SEVERE SYSTEMIC-SCLEROSIS WITH ANTI-TOPOISOMERASE-I ANTIBODIES IS ASSOCIATED WITH AN HLA-DRW11 ALLELE

SSc is an autoimmune connective tissue disease in which strong HLA ass ociations have not been described. Anti-topo I antibodies are recogniz ed, in gen- eral, in SSc patients with diffuse cutaneous involvement, whereas anti-ACAs are found in individuals with limited cutaneous invo lvement. We studied 35 Caucasian SSc patients, 44 with anti-topo I ant ibodies and 51 with neither anti-topo I nor ACA, for HLA-DR associatio ns by using DNA typing techniques. We analyzed 181 normal Caucasian in dividuals in the same fashion. A significant association was observed in the anti topo-I-positive patients with DRw11 (p = 1.7 X 10(-6), RR 4.2). The distribution of DRw11 alleles in these patients was signific antly different from that observed in controls and could be accounted for by an increase in the frequency of the DRB11104 allele (p 1.2 X 1 0(-9), RR 9.5). The DRw11 alleles were also associated with SSc with m ore tendon friction rubs (p = 0.006), which is a marker of more severe disease. In addition, a strong association was observed with anti-top o I antibodies and a particular sequence (aa 71-77) of the DQB1 chain (p = 0.02, RR 2.2). HLA associations in the case of SSc patients with anti-topo I antibodies are complex and involve at least two genes: HLA -DRw11, which appears to play a major role in determining the severity of the disease, and a DQ sequence, which associates with the developm ent of the anti-topo I antibodies.