Wegener's granulomatosis

Information and facts about Autoimmune diseases.

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.

It is part of a larger group of vasculitic syndromes that all feature positivity for ANCAs (antineutrophil cytoplasmic antibodies) and affect small and medium-sized blood vessels. Apart from Wegener's, it includes Churg-Strauss syndrome and microscopic polyangiitis.

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.

Upper airway, eye and ear disease:
Nose: pain, stuffiness, nosebleeds, rhinitis, crusting, saddle-nose deformity
Ears: conductive hearing loss due to Eustachian tube dysfunction, sensorineural hearing loss (unclear mechanism)
Eyes: pseudotumours, scleritis, conjunctivitis, uveitis
Airways:
Tracheal stenosis
Lungs: pulmonary nodules and infiltrates (often interpreted as pneumonia), cavitary lesions and pulmonary haemorrhage.
Kidney: rapidly progressive segmental necrotising glomerulonephritis (75%), leading to chronic renal failure
Arthritis (60%), often initially diagnosed as rheumatoid arthritis
Skin: nodules on the elbow, purpura, various others (see cutaneous vasculitis)
Nervous system: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex
Heart, gastrointestinal tract, other organs: rarely affected.

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 neither are negative ANCAs enough to reject the diagnosis. Perinuclear (around the nucleus) ANCAs that react with proteinase 3 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. 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 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 is also seen in cocaine abuse.

Criteria
In 1990, the American College of Rheumatology accepted classification criteria for Wegener's (Leavitt et al 1990). 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
purulent or bloody nasal discharge
Lungs: abnormal chest X-ray with:
nodules,
infiltrates or
cavities
Kidneys: urinary sediment with:
microhematuria or
red cell casts
Biopsy: granulomatous inflammation
within the arterial wall or
in the perivascular area

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.

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.

Treatment
Initial treatment is generally with prednisolone or other steroids. As it is hard to monitor whether the disease is under control, it is equally difficult to determine the required steroid dose. Most patients start off with high-dose steroids, and these are tapered while disease-modifying antirheumatic drugs (DMARDs) are initiated. Severe cases require oral cyclophosphamide 2 mg/kg per day with added glucocorticoids. Monitoring of the white blood count is essential during cyclophosphamide therapy.

Follow-up: general wellbeing and laboratory organ markers are checked on a regular basis to ascertain the patient has remained in remission.

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.

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.

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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