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1
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Chan EYH, De Mutiis C, Tullus K. Childhood-onset lupus nephritis: long-term outcomes and their predictors. Pediatr Nephrol 2025:10.1007/s00467-025-06718-0. [PMID: 39992412 DOI: 10.1007/s00467-025-06718-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/04/2025] [Accepted: 02/07/2025] [Indexed: 02/25/2025]
Affiliation(s)
- Eugene Yu-Hin Chan
- Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong SAR.
| | | | - Kjell Tullus
- Department of Paediatric Nephrologygreat Ormond Street Hospital for Children NHS Trust, London, UK.
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Kalashnikova E, Isupova E, Gaidar E, Lubimova N, Sorokina L, Chikova I, Kaneva M, Raupov R, Kalashnikova O, Aliev D, Gaydukova I, Kostik M. Outcomes of a 12-month course of early and late rituximab BCD020 biosimilar administration in juvenile systemic lupus erythematosus: A retrospective study. World J Nephrol 2024; 13:98393. [PMID: 39723361 PMCID: PMC11572657 DOI: 10.5527/wjn.v13.i4.98393] [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: 06/25/2024] [Revised: 08/23/2024] [Accepted: 09/05/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Juvenile systemic lupus erythematosus (SLE) is a severe, life-threatening disease. However, the role of rituximab in managing juvenile SLE remains undefined, although early biological intervention may improve disease outcomes. AIM To assess the differences in the outcomes of different types of rituximab administration (early and late). METHODS In this retrospective cohort study, the information of 36 children with SLE with early (less than 6 months from onset) rituximab administration (ERA), and late (more than 1 year) rituximab administration (LRA) was analyzed. We compared initial disease characteristics at onset, at baseline (start of rituximab), and at the end of the study (EOS) at 12 months, as well as outcomes and treatment characteristics. RESULTS The main differences at baseline were a higher daily median dose of corticosteroids, increased MAS frequency, and a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in the ERA group. No differences in the main SLE outcomes between groups at the EOS were observed. The part of lupus nephritis patients who achieved remission changed from 44% to 31% in ERA and 32% to 11% in the LRA group. Patients with ERA had a shorter time to achieve low daily corticosteroid dose (≤ 0.2 mg/kg) at 1.2 (0.9; 1.4) years compared to 2.8 (2.3; 4.0) years (P = 0.000001) and higher probability to achieve this low dose [hazard ratio (HR) = 57.8 (95% confidence interval (CI): 7.2-463.2), P = 0.00001 and remission (SLEDAI = 0); HR = 37.6 (95%CI: 4.45-333.3), P = 0.00001]. No differences in adverse events, including severe adverse events, were observed. CONCLUSION ERA demonstrated a better steroid-sparing effect and a possibility of earlier remission or low disease activity, except for lupus nephritis. Further investigations are required.
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Affiliation(s)
- Elvira Kalashnikova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Eugenia Isupova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Ekaterina Gaidar
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Natalia Lubimova
- Research Laboratory of Autoimmune and Autoinflammatory Diseases, World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg 197341, Sankt-Peterburg, Russia
| | - Lyubov Sorokina
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Irina Chikova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Maria Kaneva
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Rinat Raupov
- Pediatric Rheumatology, H. Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery, Saint Petersburg 196603, Sankt-Peterburg, Russia
| | - Olga Kalashnikova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
| | - Damir Aliev
- Department of Internal Medicine, Rheumatology, Examination of Temporary Disability Examination and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University, Saint Petersburg 191015, Sankt-Peterburg, Russia
- Department of Rheumatology, Clinical Rheumatological Hospital #25, Saint Petersburg 190068, Sankt-Peterburg, Russia
| | - Inna Gaydukova
- Department of Internal Medicine, Rheumatology, Examination of Temporary Disability Examination and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University, Saint Petersburg 191015, Sankt-Peterburg, Russia
- Department of Rheumatology, Clinical Rheumatological Hospital #25, Saint Petersburg 190068, Sankt-Peterburg, Russia
| | - Mikhail Kostik
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, Saint Petersburg 194100, Sankt-Peterburg, Russia
- Research Laboratory of Autoimmune and Autoinflammatory Diseases, World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg 197341, Sankt-Peterburg, Russia
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Kaleda MI, Nikishina IP. Modern treatment options for systemic lupus erythematosus in children (literature review). MODERN RHEUMATOLOGY JOURNAL 2024; 18:99-105. [DOI: 10.14412/1996-7012-2024-4-99-105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The treatment of juvenile-onset systemic lupus erythematosus (jSLE) is a complex task in view of the diversity of clinical manifestations and the course of the disease as well as the high risk of organ damage. The need to create separate therapeutic principles for jSLE is justified by the greater intensification of therapy due to both the doses used and the combination of a larger number of different drugs in a patient. However, the basis for the treatment of jSLE today is mainly the extrapolation of data obtained in studies with adult patients. The review reflects modern ideas about the spectrum of drugs used in jSLE, with particular emphasis on efficacy, safety and timing of therapy as well as possible optimization options.
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Affiliation(s)
- M. I. Kaleda
- V.A. Nasonova Research Institute of Rheumatology
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Cody E, Brunner HI. Renal disease in pediatric rheumatology. Curr Opin Rheumatol 2024:00002281-990000000-00121. [PMID: 38752864 DOI: 10.1097/bor.0000000000001027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
PURPOSE OF REVIEW This review will provide updates in the outcomes in the common rheumatologic diseases with kidney involvement. Covered are also advances in therapeutics for the use of pediatric rheumatologic diseases with kidney involvement, as well as the potential kidney complications from other rheumatologic diseases and their medications. RECENT FINDINGS Two of the more common rheumatologic diseases with kidney involvement, lupus and vasculitis, continue to show inadequate response to initial therapy of renal disease and practice continues to be driven by results of adult studies. SUMMARY There is a continued need for pediatric specific studies in rheumatologic diseases with kidney involvement as outcomes continue to be inadequate. Despite recently approved treatments for adults with rheumatic diseases and kidney involvement, therapeutic options in pediatrics remain limited, contributing to the overall morbidity and mortality.
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Affiliation(s)
- Ellen Cody
- Medical College of Wisconsin, Department of Pediatrics, Division of Nephrology, Milwaukee, Wisconsin
| | - Hermine I Brunner
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, Department of Pediatrics, Division of Rheumatology, Ohio, USA
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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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Elshaer R, Jaber S, Odeh N, Arbili L, Al-Mayouf SM. Safety and efficacy of biologics in childhood systemic lupus erythematosus: a critical systematic review. Clin Rheumatol 2024; 43:863-877. [PMID: 38079010 DOI: 10.1007/s10067-023-06833-z] [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: 08/18/2023] [Revised: 10/20/2023] [Accepted: 11/24/2023] [Indexed: 02/20/2024]
Abstract
Biologic agents are increasingly being used to treat adult patients with systemic lupus erythematosus (SLE). However, the available data on biologic agents' use in childhood-onset SLE (cSLE) remains limited. To collate available evidence related to the efficacy and safety of using biologic agents in cSLE. The study followed the PRISMA checklist for reporting the data and conducted a thorough search using PubMed, Cochrane Library, and Scopus from January 2005 to August 2023. Only articles meeting specific criteria were included, focusing on cSLE, the use of biologic agents, and having outcome measures at six- and 12-month follow-ups for safety and efficacy. Case reports were excluded, and four independent reviewers screened the articles for accuracy, with a fifth reviewer resolving any discrepancies that arose to achieve a consensus. The final selection included 18 studies with a total of 593 patients treated with biologic agents for severe and/ or refractory cSLE. The most common indication for using biologic agents was lupus nephritis. Rituximab was used in 12 studies, while belimumab was used in six studies. The studies evaluated the efficacy of biologic agents based on SLE disease activity scores, laboratory parameter improvements, and reduced corticosteroid dosage. Positive outcomes were reported, with improvements in renal, hematologic, and immunologic parameters along with mild adverse effects, mostly related to mild infections and infusion reactions. Belimumab and rituximab have shown promise as potential treatments for severe and refractory cSLE cases, leading to decreased disease activity and complete or partial remission in many patients with an acceptable safety profile. However, further research is needed to better understand their benefits and potential risks in these patients. Key Points • This review emphasizes the lack of sufficient randomized controlled trials exploring the use of biologics in childhood systemic lupus erythematosus (cSLE). • Treatment plans for cSLE are being derived from those used for adult systemic lupus erythematosus. • According to current evidence, belimumab and rituximab can be potential treatment options for refractory and severe cases of cSLE. • Additional studies are required to reach more definitive conclusions.
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Affiliation(s)
- Rawan Elshaer
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Samar Jaber
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Nour Odeh
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Lana Arbili
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Sulaiman M Al-Mayouf
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Alfaisal University, Po Box 3354, 11211, Riyadh, Saudi Arabia.
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Chan EYH, Lai FFY, Ma ALT, Chan TM. Managing Lupus Nephritis in Children and Adolescents. Paediatr Drugs 2024; 26:145-161. [PMID: 38117412 DOI: 10.1007/s40272-023-00609-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/19/2023] [Indexed: 12/21/2023]
Abstract
Lupus nephritis is an important manifestation of systemic lupus erythematosus, which leads to chronic kidney disease, kidney failure, and can result in mortality. About 35%-60% of children with systemic lupus erythematosus develop kidney involvement. Over the past few decades, the outcome of patients with lupus nephritis has improved significantly with advances in immunosuppressive therapies and clinical management. Nonetheless, there is a paucity of high-level evidence to guide the management of childhood-onset lupus nephritis, because of the relatively small number of patients at each centre and also because children and adolescents are often excluded from clinical trials. Children and adults differ in more ways than just size, and there are remarkable differences between childhood- and adult-onset lupus nephritis in terms of disease severity, treatment efficacy, tolerance to medications and most importantly, psychosocial perspective. In this article, we review the 'art and science' of managing childhood-onset lupus nephritis, which has evolved in recent years, and highlight special considerations in this specific patient population.
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Affiliation(s)
- Eugene Yu-Hin Chan
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong.
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
| | - Fiona Fung-Yee Lai
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
| | - Alison Lap-Tak Ma
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Tak Mao Chan
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong.
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, School of Clinical Medicine, Pok Fu Lam, Hong Kong.
