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Background Patients (pts) who are anti-citrullinated protein antibody (ACPA) positive tend to develop more severe erosive disease than ACPA-negative pts.1 The presence of seropositivity and erosions have been noted in EULAR treatment guidelines as poor prognostic factors to identify pts with RA who require early and aggressive clinical intervention.2 Since the disease in pts with seropositive, erosive early RA is mostly driven by immunological features, response to RA therapy may vary based on therapeutic mechanism of action (MOA). Objectives To investigate the efficacy of abatacept (ABA) vs adalimumab (ADA) in pts with seropositive, erosive early RA. Methods AMPLE (NCT00929864)3 was a 2-year, Phase IIIb study in which biologic-naive pts with RA were randomized 1:1 to either SC ABA 125 mg weekly or SC ADA 40 mg biweekly, both with background MTX. This post hoc analysis of AMPLE compared clinical outcomes between treatment groups in a subpopulation of pts with specified baseline criteria: disease duration ≤6 months, RF or ACPA seropositivity and >1 radiographic erosion. Disease activity and patient-reported outcomes were evaluated at Weeks 26, 52 and 104. Endpoints were compared between ABA and ADA groups using chi-square test for categorical variables, analysis of covariance model (ANCOVA) controlling for baseline covariates and DAS28 (CRP) stratification for continuous variables. Results Of 318 and 328 pts in the ABA and ADA groups, respectively, 38 and 45 pts had all specified baseline characteristics (Cohort 1) and 280 and 283 pts had an absence of at least 1 of the specified characteristics (Cohort 2). Overall, the baseline characteristics, including anti-cyclic citrullinated peptide titres, were well balanced between the groups, with the exception of weight. For Cohort 1, adjusted mean change (95% CI) from baseline DAS28 (CRP) with ABA vs ADA was –2.18 (–2.61, –1.75) vs –1.56 (–2.01, –1.11) at Week 26, –2.58 (–2.99, –2.17) vs –1.68 (–2.10, –1.25) at Week 52 and –2.50 (–2.97, –2.03) vs –2.0 (–2.49, –1.50) at Week 104. Similar trends of increased efficacy with ABA vs ADA were observed for changes from baseline CDAI, SDAI, HAQ-DI, pain and fatigue; no differences in radiographic progression were observed. For Cohort 2, no differences in clinical outcomes between ABA and ADA groups were observed. Given the differences in baseline weight between ABA and ADA groups in Cohort 1, sensitivity analyses that excluded pts >100 kg and adjusted for baseline weight were performed and demonstrated minimal effect of weight on treatment efficacy. Conclusions This post hoc analysis seems to indicate a trend of increased efficacy for abatacept in pts with seropositive, erosive early RA compared with the TNF inhibitor adalimumab. Given the small sample size, additional pre-specified randomized studies are needed to compare the benefit of biologic DMARDs with different MOAs in pts with early, rapidly progressing RA. References Combe B, et al. Ann Rheum Dis 2016 Dec 15. doi: 10.1136/annrheumdis-2016–210602. Aletaha D, et al. Arthritis Rheum 2010;62:2569–81. Weinblatt M, et al. Arthritis Rheum 2013;65:28–38. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, sanofi-aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, Roche, sanofi-aventis, UCB, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, UCB, DxTerity, Consultant for: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, UCB, AbbVie, Lilly, Pfizer, Roche, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Schiff Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, JNJ, UCB, Speakers bureau: AbbVie

Background SB5 has been developed as a biosimilar of reference adalimumab (ADL). The 24-week efficacy and safety results comparing SB5 and ADL were reported previously.1 Here we report results of subgroup analyses of efficacy by adalimumab serum trough concentration (Ctrough) and association between anti-drug antibodies (ADA) and Ctrough. Objectives To investigate the impact of Ctrough on efficacy and the association between ADA and Ctrough in patients with rheumatoid arthritis (RA) treated with SB5 or ADL. Methods Patients with moderate to severe RA despite methotrexate treatment were randomly assigned to receive 40 mg of either SB5 or ADL administered subcutaneously every other week up to week 24. Blood samples were taken prior to study drug administration at weeks 0, 4, 8, 12, 16, and 24 to measure Ctrough. The optimal Ctrough cut-off point of adalimumab for good EULAR response at week 24 is reported to be 1.274 μg/mL.2 Efficacy and immunogenicity were analysed in patients with Ctrough Results Ctrough was measured in 178 patients each from SB5 and ADL group. The post-dose mean Ctrough was comparable up to week 24 for SB5 (range: 3.850 to 6.761 μg/mL) and ADL (range: 3.892 to 6.773 μg/mL). Generally, efficacy was higher in patients with Ctrough ≥1.274 μg/mL for both SB5 and ADL but it was comparable between SB5 and ADL regardless of Ctrough level. At week 24, the proportion of patients achieving good EULAR response, remission or low disease activity based on DAS28 was higher in patients with Ctrough ≥1.274 μg/mL than in those with Ctrough Ctrough was higher for patients without detectable ADA, compared to those with ADA. Among patients with ADA, the proportion of patients with Ctrough ≥1.274 μg/mL was 58.0% (29/50) for SB5 and 52.1% (25/48) for ADL. Among patients without detectable ADA, the proportion of patients with Ctrough ≥1.274 μg/mL was 100.0% (121/121) for SB5 and 97.4% (114/117) for ADL. Conclusions The presence of ADA reduces Ctrough for both SB5 and ADL. In both treatment groups, almost all patients without detectable ADA, but only slightly more than half of patients with ADA, had Ctrough ≥1.274 μg/mL at week 24. Efficacy and ADA incidence were generally comparable between SB5 and ADL regardless of Ctrough level. However, patients with Ctrough ≥1.274 μg/mL generally experienced greater efficacy of both SB5 and ADL than that in patients with Ctrough References Weinblatt ME et al. Arthritis Rheumatol. 2015; 67 (suppl 10), 8L. Chen DY et al., Ann Rheum Dis. 2015; Mar;74(3):e16. Disclosure of Interest J. Kay Grant/research support from: Abbvie, Ardea Biosciences, Eli Lilly, Pfizer, Genentech, Roche, UCB, Consultant for: Alexion, Amgen, AbbVie, AstraZeneca, BI, BMS, Crescendo Bioscience, Eli Lilly, Epirus, Genentech, GSK, Hospira, Janssen, MSD, Novartis, Pfizer, Samsung Bioepis, Sandoz, Roche, UCB, M. Weinblatt Consultant for: Abbvie, Amgen, Samsung Bioepis, E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis, Pfizer, Consultant for: Abbott, AstraZeneca, Biotest, BMS, Genentech, Janssen, Lilly, Merck, Pfizer, Samsung Bioepis, Speakers bureau: Abbott, AstraZeneca, BMS Canada, Janssen, M. Genovese Grant/research support from: Abbvie, Consultant for: Abbvie, Amgen, FkB, BI, Merck, Samsung Bioepis, J. Ghil Employee of: Samsung Bioepis Co., Ltd., S. Y. Cheong Employee of: Samsung Bioepis Co., Ltd., E. Hong Employee of: Samsung Bioepis Co., Ltd.

