Rheumatoid Arthritis Clinical Trials Research Articles

Identifying Factors Associated With Treatment Response in Rheumatoid Arthritis Clinical Trials.

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.

Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis

ObjectivesVarious hypotheses exist for the explanation of placebo response rates in randomised controlled trials (RCTs) of patients with rheumatoid arthritis with IR to methotrexate (MTX). We hypothesised that placebo responses...

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Dexamethasone ameliorates arthritis through epigenetic and transcriptional regulation of CCL17 production

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which leads to poor quality of life due to the debilitating effect of inflammation. Clinical trials in rheumatoid arthritis targeting the cytokine, granulocyte macrophage‐colony stimulating factor (GM‐CSF) are showing promise although its mode of action remains largely unknown. We have previously shown that that GM‐CSF drives CCL17 production via a new interferon regulatory factor 4 (IRF4)‐dependent pathway in human monocytes and mouse macrophages, as well as in vivo. Importantly, in arthritis and pain models IRF4‐regulated CCL17 formation mediates the proinflammatory and algesic actions of GM‐CSF.Glucocorticoids (GCs) are potent anti‐inflammatory and immunosuppressive agents broadly used in anti‐inflammatory therapy, albeit with adverse side effects associated with long‐term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action on immune cells.We report here that GM‐CSF‐induced CCL17 expression is inhibited by dexamethasone, a synthetic GC, in human monocytes and mouse macrophages. Moreover, we provide evidence for the first time that dexamethasone suppresses GM‐CSF‐induced IRF4 expression via regulating the expression and activity of JMJD3, which demethylates trimethylated‐H3K27. Further, we demonstrate that dexamethasone suppresses the expression of JMJD3, via the recruitment of GC receptor‐alpha to the negative GC response element in the upstream region of JMJD3 gene. Significantly, we measured elevated levels of CCL17 in synovial fluid from patients with RA compared to healthy controls. Using synovial fluid mononuclear cells from RA patients, we provide molecular evidence for the anti‐inflammatory actions of GCs through epigenetic regulation of IRF4 expression and downstream inhibition of CCL17 production. The delineated pathway potentially provides new therapeutic options for the treatment of inflammatory diseases and their associated pain.

Development of a core outcome set for the orthopaedic management of spinal dysraphism : a study protocol.

AimsThe aim of this study is to define a core outcome set (COS) to allow consistency in outcome reporting amongst studies investigating the management of orthopaedic treatment in children with spinal dysraphism (SD).MethodsRelevant outcomes will be identified in a four-stage process from both the literature and key stakeholders (patients, their families, and clinical professionals). Previous outcomes used in clinical studies will be identified through a systematic review of the literature, and each outcome will be assigned to one of the five core areas, defined by the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). Additional possible outcomes will be identified through consultation with patients affected by SD and their families.ResultsOutcomes identified in these stages will be included in a two-round Delphi process that will involve key stakeholders in the management of SD. A final list including the identified outcomes will then be summarized in a consensus meeting attended by representatives of the key stakeholders groups.ConclusionThe best approach to provision of orthopaedic care in patients with SD is yet to be decided. The reporting of different outcomes to define success among studies, often based on personal preferences and local culture, has made it difficult to compare the effect of treatments for this condition. The development of a COS for orthopaedic management in SD will enable meaningful reporting and facilitate comparisons in future clinical trials, thereby assisting complex decision-making in the clinical management of these children.Cite this article: Bone Jt Open 2022;3(1):54–60.

Fracture in clinical studies of tofacitinib in rheumatoid arthritis.

