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Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: data from the Spanish registry BIOBADASER 2.0

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Abstract

Data on infections in patients exposed to biologic therapies are mainly focused on rheumatoid arthritis (RA). Little is known about the safety profile in other immune-mediated connective tissue diseases (ICTD). The purpose of this study was to describe and to compare the risk of serious infections (SI) in patients with RA and other ICTD on anti-TNF or rituximab and to identify predictors of SI. We analyzed RA or other ICTD patients on anti-TNF or rituximab included in the Spanish registry BIOBADASER 2.0 (2000–2011). For each disease group, incidence rate (IR), mortality rate (MR) and IR ratio (IRR) of SI with 95 % CI were estimated. Risks were then standardized by age and sex to the general population. Risk factors for SI were assessed by Poisson regression models. A total of 3,301 patients on anti-TNF (n = 3,166) or rituximab (n = 135), of which 176 (5 %) had ICTD other than RA, were analyzed. IR of SI was higher in non-RA ICTD than in RA, with an IRR of 3.15 (95 % CI 1.86, 5.31) before adjustment and 1.96 (95 % CI 1.06, 3.65) after adjustment for age, comorbidity and corticoid use. Mortality due to infections was higher in ICTD although it did not reach statistical significance. Age, disease duration, comorbidities, corticosteroids and ICTD different to RA were all independently associated with SI. Patients with ICTD other than RA are at a high risk of SI when prescribed anti-TNF or rituximab, partly due to the excess comorbidity and immunosuppressive co-treatment, but also to the inflammatory disease. When evaluating the risk/benefit ratio of off-label medications in ICTD patients, age, comorbidities and corticoid use should carefully be taken into account, applying adequate preventive measures.

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References

  1. Clinical practice guideline for the management of rheumatoid arthritis in Spain (2007) http://www.ser.es/practicaClinica/Guias_practica_clinica/Guias_finalizadas.php. Accessed 2 Nov 2013

  2. Furst DE, Keystone EC, Braun J et al (2011) Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis 70(Suppl 1):2–36

    Article  Google Scholar 

  3. Gomez Reino J, Loza E, Andreu JL et al (2011) Consensus statement of the Spanish Society of Rheumatology on risk management of biologic therapy in rheumatic patients. Reumatol Clin 7:284–298

    Article  PubMed  Google Scholar 

  4. Conti F, Ceccarelli F, Perricone C et al (2011) Rituximab infusion-related adverse event rates are lower in patients with systemic lupus erythematosus than in those with rheumatoid arthritis. Rheumatology (Oxford) 50:1148–1152

    Article  CAS  Google Scholar 

  5. Carmona L, Descalzo MA, Ruiz-Montesinos D et al (2011) Safety and retention rate of off-label uses of TNF antagonists in rheumatic conditions: data from the Spanish registry BIOBADASER 2.0. Rheumatology (Oxford) 50:85–92

    Article  CAS  Google Scholar 

  6. MedDRA (Meddra maintenance and support services organization. http://www.Meddramsso.Org/)

  7. Dixon WG, Carmona L, Finckh A et al (2010) EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology. Ann Rheum Dis 69:1596–1602

    Article  PubMed  Google Scholar 

  8. Ramos-Casals M, Brito-Zeron P, Munoz S et al (2008) A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine 87:345–364

    Article  PubMed  Google Scholar 

  9. Galloway JB, Hyrich KL, Mercer LK et al (2011) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 50:124–131

    Article  CAS  Google Scholar 

  10. Curtis JR, Xie F, Chen L et al (2011) The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis 70:1401–1406

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Diaz-Lagares C, Perez-Alvarez R, Garcia-Hernandez FJ et al (2011) Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label. Arthritis Res Ther 13:R112. doi:10.1186/ar3397

    Article  PubMed Central  PubMed  Google Scholar 

  12. Terrier B, Amoura Z, Ravaud P et al (2010) Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French auto immunity and rituximab registry. Arthritis Rheum 62:2458–2466

    Article  CAS  PubMed  Google Scholar 

  13. Tony HP, Burmester G, Schulze-Koops H et al (2011) Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID. Arthritis Res Ther 13:R75. doi:10.1186/ar3337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Alamanos Y, Tsifetaki N, Voulgari PV et al (2006) Epidemiology of primary Sjogren’s syndrome in north-west Greece, 1982–2003. Rheumatology (Oxford) 45:187–191

    Article  CAS  Google Scholar 

  15. Carmona L, Descalzo MA, Perez-Pampin E et al (2007) All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 66:880–885

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Toledano E, Candelas G, Rosales Z et al (2012) A meta-analysis of mortality in rheumatic diseases. Reumatol Clin 8:334–341

    Article  PubMed  Google Scholar 

  17. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V et al (2005) Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 52:1766–1772

    Article  CAS  PubMed  Google Scholar 

  18. Peña-Sagredo JLHM, Fernandez-Llanio N, Giménez-Ubeda E et al (2008) Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group experience. Clin Exp Rheumatol 26:854–859

    PubMed  Google Scholar 

  19. Schmedt NAF, Garbe E (2012) 9 Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 21:1216–1220

    Article  CAS  PubMed  Google Scholar 

  20. Molloy ES, Calabrese LH (2012) Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum 64:3043–3051

    Article  CAS  PubMed  Google Scholar 

  21. Atzeni F, Sarzi-Puttini P, Botsios C et al (2012) Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: comparison of adalimumab, etanercept and infliximab in the GISEA registry. Autoimmun Rev 12:225–229

