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To describe the impact of chronic, inflammatory arthritis on parenting and to develop a conceptual framework for subsequent study of mothering. A qualitative, grounded theory design guided data collection and analysis. In-depth interviews were conducted with a purposive sample of 12 women with either rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, or systemic lupus erythematosus who were mothers of at least 1 child living at home. Transcripts were analyzed using a systematic approach of coding and forming concepts and key categories to construct an explanatory framework. Peer checking and member checking enhanced analytical rigor. Analysis of participants' experiences resulted in 4 interrelated categories describing the impact of arthritis on their role as mothers: participation in mothering tasks, best described as "sometimes I can, sometimes I can't"; different types and levels of support from others; the influence of the mother's arthritis on the family; and the challenge of balancing energy and fatigue. Individuals' arthritis story, life stage, their children's developmental stage, and daily routine described the context in which mothers experienced elements of each of the 4 main categories.

Inflammatory arthritis has a dramatic impact on the experience of motherhood, with both positive and negative influences. The perspectives shared by study participants may inform practice regarding problem identification and adaptive strategies, and the explanatory model generated from the data proposes hypotheses for further study.

To determine the preferred knee in patients with both one total and one unicompartmental knee arthroplasty. Patients simply with a unicompartmental (UKA) and total knee arthroplasty (TKA) on contralateral sides were retrospectively screened from three senior knee surgeon's logs over a 15 year period. Patients safe and free from other diseases to affect gait were approached. A total of 16 patients (mean age 70 ± 8) agreed to ground reaction force testing on an instrumented treadmill at a fair pace and incline. A gender-ratio identical group of 16 healthy control subjects (mean age 67 ± 10) and 16 patients with ipsilateral medial knee OA (mean age 66 ± 7) were analysed to compare. Radiographically the mode preoperative Kellgren-Lawrence knee grade for each side was 3. Postoperatively, the TKA side had a mean coronal femoral component alignment of 7° and a mean tibial coronal alignment of 89° with a mean posterior slope of 5° in the sagittal plane. The UKA side had a mean coronal femoral component alignment of 7° and a mean tibial coronal alignment of 86° with a mean posterior slope of 4° in the sagittal plane. In 7 patients, the TKA was the first procedure, while 6 for the UKA and 3 done simultaneously. Gait analysis demonstrated in both walking conditions the UKA limb was the preferred side through all phases of loading (p < 0.05) and nearer to normal than the TKA limb when compared to healthy controls and patients with knee OA. The greatest difference was observed between the transition of weight acceptance and midstance (p = 0.008), when 22% more load was taken by the UKA side. Retrospective comparative study, Level III.

By using a dynamic metric of an everyday activity, a distinct gait difference between differing arthroplasty types were established. A more natural loading pattern can be achieved with unicompartmentals as compared to total knees.

A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available. To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials. We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline.

In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.

Emerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one 'hit' is provided by an adverse gut microbiome that activates innate immunity; the other 'hit' is underlying joint damage. Medical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability. Histological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1β, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of

The study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of

Due to the increased availability of effective treatments, patients with systemic lupus erythematosus (SLE) now have longer survival times, and factors involved in cumulative chronic damage in SLE need to be better understood. This study was undertaken to evaluate the relationship between smoking and cumulative chronic damage in SLE patients. A cross-sectional study of SLE patients was performed to investigate the possible association between smoking exposure (ever [previous or current, active or secondhand smokers] or never) and cumulative chronic damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). A systematic review of the literature was conducted by cross-searching Medline for the terms lupus and smoking. We enrolled 105 patients with SLE (96% female), with a mean ± SD age of 40.7 ± 11.4 years and a mean followup time of 8.98 years. Of the 105 patients, 74 had an SDI score of 1-10, and 31 had an SDI score of 0. The difference between smoking exposure and no smoking exposure was significant (P = 0.02 by chi-square test in contingency table analysis), and SLE patients who were never exposed to smoking had 0.78 times the risk of progressing toward a cumulative damage status (SDI score of > 0) (95% confidence interval 0.16-0.98) throughout the followup period compared to those who were ever exposed. In the systematic review of the literature, we found only a small number of articles that addressed some aspects of the relationship between smoking exposure and cumulative damage in SLE patients.

Our findings indicate that smoking exposure is associated with cumulative chronic damage, as determined by the SDI score, in patients with SLE. Smoking exposure may have deleterious effects on lupus morbidity, and more detailed studies of this association are needed.

Synovial inflammation is one of the most characteristic events in different types of arthritis, including Osteoarthritis (OA). Emerging evidence also suggests the involvement of lipids in the regulation of inflammatory processes. The aim of this study was to elucidate the heterogeneity and spatial distribution of lipids in the OA synovial membrane and explore their putative involvement in inflammation. The abundance and distribution of lipids were examined in human synovial membranes. To this end, histological cuts from this tissue were analysed by matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI). The lipidomic profile of OA synovium was characterized and compared with healthy and other forms of inflammatory arthropathies as Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) using principal component analysis and discriminant analysis methods. Lipid identification was undertaken by tandem MS analyses and database queries. Our results reveal differential and characteristic lipidomic profiles between OA and control samples. Specifically, we unveiled that OA synovium presents elevated levels of phosphatidylcholines, fatty acids and lysophosphatidic acids and lower levels of lysophosphatidylcholines compared to control tissues. The spatial distribution of particular glycerophospholipids was also correlated with hypertrophic, inflamed or vascularized synovial areas. Compared with other inflammatory arthritis, the OA tissue showed lower amounts of phosphatidylethanolamine-based plasmalogens.

This study provides a novel insight into the lipid profiles of synovial membrane and differences in abundance between OA and control tissues. The lipidomic alterations improves understanding of the pathogenic mechanisms of OA and may be important for its diagnosis.

To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation. Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior). 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively.

Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation.

To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group.

Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.

Electrogustometry is used as a measurement of taste perception. The prevailing theory is that the anodal current delivered to the tongue mucosa stimulates the sour taste receptors, but this is not universally accepted. Our aim was to evaluate to what extent electrogustometry relates to an ability to detect sour taste--rather than sweet, salt, or bitter. We compared automated electrogustometric thresholds with visual analogue scale (VAS) ratings of various tastant solutions in 114 subjects. The whole mouth, and each side of the tongue were tested separately. VAS scores from the strongest set of solutions, and the lowest electrogustometry thresholds for each location were used for statistics. There was a significant correlation between electrogustometry threshold and the whole mouth perception of the salt taste solution. Electrogustometry correlated significantly but weakly for all taste qualities when testing was confined to left and right oral tongue. The positive predictive values of electrogustometry were no better in relation to sour taste perception than to the other taste qualities.

Our results do not support the theory that electrogustometry is mediated by sour taste receptors or even that it reflects the sour taste quality. We postulate that electrogustometry measures a function of taste perception, which is different from that induced by chemical stimuli.

Osteoarthritis (OA) pain is among the leading causes of disability worldwide in older people. Since its prevalence is growing in aging, a significant burden for society is expected. This work ascertained whether level of disability in self-reported functioning differs by pain severity and usual analgesic treatment among older OA patients in Spain. The Spanish-National-Health-Survey, a large, nationally representative, cross-sectional general health survey including 23,089 persons, was analyzed. Patients aged 65 + years with a self-reported physician OA diagnosis were classified according to severity of pain (no/mild, moderate or severe pain) and treated or untreated with analgesia. Assessment of function included basic and instrumental activities-of-daily-living (BADL, IADL), mental, social, and cognitive functions, scored on a 0% (no limitation) to 100% (complete limitation) standardized metric. Caregiver need for BADL and IADL was also recorded. A total of 3526 patients were analyzed (women 73.3%; age 77.4 [SD: 7.5]). Adjusted functioning scores showed significant association with pain severity, and for BADL, IADL and social function. Patients with severe pain and treated with analgesia had higher limitation scores, ranging on average between 31.5% on BADL, 34.1% on IADL, 45.0% on mental, 42.2% on social, and 23.4% in cognitive domain. The proportions of patients needing a caregiver for BADL (43.4%) and IADL (56.2%) were also the highest in patients with severe pain and treated with analgesia.

Regardless of usual utilization of analgesics, the severity of pain seemed to be the major determinant of functional impairment, and caregiving need, in all domains of functioning in older OA patients in Spain. Existing treatment strategies are analgesics based and do not meet patient needs for adequate pain management.

Knee osteoarthritis (OA) severity is a predictor of outcomes after arthroscopic partial meniscectomy (APM). Magnetic resonance imaging (MRI) grading of OA is predictive of postoperative outcomes; this prospective study assessed whether radiographic grading is also predictive of outcomes. Patients who underwent APM between February 2015 and January 2016, underwent radiography and MRI ≤6 months before surgery, and had outcomes from the surgery date and one year later were included. Surgical failure was defined as <10-point improvement in the Knee Osteoarthritis Outcome Score pain subscore. Radiographs were evaluated using Kellgren-Lawrence (KL) grading and continuous and ordinal minimum joint space width (mJSW) measurements; cartilage loss on MRI was evaluated using a modified Outerbridge system. Predictive abilities were estimated using area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs). The study cohort included 66 knees from 64 patients (32 women; mean age, 57.1 years; range, 45-77). Radiographic grading was not predictive of outcomes (KL, AUC = 0.541 [95% CI: 0.358, 0.724]; continuous mJSW, AUC = 0.482 [95% CI: 0.305, 0.659]; ordinal mJSW, AUC = 0.534 [95% CI: 0.433, 0.634]). Comparison of radiographs showing no joint space narrowing (KL grade 0-2) with corresponding MR images demonstrated that 48% of radiographs missed a clinically significant lesion (modified Outerbridge grade ≥ 3). MRI grading was predictive of outcomes (AUC = 0.720 [95% CI: 0.581, 0.859]).

Radiographic grading of OA is not predictive of outcomes after APM; radiographs may miss clinically significant lesions. For outcome prediction, MRI should be used.

OA (Osteoarthritis) is a predominant degenerative disease, characterized by the synovial inflammation and cartilage destruction. The pathogenic mechanisms remain mostly unknown. There is an critical require for extra investigations to discover new therapeutic targets to prevent and treat OA disease, as there are currently no effective treatments except for the joint replacement. The mRNA and protein levels of Metallothionein-1(MT-1) were quantified by qPCR and ELISA in peripheral blood mononuclear cells (PBMCs), serum and synovial cells (SCs) from erosive inflammatory OA (EIOA) and primary generalized OA (PGOA) patients. Age and sex matched healthy volunteers were recruited as healthy controls (HCs). The correlation between the MT-1 level and OA activity was assessed and the anti-inflammatory effects of MT-1 was determined in vitro. The mRNA and protein levels of MT-1 were significantly increased in the PBMCs and serum of EIOA patients compared with those of PGOA patients and HCs. Serum levels of MT-1 were positively correlated with VAS score, CRP, and ESR in OA patients. And the positive correlations were also identified between the MT-1 and IL-1β, TNF-α or IL-6 in synovial cells. Furthermore, the recombinant MT-1 protein could significantly inhibit the expression of IL-1β, TNF-α and IL-6 in PBMCs and SCs from EIOA patients in vitro.

The data had shown that the MT-1 was up-regulated in EIOA patients and positively correlated with the disease activity. The recombinant MT-1 could suppress the expression of pro-inflammatory cytokines in both PBMCs and synovial cells from EIOA patients. Therefore, the MT-1 might become a novel therapeutic target for OA treatment.

The response to treatment for juvenile idiopathic arthritis (JIA) can be staged using clinical features. However, objective laboratory biomarkers of remission are still lacking. In this study, we used machine learning to predict JIA activity from transcriptomes from peripheral blood mononuclear cells (PBMCs). We included samples from children with Native American ancestry to determine whether the model maintained validity in an ethnically heterogeneous population. Our dataset consisted of 50 samples, 23 from children in remission and 27 from children with an active disease on therapy. Nine of these samples were from children with mixed European/Native American ancestry. We used 4 different machine learning methods to create predictive models in 2 populations: the whole dataset and then the samples from children with exclusively European ancestry. In both populations, models were able to predict JIA status well, with training accuracies > 74% and testing accuracies > 78%. Performance was better in the whole dataset model. We note a high degree of overlap between genes identified in both populations. Using ingenuity pathway analysis, genes from the whole dataset associated with cell-to-cell signaling and interactions, cell morphology, organismal injury and abnormalities, and protein synthesis.

This study demonstrates it is feasible to use machine learning in conjunction with RNA sequencing of PBMCs to predict JIA stage. Thus, developing objective biomarkers from easy to obtain clinical samples remains an achievable goal.

To evaluate the effects of pulsed shortwave on osteoarthritis of the knee. A double blinded, randomised, controlled trial. Thirteen female and 14 male patients with radiographic evidence of knee osteoarthritis were randomly allocated to either low dose (10 W), or high dose (20 W) or placebo high frequency pulsed shortwave. Knee radioleucoscintigraphy was performed pre and post treatment as well as objective functional and subjective evaluations. There were no significant differences between the groups in the pre and post treatment percentage change for radioleucoscintigraphy (P > 0.05). Functional and subjective measures also revealed no pre and post treatment differences between the groups (P > 0.05), except for improved knee range of motion in the placebo group (P < 0.05).

Joint inflammation in knee osteoarthritis, measured using radioleucoscintigraphy, was not altered significantly by pulsed shortwave, therefore this therapeutic modality has little or no anti-inflammatory effect on conditions such as osteoarthritis of the knee.

