wegener granulomatosis 2
TRANSCRIPT
Wegener’s
Granulomatosis
Dr Sreelekshmi Vignesh
GPST1
Respiratory Medicine
Summary
Definition
Epidemiology
Etiology
Hx & presentation
Investigations
Treatment
DDs
Mortality
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.
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.
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].
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
History
Recurrent Respiratory Tract Infections in adults ( GP
notebook)
Fevers, night sweats
Fatigue, lethargy
Loss of appetite
Weight loss
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
Presentation
ENT
Chronic Sinusitis (67%)
Rhinitis (22%)
Epistaxis (11%)
Saddle nose deformity
Ophthalmologic
Conjunctivitis
Episcleritis
Uveitis
Optic nerve vasculitis
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.
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.
Findings
Cytoplasmic antineutrophil cytoplasmic antibody (c-
ANCA) directed against PR3 is most specific for GPA
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
Granulomatous vasculitis with multinucleated
histiocyte involving elastic arteryPalisading granuloma.
Muted microabscess. Giant cell nodule with embedded giant cell
Micronodular scar Necrotizing bronchitis with fibrinoid necrosis and
palisading histiocytes.
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
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
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
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.
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]
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].
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
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
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