Clinical aspects of glucocorticoid and selective glucocorticoid receptor modulator therapy in rheumatoid arthritis

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 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.