Treatment of the mixed cryoglobulinemia syndrome

INTRODUCTION  — The mixed cryoglobulinemia syndrome is most often induced by hepatitis C virus (HCV) infection. It can also be associated with autoimmune or lymphoproliferative disorders or, rarely, can be idiopathic. Typically, it follows a chronic, smoldering course. Infrequently, mixed cryoglobulinemia may present with a rapidly progressive or even life-threatening course.The main indication for immunosuppressive therapy is progressive systemic disease affecting the kidneys, nervous system, gastrointestinal tract, skin, or digits. The prognosis is variable [ 1-5 ].

The treatment of patients with the mixed cryoglobulinemia syndrome will be reviewed here. An overview of cryoglobulinemia and a discussion of the clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome are provided elsewhere.

GENERAL APPROACH TO THERAPY  — Prior to the discovery of the association with hepatitis C virus (HCV), both prednisone and cytotoxic drugs (such ascyclophosphamide and chlorambucil ) were often used in patients with mixed cryoglobulinemia. However, except in those patients with a rapidly progressive course, there was no clear evidence that these modalities were beneficial [ 3,4 ]. Rituximab has been gradually replacing cytotoxic drug therapy in such patients.

Rituximab is significantly more expensive than cyclophosphamide , and there are no data directly comparing rituximab with cyclophosphamide in these patients. Thus, cyclophosphamide should still be considered a therapeutic option in patients with mixed cryoglobulinemia, especially in life-threatening situations.

The general approach to therapy in patients with mixed cryoglobulinemia syndrome includes two broad principles:

Initial immunosuppressive therapy – Immunosuppression is provided as initial therapy in those patients identified as having a rapidly progressive, organ-threatening, or life-threatening course, regardless of the etiology of the mixed cryoglobulinemia. Immunosuppressive therapy usually combines a short course of glucocorticoids with either rituximab or cyclophosphamide and, in some patients, plasmapheresis.

Treatment of the underlying disease – All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with HCV who have chronic active hepatitis should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy. In some cases, this will involve continuation of immunosuppression for a prolonged period. (See 'Treat the underlying disorder in all patients' below.)

IMMUNOSUPPRESSIVE THERAPY FOR SEVERE MIXED CRYOGLOBULINEMIA  — Patients with mixed cryoglobulinemia who have a rapidly progressive, organ-threatening, or life-threatening course should receive immunosuppressive therapy including rituximab or, if unavailable, cyclophosphamide [ 6,7 ]. After disease stabilization, patients should receive concurrent therapy for the underlying disorder responsible for the cryoglobulinemia (eg, antiviral therapy in patients with active hepatitis C virus [HCV] infection). Exceptions to this general principle include mixed

cryoglobulinemia due to HIV or HBV infections; in such patients, antiviral therapy should always be initiated before or at the same time as immunosuppressive therapy.

Patient selection  — In patients with mixed cryoglobulinemia syndrome who have one or more of the following manifestations, we suggest immunosuppressive therapy to rapidly improve or resolve target organ damage, rather than therapy directed at the underlying etiology alone:

Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria

Severe digital ischemia threatening amputation Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal

bleeding Rapidly progressive neuropathy Central nervous system vasculitis that may present as a stroke or acute cognitive

impairment Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory

failure Heart failure

As discussed below in detail, we usually initiate immunosuppressive therapy in patients with HCV-associated mixed cryoglobulinemia prior to instituting antiviral treatment.Support for immunosuppressive therapy in patients with severe manifestations comes from randomized trials and observational data in which rituximab was combined with disease-specific therapy (usually antiviral therapy in patients with HCV infection). The following examples illustrate the most relevant findings:

In a randomized trial, 59 patients with mixed cryoglobulinemia and severe manifestations were assigned to rituximab therapy or other immunosuppressive agents; in the 53 patients whose disease was due to HCV infection, antiviral therapy had either failed or was not indicated [ 8 ]. Clinical improvement was noted at 12 and 24 months in greater than 60 percent of patients receiving rituximab. These data provide the strongest evidence that immunosuppressive therapy is effective in patients with severe disease, including those with HCV-associated cryoglobulinemia. The comparative effects of rituximab versus other immunosuppressive drugs are presented below. (See 'Preference for rituximab' below.)

In a prospective cohort study of 93 patients with HCV-associated mixed cryoglobulinemia, 55 received antiviral therapy with pegylated interferon andribavirin alone, and 38 received rituximab (375 mg/m 2 given weekly for one month [4 doses]) followed one month later by pegylated interferon and ribavirin; median follow-up was 48 months [ 9 ]. At baseline, 81 percent of patients had neurological involvement, 33 percent had kidney involvement, and 9 percent had gastrointestinal involvement. Compared with patients who received antiviral therapy alone, patients who received combined therapy with antiviral drugs plus rituximab were more likely to have severe manifestations at baseline, including renal involvement (55 versus 18 percent [estimated glomerular filtration rate, 43 versus 59 mL/min/1.73m 2 ]). The rate of a complete clinical response (defined as an improvement in all baseline clinical features) was similar in patients receiving combination therapy as compared with antiviral therapy alone (74 versus 73 percent), but the time until clinical response was significantly shorter with combination therapy (5.4 versus 8.4 months). In addition, combination therapy was associated with a significantly larger improvement in glomerular filtration rate (GFR), a significantly larger decline in proteinuria, and a significantly greater

likelihood of achieving a complete renal response (81 versus 40 percent). The relapse rate was similar among the treatment groups.

A retrospective study evaluated the response to rituximab in 87 patients with mixed cryoglobulinemia (80 [92 percent] of whom had HCV infection) [ 10]. Approximately half of the patients had previously received antiviral therapy. Rituximab was given for the following indications: glomerulonephritis (30 percent), peripheral neuropathy (23 percent), severe cutaneous vasculitis (25 percent), and multiple manifestations (14 percent). The dose of rituximab varied, with 68 percent receiving four weekly infusions (375 mg/m 2 ) and 21 percent receiving two doses of 1000 mg separated by a two-week interval. At six months, a complete resolution of peripheral neuropathy occurred in 44 percent of patients, and complete healing of cutaneous ulcers occurred in 87 percent of patients. Glomerulonephritis improved in 95 percent of patients, with complete remission in 50 percent marked by normalization of serum creatinine and proteinuria.

The downstream autoimmune effects of HCV infection provide biological rationale for rituximab therapy in patients whose disease is triggered by HCV infection. Specifically, chronic HCV infection is associated with polyclonal or oligoclonal B lymphocyte expansion that can result in the production of autoreactive antibodies. This autoimmune process can persist and produce disease manifestations even after effective antiviral therapy and complete suppression of viremia [ 11,12 ].

