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Safety and efficacy of biologics in childhood systemic lupus erythematosus: a critical systematic review

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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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References

  1. Harry O, Yasin S, Brunner H (2018) Childhood-onset systemic lupus erythematosus: a review and update. J Pediatr 196:22-30.e2. https://doi.org/10.1016/j.jpeds.2018.01.045

    Article  PubMed  Google Scholar 

  2. Pan L, Lu M, Wang J, Xu M, Yang S (2020) Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 16:19–30. https://doi.org/10.1007/s12519-019-00229-3

    Article  PubMed  Google Scholar 

  3. Morgan T, Watson L, McCann L, Beresford M (2013) Children and adolescents with SLE: not just little adults. Lupus 22:1309–1319

    Article  CAS  PubMed  Google Scholar 

  4. Hedrich C, Smith E, Beresford M (2017) Juvenile-onset systemic lupus erythematosus (jSLE)- Pathophysiological concepts and treatments options. Best Pract Res Clin Rheumatol 31:488–504

    Article  PubMed  Google Scholar 

  5. Bundhun P, Kumari A (2017) Huang F (2017) Differences in clinical features observed between childhood-onset versus adult-onset systemic lupus erythematosus: A systematic review and meta-analysis. Medicine (Baltimore) 96(37):e8086. https://doi.org/10.1097/MD.0000000000008086

    Article  PubMed  Google Scholar 

  6. Rodriguez-Smith J, Brunner H (2019) Update on the treatment and outcome of systemic lupus erythematous in children. Curr Opin Rheumatol 31(5):464–470. https://doi.org/10.1097/BOR.0000000000000621

    Article  PubMed  Google Scholar 

  7. Wenderfer S, Ruth N, Brunner H (2017) Advances in the care of children with lupus nephritis. Pediatr Res 81(3):406–414

    Article  PubMed  Google Scholar 

  8. Smith E, Sen E, Pain C (2019) Diagnosis and treatment of childhood-onset systemic lupus erythematosus (European evidence-based recommendations from the SHARE initiative). Arch Dis Child Educ Pract Ed 104(5):259–264. https://doi.org/10.1136/archdischild-2017-314049

    Article  PubMed  Google Scholar 

  9. Lei L, Muhammad S, Al-Obaidi M, Sebire N, Cheng I, Eleftheriou D et al (2018) Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C δ. Pediatr Rheumatol Online J 16(1):61. https://doi.org/10.1186/s12969-018-0278-1

    Article  PubMed  PubMed Central  Google Scholar 

  10. Akbar L, Alsagheir R, Al-Mayouf SM (2020) Efficacy of a sequential treatment by belimumab in monogenic systemic lupus erythematosus. Eur J Rheumatol 7(4):184–189. https://doi.org/10.5152/eurjrheum.2020.20087

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bernal C, Zamora L, Navarra S (2015) Biologic therapies in systemic lupus erythematosus. Int J Rheum Dis 18:146–153

    Article  PubMed  Google Scholar 

  12. Murphy G, Isenberg D (2019) New therapies for systemic lupus erythematosus - past imperfect, future tense. Nat Rev Rheumatol 15(7):403–412. https://doi.org/10.1038/s41584-019-0235-5

    Article  PubMed  Google Scholar 

  13. Trindade V, Carneiro-Sampaio M, Bonfa E, Silva C (2021) An update on the management of childhood-onset systemic lupus erythematosus. Paediatr Drugs 23(4):331–347

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gatto M, Zen M, Iaccarino L, Doria A (2019) New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 15(1):30–48. https://doi.org/10.1038/s41584-018-0133-2

    Article  CAS  PubMed  Google Scholar 

  15. Samotij D, Reich A (2019) Biologics in the treatment of lupus erythematosus: a critical literature review. Biomed Res Int 2019:8142368. https://doi.org/10.1155/2019/8142368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peterknecht E, Keasey M, Beresford M (2018) The effectiveness and safety of biological therapeutics in juvenile-onset systemic lupus erythematosus (JSLE): a systematic review. Lupus 27(13):2135–2145. https://doi.org/10.1177/0961203318804879

    Article  CAS  PubMed  Google Scholar 

  17. Richardson W, Wislon M, Nishikawa J, Hayward R (1995) The well-built clinical question: a key to evidence-based decisions. ACP J Club 123(3):A12-13

    Article  CAS  PubMed  Google Scholar 

  18. Nwobi O, Abitbol CL, Chandar J, Seeherunvong W, Zilleruelo G (2008) Rituximab therapy for juvenile-onset systemic lupus erythematosus. Pediatr Nephrol 23(3):413–419

