IRACON Management of Lupus Nephritis: Old is gold, New is Trendy

Transcription

1 IRACON 2016 Management of Lupus Nephritis: Old is gold, New is Trendy

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3 First episode of LN (III/IV): Induction Low dose is equally considerable as high dose CYC Switch to the other agent if no improvement at 6 months Again, low dose is equally considerable as high dose ACR guidelines, 2012

4 Crescentic LN in ELNT ELNT patients: Few had severe renal disease RPRF >50% segmental necrosis / crescents ACR recommendations: CYC or MMF in same doses as non-crescentic GN i.v. Methylprednisolone pulse 3 doses Oral steroids at 1 mg/kg dose Arthritis & Rheumatism, 2002

5 First episode (Class V): Induction Proteinuria remission rate at 6 months: 70%

6 EULAR recommendations High dose CYC preferable to low dose CYC if: Acute deterioration in renal function Cellular crescents on renal histology Fibrinoid necrosis on renal histology 3 more pulses of i.v. MP if no improvement by 3 months AZA as an induction agent when CYC/MMF are contraindicated

7 First episode of LN (Class II): Induction KDIGO recommendation: Based on proteinuria <1gm/d: Steroids + steroid sparing agent guided by extra-renal manifestations >3gm/d: Steroids + CNIs as in MCD EULAR Recommendation: RAAS blockade Steroids ± AZA if proteinuria 1 gm/d ACR recommendation: Need for immunosuppressive to be guided by extra-renal manifestations

8 N Engl J Med 1978; 299:

9 N Engl J Med 1978; 299:

10 Austin; NEJM NIH Trial Five Protocols for Lupus Nephritis High dose oral Pred for 4-8 weeks than taper 2. Aza + Low dose Pred 3. CyP oral +Pred 4. CyP + Aza + Pred 5. IV CyP + Low dose Pred N Engl J Med 1986; 314:

11 N Engl J Med 1986; 314:

12 2 nd NIH: 3 treatments were compared: Monthly intravenous cyclophosphamide for 6 months, Same followed by quarterly cyclophosphamide pulses for an additional 2 years, Monthly methylprednisolone pulses for 6 months. Pulse methylprednisolone had a higher probability of doubling serum creatinine in comparison with patients assigned to cyclophosphamide. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduced the rate of exacerbations Lancet 1992; 340:

13 3 rd NIH trial: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; Bolus therapy with cyclophosphamide ( g/m2 body surface area), given monthly for 6 months and then quarterly; or Bolus therapy with both methylprednisolone and cyclophosphamide Monthly methylprednisolone was less effective than monthly cyclophosphamide. A non significant trend toward greater efficacy with combination therapy was seen Ann. Intern Med. 1996; 125:

14 Standard of treatment Cyclophosphamide Pulses gm/m 2 monthly pulses = 6 Quarterly pulses X 11/2 year = 6 Six monthly x 1 year = 2 Total = 14 pulses Methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; Ann. Intern Med. 1996; 125:

15 ELNT 90 patients of Proliferative LN High dose CyP Low dose CyP (6 monthly + 2 quar) (6 fortnightly f/b Aza) FU 41 m FU 41.3 m Renal Remiss 59 % 71% (ns) Renal Flare 29% 27% Low dose was comparable to high dose in Caucasians Arthritis Rheum. 2002; 46:

16 Arthritis Rheum. 2002; 46:

17 ELNT - 10 year FU - ESRD Ann Rheum Dis 2010; 69:

18 ELNT Only 22% presented with renal impairment and 28% presented with nephrotic syndrome, compared with 64% and 62% respectively, in the study by Boumpas et al. Milder cases of proliferative lupus nephritis, for which less-aggressive treatment is certainly justified. Few black or African Caribbean patients were included in the ELNT (9% of the cohort)

19 Early Vs current studies

20 Measures Urine analysis RBC s WBC s Casts RBC/WBC Creatinine Proteinuria Part of global outcome indices /measures Renal specific

