduce the risks of cardiovascular disease and premature death.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001321,National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on heart disease and diabetes, on general complications of diabetes, and on the HbA1c test (on this site and some others called A1C test) that measures control of blood sugar over the past 3 months,Diabetes.co.uk provides general information on type 1 diabetes, its complications, and what people with the disease can do to reduce their risks,The Canadian Diabetes Association offers a cardiovascular risk self-assessment tool and other relevant information,The American Diabetes Association has information on the benefits and challenges of tight blood sugar control and how it is tested,The Juvenile Diabetes Research Foundation funds research to prevent, cure, and treat type 1 diabetes,Diabetes UK provides extensive information on diabetes for patients, carers, and clinicians

Atrophy of the spinal cord is known to occur in multiple sclerosis (MS).,The mean upper cervical cord area (MUCCA) can be used to measure this atrophy.,Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking.,Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region.,First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A).,Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations.,In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions.,With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively).,Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group.,In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176).,However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001).,Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962).,Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods.,Cervical cord lesions do not affect MUCCA measurement performance.,•Mean upper cervical cord area (MUCCA) was obtained with five different methods.,•MUCCA was determined in a unique scan-rescan multi-vendor MR study.,•Reproducibility: MUCCA did not differ between scan-rescan images for any method.,•Robustness: MUCCA differed between methods and between scanners.,•Performance of MUCCA methods was not affected by the presence of lesions.,Mean upper cervical cord area (MUCCA) was obtained with five different methods.,MUCCA was determined in a unique scan-rescan multi-vendor MR study.,Reproducibility: MUCCA did not differ between scan-rescan images for any method.,Robustness: MUCCA differed between methods and between scanners.,Performance of MUCCA methods was not affected by the presence of lesions.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS).,However, its accurate measurement is hampered by various technical, pathological and physiological factors.,As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration.,In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS.,The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care.,We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS.,•Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors.,•Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed.,•Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.,Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors.,Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed.,Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of relapses and delays the progression of multiple sclerosis (MS).,Patients with lower adherence rates experience more inpatient visits and higher MS-related medical costs.,Fingolimod, the first oral DMT approved by the US Food and Drug Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs.,This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who initiated DMTs between October 2010 and February 2011.,Initiation was defined as no prescription fills for the same DMT in the prior 12 months.,Patients without a DMT prescription fill 12 months before the index date were considered naïve users.,Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR) for 12 months post-index.,Discontinuation was defined as a ≥60-day gap of index DMT supply.,Cox proportional hazard models compared time to discontinuation between cohorts.,Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b, 20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate.,Patients initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8).,The proportion of patients discontinuing index DMT within 12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%).,Adjusted results found that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users.,This association was generally stronger in experienced DMT users.,Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.

Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult.,Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients.,We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS).,BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device.,Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only).,Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device.,Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections.,Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87).,Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303).,No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed.,'Overall convenience' was the most important reported benefit of the autoinjection device.,Device features associated with handling and ease of use were highly rated.,Mean MSTCQ scores for 'flu-like' symptoms (P = 0.022) and global side effects (P = 0.002) significantly improved from Week 4-12.,Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (P < 0.001).,Adverse events were mild/moderate.,No new safety signals were identified.,Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a.,EU Clinical Trials Register (EU-CTR; http://www.clinicaltrialsregister.eu): 2009-013333-24

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved.,The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis.,We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).,Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT.,Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR.,Histological morphology was evaluated on light and electron microscopy images.,Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation.,Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e.,T-cells) in the optic nerve 11 days post immunisation.,Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema.,Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation.,Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL.,Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.,Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis.,Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms.,Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning.,These results add morphological substrate to our OCT findings.,The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.,The online version of this article (10.1186/s40478-019-0768-5) contains supplementary material, which is available to authorized users.

Background.,Little is known about physical activity and its association with volumes of whole brain gray matter and white matter and deep gray matter structures in persons with multiple sclerosis (MS).,Purpose.,This study examined the association between levels of physical activity and brain volumetric measures from magnetic resonance imaging (MRI) in MS.,Method. 39 persons with MS wore an accelerometer for a 7-day period and underwent a brain MRI.,Normalized GM volume (NGMV), normalized WM volume (NWMV), and deep GM structures were calculated from 3D T1-weighted structural brain images.,We conducted partial correlations (pr) controlling for demographic and clinical variables.,Results.,Moderate-to-vigorous physical activity (MVPA) was significantly associated with NGMV (pr = 0.370, p < 0.05), NWMV (pr = 0.433, p < 0.01), hippocampus (pr = 0.499, p < 0.01), thalamus (pr = 0.380, p < 0.05), caudate (pr = 0.539, p < 0.01), putamen (pr = 0.369, p < 0.05), and pallidum (pr = 0.498, p < 0.01) volumes, when controlling for sex, age, clinical course of MS, and Expanded Disability Status Scale score.,There were no associations between sedentary and light physical activity with MRI outcomes.,Conclusion.,Our results provide the first evidence that MVPA is associated with volumes of whole brain GM and WM and deep GM structures that are involved in motor and cognitive functions in MS.

Type 1 Diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells.,The etiology of this complex disease is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment.,Here, we provide a single-cell atlas of pancreatic islets of 24 T1D, autoantibody-positive, and non-diabetic organ donors across multiple quantitative modalities including ~80,000 cells using single-cell transcriptomics, ~7,000,000 cells using cytometry by time-of-flight, and ~1,000,000 cells using in situ imaging mass cytometry.,We develop an advanced integrative analytical strategy to assess pancreatic islets and identify canonical cell types.,We show that a subset of exocrine ductal cells acquires a signature of tolerogenic dendritic cells in an apparent attempt at immune suppression in T1D donors.,Our multimodal analyses delineate cell types and processes that may contribute to T1D immunopathogenesis and provide an integrative procedure for exploration and discovery of human pancreas function.

Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion.,With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab.,RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss.,Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D.,Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.

Vitamin D has immunomodulatory effects, and its deficiency has been implicated in the autoimmune process of type 1 diabetes.,Serum vitamin D levels are influenced by variants in genes involved in the synthesis, transport, hydroxylation and degradation of vitamin D.,The aim of this study was to assess if single nucleotide polymorphisms (SNPs) at the DHCR7 (rs12785878), GC (rs2282679), CYP2R1 (rs2060793) and CYP24A1 (rs6013897) loci are associated with type 1 diabetes in the Portuguese population.,Genotype and allele frequencies were determined in 350 cases of type 1 diabetes and in 490 controls.,The frequency of each SNP alone was not significantly different between patients and controls.,However, the combined analysis of the four SNPs showed that minor alleles of these variants clustered more frequently in patients.,The proportion of individuals with three or more minor alleles was significantly higher in patients than in controls (56.3% vs.,48.5; odds ratio (OR) 1.37; 95% confidence interval (CI) 1.04-1.81; p-value 0.027).,These results suggest a cumulative effect of SNPs at the DHCR7, GC, CYP2R1 and CYP24A1 loci on the susceptibility to type 1 diabetes, due to the roles of these genes in the vitamin D metabolic pathway.

