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. 2017 Apr 27;12(4):e0175207.
doi: 10.1371/journal.pone.0175207. eCollection 2017.

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study

Robert J Moots  1 , Ricardo M Xavier  2 , Chi Chiu Mok  3 , Mahboob U Rahman  4 , Wen-Chan Tsai  5 , Mustafa H Al-Maini  6 , Karel Pavelka  7 , Ehab Mahgoub  4 , Sameer Kotak  4 , Joan Korth-Bradley  4 , Ron Pedersen  4 , Linda Mele  4 , Qi Shen  4 , Bonnie Vlahos  4
Affiliations

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study

Robert J Moots et al. PLoS One. .

Erratum in

Abstract

Objective: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.

Methods: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected.

Results: Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low.

Conclusion: ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA.

Trial registration: This study was registered on www.ClinicalTrials.gov (NCT01981473).

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Conflict of interest statement

Competing Interests: Dr. Moots has been a consultant for AbbVie, BMS, Celgene, Chugai, Hospira, MSD, Napp, Pfizer, Roche, and USB Pharma (the funds have supported the development of rheumatology care in East Africa). Dr. Xavier has been a consultant for AstraZeneca, Hospira, Janssen, and Pfizer, and on the speakers’ bureau for AbbVie, AstraZeneca, Janssen, Pfizer, and Roche. Dr. Rahman is a former employee of and has stock in Pfizer. Dr. Tsai has been a consultant for AbbVie, Pfizer, and Roche. Dr. Pavelka has been a consultant for AbbVie, Amgen, BMS, Egis, MSD, Pfizer, Roche, and UCB, and on the speakers’ bureau for AbbVie, Amgen, BMS, Egis, MSD, Pfizer, and Roche, UCB. Drs. Mahgoub, Kotak, Korth-Bradley, Pedersen, Mele, Shen, and Vlahos are all employees of Pfizer and own stock in Pfizer. Dr. Kotak was an employee of Pfizer at the time the work was done and owns stock in Pfizer. Drs. Mok and Al-Maini have no conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Patient disposition.
Fig 2
Fig 2. Study design.
RA = rheumatoid arthritis; PK = pharmacokinetics; DAS28 = Disease Activity Score based on a 28-joint count; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; VAS = visual analog scale; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; PRO = patient- reported outcome; HAQ-DI = health assessment questionnaire-disability index; EQ-5D = EuroQol-5 Dimensions; SF-36 = Short-Form Health Survey; AE = adverse event. * Argentina, Australia, Bulgaria, Turkey, USA.
Fig 3
Fig 3. Proportion of patients (A) with ADA by treatment, (B) achieving LDA by treatment and ADA status, (C) achieving remission by treatment and ADA status, and (D) mean drug concentration by treatment.
ADA = antidrug antibodies; LDA = low disease activity; ETN = etanercept; ADL = adalimumab; IFX = infliximab.
Fig 4
Fig 4. Relationship between ADA status and ESR (A, C, and E) or CRP (D-F) by treatment: ETN (A, D), ADL (B, E), IFX (C, F).
Fig 5
Fig 5. Mean total score by treatment and ADA status for (A) DAS28-ESR, (B) DAS28-CRP, (C) CDAI, and (D) SDAI.
ADA = antidrug antibodies; DAS28 = disease activity score based on a 28-joint count; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; CDAI = clinical disease activity index; SDAI = simplified disease activity index; ETN = etanercept; ADL = adalimumab; IFX = infliximab.
Fig 6
Fig 6. Correlation between serum trough drug concentration and ESR (A, C, and E) or CRP (B, D, and F) by treatment: ETN (A, B), ADL (C, D), IFX (E, F).
See this image and copyright information in PMC

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