Background/Purpose:  Criteria for the diagnosis of Early Systemic Sclerosis (EaSSc) have been formalized by LeRoy and Medsger in 2001 and later validated by Koenig et al (2008), who showed that the vast majority of EaSSc patients develops a definite SSc within few years from EaSSc. The genetic factors that may affect the progression from early to definite SSc are poorly studied.

Methods:  One-hundred-fifty-eight consecutive subjects with Raynuad’s phenomenon (RP) fulfilling the EaSSc criteria and no other manifestation indicative of SSc (Fransen et al, 2012) at referral were considered. All the patients underwent high-resolution HLA Class II typing by means of PCR with sequence-specific primers ad were retrospectively evaluated in an observational fashion for the appraisal of definite SSc according to the ACR/EULAR proposed criteria for SSc (Pope et al, 2012): patients with a score >9 are classified as definite SSc, where the single items scores are: skin thickening of the fingers of both hands extending proximal to the MCP joints (9); highest between puffy fingers (2) and skin thickening of the fingers (4); highest between digital tip ulcers (2) and pitting scars (3); telangiectasia (2); abnormal nailfold capillaries (2); lung involvement (interstitial lung disease/PAH- 2), RP (3); SSc-specific antibodies (3). The time-to-event was analyzed by means of Kaplan-Meier and Cox regression analysis; multiple testing correction was performed by 1000-fold permutations test.

Results: One-hundred-nine subjects (69%) developed a definite SSc by the end of the 10-years follow-up period, with a median estimated time-to-progression equal to 45 months from referral. Twenty-eight (17.7%) patients tested positive for anti-Topoisomerase I antibodies, 96 (60.8%) for anti-centromere antibodies (ACA) and 17 (10.8%) for other SSc-specific antibodies. ACA-positivity was associated with a reduced the risk of progression (median=55 vs 23 months, HR=0.67, CI=0.458-0.979, p=0.038). The presence of the HLA DQ5-DR1 haplotype (HLA-DRB1*0101 – HLA-DQA1*0101(4) – HLA-DQB1*0501) strongly reduced the time and the risk of progression (median=108 vs 45 months; HR=0.388, CI=0.211-0.712, p=0.002, permutation p=0.009); the effect of the HLA DQ5-DR1 haplotype was independent from ACA positivity or from the duration of RP in a stepwise multivariate model. Similar results were observed when the single alleles within the HLA-DQ5-DR1 haplotypes were analyzed.

Conclusion:  The occurrence of the HLA DQ5-DR1 haplotype reduces the risk of progression from early to definite SSc independently from the autoanticorpal subsets and other factors that may affect the time-to-progression.

References: Fransen J, et al. Arthritis Care Res (Hoboken). 2012;64:351-7. – Koenig M, et al. Arthritis Rheum. 2008;58:3902-12. – LeRoy EC, Medsger TA Jr. J Rheumatol 2001;28:1573–6. – Pope J et al. ACR 2012 Late-Breaking abstract #L3

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-class-ii-human-leukocyte-antigens-in-the-progression-from-early-to-definite-systemic-sclerosis/