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Mixed cryoglobulinemia syndrome: Treatment and prognosis

Mixed cryoglobulinemia syndrome: Treatment and prognosis
Literature review current through: Jan 2024.
This topic last updated: Mar 16, 2022.

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 and depends upon the severity of the disease and response of the underlying disorder to therapy.

The treatment and prognosis 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:

(See "Overview of cryoglobulins and cryoglobulinemia".)

(See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

PRETREATMENT EVALUATION

Assessment for associated underlying disease — All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with HCV who have chronic hepatitis should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy. Some patients will require continuation of immunosuppression for a prolonged period while treatment of the underlying disease is ongoing. (See 'Disease-specific management considerations' below.)

Assessment of disease severity — In general, the severity of the mixed cryoglobulinemia syndrome guides some of the therapeutic decisions. There are no universally agreed upon definitions of disease severity. We use the following descriptions as a guide:

Mild disease – Patients with mild disease include those with clinical manifestations such as petechial rash without necrotizing lesions, mild sensory neuropathy, arthralgias, or arthritis who have no evidence of an organ threatening process (eg, glomerulonephritis, progressive neuropathy, digital ischemia). In general, such patients are often managed symptomatically while the associated underlying disease is being treated, and they generally do not require immunosuppressive therapy. (See 'Mild disease' below.)

Moderate to severe disease – Moderate to severe manifestations of mixed cryoglobulinemia can be life threatening and include the following:

Biopsy-proven glomerulonephritis associated with or without a rapidly progressive course

Digital ischemia threatening amputation or necrotizing skin ulcer(s)

Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding

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

In addition to treating the associated underlying disease (when present), patients who have one or more of these manifestations should be treated with immunosuppressive therapy to rapidly improve or resolve target-organ damage, rather than therapy directed at the underlying etiology alone. Immunosuppressive therapy usually combines a short course of glucocorticoids with rituximab and, in selected patients, plasmapheresis. (See 'Moderate to severe disease' below.)

GENERAL MEASURES IN ALL PATIENTS

Supportive measures – Pain is a frequent symptom among patients with mixed cryoglobulinemia, particularly among those with peripheral neuropathy, ulcerating skin lesions, and/or arthralgia/arthritis. All patients with mixed cryoglobulinemia should receive pain control and wound care as appropriate. Cold exposure should be avoided. (See "Basic principles of wound management" and "Overview of polyneuropathy", section on 'Treatment of symptoms and prevention of complications'.)

Prophylaxis against opportunistic infection – Patients treated with the combination of high-dose prednisone and/or other immunosuppressive agents should receive Pneumocystis pneumonia prophylaxis. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

A common prophylactic strategy for patients with normal kidney function is the use of trimethoprim-sulfamethoxazole (TMP/SMZ), which may be given as one double-strength tablet daily or three times per week or as one single-strength tablet daily. Prophylactic regimens for Pneumocystis pneumonia are discussed in detail separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Regimens'.)

Patients should also receive age-appropriate immunizations, before the initiation of immunosuppression, if possible. This is especially true for those receiving rituximab, who are B cell depleted and unlikely to mount a humoral response to vaccines (eg, COVID-19 vaccine). (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

MILD DISEASE — In general, patients with mixed cryoglobulinemia who have mild disease typically do not require immunosuppressive therapy (algorithm 1). The management of such patients should primarily focus on treatment of the underlying disease. Additional therapies should be guided by the patient's symptoms:

Patients with nonulcerating skin lesions can be managed similarly to those with idiopathic cutaneous small vessel vasculitis, with agents that include with systemic glucocorticoids, colchicine, or dapsone [1,2]. (See "Management of adults with idiopathic cutaneous small vessel vasculitis", section on 'Management'.)

Patients with mild sensory neuropathy can be treated with pain-modifying agents, including amitriptyline/nortriptyline, duloxetine, gabapentin, or pregabalin. We prefer to avoid the use of opioid analgesics for neuropathic pain. (See "Management of diabetic neuropathy", section on 'Pain management'.)

Patients with arthralgias or arthritis who have preserved kidney function can be treated with nonsteroidal antiinflammatory drugs (NSAIDs). Low-dose oral glucocorticoids (eg, prednisone 10 mg daily or equivalent) can be used if the response to NSAIDs is inadequate or if there is any concern about kidney function impairment. These medications are given in the same manner as for symptomatic treatment of rheumatoid arthritis (see "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'). Hydroxychloroquine (maximum daily dose of 5 mg/kg/day) can also be used in patients with overt arthritis [3]. We use the same regimen as that used for rheumatoid arthritis. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Hydroxychloroquine'.)

Patients with mild disease should be monitored according to their symptom severity, typically every three to six months.

MODERATE TO SEVERE DISEASE

Initial management — The overall management approach to patients with moderate to severe mixed cryoglobulinemia should involve targeted treatment of the underlying disease responsible for the cryoglobulinemia along with additional immunosuppressive therapy (algorithm 1). In most cases, immunosuppressive therapy is initiated first, and then after disease stabilization, therapy for the underlying disorder (eg, antiviral therapy in patients with chronic hepatitis C virus [HCV] infection) is added. Exceptions to this approach include mixed cryoglobulinemia due to HIV or hepatitis B virus (HBV) infections; in such patients, antiviral therapy should be initiated before or at the same time as immunosuppressive therapy (see 'Disease-specific management considerations' below). Some patients with life-threatening disease or cryoglobulinemia-associated hyperviscosity syndrome may benefit from plasmapheresis. (See 'Limited role of plasma exchange' below.)

