Najla bt Abdul Ghafar Syahir Zulkiflee Irman Shahir Ibrahim

Wegeners granulomatosis
Introduction
Clinical features Pathogenesis

Investigations
Histopathology Treatment Case studies

Introduction
Friedrich Wegener - identified the illness in the

1930s. It is a well-recognized, although uncommon, disease process of unknown cause. 1 in 30,000- 50,000 people. Initial description by Wegener are:
Necrotizing granulomatous lesions of the respiratory

tract Necrotizing glomerulonephritis Systemic vasculitis of small arteries and veins

 Hypotheses:
Abnormal immune reaction secondary to a non specific

infection or an aberrant hypersensitivity response to an inhaled antigen. Possible hereditary predisposition.

This disease begins as localized process, which

may become more widely disseminated if left untreated.

Most patients respond favorably to treatment

Early diagnosis and appropriate therapy are critical

Wegeners Granulomatosis Classic Wegeners Granulomatosis Generalized Wegeners Granulomatosis Limited Wegeners Granulomatosis Superficial Wegeners Granulomatosis

Involvement Upper & lower respiratory tract Upper & lower respiratory tract + renal Respiratory system with slowly development of renal lesion Lesion primarily of the skin & mucosa

Clinical Features & Findings Upper Respiratory Tract

Nose
Nasal crusting Epistaxis

(nosebleeds) Erosion and perforation of the nasal septum.

-The bridge of the nose can collapse
resulting in a saddlenose 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 usually occurs late Can lead to renal failure if not treated aggressively Renal masses (rare) Active urine sediment: red blood cell casts

RBC casts

Eye
Scleritis Uveitis

Orbital pseudotumor

/proptosis

Ear
Ear infections that are slow to resolve.

Recurrent otitis media.

Decrease in hearing.

Skin
palpable purpura

most common
Raynauds

phenomenondue to inadequate blood flow to fingers and toes

Ulcers

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 Constitutional symptoms of fatigue, lowgrade fever, and weight loss

Oral Manifestation on Clinical Findings

Oral lesion are seen in the minority of those affected Oral changes may be the only clinically evident findings 1.

Strawberry Gingivitis Uncommon pattern of gingival alteration appears to be an early manifestation of Wegeners Granulomatosis Before renal involvement in most cases Affected gingiva appears florid & granular hyperplasia The surface forms numerous short red bulbous projection which hemorrhagic & friable (strawberry-like appearance) Most : buccal gingiva The process of alteration begin in the interdental area & spread to lateral adjacent areas May cause destruction of underlying bone with development of tooth mobility

2. Oral ulceration Unlike strawberry gingivitis, the ulceration do not form a pattern that is unique Clinically not specific & may occur on any mucosal surface Diagnosed at a later stage of the disease

3. Other less common orofacial manifestation Facial paralysis Labial mucosal nodules Sinusitis-related toothache Arthralgia of TMJ Jaw claudication Palatal ulceration from nasal extension Oral-antral fistulae Poorly healing extraction sites Enlargement of one or more salivary glands

The Wegeners Granulomatosis (WG) pathology is due to the action of the Antineutrophil Cytoplasmic Autoantibody (ANCA)

In WG, ANCAs are bind with proteinase 3 (PR3) which is expressed in neutrophils that have been primed by inflammatory cytokines.

PR3-ANCA Neutrophils bind to vascular epithelium and release reactive oxygen species (ROS) and proteolytic enzymes which causes granuloma formation and necrosing vasculitis in the epithelial cells.

Neutrophil extracellular traps (NET) Release PR3 Stimulate ANCA release

Adhesion molecule up-regulation

membrane expression of PR3

PR3

(In WG)

(In WG)

Importance of Early Diagnosis

Untreated

80% die within first year Mean survival 5 months Worse prognosis if renal involvement
Treated

75% survival at five years

Complications
Almost any part of the body can be affected, but the major late stage complications associated with untreated Wegeners are: Renal failure due to rapidly progressive glomerulonephritis Respiratory failure from upper airway obstruction, tracheal stenosis and pulmonary involvement Myocardial infarction due to inflammation of coronary vessels Nasal septum perforation Hearing loss after formation of inflammatory granulated tissue in the middle ear

Wegeners granulomatosis

 Blood test
Urinalysis (renal involvement) ANCA detection

Radiography and CT scanning

Biopsy Histologic finding

1)Blood test
Blood urea nitrogen level : elevated
Blood creatinine level : elevated Hypoalbuminemia : present

Mild normochromic normocytic anemia present in

50% of the pt Leukocytosis with the neutrophils predominance

1)Blood test
Westergren erythrocyte sedimentation rate (ESR) and

C-reactive protein (CRP) levels are elevated in 90% of the pt with active and generalized disease

2)Urinalysis
Proteinuria (non-nephrotic or nephrotic)
Microscopic hematuria

3)ANCA Detection
The 2 types of serologic assays that are commonly used

:
Indirect Immunofluorescence (IF) Enzyme immunoassay (EIA/ELISA)

3 types of IF pattern are recognized C-ANCA (anti-neutrophil cytoplasmic antibody) P-ANCA atypical ANCA

C-ANCA IF pattern

P-ANCA IF pattern

3)ANCA Detection
C-ANCA directed against PR-3 (proteinase-3) is most

specific for WG.

