Cryoglobulinemia Treatment & Management

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