Terapia Biológica e Infecciones.
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El documento resume la terapia biológica y el riesgo de infecciones. El uso de terapia biológica se asocia con un mayor riesgo de infecciones oportunistas y serias, especialmente durante los primeros años de tratamiento. El riesgo varía según la molécula, siendo mayor para los anticuerpos anti-TNF. La profilaxis adecuada y la estratificación del riesgo son importantes para minimizar las infecciones durante el tratamiento con terapia biológica.
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- 1. Biológicos e infecciones Juan Camilo Sarmiento-Monroy, MD, MSc. Centro de Dermatología y Reumatología FUNINDERMA Centro de Estudio de Enfermedades Autoinmunes CREA 04-Mar-2016, Bogotá
- 2. Conflicto de Interés Ninguno por declarar
- 3. Contenido 1. Terapia biológica 2. Panorama general 3. Infecciones oportunistas 4. Tuberculosis 5. Perfil infeccioso y farmacodinamia 6. Estudios en vida real 7. Terapia biológica segura 8. Estratificación del riesgo 9. Vacunación 10. Conclusiones
- 4. MTX 1988 1995 1998 + 2005 20101975 mAbs Tocilizumab (2010-2015) Golimumab (2009) Etanercept (1998) Etanercept* (2007) Infliximab (1999) 2000 Adalimumab (2002) Rituximab (2006) Abatacept (2005-2011) Certolizumab pegol (2009) 2015 LEF Scott DL. Clin Pharmacol Ther. 2012 Imágenes reproducidas con autorización de los pacientes Anakinra (2001) Belimumab (2011) Infliximab* (2015) Ustekinumab (2013) Secukinumab (2014)
- 5. anti-CD20anti-IL6 AR anti-TNF Co- estimulación 1 42 3 Adaptado de: van Vollenhoven RF. Nat Rev Rheumatol. 2011 Terapia Biológica: algunas opciones LESSpA anti-Blys 5 RituximabTocilizumab Etanercept Infliximab Adalimumab Golimumab Certolizumab pegol Abatacept Belimumab
- 6. Terapia Biológica: perfil de seguridad Singh JA et al. Lancet. 2015 Thyagarajan V et al. Semin Arthritis Rheum. 2012
- 7. Terapia Biológica: panorama general Riesgo de infección • Infecciones oportunistas: Mycobacterias, virus (HZ), hongos (invasivas), Pneumocystis jirovecii, parásitos. • Impacto en morbimortalidad. • Confusión por indicación (actividad, uso de GC). • Infecciones serias: varios meta-análisis publicados a la fecha, resultados no consistentes, limitaciones. • Mayor riesgo en los 2 primeros años de tratamiento. • Estratificación individual del riesgo. • Evidencia: múltiples ensayos clínicos, estudios de extensión, registros y estudios de vida real. Singh JA, et al. Lancet. 2015 Lahiri M et al. Best Prac & Res Clin Rheum. 2015 Kopylov U, Afif W. Gastroenterol Clin N Am. 2014
- 8. Infection profile in Colombian patients with Rheumatoid Arthritis: a single-center experience Juan Camilo Sarmiento-Monroy, Iván Enrique Rodríguez-Mantilla, Nicolás Molano- González, Mónica Rodríguez-Jiménez, Adriana Rojas-Villarraga, Rubén Darío Mantilla. TB Latente (n=60) • Glucocorticoides 58 (96.6%) • Terapia biológica 43 (71.6%) – anti-TNF: 24 – anti-IL6: 5 – anti-CD20: 8 – anti-CD80/86: 23 Herpes Zóster (n=25) • Glucocorticoides 25 (100%) • Terapia biológica 19 (76%) Infecciones n VHA 20 VHB 4 VHC 2 IVU 13 NAC 10 Candidiasis 2 Lues 2 Chikungunya 7 Tejidos blandos 4 Histoplasmosis 2 TRS 8 Sarmiento-Monroy JC, et al. Estudio de corte transversal. 442 pacientes Colombianos con AR (ACR 1987). 82.8% mujeres, edad media 54.3±12 años. Subfenotipos: seropositivos (FR 93.8%, anti-CCP 86.8%), 46.5% erosivos.
- 9. Terapia Biológica e Infecciones Oportunistas
- 10. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Kourbeti IS, et al. Clin Infect Dis. 2014 RSL (PubMed, EMBASE) -2013, 70 RCT (32,504), bDMARDs (21,916) vs. controles (10,588). bDMARDs: IFX, ADA, ETN, GOL, CZP, ANK, TCZ, ABA, RTX. El uso de terapia biológica se asocia con infecciones oportunistas, especialmente infecciones por Mycobacterias y virus.
- 11. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Singh JA, et al. Cochrane Database Syst Rev. 2011 RSL (Cochrane, MEDLINE, EMBASE) -2010. 163 RCT (50,010), 46 OLE (11,954). No VIH/SIDA. Mayor riesgo de reactivación de TB (OR 4.68, 95% CI 1.18–18.60). El uso de terapia biológica se asocia con infecciones serias.
