2. Clinical/Laboratory features and Diagnosis of Wegener’s G. Iraj Salehi-Abari, MD. salehiabari@sina.tums.ac.ir Iraj Salehi-Abari Wegener G.

3. New terminology: o In January 2011 o The name of Wegener’s granulomatosis o Was changed to: o Granulomatosis with polyangiitis o Abbreviated as GPA Iraj Salehi-Abari Wegener G.

4. Definition: o Systemic necrotizing vasculitis o Small sized vessels o Granulomatous inflammation . ENT . Lung . Kidney o Associated with ANCA positivity Iraj Salehi-Abari Wegener G.

5. Epidemiology: o Prevalence: 1/20,000-30,000 o F/M ratio: Systemic GPA: # 1 Systemic GPA: # 1 Limited GPA: F > M Limited GPA: F > M o Fourth & fifth decade: Mean = 40 o Age onset < 19: 15% o White: 89-98% Iraj Salehi-Abari Wegener G.

6. Clinical findings: ELKO findings: ENT: > 80% ENT: > 80% Lung: 45-90% Lung: 45-90% Kidney: 50-80% Kidney: 50-80% Others + constitutional f. Others + constitutional f. Iraj Salehi-Abari Wegener G.

7. Clinical triad: ENT ENT Lung Lung Kidney Kidney Iraj Salehi-Abari Wegener G.

8. Initial presentation: ENT : most often: [Fowler 2012] o Sinusitis: 1/2 to 2/3 [Hoffman 1992] Lung : may be Kidney : sometimes Iraj Salehi-Abari Wegener G.

9. ENT features: o. Nose o. Sinuses o. Throat o. Ears Iraj Salehi-Abari Wegener G.

10. Nose: o Nasal crusting, Rhinitis o Nasal obstruction o Runny nose o Smell disturbances o Purulent/Bloody nasal discharge: 63% [Salehi-Abari, 2013] o Epistaxis Iraj Salehi-Abari Wegener G.

11. Nose: o Nasal ulcer: 43% [Salehi-Abari, 2013] o Severe nasal pain o Nasal septal perforation o Saddle-nose deformity: 23% [Salehi-Abari, 2013] Iraj Salehi-Abari Wegener G.

12. Saddle-nose deformity: Iraj Salehi-Abari Wegener G.

13. Atypical Sinusitis (AtS) : Was defined as one of the following conditions accompanying sinusitis o Recurrent o Chronic or intractable o Sinus mass o Rhinitis Iraj Salehi-Abari Wegener G.

14. Atypical Sinusitis (AtS) : o Otitis o Orbital cellulitis o Dacryocystitis o Mastoiditis o Severe pain in the nose o Pansinusitis Iraj Salehi-Abari Wegener G.

15. Ear: Ear: o Otitis media: 49% [Salehi-Abari, 2013] . Serous > Purulent o Hearing loss . Conductive > SNHL o Mastoiditis: 14% [Salehi-Abari, 2013] o Vertigo Iraj Salehi-Abari Wegener G.

16. Otitis media: Otitis media: o Persistent, intractable o Recurrent o Bilateral o with Sensory neural hearing loss o with Mastoiditis o Recurrent bilateral serous otitis media Iraj Salehi-Abari Wegener G.

17. Mouth: o Oral necrotic ulcer (23%) [Salehi-Abari, 2013] o Strawberry gum hyperplasia:  Pathognomonic Iraj Salehi-Abari Wegener G.

18. Ophthalmic: o Conjunctivitis o Scleritis o Keratitis o Corneal ulcer o Uveitis o Dacriocystitis o Excessive tearing Iraj Salehi-Abari Wegener G.

19. Ophthalmic: o Proptosis: 14% [Salehi-Abari, 2013] o Retinal vasculitis o Optic neuritis o Ophthalmoplegia o Red eye syndrome Iraj Salehi-Abari Wegener G.

