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Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club)

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    Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club) Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis (Journal Club) Presentation Transcript

    • Raj Kiran Medapalli, MD, MPH. Nephrology Fellow May 19 th , 2009 Mount Sinai School of Medicine Division of Nephrology Journal Club
    • Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study European Vasculitis Study Group (EUVAS) Annals of Internal Medicine 19 May 2009 Journal Club by Raj Kiran Medapalli, MD
    • Outline
      • Brief introduction to ANCA Vasculitis & CYC.
      • Review of key RCTs for induction & maintenance therapy for ANCA vasculitis.
      • Review CYCLOPS study.
      • Strengths, weaknesses & conclusions from CYCLOPS.
      • Ongoing RCTs.
    • Source: Brenner & Rector's The Kidney, 8 th Edition.
    • Source: Jennette JC & Falk RJ. Small Vessel Vasculitis. NEJM. Nov 1997.
      • Incidence: 20 cases per million individuals per year
      • Most commonly occurs in the elderly (peak age 55–70 years).
      • Before CYC, 2-year survival rates were about 20%.
      • 5-year survival rates now approach 80%.
      • Prevalence is over 200 cases per million individuals.
    • Source: Falk RJ & Jennette JC. JASN. 1997. C-ANCA, anti-Proteinase 3 P-ANCA, anti-Myeloperoxidase Anti-neutrophil cytoplasmic antibodies
    • Source: Xiao H, et al. Am J of Path. Jan 2007.
    •  
    • Cyclophosphamide (Cyc)
      • Alkalyting agent
      • Prodrug
      • Binds & crosslinks a variety of macromolecules including DNA, RNA, & proteins
      • Impairs DNA replication and transcription
      • Wegeners was a fatal dz before CYC emerged in the 1970s.
      • Devastating toxicity, which correlates with cumulative dose.
      Source: UpToDate
      • Bone marrow suppression
        • ~ 5% severe leukopenic events (WBC < 2.0/mm3)
        • IV CYC: WBC nadir within 7- 14 days & BM recovery evident by 21 days.
        • Steroid induced demargination of neutrophils further complicates this.
      • Infection
        • in 45% pts; major bacterial or fungal infxn in 5-21% pts
        • Reactivation of dormant Varicella zoster (8-33%), TB, HPV
      • Infertility
        • 12% in women < 26 yrs old, 27% if 26 to 30 yrs, 62% if > 30yrs.
        • 75% of the men develop severe oligospermia or azoospermia
      • Bladder toxicity
        • Hemorrhagic cystitis: 50% incidence in original NIH study
        • Bladder Ca: 4.8% incidence after 8.5 yrs; 16% at 15 years.
      • Secondary Malignancy
        • Solid malignancies (9.7% incidence over 2 yrs).
        • Myelodysplastic syndrome (8% incidence over 7yrs, 13% if cu.dose > 100g)
        • Acute leukemia, non-Hodgkin lymphoma, multiple myeloma (5/119 vs 1/119 over 10yrs)
      • Teratogenicity
      Source: UpToDate
    • Hoffman GS et al. Annals of Int Med. March 1992.
      • 158 WG pts, referred to NIH during the previous 24 yrs.
      • Mean F/u 8 yrs
      • Treatment
        • 133 pts CYC (2mg/kg/d) + Pred
        • 10 pts only prednisone
        • 8 pts only CYC
        • 6 pts other cytotoxics & pred.
      • CYC given for at least 1 yr after remission. Then tapered by 25-mg decrements every 2 - 3 mths until d/c or dz recurrence required a dose increase.
      • Pred: 1mg/kg/d x 4wks, then 60mg QOD within 1-3 mths & then tapered as tolerated.
      • Conversion to QOD pred median of 3.2 mths.
      • D/c of steroids median of 12 mths.
      • Partial Remission 91%
      • Complete Remission 75%
      • Median time to remission 12 months.
      • Relapse
        • At least 1 relapse in 50% of pts.
