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Showing papers in "Arthritis & Rheumatism in 2013"


Journal ArticleDOI
TL;DR: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Watts; Arthritis & Rheumatism
Abstract: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

4,249 citations


Journal ArticleDOI
TL;DR: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria and should allow for more patients to be classified correctly as having the disease.
Abstract: OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

2,743 citations


Journal ArticleDOI
TL;DR: Although EGPA relapses remain frequent, mortality has declined, at least since 1996, and multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse.
Abstract: OBJECTIVE: Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes. METHODS: A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis. RESULTS: We identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean±SD of 66.8±62.5 months. At diagnosis, their mean±SD age was 50.3±15.7 years, and 91.1% had asthma (duration 9.3±10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA-negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8-74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse. CONCLUSION: The characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.

645 citations


Journal ArticleDOI
TL;DR: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI, and individual CSMs improved in both groups throughout the 44-week trial.
Abstract: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired disorders characterized by chronic inflammation of striated muscle leading to predominantly proximal muscle weakness. The most common subsets of IIM include adult polymyositis (PM), adult and juvenile dermatomyositis (DM), myositis in overlap with cancer or another connective tissue disease and inclusion body myositis (IBM). The IIM are frequently associated with constitutional symptoms and commonly involve other organ systems including the skin, joints, lungs, gastrointestinal tract and heart. They are rare with an estimated incidence of 4-10 cases/million population per year and a bimodal incidence pattern reflecting childhood onset of juvenile DM (JDM) and a later peak in adulthood [1]. Although the precise pathogenesis is unknown, the IIM likely result from immune-mediated processes initiated by environmental factors in genetically susceptible individuals [2]. Factors strongly supporting their autoimmune basis include: the association of myositis with other autoimmune diseases such as Hashimoto thyroiditis, Grave’s disease and various connective tissue diseases, the high frequency of circulating serum autoantibodies, and their response to immunosuppressive (IS) or immunomodulatory therapy. The treatment of IIM is challenging, complicated by its rarity and heterogeneity as well as the lack of controlled trials and partially validated outcome measures. Most studies involve single referral centers using cross-sectional and retrospective analyses of small numbers of treatmentrefractory patients observed for relatively short time periods. In addition, widely disparate inclusion criteria have complicated the assessment of treatment response, as disease damage and the inclusion of misdiagnosed patients contribute to suboptimal therapeutic outcomes. Although glucocorticoids have not been formally tested in controlled trials, expert consensus is that they are the primary therapy to be followed by a variety of immunosuppressive or immunomodulatory agents alone or in combination [2]. Rituximab, a B cell depleting agent long recognized as an effective therapy for B cell lymphomas, has gained increased favor in the treatment of many autoimmune diseases and is FDA-approved for use in rheumatoid arthritis [3] as well as granulomatosis with polyangiitis and microscopic polyangiitis [4]. The effectiveness of rituximab in PM and DM has been suggested by case reports and case series in adult and pediatric patients with refractory disease [5-9]. B cells play a critical role in the initiation and propagation of the immune response and are implicated in the pathogenesis of myositis. They localize to the perivascular region of DM muscle and are found in the inflammatory infiltrates of both PM and DM [10]. In addition to functioning as the precursor of autoantibody-producing plasma cells, B cells present antigen to T cells and secrete proinflammatory cytokines [10]. Therefore, based on the autoimmune characteristics of myositis and the aforementioned immunopathogenic role of the B cell, the Rituximab in Myositis (RIM) trial assessed the effectiveness of rituximab in refractory adult PM and adult and juvenile DM using validated measures of myositis disease activity and damage, a consensus-driven definition of improvement [11-13] and a unique randomized placebo-phase trial design [14, 15].

501 citations


Journal ArticleDOI
TL;DR: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.
Abstract: Objective The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) Data from a planned 12-month interim analysis are reported Methods In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months Four primary efficacy end points were all analyzed in a step-down procedure Results At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (515% and 618%, respectively, versus 253%; both P < 00001) At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 012 and 006, respectively, versus 047 for placebo (P = 00792 and P ≤ 005, respectively) At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were –040 (significance not declared due to step-down procedure) and –054 (P < 00001), respectively, versus –015 for placebo At month 6, rates of remission (defined as a value <26 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 72% (significance not declared due to step-down procedure) and 160% (P < 00001), respectively, versus 16% for placebo The safety profile was consistent with findings in previous studies Conclusion Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX

486 citations


Journal ArticleDOI
TL;DR: Treatment with TNFα inhibitors appears to reduce radiographic progression in patients with ankylosing spondylitis, especially with early initiation and with longer duration of followup, and the protective effect of TNF α inhibitors was stronger after propensity score matching.
Abstract: Objective To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS). Methods All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n = 334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA–B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model. Results TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30–0.88, P = 0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09–5.3], P = 0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching. Conclusion Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

409 citations


Journal ArticleDOI
TL;DR: There was sociodemographic variation in SLE and LN prevalence and incidence in this nationwide Medicaid population, and the areas with lowest SES had the highest prevalence; areas with the fewest ACR rheumatologists had the lowest prevalence.
Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with substantial variation by sex, race, ethnicity and socioeconomic status (1–4). Past estimates of SLE prevalence in the adult U.S. population range from 24 to 150 per 100,000 (5, 6) and incidence from 2.2 to 5.6 per 100,000 (7, 8) (Table 1). Despite the wide variation in these estimates, rates are consistently higher in women compared to men and in African Americans compared to Caucasians. Prior studies also suggest increased prevalence among Asians, Hispanics and Native Americans (2, 9–11). To date, however, there are no U.S. nationwide administrative database examinations of the sociodemographics of adult SLE prevalence or incidence. A number of studies suggest that lupus nephritis (LN), one of the most severe manifestations of SLE, is both more common and more severe in racial and ethnic minorities, and progression to end-stage renal disease is higher in minority, uninsured, and low socioeconomic status (SES) groups (3, 11–18). Currently, no studies are available that investigate the prevalence or incidence of LN in a large, low-income U.S. population. Table 1 Previous Estimates of the Prevalence and Incidence of Systemic Lupus Erythematosus (SLE) in the U.S. per 100,000 Adults In this study we used nationwide Medicaid claims data to investigate sociodemographic differences in the incidence and prevalence of SLE and LN among U.S. adults. Medicaid is a U.S. federal-state jointly run insurance program that provides health and long-term care coverage to eligible low-income individuals (19). Within this population, we investigated whether county-level SES and the number of rheumatologists per state (approximated using American College of Rheumatology (ACR) members), were related to differences in incidence and prevalence of SLE and LN, and the degree to which these variables could explain variation by race and ethnicity. Our goal was to provide a better understanding of the burden of SLE and LN among low-income, high-risk U.S. adults, which will encourage the necessary allocation of resources for early detection and essential treatment. We hypothesized that there would be significant variation in incidence and prevalence of SLE and LN by sociodemographic group, but that SES and the number of rheumatologists would modify these differences.

359 citations


Journal ArticleDOI
TL;DR: The results suggest that central sensitization in knee OA is especially apparent among patients with reports of high levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes of knee Oa.
Abstract: Objective Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures.

357 citations



Journal ArticleDOI
TL;DR: These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities and are present in most patients with cancer-associated DM.
Abstract: Dermatomyositis (DM) is a systemic disease characterized by chronic inflammation in the skin and muscle. There is significant clinical heterogeneity with respect to lung or muscle inflammation, patterns of cutaneous inflammation, association with internal malignancy, and response to therapy. Many patients with DM have circulating autoantibodies, which are often associated with distinct clinical phenotypes (1,2). Interestingly, autoantibodies in DM tend to be mutually exclusive, suggesting that specific immune responses might play a role in shaping different phenotypes. It is well established that a subset of DM patients (10–20%) is at increased risk of internal malignancy around the time of DM diagnosis (3). Identification of patients at high risk of cancer remains a high priority for physicians treating these patients. Recent studies have identified 3 new autoantibody specificities in DM: melanoma differentiation–associated protein 5 (MDA-5), transcription intermediary factor 1γ (TIF-1γ), and nuclear matrix protein NXP-2 (also known as MORC3) (4–9). These antigens all migrate similarly on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) gels (145–155 kd). Anti–MDA-5 antibodies are found in ~10–20% of DM patients (7,10–12) (and in up to 65% of patients with clinically amyopathic disease [6,10,13,14]) and are associated with interstitial lung disease (often rapidly progressive, especially in Asians), mild or absent muscle disease, cutaneous ulceration, palmar papules, arthritis/arthralgia, and alopecia (6,11,15). Anti–TIF-1γ antibodies are frequently found in cancer-associated DM (4,13,16–18), including in 2 studies with largely Caucasians (19,20). For adult DM patients with antibodies to TIF-1γ, the percentage of patients harboring a malignancy ranges from 42% to 100%, depending on the study (4,13,16–18). In juvenile DM patients, antibodies to TIF-1γ are not associated with malignancy, but rather, with skin ulceration and more extensive cutaneous disease (21). NXP-2 has also been identified as an autoantibody target in a subset (1.6–30%) of adult DM patients (22–25). Originally identified as MJ in the juvenile DM population, this antigen appeared to be targeted by antibodies in patients with a higher risk of cutaneous calcinosis cutis (5,26). In adult DM patients, antibodies to NXP-2 are not associated with any obvious phenotype other than a trend toward increased risk of calcinosis cutis in 1 study (23). One study of adult Japanese DM patients suggested an association with malignancy (3 of 7 anti–NXP-2–positive patients had a primary malignancy); however, this association was difficult to verify given the small numbers of anti–NXP-2–positive patients (24). There are several major drawbacks of previous studies looking at antibody associations with cancer in DM. The assays used to detect these antibodies lack sensitivity and specificity, given that NXP-2, TIF-1γ proteins, and MDA-5 migrate similarly on gel electrophoresis and may not be optimally expressed using standard cell lines and culture conditions. Additionally, many of the cohorts or antibody-positive patients have been relatively small in number. In this study, we provide definitive evidence that antibodies to NXP-2 and TIF-1γ identify the vast majority of the patients with cancer-associated DM in 2 separate, well-defined DM cohorts.

