Long-term follow-up by PhD candidate Mary Safy (UMC Utrecht) of clinical trial participants with rheumatoid arthritis showed that medium-dose glucocorticoids as an add-on to methotrexate – in contrast to popular belief – did not result in more adverse effects as compared to patients not usings glucocorticoids and it reduces the need for expensive biologic drugs. In addition, she also found that smoking counteracts the efficacy of methotrexate in these patients.
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to pain, joint damage and disability. Treatment of RA is necessary to reduce and prevent the detrimental consequences of RA. The starting drug in most protocols is methotrexate (MTX) which has been proven to be safe and effective. However, glucocorticoids (GCs) – because of their rapid anti-inflammatory and immunomodulatory activity – are often prescribed as a bridging therapy because of the lag time (one to several weeks) between the start of MTX and the appearance of a clinical effect. In addition, 30-60 percent of RA patients use GCs long-term. Despite good efficacy, GCs use can result in co-morbidities such as increased risk of cardiovascular disease, infection and osteoporosis. However, there is also still much unknown about mode of action and clinical effects of GCs. The aims of the PhD thesis of Mary Safy, MD (Department of Rheumatology and Clinical Immunology, UMC Utrecht) were therefore to resolve underexplored clinical issues relating to GC therapy in RA, as well as to evaluate the effectiveness and safety of a novel first-in-class selective glucocorticoid receptor modulator (SGRM).
A previous clinical trial (CAMERA-II) had shown that the addition of medium-dose GC to MTX resulted in a faster reduction of disease activity, less erosive joint damage and less frequent start of a more expensive biologic drug. Mary Safy followed patients that had participated in CAMERA-II up to 11 years to evaluate long-term effectiveness and safety. She found that during 2 years post-trial follow-up in the former MTX plus GC group, fewer patients started a biologic, compared to the former MTX plus placebo group. Also, the former MTX+GC group had less radiographic joint damage than the former MTX + placebo group. Finally, there were no differences between groups in long-term GC-associated co-morbidities.
This observation raised Mary’s interest in the potential impact of background GC use in four randomized controlled trials evaluating the effectiveness of biologics in RA. Her analysis showed that in these trials, when comparing RA patients on stable background oral GC versus those not on GCs, no statistically significant differences were found in efficacy or safety outcomes, except for less radiographic disease progression associated with GC usage in one MTX arm.
Previous studies have indicated that smoking reduces the clinical response to RA treatment. In a post-hoc analysis of the CAMERA-II trial, Mary Safy found that in patients with RA, smoking was associated with more disease progression over time, and this effect was dose-dependent. Also, smoking dose-dependently reduced the clinical effect of MTX in patients with early RA, regardless of whether they also used GCs or not.
The uncoupling of anti-inflammatory effects from off-target actions of GCs might be beneficial to patients requiring long-term glucocorticoid treatment. Mary Safy and co-workers therefore designed and executed a Phase 2a proof-of-principle study with a SGRM, investigating its anti-inflammatory effects compared to those of GC in patients with active RA. This candidate drug showed a similar efficacy and safety profile compared to GC. However, and in contrast to GC, the SGRM did not affect the serum electrolyte balance, suggesting a selective effect.
Mary Safy-Khan
Mary Safy-Khan, MD (1987, Kabul, Afghanistan) defended her PhD thesis on October 10, 2024 at Utrecht University. The title of her thesis was “Clinical aspects of glucocorticoid and selective glucocorticoid receptor modulator therapy in rheumatoid arthritis”. Supervisor was prof. Jaap van Laar, MD PhD (Department of Rheumatology and Clinical Immunology, UMC Utrecht). Co-supervisors were Hans Jacobs, MD PhD and Marjolein de Hair, MD PhD (both Department of Rheumatology and Clinical Immunology, UMC Utrecht). Mary Safy-Khan is currently in training at Amsterdam UMC to become a general practitioner.