The magnitude of the benefit from aggressive therapy in patients with severe disease is related to the phase of illness. As an example, if polyneuropathy is already advanced when therapy is initiated, the benefit is less impressive [ 13 ].

Rituximab also appears to provide effective therapy in patients with the mixed cryoglobulinemia syndrome not associated with chronic HCV infection. In the French multicenter CryoVas survey, for example, 242 patients were identified who were HCV, HBV, and HIV negative and who had mixed cryoglobulinemia and vasculitis; 30 percent had an underlying rheumatologic disorder, 22 percent had a lymphoproliferative disorder, and the remainder had idiopathic (essential) mixed cryoglobulinemia [ 14 ]. In adjusted analyses, combination therapy with rituximab and glucocorticoids was associated with a nearly fourfold higher rate of achieving a complete clinical response as compared with glucocorticoid therapy alone. In contrast, the combination of alkylating agents (eg,cyclophosphamide ) with glucocorticoids was not significantly associated with a better clinical response than glucocorticoids alone. However, severe infections were more common with rituximab, and mortality was similar regardless of the treatment used.

Choice of immunosuppressive therapy  — In most patients selected for initial immunosuppressive therapy, we suggest rituximab rather than other immunosuppressive drugs such as cyclophosphamide or glucocorticoids alone. In addition, we suggest pulse glucocorticoid therapy followed by a rapid taper in most patients rather than prolonged glucocorticoid therapy or no glucocorticoid therapy. In those patients with life-threatening disease or cryoglobulinemia-associated hyperviscosity syndrome, we also suggest plasmapheresis. (See "Plasma exchange in the hyperviscosity syndrome due to immunoglobulins" .)

The rationale for these suggestions and the regimens used are discussed below.

However, there are settings in which we would not use rituximab to treat mixed cryoglobulinemia:

In patients with HIV infection who are not receiving highly active antiretroviral therapy (HAART) or if, in those patients receiving HAART, the viral load is not suppressed. Such patients are at high risk for enhanced viral replication as a result of rituximab therapy

In patients with HBV infection who are not receiving antiviral therapy or have chronic active hepatitis. The preferred antiviral regimens are discussed below.

These suggestions for immunosuppressive therapy, particularly the suggestion that glucocorticoids be tapered rapidly, apply to most treated patients since the great majority of such patients will have mixed cryoglobulinemia syndrome due to a chronic viral infection (mainly HCV infection). However, some patients may require alternate immunosuppressive regimens tailored to treat the underlying cause, such as autoimmune diseases (eg, rheumatoid arthritis) and lymphoproliferative disorders. This is discussed below.

Preference for rituximab  — Two open-label randomized trials suggest that rituximab is effective in patients with severe mixed cryoglobulinemia:

A multicenter trial assigned 59 patients with mixed cryoglobulinemia (93 percent with HCV infection) and severe manifestations (defined as the presence of skin ulcerations, active glomerulonephritis, or progressive peripheral neuropathy) to either rituximab therapy (1000 mg intravenous infusion at baseline and at day 14) or conventional immunosuppressive therapy [ 8 ]. Conventional immunosuppressive therapy varied according to the treating physician; of 29 patients assigned to conventional therapy, 17 received glucocorticoids alone, 5 received plasmapheresis, 4 received cyclophosphamide , and 3 received azathioprine . The primary endpoint was success of the initial therapy through 12 months; failure of treatment was due either to a lack of clinical improvement or side effects requiring that the therapy be altered. Significantly more patients receiving rituximab therapy had treatment success at 12 months (64 versus 4 percent) and at 24 months (61 versus 4 percent). Of those patients initially receiving conventional therapy who had a treatment failure, 60 percent had a favorable response to rituximab.

A single-center trial assigned 24 patients with mixed cryoglobulinemia due to HCV infection to receive either rituximab therapy (375 mg/m 2 given weekly for one month [4 doses]) or to continue their current treatments [ 15 ]. At baseline, 33 percent had active glomerulonephritis, 50 percent had peripheral neuropathy, and 25 percent had cutaneous ulcers. All patients had either failed to achieve a clinical response with antiviral therapy alone or failed to tolerate antiviral therapy. Of the twelve patients assigned to rituximab therapy, six also received glucocorticoids (mean dose 26 mg prednisone per day), one also received cyclophosphamide , and two also received plasmapheresis. Of the twelve patients assigned to continue their current treatment, three received glucocorticoids (mean dose 10 mg prednisone per day). At six months, significantly more patients in the rituximab group achieved clinical remission (10 of 12 versus 1 of 12), which was defined as a Birmingham Vasculitis Activity Score equal to zero.

These trials showed that rituximab therapy was effective in patients with mixed cryoglobulinemia and severe manifestations, allowed for reductions in glucocorticoid use, and did not lead to a worsening of hepatitis. However, neither demonstrated that rituximab was superior to cyclophosphamide therapy or plasmapheresis. In the first trial, most patients in the control group were receiving glucocorticoid therapy alone (at a mean prednisone dose

of 28 mg/day) [ 8]; in the second trial, most patients in the control group received no immunosuppressive therapy, and those who did were treated with prednisone at a low dose [ 15 ].

The efficacy of rituximab in patients with mixed cryoglobulinemia has also been shown in numerous observational studies and case series [ 13,16-20 ]. The following examples illustrate the range of findings in various patient subgroups:

Patients with cirrhosis – Most studies of rituximab have excluded patients with cirrhosis or have included very small numbers of cirrhotics. In a prospective study, 15 patients with mixed cryoglobulinemia and cirrhosis due to HCV infection were treated with rituximab (375 mg/m 2 , weekly for four weeks) [ 19 ]. The majority of patients had a complete, major, or partial response to rituximab with respect to ulcers, purpura, neuropathic pain, nephritis, or arthralgias. Most patients also had an improvement in the Child-Pugh score, an increase in serum albumin, and a decreased requirement for albumin infusions and diuretics. Of the six patients with ascites, all had an impressive reduction or disappearance of ascites. However, this unblinded study should be interpreted with caution since the diagnosis of ascites and the Child-Pugh score can be subjective. In addition, a full discussion of adverse events was not included. Although these are encouraging, further studies of rituximab in patients with cirrhosis are required before it is used widely in such patients. Thus, the presence of decompensated cirrhosis is a relative contraindication to rituximab therapy.

Patients with glomerulonephritis – Among 11 patients from two series with mixed cryoglobulinemia and biopsy-proven glomerulonephritis due to HCV infection, intravenous rituximab alone (375 mg/m 2 weekly [four doses] initially followed by two additional doses at months 2 and 3) was associated with improvements in serum creatinine and/or proteinuria in all patients, paralleled by an increase in complement factor 4 (C4) levels [ 16,17 ].

