Infliximab: 불응성 크론병 치료법으로서의 유용성과 Top-down 관해 유도 요법으로서의 가능성

이지현,이해정,박성은,최연호,Lee, Jee-Hyun,Lee, Hae-Jeong,Park, Sung-Eun,Choe, Yon-Ho 대한소아소화기영양학회 2008 Pediatric gastroenterology, hepatology & nutrition Vol.11 No.1

목 적: 종양 괴사 인자(TNF-${\alpha}$)에 대한 단 클론 항체인 infliximab으로 소아의 난치성 크론병에서의 치료와 관해 유도 치료제로서의 효과에 대한 치료 경험을 보고 하고자 한다. 방 법: 2001년 3월부터 2007년 8월까지 삼성서울병원에서 크론병으로 진단 받은 소아 청소년 중 기존 약제에 관해 유도되지 않는 불응성 크론병(스테로이드 의존성 포함)과 중증 활성 크론병을 가진 16명에서 infliximab (Remicade$^{(R)}$) 5 mg/kg를 관해 유도(0, 2, 8주) 주입하였으며 필요한 경우 8주 간격의 유지 치료를 시행하였고 누공성 크론병의 경우 누공의 상태에 따라 비정기적으로 주입하였다. 대상 환자들의 특징 및 치료 전 후의 질병 활성도, Hct, ESR, CRP, albumin을 paired t test를 이용하여 비교하였다. 결 과: 16명의 남녀비는 13/3이고 중앙 연령은 13세 (21개월~15세)였다. 투여 적응증은 불응성 크론병 7명(스테로이드 의존성 3명 포함), 중증 활성형 크론병의 관해 유도 7명, 누공성 크론병 2명이었다. Infliximab 투여 횟수는 평균 5.19${\pm}$3.41회(3~15회)였고 크론병 진단 후 infliximab 치료 시행까지의 기간 중앙값은 6.5개월(1개월~54개월)이었다. 환자들의 infliximab 투여 전PCDAI (pediatric crohn disease activity index)는 평균 34.19${\pm}$14.96이었으며 마지막 투여 후 2~4주 이내 PCDAI는 6.88${\pm}$10.31로 투여 후 통계적으로 유의한 호전을 보였다(p=0.000). 다른 혈액학적 표지자로 ESR (p=0.000), serum albumin (p=0.016), CRP (p=0.009)가 투여 전후로 의미 있는 호전을 보였으며 적혈구 용적률 (hematocrit)의 호전은 통계적으로 유의하지 않았다(p=0.075). 고식적인 치료에 관해 유도 되지 않았던 난치성 환자 4명 중 2명에서 관해 유도가 가능하였으며 스테로이드 의존성 환자 3명 중 2명에서 스테로이드 중단 1명에서 스테로이드 감량이 가능하였다. 누공이 동반되거나 중등도 이상의 크론병에서 스테로이드를 포함하는 다른 면역 조절제 사용 전에 top-down 요법을 시행한 7명 모두에서 6주 이내에 관해가 되었다. 난치성 누공 치료에서도 10명 중 9명에서 호전되었다. 결 론: Infliximab을 사용하여 소아 불응성 크론병에서 관해 유도와 유지 및 스테로이드 감량 또는 중단이 가능하였으며 중등도 이상의 크론병에서 top-down 관해 요법으로도 비교적 효과적이었다. 앞으로 장기간의 추적 관찰을 통한 효과 판정 및 부작용 관찰을 요한다. Purpose: The aim of this study is to report the efficacy of infliximab, a monoclonal antibody directed against tumor necrosis factor alpha which is used for both treatment of refractory pediatric Crohn disease (CD) and induction of remission. Methods: Among pediatric patients who were diagnosed with CD at Samsung Medical Center between March 2001 and August 2007, a total of 16 patients were given infliximab to treat conventional therapyresistant refractory CD and severe active CD for induction of remission. Patients needing maintenance therapy were treated with an infliximab infusion every 8 weeks, and fistulizing CD patients occasionally received the infusion upon the condition that a fistula developed. The efficacy of treatment was assessed by comparing the Pediatric Crohn Disease Activity Index (PCDAI), Hct, ESR, CRP, and serum albumin levels using paired t-test. Results: The male/female ratio was 13:3, and the median age was 13 years (range, 21 months~15 years). The patients included 7 cases of therapy-resistant refractory CD, 7 cases of severe active CD, and 2 cases of fistulizing CD. Mean PCDAI before infliximab therapy was 34.19${\pm}$14.96, and mean follow-up PCDAI within 2 to 4 weeks after the last infusion was significantly lower, at 6.88${\pm}$10.31 (p=0.000). Hematological markers such as ESR (p=0.000), serum albumin (p=0.016), and CRP (p=0.009) also improved significantly after infusion. Remission was achieved in 2 of 4 patients refractory to conventional therapy. Among 3 steroid-dependent patients, 2 were able to discontinue steroid therapy, and dose reduction was possible in 1 patient. Remission after top-down therapy without prior use of other immunomodulators was achieved in 6 weeks in all 7 of the patients who had severe CD. Nine of ten refractory fistulizing CD patients also showed improvement after infliximab therapy. Conclusion: Infliximab was effective in pediatric refractory CD for induction of remission and maintenance therapy, as well as in severe CD for top-down induction therapy. Furthermore, infliximab has contributed to steroid cessation and dose reduction. Long-term follow-up evaluation is needed to determine safety and efficacy of infliximab in the future.

