Cryoglobulinemia

Cryoglobulinemia can be associated with an immune-complex–mediated, small-vessel vasculitis.

Chronic infection with hepatitis C is the most common underlying condition; cryoglobulinemic vasculitis also can occur with other chronic infections (such as subacute bacterial endocarditis, osteomyelitis, HIV, and hepatitis B), with connective tissue diseases (especially Sjögren syndrome), and with lymphoproliferative disorders.

The cryoglobulins associated with vasculitis are cold-precipitable immune complexes consisting of rheumatoid factor and IgG (rheumatoid factor is an autoantibody to the constant region of IgG).

The rheumatoid factor component can be monoclonal (type II cryoglobulins) or polyclonal (type III cryoglobulins).

Type I cryoglobulins are cryoprecipitable monoclonal proteins that lack rheumatoid factor activity; these cause cold-induced hyperviscosity syndromes, not vasculitis, and are associated with B-cell lymphoproliferative diseases.

Clinical Findings

Cryoglobulinemic vasculitis typically manifests as recurrent palpable purpura (predominantly on the lower extremities) and peripheral neuropathy.

A proliferative glomerulonephritis may develop and can manifest as rapidly progressive glomerulonephritis.

Abnormal liver biochemical tests, abdominal pain, digital gangrene, and pulmonary disease may also occur.

The diagnosis is based on a compatible clinical picture and a positive serum test for cryoglobulins.

The presence of a disproportionately low C4 level or rheumatoid factor or both can be diagnostic clues to the presence of cryoglobulinemia.

Treatment

Antiviral regimens are first-line therapy for hepatitis C–associated cryoglobulinemic vasculitis that is neither life- nor organ-threatening.

Interferon-free direct-acting antiviral agents are preferred because of the excellent long-term response in clinical trials.

Patients with severe cryoglobulinemic vasculitis (eg, extensive digital gangrene, extensive neuropathy, and rapidly progressive glomerulonephritis) and hepatitis C should receive immunosuppressive therapy with corticosteroids and either rituximab or cyclophosphamide plus antiviral treatment.

Plasma exchange may provide additional benefit in selected cases.

Relapse of vasculitis with cryoglobulinemia following clearing of hepatitis C infection has been reported in a small percentage of patients.