Updated: May 25, 2021
Author: Colin C Edgerton, MD; Chief Editor: Herbert S Diamond, MD 


Practice Essentials

Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. Several types of cryoglobulins have been identified, and the potential clinical manifestations vary by cryoglobulin type.[1, 2]

Cryoglobulinemia is characterized by the presence of cryoglobulins in the serum. This may result in a clinical syndrome of systemic inflammation (most commonly affecting the kidneys and skin) caused by cryoglobulin-containing immune complexes.

Cryoglobulinemia may be classified based on cryoglobulin composition with the Brouet classification, which is as follows[3] :

  • Type I cryoglobulinemia, or simple cryoglobulinemia, is the result of a monoclonal immunoglobulin, usually immunoglobulin M (IgM) or, less frequently, immunoglobulin G (IgG), immunoglobulin A (IgA), or light chains.

  • Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. These RFs form complexes with the fragment, crystallizable (Fc) portion of polyclonal IgG. The actual RF may be monoclonal (in type II cryoglobulinemia) or polyclonal (in type III cryoglobulinemia) immunoglobulin. Types II and III cryoglobulinemia represent 80% of all cryoglobulins.

Cryoglobulinemia may also be classified based on the association of the syndrome with an underlying disease. Cryoglobulinemia without an associated disease has been known as essential, or idiopathic, cryoglobulinemia. However, the discovery of a close association between hepatitis C virus (HCV) and mixed cryoglobulinemia has cast doubt on the existence of essential, or idiopathic, cryoglobulinemia.[4]  Cryoglobulinemia associated with a particular disease (lymphoproliferative disorder, autoimmune disease, infectious disease) is known as secondary cryoglobulinemia.

In a French study of 36 patients with type I cryoglobulinemia, skin or vasomotor symptoms were present in 75%; nephropathy in 30%; and neuropathy in 47%. The underlying B cell disease was a nonmalignant monoclonal gammopathy in 36% and hematologic malignancy in 64%.Treatments included fludarabine and rituximab-based regimens. Five-year survival was 82%.[5]

In another study, of 64 patients with type I cryoglobulinemia vasculitis, Terrier et al identified 28 patients with monoclonal gammopathy of unknown significance and 36 with hematologic malignancy. Type I monoclonal cryoglobulinemia vasculitis was characterized by severe cutaneous involvement (necrosis and ulcers) in almost 50% the patients, as well as high serum cryoglobulin levels. Survival rates were 97% at 1 year; 94% at 3 years; 94% at 5 years; and 87% at 10 years. Treatments included alkylating agents, rituximab, thalidomide or lenalinomide, and bortezomib. Clinical response rates ranged from 80-86%.[6]

In a study of patients with type II cryoglobulinemia, peripheral blood mononuclear cells from 18 patients were separated into CD3+ (T cells), CD19+ (B cells), and CD14+ (monocytes) and analyzed for the presence of negative-strand HCV RNA and for HCV nonstructural protein 3 (NS3). Negative-strand HCV RNA was detected in 6 patients, most frequently in B cells (3 patients), followed by T cells (2 patients) and monocytes (2 patients). NS3 protein was also detected in 6 patients: 5 were positive in T cells, 3 in B cells, and 3 in monocytes.[7]


The mechanisms of cryoprecipitation are poorly understood, but several factors have been investigated. The solubility of cryoglobulins has been found to be partially related to the structure of component immunoglobulin heavy and light chains.[8, 9, 10] Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage.[11, 12] The ratio of antibody to antigen in circulating cryoglobulin aggregates or immune complexes affects the rate of clearance from the circulation and the resultant rate and location of tissue deposition.[13]

Some of the sequelae of cryoglobulinemia are thought to be related to immune-complex disease (eg, glomerulonephritis, chronic vasculitis), but not all persons with cryoglobulinemia present with these manifestations. Individuals with cryoglobulinemia may have intravascular cryoglobulin deposits, a reduced level of complement, and complement fragments (C3a, C5a) that act as chemotactic mediators of inflammation; however, the pathophysiologic process of this disease has not been fully explained.

