Rituximab in Pediatric Nephrology. Masoumeh Mohkam Professor of Pediatric Nephrology Shahid Beheshti University of Medical Sciences Tehran Iran

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1 بسم امیحرلا نمحرلا هلل الرححممیحرلا ن الرحیم

2 Rituximab in Pediatric Nephrology Masoumeh Mohkam Professor of Pediatric Nephrology Shahid Beheshti University of Medical Sciences Tehran Iran

3 Rituximab, a chimeric anti-cd20 monoclonal antibody

4 Rituximab Rituximab is a monoclonal antibody against CD20 antigens of premature and mature B cells. This antigen is only expressed on B cells in high levels.

5 Rituximab destroys B cells through 3 mechanisms: Complement-dependent cytotoxicity Antibody dependent cytotoxicity Apoptotic pathway (Following treatment with rituximab, B cells are prevented from proliferating and undergo apoptosis and lysis through-dependent and complement-independent mechanisms) B-cell depletion generally persists for 6 9 months in over 80% of patients, although the degree of depletion is highly variable. Selewski, DTAJNR Am J Neuroradiol 2010;80:31 Anolik JH. Arthritis Rheum 2003;48:

6 It is apparent that B cells have some functions other than antibody production, including: Lymphoid tissue development Regulation of T-cell and dendritic cell functions by cytokine production (CD80 and CTLA4) T lymphocytes activation

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12 Rituximab in pediatric nephrology Nephrotic syndrome Post transplant SLE ANCA-associated GN Membranous GN Prevention of type 1 diabetes mellitus

13 Nephrotic syndrome

14 Minimal change disease Effect of rituximab in idiopathic nephrotic syndrome, which is classically a nonimmune disease Idiopathic nephrotic syndrome is the most frequent glomerular disease during childhood Rituximab is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children Rituximab has been successfully used as a rescue therapy in some children with nephrologic problems

15 One-third of minimal change nephrotic syndrome patients have immunoglobulin deposits in the mesangium of kidney biopsy Another piece of evidence is that both B-cell and T-cell activation occur in relapse of steroid-sensitive nephrotic syndrome Kemper and colleagues have shown activation of both soluble CD23 (a marker of B-cell activation) and soluble CD25 (a marker of T-cell activation) in children with relapse Habib R, Pediatr Nephrol. 1998;8:2 Kemper MJ, Clin Nephrol. 2003;60

16 Proposed mechanisms of action of rituximab in patients with nephrotic syndrome effects on all cells expressing CD20 or sphingomielin phosphodiesterase acid-like 3 b (SMPDL-3b) protein sphingomielin phosphodiesterase acid-like 3 b acid sphingomyelinase

17 Researches assessed safety and efficacy of RTX in a multicenter series of 22 patients aged years with severe steroiddependent nephrotic syndrome or steroidresistant but cyclosporin-sensitive idiopathic nephrotic syndrome They suggested that RTX could be an effective treatment for severe steroiddependent or resistant nephrotic syndrome. Gulati A, Clin J Am Soc Nephrol. 2010;15:5 Guigonis V, Pediatr Nephrol 2008;23: Sellier-Leclerc AL, Pediatr Nephrol 2010:25:

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19 Sixty-three percent of the children who treated with rituximab were drug-free at 3 months, compared with 4% of children treated with steroid and calcineurin inhibitors alone. Ravani P, Clin J Am Soc Nephrol 2011;15:6

20 A clinical trial involving 48 children with either frequently relapsing or steroid-dependent NS who were randomly assigned to receive either a weekly dose of rituximab (375 mg/m2) or placebo for four weeks while they were in remission. These patients had severe disease and two-thirds were treated with cyclosporine. At one-year follow-up, median relapse-free duration (primary endpoint) was longer in the rituximab group compared with controls (267 versus 101 days). The relapse rate was lower in the rituximab group (1.54 versus 4.17 relapses per person-year), as was the daily prednisolone dose (8.4 versus 21 mg/m2). However, by one year, relapse had occurred in 17 of 24 patients who received rituximab and 23 of 24 who received placebo (71 versus 96 percent), and by 19 months, all patients had relapsed. ijama K. Lancet Ravani P. J Am Soc Nephrol 2015; 26:2259.

