Synonyms: Klinger's syndrome, Klinger-Wegener syndrome, Wegener-Churg-Klinger syndrome, Wegener-Klinger syndrome, granulomatosis with polyangiitis¹

Wegener's granulomatosis is a rare form of vasculitis. It is thought to be an autoimmune inflammatory process affecting endothelial cells. 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.²

Epidemiology²

• A study using information from the UK General Practice Research Database reported an overall annual incidence of 8.4/million.³
• 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.⁴
• 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. One American study found that the incidence in children was increasing.⁵
• Another study found that first-degree relatives had a moderately increased risk of developing any autoimmune/inflammatory disease, including specific associations with, for example, multiple sclerosis, Sjögren's syndrome and seropositive rheumatoid arthritis.⁶

Risk factors

The higher incidence in winter suggests an infective aetiology but the data are inconclusive. Wegener's granulomatosis 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.⁷

Presentation^2,8

As a multisystem disease, Wegener's granulomatosis often presents with nonspecific symptoms and can be difficult to recognise in primary care. The delay from onset to diagnosis ranges from 2-20 months.⁹

Symptoms

Symptoms 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 (fewer than 15% of patients), the renal and respiratory systems are most commonly affected.⁸

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.
• Subglottic 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 and eosinophilia are unusual.

Differential diagnosis⁸

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 the diagnosis.

Common conditions which enter the differential diagnosis include:

• Antiglomerular basement membrane (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 antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides (i.e. microscopic polyangiitis, Churg-Strauss syndrome).
• Rheumatoid arthritis with systemic vasculitis.
• Mixed cryoglobulinaemia.
• Renal vein thrombosis with pulmonary embolism.

Investigations⁸

• FBC, ESR.
• Serum U&Es.
• Blood test for antineutrophil cytoplasmic antibodies (ANCA), of 2 types: C-ANCA and P-ANCA - detectable in nearly all patients with active severe Wegener's granulomatosis; however, 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 subglottic stenosis.
• CXR looking for cavity formation and pulmonary infiltrates.
• Chest CT imaging to exclude lung parenchymal 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.

Management

Medical care^2,8,12

• 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. 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. It is usually tapered after one month of therapy and discontinued after three to nine months.
• 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.
• Aggressive immunosuppressive therapy is required to control pulmonary and renal involvement.
• The treatment of refractory cases remains a challenge. The antitumour necrosis factor (ant-TNF) properties of infliximab have been used to good effect in addition to standard therapies. Trials using etanercept have not shown similar benefits but a small number of patients have responded to rituximab. Rituximab and infliximab have emerged as potential treatment options for refractory patients with peripheral neuropathy and central nervous system involvement.¹⁴ Intravenous immunoglobulins has also been found to be helpful to control relapses.¹⁵

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).

Complications²

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

Prognosis^2,8

• One study reported a nine-fold increased risk of death compared with the general population in the first year. Infection, active vasculitis and renal failure appear to be the leading causes of mortality during this time. Thereafter, the risk falls until the eighth year when there is an unexpected peak.¹⁶
• Another 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
• Other leading causes of death included malignancy and, less commonly, heart failure and myocardial infarction.
• 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 more optimistic.¹⁸ 90% of patients improve with aggressive medical treatment and 75% of patients achieve remission. However, the relapse rate is 50%.
• 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.¹⁸
• The concept that successful management not only relies on the suppression of inflammation but also on minimising chronic morbidity ('damage') is gaining ground . 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

