Background/Purpose: Epidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American (INA) population. Vitamin D improves immune function and protects against infections by inducing the expression of antimicrobial proteins and peptides (APPs) such as LL-37. We therefore profiled the circulating levels of 25-hydroxyvitaminD [25(OH)D], an active metabolite of vitamin D, and APPs in serum samples obtained from a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (2010 ACR/EULAR guidelines) and were referred as “progressors”.

Methods: 2007 onward, serum samples were collected from at-risk INA FDRs. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) and LL-37 (cathelicidin) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry. A high-throughput Slow Off-Rate Modified Aptamer (SOMAmer®)-based Protein Array technology (SOMALogic Inc., US) was used for quantification of other APPs.

Results: We demonstrate that seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P< 0.05, P< 0.01 respectively). In contrast, serum LL-37 levels were higher in both study groups compared to ACPA-/FDR (P = 0.0009 and P = 0.0120 respectively). No difference was observed in LL-37 levels between ACPA+ FDR and RA patients (P = 0.1090) Linear regression analysis showed circulating 25(OH)D and LL-37 was inversely associated with anti-CCP antibody levels (P = 0.005 and P = 0.05 respectively). Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D, and LL-37 levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP levels. Expression profile of APPs was also significantly altered in progressors at RA onset and at-risk FDRs.

Conclusion: We demonstrate a differential serum abundance in the levels of 25(OH)D and APPs at RA onset in progressors. The interrelationship between vitamin D and these downstream metabolites and their potential role in RA transition requires further investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/circulating-25ohd-ll-37-and-antimicrobial-protein-and-peptide-app-levels-are-altered-prior-to-onset-of-rheumatoid-arthritis/