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Transcript of Review and Treatment Advances - Loyola University...
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Granulomatosis with Polyangiitis:
Review and Treatment AdvancesRichard Hariman MD
Assistant Professor of MedicineDivision of Rheumatology
Medical College of Wisconsin
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Disclosures
• None
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Outline
• Introduction• History• Pathogenesis• Clinical Features• Diagnosis• Recent Treatment Advances
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What is the new acronym for Wegener’s?
a) MPAb) GPAc) EGPAd) PANe) IDK
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ANCA associated vasculitides
• Microscopic Polyangiitis• Granulomatosis with Polyangiitis (Wegener’s)• Eosinophilic Granulomatosis with Polyangiitis (Churg‐Strauss)
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Robbin’s Textbook of Pathology
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Granulomatosis with polyangiitis
• Multisystem autoimmune disease of unknown etiology
• Previously referred to as Wegener’s granulomatosis
• Necrotizing granulomatous inflammation and pauci immune vasculitis in small and medium sized blood vessels
• Associated with PR3‐ANCA
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Epidemiology
• Incidence in US is 3 cases per 100,000 people• More common in northern European descent (approximately 90%)
• M:F ratio of 1.5:1• Women more likely to have limited disease• Typical age of onset 35‐55 years
• very rare to have onset in childhood• Five‐year survival 87%
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History
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History• 1897: Peter McBride, Scottish otolaryngologist
– Description of a patient with Wegener’s type symptoms in a BMJ article
• 1931: Heinz Karl Ernst Klinger – Described a 70 y/o physician
• Constitutional symptoms, joint symptoms, proptosis, widespread upper respiratory tract inflammation with saddle nose deformity, GN and pulmonary lesions
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History cont’d
• 1954: Goodman and Churg provided the definitive description based:(1) systemic necrotizing angiitis(2) necrotizing granulomatous inflammation
of the respiratory tract(3) necrotizing glomerulonephritis
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Who was Wegener?
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Friedrich Wegener
• German pathologist and Nazi Party Member
• Described 3 patients and published their distinct clinical and histopathologic findings in 1936
• In 1932 he joined the Sturmabteilung, also known as the "brown shirts," which terrorized Adolf Hitler's opponents
• As the city's pathologist, Wegener performed autopsies on people who died in the ghetto.
Minnesota Public Radio May 18th, 2011
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History behind name change
• Shift in medicine to stop using eponyms and use more scientifically descriptive names– e.g. Reiter's Syndrome
• Jan 2011 recommendations by American College of Rheumatology, American Society of Nephrology, and EULAR recommended name change to Granulomatosis with Polyangiitis (GPA)
• American College of Chest Physicians rescinded their Master Clinician Award given to Friedrich Wegener in 1989
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Google images
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Pathogenesis
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Question
• True or False?• A negative ANCA rules out Granulomatosis with polyangiitis.
