Update on classification of vasculitis and Wegener

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Update on classification of vasculitis and
Wegeners granulomatosis

• Dr.

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Overview

• Classification of vasculitis
• Wegeners granulomatosis
• Epidemiology
• Clinical features
• Pathogenesis
• Diagnosis
• Treatment
• Prognosis

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Vasculitis classification the first step
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Primary Systemic Vasculitis classification
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Classification of systemic vasculitis
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Chapel Hill Consensus Conference on the
Nomenclature of Systemic Vasculitis

• Small vessel vasculitis
• Wegeners 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

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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

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Classification of systemic vasculitis

• 2. medium-sized vasculitis arterioles,
  capillaries and venules
• Wegeners granulomatosis (WG)
• Churg-Strauss syndrome (CSS)
• Microscopic polyangiitis (MPA)
• 3. small vessel vasculitis venules, capillaries
• Henoch Schonlein purpura (HSP)
• Cryoglobulinaemic vasculitis

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Pathogenesis of vasculitis

• Antibody mediated inflammation
• Wegeners granulomatosis (WG)
• Churg-Strass syndrome (CSS)
• Microscopic polyangiitis (MPA)

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Pathogenesis of vasculitis

• Immune complex-mediated inflammation
• Henoch SchÖlein purpura (HSP)
• Cryoglobulinaemic vasculitis
• Polyarteritis nodosa (PAN)
• Cell-mediated inflammation
• Giant cell arteritis
• Takayasu arteritis
• Wegeners granulomatosis (WG)
• Churg-Strass syndrome (CSS)

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Small vessel pauci-immune vasculitis

• Wegeners 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

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Wegeners Granulomatosis
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Wegeners Granulomatosis

• Vasculitis and Granulomas in Lung and Upper
  Airway and also Glomerulonephritis

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History of Wegeners

• In 1931
• 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

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Wegeners 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

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Definitions

• Wegeners granulomatosis is a systemic vasculitis
  of the medium and small arteries, as well as
  venules, arterioles and occasionally large
  arteries
• Classic Wegeners primarily involves the upper
  and lower respiratory tracts and the kidneys

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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

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The Controversy

• Wegeners vs PR3-ANCA vasculitis
• Lancet, 22 April 2006
• Suggestion that using Wegeners name needs
  balanced discussion within the scientific
  community
• Reiter's syndrome-? reactive arthritis

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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
• Goodpastures
• Rheumatic disorders
• Autoimmune GI disorders
• CF
• Diagnostic Criteria primarily clinical

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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 (gt5 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

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Classic Symptoms

• Upper respiratory tract
• sinuses
• Nose
• ears
• trachea
• Lungs
• Kidneys

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Eye

• Scleritis
• Uveitis
• Orbital pseudotumor /proptosis

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Upper Respiratory TractEar

• Ear infections that are slow to resolve
• Recurrent otitis media
• Decrease in hearing

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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
  saddlenose deformity.

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Upper Respiratory Tract Sinuses/Trachea

• Sinuses
• Chronic sinus inflammation
• Trachea
• subglottic stenosis

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Lungs

• Nodules (which may cavitate)
• Alveolar opacities
• Pleural opacities
• Diffuse hazy opacities (which may reflect
  alveolar hemorrhage)

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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

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RBC casts
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Skin

• palpable purpura most common
• Raynauds phenomenondue to inadequate blood flow
  to fingers and toes
• Ulcers

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Miscellaneous

• JointsArthritis can occur, with joint swelling
  and pain
• NervesPeripheral 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
• Genitourinary tract
• Constitutional symptoms of fatigue, lowgrade
  fever, and weight loss

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Incidence of symptoms

• Symptom At Onset Total
• ENT 75 95
• Lung 50 85
• Joints 30 70
• Fever 25 50
• Kidney 20 75
• Cough 20 50
• Eye 15 50
• Skin 15 45
• Weight Loss 10 35
• Nervous System (Central/Peripheral) 0 10/15
• One-third of patients may be without symptoms at
  onset of disease

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Update on vasculitis J Allergy Clin Immunol 2009
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Update on vasculitis J Allergy Clin Immunol 2009
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Wegeners 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 Wegeners, 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 Wegeners

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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)

