The online version of this article (doi:10.1186/ar3397) contains supplementary material, which is available to authorized users.
Cándido Díaz-Lagares, Roberto Pérez-Alvarez contributed equally to this work.
The BIOGEAS Study group has received educational grants from Roche and Abbott supporting the design and maintenance of the webpage . All authors have declared no conflicts of interest. None has received grants from these laboratories or conducted clinical trials with rituximab or etanercept as principal investigators or received honoraria as an Advisory Board member for Roche and Abbott. The financial support of Roche and Abbott is exclusively limited to maintaining the BIOGEAS webpage.
CDL, RPA, and MRC initiated the study and contributed to design, statistical analysis, and drafting and revising the manuscript. All authors contributed to data processing, including data analysis. All authors read and approved the final manuscript.
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.
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BIOGEAS. [ http://www.biogeas.es]
- Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label
Francisco J García-Hernández
María M Ayala-Gutiérrez
José Luis Callejas
the BIOGEAS Study Group
- BioMed Central
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