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Systemic sclerosis (SSc) is a connective tissue disease characterised by skin and visceral organ involvement.1,2 The cause of SSc is still unknown; it has been suggested that one or more factors may be responsible for the disease through a complex pathogenic mechanism.3,4 Immune system dysregulation, collagen hyperproduction by altered fibroblasts, and vascular alterations can variably contribute to SSc development. The presence of Raynaud's phenomenon and diffuse microangiopathy suggests that endothelial injury may represent the first step in the pathogenesis of the disease.4 Numerous genetic, environmental, and infectious agents have been proposed as possible triggering factors.3–6 Among these, human cytomegalovirus (HCMV) infection may play a part in the pathogenesis of the SSc owing to its ability to infect both endothelial and monocyte/macrophage cells.6,7
Here, we describe the case of a 33 year old women developing SSc after a recent episode of acute HCMV infection. Her past medical history was unremarkable; of interest, the patient's mother was affected by systemic lupus erythematosus. Two months after an accidental exposure to sewer waters, the patient had a high fever, malaise, myalgias, lymphadenopathy, and a cutaneous rash. In February 2000 she was admitted to another hospital where she completely recovered within three weeks. At that time serum anti-HCMV antibodies of IgM isotype (Abbott Laboratories) were detected. Two months later, the patient developed weakness, polyarthralgias, Raynaud's phenomenon, and ischaemic lesions to the fingertips. In June 2000 she was first referred to our rheumatology unit, where a diagnosis of SSc was made based on the following findings: cutaneous hypermelanosis, sclerodactyly, puffy hands with pitting scars to fingertips, oesophageal dysmotility, mild interstitial lung disease, a scleroderma pattern at nailfold capillaroscopic examination (enlargement and loss of capillaries), and circulating antinuclear antibodies with antinucleolar pattern at indirect immunofluorescence on Hep2 cells (table 1). In addition, SSc was classified as the limited cutaneous variant according to currently accepted criteria.1 Virological investigations confirmed the presence of serum anti-HCMV antibodies, IgM type, followed one month later by seroconversion (anti-HCMV, IgG type). Moreover, the presence of HCMV RNA was demonstrated by an in situ hybridisation technique in the skin biopsy specimen, showing nuclear and cytoplasmic endothelial cell and eccrine ductular cell localisation (fig 1).
During the two year follow up the patient's clinical condition progressively worsened because of recurrent skin ulcers at the fingers, partly responsive to prostacyclin analogue (iloprost) infusion treatment.
This is the first observation of SSc following recent HCMV infection. The appearance of SSc shortly after an acute episode of viral infection suggests a possible triggering role for HCMV. The presence of HCMV sequences within endothelial and epithelial cells may be responsible for viral lytic effect, directly and/or through HCMV driven autoimmune reaction.6–9 Circulating IgG autoantibodies which can bind the HCMV late protein UL94 and induce apoptosis of endothelial cells have been recently demonstrated in patients with SSc.10 The HCMV seems to be able to trigger a host antiviral response responsible for specific autoantibodies cross reacting with endothelial autoantigens.10 This molecular mimicry mechanism had been also suggested for different disorders characterised by diffuse vascular disease, including SSc.7 The HCMV driven autoimmunity may be crucial in the cascade of events leading to typical SSc alterations—namely, endothelial cell injury and consequent up regulation of fibrogenic cytokines. A possible contribution of other cofactors,1–4 can also be taken in account; among these, the familial predisposition to autoimmune disorders, as seen in our patient.
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