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In addition to pulmonary and renal (Contd)

• Skin (hemorrhagic lesions, palpable purpura)
• Nervous system(cranial nerve abnormalities)
• GI tract/Heart, lower GU

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Wegeners 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
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PathogenesisRisk factors and inciting events

• Exact events obscure
• Infectiousstaph?
• Genetic
• single nucleotide polymorphism in a gene encoding
  a protein tyrosine phosphatase (PTPN22)
• AAT deficiency
• Environmentalinhalational?
• Silica
• lead
• mercury

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PathogenesisANCA

• 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

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Pathogenesis (Contd)

• Priming of Neutrophils
• Exposing PR3 and MPO epitopes
• ANCA binding
• Degranulation/ROS production/neutrophil-endothelia
  l cell interaction
• Increased ANCA Increased degranulation rate

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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 Wegeners.

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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

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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 (gt5 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)

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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

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Diagnosis (Contd)

• Routine Labs-nonspecific- Leukocytosis,
  thrombocytosis (gt400,000), 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

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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

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Antineutrophil cytoplasmic antibodies
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Focal or diffuse necrotizing extracapillary
glomerulonephritis is the histological hallmark
of ANCA-associated Vasculitis
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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.
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The biopsy specimen of a lung from a patient with
Wegener granulomatosis showing evidence of
vasculitis and inflammation
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C-ANCA staining pattern of ethanol-fixed normal
human neutrophil
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ANCA

• 90 of Wegener's cases are ANCA
• In limited dz, up to 40 may be ANCA neg
• 80 - 90 PR3-ANCA
• Remaining MPO-ANCA

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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

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Differential Dx of Vasculitis

• Fibromuscular dysplasia
• Cholesterol emboli
• Atrial myxoma with emboli
• Infective endocarditis
• Malignancies,ie lymphamatoid granulomatosis
• Bacteremia
• Rickettsial dz
• Amyloid
• SLE

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Differential of Pulmonary Renal Syndrome

• Goodpastures Disease
• Systemic Vasculitis
• Wegeners 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

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TreatmentTraditional

• Prednisone (initiated at 1 mg/kg daily for 1 to 2
  months. then tapered)
• Cyclophosphamide (2mg/kg daily for at least 12
  months)
• gt90 improve and 75 remit

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Treatment (Contd)

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

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Treatment (Contd)

• Use of aggressive immunotherapy is justified b/c
  survival in untreated generalized Wegeners is
  extremely poor, with up to 90 of pts dying with
  in 2 yrs from respiratory or renal failure, but
  mortality is markedly diminished with
  introduction of cyclophosphamide/corticosteroid
  therapy

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Treatment (Contd)

• Response to therapy-partial or complete
  resolution of inflammatory manifestations, such
  as inactive urine sediment, although renal
  failure can persist

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Treatment (Contd)

• IV Cyclophosphamide monthly- lowers the overall
  cumulative dose-role is incompletely defined, and
  both equal and decreased efficacy has been
  described in Wegeners, 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

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Treatment (Contd)

• Methotrexate-mild dz, higher relapse rate, cant
  use in Cr gt2.0
• Plasmapharesis-pts with renal dz needing
  dialysis, pulmonary hemorrhage, or also with
  anti-GBM

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Treatment (Contd)

• In one of largest nonrandomized prospective
  single center studies, outcomes of 158 pts with
  Wegeners 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.

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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

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Treament (Contd)

• So, based on studies, first line is daily oral
  cyclophosphamide/corticosteroid. Cyclophos at
  1.5-2 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

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Treatment (Contd)

• Duration of maintenance therapy- 12-18 months
  after stable remission
• May need more long term maintenance esp if ANCA
  continues to be positive

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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)

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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

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Prognosis

• Overall, the morbidity and mortality associated
  with Wegeners 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

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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

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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.

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Prognosis (Contd)

• Poorer outcomes with advanced age, severe renal
  impairment, DAH.
• Mortality gt75 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)

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Conclusions

• One of the most frequent pulmonary-renal
  syndromes
• Granulomas 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)

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Conclusion (Contd)

• Oral cyclophosphamide 1 - 2 mg/kg BW
  corticosteroids 0.6 -1 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

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Thank You!