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Nordmann-Gomes A, Cojuc-Konigsberg G, Hernández-Andrade A, Navarro-Sánchez V, Ramírez-Sandoval JC, Rovin B, Mejia-Vilet JM. Lupus nephritis randomised controlled trials: evidence gaps and under-represented groups. Lupus Sci Med 2024; 11:e001331. [PMID: 39706676 PMCID: PMC11664369 DOI: 10.1136/lupus-2024-001331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 11/30/2024] [Indexed: 12/23/2024]
Abstract
OBJECTIVE We performed a scoping review of randomised clinical trials (RCTs) assessing pharmacological therapies for the initial management of lupus nephritis (LN), focusing on study design, included populations and outcome definitions, to assess the generalisability of their results and identify gaps in the evidence. METHODS RCTs evaluating pharmacological interventions for the initial therapy of LN published between 2000 and 2024 were evaluated. Extracted variables included study design, selection criteria, outcome definitions, populations recruited and clinical characteristics of participants. Each study arm was included as intervention and segregated into guideline-recommended regimens (cyclophosphamide (CYC), mycophenolic acid analogues (MPAAs), calcineurin inhibitors and belimumab) or other regimens. Data were analysed by descriptive statistics, and Fragility Index (FI) was estimated to assess robustness of studies. RESULTS We included 124 intervention arms within 61 RCT, involving 7058 participants. Seventy-nine arms (63.7%) corresponded to guideline-recommended therapies: 33 (26.6%) MPAA, 28 (22.6%) NIH-CYC and 7 (5.6%) triple-drug therapies. While 100% of triple-drug therapies RCT were multinational, only 7.1% of NIH-CYC and 0% of tacrolimus RCTs were conducted in more than one country. Only 9 (14.8%) had follow-up ≥24 months. Ten (16.4%) RCTs exclusively included participants with severe or refractory LN. Only 29 (47.5%) reported serious adverse events, and few described patient-reported outcomes. Black and other race participants were under-represented, as well as participants from Middle East, North Africa, and the sub-Saharan African region. Response was variably defined and assessed at different intervals. Robustness of RCTs evaluating double-drug guideline-recommended therapies were mostly low, with FI ranging from 1 to 3. CONCLUSIONS Considering new recommendations for the management of LN, we call for broader inclusion of under-represented populations and homogenisation of study design. This study provides the rationale for evaluating unexplored treatment comparisons and conducting research on newer interventions in clinical settings where evidence is currently lacking.
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Affiliation(s)
- Alberto Nordmann-Gomes
- School of Medicine, Universidad Panamericana, Mexico City, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Adriana Hernández-Andrade
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Valeria Navarro-Sánchez
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Juan Carlos Ramírez-Sandoval
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Brad Rovin
- Internal Medicine/Nephrology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Juan M Mejia-Vilet
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Zhao X, Yang SQ, Li M, Wang YG. Effectiveness and safety of B cell-targeting biologics in the treatment of lupus nephritis: a systematic review and network meta‑analysis. Ren Fail 2024; 46:2416605. [PMID: 39440406 PMCID: PMC11500530 DOI: 10.1080/0886022x.2024.2416605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/29/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024] Open
Abstract
OBJECTIVES To evaluate the effectiveness and safety of different B cell-targeting biological agents combining with standard of care in patients with lupus nephritis (LN). METHODS Comprehensive literature searches were conducted using PubMed, Embase, Web of Science, and Central in the Cochran Library, spanning from inception to May 20th, 2024. Randomized control trials (RCTs) comparing rituximab (RTX), belimumab, ocrelizumab, obinutuzumab, and anifrolumab in LN were selected. The primary outcomes of interest were related to complete renal remission (CRR), and partial renal remission (PRR). Additionally, we delved into safety outcomes, examining the occurrence of serious adverse events (SAEs), infections, and the discontinuation rates due to adverse events. RESULTS A total of 6 RCTs with 1150 patients applying various B cell-targeting biological agents were included. Notably, ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that obinutuzumab (SUCRA 85.2%) has the highest potential superiority in improving CRR, followed by belimumab, ocrelizumab. Regarding the improvement in PRR, obinutuzumab (SUCRA 83.0%) has the highest potential superiority. In terms of safety, with a focus on SAEs, infections, and the discontinuation rates due to adverse events, the results were: SUCRA-based ranking indicated that RTX (SUCRA 74.1%) had the highest probability of postponing SAEs, followed by belimumab and obinutuzumab. Concerning infection reduction, anifrolumab (SUCRA 78.7%) had the highest potential superiority. Safety events monitoring infection occurred better with RTX than with standard therapy (OR = 3.57, 95% CI 1.02, 12.66) and were statistically different. For the discontinuation rates due to adverse events, RTX (SUCRA 88.6%) demonstrated the highest potential superiority. CONCLUSIONS Concerning the effectiveness and safety outcomes, obinutuzumab, belimumab, and RTX plus standard of care may be superior to the current standard therapy as treatments for LN. This study protocol has been registered with PROSPERO, with a registration number of CRD42024548522.
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Affiliation(s)
- Xi Zhao
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Si-Qi Yang
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Man Li
- Tianjin Beichen District Chinese Medicine Hospital, Tianjin, China
| | - Yao-Guang Wang
- Department of Nephrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Mo S, Li Y, He J, Lin L. Progress of rituximab in the treatment of systemic lupus erythematosus and lupus nephritis. Front Med (Lausanne) 2024; 11:1472019. [PMID: 39430591 PMCID: PMC11486751 DOI: 10.3389/fmed.2024.1472019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 09/18/2024] [Indexed: 10/22/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous clinical manifestations, often leading to significant morbidity and mortality, particularly due to lupus nephritis (LN). The standard therapeutic approach involving mycophenolate mofetil, cyclophosphamide, and glucocorticoids has shown limitations due to cumulative toxicity and side effects. The introduction of biologic agents, especially rituximab (RTX), a chimeric monoclonal antibody targeting CD20+ B cells, has revolutionized the treatment landscape. This review synthesized the current understanding of B cells' role in SLE and LN and evaluates RTX's therapeutic impact. B cells contribute to disease pathogenesis through autoantibody production and immune complex formation, leading to tissue damage. RTX's mechanisms of action, including Complement-Dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and induction of apoptosis, have demonstrated efficacy in both SLE and LN treatment. Clinical studies have reported remission rates and improved renal outcomes with RTX use, although challenges such as human anti-chimeric antibody development and optimal dosing persist. The review emphasized the need for continued research to elucidate RTX's long-term benefits and risks, and to explore personalized treatment strategies that incorporate B cell biology for better disease management in SLE and LN.