20. Laryngotracheal: o Hoarseness o Stridor o Subglottic stenosis: 17% [Salehi-Abari, 2013] o Upper airway obstruction Iraj Salehi-Abari Wegener G.

21. Lung: Iraj Salehi-Abari Wegener G. o Asymptomatic: 1/3 o Cough & Dyspnea o Hemoptysis: 31% [Salehi-Abari, 2013] o Pleuritis (+ pleural effusion) o Acute and fulminant alveolar hemorrhage with respiratory failure

22. Lung: Iraj Salehi-Abari Wegener G. Chest X-Ray or CT scan: o. Nodules: 46% [Salehi-Abari, 2013] o. Cavitation: 34% [Salehi-Abari, 2013] o. Opacities o. Others

23. Pneumonia: o Intractable pneumonia o Recurrent pneumonia o Multiple lobe pneumonia o Cavitate pneumonia o Fleeting pneumonia o Hemorrhagic pneumonia o Pneumonia + Sinusitis Iraj Salehi-Abari Wegener G.

24. Kidney: Renal involvement: 51% [Salehi-Abari, 2013] o Microscopic hematuria + o RBC cast o Proteinuria o pyuria o Azotemia Iraj Salehi-Abari Wegener G.

25. Renal Pathology: o Focal segmental necrotizing pauci-immune Glomerulonephritis Iraj Salehi-Abari Wegener G.

26. Attention please: Proptosis in conjunction with: o ENT or o Lung disease or o Glomerulonephritis Is highly suggestive of the WG (GPA) [Hoffman GS, 1992] and [Tarabishy AB, 2010] Iraj Salehi-Abari Wegener G.

27. Attention please: Almost all cases with vasculitis including: o Proptosis or o Sinonasal destruction or o Saddle nose deformity or o Subglottic stenosis Are the cases of GPA Iraj Salehi-Abari Wegener G.

28. Musculoskeletal: o Arthralgias o Myalgias o Arthritis: < 1/3 Iraj Salehi-Abari Wegener G.

29. Arthritis:  Mono, Oligo, Polyarthritis  Migratory, Fixed  Symmetric, Asymmetric  Small, Large  Knee, Ankle  Positive RF: 50-60% Iraj Salehi-Abari Wegener G.

30. Arthritis: o RA like: Symmetric polyarthritis o ReA like: Asymmetric lower limb oligoarthritis o ARF like: Migratory polyarthritis Iraj Salehi-Abari Wegener G.

31. Skin: In ½ of the patients o Palpable purpura, Ulcer o Nodule, Papule, Vesicle o Urticaria, livedo reticularis o Erythema nodosum o Pyoderma gangrenosum Iraj Salehi-Abari Wegener G.

32. Skin: o Leukocytoclastic vasculitis: most common o Hemorrhagic blister Iraj Salehi-Abari Wegener G.

33. Neurologic : o Peripheral neuropathy Mononeuritis multiplex Mononeuritis multiplex Polyneuropathy Polyneuropathy o Cranial neuropathy: 2, 6, 7 2, 6, 7 Iraj Salehi-Abari Wegener G.

34. Neurologic : o Cerebro-vascular accident (CVA) o Meningeal inflammation  Headache o CNS mass o Diabetes insipitus Iraj Salehi-Abari Wegener G.

35. GI tract: o Asymptomatic o Enterocolitis: Abdominal pain Abdominal pain Diarrhea, GI bleeding Diarrhea, GI bleeding Ulcer  Perforation Ulcer  Perforation Iraj Salehi-Abari Wegener G.

36. GI tract: o Cholecystitis o Ascitis o Perianal ulcer o Pancreatitis, Pancreatic mass Iraj Salehi-Abari Wegener G.

37. Heart: o Pericarditis o Myocarditis o Endocarditis o Valvulitis Iraj Salehi-Abari Wegener G.

38. Heart: o Coronary vasculitis:  MI, Angina o Arrhythmias o Conduction defects o Non-coronary > Coronary Iraj Salehi-Abari Wegener G.