Pain was analyzed in patients with fibromyalgia (FM) in a randomized, double blind, crossover study using intravenous (i.v.) administration of different drugs. In 18 patients with FM muscle pain to i.v. administration of morphine (0.3 mg/kg), lidocaine (5 mg/kg), ketamine (0.3 mg/kg), or saline was studied. Spontaneous pain intensity, muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and non-tender point areas were followed. Drug plasma concentrations and effects on physical functioning ability score (FIQ) were recorded. A personality inventory (KSP) was used to related pain response to personality traits. Thirteen patients responded to one or several of the drugs, but not to placebo. Two patients were placebo responders responding to all 4 infusions. Three were nonresponders responding to no infusions. Seven of the responders had a reduction in pain for 1-5 days. Pressure pain threshold and pain tolerance increased significantly in responders. Plasma concentrations were similar in responders and nonresponders. FIQ values improved significantly after the ketamine infusion. Responders scored higher on KSP scales for somatic anxiety, muscular tension, and psychasthenia compared with healthy controls.

FM diagnosed according to the American College of Rheumatology criteria seems to include patients with different pain processing mechanisms. A pharmacological pain analysis with subdivision into responders and nonresponders might be considered before instituting therapeutic interventions or research.

To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk.

Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

Disordered osteoclast activity has been implicated in the pathogenesis of gouty bone erosion. We sought to determine if the addition of denosumab (a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand - RANKL) to intensive urate-lowering therapy (ULT) improves gouty bone erosion. Open-label, parallel-group pilot randomized controlled trial in which 20 participants with gout with at least one confirmed conventional radiographic foot bone erosion were assigned in a 1:1 allocation to receive denosumab (60 mg subcutaneous every 6 months) added to intensive ULT (serum urate ≤5 mg/dL or 300 µmol/L at the time of randomization and continued for the duration of the study), or intensive ULT alone. The primary outcome was the change in the bilateral foot and ankle computed tomography (CT) bone erosion score from baseline to 12 months, assessed by an experienced musculoskeletal radiologist blinded to study assignment. Secondary outcomes included change in serum C-terminal telopeptide (CTX), and patient reported outcomes of pain and function. Although serum CTX declined markedly in the denosumab/ULT group compared with the ULT alone group, there was no interval change in CT erosion score in either the denosumab/ULT or ULT alone group after one year of follow-up. Other secondary outcomes did not differ between groups. There were two severe adverse events: One patient developed atrial fibrillation (on denosumab/ULT) and another atrial flutter (on ULT alone).

In this pilot study, denosumab did not offer additional benefit to intensive urate lowering therapy for gouty bone erosion.

Osteoarthritis (OA) is a common cause of disability worldwide. Knee OA care is often suboptimal. A first necessary step in quality improvement is to gain a clear insight into usual care. We developed a set of evidence-based quality indicators for multidisciplinary high-quality knee OA care. A Rand-modified Delphi method was used to develop quality indicators for knee OA diagnosis, therapy, and followup. Recommendations were extracted from international guidelines as well as existing sets of quality indicators and scored by a multidisciplinary expert panel. Based on median score, prioritization, and agreement, recommendations were labeled as having a high, uncertain, or low potential to measure quality of care and were discussed in a consensus meeting for inclusion or exclusion. Two final validation rounds yielded a core set of recommendations, which were translated into quality indicators. From a total of 86 recommendations and existing indicators, a core set of 29 recommendations was derived that allowed us to define high-quality knee OA care. From this core set, 22 recommendations were considered to be measurable in clinical practice and were transformed into a final set of 21 quality indicators regarding diagnosis, lifestyle/education/devices, therapy, and followup.

Our study provides a robust set of 21 quality indicators for high-quality knee OA care, measurable in clinical practice. These process indicators may be used to measure usual care and evaluate quality improvement interventions across the entire spectrum of disciplines involved in knee OA care.

We aimed to determine the change in hindfoot alignment after high (HTO) or low tibial osteotomy (LTO), which is commonly performed to prevent the progression of arthritis of the knee or ankle. We retrospectively reviewed the radiographic findings of patients who underwent HTO or LTO for arthritis with varus deformity of the knee or ankle joint. The hindfoot alignment view angle (HAVA), hindfoot alignment ratio (HAR), and hindfoot moment arm (HMA) were measured using the hindfoot alignment radiographs. All radiographic parameters were measured at 3, 6, and 12 months postoperatively to assess serial changes. In the HTO group, the HAVA and HMA were significantly increased at 12 months postoperatively compared to preoperatively ( P = .03 and .001, respectively). Similarly, the HAR increased from 0.23 preoperatively to 0.44 at 12 months postoperatively, which was a statistically significant change ( P = .001). In the LTO group, the 12-month postoperative HAVA, HAR, and HMA were significantly decreased ( P = .001 for each), which represented a hindfoot alignment change to the valgus position. Level III, comparative series.

After HTO, preoperative hindfoot valgus deviation was significantly decreased at 12 months and approached normal values, while the preoperative mild hindfoot varus alignment was changed to valgus deviation after LTO.

During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the extracellular matrix of the joint. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to the anomalous behavior of RA FLS. The receptor protein tyrosine phosphatase α (RPTPα), which is encoded by the PTPRA gene, is a key promoter of FAK signaling. The aim of this study was to investigate whether RPTPα mediates FLS aggressiveness and RA pathogenesis. Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assay, invasion and migration by Transwell assays, survival by annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in RPTPα-knockout (KO) mice using the K/BxN serum-transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone marrow transplantation. RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness, and responsiveness to platelet-derived growth factor, tumor necrosis factor, and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of Src on inhibitory Y(527) and decreased phosphorylation of FAK on stimulatory Y(397) . Treatment of RA FLS with an inhibitor of FAK phenocopied the knockdown of RPTPα. RPTPα-KO mice were protected from arthritis development, which was due to radioresistant cells.

By regulating the phosphorylation of Src and FAK, RPTPα mediates proinflammatory and proinvasive signaling in RA FLS, correlating with the promotion of disease in an FLS-dependent model of RA.

Finding out women's experiences diagnosed with fibromyalgia applying the Theory of Uncertainty proposed by M. Mishel. A qualitative study was conducted, using a phenomenological approach. An Association of patients in the province of Alicante during the months of June 2012 to November 2013. A total of 14 women diagnosed with fibromyalgia participated in the study as volunteers, aged between 45 and 65 years. Information generated through structured interviews with recording and transcription, prior confidentiality pledge and informed consent. Analysis content by extracting different categories according to the theory proposed. The study patients perceive a high level of uncertainty related to the difficulty to deal with symptoms, uncertainty about diagnosis and treatment complexity. Moreover, the ability of coping with the disease it is influenced by social support, relationships with health professionals and help and information attending to patient associations.

The health professional must provide clear information on the pathology to the fibromyalgia suffers, the larger lever of knowledge of the patients about their disease and the better the quality of the information provided, it is reported to be the less anxiety and uncertainty in the experience of the disease. Likewise patient associations should have health professionals in order to avoid bias in the information and advice with scientific evidence.

Child pain is associated with adverse psychosocial factors. Some studies have shown an association between children's and parental pain. Children may "learn" pain behaviour from their parents. To examine whether an association exists between parent and child pain, and, if so, whether this relationship persists after adjusting for psychosocial difficulties in the child. 1326 schoolchildren took part in a questionnaire based, cross sectional survey. Parents of study participants were sent a postal questionnaire. Occurrence of body pain was ascertained using blank body manikins and, in children, psychosocial factors were assessed using the Strengths and Difficulties Questionnaire. Three child-parent pain relationships were examined: any child pain with any parental pain or with parental widespread pain; and child low back pain with parental low back pain. The risk of child pain associated with parental reporting of pain was minor, and non-significant. Even when both parents reported widespread pain, the relative risk of pain in the child, after adjusting for age and psychosocial difficulties, was 1.2 (95% CI 0.5 to 3.2).

Parental pain is not a risk for child pain. Pain behaviour is not learned. Rather, child pain is probably attributable to individual factors and the social environment.

Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin-binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue. We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme-linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti-HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis. Synovial fluid from patients with RA contained a mean +/- SEM HGF concentration of 2.0 +/- 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 +/- 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 +/- 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 +/- 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin-1 beta induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti-HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples.

These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF-mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA-associated synovitis.

Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease of childhood, is characterised by synovitis. Clinical assessments of synovitis are imperfect, relying on composite and indirect measures of disease activity including clinician-reported measures, patient-reported measures and blood markers. Contrast-enhanced MRI is a more sensitive synovitis assessment technique but clinical utility is currently limited by availability and inter-observer variation. Improved quantitative MRI techniques may enable future development of more stringent MRI-defined remission criteria. The objective of this study was to determine the utility and feasibility of quantitative MRI measurement of synovial volume and vascularity in JIA before and twelve weeks after intra-articular glucocorticoid injection (IAGI) of the knee and to assess the acceptability of MRI to participating families. Children and young people with JIA and a new episode of knee synovitis requiring IAGI were recruited from the Great North Children's Hospital in Newcastle upon Tyne. Quantitative contrast-enhanced MRI was performed prior to and twelve weeks after IAGI, in addition to standard clinical assessment tools, including the three-variable clinical juvenile arthritis disease activity score (cJADAS) and active joint count. Eleven young people (5 male, median age 13 years, range 7-16) with JIA knee flare were recruited and 10 completed follow-up assessment. Following IAGI, the median (interquartile range) cJADAS improved from 8.5 (2.7) to 1.6 (3.9), whilst the median synovial volume improved from 38.5cm

IAGI led to a marked reduction in synovial volume, with quantitative MRI identifying more patients with an improved synovial volume than routine qualitative clinical reporting. Improvements in cJADAS scores were more variable with the patient/parent global assessment component contributing most to the scores. Further work is indicated, exploring the utility of quantitative MRI in the assessment of less accessible joints and comparing the impact of different treatment modalities.

Interferon alpha (IFN-α) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-α at sensitization protects against subsequent antigen-triggered arthritis. To understand this tolerogenic mechanism, we performed a descriptive, hypothesis-generating study of cellular and humoral responses associated with IFN-α-mediated protection against arthritis. Arthritis was evaluated at day 28 in mice given a subcutaneous injection of methylated bovine serum albumin (mBSA), together with Freund adjuvant and 0 to 5,000 U IFN-α at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-α on mBSA-specific IgG1, IgG2a, IgG2b, IgA, and IgE was evaluated by enzyme-linked immunosorbent assay (ELISA). Cytokines in circulation and in ex vivo cultures on mBSA restimulation was evaluated with ELISA and Luminex, and the identity of cytokine-producing cells by fluorescence-activated cell sorting (FACS) analysis. Administration of IFN-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4+ T cell-derived IFN-γ production, whereas IL-17 was decreased only in CD4+ T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-α on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-β) was observed in IFN-α-treated animals, combined with an increase in CD4+ T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.

Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β production, first in macrophages, and later also in CD4+ T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-β levels. This may explain why IFN-α protects against antigen-induced arthritis.

Treatment with tumour necrosis factor (TNF)-alpha inhibitors offers promising new opportunities to improve the health-related QOL of patients with rheumatoid arthritis (RA) in Denmark. As of September 2003, two such compounds -- infliximab and etanercept -- were registered for use by patients with RA. These drugs have shown the ability to reduce disease activity and to slow down or halt the development of new joint damage in otherwise treatment-resistant patients with RA. The acquisition cost of the drugs is high, with 1 year of treatment costing euros 9000-12,000 per patient. The aim of this study was to assess the potential impact on the Danish healthcare budget of prescribing infliximab or etanercept to patients with RA. Two treatment implementation scenarios were investigated. In the progressive scenario, all patients newly diagnosed with RA were offered TNFalpha inhibitors as the drug of first choice. In the modest scenario, only patients with insufficient disease suppression by conventional therapy with disease-modifying anti-rheumatic drugs (DMARDs) were offered TNFalpha inhibitor therapy. The budget impact analysis, which was part of a Danish health technology assessment of TNFalpha inhibitors, focused on the number of patients offered treatment during a 5-year period and resource use related to drug and staff costs. Simple sensitivity analyses assessed the consequences of changing the drug dosage, the number of patients offered treatment and the rate of treatment cessation. The results suggested that both implementation strategies would impose additional costs per year on the Danish healthcare service, in the range of euros 67-188 million for the progressive scenario and euros 17-49 million for the modest scenario (price level August 2002). These costs represent between half and up to five times the amount currently used on treating patients with RA.

This analysis suggests that the introduction of TNFalpha inhibitors into the treatment regimen of patients with RA could pose a considerable financial burden on the Danish healthcare system.

To determine the efficacy of the synergistic use of High Power Laser Therapy (HPLT) with glucosamine sulfate (GS) in knee osteoarthritis. This 2-arm randomized controlled trial (RCT) enrolled 90 subjects (M=53, F=37, y= 55±11.2) and randomly allocated using a stratified sampling method in experimental group (A) with HPLT+GS 1500mg (GS - Dona®, Rottapharm, Monza, Italy) (n=45) or in a control group (B) with HPLT + placebo (n=45).  Results: VAS score in Activities of day Living (ADL), Standardized stair climb test (SSCT), Zohlen's sign (RASPING) and Rabot test were used, to evaluate patients at the beginning of the study (T0), at 2 months (T1) and at 6 months (T2). In the mean scores for VAS in ADL, SSCT, RABOT and RASPING at T1, no significant differences were found between the experimental and the control group with paired T and ANOVA test. But significant differences between groups (p<0.05) in all outcomes were observed at 6 months (T2).

HPLT is useful in treating knee osteoarthritis, but when combined with Glucosamine Sulfate, thanks to the synergy of two interventions, can achieve a long-term effect up to 6 months after treatment.

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined. Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months. One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up. The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).

Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.

