Elsevier

Autoimmunity Reviews

Volume 14, Issue 10, October 2015, Pages 889-896
Autoimmunity Reviews

Review
Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review

https://doi.org/10.1016/j.autrev.2015.05.013Get rights and content

Highlights

  • Rituximab at the low dosage of 250 mg/m2 x 2 is efficacious refractory HCV-associated mixed cryoglobulinemic vasculitis

  • Low-dose rituximab is as effective as the higher dosage of 375 mg/m2 x 4 for treating mixed cryoglobulinemia

  • The low-dose regimen may improve the cost/benefit profile of rituximab therapy for mixed cryoglobulinemia.

Abstract

Objective

To evaluate whether rituximab at a low dose of 250 mg/m2 × 2 may be as effective as at higher dosages, most commonly 375 mg/m2 × 4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection.

Methods

We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search.

Results

The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant.

Conclusion

Rituximab at a low dosage of 250 mg/m2 × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC.

Introduction

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis caused by immune complexes formed by monoclonal IgM rheumatoid factor and polyclonal IgG, which precipitate at t° less than 37° and cause small vessel vasculitis [1]. It is currently considered a rare disease, although the prevalence of the vasculitis presents geographical differences, in relation to HCV infection prevalence [2]. Indeed in more than 90% of cases MC is secondary to hepatitis C virus (HCV) infection, which determines chronic stimulation and benign monoclonal expansion of B-cells producing a natural poly (auto)-reactive IgM antibody. These B cells proliferate very poorly [3], and this may explain why immunosuppressive and cytotoxic drugs are scarcely effective in MC. Over time, chronic stimulation of B-cells by HCV may give rise to genetic changes and evolution to overt lymphoma, typically splenic marginal zone lymphoma (SMZL) [4], that may regress after eradication of HCV with antiviral therapy [5], [6].

The most frequent manifestations of MC are cutaneous leucocytoclastic vasculitis leading to purpura and skin ulceration, peripheral neuropathy, glomerulonephritis [1] and central nervous system vascular lesions that may underlie cognitive impairment [7]. In some patients, MC has an acute onset and presents a life-threatening course with skin ulcers, renal involvement and abdominal vasculitis [8].

HCV clearance with sustained virological response (SVR) is the main goal in the treatment of patients with HCV-associated MC, and leads to remission of vasculitis and reduced mortality [8], [9]. So far, the best combination for achieving HCV eradication in MC patients is with pegylated interferon alpha (PEG-IFN) and ribavirin [9]. Unfortunately, many patients are ineligible/intolerant, fail to respond or relapse after initial response to this regimen; these patients may have a grim prognosis and bear high health care costs [10].

New direct-acting antiviral (DAA) agents yielding 90–100% SVR rates [11] may change this scenario, and clinical trials with IFN-free regimens for HCV-associated cryoglobulinemia are eagerly awaited [12].

Starting 15 years ago, a number of studies (open studies and case reports) have demonstrated that the anti-CD20 chimeric monoclonal antibody rituximab is highly effective for the treatment of HCV-associated MC, refractory or intolerant to antiviral therapy [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. Only recently, two randomized controlled trials [29], [30] showed that rituximab is largely superior to conventional immunosuppressive drugs for treating cryoglobulinemic vasculitis, providing further evidence of its clinical efficacy and safety in this setting. The rituximab dosage used in nearly all published reports was 375 mg/m2 given four times, the treatment schedule used for B cell NHL [13], [14], [16], [17], [18], [19], [20], [22], [23], [24], [25], [26], [27], [28], [30]. Other studies used the dosage of 1000 mg for two administrations, as for the treatment of rheumatoid arthritis [22], [27], [29], [31] and only few patients were treated with the higher dosage of 375 mg/m2 for four administrations plus two monthly maintenance dosages [15], [18], [21], [27]. However, the issue of optimal dosing of rituximab for treating MC has not been addressed so far.

Low-dose regimens of rituximab have been shown to be efficacious in different immunological disorders such as rheumatoid arthritis [32], [33], [34], systemic lupus erythematosus [35], [36], autoimmune haemolytic anemia [37], immune thrombocytopenia [38], pemphigus [39] and myasthenia gravis [40]. Remarkably, a recent meta-analysis [41] demonstrated that low-dose rituximab (500 mg × 2) has similar effectiveness and meets non-inferiority criteria compared to the licensed dose of 1000 mg × 2 for the treatment of rheumatoid arthritis.

Based on a pilot study in 6 patients [42], we designed a phase II, single-arm two-stage multicenter study to evaluate the efficacy of low-dose rituximab (250 mg/m2 given twice one week apart) in patients with refractory HCV-associated mixed cryoglobulinemia. The mid-term results in 27 of the 52 patients to be enrolled in this study were published in 2011 [43]. Here we report the final results of the study, providing confirmatory evidence of equal efficacy of low-dose compared to high-dose rituximab for the treatment of patients with HCV-associated MC who are ineligible/intolerant or unresponsive to antiviral therapy.

Section snippets

Study design

This phase 2, single-arm, two-stage multicenter study (EUDRACT n. 2008-000086-38), aimed at assessing the efficacy/safety profile of low-dose rituximab for refractory mixed cryoglobulinemia, was conducted in three university centers (Sapienza University of Rome, University of Florence and University of Pavia). The study was approved by the Internal Review Boards of all participating institutions, and written informed consent was obtained from each patient according to the ethical guidelines of

Study population

The characteristics of the study population are illustrated in Table 1. All patients had at least one of the following manifestations: purpura, peripheral neuropathy, skin ulcers or kidney disease. Both mild/moderate and severe forms of cryoglobulinemic vasculitis, e.g., neuropathy and/or purpura vs severe skin ulcers and kidney disease [10], were represented in the study cohort. All patients had anti-HCV antibodies, but in 4 cases serum HCV RNA was repeatedly undetectable.

Clinical efficacy

Supplementary Fig. 1

Discussion

After more than 15 years of experience with rituximab for the treatment of a number of immunological disorders, drug dosages and therapeutic schemes in different disease contexts are still empirical, and dose/benefit studies are relatively scarce [41], [47], [48], [49], [50], [51]. A large number of studies demonstrated that rituximab is highly efficacious and safe for the treatment of HCV-associated MC. Drug dosages most commonly used were 375 mg/m2 given 4 times, as for the treatment of B-cell

Take-home messages

  • Rituximab at the low dosage of 250 mg/m2 × 2 is as effective as the higher dosage of 375 mg/m2 × 4 for treating HCV-associated mixed cryoglobulinemia

  • The low-dose regimen may improve the cost/benefit profile of rituximab therapy for mixed cryoglobulinemia.

Disclosures

The authors disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.

Acknowledgments

This work was supported by grant FARM6KMZFY from the Agenzia Italiana per il Farmaco (AIFA). Marcella Visentini was supported by Fondazione Roma (Prot287/AI), Rome, Italy.

Laura Gragnani was supported by "Fondazione Umberto Veronesi", Alessia Piluso was supported by "FIRE", Elisa Fognani was supported by AIRC.

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