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Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

Cándido Díaz-Lagares1, Roberto Pérez-Alvarez2, Francisco J García-Hernández3, María M Ayala-Gutiérrez4, José Luis Callejas5, Agustín Martínez-Berriotxoa6, Javier Rascón7, Luis Caminal-Montero8, Albert Selva-O'Callaghan9, Joaquim Oristrell10, Carmen Hidalgo11, Ricardo Gómez-de-la-Torre12, Luis Sáez13, Jesús Canora-Lebrato14, María-Teresa Camps4, Norberto Ortego-Centeno5, María-Jesús Castillo-Palma3, Manuel Ramos-Casals1* and the BIOGEAS Study Group

Author Affiliations

1 Laboratorio de Enfermedades Autoinmunes Josep Font, IDIBAPS, Hospital Clínic, C/Villarroel, Barcelona, 08036, Spain

2 Servicio de Medicina Interna, Hospital Meixoeiro, Meixoeiro, Vigo, 36200, Spain

3 Unidad de Colagenosis, Servicio de Medicina Interna, Hospital Virgen del Rocío, Avda. Manuel Siurot, Sevilla, 41013, Spain

4 Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Carlos Haya, Avda. Carlos Haya, Málaga, 29010, Spain

5 Unidad de Enfermedades Autoinmunes Sistémicas, Hospital San Cecilio, Avda. Dr. Olóriz, Granada, 18012, Spain

6 Servicio de Medicina Interna, Hospital de Cruces, Plaza Cruces-Gurutzeta, Barakaldo, 48903, Spain

7 Servicio de Medicina Interna, Hospital Son Dureta, C/Andrea Doria, Palma de Mallorca, 07014, Spain

8 Servicio de Medicina Interna, Hospital Universitario Central de Asturias, C/Celestino Villamil, Oviedo, 33006, Spain

9 Servicio de Medicina Interna, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, 08035, Spain

10 Servicio de Medicina Interna, Hospital Parc Taulí, C/Parc Taulí, Sabadell, 08208, Spain

11 Servicio de Medicina Interna, Hospital Virgen de las Nieves, Avda. Fuerzas Armadas, Granada, 18014, Spain

12 Servicio de Medicina Interna, Hospital de Avilés, C/Camino Heros, Avilés, 33401, Spain

13 Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Paseo Isabel la Católica, Zaragoza, 50009, Spain

14 Hospital Universitario de Fuenlabrada, Camino del Molino, Fuenlabrada, 28942, Spain

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Arthritis Research & Therapy 2011, 13:R112  doi:10.1186/ar3397

Published: 11 July 2011



The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice.


The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents.


A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001).


The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection.

Infection rate; rituximab; infliximab; etanercept; adalimumab; systemic lupus erythematosus; Sjögren syndrome; vasculitis