Lupus nephritis

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IT's a presntation to decide induction treatment for lupus nephritis

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Lupus nephritis

  1. 1. Journal of American Society of Nephrology20:1103-1112,2009 SPEAKER MODERATORDR. ANKUR NANDAN VARSHNEY PROF. N. K. SINGH
  2. 2.  Most serious manifestations of SLE It present as microscopic hematuria and proteinuria (>500 mg /24 hrs) Approx half patients develop nephrotic syndrome Hypertension is common If left untreated , virtually all patient of DPGN develops ESRD within 2 years of diagnosisAl Arfaraj AS et al. Rheumatol Int2009 Jul;29(9):1057-67
  3. 3. Class I: Minimal Mesangial Lupus NephritisClass II:Mesangial Proliferative Lupus NephritisClass III: Focal Lupus Nephritis Class III (A): Active lesions—focal proliferative lupus nephritis Class III (A/C): Active and chronic lesions—focal proliferative and sclerosing lupus nephritis Class III (C): Chronic inactive lesions with glomerular scars—focal sclerosing lupus nephritisClass IV: Diffuse Lupus Nephritis class IV-S (A): Active lesions-diffuse segmental proliferative lupus nephritis class IV-G (A): Active lesions-diffuse global proliferative lupus nephritis class IV-S(A/C): Active and chronic lesions-diffuse segmental proliferative and sclerosing lupus nephritis class IV-G(A/C): Active and chronic lesions-diffuse global proliferative and sclerosing lupus nephritis class IV-S(C): Chronic inactive lesions with scars-diffuse segmental sclerosing lupus nephritis class IV-G(C): diffuse global sclerosing lupus nephritisClassV: Membranous Lupus NephritisClass VI:Advanced Sclerotic Lupus Nephritis 90% of glomeruli globally sclerosed without residual activity. Weening JJ et al. J. Am. Soc. Nephrol2004. 15 (2): 241–50.
  4. 4.  High dose immunosuppression is required Cytotoxic agents are given along with high dose steroids Treatment consists of1. Induction phase2. Maintenance phase
  5. 5. Induction CYCLOPHOSPHAMIDE Dose = 500- 750 mg/m2 iv monthly for 6 months ( NIH) 500 mg iv 2 weekly for 6 cycles (European) MYCOPHENOLATE MOFETIL 2 – 3 gm/daily until remission occur High dose steroids are used along Therapeutic responses begin after 3-16 weeks of therapy Maintenance :- 1. MYCOPHENOLATE 1.5- 2 gm /daily 2. AZATHIOPRINE 2mg/kg/DAY  Impovement in 80% of individuals occur in a span of 1-2 years (Chan TM. The American Journal of Medicine2012;125:642-648)
  6. 6.  A nitrogen mustard alkylating agent from the oxazophorines group Mechanism : a metabolite called phosphoramide mustard which forms cross links both between and within DNA strands at guanine N-7 position leading to cell death Side effects- infections ,bone marrow suppression, ovarian and testicular failure*, alopecia, hemorrhagic cystitis, bladder carcinoma, teratogenic, malignancy, nausea, diahorrea*54% by McDermott et al. Ann Rheum Dis 1996; 55: 224-229*26% by Mok CC et al. Arthritis and rheumatism 1998;41:831-837
  7. 7.  A prodrug of mycophenolic acid Mechanism : inhibitor of inosine monophosphate dehydrogenase which helps in purine synthesis needed for growth of B cells and T cells Side effects – infections, bone marrow suppression, lymphoproliferative disorders, alopecia, GI symptoms, hypokalemia, hypercholesterolemia, teratogenic
  8. 8. Journal of American Society ofNephrology 20:1103-1112,2009
