Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: A systematic review

https://doi.org/10.1016/j.semarthrit.2014.04.002Get rights and content

Abstract

Objective

To analyse the efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus (SLE).

Methods

We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials up to June 2013. The following were the selection criteria: (1) adult patients with SLE, (2) rituximab treatment, (3) placebo or active comparator, (4) outcome measures assessing efficacy and/or (5) safety. Meta-analysis, systematic literature reviews, randomised control trials (RCT), open clinical trials and cohort studies were included.

Independent extraction of articles by 2 authors using predefined data fields was performed. The quality of each study was graded using the Oxford Levels of Evidence and Jadad׳s scale.

Results

A total of 26 articles met our inclusion criteria: one RCT and its exploratory analysis, 2 open studies and 22 cohort studies, which analysed 1,231 patients. Overall, patients had active disease refractory to steroids and/or immunosuppressant drugs. Acceptable evidence suggested improvements in disease activity, arthritis, thrombocytopaenia, complement and anti-dsDNA, with a steroid-sparing effect. But relapses of disease were demonstrated too. Weak evidence suggested a response in anaemia, cutaneous and neuropsychiatric manifestations. Available evidence revealed few major adverse events. Studies had medium methodological quality and in general were applicable to current practice.

Conclusion

Rituximab has been shown to be safe and effective in the treatment of non-renal SLE, especially in terms of disease activity, immunologic parameters and steroid-sparing effect. However, it can only be recommended for organ-specific manifestations such as arthritis and thrombocytopaenia. High-quality studies are needed in order to consider the long-term effects of re-treatment on different organ-specific manifestations.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with protean manifestations in multiple organ systems. Current medical practice includes glucocorticoids, antimalarials and immunosuppressant (ISS) drugs to reduce disease activity and prevent flares. However, these treatments are not enough to control the disease. Some patients have several manifestations simultaneously and need an additional treatment to control general disease activity. Furthermore, some patients may have refractory organ-specific manifestations, such as arthritis, or life-threatening situations, such as neurological involvement. Currently, off-label use of rituximab has been used as an alternative on the basis that several abnormalities in SLE B cell populations have been identified and play a central role in the pathogenesis of SLE. Some studies have stressed the efficacy of rituximab in the treatment of most manifestations, with many of these studies focusing on nephritis [1], [2], [3], [4]. Previously, some systematic reviews tried to summarise the information concerning efficacy and safety of rituximab in the treatment of SLE [5], [6], but the data on the outcomes did not discriminate between studies that focused on nephritis and those that did not. In addition, specific outcomes relating to non-renal manifestations were not evaluated. In order to recommend rituximab, it would be useful to identify a profile of patients who are most likely to benefit from its use, particularly considering the recent approval of belimumab, which shows non-renal non-severe manifestations and flare-prevention effects. Both biologic treatments are not exclusive; the same patient may need them at some point.

Thus, the aim of this article was to systematically review the available literature regarding the efficacy and the safety of rituximab in the treatment of non-renal manifestations of SLE.

Section snippets

Methods

This study was performed by experts from the Evidence-based Medicine Study Group and the Systemic Autoimmune Diseases Study Group of the Spanish Society of Rheumatology. Initially, we conducted a systematic review on the efficacy and the safety of biologic and non-biologic ISS drugs in the treatment of non-renal SLE. The data about non-biologic ISS drugs have been recently published [7]. Now, we present data on rituximab.

Results

The literature search produced 3410 articles, of which 186 underwent full review and 24 met the inclusion criteria. We identified 2 additional studies by hand search (Fig.). The evidence table including the population studied, interventions and outcomes with their definitions is available in Appendix 3. The excluded studies and reasons for exclusion are shown in Appendix 4.

The 26 studies included 1 RCT and its exploratory analysis [10], [11], 2 open-label studies [12], [13] and 22 cohort

Discussion

We conducted a systematic review of the literature to analyse the efficacy and the safety of rituximab in the treatment of non-renal SLE. Rituximab has an off-label use, which is mainly used to treat patients with either life-threatening situations or severe involvement refractory or intolerant to standard therapy. In this sense, the rituximab studies reveal as much information about the overall disease activity as about organ-specific manifestations.