Background Recent studies have indicated that being overweight or obese could reduce the effect of anti-TNF treatment in patients (pts) with RA. 1,2 Other data show that certain biologic (b)DMARDs, such as abatacept, work independently of BMI. 3,4 Additional data on the role of BMI on treatment outcomes in clinical practice settings is required to inform clinical practice. Objectives To evaluate the impact of BMI on outcomes of disease activity in pts with RA treated with TNF and non-TNF agents (conventional or other bDMARDs). Methods Pts enrolled in a tertiary care centre RA registry, established in 2003, were analysed. The registry mostly comprises pts with established RA who were evaluated semi-annually for multiple clinical patient-reported outcomes and resource utilization parameters, and annually for composite disease activity measures such as DAS28 (CRP), CDAI and SDAI. The current analysis is based on pts enrolled in the RA registry with BMI values at time of enrolment. Pts were classified into groups based on BMI: normal (BMI 2 ), overweight (BMI ≥25 to 2 ) and obese (BMI ≥30 kg/m 2 ). Outcomes evaluated included change from baseline in DAS28 (CRP), CDAI, SDAI and joint counts at 12 months from treatment exposure. Treatments were categorized into TNF and non-TNF, which included conventional DMARDs and other non-TNF biologics. Multivariate linear regression analyses were used to evaluate impact of BMI on treatment outcomes controlling for baseline covariates of age, sex, disease duration, co-morbidities, baseline disease activity and serostatus. Separate models were run for the TNF and non-TNF groups. Results A total of 997 (78%) pts in the registry had baseline BMI values and were included in the analysis. Around 37% (n=371) had TNF exposure and were included in the TNF cohort; the remainder (63%; n=626) were included in the non-TNF cohort. Proportions of pts in the normal, overweight and obese groups for the TNF cohort were 45.5% (n=169), 27.5% (n=102) and 27.0% (n=100), respectively. For the non-TNF cohort, these were 41.7% (n=261), 33.1% (n=207) and 25.2% (n=158), respectively. In both cohorts, pts with normal BMIs were younger vs the overweight and obese BMI groups. However, obese BMI pts had higher disease activity measures at baseline (mean [SD] CDAI: 22.8 [17.8] for TNF and 24.9 [17.3] for non-TNF) vs the normal BMI pts (17.5 [15.9] for TNF and 19.9 [16.7] for non-TNF) and overweight BMI pts (20.9 [16.5] for TNF and 20.5 [15.0] for non-TNF). Adjusted mean change from baseline in disease activity in the TNF cohort was significantly reduced across all disease activity measures for the normal BMI group (p Conclusions Independent of BMI, non-anti-TNF therapy demonstrated similar outcomes in pts with RA. However, obese and overweight pts with RA (vs normal weight) had less improvement in disease activity (as measured by DAS28 [CRP]) with anti-TNF therapy. References Gremese E, et al. Arthritis Care Res 2013;65:94–100. Klaasen R, et al. Arthritis Rheum 2011;63:359–64. Gardette A, et al. Ann Rheum Dis 2015;74:1041. Disclosure of Interest E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Z. Guo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Iannaccone: None declared, M. Frits: None declared, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Biosciences, UCB, DxTerity, Consultant for: Amgen, Bristol-Myers Squibb, Crescendo Biosciences, UCB, AbbVie, Lilly, Pfizer, Roche, N. Shadick Grant/research support from: Bristol-Myers Squibb, UCB, Mallinckrodt, Amgen, Brescendo Biosciences, Consultant for: Bristol-Myers Squibb

Objective Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease-modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision-making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process. Methods Biomarkers of bone, cartilage, and interstitial matrix turnover (C-telopeptide of type I collagen [CTX-I], matrix metalloproteinase-derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA-1, a phase III clinical study of the efficacy of fostamatinib in RA) at baseline and follow-up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage, and synovial membrane cultured with the active metabolite of fostamatinib, R406, to assess the level of suppression induced by the drug. Results In OSKIRA-1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX-I and C2M. In OSKIRA-1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy. Conclusion These data demonstrate that translational biomarkers are a potential tool for early assessment and decision-making in drug development for RA treatment.

As difficult as it may now be to believe, there was a time when it was unclear whether methotrexate (MTX) would be tolerated in the long-term treatment of patients with rheumatoid arthritis (RA). Data from Scandinavian patients with psoriasis indicated that there was an incidence of hepatic cirrhosis of 26%.1 There was thus a need to establish the actual risk of clinically significant liver disease (CSLD) in patients with RA treated for many years with the drug. Because of the obvious clinical effectiveness of MTX, and the absence of effective alternatives in the first few decades of its widespread use, there was a need to demonstrate the ability to sustain treatment without creating a population of subjects with chronic liver disease. Thus, studies of hepatic safety were performed that included both baseline and annual liver biopsies.2 3 This experience along with other publications on hepatic safety of MTX4 lead to the publication of suggested guidelines for the hepatic monitoring of MTX.5 The guidelines were derived from the experience from baseline and annual liver biopsies prospectively performed over a period of many years along with regular monitoring of hepatic transaminase enzymes and serum albumin with a mean interval of 37.7 days between the sequential laboratory measures.6 It was thus possible to seek correlations of any elevation in transaminase enzymes with the evolution of hepatic histological changes by different grading systems, with particular attention paid to early fibrosis.2 In doing so, we …

Objective This 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte–macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF–IR). Methods Patients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF–IR (1–2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of 0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments. Results At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF–IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28‐CRP of 0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients. No deaths were reported, and no specific safety signals were identified. Conclusion The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.

