Synonym: Klinger's syndrome
Granulomatosis with polyangiitis (GPA) 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, 3, 4].
- A study using information from the UK General Practice Research Database reported an overall annual incidence of 8.4/million.
- One study looking at GPA 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.
- The male-to-female ratio is approximately1.2:1.
- 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.
- 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.
The higher incidence in winter suggests an infective aetiology but the data are inconclusive. GPA 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.
As a multisystem disease, GPA 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.
Symptoms may include:
- Fatigue, malaise
- Fever, night sweats
- Loss of appetite
- Weight loss
- Facial pain
- Chest pain
- Joint pains
- Hearing loss
- Abdominal pain
In children the renal and respiratory systems are most commonly affected.
The signs found in GPA 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.
- Subglottic stenosis (38% in one study) - 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.
- Unlike polyarteritis nodosa, hypertension and eosinophilia are unusual.
GPA 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.
- Legionella infection.
- Mixed connective tissue disease.
- Systemic lupus erythematosus.
- Other antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitides (ie microscopic polyangiitis, Churg-Strauss syndrome).
- Rheumatoid arthritis with systemic vasculitis.
- Mixed cryoglobulinaemia.
- Renal vein thrombosis with pulmonary embolism.
- FBC, ESR.
- Serum U&Es.
- Blood test for ANCA, of two types: c-ANCA and p-ANCA - detectable in nearly all patients with active severe GPA. However, approximately 1 of 5 patients with active limited disease negative.
- 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.
- Principles of care include rapid diagnosis, early induction of remission, maintenance of remission and prevention of drug toxicity.
- Investigations to exclude potentially life-threatening and/or vital organ damage should be instituted as a priority.
- Dilemmas sometimes occur when patients who are c-ANCA-positive have normal histology. This sometimes results from biopsy of unaffected tissue. In such circumstances the risks of treatment with potential toxic immunosuppressives should be weighed against the risks of denying treatment to an acutely ill patient in whom the diagnosis of GPA is strongly suspected.
- Patients who are asymptomatic and have no organ damage may not need immunosuppressive treatment. Such patients should initially be offered methotrexate to induce remission (with mycophenolate mofetil as an alternative for those intolerant of methotrexate).
- Cyclophosphamide should be offered to promote remission in patients who have life-threatening and/or vital organ damage. Due to its serious adverse effects (eg, renal, haematological and neurological toxicity), it is normally given as pulsed treatment intravenously every 2-4 weeks. Long-term toxicity is dependent on lifetime cumulative dose which should be ≤25 g.
- Rituximab is recommended by the National Institute for Health and Care Excellence (NICE) if:
- Further cyclophosphamide treatment would exceed the maximum cumulative cyclophosphamide dose; or
- Cyclophosphamide is contra-indicated or not tolerated; or
- The person has not completed their family and treatment with cyclophosphamide may materially affect their fertility; or
- The disease has remained active or progressed despite a course of cyclophosphamide lasting 3-6 months; or
- The person has had uroepithelial malignancy.
- Prednisolone is given in addition to cyclophosphamide or rituximab, as it helps to increase patient survival and suppress local disease.
- Aggressive immunosuppressive therapy is required to control pulmonary and renal involvement. Plasma exchange is sometimes used as an adjunct in these circumstances.
- Once the patient is in remission, cyclophosphamide should be replaced by azathioprine or methotrexate. Leflunomide or mycophenolate may be given as alternatives if there is intolerance or lack of efficacy.
- Once the patient has been in remission for at least a year, on maintenance therapy, prednisolone can be tapered off. If the patient remains in remission six months after this, immunosuppressive treatment can be withdrawn.
- Relapses should be treated by increasing prednisolone and optimising immunosuppressive therapy. Plasma exchange may be needed. Triggers for relapse (eg, infection, malignancy, change in drug therapy) should be considered.
- The treatment of refractory cases remains a challenge. Rituximab is more effective than cyclophosphamide in these circumstances. Triggers should be considered and the diagnosis reviewed.
Surgical treatment may be needed for:
- Nasal deformity.
- Subglottic stenosis.
- Obstruction of lacrimal ducts.
- Bronchial stenoses.
- Eustachian dysfunction (insertion of grommets).
- Acute kidney injury (renal transplant).
- Acute kidney injury
- Respiratory failure
- Chronic conjunctivitis
- Nasal septum perforation
- One study reported a nine-fold increased risk of death compared with the general population in the first year. Infection, active vasculitis and acute kidney injury 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.
- 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.
- 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 optimistic80% of patients now achieve remission although relapses remain frequent (50% at eight years)..
- There are refractory cases remaining 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.
- 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.
Further reading and references
Tadema H, Heeringa P, Kallenberg CG; Bacterial infections in Wegener's granulomatosis: mechanisms potentially involved Curr Opin Rheumatol. 2011 Apr 8.
Hardi L, DeCastro F, Lohr KM; Clinical images: Reticular rash in a patient with Wegener's granulomatosis. Arthritis Rheum. 2011 Mar63(3):861. doi: 10.1002/art.30142.
