Rituximab in Nephrology (Different Uses & Available Evidence) - Dr. Gawad

1. Rituximab in Nephrology Different Uses & Available Evidence Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria – EGY drgawad@gmail.com 5th - Feb - 2018

2. To get the presentation with full animations and videos please contact me on drgawad@gmail.com For more presentations visit www.NephroTubeCNE.com

3. Talk Outline • Mechanism of action • Lupus nephritis • ANCA associated vasculitis • Primary glomerular diseases • Thrombotic thrombocytopenic purpura • Renal transplantation

5. Rituximab Structure • a genetically engineered chimeric monoclonal antibody directed against the CD20 antigen. 2012; 12: 223–233. • induces apoptosis or cell lysis through complement dependent & independent mechanisms.

6. 2017;13(9):563.

7. 2017;13(9):563.

9. Talk Outline • Mechanism of action • Lupus nephritis • ANCA associated vasculitis • Primary glomerular diseases • Thrombotic thrombocytopenic purpura • Renal transplantation –Initiation of remission –Resistant disease –Relapsing disease

10. Arthritis Rheum. 2012 Apr;64(4):1215-26 144 patients with biopsy proven class III or IV LN There was no significant difference between the renal response rates at week 52 in the rituximab or placebo arms

11. Arthritis Rheum. 2012 Apr;64(4):1215-26

12. Arthritis Rheum. 2012 Apr;64(4):1215-26

13. Arthritis Rheum. 2012 Apr;64(4):1215-26 However, a significantly greater improvement in serological markers

14. 15, June, 2017;76:868-869

15. 15, June, 2017;76:868-869 BMI was inversely associated with renal response among patients treated with RTX

16. 2017 Sep;70(3):324-336

17. 2017 Sep;70(3):324-336

18. Methylprednisolone pulse (500 mg/m2) followed by RTX (1000 mg/1.73 m2) at days 1 and 15 MMF (1200 mg/m2/day) Prednisolone was rapidly tapered, with median dose of 0.3, 0.10 and 0.0 mg/kg/day at 3, 6 and 12 months respectively 2018 Jan;33(1):111-116

19. 2018 Jan;33(1):111-116

22. 2013 May;22(6):574-82 At 6 months, 11/18 patients reached renal CR and 2/18 PR 5 patients failed to show CR or PR despite peripheral B lymphocyte count depletion, and progressed to ESRD

23. 2013 Jan;28(1):106-11 Out of 233 reports, we selected 26 for analysis, which described 300 patients with a mean follow-up of 60 weeks

28. 2009 Mar;4(3):579-87

29. 2009 Mar;4(3):579-87

30. RCT for relapsing disease have not been performed. The long-term efficacy and toxicity of rituximab have not been defined. No suggestion or recommendation for Rituximab.

31. Disease Rituximab use LN (intiation of remission) • In black • Inversely related to BMI • It may allow steroid sparing in children LN (resistant) • It can be used but needs RCTs LN (relapse) • No evidence ANCA vasculitis (initiation) Not inferior to cyclophosphamide ANCA vasculitis (relapse) Superior to cyclophosphamide ANCA vasculitis (resistant) It can be used but needs RCTs ANCA vasculitis (maintenance) Superior to azathioprine Key Points

33. Talk Outline • Mechanism of action • Lupus nephritis • ANCA associated vasculitis • Primary glomerular diseases • Thrombotic thrombocytopenic purpura • Renal transplantation –Initiation of remission –Relapsing disease –Resistant disease –Maintenance

36. RITUXVAS trial

37. RITUXVAS trial

38. 2015 Jun;74(6):1178-8 RITUXVAS trial follow up (p=1.00)

39. 2015 Jun;74(6):1178-8 RITUXVAS trial follow up Relapses occurred in seven patients in the rituximab group (21%) and two in the control group (18%) (p=1.00)

40. RAVE trial

41. RAVE trial follow up

44. RAVE trial

49. No suggestion or recommendation for Rituximab.

50. (MAINRITSAN trial)

51. P = 0.002 (MAINRITSAN trial)

52. (MAINRITSAN trial)

53. March, 7, 2017; 18: 112 h t t p : / / c l i n i c a l t r i a l s . g o v / c t 2 / s h o w /NCT01697267.

54. Disease Rituximab use LN (intiation of remission) • In black • Inversely related to BMI • It may allow steroid sparing in children LN (resistant) • It can be used but needs RCTs LN (relapse) • No evidence ANCA vasculitis (initiation) • Not inferior to cyclophosphamide ANCA vasculitis (relapse) • Superior to cyclophosphamide ANCA vasculitis (resistant) • It can be used but needs RCTs ANCA vasculitis (maintenance) • Superior to azathioprine Key Points

56. Talk Outline • Mechanism of action • Lupus nephritis • ANCA associated vasculitis • Primary glomerular diseases • Thrombotic thrombocytopenic purpura • Renal transplantation – Membranous nephropathy – MCD & FSGS – MPGN – IgA – Anti-GBM disease