We are aimed to systematically assess the worldwide trend in incidence of childhood type 1 diabetes mellitus (CT1DM) from 1965 to 2012 and to discuss whether climate affect incidence of CT1DM.,We searched the relevant literatures in detail to judge the effect of different climates on incidence of CT1DM.,The climates included Mediterranean, monsoon, oceanic, continental, savanna, and rainforest.,According to different climates, we further researched relevant factor such as sunshine durations and latitudes.,The overall incidence of CT1DM in 72 countries was 11.43 (95% CI 10.31-12.55) per 100,000 children/yr.,The incidence of CT1DM in Oceanic climate [10.56 (8.69-12.42)] is highest compared with other climates; the incidence in 40°-66°34′N/S [14.71 (12.30-17.29)] is higher than other latitude groups; the incidence in sunshine durations with 3-4 hours per day [15.17 (11.14-19.20)] is highest compared with other two groups; the incidence of CT1DM from 2000 to 2012 [19.58 (14.55-24.60)] is higher than other periods; all p < 0.01.,Incidence of CT1DM was increasing from 1965 to 2012, but incidence in Oceanic climate is higher than other climates.,Furthermore, it is higher in centers with higher latitude and lower sunshine durations.,The climates might play a key role in inducing CT1DM.

To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis.,We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.,At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both).,Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01).,High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: −0.78% [−1.02 to −0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605).,Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments).,Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value.,Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease.,In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter.,In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions.,In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage.,Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique.,Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions.,Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.

Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed.,Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients.,We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients.,Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose.,There were three cases of COVID-19 infection encountered after the first dose.,Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache.,No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively.,The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period.,Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs.,COVID-19 BNT162b2 vaccine proved safe for MS patients.,No increased risk of relapse activity was noted.

COVID-19 vaccination is recommended for multiple sclerosis patients.,Disease-modifying therapies can influence the safety and efficacy of COVID-19 vaccines.,RNA, DNA, protein, and inactivated vaccines are likely safe for multiple sclerosis patients.,A few incidences of central demyelination were reported with viral vector vaccines, but their benefits likely outweigh their risks if alternatives are unavailable.,Live-attenuated vaccines should be avoided whenever possible in treated patients.,Interferon-beta, glatiramer acetate, teriflunomide, fumarates, and natalizumab are not expected to impact vaccine efficacy, while cell-depleting agents (ocrelizumab, rituximab, ofatumumab, alemtuzumab, and cladribine) and sphingosine-1-phosphate modulators will likely attenuate vaccine responses.,Coordinating vaccine timing with dosing regimens for some therapies may optimize vaccine efficacy.,Unlabelled Image

Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes.,We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.,We analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS], 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS]), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers.,Disability was assessed with the Expanded Disability Status Scale (EDSS).,We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter.,Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression.,SPMS showed the lowest baseline volumes of cortical GM and DGM.,Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%.,Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01).,The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%).,Similarly, the rate of parietal GM atrophy in SPMS (-1.24‐%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05).,Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).,This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS.,The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.,Ann Neurol 2018;83:210-222

We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS).,Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics.,Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC).,We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition.,Statistical parametric mapping v.,8 (SPM8)-derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring.,MS patients had lower GMF and BPF as compared to NC (P<.05).,Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05).,BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05).,Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI-clinical associations.,We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI.,Longitudinal studies are warranted to extend these results.

Cytokines are key drivers of inflammation in RA, and anti-cytokine therapy has improved the outcome of RA.,Janus Kinases (JAK) are intracellular tyrosine kinases linked to intracellular domains of many cytokine receptors.,There are four JAK isoforms: JAK1, JAK2, JAK3 and TYK2.,Different cytokine receptor families utilize specific JAK isoforms for signal transduction.,Phosphorylation of JAK when cytokine binds to its cognate receptor leads to phosphorylation of other intracellular molecules that eventually leads to gene transcription.,Oral JAK inhibitors (JAKi) have been developed as anti-cytokine therapy in RA.,Two JAKi, tofacitinib and baricitinib, have been approved recently for the treatment of RA, and many JAKi are currently in development.,JAKi inhibit JAK isoforms with different selectivity.,This review discusses the efficacy and safety of JAKi in RA, in particular the potential clinical significance of JAKi selectivity.

Gliostatin/thymidine phosphorylase (GLS/TP) has angiogenic and arthritogenic activities, and aberrant GLS production has been observed in the active synovial membranes of rheumatoid arthritis (RA) patients.,The human GLS gene promoter contains at least seven consensus binding sites for the DNA binding protein Sp1.,Here we examined whether Sp1 is necessary for GLS production in RA.,We also studied the effects of the Sp1 inhibitor mithramycin on GLS production in RA fibroblast-like synoviocytes (FLSs).,FLSs from RA patients were treated with specific inhibitors.,The gene and protein expression of GLS were studied using the quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and an enzyme immunoassay.,Intracellular signalling pathway activation was determined by western blotting analysis, a luciferase assay, a chromatin immunoprecipitation (ChIP) assay and a small interfering RNA (siRNA) transfection.,The luciferase and ChIP assays showed that Sp1 binding sites in the GLS promoter were essential for GLS messenger RNA (mRNA) expression.,GLS production was suppressed in FLSs by siRNA against Sp1 transfection.,Mithramycin decreased GLS promoter activity, mRNA and protein expression in FLSs.,Tumour necrosis factor-α (TNF-α) significantly increased GLS expression in RA FLSs; this effect was reduced by pre-treatment with cycloheximide and mithramycin.,Pretreatment of mithramycin and Sp1 silencing resulted in a significant suppression of GLS production in TNF-α-stimulated FLSs compared to controls.,GLS gene expression enhanced by TNF-α was partly mediated through Sp1.,As physiological concentrations of mithramycin can regulate GLS production in RA, mithramycin is a promising candidate for anti-rheumatic therapy.

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

•Monoclonal anti-CD20+ antibodies are safe drugs in patients with multiple sclerosis infected with SARS-CoV-2.,•Monoclonal anti-CD20+ antibodies may have some protective effect on the development of patients infected with SARS-CoV-2.,•The presence of healthy humoral immunity may not be essential to ensure a good clinical course following SARS-CoV-2 infection.,Monoclonal anti-CD20+ antibodies are safe drugs in patients with multiple sclerosis infected with SARS-CoV-2.,Monoclonal anti-CD20+ antibodies may have some protective effect on the development of patients infected with SARS-CoV-2.,The presence of healthy humoral immunity may not be essential to ensure a good clinical course following SARS-CoV-2 infection.,In December 2019, the first cases of SARS-CoV-2 infection were detected in Wuhan.,Within two months, it had begun to spread around the world in what became an unprecedented pandemic.,Patients with Multiple Sclerosis (MS) in a state of immunosuppression may be considered at risk for complications in the COVID-19 pandemic, although there is increasing evidence postulating a possible protective role of selective immunosuppression.,One group of such immunosuppressants used in MS comprises the anti-CD20 monoclonal antibodies (mAbs) ocrelizumab and rituximab.,Anti-CD20 mAbs bind to the surface of B cells, causing their depletion.,We describe our experience in seven cases of patients with multiple sclerosis who have been affected by SARS-COV-2 (with a clinical/serological diagnosis or PCR diagnosis) and who were being treated with anti-CD20+ monoclonal antibodies.,We review the development of patients during infection as well as the resolution of their clinical picture.,We also analyze the serology status against SARS-CoV-2 after resolution of the infection.,Although the severity of the clinical pictures was variable, patients' development was good.,Not all patients, however, developed antibodies against SARS-CoV-2.,Patients treated with anti-CD20+ have adequate resolution of COVID-19 despite the fact that the presence of antibodies against SARS-CoV-2 was not detected in all cases.,It is possible that the presence of humoral immunity is not always necessary fora good clinical course of SARS-CoV-2 infection.

