E. Keystone

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Several disease-modifying antirheumatic drugs (DMARDs) slow disease progression in patients with rheumatoid arthritis. Many experts prefer methotrexate, although trials do not uniformly show that it is superior to other DMARDs. It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone. Contribution This 24-week, randomized, double-blind, placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone. Cautions Some adverse effects, such as diarrhea, were more common with combination therapy. All patients receiving DMARD therapy need close monitoring for toxicities. The Editors Rheumatoid arthritis has considerable societal costs (1-5). Many patients with rheumatoid arthritis become disabled within a few years of disease onset (4, 5). Methotrexate is the standard treatment for rheumatoid arthritis. During the past several years, investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy (6-9). Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism (10). The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate (11), but methotrexate is thought to act primarily on purine pathways of cellular metabolism (10). Leflunomide (Arava, Aventis Pharmaceuticals, Bridgewater, New Jersey) also has antimetabolic effects, inhibiting pyrimidine intracellular pathways (12). Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind, placebo-controlled trials (13, 14). Given the diverse intracellular pathways affected by both drugs, the combination of leflunomide and methotrexate has the potential for biochemical synergy. The possibility of increased benefits should be weighed against the possible toxicities of this combination. Abnormal aminotransferase levels have been seen with both methotrexate (15) and leflunomide (14) monotherapy in patients with rheumatoid arthritis. In a small open study, we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels (16). We therefore sought to determine whether similar results could be achieved in a large, double-blind investigation of the combination of these two antimetabolic agents. Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology (ACR) criteria (17). Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate (15 to 20 mg/wk, or 10 to 15 mg/wk if this was the maximum tolerated dose). Patients were recruited from active outpatient practice centers, and study participants were approached without a particular schema. Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy, including stable dosage for at least 8 weeks. Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations, 7 to 21 days apart: at least nine tender joints, at least six swollen joints, at least 45 minutes of morning stiffness, and an erythrocyte sedimentation rate of at least 28 mm/h. Previous disease-modifying antirheumatic drugs, not including ongoing methotrexate, had failed in 11 patients. Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration, and the corticosteroid dose was required to remain constant throughout the study. Complete exclusion criteria are listed in Appendix Table 1. Study Design The 24-week, randomized, double-blind, placebo-controlled study, with evaluations occurring at 4-week intervals (Figure 1), was conducted in 20 centers in the United States and Canada between September 1998 and June 2000. The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis. All participants provided written consent, and the institutional review board at each center approved the protocol. Figure 1. Patient eligibility, randomization, assignment, and discontinuation. Include no wish to continue in study, poor adherence to treatment, protocol violation, and moving away from the study area. A randomization schedule, generated by and stored with Quintiles, Inc., Kansas City, Missouri, was used to assign sequential numbers to randomly allocated treatment codes. Randomization was done by using the Aventis standard random-code generator. Investigators allocated numbers to patients, beginning with the lowest available number. Quintiles, Inc., packaged and labeled the study medication. The randomization code used was concealed from investigators and patients throughout the study. Randomization was stratified by center. A set of 500 random numbers was generated, with treatment groups randomly assigned in a balanced manner (1:1 ratio) within each block of four consecutive random numbers (block size, 4). A set of these blocks was then sent to each investigative center. This method is identical to stratification by center because centers are balanced with respect to treatment assignment. Patients were randomly assigned to receive leflunomide, 100 mg/d, for 2 days followed by 10 mg/d or matching placebo. If substantial adverse events occurred, this dose could be reduced to 10 mg every other day. If 10 mg/d was tolerated but active disease, as defined earlier, was still present at week 8 or thereafter, an increase to 20 mg of leflunomide or matching placebo per day was required. If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day, a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator. At least 1 mg of folate supplementation per day was mandated by the protocol. Adherence to study medication, assessed at each visit by tablet counts (actual number of tablets returned compared with number expected to be returned), was similar in the two groups. The mean adherence for all patients in the intention-to-treat sample was 98.0% (98.5% for those receiving placebo and 97.4% for those receiving leflunomide). In the placebo group and leflunomide group, respectively, 90.2% (120 of 133 patients) and 87.7% (114 of 130 patients) had adherence rates of 80% to 120%. Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20% improvement in ACR criteria (ACR20) at the end of the study. To be classified as having achieved ACR20, patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study (13). The ACR20 criteria were developed to define improvement in rheumatoid arthritis (18). Clinical improvement is indicated by 20% improvement in tender and swollen joint counts and 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, pain intensity, physical function or disability measure, and level of acute-phase reactant (19). All ACR assessments were performed by the investigators, and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment. Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis. Count of tender joints was based on 68 joint assessments, and count of swollen joints was based on 66 joint assessments. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit. Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable. Secondary outcomes included ACR50 and ACR70 responder rates at week 24 (analyses of responders at study end for the nonprimary efficacy measures). The ACR50 and ACR70 were defined as at least 50% and 70% improvement, respectively, in the same criteria used to calculate ACR20 response. Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor. Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2. Measurement of Safety Safety was evaluated by adverse event reports; laboratory assays for changes in hematologic characteristics, blood chemistry, urinalysis, and liver function; and physical examination. Potential adverse events were assessed by using open-ended questions at each study visit. The assessor was blinded to reported toxicities and to any additional information obtained at the visit. The study protocol provided recommendations for dosage change and discontinuation of drug therapy, without unblinding, when patients were found to have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values greater than two times the upper limit of normal. Investigators decreased the dose of the study medication if, on repeated analysis at 72 hours, test values remained greater than two times but less than or equal to five times the upper limit of normal; only one dose adjustment was allowed before discontinuation of therapy with the study drug. Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated te

Infliximab in active early rheumatoid arthritis

Objective: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA). Methods: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group. Results: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet. Conclusions: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.

Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade

Objective: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. Methods: Patients (n  =  1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (⩽3.3), low (>3.3 to ⩽11), moderate (>11 to ⩽26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. Results: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. Conclusion: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003)

As in previous years, the consensus group to consider the use of biological agents was constituted by rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with universities in the United States, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference. The 158 rheumatologists and bioscientists from 21 countries who attended the consensus conference were chosen from a worldwide group of doctors and other scientists interested in the use of biological agents for the treatment of immune mediated inflammatory diseases. The perspective of this consensus is from the treating doctor’s point of view, rather than from the perspective of those paying for their use. The number of attendees and participants was limited so that not everyone who might have been appropriate could be invited. Additional information has come to light in the past year, both corroborating the major positive effect these drugs have had in rheumatoid arthritis (RA) and other immune mediated inflammatory diseases, as well as documenting possible new and unexpected adverse events. Therefore an update of the previous consensus statement seems both appropriate and necessary ( Ann Rheum Dis2002;61(suppl II):ii2–7 [OpenUrl][1][FREE Full Text][2] ). The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 3.99 All participants reviewed relevant clinical published articles relating to tumour necrosis factor (TNF) and interleukin 1 (IL1) blocking agents. They were given a draft consensus statement and were asked to revise the document in small discussion groups; open discussion of the revisions led to a final document, representing this updated consensus statement. Individual patients differ in the aggressiveness of … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2Bthe%2BRheumatic%2BDiseases%26rft.stitle%253DAnn%2BRheum%2BDis%26rft.issn%253D0003-4967%26rft.aulast%253DFurst%26rft.auinit1%253DD%2BE%26rft.volume%253D61%26rft.issue%253D90002%26rft.spage%253Dii2%26rft.epage%253D7%26rft.atitle%253DUpdated%2Bconsensus%2Bstatement%2Bon%2Bbiological%2Bagents%2Bfor%2Bthe%2Btreatment%2Bof%2Brheumatoid%2Barthritis%2Band%2Bother%2Brheumatic%2Bdiseases%2B%2528May%2B2002%2529%26rft_id%253Dinfo%253Apmid%252F12379612%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=annrheumdis&resid=61/suppl_2/ii2&atom=%2Fannrheumdis%2F62%2Fsuppl_2%2Fii2.atom

Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission

Objective The target outcome in early rheumatoid arthritis (ERA) is now remission. This meta-analysis compared the efficacy of initial methotrexate monotherapy versus combination therapy (methotrexate plus biological agent) for clinical remission and radiographic non-progression among ERA patients with minimal or no previous methotrexate exposure. Methods A systematic search was performed for randomised controlled trials of ERA using predefined criteria. A random effects model was used to pool the risk ratio (RR) for clinical and radiographic remission at 52–56 weeks of follow-up. Results Seven trials of combination therapy with infliximab, adalimumab, etanercept or abatacept were included. The majority of studies defined clinical remission as a 28-joint disease activity score (DAS28) of 2.6 or less. Radiographic non-progression was primarily defined as a modified total Sharp score change of less than 0.5 units. All trials demonstrated risk estimates in favour of combination therapy: the pooled RR for achieving clinical remission was 1.74 (95% CI 1.54 to 1.98) and for radiographic non-progression was 1.30 (95% CI 1.01 to 1.68). Significant heterogeneity among studies for the latter outcome was detected (p<0.001). Conclusions The efficacy of combination therapy with a biological agent is superior to methotrexate monotherapy for remission. Combination therapy has a greater initial effect on clinical remission than radiographic non-progression. Uniform definitions of remission are needed and the proportion of subjects who achieve the combined endpoint of clinical and radiographic remission should be considered as a meaningful outcome in future studies of ERA.

Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002)

A s in previous years, the consensus group to consider the use of biological agents was formed by an organising committee constituted of rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with universities in the United States, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference. The 158 rheumatologists and bioscientists from 22 countries who attended the consensus conference were chosen from a worldwide group of people felt to have experience or interest in the use of biological agents for the treatment of rheumatoid arthritis (RA) and other rheumatic diseases. Unfortunately, the number of attendees and participants was limited so that not everyone who might have been appropriate could be invited. Additional information has come to light in the past year, both corroborating the major positive effect these drugs have had in RA and documenting possible new and unexpected adverse events. In addition, the first of a new class of targeted biological agents, interleukin 1 (IL1) blocking agents, has become available. Therefore an update of the previous consensus statement1 seems both appropriate and necessary. In the present update the consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 3.2 All participants reviewed relevant clinical published articles relating to tumour necrosis factor (TNF) and IL1 blocking agents. They were given a draft consensus statement and were asked to revise the document in small discussion groups; open discussion of the revisions led to a final document, representing this updated consensus statement. Individual patients differ in the aggressiveness of their …

A Phase 2b Study of ABT-494, a Selective JAK1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-TNF Therapy.

To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.

Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases (April 2001)

TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.