Rheumatology Advance Access published May 28, 2009 Rheumatology 2009; 1 of 7
doi:10.1093/rheumatology/kep124
Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Edmund K. Li1, Lai-Shan Tam1, Tracy Y. Zhu1, Martin Li1, Catherine L. Kwok1, Tena K. Li1, Ying Ying Leung2, Kong Chiu Wong1 and Cheuk Chun Szeto1 Objective. To assess if combination rituximab and cyclophosphamide is more effective than rituximab monotherapy as an induction therapy for proliferative lupus nephritis. Methods. A randomized open-label pilot study in which 9 patients received rituximab alone and 10 patients received two doses rituximab þ intravenous cyclophosphamide. The clinical, laboratory and renal histological changes were assessed after 48 weeks of treatment. Results. At week 48, four patients had a complete response, 11 patients achieved partial response, 2 patients remained the same or stable and 2 worsened. There were no statistical differences in the proportion of patients with complete or partial response between the two groups. None of the variables was an independent predictor of response at week 48. Nine patients had significant improvement in activity indices in renal biopsies, but there were no significant differences between the two groups. Overall, 18 out of 19 patients were found to have effective B-cell depletion. The median duration of complete B-cell depletion in all patients was 22 weeks. There were no statistically significant differences in the proportion of patients with complete depletion at weeks 4, 8, 24 and 48 between the two groups except at week 2. Conclusions. Rituximab monotherapy appears to be effective as induction therapy in lupus nephritis. The addition of cyclophosphamide offers no additional improvement in clinical, laboratory and renal histological assessment or the duration of B-cell depletion at 48 weeks. Large-scale studies with longer duration are needed to confirm these findings. KEY
WORDS:
Rituximab, Cyclosphamide, Lupus nephritis, Renal biopsies.
Introduction SLE is an autoimmune disease that is thought to involve disturbances in T- and B-cell functions with the production of immune complexes secreted from activated B cells causing inflammation on multiple organs and tissues especially the kidneys. Although the long-term prognosis and survival of patients with this disease has significantly improved over the past decades with the introduction of corticosteroids and other immunosuppressive drugs, many continue to have aggressive disease while others develop toxicities from treatment accounting for significant morbidity and mortality [1]. For lupus nephritis, treatment regime consisting of corticosteroid and cyclophosphamide has generally been regarded as the ‘gold standard’ [2], whereas newer treatment regimes continue to emerge such as mycophenolate mofetil (MMF) which recently was shown to be as effective as cyclophosphamide and has less toxicity [3, 4]. Other newer agents such as mAb rituximab (anti-CD20), a chimeric monoclonal anti-B-cell antibody specific for human CD20, have also been reported to be beneficial in patients with proliferative lupus nephritis, used alone [5, 6] or in combination with cyclophosphamide [7–11] or with other immunosuppressive drugs [12, 13]. However, it is as yet not clear if rituximab used in combination with cyclophosphamide is more effective than rituximab alone. In our centre, we have chosen to investigate the potential of this new therapy in patients with proliferative lupus nephritis in a treatment protocol consisting of two treatment arms: (i) rituximab alone and (ii) combination of rituximab with cyclophosphamide to assess if the addition of cyclophosphamide to rituximab is more effective than rituximab as monotherapy. We describe herein the results seen over a 48-week period in our study 1 Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin and 2Department of Medicine and Geriatrics, Tai Po Hospital, Hong Kong.
Submitted 9 February 2009; revised version accepted 17 April 2009. Correspondence to: Edmund K. Li, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. E-mail:
[email protected]
patients with respect to the clinical manifestations of renal diseases, the clinical renal response, the proportion of patients with B-cell depletion and the histological outcome.
Methods Nineteen patients with SLE, as defined by the revised ACR criteria [14] and renal biopsies [15] documenting lupus nephritis according to the classification of the World Health Organization as proliferative glomerulonephritis Class III (focal) or intravenous (IV) (diffuse), and clinical activity (activity index of 56/24), urinary protein excretion of 51.5 g/24 h and serum albumin concentration of 435 g/l, were included after written consent. The protocol is consistent with the principles of the Declaration of Helsinki. The study was approved by the ethics committee of the Chinese University of Hong Kong. All participants gave their informed consent. Patients with life-threatening complications such as severe infections within the past 3 months, human immunodeficiency virus infection, hepatitis B or C infections, active tuberculosis, pregnancy, a history of cancer, diabetes mellitus, renal failure requiring dialysis and those who are unwilling to observe contraception during the trial were excluded. In addition, in those on oral/IV cyclophosphamide, or AZA, or MMF within 8 weeks, or prednisolone at a dose 50.5 mg/kg of body weight per day or more within 4 weeks were also excluded. Renal biopsy specimens were examined by light IF, and electron microscopy. The findings were categorized with respect to activity and chronicity [16]. Patients with membranous features would be included only when there were concomitant proliferative changes.