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Lin TW, Lin YT, Hu YC, Yu HH, Chiang BL. Rituximab as an effective add-on maintenance therapy for disease activities in childhood-onset systemic lupus erythematosus. Lupus Sci Med 2024; 11:e000987. [PMID: 38242722 PMCID: PMC10806525 DOI: 10.1136/lupus-2023-000987] [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: 06/27/2023] [Accepted: 12/23/2023] [Indexed: 01/21/2024]
Abstract
OBJECTIVES Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can result in high morbidity if not treated. This retrospective study aimed to evaluate the outcomes of rituximab treatment in a paediatric SLE cohort in Taiwan. METHODS The medical records of paediatric patients diagnosed with SLE at the National Taiwan University Hospital between January 1992 and August 2022 who received rituximab as maintenance therapy between January 2015 and August 2022 were retrospectively reviewed. To enhance our analysis, we included a contemporary comparison group, matching in case number and demographic characteristics. This study aimed to describe the indications, efficacy and safety of rituximab in the treatment of paediatric SLE and to analyse the factors associated with disease outcomes. RESULTS The study included 40 rituximab-treated patients with a median age of 14.3 years at the time of disease diagnosis. In the rituximab-treated cohort, the median score on the Systemic Lupus Erythematosus Disease Activity Index 2000 decreased from 8 before rituximab administration to 4 after 2 years. The levels of C3 and C4 increased and anti-double stranded DNA (anti-dsDNA) levels decreased significantly within 6 months. The equivalent oral prednisolone dose halved after 6 months. Finally, 8 (20%) patients achieved disease control and 35 (87.5%) patients had no flare-ups during the follow-up period (median, 2 years). Those patients who achieved disease control had a significantly shorter interval between diagnosis and rituximab administration. In terms of adverse effects, only one patient developed hypogammaglobulinaemia that required intravenous immunoglobulin (IVIG) replacement. Compared with the comparison group (n=53), the rituximab-treated cohort exhibited superior disease outcomes and a reduced incidence of flare-ups. CONCLUSIONS This study provides real-world data and illuminates rituximab's role in maintaining disease stability among patients with paediatric-onset SLE who are serologically active without major clinical deterioration. Most importantly, no mortality or development of end-stage renal disease was observed in the rituximab-treated cohort.
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Affiliation(s)
- Ting-Wei Lin
- Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Tsan Lin
- Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ya-Chiao Hu
- Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Hui Yu
- Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Bor-Luen Chiang
- Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University, Taipei, Taiwan
- Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Chan EYH, Wong SW, Lai FFY, Ho TW, Tong PC, Lai WM, Ma ALT, Yap DYH. Long-term outcomes with rituximab as add-on therapy in severe childhood-onset lupus nephritis. Pediatr Nephrol 2023; 38:4001-4011. [PMID: 37358717 DOI: 10.1007/s00467-023-06025-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/14/2023] [Accepted: 05/04/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Long-term data pertaining to rituximab as add-on therapy in childhood-onset lupus nephritis (cLN) is scarce. METHODS A retrospective cohort study was conducted on all patients with proliferative cLN, diagnosed ≤ 18 years and between 2005 and 2021, who received rituximab for LN episodes that were life/organ threatening and/or treatment resistant to standard immunosuppression. RESULTS Fourteen patients with cLN (female, n = 10) were included, with median follow-up period of 6.9 years. LN episodes (class III, n = 1; class IV, n = 11; class IV + V, n = 2) requiring rituximab occurred at 15.6 years (IQR 12.8-17.3), urine protein:creatinine ratio was 8.2 mg/mg (IQR 3.4-10.1) and eGFR was 28 mL/min/1.73 m2 (IQR 24-69) prior to rituximab treatment. Ten and four patients received rituximab at 1500 mg/m2 and 750 mg/m2, which were given at 46.5 days (IQR 19-69) after commencement of standard therapies. Treatment with rituximab resulted in improvements in proteinuria (ps < 0.001), eGFR (ps < 0.01) and serological parameters, including haemoglobin levels, complement 3 levels and anti-dsDNA antibodies, compared with baseline. Rates of complete/partial remission at 6-, 12- and 24-month post-rituximab were 28.6/42.8%, 64.2/21.4% and 69.2/15.3%. All three patients who required acute kidney replacement therapy became dialysis-free after rituximab. Relapse rate following rituximab was 0.11 episodes/patient-year. There was no lethal complication or severe infusion reaction. Hypogammaglobulinaemia was the most frequent complication (45%) but was mostly asymptomatic. Neutropenia and infections were observed in 20% and 25% of treatments. Upon last follow-up, three (21%) and two (14%) patients developed chronic kidney disease (stage 2, n = 2; stage 4; n = 1) and kidney failure, respectively. CONCLUSION Add-on rituximab is an effective and safe rescue therapy for cLN patients with life-/organ-threatening manifestations or treatment-resistance. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Eugene Yu-Hin Chan
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR.
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
| | - Sze-Wa Wong
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - Fiona Fung-Yee Lai
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - Tsz-Wai Ho
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - Pak-Chiu Tong
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - Wai-Ming Lai
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - Alison Lap-Tak Ma
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR.
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
| | - Desmond Yat-Hin Yap
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR.
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong School of Clinical Medicine, Pokfulam, Hong Kong SAR.
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10
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Pennesi M, Benvenuto S. Lupus Nephritis in Children: Novel Perspectives. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1841. [PMID: 37893559 PMCID: PMC10607957 DOI: 10.3390/medicina59101841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023]
Abstract
Childhood-onset systemic lupus erythematosus is an inflammatory and autoimmune condition characterized by heterogeneous multisystem involvement and a chronic course with unpredictable flares. Kidney involvement, commonly called lupus nephritis, mainly presents with immune complex-mediated glomerulonephritis and is more frequent and severe in adults. Despite a considerable improvement in long-term renal prognosis, children and adolescents with lupus nephritis still experience significant morbidity and mortality. Moreover, current literature often lacks pediatric-specific data, leading clinicians to rely exclusively on adult therapeutic approaches. This review aims to describe pediatric lupus nephritis and provide an overview of the novel perspectives on the pathogenetic mechanisms, histopathological classification, therapeutic approach, novel biomarkers, and follow-up targets in children and adolescents with lupus nephritis.
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Affiliation(s)
- Marco Pennesi
- Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy
| | - Simone Benvenuto
- Department of Medicine, Surgery, and Health Sciences, University of Trieste, 34127 Trieste, Italy
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11
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Keskinyan VS, Lattanza B, Reid-Adam J. Glomerulonephritis. Pediatr Rev 2023; 44:498-512. [PMID: 37653138 DOI: 10.1542/pir.2021-005259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Glomerulonephritis (GN) encompasses several disorders that cause glomerular inflammation and injury through an interplay of immune-mediated mechanisms, host characteristics, and environmental triggers, such as infections. GN can manifest solely in the kidney or in the setting of a systemic illness, and presentation can range from chronic and relatively asymptomatic hematuria to fulminant renal failure. Classic acute GN is characterized by hematuria, edema, and hypertension, the latter 2 of which are the consequence of sodium and water retention in the setting of renal impairment. Although presenting signs and symptoms and a compatible clinical history can suggest GN, serologic and urinary testing can further refine the differential diagnosis, and renal biopsy can be used for definitive diagnosis. Treatment of GN can include supportive care, renin-angiotensin-aldosterone system blockade, immunomodulatory therapy, and renal transplant. Prognosis is largely dependent on the underlying cause of GN and can vary from a self-limited course to chronic kidney disease. This review focuses on lupus nephritis, IgA nephropathy, IgA vasculitis, and postinfectious GN.
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12
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Smith EMD, Aggarwal A, Ainsworth J, Al-Abadi E, Avcin T, Bortey L, Burnham J, Ciurtin C, Hedrich CM, Kamphuis S, Levy DM, Lewandowski LB, Maxwell N, Morand EF, Ozen S, Pain CE, Ravelli A, Saad Magalhaes C, Pilkington CA, Schonenberg-Meinema D, Scott C, Tullus K, Beresford MW. Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force. Ann Rheum Dis 2023; 82:788-798. [PMID: 36627168 PMCID: PMC10314055 DOI: 10.1136/ard-2022-223328] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 12/09/2022] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE. METHODS An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus. RESULTS The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated. CONCLUSIONS These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society.
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Affiliation(s)
- Eve Mary Dorothy Smith
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Amita Aggarwal
- Department of Clinical Immunology & Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Jenny Ainsworth
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Eslam Al-Abadi
- Department of Paediatric Rheumatology, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK
| | - Tadej Avcin
- Department of Pediatric Rheumatology and Clinical Immunology, University Medical Centre Ljubljana Division of Paediatrics, Ljubljana, Slovenia
| | - Lynette Bortey
- TARGET Lupus Public Patient Involvement and Engagement Group, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
| | - Jon Burnham
- Department of Pediatric Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Coziana Ciurtin
- Centre for Adolescent Rheumatology Versus Arthritis, Division of Medicine, University College London, London, UK
| | - Christian M Hedrich
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Sylvia Kamphuis
- Department of Paediatric Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Deborah M Levy
- Department of Pediatric Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Pediatric Rheumatology, University of Toronto, Toronto, Ontario, Canada
| | - Laura B Lewandowski
- National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases Systemic Autoimmunity Branch, Bethesda, Maryland, USA
| | - Naomi Maxwell
- TARGET Lupus Public Patient Involvement and Engagement Group, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
| | - Eric F Morand
- Department of Rheumatology, Monash University, Clayton, Victoria, Australia
| | - Seza Ozen
- Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Clare E Pain
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Angelo Ravelli
- Direzione Scientifica, Istituto Giannina Gaslini Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico, Genova, Liguria, Italy
- Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno Infantili (DINIGMI), Università degli Studi di Genova, Genova, Italy
| | - Claudia Saad Magalhaes
- Department of Pediatric Rheumatology, Botucatu Medical School, Sao Paulo University Faculty of Medicine, Sao Paulo, Brazil
| | - Clarissa A Pilkington
- Department of Paediatric Rheumatology, Great Ormond Street Hospital for Children, London, UK
| | - Dieneke Schonenberg-Meinema
- Department of Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands
- Emma Children's Hospital, Amsterdam University Medical Centres, Duivendrecht, The Netherlands
| | - Christiaan Scott
- Department of Paediatric Rheumatology, University of Cape Town, Rondebosch, Western Cape, South Africa
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, London, UK
| | - Michael William Beresford
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
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Kostik M, Kalashnikova E, Rinat R, Isupova E, Gaidar E, Soloviev AA, Masalova V, Snegireva L, Kornishina T, Abramova N, Suspitsin E, Sorokina L, Kaneva M, Dubko MF, Lubimova N, Kuchuinskaya E, Kalashnikova O, Chasnyk V. Rituximab Biosimilar BCD020 Shows Superior Efficacy above Conventional Non-Biologics Treatment in Pediatric Lupus Nephritis: The Data of Retrospective Cohort Study. Biomedicines 2023; 11:biomedicines11051503. [PMID: 37239173 DOI: 10.3390/biomedicines11051503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/14/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been conclusively defined. OBJECTIVES analyze the safety and efficacy of rituximab biosimilar BCD020 in pediatric patients with lupus nephritis. METHODS in a retrospective cohort study, the data from the case histories of 25 patients with LN (10 boys and 15 girls) with an onset age of 13 (9-16) years, who failed conventional non-biologic treatment or developed corticosteroid dependence/toxicity, were included. The diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Rituximab biosimilar BCD020 was prescribed in a dosage of 375 mg/m2 every week (2-4 infusions) with repeated courses every 6-12 months (2-4 infusions) according to disease activity, B-cell depletion, and IgG levels. The dynamics of clinical and laboratory data, the activity of the disease by SLEDAI, and corticosteroid doses were assessed at the onset and during the rituximab trial. RESULTS The main patient's characteristics were: Pre-rituximab non-biologic conventional treatment included: cyclophosphamide 15 (60%), MMF 8 (32%), azathioprine 3 (12%), hydroxychloroquine 12 (48%), and pulse therapy of methylprednisolone followed by oral methylprednisolone 25 (100%). The time before rituximab was 7.0 (3.0-24.0) months, and the whole observation period was 7.0 (0; 24) months. The initial pre-rituximab treatment slightly reduced SLEDAI levels and the proportion of patients with LN. A significant reduction of SLEDAI, the anti-dsDNA level, proteinuria, hematuria, C4 complement, ESR, and the median corticosteroid dose by 80% from the initial value, as well as the proportion of patients without corticosteroids, was observed after rituximab administration. Two deaths were observed due to catastrophic SLE with macrophage activation syndrome, accompanied by a severe infection (invasive aspergillosis, n = 2). Three patients developed serious adverse events: pneumonia (n = 2), transient agranulocytosis (n = 1) after the third rituximab infusion, and meningitis, caused by Listeria monocytosis, after the first rituximab infusion. Eight patients received antibacterial treatment for different respiratory infections without hospital admissions. CONCLUSIONS Rituximab biosimilar BCD020 showed effectiveness in LN, whereas previous non-biologic treatment was insufficiently effective. Randomized controlled trials are required to evaluate the efficacy and safety of rituximab and evaluate the benefits when compared with conventional SLE treatment.
