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In medicine (rheumatology), Wegener's granulomatosis is a form of vasculitis that affects the lungs, kidneys and other organs. Due to its end-organ damage, it can be a serious disease that requires long-term immune suppression.
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Signs and symptoms
Initial signs are protean, and diagnosis can be severely delayed due to the non-specific nature of the symptoms. The rhinitis is generally the first sign in most patients.
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Diagnosis
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 ANCAs 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 neutrophils (a type of white blood cell) are associated with Wegener's.
If the patient has renal failure or cutaneous vasculitis, these are the most logical organs to obtain a biopsy from. Rarely, thoracoscopic lung biopsy is required. On histopathological examination, a biopsy will show leukocytoclastic vasculitis with necrotic changes and granulomatous inflammation (clumps of typically arranged white blood cells) on 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 aspecific and 50% provide too little information for the diagnosis of Wegener's.
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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Criteria
In 1990, the American College of Rheumatology accepted classification criteria for Wegener's. They were not intended for diagnosis, but for inclusion in randomised controlled trials. Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing Wegener's.
Nasal or oral inflammation:
painful or painless oral ulcers or
Lungs: abnormal chest X-ray with:
Kidneys: urinary sediment with:
Biopsy: granulomatous inflammation
within the arterial wall or
According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of Wegener's granulomatosis demands:
a granulomatous inflammation involving the respiratory tract, and
Several investigators have compared the ACR and Chapel Hill criteria.
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Pathophysiology
Inflammation with granuloma formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.
It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in Wegener's.[ The typical ANCAs in Wegener's are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes.][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.] This type of ANCA is also known as cANCA, with the c indicating cytoplasmic (in contrast to pANCA, which is perinuclear).
ANCAs activate neutrophils, increase their adherence to endothelium, and lead to their degranulation. This causes extensive damage to the vessel wall, particularly of arterioles.
The exact cause for the production of ANCAs is unknown, although some drugs have been implicated in secondary forms of Wegener's. As with many autoimmune disorders, the cause is probably genetic predisposition combined with molecular mimicry caused by a virus or bacterium.
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Treatment
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 IV doses. Monitoring of the 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 1 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.
Alternative treatments include:
Rituximab: a very promising drug currently in clinical trials. It has been successful when used several times as a compassionate treatment for those who cannot tolerate CYC.
Chlorambucil: a powerful immunosuppressant that has been used instead of cyclophosphamide in some cases.
Non-immunosuppressive therapies are:
Co-trimoxazole: a wide-range antibiotic often administered in conjunction with immunosuppressants. Sometimes even administered as a treatment for Wegener's.
Folic acid: often administered in addition to some of the above immunosuppressants.
In some patients with severe subglottic stenosis, tracheotomy is required to maintain an airway.
Follow-up: general wellbeing and laboratory organ markers are checked on a regular basis to ascertain the patient has remained in remission.
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Epidemiology
The incidence is 8.5 cases per million per year. 90% of the patients are whites. While it mainly occurs in the middle-aged, it has been reported in much younger and older patients.
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Prognosis
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.
Long-term complications are very common (86%): mainly chronic renal failure, hearing loss and deafness.
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History
A certain Peter McBride (1854-1946) first described the condition in 1897 in a British medical journal, especially the characteristic nasal deformation. 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.
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