Patients with severe polyneuropathy – Thirteen patients with mixed cryoglobulinemia and polyneuropathy refractory to antiviral therapy and conventional immunosuppressive medications received rituximab (375 mg/m 2 weekly [four doses] initially followed by two additional doses at months 2 and 3) [ 13 ]. Sensory symptoms disappeared or improved, while electromyography examination revealed that the amplitude of compound motor action potential had increased following treatment.

Rituximab was generally well-tolerated in these studies. Short-term infusion reactions following rituximab do not appear to be more frequent in mixed cryoglobulinemia than in rheumatoid arthritis. Severe adverse effects are uncommon, and drop-out due to adverse events, such as bradycardia (especially in older adults), is less than five percent. Special care should be taken for the prevention (eg, prophylaxis against Pneumocystis, administration of age-appropriate immunizations) and management of infections in patients who have previously been treated with immunosuppressants, especially immunocompromised renal transplant recipients with graft dysfunction due to mixed cryoglobulinemia [ 21 ].

Rituximab regimen  — In patients selected for immunosuppressive therapy with rituximab , we use one of the following three regimens (each is acceptable):

Four infusions of 375 mg/m 2 at weekly intervals (day 0, day 7, day 14, day 21) Two infusions of 1000 mg separated by a two-week interval (day 0 and day 14)

Four infusions of 375 mg/m 2 at weekly intervals (day 0, day 7, day 14, day 21) followed by additional doses at day 49 and day 77

Infusing rituximab slowly (ie, over 6 to 8 hours) or administration of half of the dose on two consecutive days, together with premedication using glucocorticoids, acetaminophen , and antihistamine drugs, reduces the risk of infusion reactions [ 10,13,17 ]. Thus, to prevent infusion reactions, we premedicate with intravenous methylprednisolone (100 mg), oral acetaminophen (1000 mg), and oral diphenhydramine (50 mg) prior to each infusion.

Lower doses of rituximab have been attempted in patients with mixed cryoglobulinemia, although they may be less effective. As an example, a study of 27 patients with HCV infection who either did not respond to or could not tolerate antiviral therapy were treated with rituximab, 250 mg/m 2 followed by a second identical dose two weeks later [ 22 ]. Although 19 of 24 patients (79 percent) who were evaluated at three months had a complete or partial response, only 3 of 19 patients evaluated at twelve months were in remission. Thirteen patients were lost to follow-up due to relapse or lack of response. Thus, response rates with low-dose rituximab appear to be inferior to conventional dosing, although the two dosing strategies have not been directly compared.

All patients who will receive rituximab therapy should first be screened for hepatitis B virus infection by measuring hepatitis B surface antigen (HBsAg) and antibodies against the total core antigen (Anti-HBc). Rituximab can induce a severe and potentially fatal reactivation of hepatitis B virus

Preference for a rapid glucocorticoid taper  — Infections are a common serious complication of patients receiving immunosuppressive treatment for mixed cryoglobulinemia, and therefore long courses of high-dose steroids in conjunction with rituximab are not recommended [ 23 ]. A rapid taper is desired. However, in patients who do not respond completely or who experience significant disease recurrence when glucocorticoids are tapered, more prolonged courses of glucocorticoids or slower tapers may be required.

Glucocorticoid regimen  — For severe presentations of the mixed cryoglobulinemia syndrome, we use initially high doses of glucocorticoids with the goal of rapidly tapering the dose. The following is an example of a regimen used by the authors and reviewers of this topic, although (as will be discussed) the specific management must be tailored to the individual:

Intravenous methylprednisolone , 7.5 to 15 mg/kg per day, is given for three days based upon the severity of the illness. This is followed by oralprednisone , 1 mg/kg per day (maximum dose, 80 mg/day) for two to four weeks, then 40 mg/day for two weeks, and then 20 mg/day for another two to four weeks. The dose is then tapered by 5 mg per week, aiming to discontinue therapy if tolerated. If patients are not also treated with rituximab , then a maintenance dose of 5 to 10 mg/day is maintained.

The ability to taper glucocorticoids depends in part upon whether the patient responds to therapy. The clinical response to immunosuppressive therapy should be judged based upon resolution of the initial signs and symptoms (eg, improvement of renal function and proteinuria, healing of ulcers, etc) and not upon the concentration of the cryoglobulin

(cryocrit). The cryoglobulin concentration does not correlate with either the clinical severity of disease or with the response to therapy [ 24 ].

In patients with viral-induced cryoglobulinemia, glucocorticoid therapy may need to be tapered more rapidly than desired if viral reactivation occurs. This is particularly true when mixed cryoglobulinemia is associated with HBV infections since glucocorticoid therapy can lead to viral reactivation.

Role of plasma exchange  — We rarely use plasma exchange in patients with mixed cryoglobulinemia. However, there are several settings in which plasma exchange may be used [ 6 ]:

In patients with symptomatic hyperviscosity syndrome due to mixed cryoglobulinemia, we suggest that plasma exchange be used in combination with other therapy to reduce the production of cryoglobulins (such as rituximab or cyclophosphamide ).

In patients with life-threatening cryoglobulinemia (including patients with acute respiratory failure and pulmonary hemorrhage or acute intestinal vasculitis due to cryoglobulinemia), we suggest that plasma exchange be used in combination with other therapy to reduce the production of cryoglobulins [ 25 ].

In patients with rapidly progressive (crescentic) glomerulonephritis who require dialysis, we suggest that plasma exchange be used (in combination with other therapy such as rituximab or cyclophosphamide ) to reduce the production of cryoglobulins. Late initiation of plasma exchange (ie, two or more weeks after the initiation of dialysis) is unlikely to be beneficial.

The evidence in support of plasma exchange comes mostly from small case reports and case series that suggest clinical improvement in patients with severe disease [ 3,4,13,26-30 ]. Support for plasma exchange is also based upon mechanistic grounds since plasma exchange removes circulating cryoglobulins. However, the concentration of the cryoglobulin (often measured as a cryocrit) does not correlate with clinical severity nor with response to therapy; thus, the decision to initiate this aggressive therapy is based upon the severity of the disease manifestations [ 24 ]. Because plasma exchange does not prevent the formation of new cryoglobulins, it should be combined with other therapy (such as rituximab or cyclophosphamide ) directed at B cell clones that produce cryoglobulins [ 6 ].

Plasma exchange prescription  — When initiated, we recommend daily plasma exchange for 10 to 14 sessions or three exchanges per week (eg, Monday, Wednesday, Friday) for two to three weeks. One plasma volume (approximately 3 liters) should be exchanged per session. The replacement fluid can be 5 percent albumin, which should be warmed to prevent precipitation of circulating cryoglobulins [ 31 ]. However, in patients who have undergone a recent kidney biopsy, fresh frozen plasma should be used as the replacement fluid rather than albumin in order to avoid severe bleeding.