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Affiliation(s)
- Mikhail Kostik
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
- Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia
| | - Elvira Kalashnikova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Raupov Rinat
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Eugenia Isupova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Ekaterina Gaidar
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Anton A Soloviev
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Vera Masalova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Ludmila Snegireva
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Tatyana Kornishina
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Natalia Abramova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Evgeny Suspitsin
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
- N.N. Petrov National Research Center of Oncology, 197758 Saint Petersburg, Russia
| | - Lubov Sorokina
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Maria Kaneva
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Margarita F Dubko
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Natalia Lubimova
- Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia
| | | | - Olga Kalashnikova
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
| | - Vyacheslav Chasnyk
- Hospital Pediatry, Saint-Petersburg State Pediatric Medical University, 194100 Saint Petersburg, Russia
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14
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Kalashnikova EM, Raupov RK, Lyubimova NA, Kuchinskaya EM, Masalova VV, Isupova EA, Gaidar EV, Dubko MF, Snegireva LS, Sorokina LS, Kornishina TL, Kaneva MA, Chikova IA, Likhacheva TS, Kolobova OL, Kalashnikova OV, Chasnyk VG, Kostik MM. The experience of rituximab therapy in patients with juvenile systemic lupus erythematosus: the preliminary results of two-center cohort study. ROSSIYSKIY VESTNIK PERINATOLOGII I PEDIATRII (RUSSIAN BULLETIN OF PERINATOLOGY AND PEDIATRICS) 2023. [DOI: 10.21508/1027-4065-2023-68-1-74-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Systemic lupus erythematosus is an immunopathological disease which is characterized by a poor prognosis. Biologics applied in the disease treatment allow reducing the corticosteroid toxicity and controlling the disease.Purpose. To evaluate the efficacy and safety of rituximab therapy in children with systemic lupus erythematosus.Material and methods. The retrospective study included data of 48 patients with systemic lupus erythematosus treated with rituximab. Systemic lupus erythematosus was diagnosed based on the SLICC classification criteria. Patients were assessed at baseline disease status, at the time of rituximab initiation and follow-up. The indications for the rituximab were: lupus nephritis, CNS involvement, and hematological involvement resistant to the standard therapy, and in cases of severe corticosteroid toxicity.Results. During rituximab therapy the significant decrease of the SELENA–SLEDAI activity index was observed. There was a significant decrease of the level of antibodies against dsDNA, normalization of the levels of hemoglobin, ESR, complement C4. The proportion of patients with cytopenia decreased up to their complete absence in patients receiving therapy for three years. The number of patients with active lupus nephritis decreased from 16 at the time of rituximab initiation to 1 after 3 years of therapy. Significant dynamics of proteinuria and hematuria was noted, except for 1 patient. The daily dose of corticosteroids was reduced by 90% from baseline in patients treated for 3 years. Serious adverse events included three deaths in patients with high systemic lupus erythematosus activity with uncontrolled macrophage activation syndrome associated with infections. Various infectious complications, hypogammaglobulinemia, which required replacement therapy with intravenous immunoglobulin, were also recorded.Conclusion. Rituximab can be considered as an option for the treatment of severe forms of systemic lupus erythematosus which are resistant to standard therapy. Further studies are required to evaluate efficacy and safety.
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Affiliation(s)
| | - R. K. Raupov
- Saint Petersburg State Pediatric Medical University; Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery
| | | | | | | | | | - E. V. Gaidar
- Saint Petersburg State Pediatric Medical University
| | - M. F. Dubko
- Saint Petersburg State Pediatric Medical University
| | | | | | | | - M. A. Kaneva
- Saint Petersburg State Pediatric Medical University
| | | | | | | | | | | | - M. M. Kostik
- Saint Petersburg State Pediatric Medical University; Almazov National Medical Research Center
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Abstract
PURPOSE OF REVIEW This manuscript provides an update on clinical and pathophysiological features of juvenile-onset systemic lupus erythematosis (jSLE), challenges applying adult-derived classification criteria, and recent advances in treatment and care. RECENT FINDINGS Significant scientific advances have improved the understanding of genetic factors (both genetic causes and risk alleles) and associated phenotypic features. Panels of urine/blood biomarker candidates aid in diagnosing jSLE, monitoring disease activity and predicting treatment response. Available classification criteria have been extensively assessed, with differences in clinical and immunological phenotypes of patients across age groups and ethnicities affecting their performance in jSLE. Therapeutic options remain limited and are based on protocols for adult-onset SLE patients. International efforts to inform development of a treat-to-target (T2T) approach for jSLE have yielded cohort-level evidence that target attainment reduces the risk of severe flare and new damage, and treatment compliance. SUMMARY Recent studies have significantly improved our understanding of jSLE pathogenesis, highlighting important differences between jSLE and adult SLE, and providing the basis of biomarker development and target-directed individualized treatment and care. Future work focused on development of a T2T approach in jSLE is eagerly awaited.
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Affiliation(s)
- Eve M D Smith
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool
| | - Hanna Lythgoe
- Department of Paediatric Rheumatology, Manchester Children's NHS Foundation Trust, Manchester, UK
| | - Christian M Hedrich
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool
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16
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Balevic SJ, Niu J, Chen J, Green D, McMahon A, Hornik CP, Schanberg L, Glaser R, Gonzalez D, Burckart GJ. Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure-Response. J Clin Pharmacol 2023; 63:105-118. [PMID: 35968821 PMCID: PMC9771895 DOI: 10.1002/jcph.2139] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/07/2022] [Indexed: 12/24/2022]
Abstract
To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure-response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure-response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults.
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Affiliation(s)
| | - Jing Niu
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration (FDA), Silver Spring, MD
| | - Jianmeng Chen
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration (FDA), Silver Spring, MD
| | - Dionna Green
- Office of Pediatric Therapeutics, Office of the Commissioner, United States Food and Drug Administration (FDA), Silver Spring, MD
| | - Ann McMahon
- Office of Pediatric Therapeutics, Office of the Commissioner, United States Food and Drug Administration (FDA), Silver Spring, MD
| | | | - Laura Schanberg
- Duke University, Durham, NC
- Duke Clinical Research Institute, Durham, NC
| | - Rachel Glaser
- Division of Rheumatology and Transplant Medicine, Office of Immunology and Inflammation, Office of New Drugs, CDER, FDA, Silver Spring, MD
| | - Daniel Gonzalez
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Gilbert J. Burckart
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration (FDA), Silver Spring, MD
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17
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Roberts JE, Berbert L, Chang J, Son MBF. Association of Race and Ethnicity With Medication Use for Pediatric Lupus in the Childhood Arthritis and Rheumatology Research Alliance Registry. ACR Open Rheumatol 2022; 4:954-963. [DOI: 10.1002/acr2.11494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Jordan E. Roberts
- Boston Children's Hospital and Harvard Medical School Boston Massachusetts
| | - Laura Berbert
- Boston Children's Hospital and Harvard Medical School Boston Massachusetts
| | - Joyce Chang
- Boston Children's Hospital and Harvard Medical School Boston Massachusetts
| | - Mary Beth F. Son
- Boston Children's Hospital and Harvard Medical School Boston Massachusetts
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18
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Cheng H, Zhang XY, Yang HD, Yu Z, Yan CL, Gao C, Wen HY. Efficacy and safety of belimumab/low-dose cyclophosphamide therapy in moderate-to-severe systemic lupus erythematosus. Front Immunol 2022; 13:911730. [PMID: 35979351 PMCID: PMC9376229 DOI: 10.3389/fimmu.2022.911730] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 07/13/2022] [Indexed: 11/14/2022] Open
Abstract
Objectives We have reported previously that Belimumab, a human monoclonal antibody that inhibits B-cell activating factor(BAFF) could be an effective and safe option to treat Neuropsychiatric manifestations of SLE (NPSLE). To avoid inadequate efficacy of Belimumab and significant adverse events of often-used dose of cyclophosphamide (CYC) for SLE, we evaluated the efficacy, safety, and possible immune mechanisms of Belimumab treatment in combination with intermittent low-dose intravenous CYC for moderate-to-severe SLE. Methods In this non blinded and parallel-group trial, we collected 82 cases of moderate-to-severe SLE patients, 40 received Belimumab treatment and 42 received conventional treatments as historical controls for 24 weeks. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups or subsets were compared before and after the treatments. Results Compared with the baseline, 6 months post Belimumab group treatment, disease activity score SLEDAI (13.78 to 3.82, P<0.05) and BILAG scores (16.40 to 5.48, P<0.05) were reduced; C3 (0.19 to 1.14, P<0.05) and C4 (0.04 to 0.22, P<0.05) increased; the absolute numbers of B and T cells were the first decreased and then significantly increased, tended to balance. Moreover, Belimumab group treatment significantly reduced the serum levels of IL-6, the ratio of B and T cells, and the proportion of infections and menstrual disorders. Conclusion Compared with conventional treatment, Belimumab with low-dose intravenous CYC significantly reduced disease activity scores and maintained the B/T cell balance for SLE patients at 24 weeks. It was more efficacy and safe (adverse events such as infection were significantly lower). It should be the mechanism that Belimumab combined with low-dose intravenous CYC therapy restores the balance of T and B cells, which proposes a potential treatment strategyfor SLE.
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Affiliation(s)
- Hao Cheng
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Xiao-ying Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Hui-dan Yang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Zhen Yu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Cheng-lan Yan
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Hong-yan Wen
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
- *Correspondence: Hong-yan Wen, ;
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19
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Smith EMD, Egbivwie N, Jorgensen AL, Ciurtin C, Al-Abadi E, Armon K, Bailey K, Brennan M, Gardner-Medwin J, Haslam K, Hawley DP, Leahy A, Leone V, Malik G, McLaren Z, Pilkington C, Ramanan AV, Rangaraj S, Ratcliffe A, Riley P, Sen E, Sridhar A, Wilkinson N, Wood F, Beresford MW, Hedrich CM. Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study. Clin Immunol 2022; 239:109028. [PMID: 35513304 DOI: 10.1016/j.clim.2022.109028] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. AIM To explore 'real world' treatment utilising longitudinal UK JSLE Cohort Study data. METHODS Data collected between 07/2009-05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. RESULT 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65-2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. CONCLUSIONS Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.
