Cryoglobulinemic vasculitis

Definitions

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• Cryoglobulins: a group of immunoglobulins (IgM, IgG, IgA) that precipitate in vitro at cold (< 37°C).
• Cryoglobulinemia: a condition characterized by elevated serum cryoglobulin concentration
• Cryoglobulinemic vasculitis: a vasculitis caused by the deposition of temperature-dependent IgG and IgM immunoglobulins/immune complexes (i.e., cryoglobulins), with subsequent inflammation of surrounding tissue

Etiology

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• Strong association with Hepatitis C Virus (HCV) (>90% of mixed cryoglobulinemia cases).
• Other triggers: HIV, HBV, autoimmune diseases (Sjögren syndrome, SLE), lymphoproliferative disorders (Waldenström macroglobulinemia, MM).

Clinical features

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• Meltzer Triad: Palpable purpura, arthralgias, and weakness (present in ~30% of pts).
• Cutaneous: Palpable purpura (predominantly on lower extremities), livedo reticularis, Raynaud phenomenon, digital ulcers/necrosis.
• Renal: Membranoproliferative glomerulonephritis (MPGN) in 50% of pts (presents with hematuria, proteinuria, HTN, and progressive AKI). c
• Neurologic: Painful, symmetric sensory or sensorimotor peripheral neuropathy (paresthesias, burning sensation).
• Systemic: Fatigue, low-grade fever, hepatosplenomegaly.

Diagnostics

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• Initial Labs: Serum cryoglobulins, positive Rheumatoid Factor (RF) (IgM directed against IgG), elevated ESR/CRP.
  • Complement levels: Characteristically extremely low C4 (C3 is often normal or only mildly decreased).
  • High-Yield Lab Note: Blood sample must be kept warm at 37°C during collection, transport, and processing to prevent premature cryoglobulin precipitation (which causes false-negative results).
• Confirmatory/Gold Standard: Biopsy of involved organ.
  • Skin: Leukocytoclastic vasculitis.
  • Kidney: MPGN with subendothelial immune complex deposits (“wire loops”) and intraluminal cryoglobulin thrombi.
• Secondary Screening: HCV RNA, HBV serologies, HIV testing, SPEP/UPEP to rule out underlying monoclonal gammopathies.