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Rituximab vs. Cyclophosphamide for Induction of Granulomatosis with Polyangiitis

Rituximab vs. Cyclophosphamide for Induction of Granulomatosis with Polyangiitis. Sukhjinder Sidhu Interior Health Pharmacy Resident Nephrology Rotation March 6, 2014. Learning Objectives. By the end of this 45-min session the audience should be able to:

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Rituximab vs. Cyclophosphamide for Induction of Granulomatosis with Polyangiitis

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  1. Rituximab vs. Cyclophosphamide for Induction of Granulomatosis with Polyangiitis Sukhjinder Sidhu Interior Health Pharmacy Resident Nephrology Rotation March 6, 2014

  2. Learning Objectives • By the end of this 45-min session the audience should be able to: • Describe the pathophysiology of granulomatosis with polyangiitis (GPA) • Describe the clinical presentation of GPA • Be able to explain the evidence for the treatment of GPA • Become aware of the special authority criteria for rituximab

  3. WB

  4. WB

  5. Review of Systems

  6. Investigations

  7. Current Problems & Medications

  8. DRPs • WB is at risk of experiencing worsening GPA symptoms and death secondary to not receiving optimal induction therapy and would benefit from initiation of induction therapy • WB has an elevated blood pressure secondary to the use of glucocorticoids and would benefit from optimization of hypertensive therapy • WB is at risk of experiencing hypoglycemia in the morning secondary to a high dose of insulin at night and would benefit from optimization of insulin management • WB is at risk of steroid-induced osteoporosis secondary to receiving too low a dose of calcium carbonate and would benefit from dose adjustment • WB is at risk of prolonged anemia secondary to a drug-drug interaction between iron sulfate and calcium carbonate and would benefit from changing administration time

  9. Granulomatosis with Polyangiitis • GPA aka Wegener’s • Necrotizing inflammation of small blood vessels • Classic triad of upper and lower respiratory tracts and kidneys • More commonly affecting caucasians with a male: female ratio of 1:1 • Mean age of onset ~40 years Langford CA, Fauci AS (2012). Harrison’s Principles of Internal Medicine, 18e.

  10. Granulomatosis with Polyangiitis Autoimmun Rev. 2010 May;9(7):483-7

  11. Granulomatosis with Polyangiitis * if new/worse – denotes a major item for assessment of flares

  12. Granulomatosis with Polyangiitis • Diagnosis • > 2 of the following: • Abnormal urinary sediment (red cast cells or > 5 rbc/hpf) • Abnormal findings on CXR • Oral ulcers/nasal discharge • Granulomatous inflammation on biopsy • Pauci-immune, segmental necrotizing & crescentic • Consider testing for ANCA • 90-95% positive for PR3-ANCA • 5-10% positive for MPO-ANCA Langford CA, Fauci AS (2012). Harrison’s Principles of Internal Medicine, 18e. Arthritis Rheum 1990 Aug;22(8):1101

  13. Goals of Therapy • Achieve remission • Prevent further kidney damage • Prevent further extra-renal damage/complications • Prevent relapse • Prevent mortality • Prevent adverse events

  14. Therapeutic Approach • Corticosteroids • Methylprednisone 500 mg IV x 3 pulses, then prednisone 1 mg/kg/day PO x 4 weeks & taper over 3-4 months • Immunosuppressants • Cyclophosphamide 0.75 g/m2IV Q 3-4 weeks x 3-6 months • Cyclophosphamide 1.5-2 mg/kg/day PO x 3-6 months • Rituximab 375 mg/m2 IV weekly x 4 doses

  15. Clinical Question

  16. Literature Search

  17. RITUXVAS NEJM 2010;363:211-20

  18. RITUXVAS – Baseline Characteristics NEJM 2010;363:211-20

  19. RITUXVAS - Results Rituximab – 76% Cyclophosphamide – 82% ARR -6% (95% CI, -33 to 21; p=0.68) Rituximab – 42% (1.00/pt-year) Cyclophosphamide – 36% (1.10/pt-year) (95% CI, 0.61 to 1.99; p=0.77) NEJM 2010;363:211-20

  20. RITUXVAS • Author’s conclusions: • The rituximab-based regimen was not superior to the conventional cyclophosphamide regimen when used as induction treatment in patients with ANCA-associated renal vasculitis

  21. RITUXVAS • Strengths • ITT • No patient lost to follow up • All patients were newly diagnosed • Limitations • Unblinded trial • Before enrollment, patients were allowed to receive plasmapheresis or methylprednisolone 2 g IV (max) • Small patient population studied • Long term effects of induction with rituximab not known • Clinical manifestations besides renal involvement unknown • Baseline characteristics appear to be unbalanced • Relapse rates unknown • Generalizability • Included patients with rapidly progressive glomerulonephritis • Large proportion of patients had compromised GFR NEJM 2010;363:211-20

  22. RAVE * > 1 BVAS/WG major item or severe enough to require treatment with cyclophosphamide NEJM 2010;363:221-32

  23. RAVE – Baseline Characteristics NEJM 2010;363:221-32

  24. RAVE - Results NEJM 2010;363:221-32

  25. RAVE - Results * death from any cause, cancer, leukopenia , thrombocytopenia , infections , drug-induced cystitis, VTE, stroke, hospitalization, infusion reactions leading to D/C NEJM 2010;363:221-32

  26. RAVE • Author’s conclusions: • … treatment with rituximab and glucocorticoids is not inferior to standard regimen in patients with severe ANCA-associated vasculitis of recent onset • … the regimen may be superior to the standard regimen of cyclophosphamide and glucocorticoids for remission induction in severe relapsing ANCA-associated vasculitis NEJM 2010;363:221-32

  27. RAVE • Strengths • ITT • Maintained blinding throughout study & no patients lost to follow-up • Crossover patients/withdrawals were accounted for as treatment failures • Patients received standard of care with glucocorticoids • Limitations • Patients included had less severe disease • Powered? • ~50% of patients had relapsing ANCA-associated vasculitis with many having failed cyclophosphamide therapy • Small population studied • Short duration of therapy • Generalizability • Not all patients newly diagnosed • Majority of patients with GPA and extra-renal manifestations • Reserved renal function

  28. KDIGO Guidelines • Cyclophosphamide and corticosteroids as initial treatment (1A) • Rituximab and corticosteroids as an alternative initial treatment in patients without severe disease or in whom cyclophosphamide is contraindicated (1B) KDIGO 2012 Clinical Practice Guideline for Glomerulonephritis

  29. BC PharmaCare • Rituximab requires special authority • Criteria • Induction of remission in severely active GPA or MPA in patients who: • have a severe intolerance/CI to cyclophosphamide • failed an adequate trial of cyclophosphamide • Prescribed by rheumatologist, nephrologist or respirologist • Completion of BVAS

  30. Application • Necessary • +ve ANCA, +ve renal biopsy, clinical manifestations present • Effective • Rituximab is non-inferior to cyclophosphamide in newly diagnosed GPA • Safety • Long-term safety of rituximab unknown • Patient Factors • Cost concerns and doesn’t meet SA criteria

  31. Therapeutic Plan • Received cyclophosphamide 1 g IV • To be followed up in 4 weeks for subsequent dose • Received co-trimoxazole for PCP prophylaxis • Amlodipine 2.5 mg PO daily • Insulin glargine regimen changed to 16 units SC QAM, 9 units SC QHS • Calcium carbonate 1250 mg PO BID • Discontinued ferrous sulfate

  32. Monitoring Plan

  33. Questions?

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