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Spondyloarthritis
Original research
Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial
  1. Emilie Ducourau1,2,
  2. Theo Rispens3,
  3. Marine Samain1,
  4. Emmanuelle Dernis4,
  5. Fabienne Le Guilchard5,
  6. Lucia Andras5,
  7. Aleth Perdriger6,
  8. Eric Lespessailles2,
  9. Antoine Martin7,
  10. Grégoire Cormier8,
  11. Thomas Armingeat9,
  12. Valérie Devauchelle-Pensec10,
  13. Elisabeth Gervais11,
  14. Benoit Le Goff12,
  15. Annick de Vries13,
  16. Eric Piver14,
  17. Gilles Paintaud15,
  18. Céline Desvignes15,
  19. David Ternant15,
  20. Hervé Watier16,
  21. Philippe Goupille1,17 and
  22. Denis Mulleman1
  1. 1Department of Rheumatology, University of Tours, EA 7501 GICC, CHRU de Tours, Tours, France
  2. 2Department of Rheumatology, CHR d'Orléans, Orléans, France
  3. 3Landsteiner Laboratory, Sanquin Research, Amsterdam, Netherlands
  4. 4Department of Rheumatology, CH du Mans, Le Mans, France
  5. 5Department of Rheumatology, CH de Blois, Blois, France
  6. 6Department of Rheumatology, CHRU de Rennes, Rennes, France
  7. 7Department of Rheumatology, CH de Saint-Brieuc, Saint-Brieuc, France
  8. 8Department of Rheumatology, CHD Vendée, La Roche-sur-Yon, France
  9. 9Department of Rheumatology, CH de Saint-Nazaire, Saint-Nazaire, France
  10. 10Department of Rheumatology, Université de Brest, Inserm UMR1227 LBAI, CHRU de Brest, Brest, France
  11. 11Department of Rheumatology, CHRU de Poitiers, Poitiers, France
  12. 12Department of Rheumatology, CHRU de Nantes, Nantes, France
  13. 13Biologicals Lab, Sanquin Diagnostic Services, Amsterdam, Netherlands
  14. 14Department of Biochemistry, University of Tours, Inserm U 1259, CHRU de Tours, Tours, France
  15. 15Department of Pharmacology-Toxicology, University of Tours, EA GICC, CHRU de Tours, Tours, France
  16. 16Department of Immunology, University of Tours, EA 7501 GICC, CHRU de Tours, Tours, France
  17. 17Inserm CIC1415, Tours, France
  1. Correspondence to Dr Denis Mulleman; denis.mulleman{at}univ-tours.fr

Abstract

Objectives Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.

Methods A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX−). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.

Results We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX− group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX− group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).

Conclusion MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.

  • anti-TNF
  • methotrexate
  • spondyloarthritis
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2019-001047

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    Footnotes

    • Contributors EDu contributed to the study conception and design, performed the statistical analysis, participated in the patients’ selection, clinical assessment and data collection, interpreted the results and drafted the manuscript. DM was responsible for coordination, conception and design of the study, participated in the patients’ selection, clinical assessment and data collection, interpreted the results and drafted the manuscript. MS contributed to the posthoc survival analysis, statistical analysis and drafted the manuscript. PG contributed to the study conception and design, participated in the patients’ selection, clinical assessment and data collection and participated in interpretation of results. eDe, FLG, LA, AP, EL, AM, GC, TA, VD-P, EG, and BLG improved the study design, participated in the patients’ selection, clinical assessment, data collection and interpretation of results. TR and AdV were responsible for antibodies towards adalimumab detection and interpreted the results. CD was responsible for serum sample management, material transfer and interpreted the results. DT was responsible for adalimumab measurement and participated in interpretation of results. EP was responsible for c-reactive protein measurement participated in interpretation of results. GP and HW participated in interpretation of results and critically reviewed the manuscript. All authors revised and approved the final manuscript.

    • Funding This work was promoted by the Regional University Hospital Centre of Tours and supported by grants from the French Ministry for Health and Sport within the framework of the Programme Hospitalier de Recherche Clinique 2012. The authors thank Hervé Brunet, Véronique Dubreuil-Chambardel and Patrick Thiennot from the Lions Club, Tours Val de France for their support and funding, and Nordic Pharma, which provided the methotrexate syringes.

    • Competing interests EDu was invited to attend international congresses by Roche and UCB; she has acted as a consultant and given lectures on behalf of her institution for BMS and Abbvie. eDe participated on behalf of her institution in clinical trials sponsored by Abbvie, Roche, BMS, Novartis, Pfizer, UCB and Sanofi; she has given lectures for Abbvie, BMS, Janssen, Pfizer, UCB, Novartis; she has acted as a consultant for BMS and UCB, Novartis; she has been invited to attend international congresses by MSD, Roche, BMS Abbvie and Novartis. FLG has been invited to attend an international congress by Abbvie, Pfizer. LA was invited to attend international congress by Abbvie, Novartis, Pfizer and UCB. EL has received speaker and consultant fees from Amgen, Expanscience, Lilly, and MSD; and research grants from Abbvie, Amgen, Lilly, MSD and UCB. GC was invited to attend international congress by Abbvie. VD-P has received speaker and consultant fees from MSD, BMS, UCB, Roche; and research grants from Roche-Chugai. EG has participated on behalf of his institution in clinical trials sponsored by Roche, Lilly, Novartis, Amgen, and BMS; she has acted as a consultant and given lectures for Abbvie, BMS, MSD, Pfizer, Roche, UCB, Novartis; she has been invited to attend international congresses by MSD, Roche, Novartis and BMS. BLG has participated on behalf of his institution in clinical trials sponsored by Roche, Lilly, Novartis, Pfizer, UCB and MSD; he has acted as a consultant and given lectures for Abbvie, BMS, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB, Novartis; he has been invited to attend international congresses by MSD, Roche, Abbvie, Sanofi and Pfizer. EP was invited to attend an international congress by Buhlmann. GP reports grants received by his research team from Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, outside of the submitted work. DT has acted as a consultant and given lectures for Sanofi, Amgen, PG participated on behalf of his institution in clinical trials sponsored by Abbvie, Roche, BMS, Boehringer, Lilly, Novartis, Pfizer, UCB, Janssen and MSD; he has acted as a consultant and given lectures for Abbvie, Biogaran, BMS, Hospira, Janssen, MSD, Pfizer, Sanofi-Genzyme, UCB; he has been invited to attend international congresses by MSD, Roche, BMS and Abbvie. DM has acted as a consultant and given lectures on behalf of his institution for Pfizer and Novartis; he has been invited to attend an international congress by Janssen-Cilag. His institution received grants for research from the non-governmental organisation Lions Club Tours Val de France. TR, MS, AP, CD, AdV, TA, AM and HW declared that they have no disclosure with the manuscript.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by the ethics committee of Tours University Hospital and was conducted in accordance with the Declaration of Helsinki. It was registered at ClinicalTrials.gov (NCT01895764).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data may be obtained from a third party and are not publicly available.