Elsevier

Autoimmunity Reviews

Volume 11, Issue 5, March 2012, Pages 357-364
Autoimmunity Reviews

Review
Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: Pooled data from European cohorts

https://doi.org/10.1016/j.autrev.2011.10.009Get rights and content

Abstract

Objective

To present a pooled analysis of the efficacy of rituximab from European cohorts diagnosed with biopsy-proven lupus nephropathy (LN) who were treated with rituximab.

Methods

Consecutive patients with biopsy-proven LN treated with rituximab in European reference centers were included. Complete response (CR) was defined as normal serum creatinine with inactive urinary sediment and 24-hour urinary albumin < 0.5 g, and partial response (PR) as a > 50% improvement in all renal parameters that were abnormal at baseline, with no deterioration in any parameter.

Results

164 patients were included (145 women and 19 men, with a mean age of 32.3 years). Rituximab was administered in combination with corticosteroids (162 patients, 99%) and immunosuppressive agents in 124 (76%) patients (cyclophosphamide in 58 and mycophenolate in 55). At 6– and 12-months, respectively, response rates were 27% and 30% for CR, 40% and 37% for PR and 33% for no response. Significant improvement in 24-h proteinuria (4.41 g. baseline vs 1.31 g. post-therapy, p = 0.006), serum albumin (28.55 g. baseline to 36.46 g. post-therapy, p < 0.001) and protein/creatinine ratio (from 421.94 g/mmol baseline to 234.98 post-therapy, p < 0.001) at 12 months was observed. A better response (CR + PR) was found in patients with type III LN in comparison with those with type IV and type V (p = 0.007 and 0.03, respectively). Nephrotic syndrome and renal failure at the time of rituximab administration predicted a worse response (no achievement of CR at 12 months) (p < 0.001 and p = 0.024, respectively).

Conclusion

Rituximab is currently being used to treat refractory systemic autoimmune diseases. Rituximab may be an effective option for patients with lupus nephritis, especially those refractory to standard treatment or who experience a new flare after intensive immunosuppressive treatment.

Highlights

► Rituximab in lupus nephritis (LN) currently seems to be good in real life, but bad in controlled trials. ► We present 164 patients with biopsy-proven LN treated with rituximab, the majority refractory to standard therapies. ► We found a clinical response in two thirds of patients at both 6 and 12 months (CR=27% at 6 months, 30% at 12 months). ► A different rate of response according to the ISN/RPS histopathological classification was found. ► Patients with mixed proliferative-membranous LN showed a 4-fold rate of CR at 12 months (70%) than type IV LN (22%). ► The main baseline features associated with not achieving CR were nephrotic syndrome and renal failure.

Introduction

Systemic lupus erythematosus (SLE) is considered the most clinically and serologically diverse systemic autoimmune diseases (SAD) because it may affect any organ and display a broad spectrum of clinical manifestations [1], [2]. Renal disease plays a key role in the prognosis of SLE and contributes significantly to the morbidity and mortality of the overwhelmingly-young, female SLE population [3]. Patients with glomerulonephritis have a higher mortality rate in comparison with those without renal involvement, and nearly 10% of patients with lupus nephritis (LN) develop end-stage renal failure requiring dialysis or transplantation [4], [5], [6]. Both nephritis and chronic corticosteroid and immunosuppressive agent use cause significant morbidity and reduced life expectation in SLE patients.

Rituximab is a chimeric antibody against CD20, a surface antigen expressed by B cells. Rituximab was first approved for the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma in 1997, and then for RA [7]. Off-label use of rituximab in SLE was first reported in 2002 and, since then, has been increasingly used in patients with SLE [8]. However, the advanced results of the LUNAR trial [9] showed that rituximab plus mycophenolate was not superior to mycophenolate in SLE patients with proliferative nephritis (types III/IV). Although definite conclusions must await full details of this trial, the negative preliminary results are discouraging [10]. This is in contrast to the good results for the off-label use of rituximab reported by various centers with long clinical experience in the management of SLE [11], [12], [13], [14], [15], [16], [17], illustrating the differences that occur between real-life and trials.

In this study, we present a pooled analysis of the efficacy of rituximab in real-life patients from European cohorts diagnosed with biopsy-proven lupus nephropathy who were treated with rituximab.

Section snippets

UK-BIOGEAS Registry

In January 2009, nine centers from UK and Spain specialized in the management of SLE patients created the UK-BIOGEAS Registry, a multicenter study devoted to evaluate the efficacy of the off-label use of rituximab in adult patients with lupus nephritis in a real-life setting. By December 2010, the database included 151 consecutive patients with lupus nephritis treated with rituximab. The inclusion criteria were: i) diagnosis of SLE based on the current classification criteria [18]; ii) adult

General description

A total of 164 patients (99 from the UK-BIOGEAS Registry and 65 from the literature search) fulfilled the inclusion criteria for the pooled analysis (Table 1). There were 145 females and 19 males, with a mean age at LN diagnosis of 32.3 years, a mean time of evolution of SLE until LN diagnosis of 8.1 years and a mean time of evolution of LN until renal biopsy of 5.8 years. Ninety-two (56%) patients were Caucasian, 46 (28%) Black, 22 (13%) Asian and four classified as “other”.

In 82 (50%) cases,

Discussion

SLE is not a benign disease. Patients with SLE have a 1.5 to 5-fold increased risk of mortality [29] and nearly 10% die within 10 years of the diagnosis [30]. Clinically, therapeutic decisions in SLE are based on personal experience and reported studies since there are no standardized therapeutic guidelines, with the exception of very recent EULAR proposals [31], [32]. The small number of RCTs in SLE may be explained by the low prevalence, the heterogeneous clinical presentation (often

Disclosure statement

The BIOGEAS Study group had received educational grants (2006–2008) from Roche and Abbott supporting the design and maintenance of the webpage www.biogeas.es. The financial support of Roche and Abbott was exclusively limited to maintaining the BIOGEAS webpage.

Take-home messages

  • Rituximab in lupus nephritis (LN) currently seems to be good in real life, but bad in controlled trials.

  • We present the results of the use of rituximab in 164 patients with biopsy-proven LN, the majority refractory to standard therapies, with a clinical response in two thirds of patients at both 6 and 12 months, and a rate of CR of 27% at 6 months rising to 30% at 12 months.

  • We found a different rate of response according to the ISN/RPS histopathological classification, with a 4-fold higher rate of

Acknowledgments

Drs. Martinez-Berriotxoa and Ruiz-Irastorza are supported by the Department of Education, Universities and Research of the Basque Government. Dr. Vital is supported by a fellowship from the National Institute of Health Research, UK.

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    1

    The members of the UK-BIOGEAS are listed in the Appendix.

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