Other sequelae are directly related to cryoprecipitation in vivo, including plugging and thrombosis of small arteries and capillaries in the extremities (gangrene) and glomeruli (acute kidney injury). Circulating large–molecular-weight cryoprotein complexes, even when unprecipitated in vivo, can lead to clinical hyperviscosity syndrome.

Type I cryoglobulins are usually monoclonal IgM and, less frequently, IgG, IgA, or light chains. Type I cryoglobulins rarely have rheumatoid factor (RF) activity and do not activate complement in vitro. This disorder is typically related to an underlying lymphoproliferative disease and, as such, may be clinically indistinguishable from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia.

Type I cryoglobulinemia may result in hyperviscosity due to high levels of circulating monoclonal cryoglobulin, leading to physical obstruction of vessels. Concentrations may reach up to 8 g/L. In addition, nonobstructive damage may be mediated by immune complex deposition and subsequent inflammatory vasculitis.

Types II and III, also known as the mixed cryoglobulinemias, are associated with chronic inflammatory states such as systemic lupus erythematosus (SLE), Sjögren syndrome, and viral infections (particularly HCV). In these disorders, the IgG fraction is always polyclonal with either monoclonal (type II) or polyclonal (type III) IgM (rarely IgA or IgG) with RF activity (ability to bind IgG). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states.[4, 14, 15, 16]

The resultant aggregates and immune complexes are thought to outstrip reticuloendothelial-clearing activity. Tissue damage results from immune complex deposition and complement activation. Of note, in HCV-related disease, HCV-related proteins are thought to play a direct role in pathogenesis and are present in damaged skin, blood vessels, and kidneys.[15, 17, 18, 19] Investgators have reported that a panel of biomarkers, including IgG subclasses, RF, and free light chains (FLC), may be potential biomarkers for the clinical evaluation of HBV-related cryoglobulinemia.[20]


Disease associations vary with the type of cryoglobulinemia, as follows:

  • Type I is observed in lymphoproliferative disorders (eg, multiple myeloma, Waldenström macroglobulinemia).
  • Types II and III are observed in chronic inflammatory diseases such as chronic liver disease, infections (chronic HCV infection), and coexistent connective-tissue diseases (SLE, Sjögren syndrome). Mixed cryoglobulinemia is rarely associated with lymphoproliferative disorders.

Infections associated with cryoglobulinemia include the following:

Other disorders associated with cryoglobulinemia include the following:

Cryoglobulinemia may occur as a familial or idiopathic disorder. Finally, cases have been reported following vaccination (eg, with pneumococcal vaccine).


Cryoglobulins are reported in otherwise healthy individuals, so the true prevalence of the disease is unknown. Overall, cryoglobulinemia is thought to be rare. However, cryoglobulinemia may be underestimated based on the medical literature (perhaps because of the various clinical presentations); Gorevic et al evaluated only 126 cases of cryoglobulinemia from over 18 years in their medical center in New York.[21] The prevalence of essential mixed cryoglobulinemia is reported as approximately 1:100,000.

The reported relative frequencies of the different types of cryoglobulinemia vary. Brouet et al reported the following frequencies[22] :

  • Type I, 25%
  • Type II, 25%
  • Type III, 50%

The prevalence of mixed cryoglobulinemia is related to the endemic presence of HCV infection. Therefore, the prevalence varies from country to country. The incidence of HCV infection in mixed cryoglobulinemia in the Mediterranean Basin is 90%.  

The female-to-male ratio is 3:1. The mean age reported is 42-52 years.


The prognosis in these patients depends on the presence of underlying diseases (eg, lymphoproliferative disorders, hepatitis B or C infection, connective-tissue disease), all of which increase the mortality rate over that of the healthy population and more accurately direct estimates of individual survival. For example, the prognosis in patients with chronic hepatitis C depends on their response to treatment; manifested by their decrease in viral load. Complete or partial remission of the manifestations of mixed cryoglobulinemic vasculitis, with high, sustained viral response rates, have been reported in more than 80% of patients with chronic HCV infection taking direct-acting viral agents.[23]

The overall prognosis is worse in persons with concomitant renal disease, lymphoproliferative disease, or plasma cell disorders. Mean survival is approximately 50% at 10 years after diagnosis.