- 12. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis Singh JA, et al. Lancet. 2015 RSL (MEDLINE, EMBASE, Cochrane, CT) -2014. 106 RCT (42,330). 9 bDMARDs analizados, comparados con csDMARDs. Asociación con un aumento en el riesgo de infecciones serias con el uso de biológicos en dosis estándar y altas, así como en aquellos expuestos previamente a csDMARDs.
- 13. Singh JA, et al. Lancet. 2015 525 infecciones serias 342 en biológico ± csDMARDs 183 en monoterapia con csDMARDs. Tendencia del riesgo en función del tiempo (número de biológicos aprobados). El uso de terapia biológica se asocia con infecciones serias. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis
- 14. Risk of Herpes Zoster in Patients With Rheumatoid Arthritis According to Biologic Disease-Modifying Therapy Yun H, et al. Arthritis Care Res (Hoboken). 2015 • Cohorte retrospectiva, Registro Medicare (2006-2011). • 29,129 pacientes adultos mayores. • Inclusión: uso previo de biológico, sin historia de malignidad ni poliautoinmunidad. • Inicio de seguimiento: nuevo biológico. • Final: incidencia de HZ, falta de adherencia (30 días), diagnóstico de malignidad u otra enfermedad autoinmune, pérdida de cobertura médica, tiempo (2011). • Regresión Cox ajustada por posibles variables confusoras. ABA 28.7%, ADA 15.9%, RTX 14.8%, IFX 12.4%, ETN 12.2%, TCZ 6.1%, CZP 5.8%, GOL 4.4%. Proporción de pacientes vacunados 0.4% (2007)-4.1% (2011). Antecedente de vacunación HZ (HR: 0.79, 95% CI: 0.39-1.61).
- 15. Risk of Herpes Zoster in Patients With Rheumatoid Arthritis According to Biologic Disease-Modifying Therapy 423 casos de HZ, diferencia no significativa con HR ajustados. El uso de glucocorticoides se encuentra asociado con HZ. Yun H, et al. Arthritis Care Res (Hoboken). 2015
- 17. Tasas de incidencia estimada de TB, 2014 Informe mundial sobre la Tuberculosis (OMS), 2015
- 18. Tasa de incidencia notificada de TB, 1993-2008 Plan Estratégico Colombia Libre de Tuberculosis 2010-2015
- 19. Tasas de mortalidad estimada por TB, 2014 Informe mundial sobre la Tuberculosis (OMS), 2015
- 20. Tasa de mortalidad por TB, 1985-2014 Informe mundial sobre la Tuberculosis (OMS), 2015
- 21. Terapia Biológica y Tuberculosis Epidemiología • Mayor incidencia (41/100,000 personas/año) en pacientes con AR expuestos a Terapia Biológica (vs. 6.2). • Cambio de perfil en países endémicos para TB. • Aproximadamente un tercio de los paciente con screening negativo para TB realizan alguna conversión de las pruebas (PPD/IGRA) durante el tratamiento con anti-TNF. • Considerar la posibilidad de infecciones por Micobacterias no tuberculosas. Hatzara C, et al. Ann Rheum Dis. 2014 Robert Horsburgh C, Barry CE. N Engl J Med. 2015
- 22. Guidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice SAFEBIO (Italian multidisciplinary task force for screening of tuberculosis before and during biologic therapy) Cantini F, et al. Autoimmun Rev. 2015 Revisión de la literatura, guias basadas en evidencia. Alto riesgo para reactivación de TB: anti-TNF (MAb). Bajo riesgo: ETN (-cept). Riesgo bajo/ausente: biológicos con otras dianas terapéuticas (UTK). Estratificación del riesgo según factores propios del paciente y farmacológicos. Paciente RR csDMARDs RR Silicosis 30 Leflunomida 11.7 ERC 25 Ciclosporina 3.8 Rx de tórax típica de TB 19 Metotrexate 3.4 TB reciente (<2 años) 15 Glucocorticoides 2.4 Exposición a TB 10.1 Otros (SSZ, AZA, CQ) 1.6 Espondilitis anquilosante 3.9 Artritis reumatoide 3.6
- 23. Risk of tuberculosis in patients with chronic immune- mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis RSL (MEDLINE, EMBASE, Cochrane) -2013. 100 RCT (75,000), 63 LTE (80,774 pt-año). Riesgo de TB activa en pacientes tratados con bDMARDs y tsDMARD (TOF). 31 casos de TB (anti-TNF), 1 con ABA, ninguno con RTX, TCZ, UTK, TOF. Souto A, et al. Rheumatology (Oxford). 2014
- 24. Risk of tuberculosis in patients with chronic immune- mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis Souto A, et al. Rheumatology (Oxford). 2014 LTE. Mayor riesgo para anti-TNF (Mab) (IR: 307, 95% CI: 184.79–454.93) > ETN (IR: 65.01, 95% CI: 18.22–136.84) > RTX (IR: 20, 95% CI: 0.10–60). Drug Tasa de incidencia por 100,000 pacientes-año (95% CI) TB Pt-año
- 25. Tuberculosis in patients treated with anti-TNF living in an endemic area. Is the risk worthwhile? Unidad de Inmunología Clínica y Reumatología, Clinica Universitaria Bolivariana, Medellin. Cohorte 440 pacientes con AR, 66 (15%) recibieron anti-TNF (IFX, ADA, ETN). Rojas-Villarraga A, et al. Biomedica 2007
- 26. Follow‐up results of isoniazid chemoprophylaxis during biological therapy in Colombia Cataño JC, Morales M. Rheumatol Int. 2015 Fundación Antioqueña de Infectología, 221 pacientes con terapia biológica (2010-2014). LTBI 98.7%, 100% profilaxis con INH (2-9m). 7 pacientes (3.2%) TB activa (2-12m de tratamiento anti-TNF). 32 pacientes (17.2%) intolerancia/toxicidad por INH.
