1. Update on classification of vasculitis and Wegener’s granulomatosis
Dr.

2. Overview Classification of vasculitis Wegener’s granulomatosis
Epidemiology
Clinical features
Pathogenesis
Diagnosis
Treatment
Prognosis

3. Vasculitis classification– the first step

4. Primary Systemic Vasculitis classification

5. Classification of systemic vasculitis

6. Small vessel vasculitis Medium-sized vessel vasculitis
Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis
Small vessel vasculitis
Wegener’s granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
Henoch-Schonlein purpura
Essential cryoglobulinemic vasculitis
Cutaneous leukocytoclastic angiitis
Medium-sized vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Large-vessel vasculitis
Giant cell (temporal) arteritis
Takayasu arteritis
WG, C-S and MPA share an indistinguishable form of necrotizing small-vessel vasculitis that affects capillaries, venules, arterioles, and small arteries. These three are distinguished from similar forms of immune-complex small-vessel vasculitis s/a HSP + cryoglobulinemic vasculitis by absence or paucity of immune-complex deposits in vessel walls. The diagnosis of specific subtypes of pauci-immune small vessel vasculitidies can be made based on the accompanying syndrome. 6

7. Classification of systemic vasculitis
2 major groups based on clinical and histopathological features of vasculitis
1. Large vessel vasculitis: aorta and major branches
Giant cell arteritis / temporal arteritis
Takayasu arteritis
2. Medium-sized vasculitis: medium arteries
Polyarteritis nodosa (PAN)
Kawasaki disease

8. Classification of systemic vasculitis
2. medium-sized vasculitis: arterioles, capillaries and venules
Wegener’s granulomatosis (WG)
Churg-Strauss syndrome (CSS)
Microscopic polyangiitis (MPA)
3. small vessel vasculitis: venules, capillaries
Henoch Schonlein purpura (HSP)
Cryoglobulinaemic vasculitis

9. Pathogenesis of vasculitis
Antibody mediated inflammation
Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)
Microscopic polyangiitis (MPA)

10. Pathogenesis of vasculitis
Immune complex-mediated inflammation
Henoch SchÖlein purpura (HSP)
Cryoglobulinaemic vasculitis
Polyarteritis nodosa (PAN)
Cell-mediated inflammation
Giant cell arteritis
Takayasu arteritis
Wegener’s granulomatosis (WG)
Churg-Strass syndrome (CSS)

11. Small vessel pauci-immune vasculitis
Wegener’s granulomatosis:
Necrotizing granulomatous inflammation, most often affecting respiratory tract
Churg-Strauss syndrome:
Occurs in association with asthma, eosinophilia, and necrotizing granulomatous inflammation
Microscopic polyangiitis:
Pauci-immune systemic vasculitis occurring in the absence of asthma and eosinophilia with no evidence of granulomatous inflammation
These three types share an indistinguishable pattern of glomerulonephritis which has necrosis and crescent formation and an absence or paucity of immunoglobulin deposition and is dubbed “pauci-immune crescentic GN”. This pattern can also occur in the absence of systemic vasculitis and is referred to in that case as renal vasculitis, renal=limited vasculitis or idiopathic rapidly progressive GN 11

13. Wegener’s Granulomatosis

14. Wegener’s Granulomatosis
Vasculitis and Granulomas in Lung and Upper Airway and also Glomerulonephritis

15. History of Wegener’s In 1931 In 1936 In 1954
Two patients died from prolonged sepsis with inflammation of blood vessels scattered throughout the body
In 1936
Wegener first described a distinct syndrome in three patients found to have necrotizing granulomas involving the upper and lower respiratory tract
In 1954
Seven more patients described, resulting in definate criteria

16. Wegener’s granulomatosis
Epidemiology:
Prevalence in US estimated at 3 per 100,000
Male : Female = 1 : 1
80-97% are Caucasian
Mean age at diagnosis: 41-56

17. Definitions
Wegener’s granulomatosis is a systemic vasculitis of the medium and small arteries, as well as venules, arterioles and occasionally large arteries
“Classic” Wegener’s primarily involves the upper and lower respiratory tracts and the kidneys

18. Definitions (Contd)
“Limited” form have clinical findings isolated to the respiratory tract- can occur in ¼ of cases, although 80% may go on to develop glomerulonephritis
Specifically, pts with limited disease are younger at disease onset, and more likely to be women

19. The Controversy Wegener’s vs PR3-ANCA vasculitis Lancet, 22 April 2006
Suggestion that using Wegener’s name “needs balanced discussion within the scientific community”
Reiter's syndrome- reactive arthritis

20. The Problem with Changing
Multiple ANCA+ diseases:
microscopic polyangiitis (MPA)
"renal-limited" vasculitis (pauci-immune glomerulonephritis without evidence of extrarenal disease)
Churg-Strauss syndrome (CSS)
Drug-induced vasculitis
Goodpasture’s
Rheumatic disorders
Autoimmune GI disorders CF
Diagnostic Criteria primarily clinical

