# Adverse events related to drug–drug interactions in tocilizumab combination therapy: a retrospective analysis and clinical implications

## TL;DR

This study identifies adverse drug interactions when combining tocilizumab with other medications, highlighting risks and suggesting monitoring strategies for safer treatment.

## Contribution

The study provides new real-world evidence on adverse events from drug combinations involving tocilizumab, offering clinical guidance for safer use.

## Key findings

- 35.6% of detected adverse events were significantly positively correlated with drug–drug interactions.
- Musculoskeletal and connective tissue disorders were most common in TCZ-DMARD and TCZ-NSAID combinations.
- Age and sex influence specific adverse events, such as infusion reactions and joint swelling in adults and gender-specific side effects.

## Abstract

Tocilizumab (TCZ) is widely used in the treatment of autoimmune diseases and usually needs to be combined with other drugs. However, limited evidence is available on TCZ drug–drug interactions (DDIs). This study aimed to identify and evaluate the adverse events (AEs) associated with DDIs between TCZ and co-administered drugs based on real-world clinical data to offer a reference basis for clinical decision-making.

A retrospective study was conducted to estimate the AEs related to DDIs between TCZ and three categories of drugs, including disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs). AE information for the target drugs from the first quarter of 2004 to the third quarter of 2025 was downloaded from the OpenVigil FDA data platform. The following four frequency statistical models were used to detect the AEs related to DDIs and to evaluate the correlation: the reporting ratio method, the Ω shrinkage measure model, the combination risk ratio model, and the chi-squared statistics model. The influence of sex and age on the drug and the target AEs was analyzed using Pearson’s chi-squared test and reporting odds ratios with 95% confidence intervals.

Eleven drugs were included for the analysis of AEs associated with TCZ combination therapy. A total of 824 AEs were detected by at least one of the four models; 35.6% (293/824) AEs were significantly positively correlated with DDIs and were related to higher reporting rates of AEs than when used alone. Musculoskeletal and connective tissue disorders were the most frequently involved system organ class for TCZ-DMARD and TCZ-NSAID combinations. The most significant DDI-related AEs identified for specific TCZ drug combinations were as follows: with DMARDs (e.g., methotrexate, hydroxychloroquine, and leflunomide), occurrence of anti-cyclic citrullinated peptide (CCP) positivity, hand deformity, and pemphigus were observed; with glucocorticoids (specifically prednisone), pemphigus, hand deformity, glossodynia, and pericarditis should be monitored; with NSAIDs (specifically diclofenac), heightened vigilance is warranted for anti-CCP positive, rheumatic fever, duodenal ulcer perforation, and Helicobacter infections. Age and sex influence DDI risks: adults (≥18 years) were more susceptible to infusion reactions with TCZ + hydroxychloroquine or TCZ + sulfasalazine, and to joint swelling with TCZ + naproxen. Male patients demonstrated a higher incidence of stomatitis with TCZ + methotrexate, and of joint swelling with TCZ + ibuprofen or TCZ + naproxen. Female patients were more susceptible to infusion-related reactions and infections with TCZ + dexamethasone, and to abdominal discomfort with TCZ + methylprednisolone.

Healthcare providers should maintain vigilance of potential DDI-related AEs when TCZ is used in combination with DMARDs, glucocorticoids, or NSAIDs. Particular attention is suggested for signals of decreased treatment efficacy, which may be associated with the formation of anti-TCZ antibodies, and for musculoskeletal, cutaneous, and gastrointestinal events. Monitoring serological parameters (e.g., CRP and Anti-CCP), skin/mucosal symptoms, and signs of infection is recommended during combination therapy to support medication safety.