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Bortolin Fonseca C, Petry R, Harlacher L, Hanauer L, Magalhães Francesconi CF, Gustavo Kotze P, Flores C. Body mass index does not influence loss of response to tumor necrosis factor inhibitors in Crohn's disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502372. [PMID: 39914694 DOI: 10.1016/j.gastrohep.2025.502372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/25/2025]
Abstract
OBJECTIVES Moderate to severe Crohn's disease (CD) treatment was revolutionized by introducing anti-tumor necrosis factor (TNF) agents, which is still a cornerstone of the treatment. It is speculated that adipose tissue may influence treatment response, especially for non-weight-adjusted agents. PATIENTS AND METHODS Research comparing the effectiveness of anti-TNFs between eutrophic and overweight patients may impact clinical management. We performed a retrospective analysis of a CD patient database. The primary endpoint was loss of response (LOR) after 54 weeks with infliximab (IFX) and adalimumab (ADA) in patients with body mass index (BMI) <25 and ≥25. Secondary endpoints were steroid-free remission and endoscopic remission rate. RESULTS One hundred seventy-nine CD patients were evaluated; 48.9% had LOR after 54 weeks of anti-TNF therapy. Fifty-four patients had a BMI ≥25, with 51 receiving IFX and 28 receiving ADA. The univariate analysis identified LOR in 56.5% of the patients with IFX and 34.9% in the ADA group (p=0.009). In the 54-week multivariate analysis, loss of response in the IFX group with BMI ≥25 had a relative risk of 1.04 [CI 0.60-1.80 (p=0.891)] compared to patients with BMI <25. Being overweight or obese led to a risk of 1.50 for LOR for ADA at 54-week time point [CI 0.60-3.74 (p=0.0387)]. Clinical remission at 54 weeks was similar between BMI groups. CONCLUSIONS Being overweight did not influence the LOR to treatment when IFX and ADA were compared, nor did it affect clinical and endoscopic remission after 54 weeks.
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Affiliation(s)
| | - Roberta Petry
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Laryssa Hanauer
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Lange NW, King K, Husain SA, Salerno DM, Tsapepas DS, Hedvat J, Yu M, Mohan S. Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials. Am J Transplant 2024; 24:1027-1034. [PMID: 38387620 DOI: 10.1016/j.ajt.2024.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/25/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.
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Affiliation(s)
- Nicholas W Lange
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, New York, USA.
| | - Kristen King
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Columbia University Renal Epidemiology Group, New York, New York, USA
| | - Syed Ali Husain
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Columbia University Renal Epidemiology Group, New York, New York, USA
| | - David M Salerno
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Demetra S Tsapepas
- Columbia University Renal Epidemiology Group, New York, New York, USA; Division of Transplantation, Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Department of Quality, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Jessica Hedvat
- Department of Pharmacy, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Miko Yu
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Columbia University Renal Epidemiology Group, New York, New York, USA
| | - Sumit Mohan
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Columbia University Renal Epidemiology Group, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
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Hirayama D, Motoya S, Ashida T, Ando K, Fujiya M, Ito T, Furukawa S, Maemoto A, Katsurada T, Hinotsu S, Sato N, Mizuno N, Ikawa Y, Nakase H. Effectiveness and Factors Associated with Response to Golimumab in Japanese Patients with Ulcerative Colitis in Real Clinical Practice: The Phoenix Study. Inflamm Intest Dis 2023; 8:115-127. [PMID: 38098492 PMCID: PMC10718581 DOI: 10.1159/000533871] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/21/2023] [Indexed: 12/17/2023] Open
Abstract
Introduction There have been limited reports on the clinical efficacy of golimumab (GLM) in Japanese patients with ulcerative colitis (UC) in real clinical practice. This study aimed to explore the real-life effectiveness and factors associated with response to GLM in Japanese patients with UC. Methods This observational, retrospective, multicenter study was conducted in hospitals with expertise in inflammatory bowel disease treatment. Sixty-three patients treated with GLM and active UC were included in the analysis. Clinical remission (CR) (partial Mayo (pMayo) score ≤2) in the induction and maintenance phases after GLM treatment and associated factors were evaluated. Results The proportion of patients achieving CR in the induction and maintenance phases was 41.3% (26/63) and 46.0% (29/63, the last observation carried forward method was used for patients who discontinued treatment for reasons other than inadequate response), respectively. The median pMayo score was 5 (interquartile range (IQR): 4-6) at baseline, 3 (IQR: 1-5) in the induction phase, and 1 (IQR: 0-3) in the maintenance phase. Hemoglobin, platelet, and C-reactive protein levels changed, consistent with the pMayo score. Multivariate logistic analysis revealed that biologic-naive status was an independent factor associated with CR in the induction (p = 0.0200) and maintenance (p = 0.0459) phases, and a disease duration of >60 months until GLM initiation was associated with CR in the induction phase (p = 0.0427). Conclusions The effectiveness of GLM in daily clinical practice has been confirmed in Japanese patients with active UC. Biologic-naive patients responded more to GLM in the induction and maintenance phases, and patients with disease duration of >60 months until initiation of GLM were more responsive in the induction phase.
