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In a phase 3 randomized trial of 1307 patients with rheumatoid arthritis receiving background methotrexate, the oral JAK1 and JAK2 inhibitor baricitinib showed superior efficacy to placebo and to the anti–tumor necrosis factor α monoclonal antibody adalimumab. Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. Progress in treatment with the use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and biologic DMARDs that target tumor necrosis factor (TNF) has made clinical remission a realistic target. 1 Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis. 2 Baricitinib, an orally available small molecule, provides reversible inhibition of JAK1 and JAK2 and has shown clinical efficacy in studies . . .

Objectives To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA). Methods AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX. Results Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results. The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%). Conclusions Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes. Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept. ClinicalTrials.gov Identifier NCT00929864.

Background Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here. Methods Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments. Results Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR (“cough”) occurred and no new safety signals were identified. Conclusion Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes. Trial registration ClinicalTrials.gov (NCT03635957)

Population stratification—allele frequency differences between cases and controls due to systematic ancestry differences—can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.

In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

Abstract Rationale Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. Objectives To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. Methods Subjects enrolled in Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. Measurements and Main Results A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. Conclusions Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

Background Many patients with rheumatoid arthritis (RA) require a trial of multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) to control their disease. With the availability of several bDMARD options, the history of bDMARDs may provide an alternative approach to understanding subphenotypes of RA. The objective of this study was to determine whether there exist distinct clusters of RA patients based on bDMARD prescription history to subphenotype RA. Methods We studied patients from a validated electronic health record-based RA cohort with data from January 1, 2008, through July 31, 2019; all subjects prescribed ≥ 1 bDMARD or targeted synthetic (ts) DMARD were included. To determine whether subjects had similar b/tsDMARD sequences, the sequences were considered as a Markov chain over the state-space of 5 classes of b/tsDMARDs. The maximum likelihood estimator (MLE)-based approach was used to estimate the Markov chain parameters to determine the clusters. The EHR data of study subjects were further linked with a registry containing prospectively collected data for RA disease activity, i.e., clinical disease activity index (CDAI). As a proof of concept, we tested whether the clusters derived from b/tsDMARD sequences correlated with clinical measures, specifically differing trajectories of CDAI. Results We studied 2172 RA subjects, mean age 52 years, RA duration 3.4 years, and 62% seropositive. We observed 550 unique b/tsDMARD sequences and identified 4 main clusters: (1) TNFi persisters (65.7%), (2) TNFi and abatacept therapy (8.0%), (3) on rituximab or multiple b/tsDMARDs (12.7%), (4) prescribed multiple therapies with tocilizumab predominant (13.6%). Compared to the other groups, TNFi persisters had the most favorable trajectory of CDAI over time. Conclusion We observed that RA subjects can be clustered based on the sequence of b/tsDMARD prescriptions over time and that the clusters were correlated with differing trajectories of disease activity over time. This study highlights an alternative approach to consider subphenotyping of patients with RA for studies aimed at understanding treatment response.

Chikungunya fever (CHIKF) is a re-emerging infectious disease caused by the chikungunya virus (CHIKV), transmitted primarily by Aedes mosquitoes. A significant number progress to chronic chikungunya arthritis, which shares similarities with rheumatoid arthritis (RA). Despite evidence of a link between CHIKV infection and subsequent RA development, a comprehensive analysis of the relationship between these two diseases is lacking. This study systematically analyzes the incidence of RA after CHIKV infection and its immunological mechanisms, following PRISMA guidelines with literature searches across multiple databases up to 3 September 2024. Eligible studies included ret- rospective and prospective designs reporting RA diagnoses after CHIKV infection. Data extraction was performed independently, and the risk of bias was assessed using appro- priate tools. Sixteen studies involving 2879 patients were included, with 449 individuals diagnosed with RA following CHIKV infection, resulting in a combined incidence of 13.7% (95% CI: 6.12% to 27.87%). High heterogeneity between studies was observed (I 2 equivalent 96%), indicating variability related to diagnostic criteria and population characteristics. This review highlights the significant RA incidence after CHIKV infection, emphasizing the need for research on autoimmune mechanisms, long-term rheumatological follow-up, early diagnostic biomarkers, and CHIKV's long-term health impacts.

Objective Patients with rheumatoid arthritis (RA) and other systemic rheumatic diseases (SRDs) are at increased risk of developing herpes zoster (HZ). Zoster recombinant adjuvanted (ZRA) is a recombinant vaccine approved by the Food and Drug Administration in 2018. Concern has been raised that the ZRA may trigger disease flares in rheumatology patients who are immunocompromised. We investigated the impact of the ZRA vaccine in patients with RA and SRD and measured the incidence of flares and side effects. Methods A flare was defined as occurring within 12 weeks of vaccine administration by either 1) documentation of RA flare in office notes, telephone encounter, or patient portal communication or 2) new or increased dose of corticosteroids. Results We identified 403 patients (239 patients with RA and 164 patients with SRD) who received the ZRA vaccine from February 1, 2018, to February 1, 2019. We measured a 6.7% (n = 27) incidence of flare. Side effects occurred in 12.7% (n = 51) of patients. All flares and side effects were regarded as mild. Three cases of HZ were reported as occurring 2, 10, and 11 months after the vaccination. Conclusion In 403 patients who received the ZRA vaccine, the incidence of disease flares was 7% or less and that of side effects was 13% or less, both of which are less than the incidence rates observed in the pivotal trials.