Beth Jonas

Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis

Context Which disease-modifying antirheumatic drugs (DMARDs) best reduce symptoms, improve function, and prevent radiographic progression in patients with rheumatoid arthritis? Contribution This systematic review of trials that compared DMARDs in adults with rheumatoid arthritis found few direct comparisons of different agents but no important differences among synthetic DMARDs or antitumor necrosis factor drugs. Combination therapy improved response rates and functional outcomes in patients whose monotherapy failed. Numbers and types of short-term adverse events were similar among DMARDs. Implication Of several monotherapies for adults with rheumatoid arthritis, no regimen is clearly superior. Combination therapies improve response rates in some patients previously receiving monotherapy. The Editors Rheumatoid arthritis is an autoimmune disease that affects more than 2 million adults in the United States. Disease onset generally occurs between 30 and 55 years of age, and women are affected more often than men. Disease hallmarks are inflammation of the synovium, progressive bone erosion, joint malalignment and destruction, and subsequent weakness of surrounding tissues and muscles. Presentations range from mild to severe, although the typical patient has a progressive course leading to functional limitations. Treatment aims at controlling pain and inflammation and slowing or arresting the progression of joint destruction. Therapies generally used in the United States include corticosteroids; synthetic disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine; and biological DMARDs, such as abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab. The American College of Rheumatology (ACR) recommends beginning DMARD therapy within 3 months of diagnosis (1). Often, treatment with a single DMARD does not adequately control symptoms, leading clinicians to consider various combination strategies. Experts do not agree about the comparative benefits of different combination therapies. Many questions remain about the risks of these agents across a spectrum of adverse events from relatively minor side effects to severe and possibly life-threatening problems. Given this uncertainty, the Agency for Healthcare Research and Quality (AHRQ) commissioned a systematic review to compare the benefits and safety of rheumatoid arthritis drugs (2). Methods We developed and followed a standardized protocol for all steps of the review. The full technical report (2) describes study methods in detail and gives evidence tables of individual studies. Literature Search We searched MEDLINE, EMBASE, The Cochrane Library, and the International Pharmaceutical Abstracts for studies from 1980 to September 2007. Search terms included Medical Subject Headings or keywords when appropriate. We combined terms for rheumatoid arthritis with 11 drugs of interest (corticosteroid, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, etanercept, infliximab, adalimumab, abatacept, anakinra, and rituximab). We limited electronic searches to studies involving adults and humans and studies in English. We manually searched reference lists of review articles and letters to the editor. In addition, we searched the Center for Drug Evaluation and Research database (September 2007) to identify unpublished research submitted to the U.S. Food and Drug Administration. In early to mid-2006, the Oregon Scientific Resource Center invited pharmaceutical manufacturers to submit dossiers on all published and unpublished studies on a specific drug. Five companies (Abbott, Amgen, Bristol-Myers Squibb, Centocor, and Genentech) provided dossiers. Study Selection Two persons, each blinded to the others results, independently reviewed titles, abstracts, and sometimes full text to identify studies meeting preestablished criteria. To assess efficacy regarding symptoms, quality of life, functional capacity, and radiographic progression, we included head-to-head controlled trials and prospective cohort studies comparing any of the therapies. For harms (specific adverse events, rates of adverse events, and discontinuation attributable to adverse events) and subgroups, we also examined data from retrospective observational studies and placebo-controlled trials. For efficacy and harm data, we selected studies with 100 or more participants and at least 12 weeks of follow-up. Finally, if we found no evidence about efficacy from direct head-to-head comparison studies, we included evidence from fair- or good-quality meta-analyses that indirectly compared placebo-controlled trial data across drugs. Data Abstraction and Quality Assessment Trained reviewers abstracted each study by using a Web-based system (SRS 4.0, TrialStat, Ottawa, Ontario, Canada). A senior reviewer read each abstracted article and evaluated completeness of data extraction. We recorded intention-to-treat results if available. We assessed the internal validity (quality) of trials on the basis of predefined criteria from the U.S. Preventive Services Task Force (rating of good, fair, or poor) (3) and the National Health Service Centre for Reviews and Dissemination (4). Elements of internal validity for trials included randomization, allocation concealment, similarity of compared groups at baseline, intention-to-treat analysis, and overall and differential loss to follow-up. To assess the quality of observational studies, we used criteria outlined by Deeks and colleagues (5). Items assessed included sample selection, adjustment for confounders, methods of outcomes assessment, length of follow-up, and statistical analysis. Data Synthesis We primarily synthesized the literature qualitatively; we reported some quantitative syntheses from fair- to good-quality meta-analyses. Drug comparisons that were not quantitatively analyzed in meta-analyses had insufficient data or noncomparable study samples and did not merit additional quantitative analyses. We examined data within 3 main drug classes (corticosteroids, synthetic DMARDs, and biological DMARDs) and between drug classes and combination therapies. Strength of Evidence Ratings We rated the strength of the available evidence in a 3-part hierarchy (high, moderate, and low) (2) based on a modified Grading of Recommendations, Assessment, Development, and Evaluation approach (6, 7). Grades reflect the strength of evidence for a given comparison with respect to specific outcomes, such as 20% improvement in ACR response criteria (ACR 20), radiographic changes, or adverse events. Role of the Funding Source Agency for Healthcare Research and Quality staff participated in formulating initial study questions and reviewed methods, data analysis, and the draft report. The funding source did not participate in the literature search, determination of study eligibility, or evaluation of individual studies. Results Characteristics of Reviewed Studies We identified 2395 citations (Figure). Working from 635 articles retrieved for full review, we included 143 published articles reporting on 101 studies (Table 1). Of the 101 included studies, 49 (48.5%) were supported by pharmaceutical companies, 20 (19.8%) by governmental or independent funds, and 11 (10.9%) by a combination of pharmaceutical and governmental funding. We could not determine the source of support for 21 (20.8%) studies. Table 1. Summary of Head-to-Head Reviewed Studies, by Drug Comparison* Figure. Study flow diagram. Numbers of included articles and included studies differ because some studies have multiple publications. RCT = randomized, controlled trial. Comparative Effectiveness and Harms We found few fair- or good-quality head-to-head trials for each drug comparison (Table 1). Most trials were efficacy trials in highly selected populations with few comorbid conditions. Most trials used ACR 20, disease activity scores to measure clinical improvement, and Sharp or Sharpvan der Heijde scores to measure radiologic progression of the disease. Trials examining quality of life used the Health Assessment Questionnaire (HAQ) or Medical Outcomes Study Short Form 36 (SF-36). Table 2 summarizes results. Table 2. Summary of Comparative Findings on Efficacy and Harms of Rheumatoid Arthritis Drugs Monotherapy versus Monotherapy Synthetic DMARDs One good systematic review that included a meta-analysis of 2 trials suggested that more patients receiving methotrexate achieved ACR 20 at 1 year than did patients receiving leflunomide (odds ratio, 1.43 [95% CI, 1.15 to 1.77]). The ACR 20 benefit was lower and more uncertain at 2 years (odds ratio, 1.28 [CI, 0.98 to 1.67]) (8). However, patients receiving methotrexate showed less improvement in health-related quality of life than did patients receiving leflunomide (odds ratio for SF-36 physical component, 3.00 [CI, 5.41 to 0.59]). Radiographic outcomes over 2 years seemed similar. For leflunomide versus sulfasalazine, data are limited to 1 trial (9) involving 358 participants with 2-year follow-up (10, 11). Leflunomide yielded more patients achieving ACR 20, ACR 50, and greater improvement in functional capacity (ACR 20, 82% vs. 60% [P= 0.008]; ACR 50, 52% vs. 25% [P= 0.040]; HAQ, 0.50 vs. 0.29 [P 0.030]). Radiographic changes were similar for the 2 drugs (Larsen score change at 2 years, 0.010 for either drug) (9). Three trials involving 479 participants and lasting up to 52 weeks compared methotrexate with sulfasalazine and found similar response rates in ACR 20, disease activity scores, or functional capacity (1214). Two trials included patients with disease for longer than 1 year and used a lower dose of weekly methotrexate (7.5 mg) than that generally used in the United States (13, 14). The overall attrition rate for these studies ranged from 19% to 28.5%. We found no statistically significant differences in frequency of serious adverse events for leflunomide, methotrexate, and sulfasalazine in 3 efficacy trial