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Affiliation(s)
- Daisuke Hirayama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Satoshi Motoya
- IBD Center, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Toshifumi Ashida
- Inflammatory Bowel Disease Center, Sapporo Tokushukai Hospital, Sapporo, Japan
| | - Katsuyoshi Ando
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Mikihiro Fujiya
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Takahiro Ito
- Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Shigeru Furukawa
- Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Atsuo Maemoto
- Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Takehiko Katsurada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shiro Hinotsu
- Department of Biostatistics and Data Management, Sapporo Medical University of Medicine, Sapporo, Japan
| | - Noriko Sato
- Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Naomi Mizuno
- Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yoshiko Ikawa
- Ikuyaku, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Levy R, Matar M, Zvuloni M, Shamir R, Assa A. Trough Concentration Response in Infliximab and Adalimumab Treated Children With Inflammatory Bowel Disease Following Treatment Adjustment: A Pharmacokinetic Model. J Pediatr Gastroenterol Nutr 2023; 76:576-581. [PMID: 37083732 DOI: 10.1097/mpg.0000000000003726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2023]
Abstract
OBJECTIVES In patients with inflammatory bowel diseases (IBD), data on trough concentration (TC) response to adjustments of anti-tumor necrosis factor (TNFα) are scarce. METHODS We included pediatric patients with IBD who were treated with anti-TNFα agents and had sequential monitoring of TC pre- and post-adjustment. Patients with positive anti-drug-antibodies or with concomitant change in immunomodulatory treatment were excluded. RESULTS For the entire cohort (86 patients), median age at diagnosis was 13.2 (interquartile range, 10.7-14.9) years [females, 48%; Crohn disease (CD), 72%]. For infliximab, 58 patients had 201 interval changes and 26 had dose increase. Increase in TC following dose increase could not be predicted due to significant variability (P = 0.9). For every 10% decrease in interval, TC was increased by 1.6 µg/mL or by 57.2% (P = 0.014). Perianal disease was associated with attenuated response. For every 10% increase in interval, TC was decreased by 0.66 µg/mL or by 4.2%. The diagnosis of CD was associated with reduced response to interval increase. For adalimumab, 28 patients had 31 and 12 events of interval decrease or increase, respectively. Interval decrease resulted in increased median TC from 4.5 (3.5-5.3) µg/mL to 8.1 (6.5-10.5) µg/mL (X1.8) while interval increase resulted in TC change from 15.5 (12.8-18.6) µg/mL to 9.7 (6.5-14.6) µg/mL (:1.6) (P < 0.001 for both). Increase in delta TC was associated with younger age, and with absence of perianal disease (P = 0.001). CONCLUSION Changes in TC following treatment adjustment can be almost linearly predicted for adalimumab while response to infliximab adjustment are more variable.
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Affiliation(s)
- Rachel Levy
- From the Department of Pediatrics "A", Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Manar Matar
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
| | - Maya Zvuloni
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Raanan Shamir
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
| | - Amit Assa
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
- The Juliet Keidan Institute of Pediatric Gastroenterology, Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
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Gu P, Luo J, Kim J, Paul P, Limketkai B, Sauk JS, Park S, Parekh N, Zheng K, Rudrapatna V, Syal G, Ha C, McGovern DP, Melmed GY, Fleshner P, Eisenstein S, Ramamoorthy S, Dulai PS, Boland BS, Grunvald E, Mahadevan U, Ohno-Machado L, Sandborn WJ, Singh S. Effect of Obesity on Risk of Hospitalization, Surgery, and Serious Infection in Biologic-Treated Patients With Inflammatory Bowel Diseases: A CA-IBD Cohort Study. Am J Gastroenterol 2022; 117:1639-1647. [PMID: 35973139 DOI: 10.14309/ajg.0000000000001855] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 04/22/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Obesity is variably associated with treatment response in biologic-treated patients with inflammatory bowel diseases (IBD). We evaluated the association between obesity and risk of hospitalization, surgery, or serious infections in patients with IBD in new users of biologic agents in a large, multicenter, electronic health record (EHR)-based cohort (CA-IBD). METHODS We created an EHR-based cohort of adult patients with IBD who were new users of biologic agents (tumor necrosis factor [TNF-α] antagonists, ustekinumab, and vedolizumab) between January 1, 2010, and June 30, 2017, from 5 health systems in California. Patients were classified as those with normal body mass index (BMI), overweight, or obese based on the World Health Organization classification. We compared the risk of all-cause hospitalization, IBD-related surgery, or serious infections among patients with obesity vs those overweight vs those with normal BMI, using Cox proportional hazard analyses, adjusting for baseline demographic, disease, and treatment characteristics. RESULTS Of 3,038 biologic-treated patients with IBD (69% with Crohn's disease and 76% on TNF-α antagonists), 28.2% (n = 858) were overweight, and 13.7% (n = 416) were obese. On a follow-up after biologic initiation, obesity was not associated with an increased risk of hospitalization (adjusted hazard ratio [aHR] vs normal BMI, 0.90; [95% confidence interval, 0.72-1.13]); IBD-related surgery (aHR, 0.62 [0.31-1.22]); or serious infection (aHR, 1.11 [0.73-1.71]). Similar results were observed on stratified analysis by disease phenotype (Crohn's disease vs ulcerative colitis) and index biologic therapy (TNF-α antagonists vs non-TNF-α antagonists). DISCUSSION In a multicenter, EHR-based cohort of biologic-treated patients with IBD, obesity was not associated with hospitalization, surgery, or serious infections. Further studies examining the effect of visceral obesity on patient-reported and endoscopic outcomes are needed.
