, David G. I. Scott2 and Chetan Mukhtyar2
Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, UK
Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK
GPA is a rare form of systemic vasculitis of unknown etiology, characterized by the involvement of the upper airway with granuloma formation and renal involvement with vasculitis. Although attributed to Wegener, it was first described by Klinger in 1931.
7.2 Definition and Classification
The Chapel Hill Consensus Conference defined GPA as “Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common” . It is also very often associated with ANCA, usually of PR3 specificity.
The usual criteria used for classifying GPA are those of the ACR (Table 7.1). For purposes of classification, a person is said to have GPA if at least two of these four criteria are present. The presence of any two or more yields a sensitivity of 88.2 % and a specificity of 92 % .
ACR (1990) criteria for the classification of GPA (Wegener’s)
Nasal or oral inflammation
Development of painful or painless oral ulcers or purulent or bloody nasal discharge
Abnormal chest radiograph
Chest radiograph showing the presence of nodules, fixed infiltrates or cavities
Microhaematuria (>5 red cells per high power field) or red cell casts in urinary sediment
Granulomatous inflammation on biopsy
Histological changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)
There are significant variations in the incidence of GPA in different parts of the world. In northern Europe, including the UK, the incidence is approximately 10/million/year and commonest age of onset is between 60 and 70 years, but GPA has been described in all ages, including children and patients in their 90s . GPA appears to be much rarer in southern Europe and in Japan (less than 3/million/year). Its prevalence ranges between 50 and 300 patients/million, with data from the UK suggesting that the prevalence of GPA is approximately 130 patients/million.
The etiology of GPA is unknown. Like many autoimmune diseases, it is generally believed to result from an environmental trigger, such as silica, interacting with a genetically predisposed host. Genetic factors have been extensively studied, but there is an association with HLA-DP. The familial genetic risk is similar to that seen in RA. No infectious triggers have been identified, although incidence figures from Norfolk have shown a periodicity every 7 or so years which is compatible with an infectious etiology. The association with PR3 ANCA suggests a possible role for the antibody in pathogenesis and this has been studied in animal models with inconclusive results. Non-MHC genetic links include associations with PTPN 22 and CTLA4. Recent Genome Wide Association Studies (GWAS) suggest genetic influences reflect the ANCA specificity (PR3 or MPO) more than the phenotype. Environmental factors have also been studied extensively and silica is probably the best documented.
7.5 Clinical Features
GPA often presents with upper airway/ENT manifestations, but can present in a number of different ways, including a severe widespread systemic illness. The prodromal phase, which may last weeks, months, or even years, consists of predominantly ENT symptoms, such as epistaxis, nasal crusting, and sinusitis, and these symptoms, particularly if followed/accompanied by a systemic illness, should alert the physician to the possibility of GPA as a diagnosis.
Fever, weight loss, myalgia, and arthralgia are common. Many patients describe a prodromal illness with a constitutional illness.
Pulmonary symptoms include cough, hemoptysis, and dyspnoea.
Skin involvement is seen in 40 % of patients and is most classically a palpable purpura, and histology of such a rash reveals a leukocytoclastic vasculitis (Fig. 7.1). Cutaneous ulceration can also occur, as can digital gangrene, but the latter is relatively rare.
Skin rash in a patient with GPA
GPA often presents with upper airway/ENT manifestations. The typical ENT symptoms are epistaxis, nasal crusting, and sinusitis. Cartilage destruction may lead to nasal collapse (Fig. 7.2).
Nasal bridge collapse in a patient with GPA
Gastrointestinal manifestations are relatively uncommon, but important to recognize. Abdominal pain, diarrhea, nausea, vomiting, and bleeding can all occur and vasculitis and granuloma can be found within the GI tract, resulting in small bowel ischemia, which can be life-threatening. More common are nonspecific symptoms and evidence of liver dysfunction as assessed by abnormal liver function tests which more probably reflect inflammation (see below).
Nervous system involvement is not uncommon and occurs in approximately 20 % of patients. It is, however, much rarer to see overt mononeuritis multiplex in GPA than in EGPA. The most common finding is a mild peripheral sensory neuropathy.
Renal involvement is very common and the kidney is one of the most important organs to be involved in GPA. The classical features are of indolent onset renal failure and it is vital that all patients with suspected GPA have regular urine checks because the presence of an abnormal sediment, particularly the combination of blood and protein in the urine, is a strong indicator of renal involvement.
Scleritis is not uncommon (10–20 %), but the most serious ocular complication/involvement associated with GPA is proptosis due to retro-orbital granuloma formation, which can lead to blindness. It is often painful and can be difficult to treat. ENT involvement in the upper airway can be associated with CNS involvement, either due to direct extension through the cribriform plate or from systemic spread, but meningeal enhancement associated with headaches is not infrequent, and specific CNS involvements including inflammation, infarction, and even diabetes insipidus have all been described.
Nonspecific myalgia and arthralgia are common and polyarthritis is well described. GPA can present in an identical way to rheumatoid arthritis with a symmetrical peripheral polyarthritis, so it needs to be considered within that differential diagnosis. Large joint arthritis can also occur, but arthralgia and myalgia are the commonest presenting symptoms.