    Article  PubMed  Google Scholar 

  19. Kumar S, Benseler SM, Kirby-Allen M, Silverman E (2009) B-cell depletion for autoimmune thrombocytopenia and autoimmune hemolytic anemia in pediatric systemic lupus erythematosus. Pediatrics 123(1):e159–e163

    Article  PubMed  Google Scholar 

  20. Jansson A, Sengler C, Kuemmerle-Deschner J, Gruhn B, Kranz A, Lehmann H et al (2011) B cell depletion for autoimmune diseases in paediatric patients. Clin Rheumatol 30(1):87–97

    Article  PubMed  Google Scholar 

  21. AlE’ed A, AlSonbul A, Al-Mayouf SM (2014) Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus. Rheumatol Int 34(4):529–533

    Article  PubMed  Google Scholar 

  22. Tambralli A, Beukelman T, Cron R, Stoll M (2015) Safety and efficacy of rituximab in childhood-onset systemic lupus erythematosus and other rheumatic diseases. J Rheumatol 42(3):541–546

    Article  CAS  PubMed  Google Scholar 

  23. Marks S, Patey S, Brogan P, Hasson N, Pilkington C, Woo P et al (2005) B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 52(10):3168–3174

    Article  CAS  PubMed  Google Scholar 

  24. Lehman T, Singh C, Ramanathan A, Alperin R, Adams A, Barinstein L et al (2014) Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide. Pediatr Rheumatol 12(1):3

    Article  Google Scholar 

  25. Podolskaya A, Stadermann M, Pilkington C, Marks S, Tullus K (2008) B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 93(5):401–406

    Article  CAS  PubMed  Google Scholar 

  26. Sawhney S, Agarwal M (2021) Rituximab use in pediatric systemic lupus erythematosus: indications, efficacy and safety in an Indian cohort. Lupus 30(11):1829–1836

    Article  CAS  PubMed  Google Scholar 

  27. Hogan J, Godron A, Baudouin V, Kwon T, Harambat J, Deschênes G et al (2018) Combination therapy of rituximab and mycophenolate mofetil in childhood lupus nephritis. Pediatr Nephrol 33(1):111–116

    Article  PubMed  Google Scholar 

  28. Willems M, Haddad E, Niaudet P, Koné-Paut I, Bensman A, Cochat P et al (2006) Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 148(5):623-627.e3

    Article  CAS  PubMed  Google Scholar 

  29. Brunner H, Abud-Mendoza C, Viola D, Calvo Penades I, Levy D, Anton J et al (2020) Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann Rheum Dis 79(10):1340–1348

    Article  CAS  PubMed  Google Scholar 

  30. Hui-Yuen J, Reddy A, Taylor J, Li X, Eichenfield A, Bermudez L et al (2015) Safety and efficacy of Belimumab to treat systemic lupus erythematosus in academic clinical practices. J Rheumatol 42(12):2288–2295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang L, Liang X, Cao Z, Wang D, Luo Y, Feng Y et al (2023) Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study. Rheumatology (Oxford) 22:kead406

    Article  Google Scholar 

  32. Wang D, Shan C, Liu J, Zhang R, Zhu G, Gao T et al (2022) Efficacy and safety of belimumab for the treatment of refractory childhood-onset systemic lupus erythematosus: a single-center, real-world, retrospective study. Front Immunol 13:1067721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kostik M, Kalashnikova E, Rinat R, Isupova EE, Gaidar E, Soloviev A et al (2023) Rituximab biosimilar BCD20 shows superior efficiacy above conventional non-biologics treatment in pediatric nephritis: the data of retrospective cohort study. Biomedicines 11(5):1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luijten K, Tekstra J, Bijlsma J, Bijl M (2012) The Systemic Lupus Erythematosus Responder Index (SRI); a new SLE disease activity assessment. Autoimmun Rev 11(5):326–329

    Article  CAS  PubMed  Google Scholar 

  35. Roberts J, Burn C, Sadun R, Smitherman E, Wenderfer S, Son M (2023) Real-world use and outcomes of belimumab in childhood-onset lupus: a single-center retrospective study. Lupus 32(9):1111–1116

