Review And Treatment Advances

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Granulomatosis withPolyangiitis:Review and Treatment AdvancesRichard Hariman MDAssistant Professor of MedicineDivision of RheumatologyMedical College of Wisconsin

Disclosures None

Outline IntroductionHistoryPathogenesisClinical FeaturesDiagnosisRecent Treatment Advances

What is the new acronym forWegener’s?a)b)c)d)e)MPAGPAEGPAPANIDK

ANCA associated vasculitides Microscopic Polyangiitis Granulomatosis with Polyangiitis (Wegener’s) Eosinophilic Granulomatosis with Polyangiitis(Churg‐Strauss)

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Granulomatosis with polyangiitis Multisystem autoimmune disease of unknownetiology Previously referred to as Wegener’sgranulomatosis Necrotizing granulomatous inflammation andpauci immune vasculitis in small and mediumsized blood vessels Associated with PR3‐ANCA

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%


History 1897: Peter McBride, Scottish otolaryngologist– Description of a patient with Wegener’s typesymptoms in a BMJ article 1931: Heinz Karl Ernst Klinger– Described a 70 y/o physician Constitutional symptoms, joint symptoms,proptosis, widespread upper respiratory tractinflammation with saddle nose deformity, GNand pulmonary lesions

History cont’d 1954: Goodman and Churg provided thedefinitive description based:(1) systemic necrotizing angiitis(2) necrotizing granulomatous inflammationof the respiratory tract(3) necrotizing glomerulonephritis

Who was Wegener?

Friedrich Wegener German pathologist and Nazi PartyMember Described 3 patients and publishedtheir distinct clinical andhistopathologic findings in 1936 In 1932 he joined theSturmabteilung, also known as the"brown shirts," which terrorizedAdolf Hitler's opponents As the city's pathologist, Wegenerperformed autopsies on people whodied in the ghetto.Minnesota Public Radio May 18th, 2011

History behind name change Shift in medicine to stop using eponyms and usemore scientifically descriptive names– e.g. Reiter's Syndrome Jan 2011 recommendations by American College ofRheumatology, American Society of Nephrology, andEULAR recommended name change toGranulomatosis with Polyangiitis (GPA) American College of Chest Physicians rescinded theirMaster Clinician Award given to Friedrich Wegener in1989

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Question True or False? A negative ANCA rules out Granulomatosiswith polyangiitis.

Pathogenesis Risk Factors Infection Genetic MHC class II allele HLA‐DRB1‐15 in African Americans Environmental

Mechanism of injury Tissue injury results from interplay between aninitiating inflammatory event and a highly specificimmune response The immune response is directed against previouslyshielded epitopes of neutrophil granule proteinsleading to autoantibodies or ANCAs– ANCAs are directed against antigens presentwithin the primary granules of neutrophils andmonocytes– Produce tissue damage via interactions withprimed neutrophils and endothelial cells

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Antineutrophil cytoplasmicantibodiesCytoplasmic (C‐ANCA)Perinuclear (P‐ANCA)Anti‐proteinase 3 (PR3‐ANCA):Anti‐myeloperoxidase (MPO‐ANCA): lysosomal granuleneutrophil azurophilic granuleconstituentAssociated with granulomatosiswith polyangiitisconstituent involved in oxygen freeradicalsAssociated with microscopicpolyangiitis and churg‐strauss disease

Immunofluorescence testingC- ANCACytoplasmic stainingP- ANCAPerinuclear staining

Caveats on immunofluorescencetesting Subjective component based upon visualinterpretation of the IF pattern No standardization Not highly specific (further ELISA testing) Pretest probability important

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 ANCAnegative

Pathologic role of ANCA Best support comes from animals and in vitroexperiments– Mouse models provide evidence that anti‐MPO antibodiesinduce necrotizing and crescentic glomerulonephritis andsystemic small vessel vasculitis– In vitro data showing PR3‐ANCA causing leukocyteactivation– Human evidence: Mother with anti MPO ANCA activedisease delivered newborn who developed pulmonaryrenal syndromeSchlieben Am J Kidney Disease 2005

Does ANCA predict flares Largest study looking at this was done withinformation obtained during Wegener’sGranulomatosis Etanercept Trial (WGET) 180 patients with serum samples drawn at three‐month intervals and ANCA assays performed at theMayo Clinic Decreases in PR 3 levels were not associated withshorter times to remission, and increases in PR3were not predictive of relapse in one yearFinkielman et al. Ann Intern Med. 2007;147(9):611