To gain more insight into the dynamics of lymphocyte depletion and develop new predictors of clinical response to rituximab in rheumatoid arthritis (RA).,RNA-based next-generation sequencing was used to analyse the B cell receptor (BCR) repertoire in peripheral blood and synovial tissue samples collected from 24 seropositive patients with RA treated with rituximab.,Clonal expansion, mutation load and clonal overlap were assessed in samples collected before, at week 4 and at week 16 or 24 after treatment and correlated to the patients’ clinical response.,After 4 weeks of rituximab-induced B cell depletion, the peripheral blood BCR repertoire of treated patients consisted of fewer, more dominant and more mutated BCR clones.,No significant changes in the synovial tissue BCR repertoire were detected until week 16 post-treatment, when a reduced clonal overlap with baseline and an increased mutation load were observed.,In patients who were non-responders at month 3 (n=5) using the European League Against Rheumatism response criteria, peripheral blood samples taken at week 4 after rituximab treatment showed more dominant clones compared with moderate responders (n=9) (median (IQR): 36 (27-52) vs 18 (16-26); p<0.01) and more clonal overlap with the baseline (median (IQR): 5% (2%-20%) vs 0% (0%-0%); p≤0.01).,Significant changes in BCR clonality are observed in peripheral blood of patients 4 weeks after rituximab treatment, while changes in synovial tissue were observed at later time points.,Incomplete depletion of the dominant baseline peripheral blood BCR repertoire in the first month of treatment might predict clinical non-response at 3 months.

The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research.,Different versions have been developed over the years to improve reliability and ease of use.,Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses.,As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable.,Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate).,DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas.,Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement.,The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale.,A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision.,A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.,The online version of this article (10.1007/s00296-018-4184-0) contains supplementary material, which is available to authorized users.

Increasing evidence shows miR-155 plays an important role in regulating inflammatory processes in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN).,Because the chemokine CXCL13 is implicated in the pathogenesis of LN, here we examined whether miR-155 can modulate the activity of CXCL13 or its receptor CXCR5.,We determined the expression of CXCL13 in normal and MRL/lpr mice and found elevated levels of CXCL13 in the kidneys of MRL/lpr mice compared with normal kidneys.,Besides, CXCL13 expression was mainly detected in the glomerulus, specifically to mesangial areas.,We then transfected a miR-155 mimic in human renal mesangial cells (HRMCs) to overexpress miR-155 and detected decreased protein levels of CXCR5 by western blot analysis.,Transfection of the miR-155 mimic into CXCL13-treated HRMCs resulted in a significantly reduced proliferation rate of HRMCs as measured by the cell-counting assay and flow cytometry.,Moreover, increased intracellular miR-155 also led to decreased phosphorylation of ERK and TGF-β1 production.,Together, these results revealed that miR-155 may play a role in the pathogenesis of LN.

To determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals.,FCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays.,The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics.,A low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10−4, false discovery rate-corrected P [PFDR] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68−6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10−4, PFDR = 0.0012, OR 2.82, 95% CI 1.56−5.1).,A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17−2.18).,Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17−2.18).,Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects.,The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti-double-stranded DNA antibody positivity compared with control subjects.,However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85-1.55) and clinical characteristics.,In Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.

The human microbiota is the community of microorganisms that live upon or within their human host.,The microbiota consists of various microorganisms including bacteria, fungi, viruses, and archaea; the gut microbiota is comprised mostly of bacteria.,Many bacterial species within the gut microbiome grow as biofilms, which are multicellular communities embedded in an extracellular matrix.,Studies have shown that the relative abundances of bacterial species, and therefore biofilms and bacterial byproducts, change during progression of a variety of human diseases including gastrointestinal, autoimmune, neurodegenerative, and cancer.,Studies have shown the location and proximity of the biofilms within the gastrointestinal tract might impact disease outcome.,Gram-negative enteric bacteria secrete the amyloid curli, which makes up as much as 85% of the extracellular matrix of enteric biofilms.,Curli mediates cell-cell attachment and attachment to various surfaces including extracellular matrix components such as fibronectin and laminin.,Structurally, curli is strikingly similar to pathological and immunomodulatory human amyloids such as amyloid-β, which has been implicated in Alzheimer's disease, α-synuclein, which is involved in Parkinson's disease, and serum amyloid A, which is secreted during the acute phase of inflammation.,The immune system recognizes both bacterial amyloid curli and human amyloids utilizing the same receptors, so curli also induces inflammation.,Moreover, recent work indicates that curli can participate in the self-assembly process of pathological human amyloids.,Curli is found within biofilms of commensal enteric bacteria as well as invasive pathogens; therefore, evidence suggests that curli contributes to complex human diseases.,In this review, we summarize the recent findings on how bacterial biofilms containing curli participate in the pathological and immunological processes in gastrointestinal diseases, systemic autoimmune diseases, and neurodegenerative diseases.

Multiple sclerosis (MS) is a T cell driven autoimmune disease of the central nervous system (CNS).,Despite its association with Epstein-Barr Virus (EBV), how viral infections promote MS remains unclear.,However, there is increasing evidence that the CNS is continuously surveyed by virus-specific T cells, which protect against reactivating neurotropic viruses.,Here, we discuss how viral infections could lead to the breakdown of self-tolerance in genetically predisposed individuals, and how the reactivations of viruses in the CNS could induce the recruitment of both autoaggressive and virus-specific T cell subsets, causing relapses and progressive disability.,A disturbed immune surveillance in MS would explain several experimental findings, and has important implications for prognosis and therapy.,A huge body of evidence suggests that viral infections promote MS; however, no single causal virus has been identified.,Multiple viruses could promote MS via bystander effects.,Molecular mimicry is an established pathogenic mechanism in selected autoimmune diseases.,It is also well documented in MS, but its contribution to MS pathogenesis is still unclear.,Bystander activation upon viral infection could be involved in the generation of the autoreactive and potentially encephalitogenic T helper (Th)-1/17 central memory (Th1/17CM) cells found in the circulation of patients with MS.,Autoreactive Th1/17CM cells could expand at the cost of antiviral Th1CM cells in patients with MS, in particular in those undergoing natalizumab therapy, because these cells are expected to compete for the same homeostatic niche.,Autoreactive Th1/17 cells and antiviral Th1 cells are recruited to the CSF of patients with MS following attacks, suggesting that viral reactivations in the CNS induce the recruitment of pathogenic Th1/17 cells.,Autoreactive Th1/17 cells in the CNS might also induce de novo viral reactivations in a circuit of self-induced inflammation.

The diverse roles of monocytes in SLE and RA,AbstractMonocytes are evolutionally conserved innate immune cells that play essential roles for the protection of the host against pathogens and also produce several inflammatory cytokines.,Thus, the aberrant functioning of monocytes may affect not only host defense but also the development of inflammatory diseases.,Monocytes are a heterogeneous population with phenotypical and functional differences.,Most recent studies have shown that monocytes are divided into three subsets, namely classical, intermediate and non-classical subsets, both in humans and mice.,Accumulating evidence showed that monocyte activation is associated with the disease progression in autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).,However, it remains to be determined how monocytes contribute to the disease process and which subset is involved.,In this review, we discuss the pathogenic role of monocyte subsets in SLE and RA on the basis of current studies by ourselves and others to shed light on the suitability of monocyte-targeted therapies in these diseases.

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.

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.

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens.,Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability.,Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study.,We have mapped 43 susceptibility loci, including 10 novel associations.,Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes.,Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells.,We found an over-representation (n=16) of transcription factors among SLE susceptibility genes.,This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Plasma cells (PCs) as effectors of humoral immunity produce Igs to match pathogenic insult.,Emerging data suggest more diverse roles exist for PCs as regulators of immune and inflammatory responses via secretion of factors other than Igs.,The extent to which such responses are preprogrammed in B-lineage cells or can be induced in PCs by the microenvironment is unknown.,In this study, we dissect the impact of IFNs on the regulatory networks of human PCs.,We show that core PC programs are unaffected, whereas PCs respond to IFNs with distinctive transcriptional responses.,The IFN-stimulated gene 15 (ISG15) system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion.,This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active systemic lupus erythematosus.,Thus, ISG15-secreting PCs represent a distinct proinflammatory PC subset providing an Ig-independent mechanism of PC action in human autoimmunity.

