Risk of serious infections in arthritis patients treated with biological drugs: a matched cohort study and development of prediction model.

OBJECTIVES: Serious infection is a concern for patients with inflammatory joint diseases treated with biological drugs (bDMARDs). The objectives were to compare risk of serious infection, defined as infection leading to hospitalization, in patients initiating bDMARD treatment with that in the general population and, second, to develop a simple clinical prediction model and to obtain risk estimates for individual patients. METHODS: This was a matched-cohort study based on nationwide registries in Denmark. Patients with RA, axial SpA and PsA initiating first bDMARD monitored in the DANBIO registry were matched 1:10 by age, gender and postal code with controls from the general population. The risk of serious infection during 12 months' follow-up was assessed with Cox regression. Prediction models were developed using logistic regression and compared using area under the receiver operating characteristic curve (AUC). RESULTS: We included 11 372 patients and 113 715 controls. During follow-up, 522 patients (4.6%) and 1434 controls (1.3%) developed a serious infection (hazard ratio 3.7, 95% CI 3.4, 4.1). Age-stratified risk was largely similar across diagnoses. A simple prediction model, the 'DANBIO infection risk score', based on age and a count of six clinical risk factors had moderate discriminative power (internal validation: AUC 0.69) that was comparable to that of the existing RABBIT (Rheumatoide Arthritis Beobachtung der BIologika-Therapie) Risk Score (external validation: AUC 0.68). CONCLUSION: Patients with inflammatory joint diseases initiating bDMARD treatment had a four times increased risk of serious infection compared with the general population. A simple prediction model, feasible for shared decision-making, was developed to obtain risk estimates for individual patients.

Overall infection risk in rheumatoid arthritis during treatment with abatacept, rituximab and tocilizumab; an observational cohort study.

OBJECTIVES: Most infections in patients with RA are treated in primary care with antibiotics. A small fraction require hospitalization. Only a few studies exist regarding the overall risk of infection (i.e. prescription of antibiotics or hospitalization due to infection) in patients initiating non-TNF-inhibitor therapy. In Danish RA patients initiating abatacept, rituximab and tocilizumab treatment in routine care, the aims were to compare adjusted incidence rates (IR) of infections and to estimate relative risk of infections across the drugs during 0-12 and 0-24 months. METHODS: This was an observational cohort study including all RA patients in the DANBIO registry starting a non-TNF-inhibitor from 2010 to 2017. Infections were defined as a prescription of antibiotics or hospitalization due to infection. Prescriptions, comorbidities and infections were captured through linkage to national registries. IRs of infections (age, gender adjusted) and rate ratios (as estimates of RR (relative risk)), adjusted for additional covariates) (Poisson regression) were calculated. RESULTS: We identified 3696 treatment episodes (abatacept 1115, rituximab 1017, tocilizumab 1564). At baseline, rituximab users were older and had more previous cancer. During 0-12 months, 1747 infections occurred. Age and gender-adjusted IRs per 100 person-years were as follows: abatacept: 76 (95% CI: 69, 84); rituximab: 87 (95% CI: 79, 96); tocilizumab: 77 (95% CI: 71, 84). Adjusted RRs were 0.94 (95% CI: 0.81, 1.08) for abatacept and 0.94 (95% CI: 0.81, 1.03) for tocilizumab compared with rituximab and 1.00 (95% CI: 0.88, 1.14) for abatacept compared with tocilizumab. RRs around 1 were observed after 24 months. Switchers and ever smokers had higher risk compared with biologic-naïve and never smokers, respectively. CONCLUSION: Overall infections were common in non-TNF-inhibitor-treated RA patients, with a tendency towards rituximab having the highest risk, but CIs were wide in all analyses. Confounding by indication may at least partly explain any differences.

Comparative Effectiveness of Certolizumab Pegol, Abatacept, and Biosimilar Infliximab in Patients With Rheumatoid Arthritis Treated in Routine Care: Observational Data From the Danish DANBIO Registry Emulating a Randomized Trial.

OBJECTIVE: Nationwide Danish guidelines regarding rheumatoid arthritis (RA) patients initiating biologic treatment (i.e., biologic disease-modifying antirheumatic drugs [DMARDs]) are issued on an approximately annual basis. For biologics-naive patients treated with concomitant methotrexate, mandatory medications included certolizumab pegol (CZP; year 2013-2014, recommended compliance 80%), abatacept (ABA; 2014-2015, 80%), and biosimilar infliximab (CT-P13; 2015-2016, 50%). We hypothesized that these guidelines could be perceived as a surrogate randomization tool in which calendar period rather than patient-specific factors defined the choice of the biologic DMARD. We undertook this study to assess compliance with guidelines (supporting the assumption of surrogate randomization) and to compare the effectiveness of CZP, ABA, and CT-P13 in patients treated according to guidelines. METHODS: This was an observational cohort study emulating a randomized trial (using intent-to-treat analyses). RA patients compliant with the treatment guidelines were identified in DANBIO, and information on prior comorbidities was obtained by linking to national registries. Outcome measures included remission rates according to the Disease Activity Score in 28 joints (DAS28) (at 6 and 12 months) and treatment retention at 1 year, compared across treatment regimens. Comorbidity/confounder-adjusted multivariable logistic and Cox regression analyses were used. RESULTS: Seven hundred seventy-six patients were included in the study (336 receiving CZP, 215 receiving ABA, 225 receiving CT-P13). Compliance with treatment guidelines was high: 70%, 65%, and 59%, respectively. Six-month DAS28 remission rates were 35%, 33%, and 42%, and 12-month rates were 35%, 31%, and 35%, respectively. Compared to CZP, adjusted odds ratios for 6- and 12-month DAS28 remission rates were 0.96 (95% confidence interval [95% CI] 0.63-1.47) and 0.74 (95% CI 0.47-1.15) for ABA and 1.38 (95% CI 0.91-2.09) and 0.96 (95% CI 0.62-1.49) for CT-P13, respectively. Adjusted hazard ratios for withdrawal (during days 0-90 and days 91-365) were 0.70 (95% CI 0.39-1.27) and 1.16 (95% CI 0.84-1.60) for ABA and 0.58 (95% CI 0.33-1.10) and 0.83 (95% CI 0.59-1.17) for CT-P13, respectively, compared to CZP. CONCLUSION: The surrogate randomization procedure enabled head-to-head comparisons of CZP, ABA, and CT-P13. Although some differences in estimated effectiveness were observed across drugs, confidence intervals were wide and statistical significance was not reached.