RHEUMATOLOGY
Rheumatology 2014;53:15371538 doi:10.1093/rheumatology/keu152 Advance Access publication 12 April 2014
Rituximab, a viable alternative for induction therapy of active lupus nephritis Next steps for evidence-based treatment
This editorial refers to Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study, by Gabriella Moroni et al., pages 15707.
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rheumatology.oxfordjournals.org/ at UCSF Library on September 7, 2014
Despite decades of clinical research aimed at finding the best approaches for the treatment of LN, it remains one of the major disease manifestations of SLE, with great impact on survival and quality of life. The recently recommended induction treatment from Kidney Disease Improving Global Outcomes (KDIGO) [1], the European League Against Rheumatism (EULAR) [2] and the ACR [3] for diffuse proliferative LN is essentially MMF or i.v. CYC in combination with glucocorticoids. For those who fail to respond to MMF or CYC, switching to the other agent or to rituximab (RTX) is suggested. But with comparatively low-quality evidence as supporting data, clinicians rely on sporadic case reports and observational studies for guidance. RTX is a chimeric mouse/human monoclonal antibody specific for human CD20, a B cell surface antigen expressed only on mature B cells. As B cells play a key role in the pathogenesis of SLE through both antibody-dependent and antibody-independent mechanisms, it is speculated that RTX in SLE or LN should be a promising treatment. A few open-label and/ or prospective studies have demonstrated the efficacy of RTX in the treatment of patients with SLE, especially those with cytopenia, nephritis or neuropsychiatric lupus [13]. These reports show consistent disease improvement. However, there were differences in patient selection criteria, sample size, RTX regimens, concomitant medication and outcome measures in these studies. Two previous multicentre randomized controlled trials—EXPLORER (the Exploratory Phase II/III SLE Evaluation of RTX) [4] and LUNAR (the LN Assessment with RTX) [5] studies, —failed to support the efficacy of RTX in the treatment of SLE patients with or without renal involvement. The reasons for their failure have been extensively discussed [6]. Many of the patients in the observational studies have received aggressive background immunosuppressive therapy before RTX, in contrast to the randomized trials, which added RTX on top of standard therapy for nonrefractory patients. The role of RTX in the treatment of LN is still controversial. In this issue of Rheumatology, Moroni et al. [7] present data from an observational study comparing RTX vs MMF and vs CYC pulses in the treatment of active LN and
concluded that RTX seemed to be at least as effective as MMF and CYC pulses in inducing remission. At the end of 3 months, proteinuria was reduced by 50% in 58.8% of patients on RTX, 64.7% on MMF and 63.1% on CYC [7]. At the end of 12 months, complete remission was present in 70.6% of patients on RTX, 52.9% on MMF and 65% on CYC. Considering the poorer renal prognostic factors in the patients treated with RTX, the authors suggested that RTX could be considered a viable alternative for induction therapy of active LN [7]. Combined with more recent data suggesting RTX could be a steroidsparing agent [8, 9], Moroni et al.’s [7] data have added new evidence supporting the option that such biologic agents deserve to be increasingly used and may be useful in the management of patients with LN, if the conclusion can be validated in controlled trials. Although the comparison between the groups was difficult because the choice of treatment allocation was at the discretion of the clinicians, patients on RTX had a significantly longer duration of SLE/LN, a greater number of renal flares and a lower dosage of prednisone at enrolment, but with comparable response rates in renal and extrarenal manifestations, immunological parameters and adverse effects at the end of 3 and 12 months treatment compared with patients on MMF or CYC [7]. It seemed that less favourable prognostic factors did not eliminate the efficacious role of RTX in induction therapy. It was at least as effective as MMF or CYC. The most interesting aspect of the present study [7] was the direct comparison between RTX and standard of care, namely CYC pulses (in spite of the Euro-Lupus CYC regimen the authors applied not having been extensively validated in non-Caucasian populations and in severe diffuse proliferative LN) and MMF for the treatment of severe forms of LN. If the data could be replicated in larger cohorts and non-Caucasian populations, it would be a valuable contribution, essentially because it challenges the view derived from the LUNAR trial that RTX is of no particular efficacy in LN. Although this study [7] provides further evidence suggesting a role for RTX in LN, several caveats are raised and warrant further study. Double-blind controlled trials are needed. Enrolment of larger samples and avoidance of selection bias will be more helpful for extrapolating the conclusions to a more general lupus population. Studies of RTX’s efficacy in Asian and African patients would be of interest, as LN is more prominent and seems to be
EDITORIAL
Editorial
Editorial
Disclosure statement: The authors have declared no conflicts of interest.
