Approach

Types ll and lll cryoglobulinaemia (mixed cryoglobulinaemia [MC]) may be associated with infectious disorders or autoimmune disorders. Hepatitis C virus (HCV) infection is the most common cause of MC, and may account for up to 90% of all cases.[10][11][12]The treatment of MC is decided on the basis of activity/severity of clinical symptoms.

Type l cryoglobulinaemia is most often associated with haematological malignancies. Treatment of the cryoglobulinaemic syndrome is directed against the underlying malignancy.

Management of hepatitis C virus (HCV) infection

MC is strongly associated with chronic HCV infection. First-line therapy for non life-threatening MC due to HCV infection should include antiviral therapy. Evidence demonstrates sustained virological response (SVR) in a significant proportion of patients with MC associated with HCV.[43][44]​ Furthermore, SVR is associated with a reduced risk of MC and extrahepatic manifestations of chronic HCV infection.

When antiviral therapy is considered in the setting of HCV-related cryoglobulinaemia, 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 cryoglobulinaemia 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.[45]​​

See Hepatitis C (Management approach).

Small case series have reported high rates of SVR among symptomatic and asymptomatic patients treated with direct-acting antivirals (with or without pegylated interferon) for HCV-related cryoglobulinaemia.[10][46][47][48][49][50]​ However, pegylated interferon is no longer recommended as a treatment option in some current guidelines. Sofosbuvir-based regimens were associated with negative HCV viraemia at week 12 (SVR12) and at week 24 (SVR24) post-treatment in one prospective study of 44 consecutive patients with HCV-related MC vasculitis.[51]

Cryoglobulinaemic vasculitis responded to therapy in all patients (evaluated by the Birmingham Vasculitis Activity Score); anaemia, fatigue, and nausea were the most common adverse effects.[51]

Significant long-term (median 24 months) clinical and immunological improvement has been reported in patients with HCV-related cryoglobulinaemic vasculitis (n=46), and asymptomatic patients with circulating cryoglobulins (n=42), who were treated with direct-acting antivirals.[52] However, after therapy cryoglobulins persisted in 22% (n=10) of patients with HCV-related cryoglobulinaemic vasculitis and 21% (n=9) of asymptomatic patients with circulating cryoglobulins. A small proportion of HCV cryoglobulinaemic vasculitis patients (11 %, n=5) relapsed after HCV eradication (including severe organ damage and death).[52]

Asymptomatic mixed cryoglobulinaemia

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

Antiviral therapy is recommended for patients with HCV infection; choice of agent is based on local guidelines.[45]​​

Mild to moderate mixed cryoglobulinaemia

For patients with mild to moderate manifestations (purpura, weakness, arthralgia, arthritis, 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]

Antiviral therapy is recommended for patients with HCV infection; choice of agent is based on local guidelines.[45]​​

Moderate to severe mixed cryoglobulinaemia

Patients with moderate to severe manifestations (leukocytoclastic vasculitis, mononeuritis multiplex, glomerulonephritis) require urgent immunosuppressive treatment before initiating therapy for chronic HCV infection.[53] Reactivation or increasing viral replication is a major concern when using immunosuppressive agents.[54] Local guidelines on treatment recommendations for HCV should be followed. Direct-acting antivirals are the standard treatment.[45]

See Hepatitis C (Management approach).​​​

A medium-dose corticosteroid is used to treat moderate glomerulonephritis and cutaneous vasculitis. High doses 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.[55] When using corticosteroids, the shortest duration of treatment to control symptoms should be considered. Long-term use of corticosteroids is not recommended.[16]

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:[56][57]​​ 

  • moderate to severe or severe-rapidly progressive MC

  • cryoglobulinaemic vasculitis

  • comorbidities that preclude other therapies

Italian consensus guidelines state that rituximab is relatively safe and effective for the moderate to severe manifestations of MC (glomerulonephritis, digital ischaemia or necrotising skin ulcers, polyarthritis, gastrointestinal vasculitis, and peripheral neuropathy).[56][57]​​ However, one Cochrane review suggested that the evidence for renal recovery is low.[58] This in part may be due to the low numbers of patients with renal manifestations of cryoglobulinaemic vasculitis included in the trials.

The effect of rituximab on cryocrit and HCV replication is uncertain.[58] Rituximab is not associated with exacerbation of hepatitis. More deaths were reported in the rituximab group in one study, but this may reflect survivor bias.[56]

Dosing regimens for rituximab may vary.[57][59][60]

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.[57]

The decision to use rituximab in MC should be individualised, with careful counselling of the patients regarding its short- and long-term adverse effects and consideration of comorbidities.[56]

Azathioprine and cyclophosphamide have been used to treat severe manifestations of the cryoglobulinaemic syndrome. However, they have not been studied in large series and may be associated with significant toxicity.[61]

Antiviral therapy is recommended for patients with HCV infection; choice of agent is based on local guidelines.[45] ​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.[62]​​​

Severe-rapidly progressive cryoglobulinaemia

Plasmapheresis with sequential immunosuppression is used in patients with severe, rapidly progressive manifestations or life-threatening disease (extremity gangrene, fulminant multi-organ involvement, severe glomerulonephritis, progressive peripheral neuropathy, and severe lower-extremity ulcers).[16][63]​​ In patients with hyperviscosity syndrome, plasmapheresis may reverse the complications acutely; however, it needs to be followed by treatment of the underlying cause.[53][64]​​ To avoid cryoglobulin precipitation, replacement fluids for plasma exchange should be warmed before infusion.​

Immunosuppressive treatment typically consists of intravenous corticosteroids with either rituximab or cyclophosphamide. Due to a better toxicity profile, rituximab is favoured as a first-line therapy for non-renal manifestations of cryoglobulinaemia.[53][57]​​[58]​​ Of note, it is mandatory to screen for hepatitis B co-infection 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 manifestations and tapered rapidly according to the clinical condition.[7][16]​​

  • Rituximab: the decision to use rituximab in MC should be individualised, with careful counselling of the patients regarding its short- and long-term adverse effects and consideration of comorbidities.[56]​ Italian guidelines suggest using rituximab (for initial and maintenance therapy) for patients with severe or life-threatening manifestations.[57]

  • Cyclophosphamide: in some studies, treatment has been started with monthly intravenous cyclophosphamide, and daily dosing has been reserved for refractory cases.[65][66] 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]

  • ​HCV infection: consider direct-acting antiviral therapy; choice of agent is based on local guidelines.[45]

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.[62] Although clinical trials have not shown improvement of renal function for cryoglobulinaemic 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.[58][62]​​

Malignancy-associated cryoglobulinaemia (type l)

Type l cryoglobulinaemia is most often associated with haematological malignancies such as multiple myeloma or Waldenstrom's macroglobulinaemia. Treatment of the cryoglobulinaemic syndrome is achieved by specific treatment of the underlying malignancy.[53]

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