Preclinical data suggest that tofacitinib would protect bone health in patients with rheumatoid arthritis (RA). To assess fracture risk in tofacitinib RA clinical trials. Post hoc analysis. We analyzed pooled data of phase I/II/III and long-term extension studies ('P123LTE cohort'), pooled data of placebo-controlled portions of phase III studies (phase III placebo-controlled cohort), and data from ORAL Surveillance [phase IIIb/IV randomized, open-label trial evaluating tofacitinib 5/10 mg twice daily (BID) vs tumor necrosis factor inhibitor (TNFi) in patients ⩾ 50 years with ⩾ 1 additional cardiovascular risk factor]. In the phase III placebo-controlled cohort, incidence rates (IRs) [95% confidence interval (CI)] of fracture were 2.11 (1.09-3.68), 2.56 (1.23-4.71), and 4.43 (1.78-9.12) per 100 patient-years (PYs) for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively [tofacitinib 5 mg BID vs placebo: hazard ratio (HR) (95% CI) = 0.55(0.18-1.65); tofacitinib 10 mg BID vs placebo: HR (95% CI) = 0.72 (0.26-2.01)]. In P123LTE, IRs (95% CI) were 2.62 (2.29-2.99) and 2.26 (2.02-2.52) per 100 PY for average tofacitinib 5 and 10 mg BID, respectively. In ORAL Surveillance, IRs (95% CI) were 2.79 (2.34-3.30), 2.87 (2.40-3.40), and 2.27 (1.87-2.74) per 100 PY for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and TNFi, respectively. In ORAL Surveillance, the risk of fracture was numerically higher than TNFi for tofacitinib 5 mg BID [HR (95% CI) = 1.23 (0.96-1.58)] and tofacitinib 10 mg BID [HR (95% CI) = 1.26 (0.97-1.62)]. In ORAL Surveillance, independent predictors of all and osteoporotic fractures with tofacitinib or TNFi included age ⩾ 65, female sex, history of fracture/osteoporosis, and baseline oral corticosteroid use. This post hoc analysis showed numerically lower fracture risk with tofacitinib versus placebo and numerically greater risk versus TNFi. We did not identify any tofacitinib-specific predictors of fractures, and predictors of fracture were generally aligned with prior literature in the general population and patients with RA. Patients with fracture risk factors should be adequately monitored and treated. NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT02831855, NCT00413699, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00661661, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT01262118, NCT01484561, NCT02281552, NCT02147587, NCT02092467.

Where's the evidence? A systematic review exploring the evidence underpinning exercise dose in clinical trials of rheumatoid arthritis

Purpose: Selecting what dose to prescribe is an essential step in the development of clinical trials evaluating exercise-based interventions. Therefore, we aimed to evaluate the evidence reported to underpin exercise dose in randomised controlled trials (RCTs) using strengthening exercise in rheumatoid arthritis.

Development and Preliminary Validation of an Electromyography-Scoring Protocol for the Assessment and Grading of Muscle Involvement in Patients With Juvenile Idiopathic Inflammatory Myopathies

IntroductionWe performed a pilot study in order to investigate the feasibility of an electromyography (EMG)-scoring protocol for the assessment of disease activity in juvenile idiopathic inflammatory myopathies (JIIM). MethodsChildren with JIIM followed up in a tertiary-level care center underwent standardized clinical, laboratory, and EMG assessment. An EMG-scoring protocol was devised by a consensus panel including a pediatric neurophysiologist and two pediatric rheumatologists, based on a combined score obtained as the sum of (1) the presence of denervation signs (fibrillation potentials) and (2) motor unit remodeling (mixed pattern of short- and long-duration motor unit action potentials). The EMG-scoring protocol was then validated following the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter for outcome measures in rheumatology and the consensus-based standards for the selection of health measurement instruments methodology. ResultsThirteen children (77% females) were included in the study, with a median age of 10 years (interquartile range: 7-17 years) and median disease duration of 11.8 months (interquartile range: 2.1-44.5). A total of 39 EMG examinations were evaluated. A strong positive association between a standardized tool for muscle strength assessment and the combined score was observed. No significant associations were found with both creatine kinase and erythrocyte sedimentation rate levels. DiscussionOur EMG-scoring protocol is the first standardized and reproducible tool for the neurophysiologic evaluation and grading of muscle involvement in patients with JIIM and could provide relevant additional information in the assessment and follow-up of these rare conditions.

Entheseal involvement in a group of psoriatic arthritis patients: An ultrasonographic study.

Psoriatic arthritis (PsA) is an inflammatory potentially destructive disease that requires early diagnosis and therapeutic approach. Its main pathogenic event and the condition's hallmark is considered to be enthesitis. Clinical examination of the enthesis can be a challenge in the clinical practice; thus, ultrasonography (US) has emerged as an indispensable imaging tool for evaluating both structural and inflammatory changes of this structure. In the present study, we aimed to analyze the type and frequency of entheseal involvement in PsA patients by US examination, performing a retrospective study on 41 patients diagnosed with PsA. Ultrasonographically confirmed enthesitis, identified according to Outcome Measures in Rheumatology group (OMERACT, initially Outcome Measures in Rheumatoid Arthritis Clinical Trials) definitions, was present in 26 of the included patients, Achilles enthesis being the most common site involved. The prevalence of tendon structure abnormalities and the presence of entesophytes underlines the importance of chronic inflammation on entheseal sites. US examination has proven to be a reliable imaging method, with significant and continuous improvement, which is clearly a requisite part for current understanding and diagnosis of enthesitis and more than this, for the patient follow-up algorithm.

Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Characteristics, Including Corticosteroid Use and Body Mass Index.

ObjectiveTo investigate the impact of baseline and time‐varying factors on the risk of serious adverse events (SAEs) in patients during long‐term certolizumab pegol (CZP) treatment.MethodsSafety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time‐varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO.ResultsData were pooled from 8747 CZP‐treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO.ConclusionAge, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP‐treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.

OPTIMAL ASSESSMENT OF FATIGUE IN RHEUMATOID ARTHRITIS: VISUAL ANALOG SCALE VERSUS FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY – FATIGUE

Background:Fatigue is an important outcome for patients with rheumatoid arthritis (RA). As recommended by the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) task force in 2008, fatigue should be measured in all RA clinical trials whenever possible. Despite these recommendations, it is largely ignored and rarely assessed in clinical practice.Objectives:The aim of this study was to compare the scales being used to measure fatigue in RA.Methods:We conducted a cross-sectional study including patients with RA (ACR/EULAR 2010). Patients with other acute or chronic diseases that may induce fatigue (such as cancer, infection or depression) were excluded. Demographic and disease-related data were collected. Fatigue was assessed using two scores. The fatigue Visual Analog Scale (VAS) ranging between 0 and 100 cm. Fatigue was considered mild if the fatigue VAS was <20 cm, moderate if 20≤VAS<50 and severe if VAS>50 cm. The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) which is a short 13-item questionnaire validated in RA. The score FACIT-F ranges between 0 and 52. Fatigue was considered mild if the FACIT-F score was ≥40, moderate if 20≤FACIT-F<40 and severe if 0≤FACIT-F<20. We used Cohen’s kappa (κ) to determine the agreement between fatigue VAS and FACIT-F. The κ result was interpreted as follows: values ≤ 0 as indicating no agreement and 0.01–0.20 as none to slight, 0.21–0.40 as fair, 0.41– 0.60 as moderate, 0.61–0.80 as substantial, and 0.81–1.00 as almost perfect agreement. A p value inferior to 0.05 was considered significant.Results:We included 100 RA patients (84 women and 16 men) with a mean age of 49.5±10 years old [18-65]. The mean disease duration was 87.3 months [1-360]. RF and ACPA were positive in 75% and 72.6% of cases respectively. The mean pain VAS was 49 cm [0-100]. The mean numbers of tender and swollen joints were 5.3 [0-36] and 1 [0-9] respectively. The mean levels of ESR and CRP were 38.1 mm [10-120] and 10.8 mg/l [2-61] respectively. The mean DAS28 ESR was 3.68 [1.90-8.33].The mean fatigue VAS was 49.1 cm [5-100]. Fatigue was mild in 9% of patients, moderate in 31% of patients, and severe in 60% of patients.The mean FACIT-F score was 27.1 [0-51]. Fatigue was mild in 26% of patients, moderate in 57% of patients and severe in 17% of patients.A fair agreement was noted between the two scores (κ=0.303, p<0.001).The fatigue VAS and FACIT-F were both correlated with the following variables: pain VAS (r=0.685, p<0.001 and r=-0.605, p<0.001), ESR (r=0.384, p<0.001 and r=-0.405, p<0.001), and DAS28 ESR (r=0.684, p<0.001 and r=-0.744, p<0.001).Conclusion:The fatigue VAS and FACIT-F are easy, brief and valid measures for monitoring this symptom and its effects on patients with RA. A fair agreement was noted between the two scores.Disclosure of Interests:None declared

POS0446 FILGOTINIB-TREATED RHEUMATOID ARTHRITIS PATIENTS WITH HIGH BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO SHOW BETTER CLINICAL RESPONSE RATES AND PATIENT-REPORTED OUTCOMES

