Cryoglobulinemia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

mixed cryoglobulinemia

asymptomatic

1st line – observation

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1st line –

observation

In patients who are asymptomatic, careful monitoring for manifestations of cryoglobulinemia such as ulcers, acrocyanosis, digital gangrene, and purpura is usually sufficient. Patients should initially be followed every 2-3 months. Multisystemic involvement may also be assessed.

Consider – hepatitis C antiviral therapy

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Consider –

hepatitis C antiviral therapy

Treatment recommended for SOME patients in selected patient group

First-line therapy for non life-threatening mixed cryoglobulinemia (MC) due to hepatitis C virus (HCV) infection should include antiviral therapy. Evidence demonstrates sustained virologic response (SVR) in a significant proportion of patients with MC associated with HCV.[45][46] Furthermore, SVR is associated with a reduced risk of MC and extrahepatic manifestations of chronic HCV infection.

The presence of cryoglobulinemia does not influence the choice of antiviral therapy. Local guidelines on treatment recommendations for HCV should be followed. Direct-acting antivirals are the standard treatment.[47]

See Hepatitis C (Treatment algorithm).

mild to moderate

1st line – corticosteroid

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1st line –

corticosteroid

For patients with mild to moderate manifestations (purpura, weakness, arthralgia, arthritis, and mild neuropathy), lower doses of corticosteroids with shortest duration of treatment to control symptoms should be considered. Long-term use of corticosteroids is not recommended.[16]

Primary options

prednisone: 10-20 mg orally twice daily

Consider – hepatitis C antiviral therapy

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Consider –

hepatitis C antiviral therapy

Treatment recommended for SOME patients in selected patient group

See Hepatitis C (Treatment algorithm).

moderate to severe

1st line – corticosteroid

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1st line –

corticosteroid

Medium-dose corticosteroids are used to treat moderate glomerulonephritis and cutaneous vasculitis.

High-dose corticosteroids are indicated in the presence of mononeuritis multiplex and severe glomerulonephritis.

The response to corticosteroids alone or in combination with interferon alfa for vasculitic manifestations is variable.[57]

Reactivation or increasing viral replication is a major concern when using immunosuppressive agents.[56]

When using corticosteroids, the shortest duration of treatment to control symptoms should be considered. Long-term use of corticosteroids is not recommended.[16]

Primary options

prednisone: 0.5 to 1.5 mg/kg/day orally

Consider – hepatitis C antiviral therapy

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Consider –

hepatitis C antiviral therapy

Treatment recommended for SOME patients in selected patient group

When antiviral therapy is considered in the setting of HCV-related cryoglobulinemia, advice should be sought from a hepatologist to stage the liver disease and assist in choosing the most appropriate therapy considering patient comorbidities such as level of cirrhosis and renal impairment, as well as the patient’s HCV genotype and whether they had been treated with HCV antiviral therapy previously. The presence of cryoglobulinemia does not influence the choice of antiviral therapy. Local guidelines on treatment recommendations for HCV should be followed. Direct-acting antivirals are the standard treatment.[47]

See Hepatitis C (Treatment algorithm).

For patients with HCV-related glomerulonephritis, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines state that all patients with stable renal function and without nephrotic syndrome should be started on direct-acting antivirals. Immunosuppressive therapy is recommended as an adjunct if there is a lack of response to direct-acting antivirals.[64]

Consider – rituximab

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Consider –

rituximab

Treatment recommended for SOME patients in selected patient group

Rituximab (a monoclonal antibody targeted to CD20 on B cells) may be considered in selected patients (who do not have evidence of active HIV or hepatitis B infection) with: moderate to severe mixed cryoglobulinemia (MC); cryoglobulinemic vasculitis; or comorbidities that preclude other therapies.[58][59]

Italian consensus guidelines state that rituximab is relatively safe and effective for the moderate to severe manifestations of MC (glomerulonephritis, digital ischemia or necrotizing skin ulcers, polyarthritis, gastrointestinal vasculitis, and peripheral neuropathy).[58][59] However, one Cochrane review suggested that the evidence for renal recovery is low.[60] This in part may be due to the low numbers of patients with renal manifestations of cryoglobulinemic vasculitis included in the trials. Dosing regimens for rituximab may vary.[59][61][62]

In the event of clinical relapse following treatment with rituximab, a second cycle of treatment has been shown to be safe and effective in patients with moderate to severe MC.[59]

The decision to use rituximab in MC should be individualized, with careful counseling of the patients regarding its short- and long-term adverse effects and consideration of comorbidities.[58]

Corticosteroids are gradually tapered after rituximab is initiated.

