Update on classification of vasculitis and Wegener’s granulomatosis

Dr.

Overview

Classification of vasculitis Wegener’s granulomatosis

Epidemiology Clinical features Pathogenesis Diagnosis Treatment Prognosis

Vasculitis classification– the first step

Primary Systemic Vasculitis classification

Classification of systemic 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

Classification of systemic vasculitis

2 major groups based on clinical and histopathological features of vasculitis1. 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

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

Pathogenesis of vasculitis

Antibody mediated inflammation Wegener’s granulomatosis (WG) Churg-Strass syndrome (CSS) Microscopic polyangiitis (MPA)

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)

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

Wegener’s Granulomatosis

Wegener’s Granulomatosis

Vasculitis and Granulomas in Lung and Upper Airway and also Glomerulonephritis

History of Wegener’s 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

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

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

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

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

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

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%

Classic Symptoms

Upper respiratory tract sinuses Nose ears trachea

Lungs Kidneys

Eye

Scleritis

Uveitis

Orbital pseudotumor /proptosis

Upper Respiratory TractEar

Ear infections that are slow to resolve

Recurrent otitis mediaDecrease in hearing

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”.

Upper Respiratory Tract Sinuses/Trachea

Sinuses Chronic sinus

inflammation Trachea

subglottic stenosis

Lungs Nodules (which may

cavitate)

Alveolar opacities

Pleural opacities Diffuse hazy

opacities (which may reflect alveolar hemorrhage)

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

RBC casts

Skin “palpable purpura”

most common

Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes

Ulcers

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 Genito–urinary tract Constitutional symptoms of fatigue, low–

grade fever, and weight loss

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

Update on vasculitis: J Allergy Clin Immunol 2009

Update on vasculitis: J Allergy Clin Immunol 2009

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

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…)

In addition to pulmonary and renal… (Contd)

Skin (hemorrhagic lesions, palpable purpura)

Nervous system(cranial nerve abnormalities)

GI tract/Heart, lower GU

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

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ENT Lung Kidney

At InitialPresentation

ThroughoutDisease Course

PathogenesisRisk 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

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

Pathogenesis (Contd)

“Priming” of Neutrophils Exposing PR3 and MPO epitopes

ANCA binding Degranulation/ROS

production/neutrophil-endothelial cell interaction

Increased ANCA = Increased degranulation rate

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.

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

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)

Criteria for ClassificationDiagnosis

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

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

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

Antineutrophil cytoplasmic antibodies

Focal or diffuse necrotizing extracapillary glomerulonephritis is the

histological hallmark of ANCA-associated Vasculitis

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.

The biopsy specimen of a lung from a patient with Wegener

granulomatosis showing evidence of vasculitis and inflammation

C-ANCA staining pattern of ethanol-fixed normal human

neutrophil

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

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

Differential Dx of Vasculitis

Fibromuscular dysplasia Cholesterol emboli Atrial myxoma with emboli Infective endocarditis Malignancies,ie lymphamatoid

granulomatosis Bacteremia Rickettsial dz Amyloid SLE

Differential of Pulmonary Renal Syndrome

Goodpasture’s DiseaseSystemic Vasculitis

Wegener’s Granulomatosis Microscopic PolyangiitisChurg-Strauss SyndromeCryoglobulinemiaHenoch-Schonlein Purpura

Connective Tissue DiseasePolymyositis/DermatomyositisProgressive Systemic SclerosisSLE

Primary Glomerular DiseaseIgA NephropathyPost-Infectious GNMembranoproliferative GN

TreatmentTraditional

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

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

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

Treatment (Contd)

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

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

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

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.

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

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

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

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)

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

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

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

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.

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)

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)

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,methotrexatefor pulmonary or upper respiratory tract manifestations: trimetoprim-sulfamethoxazole

Conclusion (Contd)