- 27. Terapia Biológica: perfil infeccioso según molécula
- 28. Terapia Biológica: Perfil según molécula Estructura • Mejor perfil de seguridad para proteínas de fusión (ABA, ETN). bDMARDs vs. csDMARDs • La probabilidad de hospitalización debido a infecciones serias es similar entre los anti-TNF y los csDMARDs. Terapia combinada-dosis • La terapia biológica en combinación, y a dosis altas se asocia con una mayor prevalencia de infecciones serias. Mecanismo de acción • Mejor perfil de seguridad (TB) para Ustekinumab vs. anti-TNF. Brassard P, et al. Clin Infect Dis 2006 Tubach F, et al. Arthritis Rheum 2009
- 29. Ensayos clínicos vs. Estudios en vida real
- 30. Terapia Biológica Eficacia y Seguridad: RCT Etanercept TEMPO, ADORE, ERA, ETA, COMET, TEAR, JESMR, CAMEO Infliximab ASPIRE, ATTRACT, RISING, BeST, SWEFOT, RISING, RRR Adalimumab ARMADA, PREMIER, STAR, GUEPARD, CONCERTO, OPERA, HONOR, HIT HARD, OPTIMA Golimumab GO-BEFORE, GO-AFTER GO-FORWARD, GO-FURTHER Certolizumab RAPID1-2, FAST4WARD, REALISTIC, CERTAIN ADACTA SAMURAI, SATORI, AMBITION, ACT- RAY, ACT-STAR, ACT-SURE OPTION, TOWARD, RADIATE, TAMARA, SURPRISE, FUNCTION SUMMACTA DANCER REFLEX SUNRISE SWITCH-RA AGREE, AIM, ATTAIN, ATTEST, ASSURE, ARRIVE AMPLE, ALLOW, ACCOMPANY, ACQUIRE ADJUST AVERT BLYSS 52 BLYSS 76 Yamaoka K et al. Expert Opin Pharmacother. 2014 Maloney DG. N Engl J Med. 2012 Boyce, et al. Clin Ther. 2012 anti-TNF BelimumabAbataceptRituximabTocilizumab
- 31. Subcutaneous Abatacept in patients with Rheumatoid Arthritis: a real-life experience Juan Camilo Sarmiento-Monroy, Catalina Villota-Eraso, Marta Juliana Mantilla-Ribero, Nicolás Molano-González, Mónica Rodríguez-Jiménez, Adriana Rojas-Villarraga, Rubén Darío Mantilla. • Estudio retrospectivo, de un solo centro. • 94 pacientes Colombianos con AR (ACR 1987). • Seguimiento desde Abril de 2014. • Estratificación según tratamiento previo: MTX-IR (n=39), Switch ABA IV-SC (n=22) y TNF-IR (n=33). • Eficacia (6 meses): DAS28-CRP, RAPID3 (mensual), respuesta EULAR. • Seguridad: reporte de RAM (mensual). Infecciones n/N (%) Tracto respiratorio superior 25/94 (26.6) Bronquitis 4/94 (4.2) Tejidos blandos 4/94 (4.2) Tracto urinario 2/94 (2.1) Herpes Zóster 2/94 (2.1) Gastroenteritis 2/94 (2.1) Otitis Media Aguda 1/94 (1.0) Absceso dental 1/94 (1.0) Candidiasis oral 1/94 (1.0) Estomatitis 1/94 (1.0) Estomatitis y candidiasis 1/94 (1.0) Sarmiento-Monroy JC, et al. Ann Rheum Dis. Abstract submitted 2016 86% mujeres, edad media 55±12 años, duración de la enfermedad 12 (IQR 14) años. Seropositividad (FR 94%, anti-CCP 84%). Infección más frecuente: respiratoria alta, no infecciones serias.