Xu-jie Zhou1,2,3, Ming-hui Zhao1,2,3 and Hong Zhang1,2,3 1 Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 2Key Laboratory of Renal Disease, Ministry of Health of China and 3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China. Accepted 20 February 2014 Correspondence to: Xu-jie Zhou, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing 100034, People’s Republic of China. E-mail: [email protected]
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References 1 KDIGO clinical practice guideline for glomerulonephritis— chapter 12: lupus nephritis. Kidney Int Suppl 2012;2: S22132. 2 Bertsias GK, Tektonidou M, Amoura Z et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;7111: 177182. 3 Hahn BH, McMahon MA, Wilkinson A et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64:797808. 4 Merrill JT, Neuwelt CM, Wallace DJ 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;62: 22233. 5 Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum 2012;64: 121526. 6 Reddy V, Jayne D, Close D, Isenberg D. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res Ther 2013;15(Suppl 1):S2. 7 Moroni G, Raffiotta F, Trezzi B et al. Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology 2014;53:15707. 8 Ezeonyeji AN, Isenberg DA. Early treatment with rituximab in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen. Rheumatology 2012; 51:47681. 9 Condon MB, Ashby D, Pepper RJ et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;72: 12806. 10 Jonsdottir T, Zickert A, Sundelin B et al. Long-term follow-up in lupus nephritis patients treated with rituximab—clinical and histopathological response. Rheumatology 2013;52:84755.
www.rheumatology.oxfordjournals.org
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in more severe forms in these ethnic populations. Corticosteroid dosing should be included in the response threshold in the future, as prednisone doses in all the current treatment groups are still high in follow-up, with mean prednisolone doses >10 and >7.5 mg/day at the end of 6 and 12 months, respectively [7]. To evaluate the long-term effect of RTX therapy, such as renal delayed response and relapse, a longer follow-up is needed. Recent data suggest that up to 30% of patients treated with RTX relapse a mean of 12 months after drug administration [6, 10]. Previous studies, such as EXPLORER, suggest that B cell depletion therapy (BCDT) disproportionately affected B cell clones, in which rapidly proliferating clones of B cells that produce anti-dsDNA, aCL and anti-nucleosome antibodies appeared preferentially affected by BCDT [4]. Since the long-term effects of BCDT are not known [10], future studies involving biomarkers indicative of prognosis as well as response to therapy would be helpful. Health-economic indicators (such as cost-minimization, cost-benefit, cost-effectiveness, cost-utility, costconsequence, market-equilibrium) are also needed to evaluate patients’ quality of life. If no difference in longterm adverse events is observed, RTX may have an advantage over CYC/MMF in drug resistance and may potentially be better than CYC with regard to cumulative toxicity. However, aiding clinical remission of LN with RTX in SLE patients seems costly. Due to the unpredictable natural history and heterogeneity of SLE, future use of highly targeted therapies for individualization is warranted. Last, but not the least, clinical decision making should be the product of consultation between clinicians and patients.
Rheumatology 2014;53:15371538 doi:10.1093/rheumatology/keu152 Advance Access publication 12 April 2014
Rituximab, a viable alternative for induction therapy of active lupus nephritis Next steps for evidence-based treatment
This editorial refers to Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study, by Gabriella Moroni et al., pages 15707.
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rheumatology.oxfordjournals.org/ at UCSF Library on September 7, 2014
Despite decades of clinical research aimed at finding the best approaches for the treatment of LN, it remains one of the major disease manifestations of SLE, with great impact on survival and quality of life. The recently recommended induction treatment from Kidney Disease Improving Global Outcomes (KDIGO) [1], the European League Against Rheumatism (EULAR) [2] and the ACR [3] for diffuse proliferative LN is essentially MMF or i.v. CYC in combination with glucocorticoids. For those who fail to respond to MMF or CYC, switching to the other agent or to rituximab (RTX) is suggested. But with comparatively low-quality evidence as supporting data, clinicians rely on sporadic case reports and observational studies for guidance. RTX is a chimeric mouse/human monoclonal antibody specific for human CD20, a B cell surface antigen expressed only on mature B cells. As B cells play a key role in the pathogenesis of SLE through both antibody-dependent and antibody-independent mechanisms, it is speculated that RTX in SLE or LN should be a promising treatment. A few open-label and/ or prospective studies have demonstrated the efficacy of RTX in the treatment of patients with SLE, especially those with cytopenia, nephritis or neuropsychiatric lupus [13]. These reports show consistent disease improvement. However, there were differences in patient selection criteria, sample size, RTX regimens, concomitant medication and outcome measures in these studies. Two previous multicentre randomized controlled trials—EXPLORER (the Exploratory Phase II/III SLE Evaluation of RTX) [4] and LUNAR (the LN Assessment with RTX) [5] studies, —failed to support the efficacy of RTX in the treatment of SLE patients with or without renal involvement. The reasons for their failure have been extensively discussed [6]. Many of the patients in the observational studies have received aggressive background immunosuppressive therapy before RTX, in contrast to the randomized trials, which added RTX on top of standard therapy for nonrefractory patients. The role of RTX in the treatment of LN is still controversial. In this issue of Rheumatology, Moroni et al. [7] present data from an observational study comparing RTX vs MMF and vs CYC pulses in the treatment of active LN and