59. Research recommendations

60. 2017 Jan;28(1):348-358 (GEMRITUX Study Group)

64. Volume 9, 2016 - Issue 11

65. 2017 Sep;28(9):2729-2737 4 weekly doses of 375 mg/m2 RTX infused intravenously

66. 2017 Sep;28(9):2729-2737 The dashed lines describe the events in RTX-treated patients 4 weekly doses of 375 mg/m2 RTX infused intravenously

67. MEmbranous Nephropathy Trial Of Rituximab (MENTOR) Sequential Therapy With Tacrolimus and Rituximab in Primary Membranous Nephropathy (STARMEN) Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO)

68. Disease Rituximab use MN • Superior to NIAT alone • Not inferior to cyclophosphamide with better safety profile • Waiting results of major ongoing trials MCD • Children: SSNS • Adults: FR, SD, SR (needs RCTs) FSGS SD but not SR (case reports) MPGN • In ig-associated MPGN, particularly in:  monoclonal gammopathy  chronic lymphocytic leukemia  cryoglobulinemia with or without HCV • Not in C3GN or DDD IgA Case reports Anti GBM disease Case reports Key Points

71. 2017 Mar 13;4:2054358117698667

72. 2017 Mar 13;4:2054358117698667

74. 2017 Feb; 10(1): 16–19 Outcomes of all adult MCD patients treated with RTX for FRNS between 2008 and 2015were retrospectively analyzed Thirteen patients received RTX The rate of relapse was reduced from 4 to 0.4/year (Wilcoxon signed rank P ≤ 0.05)

75. 2017 Feb; 10(1): 16–19

76. April, 2017, Vol.45, No. 4

77. April, 2017, Vol.45, No. 4

79. Several case reports have described successful use of rituximab in adult patients with steroid- dependent but not steroid-resistant FSGS Oncotarget. 2017 Oct 15;8(55):93438-93443 Clin J Am Soc Nephrol. 2009 Aug;4(8):1317-23 Intern Med. 2012;51(7):759-62 Wien Klin Wochenschr. 2013 Jun;125(11-12):328-33

80. Disease Rituximab use MN • Superior to NIAT alone • Not inferior to cyclophosphamide with better safety profile • Waiting results of major ongoing trials MCD • Children: SSNS • Adults: FR, SD, SR (needs RCTs) FSGS • SD but not SR (case reports) MPGN • In ig-associated MPGN, particularly in:  monoclonal gammopathy  chronic lymphocytic leukemia  cryoglobulinemia with or without HCV • Not in C3GN or DDD IgA Case reports Anti GBM disease Case reports Key Points

82. Studies of rituximab treatment in idiopathic MPGN Rituximab seems to be effective in immunoglobulin- associated MPGN, particularly in those cases associated with: • monoclonal gammopathy • chronic lymphocytic leukemia • cryoglobulinemia with or without HCV Biomed Res Int. May 9; 2017: 2180508.

83. Studies of rituximab treatment in idiopathic MPGN Biomed Res Int. May 9; 2017: 2180508.

84. Reports on rituximab treatment in C3GN and DDD Biomed Res Int. May 9; 2017: 2180508.

87. Mixed cryoglobulinemia syndrome + one or more of the following = immunosuppressive therapy (to rapidly improve TOD, rather than therapy directed at the underlying etiology alone) • Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria • Severe digital ischemia threatening amputation • Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding • Rapidly progressive neuropathy • Central nervous system vasculitis that may present as a stroke or acute cognitive impairment • Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure • Heart failure Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria Severe digital ischemia threatening amputation Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding Rapidly progressive neuropathy Central nervous system vasculitis that may present as a stroke or acute cognitive impairment Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure Heart failure © 2018

88. Rituximab for Severe Mixed Cryoglobulinemia N Engl J Med. 2013 Sep;369(11):1035-45 Autoimmun Rev. 2011 Jun;10(8):444-54 Nephron Clin Pract. 2011;119(2) Immunosuppressive therapy including rituximab or, if unavailable, cyclophosphamide After disease stabilization, patients should receive concurrent therapy for the underlying disorder Exceptions to this general principle include mixed cryoglobulinemia due to HIV or HBV infections; (antiviral therapy should always be initiated before or at the same time as immunosuppressive therapy)

89. Disease Rituximab use MN • Superior to NIAT alone • Not inferior to cyclophosphamide with better safety profile • Waiting results of major ongoing trials MCD • Children: SSNS • Adults: FR, SD, SR (needs RCTs) FSGS SD but not SR (case reports) MPGN • In Ig-associated MPGN, particularly in:  monoclonal gammopathy  chronic lymphocytic leukemia  cryoglobulinemia with or without HCV • Not in C3GN or DDD IgA Case reports Anti GBM disease Case reports Key Points

