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Aims : Patients with rheumatoid arthritis (RA) have an increased risk of venous thromboembolism (VTE), likely related to underlying inflammation. We examined VTE risk associated with two commonly used immunomodulators in RA patients, methotrexate and hydroxychloroquine. Methods and Results : Using U.S. Medicare claims data (2008-2017), we identified RA patients (≥65 years) who initiated methotrexate or hydroxychloroquine without prior use of any immunomodulators. The primary outcome was VTE, a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes included PE, DVT, and all-cause mortality. After 1:1 propensity score matching for confounding control, we identified 26,534 pairs of methotrexate and hydroxychloroquine initiators (mean (SD) age 74 (7) years; 79% female). During a total of 56,686 person-years of follow-up, 208 methotrexate and 83 hydroxychloroquine initiators developed VTE. The incidence rate of VTE was higher among methotrexate initiators (6.94/1,000 person-years) than hydroxychloroquine initiators (3.11/1,000 person-years) with a hazard ratio (HR) of 2.26 (95%CI 1.75, 2.91). Methotrexate initiators had a greater risk of PE (HR 3.30, 95%CI 2.28, 4.77) and DVT (HR 1.53, 95%CI 1.07, 2.19) than hydroxychloroquine initiators. All-cause mortality was similar between the two groups (HR 0.91, 95%CI 0.83, 1.00). Conclusion : In this large real-world cohort of older RA patients, treatment with methotrexate was associated with a 2-fold increased risk of VTE relative to hydroxychloroquine, although all-cause mortality was similar. Future experimental studies with non-user control groups are needed to determine the causal relationships between the study drugs and VTE and whether methotrexate elevates or hydroxychloroquine reduces the risk of VTE.

Objective We aimed to determine the real-world prevalence and investigate risk factors for rheumatoid arthritis (RA)-related lung disease on chest computed tomography (CT) imaging. We also investigated the impact of RA-related lung disease on mortality. Methods We studied chest CT imaging abnormalities among RA patients. We determined the presence and type of abnormalities using the chest CT imaging radiologic report. RA-related lung disease was defined as interstitial lung disease (ILD), bronchiectasis, or pleural disease. We examined whether demographics and RA characteristics were associated with RA-related lung disease using logistic regression. RA-related lung disease and mortality was described using survival curves and Cox regression. Results We analyzed 190 patients who had chest CT imaging performed for clinical indications. Mean age was 64.2 years (SD 11.8), 80.0% were female, and 75.3% were seropositive. RA-related lung disease was detected in 54 patients (28.4%); 30 (15.8%) had ILD, 27 (14.2%) had bronchiectasis, and 18 (9.5%) had pleural disease. RA-related lung disease was reported in both seropositive and seronegative RA (28.7% vs. 27.7%, p = 1.00). Male sex (OR 2.62, 95%CI 1.17–5.88) and current methotrexate use (OR 2.73, 95%CI 1.27–5.61 vs. not current) were associated with RA-related lung disease. Twenty-four (44.4%) patients with RA-related lung disease died during mean 7.0 years of follow-up. RA-related lung disease had HR of 5.35 (95%CI 0.72–39.9) for mortality compared to normal chest CT. Conclusions In this real-world study, RA-related lung disease was commonly detected on chest CT imaging regardless of RA serostatus. RA-related lung disease had high mortality, emphasizing the importance in close monitoring of these patients.

