Background/Purpose: Persistently active rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation and bone loss.¹ Although short-term administration of corticosteroids (CSs) is recommended alongside use of disease-modifying anti-rheumatic drugs (DMARDs) for active disease, CS use is often associated with exacerbation of bone loss.² Repository corticotropin injection (RCI) is FDA approved for short-term adjunctive use in the treatment of RA. A naturally sourced complex mixture of purified adrenocorticotropic hormone (ACTH_1-39) analogues and other pituitary peptides, RCI acts as an agonist for all 5 melanocortin receptors (MCRs). RCI activation of MCRs exhibits anti-inflammatory and immunomodulatory effects. In vivo data have shown RCI suppression of bone resorption via osteoclast reduction.³ As an exploratory aim of a broader 2-part, multicenter, placebo-controlled Phase 4 efficacy and safety study, biomarkers associated with bone loss were assessed to evaluate the impact of RCI treatment on bone turnover in patients with persistently active RA.

Methods: Adults with persistently active RA despite DMARD and CS use were enrolled and remained on their current stable DMARD and CS doses throughout the study. During the initial 12-week open-label (OL) period (Part 1), all patients received 80 U RCI (subcutaneously [SC], 2x/wk). Those who achieved low disease activity (defined as DAS28-ESR < 3.2) at Week 12 were subsequently entered into the double-blind (DB) period (Part 2) and randomized to RCI (80 U) or matching placebo SC 2x/wk for an additional 12 weeks. Mean levels of bone turnover biomarkers (C-terminal cross-linking telopeptide [CTX], C-terminal cross-linking telopeptide of type I collagen [CTX-I], osteoprotegrin [OPG], N-terminal propeptide of type I collagen [PINP], and soluble receptor activator of nuclear factor kappa-β ligand [sRANKL]) and cartilage degradation biomarkers (C-terminal cross-linking telopeptide of type II collagen [CTX-II] and CTX-II creatinine [CRT]) were assessed at baseline (BL) and at Weeks 12 and 24.

Results: Of the 153 patients who entered the DB period (RCI, n=77; placebo, n=76), 127 (83%) completed the study. At completion of the OL period (Week 12), mean levels of bone biomarkers (with the exception of bone formation marker PINP) remained unchanged compared with BL, and significant decreases in mean levels of cartilage degradation markers CTX-II (P=0.006) and CTX-II CRT (P< 0.001) were observed (Table 1). For those who underwent an additional 12 weeks of RCI treatment during the DB period (n=77), there was a significant increase from BL in mean sRANKL levels at both Week 12 (P=0.036) and Week 24 (P=0.010) compared with placebo, suggesting a potential increase in osteoclast differentiation; however, mean levels of all other bone and cartilage biomarkers remained stable at these time points (Table 2).

Conclusion: Bone and cartilage biomarker levels were mostly stable throughout the study, suggesting a potential bone-sparing effect of RCI.

1. Fardellone P, et al. Mediators Inflamm. 2014:484280.
2. Tada M, et al. Osteoporos Int. 2016;27(2):729-35.
3. Wright D, et al. Arthritis Rheumatol. 2018;70(Suppl 9):1-3553.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/assessment-of-bone-and-cartilage-turnover-markers-following-treatment-with-repository-corticotropin-injection-in-patients-with-persistently-active-rheumatoid-arthritis/