IF shows positive C-ANCA in 88% of all WG pt

Using both IF and ELISA, C-ANCA is detectable in 100% of

pt with active generalized WG. Some WG pt express P-ANCA specific for myeloperoxidase (MPO) Wegeners Granulomatosis Etanercept Trial (WGET) analyzed that IF show positive P-ANCA in 13% of pt with severe disease. The test result may give a false positive diagnosis.

4)Radiography and CT Scanning

Findings on radiographic are abnormal in 2/3 of adults

with WG. Most common findings are single or multiple nodules and masses Nodules are typically diffuse and approximately 50% are cavitated.

Chest X-Ray Image of WG pt

4)Radiography and CT Scanning

Findings on CT scan and high resolution CT scan

include consolidation, patchy or diffuse ground-glass opacities, or both.

CT scan image of WG pt

5)Biopsy
Renal and lung biopsy are most specific for WG.
Sampling error may occur, histopathologic findings

may be nonspecific. Biopsy may not be required if the clinical test is convincing and a biopsy site is apparent or too invasive to obtain.

5)Biopsy
Histologic examination of lung samples may reveal

classic triad of
Parenchymal necrosis Granulomatous inflammation Vasculitis

Histopathologic features
It appears as mixed inflammation centered around blood vessels.

The connective tissue adjacent to the vessel has inflammatory cellular infiltrates histiocytes lymphocytes eosinophils multinucleated giant cell

The involved vessels will demonstrate transmural inflammation. -often with areas of heavy neutrophilic infiltration, necrosis, and nuclear dust ( leukocytoclastic vasculitis)

A blood vessel with a leukocytoclastic vasculitis

 Special stains for organism:

negative no foreign material found

In oral biopsy specimens, the oral epithelium may demonstrate

pseudoepitheliomatous hyperplasia subepithelial abscess

The lesions of strawberry gingivitis

demonstrate prominent vascularity with extensive red blood cell extravasation.

(A) strawberry gingivitis. (B) Panoramic X-ray revealing diffuse bone destruction with imprecise limits on the left mandibular molars (arrow). (C) pseudoepitheliomatous hyperplasia and a mixed inflammatory infiltrate with abundant neutrophils and eosinophils (D) Micro-abscesses within the pseudoepitheliomatous hyperplastic epithelium (E) Inflammatory infiltrate featuring multinucleate giant cells (arrow)

Diagnosis of Wegeners granulomatosis

Nasal or oral Urinary sediment with

inflammation-with development of painful or painless ulcers or purulent or bloody nasal discharge Abnormal chest radiograph-nodules, fixed infiltrates or cavities

microhematuria or red cell casts Granulomatous inflamation on biopsy of artery A patient can be diagnosed with WG if at least 2 of these criteria are met. (American College of Rheumatology)

Treatment
The mainstay of treatment for Wegener granulomatosis (WG) is a

combination of corticosteroids & cytotoxic agents.

Untreated generalized or severe Wegener granulomatosis (WG) carries

up to 90% of patients dying within 2 years, usually of respiratory or renal

failure. Even non-renal WG carries a mortality rate of up to 40%.

Outcomes for this previously fatal disease in the 1970s introduction of

cyclophosphamide, which is administered in combination with

corticosteroids. Approximately 90% of patients with WG respond to

cyclophosphamide, with approximately 75% experiencing complete remission.

 Current treatment recommendations in WG depend on the severity and activity

of disease. The European Vasculitis Study Group recommends grading disease into 5 categories :
a)

Localized - Upper and/or lower respiratory tract disease without any other

systemic involvement or constitutional symptoms

b) c)

Early systemic - Any, without organ-threatening or life-threatening disease Generalized - Renal or other organ-threatening disease, serum creatinine level less than 5.6 mg/dL

d)

Severe - Renal or other vital-organ failure, serum creatinine level exceeding 5.6 mg/dL

e)

Refractory - Progressive disease unresponsive to glucocorticoids and

cyclophosphamide

Treatment plan
Remission induction

Remission maintenance

Cyclophosphamide

Azathioprine

Rituximab

Methotrexate

Corticosteroids

Leflunomide

Plasma exchange

Methotrexate

Cyclophosphamide
Generalized or severe disease generally requires aggressive

therapy. Oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion

standard for induction of remission in AAV(American AntiVivisection Society).

Eventually, intravenous cyclophosphamide used as an alternative to

oral cyclophosphamide in an effort to decrease treatment-associated

toxicities, and the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for

induction of remission in generalized/severe Wegener

granulomatosis (WG) for years.