Background Patients with rheumatoid arthritis (RA) demonstrate reduced aerobic capacity, excess cardiovascular risk, mobility limitations and are less physically active than their healthy peers. Physical activity may decrease RA disease activity through its anti-inflammatory effects and psychological and health benefits. To successfully manage RA symptoms and reduce cardiovascular risks associated with RA through increased physical activity (PA), accurate physical activity assessments are critical. Accelerometry is an objective physical activity measure, but not widely used. Validity of the Nurses’ Health Study physical activity questionnaire II (NHSPAQ) has not been determined for estimation of physical activity in RA. This study examined NHSPAQ validity in adults with RA compared to accelerometry-based metabolic equivalents determined (METs) and results of performance tests. We hypothesized NHSPAQ scores would correlate moderately (0.4–0.5) with accelerometer physical activity estimates. Methods Thirty-five adults with RA (mean age [SD] 62 (Williams et. al, Health Qual Life Outcomes 10 :28, 2012) years, 28 females (80%) recruited from a hospital-based clinic registry participated in a one-week accelerometry trial. Medical data was compiled. Participants completed the NHSPAQ, a self-paced 20-m walk test, and modified timed step test. Participants wore an accelerometer for 7 consecutive days, then completed a physical activity log and another NHSPAQ. Metabolic equivalents (METs) were derived from NHSPAQ and accelerometers using standardized formulas. NHSPAQ METs were correlated with accelerometer METs and data from performance measures. Results Average disease duration was 21 years (SD = 11), 63% patients took biologics. The average weekly METs reported were 29 (SD = 33) and accelerometer METs were 33 (SD = 22). NHSPAQ METs correlated moderately with accelerometer-derived METs ( r = 0.48 95% CI (0.15–0.70). Self-reported PA correlated moderately with Step Test performance ( r = 0.50 95% CI (0.18–0.72). Conclusion Patients with RA exhibit low physical activity levels. General fitness measures were moderately correlated with physical activity levels. A moderate significant correlation existed between NHSPAQ and accelerometry METs. These preliminary data suggest the NHSPAQ may be useful to describe physical activity levels in this population.

ObjectivesTo assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks.MethodsDMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)ResultsPatients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, pConclusionsCZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX.Trial registration numberNCT01519791.

Objective This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy. Methods Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co–primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS). Results In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group. Conclusion With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.

Objectives. Secondary SS (sSS) is a common extra-articular manifestation of RA. There are conflicting data regarding the association of sSS with worse joint damage. This study aims to characterize sSS patients in an RA cohort and study the association between sSS and joint damage. Methods. We conducted a cross-sectional study of RA patients with ≥1 year of follow-up at a large academic centre. Subjects with co-morbid diseases that can also result in sicca symptoms were excluded from the analysis. Subjects were considered to have sSS if they were reported as having sSS by their rheumatologist at recruitment into the cohort and had the diagnosis confirmed by chart review. The primary outcome was Sharp score using bilateral hand radiographs at recruitment. We constructed a linear regression model to determine the association of sSS status and Sharp score adjusted by age, gender, disease duration and ACPA and RF status. Results. We studied 829 RA subjects, mean age 57 years, 83% female, mean RA duration 13 years, 74% seropositive; 85 subjects (10.3%) had sSS. We observed a female predominance (95.3%), longer mean disease duration (16.9 years) and higher frequency of RF or ACPA positive among patients with sSS and RA. Having sSS at baseline was associated with higher Sharp scores (P = 0.03), independent of age, gender, RA disease duration and seropositive disease. Conclusion. In our RA cohort, RA subjects with sSS had worse joint damage, suggesting that sSS is a marker of more aggressive disease.

Some evidence suggests that women with rheumatoid arthritis (RA) are at increased risk for the development of cervical cancer; however, it is unclear how this increase risk is conferred. We aimed to assess the factors related to abnormal Papanicolaou (Pap) tests in women with RA to determine whether they are similar to those reported for the general population.A structured questionnaire was mailed to 503 female patients from a longitudinal RA cohort. The survey included items on sociodemographic, behavioral, and gynecological factors. Univariate and multivariable logistic regression models examined the association of self-reported abnormal Pap results with a number of potential behavioral risk factors.The questionnaire response rate was 57.5% (n=289). Median age was 61 years and 97% had ≥1 Pap test previously. Twenty-nine percent of respondents reported a previous abnormal Pap result. In the multivariable logistic model adjusted for age, number of lifetime sexual partners, age at menarche, birth control use, and history of sexually transmitted disease (STD), ever using birth control (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.18-4.52) and previous STD (OR 3.38, 95% CI 1.70-6.70) were associated with an increased risk of abnormal Pap result. Compared with either the state or national population, a greater proportion of the respondents was older, married, and previous smokers, and completed postsecondary education and obtained a Pap test.In this cross-sectional study, self-reported abnormal Pap results were associated with use of birth control and history of STD in RA patients.

Investigator-initiated trials, some of which have been referred to as comparative effectiveness trials, pragmatic trials, or strategy trials, are sometimes considered to be of greater clinical importance than industry-driven trials, because they address important but unresolved clinical questions that differ from the questions asked in industry-driven trials. Regulatory authorities have provided methodological guidance for industry-driven trials for the approval of new treatments, but such guidance is less clear for investigator-initiated trials. The European League Against Rheumatism (EULAR) task force for the update of the recommendations for the management of rheumatoid arthritis has critically looked at the methodological quality and conduct of many investigator-initiated trials, and has identified a number of concerns. In this Viewpoint paper, we highlight commonly encountered issues that are discussed using examples of well-known investigator-initiated trials. These issues cover three themes: (1) design choice (superiority vs non-inferiority designs); (2) statistical power and (3) convenience reporting. Since we acknowledge the importance of investigator-initiated research, we also propose a shortlist of points-to-consider when designing, performing and reporting investigator-initiated trials.