        • 44% with > 5 yrs of f/u had remissions > 5 yrs
        • 18.5% with > 10 yrs of f/u had remissions > 10 yrs.
      • Long term renal outcomes
        • 42% pts had CKD. Median creatinine level was 2.55 mg/dL.
        • 17/158 pts (11%) eventually required dialysis.
        • 8 of these pts underwent transplantation, once they were off immunosuppression, with a median f/u 5 yrs. Only 1 pt had recurrent WG with renal impairment.
      • Pts treated with only steroids and CYC did much poorly
      • Complications
      • Death due to Dz/Rx: 13%
      • Permanent disease-related morbidity occurred in 86% pts
      • Secondary malignancies:
        • 2.4 fold overall increase in malignancies (791 vs 333/10000 persons/yr)
        • 11-fold increase in lymphomas
      • Bladder toxicity:
        • 33-fold increase in bladder ca
      • Infections:
        • 46% pts with serious infections (req hosp and IV Rx)
        • 50% of serious infxs occured during daily steroid Rx
        • 21% occurred during QOD steroids.
        • 16% after steroids were stopped
        • 12% in periods without therapy.
      • Reactivation of Herpes Zoster
        • 20-fold increase in Herpes zoster if on CYC and Pred and
        • 10-fold increase in pts on CYC or Pred.
      • Need for less toxic regimens of CYC and/or alternate therapeutic agents
      Hoffman GS et al. Annals of Int Med. March 1992.
    • Pulse Cyc in ANCA Vasculitis - EUVAS meta analysis de Groot K et al. NDT 2001
      • A metanalyses of 3 RCTs comparing at pCYC vs cCYC (2mg/kg/d).
      • Total of 143 pts (101 with WG, 42 with MPA).
      • Different pCYC doses (15mg/kg/pulse, 0.7 & 0.75g/sqm/pulse) & regimens (Q2wks x 3 then Q3wks, Q3wks, Qmonthly).
      • In one study pulse methyl-prednisolone (10mg/kg) was used instead of daily PO steroids (starting dose: 0.85mg/kg to 1mg/kg, varying regimens).
      • Mean f/u ranged from 30 to 43 months in pCYC and 25 to 42 mths in cCYC patients.
      • Results: pCYC vs cCYC
      • Failure to induce remission: OR 0.29 (0.12 to 0.73)
      • Risk of infection: OR 0.45 (0.23-0.73)
      • Leucopenia: OR 0.36 (0.17 - 0.78)
      • Relapse: OR 1.79 (0.85-3.75)
      • No differences in ESRD or Deaths.
      • Significantly lower cumulative dose in pCYC in the 2 studies that reported it - 27.8 vs 31.1g (p<0.001) & - 16.4 vs 38.4g (p<0.001)
    • CYC vs MTX for Induction - EUVAS RCT (NORAM) de Groot K et al. Arth & Rheum Aug 2005
      • 100 pts with WG or MPA
      • Mild or no renal involvement (creat <1.7mg/dl, proteinuria <=1g/d, no RBC casts)
      • Without critical organ manifestations (hemoptysis with b/l infiltrates, cerebral infarction, GIB, pericarditis/myocarditis, rapidly progressive neuropathy).
      • ~ 35% pts had renal involvement & 50% had lung involvement in both groups.
      • 49 pts got oral CYC (2 mg/kg/d) & 51 pts got oral MTX (20–25 mg/wk).Unblinded.
      • Prednisone regimen (1 mg/kg/d, tapered to 15 mg/d at 12 wks & 7.5 mg/d by 6 months, & stopped by 12 mths).
      • All drug treatments were gradually tapered and withdrawn by 12 months.
      • Followup continued to 18 months.
      • Primary end point was the remission rate at 6 months (noninferiority testing).
      • Results MTX vs CYC
      • 6 months remission rate:
        • 89.8% vs 93.5% (p 0.041)
        • MTX grp, remission delayed in pts with more extensive disease (P = 0.04) or pulm involvement (P =0.03).