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Affiliation(s)
- Shouqi Mo
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
- Department of Rheumatology, Jieyang People's Hospital, Jieyang, China
| | - Yilan Li
- Department of General Family Medicine, Jieyang People's Hospital, Jieyang, China
| | - Junbing He
- Jieyang Medical Research Center, Jieyang People's Hospital, Jieyang, China
| | - Ling Lin
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
- Department of Rheumatology, Shantou University Medical College, Shantou, China
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Moroni G, Reggiani F, Ponticelli C. Immune-mediating and immunosuppressive pharmacotherapies for proliferative lupus nephritis. Expert Opin Pharmacother 2024; 25:2061-2076. [PMID: 39402707 DOI: 10.1080/14656566.2024.2416038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/09/2024] [Indexed: 11/01/2024]
Abstract
INTRODUCTION Proliferative lupus nephritis is a common and severe complication of systemic lupus erythematosus. Affected patients are at an increased risk of developing chronic kidney disease, end-stage kidney disease, and extra-renal comorbidities. In recent years, the prognosis for patients with proliferative lupus nephritis has improved thanks to advancements in management regimens. Despite these advances, lupus nephritis continues to present therapeutic complexities and unmet needs. AREAS COVERED Research was conducted across major databases to identify the most relevant articles pertaining to immune-mediating and immunosuppressive therapies in lupus nephritis. EXPERT OPINION The prognosis for patients with proliferative lupus nephritis remains severe. Some drugs used in this disease may be unable to control activity, and most of them have a low therapeutic index and may cause severe and life-threatening side effects. Nonetheless, better management of traditional drugs and the introduction of novel therapies have improved renal prognosis and reduced local and systemic adverse events in patients with proliferative lupus nephritis.
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Affiliation(s)
- Gabriella Moroni
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Francesco Reggiani
- Nephrology and Dialysis Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
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Kalashnikova E, Isupova E, Gaidar E, Sorokina L, Kaneva M, Masalova V, Dubko M, Kornishina T, Lubimova N, Kuchinskaya E, Chikova I, Raupov R, Kalashnikova O, Kostik M. BCD020 rituximab bioanalog compared to standard treatment in juvenile systemic lupus erythematosus: The data of 12 months case-control study. World J Clin Pediatr 2024; 13:89049. [PMID: 38596443 PMCID: PMC11000064 DOI: 10.5409/wjcp.v13.i1.89049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/02/2024] [Accepted: 01/30/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE. AIM To compare the benefits of RTX above SOCT. METHODS The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later. RESULTS Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia. CONCLUSION RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT.
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Affiliation(s)
- Elvira Kalashnikova
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Eugenia Isupova
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Ekaterina Gaidar
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Lyubov Sorokina
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Maria Kaneva
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Vera Masalova
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Margarita Dubko
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Tatiana Kornishina
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Natalia Lubimova
- Research Laboratory of Autoimmune and Autoinflammatory Diseases, Almazov National Medical Research Centre, Saint Petersburg 197341, Russia
| | - Ekaterina Kuchinskaya
- Research Laboratory of Autoimmune and Autoinflammatory Diseases, Almazov National Medical Research Centre, Saint Petersburg 197341, Russia
| | - Irina Chikova
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Rinat Raupov
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
- Department of Rheumatology, Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery, Saint-Petetrsburg 197136, Russia
| | - Olga Kalashnikova
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
| | - Mikhail Kostik
- Hospital Pediatry Department, Saint-Petersburg State Pediatric Medical University, Saint-Petersburg 194100, Russia
- Research Laboratory of Autoimmune and Autoinflammatory Diseases, Almazov National Medical Research Centre, Saint Petersburg 197341, Russia
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Cui W, Tian Y, Huang G, Zhang X, Li F, Liu X. Clinical research progress of novel biologics for the treatment of lupus nephritis. Clin Exp Med 2023; 23:4153-4162. [PMID: 37481481 DOI: 10.1007/s10238-023-01143-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/12/2023] [Indexed: 07/24/2023]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.
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Affiliation(s)
- Wenyan Cui
- The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Yunfei Tian
- The University of Hong Kong, Pok Fu Lam, Hong Kong, China
| | - Guangliang Huang
- The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Xinhui Zhang
- The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Feigao Li
- The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Xiuju Liu
- The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China.
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Nie H, Chang S, Li Y, Li F. Biomarkers Associated with Drugs for the Treatment of Lupus Nephritis. Biomolecules 2023; 13:1601. [PMID: 38002282 PMCID: PMC10669579 DOI: 10.3390/biom13111601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/17/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
The constant updating of lupus drug treatment guidelines has led to a question. How can the efficacy of treatment be more effectively monitored? Systemic lupus erythematosus (SLE) is a complex autoimmune disease that often presents clinically with multi-organ involvement, and approximately 30% of patients with SLE develop lupus nephritis (LN). Therefore, it is important to better track disease progression and drug efficacy. Now, kidney biopsy is still the gold standard for diagnosing and guiding the treatment of LN, but it is invasive and expensive. If simple, non-invasive and effective biomarkers can be found, drug intervention and prognosis can be better monitored and targeted. In this review, we focus on LN and explore biomarkers related to LN therapeutics, providing clinicians with more possibilities to track the therapeutic effect of drugs, improve treatment options and assess patient outcomes.
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Affiliation(s)
- Huiyu Nie
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Siyuan Chang
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yuanyuan Li
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Fen Li
- Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Clinical Medical Research Center for Systemic Autoimmune Diseases in Hunan Province, Changsha 410011, China
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Thakare SB, So PN, Rodriguez S, Hassanein M, Lerma E, Wiegley N. Novel Therapeutics for Management of Lupus Nephritis: What Is Next? Kidney Med 2023; 5:100688. [PMID: 37533564 PMCID: PMC10393586 DOI: 10.1016/j.xkme.2023.100688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023] Open
Abstract
Lupus nephritis is a severe, organ-threatening manifestation of systemic lupus erythematosus. The current standard of care in the treatment of lupus nephritis is limited to broad-spectrum immunosuppressants, which have significant concerns of short- and long-term toxicity. With traditional approaches, kidney survival and patient outcomes have remained suboptimal. Robust research in the therapeutics of lupus nephritis has resulted in development of many novel drugs targeting specific inflammatory response pathways. Some newer agents have shown a definitive signal of benefit when added to standard of care. With the advent of precision medicine in nephrology, lupus nephritis treatment may undergo a shift toward incorporating approaches using these newer drugs and individualizing care of our patients. This review highlights major advances in management of lupus nephritis over the last 25 years and explores the ongoing trials of emerging therapies in lupus nephritis.
