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.
- A condition characterized by elevated serum cryoglobulin concentration
- Further classified as type I, II, or III based on immunoglobulin composition and clonality (i.e., IgG, IgM, or, rarely, IgA) 
- 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
Cryoglobulinemia can cause cryoglobulinemic vasculitis, however, many patients are asymptomatic. 
Type II and III cryoglobulinemia (i.e., mixed cryoglobulinemia): 90% of cases
Viral infection: most common etiology (HCV infection in 70–90% of cases) 
- Formation of hepatitis C IgG and IgM rheumatoid factor → immune complex formation with hepatitis C antigen → complement activation and inflammation of blood vessels
- Autoimmune diseases (e.g., Sjogren syndrome, SLE, rheumatoid arthritis)
- Lymphoproliferative disorders
- Idiopathic (i.e., essential mixed cryoglobulinemia)
- Viral infection: most common etiology (HCV infection in 70–90% of cases) 
- Type I cryoglobulinemia: 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. 
Cryoglobulinemia is caused by Cold-precipitable immunoglobulins and is commonly associated with the hepatitis C virus.
Most patients with cryoglobulinemia are asymptomatic; the prevalence of symptomatic cases varies widely (2–50%) across different populations. 
- 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)
The triad of arthralgia, palpable purpura, and fatigue is seen in ∼ 80% of patients with cryoglobulinemic vasculitis. 
General principles 
- Diagnosis is based on the presence of typical clinical features and laboratory findings.
- Additional diagnostics (e.g., ANAs, CT scan) should be requested based on the suspected underlying cause.
- A biopsy may be required to confirm organ involvement.
- Cryoglobulinemia (type II and/or III; rarely type I) 
- Rheumatoid factor: elevated in almost 100% of cases 
- ↓ C4 (90% of cases)
- Hepatitis C diagnostics
- Urinalysis: microhematuria, proteinuria, erythrocyte casts
Cutaneous or renal biopsy
- Renal biopsy: required in patients with suspected renal involvement
- Skin biopsy: may be helpful in patients with atypical presentations (but not necessary to make the diagnosis)
- Inflammatory vascular changes (e.g., leukocytoclastic vasculitis )
- Membranoproliferative glomerulonephritis type I (70% of patients)
- Cryoglobulin deposits (; i.e., C3, IgG and IgM complexes) and monocyte infiltration may be detected in glomeruli.
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.
- Mild disease: symptomatic treatment; consider immunosuppressants
- Moderate to severe disease: immunosuppressants
- Life-threatening disease: immunosuppressants PLUS plasmapheresis
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|| |
|Mild disease|| || |
|Moderate to severe disease|| || |
|Life-threatening 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
Patients receiving plasmapheresis to remove circulating cryoglobulins still always require treatment with immunosuppresants to prevent formation of new cryoglobulins.
Management of the underlying cause 
Hepatitis C infection
- Immunosuppressive therapy (e.g., glucocorticoids plus rituximab or cyclophosphamide) is required before antiviral therapy in patients with severe disease.
- The presence of cryoglobulinemia does not affect the choice of antiviral therapy.
- Hepatitis B and HIV infection: concomitant antiviral therapy and immunosuppressive therapy
- Lymphoproliferative disorders: chemotherapy