      • Relapse rate at 18 months:
        • 69.5% vs 46.5%
        • High in both. 12 mth rx not enough.
      • Median time to relapse:
        • 13 mths vs 15 mths (p 0.023)
        • HR 1.85 [95% CI 1.06–3.25].
      • Median cu. dose of steroids
        • 8.8gm vs 6.2gm (p 0.001)
      • Adverse reactions
        • 2 pts from each group died.
        • Leucopenia less in MTX (p 0.012)
        • 4 life threatening infxns in each grp
        • Liver dysfxn > in MTX grp (p 0.036)
    • Adjunctive Plasma Exchange or High-Dosage Solumedrol for Severe Renal Vasculitis. EUVAS RCT (MEPEX) Jayne DRW et al. JASN 2007
      • Background: In a RCT by Pusey et al in 1991, 10/11 pts who were initially dialysis-dependent, recovered renal fxn when rxed with PE & usual Rx as compared to only 3/8 pts who did not get PE. P = 0.041.
      • 137 pts with renal bx proven ANCA associated vasculitis & creat > 5.8 mg/dl or RRT at presentation. Mean age 66yrs.
      • Randomly assigned to receive 7 plasma exchanges (n=70) or 3g of IV Solumedrol (n=67).
      • Both groups received daily CYC & oral prednisolone.
      • Results MP Vs PE
      • 3 month renal survival
        • 49% vs 69% (p 0.02)
      • Progression to ESRD at 12 mths
        • 43% vs 19%
        • Risk Diff: 24% (95% CI 6.1 - 41)
      • 1yr patient survival
        • 76% vs 73% (NS)
      • Severe adverse event rates
        • 48% vs 50% (NC)
      • No sig differences in freq or severity of path lesions at baseline.
    • Azathioprine for Maintainance Rx. (CYCAZAREM) Jayne D, et al. NEJM 2003. EUVAS RCT.
      • 155 pts with creat <5.7mg/dl at onset, treated with cCYC and prednisolone for at least 3months.
      • 61% pts with WG & 39% with MPA.
      • 144 pts who achieved remission were randomly assigned to continued cCYC (n=73,1.5 mg/kg/d) or AZT (n=71, 2 mg/kg/d). Prednisolone (10mg/d) was continued in both groups.
      • Beginning at 12 months, both groups received AZT (1.5mg/kg/d) & prednisolone (7.5 mg/d).
      • Followed for 18 months
      • Relapse was the primary end point.
      • Results AZT vs cCYC
      • Relapse rate
        • 15.5% vs 13.7%. p=0.65
        • Lower among the patients with MPA than WG 8% vs, 18% (P=0.03)
      • Severe adverse effects
        • 8 (11%) vs 7 (10%). p= 0.94
        • Overall 8 deaths (5%), 7 within first 3 months.
        • 7% of AZT pts had an allergic rxn (fever, chills & rash) which lead to drug d/c.
    • AZT vs. MTX for Maintenance Rx. FVSG RCT (WEGENT). Pagnoux C, et al. NEJM 2008.
      • 159 pts with WG or MPA.
      • pCYC (0.6 g/sqm) q2wks x3, then 0.7g/sqm qQ3wks until remission, followed by 3 additional consolidation pulses q3 wkly.
      • Pulse solumedrol x 3 d, followed by PO prednisone (1 mg/kg/d) for 3 wks, then progressively tapered to an avg dose of 12.5 mg/d at 6 months & 5 mg/d at 18 months and complete discontinuation after 24 mths.
      • 129 pts (79%) who achieved were randomized to AZT (2mg/kg/d) or MTX (0.3mg/kg/d, increased in 2.5 mg increments each wk, if tolerated, to a dose of 20 - 25 mg/wk) for 12 months , 2 to 3 weeks after the last pCYC dose.
      • Mean f/u: 29 ± 13 months.
      • Sample size was calculated on the assumption that MTX would be less toxic than AZT.