    Article  CAS  PubMed  Google Scholar 

  22. Doran MF, Crowson CS, Pond GR (2002) Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294–2300

    Article  PubMed  Google Scholar 

  23. Gottenberg JE, Ravaud P, Bardin T (2010) Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 62:2625–2632

    Article  CAS  PubMed  Google Scholar 

  24. Bj F (2002) Infectious disease in systemic lupus erythematosus: risk factors, management and prophylaxis. Best Pract Res Clin Rheumatol 16:281–291

    Article  Google Scholar 

  25. Chen IJ, Tsai WP, Wu YJ (2010) Infections in polymyositis and dermatomyositis: analysis of 192 cases. Rheumatology (Oxford) 49:2429–2437

    Article  Google Scholar 

  26. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I (2009) Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 11:R109. doi:10.1186/ar2764

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank the dedication to BIOBADASER of Angel Guillen, monitor, and Juan Manuel Barrio, technology assistant. BIOBADASER is supported by the Research Unit of the Spanish Foundation for Rheumatology (FER), the Spanish Agency for Medicines and Medical Devices (AEMyPS) and the Spanish Society of Rheumatology (SER). Grants in approximately equal amounts (all under 25,000€/year) from Roche, Abbott, BMS, MSD and Pfizer contribute to the support of the registry. This work was partially supported by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII). The pharmaceutical companies and RETICS Program had no role in this study. All researchers in this work are independent from funders. In the collaboration contracts signed by the Spanish Society of Rheumatology, independence of the BIOBADASER registry has been affirmed with respect to the analyses as well as the diffusion of data and results.

Conflict of interest

TCI and LC had financial relationships with Roche, Abbott and Pfizer; ELS had financial relationships with Roche, Abbott; SMF had financial relationships with Roche, Abbott, Pfizer, MSD and GSK. No other relationships or activities that could appear to have influenced the submitted work.

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Authors and Affiliations

  1. Rheumatology Department, Hospital Universitario Infanta Sofía, Paseo de Europa 34, San Sebastián de Los Reyes, 28702, Madrid, Spain

    Tatiana Cobo-Ibáñez & Santiago Muñoz-Fernández

  2. Research Unit, Spanish Society of Rheumatology, Marqués de Duero 5, 1º, 28001, Madrid, Spain

    Miguel Ángel Descalzo

  3. Institute for Musculoskeletal Health, Hilarión Eslava, 2-Bajo Izquierda B, 28015, Madrid, Spain

    Estibaliz Loza-Santamaría & Loreto Carmona

  4. Health Sciences School, Universidad Camilo José Cela, Madrid, Spain

    Loreto Carmona

Authors
  1. Tatiana Cobo-Ibáñez
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  2. Miguel Ángel Descalzo
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  3. Estibaliz Loza-Santamaría
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  4. Loreto Carmona
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  5. Santiago Muñoz-Fernández
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Corresponding author

Correspondence to Tatiana Cobo-Ibáñez.

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On behalf of the BIOBADASER 2.0 Study Group.

Please refer the “Appendix” section for BIOBADASER 2.0 study group members.

Appendix: BIOBADASER 2.0 study group members

Appendix: BIOBADASER 2.0 study group members

Agustí Sellas, Basilio Rodríguez, Mireia Barceló, Sandra Farietta (Hospital Universitario Vall d’Hebron), María Montoro, Ainhoa González, Elena Herráez (Hospital Gregorio Marañón), Mª Dolores Ruíz-Montesino, Carmen Vargas (Hospital Universitario Virgen Macarena), Eva Pérez-Pampín (Hospital Clínico Universitario de Santiago), Ana Mª Ortiz, Eva Tomero (Hospital Universitario de La Princesa), Alberto Sifuentes, Fred Antón, Antonio Zea (Hospital Ramón y Cajal), Francisco Javier Manero Ruiz, Chesús Beltrán, Eugenio Giménez Úbeda, Fernando Jimenez Zorzo, Jesús Marzo, Marta Medrano, Ángela Pecondón (Hospital Universitario Miguel Servet), Mª Victoria Hernández, Raimon Sanmartí, Juan D Cañete (Hospital Clínic I Provincial), Carlos Rodriguez Lozano, Antonio Naranjo, Soledad Ojeda, Félix Francisco Hernández, Celia Erausquin, Íñigo Rúa, Juan Carlos Quevedo (Hospital de Gran Canaria Dr. Negrín), Sara Manrique, Inmaculada Ureña, Maria Victoria Irigoyen, Laura Cano (Hospital General Carlos Haya), Rosa Roselló Pardo (Hospital General San Jorge), Isabel Mateo, Javier Garcia, Eugenia Enríquez (Hospital 12 De Octubre), Cristina Campos (Hospital General Universitario de Valencia), Juan José García Borras, Rosa Negueroles, Luisa Muñoz, JL Valero, D Ibáñez (Hospital La Fe).

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Cobo-Ibáñez, T., Descalzo, M.Á., Loza-Santamaría, E. et al. Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: data from the Spanish registry BIOBADASER 2.0. Rheumatol Int 34, 953–961 (2014). https://doi.org/10.1007/s00296-014-2945-y

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