21. Criteria for Classification
Nasal or oral inflammation
Development of painful or painless oral ulcers or purulent or bloody nasal discharge
Abnormal chest radiograph
Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities
Abnormal Urinary sediment
Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment
Granulomatous inflammation on biopsy
Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)
* For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%

22. Classic Symptoms Upper respiratory tract Lungs Kidneys sinuses Nose
ears
trachea
Lungs
Kidneys

23. Eye
Scleritis
Uveitis
Orbital pseudotumor /proptosis

24. Upper Respiratory Tract Ear
Ear infections that are slow to resolve
Recurrent otitis media
Decrease in hearing

25. Upper Respiratory Tract Nose
Nasal crusting
Frequent nosebleeds
Erosion and perforation of the nasal septum. The bridge of the nose can collapse resulting in a “saddle–nose deformity”.

26. Upper Respiratory Tract Sinuses/Trachea
Chronic sinus inflammation
Trachea
subglottic stenosis

27. Lungs Nodules (which may cavitate) Alveolar opacities
Pleural opacities
Diffuse hazy opacities (which may reflect alveolar hemorrhage)

28. Kidney Glomerulonephritis w/ associated hematuria and proteinuria
Can lead to renal failure if not treated aggressively
Renal masses (rare)
Active urine sediment: red blood cell casts

29. RBC casts

30. Skin “palpable purpura” most common
Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes
Ulcers

31. Miscellaneous Joints Arthritis can occur, with joint swelling and pain
Nerves Peripheral nerve involvement leads to numbness, tingling, shooting pains in the extremities, and sometimes to weakness in a foot, hand, arm, or leg
Meninges
Prostate gland
Genito–urinary tract
Constitutional symptoms of fatigue, low–grade fever, and weight loss

32. Incidence of symptoms Symptom At Onset Total ENT 75% 95% Lung 50 85
Joints
Fever
Kidney
Cough
Eye
Skin
Weight Loss
Nervous System (Central/Peripheral) 0 10/15
One-third of patients may be without symptoms at onset of disease

33. Update on vasculitis: J Allergy Clin Immunol 2009

34. Update on vasculitis: J Allergy Clin Immunol 2009

35. Wegener’s continued. . .
Renal involvement is manifested by acute renal failure with red cells, red cell and other casts , and proteinuria
Pts with microscopic polyangitis have a renal lesion that is essentially indistinguishable from that of pts with classic Wegener’s, the principle difference is the absence of granulomatosis inflammation, although some experts consider the presence of any significant upper respiratory tract involvement to be indicative of Wegener’s

36. In addition to pulmonary and renal…
Upper and lower airways, including subglottic region or trachea
Joints (myalgias, arthralgias, arthritis)
Eyes (conjuctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, nasolacrimal duct obstruction…)

37. In addition to pulmonary and renal… (Contd)
Skin (hemorrhagic lesions, palpable purpura)
Nervous system(cranial nerve abnormalities)
GI tract/Heart, lower GU

38. Wegener’s Granulomatosis
About 50% have no lung involvement at presentation.
Lung involvement:
Infiltrates
Nodules
Hemoptysis
Pleuritis
33% with lung involvement are asymptomatic.
About 80% have no renal involvement at presentation.
Klippel, 1998

39. Pathogenesis Risk factors and inciting events
Exact events obscure
Infectious—staph?
Genetic
single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22)
AAT deficiency
Environmental—inhalational?
Silica
lead
mercury

40. Pathogenesis ANCA
ANCAs may be not only markers for Wegener's granulomatosis and related disorders, but they may also be actors in pathogenesis
Neutrophils exposed to cytokines such as TNF, express PR3 & MPO (the targets for ANCAs)
Adding ANCAs to these cytokine-primed neutrophils causes them to generate oxygen radicals and release enzymes capable of damaging blood vessels

41. Pathogenesis (Contd) “Priming” of Neutrophils ANCA binding
Exposing PR3 and MPO epitopes
ANCA binding
Degranulation/ROS production/neutrophil-endothelial cell interaction
Increased ANCA = Increased degranulation rate

42. Pathogenesis (Contd)
Production of ANCA (anti-neutrophil cytoplasmic antibodies) is one of the hallmarks of WG and related forms of vasculitis(Churg-strauss, MPA, pauciimmune glomerulonephritis, drug –induced).
ANCA are directed against antigens present within the primary granules of neutrophils and monocytes, and thus produce tissue damage via interactions with primed neutrophils and endothelial calls.
~90% of pts with active generalized WG are ANCA positive, but some do not have ANCA, and those with limited forms of the dz, up to 40% may be ANCA negative, thus the absence of ANCA does not exclude the diagnosis of Wegener’s.

