wegener granulomatosis 2

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Wegener’s Granulomatosis Dr Sreelekshmi Vignesh GPST1 Respiratory Medicine

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Page 1: Wegener granulomatosis 2

Wegener’s

Granulomatosis

Dr Sreelekshmi Vignesh

GPST1

Respiratory Medicine

Page 2: Wegener granulomatosis 2

Summary

Definition

Epidemiology

Etiology

Hx & presentation

Investigations

Treatment

DDs

Mortality

Page 3: Wegener granulomatosis 2

Definition

Immune mediated multisystem disease characterised by

1. necrotising granulomata of the upper and lower

respiratory tract,

2. necrotising vasculitis- affecting small & medium sized

vessels

3. focal glomerulonephritis

Also known as Granulomatosis with Polyangitis.(GPA)

Lung – M/C organ

Aggressive airways pathology

Chronic relapsing course.

Page 4: Wegener granulomatosis 2

Epidemiology

The incidence and prevalence of GPA in the United

Kingdom is estimated at 10.2 cases and 250 cases per

million population, respectively.

UK General Practice Research Database reported an

overall annual incidence of 8.4/million

M/C in individuals of northern European descent

(approx. 90%)

M:F:: 1.5:1

Age of onset : any , typically 35-55 yrs of age.

Page 5: Wegener granulomatosis 2

Etiology Humoral Autoimmunity

Ass.presence of diffuse staining cytoplasmic ANCA (C-ANCA) directed against serine proteinase 3 antigen (PR3-ANCA), the so-called Wegener autoantigen.

Genetic association with inciting factor

defective allele for alpha-1 antitrypsin

Carrying the DPB1*0401 allele, which is also associated with chronic beryllium disease, a granulomatousdisease

Microbes

Chronic nasal carriage of Staph .aureus- associated with relapses of GPA and prophylactic treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) can reduce the likelihood of relapse by 60% -noted by Stegeman et al

(Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. January 1994;120(1):12-17. [Medline].

Page 6: Wegener granulomatosis 2

1990 Criteria for the Classification of Wegener's

Granulomatosis

1) Nasal or oral inflammation: Development of painful or painless oral ulcers or purulent or bloody nasal discharge

2) Abnormal chest radiograph: Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities

3) Urinary sediment: Microhematuria (>5RBC/HPF)

4) Granulomatous inflammation on biopsy: Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area

The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0% for WG

Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101---7

Page 7: Wegener granulomatosis 2

History

Recurrent Respiratory Tract Infections in adults ( GP

notebook)

Fevers, night sweats

Fatigue, lethargy

Loss of appetite

Weight loss

Page 8: Wegener granulomatosis 2

Presentation

Pulmonary Pulmonary infiltrates

(71%)

Cough (34%)

Hemoptysis (18%)

Chest discomfort (8%)

Dyspnea (7%)

Diffuse alveolar hemorrhage (DAH) due to alveolar capillaritis(5%-45% )

Renal

Usually assymptomatic

Present in 17% pts

Renal failure 11%

Manifests as Crescentic

necrotizing

glomerulonephritis –

urinary sediment with

more than 5 RBC/HPF

Page 9: Wegener granulomatosis 2

Presentation

ENT

Chronic Sinusitis (67%)

Rhinitis (22%)

Epistaxis (11%)

Saddle nose deformity

Ophthalmologic

Conjunctivitis

Episcleritis

Uveitis

Optic nerve vasculitis

Page 10: Wegener granulomatosis 2

Presentation

Skin : 45%

Palpable purpura or skin ulcers

Nervous System

mononeuritis multiplex, sensorimotor polyneuropathy, and

cranial nerve palsies

Musculoskeletal

Polyarticular and symmetric, rarely deforming

Both small and large joints

Cardiac

Pericarditis,coronary arteritis – MI or sudden death.

Page 11: Wegener granulomatosis 2

Investigations

FBC,U&E, ESR,CRP, Urine

Indirect Immunofluorescence test for antineutrophilcytoplasmic antibodies (ANCA), of 2 types: C-ANCA directed against PR-3 and P-ANCA

ELISA provides target antigen-specific characterization of ANCA (ie, anti-PR3) and should be used to confirm IF findings

CXR looking for cavity formation and pulmonary infiltrates

Nasal endoscopy.

Lung function tests and flow volume loop looking for subglottic stenosis.

Chest CT imaging to exclude lung parenchymalinvolvement.

CT Sinus scan to exclude sinus disease.

Bronchoscopy

Biopsy of affected tissue, which may include nasal mucosa, lung biopsy, renal biopsy, looking for presence of vasculitisand granulomas.

Page 12: Wegener granulomatosis 2

Findings

Cytoplasmic antineutrophil cytoplasmic antibody (c-

ANCA) directed against PR3 is most specific for GPA

Page 13: Wegener granulomatosis 2

Findings

Radiological findings:

M/C - single or multiple nodules and masses

Nodules are typically diffuse with cavitation in 50%

Diffuse alveolar opacities, atelectasis, and obstructive pneumonia

caused by bronchial stenosis.

Consolidation, patchy or diffuse ground-glass opacities, or both

Additional CT scan findings include stenoses of the larynx or

tracheobronchial tree, bronchial wall thickening, bronchiectasis,

pleural thickening or effusion, and lymphadenopathy

Page 14: Wegener granulomatosis 2
Page 15: Wegener granulomatosis 2

Granulomatous vasculitis with multinucleated

histiocyte involving elastic arteryPalisading granuloma.