The optimal method for assessing the efficacy of plasma exchange is uncertain. Changes in the percent cryocrit after plasmapheresis do not correlate closely with clinical activity. Clinical evaluation therefore assumes primary importance. Successful plasma exchange should lead to rapid resolution of purpuric lesions and, in a patient with acute kidney injury, a return toward the baseline serum creatinine concentration. In comparison, signs of neuropathy are not likely to remit during short-term therapy.

When used, plasma exchange should be combined with therapy to prevent the production of new cryoglobulins such as rituximab or cyclophosphamide [ 25 ].

Role of cyclophosphamide  — The use of cyclophosphamide therapy in patients with mixed cryoglobulinemia, particularly in patients with HCV or HBV infection, carries the risk of enhancing viral replication. In patients with organ-threatening or life-threatening disease, cyclophosphamide therapy may be used if rituximab therapy is unavailable, fails to produce a clinical response, or is not tolerated. When used, cyclophosphamide is typically combined with plasma exchange [ 4,32 ]. The initial cyclophosphamide dose in such patients is 2 mg/kg per day orally for two to four months. The dose should be adjusted according to the age and GFR. Dose adjustment is discussed elsewhere.

Antimicrobial prophylaxis  — The use of high-dose glucocorticoids in combination with either rituximab or cyclophosphamide carries a high risk for opportunistic infections, such as Pneumocystis pneumonia. Prophylaxis against such infections is mandatory in these patients. Patients should also receive age-appropriate immunizations, ideally several weeks before the initiation of immunosuppression

TREAT THE UNDERLYING DISORDER IN ALL PATIENTS  — All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with HCV and chronic active hepatitis should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy.

Therapy for HCV infection  — We agree with the recommendation from the European League Against Rheumatism (EULAR) and the Italian Group for the Study of Cryoglobulinemias (GISC) that patients with mixed cryoglobulinemia syndrome associated with HCV infection should be treated with antiviral therapy, with the exception of those patients with decompensated cirrhosis [ 6,33 ]. Immunosuppressive therapy should not be given without also attempting antiviral therapy [ 34-36 ].

This section will provide an overview of antiviral therapy for mixed cryoglobulinemia caused by HCV infection. The selection of patients for antiviral treatment, the general efficacy of these regimens in the treatment of chronic HCV, and the side effects associated with therapy are discussed separately.

The selection of patients who should also receive immunosuppressive therapy and the suggested immunosuppressive regimens are discussed above.

General approach to HCV therapy  — Key questions related to antiviral therapy include the following:

When should antiviral therapy be initiated? What antiviral drug should be used and what is the dose? What is the duration of antiviral therapy? How should patients receiving antiviral therapy be monitored?

In general, antiviral therapy should be delayed for one to four months in patients with severe disease who require initial therapy with immunosuppressant agents.

The specific antiviral drugs and doses used depend upon the HCV genotype (ie, interferon and ribavirin for genotypes 2, 3, and 4, with the addition of eitherboceprevir or telaprevir for genotype 1) and also upon the renal function. (See 'Drugs and dosing in HCV therapy' below.)

The duration of antiviral therapy is based upon the HCV genotype, prior treatment response, type of antiviral agent used, tolerance to treatment, and the clinical and laboratory response to treatment. In general, we favor 48 weeks of therapy in patients with genotype 1 or genotype 4, and 24 weeks in patients with genotype 2 and genotype 3.

We generally follow renal and hepatic function weekly during the first two weeks of antiviral therapy, and then monthly thereafter. HCV viral loads should be obtained at weeks 4, 12, 24, and 48, and then six months after the completion of therapy. The frequency of follow-up visits in the clinic depends upon the cryoglobulinemia disease activity, treatment regimen, comorbidities, and tolerance of therapy.

Initiation of HCV therapy  — In patients with chronic HCV infection (without decompensated cirrhosis) and mixed cryoglobulinemia, we recommend that antiviral therapy be attempted. However, among patients with severe vasculitic manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy) who have not yet been treated with antiviral therapy, we suggest that immunosuppressive therapy be initiated first and that antiviral therapy be delayed for one to four months. These recommendations and suggestions are in agreement with the EULAR and GISC guidelines [ 6,9,33 ].

The rationale for delaying antiviral therapy by one to four months in patients who require immunosuppressive therapy is as follows:

Immunosuppressive therapy can rapidly improve inflammation and resolve target organ damage. Clinical improvements due to antiviral therapy are gradual.

High-dose immunosuppressive therapy and antiviral therapy each have side effects. Thus, patients may not be able to tolerate both treatments simultaneously.

Antiviral medications may occasionally produce renal, neurological, or cutaneous manifestations that could confound the evaluation of whether immunosuppressive therapy is effective.

Drugs and dosing in HCV therapy  — The antiviral drugs and doses used to treat chronic HCV infection in patients with mixed cryoglobulinemia follow the same general principles as they do in patients who do not have mixed cryoglobulinemia.

Drug selection depends in part upon the HCV genotype: Genotype 1 – Patients with HCV genotype 1 should receive pegylated

interferon, ribavirin , and a protease inhibitor ( telaprevir or, preferably, boceprevir). As discussed later, however, patients with an estimated glomerular filtration rate (eGFR) less than 50 mL/min per 1.73 m 2 should not receive a protease inhibitor.

Genotype 2, 3, or 4 – Patients with infected HCV genotypes 2, 3, or 4 should receive pegylated interferon and ribavirin .

Between the available protease inhibitors, we prefer boceprevir in patients with mixed cryoglobulinemia because telaprevir may cause a rash in up to 56 percent of patients.

Although the rash associated with telaprevir is usually maculopapular (as opposed to purpuric), it could be confused with worsening cutaneous manifestations in patients with mixed cryoglobulinemia. Boceprevir is much less likely to cause a rash and might be favored in this circumstance.

Drug selection also depends upon the baseline eGFR. This is an important consideration in patients with mixed cryoglobulinemia because 20 to 30 percent of affected patients will have renal manifestations. We suggest the following therapeutic approach based upon the 2011 FDA guidelines pertaining to the use of pegylated interferon alfa 2a and ribavirin according to eGFR:

eGFR greater than 50 mL/min per 1.73 m 2 – Pegylated interferon and ribavirin are given at doses that are identical to those recommended for patients with chronic HCV infection who have normal renal function. (See "Treatment regimens for chronic hepatitis C virus genotype 1", section on 'Doses of peginterferon and ribavirin' and "Treatment regimens for chronic hepatitis C virus genotypes 2, 3, and 4", section on 'Doses of peginterferon and ribavirin'.)

eGFR 30 to 50 mL/min per 1.73 m 2 – Pegylated interferon alfa 2a is given subcutaneously at a dose of 180 mcg per week; ribavirin is given orally at alternating doses of 200 and 400 mg every other day.

eGFR 15 to 29 mL/min per 1.73 m 2 – Pegylated interferon alfa 2a is given subcutaneously at a dose of 135 mcg per week; ribavirin is given orally at a dose of 200 mg per day.

eGFR <15 ml/min or on dialysis (hemodialysis or peritoneal dialysis) – Treatment is controversial. We suggest one of the following: standard interferon alfa (2a or 2b), 3 million units three times weekly; pegylated interferon alfa-2b , 1 mcg/kg per week; or pegylated interferon alfa-2a , 135 mcg per week plus ribavirin at 200 mg/day with close monitoring.