21 Response criteria used in various trials

22 Guidelines compared Complete response EULAR KDIGO GEAS - upcr <50 mg/mmol [approx. <0.5 g/24 h] - Plus (near) normal (within 10% of normal GFR) renal function - A decline in the upcr to <500mg/g - Plus return of scr to previous baseline - Proteinuria 0.5 g/24h - Plus scr <1.2 mg/dl (or decrease to initial values or ±15% of baseline value in patients with scr 1.2 mg/dl [106 µmol/l]) - Plus inactive urinary sediment ( 5 RBCs/HPF (debatable), 5 WBCs/HPF, 0 RBC casts) - Plus serum albumin >3g/dl Partial response - 50% reduction in proteinuria to subnephrotic levels - Plus (near) normal renal function - It should be achieved preferably by 6 months but no later than 12 months following treatment initiation - 50% decrease in upcr - If there was nephroticrange proteinuria (upcr 3000mg/g), improvement requires a 50% reduction in upcr, and a upcr <3000 mg/g - Plus stabilization (±25%), or improvement of scr, but not to normal - In patients with baseline proteinuria <3.5g/24h, >50% reduction in proteinuria compared to initial values - In patients with 3.5 g/24h, decreased proteinuria <3.5 g/24h - Plus stabilisation (±25%) or improvement in serum creatinine with regard to initial values

23 Where MMF has scored superiority/ non inferior to Cyclophosphamide? 1.Induction - LN 2.Maintenance therapy, 3.Membranous Lupus nephritis(class V) 4.Side effect profile 5.Paediatric LN Pubertal Male

24 Induction ALMS Multicentre MMF(3000mg) Vs IV CYC Pulse Designed as a Superiority trial No difference between two groups in establishing CR Blacks and Hispanics responded better to MMF Asians and Whites failed to show a difference

25 Contrerars et al. Maintenance therapy IV quarterly Cyclo Vs MMF/Aza Conclusion In proliferative lupus nephritis, short-term therapy with iv cyclo followed by maintenance therapy with MMF or AZA appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide

26 MMF as Maintenance Therapy Conclusion: We conclude that mycophenolate mofetil is superior to azathioprine in maintaining the renal response to treatment and in preventing relapse in patients with active lupus nephritis who have had a clinical response to induction therapy with either mycophenolate mofetil or intravenous cyclophosphamide.

27 Annals of Rheumatic Diseases 2015, March Long Term follow up of MAINTAIN cohort fail to unmask differences between MMF and AZA as maintenance therapy of LN

28 Membranous nephritis Uniform recommendations ACR EULAR/EDTA-ERA Recommends Steroids + ACEi + MMF for Class V Lupus nephritis with nephrotic range of proteinuria ±CNI s

29 Side Effect profile of MMF VS Cyclo Gonadal Toxicity

30 Role of MMF is Still Unproven 1.Severe LN 2.LN with extra renal manifestations(nplse) 3.Long term data Single agent which has shown reduction in the incidence of ESRD and CKD

31 LN: Biomarkers to guide therapy Recommended: Renal Biopsy Proteinuria / Spot UPCR Active sediment Serum creatinine / egfr Assessment: At 3 months: Look for non-worsening At 6 months: Look for at least partial response Complete response: May take upto 12 months

32 28 year unmarried postgraduate in medicine presented with nephrotic syndrome Class V lupus nephritis. proteinuria of 2.4 gm/d, no active sediment, normal renal function. serum albumin is 2.5 gm/l. no extrarenal manifestations. What would be the best treatment option in this patient with membranous lupus nephritis? mg/kg steroids with ELNT cyclophosphamide mg/kg steroids with high dose cyclophosphamide mg/kg steroids with Mycophenolate mofetil mg/kg steroids with Rituximab 5. Only RAAS with 0.5 mg/kg steroids

33 A 18 year old girl diagnosed SLE since Nov April 14: proteinuria of 2.7 gms/d, hematuria: rituximab 1 gm with 3 gm iv methylprednisolone pulses. Her proteinuria decreased to 800 mg/d. Therapy was interrupted due to pulmonary tuberculosis. June 14: proteinuria 5 gm/d. MMF started. Jan 15 to Aug 15 proteinuria was 730 mg/d Sep 15: proteinuria 3gm/d due to non-compliance Jan 16: Renal biopsy: Class IV and V LN Jan to Jun 16: received 6.1 gm cumulative cyclophosphamide over 6 months followed by MMF 2 gm/d

34 2/16 3/16 4/16 5/16 9/16 11/16 Urine albumin urine RBC urine puscells nil 9 Urine casts nil nil nil nil nil nil Spot PCR hr urine protein gm/d Drugs cyc cyc cyc cyc--mmfmmf MMF

35 QUESTION TO AUDIENCE 1.Is the patient in remission. 1. Yes 2. No

36 Treatment Strategies 1.Extend treatment with initial regimens 2.Switch to effective alternative regimen 3.Rituximab 4.IV Immunoglobulin 5.Cyclosorine/tacrolimus Underused 6.AHSCT 7.Multitargeted therapy MMF+Tacrolimus+Steroids 8.Plasmapheresis 9.Leflunomide 10.Abatacept