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Affiliation(s)
- Eve M D Smith
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, UK.
| | - Naomi Egbivwie
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, UK; Liverpool University Hospitals NHS Foundation Trusts, Liverpool, UK
| | | | - Coziana Ciurtin
- Centre for Adolescent Rheumatology, University College London, London, UK
| | - Eslam Al-Abadi
- Department of Rheumatology, Birmingham Children's Hospital, Birmingham, UK
| | - Kate Armon
- Department of Paediatric Rheumatology, Cambridge University Hospitals, Cambridge, UK
| | - Kathryn Bailey
- Department of Paediatric Rheumatology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Mary Brennan
- Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Edinburgh, UK
| | | | - Kirsty Haslam
- Department of Paediatrics, Bradford Royal Infirmary, Bradford, UK
| | - Daniel P Hawley
- Department of Paediatric Rheumatology, Sheffield Children's Hospital, Sheffield, UK
| | - Alice Leahy
- Department of Paediatric Rheumatology, Southampton General Hospital, Southampton, UK
| | - Valentina Leone
- Department of Paediatric Rheumatology, Leeds Children Hospital, Leeds, UK
| | - Gulshan Malik
- Paediatric Rheumatology, Royal Aberdeen Children's Hospital, Aberdeen, UK
| | - Zoe McLaren
- Liverpool University Hospitals NHS Foundation Trusts, Liverpool, UK
| | - Clarissa Pilkington
- Department of Paediatric Rheumatology, Great Ormond Street Hospital, London, UK
| | - Athimalaipet V Ramanan
- University Hospitals Bristol NHS Foundation Trust & Bristol Medical School, University of Bristol, Bristol, UK
| | - Satyapal Rangaraj
- Department of Paediatric Rheumatology, Nottingham University Hospitals, Nottingham, UK
| | - Annie Ratcliffe
- Department of Paediatrics, Taunton & Somerset NHS Foundation Trust - Musgrove Park Hospital, Taunton, UK
| | - Phil Riley
- Paediatric Rheumatology, Royal Manchester Children's Hospital, Manchester, UK
| | - Ethan Sen
- Paediatric Rheumatology, Great North Children's Hospital, Royal Victoria Infirmary, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Arani Sridhar
- Leicester Children's Hospital, University Hospitals of Leicester NHS trust, Leicester, UK
| | - Nick Wilkinson
- Guy's & St Thomas's NHS Foundation Trust, Evelina Children's Hospital, London, UK
| | - Fiona Wood
- Department of Paediatrics, University Hospitals of Morecambe Bay NHS Foundation Trust, Royal Lancaster Infirmary, Lancaster, UK
| | - Michael W Beresford
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, UK
| | - Christian M Hedrich
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, UK
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Gallagher KL, Patel P, Beresford MW, Smith EMD. What Have We Learnt About the Treatment of Juvenile-Onset Systemic Lupus Erythematous Since Development of the SHARE Recommendations 2012? Front Pediatr 2022; 10:884634. [PMID: 35498799 PMCID: PMC9047745 DOI: 10.3389/fped.2022.884634] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 03/21/2022] [Indexed: 11/14/2022] Open
Abstract
Introduction Juvenile-onset systemic lupus erythematous (JSLE) is a rare multisystem autoimmune disorder. In 2012, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative developed recommendations for the diagnosis/management of JSLE, lupus nephritis (LN) and childhood-onset anti-phospholipid syndrome (APS). These recommendations were based upon available evidence informing international expert consensus meetings. Objective To review new evidence published since 2012 relating to the management of JSLE, LN and APS in children, since the original literature searches informing the SHARE recommendations were performed. Method MEDLINE, EMBASE and CINAHL were systematically searched for relevant literature (2012-2021) using the following criteria: (1) English language studies; (2) original research studies regarding management of JSLE, LN, APS in children; (3) adult studies with 3 or more patients <18-years old, or where the lower limit of age range ≤16-years and the mean/median age is ≤30-years; (4) randomized controlled trials (RCTs), cohort studies, case control studies, observational studies, case-series with >3 patients. Three reviewers independently screened all titles/abstracts against predefined inclusion/exclusion criteria. All relevant manuscripts were reviewed independently by at least two reviewers. Data extraction, assessment of the level of evidence/methodological quality of the manuscripts was undertaken in-line with the original SHARE processes. Specific PUBMED literature searches were also performed to identify new evidence relating to each existing SHARE treatment recommendation. Results Six publications met the inclusion/exclusion criteria for JSLE: three RCTs, one feasibility trial, one case series. For LN, 16 publications met the inclusion/exclusion criteria: eight randomized trials, three open label prospective clinical trials, five observational/cohort studies. For APS, no publications met the inclusion criteria. The study with the highest evidence was an RCT comparing belimumab vs. placebo, including 93 JSLE patients. Whilst the primary-endpoint was not met, a significantly higher proportion of belimumab-treated patients met the PRINTO/ACR cSLE response to therapy criteria. New evidence specifically addressing each SHARE recommendation remains limited. Conclusion Since the original SHARE literature searches, undertaken >10-years ago, the main advance in JSLE treatment evidence relates to belimumab. Additional studies are urgently needed to test new/existing agents, and assess their long-term safety profile in JSLE, to facilitate evidence-based practice.
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Affiliation(s)
- Kathy L Gallagher
- Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Pallavi Patel
- Department of Public Health, Liverpool City Council, Liverpool, United Kingdom
| | - Michael W Beresford
- Institute of Life Course and Medical Science, University of Liverpool, Liverpool, United Kingdom.,Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom
| | - Eve Mary Dorothy Smith
- Institute of Life Course and Medical Science, University of Liverpool, Liverpool, United Kingdom.,Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom
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21
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Eesa NN, Abdel Nabi H, Owaidy RE, Khalifa I, Radwan AR, NourEl-Din AM, Amer MA, ElShereef RR, Hassan E, Ismail F, El-Gazzar II, Khalil NM, Moshrif AH, Abualfadl E, Tharwat S, Fathi HM, Abd Elazeem MI, El-Shebini E, Samy N, Noshy N, El-Bahnasawy AS, Abdalla AM, Abousehly OS, Mohamed EF, Nasef SI, Elsaman AM, ElKhalifa M, Salem MN, Abaza NM, Fathy HM, Abdel Salam N, El-Saadany HM, El-Najjar AR, El-Hammady DH, Hammam N, Mohammed RH, Gheita TA. Systemic lupus erythematosus children in Egypt: Homeland spectrum amid the global situation. Lupus 2021; 30:2135-2143. [PMID: 34528835 DOI: 10.1177/09612033211043010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES This study aims to present the manifestations of juvenile systemic lupus erythematosus (JSLE) across Egypt, to focus on age at onset and gender-driven influence on disease characteristics, and to compare findings to other countries. METHODS The study included 404 Egyptian children with systemic lupus erythematosus (SLE) presenting to one of the specialized rheumatology centers corresponding to 13 major governorates. Juvenile cases age was ≤ 16°years at the time of recruitment. The SLE Disease Activity Index (SLEDAI) and damage index (DI) were assessed. RESULTS The mean age was 13.2 ± 2.4°years; 355 females and 49 males (7.2:1), and the disease duration was 2.3 ± 1.6 years, while age at disease onset was 11.1 ± 2.5°years. Their SLEDAI was 13.5 ± 12.3, and DI, 0.36 ± 0.78. The overall estimated prevalence of childhood-SLE patients in the recruited cohort in Egypt was 1/100,000 population (0.24/100000 males and 1.8/100000 females). 7.4% developed pre-pubertal SLE (≤ 7 years); 73.3%, peri-pubertal; and 19.3% during early adolescence. The differences according to age group were equal for gender and clinical manifestations except skin lesions present in 59.3% of pre-pubertal onset, 74.6% of peri-pubertal, and 84.2% of adolescents (p = 0.029), and renal involvement in 73.8% of peripubertal, 62.1% of pre-pubertal and 58.9% of adolescents (p = 0.03). Laboratory investigations, SLEDAI, and DI were similar among age categories. Lupus nephritis was more common in Egypt compared to JSLE from other countries. CONCLUSION Our large multicenter study identified that female gender influenced disease characteristics with more frequent skin involvement. Skin lesions were significantly higher in adolescents, while renal involvement in peri-pubertal children.
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Affiliation(s)
- Nahla N Eesa
- Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend Abdel Nabi
- Pediatrics Department, Rheumatology and Nephrology Unit, 68782Tanta University, Gharbia, Egypt
| | - Rasha El Owaidy
- Pediatrics Department, Rheumatology Unit, 68792Ain Shams University, Cairo, Egypt
| | - Iman Khalifa
- Pediatrics Department, Rheumatology and Nephrology Unit, 68900Helwan University, Cairo, Egypt
| | - Ahmed R Radwan
- Rheumatology Department, Faculty of Medicine, 68889Sohag University, Sohag, Egypt
| | - Abeer M NourEl-Din
- Pediatrics Department, 68787National Research Centre (NRC), Cairo, Egypt
| | - Marwa A Amer
- Rheumatology Department, Faculty of Medicine, 68789Alexandria University, Alexandria, Egypt
| | - Rawhya R ElShereef
- Rheumatology Department, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Eman Hassan
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 68789Alexandria University, Egypt
| | - Faten Ismail
- Rheumatology Department, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Iman I El-Gazzar
- Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha M Khalil
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 63527Cairo University, Cairo, Egypt
| | - Abdel Hafeez Moshrif
- Rheumatology Department, Faculty of Medicine, 68820Al-Azhar University, Assuit, Egypt
| | - Esam Abualfadl
- Pediatrics Department, Rheumatology and Nephrology Unit, 68900Helwan University, Cairo, Egypt
- Qena/Luxor hospitals, Qena, Egypt
| | - Samar Tharwat
- Internal Medicine, Rheumatology Unit, 68780Mansoura University, Dakahlia, Egypt
| | - Hanan M Fathi
- Rheumatology Department, Faculty of Medicine, 158405Fayoum University, Fayoum, Egypt
| | - Mervat I Abd Elazeem
- Rheumatology Department, Faculty of Medicine, 158411Beni-Suef University, Beni-Suef, Egypt
| | - Emad El-Shebini
- Internal Medicine Department, Rheumatology Unit, 68872Menoufiya University, Menoufiya, Egypt
| | - Nermeen Samy
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 68792Ain-Shams University, Cairo, Egypt
| | - Nermeen Noshy
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 68792Ain-Shams University, Cairo, Egypt
| | - Amany S El-Bahnasawy
- Rheumatology Department, Faculty of Medicine, 68780Mansoura University, Dakahlia, Egypt
| | - Ahmed M Abdalla
- Rheumatology Department, Faculty of Medicine, 435387Aswan University, Aswan, Egypt
| | - Osama S Abousehly
- Rheumatology Department, Faculty of Medicine, 68889Sohag University, Sohag, Egypt
| | - Eman F Mohamed
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine (Girls), 68820Al-Azhar University, Cairo, Egypt
| | - Samah I Nasef
- Rheumatology Department, Faculty of Medicine, Suez-Canal University, Ismailia, Egypt
| | - Ahmed M Elsaman
- Rheumatology Department, Faculty of Medicine, 68889Sohag University, Sohag, Egypt
| | - Marwa ElKhalifa
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 68789Alexandria University, Egypt
| | - Mohamed N Salem
- Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, 158411Beni-Suef University, Beni-Suef, Egypt
| | - Nouran M Abaza
- Rheumatology Department, Faculty of Medicine, 68792Ain Shams University, Cairo, Egypt
| | - Hanan M Fathy
- Pediatrics Department, Rheumatology and Nephrology Unit, 68789Alexandria University, Alexandria, Egypt
| | - Nancy Abdel Salam
- Pediatrics Department, Rheumatology and Nephrology Unit, 68789Alexandria University, Alexandria, Egypt
| | | | - Amany R El-Najjar
- Rheumatology Department, Faculty of Medicine, 68799Zagazig University, Sharkia, Egypt
| | - Dina H El-Hammady
- Rheumatology Department, Faculty of Medicine, 68900Helwan University, Cairo, Egypt
| | - Nevin Hammam
- Rheumatology Department, Faculty of Medicine, 68797Assuit University, Assuit, Egypt
- Rheumatology Department, 8785University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Reem Ha Mohammed
- Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Tamer A Gheita
- Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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22
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Kishi T, Sakai R, Tani Y, Nagata S, Katsumata Y, Miyamae T, Harigai M. Trends in actual medication use for child-onset systemic lupus erythematosus using the Japanese health insurance database 2009-18. Mod Rheumatol 2021; 32:565-570. [PMID: 34908147 DOI: 10.1093/mr/roab038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/16/2021] [Accepted: 06/29/2021] [Indexed: 11/14/2022]
Abstract
OBJECTIVES Immunosuppressive therapy is the mainstay of treatment for child-onset systemic lupus erythematosus (cSLE). Since epidemiological data on Japanese cSLE patients are not available, we evaluated the trends in how treatment choices have changed over time in Japan. METHODS Using the Japanese health insurance database provided by Medical Data Vision Co., Ltd, we identified cSLE patients and evaluated changes in the use of corticosteroids and immunosuppressive medications and maximum daily doses of prednisolone from 2009 to 2018. RESULTS Of 182 cSLE patients, 86% were female, and the median age was 14 years. Oral prednisolone was used in more than 97% of cSLE patients during the study period, and the median of the maximum daily dose in each patient decreased over time. Intravenous cyclophosphamide was used less frequently after 2016, while mycophenolate mofetil and hydroxychloroquine were used frequently after 2016. The use of mizoribine reduced after 2014, whereas the other immunosuppressive medications showed no significant change over time; the use of biological agents was very limited. CONCLUSIONS Oral prednisolone was the mainstay of treatment for cSLE, and the maximum daily dose has reduced over the past decade. The most frequently prescribed immunosuppressive therapy has shifted to mycophenolate mofetil over time.