- 32. Belimumab in refractory Systemic Lupus Erythematosus patients: a real-life experience Juan Camilo Sarmiento-Monroy, Jairo Sierra-Avendaño, Francisco Carvajal-Flechas, Adriana Rojas-Villarraga, Rubén Darío Mantilla. Sarmiento-Monroy JC, et al. 10th International Congress on Autoimmunity. Abstract No. AUT16-0574, 2016 • Estudio retrospectivo, de un solo centro. • 9 pacientes Colombianos con LES (ACR 1997). • Seguimiento entre Febrero y Octubre de 2015. • Desenlaces: ∆SLEDAI, efecto ahorrador de GC. • Seguridad: reporte de RAM (cada visita). • Dificultades administrativas en cumplimiento de esquema (dosis de carga-mantenimiento). • Solo 2 pacientes recibieron el esquema adecuado, con reducción en SLEDAI. 100% mujeres, mediana de edad 24 años, duración de la enfermedad 7 años. Actividad clínica y serológica persistente (SLEDAI basal 8). No infecciones.
- 34. Terapia Biológica ¿Qué debemos hacer antes? Adaptado de: Winthrop K. Rheum Dis Clin N Am. 2012 Schork NJ. Nature. 2015
- 35. INH 300mg QD (9m) + Piridoxina 50mg QD Vigilancia de hepatotoxicidad Prevención de reactivación Seguimiento clínico Adaptado de: Pai M, et al. Ann Intern Med. 2008 Pérez C, Borda A. Interpretación de la PPD, Fundamentos Fisiopatologicos y enfoque práctico. 2007 Terapia Biológica ¿Qué debemos hacer antes?
- 36. Terapia Biológica ¿Qué debemos hacer antes? Adaptado de: Pai M, et al. Ann Intern Med. 2008 Keystone C, et al. J Rheumatol. 2011
- 37. Chan ED, Isemanan MD. Curr Opin Infec Dis. 2008 Ramakrishnan L. Nat Rev Immunol. 2012 Tuberculosis Historia natural
- 38. Terapia Biológica y Tuberculosis Recomendaciones • Revaloración de estado de conversión por cualquier método de forma anual. • Especialmente en pacientes con alto riesgo para adquirir TB con resultados negativos durante el screening. • Pacientes con terapia biológica que recibieron profilaxis anti-TB deben ser enviados al Infectólogo o Neumólogo dos veces al año por los primeros dos años desde el final de la terapia pera determinar posibles reactivaciones o nuevos síntomas. Iannone F, et al. J Rheumatol. 2014 Cantini F, et al. Autoimmun Rev. 2015
- 39. Adaptado de: Smolen J, et al. Ann Rheum Dis. 2010
- 40. Terapia Biológica ¿Qué debemos hacer antes? Adaptado de: Ferreira I, Isenberg D. Ann Rheum Dis. 2014
- 41. La probabilidad de desarrollo de una infección seria durante los próximos 12 meses es: 8,5% Strangfeld A et al. Ann Rheum Dis. 2011 Zink A et al. Ann Rheum Dis. 2013
- 43. Terapia Biológica y Vacunación Aspectos a tener en cuenta • Factores de riesgo individuales – Personalización!. • Síndrome ASIA (adjuvantes). • Evitar vacunación en periodos de actividad. • Tipos de vacunas: inactivadas, vivas atenuadas. • Sin contraindicación, indicación condicional, contraindicación. • Recomendaciones locales. • Perfil farmacológico actual: GC, csDMARDs, bDMARDs. • Precaución con el tiempo de espera entre la interrupción de la terapia biológica y la aplicación de vacunas vivas atenuadas. Shoenfeld Y, Agmon-Levin N. J Autoimmun. 2011 Wotton CJ, Goldacre MJ. J Epidemiol Community Health. 2012
- 44. Available on line: http://www.cdc.gov/vaccines/schedules/hcp/adult.html
- 45. Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study Blumentals WA, et al. BMC Musculoskelet Disord. 2012 Cohorte retrospectiva, MarketScan database (2000-2007). 46,030 pacientes con AR. Incidencia de Influenza estacional (409.33) vs. Controles (306/pt-año). Mayor incidencia de complicaciones (x2.75) en AR. La incidencia es independiente de la presencia o ausencia de csDMARDs o biológicos. Influencia de la edad y el género.
- 46. Effect of MTX, anti–TNF, and RTX on the Immune Response to Influenza and Pneumococcal Vaccines in Patients With RA: A SLR and Meta-Analysis. Hua C, et al. Arthritis Care Res (Hoboken). 2014 RSL: evaluación de respuesta inmune a vacunas en pacientes con AR en tratamiento con MTX y/o biológicos. Eficacia evaluada con incremento de título de Ac (3-6s). 12 estudios. La respuesta a la vacunación con AH1N1 y AH3N2 se reduce en paciente con RTX.
- 47. Effect of MTX, anti–TNF, and RTX on the Immune Response to Influenza and Pneumococcal Vaccines in Patients With RA: A SLR and Meta-Analysis. Hua C, et al. Arthritis Care Res (Hoboken). 2014 La respuesta contra neumococo (23F) se encontró disminuida en pacientes con MTX y RTX.
