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| {{DiseaseDisorder infobox | | | __NOTOC__ |
| Name = Wegener's granulomatosis |
| | {{Wegener's granulomatosis}} |
| Image = Wegner's-granulomatosis-001.jpg|
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| Caption = |
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| ICD10 = {{ICD10|M|31|3|m|30}} |
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| ICD9 = {{ICD9|446.4}} |
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| ICDO = |
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| OMIM = |
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| DiseasesDB = 14057 |
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| MedlinePlus = 000135 |
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| eMedicineSubj = med |
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| eMedicineTopic = 2401 |
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| MeshID = D014890 |
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| }}
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| {{SI}}
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| {{CMG}}
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| '''Associate Editor-In-Chief:''' {{CZ}} | | '''For patient information click [[Wegener's granulomatosis (patient information)|here]]''' |
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| {{EH}}
| | '''Click [[The Heart in Wegener's Granulomatosis|here]] for The heart in Wegener's granulomatosis''' |
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| ===[[The Heart in Wegener's Granulomatosis | for the heart in Wegener's granulomatosis click here]]===
| | {{CMG}}{{APM}}{{AE}}{{ADS}}{{KW}}{{CZ}} |
| | ==[[Wegener's granulomatosis overview|Overview]]== |
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| ==Overview== | | ==[[Wegener's granulomatosis historical perspective|Historical Perspective]]== |
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| '''Wegener's granulomatosis''' is a form of [[vasculitis]] that affects the [[lung]]s, [[kidney]]s and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term [[immune suppression]].<ref name=Seo>Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. ''Am J Med'' 2004;117:39-50. PMID 15210387.</ref> It is named after Dr. [[Friedrich Wegener]], who described the disease in 1936.<ref name=Enersen>{{WhoNamedIt|synd|2823}}</ref>
| | ==[[Granulomatosis with polyangiitis classification|Classification]]== |
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| Wegener's granulomatosis is part of a larger group of vasculitic syndromes, all of which feature the presence of an abnormal type of circulating [[antibody]] termed [[antineutrophil cytoplasmic antibody|ANCA]]s (antineutrophil cytoplasmic antibodies) and affect small and medium-size [[blood vessel]]s. Apart from Wegener's, this category includes [[Churg-Strauss syndrome]] and [[microscopic polyangiitis]].<ref name=Seo/> Although Wegener's granulomatosis affects small and medium-sized vessels,<ref name="urlWegeners Granulomatosis: Vasculitis: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec04/ch033/ch033k.html |title=Wegener's Granulomatosis: Vasculitis: Merck Manual Professional |format= |work= |accessdate=2009-01-08}}</ref> it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.<ref name="isbn0-7817-4750-3">{{cite book |author=Silva, Fred; Jennette, J. Charles; Heptinstall, Robert H.; Olson, Jean T.; Schwartz, Melvin |title=Hepinstall's pathology of the kidney |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2007 |pages=677 |isbn=0-7817-4750-3 |oclc= |doi= |accessdate=}}</ref> | | ==[[Wegener's granulomatosis pathophysiology|Pathophysiology]]== |
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| ==History== | | ==[[Wegener's granulomatosis causes|Causes]]== |
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| Scottish [[Otolaryngology|otolaryngologist]] Peter McBride (1854–1946) first described the condition in 1897 in a British Medical Journal article entitled "Photographs of a case of rapid destruction of the nose and face"<ref name="pmid7057076">{{cite journal |author=Friedmann I |title=McBride and the midfacial granuloma syndrome. (The second 'McBride Lecture', Edinburgh, 1980) |journal=The Journal of laryngology and otology |volume=96 |issue=1 |pages=1–23 |year=1982 |pmid=7057076 |doi=}}</ref>. Heinz Karl Ernst Klinger (1907– ) would add information on the [[anatomical pathology]], but the full picture was presented by [[Friedrich Wegener]] (1907–1990), a German [[pathologist]], in two reports in 1936 and 1939.<ref name=Enersen/>
| | ==[[Wegener's granulomatosis differential diagnosis|Differentiating Wegener's granulomatosis from other Diseases]]== |
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| An earlier name for the disease was pathergic granulomatososis.<ref>{{cite journal |author=Fienberg R |title=Pathergic granulomatosis |journal=Am. J. Med. |volume=19 |issue=6 |pages=829–31 |year=1955 |pmid=13275478 |doi=10.1016/0002-9343(55)90150-9}}</ref> The disease is still sometimes confused with lethal midline granuloma and [[lymphomatoid granulomatosis]], both malignant [[lymphomas]].<ref name=Mendenhall>{{cite journal |author=Mendenhall WM, Olivier KR, Lynch JW Jr, Mendenhall NP |title=Lethal midline granuloma-nasal natural killer/T-cell lymphoma |journal=Am J Clin Oncol |volume=29 |issue=2 |pages=202–6 |year=2006|pmid=16601443 |doi=10.1097/01.coc.0000198738.61238.eb}}</ref>
