The current study investigated the prevalence of autoimmune diseases in FDRs of a large sample of SSc patients. Compared with the prevalence in controls families (17), SLE, hypothyroidism and hyperthyroidism were significantly increased in our families with SSc. We attempted to confirm all the reported autoimmune diseases. Furthermore, we investigated the presence of ANA and more specific autoantibodies in FDRs and spouses of patients with SSc in addition to unrelated controls.
We report the novel finding that proband’s SSc subtype appeared to modify the degree of familial autoimmunity. SSc patients with ACA and limited disease type show a positive association with familial autoimmunity while SSc patients with ATA have a negative association with this phenomenon. The usually non-overlapping SSc related autoantibodies such as ACA and ATA are associated with different clinical manifestations of disease [18
]. Our group has previously shown that SSc-affected members of multiplex families tend to share a similar autoantibody profile [16
]. Furthermore, previous HLA studies have demonstrated that the major histocompatibility genes exert their influence primarily on autoantibody expression in SSc [19
]. The DPB1*1301 allele is a strong susceptibility gene for ATA positive SSc while ACA is best explainable by DQB1*0501and DQB1*26 epi alleles. Moreover, ACA positive SSc patients have more often concomitantly PBC and/or Sjögren syndrome than other subtypes of SSc [21
]. Our results along with the above mentioned findings indicate that serological subtypes of SSc have different genetic backgrounds and carry a varying degree of genetic risk for familial autoimmunity.
We utilized control families from the study by Broadley et al. as they provided the only appropriate standard for comparison available in the literature [17
]. Our study population differed from the utilized control group in geographic location, and to some extent in genetic background. Furthermore, different questionnaires and verification processes were used. Despite these shortcomings, we think it is more accurate to utilize the data from the above mentioned control group than general population point prevalence data. Numerous other studies of the familial aggregation of diseases have made comparisons with general population point prevalence rates available in the literature. Point prevalence is the frequency of disease in a population at a single point in time. However, an obtained family history is more reflective of the lifetime cumulative risk, or more accurately, the “lifetime prevalence” of the disease among relatives. A point prevalence can be lower than the lifetime prevalence of a given disease by several orders of magnitude [23
In our comparative analysis, the most striking increase in familial prevalence was for SLE. Much data exist regarding similarities of SLE and SSc from both a genetic and immunologic perspective. The observation of familial occurrence of SSc and SLE was initially made by Arnett et al. describing eight families with cases of both SSc and SLE. None of the cases shared residence, and HLA haplotypes were shared in the majority of these cases [24
]. Furthermore, SSc and SLE share several clinical similarities. ANA positivity is a hallmark of both SSc and SLE. Similar disease manifestations may also be present. An interferon gene expression signature also has been reported in both diseases [25
]. Moreover, several overlapping susceptibility genes such as PTPN22
] have been identified in SSc and SLE. The findings of this study further support that similar genetic backgrounds contribute to the development of SSc and SLE. It is also possible that SSc and SLE share common environmental factors leading to the disease. However, there is a relative paucity of large scale case-control or cohort studies that investigate the predisposing environmental factors in SLE and SSc (reviewed in ref. [32
]). Occupational exposure to silica has been implicated in the development of both SLE [33
] and SSc (reviewed in ref. [34
]). However, almost all reported cases have been male. Silica exposure does not seem to play an important role in development of SSc in female patients [35
]. Furthermore, silica exposure does not explain most male SSc cases [36
]. Further large casecontrol studies are needed to explore the possibility of common environmental triggers predisposing to autoimmune diseases that show polyautoimmunity and/or familial autoimmunity.
Disease confirmation was a major part of this study. Hypothyroidism was the most prevalent autoimmune disease among FDRs of SSc probands after case verification. This is likely in part due to the high population prevalence of hypothyroidism in the general population [37
]. We did not determine thyroid related autoantibodies in our study. However, the most common cause of hypothyroidism in iodine sufficient areas like USA is by far Hashimoto’s thyroiditis [38
]. Therefore, the assumption was made that FDRs on supplemental thyroid hormone without history of malignancy or thyroid surgery/ablation had Hashimoto’s thyroiditis. While RA was the most frequently reported disease among FDRs, it became the second most prevalent autoimmune disease after the verification process was completed. RA was found to be incorrectly reported approximately 50% of the time, and was often confused with osteoarthritis on the questionnaire (as it was in Broadley et al. [17
]). We targeted all FDRs with a reported autoimmune disease according to a standard protocol in order to ensure that data for disease verification are missing at random. Nevertheless, it is possible that there are systematic differences between the FDRs with and without sufficient medical data for disease verification. We were able to obtain sufficient medical data in a relatively large portion of reported diagnoses (51.7%) and confirm the reported diseases in 71.6% of FDRs with sufficient medical data. Our verification and confirmation rates are consistent with a study by Cooper et al. that investigated the prevalence and accuracy of self-reported history of autoimmune diseases in FDRs of SLE patients in a Canadian cohort [39
]. In this study, sufficient medical records for verification of reported autoimmune diseases were obtained in 44% of the diagnoses. Excluding those whose medical records were not available, the confirmation rate was 76% [39
]. Furthermore, Cooper et al. reported that the diagnosis of rheumatoid arthritis was confirmed in 48% of the cases, consistent with our confirmation rate of 50% for this disease.
Maddison et al. investigated ANAs in 65 families of SSc patients. Of the enrolled 217 first degree relatives (FDRs), 58 (27%) had a positive ANA (42 speckled, 13 nucleolar, one centromere, two homogenous). Family members tended to share ANA patterns. ANA positivity was detected in nine out of 38 enrolled spouses (24%), and these all had a speckled pattern. ANA positivity also was found in 8% of a randomly selected cohort of blood donor controls for which age and sex were not available. The authors concluded that genetic and environmental factors predispose to the development of SSc and to a high prevalence of autoantibodies in FDRs and spouses of SSc probands [2
]. Barnett et al. reported ANA data in 58 SSc patients, 74 FDRs, 30 spouses, and 66 controls broadly matched to the patients, their spouses, and about half of the relatives (siblings and parents) by age. They found 95% of patients, 18% of controls, 3% of spouses, and 7% of FDRs had a positive ANA; 64% of SSc patients had more specific antibodies compared to 0% in the other groups. ANA at a titer of ≥160 was considered positive. The authors concluded that no genetic or environmental factors contribute to the presence of ANAs in SSc [3
]. We did not detect any significant difference in the ANA positivity among FDRs of SSc patients in comparison to controls after adjustment for disparities in sex and gender. This adjustment was not done in previous studies investigating rates of ANA positivity in SSc families (2–3). Omitting of this correction can lead to spurious associations because ANA positivity can be significantly influenced by age and gender [40
]. Contrary to a previously published report (2), ANA positivity was also not seen at a higher frequency in spouses of SSc patients. This finding argues against an environmental trigger leading to ANA positivity among SSc patients and their spouses.
In summary, SSc patients with ACA and limited disease type are more likely to have another family member with an autoimmune disease. Hypothyroidism and rheumatoid arthritis are the most commonly present autoimmune diseases in the FDRs of SSc patients. Furthermore, SLE is particularly more prevalent in the families of SSc probands than control families. Our study implies varying risk for familial autoimmunity among subtypes of SSc. Furthermore, our results along with reports of common susceptibility genes[6
] support a shared genetic and potentially environmental background predisposing to SSc and SLE.