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Pathogenesis• Risk Factors
• Infection
• Genetic• MHC class II allele HLA‐DRB1‐15 in African Americans
• Environmental
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Mechanism of injury
• Tissue injury results from interplay between an initiating inflammatory event and a highly specific immune response
• The immune response is directed against previously shielded epitopes of neutrophil granule proteins leading to autoantibodies or ANCAs– ANCAs are directed against antigens present within the primary granules of neutrophils and monocytes
– Produce tissue damage via interactions with primed neutrophils and endothelial cells
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Images from Genentech
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, , ,
B os c h, X. et a l. J AMA 20 07 ;29 8: 655 -6 69
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Antineutrophil cytoplasmic antibodies
Cytoplasmic (C‐ANCA) Perinuclear (P‐ANCA)
Anti‐proteinase 3 (PR3‐ANCA): neutrophil azurophilic granule constituent
Anti‐myeloperoxidase (MPO‐ANCA): lysosomal granule constituent involved in oxygen free radicals
Associated with granulomatosis with polyangiitis
Associated with microscopic polyangiitis and churg‐strauss disease
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Immunofluorescence testing
C- ANCACytoplasmic staining
P- ANCAPerinuclear staining
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Caveats on immunofluorescence testing
• Subjective component based upon visual interpretation of the IF pattern
• No standardization• Not highly specific (further ELISA testing)• Pretest probability important
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ELISA testing
• C‐ANCA should be directed against PR3• P‐ ANCA should be directed against MPO• If they do not match think about drugs (cocaine), false positives, or other causes
• 10% of patients with GPA or MPA can be ANCA negative
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Pathologic role of ANCA• Best support comes from animals and in vitro experiments– Mouse models provide evidence that anti‐MPO antibodies induce necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis
– In vitro data showing PR3‐ANCA causing leukocyte activation
– Human evidence: Mother with anti MPO ANCA active disease delivered newborn who developed pulmonary renal syndrome
Schlieben Am J Kidney Disease 2005
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Does ANCA predict flares
• Largest study looking at this was done with information obtained during Wegener’s Granulomatosis Etanercept Trial (WGET)
• 180 patients with serum samples drawn at three‐month intervals and ANCA assays performed at the Mayo Clinic
• Decreases in PR 3 levels were not associated with shorter times to remission, and increases in PR3 were not predictive of relapse in one year
Finkielman et al. Ann Intern Med. 2007;147(9):611
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Does ANCA predict flares
0102030
405060
70
Increase inANCA
No increasein ANCA
Total numberRelapse
Finkielman et al. Ann Intern Med. 2007;147(9):611
Looking at PR3
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Does ANCA predict flares
• Easy answer –No
• Complicated answer– In some patients it does correlate and can help to identify when to initiate treatment earlier
– Treatment changes are NOT made based just on a rising ANCA but may choose to increase monitoring in someone who has had previous flares correlating with increasing ANCA
Finkielman et al. Ann Intern Med. 2007;147(9):611
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Clinical Features of GPA
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Case
• 26 yo M is evaluated for a 3 month history of epistaxis and a 1 month history of intermittent night sweats and cough. He’s also had a few episodes of hemoptysis and notes some shortness of breath when walking 2 blocks.
• What clinical features should be looked for?
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Clinical features of GPA• Constitutional symptoms• ENT
– Chronic sinusitis, rhinitis, epistaxis, saddle nose deformity, conductive and sensorineural hearing loss, tracheal or subglottic granulomatous masses
ACR Slide Collection 2009
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Clinical features of GPA
• Pulmonary– Range from asymptomatic to acute fulminant involvement
– Pulmonary infiltrates, nodules, diffuse alveolar hemorrhage
Pic from UpToDate
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Clinical features of GPA
• Renal – Asymptomatic usually– Active urinary sediment with RBC casts and proteinuria
– Biopsy reveals segmental necrotizing glomerulonephritis with few or no immune deposits (pauci‐immune) and crescents commonly present
Pictures from www.clevelandclinicmeded.com and UptoDate
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Clinical features of GPA• Optho
– Conjunctivitis, episcleritis, uveitis, optic nerve vasculitis, retinal artery occlusion, proptosis
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Clinical features of GPA• Nervous system
– Mononeuritis multiplex, sensorimotor PN, and cranial nerve palsies, vasculitis of brain or spinal cord with granulomatous masses affecting different areas
• Derm– Most commonly leukocytoclastic vasculitis, palpable purpura or skin ulcers
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Clinical features cont’d• MSK
– Arthralgias more than arthritis• Cardiac
– Rarely detected ante mortem but pericarditis and coronary arteritis seen in 10‐20% of cases which can lead to MI or sudden death
• Heme– Hypercoaguable state leading to PEs, etc.