Systemic glucocorticoids plus rituximab — For most patients with moderate to severe mixed cryoglobulinemia syndrome, we suggest initial treatment with high-dose systemic glucocorticoids in combination with rituximab, rather than systemic glucocorticoids alone or in combination with cyclophosphamide. This approach is largely based on evidence from small randomized trials [4,5] and observational studies demonstrating the benefits of rituximab with or without glucocorticoids [6,7]. (See 'Dosing and efficacy of rituximab' below.)

Important considerations regarding the timing of immunosuppressive therapy in the setting of antiviral therapy are discussed further below. (See 'Timing of therapy' below and 'HIV' below and 'Hepatitis B infection' below.)

Dosing of glucocorticoids — Glucocorticoid regimens vary widely among clinicians. Most clinicians attempt to taper patients off glucocorticoids over a period of three to four months. However, the specific management must be tailored to the individual based on their clinical response. An example of a glucocorticoid regimen used by the authors and reviewers of this topic is as follows:

For life-threatening disease, some clinicians use high-dose pulse glucocorticoid therapy such as 1000 mg of intravenous (IV) methylprednisolone given for three days followed by daily oral prednisone. For less severe disease, oral prednisone is used initially. A widely used oral regimen begins with a prednisone equivalent of 1 mg/kg per day (maximum dose of 80 mg) for two to four weeks. This is then tapered to 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 as soon as possible to avoid cardiovascular and metabolic adverse effects. Rituximab may be administered without glucocorticoids (except as premedication) in selected patients, particularly those who have moderate disease (ie, without organ- or life-threatening disease) and cardiovascular or metabolic abnormalities [6,7].

A more rapid glucocorticoid taper may be required if viral reactivation occurs. This is particularly true when mixed cryoglobulinemia is associated with HBV infections. (See 'Hepatitis B infection' below.)

Dosing and efficacy of rituximab — The dose regimen of rituximab typically used is the same as that used for rheumatoid arthritis (1 g of rituximab followed 14 days later by another 1 g dose) [4]. An alternative regimen involves four infusions of rituximab 375 mg/m2 at weekly intervals (day 0, day 7, day 14, day 21) or four infusions of rituximab 375 mg/m2 at weekly intervals (day 0, day 7, day 14, day 21) [8] followed by consolidation treatment of two more infusions of 375 mg/m2 monthly for an additional two months [9]. The rationale for the two additional doses is to induce a more profound B cell depletion. Lower doses of rituximab (250 mg/m2 once weekly for two doses) have been attempted, although they appear to be less effective and associated with relapse and should not be used in patients with severe manifestations (eg, biopsy-proven glomerulonephritis) [10]. Data are lacking regarding the occurrence of anti-rituximab antibodies when rituximab is used in this setting [11]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Administration and dosing'.)

When standard-dose rituximab regimens are used, four weekly infusions of 375 mg/m2 are preferred over 1 g given two weeks apart in patients with high titer rheumatoid factor, very low C4, or a very high cryocrit (ie, ≥10 percent). In such patients, administration of 1 g of rituximab may be associated with acute passive serum sickness, which can be fatal due to the interaction of the immunoglobulin G (IgG) of rituximab with the monoclonal immunoglobulin M (IgM) anti-IgG present in the mixed (type II) cryoglobulins [12]. Two to three sessions of plasma exchange in order to reduce the cryocrit can be considered before administering rituximab. (See 'Limited role of plasma exchange' below.)

Rituximab is generally well-tolerated in patients with mixed cryoglobulinemia. Short-term infusion reactions following rituximab do not appear to be more frequent in patients with mixed cryoglobulinemia compared with those with rheumatoid arthritis. Rituximab-associated disease flare has also been reported between two and seven days after rituximab administration and is more likely to occur in patients with underlying B cell lymphoproliferative disorder [13]. Additional details regarding drug administration and methods to decrease the risk of infusion reactions as well as pretreatment testing for hepatitis B and C viruses are discussed separately (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis"). Prevention of opportunistic infections during immunosuppressive therapy is discussed further below. (See 'General measures in all patients' above.)

In addition to evidence from several observational studies [8,9,11,14-16], data from two randomized trials support the use of rituximab in patients with severe manifestations of mixed cryoglobulinemia [4,5]. These studies also show that administration of rituximab is associated with a decrease in cumulative glucocorticoid dose:

In the largest randomized trial that included 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), patients were assigned to either rituximab therapy (1000 mg intravenous infusion at baseline and at day 14) or conventional immunosuppressive therapy [4]. Conventional immunosuppressive therapy varied according to the treating clinician; 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 the proportion of patients who continued taking their initial therapy through 12 months. Reasons for treatment failure included either a lack of clinical improvement or side effects requiring that the therapy be changed. More patients receiving rituximab therapy continued with the initial treatment 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.