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Affiliation(s)
- Phillip Gu
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Jiyu Luo
- Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, UC San Diego, La Jolla, California, USA
| | - Jihoon Kim
- Division of Biomedical Informatics, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Paulina Paul
- Division of Biomedical Informatics, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Berkeley Limketkai
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, UC Los Angeles, Los Angeles, California, USA
| | - Jenny S Sauk
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, UC Los Angeles, Los Angeles, California, USA
| | - Sunhee Park
- Division of Gastroenterology, Department of Medicine, UC Irvine, Orange, California, USA
| | - Nimisha Parekh
- Division of Gastroenterology, Department of Medicine, UC Irvine, Orange, California, USA
| | - Kai Zheng
- Department of Informatics, Donald Bren School of Information and Computer Sciences, UC Irvine, Orange, California, USA
| | - Vivek Rudrapatna
- Division of Gastroenterology, Department of Medicine, UC San Francisco, California, USA
| | - Gaurav Syal
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Christina Ha
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Dermot P McGovern
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Gil Y Melmed
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Phillip Fleshner
- Division of Colorectal Surgery, Department of Surgery, Cedars-Sinai Medical System, Los Angeles, California, USA
| | - Samuel Eisenstein
- Division of Colon and Rectal Surgery, Department of Surgery, UC San Diego, La Jolla, California, USA
| | - Sonia Ramamoorthy
- Division of Colon and Rectal Surgery, Department of Surgery, UC San Diego, La Jolla, California, USA
| | - Parambir S Dulai
- Division of Gastroenterology, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Brigid S Boland
- Division of Gastroenterology, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Eduardo Grunvald
- Division of General Internal Medicine, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Uma Mahadevan
- Division of Gastroenterology, Department of Medicine, UC San Francisco, California, USA
| | - Lucila Ohno-Machado
- Division of Biomedical Informatics, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, UC San Diego, La Jolla, California, USA
| | - Siddharth Singh
- Division of Biomedical Informatics, Department of Medicine, UC San Diego, La Jolla, California, USA
- Division of Gastroenterology, Department of Medicine, UC San Diego, La Jolla, California, USA
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Khakoo NS, Ioannou S, Khakoo NS, Vedantam S, Pearlman M. Impact of Obesity on Inflammatory Bowel Disease. Curr Gastroenterol Rep 2022; 24:26-36. [PMID: 35150406 DOI: 10.1007/s11894-022-00840-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW This review highlights recent work that evaluates the impact of obesity on inflammatory bowel disease (IBD) pathogenesis and management. RECENT FINDINGS The impact of obesity on IBD prevalence, clinical course, and management, has been studied and described more so in recent years. Studies have shown that obesity increases IBD disease activity, leads to longer hospitalization courses, and increases the likelihood of the development of extraintestinal manifestations. Recent evidence has also suggested that obese IBD patients have a higher frequency of extended steroid treatment and increased use of antibiotics compared to non-obese IBD patients. The effect of obesity on patients with IBD is a topic that has garnered widespread interest in the last decade due to the increasing prevalence of both diseases. To date however, although there are still many unanswered questions. It is quite clear that obesity, and more specifically, visceral adiposity, affects numerous IBD-related outcomes in regard to pathogenesis, extra-intestinal manifestations, response to medical and surgical therapies, hospital length of stay, healthcare-related costs, and health-related quality of life. Future studies should include larger patient populations and evaluate additional factors that are altered in those with obesity including the gut microbiome, dietary patterns, and whether weight loss and/or degree of weight loss impact clinical outcomes.
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Affiliation(s)
- Nidah Shabbir Khakoo
- Department of Internal Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, USA
| | - Stephanie Ioannou
- Department of Internal Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, USA
| | | | - Shyam Vedantam
- Department of Internal Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, USA
| | - Michelle Pearlman
- Department of Medicine, Division of Digestive and Liver Diseases, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA.