21 In a multicenter prospective study Kamei et al evaluated the efficacy, safety and pharmacokinetics of a single dose of RTX for the treatment of children with refractory SDNS. They showed that all patients were able to discontinue steroids at a median of 74 days after treatment. The frequency of relapses per 6 months was significantly reduced and the steroid-free period per 6 months was significantly increased after treatment compared with those before treatment. Totally they concluded that treatment with a single dose of rituximab may be effective for refractory SDNS, but its efficacy to prevent relapses was transient in most of the patients. Kamei K, Pediatr Nephrol 2017; 32:2071. Kamei K, Pediatr Nephrol 2009;24: Fujinaga S, Pediatr Nephrol 2010;25:

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25 Information is primarily based on case series, which have mixed patient populations, including patients initially responsive to steroids and subsequently developed steroid resistance (late), as well as those with initial steroid resistance. Data was summarized by a systematic review performed before April 2017, which included seven case series and one open-label clinical trial with a total of 226 patients. For the group of patients who were initially resistant to steroids (n = 165 patients), the overall remission rate including both complete and partial remission was 42 percent. Of note, in the only clinical trial, the remission rate was considerably lower at 19 percent.

26 Nephrotic Syndrome with glomerular sclerosis Patients with more than 80% glomerular sclerosis have shown no response to rituximab Peters HP. Neth J Med. 2008;15:66

27 Kidney transplantation

28 Post transplant Rituximab may be an effective treatment for recurrence of nephrotic syndrome after transplantation and that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation. Cellular and humoral rejection Recurrence of FSGS (post TX) Post transplant HUS PTLD

29 A 12-year-old Japanese boy who underwent kidney transplantation with a kidney from his mother developed severe proteinuria immediately after the operation. Because his original disease was nephrotic syndrome (focal segmental glomerulosclerosis, or FSGS) and electron microscopic examination of the renal biopsy showed foot process fusion, we diagnosed this as a recurrence of nephrotic syndrome to the transplanted kidney. Four months after the transplantation, posttransplant lymphoproliferative disorder (PTLD) developed, which was pathologically diagnosed as diffuse large B cell lymphoma. Treatment consisting of a reduction in immunosuppression resulted in improvement in PTLD a month after the start of treatment. However, relapse occurred 2 months after the first onset of PTLD, which we treated with rituximab (CD-20 monoclonal antibody 375 mg/m 2) once weekly for a total of four doses. The PTLD resolved immediately after the rituximab treatment was started, and, interestingly, urinary protein levels also improved at the same time. Three years later, the boy shows no signs of PTLD, and no proteinuria has been detected. These findings suggest that rituximab may be an effective treatment for recurrence of nephrotic syndrome after transplantation and that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation.

30 Mark D. Indiana University, Indianapolis

31 Post transplant HUS One patient with end-stage renal failure secondary to familial HEMOLYTIC UREMIC SYNDROME (HUS) was treated with rituximab when HUS recurred in her renal transplant and was not controlled by plasmapheresis (40 plasmapheresis). Yassa SK et al. Clin Transplant 2005; 19:

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33 SLE Willems et al evaluated eleven girls with severe SLE, including 8 girls with class IV or V lupus nephritis, 2 girls with severe autoimmune cytopenia, and 1 girl with antiprothrombin antibody with severe hemorrhage, which were treated with rituximab. The mean age at onset of rituximab treatment was 13.9 years. Patients received 2 to 12 intravenous infusions of rituximab with corticosteroids. Remission was achieved in 6 of 8 patients with lupus nephritis and in the 2 patients with autoimmune cytopenia. Steroid therapy was tapered in 5 patients who responded to treatment, and low-dose prednisone treatment was maintained in 1 patient. Willems M. Journal of pediatrics 2006;148(5): Carrasco MG. Autoimmunity Reviews 2009;8(4):

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35 Nwobi et al study supported the efficacy of rituximab as adjunctive treatment for SLE in children and they showed that rituximab was well tolerated by the majority of patients. Nwobi O, Pediatric Nephrology 2008;23(3):