• Less commonly can involve GI, lower GU tract, parotid glands, thyroid, liver, or breast
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Classification of GPALimited Disease Systemic Disease‐Findings largely isolated to upper and lower respiratory tracts‐More often women‐More often ANCA negative‐More often to have chronic recurring disease and destructive upper airway lesions (saddle nose)
‐Significant multi system manifestations affecting lungs, kidneys, other organs in addition to respiratory tract
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EULAR classification of GPA
Eular Recommendations for management of primary small and medium vessel vasculitis 2009
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Diagnosis
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Diagnosis
• Based on clinical symptoms• ANCAs can aid diagnosis• Biopsy: necrotizing granulomas
– Lung– Kidney– Sinus
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• The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92%• Criteria developed before ANCA testing in wide spread use
Leavitt Arthritis Rheum 1990
1990 ACR CriteriaNasal or oral inflammation
‐Development of painful or painless oral ulcers or purulent or bloody nasal discharge
Abnormal chest radiography findings‐Nodules, fixed infiltrates, or cavities
Abnormal urinary sediment ‐Microhematuria (>5 RBCs per high‐power field or RBC casts in urine sediment)
Granulomatous inflammation on biopsy‐Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area
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Chapel Hill nomenclature• Provided names and definitions for GPA, MPA and Churg‐Strauss
• Not intended to establish diagnostic criteria• GPA, MPA, and CSS distinguished from other systemic small vessel vasculitides by absence of immune deposits
• MPA distinguished from GPA and CSS by absence of granuloma formation
• Potential value of ANCA serology was noted
Jennette Arthritis Rheum 1994
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Where the classification is heading…• There is a push for new criteria which is heavily weighted on
ANCA type– PR3 ANCA disease– MPO ANCA disease– Seronegative ANCA disease
• GPA and MPA are clinical and pathologic phenotypes but are poor predictors of natural history of these two diseases compared to ANCA serotype
• Patients with ANCA’s act more similarly and therefore can get more information regarding response to treatments and relapse potentials than with GPA vs. MPA– Example: PR3 ANCA positive patients more likely to relapse
Falk J Am Soc Nephrology 2010
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Differential diagnosis
• Pulmonary Renal syndromes– Goodpasture Syndrome
• Lack of upper airway involvement• Anti GBM antibodies• Deposition of immune complexes in basement membrane on renal biopsy
• Microscopic polyangiitis • Churg Strauss
– More asthma and eosinophilia• Cocaine‐Induced• Relapsing polychondritis
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Cocaine induced midline destructive lesions (CIMDL)
• Can mimic limited GPA clinically• Associated with positive ANCA tests but usually not directed
at PR3 or MPO and more likely to be directed at human neutrophil elastase
• Important to identify because treatment is different –immunosuppressants will NOT improve process
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Treatment
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Case cont’d
• On physical exam he has a large perforation of the nasal septum. He has some rhonchi on lung exam and is noted to have few purpuric lesions on his legs.
• Urinalysis shows 3+ protein, erythrocytes, and erythrocyte casts. CT scan of the chest reveals b/l cavitary nodules.
• He’s diagnosed with granulomatosis with polyangiitis.
• He wants to know what treatment options are available to him?
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History of treatments• Prior to any available treatments mean survival 5 months
– 82% died in first year– 90% died by second year
• With glucocorticoids mean survival 12.5 months• With addition of cytotoxic therapy survival improved
– 1954 First report of using cytotoxic agent• 38 yo male treated with nitrogen mustard with good improvement in his condition
• Other reports of tx with alkylating agents, folic acid, and purine antagonists alone or in combination with corticosteroids showed some clinical responses and significant long term remissions
Facuci et al. Ann of Int Medicine 1983
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Cyclophosphamide
• 1971 Novack published landmark study describing 4 patients with GPA who improved with cyclophosphamide therapy + corticosteroids
• 1983 Fauci showed a 93% complete remission rate in 85 patients treated with steroids + cyclophosphamide
• Mean duration of remission was 48.2 months
Facuci et al. Ann of Int Medicine 1983
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Serial CXRs – cyclophosphamide started on 8/10
Novack NEJM 1971
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Issues with cyclophosphamide
• 185 pts followed at NIH for 6‐24 years (1229 patient years)
• Standard treatment protocol– Cyclophosphamide 2 mg/kg day for at least 1 year after complete remission and then tapered by 25 mg decrements every 2‐3 months until discontinuation or until disease recurrence
– Steroids 2‐15 mg/kg for a few days and then daily prednisone for 4 weeks and then 60 mg alternate day therapy and tapered as able (usually off by 12 months)
Hoffman Ann Int Med 1992
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Issues with cyclophosphamide
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PartialRemission
Completeremission
Relapses Death from allreasons
morbidity fromdisease
Morbidity from tx
% pts
It works!