In our systematic review, we found

Conclusion

Rituximab could be considered a safe and effective short–medium term option in the treatment of non-renal SLE, reducing disease activity, steroid doses and anti-DNA levels and increasing complement levels. However, disease relapses are significant. Regarding particular involvements, the best response is in arthritis and autoimmune thrombocytopaenic purpura. We cannot draw conclusions about autoimmune haemolytic anaemia and neuropsychiatric manifestations because there are too few reliable

Acknowledgements

We want to thank the experts from the Systemic Autoimmune Diseases Study Group of the Spanish Society for Rheumatology (EAS-SER) for suggesting the research question and for their valuable and constructive suggestions during the development of this research work.

We would also like to express our very great appreciation to Ms. María Piedad Rosario-Lozano (Research Unit of the Spanish Society of Rheumatology), who checked the search strategies.

References (35)

  • E. Sousa et al.

    Treating lupus: from serendipity to sense, the rise of the new biologicals and other emerging therapies

    Best Pract Res Clin Rheumatol

    (2009)
  • A.R. Jadad et al.

    Assessing the quality of reports of randomized clinical trials: is blinding necessary?

    Control Clin Trials

    (1996)
  • P.P. Sfikakis et al.

    Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial

    Arthritis Rheum

    (2005)
  • M. Vigna-Perez et al.

    Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study

    Arthritis Res Ther

    (2006)
  • I. Gunnarsson et al.

    Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide-resistant proliferative lupus nephritis

    Arthritis Rheum

    (2007)
  • E. Murray et al.

    Off-label use of rituximab in systemic lupus erythematosus: a systematic review

    Clin Rheumatol

    (2010)
  • L. Lan et al.

    Efficacy and safety of rituximab therapy for systemic lupus erythematosus: a systematic review and meta-analysis

    J Zhejiang Univ Sci B

    (2012)
  • J.M. Pego-Reigosa et al.

    Efficacy and safety of non-biologic immunosuppressants in the treatment of non-renal systemic lupus erythematosus: a systematic review

    Arthritis Care Res

    (2013)
  • Phillips B, Ball C, Sackett D, Badenoch D, Straus S, Haynes B, et al. Oxford Centre for evidence-based medicine levels...
  • J.T. Merrill et al.

    Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial

    Arthritis Rheum

    (2010)
  • J. Merrill et al.

    Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER)

    Lupus

    (2011)
  • R.J. Looney et al.

    B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab

    Arthritis Rheum

    (2004)
  • Y. Tanaka et al.

    A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus

    Mod Rheumatol

    (2007)
  • J.E. Gottenberg et al.

    Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases

    Ann Rheum Dis

    (2005)
  • K.G. Smith et al.

    Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment

    Arthritis Rheum

    (2006)
  • F. Catapano et al.

    Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus

    Nephrol Dial Transplant

    (2010)
  • M. Tokunaga et al.

    Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system

    Ann Rheum Dis

    (2007)
  • Cited by (96)

    • Lung involvement in SLE

      2022, Handbook of Systemic Autoimmune Diseases
    • Diagnosis and treatment of articular manifestations of systemic lupus erythematosus

      2021, Revista Colombiana de Reumatologia
      Citation Excerpt :

      Additionally, polyarthritis, high disease activity (SLEDAI ≥ 10), and increased anti-dsDNA have been suggested as predictors of response to belimumab.85 Targeting CD20 with rituximab has been endorsed in several centers where it is used as an off-label therapeutic option in SLE, mostly for refractory renal disease, but also for other organ manifestations when conventional treatment has failed, including severe lupus polyarthritis.86,87 Literature data suggests the efficacy of abatacept to treat SLE patients with joint involvement.14

    View all citing articles on Scopus

    From the Systemic Autoimmune Diseases Study Group of the Spanish Society for Rheumatology (EAS-SER).

    Role of the funding source: This study was supported by the Spanish Foundation of Rheumatology (FER) with an unrestricted educational grant from Roche Farma, SA. The FER and Roche Farma had no role in the extraction and interpretation of data or in the draft of the manuscript. All authors had full access to all the data included in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr. J.M. Pego-Reigosa was supported by the Grant 316265 (BIOCAPS) from the European Union 7th Framework Programme (FP7/REGPOT-2012-2013.1).

    Competing interest: Dr. Fernandez-Nebro reports grants and personal fees from Pfizer, grants and personal fees from Roche, personal fees from BMS, personal fees from MSD and personal fees from Abbvie, outside the submitted work. Dr. López Longo reports grants and personal fees from GKS, personal fees from ABBVIE, non-financial support from UCB, non-financial support from MSD and non-financial support from Roche, outside the submitted work. Dr. Caliz reports grants, personal fees and non-financial support from Roche, personal fees and non-financial support from MSD and personal fees and non-financial support from Pheizer, outside the submitted work.

    View full text