December 6, 2010 Asthma and Rheumatic Disorders and Vasculitis

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1 December 6, 2010 Asthma 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 Science University of Missouri Kansas City School of Medicine

2 Classification of Vasculitis Necrotizing Vasculitis Polyarteritis Nodosa Microscopic Polyangiitis Churg Strauss Syndrome Granulomatous Vasculitis Wegener s Granulomatosis Lymphomatoid Granulomatosis Temporal Arteritis Takaysau s Arteritis Hypersensitivity Vasculitis Drug reaction HSP Infection EMC Auto Immunity Cancer Miscellaneous Kawasaki s Disease Bechet s Disease

3 Pulmonary-Vasculitis Syndrome With Granuloma Wegener s Granulomatosis Lymphomatoid Granulomatosis Angiocentric Granulomatosis Churg-Strauss Syndrome Without Granuloma Goodpasture s Syndrome Systemic necrotizing vasculitis Microscopic polyarteritis Hypersensitivity vasculitis

4 ANCA - Specificity canca (Proteinase 3) Wegener s granulomatosis panca Microscopic polyangiitis (MPO) PAN (Cathepsin) Churg-Strauss syndrome (Lactoferrin) RA (Elastase) Hepatitis HIV Inflammatory bowel disease

6 Prevalence of ANCA Disease canca panca percent WG MPA CSS PAN 5 15 Adapted from R.W. Simms, NEJM 339: :1998

7 Allergic Angitis and Granulomatosis Organ Involved Age (Mean) Sex ratio Fever 44 years 1.3:1(M:F) Majority Pulmonary 96 Infiltrate 93 Wheezing 82 Skin 67 Purpura 37 Nodule 35 Neuropathy 63 Hypertension 54 GI 42 Cardiac 38 Renal 38 Joints 21 Percent

8 Organ systems involved by Churg-Strauss 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

11 Diagnosis of Churg-Strauss Syndrome Historical Perspective Churg and Strauss, 1951 Lanham, 1984 American College of Rheumatology, 1990 Chapel Hill Criteria, ) Asthma 2) Necrotizing vasculitis of small and medium arteries and veins 3) Eosinophil infiltration around involved vessels and tissues 4) Extravascular granulomas 5) Fibrinoid necrosis of involved tissues 1) Asthma 2) Eosinophilia >1.5 x ) Systemic vasculitis involving 2 or more organs 1) Asthma 2) Eosinophilia >10% 3) Neuropathy 4) Pulmonary infiltrates 5) Paranasal sinus abnormality 6) Extravascular eosinophil infiltration on biopsy 1) Asthma 2) Eosinophilia 3) Eosinophil rich granulomatous inflammation involving the respiratory tract 4) Necrotizing vasculitis affecting small-to-medium sized vessels

12 Diagnosis of Churg Strauss Syndrome 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

13 ROSENWASSER CLASSIFICATION OF CSS (ACR-1990, Chapel Hill-1994) Definite: - Biopsy proven vasculitis - Asthma 3/6 ACR+ Probable: - Biopsy non-diagnostic - Asthma 3/6 AC+ Possible: - Asthma <3/6 ACR+ + NCV, +Angio,+ ANCA

14 Immune Mediators in Churg-Strauss Syndrome Schmitt et al Muschen et al Schonermark, 2000 Kiene et al Increased levels of soluble IL-2 receptor, thrombomodulin, ECP in active CSS soluble CD95 receptor decreased eosinophil apoptosis Decreased levels of IL-10 discriminated CSS from Wegener s, PAN & MPA Increased T cell IL-4, IL-13 and IFN-gamma compared with healthy controls

15 Potential CSS candidate genes Genes of eosinophilopoiesis 1) IL-3 3) GM-CSF 2) 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 vasculitis PR3 enos KIR receptors A1AT CD18

16 Other Clinical Issues Forme Fruste of CSS - prodromal SX but not full blown CSS Major Differential Diagnosis: - HES - WG - PAN - MPA (SNV overlap)

18 Incidence of Common Vasculitis NHS, UK, Vasculitis Annual Incidence per million/gp HV 31 WG 12 CSS 6 MPA 6 PAN 12 Watts et al. Seminar A&R 1995;25:28-34

19 Guidelines for Therapy of Vasculitis Obtain comprehensive base of clinical, laboratory, and pathologic data to make appropriate and specific diagnosis and to establish objective 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)

20 Treatment of Systemic Vasculitis Cyclophosphamide Azathioprine With or without Prednisone Therapy continued for one year post-remission Relapses treated as initial course Long Term Remissions

23 Immunosuppressive Effects of Cyclophosphamide in Systemic Vasculitis T and B Cell Lymphopenia (B greater than T) Monocytopenia Suppression of the induction of cutaneous delayed hypersensitivity Suppression of production of antibody Relative sparing of established cutaneous delayed hypersensitivity Suppression of in vitro blastogenic responses of lymphocytes to antigens Reduction of elevated serum and salivary immunoglobulin levels

24 Complications of Treatment of Systemic Vasculitis Decreased Marrow Reserve Hemorrhagic cystitis Nausea Herpes zoster Sterility Lymphoma

25 Newer Approaches to Therapy of Systemic Vasculitis TM/Sulfa Pulse Cyclophosphamide Methotrexate, Azathioprine Mycophenylate mesylate (Cellcept) IVIG Interferon-α-2b, Anti-IgE(Xolair)-CSS Enbrel, Remicade Rituxan

28 Etanercept 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

30 C-SS/NJC 7/1/03-6/30/05 Remicade Subject Cytoxan Other IM Prednisone IVIG Enbrel Xolair

31 Key Central Role of IL-5 5 in Asthma

32 Anti-IL IL-5 5 in Human Asthma: Reduction in Exacerbations Haldar P et al. New Engl J Med 2009;360:973 Nair 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

33 Anti-IL IL-5 5 in Human Asthma: Haldar P et al. New Engl J Med 2009;360:973 Nair P et al. New Engl J Med 2009;360:985

34 J ALLERGY IMMUNOL 2010 APR

35 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

Dr Rodney Itaki Lecturer Anatomical Pathology Discipline. University of Papua New Guinea School of Medicine & Health Sciences Division of Pathology

Vasculitis Dr Rodney Itaki Lecturer Anatomical Pathology Discipline University of Papua New Guinea School of Medicine & Health Sciences Division of Pathology Disease Spectrum Hypersensitivity vasculitis/microscopic