CERTOLIZUMAB PEGOL IN THE TREATMENT OF TAKAYASU ARTERITIS: THE FIRST EXPERIENCE AND PROSPECTS

Certolizumab pegol (CZP) is the only pegylated biological agent (BA) that does not contain an Fc fragment, which minimizes its transplacental transfer. Takayasu arteritis mostly occurs in reproductive-aged women.

Objective: to evaluate the efficacy and safety of CZP used to treat standard immunosuppressive therapy-resistant Takayasu arteritis.

Subjects and methods. The retrospective study enrolled 6 female patients aged 18 to 35 years with Takayasu arteritis who received CZP. The median disease duration before BA usage was 66 months (24 to 204 months). The median duration of immunosuppressive therapy prior to CZP treatment was 92 months (14 to 132 months). All the female patients had taken glucocorticoids and methotrexate before and during CZP therapy. Only four patients had received two to five immunosuppressive drugs at different times prior to BA administration. Three patients had previously used other BAs. The disease activity was determined by the National Institute of Health (NIH) criteria. The Indian Takayasu Clinical Activity Score (ITAS2010) was used. The disease activity was recorded in all the patients prior to CZP therapy.

Results and discussion. The median duration of CZP treatment was 17 months (6 to 24 months). The median erythrocyte sedimentation rate after CZP usage decreased from 22.5 to 10.5 mm/h; the median C-reactive protein level dropped from 7.8 to 0.39 mg/dl (p<0.05), the median daily dose of prednisolone was reduced from 20 to 8.75 mg (p<0.05). All the patients achieved complete remission an average of 4 months after starting CZP therapy. Three patients were still in remission after 12–24 months. One relapse of the disease was recorded following 24 months. ITAS2010 reduced from 1–4 to 0 in five patients and to 2 in one patient with recurrence. There was a good tolerance in five female patients. The adverse events were herpes labialis in two cases, community-acquired pneumonia in one case, and postoperative abscess in one case too.

Conclusion. CZP in Takayasu arteritis was shown to be an effective drug for remission induction and maintenance. The presented results of the first experience in treating this disease with CZP are indicative of its promising further investigation as a steroid-sparing drug in patients with refractory vasculitis. One of the important advantages of CZP is its supposed high safety throughout pregnancy. 

1. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu Arteritis. Ann Intern Med. 1994;120:919-29. doi: 10.7326/0003-4819-120-11- 199406010-00004

2. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Revmatology. 2012;20(4):5-15.

3. Танащук ЕЛ, Смитиенко ИО, Байкова ТА. Аортоартериит при HBV-ассоциированном циррозе печени: диагностика, особенности терапевтической тактики и прогноз. Клиническая медицина. 2013;(6):68-72 [Tanaschuk EL, Smitienko IO, Baikalova TA. Aortoarteritis in HBV-associated liver cirrhosis: diagnostics, therapeutic strategy and prognosis. Klinicheskaya Meditsina = Clinical Medicine. 2013;(6):68-72 (In Russ.)].

4. Насонов ЕЛ, Баранов АА, Шилкина НП. Васкулиты и васкулопатии. Ярославль: Верхняя Волга; 1999. 620 с. [Nasonov EL, Baranov AA, Shilkina NP. Vaskulity i vaskulopatii [Vasculitis and vasculopathy]. Yaroslavl: Verkhnyaya Volga; 1999. 620 p. (In Russ.)]

5. Terao C, Yoshifuji H, Mimori T. Recent advances in Takayasu arteritis. Int J Rheum Dis. 2014;17(3):238-47. doi: 10.1111/1756-185X.12309

6. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2009;68(3):318-23. doi: 10.1136/ard.2008.088351

7. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum. 2007;56(3):1000-9. doi: 10.1002/art.22404

8. Ohigashi H, Tamura N, Ebana Y, et al. Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. J Cardiol. Japanese College of Cardiology. 2017;69(5):774-8. doi: 10.1016/j.jjcc.2016.07.009

9. Мухин НА, Смитиенко ИО, Новиков ПИ и др. Артериит Такаясу: трудности диагностики, лечение и исходы в когортном исследовании у 128 больных. Клиническая фармакология и терапия. 2014;23(3):55-61 [Mukhin NA, Smitienko IO, Novikov PI, et al. Clinical manifestations and outcomes of Takayasu arteritis in the cohort study in 128 patients. Klinicheskaya Farmakologiya i Terapiya. 2014;23(3):55-61 (In Russ.)].

10. Wallis RS, Ehlers S. Tumor necrosis factor and granuloma biology: Explaining the differential infection risk of etanercept and infliximab. Semin Arthritis Rheum. 2005;34(5 Suppl):34-8. doi: 10.1016/j.semarthrit.2005.01.009

11. Tripathy NK, Gupta PC, Nityanand S. High TNF-α and low IL-2 producing T cells characterize active disease in Takayasu’s arteritis. Clin Immunol. 2006;118(2-3):154-8. doi: 10.1016/j.clim.2005.09.010

12. Park MC, Lee SW, Park YB, Lee SK. Serum cytokine profiles and their correlations with disease activity in Takayasu’s arteritis. Rheumatology (Oxford). 2006;45(5):545-8. doi: 10.1093/rheumatology/kei266

13. Mekinian A, Comarmond C, Resche-Rigon M, et al. Efficacy of biological-targeted treatments in takayasu arteritis: Multicenter, retrospective study of 49 patients. Circulation. 2015;132(18):1693- 700. doi: 10.1161/CIRCULATIONAHA.114.014321

14. Mekinian A, Neel A, Sibilia J, et al. Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study. Rheumatology. 2012;51(5):882-6. doi: 10.1093/rheumatology/ker380

15. Novikov PI, Smitienko IO, Moiseev SV. Tumor necrosis factor alpha inhibitors in patients with Takayasu’s arteritis refractory to standard immunosuppressive treatment: Cases series and review of the literature. Clin Rheumatol. 2013;32(12):1827-32. doi: 10.1007/s10067-013-2380-6

16. Skorpen CG, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy , and during pregnancy and lactation. Ann Rheum Dis. 2016;0:1-16.

17. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: Standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatol (United Kingdom). 2016;55(9):1693-7. doi: 10.1093/rheumatology/kev404

18. Baker T, Kevorkian L, Nesbitt A. FRI0162 Investigation into the binding affinity of certolizumab pegol to fcrn and functional consequences for fcrn-mediated transcytosis: comparison to infliximab, adalimumab and etanercept. Ann Rheum Dis. 2014;72(Suppl 3):A426 LP-A426.

19. Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 2010;33(8):1129-34. doi: 10.1002/art.1780330811

20. Misra R, Danda D, Rajappa SM, et al. Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatol (United Kingdom). 2013;52(10):1795-801. doi: 10.1093/rheumatology/ket128

21. Comarmond C, Plaisier E, Dahan K, et al. Anti TNF-α in refractory Takayasu’s arteritis: Cases series and review of the literature. Autoimmun Rev. 2012;11(9):678-84. doi: 10.1016/j.autrev.2011.11.025

22. Hoffman GS, Merkel PA, Brasington RD, et al. Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum. 2004;50(7):2296-304. doi: 10.1002/art.20300

23. Schmidt J, Kermani TA, Bacani AK, et al. Tumor necrosis factor inhibitors in patients with Takayasu arteritis: experience from a referral center with long-term followup. Arthritis Care Res (Hoboken). 2012;64(7):1079-83. doi: 10.1002/acr.21636

24. Кривошеев ОГ, Смитиенко ИО, Асланиди ИП и др. Стойкая ремиссия аортоартериита Такаясу, индуцированная длительным лечением инфликсимабом и подтвержденная повторной позитронно-эмиссионной томографией. Терапевтический архив. 2008;(10):90-3 [Krivosheev OG, Smitienko IO, Aslanidi IP, et al. Sustained remission of the Takayasu aortoarteritis induced with the long-term treatment with infliximab and confirmed by repeated positron emission tomography. Terapevticheskiy Arkhiv. 2008;(10):90-3 (In Russ.)].

25. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: A randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001;121(5):1088-94. doi: 10.1053/gast.2001.28674

26. Clowse ME, Fö rger F, Hwang C, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017;0:1-7. doi: 10.1136/annrheumdis-2017- 211384

27. Clowse MEB, Wolf DC, Fö rger F, et al. Pregnancy outcomes in subjects exposed to certolizumab pegol. J Rheumatol. 2015;42(12):2270-8. doi: 10.3899/jrheum.140189

28. Porter C, Kopotsha T, Smith BJ, et al. W1208 No Significant Transfer of Certolizumab Pegol Compared With IgG in the Perfused Human Placenta In Vitro. Gastroenterology. 2010;138(5):S-674. doi: 10.1016/S0016-5085(10)63101-0

29. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transer of Anti-Tumor Necrosis Factor Agents in Pregnant Patients with Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2013;11(3):286-92. doi: 10.1016/j.cgh.2012.11.011

30. Goel N, Stephens S. Certolizumab Pegol. Landes Biosci. 2014;2(2):137-47.

31. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): In vitro comparison with other antitumor necrosis factor α agents. Inflamm Bowel Dis. 2007;13(11):1323-32. doi: 10.1002/ibd.20225

32. Palframan R, Airey M, Moore A, et al. Use of biofluorescence imaging to compare the distribution of certolizumab pegol, adalimumab, and infliximab in the inflamed paws of mice with collagen-induced arthritis. J Immunol Methods. 2009;348(1-2):36-41. doi: 10.1016/j.jim.2009.06.009

33. Misra DP, Misra R. Assessment of disease activity in Takayasu’s arteritis. Indian J Rheumatol. Indian Rheumatology Association. 2015 Sept;10:S43-7. doi: 10.1016/j.injr.2015.08.006

34. Direskeneli H. Clinical assessment in Takayasu’s arteritis: major challenges and controversies. Clin Exp Rheumatol. 2017;(6):189-93. 35. Mease PJ. Certolizumab pegol for rheumatoid arthritis: Effective in combination with methotrexate or as monotherapy. Int J Clin Rheumtol. 2009;4(3):253-66. doi: 10.2217/ijr.09.12