Wegener's granulomatosis

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.^[1] It is named after Dr. Friedrich Wegener who described the disease in 1936.^[2]

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 ANCAs (antineutrophil cytoplasmic antibodies) and affect small and medium-sized blood vessels. Apart from Wegener's, this category includes Churg-Strauss syndrome and microscopic polyangiitis.^[1]

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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. Rhinitis is generally the first sign in most patients.^[1]

• Upper airway, eye and ear disease:
  • Nose: pain, stuffiness, nosebleeds, rhinitis, crusting, saddle-nose deformity due to a perforated septum
  • Ears: conductive hearing loss due to Eustachian tube dysfunction, sensorineural hearing loss (unclear mechanism)
  • Eyes: pseudotumours, scleritis, conjunctivitis, uveitis, episcleritis
• Airways:
  • Trachea: subglottal stenosis
  • Lungs: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as pneumonia), cavitary lesions, pulmonary hemorrhage causing hemoptysis), and rarely bronchial stenosis.
• Kidney: rapidly progressive segmental necrotising glomerulonephritis (75%), leading to chronic renal failure
• Arthritis: Pain or swelling (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, brain other organs: rarely affected.

Diagnosis

Wegener's granulomatosis is usually only suspected when a patient has had unexplained symptoms for a long 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.^[1]

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. These granulomas are 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.^[1]

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.

Criteria

In 1990, the American College of Rheumatology accepted classification criteria for Wegener's. These criteria 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.^[3]

• 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

According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of Wegener's granulomatosis demands:^[4]

• a granulomatous inflammation involving the respiratory tract, and
• a vasculitis of small- to medium-sized vessels.

Several investigators have compared the ACR and Chapel Hill criteria.^[5]

Pathophysiology

Inflammation with granuloma formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.^[1]

It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in Wegener's.^[1] The typical ANCAs in Wegener's are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes.^[6] 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.^[1]

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

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.^[7]

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.^[1].

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.^[7]

• In localized disease, treatment with the antibiotic co-trimoxazole is recommended, with steroids in case of treatment failure.^[8]
• 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.
• 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.
• In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
• In pulmonary hemorrhage, high doses of cyclophosphamide with pulsed methylprednisolone may be used, or alternatively CYC, steroids and plasma exchange.

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.^[7]

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.

Epidemiology

The incidence is 10 cases per million per year.^[7] 90% of the patients are white. 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 respond 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.^[1]

History

Scottish otolaryngologist Peter McBride (1854-1946) first described the condition in 1897 in a BMJ article entitled "Photographs of a case of rapid destruction of the nose and face"^[9]. 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.^[2]

An earlier name for the disease was pathergic granulomatososis.^[10] The disease is still sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis, both malignant lymphomas.^[11]

In 2006, Dr Alexander Woywodt from (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".^[12] The authors have since campaigned for other medical eponyms to be abandoned too.^[13]

References