Does ANCA predict flares70605040Total number30Relapse20100Increase in No increaseANCAin ANCALookingat PR3Finkielman et al. Ann Intern Med. 2007;147(9):611

Does ANCA predict flares Easy answer– No Complicated answer– In some patients it does correlate and canhelp to identify when to initiate treatmentearlier– Treatment changes are NOT made basedjust on a rising ANCA but may choose toincrease monitoring in someone who hashad previous flares correlating withincreasing ANCAFinkielman et al. Ann Intern Med. 2007;147(9):611

Clinical Features of GPA

Case 26 yo M is evaluated for a 3 month history ofepistaxis and a 1 month history of intermittentnight sweats and cough. He’s also had a fewepisodes of hemoptysis and notes someshortness of breath when walking 2 blocks. What clinical features should be looked for?

Clinical features of GPA Constitutional symptoms ENT– Chronic sinusitis, rhinitis, epistaxis, saddle nosedeformity, conductive and sensorineural hearingloss, tracheal or subglottic granulomatous massesACR Slide Collection 2009

Clinical features of GPA Pulmonary– Range fromasymptomatic toacute fulminantinvolvement– Pulmonaryinfiltrates, nodules,diffuse alveolarhemorrhagePic from UpToDate

Clinical features of GPA Renal– Asymptomatic usually– Active urinary sedimentwith RBC casts andproteinuria– Biopsy reveals segmentalnecrotizingglomerulonephritis withfew or no immunedeposits (pauci‐immune)and crescents commonlypresentPictures from and UptoDate

Clinical features of GPA Optho– Conjunctivitis, episcleritis, uveitis, optic nerve vasculitis,retinal artery occlusion, proptosis

Clinical features of GPA Nervous system– Mononeuritis multiplex,sensorimotor PN, and cranial nervepalsies, vasculitis of brain or spinalcord with granulomatous massesaffecting different areas Derm– Most commonly leukocytoclasticvasculitis, palpable purpura or skinulcers

Clinical features cont’d MSK– Arthralgias more than arthritis Cardiac– Rarely detected ante mortem butpericarditis and coronary arteritisseen in 10‐20% of cases which canlead to MI or sudden death Heme– Hypercoaguable state leading to PEs,etc. Less commonly can involve GI, lowerGU tract, parotid glands, thyroid, liver,or breast

Classification of GPALimited DiseaseSystemic Disease‐Findings largely isolatedto upper and lowerrespiratory tracts‐More often women‐More often ANCAnegative‐More often to havechronic recurring diseaseand destructive upperairway lesions (saddlenose)‐Significant multi systemmanifestations affectinglungs, kidneys, otherorgans in addition torespiratory tract

EULAR classification of GPAEular Recommendations for management of primary small and medium vessel vasculitis 2009


Diagnosis Based on clinical symptoms ANCAs can aid diagnosis Biopsy: necrotizing granulomas– Lung– Kidney– Sinus

1990 ACR CriteriaNasal or oral inflammation‐Development of painful or painless oral ulcers or purulent or bloodynasal dischargeAbnormal chest radiography findings‐Nodules, fixed infiltrates, or cavitiesAbnormal urinary sediment‐Microhematuria ( 5 RBCs per high‐power field or RBC casts in urinesediment)Granulomatous inflammation on biopsy‐Histologic changes showing granulomatous inflammation within thewall of an artery or in the perivascular or extravascular area 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 useLeavitt Arthritis Rheum 1990

Chapel Hill nomenclature Provided names and definitions for GPA, MPA andChurg‐Strauss Not intended to establish diagnostic criteria GPA, MPA, and CSS distinguished from othersystemic small vessel vasculitides by absence ofimmune deposits MPA distinguished from GPA and CSS by absence ofgranuloma formation Potential value of ANCA serology was notedJennette Arthritis Rheum 1994

Where the classification is heading There is a push for new criteria which is heavily weighted onANCA type– PR3 ANCA disease– MPO ANCA disease– Seronegative ANCA disease GPA and MPA are clinical and pathologic phenotypes but arepoor predictors of natural history of these two diseasescompared to ANCA serotype Patients with ANCA’s act more similarly and therefore can getmore information regarding response to treatments andrelapse potentials than with GPA vs. MPA– Example: PR3 ANCA positive patients more likely to relapseFalk J Am Soc Nephrology 2010