To investigate the possible relationships between plasma homocysteine levels and thrombotic events in a select population of rheumatoid arthritis (RA) patients with or without antiphospholipid (aPL) antibody positivity. 168 female RA patients attending the Extra-articular Involvement RA Clinic of University of Genova and 72 female subjects matched for age and vascular diseases as controls were included in the study. 30 of the RA patients showed aPL antibody positivity and 138 aPL antibody negativity on the basis of the concomitant presence or absence of high concentrations of anticardiolipin (aCL) antibodies or the presence of lupus anticoagulant (LA). All subjects were evaluated for plasma homocysteine concentrations and for the occurrence of thrombotic events. Twenty-five RA patients and 5 controls reported a history of thrombotic events. Eleven and 5 of RA patients were found to have been previously affected by venous or arterial thrombosis, respectively. Plasma levels of homocysteine in aPL antibody positive patients with thrombosis were found to be significantly higher than in aPL antibody positive RA patients without thrombosis (p < 0.001). When RA patients with thromboses were analyzed, a significant increase of plasma homocysteine levels was found in aPL antibody-positive RA patients versus aPL antibody-negative RA patients (p < 0.04) and versus related controls (p < 0.003).

The association observed between aPL antibody positivity and high levels of plasma homocysteine in RA patients may represent a possible risk factor for thrombotic events. Therefore, it is suggested that hyperhomocysteinemia might be involved in the vascular-related mortality observed in RA patients with a history of thrombosis.

Gout is caused by the accumulation of deposited monosodium urate (MSU) crystals in the joints. Recent studies have shown that interleukin-1β (IL-1β) is a key inflammatory mediator of acute gouty arthritis (AGA), and its level is regulated by microRNAs (miRNAs). The purpose of this study was to study the role of miR-221-5p in the pathogenesis of AGA. One hundred patients with AGA and 94 healthy individuals were recruited. The expression of serum miR-221-5p was determined by quantitative real-time polymerase chain reaction. The receiver operating curve (ROC) was applied for diagnostic value analysis. A luciferase reporter assay was performed to confirm the interaction of miRNA and the 3'-untranslated region (UTR) of IL-1β. Enzyme-linked immunosorbent assay was used to detect serum and proinflammatory factors. miR-221-5p had lower expression in the serum of AGA patients. The area under the curve was 0.884, the sensitivity was 82.0%, and the specificity was 80.9%. Serum miR-221-5p was negatively correlated with the expression levels of visual analog scale and IL-1β. Cell experiments showed that overexpression of miR-221-5p significantly inhibited the expression of inflammatory factors tumor necrosis factor-α, IL-8, and IL-1β, while down-regulation of miR-221-5p was the opposite. Luciferase analysis showed that IL-1β was the target gene of miR-221-5p.

This study confirmed that miR-221-5p regulates the production of inflammatory cytokines during the pathogenesis of AGA. These results suggested that miR-221-5p could be used as a potential therapeutic target for the treatment of AGA.

Mapuche, Chilean natives, represent approximately 9.8% of Chilean population and in the IX region of the country, they account for 18.4% of population over 15 years old. They preserve some socio-cultural characteristics that make them different to the rest of the population. To describe the epidemiological characteristics rheumatoid arthritis among Mapuche natives. Retrospective review of patients of Mapuche origin with rheumatoid arthritis, seen at Temuco Hospital between 1980 and 1996. Among 308 cases gathered, only 106 (93 women, aged 55 +/- 10 years old) complied with 1987 American College of Rheumatology (ACR) criteria for rheumatoid arthritis. The disease began between 29 and 52 years old in 73% of patients and the mean delay in diagnosis was 4.4 years. At diagnosis, 99% had symmetric poliarthritis, 28.3% had either fatigue, fever or weight loss, and 46.9% were in class III or in class IV of ACR-1991. Fifty three percent of patients developed Sicca syndrome, 36% developed nodules, 23% developed Raynaud phenomenon, 11% developed pulmonary involvement, 7% developed vasculitis, 5% developed neurological manifestations and 19% developed ophthalmologic involvement. Rheumatoid factor was positive in 78% and 73% had erosions. HLA DR4 was (+) in 60% of 30 patients. Thirty percent required 3 or more disease modifying drugs and prednisone over 10 mg/day. There was no correlation between functional capacity and several other features of the disease.

Mapuche rheumatoid arthritis patients are detected late and have a poor functional capacity at the time of diagnosis. They also have a higher proportion of extraarticular manifestations, more erosions and require more aggressive treatments.

To identify systemic comorbidities in patients with dry eye syndrome in South Korea. From 2010 to 2012, 17,364 participants aged 20 or older were randomly included in the nationwide Korean National Health and Nutrition Examination Survey V. The prevalence of dry eye syndrome and demographics of these patients were investigated. We performed conditional logistic regression analyses based on age, sex, residential area, education level, occupation type, and household income level to obtain the odds ratio for each systemic comorbidity among subjects with and without dry eye syndrome. The prevalence of dry eye syndrome in this study was 10.4%. Age [adjusted odds ratio (AOR): 1.02], female gender (AOR: 3.01), and indoor occupation (AOR: 1.30) were associated with a higher prevalence of dry eye syndrome and found to be less prevalent in those residing in rural areas (AOR: 0.73) and with lower education levels (AOR: 0.66-0.99). With regard to systemic comorbidities, dyslipidemia (AOR: 1.63), degenerative arthritis (AOR: 1.56), rheumatoid arthritis (AOR: 1.44), thyroid disease (AOR: 1.79), and renal failure (AOR: 2.56) were associated with a significantly higher prevalence of dry eye syndrome.

We found that patients with dry eye syndrome have a higher prevalence of several systemic comorbidities. A more comprehensive therapeutic approach considering the effect of systemic medication may be necessary in these patients.

Because in vitro studies have shown that nimesulide not only preferentially inhibits COX-2 but also reduces the action/release of pro-inflammatory cytokines, down-regulates the synthesis and/or activity of collagenase(s), and releases reactive oxygen species and other toxic substances from neutrophils, this study investigated whether nimesulide and ibuprofen could affect levels of biochemical markers of joint inflammation and collagen catabolism in patients with flare-up of knee or hip osteoarthritis. Ninety patients were included in this randomised, prospective, single- blind study. They received either nimesulide (n = 45) or ibuprofen (n = 45) for a 4-week treatment period. The following parameters were analysed by ELISA: urinary levels of C-terminal cross-linking telopeptide of type II collagen (CTX-II), a marker of type II collagen breakdown; serum levels of hyaluronan (HA), a marker of synovial inflammation and hyperplasia; and circulating levels of stromelysin-1 (matrix metalloproteinase-3 [MMP-3]), collagenase-1 (MMP-1) and collagenase-3 (MMP-13). Statistical analysis used was ANOVA. At the end of the treatment period, nimesulide but not ibuprofen markedly reduced the urinary levels of CTX-II (p < 0.001) and the serum levels of HA (p < 0.05), two markers known to prognosticate poor outcome of the osteoarthritis disease process. Nimesulide also reduced the serum levels of both MMP-3 (p < 0.05) and MMP-13 (p < 0.001). Furthermore, in the nimesulide group, the decrease in levels of CTX-II correlated significantly with the decrease in levels of HA and MMP-13.

Although nonsteroidal anti-inflammatory drugs are effective in improving pain and disability in OA patients, to date it has been unclear to what extent these drugs could affect joint metabolism and hence joint structure. Patients with flare-up of their osteoarthritis disease process exhibit enhanced levels of markers of joint inflammation and cartilage collagen breakdown, which were markedly decreased by nimesulide but not by ibuprofen.

Hyperphosphatasaemia has been observed occasionally in patients with rheumatoid arthritis (RA), and it has been suggested that the serum alkaline phosphatase (ALP) level is related to the activity of the disease. Therefore, the relationship between serum ALP and RA was studied. The serum activities of hepatobiliary enzymes (ALP isoenzymes, gamma-glutamyltranspeptidase (GTP), leucine aminopeptidase (LAP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT)), immunoglobulins, RA haemagglutinin test (RAHA), C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were observed in 288 patients with rheumatoid arthritis. Serum biliary ALP (ALP1) activity was detected in 31.6% of the patients. In patients positive for ALP1 the respective values of total ALP (ALPt) (p < 0.001), liver ALP (ALP2) (p < 0.001), bone ALP (ALP3) (p < 0.05), gamma-GTP (p < 0.001), LAP (p < 0.001), immunoglobulins IgG (p < 0.01), IgA (p < 0.01), and IgM (p < 0.01), RAHA (p < 0.001), CRP (p < 0.001), ESR (p < 0.001), and articular index (p < 0.001) were significantly higher than in patients who did not have ALP1. Significant Spearman's rank correlations (rs) were demonstrated between serum ALP2 level and the respective values of ALPt (rs = 0.9128, p < 0.001), ALP1 (rs = 0.4443, p < 0.001), ALP3 (rs = 0.5898, p < 0.001), gamma-GTP (rs = 0.2903, p < 0.001), LAP (rs = 0.3093, p < 0.001), IgA (rs = 0.2299, p < 0.01), IgM (rs = 0.1773, p < 0.05), RAHA (rs = 0.2420, p < 0.01), CRP (rs = 0.3532, p < 0.001), ESR (rs = 0.4006, p < 0.001). the articular index (rs = 0.4006, p < 0.001). However, no significant difference or correlation was noted for either AST or ALT. In many patients who showed abnormal hyperphosphatasaemia, hepatobiliary enzyme dissociation was observed: levels of ALPt (in 12.8%), ALP1 (in 31.6%), ALP2 (18.8%), gamma-GTP (in 4.3%), and LAP (in 19.3%) were abnormally high, but both AST and ALT were within normal limits.

These findings are considered to be characteristic of RA, and suggest the existence of latent or subclinical hepatobiliary involvement and an association between the expansion of hepatobiliary involvement and the mechanism of disease activation. Thus measurement of the serum levels of ALP and its isoenzymes in RA is considered to be important.

To summarize the clinical features, electrophysiological and neuropathological characteristics of peripheral nerves in patients with primary Sjögren's syndrome (SS). We retrospectively analyzed the clinical, electrophysiological and neuropathological characteristics of 5 female SS patients with neuropathy complications undergoing electrophysiology and sural nerve biopsy at our department from January 2011 to June 2013. They had an age range of 20-75 years. The course of peripheral neuropathy ranged 0.5-60 months and the whole course 12-240 months. pSS-associated neuropathy included multiple mononeuropathy (n = 1), symmetrical axonal sensorimotor polyneuropathy (n = 1) and sensory ganglioneuronopathy (n = 3). All biopsies showed varying degrees of myelinated fiber loss. Three biopsies had axonal degeneration associated with demyelination. However, there was no formation of onion bulb regeneration or plexus. Necrotizing vasculitis was diagnosed in 2 cases.

The manifestations of peripheral nerve n pSS include multiple mononeuropathy, axonal symmetric sensorimotor polyneuropathy and sensory gangioneuronopathy. Sural biopsy shows typical necrotizing vasculitis in some cases and myelinated fiber loss and axonal degeneration in others. The pathogenic mechanisms of neurological involvement in pSS remain unknown. However, vasculitis, ischemic and immunological insults resulting in sensory gangioneuronopathy have been described.

Fibromyalgia (FM) is a chronic, centralized pain condition characterized by alterations in the functional, chemical, and structural brain networks responsible for sensory and mood processing. Transcranial direct current stimulation (tDCS) has emerged as a potential treatment for FM. tDCS can alter functional connectivity (FC) in brain regions underneath and distant to the stimulating electrode, although the analgesic mechanisms of repetitive tDCS remain unknown. The aim of this study was to investigate how a clinically relevant schedule of tDCS sessions alters resting state FC and how these changes might relate to clinical pain. Resting state functional magnetic resonance imaging data were collected from 12 patients with FM at baseline, after 5 days of sham treatment, and after 5 days of real tDCS with the anode over the left primary motor cortex (M1) and the cathode over the right supraorbital cortex. Seed to whole-brain FC analyses were performed with seed regions placed in bilateral M1, primary somatosensory cortices (S1), ventral lateral (VL) and ventral posterolateral (VPL) thalami, and periaqueductal gray (PAG). Stronger baseline FC between M1-VL thalamus, S1-anterior insula, and VL thalamus-PAG predicted greater analgesia after sham and real tDCS. Sham treatment (compared with baseline) reduced FC between the VPL thalamus, S1, and the amygdala. Real tDCS (compared with sham treatment) reduced FC between the VL thalamus, medial prefrontal, and supplementary motor cortices. Interestingly, decreased FC between the VL/VPL thalamus and posterior insula, M1, and S1 correlated with reductions in clinical pain after both sham and active treatments.

These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in FC that last beyond the stimulation period and may produce analgesia by altering thalamic connectivity.

Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases that share common risk factors. However, the bidirectional relationship between RA and periodontal disease is not fully understood. This study was undertaken to describe the bacterial component of the subgingival microbiome in RA patients and to relate this to RA disease activity and periodontal status. Patients with chronic established RA (N = 78) were periodontally examined and their subgingival plaque samples were collected; their clinical and laboratory data on RA status and medication were obtained from medical records. Bacterial DNA was quantified by universal 16S rDNA qPCR, and Porphyromonas gingivalis by species-specific qPCR. For microbiome assessment, 16S rDNA amplicon sequencing was performed. Active RA was diagnosed in 58% of the patients and periodontitis in 82% (mild: 9%, moderate: 55%, severe: 18%). P. gingivalis was present in 14% of the samples. Different levels of gingival bleeding, periodontal probing depth, RA disease status, prednisolone use and smoking were associated with significantly different microbiome compositions. Two subgingival microbial community types were discerned.

In RA patients with active disease, anti-inflammatory medication as part of RA therapy was associated with better oral health status and a healthier subgingival microbiome compared to that of RA patients in remission, especially those in remission who were current smokers. RA patients in remission with current smoking status may particularly benefit from a systematic periodontal treatment program. The potential role of microbial community types in patient stratification and personalized therapy should be assessed in longitudinal studies.

The purpose of this preliminary study was to examine whether collateral meridian (CM) therapy was feasible in treating knee osteoarthritis (OA) pain. Twenty-eight patients with knee OA and knee pain were randomly allocated to 2 groups. The CM group patients received CM therapy, whereas the control patients received placebo treatment for knee pain relief. Patients in the CM group received 2 CM treatments weekly for 3 weeks. The outcome measures were pain intensity on a visual analog scale, and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index. In the CM group, the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group; a significant reduction in pain intensity (P = .02, P = .01, respectively) and improvement in knee function (P = .04, P = .03, respectively) were shown in the CM group at the second and third week.

Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery. Therefore, additional randomized control trials are warranted.

Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA. CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis. CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes.

CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.

To evaluate the efficacy. and safety of Xinfeng capsule in patients suffering rheumatoid arthritis (RA). A multi-center parallel-group designed, double-blind, randomized, controlled trial was conducted. Totally 304 RA patients were assigned to two groups: one group was administered Xinfeng capsule (XFC) plus the placebo of leflunomide and the other given leflunomide (LEF) plus the placebo of XFC for twelve weeks. The clinical and laboratory parameters were compared at baseline and fourth, eighth, and twelfth weeks. After twelve-week treatment, patients in two groups all showed some trend of effectiveness when compared in terms of American Rheumatism Association (ACR) recommended 20%, 50%, 70% improvement criteria, but it was insignificant. The validity in ameliorate modified disease activity score (DAS28) and laboratory indexes as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) were also found no difference. The score of health assessment questionnaire (HAQ), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and quality of life questionnaire with rheumatoid arthritis (RAQOL) both lower than the first week and the changes showed no difference. However, the score of SDS dropped more in XFC group than in the other. A total of 147 adverse reaction cases were reported, which shows no difference between the two groups. The most common adverse reactions were hepatic impairment, anemia, leukocytopenia, epigastric discomfort and phalacrosis.

XFC demonstrated better improvement in the scores of SDS and compared with those of LEF group.

To evaluate the safety and efficacy of an intra-articular injection of autologous protein solution (APS) for treatment of canine osteoarthritis (OA). Prospective, randomized, blinded, placebo-controlled pilot clinical trial. Client-owned dogs with single limb lameness because of OA in a stifle or elbow joint (n=21). Lame dogs, confirmed with OA by physical and lameness examination and imaging, were randomly assigned to control or treatment groups. Owners, blinded to treatment, scored pain (University of Pennsylvania Canine Brief Pain Inventory) and lameness severity (Hudson Visual Analogue Scale [HVAS]). Weight-bearing was assessed by kinetic gait analysis. Dogs were injected intra-articularly with APS (treatment group) or saline solution (control group). Evaluations were performed before injection, and 2 and 12 weeks post-injection. Compared to pretreatment values, APS treatment data showed a significant improvement in week 12 pain scores (improved 25.6% over baseline), lameness scores (improved 15% over baseline) and peak vertical force (PVF; N/kg; increased 14.9% of baseline), as well as vertical impulse (Ns/kg) and PVF normalized to stance time (N/kg/s). Control group dogs improved at week 2 in owner assigned indices, but not force plate values and had no significant improvement in scores or force plate values from pretreatment values at 12 weeks.

APS injection reduced pain and lameness scores and increased weight-bearing associated with the OA-affected joint in dogs at 12 weeks providing preliminary evidence that APS therapy may be beneficial in the treatment of OA in dogs and supporting pursuit of additional studies.

Extensor carpi ulnaris (ECU) and tibialis posterior (TP) tendons are often involved in RA and the present aim was to examine by ultrasound (US) their frequency of inflammation and sensitivity to change in comparison to joint involvement as well as clinical examinations. US, clinical and laboratory assessments were performed when starting biologic DMARD (bDMARD) and after 1, 2, 3, 6 and 12 months including bilateral grey-scale (GS) and power Doppler (PD) semi-quantitatively (0-3) scoring of ECU and TP tendons and 18 joints. Changes from baseline to follow-up were explored by Wilcoxon signed rank test, associations by Spearman's rank correlations and responses to treatment by Standardised Response Means (SRMs). 157 patients (mean age/disease duration 52.4/10.2 years) were included. ECU/TP tenosynovitis was frequent (baseline GS/PD pathology in 76/50% of patients) and more prevalent than synovitis of large joints. Tenosynovitis sum scores decreased throughout follow-up (p<0.001) and was correlated with US of joints (0.51-0.62), clinical assessments (swollen joint count (0.29-0.41) and assessor's global (0.35-0.46)) (p<0.001). US tenosynovitis sum scores had SRMs comparable to joint, clinical and laboratory assessments.

Tenosynovitis in ECU/TP tendons were frequent, sensitive to change during bDMARD treatment and were associated to joint and clinical assessments. This supports the argument for tenosynovitis to be included in US scores of RA patients, while further studies should explore which tendons.

To determine whether interleukin 1 (IL-1) polymorphisms confer susceptibility to rheumatoid arthritis (RA). We conducted metaanalyses on associations between IL-1 polymorphisms and RA susceptibility, using fixed or random effects models. A total of 18 separate comparisons were made using 10 European, 7 Asian, and 1 Latin American population samples. Metaanalysis of the IL-1B+3954 CC genotype revealed an association with RA in all subjects (odds ratio=0.776, 95% confidence interval=0.609-0.988, p=0.040). In Asians, an association between IL-1B+3954 and RA was identified. In contrast, no association was found between the IL-1B+3954 polymorphism and RA susceptibility in European populations. Metaanalyses of the IL-1B-511 and IL-1RN VNTR polymorphisms identified no association between these polymorphisms and RA.

Our metaanalysis shows that the IL-1B+3954 polymorphism was associated with the development of RA, but only in Asians.

To determine the role of CCL21 and its receptor CCR7 in the pathogenesis of rheumatoid arthritis (RA). Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays. Finally, the mechanism by which CCL21 mediates angiogenesis was determined by Western blot analysis and endothelial cell chemotaxis and tube formation assays. CCL21, but not CCL19, at concentrations present in the RA joint, induced human microvascular endothelial cell (HMVEC) migration that was mediated through CCR7 ligation. Suppression of the phosphatidylinositol 3-kinase pathway markedly reduced CCL21-induced HMVEC chemotaxis and tube formation; however, suppression of the ERK and JNK pathways had no effect on these processes. Neutralization of either CCL21 in RA synovial fluid or CCR7 in HMVECs significantly reduced the induction of HMVEC migration and/or tube formation by RA synovial fluid. We further demonstrated that CCL21 is angiogenic, by showing its ability to promote blood vessel growth in Matrigel plugs in vivo at concentrations that are present in RA joints.

Angiogenesis is dependent on endothelial cell activation, migration, and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. This study identified a novel function of CCL21 as a mediator of RA angiogenesis, supporting CCL21/CCR7 as a therapeutic target in RA.

The efficacy of erythromycin in treatment of knee effusion due to osteoarthritis was evaluated. We assessed efficacy and safety of erythromycin during 16 weeks in patients enrolled in a randomized double-blind study. One hundred and eight patients with knee effusion due to osteoarthritis (OA) received 12-week courses of erythromycin or placebo allocated randomly, and were followed for 4 months. Acetaminophen 650 mg/day was used in both groups, while they received no other anti-inflammatory drugs (such as corticosteroid or nonsteroidal anti-inflammatory drugs) during the course of the study. Our patients were divided in two groups, erythromycin in doses of 200 mg four times per day was given to the first group (51 patients) over the first 3 months of the study and in the second group we used placebo with the same dosage and schedule (53 patients). Outcomes improvement for the erythromycin-treated group was assessed by a significantly higher mean score from baseline to the end of the trial, compared with placebo group. Patients were examined monthly during the treatment period. Measurement values included recording of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire subscales (pain, stiffness and function), range of motion and knee circumference. Erythromycin produced a higher response rate than placebo in treatment of knee effusion due to OA. Significant reduction in knee circumference (P < 0.0005) and pain (P < 0.001) with functional improvement (P < 0.0005) were seen. At the first month after treatment, 11.8% (6 patients) in erythromycin and 9.4% (5 patients) in placebo groups had 50% pain reduction, which was not significant (P = 0.75). At the fourth month, 50% reduction of pain was seen in 45.1% (23 patients) of the erythromycin and 11.3% (6 patients) of the placebo group. This was statistically significant (P < 0.0005). Erythromycin treatment was well tolerated and mild adverse events caused no discontinuation during the study.

This is a placebo-controlled study of macrolid efficacy on knee effusion due to OA in a short period. Results of this research showed the better efficacy of erythromycin in controlling effusion and pain with functional improvement in patients with knee effusion due to OA.

The Quality of Well Being index (QWB) and the SF-36 are questionnaires that have received widespread use in outcomes research. The relationship between the QWB index and the SF-36 was studied in patients receiving total hip or knee replacement because of primary osteoarthritis, and the health status of these individuals was contrasted to that of the general population. The QWB and SF-36 were both administered preoperatively and postoperatively and at 3 and 6 months in individuals with hip or knee replacement. A primary care university teaching hospital. Forty-three subjects with an age range of 30 to 78 years (mean 58 yrs, SD 10.6) who received total joint replacement, either hip or knee. The change in the QWB at 3 and 6 months after a total hip replacement or total knee replacement was most associated with the change in general health (.50), bodily pain (.72), and vitality (.62) of the SF-36. Both tools (QWB, SF-36) demonstrated similar levels of responsiveness and the scores were lower than the scores from the general population.

The summary score of the QWB and various health concepts of the SF-36 respond similarly after joint replacement from osteoarthritis. The relationship between the change in the QWB and SF-36 depends on the time after surgery (3 vs. 6 months) and the type of joint replacement (knee vs. hip).

ABP 501 was evaluated in a phase 3 single-arm, open-label extension (OLE) study to collect additional safety and efficacy data in patients with rheumatoid arthritis (RA). Subjects completing the final visit in the parent phase 3 randomized, double-blind, controlled equivalence study comparing the efficacy and safety of the biosimilar ABP 501 with adalimumab reference product (RP) were enrolled in this open-label extension (OLE) study. All subjects received 40 mg ABP 501 every other week for 68 weeks. Key safety endpoints included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and anti-drug antibody (ADA) incidences. Efficacy endpoints included ACR20 (at least 20% improvement in American College of Rheumatology core set measurements from baseline) and Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP) change from baseline. Among 466/467 patients treated with ABP 501, 229 transitioned from the ABP 501 arm of the parent study (ABP 501/ABP 501) and 237 from the adalimumab RP arm (RP/ABP 501); 412/467 (88.2%) patients completed the study. The overall TEAE incidence was 63.7% (297/466); grade ≥ 3 TEAE incidence was 9.0% (42/466). The incidence of TEAEs leading to discontinuation of investigational product was 3.6% (17/466). The SAE incidence was 9.9% (46/466). Overall, 18.2% (85/466) of subjects developed binding ADAs and 6.9% (32/466) developed neutralizing ADAs in the OLE study. The ACR20 response rate was 73.3% (340/464 subjects) at OLE baseline, and 78.8% (327/415 subjects) at week 70 of the OLE study. The overall mean DAS28-CRP change from the parent study baseline was - 2.25 at the OLE study baseline (n = 440), - 2.36 at week 4 (n = 463), - 2.41 at week 24 (n = 450), - 2.55 at week 48 (n = 433), and - 2.60 at week 70 (n = 412). Efficacy was maintained throughout the study. ClinicalTrial.gov, NCT02114931.

Efficacy previously demonstrated in the parent study was maintained in this OLE study with no new safety findings. Long-term safety, immunogenicity, and efficacy were similar in the ABP 501/ABP 501 and RP/ABP 501 groups. The single switch from RP to ABP 501 did not impact immunogenicity.

To evaluate the difference in isokinetic strength of hip muscles between patients with knee osteoarthritis (OA) and matched healthy controls, and to establish the correlation between this isokinetic strength and pain and function in patients with knee OA. 25 patients with a diagnosis of unilateral knee OA, 25 patients with bilateral knee OA, and 50 matched controls were evaluated using the visual analog scale for pain, knee Lequesne index, Western Ontario and McMaster Universities questionnaire and an isokinetic test. The groups were matched for age, gender and body mass index. The results of the isokinetic test revealed lower peak torque of the hip in patients with OA of the knee than in the control group for all movements studied. Strong correlations were found between the peak torque, visual analog scale and function.

Patients with OA of the knee exhibit lower isokinetic strength in the hip muscles than healthy control subjects. Strengthening the muscles surrounding the hip joint may help to decrease pain in people with knee OA. Some correlations between pain/function and peak torque were found.

Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood-onset polyarteritis nodosa (PAN), a primary "idiopathic" systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2. The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting. Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody-associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely.

These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early-onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.

To compare the efficacy of the cyclooxygenase 2 (COX-2)-specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA). In this randomized, placebo-controlled, double-blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination). In primary measures of efficacy (OA pain score on a 100-mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34-mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was -2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events.

Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.

To describe the longitudinal health status from childhood to adulthood in patients with juvenile idiopathic arthritis (JIA), compare outcomes after 19 years with those of controls, and identify early predictors of physical functioning, pain, and physical health-related quality of life (HRQOL). Between 1995-2003, 96 patients with JIA (mean 6.1 ± 4.0 yrs, 67% female) were assessed within 18 months of diagnosis and every 6 months for the next 3 years with measures of JIA disease activity, physical functioning, pain, fatigue, and well-being. They were reassessed a mean of 18.9 ± 1.5 years later (mean age 25.1 ± 4.2 yrs) with measures of physical disability [Health Assessment Questionnaire-Disability Index (HAQ-DI)], pain, fatigue, well-being (visual analog scale), and physical and mental health-related quality of life (HRQOL; Medical Outcomes Study 12-item Short Form Health Survey, version 2). During the first 3 years, physical disability improved (p < 0.001) and the proportion of patients reporting best possible well-being increased (p = 0.013), while pain and fatigue did not change. At 3- and 19-year followups, patients had similar levels of physical disability, well-being, and pain, but fatigue increased (p = 0.016) and the number of patients with HAQ-DI = 0 decreased (p = 0.001). After 19 years, patients had worse pain and physical HRQOL than controls (p < 0.001). Pain, active joints, and physical disability during the first 3 years were associated with more disability and pain and worse physical HRQOL after 19 years (p < 0.001-0.047).