Early Infliximab Trough Levels Predict the Long-term Efficacy of Infliximab in a Randomized Controlled Trial in Patients with Active Crohn’s Disease Comparing, between CT-P13 and Originator Infliximab

Park Jihye,Cheon Jae Hee,Lee Kang-Moon,Kim Young-Ho,Ye Byong Duk,Eun Chang Soo,Kim Sung Hyun,Lee Sun Hee,Lee Joon Ho,Schreiber Stefan 거트앤리버 소화기연관학회협의회 2023 Gut and Liver Vol.17 No.3

Background/Aims: The clinical efficacy and safety of CT-P13 are comparable to originator infliximab for Crohn’s disease in CT-P13 3.4 study (NCT02096861). We performed a multivariate logistic analysis to demonstrate the association between early infliximab trough levels and treatment outcomes of CT-P13 and originator infliximab. Methods: Early serum infliximab trough levels and anti-drug antibody (ADA) levels were compared between CT-P13 (n=100) and originator infliximab (n=98) groups. Receiver operating characteristic (ROC) analysis and multivariate logistic analysis were conducted to identify optimal cutoffs of serum infliximab trough levels and predictive factors for clinical outcomes. Results: The median infliximab trough levels were not different between CT-P13 and originator infliximab groups at week 6, week 14, and in median ADA levels at week 14, respectively. ROC analysis found an infliximab concentration threshold of 4.5 μg/mL at week 6 and 4.0 μg/mL at week 14 as the cutoff value with the highest accuracy for the prediction of clinical outcomes. Serum infliximab trough levels at weeks 6 and 14 predicted clinical remission at weeks 30 and 54, and endoscopic remission at week 54. The combinations of clinical remission or C-reactive protein normalization with an early infliximab trough level improved the prediction of long-term clinical or endoscopic remission. Conclusions: A threshold in serum infliximab trough level at week 6 and week 14 was highly predictive for long-term clinical outcomes. There were no statistical differences in serum infliximab trough levels and ADA levels between CT-P13 and originator infliximab.

