EFFICACY OF ADALIMUMAB IN EARLY RHEUMATOID ARTHRITIS IN RELATION TO ITS SERUM LEVEL AND THE PRESENCE OF ANTI-DRUG ANTIBODY

Objective: to assess the relationship of the efficiency of adalimumab (ADA) therapy in early rheumatoid arthritis (RA) with the serum level of the drug and with the presence of antibody (Ab) to it.

Subjects and methods. Serum concentration of ADA and Ab against it (μg/ml) were measured using an enzyme immunoassay in 25 patients with early RA before, 12 and 24 weeks after beginning of the therapy. All patients received the disease-modifying antirheumatic drug methotrexate and ADA 40 mg subcutaneously every other week. ADA was the first biological agent for all patients.

Results. The patients were divided into the following groups: those with a serum ADA level of <2.85 (Group 1, n=7) and ≥2.85 (Group 2, n=13). After 24 weeks of treatment, Group 1 showed higher disease activity (DAS was 4.5 [3.3; 4.9]) and levels of acute-phase reactants (ESR, 44 [18; 57] mm/hr; C-reactive protein (CRP), 10.1 [4.9; 34.5] mg/ml) than Group 2 (3.5 [2.9; 3.9], 15.0 [6.0; 17.0] mm/hr, 1.9 [0.75; 6.7] mg/ml, respectively; p<0.05). Also, after
24 weeks of therapy, there was a negative correlation of ADA level and DAS28 (r=-0.46; p=0.04), CRP (r=-0.54;p=0.02) and ESR (r=-0.5; p=0.02). Anti-ADA Ab were found in 3 and 2 patients after 12 and 24 weeks, respectively. After 24 weeks of therapy, all
patients with anti-ADA Ab exhibited no clinical effect. There were few unresponsive patients (11%) among those without anti-ADA Ab.

Conclusion. In patients with early RA treated with ADA, its low serum level (<2.85 μg/ml) is associated with the higher clinical and laboratory measures of disease activity. After 12–24 weeks of ADA therapy, 10–12.5% of patients are found to have Ab to the drug and its production is associated with lower efficacy.

1. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Ревматология. Национальное руководство. Под ред. Е.Л. Насонова, В.А.Насоновой. Москва: ГЭОТАР- Медиа; 2008. С. 290–331. [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Revmatologiya. Natsional’noe rukovodstvo [Rheumatology. National Guide]. Nasonov EL, Nasonova VA, editors. Moscow: GEOTAR-media; 2008. P. 290–331.]

2. Насонов Е.Л. Фармакотерапия ревматоидного артрита – взгляд в 21 век. Клиническая медицина. 2005;83(6):8–12. [Nasonov E.L. Pharmacotherapy of rheumatoid arthritis the 21st century. Klinicheskaya meditsina. 2005;83(6):8–12. (In Russ.)]

3. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007;357:239–50. DOI: http://dx.doi.org/10.1056/NEJMoa062897.

4. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with ConcomitantTherapy Study Group. N Engl J Med. 2000;343:1594–602. DOI: http://dx.doi.org/10.1056/NEJM200011303432202.

5. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. DOI: http://dx.doi.org/10.1002/art.10697.

6. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:353–63. DOI: http://dx.doi.org/10.1002/art.20019.

7. Keystone E, Heijde D, Mason D Jr, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis:findings of afifty-twoweek, phase III, multicenter, randomized, double-blind, placebocontrolled, parallel-group study. Arthritis Rheum. 2008;58:3319–29. DOI: http://dx.doi.org/10.1002/art.23964.

8. Kay J, Matteson EL, Dasgupta B, et al. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58:964–75. DOI: http://dx.doi.org/10.1002/art.23383.

9. Bennett AN, Peterson P, Zain A, et al. Adalimumab in clinical practice. Outcome in 70 rheumatoid arthritis patients, including comparison of patients with and without previous anti-TNF exposure. Rheumatology (Oxford). 2005;44:1026–31. DOI: http://dx.doi.org/10.1093/rheumatology/keh673.

10. Elliott MJ, Maini RN, Feldmann M, et al. Randomised doubleblind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;344:1105–10. DOI: http://dx.doi.org/10.1016/S0140-6736(94)90628-9.

11. Weinblatt ME, Schiff MH, Ruderman EM, et al. Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis Rheum. 008;58:1921–30. DOI: http://dx.doi.org/10.1002/art.23493.

12. Furst DE, Schiff MH, Fleischmann RM, et al. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol. 2003;30:2563–71.

13. Wolbink GJ,Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:711–15. DOI: http://dx.doi.org/10.1002/art.21671.

14. Wijbrandts CA, Dijkgraaf MG, Kraan MC, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium. Ann Rheum Dis. 2008;67:1139–44. DOI: http://dx.doi.org/10.1136/ard.2007.080440.

15. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:921–6. DOI: http://dx.doi.org/10.1136/ard.2006.065615.

16. Bartelds GM, Wolbink GJ, Stapel S, et al. High levels of human anti-human antibodies to adalimumab in a patient not responding to adalimumab treatment. Ann Rheum Dis. 2006;65:1249–50. DOI: http://dx.doi.org/10.1136/ard.2005.049858.

17. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006;54:3782–9. DOI: http://dx.doi.org/10.1002/art.22214.

18. Sidiropoulos P, Bertsias G, Kritikos HD, et al. Infliximab treatment for rheumatoid arthritis, with dose titration based on the Disease Activity Score: dose adjustments are common but not always sufficient to assure sustained benefit. Ann Rheum Dis. 2004;63:144–8. DOI: http://dx.doi.org/10.1136/ard.2003.015933.

19. Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther. 2002;24(11):1720–40. DOI: http://dx.doi.org/10.1016/S0149-2918(02)80075-3.

20. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21(3):211–5. DOI: http://dx.doi.org/10.1097/BOR.0b013e328329ed8b.

21. Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1739–45. DOI: http://dx.doi.org/10.1136/ard.2008.092833.

22. Vermeire S, Noman M, van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut. 2007;56(9):1226–31. DOI: http://dx.doi.org/10.1136/gut.2006.099978.

23. Flood J. Tumor necrosis factor inhibitors in the treatment of chronic inflammatory diseases. A review of immunogenicity and potential implications. Manag Care. 2009 Apr;18(4 Suppl 3):1–5.

24. Van der Laken CJ, Voskuy AE, Roos JC, et al. Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for heumatoid arthritis. Ann Rheum Dis. 2007;66(2):253–6. DOI: http://dx.doi.org/10.1136/ard.2006.057406.

25. Korswagen LA, Bartelds GM, Krieckaert CL, et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 2011;63(4):877–83. DOI: http://dx.doi.org/10.1002/art.30209.

26. Aarden L, Ruuls SR, Wolbink G. Immunogenicity of anti-tumor necrosis factor antibodies-toward improved methods of anti-antibody measurement. Curr Opin Immunol. 2008;20(4):431–5. DOI: http://dx.doi.org/10.1016/j.coi.2008.06.011.

27. Van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004;63:508–16. DOI: http://dx.doi.org/10.1136/ard.2003.013052.

28. Каратеев ДЕ, Лучихина ЕЛ, Муравьев ЮВ и др. Первое российское стратегическое исследование фармакотерапии ревматоидного артрита (РЕМАРКА). Научно-практическая ревматология. 2013;51(2):117–25. [Karateev DE, Luchikhina EL, Murav'ev YuV, et al. The first Russian strategic study of pharmacotherapy for rheumatoid arthritis (REMARCA). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(2):117–25. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2013-637.

29. Fransen J, Stucki G, van Reil PL. Rheumatoid arthritis measures. Arthritis Rheum. 2003;49:214–24. DOI: http://dx.doi.org/10.1002/art.11407/.

30. Aletaha D, Nell V, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7(4):R796–806. DOI: http://dx.doi.org/10.1186/ar1740.

31. Pouw M, Krieckaert C, Nurmohamed M, et al. Key findings towards optimising adalimumab treatment: the concentration – effect curve. Ann Rheum Dis. 2013 Dec 10. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-204172.

32. Rosas J, Llinares F, de la Torre I. Clinical usefulness of serum level of adalimumab, in patients with rheumatoid arthritis. Ann Rheum Dis. 2013;72(Suppl 3):233. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-eular.734.

33. Van den Bemt BJ, den Broeder AA, Wolbink GJ, et al. Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an openlabel pharmacokinetic cohort study. BMC Musculoskeletal Disord. 2011;12:12. DOI: http://dx.doi.org/10.1186/1471-2474-12-12.

34. Mok C, van der Kleij D, Wolbink G, et al. Anti-drug antibodies, drug levels and clinical efficacy of the anti-TNF biologics in rheumatic diseases. Ann Rheum Dis. 2013;72(Suppl 3):226. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-eular.714.

35. Hernandez M, Palasti S, Inciarte J, et al. Analysis of the immunogenicity induced by tumor necrosis factor antagonists in patients with chronic inflammatory arthropathies. Ann Rheum Dis. 2013;72 (Suppl 3):429. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-eular.1298.

36. Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72:1947–55. DOI: http://dx.doi.org/10.1136/annrheumdis-2012-202220.

37. Miyasaka N; CHANGE Study Investigators. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod Rheum. 2008;18:252–62. DOI: http://dx.doi.org/10.3109/s10165-008-0045-0.

38. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of antitumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552–63. DOI: http://dx.doi.org/10.1002/1529- 0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W.

39. Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50:1051–65. DOI: http://dx.doi.org/10.1002/art.20159.

40. Van der Bijl AE, Breedveld FC, Antoni CE, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27:1021–8. DOI: http://dx.doi.org/10.1007/s10067-008-0866-4.

41. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–8. DOI: http://dx.doi.org/10.1001/jama.2011.406.

42. Bender NK, Heilig CE, Droll B, et al. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27:269–74. DOI: http://dx.doi.org/10.1007/s00296-006- 0183-7.

43. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis. 2010;69:817–21. DOI: http://dx.doi.org/10.1136/ard.2009.112847.