Patients with JIA reported similar physical functioning, well-being, and pain at 3- and 19-year followups, but more fatigue after 19 years. Patients also had worse health status than controls after 19 years. Pain, active joints, and physical disability were early predictors of unfavorable outcomes.

The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters. Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test. The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.

M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.

Folate receptor beta (FRβ) is only detectable in placenta and limited to some hematopoietic cells of myeloid lineage in healthy people. Studies have indicated that FRβ is over-expressed in activated macrophages in autoimmune diseases and some cancer cells. In this study we aimed to develop an FRβ-specific human monoclonal antibody (mAb) that could be used as a therapeutic agent to treat rheumatoid arthritis and other autoimmune diseases, as well as FRβ positive cancers. Functional recombinant FRβ protein was produced in insect cells and used as antigen to isolate a mAb, m909, from a human naïve Fab phage display library. Binding of Fab and IgG1 m909 to FRβ was measured by ELISA, surface plasmon resonance, immune fluorescence staining, and flow cytometry. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated with FRβ positive CHO cells as target cells and isolated peripheral blood monocytes as effector cells in an in vitro assay. Fab m909 bound with relatively high affinity (equilibrium dissociation constant 57 nM) to FRβ. The IgG1 m909 showed much higher (femtomolar) avidity as measured by ELISA, and it bound to FRβ positive cells in a dose-dependent manner, but not to parental FRβ negative cells. m909 did not compete with folate for the binding to FRβ on cells. m909 was not only able to select FRβ positive, activated macrophages from synovial fluid cells of arthritis patients as efficiently as folate, but also able to mediate ADCC in FRβ positive cells.

Unlike folate-drug conjugates, m909 selectively binds to FRβ, does not recognize FRα, and has at least one effector function. m909 alone has potential to eliminate FRβ positive cells. Because m909 does not compete with folate for receptor binding, it can be used with folate-drug conjugates in a combination therapy. m909 can also be a valuable research reagent.

To compare the prevalence of osteoarthritis (OA) of the hip, tibiofemoral and patellofemoral joints in a skeletal population. A total of 785 adult English skeletons (695 Saxon or Mediaeval origin) were examined for OA using established criteria. Twenty nine skeletons had hip OA, compared with 14 with patellofemoral joint OA, and only four tibiofemoral joint OA.

Tibiofemoral OA was far less prevalent in ancient skeletons than hip or patellofemoral disease. Tibiofemoral OA may be a 'new' disease.

Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study. Serum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). IgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for cases and controls.

This large cohort study demonstrates the association of changes in galactosylation with both pregnancy-induced improvement and postpartum flare in RA-patients, suggesting a role for changes in glycosylation in the pregnancy-induced improvement of RA.

Obesity is one of the only modifiable risk factors for both incidence and progression of Osteoarthritis (OA). So there is increasing interest from a public health perspective in addressing obesity in the management of OA. While evidence of the efficacy of intereventions designed to address obesity in OA populations continues to grow, little is known about their economic credentials. The aim of this study is to conduct a scoping review of: (i) the published economic evidence assessing the economic impact of obesity in OA populations; (ii) economic evaluations of interventions designed to explicitly address obesity in the prevention and management of OA in order to determine which represent value for money. Besides describing the current state of the literature, the study highlights research gaps and identifies future research priorities. In July 2014, a search of the peer reviewed literature, published in English, was undertaken for the period January 1975 - July 2014 using Medline Complete (Ebscohost), Embase, Econlit, Global Health, Health Economics Evaluation Database (HEED), all Cochrane Library databases as well as the grey literature using Google and reference lists of relevant studies. A combination of key search terms was used to identify papers assessing the economic impact of obesity in OA or economic evaluations conducted to assess the efficiency of obesity interventions for the prevention or management of OA. 14 studes were identified; 13 were cost burden studies assessing the impact of obesity as a predictor for higher costs in Total Joint Arthroplasty (TJA) patients and one a cost-effectiveness study of an intervention designed to address obesity in the managment of mild to moderate OA patients.

The majority of the economic studies conducted are cost burden studies. While there is some evidence of the association between severe obesity and excess hospital costs for TJA patients, heterogeneity in studies precludes definitive statements about the strength of the association. With only one economic evaluation to inform policy and practice, there is a need for future research into the cost-effectiveness of obesity interventions designed both for prevention or management of OA along the disease spectrum and over the life course.

Chondrocytes are one of the main cell types involved in rheumatoid inflammation, releasing mediators which add to cartilage destruction, bone damage and consequently disability. Current evidence suggests that serotonin 5-HT(3) receptor antagonists (5-HT(3)RA) show anti-inflammatory and antioxidant properties in vitro and in vivo. Yet, the mechanisms of the anti-inflammatory effects of 5-HT(3)RA have not been elucidated in detail. Therefore, we examined in detail the effects of 5-HT(3)RA on inflammatory parameters in human primary chondrocytes in vitro by studying prostaglandin E2 (PGE2) and 8-isoprostane (8-iso-PGF2α) levels by EIA and interleukin-6 (IL-6) synthesis by ELISA. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) protein levels were analyzed by Western blot. We found a significant reduction of IL-1β induced PGE2, 8-iso-PGF2β and IL-6 chondrocytes by 5-HT(3)RA especially by dolasetron.

This study provides additional support to the potential use of 5-HT(3)RAs as therapeutic agents to reduce joint inflammation.

To describe therapies with disease modifying antirheumatic drugs (DMARD) and biological agents in patients with early rheumatoid arthritis (RA) who were receiving routine clinical care in 2001 in a private practice of 5 rheumatologists in Nashville, TN, USA. A cohort of 232 patients with initial symptoms of RA in 1998 or later were enrolled between February and October 2001 into a longterm observational study, designed to evaluate treatments and longterm outcomes of RA. The baseline evaluation included review of all DMARD that had been taken since disease onset, clinical measures on a multidimensional health assessment questionnaire, joint counts, and laboratory measures. Among the 232 patients, methotrexate (MTX) was the first DMARD used in 192 patients (82.8%), including 3 in combinations. Since initiation of the first DMARD to the study visit, over a median interval of 12.1 months, 125 (66.1%) patients of the 189 whose initial DMARD was MTX as a single DMARD continued MTX as a single DMARD, 43 (22.8%) had another DMARD or biological agent added in combination with MTX, and 21 (11.1%) discontinued MTX. Since the onset of RA, 89.2% of the patients had taken MTX, 15.9% hydroxychloroquine, 3.9% sulfasalazine, 22.0% leflunomide, 9.5% etanercept, 4.3 infliximab, and 87.0% prednisone.

After a median duration of 12.1 months of DMARD therapy, almost 90% of patients with recent onset RA took MTX as the anchor drug. More than 60% took MTX as a single DMARD or in combination with traditional DMARD, while 30% took leflunomide, etanercept, or infliximab, usually in combination with MTX.

Using the International Classification of Functioning, Disability and Health as framework, we evaluated modifying effects of illness perceptions and mental health on the association between impairments in body structures and functions due to osteoarthritis (OA) and limitation in activities in the lower extremities. Self-reported limitation in activities was assessed by the Western Ontario and McMaster Universities OA index (WOMAC) function subscale in 316 patients with knee or hip pain or evidence of OA on knee or hip radiographs. Body structures and functions were evaluated during clinical and radiological assessments. Illness perceptions and mental health were assessed with the revised Illness Perception Questionnaire (IPQ-R) and the mental component summary score of the RAND 36-item Health Survey, respectively. For each patient an expected WOMAC function score was calculated, using an equation based on a multivariate model of the association of body structures and functions with limitation in activities. The median (interquartile) self-reported WOMAC function score was 22.2 (9.6-43.5). Ninety-one patients reported more and 120 patients reported less limitation in activities than expected. Patients with lumbar spine degeneration, physical or exercise therapy and high IPQ-R identity, consequences and chronic timeline scores had an increased risk to report more limitation in activities than the expected range. Low IPQ-R identity, consequences and emotional representation scores and better mental health were associated with reporting less limitation in activities than the expected range.

Illness perceptions and mental health modify the association between self-reported limitation in activities and calculated limitation in activities based on impairments in body structures and functions due to OA.

To investigate the role of magnetic resonance (MR) imaging in diagnosing early rheumatoid arthritis (RA). Twenty patients (three men, 17 women; age range, 21-72 years) with clinically and radiologically proved RA underwent evaluation to define an MR imaging criterion for diagnosing synovial inflammation due to RA. Twenty-seven patients (16 with RA, 11 without RA [control patients]; three men, 24 women; age range, 19-75 years) suspected to have early RA but without radiographic abnormalities underwent evaluation to test the accuracy of using the criterion to diagnose RA. In each patient, coronal, fat-suppressed, and gadolinium contrast material-enhanced, T1-weighted images of both hands were obtained. The MR imaging criterion was periarticular contrast material enhancement of the wrists or the metacarpophalangeal and/or proximal interphalangeal joints in both hands. In the diagnosis of early RA, sensitivity and negative predictive value were both 100%, specificity was 73%, and accuracy was 89%.

MR imaging is extremely useful in diagnosing early RA.

To investigate change in knee cartilage composition over 96 months in overweight and obese participants with constant weight compared to those with weight loss (WL), and to assess how different WL regimens are associated with these changes. We studied right knees of 760 participants (age 62.6 ± 9.0y; 465 females) with a baseline body mass index (BMI) >25 kg/m2 from the Osteoarthritis Initiative with mild to moderate or with risk factors for knee osteoarthritis. Participants losing weight (>5% of baseline BMI over 72 months; N = 380) were compared to controls with stable weight (SW, N = 380). Participants losing weight were categorized based on WL method (diet and exercise, diet only, exercise only) and compared to those with stable weight. Magnetic resonance imaging (MRI) at 3T was performed at baseline, 48- and 96-months. The association of WL and WL method with change in cartilage composition, measured with T2 mapping, was analyzed using mixed random effects models. Compared to SW, WL was associated with a significantly slower increase in global (averaged over all compartments) cartilage T2 (adjusted mean difference of change in T2 ms/year [95% CI] between the groups: 0.24 [0.20, 0.41] ms/year; P < 0.001) and global deep layer cartilage T2 0.35 [0.20, 0.42] ms/year; P < 0.001), suggesting slower cartilage deterioration. Compared to the SW group, slower increases in global T2 were observed in the diet and diet and exercise groups, but not in the exercise only group (P = 0.042, P = 0.003 and P = 0.85, respectively).

Our results suggest that WL may slow knee cartilage degeneration over 96 months, and that these potential benefits may differ by method of WL.

This study aimed to verify if the navigation system used in high tibial osteotomy (HTO) adds precision to the procedure regarding mechanical axis correction and prevention of tibial slope increases. In this historically controlled study, patients with medial osteoarthrosis and genuvarum underwent HTO between 2004 and 2012; the first 20 were operated with the conventional technique, using pre-planning correction by the Dugdale method and 18 further patients were operated with the navigation system introduced in our hospital. The two groups were similar for pre-operative mechanical axis (mean 8.10 ± 3.14 for the control and 6.60 ± 2.50 for the navigated group), pre-operative tibial slope (mean 8.95 ± 3.47 versus 8.17 ± 3.11, respectively) and Lyshom score (40.85 ± 15.46 and 44.83 ± 16.86). After surgery, the control group presented mean mechanical axis of 3.35 ± 3.27, tibial slope of 13.75 ± 3.75 and Lyshom score of 87.60 ± 11.12. The navigated group showed a postoperative mechanical axis mean of 3.06 ± 1.70, tibial slope of 10.11 ± 0.18 and Lyshom score of 91.94 ± 11.61.

The navigation system allowed a significantly better control of tibial slope. Patients operated with the navigation system had significantly better Lysholm scores.

Patellofemoral problems are a common complication of total knee arthroplasty. A high compressive force across the patellofemoral joint may affect patient-reported outcome. However, the relationship between patient-reported outcome and the intraoperative patellofemoral contact force has not been investigated. The purpose of this study was to determine whether or not a high intraoperative patellofemoral compressive force affects patient-reported outcome. This prospective study included 42 patients (42 knees) with varus-type osteoarthritis who underwent a bi-cruciate stabilized total knee arthroplasty and in whom the planned alignment was confirmed on 3D CT. Of the 42 patients, 36 were women and six were men. Their mean age was 72.3 years (61 to 87) and their mean body mass index (BMI) was 24.4 kg/m No patient had anterior knee pain after total knee arthroplasty. The compressive force across the patellofemoral joint at 140°of flexion was negatively correlated with patient satisfaction (R

Patient satisfaction, FJS-12, and patella score were affected by the patellofemoral compressive force at 60° and 140° of flexion. Reduction of the patellofemoral compressive forces at 60° and 140° of flexion angle during total knee arthroplasty may improve patient-reported outcome, but has no effect on anterior knee pain.

Activated T and B cells participate in the development and progression of Sjögren's syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS. Metformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4 Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells.

Metformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.

Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases. Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNβ-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis. We identified IFNα- and IFNβ-specific response programs (GC-A and GC-B, respectively) in SLE and IFNβ-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero.

Our findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs.

To determine whether an intraarticular injection of the neutrophil chemorepellent dipeptidyl peptidase IV (DPPIV; CD26) can attenuate inflammation and decrease the severity of arthritis in a murine model. DBA/1 mice were immunized with type II collagen/Freund's complete adjuvant to produce collagen-induced arthritis (CIA). On day 25 postimmunization, recombinant human DPPIV (rhDPPIV) or phosphate buffered saline was injected intraarticularly, and arthritis severity scores were recorded 3 times per week. The hind legs of mice in both groups were fixed, decalcified, paraffin embedded, and sectioned. Pathologic scores for inflammation and neutrophil infiltration were recorded on a scale of 1-8, and the number of neutrophils was determined by morphometric cell counts. In addition, Mac-2-positive macrophages and articular damage were assessed using anti-Mac-2 antibodies and histologic staining, respectively. Injection of rhDPPIV reduced the mean score of arthritis severity in mice with CIA. DPPIV treatment reduced the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue, and also decreased neutrophil and macrophage infiltration.