Seror R, Pagnoux C, Ruivard M, et al; Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial. Ann Rheum Dis. 2010 Dec69(12):2125-30. Epub 2010 Jul 19.
Nagato T, Otaka R, Wada T, et al; Clinical images: Otitis media and nasal granulation in Wegener's granulomatosis. Arthritis Rheum. 2009 Feb60(2):379.
Jennette JC; Nomenclature and classification of vasculitis: lessons learned from granulomatosis with polyangiitis (Wegener's granulomatosis). Clin Exp Immunol. 2011 May164 Suppl 1:7-10. doi:
Pai S, Panda M; Limited Wegener's granulomatosis presenting as lung nodules in a patient with rheumatoid arthritis: a case report. Cases J. 2008 Dec 231(1):417. doi: 10.1186/1757-1626-1-417.
Holle JU, Moosig F, Dalhoff K, et al; Conditions in subjects with rheumatic diseases: pulmonary manifestations of vasculitides. Arthritis Res Ther. 2011 Jun 3013(3):224. doi: 10.1186/ar3307.
Joshi L, Hamour S, Salama AD, et al; Renal & ocular targets for therapy in Wegener's granulomatosis. Inflamm Allergy Drug Targets. 2009 Mar8(1):70-9.
Watts RA, Al-Taiar A, Scott DG, et al; Prevalence and incidence of Wegener's granulomatosis in the UK general practice research database. Arthritis Rheum. 2009 Oct 1561(10):1412-6.
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 Dec23(12):3928-31. Epub 2008 Jun 19.
Grisaru S, Yuen GW, Miettunen PM, et al; Incidence of Wegener's granulomatosis in children. J Rheumatol. 2010 Feb37(2):440-2. Epub 2009 Dec 23.
Knight A, Sandin S, Askling J; Increased risk of autoimmune disease in families with Wegener's granulomatosis. J Rheumatol. 2010 Dec37(12):2553-8. Epub 2010 Oct 1.
Knight A, Sandin S, Askling J; Occupational risk factors for Wegener's granulomatosis: a case-control study. Ann Rheum Dis. 2010 Apr69(4):737-40. Epub 2009 Apr 12.
Tahghighi F, Moradinejad MH, Aghighi Y, et al; Evaluation of 10-year experience of Wegener's granulomatosis in Iranian children. ISRN Rheumatol. 2013 Jul 152013:694928. doi: 10.1155/2013/694928. eCollection 2013.
Granulomatosis with polyangiitis; DermNet NZ
Paddock M, Lynch C, Paska L; Wegener's granulomatosis in primary care. JRSM Short Rep. 2010 Dec 61(7):59.
Weiss PF; Pediatric vasculitis. Pediatr Clin North Am. 2012 Apr59(2):407-23. doi: 10.1016/j.pcl.2012.03.013. Epub 2012 Apr 6.
Taylor SC, Clayburgh DR, Rosenbaum JT, et al; Clinical manifestations and treatment of idiopathic and Wegener granulomatosis-associated subglottic stenosis. JAMA Otolaryngol Head Neck Surg. 2013 Jan139(1):76-81. doi: 10.1001/jamaoto.2013.1135.
Kimmel, M et al; Differential Diagnosis of the Pulmonary-Renal Syndrome, An Update on Glomerulopathies - Clinical and Treatment Aspects, 2011
Ohlsson S, Herlitz H, Lundberg S, et al; Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease. Am J Kidney Dis. 2014 Feb63(2):289-93. doi: 10.1053/j.ajkd.2013.08.032. Epub 2013 Nov 1.
Mullen K et al; Imaging of Wegener's Granulomatosis, Pulmonary, Renal and Sinus Findings.
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 Jul120(7):643.e9-14.
Ntatsaki E, Carruthers D, Chakravarty K, et al; BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014 Dec53(12):2306-9. doi: 10.1093/rheumatology/ket445. Epub 2014 Apr 11.
Watts R et al; ANCA-Associated Vasculitis, 2012
Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis; NICE Technology Appraisal Guidance, March 2014
Hernandez-Rodriguez J, Hoffman GS, Koening CL; Surgical interventions and local therapy for Wegener's granulomatosis. Curr Opin Rheumatol. 2010 Jan22(1):29-36. doi: 10.1097/BOR.0b013e328333e9e9.
Luqmani R, Suppiah R, Edwards CJ, et al; Mortality in Wegener's granulomatosis: a bimodal pattern. Rheumatology (Oxford). 2011 Apr50(4):697-702. Epub 2010 Nov 25.
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 Nov58 Suppl 5(Pt 2):829-37.
Hellmich B, Lamprecht P, Gross WL; Advances in the therapy of Wegener's granulomatosis. Curr Opin Rheumatol. 2006 Jan18(1):25-32.
Comarmond C, Cacoub P; Granulomatosis with polyangiitis (Wegener): clinical aspects and treatment. Autoimmun Rev. 2014 Nov13(11):1121-5. doi: 10.1016/j.autrev.2014.08.017. Epub 2014 Aug 20.
Seo P; Wegener's granulomatosis: managing more than inflammation. Curr Opin Rheumatol. 2008 Jan20(1):10-6.