Rheumatoid arthritis (RA) is the most common systemic rheumatic disease, affecting approximately 1.5 million adults in the United States (1). Historically, physicians have focused on the inflammatory components of the disease (e.g. synovitis), whereas RA patients have cited pain, fatigue, sleep problems and other quality of life outcomes as their main priorities (2). Both patients and physicians frequently assume that these symptoms are correlated with heightened systemic inflammation. However, many studies indicate significant discordance between inflammation, pain and fatigue among RA patients (3, 4). In a prospective observational cohort of established RA patients experiencing sustained inflammatory disease remission, 12% continued to report clinically significant pain (≥ 4 on a 10-point numeric rating scale) (5). A study including 2,096 RA patients in a clinical setting and 14,607 RA patients from a survey-based cohort reported weak correlations of 0.07–0.11 between fatigue and measures of inflammation (6). Similarly, van Hoogmoed found no association between fatigue and either the erythrocyte sedimentation rate or C-reactive protein (CRP) among 228 RA outpatients in the Netherlands (7). These observations suggest that patient-reported outcomes, such as pain, fatigue and sleep problems, should not automatically be attributed to inflammation in an inflammatory disease population, such as RA. Central, non-inflammatory pain conditions, such as fibromyalgia, tend to be associated with high levels of pain, fatigue and sleep problems (8, 9). Compared to the general population (10, 11), the prevalence of non-inflammatory pain conditions is significantly higher in RA, with 15–25% of RA patients also meeting criteria for fibromyalgia and an additional 7–15% meeting criteria for chronic widespread pain (12, 13). Thus, while it is not debated that RA is an inflammatory condition, many patients with RA also have features characteristic of non-inflammatory centralized pain conditions (e.g., fatigue, sleep disturbances). The objective of this study was to determine whether subgroups of RA patients could be characterized by a latent construct, representing the involvement of central, non-inflammatory pain processes. The latent construct was defined by grouping individuals based on the presence or absence of symptoms indicative of aberrant central nervous system involvement (e.g., fatigue, sleep problems, negative mood, catastrophic attributions and perception of overall illness burden) using cluster analysis. Whereas factor analysis aggregates variables into patterns based on correlations, cluster analysis categorizes individuals into non-overlapping subgroups (14). Cluster analysis is particularly valuable in identifying subgroups which differ in underlying pathogenic mechanisms and clinical outcomes (15). The identification of clinically distinct phenotypes within a heterogeneous population of RA patients would be the first step in understanding the pathogenic mechanisms underlying each symptom cluster and, ultimately, identifying potential targets for treatment. The variables used in this cluster analysis were markers of central pain processes, similar to those included in a previous cluster analysis examining the role of central, non-inflammatory pain in osteoarthritis (16). We hypothesized the presence of at least three subgroups: one group comprised of RA patients with well-controlled disease, minimal fatigue and low psychosocial distress; a second group of RA patients with active inflammatory joint pain and moderate levels of psychosocial distress, and a third group of RA patients with low swollen joint counts and high levels of pain, fatigue and other symptoms characteristic of a chronic, non-inflammatory, pain syndrome. This hypothesis was based on clinical observations, as well as studies in other painful chronic conditions. These studies have reported similar subgroups consisting of: a) participants predominantly affected by peripheral pain generators (e.g., joint inflammation and/or mechanical/structural markers), and b) participants in whom inflammation and/or mechanical factors appear to have minimal impact compared to the influence of central, non-inflammatory pain processes(16, 17). Additional subgroups may also exist. For example, other studies have described a group with high levels of depression but low levels of other symptoms (16, 17). However, given the low levels of depression in our patient population (18), we did not expect to identify this group in this cluster analysis.

BACKGROUND Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. METHODS All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. RESULTS Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older ( P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history ( P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. CONCLUSIONS We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

Objective.To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy.Methods.In this randomized, multicenter, double-blind, placebo-controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. All patients continued stable oral MTX (15–25 mg/wk). HRQOL assessments included Health Assessment Questionnaire-Disability Index (HAQ-DI; physical function), Medical Outcomes Study Short Form-36 questionnaire physical/mental component summary (SF-36 PCS/MCS) scores, EQ-5D assessment of current health state, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, and disease effect on productivity [10-cm visual analog scale (VAS)].Results.Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p < 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p < 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p < 0.001) and FACIT-Fatigue (p < 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p < 0.001). Improvements in physical function, HRQOL, fatigue, and productivity significantly correlated with disease activity improvement.Conclusion.In active RA, IV golimumab + MTX significantly improved physical function, HRQOL, fatigue, and productivity using multiple measurement tools; all correlated with improvements in disease activity (NCT00973479, EudraCT 2008-006064-11).

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.

textabstractObjective Remission is a key goal in managing rheumatoid arthritis (RA), with sustained remission as the preferred sequelae of short-term remission. However little is known about the predictors of sustained remission for patients reaching remission. Using two independent cohorts, we aimed to evaluate the prevalence and predictors for sustained remission. Methods The study cohort consisted of subjects with RA from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and the Korean Observational Study Network for Arthritis (KORONA). We analyzed subjects who reached remission in 2009 with follow up data for two consecutive years. Remission was defined by the Disease Activity Score 28- (DAS28-CRP) of less than 2.6. Sustained remission was defined as three consecutive annual visits in remission. Predictors for sustained remission were identified by multivariate logistic regression analysis. Results A total of 465 subjects were in remission in 2009. Sustained remission was achieved by 53 of 92 (57.5%) in BRASS and by 198 of 373 (53.1%) in KORONA. In multivariate analyses, baseline predictors of sustained remission were: disease duration less than 5 years [odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.08–3.58], Modified Health Assessment Questionnaire (MHAQ) score of 0 (OR 1.80, 95% CI 1.18–2.74), and non-use of oral glucocorticoid (OR 1.58, 95% CI 1.01–2.47). Conclusion More than half of RA subjects in remission in 2009 remained in remission through 2011. Short disease duration, no disability, and non-use of oral glucocorticoid at baseline were associated with sustained remission.