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Jasurda JS, McCabe RP, Vaughn BP. Adalimumab Concentration Changes After Dose Escalation in Inflammatory Bowel Disease. Ther Drug Monit 2021; 43:645-651. [PMID: 33346627 DOI: 10.1097/ftd.0000000000000849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 11/03/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Dose escalation of adalimumab (ADA) for loss or response in inflammatory bowel disease (IBD) is a common practice. Recent data suggest improved outcomes with an ADA concentration of 12 mcg/mL, but limited data are available on the ability to achieve a target concentration. The aim of this study was to determine the expected change in serum ADA concentration after a dose escalation performed every 7 days in patients with IBD. METHODS A retrospective cohort of patients with IBD receiving ADA was divided into every fourteen-day dosing, every 7-day dosing, and dose escalation (ie, q14 to q7 day dosing). The primary outcome was the change in ADA concentration. Multiple logistic regression was performed to identify predictors of achieving a target ADA concentration of ≥12 mcg/mL. RESULTS Overall, 380 patients were identified, of whom 200 underwent dose escalation, 100 remained on q14 days dosing, and 80 were maintained on q7 day dosing. After dose escalation, the mean ADA concentration increased by 5.5 mcg/mL (P < 0.0001). After dose escalation, a significant proportion of patients achieved an ADA concentration ≥12 mcg/mL (P = 0.0019), as well as clinical remission (P = 0.0053). Based on multiple logistic regression, age of <46 years [odds ratio (OR): 2.4; 95% confidence interval (CI): 1.3, 4.6; P < 0.01], body mass index of <29 (OR: 0.21; 95% CI: 0.1, 0.5; P < 0.0001), and initial ADA concentration of ≥3.0 mcg/mL were found to be associated with a target ADA concentration ≥12 mcg/mL (OR: 4.76; 95% CI: 2.3, 9.7; P < 0.0001). CONCLUSIONS The average expected increase in serum ADA concentration after dose escalation from q14 to q7 days was 5.5 mcg/mL. The initial ADA concentration, age, and body mass index may influence the ability to achieve a target ADA concentration after dose escalation.
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Affiliation(s)
- Jake S Jasurda
- Department of Internal Medicine, University of Minnesota
| | | | - Byron P Vaughn
- Department of Gastroenterology, Hepatology, and Nutrition, Inflammatory Bowel Disease Program, University of Minnesota, Minneapolis, Minnesota
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Cao WT, Huang R, Jiang KF, Qiao XH, Wang JJ, Fan YH, Xu Y. Predictive value of blood concentration of biologics on endoscopic inactivity in inflammatory bowel disease: A systematic review. World J Gastroenterol 2021; 27:886-907. [PMID: 33727776 PMCID: PMC7941861 DOI: 10.3748/wjg.v27.i9.886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 12/25/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although blood concentration of biologics is an important composition of disease management in inflammatory bowel disease (IBD) patients, complexity and uncertainty of biological management encourage many disputes in predicting the outcome of IBD patients through blood concentration of biologics.
AIM To verify the predictive value of blood concentration of biologics on endoscopic inactivity in IBD patients under different situations.
METHODS We searched PubMed/MEDLINE, Embase, and Web of Science up to May 2020 and identified IBD patients as the research cohort as well as the correlations between blood concentration of biologics and endoscopic inactivity in IBD patients as the research direction.
RESULTS A total of 23 articles with 30 clinical studies and 1939 IBD patients were included. The predictive cut-off value of blood concentration of infliximab on mucosal healing should be 2.7-10.6 μg/mL in IBD. Blood concentration of infliximab reaching 5.0-12.7 μg/mL or more increased the probability of fistula healing/closure in perianal fistulizing Crohn's disease. Blood concentration of adalimumab reaching 7.2-16.2 μg/mL or more could predict mucosal healing in IBD. The predictive cut-off value of blood concentration of adalimumab on fistula healing/closure should be 5.9-9.8 μg/mL in perianal fistulizing Crohn's disease. Blood concentration of vedolizumab surpassing 25.0 μg/mL indicated mucosal healing in ulcerative colitis patients under maintenance therapy and the predictive cut-off value of blood concentration on mucosal healing or endoscopic remission under induction therapy in IBD could be 8.0-28.9 μg/mL.
CONCLUSION Blood concentration of biologics should not be utilized to predict endoscopic inactivity of IBD independently due to discrepancies in clinical studies, whereas conducting therapeutic drug monitoring intensively contributes to precise therapy.
