Wegener's Granulomatosis

Synonyms: Klinger's syndrome, Klinger-Wegener syndrome, Wegener-Churg-Klinger syndrome, Wegener-Klinger syndrome¹

Wegener's granulomatosis is a rare form of vasculitis. It is a multisystem disease which can affect many parts of the body, categorised by the ELK classification: it most commonly presents with lesions in the upper respiratory tract (E - indicating ears/nose/throat, almost 100%), lungs (L - most patients) and kidneys (K - >75%). Many other areas of the body may also be affected, with joint inflammation occurring in 25-50% of all cases. The sinuses, eyes and skin may also be affected.

• One study in Norfolk found an annual incidence of 8.5/million adult population. The incidence appeared higher in the winter than in the summer.³
• There is little data on geographical distribution, but what prevalence studies are available suggest that the condition is less common in the USA (26/million) than in Europe (40-60/million).³ The condition is becoming more frequently recognised in India, but is virtually unknown in urban or rural Africa.⁴
• One study looking at Wegener's granulomatosis as a cause of renal vasculitis showed that the annual incidence of such cases in the UK was 5.8/million. The incidence was found to be lower in Japan.⁵
• The male to female ratio is approximately1:1-2.1.
• The condition can occur at any age, but peaks between the ages of 35-55.
• A study of incidence within families found evidence for a familial aggregation of a magnitude similar to that for rheumatoid arthritis, but not for a pronounced familial risk such as that noted for systemic lupus erythematosus, irritable bowel disease or multiple sclerosis.⁶

Risk factors

The higher incidence in winter suggests an infective aetiology but the data are inconclusive. Wegener's has been linked to parvovirus and to chronic nasal carriage of Staphylococcus aureus.

The involvement of the upper airways in this condition has led to the search for possible inhaled allergens. although none has yet been positively identified.⁴

Symptoms

As a multi-system disease, the symptoms are numerous and may include:

• Fatigue, malaise, fever, night sweats
• Weakness
• Loss of appetite
• Weight loss
• Rhinorrhoea
• Sinusitis
• Facial pain
• Hoarseness
• Cough
• Dyspnoea
• Wheezing
• Chest pain
• Joint pains
• Hearing loss
• Abdominal pain

In children (less than 15% of patients) the renal and respiratory systems are most commonly affected.⁹

Signs

The signs found in Wegener's granulomatosis occur as a result of the inflammation of the small vessels and may affect any part of the body.

The most commonly seen signs relate to the upper and lower airways and the renal tract and may include:

• Ulcers , sores and crusting, in and around the nose, with destruction of nasal cartilage
• Rhinorrhoea, often bloody
• Haemoptysis
• Haematuria
• Sub-glottic stenosis (20% of patients) - causing hoarseness, stridor, dyspnoea, or cough
• Rashes (up to 50%) - often small red/purple raised areas or blister-like lesions, ulcers, or nodules
• Conjunctivitis, scleritis and episcleritis
• Chronic ear infections
• Mononeuritis multiplex
• Peritonitis
• Unlike Polyarteritis nodosa, hypertension & eosinophilia are unusual

As a multi system disease, Wegener's granulomatosis is capable of mimicking numerous other diseases and it is the presence of two or more of the above signs and/or symptoms which must signal the possibility of a diagnosis of Wegener's granulomatosis.

Common conditions which enter the differential diagnosis include:

• Anti-GBM antibody disease - a rare autoimmune condition in which antibodies are directed towards the glomerular basal membrane and alveoli.¹⁰
• Legionella infection
• Mixed connective tissue disease
• Systemic lupus erythematosus
• Other ANCA-associated small vessel vasculitides (ie, microscopic polyangiitis, Churg-Strauss syndrome)
• Rheumatoid arthritis with systemic vasculitis
• Mixed cryoglobulinaemia
• Renal vein thrombosis with pulmonary embolism

• Full blood count, erythrocyte sedimentation rate (ESR)
• Serum urea and electrolytes
• Blood test for anti-neutrophil cytoplasmic antibodies (ANCA), of 2 types:C-ANCA and P-ANCA - detectable in nearly all patients with active severe Wegener's granulomatosis, but approximately 1 of 5 patients with active limited disease negative.¹¹
• Urinalysis for protein, blood and casts
• Nasal endoscopy
• Lung function tests and flow volume loop looking for sub glottic stenosis
• Chest X ray looking for cavity formation and pulmonary infiltrates
• Chest CT imaging to exclude lung parenchyma involvement
• Sinus CT scan to exclude sinus disease
• Biopsy of affected tissue which may include, nasal mucosa, lung biopsy, renal biopsy, looking for presence of vasculitis and granulomas

Medical care²

• Aggressive immunosuppressive therapy is required to control pulmonary and renal involvement.
• Cyclophosphamide is the drug of choice for the initial control of the condition. Due to its serious adverse effects (e.g. renal, haematological and neurological toxicity), it is normally given as pulsed treatment intravenously every 2-4 weeks.¹² One study found that a high cumulative dose of cyclophosphamide was associated with a significant risk of late-occurring malignancies.¹³
• Prednisolone is often given in addition as it helps to increase patient survival and suppress local disease.¹⁴
• Controlled trials suggest that once the patient is in remission, cyclophosphamide should be replaced by azathioprine. Leflunomide and methotrexate are given as adjuncts to reduce the relapse rate.¹⁵
• The treatment of refractory cases remains a challenge. The anti-tumour necrosis factor (TNF) properties of infliximab has been used to good effect in addition to standard therapies. Trials using etanercept have not shown similar benefits¹⁵ but a small number of patients have responded to rituximab. Intravenous immunoglobulins has also been found to be helpful.¹⁶

Surgical care

Surgical treatment may be needed for:

• Nasal deformity
• Subglottic stenosis
• Obstruction of lacrimal ducts
• Bronchial stenoses
• Eustachian dysfunction (insertion of grommets)
• Renal failure (renal transplant)

• Renal failure
• Respiratory failure
• Chronic conjunctivitis
• Nasal septum perforation

• Untreated Wegener's granulomatosis has a poor prognosis, with the majority of patients dying within two years.¹⁴ However, the prognosis for treated disease has improved considerably over the last decades. One study found that predictors of early death were disease duration, haemoglobin concentration, necessity of dialysis and occurrence of cough. Simultaneous renal and respiratory tract involvement were associated with the highest early death risk.¹⁷
• A study from Finland found that the delay in diagnosis is decreasing, probably due to increased recognition.¹⁸
• The judicious use of cyclophosphamide has dramatically increased the longevity of these patients and now that less toxic treatment options are becoming available, the prognosis looks even more optimistic.¹⁵
• There are refractory cases who remain resistant to treatment. A poor prognosis is thought to be related to deteriorating renal function and a situation in which the disease process is dominated by systemic vasculitis rather than granulomatosis.¹⁵
• The concept is gaining ground that successful management not only relies on the suppression of inflammation but also in minimising chronic morbidity ('damage'). This involves surveillance for associated diseases such as malignancy, venous thromboembolic events and cardiovascular disease as well as minimising the risk of adverse drug effects such as renal toxicity.¹⁹