In a subsequent single-center trial including 24 patients with mixed cryoglobulinemia due to HCV infection, patients were assigned to receive either rituximab therapy (375 mg/m2 given weekly for one month [four doses]) or to continue their current treatments [5]. 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 12 patients assigned to rituximab therapy, six also received glucocorticoids (mean dose of 26 mg prednisone per day), one also received cyclophosphamide, and two also received plasmapheresis. Of the 12 patients assigned to continue their current treatment, three received glucocorticoids (mean dose of 10 mg prednisone per day). At six months, 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.

Rituximab also appears to be effective in patients with mixed cryoglobulinemia syndrome that is not associated with chronic HCV infection. In the French multicenter CryoVas survey, 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 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 associated with a similar clinical response to that of glucocorticoids alone. However, severe infections were more common with rituximab, especially in older adult patients with kidney failure in whom high-dose glucocorticoids were also used, and mortality was similar regardless of the treatment used.

There are limited data on the efficacy and safety of rituximab in patients with mixed cryoglobulinemia who also have cirrhosis. Most studies of rituximab have excluded patients with cirrhosis or have included very small numbers of patients with cirrhosis. In a prospective study, 15 patients with mixed cryoglobulinemia and cirrhosis due to HCV infection were treated with rituximab (375 mg/m2, weekly for four weeks) [17]. 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, limitations to this study include the subjectivity of the outcome measures of ascites and the Child-Pugh score. In addition, a full discussion of adverse events was not included.

Timing of therapy — In general, patients with mixed cryoglobulinemia who have moderate to severe disease should receive immunosuppressive therapy prior to the treatment of the underlying disorder responsible for the cryoglobulinemia (eg, antiviral therapy in patients with chronic HCV infection). This is based upon the rationale that prompt immunosuppressive treatment can more rapidly improve inflammation and resolve target organ damage.

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. In addition, for patients with mixed cryoglobulinemia due to HCV infection who have immediate, life-threatening manifestations (eg, central nervous system, cardiac, or gastrointestinal vasculitis), simultaneous introduction of direct-acting antiviral therapy and immunosuppression is reasonable. (See 'Hepatitis B infection' below and 'HIV' below and 'Hepatitis C infection' below.)

Alternatives to rituximab — 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.

There is no widely accepted regimen for the use of cyclophosphamide in treating mixed cryoglobulinemia. The choice of oral versus intravenous cyclophosphamide is dictated primarily by practice style. We prefer intravenous cyclophosphamide (eg, three monthly pulses of 750 mg/m2 of body surface area) given the lower cumulative dose associated with this administration and subsequent lower risk of toxicity. If oral cyclophosphamide is used, some authors dose at 2 mg/kg/day for two months. Additional information regarding dose adjustments, monitoring, and toxicity is presented separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

Much of the limited observational data available suggesting some improvement with cyclophosphamide for the management of mixed cryoglobulinemia come from a period before it was known that the majority of cases were secondary to HCV infections [18-20]. In one series of 13 patients with mixed cryoglobulinemia, eight were treated with plasma exchange, prednisolone, and oral cyclophosphamide (2 to 3 mg/kg per day), and one received prednisolone and cyclophosphamide without plasma exchange [18]. Nine of 12 patients (75 percent) with skin disease, 9 of 9 (100 percent) with arthralgias, 6 of 9 (67 percent) with kidney disease, and none of 8 with neurologic symptoms experienced clinical improvement. Among patients who received prednisolone and cyclophosphamide, two achieved remission, and five died over a mean of 47 months.

Limited role of plasma exchange — We limit the use of plasma exchange in patients with mixed cryoglobulinemia to only a few clinical scenarios:

Patients with symptomatic hyperviscosity syndrome due to mixed cryoglobulinemia. However, this is extremely rare.

Patients with life-threatening disease manifestations such as acute respiratory failure and pulmonary hemorrhage, acute intestinal vasculitis, or rapidly progressive (crescentic) glomerulonephritis requiring dialysis [21].

Patients with severe, refractory skin ulcers due to cutaneous vasculitis.

Patients with a high cryocrit level (ie, ≥10 percent) prior to the administration of rituximab in order to avoid exacerbation of vasculitis activity. In these cases, two to three sessions of plasma exchange may be sufficient to reduce the cryocrit levels, and administering rituximab as four weekly infusions of 375 mg/m2 is preferred [9,12]. (See 'Dosing and efficacy of rituximab' above.)

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 [22]. (See 'Systemic glucocorticoids plus rituximab' above.)

When initiated, we typically perform daily plasma exchange for 10 to 14 sessions or three exchanges per week (eg, Monday, Wednesday, Friday) for two to three weeks. Plasma exchange should not be performed before at least two to three days from rituximab administration. One plasma volume (approximately 3 liters) should be exchanged per session. The replacement fluid can be 5 percent albumin solution, which should be warmed to prevent precipitation of circulating cryoglobulins [23]. 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. Since cryoprecipitation can also occur in the extracorporeal apheresis circuit in some patients, plasma exchange should ideally be performed in a warmed room with warmed apheresis tubing [24]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Limited evidence from small case reports and case series suggests clinical improvement with plasma exchange in patients with severe disease [15,18,25-30]. 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 plasma exchange is based upon the severity of the disease manifestations [31].

