rituximab vs. cyclophosphamide for induction of granulomatosis with polyangiitis
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Rituximab vs. Cyclophosphamide for Induction of Granulomatosis with Polyangiitis
Sukhjinder SidhuInterior Health Pharmacy Resident
Nephrology RotationMarch 6, 2014
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
WBID 62 y.o. female (46 kg, 102 cm) transferred from VJH on Feb 20 to CTUCC/HPI 2 month hx of:
- weakness- chronic sinusitis with an episode of epistaxis - conjunctivitis- horizontal double vision from dural meningeal inflammation/6th nerve palsy- headache- oral ulcers- feeling of ear fullness & ↓ hearing- ↓ weight (40 lbs over 4 months)- abdominal pain- neuropathy - unsteadiness on feetHx of hematemesis ?GI source ?pulmonary source
Allergies Sulfa – hematuria (Ø SOB, Ø rash)Social Hx Ø smoking x 4 months
Ø EtOHLives in Vernon
Family Hx ØVaccinations Influenza up to date
WBPMHx MPTA
Pancreatitis x 6 months Ø
Type 1 DM x 6 months Aspart 2 units TID with sliding scaleGlargine 10-12 units QPM
HTN Bisoprolol 2.5 mg PO daily
Depression Citalopram 10 mg PO daily
General Health Multivitamin i tab PO daily
Review of SystemsVitals T 36.6 BP 110/71 HR 63 RR 18 O2 sat 99% (RA)
CNS/Neuro Ø
HEENT Right eye – red, proptosis
RESP Ø
CVS Ø
GI Abdomen tender to palpate – worse in epigastric region & RUQ
GU SrCr 77 (baseline 40-55) eGFR 66 (baseline 90 - > 120)
ENDO Ø
MSK/DERM Ø rash; cachetic
CHEM Na 137 K 3.5 Cl 105 Bicarb 28 Urea 8.5 CRP 136Fe 3 Tsat 8% TIBC 38 ANCA +ve PR3 111 MPO 2.5
HEME WBC 12.7 Neuts 7.7 Plts 729 Hgb 97 MCV 81 RDW 20INR 1.1
Urinalysis ACR 21 protein/Cr 73 10-25 rbc/hpf
InvestigationsOct 20/2013 Abdomen/pelvis
CTLung bases clearEnlargement of pancreas
Jan 15/2014 Sinus CT Mild mucosal thickening consistent with chronic sinusitis
Jan 16/2014 Abdomen/pelvis CT
New nodule at left lung basePancreatic tail – schirrhous appearance
Jan 23/12014 Pituitary MRI Thickening and some nodularity of dura – differential includes infectious or inflammatory meningitis and metastases
Jan 31/2014 Abdomen/pelvis CT
Four pulmonary masses- 2 in RUL are large and cavitated
Feb 7/2014 Lung nodule cytology
Malignant cells – negativeAcid fast bacilli – negativeNecroinflammatory debris – consistent with abcess
Feb 17/2014 Chest/abdomen CT
Enlargement of previous cavitating lesions in lungsDevelopment of numerous bilateral nodular densities
Feb 23/2014 Renal biopsy Active focal pauci-immune glomerulonephritis, severe- 40-45% of glomeruli contain active cellular crescents
Current Problems & MedicationsIndication MedicationGPA Methylprednisolone 500 mg IV x 3 doses
Prednisone 50 mg PO dailySteroid-induced OP Alendronate 70 mg PO weekly
Calcium carbonate 2500 mg PO dailyVitamin D 1000 IU PO daily
DM Insulin glargine 16 units SC QAM, 12 units SC QHSInsulin aspart sliding scale
Anemia Ferrous sulfate 300 mg PO dailyPancreatitis Pancrelipase 2-3 tabs PO TID ac, 1-2 tabs PO prn acGIB Pantoprazole 40 mg PO dailyDepression Citalopram 10 mg PO dailyHTN Bisoprolol 2.5 mg PO dailyInsomnia Zopiclone 7.5 mg PO QHSPain Morphine IR 2.5 mg PO BID PRN
Acetaminophen 1000 mg PO QID PRN
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
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.