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) has revealed a crucial role for type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE).,However, it is unclear how particular leucocyte subsets contribute to the overall type I IFN signature of PBMCs and whole blood samples.Furthermore, a detailed analysis describing the differences in the IFN signature in autoimmune diseases from that observed after viral infection has not been performed to date.,Therefore, in this study, the transcriptional responses in peripheral T helper cells (CD4+) and monocyte subsets (CD16− inflammatory and CD16+ resident monocytes) isolated from patients with SLE, healthy donors (ND) immunised with the yellow fever vaccine YFV-17Dand untreated controls were compared by global gene expression profiling.It was striking that all of the transcripts that were regulated in response to viral exposure were also found to be differentially regulated in SLE, albeit with markedly lower fold-change values.,In addition to this common IFN signature, a pathogenic IFN-associated gene signature was detected in the CD4+ T cells and monocytes from the lupus patients.,IL-10, IL-9 and IL-15-mediated JAK/STAT signalling was shown to be involved in the pathological amplification of IFN responses observed in SLE.,Type I IFN signatures identified were successfully applied for the monitoring of interferon responses in PBMCs of an independent cohort of SLE patients and virus-infected individuals.,Moreover, these cell-type specific gene signatures allowed a correct classification of PBMCs independent from their heterogenic cellular composition.,In conclusion, our data show for the first time that monocytes and CD4 cells are sensitive biosensors to monitor type I interferon response signatures in autoimmunity and viral infection and how these transriptional responses are modulated in a cell- and disease-specific manner.

Interleukin 10-producing regulatory B-cells (Breg-cells) suppress autoimmune diseases while aberrant elevation of Breg-cells prevents sterilizing immunity, promotes carcinogenesis and cancer metastasis by converting resting CD4+ T-cells to regulatory T-cells (Tregs).,It is therefore of interest to discover factors that induce Breg-cells.,Here we show that IL-35 induces Breg-cells in-vivo and promotes their conversion to a unique Breg subset that produces IL-35 (IL-35+Breg).,Treatment of mice with IL-35 conferred protection from uveitis and mice lacking IL-35 or defective in IL-35-signaling produced less Breg-cells and developed severe uveitis.,Ex-vivo generated Breg-cells also suppressed uveitis by inhibiting pathogenic Th17/Th1 while promoting Tregs expansion.,We further show that IL-35 induced the conversion of human B-cells into Breg-cells and suppressed uveitis by activating STAT1/STAT3 through IL-35-Receptor comprising IL-12Rβ2/IL-27Rα subunits.,Discovery that IL-35 converts human B-cells into Breg-cells, allows ex-vivo production of autologous Breg-cells for immunotherapy and investigating Breg/IL-35+Breg cells roles in autoimmune diseases and cancer.

In Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface.,We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome.,Male NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21.,Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein.,Leukocytes from lacrimal glands were analyzed by flow-cytometry.,Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining.,The chemokine CXCL13 was measured by ELISA in sera from Sjögren's syndrome patients (n = 27) and healthy controls (n = 30).,Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores.,LTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands.,Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression.,The reduction of CXCL13, CCL21, CCL19 mRNA and the HEV-associated gene GLYCAM-1 was confirmed by PCR analysis.,CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg/mg (+/- 2.7) from 51 pg/mg (+/-5.3) in lacrimal glands of 16 week old control mice.,Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (P = 0.001), and had a significantly improved ocular surface integrity score (P = 0.005).,The mean CXCL13 concentration in sera from Sjögren's patients (n = 27) was 170 pg/ml, compared to 92.0 pg/ml for sera from (n = 30) healthy controls (P = 0.01).,Blockade of LTBR pathways may have therapeutic potential for treatment of Sjögren's syndrome.

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population.,We noted single nucleotide polymorphisms (SNPs) in the apoptotic cell engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis.,As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis.,Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models.,Genetic and cell biological studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses.,Further, neutrophils from peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis.,These data identify ‘non-canonical’ roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.

Both genetic and environmental factors are associated with susceptibility to juvenile idiopathic arthritis (JIA).,Many studies have reported that both a ‘shared epitope’ (SE) encoded by several HLA-DRB1 alleles and the peptidyl arginine deiminase type 4 (PADI4) gene polymorphisms are associated with susceptibility to rheumatoid arthritis (RA).,However, it is uncertain whether JIA and RA share the latter genetic risk factor.,Therefore, here we investigated relationships between HLA-SE and PADI4 polymorphisms with clinical subtypes of JIA.,JIA patients (39 oligoarthritis, 48 RF-positive polyarthritis, 19 RF-negative polyarthritis and 82 systemic) and 188 healthy controls were genotyped for HLA-DRB1 by PCR-sequence-specific oligonucleotide probe methodology.,Three PADI4 gene single nucleotide polymorphisms (SNPs), rs2240340, rs2240337 and rs1748033, were genotyped using TaqMan SNP Genotyping Assays.,Frequencies of the HLA-SE were higher in RF-positive polyarticular JIA than in healthy controls.,RF-positive polyarticular JIA was associated with HLA-SE (OR = 5.3, 95% CI = 2.5-11.9, pc < 0.001).,No associations were found between clinical subtypes of JIA and PADI4 allele frequency.,Nonetheless, rs2240337 in the PADI4 gene was significantly associated with anti-cyclic citrullinated peptide antibody (ACPA)-positivity in JIA.,The A allele at rs2240337 was a significant risk factor for ACPA positivity in JIA (OR = 5.6, 95% CI = 1.71-23.7 pc = 0.03).,PADI4 gene polymorphism is associated with ACPA-positivity in JIA.,The association of HLA-SE with RF-positive polyarticular JIA as well as RA is confirmed in Japanese.,Thus, HLA-SE and PADI4 status both influence JIA clinical manifestations.

Immunoglobulin (Ig) class switching is crucial for generating antibody diversity in humoral immunity and, if deregulated, also has severe pathological consequences.,How the magnitude of Ig isotype switching is controlled is still poorly understood.,Here we identify TANK-binding kinase 1 (TBK1) as a pivotal negative regulator of IgA class switching.,B cell-specific TBK1 ablation in mice resulted in uncontrolled production of IgA and development of nephropathy-like disease symptoms.,TBK1 negatively regulated IgA class switching by attenuating noncanonical NF-κB signaling, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase.,These findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and highlight a unique mechanism that controls IgA production.

Histone deacetylase 3 (HDAC3) belongs to a family of proteins which plays an important role in protein acetylation, chromatin remodeling and transcription of genes, including those that are involved in cell proliferation and cell death.,While increased expression of HDAC3 is seen in neoplastic cells, the role of HDAC3 in T cells and their role in autoimmune disease is not known.,Applying Affymetrix GeneChip Human Gene 1.0 ST Array and the mixed effects model for gene set analysis, we compared gene expression profiles between multiple sclerosis (MS) patients and healthy controls (HC).,Within the Apoptosis_GO gene set, the constitutive expression level of HDAC3 in peripheral blood mononuclear cell (PBMC) was significantly increased in MS patients when compared to controls.,Following addition of trichostatin A (TSA), an inhibitor of HDAC3, we examined the expression of p53 by flow cytometry and p53 targeted genes by real time RT-PCR in MS and HC.,Culture of PBMC with TSA resulted in increased expression of p53 in HC but not in MS patients.,TSA treated T cells from MS patients also showed reduced sensitivity to apoptosis when compared to HC, which was independent of activation of p53 targeted pro-apoptotic genes.,MS patients, when compared to controls, show an increased expression of HDAC3 and relative resistance to TSA induced apoptosis in T cells.,Increased expression of HDAC3 in PBMC of MS patients may render putative autoreactive lymphocytes resistance to apoptosis and thereby contribute to autoimmunity.

