Project description:ObjectiveDespite a wealth of studies evaluating rheumatoid arthritis (RA) therapies, it remains difficult to compare efficacies across trials due to heterogeneous study populations. We sought to identify patient/trial characteristics associated with clinical response to enable fairer comparisons.MethodsWe reviewed 565 disease-modifying antirheumatic drug studies compiled for American College of Rheumatology (ACR) management guidelines. Seventy-two articles on randomized controlled phase II/III trials from 1995 to 2018 reporting the proportion of patients achieving 20%, 50% or 70% improvement in the ACR's RA disease score (ACR20/50/70) or Disease Activity Score-28 with erythrocyte sedimentation rate or C-reactive protein (DAS28-ESR or DAS28-CRP) with follow-up more than 3 months were included. We explored associations between 34 patient/trial characteristics and ACR responses. We constructed multivariable models using these factors to compute expected response rates and to compare observed with expected response rates across therapies.ResultsAmong eligible clinical trials, later publication year, baseline DAS28-CRP score, methotrexate/biologic naivety, baseline ESR, follow-up of 52 weeks or more, number of subjects enrolled, and anticitrullinated peptide antibody seropositivity were associated with greater ACR response. Greater age, longer disease duration, higher baseline Sharp score, and steroid use were associated with lower response rates. Predictive models incorporating these factors explained 29%, 37%, and 53% of variance in ACR20, ACR50, and ACR70, respectively. Overall, comparing observed versus expected rates of response across trials more closely approximated results of head-to-head trials. For example, although observed responses numerically favored adalimumab to tofacitinib, comparison of observed versus expected results across trials more closely approximated the results from a head-to-head trial ("Oral Rheumatoid Arthritis triaL [ORAL] Strategy").ConclusionWe identified factors associated with ACR response in RA trials. Adjusting for expected outcomes yielded therapy comparisons somewhat more similar to head-to-head trials. These findings could inform other across-trial comparisons, particularly when head-to-head trials are lacking.

Project description:Rheumatoid arthritis is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis. A total of 559 human sera were profiled using a custom made panel of putative rheumatoid arthritis associated autoantigens. The cohort was comprised of 79 patients with clinical RA for whom stored serum was available from 1-10 years prior to disease onset and 80 control subjects without RA that were matched to cases based on age, gender, race, region of assignment, and time of serum sampling.

Project description:Rheumatoid arthritis is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Project description:Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-?, IL-6, IL-12p70, and IFN-?. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Project description:BACKGROUND:Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS:Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and?HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS:In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at?some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (?29?IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ?100?IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION:HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.

Project description:ImportanceRacial/ethnic minority groups, women, and elderly people experience a disproportionate burden of disease in rheumatoid arthritis (RA), making it particularly important to examine drug therapies in these populations. Despite a national health agenda to improve representation of diverse populations in randomized clinical trials (RCTs), there have been few large-scale analyses examining RCT demographic characteristics within rheumatology and none focusing on RA.ObjectiveTo characterize the representation of racial/ethnic minority groups, women, and elderly people through a comprehensive systematic review of RA RCTs.Data sourcesA literature search of PubMed's MEDLINE database was conducted to identify RA RCTs in adults 19 years and older published in English between January 1, 2008, and January 1, 2018.Study selectionRandomized double-blind RCTs examining any systemic, disease-modifying therapy were included. Secondary analyses of previously published RCTs were excluded. Of 1195 identified records, 240 articles (20.1%) met final selection criteria. The analysis focused on RCTs with at least 1 US-based site.Data extraction and synthesisData were extracted and synthesized according to the PRISMA guidelines for systematic reviews. Studies were screened for eligibility criteria. Demographic data on the age, sex, and race/ethnicity of RCT participants were extracted. Data analysis was conducted from October 25, 2018, to March 15, 2019.Main outcomes and measuresRepresentation of race/ethnicity and sex, defined as the proportion of total participants that belonged to each racial/ethnic group or sex. Trends in proportions over time were examined and compared with US demographic data.ResultsA total of 240 RCTs with 77 071 participants were included. Of 126 RCTs with at least 1 US-based site (52.5%), the enrollment of minority racial/ethnic groups was significantly lower than their representation within the US Census population (16% vs 40%; P < .001), and the enrollment of men was significantly lower than the incidence of RA in men nationally (20.4% vs 28.6%; P < .001). There was no trend toward improved representation of racial/ethnic minority groups or men over time.Conclusions and relevanceGiven the disproportionate burden of RA among racial/ethnic minority groups, it is imperative that policy makers better incentivize the inclusion of racial/ethnic minority groups in RA RCTs.

Dataset Information

Short-Term Efficacy Reliably Predicts Long-Term Clinical Benefit in Rheumatoid Arthritis Clinical Trials as Demonstrated by Model-Based Meta-Analysis.

Publications

Short-Term Efficacy Reliably Predicts Long-Term Clinical Benefit in Rheumatoid Arthritis Clinical Trials as Demonstrated by Model-Based Meta-Analysis.

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