Chapter 356.9: Cryoglobulinemic Vasculitis

DEFINITION OF CRYOGLOBULINEMIC VASCULITIS

Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins. Cryoglobulinemia may be associated with a systemic vasculitis characterized by palpable purpura, arthralgias, weakness, neuropathy, and glomerulonephritis. Although this can be observed in association with a variety of underlying disorders including multiple myeloma, lymphoproliferative disorders, connective tissue diseases, infection, and liver disease, in many instances it appears to be idiopathic. Because of the apparent absence of an underlying disease and the presence of cryoprecipitate containing oligoclonal/polyclonal immunoglobulins, this entity was referred to as essential mixed cryoglobulinemia. Since the discovery of hepatitis C, it has been established that the vast majority of patients who were considered to have essential mixed cryoglobulinemia have cryoglobulinemic vasculitis related to hepatitis C infection.

INCIDENCE AND PREVALENCE OF CRYOGLOBULINEMIC VASCULITIS

The incidence of cryoglobulinemic vasculitis has not been established. It has been estimated, however, that 5% of patients with chronic hepatitis C will develop cryoglobulinemic vasculitis.

PATHOLOGY AND PATHOGENESIS OF CRYOGLOBULINEMIC VASCULITIS

Skin biopsies in cryoglobulinemic vasculitis reveal an inflammatory infiltrate surrounding and involving blood vessel walls, with fibrinoid necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition of immunoglobulin and complement is common. Abnormalities of uninvolved skin including basement membrane alterations and deposits in vessel walls may be found. Membranoproliferative glomerulonephritis is responsible for 80% of all renal lesions in cryoglobulinemic vasculitis.

The association between hepatitis C and cryoglobulinemic vasculitis has been supported by the high frequency of documented hepatitis C infection, the presence of hepatitis C RNA and anti–hepatitis C antibodies in serum cryoprecipitates, evidence of hepatitis C antigens in vasculitic skin lesions, and the effectiveness of antiviral therapy (see below). Current evidence suggests that in the majority of cases, cryoglobulinemic vasculitis occurs when an aberrant immune response to hepatitis C infection leads to the formation of immune complexes consisting of hepatitis C antigens, polyclonal hepatitis C–specific IgG, and monoclonal IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in cryoglobulinemic vasculitis.

CLINICAL AND LABORATORY MANIFESATIONS OF CRYOGLOBULINEMIC VASCULITIS

The most common clinical manifestations of cryoglobulinemic vasculitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. Renal disease develops in 10–30% of patients. Life-threatening rapidly progressive glomerulonephritis or vasculitis of the CNS, gastrointestinal tract, or heart occurs infrequently.

The presence of circulating cryoprecipitates is the fundamental finding in cryoglobulinemic vasculitis. Rheumatoid factor is almost always found and may be a useful clue to the disease when cryoglobulins are not detected. Hypocomplementemia occurs in 90% of patients. An elevated ESR and anemia occur frequently. Evidence for hepatitis C infection must be sought in all patients by testing for hepatitis C antibodies and hepatitis C RNA.

TREATMENT OF CRYOGLOBULINEMIC VASCULITIS