      • Results AZT vs MTX
      • BVAS at diag: 23.6 vs. 21.2 p=0.07
      • Lung inv: 83% vs. 67% p=0.05
      • Renal inv: 75% in both groups.
      • Creat at entry 1.52 vs.1.4. p=0.56
      • Relapse
        • 23pts vs 21pts. P=0.71
        • 73% had a relapse after study drug discontinuation.
        • ? optimal duration of Rx
      • Adverse events
        • 29 pts vs 35 pts (P = 0.29)
      • Drug d/c or death
        • 7 pts (11%) vs.12 pts (20%). p=0.21.
        • 1 death MTX grp 2/2 aplastic anemia.
        • HR for MTX: 1.65 (0.65 to 4.18)
        • 8% in NORAM (creat <1.7).
    • Pulse vs. Daily Oral Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis The “CYCLOPS” Study European Vasculitis Study Group (EUVAS) Annals of Internal Medicine 19 May 2009
    • Study Design
      • Open-label, multicenter, RCT conducted over 18 months.
      • 149 patients from 42 hospitals in 13 European countries & Mexico.
      • 71 with MPA, 56 with WG & 22 with renal limited vasculitis.
      • Funded by the European Union.
      • Pts were enrolled by their treatment physicians.
      • Inclusion criteria :
        • Newly diagnosed Wegener granulomatosis, microscopic polyangiitis, or renal-limited microscopic polyangiitis.
        • Renal involvement attributable to active vasculitis as defined by at least 1 of the following:
            • Serum creatinine level > 1.7 and < 5.7 mg/dL.
            • Biopsy demonstrating necrotizing glomerulonephritis
            • Erythrocyte casts
            • Hematuria [> 30 erythrocytes per HPF].
            • Proteinuria [>1 g/d]).
        • Confirmatory histology or ANCA positivity.
      • Exclusion criteria :
        • Age younger than 18 or older than 80 years.
        • Coexistence of other multisystem autoimmune disease; hepatitis B or C virus or HIV infection
        • Serum creatinine level > 5.7 mg/dL.
        • Previous cancer.
        • Pregnancy.
    • Intervention Pulse (IV or PO) Cytoxan Daily PO Cytoxan Induction 15 mg/kg IV Q2wkly x 3 doses 2 mg/kg/d, until remission 15 mg/kg IV or 5 mg/kg PO on 3 consecutive days, q3wkly, until remission (physician discretion) Initial maintenance Continue above for 3 months 1.5 mg/kg/d for 3 months Max dose 1.2 g per pulse 200 mg/d Age 60-70 Reduce by 2.5 mg/kg per pulse Reduce by 25% Age >70 Reduce by 5 mg/kg per pulse Reduce by 50% Creat 3.4 to 5.7 Reduce by 2.5 mg/kg per pulse - CBC checks Day 0,10,14 Q wkly x 1 month, Q2wkly x 1 month, then monthly 3 - 4 x 10 9 /L - Withhold dose and resume at a dose reduced by 25 mg/d when WBC > 4 x 10 9 /L 2 - 3 x 10 9 /L Reduce dose by 20% 1 - 2 x 10 9 /L Reduce dose by 40%
      • Induction therapy (continued):
      • Steroids
        • Both groups also received prednisolone, 1 mg/kg orally, tapered to 12.5 mg at the end of month 3 and to 5 mg at the end of the study (month 18).
      • Maintainance therapy :
      • Cyclophosphamide
        • Both groups continued the cyclophosphamide regimens for 3 months after remission.
      • Azathioprine
        • Then switched to Azathioprine, 2 mg/kg per day orally, until month 18. Max daily dose was 200 mg.
      • Prophylaxis
      • PCP prophylaxis was given for all patients.
      • 2-Mercaptoethanesulfonate sodium (Mesna) was optional.
      • Non-responders
      • Pts who did not achieve remission at 9 months were treated according to local practice. Data was collected on these pts but they were censored during survival analysis.
