Prednisolone ≥5 mg/day doubles risk of MACE in RA patients

In patients with rheumatoid arthritis (RA), use of systemic glucocorticoids (GC) is associated with a time- and dose-dependent increase in risk of major adverse cardiovascular events (MACE), a population-based real-world study has shown. On long-term follow-up, a prednisolone dose of ≥5 mg/day is associated with a doubled risk of MACE vs no GC use, and no safe duration of use is found for this daily GC dose.

The study, conducted by researchers from the Chinese University of Hong Kong (CUHK), also showed no increased risk of MACE with a prednisolone dose of <5 mg/day. [Ann Rheum Dis 2023;82:1387-1393]

“Based on these findings, we advise judicious use of systemic GC in patients with RA to balance the risks and benefits, as well as discontinuation or tapering of GC to prednisolone ≤4 mg/day as soon as possible,” said first author, Dr Ho So of the Division of Rheumatology, Department of Medicine & Therapeutics, CUHK.

The retrospective cohort study included 12,233 patients (mean age, 57.7 years; male, 18.6 percent) with RA without MACE at baseline, who attended Hong Kong’s public hospital services between January 2006 and December 2015. The patients, identified from a citywide database, were followed up until 2018 for first occurrence of MACE (primary outcome).

At baseline, 37.7 percent of patients (n=4,606) were on systemic GC, 55.6 percent (n=6,769) were on methotrexate, and only 2.8 percent (n=341) were on biological disease-modifying antirheumatic drugs (DMARDs). Hypertension was the most common traditional cardiovascular (CV) risk factor (34.5 percent; n=4,221), followed by hyperlipidaemia (7.9 percent; n=963) and diabetes mellitus (3.4 percent; n=411).

Over a mean follow-up duration of 8.7 years, 7 percent of patients (n=860) developed MACE. In multivariable analysis, use of prednisolone ≥5 mg/day was associated with a significantly increased risk of MACE vs no GC use in time-dependent erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) Cox regression models (ESR model: hazard ratio [HR], 2.02; 95 percent confident interval [CI], 1.87–2.37; p<0.001) (CRP model: HR, 1.87; 95 percent CI, 1.60–2.18; p<0.001), after adjusting for traditional CV risk factors and other medication use.

No safe duration of use was found in patients receiving prednisolone ≥5 mg/day. “Among patients on prednisolone ≥5 mg/day, the risk of incident MACE increased by 7 percent per month in the multivariable models,” reported So.

Both intermediate-term (≤180 days) and long-term (>180 days) use of prednisolone ≥5 mg/day were significantly associated with an increased risk of MACE.

However, very-low-dose prednisolone, at <5 mg/day, was not associated with an increased risk of MACE vs no GC use (ESR model: HR, 0.83; 95 percent CI, 0.60–1.14) (CRP model: HR, 0.84; 95 percent CI, 0.62–1.15).

RA guidelines of the American College of Rheumatology conditionally recommend initiation of conventional synthetic DMARDs (csDMARDs) without short-term GC in DMARD-naïve patients with moderate-to-high disease activity, and strongly recommend against using GC for >3 months. [Arthritis Care Res (Hoboken) 2021;73:924-939] Meanwhile, the European Alliance of Associations for Rheumatology recommends consideration of short-term GC for ≤3 months when initiating csDMARD in RA patients, as well as tapering and discontinuation of GC as fast as clinically feasible. [Ann Rheum Dis 2022;82:3-18; Ann Rheum Dis 2023;82:95-106]