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Affiliation(s)
| | | | - Sonia Rodriguez
- Division of Nephrology, University Health Network, Toronto, ON, Canada
| | - Mohamed Hassanein
- Division of Nephrology and Hypertension, University of Mississippi Medical Center, Jackson, MI
| | - Edgar Lerma
- Section of Nephrology, University of Illinois at Chicago, Chicago, IL
| | - Nasim Wiegley
- University of California Davis School of Medicine, Sacramento, CA
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Chen P, Zhou Y, Wu L, Chen S, Han F. Efficacy and Safety of Biologic Agents for Lupus Nephritis: A Systematic Review and Meta-analysis. J Clin Rheumatol 2023; 29:95-100. [PMID: 35699520 PMCID: PMC9940827 DOI: 10.1097/rhu.0000000000001877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES The aim of this study was to examine the effect and safety of biological agents for lupus nephritis (LN). METHODS PubMed, EMBASE, and the Cochrane Library databases were searched from their inception up to November 2021. The outcomes were overall response, complete remission, proteinuria, renal activity index, and adverse events (AEs). Only randomized controlled trials (RCTs) were included. RESULTS Nine RCTs (1645 patients) were included. The RCTs evaluated abatacept (n = 2), belimumab (n = 1), obinutuzumab (n = 1), atacicept (n = 1), IL-2 (n = 1), ocrelizumab (n = 1), and rituximab (n = 2). The use of biological agents was associated with higher likelihoods of achieving an overall response (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.39; p < 0.001; I2 = 14.3%; pQ = 0.301) and a complete response (RR, 1.33; 95% CI, 1.16-1.54; p < 0.001; I2 = 41.8%; pQ = 0.056). The use of biological agents was not associated with improvements in the urinary protein-to-creatinine ratio (weighted mean difference, 3.83; 95% CI, -3.71 to 11.38; p = 0.319; I2 = 99.4%; pQ < 0.001). The use of biological agents in patients with LN was also not associated with an increased risk of any AEs (RR, 1.01; 95% CI, 0.98-1.04; p = 0.519; I2 = 0.0%; pQ = 0.533), serious AEs (RR, 0.95; 95% CI, 0.82-1.09; p = 0.457; I2 = 0.0%; pQ = 0.667), grade >3 AEs (RR, 0.91; 95% CI, 0.67-1.22; p = 0.522; I2 = 0.0%; pQ = 0.977), infections (RR, 1.09; 95% CI, 0.99-1.20; p = 0.084; I2 = 0.0%; pQ = 0.430), and deaths (RR, 0.67; 95% CI, 0.36-1.24; p = 0.200; I2 = 0.0%; pQ = 0.439). The meta-regression analysis showed that follow-up duration and the sample size did not influence the complete response rate, whereas publications in 2012 to 2014 influence the rate compared with 2015 to 2020. CONCLUSIONS Biological agents seem to be effective and safe for managing patients with LN.
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Affiliation(s)
- Pang Chen
- From the Department of Rheumatology, Mindong Hospital Affiliated to Fujian Medical University, Ningde
| | - Yadong Zhou
- Department of Kidney, Blood, and Rheumatology, Affiliated Fuding Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou
| | | | - Shihan Chen
- Department of Rheumatology Integrated of TCM and Western Medicine
| | - Fangduo Han
- Department of Respiratory and Critical Care Medicine, Mindong Hospital Affiliated to Fujian Medical University, Ningde, China
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Alzayer H, Sebastian KK, O’Shaughnessy MM. Rituximab Dosing in Glomerular Diseases: A Scoping Review. Can J Kidney Health Dis 2022; 9:20543581221129959. [PMID: 36275037 PMCID: PMC9583230 DOI: 10.1177/20543581221129959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022] Open
Abstract
Purpose of Review Rituximab is increasingly prescribed for glomerular diseases. However, the recently published Kidney Disease Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases lacks details on recommended dosing regimens for most individual glomerular diseases. We performed this scoping review summarizing the evidence for rituximab dosing in glomerular disease. Sources of Information PubMed database. Methods The PubMed search methodology was developed with a medical librarian and performed by the first, with review by a second, author. Randomized controlled trials (RCTs) and prospective cohort studies (PCSs) examining rituximab efficacy and/or safety in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), membranous nephropathy (MN), lupus nephritis (LN), or podocytopathies (minimal change disease or focal segmental glomerulosclerosis [FSGS]) were included. Fifty-three studies (14 RCTs and 39 PCSs) were included. Key Findings We identified 16 different rituximab dosing regimens studied as induction therapy for one or more of the 5 glomerular diseases of interest. The most frequently studied rituximab induction regimens were 1000 mg as 2 doses 2 weeks apart (17 studies, 32%) and 4 doses of 375 mg/m2/week (18 studies, 33.9%). Twenty-six studies (49%) examined rituximab as monotherapy or in conjunction with corticosteroids alone, while the remaining studies examined rituximab as part of combination immunosuppression. Adapting treatment to achieve B-cell depletion, with frequent evaluation of disease-specific biomarkers, might prove the optimal approach to achieving and maintaining remission. Rituximab might also enable steroid minimization or avoidance. Limitations Restriction of the search to a single database and to studies published in the English language, and with an accompanying abstract, could have led to selection bias. While the search was limited to prospective observational studies and RCTs, no formal assessment of study quality was performed.
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Affiliation(s)
- Husam Alzayer
- Department of Nephrology, Ministry of
Health, Arar, Saudi Arabia
- Royal College of Surgeons in Ireland,
Dublin, Ireland
| | - Kuruvilla K. Sebastian
- Department of Renal Medicine, Cork
University Hospital, Ireland
- Department of Medicine, National
University of Ireland Galway, Ireland
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11
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Moroni G, Calatroni M, Ponticelli C. Severe lupus nephritis in the present days. FRONTIERS IN NEPHROLOGY 2022; 2:984613. [PMID: 37675028 PMCID: PMC10479763 DOI: 10.3389/fneph.2022.984613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 07/22/2022] [Indexed: 09/08/2023]
Abstract
Lupus nephritis (LN) is one of the most frequent and severe organ manifestations of systemic lupus erythematosus (SLE) that is a chronic autoimmune disease. Despite improvement in patient and renal prognosis, the disease continued to be associated with a high rate of end stage kidney disease. Along the last decades, it seems that the epidemiology of LN and its clinical presentation have progressively changed. The forms with renal insufficiency at presentation seem to have progressively reduced in developed countries in favour of more mild clinical presentations with urinary abnormalities only. To this clinical change does not correspond a less severe histological lesions, in fact, the extent of active lesions at kidney biopsy are unchanged, whereas chronic lesions are becoming less frequent and less severe. Meanwhile, new types of severe LN defined by the variable association of demographic, clinical, histological characteristics at diagnosis or during the follow-up are gradually emerging and require attention in assessing the therapy and prognosis. During the last years, randomized controlled trials have reported the efficacy of new drugs in association with standard therapy to improve the rate of short- and medium-term renal response. One of the advantages is that these results were obtained with reduced dosage of corticosteroids whose protracted use is associated with increase of chronic organ damage. Optimization of therapeutical strategies, tailored on the demographic clinical and histological characteristics, with combination of old and new drugs are urgently needed for severe LN.
