J Rheum Dis.  2025 Apr;32(2):136-144. 10.4078/jrd.2024.0114.

Factors associated with anti-drug antibody production in ankylosing spondylitis patients treated with the infliximab biosimilar CT-P13

• Kim Y
• Choi N
• Shin JH
• Jo S
• Nam B
• Kim TH

• KMID: 2566238
• DOI: http://doi.org/10.4078/jrd.2024.0114

Abstract

Objective
CT-P13, a biosimilar of infliximab, is widely used for treating ankylosing spondylitis (AS). However, the formation of anti-drug antibodies (ADAs) can reduce its efficacy. This study aimed to identify risk factors associated with high ADA levels in AS patients treated with CT-P13.
Methods
A prospective observational study enrolled patients with intravenous CT-P13. Clinical data and disease activity was assessed at baseline, 24 weeks, and 54 weeks after CT-P13 treatment. Blood concentrations of CT-P13 and ADAs were measured at 24 and 54 weeks, and their correlation was investigated. Patients were grouped by ADA levels at 54 weeks. Univariable and multivariable logistic regression identified factors associated with high ADA concentrations.
Results
A total of 34 patients was enrolled. Significant decreases in Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores were observed relative to baseline after 24 weeks of CT-P13 therapy. Serum concentrations of CT-P13 and ADA levels increased following treatment. The median serum CT-P13 concentration was 17.6 [12.8, 22.7] µg/mL at 24 weeks and 23.5 [11.7, 34.2] µg/mL at 54 weeks. ADA levels were 6.7 [6.5, 9.1] AU/mL at 24 weeks and 11.4 [9.0, 28.4] AU/mL at 54 weeks. The serum concentrations of CT-P13 and ADA exhibited a negative correlation. In multivariable analysis, current smoking was associated with high ADA production at 54 weeks.
Conclusion
Smoking is identified as a significant risk factor for elevated ADAs in AS patients treated with CT-P13. The findings underscore the importance of smoking-cessation strategies in the management of AS patients.

Keyword

Ankylosing spondylitis; Anti-drug antibody; CT-P13; Infliximab biosimilar; Smoking

Figure

• 

  Figure 1 Flow diagram of study design. ADA: anti-drug antibody.

• 

  Figure 2 Changes in disease activity, blood concentration of CT-P13, and ADA level. Disease activity was evaluated using BASDAI and BASFI. BASDAI: Bath Ankylosing Spondylitis Disease Activity Index, BASFI: Bath Ankylosing Spondylitis Functional Index, ADA: anti-drug antibody.

• 

  Figure 3 Percentages of patients with ADA concentrations >10 AU/mL at 24 and 54 weeks. An antibody concentration >10 AU/mL signaled Ab+ status, while that <10 AU/mL signaled Ab− status. Ab+: antibody positive, Ab−: antibody negative.

Reference

1. Chang J, Wang G. 2024; The efficacy of tofacitinib combined with bDMARDs in the treatment of ankylosing spondylitis patients with inadequate response to bDMARDs: a retrospective study. BMC Rheumatol. 8:3. DOI: 10.1186/s41927-024-00373-y. PMID: 38267988. PMCID: PMC10809439.

2. Noureldin B, Barkham N. 2018; The current standard of care and the unmet needs for axial spondyloarthritis. Rheumatology (Oxford). 57(suppl_6):vi10–7. DOI: 10.1093/rheumatology/key217. PMID: 30445485. PMCID: PMC6238225.

3. Haroon N, Kim TH, Inman RD. 2012; NSAIDs and radiographic progression in ankylosing spondylitis Bagging big game with small arms? Ann Rheum Dis. 71:1593–5. DOI: 10.1136/annrheumdis-2012-201844. PMID: 22863576.

4. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. 2017; Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 76:355–63. DOI: 10.1136/annrheumdis-2015-208786. PMID: 27130908. PMCID: PMC5284338.

5. Cheon JH, Nah S, Kang HW, Lim YJ, Lee SH, Lee SJ, et al. 2021; Infliximab biosimilar CT-P13 observational studies for rheumatoid arthritis, inflammatory bowel diseases, and ankylosing spondylitis: pooled analysis of long-term safety and effectiveness. Adv Ther. 38:4366–87. DOI: 10.1007/s12325-021-01834-3. PMID: 34250583.