39. Genitourinary: o Ureteral obstruction o Hemorrhagic cystitis o Granulomatous prostatitis o Urethritis o Epididymitis, Orchitis o Penile necrosis Iraj Salehi-Abari Wegener G.

40. Paraclinic: o CBC, U/A, BUN/Cr, ESR, CRP, LFT o ANCA serology o Sinus X-ray, CXR o CT-scan of sinuses, HRCT of lungs o Pathology Iraj Salehi-Abari Wegener G.

41. ANCA: IF assay: more sensitive  C-ANCA  P-ANCA  Atypical (non-C, non-P) ANCA Iraj Salehi-Abari Wegener G.

42. ANCA: ELISA: more specific  PR3-ANCA  MPO-ANCA Iraj Salehi-Abari Wegener G.

43. ANCA: C-ANCA:  usually PR3-ANCA P-ANCA:  usually MPO-ANCA Iraj Salehi-Abari Wegener G.

44. ANCA in GPA:  In active severe GPA: 90%  in limited GPA: 60%  PR3-ANCA: 80-90% Iraj Salehi-Abari Wegener G.

45. ANCA in GPA:  Sensitivity:  60-90% (63%) [Salehi-Abari, 2013]  Specificity:  80-95% Iraj Salehi-Abari Wegener G.

46. Positive predictive value of c-ANCA for GPA:  In systemic disease: < 30%  In Chronic sinusitis: very Low (< 15%)  In Acute GN or RPGN: 98% Iraj Salehi-Abari Wegener G.

47. ANCA associated vasculitis: o Granulomatosis with polyangiitis (GPA) o Microscopic polyangiitis (MPA) o Churg-Strauss Syndrome (CSS) o Renal limited vasculitis (RLV) Iraj Salehi-Abari Wegener G.

48. Other Positive ANCA states: o Polyarteritis nodosa o Goodpastur’s disease o SLE, RA, Myositis o IBD, PSC o Endocarditis, HIV, CF o Hydralazine, PTU, DP, MC Iraj Salehi-Abari Wegener G.

49. Pathologic triad: . Necrosis . Granuloma: 57% [Salehi-Abari, 2013] . Vasculitis (SVV): 66% [Salehi-Abari, 2013] Iraj Salehi-Abari Wegener G.

50. Diagnosis of GPA: Upon the Judgement of o Clinical o Laboratory and o Imaging findings By an expert Rheumatologist In cooperation with an expert ENT man and an expert Infectious disease specialist Iraj Salehi-Abari Wegener G.

51. The 1990 ACR Classification Criteria for Wegener’s G.: o Oral ulcer or bloody/purulent nasal discharge o CXR: Nodule, Fixed infiltration or Cavity o U/A: > 5 RBC /HPF + RBC cast o Pathology: Granulomatous inflammation > 2 out of 4 criteria  Dx. > 2 out of 4 criteria  Dx. sensitivity: 80% [Salehi-Abari, 2013] sensitivity: 80% [Salehi-Abari, 2013] Iraj Salehi-Abari Wegener G.

52. The 1990 ACR Classification Criteria for Wegener’s G: o Not sensitive enough (< 80%)? o Can not make distinction between GPA & MPA? o All criteria have similar price? o ANCA is not included in this Criteria Iraj Salehi-Abari Wegener G.

53. EMA* diagnostic criteria of systemic GPA in the absence of biopsy: o CXR: Fixed infiltrations, nodules or cavitations > one month or bronchial stenosis o ENT: Bloody nasal discharge and crusting > 1 month or nasal ulceration; Sinusitis, Otitis media or mastoiditis > 3 months; Retro-orbital mass; Subglottic stenosis; Saddle nose deformity/destructive sinonasal disease o Glomerulonephritis:  RBC + RBC casts or > 10 dysmorphic RBC  2 + hematuria or 2+ proteinuria o Positive ANCA * Is very low sensitive too * Is very low sensitive too * European Medicine Agency algorithm Iraj Salehi-Abari Wegener G.

