Risk of Serious Infection With Low-dose Glucocorticoids in Patients With Rheumatoid Arthritis: An Instrumental Variable Analysis

Abstract

Background: Low-dose glucocorticoids are commonly used in the treatment of rheumatoid arthritis (RA). Observational studies have found an increased risk of serious infection associated with low-dose glucocorticoids, but concerns about residual confounding remain.

Methods: We identified adults with RA on stable immunomodulatory therapy for >6 months receiving no glucocorticoids or ≤5 mg/day using Medicare data from 2006 to 2015. We used provider preference for glucocorticoids as an instrumental variable (IV) to assess associations between low-dose glucocorticoid use and the risk of infection requiring hospitalization using a cause-specific proportional hazards model.

Results: We identified 163,603 qualifying treatment episodes among 120,656 patients. Glucocorticoids ≤5 mg/day were used by 25,373/81,802 (31.0%) of patients seen by a rheumatologist with low provider preference for glucocorticoids and by 36,087/81,801 (44.1%) of patients seen by a rheumatologist with high provider preference for glucocorticoids (adjusted odds ratio 1.81, 95% confidence interval 1.77, 1.84 for association between provider preference and glucocorticoids). Chronic obstructive pulmonary disease, opioids, antibiotics, previous emergency department visits, hospitalizations, and infections requiring hospitalization infections were unbalanced with regard to exposure but not to the IV. The incidence of infection requiring hospitalization was 8.0/100 person-years among patients unexposed to glucocorticoids versus 11.7/100 person-years among those exposed. The association between glucocorticoids and infection requiring hospitalization from IV analysis (hazard ratio 1.26 [1.02-1.56]) was similar to results from a standard multivariable model (hazard ratio 1.24 [1.21-1.28]).

Conclusions: Among patients with RA on stable immunomodulatory therapy, IV analysis based on provider preference demonstrated an increased risk of infection requiring hospitalization associated with low-dose glucocorticoids, similar to a traditional analysis.

Figure 1:. Cohort identification.

JAKi = janus kinase inhibitor; IBD = inflammatory bowel disease; SLE = systemic lupus erythematosus; PsA = psoriatic arthritis; AS = ankylosing spondylitis

Figure 2:. Standardized differences for covariates across the proposed IV (blue) or across the exposure (glucocorticoids, orange).

Each dot represents a dichotomous variable or category of a categorical variable (for specific values see eTable 4). Horizontal lines represent cut-offs for potentially importance standardized differences (0.1 for differences across the exposure and a more stringent 0.026 for differences across the proposed instrumental variable based on the complier rate times 0.2). SES = socioeconomic status, Geo = geography, HC use = healthcare use, DME/Dis = durable medical equipment/disability; Prev = preventive treatment (screening, immunizations)

Figure 3:. Results of a traditional multivariable model compared to instrumental variable (IV) analysis.

Unadjusted hazard ratios (HR) are from univariate cause-specifics hazards models (unadjusted hazard ratio). Adjusted hazard ratios are from multivariable cause-specific hazards models including all covariates of interest. HR_IV are from instrumental variable analyses (IV) performed using Cox models. IV analyses included covariates with SMD > 0.026 (race, urban versus rural, region, dual Medicare/Medicaid eligibility, median household income quintiles, sulfasalazine, methotrexate, current disease-modifying drug use, number of previous biologics, chronic pain, asthma, number of outpatient visits and number of rheumatology visits in the past year), along with age, age², sex, and covariates strongly associated with the outcome (emergency department visits, prior infection requiring hospitalization).