The Cockcroft-Gault equation is used to calculate eGFR for the purposes of dosing antiviral therapy ( calculator 1 and calculator 2 ). This equation is discussed in detail separately.

The patient's weight is used in the Cockcroft-Gault equation. However, the dosing body weight, rather than actual body weight, should be used. If the patient's actual body weight is not more than 20 percent above ideal body weight, then dosing weight is equal to ideal body weight. However, if the actual body weight is more than 20 percent above ideal body weight, then the dosing weight is somewhat higher. The following calculator permits calculation of ideal body weight and dosing weight ( calculator 3 ).

The above approach for dosing in the setting of kidney disease differs slightly from published guidelines and is based upon personal experience. The American Association for the Study of Liver Disease (AASLD) recommended the following [ 37 ]: patients with an eGFR greater than 60 mL/min per 1.73 m 2 should receive standard doses of pegylated interferon and ribavirin that would be utilized in patients without kidney disease; patients with an eGFR less than 60mL/min per 1.73 m 2 who are not on dialysis should receive either pegylated interferon alfa 2a at a dose of 135 mcg per week or pegylated interferon alfa 2b at a dose of 1 mcg/kg per week and ribavirin at 200 to 800 mg per day with careful monitoring. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2008 provided different recommendations [ 38 ]: patients with an eGFR greater than or equal to 50 mL/min per 1.73 m 2 should receive standard pegylated interferon and ribavirin doses; patients with an eGFR greater than or equal to 15 but less 50 mL/min per 1.73 m 2 should receive pegylated

interferon monotherapy adjusted for level of kidney function and no ribavirin; patients with an eGFR less than 15 mL/min per 1.73 m 2 should receive standard (non-pegylated) interferon with dose adjustments based upon the level of renal function.

Telaprevir and boceprevir are primarily metabolized by the liver and therefore should not require dose adjustments based upon glomerular filtration rate (GFR). However, these drugs have not been evaluated in patients with reduced kidney function. Thus, while awaiting additional safety and efficacy data, they shouldnot be used in patients with an eGFR less than 50 mL/min per 1.73 m 2 .

It should be emphasized that a multidisciplinary approach is needed to best care for patients with HCV and mixed cryoglobulinemia. The multidisciplinary team should include a nephrologist, a hepatologist, and a rheumatologist who all have experience in treating these complex patients.

Evidence for efficacy  — The presence of cryoglobulinemia does not appear to dampen the response to antiviral therapy. As noted above, the combination of pegylated interferon alfa and ribavirin is the preferred treatment for patients with mixed cryoglobulinemia due to HCV infection. Although there are no trials specifically in patients with mixed cryoglobulinemia, several observational studies suggest that combination therapy is effective:

A retrospective study compared the outcomes of 32 patients treated with standard (non-pegylated) interferon alfa-2b (3 million international units three times a week) plus ribavirin with 40 patients treated with pegylated interferon alfa-2b (1.5 mcg/kg per week) plus ribavirin [ 39 ]. These treatments were continued for at least six months (mean duration 18 months with standard interferon and 13 months with pegylated interferon), and patients were followed for a mean of 40 months after discontinuation of antiviral therapy. Six months after completion of antiviral therapy, patients who received pegylated interferon alfa plus ribavirin had somewhat higher rates of clinical remission from cryoglobulinemia (68 versus 56 percent), sustained virologic response (62 verus 53 percent), and disappearance of circulating cryoglobulins (58 versus 31 percent). Notably, severe manifestations were more common in the group receiving standard interferon (27 of 32) as compared with pegylated interferon (15 of 40); severe manifestations were treated with glucocorticoids, cyclophosphamide , and/or plasma exchange.

A pilot study of 18 patients with mixed cryoglobulinemia due to HCV infection evaluated the response to pegylated interferon alfa-2b (1 mcg/kg per week) plus ribavirin (1000 mg daily) for 48 weeks, regardless of HCV genotype [ 40 ]. This dose of pegylated interferon alfa is lower than what is typically used. Although most patients improved clinically during treatment, eight (44 percent) relapsed virologically and clinically within a few weeks after the end of treatment. At the end of follow-up, only eight patients (44 percent) achieved a sustained virologic response.

In patients with genotype 1, protease inhibitors are also recommended. However, only preliminary efficacy data are available for triple therapy with protease inhibitors, interferon, and ribavirin in patients with mixed cryoglobulinemia [ 41 ].

Interferon alfa monotherapy has been replaced by pegylated interferon and ribavirin for treatment of HCV infection in most patients. However, standard (non-pegylated) interferon

alfa is also effective in patients who have mixed cryoglobulinemia; the range of therapeutic effects is illustrated by the following examples:

A randomized, controlled, crossover trial examined the effects of non-pegylated interferon alfa (2 million international units daily for one month and then three times per week for an additional five months) in 26 patients with mixed cryoglobulinemia, 91 percent of whom had circulating HCV RNA [ 42 ]. Interferon therapy produced clinical improvements in purpura but did not change the course of peripheral neuropathy. Patients quickly relapsed after discontinuation of interferon.

In an open-label trial, 53 patients with mixed cryoglobulinemia were randomly assigned to receive non-pegylated interferon alfa monotherapy (1.5 million international units three times weekly for one week followed by 3 million international units three times weekly for an additional 23 weeks) or to no antiviral therapy [ 43 ]. All patients continued to receive other standard medications as indicated. At baseline, 75 percent of patients had glomerulonephritis, and 28 percent had neuropathy; seven patients in each group received concurrent glucocorticoid therapy. Patients who did not receive antiviral therapy had no clinical or serologic improvement. In addition, those patients who received antiviral therapy but did not obtain virologic suppression had no clinical or serologic improvement. Conversely, 60 percent of treated patients who achieved a virologic response had an improvement in clinical parameters such as purpura, serum creatinine, and proteinuria. After cessation of therapy in these patients, both viremia and the clinical manifestations of cryoglobulinemia recurred.

These and other studies suggest an important role of interferon alfa in symptomatic cryoglobulinemia associated with HCV ( figure 1 ) [ 34,42-51 ]. However, cessation of interferon therapy results in recurrence of viremia and vasculitis in almost all patients.