Treatment protocol Nineteen patients (17 females and 2 males) were randomized according to a randomization table kept by a third party to receive one of the two treatment arms: in Group 1, (rituximab group); on Day 1, patients were also given ‘pulse’ IV methylprednisolone 250 mg followed by rituximab infusion of 1000 mg. They were then given oral prednisolone 30 mg daily from Day 2 to Day 5,
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then 0.5 mg/kg for 4 weeks, then a reduction of 5 mg every 2 weeks to 5 mg/day for the rest of the study. In Group 2 (combination rituximab with cyclophosphamide group) on Day 1, patients were also given ‘pulse’ IV methylprednisolone 250 mg followed by rituximab infusion of 1000 mg as in Group 1, followed by IV cyclophosphamide infusions of 750 mg. They were then given oral prednisolone 30 mg daily from Day 2 to Day 5, then 0.5 mg/kg for 4 weeks, then a reduction of 5 mg every 2 weeks to 5 mg/day for the rest of the study as in Group 1. All patients were pre-medicated with chlorpheniramine (10 mg IV) and paracetamol (1 g orally) 30 min before IV infusions. This treatment was repeated once after 2 weeks on Day 15; thus all patients received a total of two doses of rituximab 2 weeks apart. Other immunosuppressive drugs were stopped 8 weeks prior to the study except for their baseline medications such as HCQ, oral prednisolone and statins. All patients were started on angiotensin-converting enzymes inhibitors before commencement of the trial and continued at the same dosage throughout the study period.
Assessment The total duration of the study was 48 weeks. Patients were seen monthly for the first 6 months following treatment, then every 2 months thereafter for a total of 48 weeks. Clinical and laboratory assessments were performed at the time of recruitment, before treatment and then during every follow-up. At each visit, patients were evaluated for clinical manifestations of SLE and adverse side effects related to treatment. Blood pressure and body weight were recorded, urinalysis was performed, full blood counts, renal, liver function tests, serum C3, C4 concentrations, anti-double-stranded DNA (dsDNA) antibodies, ESR, serum immunoglobulin G, A, M levels, a 24-h sample of urinary protein excretion and creatinine clearance were measured. The SLEDAI [17] and accumulated organ damage, assessed with the SLICC/ACR damage index (DI) [18], was used at every visit. A repeat renal biopsy was performed 48 weeks after initiation of the first dose of rituximab in patients who achieved complete or partial response, and were willing to have the procedure repeated for histological assessment. The percentage of CD19þ B lymphocytes was determined at weeks 2, 4, 8, 12, 24, 32 and 48 using standard direct-stain, lyse/wash techniques on whole blood using a FACSCalibur flow cytometer and CellQuest software (Becton, Dickinson, San Jose, CA, USA). [5]. Absolute B-cell numbers were calculated based on the white blood count, the percentage of lymphocytes, and the percentage of CD19þ B lymphocytes identified on flow cytometry. Effective B-cell depletion was defined as depletion of B cells to 10/high power field (hpf) (3 points) and urine white blood cell count >10/hpf (1 point). Renal response was defined as follows: ‘complete response’, if the baseline (at week 0) activity score was greater than 0 and the follow-up score was equal to 0; ‘partial response’, if the baseline activity score was greater than the follow-up score but the follow-up score was not equal to 0; ‘stable’, if the baseline activity score was equal to the follow-up score; and ‘worsening’, if the baseline activity score was less than the follow-up score. Nephrotic syndrome was defined as proteinuria >3.5 g/24 h with serum albumin 107 mol/l.
End points The proportion of patients with complete response in each of the two groups at week 48 was the primary end point. Secondary end points included the proportion of patients with partial response, proportion of patients and duration with completion CD19þ B lymphocyte depletion, histological assessment, adverse effects or deaths in each of the two groups at week 48.
Statistical analysis Statistical analysis was performed by SPSS for Windows software version 13.0 (SPSS, Chicago, IL, USA). All data are expressed as mean S.D. or median [interquartile range (IQR)] as appropriate, and analysed on intention-to-treat basis. Data between two groups were compared by Mann–Whitney U-test or independent two-sample t-test. Chi-square test was used to compare categorical data. A P-value of
