Sujith Subesinghe

Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Objectives This analysis set out to estimate the risk of opportunistic infection (OI) among patients with RA by biologic class. Methods The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis is a prospective observational cohort study established to evaluate safety of biologic therapies. The population included adults commencing biologic therapy for RA. The primary outcome was any serious OI excluding tuberculosis (TB). Event rates were compared across biologic classes using Cox proportional hazards with adjustment for potential confounders identified a priori. Analysis of the incidence of TB was performed separately. Results In total, 19 282 patients with 106 347 years of follow-up were studied; 142 non-TB OI were identified at a rate of 134 cases/100 000 patient years (pyrs). The overall incidence of OI was not significantly different between the different drug classes; however, the rate of Pneumocystis infection was significantly higher with rituximab than with anti-TNF therapy (adjusted hazard ratio = 3.2, 95% CI: 1.4, 7.5). The rate of TB fell dramatically over the study period (783 cases/100 000 pyrs in 2002 to 38 cases/100 000 pyrs in 2015). The incidence of TB was significantly lower among rituximab users than anti-TNF users, with 12 cases/100 000 pyrs compared with 65 cases/100 000 pyrs. Conclusions The overall rate of OI was not significantly different between drug classes; however, a subtle difference in the pattern of OI was seen between the cohorts. Patient factors such as age, gender and comorbidity were the most important predictors of OI.

Key findings from studies of methotrexate tapering and withdrawal in rheumatoid arthritis

Methotrexate is the dominant initial drug in the management of rheumatoid arthritis (RA). Despite its widespread use, methotrexate is associated with a number of adverse effects. Tapering its dose to the minimal amount required to maintain RA remission is, therefore, an important clinical goal. While the complete withdrawal of disease-modifying anti-rheumatic drugs is associated with a definite risk of a disease flare, it is unclear as to what the risk is specific to methotrexate withdrawal and whether this can be minimized by gradual dose reduction (termed ‘tapering’). This review examines studies of methotrexate tapering and withdrawal on RA outcomes. It covers three scenarios: tapering/withdrawing methotrexate monotherapy; tapering/withdrawing methotrexate as part of a ‘step-down’ combination disease-modifying anti-rheumatic drug regimen; and tapering/withdrawing methotrexate when it is being co-prescribed with biologic agents.

Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Objectives To compare the incidence of serious infection (SI) across biologic drugs used to treat rheumatoid arthritis (RA) using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. This analysis included patients with RA starting a new biologic. The primary outcome was SI defined as an infectious event requiring admission to hospital, intravenous antibiotics or resulting in death. Event rates were calculated and compared across biologics using Cox proportional hazards with adjustment for potential confounders. Secondary outcomes were the rate of infection by organ class and 30-day mortality following infection. Results This analysis included 19 282 patients with 46 771 years of follow-up. The incidence of SI was 5.51 cases per 100 patient years for the entire cohort (95% CI 5.29 to 5.71). Compared with etanercept, tocilizumab had a higher risk of SI (HR 1.22, 95% CI 1.02 to 1.47) and certolizumab pegol a lower risk of SI (HR 0.75, 95% CI 0.58 to 0.97) in the fully adjusted model. The 30-day mortality following SI was 10.4% (95% CI 9.2% to 11.6%). Conclusions The rate of SI was lower with certolizumab pegol than etanercept in the primary analysis but the result was no longer significant in several sensitivity analyses performed suggesting residual confounding may account for the observed difference. From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of SI than other biologics; however, the risk does not appear to be significantly higher as has previously been suggested.

Recurrent serious infections in patients with rheumatoid arthritis—results from the British Society for Rheumatology Biologics Register

Objectives To establish the rate of recurrent infection in RA patients recruited to the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis. Secondary objectives were to establish whether the organ class of index infection predicted future serious infection (SI). Methods Using data from the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis, a prospective observational cohort, we identified patients with at least one episode of SI. Incidence rates of SI, recurrent SI within the same organ class as the index infection and recurrent SI (of any class) were calculated. A Cox proportional hazards model was used to identify predictors of SI. Results In total, 5289 subjects with at least one SI contributing 19 431 patient-years follow-up were studied. The baseline annual rate of first SI was 4.6% (95% CI: 4.5, 4.7), increasing to 14.1% (95% CI: 13.5, 14.8) following an index infection. Respiratory infections were the most frequent (44% of all events). Recurrent infections mirrored the organ class of the index infection. Sepsis, increasing age and polypharmacy were significant predictors of infection recurrence in a fully adjusted model. The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent SI within 12 months, 19.7% (95% CI: 15.1, 25.7). Conclusion Recurrent infections in RA are common. Understanding patterns and predictors of recurrent infection together with the differential infection risk associated with immunosuppressive agents will help personalize RA care, tailor treatment choices better and mitigate against episodes of SI.

Rheumatoid arthritis patients with fibromyalgic clinical features have significantly less synovitis as defined by power Doppler ultrasound

BackgroundIn patients with rheumatoid arthritis (RA) clinical measures of disease activity may not reliably discriminate between patients with active inflammatory disease and those with concomitant fibromyalgia (FM). Recent work has shown RA patients with a 28 tender joint count (TJC) minus swollen joint count (SJC) of 7 or more (joint count criteria) are more likely to meet classification criteria for FM. This study aimed to determine whether RA patients meeting clinical criteria for FM had lower levels of joint inflammation as determined by ultrasound (US).MethodsRA patients with DAS28 > 2.6 were recruited. Patients underwent clinical assessment including ultrasound examination of the hands and wrists with quantification of grey scale (GS) and power Doppler (PD) synovitis. Patients completed questionnaires to assess pain, fatigue, disability and psychological comorbidity.ResultsPatients meeting either of the FM criteria had higher scores for disease activity, depression, disability and fatigue. Those meeting both the joint count and classification FM criteria had significantly lower levels of GS and PD inflammation on US.ConclusionsRA patients with concomitant FM, as determined by widespread soft tissue tenderness but fewer clinically inflamed joints, have higher disease activity scores but may have lower levels of synovial inflammation on US. This has implications for the identification and management of these patients who may not respond to conventional therapy and hence be more suitable for alternative approaches to treatment.

