Systemic sclerosis in a patient with muscle dystrophy

Background

The genesis of autoimmune diseases remains a subject of ongoing debate. Systemic sclerosis is an autoimmune connective tissue disease characterised by skin and internal organ fibrosis. Seventy per cent of systemic sclerosis patients show positive autoantibodies which are associated with different subsets of the disease. Anti-topoisomerase-I antibody (also known as anti-Scl70) is present in 20%–40% of patients and is strongly associated with the development of lung fibrosis.

Initial studies raised the possibility that viruses may play a role in the aetiology of various autoimmune diseases. A classic study by Maul et al showed that a retroviral protein region with sequence similarity of only six amino acids with topoisomerase-I, could act as an antigen.1 Additionally, some studies suggest that genetic factors may influence T cell autoreactivity to topoisomerase-I. One study identified immunodominant T cell epitopes of topoisomerase-I and found that patients with systemic sclerosis have proliferative responses to a larger number of peptides compared with controls.2 This observation suggests ‘epitope spreading’, a phenomenon that consists of the diversification of the immune response from the initial dominant epitope to other epitopes found on the same or other proteins. Epitope spreading has a crucial role in several autoimmune disease models and there is evidence for continual presentation of antigens during the course of the disease in systemic sclerosis. Topoisomerase-I contains several epitopes recognised by anti-topoisomerase-I antibodies, and especially the epitope aa489-573 has been shown to be an immunodominant site.3

Case presentation

A man in his middle 30s, with muscular dystrophy caused by the telethonin gene c.157C>T mutation diagnosed at the age of 9, autoimmune thyroid disease and gastro-oesophageal reflux, presented with persistent dry cough over the last 2 years. He also mentioned cold-induced Raynaud’s phenomenon on his hands and occasional gastric reflux. Physical examination revealed lung crackles, facial plethora, acrocyanosis of both hands, digital clubbing, proximal interphalangeal arthritis of the third finger on the right hand, dilated capillaries on his nailfolds visible to the naked eye (figure 1A) and pectoral and limb muscles atrophy with winged scapula. He had a myopathic gait and Gowers’ sign was present.

Investigations

His serum creatine kinase (CK) levels were elevated (1189 U/L). Additional workup showed positive antinuclear antibodies (1:640)—speckled pattern, anti-topoisomerase-I, anti-Ro/SSA and anti-Th/To. Nailfold videocapillaroscopy revealed an ‘active’ scleroderma pattern (figure 1B), and plain radiographs of the hands showed evidence of osteoarthritis but no signs of calcinosis. High-resolution thoracic CT revealed fibrotic interstitial disease with ground glass opacities (figure 2). Pulmonary function tests exhibited severe restrictive lung disease, reduced diffusing capacity for carbon monoxide, and arterial blood gas analysis revealed hypoxaemia and hypercapnia at rest. Echocardiography was normal without indirect signs of pulmonary hypertension. Oesophageal manometry showed ineffective motility.

Twenty-five years after the initial manifestation of muscle dystrophy, our patient developed systemic sclerosis with positive anti-topoisomerase-I antibodies and severe pulmonary fibrosis. We found no previous studies showing an association between muscular dystrophy and systemic sclerosis.

Mutant telethonin (c.157C>T) causes a premature stop codon that leads to a truncated protein at Q53.4 The penetrance of clinical muscular dystrophy in this mutation was not yet reported, but all the published cases in literature regarding this specific mutation describe it as pathogenic, causing limb-girdle muscular dystrophy (LGMD), dilated cardiomyopathy and familiar hypertrophic cardiomiopahty. Also, our patient had a negative myositis panel, no dermatological manifestations of dermatomyositis and CK levels were <10-fold above the upper limit of normal, which makes it less probable that a concurrent immune-mediated inflammatory myopathy might be relevant to the muscular dystrophy presentation of this patient. To investigate a possible explanation for the development of systemic sclerosis in our patient, we started by comparing the amino acid sequence of this truncated protein with the aa489-573 immunodominant site of topoisomerase-I (figure 3A). We performed sequence analysis using LALIGN tool5 to perform pairwise protein comparison. Surprisingly, within the immunodominant site of topoisomerase-I, we found a sequence of 11 amino acids which showed significant homology between both proteins, including a region where five out of six amino acids are either the same, or electrically equivalent, as shown in figure 3A where both amino acid sequences are compared, and also in the illustration showing both sequences’ representation, paired (figure 3B). Interestingly, we generated a 3D structure model using automated protein structure homology-modelling server SWISS-MODEL6 and based on the X-ray crystallographic structure of the titin-binding domain of telethonin (Protein data bank code: 1ya57), which predicts that the truncation of mutant telethonin disrupts the secondary structure of a β-hairpin motif and exposes this amino acid sequence (figure 3C). We, therefore, postulate that the exposure of an immunogenic site on the truncated form of telethonin could trigger an immune response. To formally prove this hypothesis, it would be necessary to synthesise the 11-amino acid peptide and test its immunoreactivity against anti-topoisomerase-I antibodies, but this is beyond the scope of this report.

Treatment

After the diagnosis of systemic sclerosis, our patient started immunosuppressive therapy with hydroxychloroquine and mycophenolate mofetil with mild clinical improvement. He later initiated treatment with antifibrotic agent nintedanib.

Outcome and follow-up

One year after initiating nintedanib, there was a gradual clinical improvement concerning the dry cough. No signs of dyspnoea developed during this period of treatment. The patient also started a rehabilitation programme which included physical therapy and respiratory kinesiotherapy, with overall respiratory symptom improvement, despite maintaining episodes of dry cough. There was no significant improvement in pulmonary function tests but no deterioration was observed. No pulmonary hypertension has developed.