314 citations


Journal ArticleDOI
TL;DR: Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.
Abstract: Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient's individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. The American College of Rheumatology is an independent, professional, medical and scientific society which does not guarantee, warrant, or endorse any commercial product or service.

Journal ArticleDOI
TL;DR: In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo, and treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.
Abstract: Objective To investigate the efficacy and safety of ocrelizumab in patients with class III/IV lupus nephritis (LN). Methods Patients were randomized 1:1:1 to receive placebo, 400 mg ocrelizumab, or 1,000 mg ocrelizumab given as an intravenous infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter, accompanied by background glucocorticoids plus either mycophenolate mofetil (MMF) or the Euro-Lupus Nephritis Trial (ELNT) regimen (cyclophosphamide followed by azathioprine). The study was terminated early due to an imbalance in serious infections in ocrelizumab-treated patients versus placebo-treated patients. We report week 48 efficacy data for patients receiving ≥32 weeks of treatment (n = 223) and safety results for all treated patients (n = 378). Results The overall renal response rate was 54.7%, 66.7%, 67.1%, and 66.9% in the placebo-treated, 400 mg ocrelizumab–treated, 1,000 mg ocrelizumab–treated, and combined ocrelizumab-treated groups, respectively. The associated treatment difference versus placebo for the combined ocrelizumab-treated groups was 12.7% (95% confidence interval [95% CI] −0.8, 26.1) (P = 0.065), with similar differences observed for both ocrelizumab-treated groups. Ocrelizumab versus placebo treatment differences were apparent in patients receiving the background ELNT regimen, but not in those receiving background MMF. A numerically greater proportion of ocrelizumab-treated patients had a ≥50% reduction in the urinary protein:urinary creatinine ratio at 48 weeks compared with placebo-treated patients (placebo-treated patients, 58.7%; 400 mg ocrelizumab–treated patients, 70.7%; 1,000 mg ocrelizumab–treated patients, 68.5%). Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab–treated patients, and 22.0% of 1,000 mg ocrelizumab–treated patients. Corresponding serious infection rates (events/100 patient-years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen. Conclusion In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.

Journal ArticleDOI
TL;DR: It is demonstrated that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment.
Abstract: Objective There is a need for comparative studies to provide evidence-based treatment guidance for biologic agents in rheumatoid arthritis (RA). Therefore, this study was undertaken as the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA. Methods Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2-year study. The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year. Results Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval −5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept–treated patients and 88.6% for SC adalimumab–treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P = 0.006). Conclusion The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.