A localized injection of the neutrophil chemorepellent DPPIV reduces inflammation and the severity of the disease in a murine model of arthritis.

Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3 Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of α-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts.

Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules.

To determine the mechanisms responsible for the recurrence of ulnar drift after metacarpophalangeal joint arthroplasty in the rheumatoid hand. A three-dimensional biomechanical model of the index finger joints was used to predict the implant loads during several activities of daily living. Post-operative clinical evaluation of Sutter metacarpophalangeal prostheses shows a high incidence of fracture and recurrent deformity. A six-component force transducer in conjunction with a six-camera motion analysis system were used to obtain kinematic and external loading data from eight patients with rheumatoid arthritis during several simulated activities. These data were used as input into a three-dimensional biomechanical model of the implant and interphalangeal joints of the index finger. Tendon lines of action and moment arms were obtained using a series of MRI scans and CAD modelling techniques. Implant forces were oriented in a radial and dorsal direction to resist the ulnarpalmarly pull of tendons associated with the metacarpophalangeal joint. Understanding the mechanisms responsible for the recurrence of ulnar drift and implant failure is a step towards improving the prosthesis design, surgical procedures and ultimately the patient's prognosis.

The recurrence of ulnar drift is attributable to fatigue failure of the prostheses. After fracture the implant is unable to support the repetitive loading patterns experienced during activities of daily living.

To assess disease features in Sle1.Yaa mice with genetic interleukin-6 (IL-6) deficiency. Sera and tissues were collected from C57BL/6 (B6), Sle1.Yaa, and Sle1.Yaa.IL-6(-/-) mice and analyzed for various features of disease. Using serum samples, autoantibody specificities were determined by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence, cytokine production was analyzed by Luminex and ELISA, and levels of blood urea nitrogen were determined by ELISA. Renal, lung, and salivary gland tissue sections were evaluated for pathologic changes. Lymphocyte phenotypes, including CD4+ T cell cytokine production, and those of follicular and extrafollicular T helper subsets, germinal center B cells, and plasma cells, were determined using flow cytometry. IL-6 deficiency not only ameliorated autoantibody production and renal disease in this model, but also effectively reduced inflammation of lungs and salivary glands. Furthermore, IL-6 deficiency abrogated differentiation of Th1 and extrafollicular T helper cells, germinal center B cells, and plasma cells in the spleen and eliminated renal T cells with IL-17, interferon-γ, and IL-21 production potential.

Our findings highlight IL-6-mediated T cell aberrations in Yaa-driven autoimmunity and support the concept of therapeutic IL-6/IL-6 receptor blockade in systemic lupus erythematosus and Sjögren's syndrome by impairing the production of autoantibodies and lymphocytic infiltration of the kidneys, lungs, and salivary glands.

To study the safety and efficacy of infliximab plus leflunomide combination therapy in adult rheumatoid arthritis (RA). Twenty patients with active RA received leflunomide 100 mg for 3 days followed by 20 mg daily for 32 weeks. At week 2 all patients started infliximab 3 mg/kg, and received a further four infusions at weeks 4, 8, 16 and 24. Adverse events led to 11 patients being withdrawn before the end of the study. The commonest adverse event was pruritus associated with an eczematous rash. Other serious reactions included infliximab infusion reactions in four patients and Stevens-Johnson syndrome in one. There was no relationship between the serum concentration of A77 1726, the active metabolite of leflunomide, and adverse events. The mean Disease Activity Score (DAS28) fell from 7.18 at week 0 to 5.18 (P<0.0001, paired t-test) at week 4 and remained between 3.85 and 4.85 up to week 32. In those patients remaining on treatment, more than 80% achieved an ACR20 response from week 8 to week 28, and up to 46% achieved an ACR70 response.

Infliximab plus leflunomide combination therapy appears to be highly efficacious in the treatment of adult RA. However, widespread use may be limited by adverse events, which were common and in some cases severe.

To identify gene expression signatures in minor salivary glands (MSGs) from patients with primary Sjogren's syndrome (SS). A 16K complementary DNA microarray was used to generate gene expression profiles in MSGs obtained from 10 patients with primary SS and 10 control subjects. The data were analyzed by 2 different strategies, one strict primary analysis and one subanalysis that allowed for inclusion of genes with no signal in more than 3 samples from each group. The results were validated by quantitative reverse transcriptase-polymerase chain reaction techniques. We found a distinct difference in gene expression levels in MSGs, enabling a simple class prediction method to correctly classify 19 of the 20 samples as either patient or control, based on the top 5 differentially expressed genes. The 50 most differentially expressed genes in the primary SS group compared with the control group were all up-regulated, and a clear pattern of genes involved in chronic inflammation was found. CXCL13 and CD3D were expressed in >/=90% of primary SS patients and in </=10% of the controls. Lymphotoxin beta, as well as a number of major histocompatibility complex genes, cytokines, and lymphocyte activation factors, manifested its role in the pathogenesis of SS. Numerous type I interferon genes related to virus infection were found among the top 200 genes, with increased expression in primary SS. Interestingly, the expression of carbonic anhydrase II, which is essential in saliva production and secretion, and the apoptosis regulator Bcl-2-like 2 were down-regulated in primary SS patients.

We have identified distinct gene expression profiles in MSGs from patients with primary SS that provide new knowledge about groups of genes that are up-regulated or down-regulated during disease, constituting an excellent platform for forthcoming functional studies.

Whether comorbid depression increases mortality in patients with rheumatoid arthritis (RA) is unknown. Our objective was to determine whether the presence of depression predicted mortality in patients with RA. We followed 1290 consecutive outpatients with RA who met our stringent inclusion criteria during an 18-year observation period. Since 1981, demographic, clinic, and self-report data were collected and entered into a computer database at the time of each clinic visit. The comorbidity data were consistently recorded beginning in 1991. Our primary independent variable was the mean of the Arthritis Impact Measurement Scales (AIMS) depression scores during the first 4 years of entry into the clinic cohort (average 4-year depression). Data were analyzed using Cox proportional hazard models. After adjusting for covariates, the hazard ratio (HR) for each unit increase in the average 4-year depression score on mortality was 1.14 (p < 0.0001). Using only the data obtained from 1991 to 2003, the mortality risk was slightly increased (HR 1.35, p < 0.0001). To reduce residual confounding due to RA disease activity and/or comorbid medical conditions, we then excluded deaths during the first 2 years after study onset. With this method, the HR for the average 4-year depression remained significant (HR 1.35, p < 0.0001). Because an AIMS depression score > or = 4 is consistent with clinical depression, we analyzed the dataset using the average 4-year depression score as a dichotomous variable (score < 4 or > or = 4). The HR of clinical depression on mortality was 2.2 (95% CI 1.2- 3.9, p = 0.01).

Depression increases the risk of mortality in RA. Our study highlights the importance of comorbid depression in patients with RA.

Intraoperative cerebral microembolization occurs in a substantial proportion of patients undergoing THA. Historically, postoperative cognitive dysfunction has been attributed to different factors, including anesthesia, but the influence of the surgery has not been thoroughly examined. We conducted a prospective, controlled clinical trial to assess intraoperative cerebral microembolization during THA and neuropsychologic outcome. The presence of a patent foramen ovale (PFO) also was investigated, using transcranial Doppler, to determine whether this affected cerebral microembolic incidence and load and whether microemboli occurred as a result of specific surgical activity. Forty-five patients were recruited who underwent THA and neuropsychologic assessment; a battery of tests was administered preoperatively and at 6 weeks and 6 months postoperatively. Overall, patients showed improvement in total neuropsychologic change scores at both postoperative intervals. The incidence of cerebral microembolization for THA was 23%. The prevalence of PFO was 37%. PFO did not appear to influence microemboli load or incidence. More microemboli were seen during femoral component insertion and impaction.

Intraoperative cerebral microembolization occurs in a substantial proportion of patients during THA recorded by transcranial Doppler. The microemboli load is low and is not influenced by the presence of PFO. Certain surgical activities seem responsible for greater cerebral microemboli generation. However, neuropsychologic outcome was not affected postoperatively by microemboli or other operative or patient variables.

We examined whether auricular acupressure (AA) can alleviate postoperative pain and decrease narcotic consumption and its adverse effects for osteoarthritis patients after total knee arthroplasty (TKA). A prospective, randomized, sham control trial comparing AA and a sham control. Department of Orthopedics, the first Hospital affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, China. Ninety patients with degenerative osteoarthritis undergoing TKA. The AA group received true AA by embedding vaccaria seeds at four specific AA points (knee joint, shenmen, subcortex, sympathesis) ipsilateral to the surgery site, while the control group received four nonacupuncture points on the auricular helix. Visual analog scale (VAS), the consumption of analgesic via patient-controlled analgesia, the incidence of analgesia-related adverse effects, Hospital for Special Surgery scores (HSS), and range of motion (ROM) were recorded. VAS scores were similar at 12, 24, 36, and 48 h postsurgery (P > 0.05), but AA group scores were lower than those of the control group at 3, 4, 5, and 7 days (P < 0.05). Patients in the AA group consumed lower doses of analgesic than those in the control group after surgery (P < 0.05). The incidence of analgesia-related adverse effects in the AA group was lower than that in the control group (P < 0.05). Although HSS scores were similar in the two groups preoperatively and at 3 months postoperatively (P > 0.05), HSS scores 2 weeks postoperatively were higher in the AA group than in the control group (P < 0.05), but there was no difference between groups in ROM (P > 0.05).

Applying auricular acupoint acupressure in the perioperative period of TKA is favorable for alleviating postoperative pain, decreasing opioid consumption and its adverse effects, and promoting early rehabilitation. Also, this intervention has the advantage of lower costs, fewer complications, simple application, and high safety.

Following a specific number of mitotic divisions, primary chondrocytes undergo proliferative senescence, thwarting efforts to expand sufficient populations in vitro suitable to meet the needs of scientific research or medical therapies. Therefore, the human telomerase reverse transcriptase (TERT) was used to immortalize human chondrocyte and establish a cell line that escape from cellular senescence. The human chondrocytes were successfully immortalized by ectopic stable expression of TERT. The established TERT-Chondrocyte cell line showed robust proliferation capacity, even in late passages up to P20, and displayed little cellular senescence. Moreover, TERT-Chondrocyte cells at 20th passage showed similar chondrocyte properties to normal chondrocytes at early passages.

Ectopic stable expression of TERT is an effective way to immortalized human chondrocyte. The immortalized chondrocytes displayed little cellular senescence, showed promise as an in vitro model to investigate osteoarthritis, and may be a promising resource for cell-based therapy for damaged cartilage.

This study documents the measurement properties of a brief, self-administered questionnaire of disease signs and symptoms in patients with rheumatoid arthritis. The Rapid Assessment of Disease Activity in Rheumatology (RADAR) questionnaire assesses joint pain/tenderness and clinical status. One hundred ninety-three pairs of RADAR forms were completed by 45 subjects and their assigned clinician evaluators. Subject-clinician agreement (intraclass correlation coefficients [ICC]) for joint pain/tenderness and clinical status ranged from 0.52 to 0.87 (P = 0.0001), with 83% greater than or equal to 0.65. The ICC for change in joint scores over 6 months was 0.83 (P = 0.0001).

The 2-page RADAR questionnaire produces valid estimates of joint count and clinical status that are sensitive to change.

A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA. In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell-mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model.

Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary.

The genetic background of rheumatoid arthritis-interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans. We performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern. We identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at

We revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at

The aim of this study was to investigate the effects of thyroid hormones tri-iodothyronine (T3), thyroxine (T4), and parathyroid hormone (PTH) from the parathyroid glands, known to regulate the developing limb and growth plate, on articular cartilage tissue regeneration using a scaffold-free in vitro model. In Phase 1, T3, T4, or PTH was applied during weeks 1 or 3 of a 4-week neocartilage culture. Phase 2 employed T3 during week 1, followed by PTH during week 2, 3, or weeks 2 to 4, to further enhance tissue properties. Resultant neotissues were evaluated biochemically, mechanically, and histologically. In Phase 1, T3 and T4 treatment during week 1 resulted in significantly enhanced collagen production; 1.4- and 1.3-times untreated neocartilage. Compressive and tensile properties were also significantly increased, as compared to untreated and PTH groups. PTH treatment did not result in notable tissue changes. As T3 induces hypertrophy, in Phase 2, PTH (known to suppress hypertrophy) was applied sequentially after T3. Excitingly, sequential treatment with T3 and PTH reduced expression of hypertrophic marker collagen X, while yielding neocartilage with significantly enhanced functional properties. Specifically, in comparison to no hormone application, these hormones increased compressive and tensile moduli 4.0-fold and 3.1-fold, respectively.

This study demonstrated that T3, together with PTH, when applied in a scaffold-free model of cartilage formation, significantly enhanced functional properties. The novel use of these thyroid hormones generates mechanically robust neocartilage via the use of a scaffold-free tissue engineering model.

The study aimed to compare the etiologic spectrum of diseases causing fever of unknown origin (FUO) and methods for definitive diagnosis in a tertiary care hospital in the Republic of North Macedonia during two different time periods. There were analysed retrospectively the causes for FUO and final diagnostic approaches in 185 patients with classic FUO that were treated at the University Hospital for Infectious Diseases in Skopje during two time periods. Seventy nine patients were treated during 1991 to 1995 and 106 patients during 2011 to 2015. When comparing these two periods, infections were present in 46.8% and 29.2% (p = 0.014), non-infective inflammatory disorders in 22.8% and 25.5% (p = 0.674), neoplasms in 10.1% and 13.2% (p = 0.522), miscellaneous in 8.9% and 12.3% (p = 0.461) and undiagnosed cases in 11.4% and 19.8% (p = 0.124), respectively. The most common causes for FUO during the first period were abscesses (8.9%), tuberculosis and systemic lupus erythematosus (7.6% each), whereas in the second period the commonest causes were adult onset Still disease and solid organ neoplasm (7.6% each), polymyalgia rheumatica, abscesses and visceral leishmaniasis (5.7% each). The newer imaging techniques and clinical course evaluation had superior diagnostic significance during the second period.