91. IgA Nephropathy Ther Clin Risk Manag. 2016 Aug 29;12:1317-27

93. Anti-GBM antibody disease Semin Arthritis Rheum. 2013 Jun;42(6):567-72 J Autoimmun. 2015;60:74. Patients who either refuse or, because of severe side effects, need to discontinue cyclophosphamide may receive rituximab therapy or, alternatively, MMF. Several reported cases

94. Anti-GBM antibody disease Semin Arthritis Rheum. 2013 Jun;42(6):567-72 J Autoimmun. 2015;60:74. initial seven consecutive days of plasma exchange and glucocorticoids two rituximab doses another seven days of plasma exchange second of the two doses of rituximab

95. Disease Rituximab use MN • Superior to NIAT alone • Not inferior to cyclophosphamide with better safety profile • Waiting results of major ongoing trials MCD • Children: SSNS • Adults: FR, SD, SR (needs RCTs) FSGS SD but not SR (case reports) MPGN • In Ig-associated MPGN, particularly in:  monoclonal gammopathy  chronic lymphocytic leukemia  cryoglobulinemia with or without HCV • Not in C3GN or DDD IgA • Case reports Anti GBM disease • Case reports Key Points

97. Refractory/ Relapsing TTP Refractory TTP: Progression of clinical symptoms or persistent thrombocytopenia despite seven daily PEX procedures Relapsing TTP: Episode of acute TTP more than 30 d after remission, and occurs in 20–50% of cases. 04 British Journal of Haematology, 2012, 158, 323–335.

98. Refractory TTP British Journal of Haematology, 2012, 158, 323–335. 03

99. Relapsing TTP 03 British Journal of Haematology, 2012, 158, 323–335.

100. Rituximab On admission, in conjunction with PEX and steroids if: acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality (1B). Refractory or Relapsing immune- mediated TTP (1B). Acquired TTP Treatment Other Options 02 British Journal of Haematology, 2012, 158, 323–335.

101. Rituximab for initial therapy of TTP 2011 Aug 18;118(7):1746-53

102. 2011 Aug 18;118(7):1746-53 Rituximab for initial therapy of TTP

103. 2016 Jun 16;127(24):3092-4 Rituximab for initial therapy of TTP

104. 2016 Jun 16;127(24):3092-4 Rituximab for initial therapy of TTP

105. Disease Rituximab use TTP (refractory, relapse) • Good evidence to use TTP (induction of remission) • Ongoing trend Tx • Induction/desensitization in Ab incompatible Tx • Acute and chronic ABMR ??!! • Recurrent GN • PTLD Key Points

107. • Induction/desensitization in Ab incompatible Tx – ABO blood group incompatible transplantation – HLA antibody incompatible transplantation • Acute and chronic ABMR • Recurrent GN • PTLD 2018 Jan;102(1):44-58

108. 2018 Jan 8

109. 2018 Jan 8

110. 2018 Jan 8

111. 2018 Jan 8

112. 2018 Jan 8

113. Disease Rituximab use TTP (refractory, relapse) Good evidence to use TTP (induction of remission) Ongoing trend Tx • Induction/desensitization in Ab incompatible Tx • Acute and chronic ABMR ??!! • Recurrent GN • PTLD Key Points

114. Key Points

115. • Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen on the surface of immature and mature B cells. • It is used in clinical nephrology related diseases & renal transplantation. • It is safe and well tolerated in most. Key Points

116. • Long-term use may be complicated by hypogammaglobulinaemia and increased infectious complications. • Optimal dosing is unclear. • The development of bio-similars and dosing targeted to B-cell response may reduce cost. Key Points

117. Disease Rituximab use LN (intiation of remission) • In black • Inversely related to BMI • It may allow steroid sparing in children LN (resistant) • It can be used but needs RCTs LN (relapse) • No evidence ANCA vasculitis (initiation) • Not inferior to cyclophosphamide ANCA vasculitis (relapse) • Superior to cyclophosphamide ANCA vasculitis (resistant) • It can be used but needs RCTs ANCA vasculitis (maintenance) • Superior to azathioprine Key Points

118. Disease Rituximab use MN • Superior to NIAT alone • Not inferior to cyclophosphamide with better safety profile • Waiting results of major ongoing trials MCD • Children: SSNS • Adults: FR, SD, SR (needs RCTs) FSGS SD but not SR (case reports) MPGN • In Ig-associated MPGN, particularly in:  monoclonal gammopathy  chronic lymphocytic leukemia  cryoglobulinemia with or without HCV • Not in C3GN or DDD IgA • Case reports Anti GBM disease • Case reports Key Points

119. Disease Rituximab use TTP (refractory, relapse) • Good evidence to use TTP (induction of remission) • Ongoing trend Tx • Induction/desensitization in Ab incompatible Tx • Acute and chronic ABMR ??!! • Recurrent GN • PTLD Key Points

120. Thank You

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