Morbidity due specifically to cryoglobulinemia may be significant, with infection and cardiovascular disease being major considerations. Hepatic failure may result from chronic viral hepatitis. 

Complications include the following:

  • Stroke, seizure, or coma
  • Blindness
  • Acute myocardial infarction
  • Pericarditis
  • Congestive heart failure
  • Respiratory distress
  • Gastrointestinal hemorrhage
  • Acute kidney injury
  • Severe cutaneous necrosis or gangrene

Kidney disease

Survival rates reported among patients with kidney involvement vary from greater than 60% at 5 years of follow-up to 30% at 7 years of follow-up. The risk of kidney failure appears to be greater in those with HCV-associated disease.[24]  The prognosis of kidney disease in the more common type II cryoglobulinemia varies. Most patients experience a slowly progressive course punctuated by acute exacerbations, with up to one third of patients undergoing some degree of clinical remission. Bryce et al, in a prospective study, found only age (and no laboratory parameters) to be a significant predictor of mortality in type II cryoglobulinemic kidney disease.[25]

Lymphoproliferative disease

Lymphoproliferative disease is more common in individuals with cryoglobulinemia. Patients with mixed cryoglobulinemia may develop benign lymphoid infiltrates in the spleen and bone marrow. Less frequently, some patients develop B-cell non-Hodgkin lymphoma. The reported incidence of malignant lymphoma in mixed cryoglobulinemia varies widely, from less than 10% of patients to as high as 40%, with onset 5-10 years after disease diagnosis.[26, 27, 28]

Patient Education

Inform patients of the symptom complexes that may indicate acute cryoglobulinemia so medical therapy can be sought early to avoid potential organ damage. Patients with less severe disease that manifests primarily as arthralgias and fatigue benefit from understanding the precipitating factor (ie, cold temperatures, trauma). Avoidance and use of NSAIDs may reduce symptoms.




Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given the usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include the following:

  • Acrocyanosis
  • Retinal hemorrhage
  • Severe Raynaud phenomenon with digital ulceration
  • Livedo reticularis
  • Purpura
  • Arterial thrombosis

Specific clinical manifestations associated with types II and III cryoglobulinemia include the following:

  • Joint involvement (usually, arthralgias in the proximal interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles)
  • Fatigue
  • Myalgias
  • Renal immune-complex disease
  • Cutaneous vasculitis
  • Peripheral neuropathy [29]

Meltzer triad (ie, purpura, arthralgia, and weakness) was first described in 1966 by Meltzer and Franklin in cases of essential mixed cryoglobulinemia. This triad is generally seen with types II and III cryoglobulinemia and is seen in up to 25-30% of patients.[30, 31]

Cutaneous manifestations

These manifestations are nearly always present in cryoglobulinemia. Observed lesions have a predilection for dependent areas (particularly the lower extremities) and include erythematous macules and purpuric papules (90-95%), as well as ulcerations (10-25%).[22, 31, 21, 32]

Lesions in nondependent areas are more common in type I cryoglobulinemia (head and mucosa), as are livedo reticularis, Raynaud phenomenon, and ulcerations. Nailfold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.[33] See the image below.

Rash on lower extremities typical of cutaneous sma Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.

Musculoskeletal manifestations

Symptoms such as arthralgias and myalgias are rare in type I cryoglobulinemia and are common in types II and III disease. Frank arthritis and myositis are rare. Arthralgias commonly affect the proximal interphalangeal and metacarpophalangeal joints of the hands, knees, and ankles. Musculoskeletal symptoms are described in more than 70% of persons with cryoglobulinemia.[34, 35, 31]

Renal manifestations

Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always the lesion in mixed cryoglobulinemia. Clinically, isolated proteinuria and hematuria are more common than nephrotic syndrome, nephritic syndrome, or acute renal failure. Renal involvement is one of the most serious complications of cryoglobulinemia and typically manifests early in the course of the disease (within 3-5 y of diagnosis). Failure to treat may result in renal failure.[22, 36, 37]

