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Cryoglobulinemia is caused by abnormal Cryoglobulins

Cryo=cold; globulin=clot; emia=blood.

Cryoglobulins are immunoglobulins or immunoglobulin-containing complexes that spontaneously precipitate from serum and plasma at low temperatures and become soluble again with rewarming. Cryoprecipitation of human serum components was first described by Wintrobe and Buell in 1933. The term “cryoglobulin” was introduced by Lerner et al in 1947.

Classification of cryoglobulins:

Brouet et al studied 86 patients with cryoglobulinemia and, based on those observations, published a classification system in 1974 that is still in use today:

Type I: composed of a single monoclonal immunoglobulin (Ig), with IgM being the most common. Serum levels of the cryoglobulin are typically very high (5 to 30 mg/mL, cryocrit >5%) and precipitation occurs rapidly with cooling (usually <24 hours).

Type II: “mixed” cryoglobulins (MC) composed of a monoclonal Ig (typically IgM) that acts as an antibody (e.g., rheumatoid factor) against polyclonal Ig (typically IgG). Serum levels are usually intermediate (1 to 10 mg/mL, cryocrit 1% to 5%), therefore precipitation may take a few days.

Type III: mixed cryoglobulins similar to Type II, but with polyclonal Ig with rheumatoid factor activity directed against polyclonal Ig. They are usually present in small quantities (0.1 to 1 mg/mL, cryocrit <1%) and precipitate slowly (up to 7 days), so are more difficult to detect.

Type II–III: an unusual variant composed of oligoclonal IgM and faint polyclonal immunoglobulins. It is thought to represent a transition from polyclonal (type III) to monoclonal (type II) mixed cryoglobulinemia as clonal expansion of B cells progresses.

Overall incidence of each cryoglobulin type:

Type I: 10% to 15%,

Type II: 50% to 60%,

Type III: 25% to 30%,

Type II–III: 10%.

“Mixed” account for 85% to 90% of all cases.

Underlying disorders are associated with type I cryoglobulinemia:

Lymphoproliferative disorders that are associated with monoclonal immunoglobulin production such as multiple myeloma, Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia, and B cell lymphomas.

Conditions associated with mixed cryoglobulinemias:

Hepatitis C (HCV) infection is the most common, followed by autoimmune/autoinflammatory diseases and lymphoproliferative processes. Only a small fraction of cases (<5%) are truly “essential” cryoglobulinemia (i.e., those with no definable underlying illness).

Other infections associated with mixed cryoglobulinemia:

After HCV, HIV is the most common. Many of these cases are associated with the transient appearance of type III cryoglobulins without associated disease. These include hepatitis B, Epstein–Barr virus, cytomegalovirus, hepatitis A, Coxiella burnetii (Q fever), Parvovirus B19, poststreptococcal nephritis, subacute bacterial endocarditis, tuberculosis, leprosy, brucellosis, coccidioidomycosis, parasitic infections, and others.

--> a patient with fever, valvular heart disease, and negative cultures in the setting of MC must be evaluated for Q fever.

Common clinical manifestations:

Hyperviscosity syndrome (bleeding, vision changes, neurologic symptoms, etc.) is the most common manifestation in type I. In MC, cutaneous manifestations are the most common, with arthralgias and neuropathy being other frequent findings.


55% to 100%

Raynaud’s phenomenon

5% to 35%


45% to 100%


10% to 40%


70% to 100%


30% to 50%

Meltzer’s triad*

40% to 80%


2% to 6%


20% to 80%






10% to 15%



Endocrine (diabetes mellitus, hypothyroid, erectile dysfunction)

Treatment options for mixed cryoglobulinemic vasculitis:

Removal of the antigenic stimulus is the primary goal.

Glucocorticoids: high-dose steroids should be used in patients with severe manifestations and short courses of low to intermediate doses can be used during flares.

Plasma exchange: although there is no controlled data supporting its use, expert opinion suggests a role in severe, life-threatening disease. It is the treatment of choice for hyperviscosity syndrome and diffuse alveolar hemorrhage.

Cyclophosphamide: is frequently employed in combination with plasma exchange to treat severe disease, and it can be considered in this setting. It is not recommended for use as monotherapy.

Colchicine: may have favorable effects on pain, weakness, purpura, and leg ulcers.

Low antigen diet: can result in substantial improvement of purpura and pain within 4 to 8 weeks. It also has a favorable effect on laboratory abnormalities. It should be considered in all patients.

Antivirals and rituximab: Antiviral (AV) agents should be considered in all patients with hepatitis C associated MC. They have demonstrated response rates of 30% to 80% in MC, but their use may be limited due to contraindications, side effects (interferon-α may exacerbate vasculitis manifestations), and slow onset of action. Rituximab (RTX) has shown great promise in treating mixed cryoglobulinemic vasculitis and should be considered in all patients with moderate-to-severe disease.






Johns Hopkins Vasculitis Center

Vasculitis Foundation

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