To the Editor:
Systemic sclerosis (SSc) is a heterogeneous disorder in which both genetic and environmental factors play a role in the pathogenesis.1 Familial occurrence of SSc is uncommon and accounts for < 2% of cases.2 Familial cases tend to have similar autoantibodies and disease features.3 HLA studies suggest that major histocompatibility complex (MHC) genes exert their influence primarily on antinuclear antibody (ANA) expression in SSc.4 Also, skin biology differences to anti-RNA polymerase III (ARA) and antitopoisomerase antibodies (ATA) were studied, suggesting both shared and ANA-specific molecular drivers.5 We hypothesize that the predisposition to develop SSc is hereditary, yet phenotype and antibodies can vary. Ethical approval was granted (London Fulham NHS Research Ethics Committee MREC 20/LO/0404 IRAS project 279682) and all patients provided written informed consent for publication.
Here we present 3 cases within 1 family, each case with different antibodies but showing typical antibody-associated SSc phenotypes (Table 1 and Figure 1).
Case characteristics.
Family tree with affected members.
Case 1. A White, 68-year-old female was referred with Raynaud phenomenon (RP), arthritis, and skin thickening over a year prior to presentation. Her symptoms had progressed over time and were accompanied with breathlessness, sicca symptoms, esophageal reflux, and weight loss. Her medical history included hypothyroidism and coronary artery disease. She was a retired hairdresser and former smoker. On examination, she had diffuse skin thickening (modified Rodnan skin score [mRSS] 26/51) and hyperpigmentation. She tested positive for ATA. Her lung function deteriorated compared to 6 months earlier (forced vital capacity [FVC] 18% and diffusing capacity for carbon monoxide [DLCO] 20%), and lung fibrosis was confirmed on high-resolution computed tomography showing subpleural reticulation in the lower lobes. Vasoactive medication was optimized and mycophenolate mofetil (MMF), which was started 2 months earlier, was continued. After 9 months, she presented with shortness of breath, atrial flutter, and raised troponins (332 ng/L). Cardiac magnetic resonance imaging showed inflammatory myocardial changes with severe ventricular dysfunction. Cardiac biopsy confirmed fibrosis and vasculopathy consistent with cardiac involvement. She was treated with intravenous cyclophosphamide, but sadly died of heart failure 3 months later.
Case 2. Her 48-year-old daughter, also a former smoker and hairdresser, presented simultaneously with widespread skin thickening (mRSS 28/51) and RP. She also had a history of hypothyroidism. She had ARA and anti-Ro antibodies. Lung function showed restrictive changes (FVC 108% and DLCO 68%) and imaging showed mild lung fibrosis. She was started on MMF and vasoactive therapy for RP with digital ulcers. Tocilizumab was added later in the context of a clinical trial and was continued for 2 years. After trial completion she remained on MMF. A year later she developed myositis, which was treated with rituximab 1000 mg intravenously. Five years after diagnosis, she developed pulmonary arterial hypertension (mean pulmonary arterial pressure 35 mmHg, pulmonary arterial wedge pressure 7 mmHg) and was started on tadalafil 40 mg.
Case 3. The 59-year-old maternal cousin to case 2 also developed SSc. She is a former smoker and had breast cancer 15 years ago. Her symptoms started 1.5 years ago with RP followed by puffy fingers, sclerodactyly, dysphagia, and esophageal reflux 3 months later. She tested positive for anticentromere antibodies (ACA). She did not develop cardiopulmonary involvement and is currently treated with calcium antagonists and proton pump inhibitors.
These 3 cases showed 3 patients within 1 family who were diagnosed with SSc with different antibodies and clinical manifestations consistent with these antibody profiles. In SSc, ANA subtypes have been demonstrated to be linked to clinical features as well as biologic pathways.5,6 In literature, most familial cases had similar manifestations and autoantibodies. Also, the majority of cases were ACA-positive with limited cutaneous SSc (lcSSc).3 A cohort of 18 multicase families identified 2 families, with 2 members with ATA-positive diffuse cutaneous SSc (dcSSc) who had similar manifestations related to ATA.3 This study reported significant antibody concordance within each family.3 Six families had discordant autoantibodies, but only 1 had both different antibodies (ACA and ATA) and matching subtypes (lcSSc and dcSSc, respectively), similar to our family.
HLA class II contributes strongly to SSc susceptibility, as was shown in a genome-wide genotyping study in 9095 patients.7 In this study, a link between HLA class I and SSc was established as well, and associations between specific alleles, disease subsets (HLA-DQA1*02:01 with lcSSc, HLA-DQA1*05:01 with dcSSc), and antibodies were found, suggesting a different genetic basis for each autoantibody (ACA: HLA-DRB1*07:01, ATA: HLA-DPA1*02:01 and HLA-DQB1*03:01).7 Earlier familial SSc studies showed identical HLA haplotypes within families, but no shared class II MHC antigens between families.8,9 Possibly, different antibodies and haplotypes in SSc suggest a different response to immunomodulatory therapies; this finding is supported by studies on molecular biology of SSc skin and genetic polymorphisms in other rheumatic diseases.5,10
In conclusion, this unique report of a multicase family affecting 3 members with different autoantibodies and clinical features supports the theory that the genetic background in SSc contributes to the risk of getting SSc but does not seem to define phenotype and antibody profile.
Footnotes
The authors declare no conflicts of interest relevant to this article.
- Copyright © 2022 by the Journal of Rheumatology