Monitoring the response to therapy — Patients with mixed cryoglobulinemia who receive immunosuppressive therapy should be closely monitored during treatment, and the frequency of monitoring is determined by the severity of disease. In patients with kidney involvement, we monitor blood pressure, serum creatinine level, complement levels, rheumatoid factor levels, and the urinalysis; patients with rapidly progressive glomerulonephritis should be evaluated weekly or biweekly, whereas those without rapidly progressive disease can be evaluated monthly. Patients with neurologic involvement should be monitored by serial neurologic examinations. Digital ischemia and skin involvement should also be monitored on physical examination.

In patients who receive rituximab, some but not all experts measure CD19+ and CD20+ B cell numbers in peripheral blood to ensure that B cell depletion has been achieved. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Monitoring' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Treatment implications of B cell depletion and repopulation'.)

Clinical response is defined by resolution of the initial signs and symptoms and depends upon the organ(s) involved. As an example, a clinical response in patients with kidney involvement is characterized by improvement in blood pressure control, resolution of hematuria, reduction in proteinuria, and an improvement in the estimated glomerular filtration rate (eGFR). The cryoglobulin concentration does not correlate with either the clinical severity of disease or with the response to therapy [31]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Treatment of relapsing disease — In general, patients with relapsing disease should be treated with the same immunosuppressive therapy that was used as initial therapy. The exception to this is in patients who were previously treated with cyclophosphamide, since repeated courses of cyclophosphamide should be avoided due to cumulative toxicity of the drug. In such patients, we treat with systemic glucocorticoids plus rituximab, as discussed above. (See 'Systemic glucocorticoids plus rituximab' above.)

DISEASE-SPECIFIC MANAGEMENT CONSIDERATIONS — All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia. As examples, patients with the hepatitis C virus (HCV) should receive antiviral therapy, while patients with an underlying lymphoproliferative disorder should receive appropriate disease-specific therapy. Occasionally, some patients with mixed cryoglobulinemia may not have an identifiable underlying disorder despite an extensive evaluation. Therapy in such patients depends upon the severity of the clinical manifestations, as discussed above. (See 'Assessment of disease severity' above.)

Infections

Hepatitis C infection — Patients with mixed cryoglobulinemia syndrome associated with HCV infection should be treated with antiviral therapy. The primary goal of antiviral therapy is to achieve a sustained virologic response (SVR). Although HCV viral clearance is usually followed by clinically significant improvement of organ involvement in cryoglobulinemia, it does not uniformly lead to clinical remission. This is due to autonomous, sustained, clonal elaboration of IgM kappa anti-IgG (rheumatoid factor) in the absence of viral replication in a minority of patients [32]. In HCV-infected patients who do improve with antiviral therapy, clinical response closely follows the HCV viral response and almost always occurs within 12 weeks of initiating treatment, but patients may continue to demonstrate improvement in features of cryoglobulinemia for as long as 6 to 12 months following initiation of antiviral therapy [33].

In general, the treatment approach for HCV in patients with mixed cryoglobulinemia is the same as that used in patients with hepatitis C who do not have mixed cryoglobulinemia. The general management of patients with chronic HCV infection, including issues relating to patient selection for treatment and specific treatment regimens, is discussed in detail elsewhere:

(See "Overview of the management of chronic hepatitis C virus infection".)

(See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

(See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

(See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

For patients with moderate to severe vasculitic manifestations, we suggest that immunosuppressive therapy (eg, glucocorticoids plus rituximab) be initiated first and that antiviral therapy be started after disease stabilization. For patients with immediate, life-threatening manifestations like central nervous system, cardiac, or gastrointestinal vasculitis, simultaneous introduction of direct, activating antiviral therapy and immunosuppression is appropriate. There are no randomized trials that have evaluated immediate versus delayed timing of antiviral therapy, and this approach is based upon the rationale that prompt immunosuppressive therapy can more rapidly improve inflammation and resolve target organ damage, whereas clinical improvements due to antiviral therapy are more gradual. This approach may also reduce the potential for intense immunosuppressive therapy to theoretically attenuate the SVR rate. The rationale for delaying antiviral therapy in such patients is discussed in more detail separately. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Patients with HCV-associated renal disease'.)

Our management strategy for mixed cryoglobulinemia associated with HCV is generally consistent with guidelines developed by professional organizations including the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA), European Association for the Study of the Liver (EASL), European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism), Italian Group for the Study of Cryoglobulinemias (GISC), and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [22,34-37].

Although randomized trials are lacking, data from several observational studies suggest that direct-acting antiviral (DAA) regimens are both safe and effective in inducing SVR in patients with HCV-associated mixed cryoglobulinemia [33,38-46]. In general, rates of SVR at 12 weeks (SVR12) after DAA therapy range from 83 to 100 percent [33,38,39,41] and are comparable with those of patients with HCV who do not have mixed cryoglobulinemia.

