december 6, 2010 asthma and rheumatic disorders and vasculitis
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December 6, 2010 December 6, 2010 Asthma and Rheumatic Disorders and VasculitisAsthma and Rheumatic Disorders and Vasculitis
Lanny J. Rosenwasser, M.D.Dee Lyons/Missouri Endowed Chair in Immunology Research
Professor of Pediatrics Allergy-Immunology Division
Childrens Mercy Hospital Kansas City, Missouri
Professor of Pediatrics, Medicine and Basic ScienceUniversity of Missouri Kansas City School of Medicine
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Classification of VasculitisNecrotizing Vasculitis
Polyarteritis NodosaMicroscopic PolyangiitisChurg Strauss Syndrome
Granulomatous VasculitisWegener’s GranulomatosisLymphomatoid GranulomatosisTemporal ArteritisTakaysau’s Arteritis
Hypersensitivity VasculitisDrug reaction HSPInfection EMCAuto Immunity Cancer
MiscellaneousKawasaki’s DiseaseBechet’s Disease
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Pulmonary-Vasculitis Syndrome
With GranulomaWegener’s GranulomatosisLymphomatoid GranulomatosisAngiocentric GranulomatosisChurg-Strauss Syndrome
Without GranulomaGoodpasture’s SyndromeSystemic necrotizing vasculitisMicroscopic polyarteritisHypersensitivity vasculitis
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ANCA - SpecificitycANCA Wegener’s granulomatosis(Proteinase 3)
pANCA Microscopic polyangiitis(MPO) PAN(Cathepsin) Churg-Strauss syndrome(Lactoferrin) RA(Elastase) Hepatitis
HIVInflammatory bowel disease
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Prevalence of ANCA
Disease cANCA pANCApercent
WG 80 14MPA 45 45CSS 10 60PAN 5 15
Adapted from R.W. Simms, NEJM 339:775-763:1998
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Allergic Angitis and GranulomatosisAge (Mean) 44 yearsSex ratio 1.3:1(M:F)Fever Majority
Organ Involved PercentPulmonary 96
Infiltrate 93Wheezing 82
Skin 67Purpura 37Nodule 35
Neuropathy 63Hypertension 54GI 42Cardiac 38Renal 38Joints 21
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Organ systems involved by ChurgOrgan systems involved by Churg--Strauss syndromeStrauss syndrome
Respiratory tract- Asthma- pulmonary infiltrates, alveolar hemorrhage, sinusitis
Nervous system- Mononeuritis multiplex, polyneuropathy, cerebral hemorrhage, stoke
Skin - palpable purpura, skin nodules, urticaria, livedo
Heart- cardiomyopathy, myocarditis, heart failure, arrhythmia
Kidney - glomerulonephritis, renal insufficiency, renal infarct
GI tract- ischemic bowel, pancreatitis, cholecystitis
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Diagnosis of ChurgDiagnosis of Churg--Strauss SyndromeStrauss SyndromeHistorical PerspectiveHistorical Perspective
Churg and Strauss, 1951 1) Asthma 2) Necrotizing vasculitis of small and mediumarteries and veins 3) Eosinophil infiltration around involvedvessels and tissues 4) Extravascular granulomas 5) Fibrinoid necrosis of involved tissues
Lanham, 1984 1) Asthma 2) Eosinophilia >1.5 x 107 3) Systemic vasculitisinvolving 2 or more organs
American College of 1) Asthma 2) Eosinophilia >10% 3) Neuropathy 4) PulmonaryRheumatology, 1990 infiltrates 5) Paranasal sinus abnormality 6) Extravascular
eosinophil infiltration on biopsy
Chapel Hill Criteria, 1994 1) Asthma 2) Eosinophilia 3) Eosinophil rich granulomatousinflammation involving the respiratory tract 4) Necrotizing vasculitis affecting small-to-medium sized vessels
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Diagnosis of Churg StraussSyndrome
• Asthma-Atopy
• Neuropathy• Eosinophilia
- Blood or Tissue• Sinus Abnormalities• Pulmonary Infiltrates/Vasculitis• (Visceral Sx, Abnl LFT’s, Hypertension)
-Angio and CT for Nodose lesions, positive ANCA
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ROSENWASSERCLASSIFICATION OF CSS
(ACR-1990, Chapel Hill-1994)
• Definite:- Biopsy proven vasculitis- Asthma 3/6 ACR+
• Probable: + NCV, +Angio,+ ANCA- Biopsy non-diagnostic- Asthma 3/6 AC+
• Possible:- Asthma <3/6 ACR+
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Immune Mediators in ChurgImmune Mediators in Churg--Strauss SyndromeStrauss Syndrome
Schmitt et al. 1998 Increased levels of soluble IL-2 receptor,thrombomodulin, ECP in active CSS
Muschen et al. 1998 soluble CD95 receptor →decreasedeosinophil apoptosis
Schonermark, 2000 Decreased levels of IL-10 discriminated CSSfrom Wegener’s, PAN & MPA
