Among patients with rheumatoid arthritis (RA) receiving stable disease-modifying antirheumatic drug (DMARD) therapy, the continued use of glucocorticoids was associated with dose-dependent increase in the risk for serious infection, with small but significant infection risk at low doses of 5 mg or less per day, according to study results published in the Annals of Internal Medicine.1

In this retrospective cohort study, researchers sought to quantify the risk for infection during an acute care hospitalization (“hospitalized infection”) with long-term, stable, low-dose glucocorticoids in patients with RA receiving stable DMARD therapy for 6 months or more. Patient information was collected using 2 databases, including Medicare claims data from 2006 to 2015 and Optum’s deidentified Clinformatics Data Mart database from 2001 to 2015. Patients were categorized by glucocorticoid dose (none, ≤5 mg/d, >5-10 mg/d, and >10 mg/d).

A total of 247,297 medication courses were identified among 172,041 patients enrolled in Medicare and 58,279 medication courses among 44,118 patients enrolled in Optum. After 6 months of stable DMARD use, 47.1% of Medicare patients and 39.5% of Optum patients were receiving glucocorticoids, most commonly at doses of 5 mg or less per day.

Median follow-up after the index date with stable DMARD use and glucocorticoid dose was 180 days (interquartile range [IQR], 90-433 days) in Medicare and 148 days (IQR, 90-347 days) in Optum. Using any discharge diagnosis, there were 20,963 (10.9 per 100 person-years) and 2177 (5.4 per 100 person-years) hospitalized infections in Medicare and Optum, respectively. When a primary diagnosis was used, infection rates were lower, with 12,568 (6.4 per 100 person-years) and 1586 (3.9 per 100 person-years) hospitalized infections in Medicare and Optum, respectively. The most common infections were urinary infection, pneumonia, bacteremia or septicemia, and skin or soft tissue infections.


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The 1-year cumulative incidence of hospitalized infection in any discharge diagnosis was higher in Medicare and Optum patients for all doses of daily glucocorticoid compared with those not receiving glucocorticoids. In Medicare patients not receiving glucocorticoids, incidence of hospitalized infection was 8.6% vs 11.0% (95% CI, 10.6%-11.5%) for patients receiving a glucocorticoid dose of 5 mg or less per day, 14.4% (95% CI, 13.8%-15.1%) for those receiving greater than 5 to 10 mg per day, and 17.7% (95% CI, 16.5%-19.1%) for those receiving greater than 10 mg per day (P <.001 for all vs no glucocorticoids). Similarly, in Optum patients not receiving glucocorticoids, incidence of hospitalized infection was 4.0% vs 5.2% (95% CI, 4.7%-5.8%) for a glucocorticoid dose of 5 mg or less per day, 8.1% (95% CI, 7.0%-9.3%) for greater than 5 to 10 mg per day, and 10.6% (95% CI, 8.5%-13.2%) for greater than 10 mg per day (P <.001 for all vs no glucocorticoids). Results were similar when a primary discharge diagnosis was used.

The association between glucocorticoid use and increased hospitalized risk was similar among older and younger patients and among those treated with biologics and nonbiologics. Similar associations were seen in sensitivity analyses, excluding patients with recent infections, chronic obstructive pulmonary disease, asthma, or extra-articular RA. C-reactive protein values obtained for a subset of Optum patients showed relatively small differences in the measure of disease activity in patients receiving glucocorticoid doses 5 mg or less per day vs those who were not receiving glucocorticoids.

Study limitations included the fact that researchers only evaluated infections that occurred during an inpatient hospitalization, an inability to compare the safety of alternate-day vs daily glucocorticoid use, and the lack of evaluation of risks for other adverse outcomes (eg, fracture, cataracts, diabetes, and cardiovascular events), which have been previously associated with low-dose glucocorticoids.2

Since the risk for hospitalized infection associated with 5 mg or less of glucocorticoids per day was similar to the risk associated with biologic therapies, clinicians “should weigh the benefits of low-dose therapy in individual patients with these potential risks,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

References

1. George MD, Baker JF, Winthrop K, et al. Risk for serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis: a cohort study. Ann Intern Med. Published online September 22, 2020. doi:10.7326/M20-1594

2. Wilson JC, Sarsour K, Gale S, Pethö-Schramm A, Jick SS, Meier CR. Incidence and risk of glucocorticoid-associated adverse effects in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2019;71(4):498-511.