Journal ArticleDOI
TL;DR: A strong relationship of valgus malalignment with progressive lateral meniscal damage is found, which may cause these effects, in part, by increasing the risk of meniscalDamage.
Abstract: Objective. To study the effect of valgus malalignment on knee osteoarthritis (OA) incidence and progression. Methods. We measured the mechanical axis from long limb radiographs from the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI) to define limbs with valgus malalignment (mechanical axis of >= 1.1 degrees valgus) and examined the effect of valgus alignment versus neutral alignment (neither varus nor valgus) on OA structural outcomes. Posteroanterior radiographs and knee magnetic resonance (MR) images were obtained at the time of the long limb radiograph and at followup examinations. Lateral progression was defined as an increase in joint space narrowing (on a semiquantitative scale) in knees with OA, and incidence was defined as new lateral narrowing in knees without radiographic OA. We defined lateral cartilage damage and progressive meniscal damage as increases in cartilage or meniscus scores at followup on the Whole-Organ Magnetic Resonance Imaging Score scale (for the MOST) or the Boston Leeds Osteoarthritis Knee Score scale (for the OAI). We used logistic regression with adjustment for age, sex, body mass index, and Kellgren/Lawrence grade, as well as generalized estimating equations, to evaluate the effect of valgus alignment versus neutral alignment on disease outcomes. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Results. We studied 5,053 knees (881 valgus) of subjects in the MOST cohort and 5,953 knees (1,358 valgus) of subjects in the OAI cohort. In both studies, all strata of valgus malalignment, including 1.1 degrees to 3 degrees valgus, were associated with an increased risk of lateral disease progression. In knees without radiographic OA, valgus alignment >3 degrees was associated with incidence (e. g., in the MOST, adjusted OR 2.5 [95% CI 1.0-5.9]). Valgus alignment >3 degrees was also associated with cartilage damage on MR imaging in knees without OA (e. g., in the OAI, adjusted OR 5.9 [95% CI 1.1-30.3]). We found a strong relationship of valgus malalignment with progressive lateral meniscal damage. Conclusion. Valgus malalignment increases the risk of knee OA radiographic progression and incidence as well as the risk of lateral cartilage damage. It may cause these effects, in part, by increasing the risk of meniscal damage.

Journal ArticleDOI
TL;DR: In this article, the authors evaluated the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).
Abstract: Objective To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. Results Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. Conclusion The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

Journal ArticleDOI
TL;DR: Circulating miRNAs are systematically altered in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.
Abstract: Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes. (Less)

Journal ArticleDOI
TL;DR: Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc-associated PAH, revealing a poor pooled 3-year survival rate.
Abstract: Objective Pulmonary hypertension (PH) is a frequent and life-limiting complication of systemic sclerosis (SSc). However, data on survival rates and their evolution over time, as well as prognostic factors in SSc complicated by PH, are still conflicting. The aim of this study was to conduct a systematic review and meta-analysis of cohort studies to assess pooled survival and prognostic factors for survival in patients with SSc–associated PH. Methods For this systematic review and meta-analysis, we searched the Medline and EMBase databases (January 1960 to January 2012). All cohort studies in which survival and/or prognostic factors for SSc–associated PH were reported were included in the analysis. We calculated the pooled survival rates and analyzed their evolution over time and identified prognostic factors for survival. Results Twenty-two studies were included, representing a total of 2,244 patients with SSc–associated PH. The pooled 1-, 2-, and 3-year survival rates were 81% (95% confidence interval [95% CI] 79–84%), 64% (95% CI 59–69%), and 52% (95% CI 47–58%), respectively. Meta-regression did not reveal a significant change in survival over time, while baseline hemodynamic measures of PH severity were significantly correlated with survival. In patients with SSc complicated by pulmonary arterial hypertension (PAH), age, male sex, diffusing capacity for carbon monoxide (DLCO), pericardial effusion, and the parameters classically associated with the severity of idiopathic PAH, including the 6-minute walk distance, mean pulmonary artery pressure, cardiac index, and right atrial pressure, were significant prognostic factors. DLCO and pericardial effusion were the only prognostic factors in patients with interstitial lung disease–related PH. Conclusion Our meta-analysis revealed a poor pooled 3-year survival rate of 52% in patients with SSc–associated PH. Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc–associated PAH. All of the prognostic factors typically observed in idiopathic PAH, including the 6-minute walk distance and right atrial pressure, were also prognostic factors in SSc–associated PAH.