Duration of therapy  — In general, the duration of antiviral therapy in patients with HCV infection and mixed cryoglobulinemia is similar to that in patients with HCV infection who do not have mixed cryoglobulinemia. The duration of therapy depends upon a variety of factors, including the HCV genotype, the response to a past attempt at antiviral therapy, and the virologic response to the present attempt at antiviral therapy. A detailed discussion of treatment duration is presented elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1" and "Treatment regimens for chronic hepatitis C virus genotypes 2, 3, and 4" .)

In general, therapy with pegylated interferon and ribavirin is continued for 48 weeks in patients infected with HCV genotypes 1 and 4, and for 24 weeks in patients infected with HCV genotypes 2 and 3. However, some experts suggest that extended durations (up to 72 weeks for genotypes 1 and 4, and 48 weeks for genotypes 2 and 3) should be considered in nonresponders [ 6 ].

Although data are limited, patients with mixed cryoglobulinemia infected with HCV genotype 1 should receive a protease inhibitor (preferably boceprevir ).

Response-guided therapy and futility rules are used in patients with mixed cryoglobulinemia due to HCV genotype 1 who are receiving regimens that include a protease inhibitor. In general, we adhere to the rules used in patients without mixed cryoglobulinemia; these rules are presented elsewhere in detail. (See"Response-guided therapy for chronic hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1", section

on 'Monitoring viral load during therapy' .) However, if the clinical features of mixed cryoglobulinemia are improving in a patient treated with antiviral therapy, we may continue pegylated interferon and ribavirin for 48 weeks even if futility rules are met.

For patients with HCV genotype 2, 3, or 4 infection who are receiving therapy with pegylated interferon and ribavirin , it is acceptable to continue pegylated interferon monotherapy as maintenance treatment if the cryoglobulinemia responds favorably to treatment, despite a lack of virologic response.

Monitoring of patients on antiviral therapy  — The frequency of monitoring patients on antiviral treatment is dependent upon multiple variables including, but not limited to:

The disease activity of the cryoglobulinemia The treatment regimen for HCV The individual patient and his/her comorbidities Presence of cirrhosis with or without portal hypertension The tolerance to therapy

In many patients, we measure a complete blood count and serum chemistries (including renal function, liver function, and blood glucose) weekly during the first two weeks of antiviral therapy, and then monthly thereafter. A thyroid-stimulating hormone should be checked after three months. We obtain HCV viral loads at weeks 4, 12, 24, and 48, and then six months after the completion of therapy. The response-guided therapy and futility rules in hepatitis C rely upon the viral load at certain intervals on therapy. Monitoring of the virologic response and futility rules are presented elsewhere. Patients with cirrhosis and portal hypotension may require more frequent monitoring due to higher risk of side effects.

In addition, patients should be monitored for signs of infection, neuropsychiatric side effects (eg, depression), and other side effects of pegylated interferon and ribavirin .

There are, however, somewhat unique aspects in the follow-up of patients with HCV infection who also have mixed cryoglobulinemia:

Flares of cryoglobulinemia or other immune-mediated events can rarely be induced by treatment with interferon alfa [ 52-55 ]. As an example, exacerbations of vasculitis due to pegylated interferon have been reported [ 56 ]. If an exacerbation of vasculitis occurs in a patient whose disease was previously stable or improving and who does not have serologic evidence of worsening disease (eg, decreasing serum complement), consideration should be given to temporarily lowering the dose of antiviral therapy or, if manifestations are severe, temporarily discontinuing therapy.

Similarly, interferon can produce side effects that may mimic some of the manifestations of cryoglobulinemia, such as arthralgias, fever, or rash. In such cases, antiviral therapy may be temporarily discontinued provided a protease inhibitor is not part of the regimen. For those patients whose regimen includes a protease inhibitor who temporarily stop therapy, the protease inhibitor should not be restarted. .

HCV viral particles may be incorporated into the cryoprecipitate and centrifuged during preparation of serum samples or may precipitate from the serum during storage. To prevent falsely low measurements of the viral load, blood specimens may require special handling. To ensure accurate quantitation of the HCV viral load, specimens should be kept at 37 degrees centigrade during serum

preparation, and any cryoprecipitate should be dissolved or suspended into the serum before measuring the viral load.

In patients receiving plasmapheresis, blood sample collection obtained to measure the viral load should be delayed until after re-equilibration, which may take several hours.

Anti-HBV therapy  — Although HCV infection is the major cause of essential mixed cryoglobulinemia, some cases (as high as 15 percent in one series) are associated with HBV infection [ 44 ].

In patients with mixed cryoglobulinemia due to HBV infection, treatment with entecavir is usually preferred in view of its antiviral efficacy, low propensity for drug resistance, and low risk for nephrotoxicity. The best data supporting these nucleoside/nucleotide analogs in HBV-associated mixed cryoglobulinemia come from case reports that describe patients who achieved remission with entecavir or lamivudine [ 57-60 ]. Other nucleoside/nucleotide analogs, such as adefovir, telbivudine , and lamivudine, have been used but have a higher risk of resistance and, with adefovir, a higher risk of nephrotoxicity [ 57,58,61 ]. The use ofnucleoside/nucleotide analogs in patients with HBV infection, as well as the dosing of these drugs in patients with reduced renal function, is described in detail elsewhere ( table 1 and table 2 ).

Interferon alfa also has activity against HBV infection, and pegylated interferon could theoretically be used in patients with non-cirrhotic chronic hepatitis B and non-severe cryoglobulinemia, although there are no data available to support this approach. In addition, using the oral nucleoside/nucleotide agents avoids the risk of immune-mediated events or disease flares associated with interferon [ 52-55 ]. Thus, we generally favor the use of nucleoside/nucleotideanalogs over pegylated interferon for treatment of HBV infection in the setting of cryoglobulinemia.

In patients with mixed cryoglobulinemia due to HBV infection who have severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy), we recommend immunosuppressive therapy with glucocorticoids; rituximab therapy should only be used in selected patients with suppressed viremia and without active hepatitis .

Patients with chronic HBV infection and cryoglobulinemia should be started on treatment with an antiviral medication as soon as possible when immunosuppressive therapy is planned, regardless of HBe and HBV DNA status. This contrasts with our suggestion to delay antiviral therapy in patients with HCV infection when immunosuppression is planned. (See 'Immunosuppressive therapy for severe mixed cryoglobulinemia' above.) Rituximab therapy could be considered, as mentioned above, for patients who do not have chronic active hepatitis and who have controlled viremia. However, the published experience with rituximab for HBV-associated mixed cryoglobulinemia is limited, and there is potential for fatal complications [ 62 ].