| | ==[[Wegener's granulomatosis epidemiology and demographics|Epidemiology and Demographics]]== |
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| In 2006, Dr. Alexander Woywodt (Preston, United Kingdom) and Dr. Eric Matteson (Mayo Clinic, USA) investigated Dr. Wegener's past, and discovered that he was, at least at some point of his career, a follower of the Nazi regime. In addition, their data indicate that Dr. Wegener was wanted by Polish authorities and that his files were forwarded to the United Nations War Crimes Commission. Finally, Dr. Wegener worked in close proximity to the genocide machinery in Lodz. Their data raise serious concerns about Dr. Wegener's professional conduct. They suggest that the eponym be abandoned and propose "ANCA-associated granulomatous vasculitis."<ref>{{cite journal |author=Woywodt A, Matteson EL |title=Wegener's granulomatosis--probing the untold past of the man behind the eponym |journal=Rheumatology (Oxford) |volume=45 |issue=10 |pages=1303–6 |year=2006 |pmid=16887845 |doi=10.1093/rheumatology/kel258}}</ref> The authors have since campaigned for other medical eponyms to be abandoned, too.<ref>{{cite journal|author=Woywodt A, Matteson E |title=Should eponyms be abandoned? Yes |journal=BMJ |volume=335 |issue=7617 |pages=424 |year=2007 |pmid=17762033 |doi=10.1136/bmj.39308.342639.AD}}</ref>
| | ==[[Wegener's granulomatosis risk factors|Risk Factors]]== |
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| ==Epidemiology== | | ==[[Wegener's granulomatosis screening|Screening]]== |
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| The [[incidence]] is 10 cases per million per year.<ref name=Bosch/> 90% of the patients are whites. While it mainly occurs in the middle-aged, it has been reported in much younger and older patients.
| | ==[[Wegener's granulomatosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Pathophysiology== | | == Diagnosis == |
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| [[Inflammation]] with [[granuloma]] formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.<ref name=Seo/> | | [[Wegener's granulomatosis diagnostic criteria|Diagnostic Criteria]] | [[Wegener's granulomatosis history and symptoms| History and Symptoms]] | [[Wegener's granulomatosis physical examination | Physical Examination]] | [[Wegener's granulomatosis laboratory findings| Laboratory Findings]] | [[Wegener's granulomatosis chest x ray|Chest X Ray]] | [[Wegener's granulomatosis CT|CT]] | [[Wegener's granulomatosis other diagnostic studies|Other Diagnostic Studies]] |
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| It is now widely presumed that the [[anti-neutrophil cytoplasmic antibody|anti-neutrophil cytoplasmic antibodies]] (ANCAs) are responsible for the inflammation in Wegener's.<ref name=Seo/> The typical ANCAs in Wegener's are those that react with [[proteinase 3]], an enzyme prevalent in [[neutrophil granulocyte]]s.<ref name=vanderWoude>van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, van der Giessen M, van der Hem GK, The TH. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. ''Lancet'' 1985;1(8426):425-9. PMID 2857806.</ref> This type of ANCA is also known as cANCA, with the ''c'' indicating ''[[cytoplasm]]ic'' (in contrast to pANCA, which is ''perinuclear'').
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| ANCAs activate [[neutrophils]], increase their adherence to [[endothelium]], and lead to their degranulation. This causes extensive damage to the vessel wall, particularly of [[arteriole]]s.<ref name=Seo/>
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| The exact cause for the production of ANCAs is unknown, although some [[medication|drugs]] have been implicated in secondary forms of Wegener's. As with many [[autoimmune disorder]]s, the cause is probably genetic predisposition combined with [[molecular mimicry]] caused by a [[virus]] or [[bacterium]].
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| ==Signs and symptoms==
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| Initial signs are protean, and diagnosis can be severely delayed due to the non-specific nature of the [[symptom]]s. The rhinitis is generally the first sign in most patients.<ref name=Seo/>
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| * [[Respiratory tract|Upper airway]], [[eye]] and [[ear]] disease:
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| ** Nose: pain, stuffiness, [[nosebleed]]s, [[rhinitis]], crusting, ''saddle-nose'' deformity due to a [[perforated septum]]
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| ** Ears: conductive [[hearing loss]] due to [[Eustachian tube]] dysfunction, sensorineural hearing loss (unclear mechanism)
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| ** Eyes: pseudotumours, [[scleritis]], [[conjunctivitis]], [[uveitis]], episcleritis
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| * Airways:
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| ** [[Vertebrate trachea|Trachea]]: subglottal [[stenosis]]
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| ** [[Lung]]s: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as [[pneumonia]]), cavitary lesions, [[pulmonary hemorrhage]] causing [[hemoptysis]]), and rarely bronchial stenosis.
