Session Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose: Vitamin D (VitD) exerts immunoregulatory activities of potential importance to rheumatoid arthritis and acts by binding to nuclear vitamin D receptors (VDRs) and regulating gene expression including cathelicidin an important mediator of host innate responses to infection. VDR genetic polymorphisms (VDrP) have been variably linked to disease activity in rheumatoid arthritis and to chronic infections. Altered host response to infection may break tolerance leading to disease. We sought to assess the association of VDR polymorphisms (Fokl, Bsm1, Apa1 and Taq1) with clinical disease activity at baseline and one year, baseline serum vitD levels, and antibody responses to common pathogens in a cohort of patients with inflammatory arthritis of less than 1 year symptom duration.
Methods: VDR SNPs at the restriction sites Bsm1 (B/b (T/C)) (rs1544410), Apa1(A/a (T/G)) (rs7975232), Taqa1(T/t (T/C)) (rs731236), Fok1 (F/f (C/T)) (rs10735810) and Cdx-2 (G/A) (rs11568820) were detected by polymerase chain reaction sequencing and analyzed using genotypic (DD vs Dd vs dd), dominant (DD, Dd vs dd), and recessive (DD vs Dd, dd) models. At first visit before DMARD treatment, 25OH VitD levels, antibody titers to E Coli and P. mirabilis (IgG, IgA and IgM), and CCP2 antibodies were measured in serum by ELISA. Smoking was assessed by self report and serum cotinine levels. Associations of VDR snps with clinical disease activity at baseline and one year and achievement of remission (DAS28CRP (3variable) <2.6) or EULAR treatment response at one year were tested.
Results: Subjects (n=228) were predominantly female (72%) and Caucasian (87%), with mean age at first visit of 47.8 years (range 17-82, SD 14), a mean DAS28CRP (3variable) 3.91 (1.35), (31% low, 50% moderate 19% high disease activity) and were RF (54%) or CCP2 positive (44%). Of the 154 subjects with one year follow-up data, 67% achieved low disease activity. The VDR minor allele frequencies were Fokl 0.42, Bsm1 0.55, Apa1 0.51, and Taq1 0.37. There was an association between Taq1 dominant alleles (TT,Tt) and at least one copy of shared epitope allele (p=0.01). No robust associations were seen between VDR polymorphisims and gender, age at first visit, RF or CCP2 or baseline disease activity. Fokl dominant alleles (FF,Ff) had higher baseline anti-E.Coli IgM titers (0.51 vs 0.34 units p<0.01) and anti-proteus IgM titers (1.34 vs 1.18 units p<0.05), and at one year had higher DAS28CRP (3 variable) scores (2.92 vs 2.44 p<0.05) and were less likely to achieve remission (41% vs 73% p<0.01). In multivariate models including CCP2, rheumatoid factor, shared epitope, smoking (ever), and baseline serum VitD, only lower baseline DAS28CRP (3 variable) (p=0.001), Fokl recessive alleles (ff) (p<0.01) and higher IgM E.Coli titers (p<0.05) predicted remission at one year.
Conclusion: Vitamin D receptor polymorphisms, especially Fokl, associate with IgM immune responses to common pathogens and associate with disease outcome in EIA but do not associate with baseline disease activity. Vitamin D receptor mediated regulation of immune responses may be important for the predisposition to inflammatory arthritis by breaking immune tolerance.
C. A. Hitchon,
C. A. Peschken,
M. M. Newkirk,
H. S. El-Gabalawy,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/vitamin-d-receptor-polymorphisms-are-associated-with-clinical-outcomes-and-igm-responses-to-common-pathogens-but-not-baseline-disease-activity-in-early-inflammatory-arthritis/