Findings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)-specific autoantibodies.,This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study.,Fifty-five individuals who were IgM rheumatoid factor positive and/or anti-citrullinated protein antibody (ACPA) positive (detected by the anti-cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study.,ACPAs were subsequently also detected using a multiplex chip-based assay.,All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up.,Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis.,Fifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6-27 months; range 1-47 months).,No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9-9.1; P = 0.088).,In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7-151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0-1.8).,These findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA.,However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical 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.

Globally, more than 12 million people have been infected with COVID −19 infection till date with more than 500,000 fatalities.,Although, Covid-19 commonly presents with marked respiratory symptoms in the form of cough and dyspnoea, a neurotropic presentation has been described of late as well.,In this brief communication we report four cases of Covid-19 who presented to our hospital with features suggestive of Guillain-Barre Syndrome (GBS).,The mechanisms by which SARS-CoV-2 causes neurologic damage are multifaceted, including direct damage to specific receptors, cytokine-related injury, secondary hypoxia, and retrograde travel along nerve fibres.,The pathogenesis of GBS secondary to Covid-19 is not well understood.,It is hypothesised that viral illnesses related GBS could be due to autoantibodies or direct neurotoxic effects of viruses.,Nervous system involvement in Covid-19 may have been grossly underestimated.,In this era of pandemic, it is very important for the physicians to be aware of association of GBS with Covid-19, as early diagnosis and treatment of this complication could have gratifying results.,To the best of our knowledge, this is the first such case series of Guillain-Barre Syndrome associated with Covid-19 to be reported from India.

Novel outbreak with coronavirus 2019 began since 31 December 2019.,Coronaviruses can cause multiple systemic infections that respiratory complications are the most obvious symptoms.,In this report, we describe the symptoms of Guillain Barre syndrome (GBS) in one infected patient with COVID-19, for the first time.,We reported a 65-years- old male patient with complaints of acute progressive symmetric ascending quadriparesis.,Two weeks prior to hospitalization, the patient suffered from cough, fever, and RT-PCR was reported positive for COVID-19 infection.,The electrodiagnostic test showed that the patient is an AMSAN variant of GBS.,COVID-19 stimulates inflammatory cells and produces various inflammatory cytokines and as a result, it creates immune-mediated processes.,GBS is an immune-mediated disorder and molecular mimicry as a mechanism of autoimmune disorder plays an important role in creating it.,It is unclear whether COVID-19 induces the production of antibodies against specific gangliosides.,Further investigations should be conducted about the mechanism of GBS in patients with COVID-19, in the future.

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs.,JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response.,The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence.,A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected.,The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed.,Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time.,Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy.,Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use.

Rheumatoid arthritis (RA) is a chronic autoimmune of an unknown etiology.,Air pollution has been proposed as one of the possible risk factors associated with disease activity, although has not been extensively studied.,In this study, we measured the relationship between exposure to air pollutants and RA activity.,Data on RA patients were extracted from the Kuwait Registry for Rheumatic Diseases (KRRD).,Disease activity was measured using disease activity score with 28 examined joints (DAS-28) and the Clinical Disease Activity Index (CDAI) during their hospital visits from 2013 to 2017.,Air pollution was assessed using air pollution components (PM10, NO2, SO2, O3, and CO).,Air pollution data were obtained from Kuwait Environmental Public Authority (K-EPA) from six different air quality-monitoring stations during the same period.,Multiple imputations by the chained equations (MICE) algorithm were applied to estimate missing air pollution data.,Patients data were linked with air pollution data according to date and patient governorate address.,Descriptive statistics, correlation analysis, and linear regression techniques were employed using STATA software.,In total, 1651 RA patients with 9875 follow-up visits were studied.,We detected an increased risk of RA using DAS-28 in participants exposed to SO2 and NO2 with β=0.003 (95% CI: 0.0004-0.005, p<0.01) and β=0.003 (95% CI: 0.002-0.005, p<0.01), respectively, but not to PM10, O3, and CO concentrations.,Conclusively, we observed a strong association between air pollution with RA disease activity.,This study suggests air pollution as a risk factor for RA and recommends further measures to be taken by the authorities to control this health problem.

Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction.,We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process.,Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA.,Monoclonal ACPAs were isolated from single SF B-cells of patients with RA.,OCs were developed from blood cell precursors with or without ACPAs.,We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array.,The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures.,Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin.,Protein citrullination by PADs is essential for OC differentiation.,Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation.,Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures.,Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin.,We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation.,Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA).,This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area.,Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback.,Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions.,The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner.,It was recommended that the prefix ‘pre-RA with:’ could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA.,An approach to dating disease onset was recommended.,In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features.,These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies.,A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.

The breast milk plays a crucial role in shaping the initial intestinal microbiota and mucosal immunity of the infant.,Interestingly, breastfeeding has proven to be protective against the early onset of immune-mediated diseases including type 1 diabetes.,Studies have shown that exosomes from human breast milk are enriched in immune-modulating miRNAs suggesting that exosomal miRNAs (exomiRs) transferred to the infant could play a critical role in the development of the infant's immune system.,We extracted exomiRs from breast milk of 52 lactating mothers (26 mothers with type 1 diabetes and 26 healthy mothers), to identify any differences in the exomiR content between the two groups.,Small RNA-sequencing was performed to identify known and novel miRNAs in both groups.,A total of 631 exomiRs were detected by small RNA sequencing including immune-related miRNAs such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR-146b, and hsa-miR-200b.,In addition, ~200 novel miRNAs were identified in both type 1 diabetes and control samples.,Among the known miRNAs, nine exomiR's were found differentially expressed in mothers with type 1 diabetes compared to healthy mothers.,The highly up-regulated miRNAs, hsa-miR-4497, and hsa-miR-3178, increased lipopolysaccharide-induced expression and secretion of tumor necrosis factor α (TNFα) in human monocytes.,The up-regulated miRNA target genes were significantly enriched for longevity-regulating pathways and FoxO signaling.,Our findings suggest a role of breast milk-derived exomiRs in modulating the infant's immune system.

To highlight pathways important for the development of autoimmune diabetes by investigating shared mechanisms of disease in polygenic and monogenic diabetes.,Genome-wide association studies have identified 57 genetic risk loci for type 1 diabetes.,Progress has been made in unravelling the mechanistic effects of some of these variants, providing key insights into the pathogenesis of type 1 diabetes.,Seven monogenic disorders have also been described where diabetes features as part of an autoimmune syndrome.,Studying these genes in relation to polygenic risk loci provides a unique opportunity to dissect pathways important for the development of immune-mediated diabetes.,Monogenic autoimmune diabetes can result from the dysregulation of multiple pathways suggesting that small effects on many immune processes are required to drive the autoimmune attack on pancreatic beta cells in polygenic type 1 diabetes.,A breakdown in central and peripheral immune tolerance is a common theme in the genetic mechanisms of both monogenic and polygenic disease which highlights the importance of these checkpoints in the development and treatment of islet autoimmunity.

Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally.,It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion.,While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease.,Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage.,The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules).,While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs.,This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

Adult-onset Still’s disease (AOSD) is a multi-systemic inflammatory disorder of unknown etiology.,To date, no single diagnostic test is available for AOSD.,Herein, we investigated the pathogenic role of microRNAs in AOSD.,MicroRNA profiles in plasma from AOSD patients and healthy controls were analyzed by microarray analysis, followed by quantitative reverse transcription PCR validation.,The biological functions of microRNAs were evaluated using in vitro cell-based assay.,Among the differentially expressed microRNAs, microRNA-134 (miR-134) expression was positively correlated with AOSD activity scores and significantly decreased after effective treatment.,An increased miR-134 level is significantly associated with the activation of Toll-like receptor 3 (TLR3).,The reporter assay identified IL-18 binding protein (IL-18BP) as the target of miR-134.,A negative correlation between miR-134 expression and IL-18BP mRNA levels were detected in peripheral blood cells following TLR3 ligand treatment.,Lower plasma IL-18BP levels and higher IL-18 levels were also observed in active AOSD patients who had higher miR-134 expression than inactive patients.,Upregulation of circulating miR-134 was associated with elevated IL-18 levels by targeting IL-18BP in AOSD patients and was positively correlated with disease activity, suggesting its involvement in AOSD pathogenesis.,MiR-134 may be a novel activity indicator or potential prognostic biomarker in AOSD.

Similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), the coronavirus disease 2019 (COVID-19) has neurological symptoms.,COVID-19 patients have such clinical symptoms as headache, vomiting, nausea, dizziness, myalgia, anosmia, ageusia, and disorder of consciousness.,These symptoms confirm that the nervous system is involved in the COVID-19 infection.,Guillain-Barré syndrome (GBS) is a heterogeneous disorder which often follows a viral infection.,According to the assessment case reports from the beginning of the COVID-19 infection so far, it is possible that GBS is linked to the COVID-19 infection.,It seems that paying attention to the neurological effects of COVID-19 is necessary.

In the midst of the COVID-19 pandemic, further understanding of its complications points towards dysregulated immune response as a major component.,Systemic lupus erythematosus (SLE) is also a disease of immune dysregulation leading to multisystem compromise.,We present a case of new-onset SLE concomitantly with COVID-19 and development of antiphospholipid antibodies.,An 18-year-old female that presented with hemodynamic collapse and respiratory failure, progressed to cardiac arrest, and had a pericardial tamponade drained.,She then progressed to severe acute respiratory distress syndrome, severe ventricular dysfunction, and worsening renal function with proteinuria and hematuria.,Further studies showed bilateral pleural effusions, positive antinuclear and antidouble-stranded DNA antibodies, lupus anticoagulant, and anticardiolipin B.,C3 and C4 levels were low.,SARS-Cov-2 PCR was positive after 2 negative tests.,She also developed multiple deep venous thrombosis, in the setting of positive antiphospholipid antibodies and lupus anticoagulant.,In terms of pathophysiology, COVID-19 is believed to cause a dysregulated cytokine response which could potentially be exacerbated by the shift in Th1 to Th2 response seen in SLE.,Also, it is well documented that viral infections are an environmental factor that contributes to the development of autoimmunity; however, COVID-19 is a new entity, and it is not known if it could trigger autoimmune conditions.,Additionally, it is possible that SARS-CoV-2, as it happens with other viruses, might lead to the formation of antiphospholipid antibodies, potentially contributing to the increased rates of thrombosis seen in COVID-19.

Osteoporosis is a frequent comorbidity in rheumatoid arthritis (RA).,Due to the improved treatment options for RA, we expect a long-term decrease in osteoporosis as an accompanying disease.,Data from the German National Database (NDB) were used to investigate whether the frequency of osteoporosis has changed in the last 10 years.,From 2007 to 2017, approximately 4000 patients were documented annually with data on therapy and comorbidity.,The cross-sectional data were summarised descriptively.,Age, sex, disease duration, disease activity and glucocorticoids were considered as influencing factors.,The Cochrane-Armitage test for trend was used to test whether the frequency of osteoporosis at the first visit changed from 2007 to 2017.,Osteoporosis frequency in RA patients (mean age 63 years, 75% female) decreased from 20% in 2007 to 6% in 2017 (p < 0.001).,The decrease affected women (22% to 17%) and men (14% to 8%) in all age groups and both short-term (≤ 2-year disease duration: 9% to 3%) and long-term RA patients (> 10-year disease duration: 28% to 20%).,Patients with high disease activity and patients who took glucocorticoids (GC) were more often affected by osteoporosis than patients in remission or without GC.,Drug prophylaxis in patients without osteoporosis increased (20% to 41% without GC, 48% to 55% with GC).,Men with GC received less prophylactic treatment than women (48% vs. 57% in 2017).,In this cohort, osteoporosis in patients with RA is less frequently observed compared to former years.,RA-specific risk factors for osteoporosis such as disease activity and GC therapy have declined but long-term GC use is still present.,Assessment of osteoporosis in RA patients should be investigated more consistently by bone density measurement.,Male RA patients still need to be given greater consideration regarding osteoporosis drug prophylaxis, especially when GC therapy is needed.

To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis.,A panel of PTMPs was developed.,Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue.,Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested.,Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis).,Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis.,The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups.,Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups.,We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been linked with the development of systemic lupus erythematosus (SLE).,Thus far, molecular mimicry has been implicated as the principal mechanism that explains this association.,In this study, we characterise a potential alternative process whereby HCMV contributes to SLE.,In a cohort of SLE patients, we show a significant association between HCMV infection and SLE through a human antibody response that targets UL44.,UL44 is an obligate nuclear-resident, non-structural viral protein vital for HCMV DNA replication.,The intracellular nature of this viral protein complicates its targeting by the humoral response - the mechanism remains unresolved.,To characterise this response, we present a thorough molecular analysis of the first human monoclonal antibody specific for UL44 derived from a HCMV seropositive donor.,This human antibody immunoprecipitates UL44 from HCMV-infected cells together with known nuclear-resident SLE autoantigens - namely, nucleolin, dsDNA and ku70.,We also show that UL44 is redistributed to the cell surface during virus-induced apoptosis as part of a complex with these autoantigens.,This phenomenon represents a potential mechanism for the bystander presentation of SLE autoantigens to the humoral arm of our immune system under circumstances that favour a break in peripheral tolerance.

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people.,Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28 null).,These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity.,However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells.,In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28 null CD4 T cells.

Several lines of evidence suggest a role for the gut microbiome in type 1 diabetes.,Treating diabetes-prone rodents with probiotics or antibiotics prevents the development of the disorder.,Diabetes-prone rodents also have a distinctly different gut microbiome compared with healthy rodents.,Recent studies in children with a high genetic risk for type 1 diabetes demonstrate significant differences in the gut microbiome between children who develop autoimmunity for the disease and those who remain healthy.,However, the differences in microbiome composition between autoimmune and healthy children are not consistent across all studies because of the strong environmental influences on microbiome composition, particularly diet and geography.,Controlling confounding factors of microbiome composition uncovers bacterial associations with disease.,For example, in a human cohort from a single Finnish city where geography is confined, a strong association between one dominant bacterial species, Bacteroides dorei, and type 1 diabetes was discovered (Davis-Richardson et al.,Front Microbiol2014;5:678).,Beyond this, recent DNA methylation analyses suggest that a thorough epigenetic analysis of the gut microbiome may be warranted.,These studies suggest a testable model whereby a diet high in fat and gluten and low in resistant starch may be the primary driver of gut dysbiosis.,This dysbiosis may cause a lack of butyrate production by gut bacteria, which, in turn, leads to the development of a permeable gut followed by autoimmunity.,The bacterial community responsible for these changes in butyrate production may vary around the world, but bacteria of the genus Bacteroides are thought to play a key role.