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| * [[Kidney]]: rapidly progressive segmental necrotising [[glomerulonephritis]] (75%), leading to [[chronic renal failure]]
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| * [[Arthritis]]: Pain or swelling (60%), often initially diagnosed as [[rheumatoid arthritis]]
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| * [[Skin]]: nodules on the elbow, [[purpura]], various others (see ''cutaneous vasculitis'')
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| * [[Nervous system]]: occasionally [[sensory neuropathy]] (10%) and rarely [[mononeuritis multiplex]]
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| * [[The Heart in Wegener's Granulomatosis|Heart]], [[gastrointestinal tract]], [[brain]] other organs: rarely affected.
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| ==Diagnosis==
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| Vasculitis such as Wegener's granulomatosis is usually only suspected when a patient has had unexplained symptoms for a longer period of time. Determination of [[antineutrophil cytoplasmic antibody|ANCA]]s can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. Cytoplasmic staining ANCAs that react with the enzyme [[proteinase 3]] (cANCA) in [[neutrophil granulocyte|neutrophils]] (a type of [[white blood cell]]) are associated with Wegener's.<ref name=Seo/>
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| If the patient has [[chronic renal failure|renal failure]] or cutaneous vasculitis, these are the most logical organs to obtain a [[biopsy]] from. Rarely, [[thoracoscopy|thoracoscopic]] lung biopsy is required. On [[histopathology|histopathological]] examination, a biopsy will show ''leukocytoclastic vasculitis'' with [[necrosis|necrotic]] changes and [[granuloma]]tous [[inflammation]] (clumps of typically arranged white blood cells) on [[light microscopy|microscopy]]. The latter is the main reason for the appellation of "Wegener's granulomatosis", although it is not an essential feature. Unfortunately, many biopsies can be non-specific and 50% provide too little information for the diagnosis of Wegener's.<ref name=Seo/>
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| [[Differential diagnosis]] (alternative possible diagnoses) can be extensive. ANCAs can be positive after the use of certain drugs, and other forms of [[vasculitis]] can present with very similar symptoms. The [[saddle nose]] deformity may also seen in [[cocaine]] abuse and in [[congenital syphilis]].
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| ==Diagnostic Criteria==
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| In 1990, the American College of Rheumatology accepted classification criteria for Wegener's. They were not intended for diagnosis, but for inclusion in [[randomized controlled trial]]s. Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing Wegener's.<ref name=Leavitt>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. PMID 2202308.</ref>
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| * Nasal or oral inflammation:
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| ** painful or painless oral ulcers ''or''
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| ** purulent or bloody nasal discharge
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| * Lungs: abnormal chest X-ray with:
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| ** nodules,
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| ** infiltrates ''or''
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| ** cavities
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| * Kidneys: urinary sediment with:
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| ** microhematuria''or''
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| ** red cell [[urinary casts|casts]]
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| * Biopsy: granulomatous inflammation
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| ** within the arterial wall ''or''
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| ** in the perivascular area
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| According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of Wegener's granulomatosis demands:<ref name=Jenette>Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, ''et al''. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. ''Arthritis Rheum'' 1994;37:187-92. PMID 8129773.</ref>
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| * a granulomatous inflammation involving the respiratory tract, and
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| * a [[vasculitis]] of small- to medium-sized vessels.
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| Several investigators have compared the ACR and Chapel Hill criteria.<ref name=Bruce>Bruce IN, Bell AL. A comparison of two nomenclature systems for primary systemic vasculitis. ''Br J Rheumatol'' 1997;36:453-8. PMID 9159539.</ref>
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| ==Diagnostic Findings==
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| ===Computed Tomography===
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| <gallery>
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| Image:Wegner's-granulomatosis-001.jpg|CT: Wegener's granulomatosis
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| Image:Wegner's-granulomatosis-002.jpg|CT: Wegener's granulomatosis
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| Image:Wegner's-granulomatosis-003.jpg|CT: Wegener's granulomatosis
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| </gallery>
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| ===Immunofluorescence===
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| <gallery>
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| Image:C_anca.jpg|Immunofluorescence pattern produced by binding of ANCA from a patient with Wegener's Granulomatosis to ethanol-fixed neutrophils
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| </gallery>
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| ==Treatment== | | ==Treatment== |
| | [[Wegener's granulomatosis medical therapy|Medical Therapy]] | [[Wegener's granulomatosis surgery|Surgery]] | [[Wegener's granulomatosis primary prevention|Primary Prevention]] | [[Wegener's granulomatosis secondary prevention|Secondary Prevention]] | [[Wegener's granulomatosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Wegener's granulomatosis future or investigational therapies|Future or Investigational Therapies]] |
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| Before steroid treatment became available, mortality within one year was over 90%, with average survival being 5 months. Steroids prolonged average survival to 8 months. The introduction of [[cyclophosphamide]] (CYC) in the 1970s was a major breakthrough.<ref name=Bosch>{{cite journal |author=Bosch X, Guilabert A, Espinosa G, Mirapeix E |title=Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review |journal=JAMA |volume=298 |issue=6 |pages=655–69 |year=2007 |pmid=17684188 |doi=10.1001/jama.298.6.655}}</ref>
| | ==Case Studies== |
| | | [[Wegener's granulomatosis case study one|Case #1]] |
| Initial treatment is generally with [[corticosteroids]] and oral [[cyclophosphamide]] (CYC), 1 mg/kg/day and 2 mg/kg/day, respectively. Occasionally CYC is given in monthly intravenous (IV) doses. Monitoring of the [[white blood cell|white blood count]] is essential during CYC therapy. Once remission is attained (normally 3 to 6 months), treatment is frequently changed to [[azathioprine]] or [[methotrexate]], which are less toxic drugs. Total duration of therapy should be at least one year, or longer in high risk patients. Corticosteroids are tapered to a low maintenance dose, 5-10 mg/day. [[Plasmapheresis]] may be beneficial in severe disease or [[pulmonary hemorrhage]]. Experience with other treatment agents is very limited.<ref name=Seo/>.