Background:Rheumatoid arthritis (RA) is a systemic inflammatory disease which includes increased innate and myeloid immune cell activation. Filgotinib (FIL), an oral JAK1 inhibitor, has shown safety and efficacy in three phase 3 studies (FINCH1-3) in adults with moderately-to-severely active RA. The baseline (BL) neutrophil-to-lymphocyte ratio (NLR) in RA has been associated with a positive response to anti-tumor necrosis factor (TNF) therapy1 and a negative response to DMARD triple therapy2. We previously reported a BL signature of clinical response in the FINCH2 (bDMARD-IR) population which included a neutrophil component3.Objectives:We conducted a post-hoc analysis to explore whether the BL NLR was associated with response to treatment in the FINCH studies.Methods:Clinical data of 3273 RA patients (pts) enrolled in the FINCH clinical trials (FINCH3, methotrexate (MTX)-naïve: NCT02886728; FINCH1, MTX-Inadequate Responder (IR): NCT02889796; FINCH2, bDMARD-IR: NCT02873936) were retrospectively analyzed for a relationship between the BL NLR and composite clinical endpoints (ACR-N, DAS28CRP, or CDAI) or PROs (Pain VAS, FACIT Fatigue, HAQ-DI) through week 24. Pts were classified as High or Low BL NLR using a cutpoint (2.7) identified as an independent predictor of treatment failure in a published RA study2. Adjusted clinical outcomes were estimated based on mixed effects linear regression models including geographic region and demographics covariates.Results:57% of pts enrolled in the FINCH trials were classified as BL NLR-High (Table 1) and FINCH3 NLR-High pts showed higher BL DAS28(CRP). FINCH1 and FINCH3 FIL+MTX-arm NLR-High pts demonstrated significantly better DAS28(CRP) response compared to NLR-Low pts (Figure 1). DAS28(CRP) differences between NLR-High and NLR-Low were detectable as early as Week 2 for FIL200mg + MTX and were sustained through Week 24. FINCH1 and FINCH3 FIL200mg + MTX NLR-High pts also demonstrated sustained clinical and PRO improvements over NLR-Low, including CDAI, ACR-N, Pain VAS, FACIT Fatigue, and HAQ-DI. The strength of these associations was dose-dependent; pts that received FIL100mg + MTX demonstrated weaker but directionally consistent trends in both populations. No significant association between NLR subgroup and clinical efficacy was observed in FINCH2 FIL+MTX-arm pts, FIL-monotherapy (FINCH3) pts, or adalimumab+MTX (FINCH1) pts.Conclusion:In FINCH1 (MTX-IR) and FINCH3 (MTX-naïve), FIL200mg + MTX -arm NLR-High pts demonstrate better sustained clinical response and PRO scores compared to NLR-Low pts. These data are the first to report an association between the BL NLR and therapeutic response in large randomized RA clinical trials. Future studies on pathobiologies reflected by the NLR biomarker may clarify its potential to guide RA disease management.

Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure

ObjectivesTo analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the...

P144 What is the role of musculoskeletal ultrasound in assessing disease activity of RA in pregnancy?

Abstract Background/Aims In rheumatoid arthritis (RA), musculoskeletal ultrasound (MSK-US) has greater sensitivity for the detection of active disease than clinical assessment using the DAS28 score, which is prone to false elevation by a spuriously high tender joint count (TJC) and/or visual analogue score (VAS) from non-RA causes. Thus, DAS28 may correlate poorly with MSK-US findings. In pregnancy, standardised disease activity of RA comprises calculation of the modified DAS28(3)CRP score, with removal of the VAS and ESR, both of which are confounded by pregnancy, and replacement with CRP; however, it is unknown whether non-specific musculoskeletal pain and/or peripheral oedema in (especially late) pregnancy might contribute to the TJC or swollen joint count (SJC) respectively and thus render this adapted score less reliable. Therefore, we conducted this study of pregnant RA patients and controls to assess the ability of the DAS28(3)CRP to detect disease activity compared with MSK-US. Methods Pregnant RA patients were recruited from the UCLH obstetric rheumatology clinic from September 2018 to March 2020. Patients underwent clinical assessment with DAS28(3)CRP and MSK-US longitudinally through pregnancy/post-partum. A control group of age-matched non-pregnant female RA patients was recruited from general rheumatology clinics and had equivalent assessments. MSK-US was undertaken using a Logiq S8. The standard protocol comprised 22-joint assessment of hands (dorsal longitudinal and transverse views of wrists, metacarpophalangeal and proximal interphalangeal joints). Quantification of Power Doppler (PD) signal was made as per the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) US definitions. PD scores were calculated as mean scores of all joints scanned. Statistical correlations were performed in SPSS using Spearman’s rank coefficient as data were non-normally distributed. Results A total of 45 MSK-US scans of pregnant/postpartum RA patients (N = 24, mean age 34.5+-3.6) were performed and compared to a control group of non-pregnant RA patients, who were scanned once each (N = 18, mean age 32.3+-5.2; p = 0.12). In the second (T2) and third trimester (T3) and the postpartum (PP), there was a significant positive correlation between DAS28(3)CRP and PD score (T2, ρ = 0.87 (p < 0.01); T3, ρ = 0.76 (p < 0.01); PP, ρ = 0.68 (p = 0.03)). Interestingly, each of these were stronger correlations than the equivalent comparison in non-pregnant RA patients (ρ = 0.51 (p = 0.03)). TJC also significantly positively correlated with PD score in each trimester of pregnancy and postpartum, but not in non-pregnant patients; difference between correlation coefficients was statistically significant for each trimester (T1, p < 0.01; T2, p = 0.05; T3, p = 0.05). Conclusion Interestingly, we found that that DAS28(3)CRP correlates better with PD signal on MSK-US in pregnancy than in non-pregnancy. Specifically, there was significantly better correlation of the TJC with PD score. It is unclear why non-inflammatory contributors to the TJC may be less prominent in pregnancy and further investigation is warranted. Disclosure C. Raine: Grants/research support; C.R. has received research funding from UCB. J. Manson: None. C. Ciurtin: None. I. Giles: Grants/research support; IG has received an unrestricted educational grant, speaker's fees and travel fees from UCB.