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Affiliation(s)
- Gabriella Moroni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy
- Nephrology and Dialysis Division, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Marta Calatroni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy
- Nephrology and Dialysis Division, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
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12
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Choi SJ, Ahn SM, Oh JS, Hong S, Lee CK, Yoo B, Kim YG. Initial Preserved Renal Function as a Predictor of Favorable Renal Response to Rituximab in Refractory or Relapsing Lupus Nephritis: A Single-center Cohort Study in Korea. JOURNAL OF RHEUMATIC DISEASES 2022; 29:22-32. [PMID: 37476702 PMCID: PMC10324915 DOI: 10.4078/jrd.2022.29.1.22] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/22/2021] [Accepted: 08/13/2021] [Indexed: 07/22/2023]
Abstract
OBJECTIVE Previous studies investigating the beneficial effect of rituximab on lupus nephritis (LN) reported controversial results There have been few reports of renal response to rituximab according to renal function We investigated the efficacy of rituximab in refractory/relapsing LN and the role of renal function as a predictor of renal response. METHODS From 2016 to 2019, we retrospectively reviewed 22 patients with refractory/relapsing LN receiving rituximab Renal responses (complete and partial) at 6 and 12 months were compared between normal (glomerular filtration rate [GFR]≥90 mL/min/173 m2, n=11) and decreased (GFR<90 mL/min/173 m2, n=11) GFR groups Multivariate Cox regression analysis was used to assess predictors of renal response. RESULTS At baseline, the decreased GFR group had a higher urine proteinuria to creatinine ratio (p=0008) and proportion of refractory LN (p=0010) and previous cyclophosphamide therapy (p=0035) than the normal GFR group The overall renal response rate was 455% (10 patients) at 6 months and 545% (12 patients) at 12 months Renal response rates were higher in the normal GFR group (818% and 909% at 6 and 12 months, respectively) than in the decreased GFR group (91% and 182% at 6 and 12 months, respectively; p<0001) Normal GFR and anti-La were associated with renal response to rituximab, with hazard ratios of 9256 (p=0008) and 5478 (p=0041), respectively. CONCLUSION Rituximab is an effective therapy for refractory/relapsing LN, particularly in patients with preserved renal function.
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Affiliation(s)
- Su Jin Choi
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Department of Rheumatology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Soo Min Ahn
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Seon Oh
- Department of Information Medicine, Asan Medical Center, Seoul, Korea
| | - Seokchan Hong
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang-Keun Lee
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bin Yoo
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong-Gil Kim
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Teng S, Tian Y, Luo N, Zheng Q, Shao M, Li L. Efficacy and safety of an anti-CD20 monoclonal antibody, rituximab, for lupus nephritis: A meta-analysis. Int J Rheum Dis 2021; 25:101-109. [PMID: 34811947 DOI: 10.1111/1756-185x.14240] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/13/2021] [Accepted: 10/22/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND The efficacy and safety of rituximab (RTX) for lupus nephritis are still a controversial issue. METHODS We systematically searched MEDLINE, EMBASE, and the Cochrane Library databases for all clinical controlled studies. RESULTS Six studies with 588 patients were included in our meta-analysis. RTX increased total renal remission rates (TR, odds ratio [OR] 2.16, 95% CI 1.31 to 3.55, P = .003) and complete renal remission rate (CR, OR 2.42, 95% CI 1.18 to 4.94, P = .02) compared with the control group. Subgroup analyses showed that rituximab was more effective at increasing the rate of TR and CR for lupus nephritis patients compared with mycophenolate mofetil (TR, OR 4.6, 95% CI 1.29 to 16.47, P = .02; CR, OR 2.56, 95% CI 1.19 to 5.47, P = .02) and cyclophosphamide (TR, OR 2.89, 95% CI 1.31 to 6.40, P = .009; CR, OR 2.75, 95% CI 1.19 to 6.4, P = .02). Rituximab also had advantage in reducing Systemic Lupus Erythematosus Disease Activity Index score (-2.49, 95% CI -3.77 to -1.22, P = .0001). There were no significant differences between the RTX group and control group on the change of proteinuria (-0.36 g/d, 95% CI -0.71 to -0.00 g/d, P = .05) and serum creatinine (0.13 mg/dL, 95% CI -0.15 to 0.42 mg/dL, P = .36). RTX treatment did not increase the risk of adverse events compared to the control group. CONCLUSIONS This study provides clear beneficial effects of RTX in patients with lupus nephritis. In addition, RTX therapy did not increase the risk of adverse events compared to the control group.
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Affiliation(s)
- Siyuan Teng
- Department of Nephrology, the Second Hospital of Dalian Medical University, Dalian, China
| | - Yu Tian
- Department of Vascular Surgery, the Second Hospital of Dalian Medical University, Dalian, China
| | - Nan Luo
- Department of Infection, the Second Hospital of Dalian Medical University, Dalian, China
| | - Qiang Zheng
- Department of Nursing, the Second Hospital of Dalian Medical University, Dalian, China
| | - Mingfang Shao
- Department of Vascular Surgery, the Second Hospital of Dalian Medical University, Dalian, China
| | - Lei Li
- Department of Vascular Surgery, the Second Hospital of Dalian Medical University, Dalian, China
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14
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Kostopoulou M, Fanouriakis A, Cheema K, Boletis J, Bertsias G, Jayne D, Boumpas DT. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations. RMD Open 2021; 6:rmdopen-2020-001263. [PMID: 32699043 PMCID: PMC7425195 DOI: 10.1136/rmdopen-2020-001263] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/08/2020] [Accepted: 05/22/2020] [Indexed: 01/24/2023] Open
Abstract
Objectives To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. Methods According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. Results We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500–700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). Conclusions There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.