In general, treatment of HCV-associated mixed cryoglobulinemia with DAAs and immunosuppressive therapy is associated with an improvement in clinical manifestations [9,47]. As an example, in a cohort study with 148 patients with symptomatic HCV-associated mixed cryoglobulinemia treated with a sofosbuvir-based interferon-free DAA regimen, 73 percent of patients had a complete clinical response, 23 percent had a partial response, and 5 percent had no clinical response after a median follow-up time of 15.3 months [46]. At baseline, the main clinical features of mixed cryoglobulinemia included arthralgia (64 percent), neuropathy (58 percent), purpura (57 percent), glomerulonephritis (17 percent), skin necrosis (10 percent), and other visceral involvement (6 percent); 43 patients (29 percent) had severe mixed cryoglobulinemia. During antiviral therapy, 14 percent of patients concurrently received glucocorticoids, rituximab, or plasma exchange. With a median follow-up of 15.3 months, 97 percent of patients achieved an SVR12, and 53 percent no longer had detectable cryoglobulins. Purpura resolved in 97 percent of patients, kidney involvement in 92 percent, arthralgia in 86 percent, and neuropathy in 77 percent.

While treatment with DAAs seems to be associated with high rates of clinical response [33,41-43], circulating cryoglobulins often persist, and patients may develop clinical relapse [44].

Of note, treatment with rituximab alone (without DAAs) has been associated with a clinical response in patients with severe HCV-associated mixed cryoglobulinemia. In a series of 31 patients with severe cryoglobulinemic vasculitis who were treated with rituximab and followed for a mean of 72 months, a decrease in the HCV viral load was observed, possibly due to the depletion of B cells, which are a reservoir for HCV [11].

Hepatitis B infection — Although HCV infection is the major cause of mixed cryoglobulinemia syndrome, some cases (as many as 5 percent) are associated with HBV infection [9]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

In patients with mixed cryoglobulinemia due to HBV infection who have moderate to severe manifestations (eg, glomerulonephritis, cutaneous ulcers, progressive neuropathy), we suggest that treatment with antiviral therapy (eg, entecavir) be started concomitantly with glucocorticoids and rituximab, 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 'Hepatitis C infection' above.)

Data supporting the use of rituximab for HBV-associated mixed cryoglobulinemia are limited to a few case reports in which rituximab use led to sustained remission [48,49]. However, rituximab should not be given during an active hepatitis flare (see "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'HBV flare'), as there is potential for fatal complications [50]. In addition, rituximab has been shown to increase the risk of HBV reactivation. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Type of immunosuppressive therapy'.)

The rationale for beginning antiviral therapy (preferably with entecavir) as soon as possible when immunosuppression is planned is to avoid increased HBV replication and subsequent flare. Also, HBV viral suppression may induce remission of mixed cryoglobulinemia.

In the absence of data, we suggest that antiviral therapy in such patients be continued for at least two years following rituximab. Monitoring of chronic HBV infection in patients treated with antiviral therapy is presented elsewhere. (See "Entecavir in the treatment of chronic hepatitis B virus infection" and "Hepatitis B virus: Overview of management".)

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 [51-54]. Other nucleoside/nucleotide analogs, such as adefovir and telbivudine, have been used but have a higher risk of resistance and, with adefovir, a higher risk of nephrotoxicity [52,55]. The use of nucleoside/nucleotide analogs in patients with HBV infection, as well as the dosing of these drugs in patients with reduced kidney function, is described in detail elsewhere (table 1 and table 2). (See "Entecavir in the treatment of chronic hepatitis B virus infection" and "Hepatitis B virus: Overview of management", section on 'Antiviral therapy'.)

HIV — Mixed cryoglobulinemia has occasionally been associated with HIV infection, particularly in patients who are co-infected with HCV [56]. Cryoglobulinemia rarely causes symptoms in such patients [57]. Severe manifestations tend to occur during the chronic phase of infection and have rarely been reported during the acute phase [58].

The optimal management of patients with mixed cryoglobulinemia and HIV infection is unclear, and data are limited to case reports [57,58]. In patients who have HIV and moderate to severe mixed cryoglobulinemia, we use the same approach to the timing of immunosuppressive therapy as for patients with HBV infection and suggest that immunosuppressive therapy be administered concomitantly with antiviral therapy. In most cases, HIV-infected patients will already be receiving antiretroviral therapy (ART) and can be treated with immunosuppressive therapy without delay. HIV-infected patients who are not already being treated with ART should initiate ART prior to or at the same time as receiving immunosuppressive therapy for mixed cryoglobulinemia. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Systemic rheumatic diseases — Mixed cryoglobulinemia can occur in patients with various autoimmune disorders, such as Sjögren's disease, systemic lupus erythematosus, or rheumatoid arthritis. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

In addition to treatment of the underlying disease, 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. (See 'Moderate to severe disease' above.)

Lymphoma — Mixed cryoglobulinemia can occur in patients with non-Hodgkin lymphoma, although cryoglobulinemia occurring with lymphoma are usually type I. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

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. (See "Treatment protocols for lymphoma".)

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 [59].