  9. 9.  Chan TM , Li FK , Tang CSO, et al. Efficacy of mycophenolate mofetil in diffuse proliferative lupus nephritis. N Engl J Med.2000;343;1156-1162 showed that prednisolone + MMF and prednislone + cyclophosphamide are equally effective (n=42) Ong LM , Hooi LS , Lim TO, et al .randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis . Nephrology,2005; 10; 504-510 showed that prednisolone + MMF and prednisolone + pulse cyclophosphamide are equally effective (n=44) Ginzler EM , Dooley MA , Aranow C , et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005; 353 ;2219-2228 showed that prednisolone + MMF is more effective than prednisolone + pulse cyclophosphamide (n=140 )
  10. 10.  A prospective, randomized, open label, parallel – group, multicentre study Hypothesis was stated that more patient with lupus nephritis would respond to MMF than to Cyclophosphamide during 24 weeks
  11. 11.  Patients aged between 12 yrs and 75 yrs Diagnosis of SLE by ACR criteria (Hochberg MC. Arthritis Rheum 40:1725,1997) Lupus nephritis( active, active/chronic) as confirmed by renal biopsy as ISN class III , IV-S, IV-G, V, III+V ,IV+V within 6 months before randomization Must have clinically significant level of proteinuria ( atleast 2g/day)
  12. 12.  Treatment with either MMF or cyclophosphamide within the previous year Continuous dialysis for > 2 weeks before randomization or anticipated duration longer than 8 weeks Pancreatitis Gastrointestinal hemorrhage within 6 months or active peptic ulcer within 3 months Severe viral infection Severe cardiovascular disease Bone marrow insufficiency with cytopenias not attributable to SLE Current infection requiring iv antibiotics
  13. 13.  Stratified by race and biopsy class, patients were randomly assigned to treatment with MMF and cyclophosphamide in a ratio of 1:1 Cyclophosphamide was given in monthly pulses of 0.5- 1 g/m2 as per NIH protocol Oral MMF was given twice daily as 0.5 g in first week, 1.0 g in 2nd week, 1.5 g in 3rd week. Dose were decreased to 2 g /day in response to adverse effect Both groups received oral prednisone
  14. 14.  Induction period was defined as 24 weeks based on prior studies to predict outcome and minimizing adverse effect.(conteras et al;NEJM350:971-980,2004. Houssiau et al;arthritis rheu 50:3934-3940,2004) Patients were assessed at 2nd week , 4th week and then every 4 weekly Patients were withdrawn if1. At week 12 there serum creatinine was >30% above baseline on two successive measurements separated by at least 12 weeks2. When they required other immunosuppressive therapy3. If MMF dosage fell below 2 g/day for >14 days or was stopped for >7 days
  15. 15. Patient disposition. *Hepatitis/cytomegalovirus infection (n = 16) or other illness (n = 4). Appel G B et al. JASN 2009;20:1103-1112©2009 by American Society of Nephrology
  16. 16. Characteristic MMF(n=185) Cyclophosphami Total(n=370) deGender (n [%]) male 28 (15.1) 29 (15.7) 57 (15.4) female 157 (84.9) 156 (84.3) 313 (84.6)Race (n [%]) white 75 (40.5) 72 (38.9) 147 (39.7) Asian 62 (33.5) 61 (33.0) 123 (33.2) other 48 (25.9) 52 (28.1) 100 (27.0)Ethnicity (n [%]) Hispanic 64 (34.6) 67 (36.2) 131 (35.4) non- 121 (65.4) 118 (63.8) 239 (64.6)Hispanic
  17. 17. Characteristic MMF Cyclophosphamide TotalRegion (n [%]) Asia 57 (30.8) 60 (32.4) 117 (31.6) Latin America 56 (30.3) 50 (27.0) 106 (28.6) United 37 (20.0) 38 (20.5) 75 (20.3)States/Canada rest of world 35 (18.9) 37 (20.0) 72 (19.5)Renal biopsy class(n [%]) III/III + V 32 (17.3) 26 (14.1) 58 (15.7) IV/IV + V 124 (67.0) 128 (69.2) 252 (68.1) V only 29 (15.7) 31 (16.8) 60 (16.2)Scarring on renal 66 (35.7) 56 (30.3) 122 (33.0)biopsy (n [%])Serum creatinine 108.6 ± 1.2 92.7 ± 1.0 (56.9 ± 100.6 ± 1.1(μmol/L [mg/dl]; (97.2 ± 1.1) 0.6) (80.0 ± 0.9)mean ± SD)Urine 4.1 ± 4.2 4.1 ± 3.2 4.1 ± 3.7protein/creatinineratio (mean ± SD)