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Affiliation(s)
- Takayuki Kishi
- Department of Pediatrics, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Ryoko Sakai
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Yumi Tani
- Department of Pediatrics, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Satoru Nagata
- Department of Pediatrics, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Yasuhiro Katsumata
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Takako Miyamae
- Department of Pediatrics, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Masayoshi Harigai
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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23
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Ong MS, Rothman D, Barmettler S, Son MB, Lo M, Roberts J, Natter M. New-onset Hypogammaglobulinemia and Infectious Complications Associated with Rituximab Use in Childhood-onset Rheumatic Diseases. Rheumatology (Oxford) 2021; 61:1610-1620. [PMID: 34329428 DOI: 10.1093/rheumatology/keab626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/01/2021] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To investigate the incidence and risk factors for hypogammaglobulinemia and infectious complications associated with rituximab treatment in childhood-onset rheumatic diseases. METHODS We performed a single-center retrospective study of patients (n = 85) treated at Boston Children's Hospital (BCH) from 2009 to 2019. Study subjects included patients (ages 6 to 24) who received rituximab for the treatment of a childhood-onset rheumatic disease. RESULTS New-onset hypogammaglobulinemia developed in 23 (27.1%) patients within 18 months of rituximab induction treatment. 22 patients (25.9%) developed at least one infectious complication in the 18 months following the first rituximab infusion; of these, 11 (50%) had serious infections requiring inpatient treatment. After adjusting for potential confounders, exposure to pulse corticosteroid therapy in the month prior to rituximab use was a significant predictor of both new-onset hypogammaglobulinemia (OR 3.94; 95% CI 1.07-16.0; p = 0.044) and infectious complications (OR 15.3; 95% CI 3.04-126.8; p = 0.003). Post-rituximab hypogammaglobulinemia was the strongest predictor of serious infectious complications (OR 7.89; 95% CI 1.41-65.6; p = 0.028). Younger age at rituximab use was also a significant predictor of new-onset hypogammaglobulinemia (OR 0.83; 95% CI 0.70-0.97; p = 0.021). Compared with other rheumatic diseases, patients with vasculitis had a higher likelihood of developing infectious complications, including serious infections. CONCLUSION Although rituximab was well tolerated in terms of infectious complications in the majority of patients with childhood-onset rheumatic diseases, a substantial proportion developed new-onset hypogammaglobulinemia and infectious complications following treatment. Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions.
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Affiliation(s)
- Mei Sing Ong
- Department of Population Medicine, Harvard Medical School & Harvard Pilgrim Health Care Institute, Boston MA, United States
| | - Deborah Rothman
- Pediatric Rheumatology, Massachusetts General Hospital, Boston MA, United States
| | - Sara Barmettler
- Allergy and Immunology, Massachusetts General Hospital, Boston MA, United States
| | - Mary Beth Son
- Pediatric Rheumatology, Boston Children's Hospital, Boston MA, United States
| | - Mindy Lo
- Pediatric Rheumatology, Boston Children's Hospital, Boston MA, United States
| | - Jordan Roberts
- Pediatric Rheumatology, Boston Children's Hospital, Boston MA, United States
| | - Marc Natter
- Pediatric Rheumatology, Massachusetts General Hospital, Boston MA, United States.,Computational Health Informatics Program, Boston Children's Hospital, Boston MA, United States.,Department of Pediatrics, Harvard Medical School, Boston MA, United States
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24
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Sawhney S, Agarwal M. Rituximab use in pediatric systemic lupus erythematosus: Indications, efficacy and safety in an Indian cohort. Lupus 2021; 30:1829-1836. [PMID: 34315295 DOI: 10.1177/09612033211034567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Introduction: Children with systemic lupus erythematosus have a more challenging and difficult course as compared to their adult counterparts. Today, the aim of therapy for any child with lupus is to keep the child in a state of sustained remission with minimal or no use of steroids. This laudable goal is often difficult to achieve for the child with lupus. In addition to the use of disease modifying agents, sometimes in combination, Rituximab (RTX) is also used as an off-label indication to manage such patients.Objectives: To study the use, efficacy and safety of RTX in a cohort of patients with pediatric lupus followed at a single tertiary level center in Northern India.Methods: This paper is a retrospective review looking at the use of RTX in children with systemic lupus at a tertiary level pediatric rheumatology center in North India over a period of seventeen years. This paper describes the indications, use, efficacy and safety of RTX in childhood systemic lupus erythematosus.Results: RTX was used in 17 of 225 pediatric lupus patients (7.5%), with the most common indication being resistant renal disease (53%). Significant improvement was seen in all domains studied: The mean SLEDAI was 16.25 prior to RTX and reduced to 1.43 six months after the RTX (p value 0.001), steroid use dropped from 100% pre- RTX to 33% at 2 years, there was a sustained reduction in proteinuria in the patients with nephritis from a mean urine spot protein creatinine ratio of 3.1 pre RTX to 0.4 at one year post RTX (p= .006). Finally, 82% of the children had no flare during the follow up (median 24 months). No patient had any adverse event.Conclusions: This study confirms that RTX is very effective in childhood lupus and can be safely used even in a country with a very high burden of infectious diseases. This data adds to the scarce literature in this area from the developing world.
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Affiliation(s)
- Sujata Sawhney
- Division of Pediatric Rheumatology, 28928Sir Ganga Ram Hospital, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India
| | - Manjari Agarwal
- Division of Pediatric Rheumatology, 28928Sir Ganga Ram Hospital, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India
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25
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Liccioli G, Simonini G, Melani F, Giovannini M, Ricci S, Sarti L, Cavallin M, Barni S, Marrani E, Mori F. Hypersensitivity to Rituximab in Children. Pharmacology 2020; 106:341-344. [PMID: 33202411 DOI: 10.1159/000511458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 09/03/2020] [Indexed: 11/19/2022]
Abstract
Biological agents have had an increased usage during the past years, also in pediatric population. Monoclonal antibodies can cause adverse drug reactions with different pathomechanisms, including type I IgE-mediated hypersensitivity reactions (HR). In this report, we describe 2 children who had a diagnosis of anaphylaxis to rituximab (RTX), confirmed by positive in vivo tests in both cases and elevated tryptase value in one case. We also made a review of the few cases of HR to RTX in pediatric population reported in literature and discuss differential diagnosis and utility of allergy investigations.
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Affiliation(s)
- Giulia Liccioli
- Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy,
| | - Gabriele Simonini
- Rheumatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | - Federico Melani
- Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's University Hospital, Florence, Italy
| | - Mattia Giovannini
- Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | - Silvia Ricci
- Department of Health Sciences, University of Florence, Meyer Children's University Hospital, Florence, Italy
| | - Lucrezia Sarti
- Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | - Mara Cavallin
- Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's University Hospital, Florence, Italy
| | - Simona Barni
- Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | - Edoardo Marrani
- Rheumatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
| | - Francesca Mori
- Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy
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26
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Desai AK, Baloh CH, Sleasman JW, Rosenberg AS, Kishnani PS. Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort. Front Immunol 2020; 11:1727. [PMID: 32849613 PMCID: PMC7424004 DOI: 10.3389/fimmu.2020.01727] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 06/29/2020] [Indexed: 01/19/2023] Open
Abstract
Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26–39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1–11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11–55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.
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Affiliation(s)
- Ankit K Desai
- Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States
| | - Carolyn H Baloh
- Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University Health System, Durham, NC, United States
| | - John W Sleasman
- Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University Health System, Durham, NC, United States
| | - Amy S Rosenberg
- Division of Biologics Review and Research 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, US FDA, Bethesda, MD, United States
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States
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27
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Wenderfer SE, Chang J, Hicks MJ. Approach to Classification and Management of Childhood-Onset Lupus Nephritis. CURRENT PEDIATRICS REPORTS 2020. [DOI: 10.1007/s40124-020-00207-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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28
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Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM. Juvenile-onset systemic lupus erythematosus: Update on clinical presentation, pathophysiology and treatment options. Clin Immunol 2019; 209:108274. [PMID: 31678365 DOI: 10.1016/j.clim.2019.108274] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 12/25/2022]
Abstract
Juvenile-onset systemic lupus erythematosus (jSLE) accounts for up to 20% of all SLE patients. Key differences between juvenile- and adult-onset (aSLE) disease include higher disease activity, earlier development of damage, and increased use of immunosuppressive treatment in jSLE suggesting (at least partial) infectivity secondary to variable pathomechanisms. While the exact pathophysiology of jSLE remains unclear, genetic factors, immune complex deposition, complement activation, hormonal factors and immune cell dysregulation are involved to variable extents, promising future patient stratification based on immune phenotypes. Though less effective and potentially toxic, jSLE patients are treated based upon evidence from studies in aSLE cohorts. Here, age-specific clinical features of jSLE, underlying pathomechanisms, treatment options and disease outcomes will be addressed. Future directions to improve the care of jSLE patients, including implementation of the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, biomarkers, treat to target and personalized medicine approaches are discussed.