Pulmonary manifestations

A reduction in forced expiratory flow rates and the presence of interstitial infiltrates revealed by chest radiographs are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare.[38, 39, 40, 41]


Neuropathy is common in types II and III disease (as determined with electromyographic and nerve conduction studies), affecting 70-80% of patients. Symptomatic disease was once reported as less common (5-40%); however, more recently, subjective symptoms have been reported up to 91% of patients. Sensory fibers are more commonly affected than motor fibers, with pure motor neuropathy in approximately 5% of patients.[42, 31, 43, 44]

Other manifestations

Patients with cryoglobulinemia may also present with the following:

  • Abdominal pain has been reported in 2-22% of patients; vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported
  • Sicca symptoms have been reported in 4-20% of patients [31, 38]
  • Acrocyanosis has been reported in up to 9% of patients
  • Arterial thrombosis has been reported in 1% of patients
  • A high incidence of new cases of thyroid autoimmunity and dysfunction hase been found in patients (particularly women) with hepatitis C–associated mixed cryoglobulinemia. [45]

Physical Examination

Skin manifestations include the following:

  • Ischemic necrosis (40% in type I, 0-20% in mixed types)
  • Palpable purpura (15% in type I, 80% in mixed types)
  • Livedoid vasculitis (1% in type I, 14% in type III)
  • Cold-induced urticaria (15% in type I, 10% in type III)
  • Hyperkeratotic spicules in areas exposed to cold
  • Scarring of tip of nose, pinnae, fingertips, and toes
  • Acrocyanosis
  • Nailfold capillary abnormalities

Pulmonary manifestations include the following:

Gastrointestinal manifestations include the following:

  • Abdominal pain (2-22%)
  • Hemorrhage
  • Hepatomegaly or signs of cirrhosis (ie, palmar erythema, abdominal wall collateral vessels, spider angiomata)

Renal manifestations include the following:

  • Membranoproliferative glomerulonephritis described in all types (more common in type II)
  • Intraluminal cryoglobulin deposition
  • Hypertension
  • Nephrotic-range proteinuria with resultant edema

Joint manifestations include the following:

  • Arthralgias (5% of type I, 20-58% of mixed)
  • Frank arthritis and progressive joint deformity (distinctly rare)

Nervous system manifestations include the following:

  • Sensorimotor neuropathy
  • Visual disturbances
  • CNS involvement (rare, although pseudotumor cerebri and cerebral vascular events have been described)

Fever is another manifestation.





Laboratory Studies

To evaluate for serum cryoglobulins, the blood specimen must be collected in warm tubes (37°C) in the absence of anticoagulants. The blood sample must be allowed to clot before removal of serum with centrifugation (at 37°C).

The period required for the serum sample to incubate (at 4° C) depends on the type of cryoglobulin present, as follows:

  • Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL)
  • Type III cryoglobulins may require 7 days to precipitate a small sample (< 1 mg/mL)

Repeat centrifugation is performed to determine cryocrit (volume of precipitate as a percentage of original serum volume). Cryoglobulin concentration may be determined via spectrophotometric analysis. Specific immunologic assays may be used to identify cryoglobulin components (immunoglobulins, light chains, clonality).

Additional laboratory findings in cryoglobulinemia include the following:

  • Urinalysis: Abnormalities may represent evidence of renal disease
  • Complete blood cell count: Leukocytosis may be a manifestation of concomitant infection or leukemia. Anemia may be present
  • Serum chemistry: Patients with renal insufficiency may present with elevated serum creatinine levels and electrolyte abnormalities
  • Liver function studies: Liver function studies may reveal evidence of underlying hepatitis; obtain hepatitis serology
  • Rheumatoid factor (RF): RF is positive in types II and III
  • Antinuclear antibody (ANA): ANA is indicated upon clinical suspicion of underlying connective-tissue disease (eg, systemic lupus erythematosus [SLE], Sjögren syndrome)
  • Erythrocyte sedimentation rate (ESR): Elevations may be secondary to rouleaux formation.
  • Complement evaluation (CH50, C3, C4): Patients may display hypocomplementemia (especially low C4 levels).
  • Hepatitis C virus (HCV) testing is required. HCV antibody or HCV RNA testing may be diagnostic. If HCV test results are negative and clinical suspicion remains high, these tests may be performed on the cryoprecipitate. [46]