55. The ‘Iran criteria’* for diagnosis of GPA Entry Criteria: No other diagnosis upon Hx & Ph.E ELK criteria: o ENT up to 3 points o Lung up to 2 points o Kidney up to 1 point AB criteria: o ANCA up to 2 points o Biopsy up to 3 points Total points = 11 *. Iraj Salehi-Abari, M Motassaddi z., M Hasibi, et al.,...Indian Journal of Rheumatology, 2013,...ELSEVIER Iraj Salehi-Abari Wegener G.

56. The ENT criterion Up to 3 points More than one episode of bloody nasal discharge with nasal crusting, or nasal ulcer or severe nasal pain 1 p. More than one episode of bloody nasal discharge with nasal crusting, or nasal ulcer or severe nasal pain 1 p. Oral necrotic ulcer, or strawberry gum hyperplasia 1 p. Oral necrotic ulcer, or strawberry gum hyperplasia 1 p. Sinusitis; persistent or recurrent or intractable 1 p. Sinusitis; persistent or recurrent or intractable 1 p. Otitis media; persistent or recurrent or intractable or bilateral, or otitis media with SNHL 1 p. Otitis media; persistent or recurrent or intractable or bilateral, or otitis media with SNHL 1 p. Iraj Salehi-Abari Wegener G.

57. The ENT criterion Up to 3 points Proptosis 2 p. Proptosis 2 p. Saddle nose deformity 2 p. Saddle nose deformity 2 p. Subglottic stenosis 2 p. Subglottic stenosis 2 p. CT-scan findings: Pansinusitis or sinus mass 1 p. Pansinusitis or sinus mass 1 p. Sinonasal destruction 2 p. Sinonasal destruction 2 p. Mastoiditis 1 p. Mastoiditis 1 p. Iraj Salehi-Abari Wegener G.

58. The Lung criterion: Up to 2 points Hemoptysis 1 p. Hemoptysis 1 p. CXR or HRCT: Nodules 2 p. Nodules 2 p. Cavity 2 p. Cavity 2 p. Fixed infiltration 1 p. Fixed infiltration 1 p. Iraj Salehi-Abari Wegener G.

59. The Kidney criterion Up to 1 point o Hematuria: > 5 RBC or > 5 RBC or > 1+ or > 1+ or o Proteinuria: > 1+ or > 1+ or o RBC cast Iraj Salehi-Abari Wegener G.

60. The ANCA criterion Up to 2 points Positive ANCA or p-ANCA or Anti-MPO 1 p. Positive ANCA or p-ANCA or Anti-MPO 1 p. C-ANCA or Anti- PR3 2 p. C-ANCA or Anti- PR3 2 p. Iraj Salehi-Abari Wegener G.

61. The Biopsy criterion Up to 3 points Small vessel vasculitis (“SVV”) without Eosinophilia 1 p. Small vessel vasculitis (“SVV”) without Eosinophilia 1 p. “Granulomatous” inflammation without Eosinophilia 2 p. “Granulomatous” inflammation without Eosinophilia 2 p. Iraj Salehi-Abari Wegener G.

62. New GPA typing: Limited GPA : E &/or L  E + L  E  L Systemic GPA : [(E &/or L) + K]  E + L + K  E + K  L + K Iraj Salehi-Abari Wegener G.

63. The ‘Iran criteria’* for diagnosis of GPA o ENT; up to 3 p./Lung; up to 2 p./Kidney; up to 1 p. / ANCA; up to 2 p./Biopsy; up to 3p.: With total points of 11 [(E &/or L) + K] & > 5 points out of 11  Systemic GPA [(E &/or L) + K] & > 5 points out of 11  Systemic GPA (E &/or L) & > 4 points out of 11  Limited GPA (E &/or L) & > 4 points out of 11  Limited GPA *. Sensitivity: 100% *. Sensitivity: 100% Iraj Salehi-Abari Wegener G.

