Abstract
The aims of this thesis were to: 1) resolve various underexplored clinical issues relating to glucocorticoid (GC) therapy for rheumatoid arthritis (RA), and 2) evaluate the effectiveness and safety of selective glucocorticoid receptor modulators (SGRMs). 1) Underexplored clinical issues relating to GC therapy The second Computer-Assisted Management in Early Rheumatoid
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Arthritis (CAMERA-II) trial had shown that the addition of medium-dose prednisone resulted in a significantly faster reduction of disease activity, less erosive joint damage after two years, and less frequent initiation of tumour necrosis factor (TNF)-inhibitor treatment.[1] Our 2-year post-trial follow-up evaluating the longerterm effectiveness and safety of low-dose GCs revealed that in the former methotrexate (MTX) plus prednisone (pred) strategy group, fewer patients during the follow-up initiated a first biological disease modifying antirheumatic drug (bDMARD), compared to in the former MTX plus placebo (plac) group. Also, the former MTX+pred group had less radiographic joint damage than the former MTX+plac group. There were no significant differences in the onset of GC-related comorbidities between the former strategy groups. (Chapter 2). This observation raised our interest in the potential impact of background GC use in randomised clinical trials (RCTs) evaluating the effectiveness of bDMARDs. Our research showed that in these trials, comparing RA patients on stable background oral GC versus those not on GCs, no statistically significant differences were found in efficacy outcome measures, except for less radiographic progression associated with GC usage in one MTX arm. Serious adverse event rates did not show any significant differences either (Chapter 3). Our study in a subgroup of patients from the CAMERA-II trial showed that MBDA and disease activity score assessing 28 joints (DAS28) had similar response profiles, i.e., MBDA was able to track treatment response in CAMERA-II, similarly to DAS28 (Chapter 4). Previous studies had indicated that current smoking reduces the clinical response to DMARDs in RA. We found that current smoking was associated with higher DAS28 over time, and this negative effect was dosedependent. Additionally, smoking significantly reduced the clinical effect of MTX-based strategy in patients with early RA, regardless of whether they also received pred or not (Chapter 5). 2) Effectiveness and safety of SGRMs. For our systematic review of studies investigating the efficacy and safety of SGRMs compared to GCs in arthritis (Chapter 6), the only compound that was investigated in a clinical trial setting, known as PF-04171327, showed better efficacy/safety balance in comparison to GCs. This was due to its superior clinical anti-inflammatory efficacy and similar safety. In our phase 2a proof-of-principle controlled trial investigating the antiinflammatory effects of the SGRM “AZD9567” compared to those of pred (Chapter 7), patients with active RA were randomised to either AZD9567 or pred orally for 14 days. At day 15 from baseline, AZD9567 showed a similar efficacy and safety profile, compared to pred. However, unlike pred, AZD9567 did not affect the serum sodium: potassium ratio, suggesting it is more selective than pred.
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