Эффективность и переносимость цертолизумаба пэгола при болезни Крона в реальной клинической практике
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Материалы и методы. Всех пациентов с БК, которым назначили лечение ЦЗП, проспективно наблюдали в течение не менее 6 мес либо до момента отмены препарата. Эффективность в исследовании оценивали следующим образом: ответ на терапию к 6-й неделе, поддержание клинического ответа (6-я и 26-я недели), динамика эндоскопических показателей к 10-й и 54-й неделе терапии, длительное поддержание ремиссии, заживление свищей. Применяли унивариантный и мультивариантный анализы предикторов ответа на лечение.
Результаты и обсуждение. В исследование включены 39 пациентов: 12 (30,7%) мужчин и 27 (69,3%) женщин, средняя продолжительность наблюдения составила 104 нед. Межквартильный диапазон находился в пределах от 28 до 158 нед. Клиническое улучшение наступило у 38 из 39 (97,4%) больных БК.
Проведен сравнительный анализ ответа на терапию ЦЗП у «бионаивных» пациентов и у ранее получавших другой ингибитор фактора некроза опухоли-α (ФНО-α). В группе «бионаивных» ответ на терапию через 1 мес, 6 мес и в конце периода наблюдения наступил у 100,0; 95,0 и 95,0%, соответственно. В группе пациентов, ранее получавших генно-инженерные биологические препараты, ответ наступил у 94,4; 88,9 и 77,7%. Через 54 нед эндоскопические ответ и ремиссия наблюдались у 46,2 и 30,1% больных, полное заживление слизистой оболочки на фоне поддерживающей терапии ЦЗП сохранялось у 20,5% больных БК.
В группе больных с перианальными поражениями (n=13) полное закрытие всех свищей отмечалось у 5 (38,6%) пациентов, частичный ответ – у 4 (30,7%) больных, у 4 (30,7%) закрытия свищей не произошло.
Нежелательных явлений в исследовании не зарегистрировано. Эскалация дозы потребовалась трем больным БК (7,7%). Эскалация дозы в нашем исследовании потребовалась пациентам с исходно высокой активностью заболевания и предшествующей неэффективностью двух других ингибиторов ФНО-α. Достоверными предикторами вторичной потери ответа и необходимости эскалации дозы препарата явились сохраняющийся уровень С-реактивного белка >5 мг/л через 2 нед после начала терапии ЦЗП и курение.
Заключение. Полученные результаты демонстрируют эффективность и приемлемый для длительной терапии БК профиль переносимости ЦЗП в реальной клинической практике.
Ключевые слова: болезнь Крона, люминальная форма, перианальная форма, клиническая ремиссия, заживление слизистой оболочки кишки, цертолизумаба пэгол.
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Aim. To assess the efficacy and tolerance of certolizumab pegol (CP) in patients with Crohn's disease (CD) treated in the Department of inflammatory bowel diseases of the A.S. Loginov Moscow Clinical Research Center and to determine the predictors of response to therapy.
Materials and methods. All patients with CD who had received the treatment of CP were observed prospectively for at least 6 months or until the date of discontinuation of the drug. The effectiveness of the study was assessed response to therapy by the 6th week, maintaining the clinical response (6th and 26th weeks), the dynamics of endoscopic parameters by the 10th and 54th week of therapy, long-term maintenance of remission, healing fistula. Used univariant and multivariate analyses of predictors of response to treatment.
Results and discussion. The study included 39 patients: 12 (30.7%) men and 27 (69.3%) female, the average duration of observation was 104 weeks. The interdepartmental range was in the range from 28 to 158 weeks. Clinical improvement occurred in 38 out of 39 (97.4 %) patients with CD.
Comparative analysis of response to treatment with CP have bionaive patients previously treated with another inhibitor of TNF-α. In the group of bionaive response to therapy in a month, 6 months and at the end of the observation period occurred at 100.0%, 95.0% and 95.0%, respectively. In the group of patients previously treated with GSI, the response rate was about 94.4 %, 88.9 % and 77.7% week 54 endoscopic response and endoscopic remission was maintained in 46,2% and 30,1% patients, complete healing of the mucosa on the background of maintenance therapy, CP, was preserved in 20.5% of patients with Crohn's disease.
In the group of patients with perianal lesions (n=13) complete closure of all fistulas was observed in 5 (38.6 %) patients, partial response was observed in 4 patients (30,7%) patients, in 4 (30.7 %) closure of fistulas occurred.
The frequency of adverse events was 0 cases (0.0%). The dose escalation was required in 3 patients (7,7%) patients with CD. Dose escalation in our study required patients with high initial CDAI and previous inefficiencies of the other two inhibitors of TNF-α. Reliable predictors of secondary loss of response and need for dose escalation of the drug has been the continued level of CRP >5 mg/l after 2 weeks initiation of therapy CP and smoking.
Conclusion. The obtained results demonstrate the efficacy and tolerability profile of CP appropriate for long-term CD therapy in real clinical practice.