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Affiliation(s)
- Eve Mary Dorothy Smith
- Department of Women's & Children's Health, Institution of Translational Medicine, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Eaton Rd, Liverpool L12 2AP, UK.
| | - Hanna Lythgoe
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Eaton Rd, Liverpool L12 2AP, UK
| | - Angela Midgley
- Department of Women's & Children's Health, Institution of Translational Medicine, University of Liverpool, UK
| | - Michael William Beresford
- Department of Women's & Children's Health, Institution of Translational Medicine, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Eaton Rd, Liverpool L12 2AP, UK
| | - Christian Michael Hedrich
- Department of Women's & Children's Health, Institution of Translational Medicine, University of Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Eaton Rd, Liverpool L12 2AP, UK.
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29
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Rianthavorn P, Prurapark P. Risk factors of infection-associated mortality in children with lupus nephritis in under-resourced areas. Lupus 2019; 28:1727-1734. [PMID: 31635558 DOI: 10.1177/0961203319882498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Treatment of lupus nephritis class III, IV and V with immunosuppressive therapy increases patient survival but poses a risk of infection-related mortality. This study was conducted to evaluate risk factors for fatal infection in children with lupus nephritis in under-resourced areas. METHODS Medical records of patients, who were admitted to a tertiary-care university-based hospital from January 2002 to July 2018 with the diagnosis of systemic lupus erythematosus, were reviewed. Only patients aged less than 18 years with lupus nephritis and documented infection were included in the study. The primary outcome was infection-associated mortality. The logistic regression model was used to identify independent variables associated with fatal infection. Predicted probabilities of infection-related mortality adjusted for factors significant in multivariate analysis were calculated using marginal effects at representative values. RESULTS Infection-related deaths occurred in 27 of 179 patients (15.1%). Hospital-acquired infections occurred in 72 of 375 episodes of hospital admissions (19.2%) and 13 hospital-acquired infections (18.1%) resulted in fatal infection. Invasive fungal infections were the leading cause of death (44.4%) and pulmonary infections were the predominant site (55.5%). Haemoglobin levels and glomerular filtration rates were significantly lower in deceased versus surviving patients. Percentages of patients with hospital-acquired infections, invasive fungal infections and pulmonary infections were significantly higher in deceased than surviving patients. Urine protein, the neutrophil-to-lymphocyte ratio, cumulative methylprednisolone dose and daily prednisolone dose were significantly higher in deceased than surviving patients. In multivariate analysis, a neutrophil-to-lymphocyte ratio more than 20, invasive fungal infections and high daily prednisolone dose were independently predictive of fatal infection with adjusted odds ratio of 3.02 (95% confidence interval 1.02-8.97, p = 0.04), 15.08 (95% confidence interval 4.72-48.24, p < 0.001) and 1.03 (95% confidence interval 1.01-1.06, p = 0.04), respectively. A high daily prednisolone dose intensified the impact of invasive fungal infections and high neutrophil-to-lymphocyte ratio on predicted probability of infection-associated mortality. CONCLUSIONS Prevention of invasive fungal infections and minimization of daily prednisolone should be emphasized in routine clinical practice of children with lupus nephritis in under-resourced areas to achieve better survival. Children with lupus nephritis and a high neutrophil-to-lymphocyte ratio should be under cautious surveillance for infection.
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Affiliation(s)
- P Rianthavorn
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand
| | - P Prurapark
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand
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Wilkinson MGL, Rosser EC. B Cells as a Therapeutic Target in Paediatric Rheumatic Disease. Front Immunol 2019; 10:214. [PMID: 30837988 PMCID: PMC6382733 DOI: 10.3389/fimmu.2019.00214] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 01/24/2019] [Indexed: 12/12/2022] Open
Abstract
B cells carry out a central role in the pathogenesis of autoimmune disease. In addition to the production of autoantibodies, B cells can contribute to disease development by presenting autoantigens to autoreactive T cells and by secreting pro-inflammatory cytokines and chemokines which leads to the amplification of the inflammatory response. Targeting both the antibody-dependent and antibody-independent function of B cells in adult rheumatic disease has led to the advent of B cell targeted therapies in clinical practice. To date, whether B cell depletion could also be utilized for the treatment of pediatric disease is relatively under explored. In this review, we will discuss the role of B cells in the pathogenesis of the pediatric rheumatic diseases Juvenile Idiopathic Arthritis (JIA), Juvenile Systemic Lupus Erythematosus (JSLE) and Juvenile Dermatomyositis (JDM). We will also explore the rationale behind the use of B cell-targeted therapies in pediatric rheumatic disease by highlighting new case studies that points to their efficacy in JIA, JSLE, and JDM.
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Affiliation(s)
- Meredyth G Ll Wilkinson
- Infection, Immunity, Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Arthritis Research UK Centre for Adolescent Rheumatology, University College London, UCLH and GOSH, London, United Kingdom.,NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, United Kingdom
| | - Elizabeth C Rosser
- Infection, Immunity, Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Arthritis Research UK Centre for Adolescent Rheumatology, University College London, UCLH and GOSH, London, United Kingdom.,NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, United Kingdom
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Abstract
Childhood-onset systemic lupus erythematosus (SLE) is a subset of SLE with an onset before 18 years of age. Patients with early onset SLE tend to have a greater genetic component to their disease cause, more multisystemic involvement, and a more severe disease course, which includes greater risks for developing nephritis and end-stage kidney disease. Five- and 10-year mortality is lower than in adult-onset SLE. Although patient and renal survival have improved with advances in induction and maintenance immunosuppression, accumulation of irreversible damage is common. Cardiovascular and infectious complications are frequent, as are relapses during adolescence and the transition to adulthood.
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Peterknecht E, Keasey MP, Beresford MW. The effectiveness and safety of biological therapeutics in juvenile-onset systemic lupus erythematosus (JSLE): a systematic review. Lupus 2018; 27:2135-2145. [PMID: 30336753 DOI: 10.1177/0961203318804879] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE To systematically review and summarize the available literature regarding the effectiveness and safety of biologics in the treatment of juvenile-onset systemic lupus erythematosus. METHODS PubMed was systematically searched for relevant literature (2012-2017 inclusive) using the following criteria: (1) patients diagnosed with juvenile-onset systemic lupus erythematosus (≤18 years at diagnosis); (2) treatment with any biological agent; and (3) outcome measures assessing effectiveness and safety. Systematic literature reviews, meta-analyses, randomized controlled trials, cohort studies, case control studies, cross sectional surveys and case-series with ≥3 patients were included. Independent extraction of articles by two authors using predefined criteria was performed. The quality of each study was assessed using CASP tools and Oxford CEBM Levels of Evidence. RESULTS Nine articles met inclusion criteria: six cohort studies, two case series and one pilot study, totalling 230 patients. All but one article reported the effects of rituximab, the other those of belimumab. Overall, patients had active disease refractory to standard of care regimens using corticosteroids and immunosuppressants. Available evidence for rituximab demonstrated improvements in disease activity, complement levels and anti-dsDNA titres accompanying a steroid-sparing effect. CONCLUSION Rituximab can be considered an effective treatment in juvenile-onset systemic lupus erythematosus patients with severe disease manifestations and/or refractory disease. Based on current evidence, use of belimumab in juvenile-onset systemic lupus erythematosus patients cannot be recommended. The long-term safety of these biological agents remains uncertain. Further prospective studies, ideally robust randomized controlled trials, are urgently needed to obtain more accurate data on the effectiveness and long-term safety of rituximab, belimumab and other biologics in juvenile-onset systemic lupus erythematosus.
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Affiliation(s)
- E Peterknecht
- 1 University of Liverpool Medical School, University of Liverpool, Liverpool, UK
| | - M P Keasey
- 2 Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, USA
| | - M W Beresford
- 3 Clinical Academic Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
- 4 Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Mesnyankina AA, Solovyev SK, Aseeva EA, Nasonov EL. THE EFFICIENCY OF BIOLOGICAL THERAPY AND THE FEATURES OF HUMORAL IMMUNITY IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. ACTA ACUST UNITED AC 2018. [DOI: 10.14412/1995-4484-2018-302-309] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Objective: to investigate the effect of various biological agents (BAs), including combined treatment with rituximab (RTM) and belimumab (BLM), on the activity of systemic lupus erythematosus (SLE) and to evaluate their efficacy and impact on some parameters of humoral immunity.Subjects and methods. BAs were prescribed to 54 patients with a reliable diagnosis of SLE with high and medium activity according to SLEDAI-2K; 40 of them received RTM, 7 – BLM; 7 – combined therapy with RTM and BLM. Clinical and laboratory examinations were made in all the patients at the time of their inclusion and then every 3 months during a year. The results were assessed using SLEDAI-2K, BILAG index, Lupus Erythematosus National Assessment (SELENA)-SLEDAI Flare index (SFI) (a moderate, severe exacerbation), and SLE Responder Index (SRI).Results and discussion. At 3, 6, and 12 months after start of therapy, the use of BAs in all the patients resulted in a disease activity reduction. It was statistically significant (p < 0.00001) in the RTM group; and no statistical analysis was carried out in the BLM and RTM+BLM groups due to the small numbers of patients. At the same time, there was a progressive decrease in the levels of anti-double-stranded DNA (ds-DNA) antibodies (Abs) and an increase in the concentration of the complement fractions C3 and C4 in the RTM and RTM+BLM groups (p < 0.05) at one-year follow-up. After 12 months of therapy with BAs, there was a decrease in IgG (p < 0.02) and IgM (p < 0.03) levels; but overall it remained within the reference ranges. Prior to therapy, irreversible organ damages were recorded in 23 (42.6%) of the 54 patients. The increased damage index at 12 month was observed only in patients receiving RTM, which is probably due to the use of higher-dose glucocorticoids.Conclusion. All three methods of therapy with BAs in SLE patients demonstrated good efficiency shown as a significant decrease in clinical and laboratory activity measures that were assessed by SLEDAI-2K and the levels of anti-ds-DNA and complement components C3 and C4. The decrease in immunoglobulin levels did not go beyond the reference values. Therapy with BLM and RTM+BLM allowed for managing patients with the low and average doses of oral glucocorticoids, which contributed to the reduction of not only the activity, but also risk of irreversible organ damages.
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Speth F, Hinze C, Häfner R. Combination of ofatumumab and fresh frozen plasma in hypocomplementemic systemic lupus erythematosus: a case report. Lupus 2018; 27:1395-1396. [PMID: 29439647 DOI: 10.1177/0961203318756289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- F Speth
- 1 Department of Pediatric Rheumatology, Universitatsmedizin Rostock Kinder und Jugendklinik, Rostock, Germany
| | - C Hinze
- 2 Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
| | - R Häfner
- 3 Children's Hospital, German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
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Groot N, de Graeff N, Marks SD, Brogan P, Avcin T, Bader-Meunier B, Dolezalova P, Feldman BM, Kone-Paut I, Lahdenne P, McCann L, Özen S, Pilkington CA, Ravelli A, Royen-Kerkhof AV, Uziel Y, Vastert BJ, Wulffraat NM, Beresford MW, Kamphuis S. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. Ann Rheum Dis 2017; 76:1965-1973. [PMID: 28877866 DOI: 10.1136/annrheumdis-2017-211898] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 07/18/2017] [Accepted: 08/13/2017] [Indexed: 12/13/2022]
Abstract
Lupus nephritis (LN) occurs in 50%-60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high-quality care for all children with SLE.