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Affiliation(s)
- Wan-Ting Cao
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Rong Huang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Ke-Fang Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Xue-Hui Qiao
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Jing-Jing Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Yi-Hong Fan
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
| | - Yi Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China
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Nakase H, Matsumoto T, Watanabe K, Hisamatsu T. The shining DIAMOND for evidence-based treatment strategies for Crohn's disease. J Gastroenterol 2020; 55:824-832. [PMID: 32661927 DOI: 10.1007/s00535-020-01702-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/18/2020] [Indexed: 02/04/2023]
Abstract
Anti-tumor necrosis factor (TNF)-α antibodies are effective therapeutic agents to treat inflammatory bowel disease (IBD). In the biologic era, the development of immunogenicity has been a critical issue for secondary loss of response. The superiority of anti-TNF therapy in combination with immunomodulators (IMs) is well-established for infliximab (IFX) but less evident for adalimumab (ADA). To clarify the contribution of thiopurines to ADA-treated patients with Crohn's disease (CD), the deep remission of immunomodulator and adalimumab combination therapy for Crohn's disease (DIAMOND) studies provided the first randomized comparison of efficacy between ADA monotherapy and ADA with thiopurine. The results of the DIAMOND and DIAMOND2 studies revealed the appropriate ADA therapeutic strategy for immunosuppressant-naïve patients with active CD based on therapeutic drug monitoring, endoscopic findings and clinical issues regarding the use of thiopurines.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Medicine, Iwate Medical University, Morioka, Iwate, Japan
| | - Kenji Watanabe
- Division of Internal Medicine, Center for Inflammatory Bowel Disease, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
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10
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Bergstra SA, Allaart CF, Vega-Morales D, De Buck M, Murphy E, Salomon Escoto K, Huizinga TWJ. Body mass index and treatment survival in patients with RA starting treatment with TNFα-inhibitors: long-term follow-up in the real-life METEOR registry. RMD Open 2020; 6:rmdopen-2020-001203. [PMID: 32506054 PMCID: PMC7299513 DOI: 10.1136/rmdopen-2020-001203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/09/2020] [Accepted: 05/14/2020] [Indexed: 01/22/2023] Open
Abstract
Objectives To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry. Methods Data from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI<18.5 kg/m2; 46% normal weight, BMI 18.5–25 kg/m2; 32% pre-obesity, BMI 25–30 kg/m2; 13% obesity class I, BMI 30–35 kg/m2; 3.4% obesity class II, BMI 35–40 kg/m2; and 1.6% obesity class III, BMI >40 kg/m2. Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan–Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days. Results Patients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found. Conclusion Both underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients.
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Affiliation(s)
| | | | | | - Marieke De Buck
- Rheumatology, Haaglanden Medical Center, The Hague, Netherlands
| | | | - Karen Salomon Escoto
- Rheumatology, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, Massachusetts, USA
| | - Tom W J Huizinga
- Rheumatology, Leiden University Medical Center, Leiden, Netherlands
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11
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Sánchez-Hernández JG, Pérez-Blanco JS, Rebollo N, Muñoz F, Prieto V, Calvo MV. Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease. Eur J Pharm Sci 2020; 150:105369. [PMID: 32416256 DOI: 10.1016/j.ejps.2020.105369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/04/2020] [Accepted: 04/28/2020] [Indexed: 12/22/2022]
Abstract
Inflammatory bowel disease (IBD) is commonly treated with adalimumab. The main objective of the study was to develop a population pharmacokinetic model of adalimumab in IBD patients evaluating the potential biomarkers of disease activity and other factors and its implications in adalimumab dosing. A prospective observational study was performed in adult patients diagnosed with Crohn's disease and ulcerative colitis treated with adalimumab and following a proactive therapeutic drug monitoring of serum concentrations. Adalimumab serum concentrations (ASC) were quantified mainly prior the administration using an enzyme-linked immunosorbent assay (ELISA). A population pharmacokinetic model was developed based on 303 ASC data of 104 IBD patients using non-linear mixed effect modelling approach. Sixty-five ASC from 20 additional patients were randomly selected as an external validation group. A one-compartment model with first order absorption and elimination best describe the ASC time course. Body mass index (BMI), faecal calprotectin (FCP), unexplained decline in ASC and the specific administration pen device exhibited significant influence on apparent clearance (p-value < 0.001). FCP was the inflammatory activity biomarker showing the most relevant impact on adalimumab exposure, higher than C-reactive protein and albumin, and may be useful for adalimumab dosing adjustment. The population-based pharmacokinetic model developed adequately characterized adalimumab exposure in IBD patients. The unexplained decline in ASC, FCP, BMI and the specific administration pen device were identified as meaningful variables significantly influencing adalimumab pharmacokinetics.