PROGNOSIS — The course of mixed cryoglobulinemia varies widely, and the prognosis is influenced by the severity of the organ involvement and the comorbidities associated with the underlying disease. The prognosis in patients with severe organ involvement is generally poor, particularly for those who develop acute pulmonary hemorrhage, intestinal vasculitis with gastrointestinal hemorrhage or ischemia, or rapidly progressive glomerulonephritis [21,60,61]. In a case series and systematic review that analyzed the outcomes of 279 patients with organ-threatening or life-threatening manifestations, survival was 78 percent during an average follow-up of 14 months [61]. However, survival appeared to vary according to the organ system involved [61]:

Pulmonary hemorrhage – only 22 percent survived

Central nervous system vasculitis – 66 percent survived

Gastrointestinal vasculitis – 67 percent survived

Glomerulonephritis – 79 percent survived

Cardiac vasculitis – 100 percent survived

Cohort studies with data during the availability of antiviral therapy demonstrate an improving trend in the prognosis of patients with hepatitis C virus (HCV)-associated mixed cryoglobulinemia syndrome [46,62-64]. As an example, in a study of 146 patients with mixed cryoglobulinemia and kidney involvement were followed for over 10 years in an Italian cohort, the 10-year patient survival was approximately 80 percent. Those with worse kidney function at baseline had a worse prognosis [63]. Cardiovascular disease was the cause of death in more than 60 percent of patients.

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 [65]. The four independent predictors of death in this cohort were age greater than 65 years, kidney involvement (with reduced kidney function), pulmonary involvement, and gastrointestinal involvement. The 10-year survival among patients with kidney function impairment was approximately 50 percent, similar to patients with HCV-associated mixed cryoglobulinemia and kidney involvement prior to the availability of interferon therapy.

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

Kidney 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 [27,66,67]. Affected patients present with findings similar to those in the primary disease: purpura, hypocomplementemia, hematuria, proteinuria, and kidney function impairment. These findings, however, should not deter transplantation since most patients do not lose the graft to recurrent disease [66].

There is potential theoretical concern that maintenance immunosuppressive therapy after transplantation might exacerbate the underlying hepatitis C virus (HCV) infection, but this has not proven to be a major problem [66]. The approach to therapy in patients after kidney transplantation is discussed separately. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Hepatitis C virus infection".)

SUMMARY AND RECOMMENDATIONS

General principles – 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. (See 'Introduction' above.)

Assessment of disease severity – In general, the severity of the mixed cryoglobulinemia syndrome guides some of the therapeutic decisions. There are no universally agreed upon definitions of disease severity. We use the following descriptions as a guide (see 'Assessment of disease severity' above):

Mild disease – Patients with mild disease include those with clinical manifestations such as petechial rash without necrotizing lesions, mild sensory neuropathy, or arthralgias who have no evidence of an organ threatening process (eg, glomerulonephritis, progressive neuropathy, digital ischemia).

Moderate to severe disease – Moderate to severe or life-threatening manifestations of mixed cryoglobulinemia include the following:

-Biopsy-proven glomerulonephritis associated with or without a rapidly progressive course

-Digital ischemia threatening amputation

-Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding

-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

Treatment

General measures – General measures for all patients with mixed cryoglobulinemia include supportive measures, such as pain control and wound care, as well as prophylaxis against opportunistic infections (such as Pneumocystis pneumonia) in patients who are receiving immunosuppressive therapy. Patients should also receive age-appropriate immunizations, before the initiation of immunosuppression, if possible. (See 'General measures in all patients' above.)

Mild disease – Patients with mixed cryoglobulinemia who have mild disease typically do not require immunosuppressive therapy (algorithm 1). The management of such patients should primarily focus on treatment of the underlying disease. Additional therapies should be guided by the patient's symptoms. (See 'Mild disease' above.)

Moderate to severe disease – The overall management approach to patients with moderate to severe mixed cryoglobulinemia involves targeted treatment of the underlying disease along with additional immunosuppressive therapy (algorithm 1).

In most cases, immunosuppressive therapy is initiated first, and then after disease stabilization, therapy for the underlying disorder (eg, antiviral therapy in patients with chronic HCV infection) is added. Exceptions to this approach include mixed cryoglobulinemia due to HIV or hepatitis B virus (HBV) infections; in such patients, antiviral therapy should always be initiated before or at the same time as immunosuppressive therapy. (See 'Initial management' above and 'Timing of therapy' above.)

-For most patients with moderate to severe mixed cryoglobulinemia syndrome, we suggest treatment with high-dose systemic glucocorticoids in combination with rituximab, rather than systemic glucocorticoids alone or in combination with cyclophosphamide (Grade 2C). In selected patients with moderate disease, rituximab may be administered without glucocorticoids. The use of cyclophosphamide is generally limited to scenarios in which rituximab therapy is unavailable, fails to produce a clinical response, or is not tolerated. (See 'Systemic glucocorticoids plus rituximab' above and 'Alternatives to rituximab' above.)

-For patients with life-threatening disease; cryoglobulinemia-associated hyperviscosity syndrome; severe, refractory skin ulcers due to cutaneous vasculitis; or a high cryocrit level (ie, ≥10 percent), we suggest the use of plasmapheresis in addition to immunosuppressive therapy (Grade 2C). (See 'Limited role of plasma exchange' above.)

Disease-specific management – All patients should receive therapy directed against the underlying etiology of the mixed cryoglobulinemia (eg, antiviral therapy). Occasionally, some patients with mixed cryoglobulinemia may not have an identifiable underlying disorder despite an extensive evaluation. (See 'Assessment for associated underlying disease' above and 'Disease-specific management considerations' above.)