Keywords: Crohn’s disease, luminal form, perianal form, clinical remission, healing of mucosa, certolizumab pegol.
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3. Sartor RB, Hoentjen F. Proinflammatory cytokines and signaling pathways in intestinal innate immune cells. Mucos Immunol. 2005;30:681-701. doi: 10.1016/B978-012491543-5/50039-5
4. Sipponen T, Nuutinen H, Turunen U, Färkkilä M. Endoscopic evaluation of Crohn's disease activity: comparison of the CDEIS and the SES-CD. Inflamm Bowel Dis. 2010 Dec;16(12):2131-6. doi: 10.1002/ibd.21300
5. [Knyazev OV, Kagramanova AV, Ruchkina IN, Fadeeva NA, Lishchinskaya AA, Boldyreva ON, Zhulina EYu, Shcherbakov PL, Orlova NV, Kirova MV, Parfenov AI. Efficacy of adalimumab in Crohn's disease in real clinical practice. Terapevticheskiy Arkhiv = Therapeutic Archive. 2017;89(2):20-7 (In Russ)].
6. Rubin DT, Kane S, Jaganathan S, Palmer L, Anissa Cyhaniuk A. Web Exclusive: Real-World Anti-TNF Dose Escalation in Patients With Crohn's Disease. Am J Pharm Benefits. 2015;7(5):e135-e140.
7. De Silva PSA, Nguyen DD, Sauk J, Korzenik J, YajnikV, Ananthakrishnan AN. Long-term outcome of a third anti-TNF monoclonal antibody after the failure of two prior anti-TNFs in inflammatory bowel disease. Aliment Pharmacol Ther. 2012 Sep;36(5):459-66. doi: 10.1111/j.1365-2036.2012.05214.x
8. Han PD, Cohen RD. Managing immunogenic responses to infliximab: treatment implications for patients with Crohn’s disease. Drugs. 2004;64:1766-7. doi: 10.2165/00003495-200464160-00004
9. Reich K, Ortonne JP, Gottlieb AB, Terpstra IJ, Coteur G, Tasset C, Mease P. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension. Br J Dermatol. 2012;167(1):180-90. doi: 10.1111/j.1365-2133.2012.10941.x
10. Harrold LR, Litman HJ, Saunders KC, Dandreo KJ, Gershenson B, Greenberg JD, Low R, Stark J, Suruki R, Jaganathan S, Kremer JM, Yassine M. One-year risk of serious infection in patients treated with certolizumab pegol as compared with other TNF inhibitors in a real-world setting: data from a national U.S. rheumatoid arthritis registry. Arthritis Res Ther. 2018 Jan 2;20(1):2. doi: 10.1186/s13075-017-1496-5
11. Vande Casteele N, Feagan BG, Vermeire S, Yassine M, Coarse J, Kosutic G, Sandborn WJ. Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease. Aliment Pharmacol Ther. 2018 Jan;47(2):229-37.
doi: 10.1111/apt.14421
12. Vavricka SR, Spasojevic M, Rogler G, Schoepfer AM, Seibold F, Borovicka J, Frei P, Zeitz J, Greuter T, Manser C, Scharl M, Misselwitz B, Straumann A, Michetti P, Biedermann L; Long-Term Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: The FACTS III Survey. Dig Dis. 2017;35(5):423-32.
doi: 10.1159/000475494
13. Sandborn WJ, Wolf DC, Kosutic G, Parker G, Schreiber S, Lee SD, Abraham B, Afzali A, Arsenescu RI, Gutierrez A, Spearman M, Coarse J, Feagan BG. Effects of Transient and Persistent Anti-drug Antibodies to Certolizumab Pegol: Longitudinal Data from a 7-Year Study in Crohn's Disease. Inflamm Bowel Dis. 2017 Jul;23(7):1047-56.
doi: 10.1097/MIB.0000000000001100
14. Sandborn WJ, Schreiber S, Hanauer SB, et al. Reinduction with Certolizumab Pegol in Patients with Relapsed Crohn’s Disease: Results from the PRECiSE 4 Study. Clin Gastroenterol Hepatol. 2010;8:696-702. doi: 10.1016/j.cgh.2010.03.024
15. Lichtenstein GR. Continuous Therapy with Certolizumab Pegol Maintains Remission of Patients with Crohn’s Disease for up to 18 Months. Clin Gastroenterol Hepatol. 2010;8:600-9. doi: 10.1016/j.cgh. 2010.01.014
В.А. Рогозина, А.И. Парфенов
ГБУЗ «Московский клинический научно-практический центр имени А.С. Логинова Департамента здравоохранения г. Москвы», Москва, Россия
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O.V. Knyazev, A.V. Kagramanova, A.A. Lishchinskaya, N.G. Samsonova, N.V. Orlova, V.A. Rogozina, A.I. Parfenov
А.S. Loginov Moscow Clinical Research Center, Moscow Healthcare Department, Moscow, Russia