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Morbidity issues• Morbidity of Disease
– Chronic renal insufficiency (42%)
– Hearing loss (35%)– Cosmetic and functional nasal deformities ( 28%)
– Tracheal stenosis (13%)– Visual loss (8%)– Chronic sinus dysfunction (47%)
– Pulmonary insufficiency (17%)
• Morbidity of Treatment– Hair loss (17%)– Fertility issues (57%)– Cyclophosphamide cystitis (43%)– Bladder cancer (2.8%)– 2.4 fold increase in malignancies– Serious infections (46%)– Myelodysplasia (2%)– GC induced cataracts (21%)– Fractures (11%)– AVN (3%)– GC induced DM (8%)
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How to minimize toxicity?
Oral vs. Intravenous Cyclophosphamide
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• Open label study of 149 patients with newly diagnosed generalized ANCA associated vasculitis with renal involvement which was not immediately life threatening
• Pulse cyclophosphamide 15 mg/kg every 2‐3 weeks vs. daily oral cyclophosphamide 2 mg/kg per day continued for 3 months after remission obtained and then switched to azathioprine for maintenance until month 18
• Both groups given steroids for entire course of study (18 months)
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Time to remission
de Groot K et al. Ann Intern Med 2009;150:670-680
©2009 by American College of Physicians
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Measures of disease activity for the pulse
and daily oral cyclophosphamide
de Groot K et al. Ann Intern Med 2009;150:670-680
BVAS
CRP
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Relapse data
• 14.5% (19/131) patients who had achieved remission by 9 months had relapse– 13 (7 major and 6 minor) in pulse group– 6 (3 major and 3 minor) in daily group– NOT statistically significant but study was not designed or powered to test the effect of intervention on relapse rate
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IV PulsePO Daily CYC IV Pulse CYCPros‐Trend towards lower rate of relapse‐Consistently suppressing lymphocytes which play role in disease activity
Pros‐Equal induction rates‐Lower overall cumulative dose‐Lower rate of neutropenia and infections‐Potential for better monitoring of patient compliance
Cons‐More leukopenia‐More infection‐Bladder toxicity‐Compliance issues
Cons‐Trend towards higher rate of relapse (differing studies)‐Don’t have as much consistent suppression of lymphocytes
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Alternative Treatments
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Case
• 33 yo female with granulomatosis with polyangiitis, considering having kids in the near future. What are her treatment options?
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Biologic therapy• Anti TNF agents
– In animal models inhibition of TNF alpha markedly decreases the formation of granulomas
– CD4 + T cells from patients with GPA produce elevated levels of TNF alpha
– Serum levels of TNF alpha receptor correlate with disease activity
– TNF alpha positive cells infiltrate renal lesions– In vitro TNF alpha priming of activated neutrophils markedly enhances ability of ANCA to stimulate the degranulation of neutrophils
– Uncontrolled studies showed treatment with TNF alpha inhibitors significantly decreased disease activity scores in patients with GPA
Stone et al. NEJM 2005
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• Randomized double blind placebo controlled trial with 180 patients– PO CTX + steroids (severe disease) and methotrexate + steroids (limited disease) with etanercept vs. placebo (no etanercept)
– Steroids tapered off usually after 6 months– CTX stopped after 3‐6 months if in remission– Maintenance therapy with azathioprine or methotrexate for 12 months and then tapered
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WGET results• Results
– Primary outcome was defined as BVAS of 0 for at least 6 months
• No difference in time to reach remission– Secondary outcomes
• No difference in sustained remissions, sustained periods of low levels of disease, time to sustained remission, or number of disease flares
• Adverse events– 6 solid cancers in etanercept group (p = 0.01)– # of severe events, life threatening events, or death in each group similar at slightly over 50%