43. Pathogenesis (Contd) Most common targeted antigens in WG :
Proteinase 3 (PR3), observed in 70-80% of pts
Myeloperoxidase (MPO)-target in approximately 10%
Dual postivity is rare and , and generally indicated the presence of another condition such as SLE
~70% of pts with MPA are ANCA positive and most have MPO-ANCA, with only a minority having PR3

44. Criteria for Classification
Diagnosis
Criteria for Classification
Nasal or oral inflammation
Development of painful or painless oral ulcers or purulent or bloody nasal discharge
Abnormal chest radiograph
Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities
Abnormal urinary sediment
Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment
Granulomatous inflammation on biopsy
Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)

45. Diagnosis (Contd)
American College of Rheumatology –not intended to be used in routine clinical practice and established before ANCA.
Presence of 2 or more yield 88% sensitivity and 92% specificity
Nasal or oral inflammation
Abnormal chest radiograph (nodules, alveolar opacities)
Abnormal urine sediment
Granulomatous inflammation on biopsy of an artery or perivascular area

46. Diagnosis (Contd)
Routine Labs-nonspecific- Leukocytosis, thrombocytosis (>400,000), marked ESR, and normocytic,normochromic anemia, mildly elevated RF
ANCA- as previously described
Tissue Biopsy- dx should be confirmed by tissue bx at site of active disease
.Nasopharyngeal bx less invasive, but may not see full pathogenesis due to small amount of tissue- acute and chronic inflammation
Renal bx-segmental necrotizing glomerulnephritis w or w/o cresents
Skin-leukocytoclastic vasculitis with little or no complement and immunoglobulin
Lung-granulomatous and vasculitis

47. Diagnosis (Contd)
Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis
Sinuses
Nose
Skin--leukocytoclastic vasculitis with little or no complement and immunoglobulin on immunofluorescence
Kidney--segmental necrotizing glomerulonephritis that is usually pauci-immune on immunofluorescence / EM
Lung--vasculitis and granulomatous inflammation
(Only large sections of lung tissue obtained via thoracoscopic or open lung biopsy are likely to show all of the histologic features)
Seropositivity for C-ANCAs

49. Antineutrophil cytoplasmic antibodies

50. Focal or diffuse necrotizing extracapillary glomerulonephritis is the histological hallmark of ANCA-associated Vasculitis

51. Massive necrosis is usually associated to diffuse circumferential extracapillary proliferation. From a clinical point of view, the patient is affected by rapidly progressive renal failure.

52. The biopsy specimen of a lung from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation

53. C-ANCA staining pattern of ethanol-fixed normal human neutrophil

54. ANCA ~90% of Wegener's cases are ANCA+ 80 - 90 % PR3-ANCA
In limited dz, up to 40% may be ANCA neg
% PR3-ANCA
Remaining MPO-ANCA

55. Is ANCA sufficient? Concensus is that tissue dx is necessary
Rarely may initiate tx w/o biopsy
Should attempt to confirm w/ biopsy when able

56. Differential Dx of Vasculitis
Fibromuscular dysplasia
Cholesterol emboli
Atrial myxoma with emboli
Infective endocarditis
Malignancies,ie lymphamatoid granulomatosis
Bacteremia
Rickettsial dz
Amyloid
SLE

57. Differential of Pulmonary Renal Syndrome
Goodpasture’s Disease
Systemic Vasculitis
Wegener’s Granulomatosis
Microscopic Polyangiitis
Churg-Strauss Syndrome
Cryoglobulinemia
Henoch-Schonlein Purpura
Connective Tissue Disease
Polymyositis/Dermatomyositis
Progressive Systemic Sclerosis
SLE
Primary Glomerular Disease
IgA Nephropathy
Post-Infectious GN
Membranoproliferative GN

58. Treatment Traditional
Prednisone (initiated at 1 mg/kg daily for 1 to 2 months. then tapered)
Cyclophosphamide (2mg/kg daily for at least 12 months)
>90% improve and 75% remit

59. Treatment (Contd)
Many physicians favor use of daily oral cyclophosphamide/corticosteroid combination therapy in the initial treatment of all pts dx with Wegener’s, and
Once remission is induced (which requires a minimum of 3-6 months for most pts), other less toxic immunosuppressives can be employed

60. Treatment (Contd)
Use of aggressive immunotherapy is justified b/c survival in untreated generalized Wegener’s is extremely poor, with up to 90% of pt’s dying with in 2 yrs from respiratory or renal failure, but mortality is markedly diminished with introduction of cyclophosphamide/corticosteroid therapy

61. Treatment (Contd)
Response to therapy-partial or complete resolution of inflammatory manifestations, such as inactive urine sediment, although renal failure can persist

