AZD9567 versus prednisolone in patients with active rheumatoid arthritis: A phase IIa, randomized, double-blind, efficacy, and safety study.

Oral corticosteroid use is limited by side effects, some caused by off-target actions on the mineralocorticoid receptor that disrupt electrolyte balance. AZD9567 is a selective, nonsteroidal glucocorticoid receptor modulator. The efficacy, safety, and tolerability of AZD9567 and prednisolone were assessed in a phase IIa study. Anti-inflammatory mechanism of action was also evaluated in vitro in monocytes from healthy donors. In this randomized, double-blind, parallel-group, multicenter study, patients with active rheumatoid arthritis were randomized 1:1 to AZD9567 40 mg or prednisolone 20 mg once daily orally for 14 days. The primary end point was change from baseline in DAS28-CRP at day 15. Secondary end points included components of DAS28-CRP, American College of Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70), and safety end points, including serum electrolytes. Overall, 21 patients were randomized to AZD9567 (n = 11) or prednisolone (n = 10), and all completed the study. As anticipated, AZD9567 had a similar efficacy profile to prednisolone, with no clinically meaningful (i.e., >1.0) difference in change from baseline to day 15 in DAS28-CRP between AZD9567 and prednisolone (least-squares mean difference: 0.47, 95% confidence interval: -0.49 to 1.43). Similar results were observed for the secondary efficacy end points. In vitro transcriptomic analysis showed that anti-inflammatory responses were similar for AZD9567, prednisolone, and dexamethasone. Unlike prednisolone, AZD9567 had no effect on the serum sodium:potassium ratio. The safety profile was not different from that of prednisolone. Larger studies of longer duration are required to determine whether AZD9567 40 mg may in the future be an alternative to prednisolone in patients with inflammatory disease.

Current Smoking Negatively Affects the Response to Methotrexate in Rheumatoid Arthritis in a Dose-responsive Way, Independently of Concomitant Prednisone Use.

OBJECTIVE: Current smoking reduces clinical response to several disease-modifying antirheumatic drugs. It is unknown if this is also the case for prednisone. We aimed to determine whether current smoking affects the clinical response to concomitant prednisone in a methotrexate (MTX)-based treatment strategy. METHODS: In the CAMERA-II trial (isrctn.com identifier: 70365169), patients with early rheumatoid arthritis (RA) initiated an MTX-based strategy and were randomized to concomitant prednisone (MTX + pred) or placebo (MTX + PBO) for 24 months. Linear mixed modeling was performed with Disease Activity Score assessing 28 joints (DAS28) as the dependent variable, and strategy group and current smoking status as independent variables, correcting for relevant covariates. The interaction between current smoking and strategy was tested to find out whether the effect of current smoking on clinical response was different between the strategy groups with prednisone or PBO. RESULTS: Current smoking was significantly associated with higher DAS28 over time (mean difference with nonsmokers 0.57 [95% CI 0.22-0.92, P < 0.01]). This association was not different between the strategy groups with prednisone or PBO (P = 0.73). The negative effect of current smoking on DAS28 was dose dependent. CONCLUSION: Current smoking in patients with early RA significantly reduces the clinical effect of an MTX-based strategy, independent of whether concomitant prednisone is used. This effect is dose dependent.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.