Systemic sclerosis and cryoglobulinemia: Our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature

Objective

Systemic sclerosis (SSc) is an immune-mediated disorder characterized by multiple organ fibrotic alterations and diffuse microangiopathy. The SSc can be associated with other connective tissue diseases and less frequently with systemic vasculitides, including cryoglobulinemic vasculitis (CV). The aim of the present study was to investigate the prevalence of CV in a large series of SSc patients.

Methods

The presence of serum cryoglobulins was detected in 246 SSc patients (24 M and 222 F, age 61 ± 13.5 SD years, disease duration 9.3 ± 6.7 SD years); the observed clinico-serological findings, in particular the presence of SSc–CV overlapping syndrome, were carefully analyzed and compared with previous data reported in the literature.

Results

The presence of circulating cryoglobulins was found in 7/246 (2.8%) of SSc patients; namely, 2 subjects only trace amounts of cryoglobulins, while 5 (2%) showed mixed cryoglobulinemia (type II, IgG-IgMk), low C4, rheumatoid factor seropositivity, and hepatitis C virus infection. Among SSc patients with serum mixed cryoglobulins, 4 (1.6%) developed a clinically overt CV, while the other one was totally asymptomatic with regard to typical vasculitic manifestations. Patients with SSc–CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. In all cases, the diagnosis of SSc preceded the clinical onset of CV, from 3 to 17 years. The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc–CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the knee amputation, the other three subjects died because of severe heart failure, and in two cases because of untreatable pulmonary hypertension.In the literature, the prevalence of mixed cryoglobulinemia in scleroderma patients is quite rare (range 0.3–2%); while, the association of SSc with clinically overt CV is only anecdotally described, always in the absence of HCV infection.

Conclusion

The SSc–CV overlapping syndrome described here is characterized by markedly severe vascular manifestations responsible for very poor prognosis; these peculiar clinical manifestations suggest a synergic activity of typical scleroderma microangiopathy and cryoglobulinemic vasculitis.