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TL;DR: The presence of renal disease, in particular proliferative nephritis causing renal insufficiency, significantly reduces the survival and life expectancy of SLE patients.
Abstract: Objective To study the effect of renal disease on the standardized mortality ratio (SMR) and life expectancy of patients with systemic lupus erythematosus (SLE). Methods Patients whose diagnosis met ≥4 American College of Rheumatology criteria for SLE were longitudinally followed up from 1995 to 2011. The cumulative survival rate, SMR, and life expectancy were calculated, and the effect of renal involvement, histologic class of lupus nephritis, renal damage, and end-stage renal disease (ESRD) on these parameters was evaluated. Results Of the 694 SLE patients studied, 368 (53%) had renal disease, and the distribution of histologic classes (among 285 patients) was class I (1%), class II (6%), class III (19%), class IV (47%), class III/IV + class V (10%), and class V (16%). Renal damage was present in 79 patients (11%), and 24 (3%) developed ESRD. The age- and sex-adjusted hazard ratios (HRs) of mortality in SLE patients with renal disease, those with renal damage, and those with ESRD, as compared to those without, were 2.23 (95% confidence interval [95% CI] 1.29–3.85), 3.59 (95% CI 2.20–5.87), and 9.20 (95% CI 4.92–17.2), respectively. Proliferative lupus nephritis (adjusted HR 2.28, 95% CI 1.22–4.24), but not the pure membranous type (adjusted HR 1.09, 95% CI 0.38–3.14), was associated with a significant increase in mortality. The age- and sex-adjusted SMRs of SLE patients without renal involvement, those with lupus nephritis, those with proliferative nephritis, those with pure membranous nephritis, those with renal damage, and those with ESRD were 4.8 (95% CI 2.8–7.5), 9.0 (95% CI 6.7–11.9), 9.8 (95% CI 6.5–14.1), 6.1 (95% CI 2.0–14.1), 14.0 (95% CI 9.1–20.5), and 63.1 (95% CI 33.6–108.0), respectively. The life expectancy of SLE patients with renal disease and those with renal damage was reduced by 15.1 years and 23.7 years, respectively, compared to the general population. Conclusion The presence of renal disease, in particular proliferative nephritis causing renal insufficiency, significantly reduces the survival and life expectancy of SLE patients.

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TL;DR: Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of antiphospholipid syndrome.
Abstract: Objective The primary objective of this study was to evaluate the safety of rituximab in antiphospholipid antibody (aPL)–positive patients with non-criteria manifestations of antiphospholipid syndrome (APS). The secondary objectives were to evaluate the effect of rituximab on the aPL profile and to evaluate the efficacy of rituximab treatment for non-criteria manifestations of APS. Methods In this 12-month, phase II pilot study, adult aPL-positive patients with thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and/or cognitive dysfunction received 2 doses of rituximab (1,000 mg) on days 1 and 15. Antiphospholipid antibody profiles and clinical outcome measures, which were categorized as complete response, partial response, no response, or recurrence, were analyzed at preset time points. Results Two of 19 patients experienced infusion reactions, resulting in early termination. Twelve serious adverse events and 49 nonserious adverse events were recorded. All patients who had positive results of lupus anticoagulant, anticardiolipin, and anti–β2-glycoprotein I antibody tests at baseline had positive results at 24 weeks and 52 weeks. The numbers of patients with a complete response, a partial response, no response, and recurrence for the clinical outcome measures at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively. Conclusion The results of this uncontrolled and nonrandomized pilot study suggest that the safety of rituximab in aPL-positive patients is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

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TL;DR: Modifications of the AECG criteria, including the addition of a SGUS score, notably improved diagnostic performance and suggested modifications of the American-European Consensus Group (AECG) classification criteria.
Abstract: Objective To determine the accuracy of salivary gland ultrasonography (SGUS) for diagnosing primary Sjogren's syndrome (SS) and to suggest modifications of the American–European Consensus Group (AECG) classification criteria. Methods We conducted a cross-sectional study in a prospective cohort of patients with suspected primary SS that was established between 2006 and 2011. The echostructure of the bilateral parotid and submandibular glands was graded from 0 to 4, and the gland size was measured; blood flow to the parotid gland was assessed using Doppler waveform analysis. The reference standard was a clinical diagnosis of primary SS as determined by a group of experts blinded to the results of SGUS. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic value of the 0–4-point echostructure grade for each of the 4 major salivary glands, the sum of the grades for the 4 glands, and the highest grade among the 4 glands. Results Of the 158 patients in the study, 78 had a diagnosis of primary SS according to the experts, including 61 patients (78.2%) who met the AECG criteria. Doppler waveform analysis and gland size measurement showed poor diagnostic performance. The results of ROC curve analysis showed that the highest grade among the 4 glands provided the best diagnostic value. The optimal grade cutoff was 2 (62.8% sensitivity and 95.0% specificity). A weighted score was constructed using scores for the 5 variables selected by logistic regression analysis, as follows: (salivary flow × 1.5) + (Schirmer's test × 1.5) + (salivary gland biopsy × 3) + (SSA/SSB × 4.5) + (SGUS × 2). According to ROC curve analysis, a score of ≥5 of 12.5 had 85.7% sensitivity and 94.9% specificity, compared with 77.9% sensitivity and 98.7% specificity for the AECG criteria. The addition of SGUS to the AECG criteria increased sensitivity to 87.0% but did not change specificity. Conclusion Modifications of the AECG criteria, including the addition of a SGUS score, notably improved diagnostic performance.