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Affiliation(s)
- Noortje Groot
- Wilhelmina Children's Hospital, Utrecht, The Netherlands
- Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Stephen D Marks
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Paul Brogan
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Tadej Avcin
- University Children's Hospital Ljubljana, Ljubljana, Slovenia
| | | | - Pavla Dolezalova
- 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Brian M Feldman
- Division of Rheumatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | - Pekka Lahdenne
- Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
| | - Liza McCann
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Seza Özen
- Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | | | - Angelo Ravelli
- Università degli Studi di Genova and Istituto Giannina Gaslini, Genoa, Italy
| | | | - Yosef Uziel
- Meir Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Bas J Vastert
- Wilhelmina Children's Hospital, Utrecht, The Netherlands
| | | | - Michael W Beresford
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Sylvia Kamphuis
- Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands
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Liossis SNC, Staveri C. B Cell-Based Treatments in SLE: Past Experience and Current Directions. Curr Rheumatol Rep 2017; 19:78. [DOI: 10.1007/s11926-017-0707-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Groot N, de Graeff N, Avcin T, Bader-Meunier B, Brogan P, Dolezalova P, Feldman B, Kone-Paut I, Lahdenne P, Marks SD, McCann L, Ozen S, Pilkington C, Ravelli A, Royen-Kerkhof AV, Uziel Y, Vastert B, Wulffraat N, Kamphuis S, Beresford MW. European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: the SHARE initiative. Ann Rheum Dis 2017; 76:1788-1796. [PMID: 28630236 DOI: 10.1136/annrheumdis-2016-210960] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 05/02/2017] [Accepted: 05/04/2017] [Indexed: 01/01/2023]
Abstract
Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80% agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high-quality standards of care for children with cSLE.
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Affiliation(s)
- Noortje Groot
- Wilhelmina Children's Hospital, Utrecht, Netherlands
- Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | | | - Tadej Avcin
- University Children's Hospital Ljubljana, Ljubljana, Slovenia
| | | | - Paul Brogan
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Pavla Dolezalova
- General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Brian Feldman
- The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | | | - Pekka Lahdenne
- Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
| | - Stephen D Marks
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Liza McCann
- Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Seza Ozen
- Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | | | - Angelo Ravelli
- Università degli Studi di Genova and Istituto Giannina Gaslini, Genoa, Italy
| | | | - Yosef Uziel
- Meir Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Bas Vastert
- Wilhelmina Children's Hospital, Utrecht, Netherlands
| | | | - Sylvia Kamphuis
- Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Michael W Beresford
- Alder Hey Children's NHS Foundation Trust, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Affiliation(s)
- Ethan S Sen
- Department of Paediatric Rheumatology, Bristol Royal Hospital for Children and School of Clinical Sciences, University of Bristol, Bristol, UK
| | - Athimalaipet V Ramanan
- Department of Paediatric Rheumatology, Bristol Royal Hospital for Children and School of Clinical Sciences, University of Bristol, Bristol, UK.
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Legeay C, Bittencourt H, Haddad E, Spiesser-Robelet L, Thépot-Seegers V, Therrien R. A Retrospective Study on Infusion-Related Reactions to Rituximab in a Heterogeneous Pediatric Population. J Pediatr Pharmacol Ther 2017; 22:369-374. [PMID: 29042839 DOI: 10.5863/1551-6776-22.5.369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES To assess risks and outcomes of infusion-related reactions to rituximab in a heterogeneous pediatric population. METHODS All patients who received rituximab between July 2010 and July 2012 were retrieved from the pharmacy software and included for analysis. Data were collected according to 4 categories: demographic data, infusion data, infusion-related reactions, and biological data considered as risk factors (i.e., absolute lymphocyte count, lactate dehydrogenase levels). RESULTS Sixty-seven patients treated for a total of 17 different indications were included. A total of 282 rituximab infusions were administered. Forty-three, mostly grade 1 or 2, infusion-related reactions occurred in 30 patients. Reactions occurred in 39.2% "first-dose" infusions, but this rate dropped drastically to 2.7% in subsequent doses. In multivariate analysis, high absolute lymphocyte count was the only risk factor for infusion-related reaction (OR = 1.03; 95% CI: 1.01-1.06; p = 0.014). CONCLUSIONS Rituximab infusion-related reactions in a heterogeneous pediatric population were frequent on first infusion, but rare in subsequent ones. Overall, these reactions were mild and manageable through pharmacological treatment. Patients with an elevated absolute lymphocyte count before infusion were at greater risk for an infusion-related reaction.
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Affiliation(s)
- Clément Legeay
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
| | - Henrique Bittencourt
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
| | - Elie Haddad
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
| | - Laurence Spiesser-Robelet
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
| | - Valérie Thépot-Seegers
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
| | - Roxane Therrien
- Department of Pharmacy (CL, RT), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Oncology-Haematology (HB), CHU Ste Justine, University of Montreal, Montréal, Quebec, Canada; Department of Pediatrics, Department of Microbiology, Infectiology and Immunology (EH), University of Montreal, Montreal, Quebec, Canada; Department of Pharmacy (JSR), CHU d'Angers, University of Angers, Angers, France; Department of Medical Information (VTS), CHU d'Angers, University of Angers, Angers, France
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Mahmoud I, Jellouli M, Boukhris I, Charfi R, Ben Tekaya A, Saidane O, Ferjani M, Hammi Y, Trabelsi S, Khalfallah N, Tekaya R, Gargah T, Abdelmoula L. Efficacy and Safety of Rituximab in the Management of Pediatric Systemic Lupus Erythematosus: A Systematic Review. J Pediatr 2017; 187:213-219.e2. [PMID: 28602379 DOI: 10.1016/j.jpeds.2017.05.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 01/31/2017] [Accepted: 05/01/2017] [Indexed: 01/19/2023]
Abstract
OBJECTIVES To evaluate the efficacy and safety of rituximab for treating pediatric systemic lupus erythematosus (pSLE). STUDY DESIGN We performed a systematic review to evaluate the efficacy and safety of rituximab in children with pSLE. Data from studies performed before July 2016 were collected from MEDLINE, the Cochrane Library, Scopus, and the International Rheumatic Disease Abstracts, with no language restrictions. Study eligibility criteria included clinical trials and observational studies with a minimal sample size of 5 patients, regarding treatment with rituximab in patients with refractory pSLE (aged <18 years at the time of diagnosis). Independent extraction of articles was performed by 2 investigators using predefined data fields. RESULTS Twelve case series met the criteria for data extraction for the systematic review with a good quality assessment according to an 18-criteria checklist using a modified Delphi method. Among them, 3 studies were multicenter and 3 were prospective. The total number of patients was 272. Studies collected patients with active disease refractory to steroids and immunosuppressant drugs. Refractory lupus nephritis was the most common indication (33%). Acceptable evidence suggested improvements in renal, neuropsychiatric and haematological manifestations, disease activity, complement and anti-double stranded Desoxy-Nucleo-Adenosine, with a steroid-sparing effect. However, there was poor evidence suggesting efficacy on arthralgia, photosensitivity, and mucocutaneous manifestations of SLE in children. An overall acceptable safety profile with few major adverse events was shown. CONCLUSION Rituximab exhibited a satisfactory profile regarding efficacy and safety indicating that this agent is a promising therapy for pSLE and should be further investigated.
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Affiliation(s)
- Ines Mahmoud
- Department of Rheumatology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia.
| | - Manel Jellouli
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Imen Boukhris
- Department of Internal Medicine, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Rim Charfi
- Department of Clinical Pharmacology, National Centre of Pharmacovigilance, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Aicha Ben Tekaya
- Department of Rheumatology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Olfa Saidane
- Department of Rheumatology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Maryem Ferjani
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Yousra Hammi
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Sameh Trabelsi
- Department of Clinical Pharmacology, National Centre of Pharmacovigilance, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Narjess Khalfallah
- Department of Internal Medicine, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Rawdha Tekaya
- Department of Rheumatology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Tahar Gargah
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
| | - Leila Abdelmoula
- Department of Rheumatology, Charles Nicolle Hospital, Faculty of Medicine, Manar University, Tunis, Tunisia
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Update on the pathogenesis and treatment of childhood-onset systemic lupus erythematosus. Curr Opin Rheumatol 2017; 28:488-96. [PMID: 27341622 DOI: 10.1097/bor.0000000000000317] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW This article will provide an update of studies published in the last year regarding epidemiology, pathogenesis, major disease manifestations and outcomes, and therapies in childhood-onset systemic lupus erythematosus (cSLE). RECENT FINDINGS Recent studies on cSLE epidemiology supported previous findings that cSLE patients have more severe disease and tend to accumulate damage rapidly. Lupus nephritis remains frequent and is still a significant cause of morbidity and mortality. In the past year unfortunately there were no new reproducible, biomarker studies to help direct therapy of renal disease. However, some progress was made in neuropsychiatric disease assessment, with a new and promising automated test to screen for cognitive dysfunction reported. There were no prospective interventional treatment trials designed for patients with cSLE published in the last year, but some studies involving children are currently active and might improve the therapeutic options for patients with cSLE. SUMMARY There is a need to get a better understanding of pathogenesis and identify new biomarkers in cSLE to more accurately predict outcomes. New insights into characterization of different clinical manifestations may enable to optimize individual interventions and influence the prognosis.
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Jebali H, Hajji M, Rais L, Hamida FB, Beji S, Zouaghi MK. Clinicopathological findings and outcome of lupus nephritis in Tunisian children: a review of 43 patients. Pan Afr Med J 2017; 27:153. [PMID: 28904681 PMCID: PMC5567971 DOI: 10.11604/pamj.2017.27.153.10915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 05/16/2017] [Indexed: 12/02/2022] Open
Abstract
We report clinical and renal histological data, treatment modalities and outcome of 43 Tunisian children with biopsy-proven lupus nephritis seen over a 23-year period. There were 39 girls and 4 boys with a mean age of 12.5 years at diagnosis of lupus nephritis and followed for a mean period of 77 months. Renal symptoms included urinary abnormalities in all patients, hypertension in 40% of cases, nephrotic syndrome in 60% of cases and renal failure in 25% of cases. Class IV and class III nephritis were observed in 48.8 % and 30.2 % respectively. Corticosteroids were used in all cases, associated to immunosuppressive therapy in 23%. Overall survival was 86% at 5 years and 74% at 10 and 15 years. Renal survival was 83% at 5 and 10 years and 63% at 15 years. Initial renal failure and tubulointerstitial fibrosis were significantly increased risk for the development of end-stage renal disease in our study group. Renal histological findings provide the basis for treatment recommendations. Timely performed renal biopsy is greatly needed to accurately determine the prognosis and to guide treatment in children lupus nephritis.