Document references

1. Jennette JC; Nomenclature and classification of vasculitis: lessons learned from Clin Exp Immunol. 2011 May;164 Suppl 1:7-10. doi: [abstract]
2. Mowad C et al; Wegener Granulomatosis, Medscape, Jun 2010
3. Watts RA, Al-Taiar A, Scott DG, et al; Prevalence and incidence of Wegener's granulomatosis in the UK general practice Arthritis Rheum. 2009 Oct 15;61(10):1412-6. [abstract]
4. Watts RA, Scott DG, Jayne DR, et al; Renal vasculitis in Japan and the UK--are there differences in epidemiology and clinical phenotype? Nephrol Dial Transplant. 2008 Dec;23(12):3928-31. Epub 2008 Jun 19. [abstract]
5. Grisaru S, Yuen GW, Miettunen PM, et al; Incidence of Wegener's granulomatosis in children. J Rheumatol. 2010 Feb;37(2):440-2. Epub 2009 Dec 23. [abstract]
6. Knight A, Sandin S, Askling J; Increased risk of autoimmune disease in families with Wegener's granulomatosis. J Rheumatol. 2010 Dec;37(12):2553-8. Epub 2010 Oct 1. [abstract]
7. Knight A, Sandin S, Askling J; Occupational risk factors for Wegener's granulomatosis: a case-control study. Ann Rheum Dis. 2010 Apr;69(4):737-40. Epub 2009 Apr 12. [abstract]
8. Valentini PR et al; Pediatric Wegener Granulomatosis, Medscape, Apr 2011
9. Paddock M, Lynch C, Paska L; Wegener's granulomatosis in primary care. JRSM Short Rep. 2010 Dec 6;1(7):59.
10. Swiatecka-Urban A et al; Anti-GMB Antibody Disease, Medscape, Mar 2009
11. Finkielman JD, Lee AS, Hummel AM, et al; ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis. Am J Med. 2007 Jul;120(7):643.e9-14. [abstract]
12. Lapraik C, Watts R, Bacon P, et al; BSR and BHPR guidelines for the management of adults with ANCA associated Rheumatology (Oxford). 2007 Oct;46(10):1615-6. Epub 2007 Sep 5.
13. Faurschou M, Sorensen IJ, Mellemkjaer L, et al; Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008 Jan;35(1):100-5. Epub 2007 Oct 15. [abstract]
14. Holle JU, Gross WL; Neurological involvement in Wegener's granulomatosis. Curr Opin Rheumatol. 2011 Jan;23(1):7-11. [abstract]
15. Martinez V, Cohen P, Pagnoux C, et al; Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum. 2008 Jan;58(1):308-17. [abstract]
16. Luqmani R, Suppiah R, Edwards CJ, et al; Mortality in Wegener's granulomatosis: a bimodal pattern. Rheumatology (Oxford). 2011 Apr;50(4):697-702. Epub 2010 Nov 25. [abstract]
17. Zycinska K, Wardyn KA, Tyszko P, et al; Analysis of early death based on the prediction model in Wegener's granulomatosis with pulmonary and renal involvement. J Physiol Pharmacol. 2007 Nov;58 Suppl 5(Pt 2):829-37. [abstract]
18. Hellmich B, Lamprecht P, Gross WL; Advances in the therapy of Wegener's granulomatosis.; Curr Opin Rheumatol. 2006 Jan;18(1):25-32. [abstract]
19. Seo P; Wegener's granulomatosis: managing more than inflammation. Curr Opin Rheumatol. 2008 Jan;20(1):10-6. [abstract]

Internet and further reading

• Seror R, Pagnoux C, Ruivard M, et al; Treatment strategies and outcome of induction-refractory Wegener's granulomatosis Ann Rheum Dis. 2010 Dec;69(12):2125-30. Epub 2010 Jul 19. [abstract]
• Nagato T, Otaka R, Wada T, et al; Clinical images: Otitis media and nasal granulation in Wegener's granulomatosis. Arthritis Rheum. 2009 Feb;60(2):379.
• Tadema H, Heeringa P, Kallenberg CG; Bacterial infections in Wegener's granulomatosis: mechanisms potentially involved Curr Opin Rheumatol. 2011 Apr 8. [abstract]
• Hardi L, DeCastro F, Lohr KM; Clinical images: Reticular rash in a patient with Wegener's granulomatosis. Arthritis Rheum. 2011 Mar;63(3):861. doi: 10.1002/art.30142.

Acknowledgements