  18. 18. Characteristic MMF Cyclophosphamide TotalRange of GFR (ml/min per1.73 m2; n [%]) ≥90 80 (43.2) 86 (46.7) 166 (45.0) ≥60 to <90 53 (28.6) 52 (28.3) 105 (28.5) ≥30 to <60 32 (17.3) 34 (18.5) 66 (17.9) <30 20 (10.8) 12 (6.5) 32 (8.7)Range of anti-dsDNAantibody titer (IU/ml; n[%]) <30 (negative) 32 (18.4) 23 (13.5) 55 (15.9) 30 to 60 (low 25 (14.4) 24 (14.0) 49 (14.2)positive) >60 to 200 52 (29.9) 40 (23.4) 92 (26.7)(positive) >200 (strong 65 (37.4) 84 (49.1) 149 (43.2)positive)Range of C3concentration (g/L; n [%]) >1.8 1 (0.6) 1 (0.6) 2 (0.6) 0.9 to 1.8 50 (28.4) 34 (19.5) 84 (24.0)(normal) <0.9 (low) 125 (71.0) 139 (79.9) 264 (75.4)
  19. 19. Characteristic MMF(n=185) Cyclophosphami Total de(n=185) ( n=370)Range of C4concentration(g/L; n [%]) >0.47 2 (1.1) 1 (0.6) 3 (0.9) 0.16 to 70 (39.8) 47 (27.2) 117 (33.5)0.47 (normal) <0.16 104 (59.1) 125 (72.3) 229 (65.6)Age at 32.4 ± 11.2 31.3 ± 10.3 31.9 ± 10.7enrollment (yr;mean ± SD)Age at diagnosis 30.2 ± 11.0 28.8 ± 10.2 29.5 ± 10.6of lupusnephritis (yr;mean ± SD)Time since 1.0 (1 to 21) 1.0 (1 to 23) 1.0 (1 to 23)diagnosis oflupus nephritis(yr; median[range])
  20. 20.  RESPONSE : defined as1. Decrease in urine protein/creatinine ratio to < 3 in patients with baseline range >32. By > 50% decrease in patients with subnephrotic baseline protein/creatinine ratio (<3)3. Stabilization or improvement in serum creatinine NON RESPONDER : defined as1. Received pulse methylprednisolone for any renal or extra renal flare2. Who did not complete 24 week induction therapy
  21. 21.  Key secondary end points included ◦ the proportion of patients who achieved complete remission, defined as return to normal serum creatinine, urine protein <0.5 g/d, and inactive urinary sediment (<5 white blood cells per high-power field and <5 red blood cells per high-power field, and a reading of lower than 2 on dipstick and absence of red cell casts); ◦ proportion of patients who achieved any one of these renal outcomes; combined renal and extrarenal remission, defined as absence of A and B scores on the British Isles Lupus Assessment Group system; ◦ mean change on the Safety of Exogenous Estrogens in Lupus Erythematosus National Assessment/Systemic Lupus Erythematosus Disease Activity Index
  22. 22. Response rates of study population and by racial group. Appel G B et al. JASN 2009;20:1103-1112©2009 by American Society of Nephrology
  23. 23. Parameter MMF ( n= 185) Cyclophosphami Odd’s Ratio de ( n= 185 ) (95% CI)Responders with 88 (56.4) 83 (53.9) 1.1(0.7 to 1.8)renal biopsyclass III or IVPatients with 16 (55.2) 15(48.4)class VRenal remissioncriteriaSerum creatinine 130 (70.3) 125 (67.6) 2.7(-6.7 to 12.1)Urine protein 44 (23.8) 50 (27) -3.2(-12.1to 5.6)Urine sediments 58 (31.4) 44 (23.8) 7.6(-1.5to16.6)All three 16 (8.6) 15 (8.1) 0.5(-5.1to6.2)
  24. 24. parameter MMF Cyclophosphami Total deRenal and extra 54(29.7) 45(24.9) 4.8(4.3 to 14)renal remissionAbsence ofBILAG scoreSELENA-SLEDAI -6.2 +/- 10.1 -6.6 +/-8change in scorefrom baseline toendpointAnti-DsDNA 117(67.2) 124(72.5)>60 at baselineAnti-DsDNA>60 72(41.4) 91(53.2)at end pointLow C3 at 125(71) 139(79.9)baselineLow C3 at end 70(39.8) 90(51.7)pointLow C4 at 104(59.1) 125(72.3)baselineLow C4 at end 51(29) 72(41.6)point
