Immunogenicity of biological drugs in inflammatory rheumatic disease: Clinical relevance and therapeutic drug monitoring

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 14-06-2017Esta tesis doctoral trata sobre la inmunogenicidad de las terapias biológicas y su relevancia clínica en pacientes con enfermedades reumáticas. Esta investigación fue motivada por la observación clínica de que un porcentaje significativo de pacientes perdía eficacia del tratamiento a pesar de una buena respuesta inicial y de continuar con el mismo régimen terapéutico. Entonces, nos propusimos analizar qué factores podrían influir en el aclaramiento del fármaco. Nuestros primeros estudios se realizaron en pacientes con artritis reumatoide (AR) y espondiloartritis (SpA) tratados con infliximab (Ifx). Se demostró que los pacientes con niveles séricos más bajos de Ifx y/o presencia de anticuerpos anti-infliximab (ATI) se tenían una peor respuesta clínica. También se observó que los pacientes que recibían simultáneamente metotrexato (MTX) presentaban con menor frecuencia ATI en el suero o se detectaban niveles más bajos de ATI que en los pacientes en monoterapia. El desarrollo de ATI se asoció con una peor supervivencia de Ifx y con mayor incidencia de eventos adversos como reacciones relacionadas con la infusión. La asociación entre los niveles de fármaco y los resultados clínicos también se evaluó con otros biológicos como golimumab y tocilizumab Observamos que la monitorización de niveles séricos de fármaco y/o anticuerpos frente al fármaco contra el primer TNFi podría influir en futuras decisiones terapéuticas. Por otra parte, vimos que las intensificaciones de tratamiento con Ifx tienen un efecto limitado y no está asociada con una mejora clínica significativa. En una revisión sobre las estrategias de optimización o discontinuación en los pacientes de SpA objetivamos que la estrategia de optimización de dosis es factible en SpA con baja actividad, pero la estrategia de suspensión no se recomienda porque conduce al desarrollo de brotes en la mayoría de los casos. Se realizaron dos estudios observacionales que compararon la estrategia de optimización frente al régimen de terapia estándar en pacientes con AR y SpA. Ambos muestran que la estrategia de disminución de dosis es factible en la práctica clínica con una evolución clínica similar a los pacientes bajo un régimen de terapia estándar. Por último, se realizaron dos estudios que demuestran que un seguimiento clínico adecuado junto con herramientas como el control de los niveles séricos de fármacos pueden ayudar a que las estrategias de optimización se lleven a cabo de manera más segura con una reducción significativa de costes.In the present thesis work, we show the data from a research line about the immunogenicity of biologics and its clinical relevance in rheumatic patients under biological therapy. This research was motivated due to the clinical observation that a significant percentage of patients lost treatment efficacy to treatment with biological drugs, despite an initial good response and that they continued with the same treatment regimen. Then, our purpose was to investigate which factors influenced on this treatment failure. Our first studies were carried out in rheumatoid arthritis (RA) and Spondyloarthritis (SpA) patients under infliximab (Ifx) therapy. In these works, we demonstrated that lower Ifx levels and/or detectable ATI were associated with a poor clinical response. In addition, it was seen that patients receiving methotrexate (MTX) co-therapy less frequently developed antibodies to Ifx (ATI) or showed lower ATI levels than patients under monotherapy. Another important aspect was that ATI development was associated with treatment survival and with the incidence of adverse events such as infusion related reactions. The association between drug levels and clinical outcomes was also evaluated with other biological drugs such as golimumab and tocilizumab. Later, we noticed that serum trough drug and anti-drug antibodies (ADA) monitoring to the first TNFi could have an influence on future therapeutic decisions. On the other hand, we saw that Ifx intensification strategies have a limited effect and are not associated with a significant clinical improvement. We made a review on tapering or discontinuation strategies in SpA patients, concluding that tapering strategy is successful in SpA with low disease activity but discontinuation strategies are not recommended because they lead to flare in most cases. Two observational studies comparing the tapering strategy with the standard therapy regimen in RA and SpA patients were performed. Both show that tapering is feasible in clinical practice with similar clinical evolution than patients under a standard therapy regimen. Finally, we carried out two studies demonstrating that adequate clinical monitoring together with tools such as drug monitoring support the treatment optimization, in order to treat patients more safely and with a significant reduction of costs

Poor health and functioning in patients with axial spondyloarthritis during the COVID-19 pandemic and lockdown: REUMAVID study (phase 1)

To evaluate the overall health and functioning in patients with axial spondyloarthritis (axSpA) and related factors affecting these during the COVID-19 pandemic and lockdown measure

Correspondence on: 'EULAR definition of difficult-to-treat rheumatoid arthritis'.

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The immunogenicity to the first anti-TNF therapy determines the outcome of switching to a second anti-TNF therapy in spondyloarthritis patients

Introduction: Anti-TNF drugs have proven to be effective against spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF drug is related to the previous development of ADA to the first anti-TNF drug SpA patients. Methods: Forty-two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF therapy. Clinical activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the first and second anti-TNF therapy) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration. Results: All patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF drug. Eleven of 42 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first anti-TNF drug (3.52 ± 1.03 without ADA vs. 3.14 ± 0.95 with ADA, p = 0.399) and to the second anti-TNF drug (3.36 ± 0.94 without ADA vs. 3.09 ± 0.91 with ADA, p = 0.466). At 6 months after switching, patients with previous ADA had lower disease activity (1.62 ± 0.93 with ADA vs. 2.79 ± 1.01 without ADA, p = 0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs. 3 out of 11 (27.3%) with ADA, p = 0.002). Conclusions: In SpA the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p

Translation and cross-cultural adaptation of the mSQUASH into Spanish

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.</p