Wegener's granulomatosis, or granulomatosis with polyangiitis (GPA), is an immune-mediated multisystem disease characterized by necrotizing granulomata in the respiratory tract, vasculitis affecting small to medium vessels, and focal glomerulonephritis. The condition has a higher prevalence in individuals of Northern European descent and typically presents with respiratory, renal, and possibly systemic symptoms; diagnosis is supported by criteria including nasal inflammation, abnormal chest radiographs, and urinary sediment findings. Treatment generally involves immunosuppressive therapy such as cyclophosphamide or rituximab, and while the 5-year survival rate is reasonable, relapse rates remain high, with factors contributing to relapse including treatment intensity and organ involvement.

1. Wegener’s
Granulomatosis
Dr Sreelekshmi Vignesh
GPST1
Respiratory Medicine

2. Summary
 Definition
 Epidemiology
 Etiology
 Hx & presentation
 Investigations
 Treatment
 DDs
 Mortality

3. 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.

4. 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.

5. 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 granulomatous
disease
 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].

6. 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

7. History
 Recurrent Respiratory Tract Infections in adults ( GP
notebook)
 Fevers, night sweats
 Fatigue, lethargy
 Loss of appetite
 Weight loss

8. 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

9. Presentation
ENT
 Chronic Sinusitis (67%)
 Rhinitis (22%)
 Epistaxis (11%)
 Saddle nose deformity
Ophthalmologic
 Conjunctivitis
 Episcleritis
 Uveitis
 Optic nerve vasculitis

10. 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.

11. Investigations
 FBC,U&E, ESR,CRP, Urine
 Indirect Immunofluorescence test for antineutrophil
cytoplasmic 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 parenchymal
involvement.
 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 vasculitis
and granulomas.

12. Findings
 Cytoplasmic antineutrophil cytoplasmic antibody (c-
ANCA) directed against PR3 is most specific for GPA

13. 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

15. Granulomatous vasculitis with multinucleated
histiocyte involving elastic artery
Palisading granuloma.
Muted microabscess. Giant cell nodule with embedded giant cell

16. Micronodular scar Necrotizing bronchitis with fibrinoid necrosis and
palisading histiocytes.

17. 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

18. 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

19. 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

20. 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.

21. 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]

22. 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].

23. 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

24. 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:
angelovalerio.marzano@policlinico.mi.it, 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

25. Qns?