Overlapping Syndrome of Systemic Scleroderma and Cryoglobulinemic Vasculitis

A 58-year-old woman with a 10-year history of Raynaud phenomenon presented with moist cough, and a 2-month progression of general edema and relapsing digital ulcer of the toes. Physical examination revealed fine crepitations in the lungs, sclerodactyly with digital ulceration, pretibial edema, and extremities with eczema-like eruptions (Figure 1B ). Her C-reactive protein and serum creatinine levels were 1.5 mg/dL (reference: <0.3 mg/dL) and 1.0 mg/dL (0.4-0.8), respectively. Hemoglobin, platelet, CH50, C3, and C4 levels were low (8.4 g/dL [10.8-14.9], 10.9 × 10⁴/μL [15.0-36.1], <10.0 U/mL [23-46], 30.7 mg/dL [65-135], and 3.1 mg/dL [13-35], respectively). Urinalysis revealed microhematuria; 185 red blood cells per high power field (<5) and proteinuria, 565.2 mg/gCr (<300). Anti-centromere and anti-mitochondria M2 antibodies were positive (>240.0 U/mL [<7] and 84.7 index [<7], respectively). Rheumatoid factor, SS-A antibody, SS-B antibody, MPO-ANCA, PR3-ANCA, and hepatitis C virus were all negative. Mixed cryoglobulinemia type 3 involving IgG and IgM was detected. The brain natriuretic peptide level was 309.4 pg/mL (<18.4). The estimated right ventricular systolic pressure on transthoracic echocardiography was 39.7 mm Hg. Chest computed tomography showed massive pericardial and pleural effusion (Figure 1A). Skin biopsy of the eczema-like eruption revealed leukocytoclastic vasculitis (Figure 1C). Renal biopsy revealed membranous proliferative glomerulonephritis (Figure 1D-1G), with positive immunofluorescence for IgG, IgM, and C3 in the paramesangial and basement membranes, compatible with cryoglobulinemic glomerulonephritis. The patient was diagnosed with cryoglobulinemic vasculitis, manifesting as membranous proliferative glomerulonephritis, with eruptions, endocarditis, and pulmonary arterial hypertension, caused by limited cutaneous systemic sclerosis-associated mixed cryoglobulinemia. Intravenous methyl prednisolone 1 g/d was administered for 3 days, followed by oral prednisolone 40 mg/d for 1 month. After 1 month, her symptoms and laboratory data improved. Prednisolone was tapered to 5 mg/d, and she has been followed without relapse for 5 years.

Systemic sclerosis is a connective tissue disease characterized by varying skin fibrosis and visceral organ involvement. Clinical complications, including Raynaud phenomenon, digital ulcers, renal crisis, and pulmonary arterial hypertension, are attributable to endothelial dysfunction and diffuse microangiopathy. Vasculopathy of small vessels is one of the first and more severe systemic sclerosis manifestations; overt vascular inflammation is less frequently observed. A typical vasculitic process with inflammatory infiltrates involving the blood vessels has been occasionally reported in patients with systemic sclerosis¹; however, systemic vasculitis, particularly with mixed cryoglobulinemia, is rare.^2, 3 Overlapping systemic sclerosis-cryoglobulinemic vasculitis syndrome has been proposed to be caused by mixed cryoglobulinemia.² Cryoglobulinemic vasculitis and scleroderma often manifest as skin ulcers. Conversely, pulmonary hypertension, a more serious systemic sclerosis complication (prevalence rate; 10–15%), is rarely noted in mixed cryoglobulinemia syndrome.⁴ Manifestation as limited cutaneous systemic sclerosis complicated by nonhealing skin ulcers, pulmonary arterial hypertension, and serum anticentromere antibodies was consistent with the diagnosis of overlapping systemic sclerosis-cryoglobulinemic vasculitis syndrome. Moreover, there was no hepatitis C virus infection, and cryoglobulinemic glomerulonephritis caused by mixed cryoglobulinemia type 3 was detected; two similar cases have been reported previously.³

We demonstrate the clinical features of overlapping systemic sclerosis-cryoglobulinemic vasculitis syndrome associated with severe vasculitis in limited cutaneous systemic sclerosis, which was not attributable to hepatitis C virus infection. Cryoglobulinemia is rarely considered as a differential diagnosis. Moreover, sample processing for its detection requires special procedures, such as keeping blood samples warm; therefore, its incidence may be underestimated because of the low detection rate. We recommend that clinicians consider the possibility of vasculitis when assessing digital ulceration in systemic sclerosis.

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-Taro Horino, MD, PhD^a, Kazu Hamada-Ode, MD, PhD^a, Osamu Ichii, DVM, PhD^b, Yoshio Terada, MD, PhD^a

This article originally appeared in the June 2019 issue of The American Journal of Medicine.