Conversion of Functional Assessment of Chronic Illness Therapy–Fatigue to Patient‐Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials

The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT-F items are identified as relevant to patients with RA. The Patient-Reported Outcomes Measurement Information System (PROMIS) uses an item response theory-calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT-F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. Crosswalk tables and pattern-scoring methods converted FACIT-F scores to PROMIS Fatigue for both the 13-item FACIT-F and the 10-item RA-optimized FACIT-F instrument, in 2 RA clinical trials evaluating baricitinib, RA-BEAM, and RA-BEACON. RA-BEAM patients had an inadequate response to methotrexate. RA-BEACON patients had an inadequate response or intolerance to ≥1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. Baseline FACIT-F-derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13-item or 10-item FACIT-F. All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10-item FACIT-F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.

Low Incidence of Inflammatory Bowel Disease Adverse Events in Adalimumab Clinical Trials Across Nine Different Diseases.

ObjectiveAdalimumab is approved for treatment of Crohn’s disease and ulcerative colitis. Thus, we postulated that exacerbation or new‐onset of inflammatory bowel disease (IBD) would be rare events in patients treated with adalimumab for non‐IBD indications. The objective was to evaluate the incidence of IBD adverse events (AEs) across adalimumab trials.MethodsIBD AE rates in 75 adalimumab clinical trials in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, pediatric enthesitis‐related arthritis, uveitis, hidradenitis suppurativa, adult and pediatric psoriasis, psoriatic arthritis, nonpsoriatic arthritis peripheral spondyloarthritis (SpA), axial SpA, including nonradiographic axial SpA, and ankylosing spondylitis, were analyzed. Search terms for IBD AEs (new onset or worsening/flare) included IBD, ulcerative colitis, Crohn’s disease, and ulcerative proctitis.ResultsThis analysis included 24,114 patients, representing 36,508 patient‐years of adalimumab exposure. The overall rate of IBD AEs in adalimumab‐treated patients was 0.1 (95% confidence interval [95% CI] 0.1–0.2)/100 patient‐years (41 events), ranging from no events (psoriatic arthritis, uveitis, and pediatric trials) to 0.8 (95% CI 0.2–2.2)/100 patient‐years in peripheral SpA. The rate of IBD in axial SpA was 0.6 (95% CI 0.4–1.0)/100 patient‐years. During placebo‐controlled trials, the overall IBD rate was 0.1 (95% CI 0.0–0.3)/100 patient‐years for adalimumab groups (3 events in 6,781 patients; 2,752 patient‐years of exposure) and 0.1 (95% CI 0.0–0.4)/100 patient‐years for placebo groups (1 event in 3,493 patients; 1,246 patient‐years of exposure). IBD rates in axial SpA were 0.5 (95% CI 0.1–1.4)/100 patient‐years for adalimumab and 0.6 (95% CI 0.0–3.1)/100 patient‐years for placebo.ConclusionThe rates of IBD AEs in adalimumab clinical trials were generally low across the evaluated diseases, including axial SpA; all events occurred in adult patients.