To determine whether delaying the introduction of gluten in infants with a genetic risk of islet autoimmunity is feasible, safe, and may reduce the risk of type 1 diabetes-associated islet autoimmunity.,A total of 150 infants with a first-degree family history of type 1 diabetes and a risk HLA genotype were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed 3 monthly until the age of 3 years and yearly thereafter for safety (for growth and autoantibodies to transglutaminase C [TGCAs]), islet autoantibodies to insulin, GAD, insulinoma-associated protein 2, and type 1 diabetes.,Adherence to the dietary-intervention protocol was reported from 70% of families.,During the first 3 years, weight and height were similar in children in the control and late-exposure groups, as was the probability of developing TGCAs (14 vs.,4%; P = 0.1).,Eleven children in the control group and 13 children in the late-exposure group developed islet autoantibodies (3-year risk: 12 vs.,13%; P = 0.6).,Seven children developed diabetes, including four in the late-exposure group.,No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children.,Delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children.

The interactions of CD4+ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases.,Recent studies of human tissues and blood samples have established a new subset of CD4+ B helper T cells named peripheral helper T (Tph) cells.,Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues.,Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells.,The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues.,However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio.,Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells.,In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.

Functionally distinct T-helper (Th) subsets orchestrate immune responses.,Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation.,Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells.,We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD.,We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD.,In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases' cleavage and ultimately to cell death.,In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death.,Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that this mechanism could explain the persistence of inflammatory IL-17-producing cells in autoimmune diseases, such as MS, where their generation is particularly substantial.

An individual patient’s response to a particular drug is influenced by multiple factors, which may include genetic predisposition.,Pharmacogenetic studies attempt to discover and estimate the contributions of genetic variants to the variability in response to a drug treatment.,The task of identifying the genetic contribution is often complicated by response phenotypes that are based on imprecise or subjective clinical observations.,Because the success of a pharmacogenetic study depends on the analysis of a heritable phenotype, it is important to identify phenotypes with a significant heritable component to ensure reliable and reproducible results in subsequent genetic association studies.,We retrospectively analyzed data collected from 436 rheumatoid arthritis patients treated with golimumab during the phase III GO-FURTHER study.,We investigated the reliability of several potential response outcomes after golimumab treatment.,Using whole-genome sequencing of the clinical trial cohort, we estimated the heritability of each potential outcome measure.,We further performed a longitudinal analysis of the clinical data to estimate variability of outcome measures over time and the degree to which each response metric could be confounded by placebo response.,We determined that the high degree of within-patient variation over time makes a single follow-up visit insufficient to assess an individual patient’s response to golimumab treatment.,We found that different potential response outcomes had varying degrees of heritability and that averaging across multiple follow-up visits yielded higher heritability estimates than single follow-up estimates.,Importantly, we found that the change in swollen and tender joint counts were the most heritable outcome metrics we tested; however, we showed that they are also more likely to be confounded by a placebo response than objective phenotypes like the change in C-reactive protein levels.,Our rigorous approach to finding robust and heritable response phenotypes could be beneficial to all pharmacogenetic studies and may lead to more reliable and reproducible results.,Clinicaltrials.gov NCT00973479.,Registered 4 September 2009.,The online version of this article (doi:10.1186/s13075-017-1299-8) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA) affects millions world-wide.,While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients.,No biomarker currently exists that identifies non-responders before treatment.,A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge).,An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies.,Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed.,Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.,Rheumatoid arthritis patients respond differently to anti-TNF treatment.,Using community-based challenge, the authors show that currently available data does not reveal meaningful genetic predictors of response to anti-TNF therapy, thus confirming clinical observations.

Microbial metabolites, produced in the intestine, have significant effects on inflammatory diseases throughout the body.,Short-chain fatty acids (SCFAs) have protective effects on experimental autoimmune encephalitis (EAE) responses but the detailed roles of SCFAs and their receptors in regulating autoimmune CNS inflammation have been unclear.,SCFAs metabolically regulate T cells and change the phenotype of antigen presenting cells to efficiently induce IL-10+ regulatory T cells.,In line with the overall protective effect, blood levels of major SCFAs, such as acetate, propionate and butyrate, are significantly decreased in long-term active progressive multiple sclerosis (MS) patients.,Importantly, SCFAs can induce CD4+ effector T cells, which are highly inflammatory when transferred into mice, suggesting that the direct effect of SCFAs on T cells can even be pro-inflammatory in the CNS.,In contrast to the moderate protective effect of SCFAs, mice deficient in GPR41 or GPR43 are more resistant to EAE pathogenesis.,Thus, despite the overall protective function of SCFAs, SCFAs and their receptors have the potential to regulate autoimmune CNS inflammation both positively and negatively.

The pathogenesis of multiple sclerosis (MS), an autoimmune disease affecting the brain and spinal cord, remains poorly understood.,Patients with MS typically present with recurrent episodes of neurological dysfunctions such as blindness, paresis, and sensory disturbances.,Studies on experimental autoimmune encephalomyelitis (EAE) animal models have led to a number of testable hypotheses including a hypothetical role of altered gut microbiota in the development of MS.,To investigate whether gut microbiota in patients with MS is altered, we compared the gut microbiota of 20 Japanese patients with relapsing-remitting (RR) MS (MS20) with that of 40 healthy Japanese subjects (HC40) and an additional 18 healthy subjects (HC18).,All the HC18 subjects repeatedly provided fecal samples over the course of months (158 samples in total).,Analysis of the bacterial 16S ribosomal RNA (rRNA) gene by using a high-throughput culture-independent pyrosequencing method provided evidence of a moderate dysbiosis in the structure of gut microbiota in patients with MS.,Furthermore, we found 21 species that showed significant differences in relative abundance between the MS20 and HC40 samples.,On comparing MS samples to the 158 longitudinal HC18 samples, the differences were found to be reproducibly significant for most of the species.,These taxa comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes.,The phylogenetic tree analysis revealed that none of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies; this suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions.,Correcting the dysbiosis and altered gut microbiota might deserve consideration as a potential strategy for the prevention and treatment of MS.

Many patients with plasma cell disorders suffer from peripheral neuropathy, but differential diagnosis with chronic inflammatory demyelinating polyneuropathy (CIDP) is difficult.,We aimed to (1) identify factors useful for differential diagnosis between peripheral neuropathy associated with plasma cell disorders versus CIDP and (2) determine whether neuropathy presentations and severity varied across the spectrum of different plasma cell disorders.,A retrospective chart review of 18 monoclonal gammopathy of unknown significance (MGUS) patients, 15 POEMS syndrome patients and 34 CIDP patients between January 2005 and December 2016 was conducted.,The peripheral neuropathy associated with plasma cell disorders seemed to be more sensory oriented compared to CIDP.,MGUS patients were significantly older than CIDP patients (median age 70 vs. 59, respectively, p = 0.027).,POEMS syndrome patients showed significantly higher platelet count at the time of neuropathy presentation compared to CIDP (p = 0.028).,Lambda type MGUS patients were associated with less severe symptoms compared to POEMS syndrome patients despite harboring lambda monoclonal gammopathy as a common denominator.,Kappa type MGUS patients showed predominantly axonal type neuropathy compared to its counterpart and POEMS syndrome.,Careful inspection of clinical profiles and symptoms of patients presenting with neuropathy can help to discriminate those with underlying plasma cell disorders.,The phenotype of neuropathy, platelet count and age at presentation seem to be the most useful indicators.