- 48. Conocer el perfil de seguridad de cada molécula. Una buena historia clínica. Estratificación individual del riesgo de infección. Evaluación de TB latente/activa. Dar tratamiento para TB latente y vigilar tolerancia. Identificación oportuna de infecciones latentes/activas y necesidad de tratamiento específico. Terapia Biológica Enfoque preventivo
- 49. Determinación de memoria inmunológica. Desparasitación sistemática. Vacunación (según el paciente). Remisión oportuna al Infectólogo. Discutir los posibles riesgos. Brindarle confianza y educar al paciente. Terapia Biológica Enfoque preventivo
- 50. Terapia Biológica e Infecciones Conclusiones Optimización de terapia convencional. Selección adecuada de pacientes. Conocimiento del perfil de cada molécula. Evaluación sistemática del riesgo. Búsqueda activa de infecciones. La prevención de complicaciones es responsabilidad de todos. Experiencia del mundo real. Múltiples aspectos por resolver.
- 51. Gracias!
Notas del editor
- John Vane, 1982 premio nobel de medicina y fisiologia 1971 eficaces inhibidores de la sintesis de PG, mediacion procesos de dolor e inflamacion 1988 aprobado por la union europea para tratamiento de LNH - Primer mAb aprobado por FDA para tto de linfoma Sep 2006 aprobado +MTX UE y FDA tx AR activa severan refractaria Inoculacion ag ratones, LB de bazo, celulas de mieloma, cultivo, produccion anticuerpos monoclonales, cultivo hibridomas, purificacion Niels K. Jerne, Georges Köhler y Cesar Milstein, Jerne, Kölher y Milstein nobel de medicina 1984** Sales de oro en Francia desde 1928, Jacques Forestier ** Grupo de fármacos biotecnológicos (mAbs, proteínas de fusión, pequeñas moléculas, tolerágenos) que bloquean vías patogénicas específicas. Identificación de nuevas dianas terapéuticas. Mejoría de eficacia y seguridad. Nuevas alternativas en pacientes refractarios. Alto costo: 14.400-16.800 USD/año
- csDMARD: convencionales/tradicionales, compuestos químicos sintéticos tsDMARD: Tofacitinib, “targeted synthetic” bDMARD: biológicos bsDMARD: biosimilares Diferencias: estructura, morfología, fk, actividad, tiempo de acción, vida media, fd
- • Asociadas a la infusión: síntomas constitucionales, rash, edema, broncospasmo, hipo-hipertensión. • Asociadas a la inyección: cefalea, náuseas, locales, toxidermia • Infecciones: reactivación de TB, hepatitis, herpes zoster. • Neoplasias: órgano sólido, cutáneas, hemato-linfoides. • Gastrointestinales: hepatotoxicidad, perforación, constipación/diarrea. • Cardio-pulmonares: IAM, ICC, EPPD. • Neurológicas: enfermedad desmielinizante, ACV, parestesias, mareo. • Hematológicas: anemia, citopenias. • Metabólicas: dislipidemia. • Inmuno-mediadas: lupus-like, psoriasis. • Situaciones especiales: gestación, lactancia, vacunación, cirugías.
- OBJECTIVE: Biologic agents are increasingly used to treat patients with rheumatoid arthritis (RA). We aimed to review their association with opportunistic infections (OIs), including fungal, viral (with a focus on herpesvirus-related infections), tuberculosis and other mycobacterial infections. METHODS: We searched PubMed and EMBASE through June 24, 2013, and complemented the search with the reference lists of eligible articles. The analysis included randomized trials on RA that compared any approved biologic agent with controls and reported the risk of OIs. RESULTS: A total of 70 trials that included 32 504 patients (21 916 patients receiving biologic agents and 10 588 receiving placebo) were deemed eligible. Biologic agents increased the risk of OIs (pooled Peto odds ratio [OR], 1.79; 95% confidence interval [CI], 1.17-2.74; I(2) = 3%), resulting in 1.7 excess infections per 1000 patients treated (number needed to harm, 582). A significant risk was noted for mycobacterial (OR, 3.73; 95% CI, 1.72-8.13; I(2) = 0), and viral (OR, 1.91; 95% CI, 1.02-3.58; I(2) = 0) infections. Interestingly, no significant differences were found for invasive and superficial fungal infections (1.31; 95% CI, .46-3.72), invasive fungal infections (2.85; .68-11.91), P. jirovecii pneumonia (1.77; .42-7.47), varicella-zoster virus (1.51; .71-3.22), as well as overall mortality attributed to OIs (1.91; .29-12.64). CONCLUSIONS: Among patients with RA, biologic agents are associated with a small but significant risk of specific OIs. This increase is associated with mycobacterial diseases and does not seem to affect overall mortality. Because OIs are a relatively rare complication of biologic agents, large registries are needed to identify the exact effect in different OIs and to compare the different biologic agents. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
- BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics. Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections. Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics.
- BACKGROUND: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. METHODS: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. FINDINGS: The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. INTERPRETATION: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.
- BACKGROUND: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. METHODS: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. FINDINGS: The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. INTERPRETATION: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.