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Things to learn from WGET study
1. Standard therapy fails to induce durable remissions in the majority of patients
– Only 42% in both groups did not have a flare during trial
2. Even with shorter courses of cyclophosphamide, adverse effects are common and frequently severe with or without adding anti TNF therapy
3. Etanercept not effective
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Plasma exchange
• Retrospective studies have suggested benefit for severe renal disease and pulmonary hemorrhage
• Supposedly effective by removing ANCAs• Pusey et al found in randomized controlled trial that compared 25 pts with necrotizing glomerulonephritis tx with immunosuppressants with PLEX vs. 23 w/o showed greater likelihood of renal recovery in PLEX group
• Recent randomized controlled trial of 137 pts with severe renal vasculitis showed improvement with PLEX
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Rituximab
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B lymphocytes
• Percentage of activated peripheral B lymphocytes correlates with disease activity and severity
• B lymphocytes are thought to be essential for production of potentially pathogenic ANCA
• Cyclophosphamide’s primary target of therapeutic effects is thought to be B lymphocyte
Cartom-Ceba Current Opinions in rheumatology 2011
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Rituximab
• Chimeric monoclonal antibody directed against CD20– CD 20 functions as a calcium channel subunit and plays role in B lymphocyte activation, proliferation, and differentiation
– Binding of Rituximab to CD 20 causes death of target cell
– Circulating peripheral B lymphocytes remain undetectable in peripheral blood for 6‐12 months after treatment with Rituximab
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Early rituximab success• 66 yo male with GPA in 1994 who developed cyclophosphomide toxicity during subsequent treatment flares and was relapsing on prednisone and azathioprine and mycophenolate mofetil
• Compassionate use basis for Rituximab under hypothesis that remission could be induced by B lymphocyte depletion resulting in rapid removal of potentially pathogenic ANCA
• Remission achieved quickly and prednisone was discontinued
• This case led to Rituximab use in more than 200 reported cases of severe refractory AAV with good results
Cartom-Ceba et al. Current Opinions in rheumatology 2011
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RAVE trial
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RAVE trial• Randomized, double blind non inferiority trial of Rituximab (375 mg/m2 weekly for 4 weeks) + steroids compared to daily PO cyclophosphamide + steroids
• Primary end point – disease remission at end of 6 months without use of prednisone
• If remission between 3‐6 months in cyclophosphamide group then could switch to azathioprine for maintenance
• Steroid dosing: 1‐3 pulse doses of methylprednisolone(1000mg) then 1mg/kg prednisone/day, then tapered by 6 months
• 197 GPA and MPA patients that were ANCA positive
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RAVE trial• No differences in
adverse events– 6 months too short to see cyclophosphamide side effects
• Among patients with severe renal disease (excluded cr >4) and/or alveolar hemorrhage (excluded ventilated patients) there was no difference
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Rituximab
Cyclophosphomide
P = 0.10P<0.0001 P= 0.01
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RAVE trial conclusions
• Rituximab was not inferior to cyclophosphamide treatment for induction of remission in severe ANCA associated vasculitis (p< 0.0001)
• Rituximab may be superior to cyclophosphamide in treating relapses
• FDA approved Rituximab for remission induction in severe GPA or MPA
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Questions about rituximab
1. What dosing schedule• 375 mg/m2 for 4 weeks or 1000 mg Q2 weeks for 2
doses2. Trials only looked at ANCA positive patients (did not look at
ANCA negative or limited disease)3. Utilization of Rituximab as maintenance therapy?