For patients with HCV-related glomerulonephritis, the KDIGO guidelines state that all patients with stable renal function and without nephrotic syndrome should be started on direct-acting antivirals. Immunosuppressive therapy is recommended as an adjunct if there is a lack of response to direct-acting antivirals.[64]

Primary options

rituximab: consult specialist for guidance on dose

severe-rapidly progressive

1st line – plasmapheresis

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1st line –

plasmapheresis

Plasmapheresis with sequential immunosuppression is used in patients with severe, rapidly progressive manifestations or life-threatening disease (extremity gangrene, fulminant multiorgan involvement, severe glomerulonephritis, progressive peripheral neuropathy, and severe lower-extremity ulcers).[16][65]

In patients with hyperviscosity syndrome, plasmapheresis may reverse the complications acutely; however, it needs to be followed by treatment of the underlying cause.[55][66]

To avoid cryoglobulin precipitation, replacement fluids for plasma exchange should be warmed before infusion.

Plus – immunosuppressive therapy

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Plus –

immunosuppressive therapy

Treatment recommended for ALL patients in selected patient group

Immunosuppressive treatment typically consists of intravenous corticosteroids with either rituximab or cyclophosphamide. Due to a better toxicity profile, rituximab is favored as a first-line therapy for nonrenal manifestations of cryoglobulinemia.[55][59][60] Of note, it is mandatory to screen for hepatitis B coinfection and consult specialists to manage it while using potent immunosuppression, especially rituximab.

Corticosteroids: for severe manifestations, corticosteroids are used as bridge therapy. Pulse-dose corticosteroids are used for severe vasculitis and glomerulonephritis and tapered rapidly according to the clinical condition.[7][16]

Rituximab: the decision to use rituximab in MC should be individualized, with careful counseling of the patients regarding its short- and long-term adverse effects and consideration of comorbidities.[58] Italian guidelines suggest using rituximab (for initial and maintenance therapy) for patients with severe or life-threatening manifestations.[59]

Cyclophosphamide: in some studies, treatment has been started with monthly intravenous cyclophosphamide, and daily dosing has been reserved for refractory cases.[67][68] Treatment with oral cyclophosphamide for 5-6 weeks during tapering of apheretic sessions has been shown to prevent the rebound effect observed after discontinuation of plasmapheresis.[4]

For patients with rapidly progressive HCV-related glomerulonephritis, KDIGO guidelines recommend that direct-acting antivirals and immunosuppressive treatment should be started without delay, with or without plasmapheresis.[64] Although clinical trials have not shown improvement of renal function for cryoglobulinemic vasculitis after rituximab, the KDIGO guidelines recommend rituximab as the first-line immunosuppressive therapy in patients with histologically active HCV-associated glomerulonephritis concurrently with antiviral therapy.[60][64]

ECG monitoring is advised with methylprednisolone treatment.

Primary options

methylprednisolone sodium succinate: 500-1000 mg/day intravenously for 3 days

-- AND --

rituximab: consult specialist for guidance on dose

cyclophosphamide: consult specialist for guidance on dose

Consider – hepatitis C antiviral therapy

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Consider –

hepatitis C antiviral therapy

Treatment recommended for SOME patients in selected patient group

Evidence demonstrates sustained virologic response (SVR) in a significant proportion of patients with mixed cryoglobulinemia (MC) associated with hepatitis C virus (HCV).[45][46] Furthermore, SVR is associated with a reduced risk of MC and extrahepatic manifestations of chronic HCV infection.

For patients with rapidly progressive HCV-related glomerulonephritis, direct-acting antivirals should be started without delay.[64]

See Hepatitis C (Treatment algorithm).

malignancy-associated cryoglobulinemia (type I)

1st line – treatment of underlying malignancy

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1st line –

treatment of underlying malignancy

Type I cryoglobulinemia is most often associated with hematologic malignancies such as multiple myeloma or Waldenstrom macroglobulinemia.

Treatment of the cryoglobulinemic syndrome is achieved by specific treatment of the underlying malignancy.[55]

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