Joint Ventures: Unpacking the History and Modern Use of Steroids in Rheumatology

In this episode of Joint Ventures, hosts Jack Arnold, MBBS, MRCP, PhD, academic clinical lecturer in rheumatology at the University of Leeds, and Rihards Buss, MD, consultant rheumatologist at Freeman Hospital in Newcastle, take on a topic every rheumatologist lives with daily: corticosteroids.

The conversation is built around a recent Lancet Rheumatology review of glucocorticoid use in inflammatory rheumatic disease, moving from the drug's 1948 discovery through its mechanisms of action and into how guideline recommendations for rheumatoid arthritis (RA) and lupus compare with what registry data show clinicians are actually doing.¹

The Discovery of Corticosteroids and the First RA Trial

Buss opens with the discovery story behind what he calls one of the most consequential drug discoveries of the 20th century. Biochemist Edward Kendall at the Mayo Clinic isolated a series of adrenal gland compounds, eventually reaching compound E, later renamed cortisone. Rheumatologist Philip Hench, also at Mayo, had separately observed that RA symptoms improved when patients became pregnant or jaundiced and theorized the body was producing an unidentified substance responsible.

The pair recognized Kendall's compound was Hench's hypothesized substance, leading to the first clinical trial of cortisone, in 18 patients with RA, in 1948, a result significant enough to earn them the 1950 Nobel Prize in Physiology or Medicine. That trial also established the pattern rheumatologists still contend with today: symptoms returned quickly once steroids were withdrawn, and patients kept on high-dose cortisone for 3 months developed Cushingoid features.

Genomic and Non-Genomic Mechanisms of Action

Arnold walks through how glucocorticoids work at the cellular level. Activated glucocorticoid receptor dimers can transactivate metabolic genes, a pathway linked to hyperglycemia, osteoporosis, and skin thinning, or transrepress pro-inflammatory transcription factors such as NF-κB and AP-1, which drives most of the anti-inflammatory effect. He cautions the split is not as clean as textbooks suggest, since glucocorticoid receptor signaling touches roughly a fifth of the human genome and both pathways contribute to wanted and unwanted effects alike.

A separate, faster non-genomic mechanism acts within seconds to minutes, which Arnold connects to why pulse-dose IV steroids are used in severe disease such as lupus nephritis. He also flags early-stage candidates targeting tissue-level steroid metabolism, including dissociated steroids such as vamorolone, though both hosts agree this work remains speculative for now.

Steroid Use in RA: Guidelines vs Real-World Practice

Buss lays out a consistent international message on paper: EULAR, ACR, and Asia-Pacific guidelines frame steroids in RA as a short bridging therapy at the lowest effective dose while disease-modifying antirheumatic drugs take effect, with the 2021 ACR guideline going furthest by recommending against steroid use even as a bridge. Registry data tell a different story: chronic steroid use, defined as more than six months of continuous therapy, ranges from 27% in a German RA cohort to 46% in a US cohort, and Australian OPAL Consortium data show chronic use actually rose slightly, from 44.2% in 2009 to 46.3% in 2022, despite an expanding array of targeted therapies.

Arnold calls the trend "shocking" given how much the therapeutic arsenal has grown. Buss highlights emerging comfort with chronic prednisolone at 5 mg per day or less, citing data showing no clear mortality, cardiovascular, or osteoporosis signal at that threshold, though infection risk does rise, and says he is not yet fully confident recommending indefinite low-dose use to his own patients.

Glucocorticoids in Lupus: Higher Stakes, Slower Tapers

Arnold explains why steroid dependence is a harder problem in lupus than in RA. Guidelines again call for minimizing glucocorticoid exposure, typically through early hydroxychloroquine alongside immunosuppressants and biologics such as belimumab, with pulse-dose IV methylprednisolone reserved for high disease activity. Cohort data show the same gap seen in RA, only starker: about 40% of patients in Spain's RELESSER cohort remained on more than 7.5 mg per day of prednisolone equivalent one year after diagnosis, and more than half in the Asia Pacific Lupus Collaboration cohort were still on steroids after 4 years.

Arnold attributes this to the outsized consequences of a lupus flare, particularly in lupus nephritis, where relapse can accelerate progression toward end-stage renal disease. Buss adds that uncontrolled lupus itself carries cardiovascular and infection risks that mirror steroid toxicity. Both hosts point to belimumab as the best-documented steroid-sparing option in lupus trials, and highlight the newly published British Society for Rheumatology lupus guideline, which recommends agreeing on a tapering plan when steroids are initiated rather than improvising later.²

Buss closes by recommending the Lancet Rheumatology review that anchored the discussion, nearly 80 years after that first RA trial.¹

References

1. Buttgereit F, Tam LS. Glucocorticoid treatment in patients with inflammatory rheumatic diseases: current practice and open questions. Lancet Rheumatol. 2026;8(5):e389-e400. doi:10.1016/S2665-9913(26)00072-X

2. Md Yusof MY, Smith EMD, Lythgoe H, et al; British Society for Rheumatology Guidelines Steering Group. The 2026 British Society for Rheumatology guideline for the management of children, young people and adults with systemic lupus erythematosus. Rheumatology (Oxford). 2026;65(6):keag223. doi:10.1093/rheumatology/keag223