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Affiliation(s)
- Myrto Kostopoulou
- Department of Nephrology, "G. Gennimatas" General Hospital, Athens, Greece .,Department of Nephrology and Renal Transplantation Unit, "Laikon" Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Antonis Fanouriakis
- Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine, General University Hospital Attikon, Athens, Greece.,Department of Rheumatology, "Asklepieion" General Hospital, Athens, Greece
| | - Kim Cheema
- Department of Medicine, Cambridge University, Cambridge, UK
| | - John Boletis
- Department of Nephrology and Renal Transplantation Unit, "Laikon" Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - George Bertsias
- Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece
| | - David Jayne
- Department of Medicine, Cambridge University, Cambridge, UK
| | - Dimitrios T Boumpas
- Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine, General University Hospital Attikon, Athens, Greece.,Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,Joint Academic Rheumatology Program, Medical School, National and Kapodestrian University of Athens, Athens, Greece, and Medical School, University of Cyprus, Nicosia, Cyprus
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Wang S, Shang J, Xiao J, Zhao Z. Clinicopathologic characteristics and outcomes of lupus nephritis with positive antineutrophil cytoplasmic antibody. Ren Fail 2021; 42:244-254. [PMID: 32228220 PMCID: PMC7067160 DOI: 10.1080/0886022x.2020.1735416] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Aims: The aim was to determine whether anti-neutrophil cytoplasmic antibody (ANCA)-positive serology in patients with lupus nephritis (LN) is associated with different clinicopathologic features and outcomes.Methods: In our retrospective analysis, 283 patients were enrolled between 2013 and 2018. Thirty-six patients were ANCA-positive, and this group was compared with the remaining 247 patients who were confirmed as ANCA-negative at the time of biopsy.Results: ANCA-positive LN patients exhibited higher anti-dsDNA antibody titers and serum creatinine levels and lower serum hemoglobin concentrations than ANCA-negative LN patients. On pathological evaluation, segmental endocapillary hypercellularity observed by light microscopy was significantly more common in the ANCA-positive group. This feature was not significantly different in the treatment group, but the response to treatment was significantly different, as was remission (76.1% vs 69.4%, p < 0.001), between the ANCA-negative and ANCA-positive groups. During follow-up, the times to renal replacement therapy (RRT) and death were significantly different between the two unmatched groups (chi-square test, p = 0.041). Multivariate Cox analysis revealed that neurological disorders, ANCA positivity, and the chronicity index (CI) remained independent risk factors for patient survival. Pulmonary infection was the main cause of death and was most often due to fungal infection.Conclusion: ANCA-positive LN patients typically exhibited higher anti-dsDNA antibody titers, lower serum hemoglobin concentrations and worse renal function than ANCA-negative LN patients. Fungal infection was the main cause of death. We observed that ANCA positivity was an independent risk factor for patient survival.
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Affiliation(s)
- Shuai Wang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jin Shang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Xiao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhanzheng Zhao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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The growing role of precision medicine for the treatment of autoimmune diseases; results of a systematic review of literature and Experts' Consensus. Autoimmun Rev 2020; 20:102738. [PMID: 33326854 DOI: 10.1016/j.autrev.2020.102738] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment failure. Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient, thus it could be a new approach for management of AIDS which considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. In this work, the growing body of evidence is summarized regarding the predictive factors for drug response in patients with AIDs, applying the precision medicine principles to provide high-quality evidence for therapeutic opportunities in improving the management of these patients.
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Parodis I, Stockfelt M, Sjöwall C. B Cell Therapy in Systemic Lupus Erythematosus: From Rationale to Clinical Practice. Front Med (Lausanne) 2020; 7:316. [PMID: 32754605 PMCID: PMC7381321 DOI: 10.3389/fmed.2020.00316] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/01/2020] [Indexed: 11/25/2022] Open
Abstract
B cell hyperactivity and breach of tolerance constitute hallmarks of systemic lupus erythematosus (SLE). The heterogeneity of disease manifestations and relatively rare prevalence of SLE have posed difficulties in trial design and contributed to a slow pace for drug development. The anti-BAFF monoclonal antibody belimumab is still the sole targeted therapy licensed for SLE, lending credence to the widely accepted notion that B cells play central roles in lupus pathogenesis. However, more therapeutic agents directed toward B cells or B cell-related pathways are used off-label or have been trialed in SLE. The anti-CD20 monoclonal antibody rituximab has been used to treat refractory SLE during the last two decades, and the anti-type I IFN receptor anifrolumab is currently awaiting approval after one phase III clinical trial which met its primary endpoint and one phase III trial which met key secondary endpoints. While the latter does not directly affect the maturation and antibody production activity of B cells, it is expected to affect the contribution of B cells in proinflammatory cytokine excretion. The proteasome inhibitor bortezomib, primarily directed toward the plasma cells, has been used in few severe cases as an escape regimen. Collectively, current clinical experience and primary results of ongoing clinical trials prophesy that B cell therapies of selective targets will have an established place in the future personalized therapeutic management of lupus patients.
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Affiliation(s)
- Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Marit Stockfelt
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Christopher Sjöwall
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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Stolyar L, Lahita RG, Panush RS. Rituximab use as induction therapy for lupus nephritis: a systematic review. Lupus 2020; 29:892-912. [PMID: 32486934 DOI: 10.1177/0961203320928412] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Rituximab (RTX) has important usage in rheumatoid arthritis and vasculitis. There remains a need for more, better, and safer treatments for patients with lupus nephritis (LN). RTX has been trialed in such patients without definitive conclusions about its effectiveness. As a role for RTX has not been clearly established for LN, we carried out a systematic review and analysis. METHODS We identified 31 studies of RTX for class I-VI LN, and assessed complete renal response (CRR) and partial renal response (PRR) using criteria including serum creatinine, proteinuria, and urinary sediment. Due to differences in the pediatric presentation of the disease, studies focusing on pediatric patients were excluded. RESULTS One randomized controlled trial (RCT) showed superiority of RTX+cyclophosphamide (CYC) versus CYC alone (64% vs. 21% CRR and 19% vs. 36% PRR). Six prospective and retrospective studies utilizing RTX monotherapy found 66% CRR or PRR in all patients. Eleven studies that investigated RTX in combination with CYC or mycophenolate mofetil (MMF) also found 66% CRR or PRR in all patients. In total, the CRR for Caucasian, East Asian, and Hispanic patients were 77%, 38%, and 28%, respectively. CONCLUSIONS RTX appeared to benefit certain LN patients, but most studies were not randomized or properly controlled, were heterogeneous in design, subjects, and LN types, and were not comparable, and must therefore be interpreted cautiously. RTX alone may not deplete B cells sufficiently for the perturbations of LN. In addition, RTX may induce responses differently among patients of different ethnic and racial backgrounds. Furthermore, there were wide variations in the baseline characteristics of the patients, namely LN class, time course of disease, age, and prior immunosuppressive use. We suggest a prospective RCT in patients aged 18-65 years with class IV LN. Ideally, the patients would not have received prior immunosuppression and would better represent different ethnicities. The treatment groups would be RTX, RTX+belimumab, CYC, and MMF groups, with pulse-dose steroids during induction followed by maintenance steroids and MMF. The CRR and PRR would be assessed at 12 and 24 months. This or a similar study might clarify RTX's role in the treatment of LN.
