Background Mixed connective tissue disease or Sharp syndrome (MCTD) was described in 1972 [1] as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SS) associated with antibodies to U1 small ribonuclear protein (U1 RNP). The long-term follow-up studies revealed a tendency for MCTD to evolve into SLE or SS over time [2].

Objectives To reveal genetic markers associated with MCTD and to estimate their discriminating and prognostic value.

Methods For the twenty-five year period (1980–2005) MCTD was diagnosed in 29 patients (25 women and 4 men) observed at Byelorussian Republican Rheumatologic Center. There were 17 cases of overlapping SLE and RA, 7 patients had features of SLE and SS, and combination of SS and RA was revealed in 5 patients. A number of some genetic markers as HLA-A; (8 loci) and HLA-B (17 loci) antigens, AB0 and Rhesus (Rh₀⁺, Rh₀^–) blood groups and haptoglobin phenotype (Hp_1–1, Hp_2–1, Hp_2–2) were investigated in patients with MCTD as well as in patients with RA (n=260), SLE (n=182), SS (n=52) and healthy individuals of the control group (n=120) for the comparison. All the patients fulfilled the ACR criteria for the corresponding diseases.

Results The least differences in A and B loci were revealed between patients with MCTD and SLE (locus A: χ²=5.3, df=8, p=0.725; locus B: χ²=10.9, df=16, p=0.813) and the greatest differences – between patients with MCTD and healthy individuals of the control group (locus A: χ²=11.7, df=8, p=0.165; locus B: χ²=15.5, df=17, p=0.557). The differences in pairs MCTD vs RA and MCTD vs SS had the intermediate significance level of χ² criterion. HLA-A₁ antigen was determined in patients with MCTD more often than in the control group (40.9% vs 18.3%, p_2-t=0.0231, two-way Fisher's exact test) as well as HLA-B₈ (31.8% vs 10.8%, p_2-t=0.017) and phenotype A₁B₈ (27.3% vs 8.3%, p_2-t=0.0198). The same significant differences of HLA phenotype were revealed between MCTD patients and RA and SS patients in contrast to the SLE patients, characterized by the HLA profile similar to MCTD patients. The following frequency of erythrocyte antigens and haptoglobin phenotypes in MCTD patients was determined: I(0) 41.7%; II(A) 16.7%; III(B) 33.3%; IV(AB) 8.3%; Rh₀⁺ 100.0%; Hp_1–1 22.2%; Hp_2–1 44.5%; Hp_2–2 33.3%. II (A) blood group was determined rarer in MCTD than in RA (40.1%), SLE (42.0%) and SS (50.8%) and in the control group (37.2%). The only significant difference of erythrocyte antigens was between MCTD and SS patients (p=0.043, one-way Fisher's exact test, and p_2-t=0,073).

Conclusions HLA-A₁, HLA-B₈ and phenotype A₁B₈ were associated with MCTD. The findings agree with recently published data identified HLA-B8 as risk allele for MCTD [3] and highlight the genetic and clinical similarity between MCTD and SLE in Byelorussian MCTD cohort.

1. Sharp G.C. et al. Am. J. Med. 1972;52(2):148–59.

2. Venables P.J. Lupus. 2006;15(3):132–7.

3. Flåm S.T. et al. Rheumatology (Oxford). 2015;54(3):528–35.

Disclosure of Interest None declared