Elsevier

Journal of Autoimmunity

Volume 63, September 2015, Pages 88-93
Journal of Autoimmunity

Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: Long-term follow up data of a randomized controlled multicentre study

https://doi.org/10.1016/j.jaut.2015.07.012Get rights and content

Highlights

  • Rituximab retreatment at clinical relapse appears useful in the long term for severe cryoglobulinemic vasculitis.

  • Rituximab retreatment at clinical relapse is associated with a low incidence of severe hypogammaglobulinemia.

  • Rituximab retreatment at clinical relapse saves on the use of glucocorticoids in severe cases of cryoglobulinemic vasculitis.

Abstract

Objective

To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV).

Methods

Thirty patients with severe HCV-related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response > 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease.

Results

The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease. 17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non-severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients.

Conclusions

A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia.

Introduction

Cryoglobulinemic vasculitis (CV) is a systemic vasculitis, usually triggered by HCV infection [1], and characterized by an expansion of oligo-monoclonal B cells that produce IgM with rheumatoid factor (RF) activity, which can lead to the formation of immune complexes consisting of RF, HCV and polyclonal HCV-specific IgG, precipitating in blood vessel walls or glomerular capillaries. CV is characterized by the typical clinical triad of purpura, weakness, and arthralgia and often by severe organ involvement including glomerulonephritis, peripheral neuropathy, and skin ulcer [2]. Treatment of HCV-related CV may target either the viral trigger or the downstream B cell arm of autoimmunity. Anti-viral therapy has a strong rationale, is effective in many milder cases, but it may also prove ineffective, contraindicated, or not tolerated, and sometimes may worsen CV.

The new direct acting antiviral drugs for HCV are being investigated in HCV-related CV. Importantly, antiviral treatment is presently not the first choice, based on clinical priorities, in HCV-positive patients with severe CV organ involvement [3], [4], [5], [6], [7], [8].

Rituximab (RTX) is an anti CD20 monoclonal antibody, which depletes the expanded population of B cells, and proved to be an effective strategy in CV. Recently, two independent controlled randomized trials reported a large efficacy and good safety of RTX in severe manifestations of CV [9], [10]. In the Italian study, 59 patients with severe manifestations of CV (skin ulcers, active glomerulonephritis or refractory peripheral neuropathy), either HCV related or not, were randomized to receive RTX or the best available treatment (high-dose glucocorticoids, azathioprine or cyclophosphamide, or plasmapheresis), and then they were followed for 24 months. In HCV-positive patients, treatment with antiviral agents had previously failed or was not indicated. Patients who did not respond to conventional treatment could be rescued by RTX [9].

Survival of treatment was always statistically higher in the RTX group at 3, 6, 12 and 24 months [9]. As compared to conventional therapy, the overall rate of serious adverse events was similar in the RTX treated patients, with severe infections occurring in patients who had previously received high-dose glucocorticoids or with hypogammaglobulinemia. Interestingly, the median time to relapse after RTX treatment was 1.5 years [9].

Since the issue of RTX retreatment in systemic vasculitis (as well as in other rheumatic diseases) is still open, the aim of the present study was to evaluate the very long-term efficacy and safety of a retreatment regimen with RTX alone administered only in the case of clinical relapse in CV. Patients who were treated with RTX in the course of the aforementioned study [9], and managed with RTX alone also after the end of the trial were evaluated.

Section snippets

Patients and methods

Thirty patients, 24 females and 6 males, with a mean (SD) age of 63 (11) years (median 65, range 37–78 years), suffering from severe HCV-related CV and treated with RTX during the 24-month trial, were studied [9]. All the patients were HCV-positive and they remained untreated with antiviral drugs during the published 24-month study [9] and also in the available follow-up.

After the end of the trial, patients were managed with RTX alone (1 g intravenous infusion two weeks apart) only in the case

Long-term follow-up and survival of the rituximab regimen

The mean follow up after the first RTX cycle given during the trial [9] was 72.6 (20.4) months. As concerns the follow-up after the end of the trial [9], 24/30 patients (80%) were observed for more than 24 months after the trial [mean follow up 79.3 (10) months] and 6/24 (20%) for less than 24 months [mean follow up 35.8 (6.7) months].

At the last follow-up, 21/30 (70%) patients were still under an active follow-up from the same Centre, 3/30 (10%) patients were lost during the follow-up, and

Discussion

The indication for retreatment with RTX is an open issue in rheumatic diseases, including some systemic vasculitis where RTX has become a cornerstone of the treatment strategy [11], [12], [13]. Based on the results of this study, a retreatment regimen, which implies the use of RTX only at clinical relapse, appears beneficial in CV.

No large data have been published up to now about the retreatment schedule of RTX in a complex disease as CV, where the clinician has to take into account also the

Conclusions

Although analysed retrospectively, a regimen where RTX is administered only at clinical relapse appears useful for the long-term management of most cases of severe CV. In these patients major safety concerns are usually represented by concomitant HCV infection and liver damage, by a more advanced age, lower serum immunoglobulin levels and co-morbidities, thus immunosuppressors and glucocorticoids should be spared, whenever possible.

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