한국인 크론병의 Infliximab 유지치료 시 Infliximab 단독 투여와 Infliximab과 Azathioprine 병합 투여 비교

원현선 ( Hyun Sun Won ),박동일 ( Dong Il Park ),전창욱 ( Chang Uk Chon ),석효선 ( Hyo Sun Seok ),김태완 ( Tae Wan Kim ),허운제 ( Woon Je Heo ),이창균 ( Chang Kyun Lee ),은창수 ( Chang Soo Eun ),한동수 ( Dong Soo Han ),이석호 ( Suc 대한장연구학회 2011 Intestinal Research Vol.9 No.3

Background/Aims: The benefits and risks of concomitant immunomodulators with infliximab maintenance therapy in patients with luminal Crohn`s disease (CD) have not been adequately evaluated. We studied the influence of immunomodulator discontinuation in patients in remission with infliximab therapy through a restrospective case- control study. Methods: Medical records of 37 patients with luminal CD who received infliximab at four medical centers were retrospectively analyzed. We compared clinical and follow-up data of patients who were treated with infliximab alone with that of patients with combination therapy. Results: Among 37 patients, 31 (83.7%) were treated with infliximab plus azathioprine and six (16.2%) were treated with infliximab alone. Of the 31 patients receiving combination maintenance therapy, 26 (83.9%) were in complete remission after 12 months, as compared with five of six patients (83.3%) receiving infliximab alone. No significant difference was observed in remission rate between two groups (P=0.735). In total, 16.1% of patients in combination therapy and 16.7% in infliximab alone group reported side effects (P=1.000), but serious adverse events such as reactivation of tuberculosis were noted in only one patient in combination therapy group. Conclusions: Concomitant immunomodulators did not improve efficacy in patients with luminal CD who received scheduled infliximab maintenance. (Intest Res 2011;9:189-195)

Infliximab versus Cyclosporine Treatment for Severe Corticosteroid-Refractory Ulcerative Colitis: A Korean, Retrospective, Single Center Study

( Eun Hye Kim ),( Duk Hwan Kim ),( Soo Jung Park ),( Sung Pil Hong ),( Tae Il Kim ),( Won Ho Kim ),( Jae Hee Cheon ) 대한소화기학회 2015 Gut and Liver Vol.9 No.5

Background/Aims: In patients with corticosteroid-refractory ulcerative colitis (UC), cyclosporine or infliximab may be added to the treatment regimen to induce remission. Here, we aimed to compare the efficacy of cyclosporine and infliximab. Methods: Between January 1995 and May 2012, the medical records of 43 patients with corticosteroid-refractory UC who received either infliximab or cyclosporine as a rescue therapy at a tertiary care hospital in Korea were reviewed. Results: Among the 43 patients, 10 underwent rescue therapy with cyclosporine and the remaining 33 patients received infliximab. A follow-up of 12 months was completed for all patients. The colectomy rate at 12 months was 30% and 3% in the cyclosporine and the infliximab groups, respectively (p=0.034). However, the Cox proportional hazard model indicated that the treatment of rescue therapy was not an independent associate factor for preventing colectomy (p=0.164). In the subgroup analysis, infliximab with azathioprine was superior to cyclosporine for preventing colectomy (hazard ratio of infliximab with azathioprine compared with cyclosporine only, 0.073; 95% confidence interval, 0.008 to 0.629). Conclusions: No difference between infliximab and cyclosporine with respect to preventing colectomy was noted. However, infliximab with azathioprine may be more effective than cyclosporine alone for preventing colectomy. (Gut Liver 2015;9:601-606)

궤양성 대장염에서 진단시기별 예후의 차이

채현범 ( Hyun Beom Chae ),정윤숙 ( Yoon Suk Jung ),박동일 ( Dong Il Park ),이창균 ( Chang Kyun Lee ),허규찬 ( Kyu Chan Huh ),신정은 ( Jeong Eun Shin ),김재학 ( Jae Hak Kim ),김유선 ( You Sun Kim ),정윤호 ( Yun Ho Jung ),정성애 ( S 대한소화기학회 2014 대한소화기학회지 Vol.64 No.2

