Tedavisi zor nefrotik sendromlu çocuklarda rituksimab tedavisi

Amaç: Rituksimab (RTX), tedavisi zor nefrotik sendromlu (sık tekrarlayan, steroide bağımlı ve steroide dirençli) hastalar için kurtarma tedavisi olarak önerilmektedir. Amacımız zor nefrotik sendromlu çocuklarda RTX tedavisinin etkinliğini ve uzun dönem sonuçlarını değerlendirmek ve deneyimlerimizi paylaşmaktır. Gereç ve Yöntem: RTX ile tedavi edilen zor nefrotik sendromlu çocukların tıbbi kayıtları geriye dönük olarak değerlendirildi. Oniki ayda nükssüz sağkalım oranı ve B hücre deplesyonun izlemi değerlendirildi. Bulgular: Çalışmaya 8'i steroide bağımlı (SBNS), 6'sı sık tekrarlayan (STNS) ve 6'sı steroide dirençli nefrotik sendromlu (SDNS) 20 çocuk dahil edildi. RTX tedavisi alan STNS/SBNS hastalarının tedavi öncesi ve sonrası 1 yıllık ortalama nüks sayısı karşılaştırıldı. Ortalama nüks sayısı 2 (1-4)’den 0 (0-1) kez/yıla geriledi. RTX tedavisi sonrası ortalama takip süresi 23 ay (12-59) ve 8 hastada nüks gelişti. RTX tedavisi sonrası nüks eden 5 hastaya, tekrarlayan dozlarda RTX uygulandı. Bu hastalarda, CD19+B hücreleri remisyon sırasında yeniden ortaya çıkarken, hafıza B hücrelerinin deplesyonu devam etti. Sonuç: RTX tedavisi, STNS/SBNS hastalarında remisyon süresini uzattı, ancak SDNS hastalarında etkisiz kaldı. Bu hastalarda remisyonun idamesi için RTX dozunun tekrarlanabileceği ve tekrarlama dozlarının zamanlamasında en iyi hafıza B hücre sayısının yardımcı olabileceği saptandı.

Rituximab treatment in children with difficult-to-treat nephrotic syndrome

Purpose: Rituximab (RTX) has been offered as rescue therapy for patients with difficult-to-treat nephrotic syndrome (frequent relapsing, steroid-dependent and steroid resistant). We aimed to assess the efficacy and long-term outcomes of RTX treatment in children with difficult nephrotic syndrome and shared our experiences Materials and Methods: Medical records of children with difficult nephrotic syndrome who were treated with RTX were retrospectively evaluated.The relapse-free survival rate at 12 month and monitoring of B-cell depletion were assessed. Results: In the study included 20 children of which 8 had steroid-dependent (SDNS), 6 had frequent relapsing (FRNS), and 6 had steroid-resistant nephrotic syndrome (SRNS). The median number of relapses at 1 year before and after treatment in FRNS/SDNS patients receiving RTX treatment were compared. The median number of relapses decreased from 2 (1-4) to 0 (0-1) times/year. The mean duration of the follow-up period after RTX treatment was 23 (12-59) months, and 8 patients developed relapse. Repeated doses of RTX were administered to 5 patients who relapsed after RTX treatment. In these patients, CD19+B cells re-emerged during remission, while depletion of memory B-cells remained. Conclusion: The RTX treatment prolonged the remission time in FRNS/SDNS patients, but it was ineffective in SRNS patients. It was determined that the RTX doses can be repeated to maintain remission in these patients, and the best memory B-cell counts can help in timing the repeat doses.