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TL;DR: The antiinflammatory effects of AD-MSCs are probably not dependent onAD-MSC adipose tissue sources and donors but rather on the inflammatory status of OA chondrocytes and synoviocytes, suggesting that AD- MSCs may be useful for therapies in osteoarticular diseases.
Abstract: Objective To examine the effect of different sources of Good Manufacturing Practice clinical grade adipose-derived mesenchymal stem cells (AD-MSCs) on inflammatory factors in osteoarthritic (OA) chondrocytes and synoviocytes. Methods AD-MSCs from infrapatellar Hoffa fat, subcutaneous (SC) hip fat, and SC abdominal fat were cocultured in Transwells with chondrocytes or synoviocytes. Inflammatory factors (interleukin-1β [IL-1β], tumor necrosis factor α, IL-6, CXCL1/growth-related oncogene α, CXCL8/IL-8, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α, and CCL5/RANTES) were evaluated by quantitative reverse transcription–polymerase chain reaction or multiplex bead–based immunoassay. The role of different immunomodulators was analyzed. Results All the inflammatory factors analyzed were down-modulated at the messenger RNA or protein level independently by all 3 AD-MSC sources or by allogeneic AD-MSCs used in coculture with chondrocytes or synoviocytes. Inflammatory factor down-modulation was observed only when AD-MSCs were cocultured with chondrocytes or synoviocytes that produced high levels of inflammatory factors, but no effect was observed in cells that produced low levels of those factors, thus highlighting a dependence of the AD-MSC effect on existing inflammation. The immunomodulators IL-10, IL-1 receptor antagonist, fibroblast growth factor 2, indoleamine 2,3-dioxygenase 1, and galectin 1 were not involved in AD-MSC effects, whereas the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway exerted a role in the mechanism of antiinflammatory AD-MSC action. Conclusion The antiinflammatory effects of AD-MSCs are probably not dependent on AD-MSC adipose tissue sources and donors but rather on the inflammatory status of OA chondrocytes and synoviocytes. AD-MSCs seem to be able to sense and respond to the local environment. Even though a combination of different molecules may be involved in AD-MSC effects, the COX-2/PGE2 pathway may play a role, suggesting that AD-MSCs may be useful for therapies in osteoarticular diseases.

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TL;DR: A systematic review of the literature on the screening and diagnosis of PAH in CTD provided consensus-based, evidence-driven recommendations that will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.
Abstract: Objective Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH. Methods We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations. Results The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro–brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present. Conclusion We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

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TL;DR: Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels of antibodies against CEP-1, Fibβ36-52, and filaggrin, increasing during the predating time period closer to the onset of symptoms.
Abstract: Objective The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this stud ...

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TL;DR: RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA, suggesting an important role of the lung in the pathogenesis of RA.
Abstract: Objective To evaluate the generation of rheumatoid arthritis (RA)–related autoantibodies in the lung. Methods Simultaneous collection of serum and induced sputum was performed in 21 healthy controls, 49 at-risk subjects without inflammatory arthritis but at risk of RA due to family history or seropositivity for anti–citrullinated protein antibodies, and 14 subjects with early RA. Samples were tested for anti–cyclic citrullinated peptide 2 (anti-CCP2), anti-CCP3, anti-CCP3.1, rheumatoid factor isotypes IgM, IgG, and IgA, and total IgM, IgG, and IgA. Results One or more autoantibodies were present in sputum of 39% of at-risk seronegative subjects, 65% of at-risk seropositive subjects, and 86% of subjects with early RA. In at-risk seronegative subjects, the rate of anti-CCP3.1 positivity and the median number of autoantibodies were elevated in sputum versus serum. In subjects with early RA, the rate of positivity for several individual autoantibodies and the median number of autoantibodies were higher in serum than in sputum. Results in at-risk seropositive subjects were intermediate between these groups. In at-risk subjects with autoantibody positivity in sputum, the ratios of autoantibody to total Ig were higher in sputum than in serum, suggesting that these autoantibodies are generated or sequestered in the lung. Conclusion RA-related autoantibodies are detectable in sputum in subjects at risk of RA and in subjects with early RA. In a subset of at-risk subjects, the presence of sputum autoantibodies in the absence of seropositivity, and the increased autoantibody-to–total Ig ratios in sputum, suggest that the lung may be a site of autoantibody generation in the early development of RA. These findings suggest an important role of the lung in the pathogenesis of RA.