Objective Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). Methods Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15–25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape

Objective Loss of participants in longitudinal data collection can affect the validity of outcomes in rheumatoid arthritis (RA) registries. Prior research indicates that demographics and socioeconomic and psychosocial factors contribute to attrition. This study analyzed the characteristics of an RA registry that may contribute to attrition in a hospital-based population. Methods Subjects consisted of RA patients enrolled in the Brigham and Women's Rheumatoid Arthritis Sequential Study. Demographics and clinical and psychological factors were evaluated in univariate analyses to determine differences between participants who dropped out and those who completed 5 years of followup. Univariate factors with a P value

Rheumatoid arthritis (RA) is a chronic disease that can cause severe joint damage and disability. During the last decades, the number of therapeutic agents and the knowledge about treatment strategies for RA have increased substantially (1). This has left clinicians with more treatment choices, but also in need of tools to identify the right patients to treat aggressively with more effective, but expensive medication with potentially serious adverse events. Risk model matrices have been proposed as clinical tools to identify RA patients at high risk of rapid radiographic progression (RRP) (2–5) or with probable response to disease modifying anti-rheumatic drug (DMARD) treatment (6). In addition, models to predict response to anti-TNF therapy in ankylosing spondylitis (AS) have been published recently (7), highlighting the interest in risk models within rheumatology. Clinicians might apply current risk models in their daily practice, but we have limited knowledge about whether the use of the models should be restricted to patient populations similar to the study populations used for the model development. Risk models are common in cardiology, with the Framingham Risk Scores (8) and the Systematic Coronary Risk Evaluation (SCORE) (9) as examples of risk models for cardiovascular disease. Several publications have discussed the validation and development of such models, focusing on statistical methods to assess model fit and compare the classification abilities of different models(10–14). Statistics have been developed to measure the degree of correct reclassification by a new model compared to a previous model, such as reclassification calibration statistics, net reclassification improvement and integrated discrimination improvement (Table 1). These methods add information to traditional discriminatory abilities, for example the c-statistics. Table 1 An overview of statistical methods to assess risk models (12;14) Risk models developed in clinical trials may not be directly applicable to daily clinical settings, as selected patient groups are included in trials, often with aggressive disease of short duration. In this paper, we assess the performance of three models for prediction of RRP in RA in an observational cohort representing a broad RA population. All three models were developed in clinical trials populations. We apply statistical methods previously used to assess risk models in other specialties.

Objective To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs. Methods This 24-week, multicenter, open-label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively. Results Overall, 69 patients (7.8%) reported ≥1 SAEs. The rate of SAEs per 100 person-years was 28.3 (95% confidence interval [95% CI] 23.1–34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0–39.2), 30.3 (95% CI 22.2–40.2), and 20.6 (95% CI 10.3–36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28-joint count were generally similar among treatment groups. Conclusion The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.

Objective.To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).Methods.Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined.Results.At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were −31.3 (2.45) versus −17.8 (2.45), p < 0.001 for pain; −29.1 (2.26) versus −16.7 (2.42), p < 0.001 for PtGA; −0.647 (0.064) versus −0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function.Conclusion.Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Objectives Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA).\ud \ud Methods Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12.\ud \ud Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP

There is little disagreement that screening for latent tuberculosis (TB) infection (LTBI) prior to biologic therapy is necessary. Unfortunately, there is much less agreement with regard to how best to accomplish this task. A decade ago, we had just one screening tool, the tuberculin skin test (TST), and screening algorithms for such patients were presumably straightforward. With the recent introduction and fairly widespread adoption of interferon γ release assays (IGRAs), clinicians have a new tool that theoretically improves their ability to screen. However, since the introduction of IGRAs, the studies conducted within the biologic therapy setting that compare IGRAs and TST have been fraught with a lack of statistical power and heterogeneity (eg, differing underlying inflammatory disease states, variable immunosuppressive therapies or underlying BCG status),1 ,2 and firm conclusions regarding the relative sensitivity of these two screening tests (Quantiferon-Gold TB In-tube (QFT-IT) or the T-SPOT. TB assay) is only now becoming more clear. Kleinert et al and Mariette et al have published two studies to overcome some of these limitations,3 ,4 and along with other data, we believe the time has arrived to offer a screening algorithm that is practical in its approach. While we believe IGRAs have become the preferred screening tool in this setting, unfortunately these recent data argue that an IGRA alone is insufficient to identify all patients at risk. TB is rumoured to infect nearly a third of the world's population. The risk of LTBI progression to active TB is clearly heightened by antitumour necrosis factor α (anti-TNF) therapy, and the absolute risk of this complication is driven by the background prevalence of LTBI in a particular region and the probability of infection in an individual. Within low prevalence countries, rates of anti-TNF-associated TB are typically 5–10-fold higher than background general populations, …

Objectives Evaluate the effi cacy of intravenous golimumab 2 mg/kg+methotrexate (MTX) in patients with active rheumatoid arthritis (RA) receiving MTX. Methods Patients (n=592) with active disease (≥6/66 swollen, ≥6/68 tender joints, C-reactive protein ≥1.0 mg/dl, rheumatoid factor positive and/or anticyclic citrullinated protein antibody positive at screening) despite MTX (15‐25 mg/week) participated in this double-blind, placebo-controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg, or placebo infusions at weeks 0 and 4 and every (q) 8 weeks; patients continued MTX. Placebo patients with

Melanoma differentiation-associated gene 5 (MDA5) is an autoantigen target that has been described in individuals with dermatomyositis (DM). Anti-MDA5 autoantibodies can be detected in 10%–30% of cases of DM, and when present, confer a substantial risk of mortality, usually from interstitial lung disease (ILD). Serologic detection of anti-MDA5 antibodies correlates with a specific …

