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Blood Transfus. 2010 July; 8(3): 196–198.
PMCID: PMC2906198

Clinical improvement induced by rituximab in two cases of type II mixed cryoglobulinaemia syndrome unresponsive to conventional treatments


Type II mixed cryoglobulinaemia syndrome is a systemic vasculitis related in many cases to hepatitis C virus (HCV) infection and to immune complex deposition in several organs. It is characterised by non-neoplastic proliferation of rheumatoid factor (RF)-positive B-cell clones leading to the development of cryoglobulinaemia1. Therapeutic strategies can target either the viral trigger (HCV) if present, or pathogenic events triggering the infection, e.g. the proliferating B cells directly. Antiviral therapy should be considered the first-line treatment; however, it may contraindicated, poorly tolerated or ineffective and the best treatment has not yet been defined26. Rituximab, an anti-CD20 monoclonal antibody, selectively targets the B-cell compartment RF-positive cells and results in prolonged depletion of B cells from the peripheral blood. For this reason, rituximab could be considered a good alternative treatment in selected patients with cryoglobulinaemia.

We report here clinical and biological data on two patients with type II mixed cryoglobulinaemia syndrome associated with chronic HCV infection unresponsive to conventional treatments, including therapeutic plasmapheresis, who were successfully treated with rituximab in our Haematology Unit. The rituximab treatment had a major clinical impact in both of these difficult to manage patients: cutaneous manifestations, including purpura, and peripheral neuropathy improved and corticosteroid requirements were reduced.

Patients and methods

We treated two patients, a 70-year old female patient (patient n. 1) and a 60-year old male patient (patient n. 2), who had been affected by type II mixed cryoglobulinaemia for 7 and 5 years, respectively. Both patients had antibodies to HCV, as determined by enzyme-linked immunosorbent assays (Ortho-Clinical Diagnostics Systems, Raritan, NJ, USA) and by recombinant-based immunoblot assays (Ortho Diagnostic Systems) and were positive for serum HCV RNA by nested polymerase chain reaction (PCR). Over the years they were treated in our Haematology Unit with therapeutic plasmapheresis associated with corticosteroids, cyclophosphamide and interferon plus ribavirin but these therapies were not tolerated and were, therefore, stopped. The patients started treatment with rituximab alone. The therapeutic schedule consisted of a single course of rituximab (Mabthera; Roche, Milan, Italy) given at a dose of 375mg/m2 by intravenous infusion on days +1, +8, +15, and +22, as in the treatment of B-cell lymphoma. Only medium-to low doses of corticosteroids (prednisone < 0.5mg/kg/day) were allowed as concomitant treatment for the type II mixed cryoglobulinaemia, with no further increase in dosage. The patients were evaluated at baseline and then monthly for 6 months. The evaluations consisted of a complete physical examination and laboratory studies, including assessment of: (i) purpura, scored as +++ (diffuse and persistent involvement of the trunk and the lower limbs), ++ (diffuse and persistent involvement of the lower limbs), + (limited or fluctuating involvement of the lower limbs) or 0 (no purpura); (ii) neuropathy, with symptoms graded from 0 to 10 according to a patient-scored visual analogue scale, and electromyography of the lower limbs, performed at baseline and repeated after 3 months of rituximab treatment; (iii) lymphoma features, determined on a bone marrow biopsy at baseline, flow cytometry analysis of lymphoid markers on peripheral blood mononuclear cells at baseline and then monthly and on bone marrow mononuclear cells at baseline and after 3 months of treatment; (iv) routine laboratory parameters such as serum liver enzymes, RF, quantification of serum cryoglobulins and of HCV serum viral load. HCV genotyping was done as previously described and serum HCV RNA was quantified before and after treatment (at baseline and at months +3 and +6) by quantitative PCR (TAQMAN, Roche Diagnostics, Basel, Switzerland).


Both patients completed the full course of rituximab therapy and had good responses (Table I). Purpura disappeared within 1 month in one patient and within 2 months in the other. Symptoms of peripheral neuropathy improved in both patients; however, electromyographic findings at month +3 were unchanged with respect to those at baseline. As regards lymphoma features, depletion of CD20+ peripheral blood B cells was achieved by month +1 and maintained until month +6 in both patients. In contrast, in the bone marrow there was a reduction of only 25%. Serum levels of RF and cryoglobulins decreased, while aminotransferase levels, normal at baseline, remained within the normal ranges. By contrast, HCV serum viral load increased during the therapy in patient n. 2 and then decreased to the previous value afterwards; there were minimal fluctuations in patient 1. Corticosteroid treatment was no longer required by either patient and was, therefore, first reduced and then suspended shortly after the start of rituximab therapy. Rituximab appeared to be well-tolerated by both patients and was not associated with minor or major adverse events such as serious infections. In the long-term, both patients relapsed after interruption of therapy at month +6 and month +12, with recurrence of cutaneous manifestations and neuropathic symptoms related to mixed cryoglobulinaemia leading us to re-treat the patients obtaining the same results.

Table I


The currently available therapeutic approaches to inhibit cryoglobulin synthesis and their pathogenic effects may fail or be poorly tolerated or contraindicated in many patients and additional therapeutic options are required. There is a strong rationale for using rituximab in type II mixed cryoglobulinaemia because there is biological evidence that this monoclonal antibody targets RF-positive cell clones and is effective in B-cell lymphoproliferative disorders as well as in some autoimmune diseases. We administered rituximab, with the usual regimen of four, weekly doses, in two patients with type II mixed cryoglobulinaemia who were unresponsive to standard treatment and observed good effects on purpura confirming the efficacy of rituximab in immune complex-mediated small-vessel vasculitis. An improvement in subjective symptoms of sensory peripheral polyneurophathy was also noted despite there being no electromyographic changes, perhaps because the neural damage was irreversible given the prolonged duration of the polyneuropathy. Rituximab was also effective in reducing corticosteroid requirements; this is an additional benefit in patients concomitant HCV viral infection. As far as routine laboratory parameters are concerned, a reduction of RF was observed without changes in the levels of serum liver enzymes. No worsening of liver disease was noted despite HCV serum viral load increasing in one patient and fluctuating in the other. Interestingly, although B-cell depletion was achieved in the peripheral blood, the reduction of B cells in the bone marrow was less marked, so that the B-cell mediated autoimmune response was not completely suppressed. This is consistent with the notion that rituximab is effective in type II mixed cryoglobulinaemia syndrome but does not cause complete suppression of the B-cell-mediated autoimmune response. In conclusion, we believe that rituximab may represent an effective therapeutic option for patients with type II mixed cryoglobulinaemia syndrome, enabling them to obtain remission without the collateral effects of corticosteroids and other immunosuppressive agents. Data on the efficacy and long-term safety of rituximab are of major interest and controlled randomised trials are needed to compare this drug with standard available treatments and clearly define its indications, cost-efficacy profile, and treatment schedules in different settings.


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