      • No patients received plasmapheresis.
      • Primary outcome
      • Time to remission
      • Secondary outcomes
      • Proportion of patients who achieved remission at 6 & 9 months
      • Proportion with major and minor relapses.
      • Death
      • Change in renal function
      • Adverse events, including leukopenia and infection
      • Cumulative dose of cyclophosphamide and prednisolone
      • Follow-up :
      • Assessed these outcomes at baseline; every 1.5 months until 9 months, then every 3 months until 18 months; and at relapse.
      • Birmingham Vasculitis Activity Score (BVAS) (measures manifestations of active vasculitis during the last 4 weeks) at every visit.
      • Vasculitis Damage Index (measures of cumulative damage from any cause since disease onset), at baseline and every 3 months.
      • Definitions
      • Remission : absence of new or worse signs of dz activity on BVAS & no more than 1 item indicating persistent disease activity (BVAS ≤1).
      • Major relapse : recurrence or first appearance of at least 1 BVAS item indicating threatened vital organ function.
      • Minor relapse : recurrence or1st appearance of at least 3 BVAS items related to nonvital organs.
    • Birmingham Vasculitis Activity Scores (BVAS)
      • Measures manifestations of active vasculitis in the preceding 4 weeks.
      • Ref: Luqmani R.A, et al. Q J Med 1994; 87:671-678.
      • Departments of Rheumatology and Nephrology, University of Birmingham,
      • Edgbaston, West Midlands, UK.
    • Birmingham Vasculitis Activity Scores (BVAS)
      • - Score range: 0 to 63
      • Renal, GI and CNS systems given higher weightage.
    •  
    •  
    •  
    •  
    • Time to Remission
      • 131 pts achieved remission by 9 months.
      • 67 pts [88.1%] in the pulse group vs. 64 pts [87.7%] in the daily oral group.
      • HR: 1.098 [95% CI: 0.78 to 1.55;P = 0.59].
      • Median time to remission was 3 months for both groups (pulse group range: 0.5 to 8 months; daily oral group range: 1 to 7.5 months).
      • Of the 18 pts who did not achieve remission, 5 pts in the daily oral group died, 3 in the pulse group died, and 4 pts in each group withdrew or were lost to f/u.
      • 2 patients did not achieve remission by 9 months but remained in the study; censored becos they did not receive protocol-based treatment.
    • Main Outcome Parameters by Treatment Group
      • Relapse
      • 19 (14.5%) of the 131 patients who achieved remission by 9 months relapsed.
      • 13 (7 with major and 6 with minor relapse) in the pulse group.
      • 6 (3 with major and 3 with minor relapse) in the daily oral group.
      • HR: 2.01 [95% CI, 0.77 to 5.30]. But study not powered to detect this diff.
      • Similar to CYCAZAREM: used a similar cCYC regimen for induction & did
      • not have a consolidation phase.
      • Relapse rate < trials which stopped steroids @ 6(WGET) or 12 mths (NORAM).
    • Main Outcome Parameters by Treatment Group
      • Deaths : 14 died: 5 in the pulse group & 9 in the daily oral group (P = 0.79).
      • Median time to death did not differ: 3.5 mths in pCYC vs 4 in cCYC grp
      • Death associated with active dz or rx in 3 pts in pCYC grp & 7 in cCYC grp
      • Death 2/2 sepsis in 5 of the daily oral group pts & 1 of the pulse group pts.
      • Early deaths before remission similar to CYCAZAREM, but more late deaths after remission [? 2/2 higher % MPA pts (48% vs 39%) who have more chronic lesions than WG, poorer eGFR @entry 37 vs 50ml/min; & more men (59% vs 47%) who have been shown to have greater dz extent in the past].
    • Renal Outcomes
      • eGFR
        • In the pulse group, the median eGFR improved from 32 to 45 mL/min/1.73 m2 (P= 0.010).