    Article  CAS  PubMed  Google Scholar 

  36. Chalhoub N, Wenderfer S, Levy D, Rouster-Stevens K, Aggarwal A, Savani S et al (2022) International consensus for the dosing of corticosteroids in childhood-onset systemic lupus erythematosus with proliferative lupus nephritis. Arthritis Rheumatol 74(2):263–273. https://doi.org/10.1002/art.41930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Athanassiou P, Athanassiou L (2023) Current treatment approach, emerging therapies and new horizons in systemic lupus erythematosus. Life (Basel) 13(7):1496. https://doi.org/10.3390/life13071496

    Article  CAS  PubMed  ADS  Google Scholar 

  38. Chen F, Zheng Y, Chen X, Wen Z, Xu Y, Yang J, Xu K (2022) Belimumab in childhood systemic lupus erythematosus: a review of available data. Front Immunol 13:940416. https://doi.org/10.3389/fimmu.2022.940416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Navarra S, Guzmán R, Gallacher A, Hall S, Levy R, Jimenez R et al (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377(9767):721–731. https://doi.org/10.1016/S0140-6736(10)61354-2

    Article  CAS  PubMed  Google Scholar 

  40. Al-Mayouf SM, Akbar L, Abdwani R, Ginesi G, Volpi S, Gattorno M et al (2022) Performance of the EULAR/ACR 2019 classification criteria for systemic lupus erythematous in monogenic lupus. Clin Rheumatol 41(9):2721–2727. https://doi.org/10.1007/s10067-022-06209-9

    Article  PubMed  Google Scholar 

  41. Levy R, Gonzalez-Rivera T, Khamashta M, Fox N, Jones-Leone A, Rubin B et al (2021) 10 Years of belimumab experience: What have we learnt? Lupus 30(11):1705–1721. https://doi.org/10.1177/09612033211028653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rovin B, Furie R, Latinis K, Looney R, Fervenza F, Sanchez-Guerrero J et al (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64(4):1215–1226. https://doi.org/10.1002/art.34359

    Article  CAS  PubMed  Google Scholar 

  43. Merrill J, Neuwelt C, Wallace D, Shanahan J, Latinis K, Oates J et al (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62(1):222–233. https://doi.org/10.1002/art.27233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Olfat M, Silverman E, Levy D (2015) Rituximab therapy has a rapid and durable response for refractory cytopenia in childhood-onset systemic lupus erythematosus. Lupus 24(9):966–972. https://doi.org/10.1177/0961203315578764

    Article  CAS  PubMed  Google Scholar 

  45. Watson L, Beresford M, Maynes C, Pilkington C, Marks D, Glackin Y et al (2015) The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE. Lupus 24(1):10–17. https://doi.org/10.1177/0961203314547793

    Article  CAS  PubMed  Google Scholar 

  46. Mahmoud I, Jellouli M, Boukhris I, Charfi R, Ben Tekaya A, Saidane O et al (2017) Efficacy and safety of rituximab in the management of pediatric systemic lupus erythematosus: a systematic review. J Pediatr 187:213-219.e2. https://doi.org/10.1016/j.jpeds.2017.05.002

    Article  CAS  PubMed  Google Scholar 

  47. Ahmed A, Osman N, Furie R (2022) An evaluation of anifrolumab for use in adults with systemic lupus erythematosus. Expert Rev Clin Immunol 18(11):1095–1106

    Article  CAS  PubMed  Google Scholar 

  48. van Schaik M, Arends E, Soonawala D, van Ommen E, de Leeuw K, Limper M et al (2022) Efficacy of belimumab combined with rituximab in severe systemic lupus erythematosus: study protocol for the phase 3, multicenter, randomized, open-label Synbiose 2 trial. Trials 23(1):939

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was not funded by any agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

    Rawan Elshaer, Samar Jaber, Nour Odeh, Lana Arbili & Sulaiman M. Al-Mayouf

  2. Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Alfaisal University, Po Box 3354, 11211, Riyadh, Saudi Arabia

    Sulaiman M. Al-Mayouf

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  1. Rawan Elshaer
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  2. Samar Jaber
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Contributions

All authors contributed to the conduct of this manuscript. The search, data extraction and manuscript writing were all divided among the authors. All co-authors take full responsibility for the integrity and accuracy of all aspects of the work.

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Correspondence to Sulaiman M. Al-Mayouf.

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Ethics committee of the Research Affairs Council at king Faisal Specialist Hospital & Research Center approved the study protocol. Also, Ethical approval was also obtained by ethics committee of the collaborative centers.

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Elshaer, R., Jaber, S., Odeh, N. et al. Safety and efficacy of biologics in childhood systemic lupus erythematosus: a critical systematic review. Clin Rheumatol 43, 863–877 (2024). https://doi.org/10.1007/s10067-023-06833-z

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