ARTHRITIS & RHEUMATISM Vol. 56, No. 9, September 2007, pp 3159–3166 DOI 10.1002/art.22834 © 2007, American College of Rheumatology HLA–DRB4 as a Genetic Risk Factor for Churg-Strauss Syndrome Augusto Vaglio, 1 Davide Martorana, 1 Umberto Maggiore, 1 Chiara Grasselli, 1 Adele Zanetti, 1 Alberto Pesci, 1 Giovanni Garini, 1 Paolo Manganelli, † Paolo Bottero, 2 Bruno Tumiati, 3 Renato A. Sinico, 4 Mario Savi, 1 Carlo Buzio, 1 and Tauro M. Neri, 1 on behalf of the Secondary and Primary Vasculitis Study Group Objective. To explore the association between HLA alleles and Churg-Strauss syndrome (CSS), and to investigate the potential influence of HLA alleles on the clinical spectrum of the disease. Methods. Low-resolution genotyping of HLA–A, HLA–B, and HLA–DR loci and genotyping of TNFA 238A/G and TNFA 308A/G single-nucleotide poly- morphisms were performed in 48 consecutive CSS pa- tients and 350 healthy controls. Results. The frequency of the HLA–DRB1*07 allele was higher in the CSS patients than in controls (27.1% versus 13.3%;  2  12.64, P  0.0003, corrected P [P corr ]  0.0042, odds ratio [OR] 2.42, 95% confi- dence interval [95% CI] 1.47–3.99). The HLA–DRB4 gene, present in subjects carrying either HLA– DRB1*04, HLA–DRB1*07, or HLA–DRB1*09 alleles, was also far more frequent in patients than in controls (38.5% versus 20.1%;  2  16.46, P  0.000058, P corr  0.000232, OR 2.49, 95% CI 1.58–3.09). Conversely, the frequency of the HLA–DRB3 gene was lower in patients than in controls (35.4% versus 50.4%;  2  7.62, P  0.0057, P corr  0.0228, OR 0.54, 95% CI 0.35–0.84). CSS has 2 major clinical subsets, antineutrophil cytoplasmic antibody (ANCA)–positive, with features of small-vessel vasculitis, and ANCA-negative, in which organ damage is mainly mediated by tissue eosinophilic infiltration; analysis of HLA–DRB4 in patients categorized by dif- ferent numbers of vasculitic manifestations (purpura, alveolar hemorrhage, mononeuritis multiplex, rapidly progressive glomerulonephritis, and constitutional symptoms) showed that its frequency strongly corre- lated with the number of vasculitis symptoms (P for trend  0.001). Conclusion. These findings indicate that HLA– DRB4 is a genetic risk factor for the development of CSS and increases the likelihood of development of vasculitic manifestations of the disease. Churg-Strauss syndrome (CSS) is a rare vasculitic disease characterized by granulomatous and eosinophil- rich inflammation and systemic necrotizing vasculitis affecting small and medium-sized vessels (1,2). It usually occurs in patients with asthma and eosinophilia, and has a heterogeneous clinical spectrum that includes consti- tutional symptoms, sinusitis, pulmonary infiltration, peri- pheral neuropathy, and skin (e.g., purpura, nodules), renal (e.g., isolated urinary abnormalities, rapidly pro- gressive glomerulonephritis [RPGN]), and gastrointesti- nal manifestations (3–6). Antineutrophil cytoplasmic antibodies (ANCAs) are present in 40% of patients, usually in those developing clinical features resulting from active small-vessel vasculitis (e.g., RPGN, purpura) (7,8). The pathogenesis of CSS has not been clearly elucidated. Eosinophils probably directly mediate organ damage, but T cells may also play a role, since serum interleukin-2 (IL-2) receptor levels are persistently high Supported in part by the Associazione Emma ed Ernesto Rulfo per la Genetica Medica and the Italian Ministry of Education, University and Research. 1 Augusto Vaglio, MD, Davide Martorana, PhD, Umberto Maggiore, MD, Chiara Grasselli, MD, Adele Zanetti, MD, Alberto Pesci, MD, Giovanni Garini, MD, Mario Savi, MD, Carlo Buzio, MD, Tauro M. Neri, MD: University of Parma, Parma, Italy; 2 Paolo Bottero, MD: Fornaroli Hospital, Magenta, Italy; 3 Bruno Tumiati, MD: Santa Maria Nuova Hospital, Reggio Emilia, Italy; 4 Renato A. Sinico, MD: San Carlo Borromeo Hospital, Milan, Italy. † Dr. Manganelli is deceased. Drs. Vaglio and Martorana contributed equally to this work. Address correspondence and reprint requests to Augusto Vaglio, MD, Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Universita ` degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: augusto.vaglio@virgilio.it. Submitted for publication January 19, 2007; accepted in revised form May 16, 2007. 3159