Monitoring – Patients with mixed cryoglobulinemia who receive immunosuppressive therapy should be closely monitored during treatment, and the frequency of monitoring is determined by the severity of disease. In patients with kidney involvement, we monitor blood pressure, serum creatinine level, complement levels, rheumatoid factor levels, and the urinalysis; patients with rapidly progressive glomerulonephritis should be evaluated weekly or biweekly, whereas those without rapidly progressive disease can be evaluated monthly. Patients with neurologic involvement should be monitored by serial neurologic examinations. Digital ischemia and skin involvement should also be monitored on physical examination. (See 'Monitoring the response to therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to an earlier version of this topic review.

  1. Monti G, Saccardo F, Rinaldi G, et al. Colchicine in the treatment of mixed cryoglobulinemia. Clin Exp Rheumatol 1995; 13 Suppl 13:S197.
  2. Invernizzi F, Monti G. Colchicine and mixed cryoglobulinemia. Arthritis Rheum 1993; 36:722.
  3. Ferri C, Sebastiani M, Antonelli A, et al. Current treatment of hepatitis C-associated rheumatic diseases. Arthritis Res Ther 2012; 14:215.
  4. De Vita S, Quartuccio L, Isola M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64:843.
  5. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64:835.
  6. Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 2004; 19:3054.
  7. Quartuccio L, Soardo G, Romano G, et al. Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids. Rheumatology (Oxford) 2006; 45:842.
  8. Ferri C, Cacoub P, Mazzaro C, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev 2011; 11:48.
  9. Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers 2018; 4:11.
  10. Colantuono S, Mitrevski M, Yang B, et al. Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Clin Rheumatol 2017; 36:617.
  11. Roccatello D, Sciascia S, Baldovino S, et al. Improved (4 Plus 2) Rituximab Protocol for Severe Cases of Mixed Cryoglobulinemia: A 6-Year Observational Study. Am J Nephrol 2016; 43:251.
  12. Sène D, Ghillani-Dalbin P, Amoura Z, et al. Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis. Arthritis Rheum 2009; 60:3848.
  13. Sy-Go JPT, Thongprayoon C, Herrera Hernandez LP, et al. Rituximab-Associated Flare of Cryoglobulinemic Vasculitis. Kidney Int Rep 2021; 6:2840.
  14. Terrier B, Krastinova E, Marie I, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood 2012; 119:5996.
  15. Cavallo R, Roccatello D, Menegatti E, et al. Rituximab in cryoglobulinemic peripheral neuropathy. J Neurol 2009; 256:1076.
  16. Rossi D, Sciascia S, Fenoglio R, et al. Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy. Minerva Med 2021; 112:162.
  17. Petrarca A, Rigacci L, Caini P, et al. Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and severe liver disease. Blood 2010; 116:335.
  18. Frankel AH, Singer DR, Winearls CG, et al. Type II essential mixed cryoglobulinaemia: presentation, treatment and outcome in 13 patients. Q J Med 1992; 82:101.
  19. Mazzi G, Raineri A, Zucco M, et al. Plasma-exchange in chronic peripheral neurological disorders. Int J Artif Organs 1999; 22:40.
  20. Verdickt W, Dequeker J. Plasmapheresis combined with corticosteroids and cyclophosphamide in mixed monoclonal cryoglobulinaemia. Acta Clin Belg 1982; 37:237.
  21. Ramos-Casals M, Robles A, Brito-Zerón P, et al. Life-threatening cryoglobulinemia: clinical and immunological characterization of 29 cases. Semin Arthritis Rheum 2006; 36:189.
  22. Pietrogrande M, De Vita S, Zignego AL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 2011; 10:444.
  23. Evans TW, Nicholls AJ, Shortland JR, et al. Acute renal failure in essential mixed cryoglobulinemia: precipitation and reversal by plasma exchange. Clin Nephrol 1984; 21:287.
  24. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 2013; 28:145.
  25. D'Amico G, Colasanti G, Ferrario F, Sinico RA. Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989; 35:1004.
  26. Rockx MA, Clark WF. Plasma exchange for treating cryoglobulinemia: a descriptive analysis. Transfus Apher Sci 2010; 42:247.
  27. Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange in renal diseases. J Am Soc Nephrol 1996; 7:367.
  28. Guillevin L, Pagnoux C. Indications of plasma exchanges for systemic vasculitides. Ther Apher Dial 2003; 7:155.
  29. Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010; 25:83.
  30. Campise M, Tarantino A. Glomerulonephritis in mixed cryoglobulinaemia: what treatment? Nephrol Dial Transplant 1999; 14:281.
  31. Valbonesi M, Florio G, Montani F, Mosconi L. A method for the study of cryoglobulin solubilization curves at 37 degrees C. Preliminary studies and application to plasma exchange in cryoglobulinemic syndromes. Int J Artif Organs 1983; 6:87.
  32. Saadoun D, Resche-Rigon M, Thibault V, et al. Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum 2006; 54:3696.
  33. Saadoun D, Pol S, Ferfar Y, et al. Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology 2017; 153:49.