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Affiliation(s)
- José Germán Sánchez-Hernández
- Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
| | - Jonás Samuel Pérez-Blanco
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Noemí Rebollo
- Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Fernando Muñoz
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; Gastroenterology Service, University Hospital of Salamanca, Salamanca, Spain
| | - Vanessa Prieto
- Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; Gastroenterology Service, University Hospital of Salamanca, Salamanca, Spain
| | - María Victoria Calvo
- Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
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12
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Dai ZH, Xu XT, Ran ZH. Associations Between Obesity and the Effectiveness of Anti–Tumor Necrosis Factor-α Agents in Inflammatory Bowel Disease Patients: A Literature Review and Meta-analysis. Ann Pharmacother 2020; 54:729-741. [DOI: 10.1177/1060028019900660] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: A total of 15% to 40% of adult inflammatory bowel disease (IBD) patients are obese. The influence of obesity on anti-tumor necrosis factor-α (anti-TNF-α) treatment in IBD patients is not consistent. Objective: To determine the association between obesity and the efficacy of anti-TNF treatment in IBD patients. Methods: We performed a systematic search from January 1990 through November 2019 on MEDLINE, Web of Science, Google Scholar, ClinicalTrials.gov, and Cochrane library. We included randomized controlled trials and observational cohort studies that investigated the outcome of anti-TNF treatment in IBD patients with stratification according to body mass index or body weight. The odds ratio (OR) and its 95% CI were calculated. Results: In this pooled meta-analysis, we observed that obesity increased the odds of failure of anti-TNF therapy (OR = 1.195; 95% CI = 1.034-1.380; P = 0.015; I2 = 47.8%). After performing subgroup analyses, obesity was associated with higher odds of anti-TNF treatment failure in ulcerative colitis (UC) patients (OR = 1.413; 95% CI = 1.008-1.980; P = 0.045; I2 = 20.0%) but not in Crohn’s disease patients (OR = 1.099; 95% CI = 0.928-1.300). Obesity significantly increased the odds of treatment failure of both dose-fixed and weight-based anti-TNF agents (OR = 1.121, 95% CI = 1.027-1.224, P = 0.011, and OR = 1.449, 95% CI = 1.006-2.087, P = 0.046, respectively). Conclusion and Relevance: In our meta-analysis, obesity was associated with the inferior response of anti-TNF treatments in UC patients. Clinicians should be aware that obese UC patients may require higher doses in anti-TNF treatment.
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Affiliation(s)
- Zhang-han Dai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Xi-tao Xu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-hua Ran
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
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13
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Han M, Jung YS, Cheon JH, Park S. Comparison of Real-World Outcomes of Infliximab versus Adalimumab in Biologic-Naïve Korean Patients with Ulcerative Colitis: A Population-Based Study. Yonsei Med J 2020; 61:48-55. [PMID: 31887799 PMCID: PMC6938779 DOI: 10.3349/ymj.2020.61.1.48] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Data on the comparative effectiveness of infliximab (IFX) or adalimumab (ADA) in patients with ulcerative colitis (UC) are extremely limited, especially in the Asian population. We compared clinically important outcomes [colectomy, UC-related emergency room (ER) visits, UC-related hospitalizations, and need for corticosteroids] for these two biologics in biologic-naïve Korean patients with UC. MATERIALS AND METHODS Using National Health Insurance claims, we collected data on patients who were diagnosed with UC and exposed to IFX or ADA between 2010 and 2016. RESULTS A total of 862 new users of biologics were included, of whom 630 were treated with IFX and 232 were treated with ADA. Over a median follow-up of 1.8 years after starting biologic therapy, there were no significant differences in the risk of colectomy [adjusted hazard ratio (aHR), 1.87; 95% confidence interval (CI), 0.30-11.63], ER visits (aHR, 1.58; 95% CI, 0.79-3.16), hospitalizations (aHR, 0.83; 95% CI, 0.59-1.17), and corticosteroid use (aHR, 1.16; 95% CI, 0.76-1.78) between IFX and ADA users. These results were stable even when only patients who used biologics for ≥6 months were analyzed. Additionally, these results were unchanged in patients treated with biologic monotherapy or combination therapy with immunomodulators. CONCLUSION In this nationwide population-based study, there was no significant difference in the risk of colectomy, ER visits, hospitalizations, and corticosteroid use between IFX and ADA users. Our findings indicate that IFX and ADA have comparable effectiveness in biologic-naïve Korean patients with UC.
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Affiliation(s)
- Minkyung Han
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Suk Jung
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
| | - Sohee Park
- Department of Biostatistics, Graduate School of Public Health, Yonsei University, Seoul, Korea.
