International Journal of Perspective Clinical Rheumatology Comarmond & Cacoub What is the best treatment option for granulo- matosis with polyangiitis? 10 Perspective 2015/07/30 What is the best treatment option for granulomatosis with polyangiitis? Int. J. Clin. Rheumatol. Granulomatosis with polyangiitis is a systemic necrotizing vasculitis that affects small- Cloé Comarmond1,2,3,4 and medium-size blood vessels. It is often associated with antineutrophil cytoplasmic & Patrice Cacoub*,1,2,3,4 antibodies. The main manifestations involve the upper and/or lower respiratory tract 1Département de Médecine Interne et Immunologie Clinique, Assistance and kidneys. Limited forms of granulomatosis with polyangiitis predominantly affect Publique-Hôpitaux de Paris (AP-HP), the upper respiratory tract, whereas generalized forms include renal manifestations, Groupe Hospitalier Pitié-Salpêtrière, alveolar hemorrhage and altered general condition. The combination of 83 boulevard de l’hôpital, F-75013, Paris, immunosuppressant drugs and corticosteroids has converted this typically fatal illness France into one in which 80% of patients achieve remission. However, despite considerable 2Département Hospitalo-Unviversitaire I2B, UPMC Univ Paris 06, F-75013, Paris, therapeutic progress over the last decades, relapses remain frequent (50% at 5 years), France and maintenance treatment is now the main therapeutic challenge. 3INSERM UMR 7211, F-75005, Paris, INSERM, UMR_S 959, F-75013, Paris, Keywords: ANCA • characteristics • granulomatosis with polyangiitis • treatment France 4CNRS, UMR 7211, F-75005, Paris, France *Author for correspondence: Clinical aspects from UK (2005), from Germany (2006) and Tel.: +33 142 17 80 27 Since 1931, when granulomatosis with poly- Australia (2004) with considerably higher Fax: +33 142 17 80 33 angiitis (GPA), formerly known as Wegener’s and increasing prevalence rates (65–95 cases [email protected] granulomatosis, was first described by Ger- per one million), reflecting the better out- man pathologists Heinz Klinger and Fried- come of patients with GPA during the last 10.2217/ijr.15.26 rich Wegener, and the 1980s when antineu- two decades [3–5]. The annual incidence is trophil cytoplasmic antibodies (ANCA) were about 10 cases per million inhabitants in identified, considerable progress has been northern Europe. The age at diagnosis is made with regard to the diagnosis, treat- between 45 and 60 years. Men and women ment and pathophysiology of this disease. are affected with similar frequency. Rare It is a systemic, necrotizing vasculitis asso- cases of GPA may occur in black subjects, as 4 ciated with the presence of ANCA with a well as in children. cytoplasmic staining pattern directed against According to the 2012 revised Chapel Hill proteinase 3 (PR3). GPA is characterized by criteria [6], GPA is defined as a necrotizing granulomatous and necrotizing inflamma- granulomatous inflammation of the upper 2015 tory lesions located mainly in the upper and and lower respiratory tracts, with necrotizing lower respiratory tracts, and is often associ- vasculitis of small- and medium-size vessels, ated with pauci-immune glomerulonephritis, in other words, the capillaries, veins, arteri- which may be rapidly progressive. oles and arteries. Necrotizing glomerulone- GPA is a rare disease with a prevalence in phritis is common but is not essential for the France estimated at 22 per million inhabit- classification. This classification specifies that ants in 2000 [1] . The incidence has been eval- the granulomatous inflammation does not uated between 7 and 12 new cases per mil- necessarily need to be histologically proven lion inhabitants per year, although this has and can be predicted by noninvasive studies. probably risen in the last few decades [2]. In In some patients, the combination of sug- Europe, GPA seems to be more frequent in gestive clinical characteristics and the pres- the Nordic countries. There are newer data ence of cytoplasmic-staining ANCA and/or part of 10.2217/ijr.15.26 © 2015 Future Medicine Ltd Int. J. Clin. Rheumatol. (2015) 10(4), 227–234 ISSN 1758-4272 227 Perspective Comarmond & Cacoub anti-PR3 may be sufficient for making the diagnosis tic stenosis, sometimes associated with endobronchial of GPA and initiating treatment [7,8]. It is preferable to locations, are found in approximately 16% of cases but have histological evidence however, especially as renal are rarely hallmarks of GPA [13,14]. histology is a prognostic factor that determines the The most typical renal involvement is focal segmen- therapeutic approach, particularly for the administra- tal necrotizing glomerulonephritis associated with extra- tion of plasma exchange. capillary proliferation with pauci-immune crescent