Patient: Female, 40,Final Diagnosis: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP),Symptoms: Gait disorder,Medication: -,Clinical Procedure: -,Specialty: Rheumatology,Rare disease,Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE).,We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP.,A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy.,Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait.,Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds-DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia.,Electromyography (EMG) confirmed the diagnosis of CIDP.,The patient’s neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids.,The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids.,Most patients with CIDP are treated successfully with steroids if the diagnosis is made early.,IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids.

In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor.,Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA.,We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC).,Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease.,We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs).,We found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both).,Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs.,Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581).,Our data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non-HLA genetic variants in ACPA-positive RA.

To determine the prevalence of anticitrullinated protein antibodies (ACPAs) and their association with known rheumatoid arthritis (RA) risk factors in the general population.,Lifelines is a multidisciplinary prospective population-based cohort study in the Netherlands.,Cross-sectional data from 40 136 participants were used.,The detection of ACPA was performed by measuring anti-CCP2 on the Phadia-250 analyser with levels ≥6.2 U/mL considered positive.,An extensive questionnaire was taken on demographic and clinical information, including smoking, periodontal health and early symptoms of musculoskeletal disorders.,RA was defined by a combination of self-reported RA, medication use for the indication of rheumatism and visiting a medical specialist within the last year.,Of the total 40 136 unselected individuals, 401 (1.0%) had ACPA level ≥6.2 U/mL.,ACPA positivity was significantly associated with older age, female gender, smoking, joint complaints, RA and first degree relatives with rheumatism.,Of the ACPA-positive participants, 22.4% had RA (15.2% had defined RA according to our criteria and 7.2% self-reported RA only).,In participants without RA, 311 (0.8%) were ACPA-positive.,In the non-RA group, older age, smoking and joint complaints remained significantly more frequently present in ACPA-positive compared with ACPA-negative participants.,In this large population-based study, the prevalence of ACPA levels ≥6.2 U/mL was 1.0% for the total group and 0.8% when excluding patients with RA.,Older age, smoking and joint complaints were more frequently present in ACPA-positive Lifelines participants.,To our knowledge, this study is the largest study to date on ACPA positivity in the general, mostly Caucasian population.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders.,Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43).,Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes.,Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients.,MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort.,Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.,The gut microbiome has been implicated in several autoimmune disorders.,Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.

To compare periodontal findings in systemic lupus erythematosus (SLE) patients and healthy controls, and to determine, whether there is a correlation between periodontal parameters and SLE biomarkers.,This cross-sectional study was conducted in the Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between November 2012 and February 2014.,Twenty-five participants diagnosed with SLE and 50 healthy controls were selected.,Periodontal assessment consisted of clinical attachment level (CAL), probing depth (PD), bleeding on probing, and plaque scores.,For the SLE group, several laboratory tests were obtained, such as, white blood cell count, hemoglobin level, platelet count, anti-nuclear antibody, anti-double-stranded DNA antibody, calcium level, and vitamin D.,Periodontal findings in SLE patients and controls were not significantly different.,The SLE patients who had no flare-ups for more than a year showed significant bleeding on probing and deeper PD compared with those who had flare-ups less than a year before starting the study.,The SLE patients with arthritis symptoms showed more CAL than those without arthritis.,In the SLE patients, no significant correlation was found between their periodontal findings and SLE biomarkers.,Periodontal health was not different between SLE patients and healthy controls.,In SLE patients however, flare-ups and presence of arthritis had a significant relation with periodontal health.

Background.,Oxidative stress is well documented in multiple sclerosis (MS) lesions, but its correspondence at peripheral level is still controversial.,Objective.,To evaluate peripheral oxidative stress markers in MS patients.,Methods.,We studied total blood levels of Coenzyme Q10 (CoQ10), oxidized and reduced forms of glutathione, malondialdehyde, reactive oxygen species (ROS), anti-oxidized-low-density lipoproteins (anti-oxLDL) antibodies, and antioxidant power (PAO) in 87 patients with different MS clinical phenotypes and in 77 controls.,Results.,CoQ10 was lower whereas anti-oxLDL antibodies titer was higher in MS patients than in controls.,The benign variant of MS displayed both higher CoQ10 and higher anti-oxLDL than other MS clinical variants.,Female patients had lower CoQ10 and PAO and higher ROS than male patients.,Differences were greater in younger patients with shorter disease duration.,Surprisingly, there was no difference for these markers between treated and untreated patients.,Conclusion.,We found lower antioxidant agents and higher anti-oxLDL antibodies in MS, and the highest antibody titers occurred in the benign form.,We suggest that natural anti-oxLDL antibodies can be protective against MS, saving blood brain barrier integrity.,Our findings also suggest that milder MS is associated with a distinct oxidative stress pattern, which may provide a useful biomarker of disease prognosis.

Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue.,This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.,The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education.,The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively.,Student’s t-test was used to compare MS patients and healthy controls.,Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.,In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N.,Patients with MS had higher AS (p < 0.001), FQ (p < 0.0001), and BDI-II (p < 0.0001) scores than controls.,In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.,Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS.,Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy.,However, subjective fatigue is not related with cognitive impairment.,Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.

To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.,This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX.,ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose.,Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR).,Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected.,Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups.,The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively.,All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive.,In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations.,There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients.,DAS28-ESR LDA and remission rates were higher in patients without ADA.,The rate of targeted medical events reported was low.,ADA were detected in ADL- and IFX-treated but not ETN-treated patients.,Patients without ADA generally showed numerically better clinical outcomes than those with ADA.,This study was registered on www.ClinicalTrials.gov (NCT01981473).

Rheumatoid factors are antibodies directed against the Fc region of immunoglobulin G.,First detected in patients with rheumatoid arthritis 70 years ago, they can also be found in patients with other autoimmune and nonautoimmune conditions, as well as in healthy subjects.,Rheumatoid factors form part of the workup for the differential diagnosis of arthropathies.,In clinical practice, it is recommended to measure anti-cyclic citrullinated peptide antibodies and rheumatoid factors together because anti-cyclic citrullinated peptide antibodies alone are only moderately sensitive, and the combination of the two markers improves diagnostic accuracy, especially in the case of early rheumatoid arthritis.,Furthermore, different rheumatoid factor isotypes alone or in combination can be helpful when managing rheumatoid arthritis patients, from the time of diagnosis until deciding on the choice of therapeutic strategy.

To evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) from Japan and South Korea.,In this phase III, open-label continuation study (BEL114333; NCT01597622), eligible completers of BEL113750 (NCT01345253) or BEL112341 (NCT01484496) received intravenous belimumab 10 mg/kg every 28 days for ≤7 years.,Primary endpoint was safety.,Secondary endpoints: SLE Responder Index (SRI)4 response rate, proportion of patients meeting individual SRI4 criteria, SLE flares and prednisone use.,Analyses were based on observed data from the first belimumab exposure (either in parent or current study) through to study end.,Of 142 enrolled patients who received belimumab, 73.2% completed the study.,The study population comprised patients with moderate SLE, mean (SD) Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) baseline score of 9.3 (3.9) and 98.6% receiving corticosteroids.,Most patients (97.9%) experienced adverse events (AEs); 33.8% experienced serious AEs.,Increase in SRI4 (Year 1, Week 24: 47.8%; Year 6, Week 48: 68.2%) and SELENA-SLEDAI responders suggested reductions in disease activity.,Proportions of patients with no worsening in Physician Global Assessment/no new organ damage remained stable throughout.,Severe SLE flares occurred in 14.8% of patients.,Among patients with baseline prednisone-equivalent dose >7.5 mg/day (n=81), the median (min, max) number of days anytime post-baseline that the daily dose was ≤7.5 mg/day or had been reduced by 50% from baseline was 584 (0, 2267).,Favourable safety profile and treatment responses were maintained for ≤7 years in patients with SLE from Japan and South Korea.

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.