Other studies to consider are as follows:

  • Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and quantitative immunoglobulin: Perform upon suspicion for underlying gammopathy
  • Serum viscosity: Measure serum viscosity if symptoms warrant
  • Further diagnostic laboratory tests, based on the level of suspicion for other associated disease: for example, one study demonstrated that patients with mixed cryoglobulinemia associated with hepatitis C virus (HCV) infection have elevated levels of interferon-inducible protein 10 and that these levels correlate with disease activity [47]

Imaging Studies

Indications for imaging studies include the following:

  • A chest radiograph can be performed in patients with pulmonary manifestations; it may reveal interstitial involvement or pleural effusions.
  • CT imaging may be considered upon high suspicion of underlying malignancy.
  • Transesophageal echocardiography should be obtained if bacterial endocarditis is suspected.
  • Angiography may be considered to evaluate for evidence of vasculitis.


Indications for procedures include the following:

  • Tissue biopsy may be required for diagnosis when patients with vasculitis, renal disease, or both are evaluated.
  • Electromyography and nerve conduction studies may be used to confirm neuropathy when history or physical examination findings are suggestive.
  • Further diagnostic procedures (eg, bone marrow biopsy, liver or kidney biopsy) usually depend on coexistent disease, especially HCV infection.

Histologic Findings

Skin: Purpura are histologically characterized by dermal vasculitis that extends variably to the subcutaneous interstitial space. HCV-associated proteins have been found in vasculitic skin biopsy samples, suggesting a role for these antigens in pathogenesis of the lesions.

Other organs: Autopsy studies have revealed unsuspected vasculitis of multiple organs (heart, lung, gastrointestinal tract, central nervous system, liver, muscle, adrenals).[21] Histologic evaluation of affected lung, kidney, and muscle reveals eosinophilic material in the lumen of small vessels with frequent extension into the vessel intima and inflammation of the vessel wall.[48]

Although biopsy samples generally exhibit inflammatory vascular changes (eg, leukocytoclastic vasculitis in patients with vasculitic purpura), intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli. See the image below.

Renal biopsy sample that shows membranoproliferati Renal biopsy sample that shows membranoproliferative glomerulonephritis in a patient with hepatitis C–associated cryoglobulinemia (hematoxylin and eosin; magnified X 200).


Approach Considerations

Admit the patient to an inpatient medical service upon evidence of active vasculitis involving renal, cardiopulmonary, or neurologic systems that requires use of aggressive immunosuppressive therapy.  Consider corticosteroid therapy for at least initial therapy in patients with more severe symptoms such as vasculitis, neurologic findings, severe cutaneous disease, or renal involvement or in those who otherwise meet criteria for inpatient medical care. These patients may require additional immunosuppressive therapy and are best treated by a specialist. Patients who develop end-organ compromise secondary to active vasculitis may need to be monitored in an intensive care unit setting. 

Consider transferring patients who meet criteria for admission to a facility able to accommodate patients who require possible subspecialty consultation with a rheumatologist, hematologist, gastroenterologist/hepatologist, or nephrologist. In patients with evidence of potential end-organ compromise, consider transfer to a facility able to accommodate intensive or critical care patients.

Outpatient management is reasonable in patients suspected of having mild vasculitis that is expected to respond to outpatient oral immunosuppressive therapy or in patients treated for vague symptoms of arthralgias, fatigue, or malaise without evidence of active vasculitis. Consider the use of NSAIDs in patients with mild symptoms without evidence of vasculitis.