Introduction Filgotinib (FIL), inhibiteur preferentiel de JAK1 per os, a ameliore les signes et les symptomes de la polyarthrite rhumatoide (PR) dans 3 essais de phase 3. Malgre l’efficacite du FIL et des autres JAKi, il existe certaines incertitudes concernant le risque thromboemboliques veineux (TEV), d’evenements cardiovasculaires majeurs (ECM) et d’elevation des taux de plaquettes, qui pourrait resulter de l’inhibition de JAK2 et de la modulation de la thrombopoietine, et avoir un lien de causalite avec les TEV. Patients et methodes Les patients (pts) des etudes DARWIN1–2, FINCH1–3 et des extensions DARWIN3 et FINCH4 ont ete inclus. Les evenements ont ete analyses en fonction du traitement recu. L’analyse de la tolerance controlee par placebo (PBO) jusqu’a S12 comprenait des donnees provenant de patients ayant recu FIL100, FIL200 ou PBO jusqu’a 12S ; certains pts traites par PBO avaient des donnees supplementaires jusqu’a S24. L’analyse controlee par traitement actif incluait les donnees des patients ayant recu FIL100, FIL200 ou adalimumab (ADA) avec un traitement anterieur par methotrexate (MTX) et des patients ayant recu FIL100 + MTX, FIL200 + MTX, FIL200 ou MTX jusqu’a 52S. L’analyse FIL200 vs FIL100 incluait les donnees des pts jusqu’a 5,5 ans. Les donnees ont ete analysees selon l’apparition ou non d’un ECM ou d’un TEV. Pour l’analyse controlee par traitement actif (sauf ECM dans l’analyse controlee par MTX), les taux d’incidence ajustes en fonction de l’exposition (TIAE) et les IC95 % ont ete calcules a l’aide de la loi de Poisson, et les differences de traitement ont ete fournies avec les IC correspondants, sur la base des limites de confiance des estimations ponctuelles individuelles. Pour les analyses FIL200 vs FIL100 et ECM dans l’analyse controlee par MTX, les TIAE, la difference des TIAE, et les IC95 % ont ete calcules par la regression de Poisson avec le groupe de traitement comme covariable. Les suspicions d’ECM (deces cardiovasculaire (CV), infarctus du myocarde, AVC) et de TEV (thrombose veineuse profonde (TVP) et embolie pulmonaire (EP)) ont ete adjudiquees en aveugle par un comite independant d’evaluation de la tolerance CV. Resultats Les facteurs de risque CV etaient frequents a l’inclusion ( Fig. 1 ). Aucun TEV ne s’est produit pendant la periode controlee par PBO de 12S ( Fig. 2 ). Il y a eu 13 TEV au total. Les TIAE/100 patients-annees d’exposition (PAE) etaient comparables pour tous les traitements (TIAE [n] : FIL200, 0,2 [7] ; FIL100, 0,1 [1] ; ADA, 0,3 [1] ; MTX, 0,5 [2] ; PBO (jusqu’a S24), 0,7 [2] ; Fig. 2 ). L’incidence brute des ECM pendant la periode controlee par PBO est illustree a la Fig. 3 . Il y a eu 32 ECM au total. Les TIAE etaient comparables pour tous les traitements (TIAE [n] : FIL200, 0,6 [16] ; FIL100, 0,6 [10] ; ADA, 0,3 [1] ; MTX, 0,5 [2] ; PBO (jusqu’a S24), 1,0 [3] ; Fig. 3 ). La numeration plaquettaire n’a pas augmente au cours de l’etude. A S52, les taux plaquettaires moyen ont legerement diminue dans tous les bras de traitement. Conclusion Aucun signal de tolerance pour les ECM et les TVE n’a ete observe dans le developpement clinique du FIL dans la PR. Les TIAE des TEV et des ECM etaient faibles et conformes aux taux attendus chez des patients PR (TIAE 0,4/100 PAE pour les TEV et 1,0/100 PAE pour les ECM) [1] , [2] .

To develop a multimorbidity index (MMI) based on health-related quality of life (HRQol).The index was developed in an observational RA cohort. In all, 40 morbidities recommended as core were identified using ICD-9 codes. MMIs of two types were calculated: one by enumerating morbidities (MMI.count) and the other by weighting morbidities based on their association with HRQol as assessed by EQ-5D in multiple linear regression analysis (using β-coefficients; MMI.weight). MMIs were compared to the Charlson comorbidity index (CCI) and externally validated in an international RA cohort (COMORA Study).In all, 544 out of 876 patients were multimorbid. MMI.count was in the range 1-16 (median = 2) and MMI.weight in the range 0-38 (median = 1). Both indices were more strongly associated with EQ-5D than CCI (Spearman: MMI.count = -0.20, MMI.weight = -0.26, and CCI = -0.10; p0.01). R(2) obtained by linear regression using EQ-5D as a dependent variable and various indices as independent variables, adjusted for age and gender, was the highest for MMI (R(2): MMI.count = 0.05, MMI.weight = 0.11, and CCI = 0.02). When accounting for clinical disease activity index (CDAI) R(2) increased: MMI.count = 0.18, MMI.weight = 0.22, and CCI = 0.17, still showing higher values of MMI compared with CCI. External validation in different RA cohorts (COMORA, n = 3864) showed good performance of both indices (linear regression including age, gender, and disease activity R(2) = 0.30 for both MMIs).In our cohort, MMI based on EQ-5D performed better than did CCI. Findings were reproducible in another large RA cohort. Not much improvement was gained by weighting; therefore a simple counted index could be useful to control for the effect of multimorbidity on patient's overall well-being.

Current recommendations advocate treatment with disease-modifying anti-rheumatic drugs (DMARDs) in all patients with active rheumatoid arthritis (RA). We analyzed short-term disease outcome in patients according to the consistency of DMARD use in a clinical rheumatology cohort.Patients in an RA registry (n = 617) were studied for DMARD use at semi-annual study time points during the first 18 months of follow-up and were divided into 4 groups according to the number of study time points with any DMARD use [0-1 study time points (n = 31), 2 study time points (n = 24), 3 study time points (n = 77), and 4 study time points (n = 485)]. The primary outcome analyses were performed at 24 months and included Disease Activity Score 28 (DAS28-CRP), modified Health Assessment Questionnaire (MHAQ) change, Short Form Health Survey-12 physical and mental summary scores (SF-12 PCS, SF-12 MCS), EuroQol 5-Dimensional health index (EQ-5D), and radiographic progression. Unadjusted, adjusted, and analyses stratified for seropositivity and disease activity were performed. A secondary analysis investigated 36-month outcomes.No significant 24-month outcome differences could be found between the DMARD use categories. For seropositive patients, there was evidence of a linear trend for SF-12 PCS (p = 0.02) and EQ-5D (p = 0.01) with worse outcomes for inconsistent DMARD users. At 36 months, there was a linear trend for higher DAS28-CRP scores for inconsistent users (p0.01).Overall, we found poor correlation between inconsistent DMARD use and short-term disease outcome. However, outcome in the longer term could be negatively influenced by inconsistent DMARD use, as well as short-term outcome in seropositive patients.