PDF

___

1. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629-39.
2. International Study of Kidney Disease in Children. Early identification of frequent relapsers among children with minimal change nephrotic syndrome. A report of the International Study of Kidney Disease in Children. J Pediatr. 1982;101:514-8.
3. Mekahli D, Liutkus A, Ranchin B, Yu A, Bessenay L, Girardin E et al. Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol. 2009;24:1525-32.
4. Husen MV, Kemper MJ. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011;26:881-92.
5. Iijima K, Sako M, Nozu K. Rituximab for nephrotic syndrome in children. Clin Exp Nephrol. 2017;21:193-202.
6. Maloney DG, Smith B, Rose A. Rituximab: Mechanism of Action and Resistance. Semin Oncol. 2002;29:2-9.
7. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients’ management. Nat. Rev. Nephrol. 2013;9:154-69.
8. Schwartz GJ , Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629-37.
9. Kallash M, Smoyer WE, Mahan JD. Rituximab use in the management of childhood nephrotic syndrome. Front Pediatr 2019;7:178.
10. Evoli A, Alboini PE, Damato V, Iorio R, Provenzano C, Bartoccioni E et al. Myasthenia gravis with antibodies to MuSK: an update. Ann N Y Acad Sci. 2018;1412:82-9.
11. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K et al, on behalf of the Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014;384:1273-81.
12. Iijima K, Sako M, Kamei K, Nozu K. Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials. Pediatr Nephrol. 2018;33:1449-55.
13. Maxted AP, Dalrymple RA, Chisholm D, McColl J, Tse Y, Christian MT et al. Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome. Pediatr Nephrol. 2019;34:855-63.
14. Kimata T, Hasui M, Kino J, Kitao T, Yamanouchi S, Tsuji S et al. Novel Use of Rituximab for Steroid-Dependent Nephrotic Syndrome in Children. Am J Nephrol. 2013;38:483-8.
15. Kamei K, Ishikura K, Sako M, Aya K, Tanaka R, Nozu K et al, on behalf of the Rituximab for Childhood-Onset Refractory Nephrotic Syndrome (RCRNS) Study Group. Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab. Pediatr Nephrol. 2017;32:2071-8.
16. Fujinaga S, Someya T, Watanabe T, Ito A, Ohtomo Y, Shimizu T et al. Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab. Eur J Pediatr. 2013;172:513-8.
17. Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T et al. Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2011;26:1823-8.
18. Kim JH, Park E, Hyun HS, Cho MH, Ahn YH, Choi HJ et al. Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome. Kidney Res Clin Pract. 2017;36:257-63. 19. Colucci M, Carsetti R, Cascioli S, Serafinelli J, Emma F, Vivarelli M. B cell phenotype in pediatric idiopathic nephrotic syndrome. Pediatr Nephrol. 2019;34:177-81.
20. Bhatia D, Sinha A, Hari P, Sopory S, Saini S, Puraswani M et al. Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr Res. 2018;84:520-6.
21. Lebrun C, Cohen M, Rosenthal-Allieri MA, Bresch S, Benzaken S, Marignier R et al. Only Follow-Up of Memory B Cells Helps Monitor Rituximab Administration to Patients with Neuromyelitis Optica Spectrum Disorders. Neurol Ther. 2018;7:373-83.
22. Trouvin A.-P, Jacquot S, Grigioni S, Curis E, Dedreux I, Roucheux A, Boulard H, Vittecoq O, Le Loët X, Boyer O, Goëb V. Usefulness of monitoring of B cell depletion in rituximab-treated rheumatoid arthritis patients in order to predict clinical relapse: a prospective observational study. Clin Exp Immunol. 2015;180:11-8.
23. Lebrun C, Bourg V, Bresch S, Cohen M, Rosenthal-Allieri MA, Desnuelle C et al. Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis. J Neuroimmunol. 2016;298:79-81.
24. Colucci M, Carsetti R, Cascioli S, Casiraghi F, Perna A, Ravà L et al. B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome. J Am Soc Nephrol. 2016;27:1811-22.
25. Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, et al. Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome. J Am Soc Nephrol. 2012;23:1117-24.
26. Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M et al. Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2014;29:1181-7.
27. Jacek Z, Magdalena SD, Aleksandra Z, Magdalena DD, Lidia HK, Grażyna K et al. Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome. Clin Exp Pharmacol Physiol. 2019;46:313-21.
28. Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and –dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol. 2010;5:2207-12.
29. Kamei K, Ishikura K, Sako M, Ito S, Nozu K, Iijima K. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol. 2020;35:17-24.