for- According to the criteria of the American College mation (i.e., without immunoglobulin or complement of Rheumatology (ACR; 1990) [9], GPA is defined by deposition by immunofluorescence). It is observed in 40 the presence of at least two of the following criteria: to 100% of cases according to the series and the specialty sinus involvement; lung x-ray showing nodules, a fixed of the clinicians managing these patients (nephrolo- pulmonary infiltrate or cavities; urinary sediment with gists, rheumatologists, internists). It usually leads to hematuria or red cell casts; and histological granulo- microscopic hematuria and proteinuria. There may be mas within an artery or in the perivascular area of an involvement of the interlobular arteries, veins and peri- artery or arteriole. The sensitivity and specificity of the tubular capillaries. It is the renal damage that negatively ACR criteria are 88.2 and 92.0%. impacts the prognosis of this disease. The initial glo- The exact cause of GPA has yet to be identified and merular filtration rate is significantly and independently is probably not unique. Environmental factors, such as linked to mortality [15] . The kidney biopsy puncture is dust inhalation, or exposure to silica, are most likely done for both the diagnosis and the prognosis (the num- involved, but these are only seen in 10% of patients with ber of normal glomeruli on biopsy is an important prog- GPA. It has been suggested that infectious agents may nostic factor) [16] . Urogenital manifestations are much play a role in triggering the disease, particularly through rarer and have only been described in men. They can be a mechanism of molecular mimicry. Nasal carriage of both a hallmark of the disease or occur during relapse. Staphylococcus aureus could be a factor for flares of the These manifestations can include prostatitis, orchitis, disease [10] . Some familial cases reporting the occur- epididymitis, renal pseudotumor, ureteral stenosis or rence of GPA cases among siblings have been published. penis ulceration [17] . The role of genetic factors in the occurrence of GPA Involvement of the peripheral nervous system affects was recently demonstrated in a genome-wide associa- about one-third of patients. It is characterized by mono- tion study of 1683 cases of GPA and 489 of microscopic neuritis multiplex or, less commonly, by sensorimotor polyangiitis [11] . The cases of vasculitis with anti-PR3 neuropathy. Involvement of the central nervous system ANCA were associated with the HLA-DP, SERPINA1 is much rarer (6 to 13%) [18] and may be caused by (gene encoding for α1-antitrypsin) and PRTN3 (gene granulomatous deposits, intracerebral vascular lesions encoding for proteinase 3) genes, while the cases of vas- or an extension of sinus lesions. Pachymeningitis is the culitis with antimyeloperoxidase ANCA shared a differ- most suggestive manifestation. Cases of granuloma- ent gene pool, in association with the HLA-DQ gene. tous infiltration of the pituitary stalk responsible for Constitutional signs (fever, asthenia, weight loss) are panhypopituitarism have also been reported. frequent (50%) but nonspecific. Muco-cutaneous lesions, mainly vascular purpura Ear, nose and throat (ENT) signs are present in to the lower limbs, are reported in 10 to 50% of cases; 70 to 100% of cases at diagnosis. These can include they can be ulcerating, necrotic and widespread. There crusting rhinorrhea, sinusitis, chronic otitis media or may be subcutaneous nodules, pyoderma gangreno- damage of the facial cartilage with deformities causing sum, raspberry-red gingivitis and intraoral and/or saddle-nose (resulting in a scooped out or depressed genital ulcerations. appearance of the nose), and/or perforation of the Ocular involvement occurs fairly frequently (14 nasal septum, the palate or the pinna of the ear [12] . to 60%), usually in the form of necrotizing nodular Nasal-sinus involvement is the most common manifes- episcleritis. Scleritis, corneal ulcerations and retinal tation of GPA, the most common hallmark of the dis- vasculitis also occur [19] . Involvement of the eye socket ease, and may be the only sign in the localized forms. in GPA is rarer but can be suggestive of the disease, Nasal obstruction with hyposmia or anosmia is often especially when it presents as a granulomatous retro- the first symptom. orbital pseudotumor or as dacryoadenitis [20,21] . It can Lung involvement affects 50 to 90% of patients. It is be either a primary form or occur secondary to sinus characterized by alveolar hemorrhage of variable sever- inflammation, and it typically manifests as inflamma- ity (small quantity or more massive, leading to acute tory exophthalmia, which may or may not be associ- respiratory failure), and/or parenchymatous nodules,