6. Sakane H, Okamura K, Inoue M, Inoue H, Yonemoto Y, Mitomi H, et al. 2022; Anti-drug antibodies and rheumatoid factor level in patients with rheumatoid arthritis using the infliximab biosimilar CT-P13. BMC Rheumatol. 6:74. DOI: 10.1186/s41927-022-00304-9. PMID: 36474258. PMCID: PMC9727853.

7. Chang S, Hanauer S. 2017; Extrapolation and interchangeability of infliximab and adalimumab in inflammatory bowel disease. Curr Treat Options Gastroenterol. 15:53–70. DOI: 10.1007/s11938-017-0122-6. PMID: 28164249.

8. Park W, Yoo DH, Jaworski J, Brzezicki J, Gnylorybov A, Kadinov V, et al. 2016; Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther. 18:25. DOI: 10.1186/s13075-016-0930-4. PMID: 26795209. PMCID: PMC4721187.

9. Blair HA, Deeks ED. 2016; Infliximab biosimilar (CT-P13; infliximab-dyyb): a review in autoimmune inflammatory diseases. BioDrugs. 30:469–80. DOI: 10.1007/s40259-016-0193-2. PMID: 27650650.

10. van der Linden S, Valkenburg HA, Cats A. 1984; Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27:361–8. DOI: 10.1002/art.1780270401. PMID: 6231933.

11. Lee SJ, Baek K, Lee S, Lee YJ, Park JE, Lee SG. 2020; Post-marketing pooled safety analysis for CT-P13 treatment of patients with immune-mediated inflammatory diseases in observational cohort studies. BioDrugs. 34:513–28. DOI: 10.1007/s40259-020-00421-2. PMID: 32356239. PMCID: PMC7223987.

12. Husman J, Černá K, Matthes K, Gilger M, Arsova M, Schmidt A, et al. 2024; Subcutaneous infliximab in Crohn's disease patients with previous immunogenic failure of intravenous infliximab. Int J Colorectal Dis. 39:151. DOI: 10.1007/s00384-024-04727-3. PMID: 39317813. PMCID: PMC11422436.

13. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, et al. 2013; A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 72:1605–12. DOI: 10.1136/annrheumdis-2012-203091. PMID: 23687259. PMCID: PMC3786643.

14. Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, et al. 2017; Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs. 31:299–316. DOI: 10.1007/s40259-017-0231-8. PMID: 28612180. PMCID: PMC5548814.

15. Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. 2015; Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis. BioDrugs. 29:241–58. DOI: 10.1007/s40259-015-0134-5. PMID: 26280210.

16. Edlund H, Steenholdt C, Ainsworth MA, Goebgen E, Brynskov J, Thomsen OØ, et al. 2017; Magnitude of increased infliximab clearance imposed by anti-infliximab antibodies in Crohn's disease is determined by their concentration. AAPS J. 19:223–33. DOI: 10.1208/s12248-016-9989-8. PMID: 27739011.

17. Krishna M, Nadler SG. 2016; Immunogenicity to biotherapeutics - the role of anti-drug immune complexes. Front Immunol. 7:21. DOI: 10.3389/fimmu.2016.00021. PMID: 26870037. PMCID: PMC4735944.

18. Gecse KB, Lovász BD, Farkas K, Banai J, Bene L, Gasztonyi B, et al. 2016; Efficacy and safety of the biosimilar infliximab CT-P13 treatment in inflammatory bowel diseases: a prospective, multicentre, nationwide cohort. J Crohns Colitis. 10:133–40. DOI: 10.1093/ecco-jcc/jjv220. PMID: 26661272.

19. Bronswijk M, Moens A, Lenfant M, Tops S, Compernolle G, Van Assche G, et al. 2020; Evaluating efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar CT-P13: experience from a large tertiary referral center. Inflamm Bowel Dis. 26:628–34. DOI: 10.1093/ibd/izz271. PMID: 31648296.

20. Yoo DH, Oh C, Hong S, Park W. 2015; Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product. Expert Rev Clin Immunol. 11 Suppl 1:S15–24. DOI: 10.1586/1744666X.2015.1090314. PMID: 26395833.

21. McKeage K. 2014; A review of CT-P13: an infliximab biosimilar. BioDrugs. 28:313–21. DOI: 10.1007/s40259-014-0094-1. PMID: 24723086.

22. Smits LJ, Derikx LA, de Jong DJ, Boshuizen RS, van Esch AA, Drenth JP, et al. 2016; Clinical outcomes following a switch from Remicade to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohns Colitis. 10:1287–93. DOI: 10.1093/ecco-jcc/jjw087. PMID: 27095751.

23. Mattey DL, Dawson SR, Healey EL, Packham JC. 2011; Relationship between smoking and patient-reported measures of disease outcome in ankylosing spondylitis. J Rheumatol. 38:2608–15. DOI: 10.3899/jrheum.110641. PMID: 21965641.

24. Farouk HM, Abdel-Rahman MA, Hassan RM. 2021; Relationship between smoking, clinical, inflammatory, and radiographic parameters in patients with ankylosing spondylitis. Egypt Rheumatol Rehabil. 48:26. DOI: 10.1186/s43166-021-00076-z.

25. Nam B, Koo BS, Choi N, Shin JH, Lee S, Joo KB, et al. 2022; The impact of smoking status on radiographic progression in patients with ankylosing spondylitis on anti-tumor necrosis factor treatment. Front Med (Lausanne). 9:994797. DOI: 10.3389/fmed.2022.994797. PMID: 36325390. PMCID: PMC9618882.

26. Kaan U, Ferda O. 2005; Evaluation of clinical activity and functional impairment in smokers with ankylosing spondylitis. Rheumatol Int. 25:357–60. DOI: 10.1007/s00296-004-0451-3. PMID: 14991231.

27. Zhao SS, Goodson NJ, Robertson S, Gaffney K. 2020; Smoking in spondyloarthritis: unravelling the complexities. Rheumatology (Oxford). 59:1472–81. DOI: 10.1093/rheumatology/keaa093. PMID: 32236486.

28. Addissouky TA, El Sayed IET, Ali MMA, Wang Y, El Baz A, Elarabany N, et al. 2024; Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting. Bull Natl Res Cent. 48:16. DOI: 10.1186/s42269-024-01174-6.

29. Khan D, Zhou H, You J, Kaiser VA, Khajuria RK, Muhammad S. 2024; Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation. Cell Commun Signal. 22:214. DOI: 10.1186/s12964-024-01594-x. PMID: 38570838. PMCID: PMC10988825.

30. Jacobs M, Verschraegen S, Salhi B, Anckaert J, Mestdagh P, Brusselle GG, et al. 2022; IL-10 producing regulatory B cells are decreased in blood from smokers and COPD patients. Respir Res. 23:287. DOI: 10.1186/s12931-022-02208-1. PMID: 36253785. PMCID: PMC9578234.

31. Rubio Vargas R, van den Berg R, van Lunteren M, Ez-Zaitouni Z, Bakker PA, Dagfinrud H, et al. 2016; Does body mass index (BMI) influence the Ankylosing Spondylitis Disease Activity Score in axial spondyloarthritis?: data from the SPACE cohort. RMD Open. 2:e000283. DOI: 10.1136/rmdopen-2016-000283. PMID: 27403336. PMCID: PMC4932251.

32. Mc Gettigan N, Afridi AS, Harkin G, Lardner C, Patchett S, Cheriyan D, et al. 2021; The optimal management of anti-drug antibodies to infliximab and identification of anti-drug antibody values for clinical outcomes in patients with inflammatory bowel disease. Int J Colorectal Dis. 36:1231–41. DOI: 10.1007/s00384-021-03855-4. PMID: 33515082.

33. Michelsen B, Berget KT, Kavanaugh A, Haugeberg G. 2022; Association between TNFi anti-drug antibodies, smoking, and disease activity in patients with inflammatory arthritis: results from a Norwegian cross-sectional observational study. Rheumatol Ther. 9:1171–9. DOI: 10.1007/s40744-022-00464-7. PMID: 35594016. PMCID: PMC9314485.