목적: 궤양성 대장염 환자에서 infliximab 사용이 승인된 2006년을 기준으로 infliximab 사용이 증가하면서 그 이전과 이후에 진단된 환자들의 질병의 예후 및 치료약제의 사용이 어떻게 달라졌는지 알아보고자 하였다. 대상 및 방법: 1987년부터 2012년까지 12개 병원에서 궤양성 대장염을 진단받은 1,422명을 대상으로 후향적 연구를 시행하였다. 진단 연도에 따라 두 군(A군: 1987-2005, B군: 2006-2012)으로 나누어 진단 당시 나이, 성별, 추적기간, 이환기간, 질병의 위치, 질병과 관련된 입원과 수술, 약물 사용에 차이를 보이는지 등에 대해 통계적 분석을 시행하였다. 결과: 진단 당시의 평균 연령은 42.2세였고, 평균 추적기간은 4.7년이었다. Infliximab을 사용한 환자는 89명으로 전체의 6.3%였다. 단변량 분석에서 B군에서의 infliximab 사용이 통계적으로 유의하게 많았고(4.5% vs. 7.6%, p=0.016), 경구 스테로이드의 사용은 유의하게 적었다(60.1% vs. 53.3%, p=0.009). 궤양성 대장염에 관련된 입원(45.8% vs. 40.1%, p=0.031)과 수술(6.4% vs. 3.5%, p=0.010)은 B군에서 통계적으로 유의하게 낮았다. 수술적 치료를 받은 환자군과 받지않은 환자군과의 단변량 분석을 시행한 결과, 수술적 치료를 받은 환자군에서 전대장염의 비율이 높았고(p=0.026), 경구 스테로이드의 사용이 많았다(p=0.007). 다변량 분석에서는 경구 스테로이드 사용만이 유의한 차이를 보였다(OR 1.85, 95% CI 1.03-3.30, p=0.039). 결론: 2006년 이후 진단된 궤양성 대장염 환자에서 2006년 이전 진단된 환자들에 비하여 infliximab 의 사용이 유의하게 증가하였고, 수술률도 유의하게 낮은 것으로 나타났다. 또한, 스테로이드 불응성 궤양성 대장염 환자에서 infliximab의 사용이 효과적인 치료로 사용될 수 있을 것으로 생각된다. Background/Aims: Infliximab was approved for the treatment of ulcerative colitis (UC) in 2006 and has recently been used as rescue therapy in steroid-refractory UC. The aim of this study was to investigate the differences of medication use and prognosis in UC patients according to the periods of diagnosis. Methods: From 1987 to 2012, a total of 1,422 patients with UC were retrospectively reviewed in 12 hospitals. The study population was divided into two groups according to the periods of diagnosis as follows, group A: 1987 2005, group B: 2006-2012. Analyzed variables were compared by using chi-square test and logistic regression analysis. Results: Mean age of the subjects was 42.2 years, and the mean follow-up period was 4.7 years. In univariate analysis, the use of infliximab in group B was significantly higher than group A (4.5% vs. 7.6%, p=0.016), and UC related hospitalization (45.8% vs. 40.1%, p=0.031) and UC-related surgery (6.4% vs. 3.5%, p=0.010) in group B was significantly lower than that of group A. The use of oral steroid in surgery group was significantly higher than non-surgery group in multivariate analysis (OR 1.85, 95% CI 1.03-3.30, p=0.039). Conclusions: Infliximab might play an important role for the treatment of steroid-refractory UC. Well designed prospective trials based on the efficacy and safety of infliximab are required in the future. (Korean J Gastroenterol 2014,64:93-97)

증례 : 크론병 환자에서 Infliximab 치료 후 발생한 중증 다발성 결핵 1예

김희욱 ( Hee Wook Kim ),장성일 ( Sung Iii Jang ),김번 ( Bun Kim ),윤영훈 ( Young Hoon Youn ),변민광 ( Min Kwang Byun ),박효진 ( Hyo Jin Park ),이상인 ( Sang In Lee ) 대한내과학회 2012 대한내과학회지 Vol.83 No.3

