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Randomized Controlled Trial
. 2020 Jan;6(1):e001047.
doi: 10.1136/rmdopen-2019-001047. Epub 2020 Jan 9.

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial

Emilie Ducourau  1   2 , Theo Rispens  3 , Marine Samain  1 , Emmanuelle Dernis  4 , Fabienne Le Guilchard  5 , Lucia Andras  5 , Aleth Perdriger  6 , Eric Lespessailles  2 , Antoine Martin  7 , Grégoire Cormier  8 , Thomas Armingeat  9 , Valérie Devauchelle-Pensec  10 , Elisabeth Gervais  11 , Benoit Le Goff  12 , Annick de Vries  13 , Eric Piver  14 , Gilles Paintaud  15 , Céline Desvignes  15 , David Ternant  15 , Hervé Watier  16 , Philippe Goupille  1   17 , Denis Mulleman  18
Affiliations
Randomized Controlled Trial

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial

Emilie Ducourau et al. RMD Open. 2020 Jan.

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.

Keywords: anti-TNF; methotrexate; spondyloarthritis.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Adalimumab concentrations by treatment group. MTX+: methotrexate+adalimumab. MTX−: adalimumab alone. W-2=baseline, W4=4 weeks, W8=8 weeks, W12=12 weeks, W26=26 weeks. Four patients had a baseline adalimumab concentration above the lower limit of quantification because they previously received infliximab, which interfered with adalimumab detection. Horizontal lines are median, box edges are IQR and whiskers are range. The difference was statistically significant at W4, W8, W12 and W26.
Figure 2
Figure 2
Adalimumab concentrations by anti-drug antibody (ADA) status. MTX+: methotrexate+adalimumab. MTX−: adalimumab alone. W2=baseline, W4=4 weeks, W8=8 weeks, W12=12 weeks, W26=26 weeks. Horizontal lines are median, box edges are IQR and whiskers are range. The difference was statistically significant between ADA-high and ADA-low at W4, W8, W12 and W26.
Figure 3
Figure 3
Ankylosing Spondylitis Disease Activity Score (ASDAS) by anti-drug activity (ADA) status. W0=0 week, W4=4 weeks, W8=8 weeks, W12=12 weeks, W26=26 weeks. The difference was only statistically significant between ADA-neg and ADA-high at W26.
Figure 4
Figure 4
Adalimumab maintenance according to (A) anti-drug antibody (ADA)+ versus ADA− at week 26 (W26), (B) methotrexate (MTX) long duration, that is >W26, versus no MTX or MTX short duration, that is ≤W26 and (C) adalimumab concentrations<1st quartile at W8, that is <4 µg/mL, versus adalimumab concentration ≥1st quartile, that is ≥4 µg/mL.
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