Medical Care

Treatment of cryoglobulinemia varies according to the disease type and should be tailored according to clinical severity, underlying conditions, and prior therapies.[49] The goal of therapy is to treat underlying conditions, as well as to limit the precipitant cryoglobulin and the resultant inflammatory effects.[46]

Asymptomatic cryoglobulinemia does not require treatment. Some authors recommend intervening as little as possible except when faced with severe deterioration of renal or neurologic function.

Secondary cryoglobulinemia is best managed with treatment of the underlying malignancy or associated disease. Otherwise, cryoglobulinemia is treated simply with suppression of the immune response. A paucity of controlled studies evaluating the relative efficacy of various therapies limits the use of existing data.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used in patients with arthralgia and fatigue.

Immunosuppressive medications (eg, corticosteroid therapy and/or cyclophosphamide or azathioprine) are indicated upon evidence of organ involvement such as vasculitis, renal disease, progressive neurologic findings, or disabling skin manifestations.

Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for reduction of immunoglobulin production. Some authors recommend using concomitant cytotoxic medications or corticosteroids to reduce a rebound phenomenon that may develop after plasmapheresis.

Hepatitis-related cryoglobulinemia

Pegylated interferon alfa (IFN-alfa) combined with ribavirin has demonstrated efficacy in patients with cryoglobulinemia associated with hepatitis C virus (HCV) infection, and efficacy in patients with chronic myelogenous leukemias and low-grade lymphomas has been reported. The details of therapy and the recommended approach vary based on the clinical setting, and expert opinion should be sought.[50]

Emery et al reported that treatment with direct-acting antivirals (DAAs) in patients with HCV-related mixed cryoglobulinemia resulted in high rates of sustained virological response, with excellent safety and tolerability were excellent. Cryoglobulins disappeared in 5 of 18 (29.4%) symptomatic patitents and 27 of 65 (52.9%) asymptomatic patients. However, only 1 of the 7 patients with severe vasculitis had a complete clinical response, with 3 showing a partial response and 2 showing no improvement, and all four patients with life-threatening vasculitis required plasmapheresis; three also received rituximab.[51]

A Kidney Disease: Improving Global Outcomes (KDIGO) guideline on the management of HCV in patients with chronic kidney disease recommends treating patients who have severe cryoglobulinemia induced by HCV should be treated with immunosuppressive agents (generally with rituximab as the first-line agent) with or without plasma exchange, in addition to DAAs.[52]

Uncontrolled studies suggest that rituximab is effective in controlling disease manifestations such as vasculitis, peripheral neuropathy, arthralgias, low-grade B-cell lymphomas, renal disease, and fever.[53, 54] Rituximab therapy has been used predominantly in HCV-related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral (IFN-alfa) therapy. Rituximab therapy is reportedly well tolerated in this patient population; however, treatment has resulted in increased titers of HCV RNA of undetermined significance.[55]

Rituximab was well tolerated and effective in a randomized controlled trial that compared rituximab with immunosuppressive therapy for HCV-associated cryoglobulinemic vasculitis in 24 patients in whom antiviral therapy had failed to induce remission. These researchers observed no adverse effects of rituximab on HCV plasma viremia or on hepatic transaminase levels.[56]

In a study of long-term rituximab treatment in 31 patients with severe mixed cryoglobulinemia, complete remission of pretreatment active manifestations was observed in all cases of purpuric lesions and non-healing vasculitic ulcers, and in 80% of peripheral neuropathies. Cryoglobulinemic nephropathy improved significantly during follow-up, starting from the second month of rituximab treatment.[57]

In this study, rituximab was administered in a dose of 375 mg/m2, according to a '4 + 2' protocol (days 1, 8, 15, and 22 plus a single dose 1 and 2 months later). This protocol was also followed in nine patients who suffered relapse, after a mean of 31.1 months, again with beneficial effects. With this protocol, the probability of remaining symptom-free for 10 years without any therapy was about 60%, while the probability of living symptom-free 5 years after relapsing was 80%.[57]