- OBJECTIVE: To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. METHODS: Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. RESULTS: Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. CONCLUSION: Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs
- OBJECTIVE: To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. METHODS: Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. RESULTS: Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. CONCLUSION: Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs
- The number of incident TB cases relative to population size (the incidence rate) varies widely among countries (Figure 2.6, Figure 2.7). The lowest rates are found predomi- nantly in high-income countries including most countries in western Europe, Canada, the United States of America, Aus- tralia and New Zealand. In these countries, the incidence rate is less than 10 cases per 100 000 population per year. Most countries in the Region of the Americas have rates below 50 per 100 000 population per year and this is the region with the lowest burden of TB on average. Prevalencia: 48/100.000 hab. Incidencia: 33/100.000 hab. Mortalidad: 1,8/100.000 hab.
- The number of incident TB cases relative to population size (the incidence rate) varies widely among countries (Figure 2.6, Figure 2.7). The lowest rates are found predomi- nantly in high-income countries including most countries in western Europe, Canada, the United States of America, Aus- tralia and New Zealand. In these countries, the incidence rate is less than 10 cases per 100 000 population per year. Most countries in the Region of the Americas have rates below 50 per 100 000 population per year and this is the region with the lowest burden of TB on average. Prevalencia: 48/100.000 hab. Incidencia: 33/100.000 hab. Mortalidad: 1,8/100.000 hab.
- There is considerable variation among countries (Figure 2.17), ranging from <1 TB death per 100 000 popula- tion (examples include most countries in western Europe, Canada, the United States of America, Australia and New Zealand) to more than 40 deaths per 100 000 population in much of the African Region as well as ve HBCs (Afghani- stan, Bangladesh, Cambodia, Indonesia and Myanmar).
- There is considerable variation among countries (Figure 2.17), ranging from <1 TB death per 100 000 popula- tion (examples include most countries in western Europe, Canada, the United States of America, Australia and New Zealand) to more than 40 deaths per 100 000 population in much of the African Region as well as ve HBCs (Afghani- stan, Bangladesh, Cambodia, Indonesia and Myanmar).
- Since the introduction of biologics for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis (Pso) an increased risk of tuberculosis (TB) reactivation in patients with latent tuberculosis infection (LTBI) has been recorded for anti-TNF agents, while a low or absent risk is associated with the non-anti-TNF targeted biologics. To reduce this risk several recommendation sets have been published over time, but in most of them the host-related risk, and the predisposing role to TB reactivation exerted by corticosteroids and by the traditional disease-modifying anti-rheumatic drugs has not been adequately addressed. Moreover, the management of the underlying disease, and the timing of biologic restarting in patients with TB occurrence have been rarely indicated. A multidisciplinary expert panel, the Italian multidisciplinary task force for screening of tuberculosis before and during biologic therapy (SAFEBIO), was constituted, and through a review of the literature, an evidence-based guidance for LTBI detection, identification of the individualized level of risk of TB reactivation, and practical management of patients with TB occurrence was formulated. The literature review confirmed a higher TB risk associated with monoclonal anti-TNF agents, a low risk for soluble receptor etanercept, and a low or absent risk for non-anti-TNF targeted biologics. Considering the TB reactivation risk associated with host demographic and clinical features, and previous or current non-biologic therapies, a low, intermediate, or high TB reactivation risk in the single patient was identified, thus driving the safest biologic choice. Moreover, based on the underlying disease activity measurement and the different TB risk associated with non-biologic and biologic therapies, practical indications for the treatment of RA, PsA, AS, and Pso in patients with TB occurrence, as well as the safest timing of biologic restarting, were provided.
- OBJECTIVE: The aim of this study was to assess the risk of active tuberculosis (TB) in patients with immune-mediated inflammatory diseases treated with biologics and tofacitinib in randomized controlled trials (RCTs) and long-term extension (LTE) studies. METHODS: A systematic review of the English-language literature by was performed by searching the Medline, Embase, Cochrane and Web of Knowledge databases. The search strategy focused on synonyms of diseases, biologics and tofacitinib. Data from RCTs were combined to assess the rate of TB using a random effects model. The incidence rate (IR) of TB and its association with disease, location and treatment were assessed in LTE studies. RESULTS: The search captured 11 130 articles and abstracts. One-hundred RCTs (75 000 patients) and 63 LTE studies (80 774.45 patient-years) met the inclusion criteria. There were 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib. The odds ratio for TNF inhibitors was 1.92 (95% CI 0.91, 4.03, P = 0.085). In LTE studies, the IR of TB was >40/100 000 with tofacitinib and all biologics except rituximab. IR was higher in RA patients with anti-TNF monoclonal antibodies [307.71 (95% CI 184.79, 454.93)] than in those with rituximab [20.0 (95% CI 0.10, 60)] and etanercept [67.58 (95% CI 12.1, 163.94)] or AS, PsA and psoriasis with etanercept [60.01 (95% CI 3.6, 184.79)]. The IR of TB was higher in high-background TB areas. CONCLUSION: RCTs are not sensitive enough to assess the risk of reactivation of latent TB infection (LTBI). Disease, treatment and background TB rate are associated with different frequencies of active TB. The benefit/risk balance of preventing reactivation of LTBI in different backgrounds should be considered in clinical practice.