  25. 25. Parameter MMF (n= 185) Cyclophosphamide ( n= 185)Completed 24 week open label induction 150 (81.1) 156 (84.3)phaseWithdrawn prematurely 35 (18.9) 29 (15.7)Reasons for withdrawlAdverse event 21 (60) 12(41.4)Deteoriation with respect to serum 0 2 (6.9)creatinine after 12 and 16 weekDosage reduction of MMF <2g/d for >14 1(2.9) 0dayLost to follow up 1(2.9) 2(6.9)Patient died 3 (8.6) 1(3.4)Withdrew consent 6 (17.1) 5 (17.2)Physician decision 1 (2.9) 3 (10.3)Sponsor decision 2 (5.7) 1 (3.4)Non compliance 0 1 (3.4)Reason not noted 0 2 (6.9)
  26. 26. Parameter MMF (n=184) Cyclophosphamide (n=180)Deaths 9 (4.9) 5 (2.8)Withdrawals as a result 24 (13.0) 13 (7.2)of AEsAll AEs 177 (96.2) 171 (95.0) diarrhea 52 (28.3) 23 (12.8) headache 38 (20.7) 47 (26.1) peripheral edema 35 (19.0) 30 (16.7) arthralgia 29 (15.8) 43 (23.9) nausea 27 (14.7) 82 (45.6) hypertension 26 (14.1) 25 (13.9)
  27. 27. Parameter MMF Cyclophosphamide 25 (13.6) 29 (16.1)nasopharyngitis vomiting 25 (13.6) 68 (37.8) cough 24 (13.0) 16 (8.9) anemia 23 (12.5) 12 (6.7) alopecia 20 (10.9) 64 (35.6) abdominal pain 19 (10.3) 13 (7.2) back pain 19 (10.3) 16 (8.9) muscle spasms 19 (10.3) 17 (9.4) rash 19 (10.3) 21 (11.7)urinary tract infection 19 (10.3) 17 (9.4)
  28. 28.  MMF did not show any superiority over cyclophosphamide for induction therapy for lupus nephritis However, there were important racial differences as the Blacks and Hispanics who are at increased risk of aggressive disease, responded more to MMF than cyclophosphamide Though the most common side effects were infections and GI side effects that occur comparatively in both groups, alopecia an undesirable side effect occur mainly in cyclophosphamide group
  29. 29.  Convenience of twice daily oral medication versus hospitalization for monthly infusion for cyclophosphamide was not addressed Impact of cyclophosphamide to cause ovarian dysfunction on women of child bearing age was not discussed 24 weeks may be too short to differentiate between treatments as disease may continue to improve and side effects may continue to emerge later with cyclophosphamide (Ioannidis et al. Kidney Int 57:258-264,2000)
  30. 30.  Conteras et al. N Engl J Med.2004;350:971-980Showed in a randomized trial (n=59) that 72 month survival rate free of renal failure higher in MMF and AZA group than quarterly cyclophosphamide group Houssiau et al. Ann Rheum Dis.2010;69:2083- 2089 showed in a randomized trial (n=105) that MMF not more effective than AZA in prolonging time to renal flare
  31. 31. Dooley et al.N Eng J med2011;365:1886-95
  32. 32.  Mycophenolate was superior to azathioprine in maintaining a renal response to treatment and preventing relapse in patients with lupus nephritis who had a response to induction therapy
  33. 33.  LUNAR study: a trial on stage III and IV lupus nephritis showed that add on rituximab had no clinical impact in patients treated with corticosteroid and MMF.(Furie et al.Ann Rheum Dis.2010;69(suppl 3):549a EXPLORER study : Rituximab(anti CD20 monoclonal antibody) showed an impact on serological parameters but not on clinical efficacy in patients with active nonrenal lupus.(Merrill et al.Lupus.2011;20:709-716)
  34. 34.  A phase III trial with Belimumab (a monoclonal antibody against the ligand of BlyS/BAFF receptor on B cells that promotes B cell survival and differentiation to plasmablasts) showed efficacy with extrarenal lupus but there is insufficient data in lupus nephritis.(Navarra et al.Lancet.2011;377:721- 731)
  35. 35.  On the basis of above studies, physicians may consider MMF as an alternative to Cyclophosphamide in induction treatment of lupus nephritis depending upon:1. Adverse effects2. Socioeconomic factors3. Racial factors(Chan TM. The American Journal of Medicine2012;125:642- 648)

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