In patients with relapsing mixed cryoglobulinemia vasculitis, low-dose rituximab proved effective, safe, and cost-effective for long-term management. Colantuono et al used a cycle of two 250 mg/m2 doses given 1 week apart. Of the 37 patients studied (34 of them HCV-positive) 30 (81%) achieved a clinical response. Relapse occurred in 22 patients; mean time to relapse was 17.1 ± 14.1 months in patients treated with only one cycle, versus 45.7 ± 30.6 months  in those  treated with 2 or more cycles (P = 0.0037). Most relapses responded to retreatment.[58]

Case reports have detailed the remission of hepatitis B–related cryoglobulinemic vasculitis with entecavir therapy.[59]  In a study of 17 HBV-positive patients with cryoglobulinemic vasculitis, Mazzaro et al reported success using entecavir, adefovir, or lamivudine. After treatment, no disease progression was noted and regression of purpura and a reduction of cryocrit were observed. HBV-DNA became undetectable in all patients.[60]

Other potential therapies for refractory cryoglobulinemic vasculitis include mycophenolate mofetil and belimumab. However, tumor necrosis factor (TNF) inhibitors are not effective.[61]



The following specialist consultations are beneficial:

  • Rheumatologist or clinical immunologist
  • Nephrologist upon evidence of renal disease (ie, hypertension, abnormal findings on urinalysis)
  • Hematologist upon evidence of underlying hematological disease or for plasmapheresis
  • Gastroenterologist or hepatologist for patients with underlying hepatitis


Medication Summary

The overall aim of therapy is treatment of any underlying condition and general suppression of the immune response. Mild anti-inflammatory medications (eg, NSAIDs) are effective in mild cases, and corticosteroid therapy is reserved for the more severe or refractory cases. Patients who require potent immunosuppression or other more aggressive therapies for severe disease should be treated by a specialist. Cyclophosphamide may be used as a steroid-sparing agent or administered concomitantly in severe cases of vasculitis, particularly in patients with renal disease. Azathioprine is commonly used as a steroid-sparing agent, and chlorambucil has also been used for severe vasculitis.

Nonsteroidal anti-inflammatory drugs

Class Summary

NSAIDs such as ibuprofen, naproxen, and indomethacin have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. NSAIDs may have additional mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. NSAIDs are used to reduce the resultant inflammatory response of cryoglobulin precipitation.

Ibuprofen (Advil, Motrin, Excedrin IB, Ibuprin)

NSAIDs are the DOC in patients with mild symptoms of arthralgia or fatigue. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.


Class Summary

These medications are used to reduce the resultant immune response from cryoglobulin precipitation, particularly in patients with more severe symptoms or some evidence of organ damage.

Prednisone (Sterapred)

DOC in patients with evidence of acute vasculitis.

Immunosuppressive agents

Class Summary

These are commonly used as steroid-sparing agents.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, interfering with growth of normal and neoplastic cells.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.


Class Summary

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. IFN-alfa is generally administered subcutaneously.

Interferon alfa-2b (Intron A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Has antiviral activity in HCV infection.

Peginterferon alfa-2a (Pegasys)

Used in combination with ribavirin to treat patient with chronic HCV infection who have compensated liver disease and have not received IFN-alfa previously. Consists of interferon alfa-2a attached to a 40-kD branched PEG molecule. Predominantly metabolized by the liver.

Peginterferon alfa 2b (PEG-Intron)

Escherichia coli recombinant product. Used to treat chronic HCV infection in patients not previously treated with INF-alfa who have compensated liver disease. Exerts cellular activities by binding to specific membrane receptors on cell surface, which, in turn, may suppress cell proliferation and may enhance phagocytic activity of macrophages. May also increase cytotoxicity of lymphocytes for target cells and inhibit virus replication in virus-infected cells.

Antiviral agents

Class Summary

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Ribavirin (Virazole)

Antiviral nucleoside analogs. Chemical name is 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on the course of HCV infection. When used with IFN, significantly augments rate of sustained virologic response.

Antiviral Agent, Oral

Class Summary

This agent inhibits the viral reverse transcriptase enzyme, which limits viral replication.

Entecavir (Baraclude)

Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Antineoplastic agents

Class Summary

These agents inhibit cell growth and proliferation.