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37 ANCA associated vasculitis

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41 Membranous GN

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43 Identification of CD20+ cells in renal biopsies from patients with IMN, constitutes the rationale for using rituximab for this indication Remuzzi et al. reported on eight patients with persistent IMN, in whom four weekly infusions of rituximab were administered. Mean urinary protein levels were significantly reduced after 4 weeks. Only two patients achieved full remission ( 1 g/day of urinary protein) by 5 months. Cohen CD. J Nephrol 2005;18: Remuzzi G. Lancet 2002;360:

44 IMN complicated by autoimmune hemolytic anemia Rossi et al used rituximab to successfully treat another case of IMN and nephrotic syndrome (with proteinuria of 14 g/day) complicated by autoimmune hemolytic anemia By 6 months proteinuria was just 0.3 g/day, and was maintained at low levels with normal levels of Hb for 1 year of follow-up. Rossi P et al. Rheumatology (Oxford) 2005;44:

45 Thrombotic microangiopathies HUS - TTP

46 Thrombotic microangiopathies Four episodes of HUS were successfully treated with rituximab, although the graft was eventually lost because of persistent hemorrhage. Another form of thrombotic microangiopathy, THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP), is associated with deficiency of the metalloproteinase ADAMTS13, generally as a result of autoantibodies directed against it. A larger single cohort of 11 patients with recurrent or refractory TTP (most with renal involvement) who were treated with standard protocol rituximab has recently been published. All 11 patients achieved remission and had significant increases in ADAMTS13 plasma activity.

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49 Rituximab in Prevention of type 1 diabetes mellitus It is not well studied in autoimmune diseases that have a cell-mediated pathogenesis. However, rituximab perhaps marks the beginning of new therapeutic strategies for type 1 diabetes, particularly if used in combination with insulin secretogogues and/or other immunomodulatory agents. In a preliminary trial to determine its safety and efficacy in preserving C-peptide levels in 87 patients with new-onset type 1 diabetes, the mean AUC for Cpeptide levels during a mixed-meal tolerance test was significantly higher in the rituximab versus placebo group (0.56 versus 0.47 pmol/ml). The clinical significance of this modest difference in the AUC is unclear. More patients in the rituximab compared with the placebo group developed side effects (eg, fever, rash, pruritus, nausea, vomiting) after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. The actual mechanism of the effect of rituximab in type 1 diabetes remains to be established. This drug may reduce the production of proinflammatory cytokines that enhance the immune response locally within the pancreas or the pancreatic lymph nodes. It is also possible that antigen presentation exerted by B lymphocytes, which is required for T-lymphocyte activation, is somehow affected by rituximab. Additional anti-b-lymphocyte agents, such as humanized anti-cd20 antibodies, should be tested in newly diagnosed type 1 diabetic patients. Pescovitz MD, N Engl J Med 2009; 361:2143.

50 Side Effects of Rituximab Rituximab infusion is safe and well tolerated in most pediatric patients These side effects are mostly mild and transient and often happened during intravenous infusion. Other adverse effects included: Infusion-related fever Abdominal pain Diarrhea Vomiting Skin rash Bronchospasm Tachycardia Hypertension

51 Serious adverse events Agranulocytosis Severe pneumonia due to influenza H1N1 virus, Cardiomyopathy requiring heart transplantation Rapid progression to renal failure Pancolitis, ulcerative colitis Enteroviral meningoencephalitis progressive multifocal leukoencephalopathy (by JC polyomavirus) El-Hallak M. J Pediatr 2007, 150: Fatal pulmonary fibrosis Pradhan M,P.J Am Nephrol 23:975. Quartier ClinSoc Infect Dis2012; 2003, Bitzan M, Pediatric Nephrology 2009;44(9) 36:e47-e49. Ahn YH. Pediatr Nephrol 2014; 29:1461.

52 ای که می پررسی نشان عشق چیست عشق چیزری جز ظهور مهر نیست. عشق یعنی مشکلی اسان کنی دردی از در مانده ای دررمان کنی. در میان این همه غوغا و شرر عشق یعنی کاهش رنج بشر عشق یعنی گل به جای خارر باش پل به جای این همه دیوار باش