65. “Amir Alam Hospital approach”* toward diagnosis of GPA (Wegener’s): Step I: o History and General physical examination o ENT examination by ENT man o U/A, ANCA serology, CBC, BUN/Cr, ESR, LFT o Sinus X-rays, CXR o R/O TB, CSS, MPA, Mucormycosis, Cocaine abuse according to above findings Step II: o CT- scan of sinuses o HRCT of lungs Step III: o ENT endoscopy and biopsy: 1. Sinus, 2. Nose, 3. Middle ear Step IV: o Skin biopsy o Kidney biopsy o Lung biopsy: 1. Transbronchial, 2. Thoracoscopic, 3. Open thoracotomy *. Iraj Salehi-Abari, M. Motassaddi z., M. Hasibi, et al.,...,Indian Journal of Rheumatology, 2013,……ELSEVIER *. Iraj Salehi-Abari, M. Motassaddi z., M. Hasibi, et al.,...,Indian Journal of Rheumatology, 2013,……ELSEVIER Iraj Salehi-Abari Wegener G.

68. “Amir Alam Hospital recommendation”* for early detection of GPA in atypical sinusitis “Early Rheumatologic consultation in the patients with atypical sinusitis for early detection of Granulomatosis with polyangiitis” “Early Rheumatologic consultation in the patients with atypical sinusitis for early detection of Granulomatosis with polyangiitis” o Definite GPA in 13% of AtS o Probable GPA in another 13% of AtS *. Iraj Salehi-Abari, M Motassaddi Z., M Hasibi, et al., …, Rheumatology Current Research, 2012, …., USA OMICS PUBLISHING Iraj Salehi-Abari Wegener G.

69. Atypical Sinusitis (AtS) : Was defined as one of the following conditions accompanying sinusitis o Recurrent o Chronic or intractable o Sinus mass o Rhinitis Iraj Salehi-Abari Wegener G.

70. Atypical Sinusitis (AtS) : o Otitis o Orbital cellulitis o Dacryocystitis o Mastoiditis o Severe pain in the nose o Pansinusitis Iraj Salehi-Abari Wegener G.

71. GPA manifestations: ELKO ENT ENT Lung Lung Kidney Kidney Others OthersAB ANCA ANCA Biopsy Biopsy Iraj Salehi-Abari Wegener G.

72. Different GPA patterns: (E + O) + A (E + O) + A (E + O) + B (E + O) + B (E + O) + AB (E + O) + AB (L + O) + A (L + O) + A (L + O) + B (L + O) + B (L + O) + AB (L + O) + AB Iraj Salehi-Abari Wegener G.

73. Different GPA patterns: (EL + O) + A (EL + O) + A (EL + O) + B (EL + O) + B (EL + O) + AB (EL + O) + AB (LK + O) + A (LK + O) + A (LK + O) + B (LK + O) + B (LK + O) + AB (LK + O) + AB Iraj Salehi-Abari Wegener G.

74. Different GPA patterns: (EK + O) + A (EK + O) + A (EK + O) + B (EK + O) + B (EK + O) + AB (EK + O) + AB (ELK + O) + A (ELK + O) + A (ELK + O) + B (ELK + O) + B (ELK + O) + AB (ELK + O) + AB EL + O EL + O ELK + O Total: 20 patterns ELK + O Total: 20 patterns Iraj Salehi-Abari Wegener G.

75. Different GPA patterns: In 6 patterns out of 20: No ENT In 6 patterns out of 20: No ENT In 6 patterns out of 20: No Lung In 6 patterns out of 20: No Lung In 10 patterns out of 20: No Kidney In 10 patterns out of 20: No Kidney In 3 patterns out of 20: No Lung, No Kidney In 3 patterns out of 20: No Lung, No Kidney In 3 patterns out of 20: No ENT, No Kidney In 3 patterns out of 20: No ENT, No Kidney Iraj Salehi-Abari Wegener G.

