TNFi Treatment Increases Risk of Antimicrobial Usage in Patients With RA


An increased frequency of serious infections and antimicrobial prescriptions was seen in patients with rheumatoid arthritis currently being treated with a TNFi.

Patients with rheumatoid arthritis (RA) receiving a tumor necrosis factor α inhibitor (TNFi) are more commonly treated for infections than previously believed. Additionally, while they are prescribed more antimicrobials for treatment of infection preceding TNFi initiation than the general population, this number increases and remains consistently higher after initiation, according to a study published in ACR Open Rheumatology.1

“A growing body of evidence shows an increased frequency of serious infections leading to hospitalization in patients treated with TNFi. In the Icelandic population, infections are registered as the third most common adverse effect of TNFi therapy, and they are responsible for 10% of treatment discontinuation in all rheumatic patients, regardless of disease,” investigators stated. “Thus, it is clear that infections are a significant cause of morbidity in patients on TNFi therapy.”

Investigators utilized ICEBIO, an Icelandic nationwide registry, to obtain data on biologic-naïve patients with RA, including patient characteristics, disease activity, and treatment. The registry updates information at treatment initiation, 6 months, and annually. This study focused on patients treated between January 2005 and December 2015.

Patients with RA were matched 1:5 for age, sex, and calendar time to randomly selected controls. Information on disease activity, such as visual analog scales (VAS), Health Assessment Questionnaire (HAQ) scores, body mass index (BMI), Disease Activity Score 28-joint count and C-reactive protein (DAS28-CRP), and smoking history, were extracted from ICEBIO at baseline and month 18. Variables were used to create multivariable models as well as stratified analyses based on sex.

Prescription data for oral antimicrobials were collected from the Icelandic Prescription Medicines Register (IPMR) for all patients in the 2 years before and 2 years after TNFi initiation. Prescriptions were measured using both the number of filled prescriptions (NP) as well as defined daily doses (DDD).

Data was collected from 359 eligible patients with RA and 1795 controls. The mean age was 52.9 years, mean HAQ score at baseline was 1.2 ± 0.7, and the mean DAS28-CRP was 4.8 ± 1.1. TNFis included were infliximab (47%), etanercept (33%), golimumab (9%), adalimumab (6%), and infliximab biosimilars (3%).

Patients with RA filled 2262 antimicrobial prescriptions over the study period, whereas controls filled 5287 prescriptions. Before TNFi initiation, patients in the RA cohort received more prescriptions for antimicrobials when compared with the comparator group comparators (mean ± SD: 2.8 ± 3.4 vs 1.6 ± 2.7; P < 0.001). They were also prescribed twice the DDDs (32.3 ± 68.6 vs 15.2 ± 30.3; P < 0.001) and had a higher mean DDD per prescription (11.7 ± 11.5 vs 9.6 ± 7; P < 0.001).

After beginning TNFi therapy, mean NP (2.8 ± 3.4 to 3.5 ± 3.9; P < 0.001) and mean total DDDs (32.3 ± 68.6 to 34.4 ± 57.7; P = 0.049) increased for those with RA.

Women had a significantly higher mean NP when compared with men both before and after initiating TNFi treatment (3.2 ± 3.7 vs 1.7 ± 2.3; 4.0 ± 4.0 vs 2.3 ± 3.1; P < 0.001, respectively). However, prescriptions increases were seen in both sexes after beginning TNFi therapy.

Univariable analysis indicated that risk of prescription was increased by HAQ score at baseline, prior antimicrobial prescriptions, and VAS scores. Age, BMI, smoking, steroid usage, and TNFi type were not associated with antimicrobial use changes.

The reliability of the ICEBIO registry, the ability to exclude steroids as a confounder, and the collection of nationwide data strengthened the study. However, generalizability was limited due to the majority of patients receiving infliximab, which is not as regularly prescribed in other countries.

“These data suggest that the need for outpatient antimicrobials increases with TNFi treatment and remains elevated, in contrast to a temporary increase in severe infections,” investigators concluded. “Further studies are needed to understand if this continues over more extended periods and to understand the impact on the quality of life.”


Bjornsson AH, Palsson O, Kristjansson M, et al. Outpatient Use of Antimicrobials in Patients With Rheumatoid Arthritis Before and After Treatment With Tumor Necrosis Factor Inhibitors: A Nationwide Retrospective Cohort Study [published online ahead of print, 2021 Nov 29]. ACR Open Rheumatol. 2021;10.1002/acr2.11382. doi:10.1002/acr2.11382

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