Granulomatosis with Polyangiitis
Autoimmun Rev. 2010 May;9(7):483-7
Granulomatosis with PolyangiitisSigns/Symptoms
General Arthralgia/arthritis, fever, ↓ weight
CNS Meningitis*, stroke*, cranial nerve palsy*, sensory peripheral neuropathy*HEENT Conjunctivitis, scleritis*, double/reduced vision, proptosis, retinal
exudates/hemorrhage*, deafness*, bloody nasal discharge, nasal crusting/ulcer, rhinorrhea, oral ulcers, sinus involvement, swollen salivary glands, subglottic inflammation
RESP Nodules, cavities or other infiltrate, alveolar hemorrhage*, respiratory failure*
CVS PericarditisGI Mesenteric ischemia, pancreatitis
GU Hematuria* (no RBC casts; > 10 rbc/hpf), RBC casts, ↑ Cr > 30% or ↓ CrCl > 25%
DERM Purpura, skin ulcer, gangrene*
* if new/worse – denotes a major item for assessment of flares
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
Goals of Therapy
• Achieve remission – Prevent further kidney damage– Prevent further extra-renal damage/complications
• Prevent relapse• Prevent mortality• Prevent adverse events
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/m2 IV 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
Clinical QuestionP Female patient with ANCA-positive granulomatosis with polyangitiis presenting
with extrarenal manifestationsI Rituximab therapy with standard glucocorticoid therapy
C Cyclophosphamide therapy with standard glucocorticoid therapy
O Induce remissionPrevent relapse
Prevent mortalityØ Increased risk of adverse events
Literature SearchDatabases PubMed, Embase, Google Scholar
Search Terms Cyclophosphamide/therapeutic UseAntibodies, Monoclonal/therapeutic useImmunosuppressive Agents/therapeutic useANCA/drug therapy
Limits Ø
Results RCT- RITUXVAS- RAVE
RITUXVASD Open-label, two-group, parallel-design, superiority RCT (N=44)
P Inclusion:- New diagnosis of ANCA-associated vasculitis- ANCA +ve- Renal involvement (necrotizing GN on biopsy or red cell casts or hematuria [> 30 rbc/hpf])
Exclusion:- Previous cyclophosphamide use > 2 weeks- Co-existence of another multisystem autoimmune disease
I Rituximab 375 mg/m2 IV weekly x 4 weeks Cyclophosphamide 15 mg/kg IV x 2 pulses
C Cyclophosphamide 15 mg/kg IV Q 3 weeks x 3-6 months Azathioprine until 12 months
O Sustained remission (> 6 months) rates (BVAS = 0) and rates of severe adverse events at 1 year
NEJM 2010;363:211-20
RITUXVAS – Baseline CharacteristicsRituximab (n=33) Cyclophosphamide (n=11)
Age 68 67
Wegener’s diagnosis 55% 36%
ANCA +ve 100% 100%
GFR 20 ml/min/1.73m2 12 ml/min/1.73m2
BVAS 19 18
Dialysis requiring 24% 9%
NEJM 2010;363:211-20
RITUXVAS - Results
NEJM 2010;363:211-20
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)
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
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
RAVED MC, DB, DD, non-inferiority RCT, N=197, duration = 6 months
P Inclusion:- GPA or MPA- Positive serum assay for PR3/MPO-ANCA- New diagnosis or severe disease flareBVAS/WG > 3- Severe disease*
Exclusion:- Churg-Strauss syndrome or anti-GBM disease- Limited disease activity- Alveolar hemorrhage requiring ventilation- SrCr > 354 umol/L- WBC < 4 or platelets < 120- Glucocorticoid use > 14 days- Cyclophosphamide use within 4 months- Previous therapy with rituximab
I Rituximab 375 mg/m2 IV weekly x 4 weeks + placebo
C Cyclophosphamide 2 mg/kg/day PO (adjustments for renal function) + placebo - Option to switch to azathioprine if remission attained between 3-6 months
O Remission of disease (BVAS/WG of 0) without the use of prednisone at six months
* > 1 BVAS/WG major item or severe enough to require treatment with cyclophosphamide
NEJM 2010;363:221-32
RAVE – Baseline CharacteristicsRituximab (n=99) Cyclophosphamide (n=98)
Age at symptom onset 54 + 16.8 51 + 14.1Wegener’s 75% 76%Newly diagnosed 48% 49%BVAS/WG 8.5 + 3.2 8.2 + 3.2Vasculitis Damage Index 1.4 + 1.8 1.0 + 1.4
Constitutional signs or symptoms
56% 66%
Ear, nose and throat involvement
61% 56%
Pulmonary involvement 52% 54%
Renal involvement 66% 66%
CrCl 54 + 3 69 + 4
Neurologic involvement 25% 15%
ANCA-positive 98% 96-100%
NEJM 2010;363:221-32
RAVE - Results
NEJM 2010;363:221-32
RAVE - ResultsRituximab
(n=99)Cyclophosphamide
(n=98)P-value
Primary outcome 64% 53% Non-inferiority: < 0.001Superiority: 0.09
Remission while receiving < 10 mg prednisone
71% 62% 0.10
Severe disease flares 0.011/pt-month 0.018/pt-month 0.81
ANCA negativity 47% 24% 0.004
Selected adverse events* 31 33
Subgroup Analysis
Relapsing disease at baseline
67% 42% 0.01
* 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
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
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
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
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
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
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
Monitoring PlanEfficacy Toxicity
Vital ↑ BPHEENT Improvement/absence of sinusitis,
conjunctivitis, double vision, oral ulcers, ear fullness, ↓ hearingAbsence of epistaxis/ hematemesis
Moon face, cataracts, alopecia
CNS Improvement in weakness Insomnia, shakiness, mood changesCVS EdemaRESP Improvement/no change in pulmonary
nodulesGI Bloated abdomen, nausea, vomiting, ↓
appetiteGU Improvement/no change in SrCr Cystitis, bladder cancerENDO HyperglycemiaMSK/DERM Improvement in neuropathy Muscle wasting, delayed wound healingCHEM/HEME Absence of hematuria, improvement/
stable proteinuria↑ infections, ↓ Hgb, ↓WBC (nadir 8-15 days), ↓ platelets (nadir 10-15 days)
Questions?
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