- OBJECTIVE: The aim of this study was to assess the risk of active tuberculosis (TB) in patients with immune-mediated inflammatory diseases treated with biologics and tofacitinib in randomized controlled trials (RCTs) and long-term extension (LTE) studies. METHODS: A systematic review of the English-language literature by was performed by searching the Medline, Embase, Cochrane and Web of Knowledge databases. The search strategy focused on synonyms of diseases, biologics and tofacitinib. Data from RCTs were combined to assess the rate of TB using a random effects model. The incidence rate (IR) of TB and its association with disease, location and treatment were assessed in LTE studies. RESULTS: The search captured 11 130 articles and abstracts. One-hundred RCTs (75 000 patients) and 63 LTE studies (80 774.45 patient-years) met the inclusion criteria. There were 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib. The odds ratio for TNF inhibitors was 1.92 (95% CI 0.91, 4.03, P = 0.085). In LTE studies, the IR of TB was >40/100 000 with tofacitinib and all biologics except rituximab. IR was higher in RA patients with anti-TNF monoclonal antibodies [307.71 (95% CI 184.79, 454.93)] than in those with rituximab [20.0 (95% CI 0.10, 60)] and etanercept [67.58 (95% CI 12.1, 163.94)] or AS, PsA and psoriasis with etanercept [60.01 (95% CI 3.6, 184.79)]. The IR of TB was higher in high-background TB areas. CONCLUSION: RCTs are not sensitive enough to assess the risk of reactivation of latent TB infection (LTBI). Disease, treatment and background TB rate are associated with different frequencies of active TB. The benefit/risk balance of preventing reactivation of LTBI in different backgrounds should be considered in clinical practice.
- Caso 1: Paciente femenina de 33 años con diagnostico de 1 año de espondilitis anquilosante y uveitis anterior cronica, en manejo con PDN y MTX. Inicio INFX 200mg cada 8semanas con remision de sintomatologia. Despues de 3 meses ingresa con adenopatia cervical dolorosa derecha. BACAF con inflamacion granulomatosa caseificante, cultivos positivos. Caso 2: paciente masculino 47 años con EA 3 años evolucion sin respuesta a MTX. Inicio INFX 200mg cada 8semanas con PPD previa 3 meses negativa. Ingreso con diarrea, diaforesis nocturan, fiebre, anorexia, perdida de peso, dolor abdominal sin signos de irritacion peritoneal. TAC Abdominal aumento densidad grasa y adenopatias raiz del mesenterio. Biopsia por laparoscopia, con inflamacion granulomatosa caseificante. Case 3: Paciente femenina de 45 años con AR 14 años de evolucion. Tto PDN, MTX, CLQ. Alto indice articular (>10). INFX 200mg cada 8 semanas. Ingreso por malestar general y sindrome febril, artralgias. Rx Torax opacidades alveolares principalemtne en lobulo superior. Realizaron TACAR nodulos pulmonares con imágenes espiculadas. Fibrobroncoscopia+BAL positiva para TB. Caso 4: Paciente femenina de 72 años con AR hace 3 años y multiples comorbilidades (FA, falla cardiaca, HTA). Tto 2 años con adalimumab. Cuadro clinico de dolor toracico, disnea, tos, astenia y adinamia. Iniciamente neumonia, reingreso con TEP, y finalmente pericarditis y adenopatias mediastinales. Biospia de pericardio con presencia de TB.
- The use of biological therapy has been linked with an increased risk of tuberculosis (TB) reactivation. The aim of this study was to present the follow-up results for isoniazid (INH) chemoprophylaxis in patients receiving different biological therapies. In this prospective observational study, patients with latent tuberculosis infection (LTBI) were given INH chemoprophylaxis between 2 and 9 months prior to the beginning of biological therapy. All patients were followed up monthly for any signs or symptoms of active TB or INH toxicity. A total of 221 patients, 122 females (55.2 %), with a mean age of 46.8 ± 11.3 years (16-74) were enrolled. LTBI was identified in 218 patients (98.7 %), all of whom received INH chemoprophylaxis. Seven patients (3.2 %) developed active tuberculosis, and 32 (17.2 %) patients developed intolerance or toxicity related to INH. Chemoprophylaxis with INH seems to be effective and safe for the prevention of most TB reactivation in individuals with LTBI, but toxicity must be monitored during follow-up.
- Hepatotoxicidad por INH Incremento de 3x ALT y/o AST + ictericia Incremento de 5x ALT y/o AST + paciente asintomático
- No existe un gold standard en el diagnóstico de tuberculosis latente. La PPD y el IGRA se deben complementar en el estudio de TB latente para identificar los verdaderos pacientes que requieren tratamiento. Pobre concordancia entre PPD e IGRA, especialmente en poblaciones con alta incidencia de BCG. Mayor utilidad de IGRA en poblaciones con alta incidencia de BCG y pacientes inmunosuprimidos. Necesidad de realizar estudios en nuestra población para evaluar concordancia y valores predictivos acorde con la prevalencia.