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Affiliation(s)
- Liya Stolyar
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Robert G Lahita
- Department of Medicine, St. Joseph's Regional Medical Centre, Paterson, USA
| | - Richard S Panush
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
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Wu S, Wang Y, Zhang J, Han B, Wang B, Gao W, Zhang N, Zhang C, Yan F, Li Z. Efficacy and safety of rituximab for systemic lupus erythematosus treatment: a meta-analysis. Afr Health Sci 2020; 20:871-884. [PMID: 33163054 PMCID: PMC7609121 DOI: 10.4314/ahs.v20i2.41] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Given the inconsistency of previous studies and the newly emerging evidence, we decided to conduct a meta-analysis. Methods: The meta-analysis included 2 randomized controlled trials and 13 observational studies 742 patients in total. Qualified studies were properly searched from databases . Data were analyzed by the RevMan 5.3 software. Results were demonstrated as WMD , SMD and RR with 95% CIs, I2 and P value. Results: we observed that a remarkable increase of complement C3 in the rituximab group than placebo group (WMDfixed= 7.67mg/dL, 95%CIs=−0.16~15.50, I2=0%, P=0.05). A significant increase of complement C4 was observed in the rituximab group than placebo group (WMDfixed=3.14mg/dL, 95%CIs=1.06~5.22, I2=0%, P=0.003). Notably decreased peripheral CD19+B cells in rituximab group than placebo group (WMDfixed=−117.93n/µl, 95%CIs=−172.94~−62.91, I2=0%, P<0.0001) in RCTs. Patients with severe or refractory SLE got more satisfactory efficacy results after receiving rituximab in observational studies, such as British Isles Lupus Assessment Group index score, SLE Disease Activity Index score, complement C3/C4, anti-dsDNA antibodies, peripheral CD19+B cells and so on. Safety profiles were no difference between rituximab and placebo groups. Conclusion: although the efficacy of rituximab is highly controversial for SLE, our study shows that rituximab presents a satisfying efficacy and safety for SLE.
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Fanouriakis A, Kostopoulou M, Cheema K, Anders HJ, Aringer M, Bajema I, Boletis J, Frangou E, Houssiau FA, Hollis J, Karras A, Marchiori F, Marks SD, Moroni G, Mosca M, Parodis I, Praga M, Schneider M, Smolen JS, Tesar V, Trachana M, van Vollenhoven RF, Voskuyl AE, Teng YKO, van Leew B, Bertsias G, Jayne D, Boumpas DT. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 2020; 79:713-723. [PMID: 32220834 DOI: 10.1136/annrheumdis-2020-216924] [Citation(s) in RCA: 465] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 03/16/2020] [Accepted: 03/17/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN). METHODS Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. RESULTS The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. CONCLUSIONS We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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Affiliation(s)
- Antonis Fanouriakis
- Rheumatology and Clinical Immunology Unit, "Attikon" University Hospital, Athens, Greece
- Department of Rheumatology, "Asklepieion" General Hospital, Athens, Greece
| | - Myrto Kostopoulou
- Department of Nephrology, "G. Gennimatas" General Hospital, Athens, Greece
| | - Kim Cheema
- Department of Medicine, Cambridge University, Cambridge, UK
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital LMU Munich, Munich, Germany
| | - Martin Aringer
- Division of Rheumatology, Department of Medicine III, University Medical Center & Faculty of Medicine Carl Gustav Carus at the TU Dresden, Dresden, Germany
| | - Ingeborg Bajema
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - John Boletis
- Nephrology Department and Renal Transplantation Unit, "Laikon" Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Eleni Frangou
- Department of Nephrology, Limassol General Hospital, Limassol, Cyprus
| | - Frederic A Houssiau
- Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Jane Hollis
- Lupus nurse specialist, Addenbrooke's Hospital, Cambridge, UK
| | - Adexandre Karras
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Stephen D Marks
- University College London Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
| | - Gabriella Moroni
- Nephrology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marta Mosca
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Manuel Praga
- Nephrology Department, Research Institute Hospital Universitario 12 de Octubre (i+12), Department of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Matthias Schneider
- Department of Rheumatology & Hiller Research Unit Rheumatology, UKD, Heinrich-Heine University, Duesseldorf, Germany
| | - Josef S Smolen
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Vladimir Tesar
- Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | - Maria Trachana
- Pediatric Immunology and Rheumatology Referral Center, First Pediatric Clinic, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ronald F van Vollenhoven
- Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Alexandre E Voskuyl
- Rheumatology and Immunology Center, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Y K Onno Teng
- Centre of expertise for Lupus-, Vasculitis- and Complement-mediated Systemic autoimmune diseases, Department of Internal Medicine - section Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - George Bertsias
- Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece
| | - David Jayne
- Department of Medicine, Cambridge University, Cambridge, UK
| | - Dimitrios T Boumpas
- Rheumatology and Clinical Immunology Unit, "Attikon" University Hospital, Athens, Greece
- Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Zhou J, Tao MJ, Jin LR, Sheng J, Li Z, Peng H, Xu L, Yuan H. Effectiveness and safety of common therapeutic drugs for refractory lupus nephritis: A network meta-analysis. Exp Ther Med 2020; 19:665-671. [PMID: 31897105 PMCID: PMC6923745 DOI: 10.3892/etm.2019.8257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 11/06/2019] [Indexed: 12/02/2022] Open
Abstract
Previous studies have indicated that various drugs may be beneficial for the treatment of patients with refractory lupus nephritis (RLN). The present study aimed to evaluate the effectiveness and safety of common therapeutic drugs for the treatment of RLN using a network meta-analysis (NMA). NMA was performed using Stata 14.0 software. The odds ratio (OR) and 95% CI were calculated. A total of 19 studies comprising 1,127 patients were included. Common therapeutic drugs for RLN included glucocorticoids (GC), cyclophosphamide (CTX), mycophenolate mofetil (MMF), tacrolimus (TAC), leflunomide (LEF), cyclosporine A and rituximab (RTX). Evaluation of the effectiveness revealed that MMF + GC produced significantly higher overall responses (i.e. complete remission plus partial remission) and that MMF + GC (OR=2.58; 95% CI, 1.67–3.97), CTX + RTX + GC (OR=3.89; 95% CI, 1.60–9.45), CTX + LEF + GC (OR=3.05; 95% CI, 1.05–8.84) and CTX + TAC + GC (OR=6.22; 95% CI, 1.93–20.05) had significantly higher overall responses compared with those to the traditional treatment regimen (CTX + GC). Ranking probability based on the surface under the cumulative ranking curve indicated that CTX + TAC + GC had the highest probability (80.6%) of being the best treatment for achieving an overall response. In the safety evaluation, MMF + GC had a lower risk of infection than CTX + GC (OR=0.32; 95% CI, 0.11,0.88). There were no statistically significant differences in adverse reactions, including gastrointestinal reactions and leukopenia between any two treatment regimens. In conclusion, the regimen of CTX + TAC + GC exhibited a trend in superiority regarding clinical efficacy among common therapeutic drug treatments for RLN, while the regimen of CTX + GC had a higher probability to cause adverse effects among the nine interventions compared.