        • In the daily oral group, the median eGFR improved from 29 to 45 mL/min/1.73 m2 (P = 0.010).
        • GFR did not differ between study groups at any time point.
      • ESRD
        • 6 pts (5 in the pulse group & 1 in the daily oral group) developed ESRD, 3 pts in the context of uncontrolled disease during induction.
        • The 2 groups did not differ in the development of ESRD (P = 0.105).
    • Measures of disease activity
      • BVAS for new or worse disease decreased promptly with rx & were similar in both groups at all time points.
      • All-cause damage [Vasculitis Damage Index (VDI)], increased in both groups from a median of 0 at entry to 2 at months 6 & 18. NS btwn groups.
      • CRP levels similar in both treatment groups at study start and decreased
      • rapidly in both groups after initiation of induction therapy.
    • Cumulative dose
      • Cyclophosphamide
        • Daily oral group received nearly twice the dose administered to the pulse group (15.9 g vs. 8.2 g; P < 0.001).
      • Prednisolone
        • The groups did not differ in prednisolone dose at any time point, with a mean cumulative dose of about 7.5g in both grps.
    • Adverse events
      • Leucopenia
      • Pts were less likely to have leukopenia in the pulse group than in the daily oral group 26% vs. 45%. P = 0.016.
      • Median time to 1st episode: 219 days vs 68 days. HR: 0.41 (0.23-0.71).
      • Infections
      • Median time to 1st infection: 147 (pCYC) vs 68 days. HR 0.88 (0.42-1.83).
    • Strengths of the study
      • Largest trial to date comparing the efficacy fo pCYC vs. cCYC.
      • EUVAS has the largest experience with RCTs in ANCA-Vasculitis.
      • Funded by the European Union.
      • Used clinically relevant inclusion & exclusion criteria. Renal involment was necessary to be included in the trial.
      • Used a consensus Rx regimen.
    • Weaknesses of the study
      • Not powered to to detect differences in relapse rate which is the key question that needs to be answered. Sample size was determined based on clinical (rare dz: 12/million) & monetary limitations (funding was for 5 yrs only), rather than statistical calculations.
      • 18 month f/u not be enough to determine the optimal duration for therapy (Rx was continued until month 18 in all pts).
      • Not placebo controlled & outcomes were measured by a subjective tool (BVAS), which can lead to bias. (But, no objective bio markers of dz remission & same tools used in all previous trials).
      • The addition of a 3-month consolidation phase to the daily oral cyclophosphamide regimen might bias the results against that group by increasing the risk for hematologic toxicity without improving efficacy.
    • Conclusions
      • pCYC is a reasonable alternative to cCYC for induction of remission in pts with ANCA associated vasculitis & moderate renal dysfunction/ involvement (creat<5.7& no RRT at onset).
      • AZT is a reasonable alternative for maintainace rx after induction with pCYC or cCYC.
      • No difference in rate of remission or time to remission.
      • Cumulative dose was reduced by approximately 50% in the pCYC grp.
      • Fewer episodes of leukopenia and possibly lesser infections, but other side effects not significantly different.
      • pCYC is simpler to monitor, better compliance and also permits pre-hydration and administration of Messna.
      • More relapses with pCYC (NS, but study not powered to detect differences). However, overall the relapse rate was similar to CYCAZAREM which used cCYC and Azathioprine for maintainance.
      • 3-month consolidation phase seems to have little effect on relapse in 18 months and can probably be eliminated, especially in cCYC group.
      • Higher relapse rate in trials that discontinued steroids at 6 months (WGET) & 12 months (NORAM) than in trials that continued steroids for 18 months (CYCLOPS & CYCAZAREM). Optimum duration of Rx remains unclear.
    • Ongoing trials at EUVAS
      • MYCYC: MMF vs. cyclophosphamide for remission induction.
      • IMPROVE: Compares MMF with azathioprine for remission therapy in renal vasculitis. Completed recruitment.