To the Editor: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported in diseases involving the central nervous system (CNS). However, SIADH is rarely reported in patients with systemic lupus erythematosus (SLE)1,2,3,4,5,6. We present a case of a 34-year-old woman with a history of SLE who was diagnosed with SLE in 2009 with polyarthritis, leukopenia, oral ulcers, alopecia, photosensitive rash, diffuse proliferative glomerulonephritis, positive antinuclear antibody, and elevated dsDNA. Two months prior to presentation, she was transitioned from mycophenolate mofetil (MMF) 500 mg bid to azathioprine (AZA) 50 mg daily because of the desire to attempt conception. One month later, she started having daily fevers, sore throat, photosensitive rash, tender posterior cervical lymphadenopathy, abdominal pain, and leukopenia. Because of the leukopenia, she was switched from AZA back to MMF. Her worsening leukopenia and elevated inflammatory markers were suggestive of an SLE flare and she was given a higher dose of prednisone. One month later, she developed abdominal pain, nausea, and vomiting. Her medications included … Address correspondence to Dr. N. Yang, 60 Fenwood Road, Suite 3032X, Boston, Massachusetts 02115, USA. E-mail: nyang2{at}partners.org

Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome.Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables.Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10).Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent.

Objective. Treatment algorithms in RA include factors associated with poor prognosis; however, many patients remain erosion free despite years of disease. Our objective was to characterize the group of RA patients without erosions and identify its clinical predictors. Methods. Our study was conducted within a prospective observational cohort of RA patients recruited from the outpatient practice of an academic medical centre. We studied patients with bilateral hand radiographs at cohort baseline and 2-year follow-up assessed with Sharp/van der Heijde scores (SHS). The primary outcome was erosion-free status at baseline and 2-year follow-up. We assessed baseline values of the following as potential correlates: age at RA onset, gender, RA duration, BMI, 28-joint DAS (DAS-28), CRP, anti-CCP status, tender and swollen joint counts, functional status [multidimensional HAQ (MDHAQ)], tobacco use and RA treatments. Variables with P4 0.25 in the univariate analyses were assessed using backward selection in multivariable logistic regression models. Results. Of the 271 subjects included, 21% (n = 56) were considered erosion free. Forty-six per cent (n = 26) of this group was anti-CCP positive compared with 56% (n = 121) in subjects with erosions present. Mean RA duration for erosion-free subjects was 3.9 years compared with 4.6 years in erosive subjects. Treatments for RA did not differ between the two groups. In the multivariable-adjusted analysis, significant predictors of erosion-free status were younger age at onset and shorter RA duration. Conclusion. In our cohort, 21% of subjects were erosion free at baseline and 2 years. Few baseline clinical characteristics significantly predicted erosion-free status.

Objective.To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).Methods.Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.Results.Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.Conclusion.In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

Objective.This Year 5 analysis of an open-label extension (OLE) study assessed radiographic progression, clinical efficacy, and safety of adalimumab with concomitant methotrexate (MTX) for patients with active rheumatoid arthritis.Methods.In a double-blind study (DE019, NCT00195702), inadequate responders to MTX were randomized to MTX plus either adalimumab 40 mg eow, adalimumab 20 mg weekly, or placebo for 52 weeks. Eligible patients entered an ongoing OLE and received adalimumab 40 mg eow plus MTX. Longterm efficacy and safety were evaluated.Results.Of 457 patients who had enrolled in the OLE, 304 remained in the study at Year 5, including 112, 107, and 85 from the original adalimumab 40 mg, adalimumab 20 mg, and placebo groups, respectively. Year 5 radiographs demonstrated mean changes in modified total Sharp score for the original adalimumab 40 mg eow and 20 mg weekly groups of 0.8 and 2.6, respectively, versus 3.9 for placebo; 58% from the adalimumab 40 mg eow group had no radiographic progression versus 40% of those who initially received placebo. Of patients who received adalimumab 40 mg eow for 5 years, 26.1% achieved clinical remission (Disease Activity Score 28-joint count < 2.6), had no radio graphic progression (change in modified total Sharp score ≤ 0.5), and had normal function (Health Assessment Questionnaire ≤ 0.5), versus 11.9% of those who initially received placebo. Serious infection rate for 553 patients who received at least one dose of adalimumab was 4.4/100 patient-years.Conclusion.A 52-week delay in adding adalimumab to MTX led to worse radiographic, functional, and clinical outcomes at Year 5 for most patients who initially received placebo instead of adalimumab.

Objective The American College of Rheumatology (ACR) hybrid (a modified mean percent response to treatment) was officially recommended by the ACR as a revision to 20%, 50%, and 70% response criteria (ACR20/50/70) scores, but has not been tested in clinical trials. We performed a post hoc analysis of a phase III study of certolizumab pegol (Rheumatoid Arthritis Prevention of Structural Damage 1 [RAPID 1]) using the ACR hybrid. Methods Patients with active rheumatoid arthritis were randomized to certolizumab pegol (200 mg or 400 mg every other week) plus methotrexate or placebo plus methotrexate. ACR hybrid scores were compared with ACR20/50/70 outcomes. Results Differences between active treatment and placebo were significant throughout the study using the ACR20 and ACR hybrid outcomes. In the certolizumab pegol 200 mg group, the median ACR hybrid score at week 52 (last observation carried forward) was 49.99. A total of 258 (65.8%) of 392 and 172 (43.9%) of 392 patients had ACR20 and ACR50 responses, respectively. An additional 55 patients (14.0%) and 59 patients (15.1%) had mean improvements in ACR core measures of ≥20% and ≥50%, respectively, and therefore had positive ACR hybrid scores, despite lacking ACR20 and ACR50 responses, respectively. In the placebo group, median ACR hybrid scores were

