Disease Features, Disease Type, HLA Types, and Autoantibody Profile in 17 Multicase SSc Families

Purpose: To determine whether familial SSc represents a unique disease subset and whether the SSc disease features "breed true" in families.
Methods: 18 multicase families composed of 37 SSc cases and 38 unaffected first degree family members (FDRs) as well as 512 single cases and 508 their unaffected FDRs were investigated in the Scleroderma Family Registry and DNA Repository. The medical records of all multicase SSc patients (n=37) and of 168 single case SSc patients were abstracted for disease features. All SSc cases were verified by medical record review. Sera on all subjects were tested for presence of autoantibodies. Oligotyping was used to assign HLA class II alleles.
Results: ANA positivity among multicase families was 97% (n=36); in 11 families both affected subjects had the same ANA pattern. Furthermore 12 families were concordant for disease type, concordance for this feature was statistically more common than discordance (P=0.026). In 12 families both affected members were concordant for SSc specific autoantibodies, whereas 6 families were discordant. Concordance for SSc specific autoantibodies was also statistically more common than discordance (P=0.026). Further clinical and serological features of multicase families are shown in Table 1.
Among non-familial cases, 472 SSc patients (92.5%) had a positive ANA, of whom 113 cases (22.2%) were anti-topo I and 116 (22.7%) ACA positive. Only ACA were significantly more common among multicase families (43% versus 23%, P=0.005, OR=2.59, CI: 1.24-5.38). In the single-case group, 298 SSc cases (58%) had limited disease, whereas 214 (42%) patients had diffuse involvement. Limited disease was significantly more common among the multicase families (75% versus 58%, P=0.047, OR=2.15, CI:0.95-5.04).
Among the unaffected FDRs of the multicase families, 4 cases had a positive ANA (10.5%), none had other autoantibodies, whereas 70 FDRs of singleton cases had a positive ANA (13.8%), 1 had RNP antibodies and 2 unaffected FDRs had Anti-Ro antibodies. The autoantibody profiles of unaffected FDRs of multicase and singleton families were not significantly different.
The frequency of other SSc-related disease features did not differ significantly between familial and non-familial SSc cases. HLA typing data on 9 multicase SSc sib pairs showed that HLA type sharing did not differ significantly from that what was predicted by chance alone.
Conclusion: These findings suggest that the concordance for disease type and SSc specific autoantibodies is more common among SSc family members and the ACA positive limited SSc has a stronger genetic basis, and that the familial SSc does not represent a unique disease subset.
Features of Multicase SSc Patients

Features of Multicase SSc Patients

Family	Disease Type	ANA Pattern	SSc specific AB	Family Relationship
1	Diffuse Diffuse	Sp Sp/Nuc	Anti-topo Anti-topo	Mother Daughter
2	Diffuse Limited	Negative Nuc	None None	Mohter Son
3	Unknown Diffuse	Sp Nuc	None None	Mother Daughter
4	Limited Limited	Cent Cent	ACA ACA	Sister Sister
5	Limited Limited	Sp/Nuc Cent	Anti-topo ACA	Sister Sister
6	Limited Limited	Sp/Nuc Sp	Anti-topo Anti-topo	Daughter Mother
7	Limited Limited	Cent Cent	ACA ACA	Sister Sister
8	Limited Limited	Cent/Cyto Nuc	ACA None	Sister Brother
9	Diffuse Limited	Sp Sp	None Anti-topo	Mother Daughter
10	Diffuse Diffuse	Sp Sp	Anti-topo Anti-topo	Sister Sister
11	Limited Limited	Cent Cent	ACA ACA	Daughter Mother
12	Limited Limited	Sp Sp	None None	Daughter Mother
13	Limited Limited	Cent Cent	ACA ACA	Sister Sister
14	Diffuse Limited	Sp Cent	Anti-topo ACA	Sister Sister
15	Limited Limited Limited	Cent/Cyto Cent Cent	ACA ACA ACA	Sister Sister Sister
16	Limited Limited	Sp Cent	None ACA	Daughter Mother
17	Limited Diffuse	Sp/Nuc Sp	Anti-topo Anti-topo	Sister Sister
18	Diffuse Limited	Sp Cent/Cyto	None ACA	Brother Sister

 S. Assassi, None; F.C. Arnett, None; J.D. Reveille, None; P. Gourh, None; F.K. Tan, None; M.D. Mayes, None.