크론병이 스테로이드에 불응성이거나 의존적인 경우, 누공병변을 동반한 경우에 TNF-α 억제제인 infliximab이 효과적이나 결핵을 일으키는 부작용이 있다. 저자들은 결핵의 병력이 없고 선별검사상 음성인 크론병 환자에서 infliximab사용 후다 발성 중증 결핵이 합병된 1예를 경험하였기에 문헌고찰과 함께 보고하는 바이다. Infliximab, a tumor necrosis factor-a (TNF-a) inhibitor, has been approved for the treatment of a variety of inflammatory illnesses, including Crohn`s disease. However, infliximab can increase the risk of reactivation of latent tuberculosis (Tbc) infection by affecting host immune responses. Therefore, a screening test should be performed before the initiation of infliximab therapy, and patients with evidence of latent infection should be treated with prophylactic anti-Tbc therapy, Here, we report a case of multifocal disseminated tuberculosis after treatment with infliximab in a patient diagnosed with Crohn`s disease who had no past history of Tbc and showed a negative screening test.

난치성 포도막염에서 인플릭시맵 치료 결과

김준형(Joon Hyung Kim),이동욱(Dong Wook Lee),조남천(Nam Chun Cho) 대한안과학회 2016 대한안과학회지 Vol.57 No.1

Purpose: To investigate the effectiveness of infliximab as treatment for refractory uveitis that recurred in spite of immunosuppressive agents. Methods: Thirty patients who were treated for refractory uveitis from 2002 to 2011 were included in this study. We retrospectively reviewed the medical records of 15 patients who were treated with Infliximab and 15 patients not treated with Infliximab. Infliximab was injected intravenously (5 mg/kg) 3 times every 4 weeks, and the patients were followed-up at 1 week, 2 weeks, and every month thereafter. Anterior chamber cell reaction with a score greater than 0.5+ was defined as recurrence of uveitis. Results: Among 15 patients treated with Infliximab, only one showed no response to the medication. The recurrence rate was significantly higher in patients receiving Infliximab treatment (1.1 ± 0.2 times) than in those not receiving Infliximab treatment (3.1± 0.3 times) (p=0.022). Conclusions: Infliximab can be used effectively on patients with refractory uveitis. However, a future prospective randomized study is needed to demonstrate the effectiveness of Infliximab and to determine an accurate protocol regarding dosage and number of injections

크론병 환자에서 임신 초기 Infliximab 투여 후 정상 분만한

장영우 ( Young Woo Jang ),박영숙 ( Young Sook Park ),김성환 ( Seong Hwan Kim ),조윤주 ( Yun Ju Jo ),조영관 ( Young Kwan Jo ),안상봉 ( Sang Bong Ahn ),서용수 ( Yong Soo Seo ),홍영옥 ( Young Ok Hong ) 대한소화기학회 2013 대한소화기학회지 Vol.61 No.1

Infliximab is a chimeric IgG1 monoclonal antibody to tumor necrosis factor (TNF)-α used in the treatment of steroid refractory or dependent Crohn`s disease (CD). Patients with active CD are more likely to experience stillbirth, preterm labor, or small for gestational aged babies. The safety of administering infliximab in pregnant patients is not well documented. A 25-year-old woman, who was diagnosed with small bowel CD three years ago, was admitted to our hospital due to the aggravation of abdominal pain. She had been treated with mesalazine, azathioprine and intermittent steroid for three years. After admission, she did not respond to steroid therapy, we decided to try infliximab. After the administration of infliximab, epigastric pain was relived and Crohn`s disease activity index score decreased significantly. However after the fourth infusion of infliximab, the patient became aware that she was ten gestational weeks old pregnancy state After then, infliximab was stopped and maintained by mesalazine. The patient gave birth to a healthy baby via normal vaginal delivery without the recurrence of CD. This case suggests that infliximab administration is safe during the early period of pregnancy. Thus, we report this case with a review of literature. (Korean J Gastroenterol 2013;61:37-41)

크론병 환자에서 Infliximab 사용과 관련된 시신경염: 증례 보고 및 문헌 고찰

박수환(Su Hwan Park),강민승(Min Seung Kang),김상윤(Sang Yoon Kim),이지은(Ji-Eun Lee),김수진(Su Jin Kim) 대한안과학회 2021 대한안과학회지 Vol.62 No.8

