Polypharmacy Common in Rheumatoid Arthritis, Driving Risk of Serious Drug Interactions

Polypharmacy is highly prevalent among individuals with rheumatoid arthritis (RA) and significantly increases the likelihood of potentially serious drug-to-drug interactions, according to a new Brazilian study published in Revista da Associação Médica Brasileira.

Specifically, researchers found that 81.1% of patients with RA were taking 5 or more medications at the same time—a rate strongly associated with older age and multiple comorbidities.

The retrospective analysis included medical records of 370 adults with RA treated in a public outpatient clinic between January 2021 and March 2022. Investigators identified 2018 potential drug interactions using the MedScape drug interaction platform, with 27.5% classified as mild, 54.4% as moderate, and 17.8% as severe. Serious interactions often involved combinations of antirheumatic drugs, particularly immunosuppressants, which can elevate infection risk.

“Our findings highlight the clinical relevance of polypharmacy in RA management, as the combination of immunosuppressants and medications for comorbidities significantly increases the risk of adverse events, hospitalizations, and treatment complexity,” the authors said. “Furthermore, it guides health care professionals toward safer choices with less potential for harm, enabling individualized therapeutic decisions based on the patient’s profile.”

Older Age, More Comorbidities Linked to Higher Risk

On average, patients with polypharmacy—taking 5 or more medications for at least 30 days—were about 6 years older (61.3 vs 55.4 years) and had triple the median number of comorbidities compared with those on fewer medications (3 vs 1). Common comorbidities included arterial hypertension (40.9%), osteoporosis or osteopenia (34.1%), and dyslipidemia (29.4%).

Glucocorticoids, vitamin D, leflunomide, calcium, methotrexate, and folic acid were the 6 most frequently prescribed medications, with more than 40% of the cohort taking them. Cardiovascular drugs such as simvastatin, losartan, and hydrochlorothiazide were also common, and many patients reported using omeprazole, reflecting the multimorbidity burden in this population.

Most Frequent Severe Interactions

The most common severe interaction involved prednisone and simvastatin (19.5% of cases), a combination that can contribute to muscle toxicity. Another frequent pairing was leflunomide and methotrexate (17.2%), associated with heightened risks of hepatotoxicity and bone marrow suppression. Other high-risk combinations included amitriptyline with fluoxetine, acetylsalicylic acid (Aspirin) with methotrexate, and amlodipine with simvastatin. All other interactions occurred in less than 4% of the cohort, with several increasing infection risk.

Although some of these therapy combinations are intentional parts of RA management—for example, combining methotrexate or leflunomide with biologics to improve long-term disease control—they require close monitoring.

“It is essential to consider the increased risk of infection by using this combination, which may be evident to the rheumatologist, but not always to the general practitioner,” the researchers said. “In addition, RA patients in this study have several comorbidities that may require treatment from specialists in other medical fields, who may not be familiar with rheumatological medications.”

With this in mind, the authors recommended regular medication reviews, close collaboration between rheumatologists and other treating physicians, and systematic use of interaction-checking tools to minimize preventable harm.

“This approach is critical to optimizing patient safety and treatment outcomes in rheumatoid arthritis care,” they said.

Adding to the Evidence

These findings add to a growing body of evidence linking polypharmacy in RA to greater treatment complexity, higher infection risk, and increased health care utilization, underscoring the need for proactive strategies to safeguard patient outcomes.

A large German claims-based study of nearly 12,000 patients with psoriatic arthritis (PsA) found that polypharmacy affected 49% of patients compared with 17% of matched controls without inflammatory arthritis.² Polypharmacy rates were higher in women (52%) than men (45%) and rose sharply with age and comorbidity burden. Compared with controls, patients with PsA used significantly more drugs across all therapeutic categories, particularly musculoskeletal, immunomodulatory, cardiovascular, metabolic, and nervous system drugs. The authors concluded that polypharmacy in PsA reflects both disease-specific and comorbidity-related medications, highlighting the need to assess whether broader use of biologic DMARDs could reduce reliance on analgesics, glucocorticoids, and other comedications.

Another large multicenter cross-sectional study in Brazil involving 792 patients with RA found that 67.9% were taking 5 or more medications, and most (89%) were women with long-standing disease.³ Polypharmacy was strongly associated with the number of comorbidities and with use of corticosteroids, methotrexate, and biologic DMARDs. The authors concluded that the high prevalence of polypharmacy in RA represents a significant management challenge not addressed by existing treatment guidelines, warranting targeted strategies to reduce medication burden and associated risks.

References

1. Boeing LB, Fogaça NS, Kahlow BS, Skare T, Nisihara R. Polypharmacy and drug interactions in the management of rheumatoid arthritis. Rev Assoc Med Bras (1992). 2025;71(7):e20250151. doi:10.1590/1806-9282.20250151
2. Albrecht K, Regierer AC, Strangfeld A, Marschall U, Callhoff J. High burden of polypharmacy and comorbidity in persons with psoriatic arthritis: an analysis of claims data, stratified by age and sex. RMD Open. 2023;9(1):e002960. doi:10.1136/rmdopen-2022-002960
3. Gomides APM, Albuquerque CP, Santos ABV, et al. High levels of polypharmacy in rheumatoid arthritis-a challenge not covered by current management recommendations: data from a large real-life study. J Pharm Pract. 2021;34(3):365-371. doi:10.1177/0897190019869158