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

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

Pulmonary-Vasculitis Syndrome

With GranulomaWegener’s GranulomatosisLymphomatoid GranulomatosisAngiocentric GranulomatosisChurg-Strauss Syndrome

Without GranulomaGoodpasture’s SyndromeSystemic necrotizing vasculitisMicroscopic polyarteritisHypersensitivity vasculitis

ANCA - SpecificitycANCA Wegener’s granulomatosis(Proteinase 3)

pANCA Microscopic polyangiitis(MPO) PAN(Cathepsin) Churg-Strauss syndrome(Lactoferrin) RA(Elastase) Hepatitis

HIVInflammatory bowel disease

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

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

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

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

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

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+

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

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

Other Clinical Issues

• Forme Fruste of CSS - prodromal SX but not full blown CSS• Major Differential Diagnosis:

- HES- WG- PAN- MPA (SNV overlap)

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

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)

Treatment of Systemic Vasculitis

CyclophosphamideAzathioprineWith or without PrednisoneTherapy continued for one year post-remissionRelapses treated as initial courseLong Term Remissions

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

Complications of Treatment of Systemic Vasculitis

• Decreased Marrow Reserve• Hemorrhagic cystitis• Nausea• Herpes zoster• Sterility• Lymphoma

Newer Approaches to Therapy of Systemic Vasculitis

TM/SulfaPulse CyclophosphamideMethotrexate, AzathioprineMycophenylate mesylate (Cellcept)IVIGInterferon-α-2b, Anti-IgE(Xolair)-CSSEnbrel, RemicadeRituxan

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

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 + - + - - +

Key Central Key Central Role of ILRole of IL--5 in 5 in AsthmaAsthma

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

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

J ALLERGY IMMUNOL 2010 APR

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