Human herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood disorder diagnosed in ~1,000 individuals in the USA each year. It involves polyclonal lymphoproliferation, constitutional symptoms, systemic inflammation and an uncontrollable cytokine storm resulting in life-threatening multi-organ failure. Diagnosis and treatment can be difficult due to limited etiological understanding and heterogeneous presentation - clinical, laboratory, and histopathological abnormalities overlap with infectious, autoimmune and oncological diseases. iMCD symptoms and disease progression are largely believed to be driven by interleukin-6 (IL-6). However, approximately 66% of iMCD patients did not respond to anti-IL-6 therapy, siltuximab, the only FDA-approved iMCD therapy, in its phase II study (NCT01024036). Few treatment options exist for anti-IL-6 refractory patients because alternative driver cytokines and signaling pathways are not known. Herein we report the largest study to-date of iMCD serum proteomes with correlative anti-IL6 response data from 92 iMCD patients in disease flare (n=75 of which were collected as part of NCT01024036), in order to: (1) molecularly define iMCD, (2) identify predictors of response to anti-IL6 therapy, and (3) gain insights into the pathogenesis of iMCD. Proteomes of HHV8-positive MCD (n=20), Hodgkin lymphoma (n=20), rheumatoid arthritis (n=20) and healthy individuals (n=44) were also analyzed. Of the ~1,300 analytes measured using SomaLogic SOMAscan, 1,178 passed QC and were included in analyses. Each analyte was log2 transformed and capped at the 2.5th and 97.5th percentiles. Clinical and laboratory data collected at the time of sample draw were used to calculate disease activity following a modified CHAP scale: C-reactive protein, hemoglobin and albumin; missing performance status. Response to siltuximab was determined in NCT01024036. Data analysis was performed using the Medidata Rave Omics machine learning platform and R v3.4.4. Clustering of baseline proteomic data for iMCD patients identified six clusters that ranged in size from seven to 27 subjects. No associations with race, site, sex, age, or batch were found. Analytes identified among the strongest differentiators include cytokines, chemokines and inflammatory molecules. Interestingly, the largest cluster was associated with response to siltuximab (p Disclosures Guilfoyle: Janssen Pharmaceuticals, Inc.: Employment. Tendler:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Reddy:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinblatt:Amgen: Consultancy, Research Funding; Sanofi/Regeneron: Consultancy, Research Funding; Crescendo Bioscience: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; UCB Pharmaceuticals: Consultancy, Research Funding. Bower:Merck: Honoraria; ViiV: Honoraria; Gilead: Honoraria; Janssen Pharmaceuticals: Honoraria. Masaki:Ono: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Beineke:Medidata Solutions: Employment, Equity Ownership. Miljovska:Medidata Solutions: Employment. Katz:Medidata Solutions: Employment. Shenoy:Medidata Solutions: Consultancy. Oromendia:Medidata Solutions: Employment, Equity Ownership. Mezey:Medidata Solutions: Consultancy. Wiser:Medidata Solutions: Employment, Equity Ownership. Benbanaste:Medidata Solutions: Employment, Equity Ownership. Lee:Medidata Solutions: Employment. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Fajgenbaum:Janssen Pharmaceuticals, Inc.: Research Funding.

The objective of this study was to evaluate current approaches to economic modeling in rheumatoid arthritis (RA) and propose a new conceptual model for evaluation of the cost-effectiveness of RA interventions. We followed recommendations from the International Society of Pharmacoeconomics and Outcomes Research-Society of Medical Decision Making (ISPOR-SMDM) Modeling Good Research Practices Task Force-2. The process involved scoping the decision problem by a working group and drafting a preliminary cost-effectiveness model framework. A systematic literature review (SLR) of existing decision-analytic models was performed and analysis of an RA registry was conducted to inform the structure of the draft conceptual model. Finally, an expert panel was convened to seek input on the draft conceptual model. The proposed conceptual model consists of three separate modules: 1) patient characteristic module, 2) treatment module, and 3) outcome module. Consistent with the scope, the conceptual model proposed six changes to current economic models in RA. These changes proposed are to: 1) use composite measures of disease activity to evaluate treatment response as well as disease progression (at least two measures should be considered, one as the base case and one as a sensitivity analysis); 2) conduct utility mapping based on disease activity measures; 3) incorporate subgroups based on guideline-recommended prognostic factors; 4) integrate realistic treatment patterns based on clinical practice/registry datasets; 5) assimilate outcomes that are not joint related (extra-articular outcomes); and 6) assess mortality based on disease activity. We proposed a conceptual model that incorporates the current understanding of clinical and real-world evidence in RA, as well as of existing modeling assumptions. The proposed model framework was reviewed with experts and could serve as a foundation for developing future cost-effectiveness models in RA.

Objective. The Centers for Disease Control (CDC) recommends pneumococcal vaccination for immunocompromised patients. Data suggest that rates of vaccination in this population are not optimal. To support continuous quality improvement efforts, we electronically measured vaccination status among rheumatology outpatients over time. Methods. Using data from administrative (billing) and electronic health record sources, we identified rheumatology clinic patients seen between 1 February 2008 and 31 January 2010 and prescribed an immunosuppressive medication. CDC recommendations for pneumococcal vaccination were applied. We calculated the proportion of eligible patients who were up-to-date with pneumococcal vaccination: (i) while on an immunosuppressive medication and (ii) before newly starting an immunosuppressive medication in the last 12 months. Results. We identified 2763 rheumatology clinic patients on immunosuppressive medications, with 568 initiated in the last 12 months. The mean age was 57 years, 75% were female and 77% were Caucasian. The most frequent disease was RA (50%) and the most common immunosuppressive medication was MTX (59%). Of patients on immunosuppressive medications, 1491/2763 (54%) were up to date with pneumococcal vaccination. Among new initiators of immunosuppressive medications, 258/568 (45%) were vaccinated before starting the immunosuppressive medication. Patients treated by rheumatologists in practice for 410 years were more likely to be up to date with pneumococcal vaccination (72%) than those with providers in practice >10 years (52%, P < 0.001). Conclusion. The proportion of patients who are up to date with documented pneumococcal vaccination was suboptimal in our rheumatology practice. The ability to continuously repeat electronic measurement permits us to initiate continuous quality improvement efforts.