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| A [[systematic review]] of 84 trials examined the evidence for various treatments in Wegener's granulomatosis. Many trials include data on pooled groups of patients with Wegener's and microscopic polyangiitis. In this review, cases are divided between localized disease, non-organ threatening, generalized organ-threatening disease and severe renal vasculitis and immediately life-threatening disease.<ref name=Bosch/>
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| * In localized disease, treatment with the antibiotic [[co-trimoxazole]] is recommended, with steroids in case of treatment failure.<ref name="pmid8637536">{{cite journal |author=Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG |title=Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group |journal=N. Engl. J. Med. |volume=335 |issue=1 |pages=16–20 |year=1996 |pmid=8637536 |doi= |url=http://content.nejm.org/cgi/content/abstract/335/1/16}}</ref>
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| * In generalized non-organ threatening disease, remission can be induced with [[methotrexate]] and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate used as maintenance.
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| * In case of organ-threatening disease, pulsed [[intravenous]] cyclophosphamide with steroids is recommended. Once remission has been achieved, [[azathioprine]] and steroids can be used to maintain remission.
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| * In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
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| * In [[pulmonary hemorrhage]], high doses of cyclophosphamide with pulsed [[methylprednisolone]] may be used, or alternatively CYC, steroids, and plasma exchange.
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| In severe disease not responsive to previously mentioned treatment, the review is positive about [[mycophenolate mofetil]], 15-deoxyspergualin, [[anti-thymocyte globulin]], [[rituximab]] and [[infliximab]]; data was less favourable for [[intravenous immunoglobulin]] (IVIG) and [[etanercept]].<ref name=Bosch/>
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| In some patients with severe subglottic stenosis, [[tracheotomy]] is required to maintain an airway.
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| Follow-up: general well-being and laboratory organ markers are checked on a regular basis to ascertain the patient has remained in remission.
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| ==Prognosis==
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| 25 to 40% of patients suffer from flare-ups, but a majority responds well to treatment. Anatomical problems ([[sinusitis]], tracheal stenosis) may require surgery in a small proportion. Relapses can be long and troublesome.
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| Long-term complications are very common (86%): mainly [[chronic renal failure]], hearing loss and [[deafness]].<ref name=Seo/>
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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| * [http://www.rheumatology.org/publications/classification/wegener.asp?aud=mem Classification criteria] by the American College of Rheumatology
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| * [http://vasculitisfoundation.org Vasculitis Foundation] Formerly the Wegener's Granulomatosis Association
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| * [http://www.weareb.org/WG/ Wegener's Granulomatosis Info]
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| * [http://wegenersnet.org WegenersNet] A Wegener's Granulomatosis Community Portal
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| {{SIB}}
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| {{Diseases of the musculoskeletal system and connective tissue}}
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| {{Symptoms and signs}}
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| [[de:Wegener-Granulomatose]]
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| [[fr:Granulomatose de Wegener]] | | [[fr:Granulomatose de Wegener]] |
| [[nl:Ziekte van Wegener]]
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| [[ja:ウェゲナー肉芽腫症]] | | [[ja:ウェゲナー肉芽腫症]] |
| [[pt:Granulomatose de Wegener]] | | [[pt:Granulomatose de Wegener]] |
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| [[Category:Pulmonology]] | | [[Category:Pulmonology]] |
| [[Category:Autoimmune diseases]] | | [[Category:Autoimmune diseases]] |
| [[Category:Signs and symptoms]]
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