Beginning antiviral therapy (preferably with entecavir ) as soon as possible when immunosuppression is planned serves two purposes:

It can protect against a HBV flare, especially when rituximab is used. Rituximab therapy should not be started in patients with chronic HBV unless antiviral therapy

is also given and not in patients with chronic active hepatitis. Otherwise, potentially fatal hepatitis may result. (See "Hepatitis B virus reactivation associated with immunosuppression" .)

It can protect against the increased HBV replication associated with glucocorticoid therapy. (See "Hepatitis B virus reactivation associated with immunosuppression" .)  

HBV viral suppression may induce remission of mixed cryoglobulinemia.

In the absence of data, we suggest that antiviral therapy in such patients be continued indefinitely. Monitoring of chronic HBV infection in patients treated with antiviral therapy is presented elsewhere.

Autoimmune disorders  — Mixed cryoglobulinemia can occur in patients with various autoimmune disorders, such as Sjögren syndrome, systemic lupus erythematosus, or rheumatoid arthritis.Such patients should be treated for their underlying disorder.

In patients with mixed cryoglobulinemia due to autoimmune disorders who have severe vasculitic manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy), we also suggest combination therapy with rituximab (or cyclophosphamide as an alternative) and glucocorticoids, as mentioned above.

Lymphoma  — Mixed cryoglobulinemia can occur in patients with non-Hodgkin lymphoma, although cryoglobulinemia occurring with lymphoma are usually type I. Such patients should be referred to an appropriate specialist and treated for the underlying malignancy. An overview of such protocols, with links to discussions of specific lymphomas, is presented elsewhere.

Rituximab is commonly used in the treatment of B-cell lymphomas typically associated with mixed cryoglobulinemia, which may be helpful for treating the malignancy as well as the autoimmune disorder [ 63 ].

Idiopathic disease  — Occasional patients with mixed cryoglobulinemia may have no identifiable underlying disorder despite an extensive evaluation. Therapy depends upon the severity of the clinical manifestations:

Severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy) – In such patients, the immunosuppressive protocols outlined above, including the use of rituximab , should be followed. (See 'Choice of immunosuppressive therapy' above.)

Mild to moderate manifestations – Such patients can be managed with colchicine (1 to 2 mg/day orally) or low doses of glucocorticoids (eg, prednisone , 10 to 25 mg/day). If prednisone is used, we attempt to taper the dose to less than 10 mg/day by six months, depending upon the clinical response [ 14].

PROGNOSIS  — The short-term prognosis in patients with very severe manifestations is generally poor, particularly for the patients who develop acute pulmonary hemorrhage, intestinal vasculitis with gastrointestinal hemorrhage or ischemia, or rapidly progressive glomerulonephritis [ 25,64 ]. In one series of 29 patients with these manifestations, for example, the mortality was 66 percent during an average follow-up of 3.6 years [ 25 ].

The long-term prognosis of patients with HCV-associated mixed cryoglobulinemia syndrome appears to have improved with the use of antiviral therapy, although long-term follow-up of

cohorts receiving modern therapy (ie, pegylated interferon, ribavirin , with or without protease inhibitors) is not available. However, the introduction of interferon monotherapy in some patients illustrates an improving trend:

A report of 105 patients with renal involvement (85 percent of whom were anti-HCV antibody positive) provided data on the long-term prognosis priorto treatment with interferon [ 65 ]. The 10-year patient survival was 49 percent after the diagnosis, with most deaths attributed to cardiovascular or hepatic disease or infection. Only 14 percent developed end-stage renal disease (ESRD) at 10 years, possibly because patients with severe disease died from other causes before the onset of ESRD.

A study of 146 patients with mixed cryoglobulinemia and renal involvement were followed for over 10 years in an Italian cohort that began in 1995; 38 percent of patients received interferon monotherapy [ 1 ]. The 10-year patient survival was approximately 80 percent. Those with worse renal function at baseline had a worse prognosis. Cardiovascular disease was the cause of death in more than 60 percent of patients.

As noted above, not all patients with HCV infection and cryoglobulinemia respond to interferon treatment. In addition, the vasculitic manifestations of cryoglobulinemia in patients who do have a virologic response to antiviral therapy may persist or recur after cessation of antiviral therapy [ 66 ].

The prognosis of patients with mixed cryoglobulinemia syndrome who do not have a viral etiology may be similar or worse than in patients with a chronic viral infection. In a French cohort of 242 patients with non-infectious mixed cryoglobulinemia, the one-, two-, five-, and ten-year patient survival rates were 91, 89, 79, and 65 percent, respectively [ 67 ]. The four independent predictors of death in this cohort were age greater than 65 years, renal involvement (with reduced renal function), pulmonary involvement, and gastrointestinal involvement. The 10-year survival among patients with renal impairment was approximately 50 percent, similar to patients with HCV-associated mixed cryoglobulinemia and renal involvement prior to the availability of interferon therapy.

END-STAGE RENAL DISEASE  — Those patients who progress to end-stage renal disease (ESRD) can be treated with dialysis or renal transplantation. Survival on either hemodialysis or peritoneal dialysis is broadly similar to that in patients with other renal diseases.

Renal transplantation has been successfully performed in mixed cryoglobulinemia. Clinically significant disease can recur in 50 to 70 percent of cases, even in patients in clinical and serologic remission at the time of transplantation [ 27,68,69 ]. Affected patients present with findings similar to those in the primary disease: purpura, hypocomplementemia, hematuria, proteinuria, and renal impairment. These findings, however, should not deter transplantation since most patients do not lose the graft to recurrent disease [ 68 ].

There is potential theoretical concern that maintenance immunosuppressive therapy after transplantation might exacerbate underlying HCV infection, but this has not proven to be a major problem [ 68 ]. The approach to therapy in patients after renal transplantation is discussed separately.

SUMMARY AND RECOMMENDATIONS

The mixed cryoglobulinemia syndrome is most often induced by hepatitis C virus (HCV) infection and, occasionally, hepatitis B. It can also be associated with autoimmune or lymphoproliferative disorders and, rarely, can be idiopathic. Typically, it follows a chronic, smoldering course. Infrequently, mixed cryoglobulinemia may present with a rapidly progressive or even life-threatening course. (See 'Introduction' above.)

The general approach to therapy in patients with mixed cryoglobulinemia syndrome includes two broad principles (see 'General approach to therapy'above):

Initial immunosuppressive therapy – Immunosuppression is provided as initial therapy in those patients identified as having a rapidly progressive, organ-threatening, or life-threatening course, regardless of the etiology of the mixed cryoglobulinemia. Immunosuppressive therapy usually combines a short course of glucocorticoids with either rituximab or cyclophosphamide and, in some patients, plasmapheresis. (See 'Immunosuppressive therapy for severe mixed cryoglobulinemia' above.)

