Cryoglobulinemia — One Name for Two Diseases

This comprehensive review redefines cryoglobulinemia as two distinct clinical entities: type I, a hyperviscosity-driven vasculopathy linked to monoclonal gammopathies; and types II/III (mixed), an immune-complex small-vessel vasculitis often associated with chronic infections or autoimmune conditions. Diagnostic advances especially in cryoglobulin detection and immunophenotyping have improved disease classification. Mixed forms, historically tied to hepatitis C virus, now occur increasingly with autoimmune diseases like Sjögren’s and lupus. Clinical manifestations differ by type, with vascular purpura and neuropathy prevalent in mixed forms, and thromboses and ischemia in type I. Treatment emphasizes targeting the underlying condition, with direct-acting antivirals for HCV, B-cell depletion in autoimmune cases, and clone-directed therapy (e.g., rituximab, bortezomib, anti-CD38 agents) for monoclonal disease. Novel approaches include interleukin-2, belimumab, and CD38-directed trials. The authors call for translational research to develop targeted therapies and improve prognosis in noninfectious and hematologic variants.

This comprehensive review redefines cryoglobulinemia as two distinct clinical entities: type I, a hyperviscosity-driven vasculopathy linked to monoclonal gammopathies; and types II/III (mixed), an immune-complex small-vessel vasculitis often associated with chronic infections or autoimmune conditions. Diagnostic advances especially in cryoglobulin detection and immunophenotyping have improved disease classification. Mixed forms, historically tied to hepatitis C virus, now occur increasingly with autoimmune diseases like Sjögren’s and lupus. Clinical manifestations differ by type, with vascular purpura and neuropathy prevalent in mixed forms, and thromboses and ischemia in type I. Treatment emphasizes targeting the underlying condition, with direct-acting antivirals for HCV, B-cell depletion in autoimmune cases, and clone-directed therapy (e.g., rituximab, bortezomib, anti-CD38 agents) for monoclonal disease. Novel approaches include interleukin-2, belimumab, and CD38-directed trials. The authors call for translational research to develop targeted therapies and improve prognosis in noninfectious and hematologic variants.