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Affiliation(s)
- Hela Jebali
- Nephrology Departement, La Rabta Hospital, Tunis, Tunisia
| | - Meriam Hajji
- Nephrology Departement, La Rabta Hospital, Tunis, Tunisia
| | - Lamia Rais
- Nephrology Departement, La Rabta Hospital, Tunis, Tunisia
| | - Fethi Ben Hamida
- Laboratory of Kidney pathology LR00SP01, Charles Nicolle Hospital, Tunis, Tunisia
| | - Soumaya Beji
- Nephrology Departement, La Rabta Hospital, Tunis, Tunisia
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Basu B, Roy B, Babu BG. Efficacy and safety of rituximab in comparison with common induction therapies in pediatric active lupus nephritis. Pediatr Nephrol 2017; 32:1013-1021. [PMID: 28191596 DOI: 10.1007/s00467-017-3583-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 12/21/2016] [Accepted: 12/21/2016] [Indexed: 01/23/2023]
Abstract
BACKGROUND Childhood-onset lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Despite treatment-related toxicities, cyclophosphamide (CYC) and glucocorticoid-based treatment protocols are still considered standard therapy in managing this multisystem disorder. An effective and safe alternative induction regimen is needed. METHODS Forty-four pediatric patients with active LN aged 3.5-13.8 (median 8.4) years, of whom 32 entered the study at diagnosis of SLE, were followed over 36 months. Induction therapy consisted of methylprednisolone pulses followed by either rituximab (RTX) (n = 17), mycophenolate mofetil (MMF) (n = 12) or pulse-CYC (n = 15), with tapering dose of prednisolone orally. MMF was added as maintenance immunosuppressant (800 mg/m2 daily) in all children from the third month onward. RESULTS Flare-free survival was significantly higher at 36 months with RTX compared with MMF and CYC (100% for RTX vs. 83% for MMF. and 53% for CYC, p = 0·006). Twelve patients (76.5%) achieved complete remission with RTX compared with five (41.7%) and seven (46.7%) with MMF and CYC, respectively, at last follow-up. Requirement of mean daily dosage of prednisone was significantly lower in RTX group [p = 0.005 (RTX vs MMF); 0.0001 (RTX vs CYC) at 36 months] compared with other groups after the 3-month follow-up. In comparison with few minor adverse events in the other two cohorts, several serious adverse events occurred in the CYC group. CONCLUSIONS Efficacy and medium-term safety of RTX induction followed by MMF maintenance therapy in inducing and maintaining remission among children with LN were evident in this study.
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Affiliation(s)
- Biswanath Basu
- Division of Pediatric Nephrology, Department of Pediatrics, NRS Medical College & Hospital, Kolkata, 700014, West Bengal, India.
| | - Birendranath Roy
- Department of Pediatrics, NRS Medical College & Hospital, Kolkata, India
| | - Binu George Babu
- Division of Pediatric Nephrology, Department of Pediatrics, NRS Medical College & Hospital, Kolkata, India.,Department of Pediatrics, Caritas Hospital, Kerala, India
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Advances in the care of children with lupus nephritis. Pediatr Res 2017; 81:406-414. [PMID: 27855151 DOI: 10.1038/pr.2016.247] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/07/2016] [Indexed: 12/27/2022]
Abstract
The care of children with lupus nephritis (LN) has changed dramatically over the past 50 y. The majority of patients with childhood-onset systemic lupus erythematosus (cSLE) develop LN. In the 1960's, prognosis in children was worse than in adults; therapies were limited and toxic. Nearly half of cases resulted in death within 2 y. Since this time, several diagnostic recommendations and disease-specific indices have been developed to assist physicians caring for patients with LN. Pediatric researchers are validating and adapting these indices and guidelines for the treatment of LN in cSLE. Classification systems, activity, and chronicity indices for kidney biopsy have been validated in pediatric cohorts in several countries. Implementation of contemporary immunosuppressive agents has reduced treatment toxicity and improved outcomes. Biomarkers sensitive to LN in children have been identified in the kidney, urine, and blood. Multi-institutional collaborative networks have formed to address the challenges of pediatric LN research. Considerable variation in evaluation and treatment has been addressed for proliferative forms of LN by development of consensus treatment practices. Patient survival at 5 y is now 95-97% and renal survival exceeds 90%. Moreover, international consensus exists for quality indicators for cSLE that consider the unique aspects of chronic disease in childhood.
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Dauti A, Gerstl B, Chong S, Chisholm O, Anazodo A. Improvements in Clinical Trials Information Will Improve the Reproductive Health and Fertility of Cancer Patients. J Adolesc Young Adult Oncol 2017; 6:235-269. [PMID: 28207285 DOI: 10.1089/jayao.2016.0084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
There are a number of barriers that result in cancer patients not being referred for oncofertility care, which include knowledge about reproductive risks of antineoplastic agents. Without this information, clinicians do not always make recommendations for oncofertility care. The objective of this study was to describe the level of reproductive information and recommendations that clinicians have available in clinical trial protocols regarding oncofertility management and follow-up, and the information that patients may receive in clinical trials patient information sheets or consent forms. A literature review of the 71 antineoplastic drugs included in the 68 clinical trial protocols showed that 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data. When the clinical trial protocols were reviewed, only 22% of the protocols reported the teratogenic risks and 32% of the protocols reported the gonadotoxic risk. Only 56% of phase 3 protocols had gonadotoxic information and 13% of phase 3 protocols had teratogenic information. Nine percent of the protocols provided fertility preservation recommendations and 4% provided reproductive information in the follow-up and survivorship period. Twenty-six percent had a section in the clinical trials protocol, which identified oncofertility information easily. When gonadotoxic and teratogenic effects of treatment were known, they were not consistently included in the clinical trial protocols and the lack of data for new drugs was not reported. Very few protocols gave recommendations for oncofertility management and follow-up following the completion of cancer treatment. The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials.
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Affiliation(s)
- Angela Dauti
- 1 College of Arts and Sciences, Department of Chemistry, New York University , New York City, New York.,2 Population Sciences Department, Dana-Farber Cancer Institute , Boston, Massachusetts.,3 Department of Women's and Children's Medicine, School of Medical Sciences, University of New South Wales , Sydney, Australia
| | - Brigitte Gerstl
- 4 Kids Cancer Centre, Sydney Children's Hospital , Sydney, Australia
| | - Serena Chong
- 3 Department of Women's and Children's Medicine, School of Medical Sciences, University of New South Wales , Sydney, Australia
| | - Orin Chisholm
- 5 Department of Pharmaceutical Medicine, School of Medical Sciences, University of New South Wales , Sydney, Australia
| | - Antoinette Anazodo
- 3 Department of Women's and Children's Medicine, School of Medical Sciences, University of New South Wales , Sydney, Australia .,4 Kids Cancer Centre, Sydney Children's Hospital , Sydney, Australia .,6 Nelune Comprehensive Cancer Centre, Prince of Wales Hospital , Randwick, Australia
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Abstract
Systemic lupus erythematosus (SLE) is a rare, severe, multisystem autoimmune disorder. Childhood-onset SLE (cSLE) follows a more aggressive course with greater associated morbidity and mortality than adult-onset SLE. Its aetiology is yet to be fully elucidated. It is recognised to be the archetypal systemic autoimmune disease, arising from a complex interaction between the innate and adaptive immune systems. Its complexity is reflected by the fact that there has been only one new drug licensed for use in SLE in the last 50 years. However, biologic agents that specifically target aspects of the immune system are emerging. Immunosuppression remains the cornerstone of medical management, with glucocorticoids still playing a leading role. Treatment choices are led by disease severity. Immunosuppressants, including azathioprine and methotrexate, are used in mild to moderate manifestations. Mycophenolate mofetil is widely used for lupus nephritis. Cyclophosphamide remains the first-line treatment for patients with severe organ disease. No biologic therapies have yet been approved for cSLE, although they are being used increasingly as part of routine care of patients with severe lupus nephritis or with neurological and/or haematological involvement. Drugs influencing B cell survival, including belimumab and rituximab, are currently undergoing clinical trials in cSLE. Hydroxychloroquine is indicated for disease manifestations of all severities and can be used as monotherapy in mild disease. However, the management of cSLE is hampered by the lack of a robust evidence base. To date, it has been principally guided by best-practice guidelines, retrospective case series and adapted adult protocols. In this pharmacological review, we provide an overview of current practice for the management of cSLE, together with recent advances in new therapies, including biologic agents.
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Favoino E, Prete M, Marzullo A, Millo E, Shoenfeld Y, Perosa F. CD20-Mimotope Peptide Active Immunotherapy in Systemic Lupus Erythematosus and a Reappraisal of Vaccination Strategies in Rheumatic Diseases. Clin Rev Allergy Immunol 2016; 52:217-233. [DOI: 10.1007/s12016-016-8551-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Hawcutt DB, Cooney L, Oni L, Pirmohamed M. Precision Dosing in Children. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2016. [DOI: 10.1080/23808993.2016.1138845] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Olfat M, Silverman ED, Levy DM. Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. Lupus 2015; 24:966-72. [DOI: 10.1177/0961203315578764] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/02/2015] [Indexed: 11/16/2022]
Abstract
Objectives Autoimmune thrombocytopenia (AITP) and hemolytic anemia (AIHA) are common in childhood-onset systemic lupus erythematosus (cSLE) and may be refractory to conventional therapies. Our objectives were to: (a) examine our experience; (b) determine the rate and durability of response to rituximab; and (c) evaluate its safety in our cSLE population with refractory cytopenias. Methods We performed a single-center retrospective cohort study of cSLE patients with refractory AITP or AIHA treated with rituximab between 2003 and 2012. Outcomes included the time to complete clinical response, time to B-cell depletion, duration of response and time to flare. Adverse events were also analyzed. Results Twenty-four (6%) of 394 cSLE patients received rituximab for refractory cytopenia. The indication was AITP in 16 (67%), AIHA in five (21%) and both in three (13%) patients. The median (interquartile range (IQR)) time from cytopenia onset to rituximab therapy was 16 (7–27) months for AITP and 10 (2–29) months for AIHA. Complete response following the first course of rituximab occurred at a median (IQR) of 48 (14–103) days, only one patient failed to respond. Five (21%) patients had one or more flare episodes at 22 (15–27) months. Infusion reactions were rare and one infection with herpes zoster required hospitalization in the first 12 months. Three of four patients with low IgG levels prior to the first rituximab course developed persistent hypogammaglobulinemia, and three patients have required intravenous immunoglobulin replacement. Conclusion Rituximab appears to be a well-tolerated, safe and long-lasting therapy for cSLE patients with refractory AITP and/or AIHA. Caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia.
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Affiliation(s)
- M Olfat
- Division of Rheumatology, Hospital for Sick Children, Canada
| | - E D Silverman
- Division of Rheumatology, Hospital for Sick Children, Canada
- University of Toronto, Canada
| | - D M Levy
- Division of Rheumatology, Hospital for Sick Children, Canada
- University of Toronto, Canada
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Worch J, Makarova O, Burkhardt B. Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults? Cancers (Basel) 2015; 7:305-28. [PMID: 25643241 PMCID: PMC4381260 DOI: 10.3390/cancers7010305] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 01/19/2023] Open
Abstract
Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials.
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Affiliation(s)
- Jennifer Worch
- Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, 48149, Germany.
| | - Olga Makarova
- Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, 48149, Germany.
| | - Birgit Burkhardt
- Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, 48149, Germany.
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