Vitamin D Status and Its Associations with Disease Activity and Severity in African Americans with Recent-onset Rheumatoid Arthritis

Objective. To examine the prevalence of vitamin D insufficiency and the associations of vitamin D concentration with disease status in African Americans with rheumatoid arthritis (RA). Methods. Study participants (n = 266) were enrolled in the Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) Registry. The vitamin 25(OH)-D was measured on baseline plasma, and associations of 25(OH)-D with disease status (baseline and at 3 years’ disease duration) were examined using univariate and multivariate regression. Results. The prevalence of 25(OH)-D insufficiency (≤ 37.5 nmol/l or 15 ng/ml) was 50%, with the highest prevalence in winter. In unadjusted analyses, vitamin D concentrations were inversely associated with baseline pain (p = 0.04), swollen joints (p = 0.04), and Disease Activity Score (DAS28, p = 0.05) but not with measures at 3 years’ disease duration. There were no multivariate associations of 25(OH)-D with any disease measures at baseline or at 3 years, with the exception of a positive borderline association with rheumatoid factor positivity at enrollment (p = 0.05). Conclusion. Vitamin D insufficiency is common in African Americans with recent-onset RA. Unadjusted associations of circulating vitamin D with baseline pain, swollen joints, and DAS28 were explained by differences in season, age, and gender and were not significant in multivariate analyses. In contrast to reports of Northern Europeans with early inflammatory arthritis, there are not strong associations of 25(OH)-D concentration with symptoms or disease severity in African Americans with RA.

Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis

BackgroundThere are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks.MethodsThis was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria.ResultsThe mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo.ConclusionsThere was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.

