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Cryoglobulinemic vasculitis is a type of small-vessel vasculitis characterized by the deposition of cryoglobulins. It is most commonly caused by type II and III cryoglobulinemia. Patients typically present with fatigue and other constitutional symptoms, along with palpable purpura, arthralgia, myalgias, and glomerulonephritis. Diagnosis is based on clinical features and laboratory findings, e.g., cryoglobulinemia; additional studies should be requested based on suspected organ involvement (e.g., kidney biopsy) and the underlying etiology (e.g., hepatitis C diagnostics). Management includes specific treatment of the underlying etiology (e.g., direct-acting antivirals for HCV infection), in addition to management of cryoglobulinemic vasculitis, which usually involves immunosuppressive agents (e.g., glucocorticoids plus rituximab) and is guided by disease severity. Plasmapheresis may also be considered in patients with life-threatening disease.
- 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
Type II and III cryoglobulinemia (i.e., mixed cryoglobulinemia): 90% of cases
- Viral infection: most common etiology (HCV infection in 70–90% of cases) 
- 10% of cases (e.g., in multiple myeloma, CLL) :
Cryoglobulinemic vasculitis is more commonly associated with type II and III cryoglobulinemia than with type I cryoglobulinemia. Type I cryoglobulinemia typically manifests as a hyperviscosity syndrome. 
- Nonspecific systemic symptoms: fatigue; , malaise, myalgia, arthralgia 
- Cutaneous lesions (nearly 100% of cases): palpable purpura, ulceration, necrosis
- Vasomotor symptoms: Raynaud phenomenon, acrocyanosis
- Glomerulonephritis (severe cases or late complication)
General principles 
- Diagnosis is based on the presence of typical clinical features and laboratory findings.
- Additional diagnostics (e.g., CT scan) should be requested based on the suspected underlying cause. ,
- A biopsy may be required to confirm organ involvement.
- Urinalysis: microhematuria, proteinuria, erythrocyte casts
Cutaneous or renal biopsy
A biopsy should be performed in patients with suspected renal involvement.
General principles 
- Consult rheumatology for all patients.
- Start specific therapy for the underlying etiology (e.g., direct-acting antivirals for hepatitis C infection).
- Management is guided by disease severity.
Patients with rapidly progressive glomerulonephritis, CNS involvement, GI ischemia, or alveolar hemorrhage should receive prompt treatment with a combination of glucocorticoid pulses, rituximab, and plasmapheresis. 
|Recommended pharmacotherapy for cryoglobulinemia based on disease severity |
|Disease severity|| |
|Moderate to severe disease|
- Requires urgent initiation for patients with severe or life-threatening disease
- Should always be given in combination with immunosuppressants (e.g., high-dose glucocorticoids plus either cyclophosphamide or rituximab)
- Rate: three exchanges per week for 2–3 weeks
Management of the underlying cause 
- Hepatitis C infection
- Hepatitis B and HIV infection: concomitant antiviral therapy and immunosuppressive therapy
- Lymphoproliferative disorders: chemotherapy
- Monitor for .
- Consider .