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14
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Rodin I, Chan J, Meleady L, Hii C, Lawrence S, Jacobson K. High body mass index is not associated with increased treatment failure in infliximab treated pediatric patients with inflammatory bowel disease. JGH OPEN 2019; 4:446-453. [PMID: 32514452 PMCID: PMC7273726 DOI: 10.1002/jgh3.12277] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/16/2019] [Accepted: 10/22/2019] [Indexed: 12/18/2022]
Abstract
Background and Aim While weight gain during infliximab therapy in inflammatory bowel disease (IBD) is common, there has been limited research evaluating its impact on infliximab efficacy. Methods Primary aims of this study were to determine the frequency of excess weight gain (body mass index [BMI] > 25 kg/m2) in children with IBD on maintenance infliximab and evaluate the impact on infliximab dosing, serum trough levels, and treatment failure. Secondary aims were to determine differences in weight gain, treatment characteristics, and clinical/biochemical variables between patients with therapeutic and subtherapeutic maintenance therapy trough levels. We performed a retrospective study of 253 pediatric IBD (75.1% Crohn's disease, 23.3% ulcerative colitis, 1.6% IBD-unclassified) patients on infliximab followed at BC Children's Hospital between January 2013 and January 2018. Results Median age at infliximab initiation was 13.9 years, median length of follow up was 56.9 months, and 55.7% were males; 10.3% of the cohort demonstrated excess weight gain (7.5% overweight, 2.8% obese). Average mg/kg dosing was not statistically different between groups (normal, overweight, and obese: 6.7, 6.4, and 6.7 mg/kg, respectively, P = 0.52). Median BMI of patients with therapeutic and subtherapeutic trough levels was similar at 19.9 kg/m2 (interquartile range [IQR], 17.3-23.8) and 19.7 kg/m2 (IQR, 17.4-21.9), respectively. BMI had no effect on secondary loss of response to infliximab, with no significant difference between normal and high BMI subgroups (13.4 vs. 16.7%, P = 0.9). Conclusions In a subgroup of pediatric IBD patients on maintenance infliximab, excess weight gain was not associated with higher weight-based dosing, lower serum trough levels, or increased risk of treatment failure.
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Affiliation(s)
- Isaac Rodin
- MD Undergraduate Program University of British Columbia Vancouver Canada
| | - Justin Chan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine University of British Columbia Vancouver Canada.,British Columbia Children Hospital Research Institute, University of British Columbia Vancouver Canada
| | - Laura Meleady
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine University of British Columbia Vancouver Canada.,British Columbia Children Hospital Research Institute, University of British Columbia Vancouver Canada
| | - Clare Hii
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine University of British Columbia Vancouver Canada.,British Columbia Children Hospital Research Institute, University of British Columbia Vancouver Canada
| | - Sally Lawrence
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine University of British Columbia Vancouver Canada.,British Columbia Children Hospital Research Institute, University of British Columbia Vancouver Canada
| | - Kevan Jacobson
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine University of British Columbia Vancouver Canada.,British Columbia Children Hospital Research Institute, University of British Columbia Vancouver Canada.,Department of Cellular and Physiological Sciences University of British Columbia Vancouver Canada
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15
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Szilagyi A. Relationship(s) between obesity and inflammatory bowel diseases: possible intertwined pathogenic mechanisms. Clin J Gastroenterol 2019; 13:139-152. [PMID: 31452062 PMCID: PMC7101293 DOI: 10.1007/s12328-019-01037-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/17/2022]
Abstract
The inflammatory bowel diseases, Crohn's and ulcerative colitis have increased in incidence and prevalence from the mid-eighteen to the late nineteen centuries. From then to the current twenty-first century there has been a more rapid expansion of these disease to areas previously experiencing low rates. This latter expansion coincides with the current obesity pandemic which also began toward the end of the last century. Although the two diseases have radically different frequencies, there are interesting links between them. Four areas link the diseases. On an epidemiological level, IBD tends to follow a north-south gradient raising the importance of vitamin D in protection. Obesity has very weak relationship with latitude, but both diseases follow adult lactase distributions colliding in this plane. Is it possible that obesity (a low vitamin D condition with questionable response to supplements) reduces effects in IBD? On a pathogenic level, pro-inflammatory processes mark both IBD and obesity. The similarity raises the question of whether obesity could facilitate the development of IBD. Features of the metabolic syndrome occur in both, with or without obesity in IBD. The fourth interaction between the two diseases is the apparent effect of obesity on the course of IBD. There are suggestions that obesity may reduce the efficacy of biologic agents. Yet there is some suggestion also that obesity may reduce the need for hospitalization and surgery. The apparent co-expansion of both obesity and IBD suggests similar environmental changes may be involved in the promotion of both.
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Affiliation(s)
- Andrew Szilagyi
- Division of Gastroenterology, Department of Medicine, Jewish General Hospital, McGill University Medical School, 3755 Cote St Catherine Rd, Room E110, Montreal, QC, H3T 1E2, Canada.