62. Treatment (Contd)
IV Cyclophosphamide monthly- lowers the overall cumulative dose-role is incompletely defined, and both equal and decreased efficacy has been described in Wegener’s, which may be due to different pt populations in the studies, nonresponders had more severe disease, and those with incomplete response-switching to oral daily regimen may induce remission

63. Treatment (Contd)
Methotrexate-mild dz, higher relapse rate, can’t use in Cr >2.0
Plasmapharesis-pts with renal dz needing dialysis, pulmonary hemorrhage, or also with anti-GBM

64. Treatment (Contd)
In one of largest nonrandomized prospective single center studies, outcomes of 158 pts with Wegener’s treated with varying regimens at NIH were reported
Standard low dose cyclophosphamide plus prednisone(133), cyclophos alone (8), glucocorticoids alone(10), or other cytotoxic agents plus steroids(6).
Cyclophos administered for a mean of 2 yrs.

65. Treatment (Contd) Mean follow up 8 yrs-In cyclophos and steroids:
Survival 80%, with deaths due to Wegners, side effects or both
Significant clinical improvement was observed in more than 90% of pts, with 75% achieving complete remission
Among the 98 pts followed for more than 5 yrs, more than half experienced remission of greater than 5 yrs

66. Treament (Contd)
So, based on studies, first line is daily oral cyclophosphamide/corticosteroid. Cyclophos at mg/kg/day, steroid (1mg/kg/day).
IV Cyclophosphamide can be used, not well studied, but associated with higher relapse and longer to remission
Methotrexate-maybe used in mild disease, or in maintenance, but either way, higher relapse rate
Azathioprine-maintence, esp in pts with renal insuffiency
Steroids- no significant benefit in maintenance

67. Treatment (Contd)
Duration of maintenance therapy months after stable remission
May need more long term maintenance esp if ANCA continues to be positive

68. AND daily cyclophos is very toxic
Treatment (Contd)
50% in remission relapse
AND daily cyclophos is very toxic
pancytopenia,
infection,
hemorrhagic cystitis
bladder cancer (increased 33-fold)
lymphoma (increased 11-fold)

69. Treatment (Contd)
Monthly IV cyclophosphamide -- less toxic but less effective
Weekly methotrexate -- maintains remission
Trimethoprim-sulfamethoxazole -- controversial (?effective for disease limited to the respiratory tract), reduces the relapse rate
Steroids —prednisone vs solumedrol
Plasmapheresis -unproven, awaiting MEPEX trial
Recommended for anti-GBM+, pulm hemmorhage, renal failure
IVIG— recommended in the setting of infection during PLEX

70. Prognosis
Overall, the morbidity and mortality associated with Wegener’s granulomatosis and microscopic polyangiitis, results from the combined effects of irreversible organ dysfunction b/c of inflammatory injury occurring before and the early phase of effective therapy, consequences of immunsuppressive therapy, and natural hx of disease

71. Prognosis (Contd)
Morbidity-consequences of therapy (glucocorticoid toxicity, increased risk of malignancy ie bladder cancer, skin ca, sterility, organ failure); disease related damage (partial hearing loss and persistent proteinuria);increased risk of DVT/PE in ANCA

72. Prognosis (Contd)
Renal –ESRD eventually occurs in 20-25% of pts. Poor renal outcome associated with more severe renal dysfunction at presentation, lack of response to initial treatment,and enhanced amount of fibrotic changes on renal bx
Mortality- Major causes of death are complications of underlying disease and therapy. 90% mortality rate in 2 yrs in untreated. Higher mortality in elderly, those with florid organ failure at presentation.

73. Prognosis (Contd)
Poorer outcomes with advanced age, severe renal impairment, DAH.
Mortality >75% if untreated with median survival of 5 months. Drastic improvement since 1970s in mortality.
Permanent morbidity:
CKD 42%
Hearing Loss 35%
Nasal Deformity 28%
Tracheal Stenosis 13%
Severe Infection 50% (Treatment)

74. Conclusions One of the most frequent pulmonary-renal syndromes
Granuloma’s in upper respiratory tract: rhinitis, sinusitis, pharyngits, stomatitis, pulmonary infiltrates (nodules with cavitations) with hemoptoe, respiratory insufficiency, diffusion disturbances
Most frequently RPGN-crescentic GN with pauci –immune GN
ANCA positive (large majority C-ANCA)

75. Conclusion (Contd)
Oral cyclophosphamide mg/kg BW + corticosteroids mg/kg BW.
I.V. pulse of cyclophosphamide 500 mg/m² every month for 3 months + corticosteroids- results are not better?
Follow ANCA titers
In case of dialysis need, plasmapheresis is to be considered, together with pulses of cyclophophamide.
Maintenance therapy: low dose of cyclophophamide,methotrexate
for pulmonary or upper respiratory tract manifestations: trimetoprim-sulfamethoxazole

76. Thank You!