  34. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68:310.
  35. AASLD-IDSA HCV Guidance Panel. Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis 2018; 67:1477.
  36. European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60:392.
  37. Jadoul M, Berenguer MC, Doss W, et al. Executive summary of the 2018 KDIGO Hepatitis C in CKD Guideline: welcoming advances in evaluation and management. Kidney Int 2018; 94:663.
  38. Sise ME, Bloom AK, Wisocky J, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology 2016; 63:408.
  39. Emery JS, Kuczynski M, La D, et al. Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia. Am J Gastroenterol 2017; 112:1298.
  40. Sollima S, Milazzo L, Peri AM, et al. Persistent mixed cryoglobulinaemia vasculitis despite hepatitis C virus eradication after interferon-free antiviral therapy. Rheumatology (Oxford) 2016; 55:2084.
  41. Gragnani L, Visentini M, Fognani E, et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology 2016; 64:1473.
  42. Saadoun D, Thibault V, Si Ahmed SN, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis 2016; 75:1777.
  43. Bonacci M, Lens S, Londoño MC, et al. Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus-Associated Cryoglobulinemia Treated With Direct-Acting Antivirals. Clin Gastroenterol Hepatol 2017; 15:575.
  44. Bonacci M, Lens S, Mariño Z, et al. Long-Term Outcomes of Patients With HCV-Associated Cryoglobulinemic Vasculitis After Virologic Cure. Gastroenterology 2018; 155:311.
  45. Lauletta G, Russi S, Pavone F, et al. Direct-acting antiviral agents in the therapy of hepatitis C virus-related mixed cryoglobulinaemia: a single-centre experience. Arthritis Res Ther 2017; 19:74.
  46. Cacoub P, Si Ahmed SN, Ferfar Y, et al. Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis. Clin Gastroenterol Hepatol 2019; 17:518.
  47. Cacoub P, Saadoun D. Extrahepatic Manifestations of Chronic HCV Infection. N Engl J Med 2021; 384:1038.
  48. Pasquet F, Combarnous F, Macgregor B, et al. Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report. J Med Case Rep 2012; 6:39.
  49. Terrier B, Marie I, Lacraz A, et al. Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature. J Autoimmun 2015; 65:74.
  50. Khan ZH, Ilyas K, Ghazanfar H, et al. Fatal Fulminant Hepatitis from Rituximab-induced Hepatitis B Reactivation in a Patient with Follicular Lymphoma: A Case Report and a Brief Review of Literature. Cureus 2018; 10:e2257.
  51. Sawabe T, Uenotsuchi T, Imafuku S, et al. Remission of hepatitis B virus-related vasculitis with lamivudine. Ann Intern Med 2004; 140:672.
  52. Stecevic V, Pevzner MM, Gordon SC. Successful treatment of hepatitis B-associated vasculitis with lamivudine. J Clin Gastroenterol 2003; 36:451.
  53. Kawakami T, Ooka S, Mizoguchi M, et al. Remission of hepatitis B virus-related cryoglobulinemic vasculitis with entecavir. Ann Intern Med 2008; 149:911.
  54. Enomoto M, Nakanishi T, Ishii M, et al. Entecavir to treat hepatitis B-associated cryoglobulinemic vasculitis. Ann Intern Med 2008; 149:912.
  55. Boglione L, D'Avolio A, Cariti G, Di Perri G. Telbivudine in the treatment of hepatitis B-associated cryoglobulinemia. J Clin Virol 2013; 56:167.
  56. Scotto G, Cibelli DC, Saracino A, et al. Cryoglobulinemia in subjects with HCV infection alone, HIV infection and HCV/HIV coinfection. J Infect 2006; 52:294.
  57. Bonnet F, Pineau JJ, Taupin JL, et al. Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol 2003; 30:2005.
  58. Genet P, Courdavault L, Wifaq B, Gerbe J. Symptomatic Mixed Cryoglobulinemia during HIV Primary Infection: A Case Report. Case Rep Infect Dis 2011; 2011:525841.
  59. Saadoun D, Pineton de Chambrun M, Hermine O, et al. Using rituximab plus fludarabine and cyclophosphamide as a treatment for refractory mixed cryoglobulinemia associated with lymphoma. Arthritis Care Res (Hoboken) 2013; 65:643.
  60. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004; 33:355.
  61. Retamozo S, Díaz-Lagares C, Bosch X, et al. Life-Threatening Cryoglobulinemic Patients With Hepatitis C: Clinical Description and Outcome of 279 Patients. Medicine (Baltimore) 2013.
  62. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995; 47:618.
  63. Roccatello D, Fornasieri A, Giachino O, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2007; 49:69.
  64. Lauletta G, Russi S, Conteduca V, et al. Impact of Cryoglobulinemic Syndrome on the Outcome of Chronic Hepatitis C Virus Infection: A 15-Year Prospective Study. Medicine (Baltimore) 2013.
  65. Terrier B, Carrat F, Krastinova E, et al. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis 2013; 72:374.
  66. Tarantino A, Moroni G, Banfi G, et al. Renal replacement therapy in cryoglobulinaemic nephritis. Nephrol Dial Transplant 1994; 9:1426.
  67. Hiesse C, Bastuji-Garin S, Santelli G, et al. Recurrent essential mixed cryoglobulinemia in renal allografts. Report of two cases and review of the literature. Am J Nephrol 1989; 9:150.
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References

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