Biologics May Increase Risk of Infection in Patients With Rheumatoid Arthritis

Patients receiving csDMARDs had a significant reduction (40%) in non-serious infection (NSI) risk when compared with biologics.

There may be a link between non-serious infections (NSI) and targeted immunomodulatory therapy in patients with rheumatoid arthritis (RA), according to a study published in Arthritis and Rheumatology.1 Although NSI occur regularly in this patient population, biologics were significantly associated with a greater risk of NSI. Both NSI and serious infections are caused by immunological dysfunction, immunocompromising comorbidities, lifestyle, and the use of immunomodulatory medications, which can lead to morbidity and mortality.

“Serious infections are the tip of the iceberg. NSI, defined as those events managed outside of a hospital admission, have been reported in 20-30% of RA patients each year and are the most common adverse events in large clinical trials,” stated investigators. “In elderly RA patients, rates of NSI are estimated at 47.5 per 100 patient-years. Although these events are not life-threatening, their burden is high and recurrent NSI may lead to variable periods of treatment discontinuation.”

In this prospective, observational cohort study, investigators used data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) to determine frequency and predictors of NSI and compared incidence across biologics. NSI was defined as instances of infection that were managed without the need to be admitted into a hospital or receive intravenous therapy. The primary outcome was any NSI reported by either physicians or the patient and were coded by the Medical Dictionary for Regulatory Activities terminology (MedRA) with severity included.

Information was gathered through clinician questionnaires and patient diaries, and included demographics, disease duration, smoking status, any comorbidities, disease-modifying antirheumatic drug (DMARD) and corticosteroid exposure, Disease Activity Score 28-erythrocyte sedimentation rate (DAS28- ESR), and Health Assessment Questionnaire (HAQ) scores. Drug exposure was categorized by tumor necrosis factor (TNF) inhibitor, IL-6 inhibitor, B cell depletion, or conventional synthetic disease-modifying antirheumatic drug (csDMARD) only. Investigators collected follow-up data every 6 months for the first 3 years of the study, and annually thereafter. Serious adverse events, non-serious adverse events, and new prescriptions (including antibiotics) were recorded in the patient diaries. Investigators used TNFi (etanercept) as the reference drug for comparison since it was the most commonly used medication in the register.

In total, 23,584 patients registered in the BSRBR-RA until January 2019. There were 17,304 NSI in 8145 patients, averaging out to roughly 27 per person, per year (95% confidence interval [CI] 26.6 to 27.4). The most common infections included respiratory (36%), urinary, ear nose and throat (ENT), and skin infections. The mean age of participants was 57 years, and the disease duration was 10 years.

Investigators found that increased age, female gender, comorbidity, corticosteroid therapy, higher DAS28 scores, and higher HAQ-DI scores increased the risk of NSI. However, patients receiving csDMARDs had a significant reduction (40%) in NSI risk when compared with biologics. IL-6 inhibition and rituximab had higher NSI risks when compared with TNFi [adjusted HR 1.45 (95% CI 1.29 to 1.63) and adjHR 1.28 (1.14 to 1.45)]. Every biologic drug examined had a greater risk of NSI when compared with csDMARDs.

Strengths of the study included the substantial size of the cohort and the quality of real-world data, which limited missing data on baseline co-variates and coding of biologics. Data was obtained from multiple sources, which allowed investigators to evaluate non-serious events. Comparing TNFi, rather than csDMARDs, created a more clinically relevant strategy for physicians to consider different therapeutic options in patients who did not respond well to csDMARDs.

However, investigators were unable to ascertain the risk of NSI with certain agents, such as golimumab, abatacept, tofacitinib, and baricitinib, because there were few patients receiving these drugs in the registry. Additionally, medication choice may have also been influenced by drug costs, national guidelines, and local treatment pathways.

“NSI events are common in patients with RA, with similar predictors to those observed with serious infections. An NSI history should be routinely captured in clinical practice. Biologics associate with a greater risk of NSI, with differences in the incidence and risk between therapies,” concluded investigators. “These results provide clinicians with information on how to identify patients at greater risk of NSI and guide them on best possible drug strategies.”

Reference:

Bechman K, Halai K, Yates M, et al. Non-serious infections in patients with rheumatoid arthritis; results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis [published online ahead of print, 2021 Apr 12]. Arthritis Rheumatol. 2021;10.1002/art.41754. doi:10.1002/art.41754