Mixed Cryoglobulinemia

Mixed cryoglobulinaemia (type II and III) is a small vessel immune complex vasculitis caused by cold precipitable immunoglobulins containing polyclonal IgG with monoclonal (type II) or polyclonal (type III) IgM rheumatoid factor.

• Hepatitis C is the cause in 80 to 90% of type II. Others: hepatitis B, HIV, lymphoproliferative disease (B cell lymphoma, CLL), connective tissue disease (Sjögren, SLE), essential (idiopathic).

• Incidence has fallen with antiviral treatment of hepatitis C.

• Organ involvement: skin, joints, peripheral nerves, kidneys (membranoproliferative glomerulonephritis).

• Meltzer triad: palpable purpura (lower limbs), arthralgia, weakness.

• Peripheral neuropathy (sensory, mononeuritis multiplex), Raynaud, livedo, leg ulcers, cold-induced acrocyanosis.

• Glomerulonephritis: haematuria, proteinuria, nephrotic syndrome, hypertension.

• Sicca, hepatic disease, lymphoproliferation.

• Cryoglobulins (collect and process blood at 37 C, observe for 7 days), cryocrit, rheumatoid factor (high), low C4 with relatively normal C3, low CH50.

• Hepatitis C RNA and genotype, hepatitis B, HIV, liver tests, elastography.

• Serum protein electrophoresis and immunofixation, flow cytometry or marrow for lymphoproliferative disorder.

• Skin biopsy (leukocytoclastic vasculitis), renal biopsy (membranoproliferative GN with intraluminal thrombi), nerve conduction studies.

• Urinalysis, creatinine.

• Hepatitis C associated: direct-acting antivirals (sofosbuvir/velpatasvir 400/100 mg daily for 12 weeks) lead to clinical remission in the majority.

• Severe or organ threatening disease (glomerulonephritis, neuropathy, ulcers, widespread vasculitis): rituximab 375 mg/m2 weekly for 4 doses (or 1 g on days 1 and 15) with methylprednisolone 500 to 1000 mg IV for 3 days then prednisolone 0.5 to 1 mg/kg; antivirals together or sequentially.

• Plasmapheresis for rapidly progressive disease or hyperviscosity (3 to 4 L exchanges, 3 times weekly for 2 to 3 weeks).

• Cyclophosphamide 2 mg/kg is an alternative if rituximab unavailable.

• Mild disease: NSAIDs, low dose prednisolone, colchicine 0.5 mg twice daily, avoid cold exposure.

• Non-HCV causes: treat the underlying disease (B cell lymphoma chemotherapy, hepatitis B antivirals such as tenofovir 245 mg daily, connective tissue disease immunosuppression).

• Monitor cryocrit, complements, creatinine, proteinuria; monitor for lymphoma.