• Relapses occur after reconstitution of B cells and were accompanied or preceded by increase in PR3 ANCA levels
4. What if any maintenance therapy should be given to newly diagnosed patients after treatment with Rituximab
5. Long term side effects and relapse rates
Cartom-Ceba et al. Current Opinions in rheumatology 2011
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Relapses
• Most occur within first year after immunosuppression stopped
• Risk factors– PR3 ANCA positivity– Lung involvement– Upper respiratory tract involvement
• Patients should be monitored indefinitely for potential relapse
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Design
• Multi‐center, randomized, double‐blind noninferiority trial comparing rituximab followed by placebo vs CYC for 3‐6 months followed by AZA for 12‐15 months
• Tapered glucocorticoids by 5.5 months if remission
• Primary outcome complete remission by 6 months with remission maintained through 18 months
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Results
• 197 pts randomized to rituximab group and CYC followed by AZA
• At 12 and 18 months, 48% and 39% of pts in rituximab group maintained complete remissions compared to 39% and 33% respectively in CYC group
• No significant difference between two groups in any efficacy outcome measure, including duration of complete remission and frequency or severity of relapses
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Relapses and adverse events
• Higher relapses– PR3‐ANCA than MPO‐ANCA– GPA vs MPA– Relapsing disease vs new disease
• No difference between treatment groups• Among 101 relapsing patients at baseline, Rituximab superior to conventional at 6(p=0.01) and 12(p=0.009) months, but not 18 (p=0.06) months when most patients reconstituted B cells
• No significant difference in adverse events
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Study conclusions
• Single course of rituximab followed by placebo as effective as conventional tx with CYC followed by azathioprine for induction and maintenance of remission for 18 months
• Relapse percentage low when ANCA and B cells low
• Adverse events similar except fewer cases of leukopenia and pneumonia in rituximab group
• Question of when to re‐dose rituximab
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Maintenance therapy
• Best data for azathioprine and methotrexate• Factors influencing choice
– Renal insufficiency– Desire for children/pregnancy
• Usually continued for 12‐18 months after remission induced
• Rituximab?
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Future therapies
• Mycophenolate data mixed but have shown some efficacy for maintenance and treatment relapses
• Anti‐T cell antibodies have been tested but unproven• IVIG• 15‐Deoxyspergualin (gusperimus): anti‐proliferative effect on antigen‐stimulated B cells– Studied in small number of patients, partial or complete remission in six to eight out of 20 cases
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Example treatment time line
• Inducing remission– CYC (IV or PO) + steroids
until complete remission (3‐6 months)
• Inducing remission– Rituximab + steroids
• Maintenance therapy‐Methotrexate or azathioprine for 12‐18 months or longer if continued relapsesSteroids stopped somewhere around 6‐8 monthsTr
aditi
onal
• Maintenance therapy‐None?‐Repeated Rituximab doses at specified times or according to ANCA levels and B cells?‐Azathioprine or methotrexate?
Ritu
xim
ab
0-6 months 6months-?
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Summary1. Name Change ‐ Granulomatosis with Polyangiitis (GPA)2. Classification Criteria Change? ANCA type classified rather
than by name3. Do ANCA’s predict flare – no but…4. Treatment
• Cyclophosphamide works well but has issues with relapses and side effects
• Etanercept does NOT work• Rituximab is promising. Non inferior for induction and
better for treating relapses• Long term side effects and relapse rate
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References• Eular Recommendations for management of primary small and medium vessel vasculitis. Ann Rheum Dis
2009;68(3):310‐317 • Cartin‐Ceba et al. Treatment of antineutrophil cytoplasmic antibody associated vasculitis with rituximab. Current
Opinions in Rheumatology. 2011;24:15‐23.• deGroot et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic
antibody – associated vasculitis. Ann Intern Med. 2009; 150: 670‐680.• Falk RF, Jennette JC. Anca disease; where is this field heading? J Am Soc Nephrology 2010;21:745.• Fauci et al. Wegener’s Granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21
years. Ann Intern Med. 1983; 98 (1): 76‐85.• Finkelman et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener
Granulomatosis. Ann Intern Med. 2007;147(9):611 • Hoffman et al. Wegener Granulomatosis: An analysis of 158 patients. Ann Intern Med. 1992;116:488‐498. • Jenette JC. Nomenclature and classification of vasculitis: lessons learned from granulomatosis with polyangiitis
(Wegener’s granulomatosis). Clinical and Experimental Immunology. 2011; 164:7‐10.• Jennette et al. Nomenclature of systemic vasculitidies. Proposal of an international consensus conference.
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