The objective of this review is to report on the progress of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry data collection and summarize previous research in understanding therapeutic response to DMARDs using clinical and genetic data. The BRASS Registry, established in 2003, is a large, single-centre, prospective and observational cohort of 1100 RA patients. Patients with either new-onset or established RA disease are recruited from the practices of rheumatologists. Annual visits collect information on demographics, 28-joint DAS-CRP3 (DAS-28-CRP3), medication use, comorbidities and functional status (Modified Health Assessment Questionnaire, Short Form Health Survey 12). Two published studies have utilized BRASS to examine genetic predictors of treatment response. In a cross-sectional study, examining the association between candidate single nucleotide polymorphisms (SNPs) and disease activity in a subset of 120 RA patients on MTX monotherapy, the minor allele of ATIC rs4673993 was associated with low disease activity (P=0.01, DAS-28-CRP3≤3.2). In an international collaboration, 55 BRASS patients receiving anti-TNF therapy were genotyped for 31 SNPs associated with the risk of RA. With our collaborators, we discovered an SNP at the protein tyrosine phosphatase, receptor type, C (PTPRC) gene locus that was associated with EULAR 'good response'. With accurate data collection and the capacity to run genome-wide association studies and SNP analyses, the BRASS Registry has the ability to determine the contribution of genetic variants to disease onset and to assess their usefulness as biomarkers for treatment response and drug toxicity.

We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.

Objective We previously observed the association of the co-occurrence of the HLA–DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)–positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs. Methods SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription–PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay. Results A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti–cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5. Conclusion The RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.

Platelet Microparticles Drive Inflammatory Arthritis Platelets are best known for their critical role in blood clot formation during wound repair, but an appreciation for their role in inflammatory processes is growing. Platelet-derived cellular microparticles (MPs) are small membrane vesicles released from platelets in response to cell activation that can transport biomolecules throughout the body that have also been implicated in inflammatory processes. Boilard et al. (p. 580 ; see the Perspective by Zimmerman and Weyrich ) have now found that platelet-derived MPs probably contribute to the inflammatory processes underlying rheumatoid arthritis, an autoimmune disease. The majority of MPs in synovial fluid from patients with various types of inflammatory arthritis were platelet-derived and, importantly, platelet-derived MPs were lacking in synovial fluid from osteoarthritis patients. Furthermore, platelet depletion abrogated disease development in a mouse model of inflammatory arthritis.

We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (Por = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.

A 54-year-old woman was admitted to the hospital because of respiratory failure, hypotension, and a cavitary lesion in the lung. She had had cough and shortness of breath for a week, which abruptly worsened, and she collapsed at home. In the emergency department, she was hypotensive and unresponsive; chest imaging showed consolidation of the right upper lobe with a cavity. Tension pneumothorax developed after insertion of a jugular venous catheter. Despite placement of a chest tube and mechanical ventilation, the patient died. An autopsy was performed.

Objective.We evaluated the T-SPOT.TB assay to identify latent tuberculosis infection (LTBI) in patients with rheumatic disease receiving immunosuppressive medication including tumor necrosis factor (TNF) antagonists.Methods.A total of 200 patients seen in the Arthritis Center at Brigham and Women’s Hospital were enrolled for study. Most patients were US-born women with rheumatoid arthritis. A medical history was obtained using a questionnaire, whole blood was drawn for the T-SPOT.TB assay, and tuberculin skin testing (TST) was performed.Results.Both tests were performed on 179 subjects, who had no history of a positive TST. All subjects had a strong response to the T-SPOT.TB test positive control, and there were no indeterminate results. Among these 179 subjects, 2 had a positive TST and 10 had a positive T-SPOT.TB test. No subject was positive for both tests. Patients with a positive T-SPOT.TB test did not have typical risk factors for LTBI based on clinical evaluation.Conclusion.The lack of concordance between the TST and the T-SPOT.TB assay may indicate that the immunoassay is more sensitive, particularly in a patient population taking immunosuppressive medications. It is equally likely that the low prevalence of LTBI in this low-risk population led to an increase in the false-positive rate despite the high sensitivity and specificity of the T-SPOT.TB assay. In the context of our patient population, the T-SPOT.TB assay is likely to be most useful in evaluation of patients with a positive TST, since these patients have a higher pretest probability of having LTBI.

Objective Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). Methods We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Results Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect.Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time.The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p0.001). Associations were found between SE and serum levels of rheumatoid factor (p0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p0.001, with correlation of 0.25) but not with serum C-reactive protein.The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Over the past decade, biological immunotherapy has revolutionised the treatment of rheumatoid arthritis (RA). The most widely used of these therapies targets tumour necrosis factor-alpha (TNF-alpha). Approximately 20% of patients fail to respond to TNF-alpha antagonism, however, and a significant number of additional patients become refractory to anti-TNF-alpha therapy over time. Thus investigators have sought to target other pathogenic elements of RA using novel biological therapies. Abatacept is the first immunotherapy directed against the process of T-cell costimulation. Abatacept has shown clinical effectiveness in RA by improving disease activity, quality of life measures and radiographic progression of disease. In this article, we review the immunology of T-cell activation and costimulation, define the role of abatacept in this process, and discuss the clinical trials that led to the approval of abatacept as the latest biological therapy in RA in the USA and Canada. We also address the role of abatacept in the greater context of biological therapy for RA.

Objective With the growth in patient registries in rheumatic disease research, it is important to validate the collected information. We examined the convergent validity of self-reported medication use for rheumatoid arthritis (RA). Methods In the setting of the Brigham Rheumatoid Arthritis Sequential Study (BRASS), a large registry of patients with RA, we examined the agreement between patients' self-report of current and past RA medication use and information from medical records. For a sample of patients in BRASS, these 2 sources of information were compared using the kappa statistic as well as the percent agreement. Results The 91 patients selected for assessment were typical of a prevalent RA cohort: >80% were women and the mean disease duration was 16 years. The agreement for current medication use was excellent, ranging from 0.71 for sulfasalazine to 0.96 for methotrexate. However, for past medication use agreement was lower, ranging from 0.13 for methotrexate to 0.74 for aurothioglucose. The weighted kappa for cumulative oral glucocorticoid dose was 0.67. Conclusion Self-report of current medication use and cumulative oral glucocorticoid dose appears to have moderate to excellent validity. However, self-report of past medication use may not be valid.

Introduction This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed. Methods The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ≥16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ≥1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (