Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long‐Term Treatment Response in Rheumatoid Arthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 67; no. 8; pp. 2011 - 2019
• Main Authors: Warren, Richard B., Fu, Bo, Wilson, Anthony G., Fairburn, K., Hui, M., Coady, D., Morley, C., Bracewell, C., Armstrong, D., Hailwood, S., Kumar, N., O'Reilly, S. C., Ding, T., Badcock, L. J., Regan, M. R., Summers, G. D., Stevens, R., Kelly, C. A., Hamilton, J., Saravanan, V., Cope, A., Garrood, T., Das, D., Wakefield, R. J., Buch, M., Parker, B., Gaffney, K., Crook, P. R., Szebenyi, B., Gillott, T., McHale, J. F., Jones, A. C., Lanyon, P., Doherty, M., Abhishek, A., Das, L., Pattrick, M., Bowden, A. P., Speden, D. J., Ledingham, J. M., Cooper, A., Wong, E., Shaban, R., Woolf, A. D., Davis, M., Hutchinson, D., Kennedy, T. D., Bhalla, A., Dixon, W. G., Buckley, C. D., Carruthers, D. C., Grindulis, K. A., Raza, K., Till, S., Dunkley, L., Tattersall, R., Maxwell, J., Kuet, K.-P., Plant, M. J., Clarke, F., Fordham, J. N., Pathare, S. K., Marguerie, C. P., Dunn, N., Clewes, A. R., Dawson, J. K., Klocke, R., John, H., Shand, L., Foster, H., Griffiths, B., Walker, D. J., Lorenzi, A., Friswell, M., Dunne, C. A., Mukherjee, S., Mulherin, D., Chalam, S. V., Price, T., McKenna, F., Allen, M., Chaudhuri, K., Dubey, S., Price‐Forbes, A., Samanta, A., Sheldon, P., Kinder, A., Neame, R., Bukhari, M., Hider, S., Hassell, A., Kamath, S., Packham, J., Dutta, S., Price, S., Quinn, D., Brown, A., Saleem, B., Foo, B.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-05-2015; John Wiley and Sons Inc
• Subjects: Adalimumab; Adult; Aged; Antibodies - immunology; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - therapeutic use; Antirheumatic Agents - blood; Antirheumatic Agents - immunology; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Cohort Studies; Confidence intervals; Enzyme-Linked Immunosorbent Assay; Etanercept; Female; Gangrene; Humans; Hydroxychloroquine - therapeutic use; Immunoglobulin G - blood; Immunoglobulin G - immunology; Immunoglobulin G - therapeutic use; Immunoglobulins; Male; Methotrexate - therapeutic use; Middle Aged; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor - blood; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - therapeutic use; Rheumatoid Arthritis; Sulfasalazine - therapeutic use; Treatment Outcome; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-TNF
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.39169

Objective
To investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.
Methods
A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.
Results
Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.
Conclusion
Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.