concluded that RTX seemed to be at least as effective as MMF and CYC pulses in inducing remission. At the end of 3 months, proteinuria was reduced by 50% in 58.8% of patients on RTX, 64.7% on MMF and 63.1% on CYC [7]. At the end of 12 months, complete remission was present in 70.6% of patients on RTX, 52.9% on MMF and 65% on CYC. Considering the poorer renal prognostic factors in the patients treated with RTX, the authors suggested that RTX could be considered a viable alternative for induction therapy of active LN [7]. Combined with more recent data suggesting RTX could be a steroidsparing agent [8, 9], Moroni et al.’s [7] data have added new evidence supporting the option that such biologic agents deserve to be increasingly used and may be useful in the management of patients with LN, if the conclusion can be validated in controlled trials. Although the comparison between the groups was difficult because the choice of treatment allocation was at the discretion of the clinicians, patients on RTX had a significantly longer duration of SLE/LN, a greater number of renal flares and a lower dosage of prednisone at enrolment, but with comparable response rates in renal and extrarenal manifestations, immunological parameters and adverse effects at the end of 3 and 12 months treatment compared with patients on MMF or CYC [7]. It seemed that less favourable prognostic factors did not eliminate the efficacious role of RTX in induction therapy. It was at least as effective as MMF or CYC. The most interesting aspect of the present study [7] was the direct comparison between RTX and standard of care, namely CYC pulses (in spite of the Euro-Lupus CYC regimen the authors applied not having been extensively validated in non-Caucasian populations and in severe diffuse proliferative LN) and MMF for the treatment of severe forms of LN. If the data could be replicated in larger cohorts and non-Caucasian populations, it would be a valuable contribution, essentially because it challenges the view derived from the LUNAR trial that RTX is of no particular efficacy in LN. Although this study [7] provides further evidence suggesting a role for RTX in LN, several caveats are raised and warrant further study. Double-blind controlled trials are needed. Enrolment of larger samples and avoidance of selection bias will be more helpful for extrapolating the conclusions to a more general lupus population. Studies of RTX’s efficacy in Asian and African patients would be of interest, as LN is more prominent and seems to be
EDITORIAL
Editorial
Editorial
Disclosure statement: The authors have declared no conflicts of interest.
Xu-jie Zhou1,2,3, Ming-hui Zhao1,2,3 and Hong Zhang1,2,3 1 Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 2Key Laboratory of Renal Disease, Ministry of Health of China and 3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China. Accepted 20 February 2014 Correspondence to: Xu-jie Zhou, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, No.8 Xi Shi Ku Street, Xi Cheng District, Beijing 100034, People’s Republic of China. E-mail: [email protected]
1538
References 1 KDIGO clinical practice guideline for glomerulonephritis— chapter 12: lupus nephritis. Kidney Int Suppl 2012;2: S22132. 2 Bertsias GK, Tektonidou M, Amoura Z et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;7111: 177182. 3 Hahn BH, McMahon MA, Wilkinson A et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64:797808. 4 Merrill JT, Neuwelt CM, Wallace DJ 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;62: 22233. 5 Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum 2012;64: 121526. 6 Reddy V, Jayne D, Close D, Isenberg D. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res Ther 2013;15(Suppl 1):S2. 7 Moroni G, Raffiotta F, Trezzi B et al. Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology 2014;53:15707. 8 Ezeonyeji AN, Isenberg DA. Early treatment with rituximab in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen. Rheumatology 2012; 51:47681. 9 Condon MB, Ashby D, Pepper RJ et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;72: 12806. 10 Jonsdottir T, Zickert A, Sundelin B et al. Long-term follow-up in lupus nephritis patients treated with rituximab—clinical and histopathological response. Rheumatology 2013;52:84755.
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at UCSF Library on September 7, 2014
in more severe forms in these ethnic populations. Corticosteroid dosing should be included in the response threshold in the future, as prednisone doses in all the current treatment groups are still high in follow-up, with mean prednisolone doses >10 and >7.5 mg/day at the end of 6 and 12 months, respectively [7]. To evaluate the long-term effect of RTX therapy, such as renal delayed response and relapse, a longer follow-up is needed. Recent data suggest that up to 30% of patients treated with RTX relapse a mean of 12 months after drug administration [6, 10]. Previous studies, such as EXPLORER, suggest that B cell depletion therapy (BCDT) disproportionately affected B cell clones, in which rapidly proliferating clones of B cells that produce anti-dsDNA, aCL and anti-nucleosome antibodies appeared preferentially affected by BCDT [4]. Since the long-term effects of BCDT are not known [10], future studies involving biomarkers indicative of prognosis as well as response to therapy would be helpful. Health-economic indicators (such as cost-minimization, cost-benefit, cost-effectiveness, cost-utility, costconsequence, market-equilibrium) are also needed to evaluate patients’ quality of life. If no difference in longterm adverse events is observed, RTX may have an advantage over CYC/MMF in drug resistance and may potentially be better than CYC with regard to cumulative toxicity. However, aiding clinical remission of LN with RTX in SLE patients seems costly. Due to the unpredictable natural history and heterogeneity of SLE, future use of highly targeted therapies for individualization is warranted. Last, but not the least, clinical decision making should be the product of consultation between clinicians and patients.