A changing pattern of diseases causing FUO during the examined periods was evident. Infections continue to be the most common cause but with decreasing incidence when compared to 20 years ago. Even nowadays clinical evaluation and follow-up still remain the vital diagnostic tools in determining the etiology of FUO.

Cardiovascular morbidity and mortality appear to be enhanced in rheumatoid arthritis (RA), which might be due to an increased prevalence of cardiovascular risk factors such as dyslipidemia. It was recently shown that effective disease modifying antirheumatic drug treatment had a favorable influence on the lipid profile in patients with active RA. As infliximab markedly reduces disease activity in RA, we investigated the effects of infliximab on the lipid profile. Infliximab was administered at baseline and at 2 and 6 weeks in patients with active RA. Total cholesterol and HDL-cholesterol concentrations were measured and their ratio, the atherogenic index (an important cardiovascular risk factor indicator), was assessed. Sixty-nine patients were enrolled. The Disease Activity Index score (DAS-28) was 5.9 (SD +/- 1.4) at baseline and decreased to 4.6 (+/- 1.4) after 2 weeks and further to 4.1 (+/- 1.5) after 6 weeks. Total cholesterol level was 5.2 mmol/l at baseline and increased to 5.7 mmol/l (p < 0.001) at 2 weeks, and was 5.6 mmol/l (p < 0.001 vs baseline) at Week 6. For HDL-cholesterol these values were 1.5, 1.6 (p < 0.001), and 1.6 mmol/l (p < 0.001 vs baseline), respectively. Changes in disease activity were significantly inversely associated with changes in total cholesterol and HDL-cholesterol levels. The atherogenic index, however, remained constant. Corticosteroid use at baseline was associated with significantly higher total cholesterol and HDL-cholesterol levels and a lower (more favorable) atherogenic index at baseline.

Infliximab treatment was associated with a significant increase of both total cholesterol and HDL-cholesterol levels, which correlated with decreasing disease activity. However, this was not accompanied by a favorable effect on the atherogenic index. The favorable effect of infliximab on cardiovascular comorbidity might not be mediated by effects on lipid metabolism, but longterm investigations are needed to confirm this.

To explore relationships between immunological status, clinical features, radiographic damage, disease activity, and functional disability in Tunisian patients with rheumatoid arthritis (RA). The study was carried out in 112 patients with RA. Demographic characteristics, disease duration, disease activity score 28 (DAS28), the Health Assessment Questionnaire (HAQ), and the Sharp/van der Heijde score were collected. Anticyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) were performed. We found that anti-CCP positivity was associated with longer disease duration (P = 0.001), presence of RF (P = 4.89 × 10(-8) ), and night pain positivity (P = 0.025). Patients with positive RF had more night pain and higher anti-CCP positivity (for all P ≤ 0.05). Anti-CCP titer was correlated with disease duration (P = 0.034) and Sharp total score (P = 1.2 × 10(-4) ). Moreover, there was a significant correlation between RF and anti-CCP antibodies titers (P = 0.011). Indeed, DAS28 correlated with HAQ (P = 1.8 × 10(-7) ) and morning stiffness duration (P = 0.045). In multivariate regression analysis, the main factors associated with anti-CCP titers were radiographic damage (P = 1.625 × 10(-4) ) and RF (P = 0.013). For DAS28, only HAQ (P = 2.9 × 10(-4) ) was associated.

These findings suggest that anti-CCP antibodies are associated with RF and more severe joint damage. Moreover, disease activity is associated with functional disability.

Thymus and activation-regulated chemokine (TARC) attracts cells that express the C-C chemokine receptor type 4 (CCR4), including CD4 T cells. As expression of CCR4 is increased on peripheral T cells and intra-articular interleukin (IL)-17-producing cells in patients with rheumatoid arthritis (RA), we investigated whether TARC plays a role in the attraction of T cells to the synovial compartment. In addition, we assessed the role of classical dendritic cells (cDCs) in the production of TARC in RA. TARC was measured in synovial fluid (SF) samples from RA and osteoarthritis (OA) patients. Spontaneous and thymic stromal lymphopoietin (TSLP)-induced TARC production by mononuclear cells (MCs) and CD1c cDCs from peripheral blood (PB) and SF was assessed. The role of TARC in CD4 T-cell migration towards cDCs was assessed and the contribution of CD1c-expressing cells to TARC production was studied. TARC concentrations were higher in SF of RA patients compared to OA patients. MCs from SF produced TARC spontaneously and produced more TARC upon stimulation than paired PBMCs. Blocking TARC strongly inhibited CD4 T-cell chemotaxis by TSLP-stimulated cDCs, associated with decreased production of tumour necrosis factor (TNF)-α. Depletion of cDCs from SFMCs strongly reduced TARC production.

TARC levels are increased in RA SF and our data indicate that this results from production by SFMCs and in particular CD1c cDCs. TARC attracts T cells and TARC secretion by MCs is crucially dependent on the presence of CD1c cDCs. Considering the potential of SF cDCs to activate T cells and induce pro-inflammatory cytokine secretion, targeting intra-articular cDCs constitutes a novel therapeutic approach in RA.

This investigation examined the prevalence, symptoms, risk factors, and quality-of-life burden of swallowing disorders in rheumatoid arthritis (RA), a chronic, progressive autoimmune inflammatory disease. One hundred individuals with RA (84 women, 16 men; mean age = 61.1 years, SD = 13.1) were interviewed regarding the presence, nature, and impact of swallowing symptoms and disorders. Associations between swallowing disorders, medical factors, RA disease severity, and quality of life were examined. Forty-one percent of participants reported a current swallowing disorder that began gradually and was longstanding (most experiencing symptoms on a daily basis for at least 4 years). Symptoms compatible with solid food dysphagia contributed disproportionately to reporting a current swallowing disorder. Risk factors for dysphagia included a self-reported voice disorder, thyroid problems, esophageal reflux, and being physically inactive. Swallowing disorders increased with self-reported RA disease severity and contributed to a significantly greater burden on overall quality of life.

Chronic, longstanding swallowing disorders are common in individuals with RA and appear to increase with disease severity. Those individuals with dysphagia reported greater reductions in quality of life as compared to those without, highlighting the need for improved awareness, exploration, and management of swallowing disorders in this population.

To compare the presence of cardiovascular (CV) risk factors and established CV disease in patients with psoriatic arthritis (PsA) and the general population and to compare the 10-year risk of a fatal CV event calculated by the Systematic Coronary Risk Evaluation (SCORE) algorithm. Patients with PsA (n=338) and controls (n=50 468) were recruited from the Nord-Trøndelag Health Study 3. Age-adjusted and sex-adjusted prevalence rates of CV risk factors and comorbidity were calculated and the SCORE algorithm was applied. There was an increased prevalence of angina pectoris (5.0% vs 3.6%, p=0.01), history of percutaneous coronary intervention (2.4% vs 1.4%, p=0.04), hypertension (45.3% vs 39.3%, p=0.01), obesity (32.0% vs 22.4%) and tobacco smoking (21.3% vs 16.4%, p=0.02) in patients with PsA compared with controls. Patients with PsA had elevated levels of C reactive protein (CRP; p<0.001), body mass index (BMI; p<0.001) and triglycerides (p=0.01). The median calculated CV risk in patients with PsA was low and comparable with controls (0.87 vs 0.83, p=0.24). The distribution across CV risk classes was similar among patients with PsA and controls.

Patients with PsA have a higher risk of CV disease than the background population, although there was no difference between groups in 10-year risk of a fatal CV event estimated by SCORE. However, patients with PsA had elevated levels of CV risk factors not included in the SCORE algorithm, such as BMI, triglycerides and CRP.

The disease activities of rheumatoid arthritis (RA) tend to fluctuate between visits to doctors, and a self-assessment tool can help patients accommodate to their current status at home. The aim of the present study was to develop a novel modality to assess the disease activity of RA by a smartphone without the need to visit a doctor. This study included 65 patients with RA, 63.1 ± 11.9 years of age. The 28-joint disease activity score (DAS28) was measured for all participants at each clinic visit. The patients assessed their status with the modified Health Assessment Questionnaire (mHAQ), a self-assessed tender joint count (sTJC), and a self-assessed swollen joint count (sSJC) in a smartphone application. The patients' trunk acceleration while walking was also measured with a smartphone application. The peak frequency, autocorrelation (AC) peak, and coefficient of variance of the acceleration peak intervals were calculated as the gait parameters. Univariate analyses showed that the DAS28 was associated with mHAQ, sTJC, sSJC, and AC (p<0.05). In a stepwise linear regression analysis, mHAQ (β = 0.264, p<0.05), sTJC (β = 0.581, p<0.001), and AC (β = -0.157, p<0.05) were significantly associated with DAS28 in the final model, and the predictive model explained 67% of the DAS28 variance.

The results suggest that noninvasive self-assessment of a combination of joint symptoms, limitations of daily activities, and walking ability can adequately predict disease activity of RA with a smartphone application.

Controversy exists regarding the safety of bilateral simultaneous total hip arthroplasty, in part because of the potentially higher prevalence of pulmonary fat embolism. The purpose of the present study was to determine if unilateral and bilateral simultaneous total hip arthroplasty procedures resulted in different prevalences of fat embolization, different degrees of hemodynamic compromise, or different levels of hypoxemia or mental status changes. One hundred and fifty-six consecutive patients undergoing primary total hip arthroplasty were prospectively enrolled in the study. The study group included fifty patients undergoing bilateral simultaneous total hip arthroplasty and 106 patients undergoing unilateral total hip arthroplasty. One hundred hips were treated with a cemented stem, and 106 were treated with a cementless stem. Arterial and right atrial blood samples were obtained before implantation (baseline); at one, three, five, and ten minutes after implantation of the acetabular and femoral components; and at twenty-four and forty-eight hours after the operation. Arterial blood pressure, right atrial pressure, arterial oxygen tension, and carbon-dioxide tension were also monitored at these times. The presence of lipid and cellular contents of bone marrow was determined. The prevalence of fat embolism was not significantly different between the groups managed with bilateral and unilateral total hip arthroplasty or between the groups managed with cemented and cementless stems. Similarly, the prevalence of bone-marrow-cell embolization was not significantly different between the groups managed with bilateral and unilateral total hip arthroplasty or between the groups managed with cemented and cementless stems. Patients with bone-marrow-cell embolization had a significantly lower arterial oxygen tension (p = 0.022) and oxygen saturation (p = 0.017) than did patients without bone-marrow-cell embolization on the first postoperative day. Four patients with bone-marrow cells in the blood samples that were obtained from the right atrium on the first postoperative day had development of diffuse encephalopathy with confusion and agitation that lasted for about twenty-four hours.

The prevalence of fat and bone-marrow-cell embolization was similar in the groups managed with bilateral simultaneous and unilateral total hip arthroplasty as well as in the groups managed with cemented and cementless stems.

Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process. Eleven pairs of fibroblast strains obtained from nonlesional skin biopsies of SSc patients and age/sex/ethnicity-matched normal controls were examined for catalytic function of nuclear topo I. Immunoprecipitation (IP)-Western blots were used to examine sumoylation of fibroblast topo I. Real-time quantitative RT-PCR was used to measure transcript levels of SUMO1 and COL1A2 in the fibroblasts. Topo I in nuclear extracts of SSc fibroblasts generally showed a significantly lower efficiency than that of normal fibroblasts in relaxing equivalent amounts of supercoiled DNA. Increased sumoylation of topo I was clearly observed in 7 of 11 SSc fibroblast strains. Inhibition of SUMO1 with SUMO1 siRNA improved the catalytic efficiency of topo I in the SSc fibroblasts. In contrast, sumoylation of recombinant topo I proteins reduced their catalytic function.

The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute.

Our objective was to compare the use of both anteroposterior (AP) extended-knee X-ray and semi-flexed X-ray (current gold standard) versus the use of semi-flexed X-ray alone to detect femoro-tibial osteoarthritis (OA). Individuals 40 to 75 years of age with symptomatic hip and/or knee OA (Kellgren/Lawrence [KL] score≥2) were recruited using a multiregional prevalence survey in France. Both AP and schuss X-rays were performed and read; two years later, the same examiner, blinded to the results of the first reading, performed a second reading of the schuss X-ray. We compared the KL stages of each knee and analyzed osteophyte detection and localization, joint space narrowing (JSN), and the relationship to obesity. The analysis included 350 participants with OA of various stages. Comparing the two readings showed that a higher proportion of patients had KL≥2 when the two X-ray views were combined (right knee: P<0.0001; left knee: P<0.001). There were no differences when using the schuss X-ray alone versus in combination with an AP X-ray in terms of detecting JSN, osteophytes. A comparison of schuss X-ray alone versus AP X-ray alone demonstrated the superiority of the schuss view for evaluating JSN (P=0.0001 and P=0.0001) and no difference in osteophyte detection.

Our study shows that the schuss view alone was sufficient for detecting knee osteophytes and JSN. Using one X-ray rather than two will reduce medical costs and irradiation burden. Using two views seems preferable for epidemiological studies.

