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Clinical and epidemiological research
Concise report
High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort
  1. Meghna Jani1,2,
  2. John D Isaacs3,
  3. Ann W Morgan4,
  4. Anthony G Wilson5,
  5. Darren Plant6,
  6. Kimme L Hyrich2,6,
  7. Hector Chinoy1,6,
  8. Anne Barton1,6
  9. on behalf of BRAGGSS
  1. 1Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  2. 2Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
  3. 3Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University and National Institute of Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
  4. 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute of Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  5. 5University College of Dublin School of Medicine and Medical Science, Dublin, Ireland
  6. 6National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science, Manchester, UK
  1. Correspondence to Professor Anne Barton, Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre, Stopford Building, Oxford Road, Manchester M13 9PT, UK; anne.barton{at}manchester.ac.uk

Abstract

Objectives To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels.

Methods This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels.

Results ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations.

Conclusions This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.

  • DMARDs (biologic)
  • Anti-TNF
  • Rheumatoid Arthritis
  • TNF-alpha
  • Treatment

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/annrheumdis-2015-208849

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    Footnotes

    • Handling editor Tore K Kvien

    • HC and AB joint last authors.

    • Twitter Follow Meghna Jani at @MeghnaJani and Hector Chinoy at @drhectorchinoy

    • Collaborators BRAGGSS Collaborators: Prouse PJ, Moitra RK, Shawe DJ, Nisar M, Fairburn K, Nixon J, Barnes T, Hui M, Coady D, Wright D, Morley C, Raftery G, Bracewell C, Bridges M, Armstrong D, Chuck AJ, Hailwood S, Kumar N, Ashok D, Reece R, O’Reilly SC, Ding T, Badcock LJ, Deighton CM, Raj N, Regan MR, Summers GD, Williams RA, Lambert JR, Stevens R, Wilkinson C, Kelly CA, Hamilton J, Heycock CR, Saravanan V, Cope A, Garrood T, Ng N, Kirkham B, Green M, Gough A, Lawson C, Das D, Borbas E, Wazir T, Emery P, Bingham S, Morgan A, Bird HA, Conaghan PG, Pease CT, Wakefield RJ, Buch M, Bruce I, Barton A, Gorodkin R, Ho P, Hyrich KL, Parker B, Smith W, Jenkins E, Mukhtyar C, Gaffney K, Macgregor AJ, Marshall T, Merry P, DeSilva C, Birrell FN, Crook PR, Szebenyi B, Bates D, James D, Gillott T, Alvi A, Grey C, Browning J, McHale JF, Gaywood IC, Jones AC, Lanyon P, Pande I, Doherty M, Gupta A, Courtney PA, Srikanth A, Abhishek A, Das L, Pattrick M, Snowden HN, Bowden AP, Smith EE, Klimiuk P, Speden DJ, Naz S, Ledingham JM, Hull RG, McCrae F, Cooper A, Young-Min SA, Wong E, Shaban R, Woolf AD, Davis M, Hutchinson D, Endean A, Mewar D, Tunn EJ, Nelson K, Kennedy TD, Dubois C, Pauling J, Korendowych E, Jenkinson T, Sengupta R, Bhalla A, McHugh N, Chinoy H, O'Neill T, Herrick AL, Jones AK, Cooper RG, Dixon WG, Harrison B, Buckley CD, Carruthers DC, Elamanchi R, Gordon PC, Grindulis KA, Khattak F, Raza K, Situnayake K, Akil M, Till S, Dunkley L, Tattersall R, Kilding R, Tait T, Maxwell J, Till S, Kuet K-P, Plant MJ, Clarke F, Fordham JN, Tuck S, Pathare SK, Paul A, Marguerie CP, Rigby SP, Dunn N, Abbas I, Filer C, Abernethy VE, Clewes AR, Dawson JK, Kitas G, Erb N, Klocke R, Whallett AJ, Douglas K, Pace A, Sandhu R, John H, Shand L, Lane S, Isaacs JD, Foster H, Griffiths B, Griffiths I, Kay L, Ng W-F, Platt PN, Walker DJ, Peterson P, Lorenzi A, Friswell M, Thompson B, Lee M, Pratt A, Hopkinson ND, Dunne CA, Quilty B, Marks J, Mukherjee S, Mulherin D, Chalam SV, Price T, Sheeran T, Venkatachalam S, Baskar S, Al-Allaf W, McKenna F, Shah P, Filer A, Bowman SJ, Jobanputra P, Rankin EC, Allen M, Chaudhuri K, Dubey S, Price-Forbes A, Ravindran J, Samanta A, Sheldon P, Hassan W, Francis J, Kinder A, Neame R, Moorthy A, Bukhari M, Ottewell L, Palkonyai E, Hider S, Hassell A, Menon A, Dowson C, Kamath S, Packham J, Dutta S, Price S, Roddy E, Paskins Z, O'Reilly DT, Rajagopal V, Bhagat S, Chattopadhyay CB, Green M, Quinn D, Isdale A, Brown A, Saleem B, Foo B, Al Saffar Z, Koduri G.

    • Contributors MJ, HC and AB were involved in the study conception, design and interpretation of results. The rest of the authors were involved in acquisition of data, final interpretation and review of manuscript. Funding for the study was provided by the first author’s MRC fellowship. AB is the principal investigator of BRAGGSS.

    • Funding MJ is supported by an NIHR clinical lectureship and was an MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant number G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit.

    • Competing interests MJ reports honoraria from UCB, Abbvie and Pfizer, outside the submitted work. JDI: advisory boards Pfizer, Roche, Abbvie, Janssen, Grants Roche, Pfizer, UCB. AWM has provided consultancy to GSK outside the submitted work. KLH reports honoraria from Abbvie and Pfizer outside of submitted work. HC has received honoraria, lecture fees and/or research grants from Abbvie, Janssen, MSD, Pfizer, UCB, Roche, Celgene and Servier, outside the submitted work. AB reports honoraria and/or grants from Pfizer, Abbvie, Eli-Lilly and Sanofi-Aventis outside the submitted work.

    • Ethics approval UK Multicentre Research Ethics Committee (COREC 04/Q1403/37).

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