Rituximab
Rituximab combined with high-dose glucocorticoids represents an alternative to

cyclophosphamide for induction of remission in WG; it is the first treatment ever approved by the Food and Drug Administration (FDA ) or AAV.
Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that induces

apoptosis of B cells. Infusion of rituximab typically causes depletion of circulating B cells and therefore may decrease the production of autoantibodies such as Anti-neutrophil cytoplasmic antibodies (ANCAs).
Adverse effects include infusion reactions, mucocutaneous reactions, increased

risk of infections (to include opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy.

Glucocorticoids
Glucocorticoids are usually given orally, but, if a rapid response is

needed, such as in the case of rapidly progressive glomerulonephritis and/or alveolar hemorrhage, intravenous pulse methylprednisolone (0.5-1 g/day for 3 consecutive days) can be used and then followed by oral prednisone. Initial high-dose glucocorticoids (1 mg/kg/day) should be continued for at least 1 month. Doses should not be reduced to less than 15 mg/day within

the first 3 months. The dose should then be slowly tapered to a

maintenance dose of 10 mg/day or less during remission.Methods to prevent glucocorticoid-induced osteoporosis should be followed.

Plasma exchange
Plasma exchange may be considered in patients with rapidly progressive

renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function.Plasma exchange has not been shown to improve overall survival rates or relapse rates but has been associated with improved long-term survival, free of hemodialysis.The proposed mechanism of action of plasma exchange in AAV includes removal of pathologic circulating factors (eg, ANCA, activated lymphocytes), removal of excess physiologic factors (eg,

complement, coagulation factors, cytokines/chemokines), replacement of

deficient plasma factors, and other, less well-defined mechanisms. Potential adverse events associated with plasma exchange include electrolyte disturbances, anaphylaxis, hemorrhage, and transfusion-related lung injury.

Methotrexate
Localized, milder disease generally requires less

aggressive therapy. A combination of methotrexate (oral or subcutaneous) and glucocorticoids can be considered as a less-toxic alternative to cyclophosphamide for the induction of remission of nonorgan-threatening or non life-threatening WG.

 Once induction of remission has occurred, maintenance

of remission should be continued for at least 18 months, often longer. Agents that can be used in remission maintenance include azathioprine, methotrexate, and leflunomide.

Azathioprine
Azathioprine has been proven inferior to

cyclophosphamide during the induction phase of treatment. Azathioprine impairs leukocyte proliferation by inhibiting purine synthesis.

Methotrexate
Methotrexate (20-25 mg weekly, oral or subcutaneous)

has been used for the maintenance of remission if the serum creatinine level is less than 1.5 mg/dL.
Methotrexate has been shown to be similar to

azathioprine in terms of adverse effects, efficacy in maintaining remission, and rates of relapse.
The rate of relapse with methotrexate ranges from 37-

58%.

Leflunomide
Leflunomide (20-30 mg/day) is as effective as methotrexate,

but it is associated with more adverse effects. Leflunomide targets T cells by inhibiting the mitochondrial enzyme

dihydroorotate dehydrogenase and thus limits pyrimidine

synthesis. It is used in the treatment of rheumatoid arthritis. Leflunomide is metabolized by the liver and thus may be used

in patients with renal insufficiency.

Adverse effect is increased peripheral neuropathy symptoms.

Case studies
42-year old white male
History of sinusitis for almost 2 years Treated with different antibiotics without any

improvement
Developed lung mass on chest radiograph

Upon admission,
Not in severe distress
Tympanic membrane with positive light reflexes Erythematous throat with no other lesions

Lungs were clear to auscultation bilaterally

Abdomen were not distended nor tender No edema, clubbing or cyanosis of extremities

Admission diagnosis
Pansinusitis (that failed outpatient treatment)
Lung mass

Investigations: -MRI of brain: NAD(to rule out possible cavernous sinus thrombosis) -CT scan of lung: large left upper lobe lesion * -CT scan of abdomen & pelvis: NAD

Differential diagnosis
*Wegeners granulomatosis *Lung carcinoma

*Tuberculosis

*Fungal pneumonia

On day 3 of admission
Developed joint pain (right shoulder and both hands)
Given indomethacin and symptoms improved within 2

days Investigations: C-reactive protein (CRP) & ESR were elevated*.

On day 10 of admission
Developed painful ulcer (left side of tongue)
Symptoms improved with indomethacin &

levofloxacin Investigations: Serum C-ANCA & HIV test was performed*.

On day 13 of admission
Patient was discharged taking levofloxacin, ibuprofen

and loratadine C-ANCA result was still pending on discharge

2 days later
Patient came back with dysphagia, flank pain* &

purpuric rash (both his lower extremities up to his abdomen) Dysuria* & hematuria* Ulcer on uvula Investigations: -Urinalysis and urine culture (positive for nitrites, blood, WBC and bacteria) ESR & CRP still elevated C-ANCA result still pending

Diagnosis
Wegeners granulomatosis
Treatment:

-Monthly intravenous cyclophosphamide therapy for 6 months and steroids Tolerated well Does not show any signs of relapse