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Affiliation(s)
- Jun Zhou
- Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Meng-Jun Tao
- Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Lai-Run Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
| | - Jun Sheng
- Department of Rheumatology, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Zhi Li
- Department of Rheumatology, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Hui Peng
- Hospital Infection Control Office, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Liang Xu
- Department of Rheumatology, Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Hui Yuan
- Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, Wuhu, Anhui 241002, P.R. China
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Nasonov EL, Beketova TV, Ananyeva LP, Vasilyev VI, Solovyev SK, Avdeeva AS. PROSPECTS FOR ANTI-B-CELL THERAPY IN IMMUNO-INFLAMMATORY RHEUMATIC DISEASES. RHEUMATOLOGY SCIENCE AND PRACTICE 2019. [DOI: 10.14412/1995-4484-2019-3-40] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- E L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia
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Kaegi C, Wuest B, Schreiner J, Steiner UC, Vultaggio A, Matucci A, Crowley C, Boyman O. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders. Front Immunol 2019; 10:1990. [PMID: 31555262 PMCID: PMC6743223 DOI: 10.3389/fimmu.2019.01990] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/06/2019] [Indexed: 12/20/2022] Open
Abstract
Background: During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. Objective: To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Conclusions: Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality trials with larger patient numbers.
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Affiliation(s)
- Celine Kaegi
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Benjamin Wuest
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Jens Schreiner
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Urs C Steiner
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Alessandra Vultaggio
- Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Andrea Matucci
- Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Catherine Crowley
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Onur Boyman
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
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Liu B, Ou Q, Tang Y, Fu S, Liang P, Yu Y, Xu Z, Chen Y, Xu A. Corticosteroids combined with doublet or single-agent immunosuppressive therapy for active proliferative lupus nephritis. Clin Rheumatol 2019; 38:2519-2528. [PMID: 31081535 DOI: 10.1007/s10067-019-04596-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 04/22/2019] [Accepted: 05/06/2019] [Indexed: 01/21/2023]
Abstract
OBJECTIVES We performed a meta-analysis to assess whether corticosteroids (C) plus (+) doublet immunosuppressive therapy (IT) is superior to the classical combination of C with single-agent IT in active proliferative lupus nephritis (LN). METHOD Randomized trials evaluating the benefits and risks of C+doublet versus single-agent IT in active proliferative LN were obtained by searching PubMed, EMBASE, and Cochrane Central Register. The primary outcome was overall response rate (ORR). The secondary outcomes were the change from baseline in Systemic Lupus Erythematosus Disease Activity Index (SLE-DAI) score, negative conversion ratio of anti-double-stranded DNA (anti-dsDNA), and adverse events. The PROSPERO registry number is CRD42017068491. RESULTS Eleven trials with 1855 patients were included. Compared with C+single-agent IT, C+doublet IT had a significantly higher ORR (relative risk [RR], 1.22; 95% confidence interval [CI], 1.09 to 1.35; P < 0.01). In a subgroup analysis, C+doublet IT without biologics had a significantly higher ORR than C+single-agent IT (RR, 1.30; 95% CI, 1.13 to 1.50; P < 0.01), while C+doublet IT including biologics improved ORR only for refractory severe LN (RR, 1.46; 95% CI, 1.09 to 1.96; P = 0.012). A larger change from baseline in SLE-DAI scores (standardized mean difference, - 0.49; 95% CI, - 0.68 to - 0.30; P < 0.01) and a higher negative conversion ratio of anti-dsDNA (RR, 1.34; 95% CI, 1.06 to 1.69; P = 0.014) were observed with C+doublet IT than with C+single-agent IT. The rates of adverse events were similar between the two regimens. CONCLUSIONS Compared with single-agent IT, the combination of C and doublet IT without biologics improved clinical outcomes in active proliferative LN. Key Points • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy without biologics had a significantly higher overall response rate in active proliferative lupus nephritis. • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy including biologics improved overall response rate only for refractory severe lupus nephritis. • A larger change from baseline in SLE-DAI scores and a higher negative conversion ratio of anti-dsDNA were observed with corticosteroids + doublet immunosuppressive therapy than with corticosteroids + single-agent immunosuppressive therapy.
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Affiliation(s)
- Bo Liu
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Qiyun Ou
- Department of Ultrasound in Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Ying Tang
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Sha Fu
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Peifen Liang
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yunfang Yu
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Zhenjian Xu
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Yongjian Chen
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, Guangdong, People's Republic of China
| | - Anping Xu
- Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
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Kronbichler A, Brezina B, Gauckler P, Quintana LF, Jayne DRW. Refractory lupus nephritis: When, why and how to treat. Autoimmun Rev 2019; 18:510-518. [PMID: 30844548 DOI: 10.1016/j.autrev.2019.03.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Refractory lupus nephritis indicates an inadequate response to lupus nephritis therapy. It implies persisting or worsening disease activity despite therapy, but the definition is complicated by the parameters of response, proteinuria and renal function, that do not discriminate clearly between activity and irreversible damage. Understanding the causes of refractory disease and developing treatment strategies is important because these patients are more likely to develop poor outcomes, especially end stage renal disease. This review explores current concepts and definitions of refractory disease and summarises treatment approaches that have been used in observational cohort studies and case series. We highlight the importance of optimising adherence to the prescribed immunosuppressive and supportive measures and avoidance of diagnostic delay. Treatment options include higher dose glucocorticoid, switching between cyclophosphamide and mycophenolate acid derivates, or addition of rituximab, the latter potentially in combination with belimumab. Less evidence supports extracorporeal treatment (plasma exchange or immunoadsorption), calcineurin inhibitors (cyclosporine A or tacrolimus), intravenous immunoglobulin and stem cell transplantation. Improvements in understanding what refractory disease is and how definitions can be integrated into treatment pathways has the potential to enhance lupus nephritis outcomes.
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Affiliation(s)
- Andreas Kronbichler
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, Cambridge University Hospitals, United Kingdom; Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Biljana Brezina
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, Cambridge University Hospitals, United Kingdom
| | - Philipp Gauckler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Luis F Quintana
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, Cambridge University Hospitals, United Kingdom; Servicio de Nefrología y Trasplante Renal, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - David R W Jayne
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Hills Road, CB2 0QQ, Cambridge, Cambridge University Hospitals, United Kingdom; Department of Medicine, University of Cambridge, CB2 0QQ Cambridge, United Kingdom.