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TL;DR: This paper found that anti-CarP antibodies were associated with RA in patients with arthralgia, and their presence predicts the development of RA independent of anti-CCP-2 antibodies.
Abstract: Objective Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti–carbamylated protein (anti-CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti-CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA. Methods Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM-RF) and/or anti–cyclic citrullinated peptide 2 (anti–CCP-2) and 32 healthy controls were tested for anti-CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM-RF positive/anti–CCP-2 antibody negative and 229 were anti–CCP-2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti-CarP antibodies and those who were negative for anti-CarP antibodies during followup. Results Anti-CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6–24). The presence of anti-CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti–CCP-2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06–2.29], P = 0.023), as well as in the anti–CCP-2 antibody–positive subgroup (odds ratio 2.231 [95% confidence interval 1.31–3.79], P = 0.003). Conclusion Anti-CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti–CCP-2 antibodies.

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TL;DR: In an OA cohort with a high prevalence of multiple troublesome joints and comorbidity, only half achieved a good TJA outcome, defined as improved pain and disability.
Abstract: Objective To evaluate patient predictors of good outcome following total joint arthroplasty (TJA). Methods A population cohort with hip/knee arthritis (osteoarthritis [OA] or inflammatory arthritis) ages ≥55 years was recruited between 1996 and 1998 (baseline) and assessed annually for demographics, troublesome joints, health status, and overall hip/knee arthritis severity using the Western Ontario and McMaster Universities OA Index (WOMAC). Survey data were linked with administrative databases to identify primary TJAs. Good outcome was defined as an improvement in WOMAC summary score greater than or equal to the minimal important difference (MID; 0.5 SD of the mean change). Logistic regression and Akaike's information criterion were used to determine the optimal number of predictors and the best model of that size. Log Poisson regression was used to determine the relative risk (RR) for a good outcome. Results Primary TJA was performed in 202 patients (mean age 71.0 years; 79.7% female; 82.7% with >1 troublesome hip/knee; 65.8% knee replacements). Mean improvement in WOMAC summary score was 10.2 points (SD 18.05; MID 9 points). Of these patients, 53.5% experienced a good outcome. Four predictors were optimal. The best 4-variable model included pre-TJA WOMAC, comorbidity, number of troublesome hips/knees, and arthritis type (C statistic 0.80). The probability of a good outcome was greater with worse (higher) pre-TJA WOMAC summary scores (adjusted RR 1.32 per 10-point increase; P < 0.0001), fewer troublesome hips/knees (adjusted RR 0.82 per joint; P = 0.002), OA (adjusted RR for rheumatoid arthritis versus OA 0.33; P = 0.009), and fewer comorbidities (adjusted RR per condition 0.88; P = 0.01). Conclusion In an OA cohort with a high prevalence of multiple troublesome joints and comorbidity, only half achieved a good TJA outcome, defined as improved pain and disability. A more comprehensive assessment of the benefits and risks of TJA is warranted.

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TL;DR: The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain, which may lead to the identification of early structural andfunctional brain alterations in response to pain.
Abstract: Objective There is vast evidence to support the presence of brain aberrations in patients with fibromyalgia (FM), and it is possible that central plasticity is critical for the transition from acute to chronic pain. The aim of the present study was to investigate the relationship between brain structure and function in patients with FM. Methods Functional connectivity of the brain during application of intermittent pressure–pain stimuli and measures of brain structure were compared between 26 patients with FM and 13 age- and sex-matched healthy controls. Magnetic resonance imaging (MRI) was performed to obtain high-resolution anatomic images and functional MRI scans of the brain, which were used for measurements of pain-evoked brain activity. Results FM patients displayed a distinct overlap between decreased cortical thickness, decreased brain volumes, and decreased functional regional coherence in the rostral anterior cingulate cortex. The morphometric changes were more pronounced with longer exposure to FM pain. In addition, there was evidence of an association between structural and functional changes in the mesolimbic areas of the brain and the severity of comorbid depression symptoms in FM patients. Conclusion The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain. These data may lead to the identification of early structural and functional brain alterations in response to pain, which could be used to develop markers for predicting the development of FM and other pain disorders.