Treatment of the underlying disease – All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with HCV should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy. In some cases, this will involve continuation of immunosuppression for a prolonged period. (See 'Treat the underlying disorder in all patients' above.)

In patients with mixed cryoglobulinemia syndrome and severe disease-associated manifestations, we recommend immunosuppressive therapy plus treatment of the underlying etiology, rather than therapy directed at the underlying etiology alone ( Grade 1B ). Severe disease-associated manifestations include (see 'Patient selection' above):

Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria

Severe digital ischemia threatening amputation Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal

bleeding Rapidly progressive neuropathy Central nervous system vasculitis that may present as a stroke or acute cognitive

impairment Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory

failure Heart failure In patients with mixed cryoglobulinemia due to HIV or HBV infections, antiviral

therapy should always be initiated before or at the same time as immunosuppressive therapy. (See 'Immunosuppressive therapy for severe mixed cryoglobulinemia' above.)

In most patients selected for initial immunosuppressive therapy, we suggest rituximab rather than other immunosuppressive drugs such ascyclophosphamide or glucocorticoids alone ( Grade 2B ). In addition, we suggest pulse glucocorticoid therapy followed by a rapid taper in most patients rather than prolonged glucocorticoid therapy or no glucocorticoid therapy ( Grade 2C ). In those patients with life-threatening disease or cryoglobulinemia-associated hyperviscosity syndrome, we also suggest plasmapheresis in addition to immunosuppressive therapy ( Grade 2C ). (See'Choice of immunosuppressive therapy' above and 'Preference for rituximab' above and 'Role of plasma exchange' above.)

The rituximab , glucocorticoid, and plasmapheresis regimens used are discussed above.

We would not use rituximab to treat mixed cryoglobulinemia in the following patients :

In patients with HIV infection who are not receiving highly active antiretroviral therapy (HAART). Such patients are at high risk for enhanced viral replication as a result of rituximab therapy. (See "Selecting antiretroviral regimens for the treatment naive HIV-infected patient" .)

In patients with HBV infection who are not receiving antiviral therapy or have chronic active hepatitis. (See 'Anti-HBV therapy' above.)

The use of cyclophosphamide therapy in patients with mixed cryoglobulinemia, particularly in patients with HCV or HBV infection, carries the risk of enhancing viral replication. In patients with organ-threatening or life-threatening disease, cyclophosphamide therapy may be used as an alternative torituximab if rituximab therapy is unavailable, fails to produce a clinical response, or is not tolerated. When used, cyclophosphamide can be used in combination with glucocorticoids with or without plasma exchange, similar to rituximab. The cyclophosphamide dose in such patients is 2 mg/kg per day orally for two to four months. The initial dose should be adjusted according to the age and glomerular filtration rate (GFR). (See 'Role of cyclophosphamide' above.)

Prophylaxis against opportunistic infections, such as Pneumocystis pneumonia, should be provided in patients with mixed cryoglobulinemia who are receiving immunosuppressive therapy. Patients should also receive age-appropriate immunizations, ideally several weeks before the initiation of immunosuppression. (See 'Antimicrobial prophylaxis' above.)

The following approach to therapy applies to most patients with mixed cryoglobulinemia due to HCV infection (see 'Therapy for HCV infection' above):

In general, antiviral therapy should be delayed for one to four months in patients with severe disease who require initial therapy with immunosuppressant agents. (See 'Initiation of HCV therapy' above.)

The specific antiviral drugs and doses used depend upon the HCV genotype (ie, pegylated interferon and ribavirin for genotypes 2, 3, and 4, with the addition of a either boceprevir or telaprevir for genotype 1) and also upon the renal function. Antiviral therapy is contraindicated in patients with decompensated cirrhosis. (See 'Drugs and dosing in HCV therapy' above.)

The duration of antiviral therapy is based upon the HCV genotype (ie, genotype 1 versus genotypes 2, 3, and 4), prior treatment response, tolerance to treatment, and the clinical and laboratory response to treatment. In general we favor 48 weeks of therapy in patients with genotype 1 or genotype 4, and 24 weeks in patients with genotype 2 and genotype 3.

We generally follow renal and hepatic function weekly during the first two weeks of antiviral therapy, and then monthly thereafter. HCV viral loads should be obtained at weeks 4, 12, 24, and 48, and then six months after the completion of therapy. The frequency of follow-up visits in the clinic depends upon the cryoglobulinemia disease activity, treatment regimen, comorbidities, and tolerance of therapy. Patients with cirrhosis and portal hypertension may require more frequent monitoring due to higher risk of side effects. In patients with mixed cryoglobulinemia due to HBV infection, treatment with entecavir is usually preferred in view of its antiviral efficacy, low propensity for drug resistance, and low risk for nephrotoxicity. Antiviral therapy is usually continued indefinitely. In patients with mixed cryoglobulinemia due to HBV infection who have severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy), initial immunosuppressive therapy with glucocorticoids can be used. However, antiviral therapy should be initiated as soon as possible when immunosuppressive therapy is planned (preferably prior to the initiation of immunosuppressive therapy), regardless of HBe and HBV DNA status. If addition

of rituximab is considered, antiviral therapy in mandatory and rituximab should not be used in patients with chronic active hepatitis. Otherwise, potentially fatal hepatitis may result

Patients with mixed cryoglobulinemia due to autoimmune disorders who have severe vasculitic manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy) should receive immunosuppressive therapy with rituximab (or cyclophosphamide as an alternative) and glucocorticoids. The regimen is similar to the regimen used for all other patients with mixed cryoglobulinemia and severe manifestations. In patients with mild to moderate clinical manifestations, therapy is directed at the underlying etiology.

Patients with mixed cryoglobulinemia due to lymphoma should be referred to an appropriate specialist and treated for the underlying malignancy.Rituximab is commonly used in the treatment of B-cell lymphomas typically associated with mixed cryoglobulinemia

Occasional patients with mixed cryoglobulinemia may have no identifiable underlying disorder. Therapy depends upon the severity of the clinical manifestations (see 'Idiopathic disease' above):

Severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy) – In such patients, the immunosuppressive protocols outlined above should be followed.

Mild to moderate manifestation – Such patients can be managed with colchicine (1 to 2 mg/day orally) or low doses of glucocorticoids (eg, prednisone , 10 to 25 mg/day). If prednisone is used, we attempt to taper the dose to less than 10 mg/day by six months, depending upon patient response.

The 10-year survival among patients with mixed cryoglobulinemia varies depending upon organ involvement and the underlying cause of the disorder, ranging from 50 to 80 percent. However, the short-term prognosis in patients with very severe manifestations is generally poor, particularly for the patients who develop acute pulmonary hemorrhage, intestinal vasculitis with gastrointestinal hemorrhage or ischemia, or rapidly progressive glomerulonephritis.