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Clinical relevance of monitoring serum adalimumab levels in axial spondyloarthritis

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Abstract

Our aim was to assess the relationship between serum adalimumab levels, anti-drug antibodies (ADA) and disease activity in patients with axial spondylarthritis (SpA). We have carried out a single-centre cross-sectional study. adalimumab and ADA levels were analysed with ELISA and correlated with SpA activity using BASDAI and ASDAS scores. Adalimumab cut-off value was calculated to discriminate inactive disease/low disease activity (BASDAI < 4; ASDAS < 2.1) from moderate/high disease activity (BASDAI ≥ 4; ASDAS ≥ 2.1), using a receiver operating characteristic (ROC) curve. Up to January 2016, 51 consecutive patients were included. The median (range) age was 46.6 (18–68) and 47.1% were women. ADA prevalence was 27.5%, with none detected in the 21.6% receiving concomitant disease-modifying antirheumatic drugs (DMARDs) (p = 0.021). Adalimumab level was normal (> 3 mg/l) in 36 patients (70.6%), all without ADA. Fifteen patients (29.4%) had subtherapeutic adalimumab levels (< 3 mg/l), with ADA in 14 (93%). Median adalimumab (mg/l) was significantly higher in patients with inactive disease/low disease activity: BASDAI < 4 vs ≥ 4: 9.5 vs 2.6 (p < 0.01); ASDAS-CRP < 2.1 vs ≥ 2.1: 9.3 vs 0.3 (p < 0.001); ASDAS-ESR < 2.1 vs ≥ 2.1: 9.9 vs 3.0 (p < 0.001), and this finding was consistent with the result of the multivariate model. Patients with inactive disease/low disease activity presented significantly lower ADA levels. The adalimumab level cut-offs and area under the curve (AUC) obtained in the ROC curves were: ASDAS-CRP (< 2.1) 4.6 mg/l (AUC 81.2%; 95% CI 67.5–94.9; p < 0.001); ASDAS-ESR (< 2.1) 7.7 mg/l (AUC 82.4%; 95% CI 69.3–95.5; p < 0.001); BASDAI (< 4) 6.4 mg/l (AUC 73.5%; 95% CI 58.6–88.3; p < 0.01). In conclusion, presence of ADA in axial SpA patients treated with adalimumab was associated with lower serum drug levels. ADA levels were lower and adalimumab levels were higher in patients with inactive disease/low disease activity based on BASDAI and ASDAS indices. Concomitant treatment with MTX reduces de likelihood of finding ADA. Serum adalimumab levels above 4.6 mg/l are recommended to avoid compromising efficacy.

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Acknowledgements

Jordi Bozzo Ph.D. CMPP (Grifols, S.A.) is acknowledged for his editorial assistance in the preparation of the manuscript.

Funding

The study was supported by a grant from “Asociación para la Investigación en Reumatología de la Marina Baixa” (AIRE-MB) and from the “Fundación Española de Reumatología” (FER 2012). The funds were used for the acquisition of the ELISA kits.

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Authors and Affiliations

  1. Sección de Reumatología, Hospital Marina Baixa, Av. Alcalde En Jaume Botella Mayor 7, 03570, Villajoyosa, Alicante, Spain

    José Miguel Senabre Gallego, Jose Rosas, Gregorio Santos-Soler, Esteban Salas-Heredia, Ana Pons-Bas, José Antonio Bernal-Vidal & Catalina Cano-Pérez

  2. Laboratory Department, Hospital Marina Baixa, Villajoyosa, Alicante, Spain

    Mariana Marco-Mingot

  3. Infectious Disease Department, Hospital General Universitario de Elche, Elche, Alicante, Spain

    José Alberto García-Gómez

  4. Center of Operations Research, Universitas Miguel Hernández, Elche, Alicante, Spain

    Xavier Barber-Vallés

  5. Systemic Autoimmune Disease Research Unit, HGR-36-CIBIOR IMSS, Puebla, Mexico

    Mario García-Carrasco

  6. Department of Rheumatology and Immunology, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico

    Mario García-Carrasco

  7. Clinical Medicine Department, Universitas Miguel Hernández, Elche, Alicante, Spain

    Emilio Flores-Pardo

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  1. José Miguel Senabre Gallego
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Contributions

JMS-G: conception, design, interpretation of data, writing original draft, final approval. JR: conception, data acquisition (patient recruitment), review and editing draft. MM-M: laboratory analysis. JAG-G: statistical analysis. GS-S: data acquisition (patient recruitment). ES-H: data acquisition (patient recruitment). AP-B: study coordination and data acquisition (sample collection). XB-V: statistical analysis. JAB-V: data acquisition (patient recruitment). CC-P: data acquisition (sample collection). MG-C: conception, review and editing draft. EF-P: conception, design, review and editing draft.

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Correspondence to José Miguel Senabre Gallego.

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Conflict of interest

Dr. Senabre Gallego reports grants from Fundación Española de Reumatología, grants from Asociación para la Investigación en Reumatología de la Marina Baixa, assistance with translation of the manuscript from Grifols, S.A., during the conduct of the study; personal fees and non-financial support from Abbvie, non-financial support from BMS, personal fees from Celgene, personal fees from Janssen, non-financial support from Lilly, non-financial support from MSD, personal fees from Novartis, non-financial support from Pfizer, non-financial support from Roche, non-financial support from UCB, outside the submitted work. Dr. Rosas reports payment for the development of educational presentations including service on speakers’ bureaus from Abbvie, MSD, Pfizer and UCB. Dr. Santos Soler reports travel/accommodations expenses covered from Pfizer, outside the submitted work. Mrs. Pons Bas reports travel/accommodations expenses covered from Pfizer, outside the submitted work. Dr. Bernal Vidal reports travel/accommodations expenses covered from Pfizer, outside the submitted work. Mrs. Cano Pérez reports travel/accommodations expenses covered from Pfizer, outside the submitted work.

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The study was approved by our local Ethics Committee for Clinical Research of Hospital de San Juan, Alicante. All study procedures were performed according to the ethical principles of the Declaration of Helsinki and Good Clinical Practice.

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Informed consent was obtained from all individual participants included in the study.

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Senabre Gallego, J.M., Rosas, J., Marco-Mingot, M. et al. Clinical relevance of monitoring serum adalimumab levels in axial spondyloarthritis. Rheumatol Int 39, 841–849 (2019). https://doi.org/10.1007/s00296-019-04288-7

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