Sleep Disturbances are a Significant Predictor of Chikungunya Arthritis Flare Severity.

Objective:The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship.Methods:A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flare-pain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds.Results:The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis.Conclusion:There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.

A Review on Rheumatoid Arthritis Interventions and Current Developments.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation, swelling, and joint destruction primarily affecting the peripheral joints. In recent years, RA has become an alarming concern affecting more than 1.5% of the population worldwide. The majority of the drugs in clinical trials for rheumatoid arthritis are immunomodulatory. The development of novel drugs for RA is impending and scientists are exploring new strategies through various innovative approaches for RA drug development. Treat-to-target and window of opportunity hypothesis are the new approaches that are used to treat, improve outcomes, and prevent long-term use of ineffective therapy, respectively. Novel therapeutic agents (e.g. GM-CSF inhibitors, Matrix metalloproteinase inhibitors) and delivery systems (e.g., Liposomes, Superparamagnetic iron oxide nano particles (SPIONs)) are under investigation for more target based therapy with reduced side effects and toxicity. The new drug discovery and repositioning of previously FDA-approved drugs are also being considered for chronic inflammatory disorder. The review encompasses a vast array of information, including genetics, etiology, clinical symptoms, current treatment, and newer therapeutics approaches, focused on the development of RA interventions. The introduction of the bioinformatics-based approach in RA has also been significantly discussed in the review. This review provides a general understanding of the challenges and uncertainties in the treatment of RA and summarizes the evolving scenario as well as innovative approaches taken into consideration for drug development in rheumatoid arthritis.

Use of Herbal Medications for Treatment of Osteoarthritis and Rheumatoid Arthritis.

Arthritis is a chronic condition that affects nearly a quarter of the United States population. Osteoarthritis (OA) and rheumatoid arthritis (RA) are two major forms of arthritis associated with severe joint pain and reduced quality of life. Various pharmacological interventions may be utilized for arthritis treatment when non-pharmacological therapy is insufficient. However, pharmacological therapy can be associated with serious side effects and high costs. Therefore, alternative therapies have been under investigation. Herbal medications have shown the potential for safe and effective management of arthritis. For this review, we attempt to summarize the mechanisms, safety, and efficacy of herbal treatments for OA and RA. After searching electronic databases, we identified nine herbs among 23 clinical trials used for the treatment of OA or RA patients. Improvement of OA and RA symptoms, pain, and inflammation was demonstrated. The herbs exhibited strong anti-inflammatory and anti-oxidant activities, contributing to a reduction in inflammation and tissue damage. Several herbs elucidated new mechanisms for OA and RA treatment as well. Though these herbs have shown promise for OA and RA treatment, more studies and clinical trials are required for determining safety and efficacy, bioactivity, and optimal bioavailability.

Model-Based Meta-Analysis Compares DAS28 Rheumatoid Arthritis Treatment Effects and Suggests an Expedited Trial Design for Early Clinical Development.

A nonlinear mixed effects modeling approach was used to conduct a model‐based meta‐analysis (MBMA) of longitudinal, summary‐level, baseline‐corrected 28‐joint Disease Activity Score (ΔDAS28) clinical trial data from seven approved rheumatoid arthritis (RA) drugs (abatacept, adalimumab, certolizumab, etanercept, rituximab, tocilizumab, and tofacitinib), representing 130 randomized clinical trials in 27,355 patients. All of the drugs except tocilizumab were found to have relatively similar ΔDAS28 time courses and efficacy (baseline‐corrected and placebo‐corrected) at 24 weeks and beyond of approximately 0.87–1.3 units in the typical RA patient population. Tocilizumab was estimated to have a differentially greater response of 1.99 at 24 weeks, likely due to its disproportionate effect on the acute‐phase cytokine interleukin‐6. Baseline DAS28, disease duration, percentage of male participants, and the year of conduct of the trial were found to have statistically significant effects on the timing and/or magnitude of ΔDAS28 in the control arms. Clinical trial simulations using the present MBMA indicated that abatacept, certolizumab, etanercept, tocilizumab, and tofacitinib would be expected to have a greater than 70% probability of showing a statistically significant difference vs. control at Week 6 with a sample size of ~ 30 patients per arm. In future RA clinical trials, an interim analysis conducted as early as 6 weeks after treatment initiation, with relatively small sample sizes, should be sufficient to detect the ΔDAS28 treatment effect vs. placebo.