      • RITUXVAS: Rituximab based regimen vs. standard cyclophophamide/ azathioprine regimen in the treatment of active, ‘generalised’ ANCA associated vasculitis. Completed recruitment.
      • REMAIN: Long-term low dose immunosuppression vs. treatment withdrawal for renal vasculitis.
      • STAVE: Meta-analysis of the effect of different corticosteroid dosing regimens on relapses.
    • Summary of Rx options for induction
      • Standard Induction
        • Daily oral cyclophosphamide [2 mg/kg/d]
        • PO Prednisone (1 mg/kg/day, max 60mg/d) x 4 weeks. If significant improvement then taper to 0.25 mg/kg/d by 12 weeks & further as tolerated. Median duration of steroid Rx is 6-12 months, but in CYCOPS & CYCAZAREM continued until 18 months, with better results]
        • Prophylactics:
        • Bactrim SS daily or Bactrim DS q MWF for PCP prophylaxis.
        • In pts allergic to Bactrim: Dapsone (100 mg/day), Atovaquone (1500 mg/day), or monthly aerosolized Pentamidine.
        • Mesna: Binds and detoxifies acrolein. Dose same as the dose of CYC. Give at 0 & 2 hrs (either IV or PO; for PO use, the IV formulation is diluted in soda).
        • Nystatin swish and swallow orally: 600,000 units 4 times/day
        • Sperm cryopreservation + Testosterone 100 mg IM every 15 days in males.
        • Leuprolide 3.75 mg IM monthly in females. Emergency in vitro fertilization can be performed, but requires significant hormonal manipulation and can lead to a three to five week delay in therapy.
        • Calcium 1200mg and Vitamin D 800mg, while on steorids.
        • Pepcid 20mg QD, while on steroids.
      • Alternative induction regimens (to minimize use of Cyc)
      • IV or PO Pulse Cyclophosphamide (EUVAS - CYCLOPS)
        • 15 mg/kg IV Q2wkly x 3 doses
        • Then 15 mg/kg IV Q3wkly or 5 mg/kg PO on 3 consecutive days Q3wkly until remission
        • ? Continue for 3 more months after remission (consolidation phase)
      • Methotrexate (EUVAS – NORAM)
        • In pts with mild or no renal dysfunction (creat <1.7, prot,1g, no RBC casts) and without other critical organ inv.
        • Start PO MTX @ 15 mg/week, if tolerated increase in 2.5mg increments each week to 20–25 mg/week by 12 weeks. Maintain until month 10 & if remission sustained taper by 2.5mg each month until discontinuation.
        • In another study by FVSG (WEGENT), MTX was studied for maintainance only and was started as above after induction with IV pCYC + 3 consolidation doses & tapered after 12 mths (of maintainance rx) and d/c.
      • 7 plasma exchanges, in addition to cCYC & steroids (EUVAS - MEPEX)
        • In patients with severe renal failure (creat > 5.8 or dialysis dependent at presentation) or concomitant anti-GBM abs or pulmonary hemorrhage
    • Rx options for maintainance
      • Cyclophosphamide (Original NIH Study)
        • 1.5 mg/kg per day. Given for at least 1 yr after remission. Then tapered by 25-mg decrements every 2 - 3 mths until d/c or dz recurrence required a dose increase.
      • Azathioprine (EUVAS – CYCAZAREM & CYCLOPS)
        • Start at 2 mg/kg/d for 18 months (reduced to 1.5 mg/kg/d at 1 yr from the time of initiation of cCYC induction therapy in CYCAZAREM).
        • Prednisolone was given at 10mg/d until 1yr, then 7.5mg/d until month 18 in CYCAZAREM.
        • Prednisolone, 1 mg/kg orally, tapered to 12.5 mg at the end of month 3 and to 5 mg at month 18 in CYCLOPS
      • Methotrexate (EUVAS -NORAM & FVSG-WEGENT)
        • As previously described.
        • Leukovorin 10mg Qweekly given 24 hours after MTX.
    • EUVAS Guidelines
    • Thank You.