Rituximab (Rituxan)

Genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

Immunomodulates response against malignant cells.


Questions & Answers


What are cryoglobulins?

What is cryoglobulinemia?

What is the Brouet classification of cryoglobulinemia?

How is cryoglobulinemia classified based on etiology?

What are the most common symptoms of type I cryoglobulinemia?

What is the pathophysiology of cryoglobulinemia?

What is the role of immune-complex disease in the pathogenesis of cryoglobulinemia?

What is the pathophysiology of type I cryoglobulinemia?

What is the pathophysiology of types II and III cryoglobulinemia?

What is the role of resultant aggregates in the pathophysiology of cryoglobulinemia?

What is the prevalence of cryoglobulinemia in the US?

What are the reported frequencies of the different types of cryoglobulinemia in the US?

What is the global prevalence of cryoglobulinemia?

What is the mortality and morbidity associated with cryoglobulinemia?

How does renal disease affect mortality in cryoglobulinemia?

What is the prevalence of lymphoproliferative disease in cryoglobulinemia?

How does the prevalence of cryoglobulinemia vary by sex and age?


What are the signs and symptoms of type I cryoglobulinemia?

What are the signs and symptoms of types II and III cryoglobulinemia?

What are the characteristics of dependent area lesions in cryoglobulinemia?

What are the characteristics of nondependent area lesions in cryoglobulinemia?

What are the musculoskeletal symptoms of cryoglobulinemia?

What are the renal symptoms of cryoglobulinemia?

What are the pulmonary symptoms of cryoglobulinemia?

What is the prevalence of neuropathy in cryoglobulinemia?

What are less common symptoms of cryoglobulinemia?

Which skin exam findings are characteristic of cryoglobulinemia?

Which pulmonary findings are characteristic of cryoglobulinemia?

Which GI findings are characteristic of cryoglobulinemia?

Which renal findings are characteristic of cryoglobulinemia?

Which joint findings are characteristic of cryoglobulinemia?

Which nervous system findings are characteristic of cryoglobulinemia?

Which systemic finding is characteristic of cryoglobulinemia?

What are possible etiologies of cryoglobulinemia by type?

What is the role of infection in the etiology of cryoglobulinemia?

Which disorders may cause cryoglobulinemia?


What are the differential diagnoses for Cryoglobulinemia?


How should blood be collected for testing in the workup of cryoglobulinemia?

How are serum samples tested in the workup of cryoglobulinemia?

Which lab findings suggest cryoglobulinemia?

Which lab studies may be considered in the workup of cryoglobulinemia?

What is the role of imaging studies in the workup of cryoglobulinemia?

What are the indications for procedures in the workup of cryoglobulinemia?

Which histologic findings of the skin are characteristic of cryoglobulinemia?

What are the histologic findings of the organs are characteristic of cryoglobulinemia?

Which histologic findings suggest cryoglobulinemia?


What is the focus of treatment for cryoglobulinemia?

What are the treatment options for asymptomatic cryoglobulinemia?

What is the treatment options for secondary cryoglobulinemia?

What is the role of NSAIDs in the treatment of cryoglobulinemia?

What is the role of immunosuppressive medications in the treatment of cryoglobulinemia?

What is the role of plasmapheresis in the treatment of cryoglobulinemia?

What is the role of combination therapy in the treatment of cryoglobulinemia?

What is the role of antiviral drugs in the treatment of cryoglobulinemia?

What is the role of rituximab in the treatment of cryoglobulinemia?

What are treatment options for cryoglobulinemic vasculitis?

Which specialist consultations are needed for the treatment of cryoglobulinemia?


What is the role of medications in the treatment of cryoglobulinemia?

Which medications in the drug class Antineoplastic agents are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Antiviral Agent, Oral are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Antiviral agents are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Interferons are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Immunosuppressive agents are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Corticosteroids are used in the treatment of Cryoglobulinemia?

Which medications in the drug class Nonsteroidal anti-inflammatory drugs are used in the treatment of Cryoglobulinemia?