76. Different GPA patterns: In 8 patterns out of 20: ANCA negativity In 8 patterns out of 20: ANCA negativity In 8 patterns out of 20: nl Biopsy In 8 patterns out of 20: nl Biopsy In 2 patterns out of 20: negative ANCA, nl Bx In 2 patterns out of 20: negative ANCA, nl Bx In 2 patterns out of 20: No ENT, (-) ANCA In 2 patterns out of 20: No ENT, (-) ANCA In 2 patterns out of 20: No ENT, nl Biopsy In 2 patterns out of 20: No ENT, nl Biopsy Iraj Salehi-Abari Wegener G.

77. Attention please o Normal ENT: No R/O GPA o Normal Lung: No R/O GPA o Normal Kidney: No R/O GPA o (-) Biopsy: No R/O GPA o (-) ANCA: No R/O GPA o nl ENT & (-) Biopsy: No R/O GPA Iraj Salehi-Abari Wegener G.

78. Attention please o nl ENT & (-) ANCA: No R/O GPA o (-) ANCA & (-) Biopsy: NO R/O GPA o nl Lung & nl Kidney: No R/O GPA o nl Lung, nl Kidney, (-) Biopsy: No R/O GPA o nl Lung, nl Kidney, (-) ANCA: No R/O GPA But: o nl ENT, nl Lung, nl Kidney: R/O GPA Iraj Salehi-Abari Wegener G.

79. Attention please o The suggestion of GPA may be easy but confirmation of the diagnosis of GPA may be one of the most important medical challenges for a Rheumatologist in the world. o You have to know that less than 1% of Rheumatologists are expert in GPA in the world. Iraj Salehi-Abari Wegener G.

80. Granulomatous diseases of nose and paranasal sinuses: o Infections: TB, Leprosy, Rhinoscleroma, Syphilis, Histoplasmosis, Leishmaniasis, Rhinosporidiosis o Vasculitides: GPA, CSS o Malignancy: lethal midline granulomatosis, Nonkeratinizing nasopharyngeal carcinoma o Other: Sarcoidosis, Cocaine abuse,… Iraj Salehi Wegener G.

81. The most important differential diagnosis of Limited GPA :  Mucormycosis:  Rhino-Sinu-Orbito-Cerebral syndrome ??!!  Angiocentric Lymphoma:  Lethal midline granuloma  Cocaine abuse Iraj Salehi-Abari Wegener G.

82. The most important differential diagnosis of Systemic GPA :  Mucormycosis:  [(ENT + Lung) + Kidney] features ??!!  CSS, MPA  Sarcoidosis, TB Iraj Salehi-Abari Wegener G.

83. Amir Alam Hospital (AAH) big achievement: o In the world: about 80% of Limited GPA cases eventually will become systemic with kidney involvement o But in Amir Alam Hospital: only 51%* of these cases become systemic, due to the earlier diagnosis and management of GPA *. Iraj Salehi-Abari, M Motassaddi z., M Hasibi, et al.,...Indian Journal of Rheumatology, 2013,……ELSEVIER Iraj Salehi-Abari Wegener G.

84. In the world: o Many cases of Angioinvasive Rhino-Sinu-Orbito- Cerebral syndrome of Mucormycosis are wrong and they are missed cases of GPA or Overlap of both. o Mucormycosis has still been over diagnosed and there is still under estimation of the diagnosis of GPA in the world. Iraj Salehi-Abari Wegener G.

85. In Amir Alam Hospital: o There is the most important tertiary otolaryngology referral center of Iran and: o There is one of the best expert Infectious disease specialist of Iran but: o There is not an expert Rheumatologist and: o We need more cooperation for the earlier diagnosis of GPA Iraj Salehi-Abari Wegener G.