37 Proliferative Lupus Nephritis III/IV Membranous LN MMF + Steroids Cyclo + Steroids MMF+ Steroids RESISTANT RESISTANT Cyclo + Steroids MMF + Steroids Cyclo + Steroids Add or Switch CNI s + Steroids Add or Switch CNI s+ Steroids RESISTANT Switch or Add Rituximab Switch or Add Rituximab

38 Observational studies: Rituximab 11 observational studies (5 retrospective, 6 prospective) patients - >90% refractory 375mg/m 2 * 4 weeks or 1g * 2 Background immunosuppression (CYC/MMF) continued in 8 trials, follow up 6-12 months CR of 36.1%, PR of 37.4% B Duxbury et al. Rituximab in systemic lupus erythematosus: an updated systematic review and meta-analysis. Lupus (2013) 22,

39 Registry data: Rituximab French Autoimmunity and rituximab 23/31 with LN responding UK BIOGEAS and other European cohorts: 126 patients of LN received RTX, either refractory or relapsed, 67% response rates Class V showed least response Terrier B, Amoura Z, Ravaud P, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010; 62: Diaz-Lagares C, Croca S, Sangle S, et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: Pooled data from European cohorts. Autoimmun Rev 2012; 11

40 Randomised controlled trial: LUNAR Biopsy proven lupus nephritis Methyl pednisolone 1g*2 followed by 0.75mg/kg prednisone, MMF3g/day Rituximab 1g D1, D15, D168, D182 Placebo CR, PR and NR at 52 weeks

41 CR PR Overall response

42 LUNAR the flip side or the brighter side? Background immunosuppression Selection of cases induction, Class V LN Differences in partial response Ethnicity differences

43 Post 2013 Intensified B cell depletion therapy RTX : 375 mg/m2 on days 2, 8, 15, and 22. Two more doses: 1 and 2 months following the last weekly infusion. 10 mg/kg cyclophosphamide (days 4 and 17) and 3 iv pulses of 15 mg/kg (days 1, 4, and 8) methylprednisolone followed by oral prednisone, 0.8 mg/ kg/day for 2 weeks rapidly tapered until 5 mg in 3 months. Patients had been followed-up for a mean of 44.5 (24 93)months. Proteinuria (baseline: 4.9 g/24 h; 3 months: 0.97; end of follow-up: 0.22) Of the 12 patients, 9 (75%) have remained well after one cycle of IBCDT, with no flare (mean 51.6 months [25 93]). Three patients relapsed after 36, 41, and 72 months, respectively. Following retreatment, they again showed complete remission over months of observation Autoimmunity Reviews 14 (2015)

44 Long term renal survival: Predictors Lupus, 2016

45 Lupus, 2016

46 Predictors of renal survival: Flares Lupus, 2003

47 Renal survival prediction by biomarkers Cohort 1 n=28 (Pediatric); Cohort 2 n=69 (Adult) Lupus, 2016

48 Renal survival prediction by biomarkers Total follow-up period: 60 months, Mean follow-up period at decline: 6 months Total renal function decline: 29% and 30% Lupus, 2016

49 LN flares: what does the literature say? 42 patients with DPGN Induction with steroids + DMARD 21 for MMF 21 for Oral CYC 6 months 6 months Maintenance: Low dose steroids with azathioprine for next 6 months 6 months 6 months Relapse rate: 15% Relapse rate: 11% NEJM, 2000

50 Predictors and risk of LN flare 55 LN: DPGN 6-9 months oral CYC AZA After 1 year CR: 37 PR: 12 Follow-up: relapse of LN/doubling of Cr Median follow-up: 48 months Risk of renal flare: 6% at 1 year 21% at 3 years 32% at 5 years Median time to flare: 43 months Predictors: ing creatinine High histologic activity score Lower cumulative dose of CYC

51 Euro-Lupus Nephritis Trial LD HD Median Follow-up (months) Treatment failure (%) Renal remission (%) Renal flare rate (%) 27 29

52 LN flares: Conventional serum markers 46 LN patients, Follow-up: 64 months, Relapse: 17 at mean 40 months Lupus, 2003

53 2012 KDIGO Maintenance Therapy No clear guidelines 3.5 yrs mean duration Seven RCTs analysed in KDIGO 1.If CR is achieved to continue for atleast 1 year 2.If PR alone is achieved continue immunosuppressants 3.If frequent relapses continue immunosuppression No evidence regarding conversion of PR to CR

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55 AZA or MMF was prescribed per protocol for 5 years Inefficacy or intolerance Annals of Rheumatic Disease March 2015 The decision to stop or to continue immunosuppressive treatment was left to the patient s and physician s decision.