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Abstract
BACKGROUND Long-term treatment programs with low toxicity represent a therapeutic challenge in lupus nephritis (LN). Although a therapeutic benefit of rituximab (RTX) has been reported in LN patients who have failed conventional treatment, the results are controversial. We aimed to assess the clinical efficacy and safety of RTX as a new immunosuppressive medicine in the treatment of LN with a meta-analysis. METHODS Based on predetermined criteria, PubMed, Embase, and Cochrane Library were used to identify the eligible studies. Cochrane Review Manager version 5.3 was applied to pool the data extracted from individual investigations and provide summary effect estimates. RESULTS Twenty-four studies with 940 patients were analyzed. In case series trials with specific LN assessment, the complete remission (CR) rate at 12 months was 35.9% (95% CI: 24.2%-49.5%), and total remission (TR: CR plus partial remission) was 73.4% (95% CI: 66.0%-79.7%). In controlled trials, RTX was associated with a higher probability of TR (OR =2.02, 95% CI: 1.23-3.32, P<0.01). The CR in the RTX group was higher than that in the control group, although there was no significant difference between the two groups (OR =1.98, 95% CI: 0.90-4.39, P>0.05). Additionally, RTX treatment significantly decreased proteinuria (mean difference: -2.79, 95% CI: -3.95 to -1.62, P<0.01) as well as the renal activity index in patients with LN (mean difference: -3.46, 95% CI: -4.43 to -2.50, P<0.01). In controlled trials, the relative risks of the adverse events of infection and infusion reaction were not notably different between the two groups. CONCLUSION RTX is a promising therapy for the treatment of LN due to significant clinical efficacy and a favorable safety profile. In future studies, larger study populations and longer-term time points may identify additional important patient-centered outcomes.
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Affiliation(s)
- Zhiqing Zhong
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China,
| | - Hongyan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, 510800 Guangzhou, China
| | - Hongzhen Zhong
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China,
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China,
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Tunnicliffe DJ, Palmer SC, Henderson L, Masson P, Craig JC, Tong A, Singh‐Grewal D, Flanc RS, Roberts MA, Webster AC, Strippoli GFM. Immunosuppressive treatment for proliferative lupus nephritis. Cochrane Database Syst Rev 2018; 6:CD002922. [PMID: 29957821 PMCID: PMC6513226 DOI: 10.1002/14651858.cd002922.pub4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.
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Affiliation(s)
- David J Tunnicliffe
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCentre for Kidney ResearchWestmeadAustralia
| | - Suetonia C Palmer
- University of Otago ChristchurchDepartment of Medicine2 Riccarton AvePO Box 4345ChristchurchNew Zealand8140
| | - Lorna Henderson
- NHS LothianRenal DepartmentRoyal Infirmary of EdinburghEdinburghUKEH16 4SA
| | - Philip Masson
- Royal Free London NHS Foundation TrustDepartment of Renal MedicineLondonUK
| | - Jonathan C Craig
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- Flinders UniversityCollege of Medicine and Public HealthAdelaideSAAustralia5001
| | - Allison Tong
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCentre for Kidney ResearchWestmeadAustralia
| | - Davinder Singh‐Grewal
- The Sydney Children's Hospitals NetworkDepartment Paediatric RheumatologyThe Children's Hospital at WestmeadCnr Hainsworth and Hawkesbury RoadsWestmeadNSWAustralia2145
| | - Robert S Flanc
- Monash Medical CentreDepartment of NephrologyClayton RdClaytonVICAustralia3168
| | - Matthew A Roberts
- Monash UniversityEastern Health Clinical SchoolBox HillVICAustralia3128
| | - Angela C Webster
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- The University of Sydney at WestmeadCentre for Transplant and Renal Research, Westmead Millennium InstituteWestmeadNSWAustralia2145
| | - Giovanni FM Strippoli
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- University of BariDepartment of Emergency and Organ TransplantationBariItaly
- DiaverumMedical Scientific OfficeLundSweden
- Diaverum AcademyBariItaly
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Alshaiki F, Obaid E, Almuallim A, Taha R, El-Haddad H, Almoallim H. Outcomes of rituximab therapy in refractory lupus: A meta-analysis. Eur J Rheumatol 2018; 5:118-126. [PMID: 30185361 DOI: 10.5152/eurjrheum.2018.17096] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Accepted: 11/14/2017] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE Conventional treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) is associated with damage accrual, hence increased morbidity rate. Off-label use of rituximab (RTX) has shown significant promise in this patient group; however, data are still controversial. We aimed to analyze the outcomes of RTX therapy in refractory lupus using a meta-analysis approach. METHODS Electronic search of the medical literature was conducted using a combination of relevant keywords to retrieve studies on the safety and efficacy of RTX in SLE and LN patients. Results were screened against our inclusion and exclusion criteria and two reviewers independently extracted the data for analysis. Comprehensive meta-analysis software was used to pool the data from individual studies and provide summary effect estimates. RESULTS Thirty-one studies that enrolled 1112 patients were finally eligible for the meta-analysis. The overall global, complete, and partial response rates to RTX therapy were 72%, 46%, and 32%, respectively. RTX significantly decreased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Activity Group (BILAG) scores (p<0.001). Prednisone dose was significantly reduced after RTX treatment in both SLE and LN groups (p<0.001), and proteinuria was lowered in SLE (p<0.001) than in LN patients (p=0.07). Infection and infusion-related reactions were the most common side effects. CONCLUSION RTX therapy in refractory SLE and LN patients proved clinical efficacy and favorable safety outcomes. Larger well-designed randomized clinical trials are warranted.
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Affiliation(s)
- Fatma Alshaiki
- Department of Medicine, East Jeddah Hospital, Jeddah, Saudi Arabia
| | - Elaf Obaid
- Department of Medicine, Umm Al-Qura University School of Medicine, Makkah, Saudi Arabia
| | - Abdulqader Almuallim
- Department of Medicine, Umm Al-Qura University School of Medicine, Makkah, Saudi Arabia
| | - Rabab Taha
- Department of Medicine, Dr. Sloiman Fakeeh Hospital, Jeddah, Saudi Arabia
| | - Hadeel El-Haddad
- Department of Medicine, Dr. Sloiman Fakeeh Hospital, Jeddah, Saudi Arabia
| | - Hani Almoallim
- Department of Medicine, Umm Al-Qura University School of Medicine, Makkah, Saudi Arabia.,Department of Medicine, Dr. Sloiman Fakeeh Hospital, Jeddah, Saudi Arabia.,Alzaidi Chair of Research in Rheumatic Diseases, Umm Al-Qura University, Makkah, Saudi Arabia
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Giacomelli R, Afeltra A, Alunno A, Baldini C, Bartoloni-Bocci E, Berardicurti O, Carubbi F, Cauli A, Cervera R, Ciccia F, Cipriani P, Conti F, De Vita S, Di Benedetto P, Doria A, Drosos AA, Favalli EG, Gandolfo S, Gatto M, Grembiale RD, Liakouli V, Lories R, Lubrano E, Lunardi C, Margiotta DPE, Massaro L, Meroni P, Minniti A, Navarini L, Pendolino M, Perosa F, Pers JO, Prete M, Priori R, Puppo F, Quartuccio L, Ruffatti A, Ruscitti P, Russo B, Sarzi-Puttini P, Shoenfeld Y, Somarakis GA, Spinelli FR, Tinazzi E, Triolo G, Ursini F, Valentini G, Valesini G, Vettori S, Vitali C, Tzioufas AG. International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)? Autoimmun Rev 2017; 16:911-924. [DOI: 10.1016/j.autrev.2017.07.012] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 05/20/2017] [Indexed: 02/06/2023]
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