BACKGROUND Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. METHODS All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. RESULTS Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older ( P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history ( P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. CONCLUSIONS We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

Summary Background Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. Methods We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1·30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. Findings 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11·8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1·24 and 1·30 per 100 patient-years and a hazard ratio of 0·95 (95% CI 0·81–1·11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0·67 vs 0·97 per 100 patient-years; hazard ratio 0·69 [0·57–0·83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0·30) and diclofenac (0·32). Interpretation Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

Etanercept, a recombinant human tumor necrosis factor (TNF) inhibitor that binds both soluble and cell-bound TNF, has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis (RA). Because TNF receptors are found on many types of cells that modulate the immune response, we evaluated the general immune function of a subset of RA patients in a blinded clinical study. No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes, T cell proliferative responses, neutrophil function, delayed-type hypersensitivity (DTH) reactions, serum immunoglobulin levels, or incidence of infections. Although this observational study was relatively small and could detect only major changes in immunological status, the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies, which suggest that etanercept does not alter overall global immune function.

Proton pump inhibitors are recommended to decrease NSAID-associated GI injury, while standard-dose histamine2-receptor antagonists (H2RAs) are not. However, a Cochrane review suggested that high-dose H2RAs provide significant benefit in NSAID users. Importantly, the benefit of antisecretory therapy in patients taking NSAIDs plus low-dose aspirin is uncertain. In addition, most NSAID users at increased risk for GI events do not receive or adhere to protective co-therapy, and decreased adherence is associated with an increased risk of ulcers and bleeding. We performed two 24-wk double-blind, randomized trials to determine if a single-tablet combination of ibuprofen (800mg) and famotidine (26.6mg) (HZT-501) given thrice daily (providing 80mg famotidine daily) will significantly decrease ulcers as compared to ibuprofen alone. METHODS: Patients 40-80 yrs expected to require daily NSAID therapy ≥6 mos with no history of ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and

Proton pump inhibitors are recommended to decrease NSAID-associated GI injury, while standard-dose histamine2-receptor antagonists (H2RAs) are not. However, a Cochrane review suggested that high-dose H2RAs provide significant benefit in NSAID users. Importantly, the benefit of antisecretory therapy in patients taking NSAIDs plus low-dose aspirin is uncertain. In addition, most NSAID users at increased risk for GI events do not receive or adhere to protective co-therapy, and decreased adherence is associated with an increased risk of ulcers and bleeding. We performed two 24-wk double-blind, randomized trials to determine if a single-tablet combination of ibuprofen (800mg) and famotidine (26.6mg) (HZT-501) given thrice daily (providing 80mg famotidine daily) will significantly decrease ulcers as compared to ibuprofen alone. METHODS: Patients 40-80 yrs expected to require daily NSAID therapy ≥6 mos with no history of ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and

VARIETY of musculoskeletal syndromes have been associated with malignancy.’ Among these, hypertrophic pulmonary osteoarthropathy, dermatomyositis, and carcinomatous polyarthritis are the most frequently recognized.‘** Shoulder-hand syndrome, a variant of reflex sympathetic dystrophy, is another rheumatic disorder that has occasionally been associated with malignant neoplasms.3-‘5 Although brain and lung malignancies are the tumors most frequently associated with this syndrome,6*7,9-‘3 carcinoma of the bladder,8*14 uterus,15 breast,‘*” and esophagus, ‘*I4 have also been reported. Recently, a syndrome that has been termed “palmar fasciitis and arthritis” has been reported to occur in association with ovarian adenocarcinoma.3 This disorder differs from the usual case of shoulder-hand syndrome in that the progression and extent of rheumatic disease are much more dramatic. Specifically, the fasciitis is more severe, the arthritis more inflammatory, and both are more rapidly progressive than generally seen in shoulder-hand syndrome. Com

A HETEROGENEOUS group of disorders can produce inflammation of blood vessels in the CNS, including rheumatic diseases, systemic vasculitis, infections, neoplasms, toxic agents, radiation, and other disease processes.’ In addition, granulomatous angiitis of the CNS, in which inflammation is restricted to the vessels of the CNS, has become a well recognized clinicopathologic entity.2,3 CNS vasculitis is uncommon and the frequency of defined cases is reduced by the lack of angiographic or pathologic confirmation. Cerebral angiography has become the clinician’s “gold standard” for definition of cerebral vasculitis because histopathology is often difficult or impossible to obtain.4 In this retrospective review we report the spectrum of disease, clinical characteristics, diagnostic evaluation, and outcome of 16 patients with cerebral angiograms consistent with cerebral arteritis.