Biologic Prescribing Decisions Following Serious Infection; Results from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA)

Objectives To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Methods Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. Results In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Conclusions Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.

Cocaine and ANCA associated vasculitis-like syndromes - A case series

OBJECTIVES We analysed the spectrum of clinical manifestations of cocaine associated pseudovasculitis. METHODS Clinical, serological, radiological and histological features of 14 patients with cocaine pseudovasculitis syndromes were included. RESULTS Twelve patients had significant sinus thickening or erosive disease. Other multi-system manifestations included vasculitic rashes, pulmonary lesions and peripheral neuropathy. All patients had positive ANCA titres at presentation. All patients were managed with corticosteroids +/- methotrexate and co-trimoxazole, 2 patients received cyclophosphamide. CONCLUSIONS Advanced erosive nasal septal defects and atypical ANCA patterns are suggestive of cocaine induced pseudovasculitis. Complete drug cessation may negate the need for exposure to potent immunosuppressive agents.

OP0153 Recurrent infections in rheumatoid arthritis patients, results from the bsrbr

Background Rheumatoid arthritis (RA) patients have an increased susceptibility to infection. Objectives 1.To establish the rate of recurrent infection in RA patients recruited to the British Society of Rheumatology Biologics Registry Rheumatoid Arthritis (BSRBR-RA).2.To establish whether the organ class of index infection predicted future serious infection. Methods The BSRBR-RA is a prospective observational cohort, previously described. Patients with at least one episode of serious infection requiring hospitalisation were included if they occurred whilst on anti-rheumatic drug therapy or within 5 drug half-lives of stopping. Infections were coded by MedDRA classification in to 7 categories. Infections occurring over 14 days after the first index infection were considered as new events. Event rates were calculated and compared using a Cox proportional hazards model with adjustments made for age, gender, disease duration, baseline DAS28 score, smoking status and seropositivity. Results See Table 1.Table 1 Overall Patients with infection Respiratory Gastrointestinal Genitourinary Musculoskeletal Sepsis Skin/Soft Tissue Other Age, years (SD) 57.3 (12.5) 61.5 (11.7) 60.0 (11.5) 61.7 (11.1) 59.8 (11.9) 58.7 (10.5) 63.5 (11.2) 57.9 (11.9) 55.3 (11.4) Female (%) 75.7 72.6 74.8 77.4 89.2 70.2 76.6 79.5 83.3 Baseline DAS28 (SD) 6.2 (1.2) 6.4 (1.2) 6.3 (1.2) 6.3 (1.1) 6.3 (1.2) 6.5 (1.2) 6.4 (1.1) 6.4 (1.1) 6.3 (1.1) Baseline HAQ (SD) 1.9 (0.7) 2.1 (0.6) 2.0 (0.6) 2.1 (0.6) 2.1 (0.6) 2.1 (0.6) 2.2 (0.5) 2.0 (0.6) 1.9 (0.6) Steroid use,n (%) 8346 (38.2) 2632 (49.4) 2832 (43.8) 493 (51.5) 1226 (44.5) 390 (51.6) 316 (57.3) 1583 (45.2) 1267 (39.6) Current smoker, n (%) 4682 (21.7) 1159 (21.9) 1422 (22.1) 165 (17.3) 452 (16.4) 186 (24.8) 122 (22.4) 692 (19.9) 573 (18.0) RhFactor positive, n (%) 13,340 (63.2) 3533 (67.5) 4176 (66.1) 626 (66.2) 1737 (64.6) 527 (71.4) 361 (66.1) 2241 (65.6) 2003 (64.0) Recurrent infection rate, % per annum (95% CI) – 12.7 (12.1–13.2) 15.0 (13.9–16.2) 10.8 (9.2–12.8) 14.5 (12.7–16.5) 10.1 (8.7–11.8) 19.7 (15.1–25.7) 11.2 (10.1–12.5) 9.1 (7.3 -11.4) Adjusted Hazard Ratio for annual incidence of recurrent infection (95% CI) – – REF 0.79 (0.65–0.95) 0.97 (0.83–1.14) 0.81 (0.67–0.96) 1.33 (1.01–1.76) 0.87 (0.77–1.0) 0.70 (0.54–0.91) In total, 21,943 subjects with 115,423 patient-years follow up were studied, 5365 subjects reported at least one serious infection. Comparing organ classes of prior infection at baseline, each group had comparable age, disease duration, baseline DAS28 and HAQ scores. The cohort characteristics are tabulated. The baseline annual rate of first serious infection was 4.6% (95% CI 4.5–4.7). Following an index infection, the annual rate of serious infection was 12.7% (95% CI 12.1–13.3). Respiratory infections were the most common (41.4% of all events). The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent serious infection within 12 months:19.7%. Compared to an index respiratory tract infection, sepsis conferred a 33% increased hazard for recurrent serious infection within a year (HR 1.33, 95% CI 1.01–1.76). Increasing age was a significant predictor of infection recurrence. Conclusions There is a high risk of recurrent infection in RA patients with past serious infection. Work is ongoing to determine whether organ class of recurrent infection event mirrors index events and the impact of biologic treatment decisions following the index infection. Disclosure of Interest None declared