Background/Purpose: Healthcare providers have been alerted to the potential drug hypersensitivity reactions (HSRs, an adverse drug reaction that are uncommon but may be severe and can result in mortality) in patients (pts) with RA, especially those receiving intravenously (IV) administered biologics. One case of a fatal HSR has been reported and associated with tocilizumab (TCZ). The risks of HSRs in population-based RA cohorts are unclear, as is understanding whether risks differ by specific agent. We compared drug-specific risks for HSR among RA pts enrolled in the US Medicare.

Methods: Using Medicare data from 2006-2011 for 100% of pts with RA, we identified new users of infliximab (INF), abatacept (ABA), rituximab (RIT), TCZ and injected biologics (e.g. anti-TNF therapy).For each biologic administration (Adm), follow up started on the date of drug infusion/injection and ended at the earliest date of: HSR, subsequent biologic Adm, death, coverage loss, 30-day follow-up period, or Dec 31, 2011. We identified HSR using validated claims-based algorithms in three settings: A) Inpatient (IP) or emergency departments (ER) for anaphylactic shock, B) Outpatient (OTP) for anaphylactic shock plus a diagnosis of bronchospasm, stridor, hypotension, epinephrine, injection of diphenhydramine and CPR (Disease and symptom list); C) IP or ER for unspecified allergy plus a diagnosis from the above disease and symptom list. We calculated the incidence rate (IR) of HSR for each biologic within 0-1, 2-14 and 15-30 days of Adm. Robust Poisson regression was used to compare the HSR risks across biologics adjusting for age, gender, Charlson comorbidity score, concomitant steroid (GCs) and methotrexate (MTX) use. Sensitivity analysis was conducted using a nested case-crossover design to reduce within-person confounding.

Results: We identified 429,565 biologic Adms or prescription fills among 54,902 new biologic users. Of these, 29.9% were for ABA, 4.5% RIT, 2.2% TCZ, 23.2% INF, 43.8% injected biologics. Of 137 HSR cases we identified during follow-up, 77% occurred in an IP setting, 17.5% ED and 5.5% OTP. Among 64 cases occurring within 1 day of biologic Adm, 33%, 13.2%, 59.4% were identified by criterion A, B, and C respectively.  The IRs for HSR ranged from 3.0 to 337.2 per 1,000,000 person years across different biologics and timing of exposure. After adjustment, and using abatacept 15-30 days as the referent, ABA, INF, RIT and TOC infusions were associated a significant higher risk of HSR (Table). Concomitant GCs had significant positive association with HSR whereas MTX had a significant inverse association with HSR. Sensitivity analysis yielded similar results. There were no additional deaths occurring within 30 days aside associated with HSRs.

Conclusion: Among RA pts taking biologics, rituximab and tocilizumab were most strongly associated with HSRs within one day of administration. The absolute IR of HSR events for all biologic exposures were low.