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TL;DR: Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible to developing lymphoproliferation, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
Abstract: Objective Primary Sjogren's syndrome (SS) is an autoimmune disease associated with a high risk of developing non-Hodgkin's lymphoma. This study was undertaken to determine the nature of B cells driving lymphoproliferation in primary SS. Methods B cell subsets and function were analyzed in peripheral blood from 66 adult patients with primary SS (including 14 patients with B cell lymphoproliferative disease [LPD]) and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. The reactivity of recombinant antibodies isolated from single B cells from patients with primary SS and LPD was tested using an enzyme-linked immunosorbent assay. Results We observed an expansion of an unusual CD21−/low B cell population that correlated with lymphoproliferation in patients with primary SS. A majority of CD21−/low B cells from patients with primary SS expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment, since their Ig genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21−/low B cells from patients with primary SS remained responsive to Toll-like receptor (TLR) stimulation. Molecules specifically expressed in CD21−/low B cells that are likely to induce their unresponsive stage were detected in gene array analyses. Conclusion Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21−/low B cells are susceptible to developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

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TL;DR: The pattern of risks suggests that familial factors influence RA in men and women equally and that these factors are of less importance for late-onset RA, and that heritability of RA is lower than previously reported.
Abstract: Objective To estimate familial aggregation of rheumatoid arthritis (RA) in 3 large population-representative samples and to test if familial aggregation is affected by rheumatoid factor (RF)/anti–citrullinated protein antibody (ACPA) status, type of relative, sex, and age at onset of RA. Methods A register-based nested case–control study was performed in the Swedish total population. Data on patients with RA were ascertained through the nationwide Swedish Patient Register (n = 88,639), the clinical Swedish Rheumatology Quality Register (n = 11,519), and the Epidemiological Investigation of Rheumatoid Arthritis case–control study (n = 2,871). Data on first- and second-degree relatives were obtained through the Swedish Multigeneration Register. Familial risks were calculated using conditional logistic regression. Results Consistent across data sources, the familial odds ratio for RA was ∼3 in first-degree relatives of RA patients and 2 in second-degree relatives. Familial risks were similar among siblings, parents, and offspring. Familial aggregation was not modified by sex, but was higher in RA patients with early-onset disease and in RF/ACPA-positive RA patients. The observed familial risks were consistent with a heritability of ∼50% for ACPA-positive RA and ∼20% for ACPA-negative RA. Conclusion The pattern of risks suggests that familial factors influence RA in men and women equally and that these factors are of less importance for late-onset RA. Familial factors are more important for seropositive RA, but there is significant familial overlap between seropositive RA and seronegative RA. Even if the familial risk is assumed to be completely due to genetics, the observed risks suggest that heritability of RA is lower than previously reported, in particular for ACPA-negative RA.

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TL;DR: There are very large inter-individual differences in these central nervous system factors that influence pain perception, such that some individuals with significant peripheral nociceptive input will feel little or no pain, whereas others are very pain sensitive, and they can experience pain with minimal or no identifiable abnormal peripheral nodal input.
Abstract: Pain is a prominent component of many rheumatologic conditions, and is the result of a complex physiologic interaction of central and peripheral nervous system signaling that results in a highly individualized symptom complex. Pain is frequently categorized as acute or chronic (generally greater than three months duration). Chronic pain is not simply acute pain that has lasted longer, and is more likely to be influenced by input from the central nervous system, whereas acute pain is often attributable primarily to inflammation and/or damage in peripheral structures (i.e., nociceptive input). The prominent role of central factors in chronic pain is highlighted by the fact that there is currently no chronic pain condition in which the degree of tissue inflammation or damage alone (e.g., as measured by radiographs, magnetic resonance imaging (MRI), or endoscopy) accurately predicts the presence or severity of pain. Central factors alter pain processing by setting the “gain”, such that when peripheral input is present, it is processed against a background of central factors that can enhance or diminish the experience of pain. There are very large inter-individual differences in these central nervous system factors that influence pain perception, such that some individuals with significant peripheral nociceptive input (e.g. from joint damage or inflammation) will feel little or no pain, whereas others are very pain sensitive, and they can experience pain with minimal or no identifiable abnormal peripheral nociceptive input. This emerging knowledge has important implications for pain management in individuals with chronic rheumatologic disorders.