Maximizing DMARDs to Strive for Steroid-Free Remission in RA Save

In 1950, three scientists were awarded the Nobel Prize for their groundbreaking discovery of steroids, heralded at the time as a "miracle cure" for rheumatoid arthritis (RA). However, just a year after their introduction, evidence began to surface regarding the harmful side effects and withdrawal symptoms such as pain and fatigue that were independent of RA itself. Despite these concerns, steroids became a cornerstone of RA treatment due to their rapid effectiveness and affordability, especially when alternative treatments were scarce.

Fast forward a few decades and the landscape of RA treatment has evolved dramatically. We now have a wide array of steroid-sparing disease-modifying antirheumatic drugs (DMARDs), including biologic DMARDs (bDMARDs) like TNF inhibitors and targeted synthetic DMARDs (tsDMARDs) such as JAK inhibitors. The current standard of care is a treat-to-target (T2T) approach, promoting the early and aggressive use of DMARDs to achieve low disease activity or remission, thereby preventing disease progression and joint damage.

At the 2024 ACR meeting, Dr. Jinoos Yazday presented data from the RISE registry highlighting trends in the treatment of rheumatoid arthritis (RA) over the past decade. According to the study (abstract 0516), the use of b/tsDMARDs has seen a gradual uptick, with 37% of individuals using these therapies in 2014 compared to nearly 50% in 2023. However, there remains a notable gap in the treatment of older adults with RA, who are less likely to receive b/tsDMARDs despite evidence from other studies suggesting that older adults tolerate medications like tocilizumab similarly to younger individuals.

This gap is particularly concerning for older adults newly diagnosed with RA at age 65 or older, known as late-onset RA (LORA). Less than 10% of these individuals receive bDMARDs, in contrast to the 25% of younger-onset RA patients, even though those with LORA tend to exhibit higher disease activity and more radiographic erosive changes (abstract 2224). Conversely, glucocorticoid  (GC) use is more common in those with LORA (50%) compared to patients with younger-onset RA (33%). As DMARDs are steroid-sparing and their underuse may contribute to long-term GC use, especially in older adults with LORA (abst 2606).

As our understanding of the risks associated with long-term steroid use has deepened, guidelines now recommend limiting steroid use to the lowest possible dose for the shortest duration. Prolonged steroid use, even at low doses (greater than 5mg/day) for more than three months, has been linked to severe side effects such as increased risk of serious infections, osteoporosis, and major cardiovascular events (MACE). Dr. Beth Wallace presented findings from the VARA registry showing that not only the dose and duration but also the recency of steroid use correlate with a heightened risk of MACE (abst 1719). Additionally, Dr. Diane Lacaille’s research highlighted that the mortality risk associated with long-term steroid use persists well after cessation (abst 2673). According to her study using Canadian data, each year of steroid use increases cardiovascular disease (CVD) mortality by 7.5% and infection mortality by 6.8%. Although risks decrease over time after stopping steroids, they never fully return to pre-steroid levels for those who used them for more than two to three years.

Given the persistent and serious side effects of steroids, rheumatologists should strive for steroid-free remission. Furthermore, the targets for treatment may need to be refined. Dr. Weinblatt discussed the advantages of achieving remission over low disease activity in terms of functional outcomes for RA patients (abst 2673). He suggested that our current definition of low disease activity might be too broad, potentially missing opportunities for better patient outcomes.

One approach to achieving remission without steroids could involve considering the rapid effectiveness of certain b/ts DMARDs. The JAK-pot study demonstrated that JAK inhibitors and TNF inhibitors result in quicker improvements in disease activity compared to abatacept or IL-6 inhibitors (abst 0501). This faster onset of efficacy might allow for a more rapid tapering off of glucocorticoids. A faster and more aggressive T2T approach during the “window of opportunity” could be particularly beneficial for those with early RA (diagnosis within 5 years), as active RA may increase the risk of interstitial lung disease (ILD) and other RA-related lung conditions (abst 0802).

In conclusion, while steroids once revolutionized RA treatment, their long-term use is fraught with significant risks. Advances in DMARDs and a more aggressive T2T strategy offer promising paths toward reducing steroid dependence, achieving remission, and ultimately improving outcomes for RA patients.