A few studies on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatments have shown the therapeutic efficacy of mycophenolate mofetil (MMF). However, the therapeutic efficacy of MMF compared with that of cyclophosphamide (CYC) in patients with AAV has not been established. We conducted a systematic review and meta-analysis to assess the efficacy of MMF as a remission induction therapy in patients with AAV comparing it with the efficacy of CYC. We searched randomised controlled trials (RCTs) comparing the efficacy of MMF with that of CYC in patients with AAV on three different websites: PubMed, Cochrane Library and Google Scholar. We compared the difference in the relative risk (RR) of each outcome based on a Mantel-Haenszel random-effects model. We analysed data from four RCTs with 300 patients for the study. The 6-month remission rate (RR 1.09, 95% CI 0.86 to 1.38, p=0.48), the 6-month ANCA negativity (RR 1.31, 95% CI 0.91 to 1.90, p=0.15) and the long-term relapse rate (RR 1.36, 95% CI 0.80 to 2.31, p=0.26) were all similar between the two treatments. The rates of death, infection and leucopenia were also similar between the two groups (RR 1.05, 95% CI 0.40 to 2.74, p=0.93; RR 1.26, 95% CI 0.79 to 2.01, p=0.33; RR 0.45, 95% CI 0.16 to 1.32, p=0.15, respectively).

We found no difference between the therapeutic efficacy of MMF and that of CYC in patients with AAV. MMF may be an alternative remission induction therapy in patients with non-life-threatening AAV.

We determined the clinical characteristics of acute gout and pseudogout in hospitalized patients and examined the morbidity of inappropriate treatment and misdirected investigation when the diagnosis of acute crystal-induced synovitis was delayed. We reviewed the medical records of 67 hospitalized adults seen in consultation consecutively by one hospital-based rheumatologist during a 64-month period between 1986 and 1991 with the diagnosis of acute gout or pseudogout. Gout was diagnosed in 41 patients, pseudogout in 24, and both crystal-induced diseases in two. The average age was 75.3 years. Polyarticular disease was common in both gout (49%) and pseudogout (42%). Fever attributable to synovitis was present in 34% of the patients and was more prevalent in patients with polyarticular (50%) than monoarticular (20%) inflammation. A quarter of the patients encountered errors in diagnosis, treatment, or both before rheumatologic consultation. Eleven patients experienced delays in diagnosis, and six patients had the correct diagnosis but received ineffective treatment.

Fever and polyarticular arthritis are noteworthy features in the hospitalized patient with acute gout or pseudogout. When the diagnosis of crystal-induced synovitis is overlooked, misdirected investigation and inappropriate treatment compound the morbidity of continued pain.

Despite the potential burden of foot pain, some of the most fundamental epidemiologic questions surrounding the foot remain poorly explored. The prevalence of foot pain has proven to be difficult to compare across existing studies due to variations in case definitions. The objective of this study was to investigate the prevalence of foot pain in several international population-based cohorts using original data and to explore differences in the case definitions used. Foot pain variables were examined in 5 cohorts: the Chingford 1000 Women Study, the Johnston County Osteoarthritis Project, the Framingham Foot Study, the Clinical Assessment Study of the Foot, and the North West Adelaide Health Study. One question about foot pain was chosen from each cohort based on its similarity to the American College of Rheumatology pain question. The precise definition of foot pain varied between the cohorts. The prevalence of foot pain ranged from 13% to 36% and was lowest in the cohort in which the case definition specific to pain was used, compared to the 4 remaining cohorts in which a definition included components of pain, aching, or stiffness. Foot pain was generally more prevalent in women and obese individuals and generally increased with age, with the prevalence being much lower in younger participants (ages 20-44 years).

Foot pain is common and is associated with female sex, older age, and obesity. Estimates of the prevalence of foot pain are likely to be affected by the case definition used. Therefore, in future population studies, the use of consistent measures of data collection must be considered.

Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2.

Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.

The aim of this study is to explore whether the polymorphisms of rs475688 and rs3825016 in the solute carrier family 22 member 12 (SLC22A12) gene are associated with the susceptibility to gout or hyperuricaemia. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95% confidence interval (CI) were used to evaluate the associations. Q-test and I2 statistics were used to evaluate the heterogeneity. Publication bias was evaluated using Begg's funnel plots and Egger regression test. A total of 7 articles involving 1216 patients and 1844 healthy controls were included in this meta-analysis. Significant association was detected between rs475688 polymorphism and gout susceptibility in three genetic models (C vs. T: OR=1.464, 95% CI 1.078-1.989, p=0.015; CC+CT vs. TT: OR=2.028, 95% CI 1.488-2.763, p=0.000; CC vs. CT+TT: OR=2.226, 95% CI 1.746-2.838, p=0.000). Significant association was observed between rs3825016 polymorphism and hyperuricaemia susceptibility only in allelic comparison (C vs. T: OR=1.274, 95% CI 1.101-1.474, p=0.001).

The rs475688 polymorphism is associated with gout susceptibility. The correlation between rs3825016 polymorphism of SLC22A12 and hyperuricaemia susceptibility is possible.

To examine the trend of Prosthetic Joint Infections (PJI) following primary total hip arthroplasty (THA) and the antimicrobial resistance of the bacteria causing these infections. We identified a population-based cohort of patients in the Danish Hip Arthroplasty Register (DHR) who had primary THA and received their surgery in Jutland or Funen between 2005 and 2014. We followed the patients until revision, emigration, death, or up to 1-year of follow-up. Data from the DHR were combined with those from microbiology databases, the National Register of Patients, and the Civil Registration System. We estimated the cumulative 1-year incidence of PJI for two 5-year periods; 2005-2009 and 2010-2014. The hazard ratio of PJI as a measure of relative risk after adjusting for multiple risk factors was calculated. Of 48,867 primary THAs identified, 1120 underwent revision within 1 year. Of these, 271 were due to PJI. The incidence of PJI was 0.53% (95% confidence interval (CI): 0.44; 0.63) during 2005-2009 and 0.57% (95% CI: 0.49; 0.67) during 2010-2014. The adjusted relative risk was 1.05 (95% CI: 0.82; 1.34) for the 2010-2014 period vs the 2005-2009 period. The most common micro-organisms identified in the 271 PJI were Staphylococcus aureus (36%) and coagulase-negative staphylococci (CoNS) (33%); others commonly identified included Enterobacteriaceae, enterococci, and streptococci. Antimicrobial resistance to beta-lactams and gentamicin did not change during the study period.

The risk of PJI within 1-year after primary THA and the antimicrobial resistance of the most prevalent bacteria remained unchanged during the 2005-2014 study period.

Genuine uncertainty on superiority of one intervention over the other is called equipoise. Physician-investigators in randomized controlled trials (RCT) need equipoise at least in studies with more than minimal risks. Ideally, this equipoise is also present in patient-participants. In pediatrics, data on equipoise are lacking. We hypothesize that 1) lack of equipoise at enrolment among parents may reduce recruitment; 2) lack of equipoise during participation may reduce retention in patients assigned to a less favoured treatment-strategy. We compared preferences of parents/patients at enrolment, documented by a questionnaire (phase 1), with preferences developed during follow-up by an interview-study (phase 2) to investigate equipoise of child-participants and parents in the BeSt-for-Kids-study (NTR 1574). This trial in new-onset Juvenile Idiopathic Arthritis-patients consists of three strategies. One strategy comprises initial treatment with a biological disease-modifying-antirheumatic-drug (DMARD), currently not standard-of-care. Semi-structured interviews were conducted with 23 parents and 7 patients, median 11 months after enrolment. Initially most parents and children were not in equipoise. Parents/patients who refused participation, regularly declined due to specific preferences. Many participating families preferred the biological-first-strategy. They participated to have a chance for this initial treatment, and would even consider stopping trial-participation when not randomized for it. Their conviction of superiority of the biological-first strategy was based on knowledge from internet and close relations. According to four parents, the physician-investigator preferred the biological-first-strategy, but the majority (n = 19) stated that she had no preferred strategy. In phase 2, preferences tended to change to the treatment actually received.

Lack of equipoise during enrolment did not reduce study recruitment, mainly due to the fact that preferred treatment was only available within the study. Still, when developing a trial it is important to evaluate whether the physicians' research question is in line with preferences of the patient-group. By exploring so-called 'informed patient-group'-equipoise, successful recruitment may be enhanced and bias avoided. In our study, lack of equipoise during trial-participation did not reduce retention in those assigned to a less favoured option. We observed a change for preference towards treatment actually received, possibly explained by comparable outcomes in all three arms.

The chemokine molecule CXCL5 (C-X-C motif chemokine ligand 5, also known as epithelial neutrophil activating peptide 78 -ENA78-) constitutes a link between obesity, inflammation and insulin resistance (IR) in the general population. CXCL5 has also been found to play a role in rheumatoid arthritis (RA) pathogenesis. Since chronic inflammation promotes IR and impairs pancreatic beta cell function in RA patients, we assessed the role of CXCL5 in the development of IR in RA. Cross-sectional study that encompassed 141 non-diabetic patients with RA. IR assessed by homeostatic model assessment (HOMA2), insulin and C-peptide serum levels and lipid profile, and CXCL5 serum levels were studied. Regression analysis was performed to evaluate how CXCL5 was related to IR, disease activity, and disease characteristics in RA patients. HOMA2-IR indexes showed high values for both IR and beta cell production (%B), and low insulin sensitivity (%S) in patients with RA. C reactive protein (beta coef. 0.2 [95%CI -1.5-1.9], p=0.80) and disease activity through DAS28 (beta coef. 13 [95%CI -14-41], p=0.34) revealed no relation with CXCL5. Other disease characteristics, such as disease duration, serological status, or use of methotrexate or anti-TNF alpha therapies, were not associated with CXCL5 serum levels. While glucocorticoids were related to insulin, C-peptide serum levels, and HOMA2-IR and HOMA2-%B-C peptide, the use of prednisone was not associated with CXCL5 serum levels. Insulin and C peptide serum levels and IR indexes showed strong correlations among each other, but not with CXCL5 (insulin r2=-0.034, p=0.69; C peptide r2=-0.050, p=0.56).

CXCL5 is not related to IR in RA patients. Therefore, the mechanisms leading to IR in patients with RA may be different from those in the general population.

This paper aims to explore the functional significance of the P2X7 receptor in preclinical models of rheumatoid arthritis. Preclinical studies in vivo were performed using the rat streptococcal cell wall (SCW) arthritis model. Ex vivo cultures of lipopolysaccharide (LPS)/benzoylbenzoyl adenosine triphosphate (BzATP)-stimulated human monocytes were generated to test the activities of a novel, highly specific inhibitor of human P2X7, AZD9056, on interleukin (IL)-1 and IL-18 release. P2X7 receptor expression was detected in inflamed synovial tissue after onset of SCW-induced arthritis in rats. Inhibition of P2X7 therein led to reduced articular inflammation and erosive progression. No effect was noted on acute-phase responses. Ex vivo, AZD9056 inhibited IL-1 and IL-18 release to BzATP in LPS-primed human monocytes.

P2X7 receptor inhibition could represent a novel approach to the treatment of inflammatory arthritis. However, confirmatory clinical studies are warranted to further explore this possibility.

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease. As a member of FCRLs clusters, Fc receptor-like 3 (FCRL3) has been recognized as a neoteric autoimmune activation factor for RA. The aim of our study is to evaluate the correlation between four single-nucleotide polymorphisms (SNPs) on FCRL3 and RA risk in a Chinese Han population. The hospital-based case-control study included 630 RA patients together with 696 healthy individuals as the control group and all subjects are Chinese ancestry. Four tagging single-nucleotide polymorphisms (tag-SNPs) on FCRL3 were selected and genotyped by TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were employed to evaluate the correlations between FCRL3 polymorphisms and RA. A systematic meta-analysis was also carried out based on the present study and previously published studies to further examine the association between FCRL3 variations and RA risk. Significant association was found between -169T/C SNP and RA risk (CC vs. TT, OR=1.62, 95% CI=1.18-2.22; TC/CC vs. TT, OR=1.47, 95% CI=1.18-1.84; C vs. T, OR=1.32, 95% CI=1.12-1.54). Apart from that, mutations of -169T/C was significantly correlated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) positive status. The meta-analysis also suggested that -169T/C mutation might have positive correlation with risk of RA in the overall population, particularly for Asian. Stratified analysis based on clinical characteristics of RF and ACPA also provided evidence that -169T/C polymorphisms could alter phenotypes of RA.

The FCRL3 -169T/C variant was significantly linked with an increased RA risk in the Chinese Han population. Moreover, this meta-analysis also provides notion that -169T/C variant could act as a susceptible factor for RA. However, further investigations about the functional impacts of this polymorphism are essential to confirm the above conclusions.

To compare risk of cardiovascular disease and mortality in patients with incident RA, diabetes mellitus (DM) and the general population (GP). Patients diagnosed with incident RA were matched 1:5 by age, sex and year of RA diagnosis with the GP. In the same period, patients with incident DM were included. Outcomes were heart failure (HF), myocardial infarction (MI), coronary revascularization, stroke, major adverse cardiovascular events (MACE) and death up to 10 years after diagnosis. We included 15 032 patients with incident RA, 301 246 patients with DM and 75 160 persons from the GP. RA patients had an increased risk of HF [hazard ratio (HR) 1.51, 95% CI: 1.38, 1.64], MI (HR 1.58, 95% CI: 1.43, 1.74), percutaneous coronary intervention (PCI; HR 1.44, 95% CI: 1.27, 1.62), coronary artery bypass grafting (CABG; HR 1.30, 95% CI: 1.05, 1.62) and stroke (HR 1.22, 95% CI: 1.12-1.33) compared with the GP. However, the 10-year all-cause mortality was at the same level as observed in the GP. Cardiac death and MACE were increased in RA compared with the GP. When compared with patients with DM, RA patients had a lower adjusted risk of HF (HR 0.79, 95% CI: 0.73, 0.85), CABG (HR 0.62, 95% CI: 0.51, 0.76) and stroke (HR 0.82, 95% CI: 0.76, 0.89), and similar risk of MI and PCI. DM patients had the highest risk of 10-year mortality, cardiac death and MACE.

This study demonstrates that RA is associated with an increased risk of HF, MI, stroke and coronary revascularization than found in the GP but without reaching the risk levels observed in DM patients.