목적: 크론병으로 infliximab 치료를 받는 환자에서 발생한 시신경염 1예를 문헌고찰과 함께 보고하고자 한다. 증례요약: 22세 남자 환자가 2-3주 전부터 좌안의 시야가 흐려지는 증상으로 내원하였다. 좌안의 최대교정시력이 0.4로 저하되어 있었고, 상대구심동공운동장애가 관찰되었으나, 안구운동 시의 통증과 동공부등은 없었다. 좌안의 색각이 저하되어 있었고, 시야검사상 좌안의 중심하측시야결손이 보였으나, 안저검사상 시신경유두 및 황반의 특이 소견은 없었다. 시신경병증의 원인 감별을 위해 시행한 안와 자기공명영상에서 좌측 시신경이 조영증강되었고, 그 외 다른 문제는 관찰되지 않았다. 환자는 크론병으로 종양괴사인자(tumor necrosis factor, TNF)-α 억제제 중 하나인 infliximab 600 mg을 2개월마다 주사치료 중이었고, 이와 연관된 구후시신경염으로 의심하에 고용량 스테로이드 정맥주사 및 경구복용을 하였고, 이 후 3개월째 시력 및 시야가 호전되었다. 결론: TNF-α 억제제의 사용이 시신경염을 유발할 수 있으므로, 시신경염 발생 시 환자의 약제 사용 여부에 대한 면밀한 병력 청취를 통해, 원인 감별 및 치료 방향 설정을 해야 할 것이다. Purpose: We report a case of optic neuritis related to infliximab treatment in a patient with Crohn’s disease, along with a review of the relevant literature. Case summary: A 22-year-male patient complained of blurred vision in the left eye for 2-3 weeks. His best-corrected visual acuity was 8/20 in the left eye. Relative afferent pupillary defect was detected in the left eye and the pupils were of equal size. There was no pain on ocular movement. The results of slit-lamp and fundus examinations were normal. A visual field test revealed a central to inferior visual field defect in the left eye. Orbit magnetic resonance imaging revealed perineural enhancement of the left optic nerve. He had a 5-year history of Crohn’s disease and had been treated with intravenous infliximab (600 mg every 2 weeks). A diagnosis of retrobulbar optic neuritis associated with infliximab was made. He was infused with high-dose methylprednisolone, which was changed to per oral administration. His visual acuity and visual field defect improved after 3 months. Conclusions: Tumor necrosis factor-α inhibitors, such as infliximab, may cause optic neuritis. Therefore, history-taking is important for differential diagnosis and appropriate treatment.

Pustular psoriasis induced by infliximab in a patient with Crohn's disease

( Dong Uk Cheon ),( Ju Wang Jang ),( Sung Soo Han ),( Hyun-min Seo ),( Hee Joon Yu ),( Joung Soo Kim ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.1

Infliximab is a chimeric monoclonal antibody inducing potent anti-inflammatory responses by neutralizing biological activity of tumor necrosis factor (TNF)-α. It is widely used to treat various immune system-associated diseases such as Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis. However, infliximab can cause cutaneous adverse effects including erythema, urticaria, pruritus and lupus-like eruption. Rarely, it can provoke paradoxical aggravation or induction of psoriasis. A 28-year-old man with a history of Crohn's disease presented with erythematous scaly plaques with pustules on whole body which has lasted for a month. Punch biopsy was performed and histopathologic findings were consistent with pustular psoriasis. He had been treated with infliximab (10 mg/kg, intravenously) every 8 weeks for the past six years. We stopped using infliximab considering the possibility of paradoxical skin eruptions resulted from infliximab and most of the lesions showed complete regression. Though the exact pathophysiology of this paradoxical skin reaction is not clear, hypothesis has been suggested that a production of interferon-α is induced by dermal plasmacytoid dendritic cells and upregulated certain chemokine receptors provoke the migration and activation of T lymphocytes into the skin. Herein, we report an interesting case of pustular psoriasis paradoxically induced by infliximab.