Muted microabscess. Giant cell nodule with embedded giant cell

Page 16: Wegener granulomatosis 2

Micronodular scar Necrotizing bronchitis with fibrinoid necrosis and

palisading histiocytes.

Page 17: Wegener granulomatosis 2

Treatment

Induction of remission in GPA is approached as follows:

Cyclophosphamide with high-dose glucocorticoids (criterion standard)

Rituximab with high-dose glucocorticoids

Methotrexate (oral or subcutaneous) with high-dose glucocorticoids, in non–organ-threatening or non–life-threatening GPA[5]

Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function

Page 18: Wegener granulomatosis 2

Treatment

Severe/ generalised WG :

Cyclophosphamide with high dose glucocorticoids is the drug of

choice for 3-6 months

Cyclophosphamide : oral 2mg/kg/day/ intermittent IV – pulsed therapy

15mg/kg every 2wks of first three pulses.

Prednisolone -1mg/kg/day slowly tapered to not less than 15mg/kg/day

within first three months then tapered to 10mg/kg/day over 6-18

months

MESNA- given IV to reduce toxic effects of cyclophosphamide

Pneumocyctis Jiroveci Prophylaxis with TMP-SMZ

Monitor FBC, Urine,add Vitamin D, Ca supplemetns, Alendronic acid

Mild/Localised WG

Methotrexate 20-25mg weekly oral/sc + steroids

Page 19: Wegener granulomatosis 2

Treatment

Maintenance of remission

Once induction of remission has occurred, treatment for maintenance of remission should be continued for at least 18 months, often longer

Azathioprine (2 mg/kg/day) is safer than, and as effective as, cyclophosphamide in maintaining remission

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

Leflunomide (20-30 mg/day) is as effective as methotrexate, but it is associated with more adverse effects

Page 20: Wegener granulomatosis 2

DDs

Anti–glomerular basement membrane antibody disease-Good Pasture’s Syndrome

Legionella infection

Mixed connective tissue disease.

Systemic lupus erythematosus.

Other antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides (ie microscopic polyangiitis, Churg-Strauss syndrome).

Rheumatoid arthritis with systemic vasculitis.

Mixed cryoglobulinaemia.

Renal vein thrombosis with pulmonary embolism.

Page 21: Wegener granulomatosis 2

Mortality

According to a meta-analysis, with current treatments,

the 5-year survival rate ranges from 74-79%.(1) The 1-

year mortality rate is still high, around 11% (range, 2.2-

25%), depending on disease severity and the intensity of

treatment(2)

(1) Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp

Rheumatol. September-October 2008;26:S94-S104. [Medline].

(2) ittle MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis:

relative contribution of adverse events and active vasculitis. Ann Rheum Dis. June

2010;69(6):1036-43. [Medline]

Page 22: Wegener granulomatosis 2

Relapse

Relapse is common in GPA. Typically, up to half of

patients with GPA experience relapse within 5 years. (1)

The rate (18-40% at 24 mo) and time to first relapse

(15-29 mo) varies. Factors associated with relapse

include treatment (< 10 g of cyclophosphamide in the

first 6 mo, maintaining a high dose of prednisone [>20

mg/day] for < 2.75 mo, and goal of 0 dose of

glucocorticoids), ANCA status at diagnosis, and target

organ involvement (lung involvement, cardiac

involvement, renal involvement, chronic nasal carriage

of S aureus.(2)

(1) Renaudineau Y, Le Meur Y. Renal involvement in Wegener's Granulomatosis. Clinic

Rev Allerg Immunol. October 2008;35:22-29. [Medline].

(2) Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of

antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the

European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis.

July 2008;67:1004-1010. [Medline].

Page 23: Wegener granulomatosis 2

Learning points

Multisystem disease- necrotising vasculitis &

granulomatous inflammation

Radiological findings – pulmonary infiltrates

Cough , hemoptysis, renal findings : microsopic

hematuria.

IF +ELISA confirms c-ANCA against PR-3

Biopsy- vasculitis & granuloma

Rx- Immunosuppressive therapy (Cyclophosphamide) +

prednisolone

Page 24: Wegener granulomatosis 2

References Emedicine

BMJ

American College of Rheumatology

GP notebook

Patient.co.uk

From the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and the Department of Pathology, National Defense Medical College, Saitama, Japan. Accepted for publication August 21, 1996.Eugene J, Mark MD,Douglas B, FLIEDER, MD AND OSAMU MATSUBARA, MD

SHORT REPORT Localized Wegener’s granulomatosis,A.V. Marzano,†,* Y. Balice,† M. Papini,‡ R. Testa,‡ E. Berti,†,§ C. Crosti†,†U.O. Dermatologia, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia,Intensiva e Scienze Dermatologiche, Universita` degli Studi di Milano, Milan, Italy,‡Sez. Clinica Dermatologica e Venerologica di Terni, Dipartimento di Specialita` Medico-Chirurgiche e Sanita` Pubblica, Universita`,di Perugia, Terni, Italy,§Dipartimento di Medicina Clinica e Prevenzione, Universita` degli Studi di Milano-Bicocca, Milan, Italy,*Correspondence: A.V. Marzano. E-mail: [email protected], July 2010

Treated Wegener's Granulomatosis: Distinctive Pathological Findings in the Lungs of 20 Patients and What They Tell Us About the Natural History of the Disease EUGENE J, MARK, MD, DOUGLAS B, FLIEDER, MD AND OSAMU MATSUBARA, MD

Page 25: Wegener granulomatosis 2

Qns?