56 Data from India 9 observational studies (1 prospective) 3 from North, 1 from East, 1 from Central and 4 from South Response rates varying between 45-82% 3 in pediatric lupus nephritis response rates of 85%

57 Comparison of three induction regimens Registry data 40 HD CYC 14 ELNT CYC 20 MMF CR+PR similar between the three groups. (30/40 in the hd cyc group, 12/14 in the elnt cyc group and 15/20 in the mmf group) (p=0.69) Complete response rate was higher in the individuals who received Cyclophosphamide (hd cyc + elnt cyc) as compared to mmf (17/34 vs 2/13, p=0.05). Keerthi T, Varaprasad IR, Uppin M, Rajasekhar L. Outcome of therapy in biopsy proven lupus nephritis with cyclophosphamide or mycophenolate: registry data from a South Indian tertiary care centre. Indian J Rheumatol (Accepted for publication)

58 Kidney International 2016; 89:

59 Screened (n = 173) Biopsy diagnosis of lupus nephritis class III/IV/V Randomized (n = 100) Reasons for exclusion (n = 73) Crescentic LN (n = 24) S.creatinine >265.0 µmol/l (n = 16) Previously received CYC or MMF (n = 21) Refused consent (n = 5) Pregnant (n = 1) CNS or pulmonary lupus (n = 6) 50 assigned to receive low fixed dose intravenous CYC Withdrawn (n = 9) Death (n = 2) Adverse events (n = 3) Lost to follow up (n = 4) 50 assigned to receive MMF as induction agent Withdrawn (n = 8) Death (n = 5) Adverse events (n = 1) Lost to follow up (n = 2) Completed 24 weeks of follow up (n = 41) Completed 24 weeks of follow up (n = 42) Azathioprine (2 mg/kg) + Prednisolone

60 Treatment outcomes at 24 weeks CR+PR CR Graph showing comparison of overall and complete response rates (intention to treat analysis) of subjects in two study groups.

61 Outcomes: 1 year (APP) 69/83 (83%) subjects have completed one year follow-up. Parameters 6 months 12 months CYC (n=34) MMF (n=35) P value CYC (n=34) MMF (n=35) Response 27 (81.8) 28 (80) NS 32 (94.1) 29 (85.3) NS P value Remission 17 (51.5) 21 (60) NS 29 (85.3) 28 (82.3) NS Resistance 6 7 NS 2 6 NS Death 1 4 NS 1 5 NS

62 8 year old boy lupus nephritis Class IV. no hypertension, SPCR 3.5, 24hr UP 0.8 gm, creatinine 0.8 mg/dl, creatinine clearance 85 ml/min. Ht 127 cm, weight 25 kg, BSA gm cumulative CYC over 6 months between May 13 to Oct 13. Maintanence therapy started with azathioprine 50 mg. Feb 14 SPCR was In Jul 16, he developed proteinuria, SPCR 3.9.

63 1.What is the risk of sterility with cyclophosphamide in prepubertal children 1.Risk is minimal 2.Risk increases as puberty approaches 3.Irreversible gonadal toxicity is the rule at all ages 4.Irreversible gonadal toxicity is seen in females.

64 What do the guidelines tell us about the first choice of immunosuppressive in paediatric lupus nephritis? 1.Cyclphosphamide 2.Mycophenolate mofetil 3.Rituximab 4.Tacrolimus

65 Steroids in lupus nephritis- the time line Class IV lupus nephritis Introduction of corticosteroids % 5 year survival 55% 5 year survival Moderate vs high dose glucocorticoids 1976: Pulse methyl prednisolone for DPGN Medium dose with methylprednisone pulses + HCQ vs HC(6mth response: 80% vs 47%) MPA EC with low and high dose GC regimens: 20% CR at 24 weeks in both groups

66 A no steroid regimen Biopsy proven lupus nephritis 58% response rates at 52 weeks Repeat renal biopsy in 13: 8 had D1 and D15 rituximab and methylprednisolone + MMF HR 1 responded to repeat treatment 26% relapse at 72 weeks Remission mean time No response rpt biopsy Ann Rheum Dis 2013;72: Relapse rpt biopsy

67 Low dose rhil-2 in SLE rhil-2 1mIU alternate days for 2 weeks 2 weeks break : 3 cycles Nephritis: 18 & 10 patients with proteinuria: 2.71 & 2.18 gm/day Nature Medicine, 2016

68 Nature Medicine, 2016

69 LN New regimen: Mixed martial arts

70 Individualized therapy in LN

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