The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture

OBJECTIVE To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. METHODS In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. RESULTS The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody-positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test). CONCLUSION HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which approximately 50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence

Biologics are an important therapeutic option for treating patients with juvenile idiopathic arthritis (JIA). In adults, they are associated with rare but severe adverse events such as serious infections and malignancies. We reviewed systematically the evidence on the efficacy and safety of biologics for the treatment of JIA. We searched electronic databases up to August 2006. We limited evidence to prospective studies for efficacy but included retrospective observational evidence for safety. Outcomes of interest were clinical response, radiographic progression, quality of life, and adverse events. One randomized controlled trial (RCT) and 11 uncontrolled prospective studies provided data on efficacy; three additional studies assessed safety. The only RCT and six uncontrolled trials support the general efficacy of etanercept for the treatment of JIA. Internal and external validity of these studies are limited. The evidence on other biologic agents such as adalimumab, abatacept, anakinra, infliximab, rituximab, and tocilizumab is sparse or entirely missing. Because of the lack of sound long-term safety data, evidence is insufficient to draw firm conclusions about the balance of risks and benefits of any biologic agent for the treatment of JIA. Clinicians have to be aware of the lack of evidence supporting a long-term net benefit when considering biologics for patients with JIA.

Most common single-nucleotide polymorphisms associated with rheumatoid arthritis in persons of European ancestry confer risk of rheumatoid arthritis in African Americans.

OBJECTIVE Large-scale genetic association studies have identified >20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA risk in an African American population. METHODS Twenty-seven candidate single-nucleotide polymorphisms (SNPs) were genotyped in 556 autoantibody-positive African Americans with RA and 791 healthy African American control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were compared with previously published ORs for RA patients of European ancestry. We then calculated a composite genetic risk score (GRS) for each individual based on the sum of all risk alleles. RESULTS Overlap of the ORs and 95% CIs between the European and African American populations was observed for 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, and TNFAIP3 rs6920220) demonstrated ORs in the opposite direction from those reported for RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African American patients relative to control subjects were enriched for the risk alleles validated in European RA patients (P = 0.00005). CONCLUSION The majority of RA risk alleles previously validated for RA patients of European ancestry showed similar ORs in our population of African Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel RA risk alleles in African Americans.

Associations of cigarette smoking with rheumatoid arthritis in African Americans

OBJECTIVE To examine the associations of cigarette smoking with rheumatoid arthritis (RA) in African Americans, and to determine whether this association is impacted by the HLA-DRB1 shared epitope (SE). METHODS Smoking status, cumulative smoking exposure, and SE status were determined in African American patients with RA and African American healthy controls. Associations of smoking with RA were examined using age- and sex-adjusted logistic regression analyses. Additive and multiplicative SE-smoking interactions were examined. RESULTS After adjustment for age and sex, ever smoking (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.07, 1.97) and current smoking (OR 1.56, 95% CI 1.07, 2.26), relative to never smoking, were more common in African American patients with RA (n = 605) than in controls (n = 255). The association of smoking with RA was limited to those with a cumulative exposure exceeding 10 pack-years, associations that were evident both in autoantibody-positive and in autoantibody-negative disease. There was evidence of a significant additive interaction between SE status and heavy smoking (≥10 pack-years) in relation to RA risk (attributable proportion [AP] due to interaction 0.58, P = 0.007), with similar results for the additive interaction between SE status and ever smoking (AP 0.47, P = 0.006). There was no evidence of multiplicative interactions. CONCLUSION Among African Americans, cigarette smoking is associated not only with the risk of autoantibody-positive RA but also with the risk of autoantibody-negative disease. The risk of RA attributable to smoking is limited to African Americans with more than 10 pack-years of exposure and is more pronounced among individuals positive for the HLA-DRB1 SE.

Genetic variants of STAT4 associated with rheumatoid arthritis in persons of Asian and European ancestry do not replicate in African Americans

Rheumatoid arthritis (RA) was recently genetically associated with signal transducer and activator of transcription 4 ( STAT4 ) in white individuals.1 This study included over 6000 participants to produce an odds ratio (OR) of 1.32 at rs7574865 (p<0.001). Three other single-nucleotide polymorphisms (SNP) located in intron 3 of STAT4 (rs8179673, rs10181656, rs6752770), three SNP in strong linkage disequilibrium with rs7574865 (r2=1.0; rs7582694, rs7568275, rs11889341) and a haplotype driven by the T allele of rs7574865 are also associated with RA susceptibility.1 Association with rs7574865 replicated in several Asian and European-based populations (see table 1). As racial/ethnic differences have been observed at RA susceptibility loci, including CTLA4, PADI4, PTPN22, RUNX1 and SLC22A4 , we aimed to determine if an association with these STAT4 markers and RA susceptibility is consistent in African Americans. View this table: Table 1 Previously published genetic associations with the T allele of rs7574865 …

A functional RANKL polymorphism associated with younger age at onset of rheumatoid arthritis.

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.

Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans

OBJECTIVE To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. METHODS Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed. RESULTS There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P(additive) = 0.000003) and rs1208 (P(additive) = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies. CONCLUSION Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.