- PURPOSE OF REVIEW: The spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) is a major medical and public health concern for the world. These two forms of highly drug-resistant TB threaten to make TB into an untreatable and highly fatal disease, particularly in resource-poor countries with a high prevalence of AIDS. The focus of this review is to highlight the current extent of the problem. RECENT FINDINGS: There is a great variability in clinical outcomes for MDR-TB, in part due to differences in the definitions of outcome measures and retrospective nature of the studies. Outcomes for XDR-TB are uniformly worse than those for MDR-TB. SUMMARY: A multifaceted approach is needed to prevent a more widespread epidemic of MDR-TB and XDR-TB. Rapid diagnostic assays to detect highly drug-resistant TB are essential in preventing delays in treatment of MDR-TB and XDR-TB and curbing their spread. Development of new drugs to effectively treat all forms of TB in a shorter period of time is urgently needed.
- Abstract BACKGROUND: Patients with rheumatoid arthritis (RA) are known to be at increased risk of infection, particularly if they are taking drugs with immunomodulatory effects. There is a need for more information on the risk of influenza in patients with RA. METHODS: A retrospective cohort study was carried out using data gathered from a large US commercial health insurance database (Thomson Reuters Medstat MarketScan) from 1 January 2000 to 31 December 2007. Patients were ≥18 years of age, with at least two RA claims diagnoses. The database was scanned for incidence of seasonal influenza and its complications on or up to 30 days after an influenza diagnosis in RA patients and matched controls. Other factors accounted for included medical conditions, use of disease-modifying anti-rheumatic drugs (DMARDs), use of biological agents, influenza vaccination and high- or low-dose corticosteroids. Incidence rate ratios (IRRs) were calculated for influenza and its complications in patients with RA. RESULTS: 46,030 patients with RA and a matching number of controls had a median age of 57 years. The incidence of influenza was higher in RA patients than in controls (409.33 vs 306.12 cases per 100,000 patient-years), and there was a 2.75-fold increase in incidence of complications in RA. Presence or absence of DMARDs or biologics had no significant effect. The adjusted IRR of influenza was statistically significant in patients aged 60-69 years, and especially among men. A significantly increased rate of influenza complications was observed in women and in both genders combined (but not in men only) when all age groups were combined. In general, the risk of influenza complications was similar in RA patients not receiving DMARDs or biologics to that in all RA patients. Pneumonia rates were significantly higher in women with RA. Rates of stroke/myocardial infarction (MI) were higher in men, although statistical significance was borderline. CONCLUSIONS: RA is associated with increased incidence of seasonal influenza and its complications. Gender- and age-specific subgroup data indicate that women generally have a greater rate of complications than men, but that men primarily have an increased rate of stroke and MI complications. Concomitant DMARD or biological use appears not to significantly affect the rate of influenza or its complications.
- Abstract OBJECTIVE: To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines. METHODS: We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3-6 weeks after vaccination, was extracted by one investigator and verified by another. RESULTS: In total, 12 studies were included. RA patients mainly received MTX, anti-tumor necrosis factor α (anti-TNFα), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17-1.12] for H1N1, OR 0.11 [95% CI 0.04-0.31] for H3N2, and OR 0.29 [95% CI 0.10-0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95% CI 0.36-2.37] for H1N1, OR 0.79 [95% CI 0.34-1.83] for H3N2, and OR 0.79 [95% CI 0.37-1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18-0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20-0.54] for serotype 6B and OR 0.58 [95% CI 0.36-0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95% CI 0.57-1.59] for 6B and OR 1.20 [95% CI 0.57-2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11-0.58] for 6B and OR 0.21 [95% CI 0.04-1.05] for 23F). CONCLUSION: MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFα therapy in RA patients.
- Abstract OBJECTIVE: To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines. METHODS: We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3-6 weeks after vaccination, was extracted by one investigator and verified by another. RESULTS: In total, 12 studies were included. RA patients mainly received MTX, anti-tumor necrosis factor α (anti-TNFα), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17-1.12] for H1N1, OR 0.11 [95% CI 0.04-0.31] for H3N2, and OR 0.29 [95% CI 0.10-0.81] for B) but not for anti-TNFα (308 patients; OR 0.93 [95% CI 0.36-2.37] for H1N1, OR 0.79 [95% CI 0.34-1.83] for H3N2, and OR 0.79 [95% CI 0.37-1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18-0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20-0.54] for serotype 6B and OR 0.58 [95% CI 0.36-0.94] for 23F) but not for anti-TNFα (258 patients; OR 0.96 [95% CI 0.57-1.59] for 6B and OR 1.20 [95% CI 0.57-2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11-0.58] for 6B and OR 0.21 [95% CI 0.04-1.05] for 23F). CONCLUSION: MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFα therapy in RA patients.