Kiene et al. 2001 Increased T cell IL-4, IL-13 and IFN-gamma compared with healthy controls
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Potential CSS candidate genesPotential CSS candidate genesGenes of eosinophilopoiesis1) IL-3 3) GM-CSF2) IL-5 4) STAT6
Genes of eosinophil adhesion/migration and chemoattraction and activation
• p-selectin 6) eoxtaxin 2• VLA-4 7) IL-4• VCAM-1 8) IL-13• CCR3 9) FIP1L1• eotaxin 1
Genes for eosinophil apoptosis• CD95 receptor
Genes associated with vasculitisPR3 eNOS KIR receptorsA1AT CD18
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Other Clinical Issues
• Forme Fruste of CSS - prodromal SX but not full blown CSS• Major Differential Diagnosis:
- HES- WG- PAN- MPA (SNV overlap)
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Incidence of Common VasculitisNHS, UK, 1998-1994
Vasculitis Annual Incidence per million/GP
HV 31WG 12CSS 6MPA 6PAN 12
Watts et al. Seminar A&R 1995;25:28-34
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Guidelines for Therapy of Vasculitis
Obtain comprehensive base of clinical, laboratory, and pathologicdata to make appropriate and specific diagnosis and to establishobjective baseline to follow effect of therapy.
Identify and remove offending antigen or agent, if applicable.
Treat primary vasculitis process:Anti-inflammatory agents (steroids, non-steroidal anti-inflammatory
drugs, antibiotics)
Immunosuppressive agents and immuno modulatory agents (steroids,cytotoxic drugs, IV gammaglobulin, monoclonal antibodies, biologicals)
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Treatment of Systemic Vasculitis
CyclophosphamideAzathioprineWith or without PrednisoneTherapy continued for one year post-remissionRelapses treated as initial courseLong Term Remissions
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Immunosuppressive Effects of Cyclophosphamide in
Systemic Vasculitis
T and B Cell Lymphopenia (B greater than T)MonocytopeniaSuppression of the induction of cutaneous delayed hypersensitivitySuppression of production of antibodyRelative sparing of established cutaneous delayed hypersensitivitySuppression of in vitro blastogenic responses of lymphocytes to
antigensReduction of elevated serum and salivary immunoglobulin levels
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Complications of Treatment of Systemic Vasculitis
• Decreased Marrow Reserve• Hemorrhagic cystitis• Nausea• Herpes zoster• Sterility• Lymphoma
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Newer Approaches to Therapy of Systemic Vasculitis
TM/SulfaPulse CyclophosphamideMethotrexate, AzathioprineMycophenylate mesylate (Cellcept)IVIGInterferon-α-2b, Anti-IgE(Xolair)-CSSEnbrel, RemicadeRituxan
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Etanercept Plus Standard Therapy for WGEtanercept Plus Standard Therapy for WG
• RCT of Etanercept Add On to Conventional Therapy
• No Advantage of Etanercept to Standard Therapy
• Infliximab vs. Etanercept?
NEJM 352:352-36, 2005
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CC--SS/NJCSS/NJC7/1/03 7/1/03 -- 6/30/056/30/05
RemicadeSubject Cytoxan Other IM Prednisone IVIG Enbrel Xolair
1 + - + - - +2 + - + - - +3 - + + + + -4 + - + - - -5 - - + + + +6 + - + - - +7 + - + - - +8 - - + + - -9 + - + - - -10 - + + - - -11 + - + - - +
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Key Central Key Central Role of ILRole of IL--5 in 5 in AsthmaAsthma
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AntiAnti--ILIL--5 in Human Asthma:5 in Human Asthma:Reduction in ExacerbationsReduction in Exacerbations
Haldar P et al. New Engl J Med 2009;360:973Nair P et al. New Engl J Med 2009;360:985
• Severe (CCS-dependent) asthma
• Sputum eosinophilia required for enrollment
• No improvement in FEV1, control, symptoms
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AntiAnti--ILIL--5 in Human Asthma:5 in Human Asthma:
Haldar P et al. New Engl J Med 2009;360:973Nair P et al. New Engl J Med 2009;360:985
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J ALLERGY IMMUNOL 2010 APR
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Table 5. Clinical outcome of 94 patients with CSS
Clinical Outcome No.(%)
Remission of Vasculitis 86/94 (91.5)Relapse of Vasculitis 22/86 (25.6)Treatment Failure 8/94 (8.5)Death during follow-up 23 (24.5)
Guillevin L, et. Al. Medicine 78:26-37, 1999
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