Differential diagnosis Pulmonary Renal syndromes– Goodpasture Syndrome Lack of upper airway involvement Anti GBM antibodies Deposition of immune complexes in basement membrane on renalbiopsy Microscopic polyangiitis Churg Strauss– More asthma and eosinophilia Cocaine‐Induced Relapsing polychondritis

Cocaine induced midline destructivelesions (CIMDL) Can mimic limited GPA clinically Associated with positive ANCA tests but usually not directedat PR3 or MPO and more likely to be directed at humanneutrophil elastase Important to identify because treatment is different –immunosuppressants will NOT improve process


Case cont’d On physical exam he has a large perforation of thenasal septum. He has some rhonchi on lung examand is noted to have few purpuric lesions on his legs. Urinalysis shows 3 protein, erythrocytes, anderythrocyte casts. CT scan of the chest reveals b/lcavitary nodules. He’s diagnosed with granulomatosis withpolyangiitis. He wants to know what treatment options areavailable to him?

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 goodimprovement in his condition Other reports of tx with alkylating agents, folic acid,and purine antagonists alone or in combination withcorticosteroids showed some clinical responses andsignificant long term remissionsFacuci et al. Ann of Int Medicine 1983

Cyclophosphamide 1971 Novack published landmark studydescribing 4 patients with GPA who improvedwith cyclophosphamide therapy corticosteroids 1983 Fauci showed a 93% complete remissionrate in 85 patients treated with steroids cyclophosphamide Mean duration of remission was 48.2 monthsFacuci et al. Ann of Int Medicine 1983

Serial CXRs – cyclophosphamidestarted on 8/10Novack NEJM 1971

Issues with cyclophosphamide 185 pts followed at NIH for 6‐24 years (1229 patientyears) Standard treatment protocol– Cyclophosphamide 2 mg/kg day for at least 1 year aftercomplete remission and then tapered by 25 mgdecrements every 2‐3 months until discontinuation or untildisease recurrence– Steroids 2‐15 mg/kg for a few days and then dailyprednisone for 4 weeks and then 60 mg alternate daytherapy and tapered as able (usually off by 12 months)Hoffman Ann Int Med 1992

Issues with cyclophosphamide1009080706050% pts403020100PartialRemissionCompleteremissionIt works!RelapsesDeath from allreasonsmorbidity fromdiseaseMorbidity from tx

Morbidity issues Morbidity of Disease Morbidity of Treatment– Chronic renal– Hair loss (17%)insufficiency (42%)– Fertility issues (57%)– Hearing loss (35%)– Cyclophosphamide cystitis (43%)– Cosmetic and– Bladder cancer (2.8%)functional nasal– 2.4 fold increase in malignanciesdeformities ( 28%)– Serious infections (46%)– Tracheal stenosis (13%)– Myelodysplasia (2%)– Visual loss (8%)– GC induced cataracts (21%)– Chronic sinus– Fractures (11%)dysfunction (47%)– AVN (3%)– Pulmonary– GC induced DM (8%)insufficiency (17%)

How to minimize toxicity?Oral vs. IntravenousCyclophosphamide

Open label study of 149 patients with newly diagnosedgeneralized ANCA associated vasculitis with renalinvolvement which was not immediately life threatening Pulse cyclophosphamide 15 mg/kg every 2‐3 weeks vs.daily oral cyclophosphamide 2 mg/kg per day continuedfor 3 months after remission obtained and thenswitched to azathioprine for maintenance until month18 Both groups given steroids for entire course of study (18months)

Time to remissionde Groot K et al. Ann Intern Med 2009;150:670-680 2009 by American College of Physicians

BVASMeasures of diseaseactivity for the pulseand daily oralcyclophosphamideCRPde Groot K et al. Ann Intern Med 2009;150:670-680

Relapse data 14.5% (19/131) patients who had achievedremission 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 notdesigned or powered to test the effect ofintervention on relapse rate

PO Daily CYCIV Pulse CYCPros‐Trend towards lower rate ofrelapse‐Consistently suppressinglymphocytes which play role indisease act