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16
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Renton WD, Ramanan AV. Biological therapeutic drug monitoring: a step towards precision medicine? Arch Dis Child 2019; 104:212-213. [PMID: 30262510 DOI: 10.1136/archdischild-2018-315819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 08/14/2018] [Accepted: 08/31/2018] [Indexed: 11/03/2022]
Affiliation(s)
- William D Renton
- Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Athimalaipet V Ramanan
- Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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17
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Kaeley GS, MacCarter DK, Pangan AL, Wang X, Kalabic J, Ranganath VK. Clinical Responses and Synovial Vascularity in Obese Rheumatoid Arthritis Patients Treated with Adalimumab and Methotrexate. J Rheumatol 2018; 45:1628-1635. [PMID: 30173153 DOI: 10.3899/jrheum.171232] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Obese patients with rheumatoid arthritis (RA) report more joint swelling and tenderness and often have poorer responses to therapy than nonobese patients. The aim of this posthoc analysis of the MUSICA trial was to compare imaging and clinical disease activity measures in obese and nonobese patients with RA. METHODS MUSICA evaluated methotrexate (MTX) 20 mg/week versus 7.5 mg/week in combination with adalimumab (ADA) in RA patients with an inadequate response to MTX. Patients were categorized by baseline body mass index as normal (< 25), overweight (≥ 25 to < 30), or obese (≥ 30). Synovial vascularity and hypertrophy, swollen and tender joint counts (SJC and TJC), American College of Rheumatology (ACR) responses, and low disease activity (LDA), defined as Clinical Disease Activity Index < 10 and 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP) < 3.2, were assessed at weeks 12 and 24. RESULTS Patient characteristics were similar among groups at baseline. Obese patients had numerically smaller changes from baseline to weeks 12/24 in SJC, TJC, DAS28-CRP, and synovial hypertrophy and vascularity versus nonobese patients. Significantly fewer obese patients reached ACR20/50 at weeks 12 and 24, and LDA at Week 12; this difference was especially apparent in patients receiving 7.5 mg/week MTX but was no longer significant at Week 24. CONCLUSION Obese patients with RA had worse clinical and ultrasonographic responses than nonobese patients, which were partly overcome with time. Obese patients may experience better and faster clinical improvements if ADA is initiated with high-dose (20 mg/week) rather than low-dose MTX. [ClinicalTrials.gov: NCT01185288].
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Affiliation(s)
- Gurjit S Kaeley
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles
| | - Daryl K MacCarter
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles
| | - Aileen L Pangan
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles
| | - Xin Wang
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles
| | - Jasmina Kalabic
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles
| | - Veena K Ranganath
- From the Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine, Jacksonville, Florida; Department of Rheumatology, North Valley Hospital, Whitefish, Montana; Global Medical Affairs, AbbVie Inc., North Chicago, Illinois; Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois; Division of Rheumatology, University of California at Los Angeles, Los Angeles, California, USA; Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany. .,G.S. Kaeley, MD, Division of Rheumatology and Clinical Immunology, University of Florida College of Medicine; D.K. MacCarter, MD, Department of Rheumatology, North Valley Hospital; A.L. Pangan, MD, Immunology Clinical Development, AbbVie Inc.; X. Wang, PhD, Data and Statistical Sciences, AbbVie Inc.; J. Kalabic, MD, Pharmaceutical Development, AbbVie Deutschland GmbH & Co. KG; V.K. Ranganath, MD, Division of Rheumatology, University of California at Los Angeles.
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Gorovits B, Baltrukonis DJ, Bhattacharya I, Birchler MA, Finco D, Sikkema D, Vincent MS, Lula S, Marshall L, Hickling TP. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clin Exp Immunol 2018; 192:348-365. [PMID: 29431871 PMCID: PMC5980437 DOI: 10.1111/cei.13112] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2018] [Indexed: 12/13/2022] Open
Abstract
We examined the assay formats used to detect anti-drug antibodies (ADA) in clinical studies of the anti-tumour necrosis factor (TNF) monoclonal antibodies adalimumab and infliximab in chronic inflammatory disease and their potential impact on pharmacokinetic and clinical outcomes. Using findings of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti-TNF factor adalimumab and infliximab. Among studies of adalimumab and infliximab, the immunoassay method used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme-linked immunosorbent assay or radioimmunoassay was used [85 of 91 (93%) and 134 of 154 (87%), respectively]. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0-87%; infliximab, 0-79%). Pharmacokinetic and clinical outcomes were only reported for ADA-positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion-related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics.
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Affiliation(s)
| | | | | | | | | | | | | | - S. Lula
- Envision Pharma GroupLondonUK
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19
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Wright EK, Kamm MA, De Cruz P, Hamilton AL, Selvaraj F, Princen F, Gorelik A, Liew D, Prideaux L, Lawrance IC, Andrews JM, Bampton PA, Jakobovits SL, Florin TH, Gibson PR, Debinski H, Macrae FA, Samuel D, Kronborg I, Radford-Smith G, Gearry RB, Selby W, Bell SJ, Brown SJ, Connell WR. Anti-TNF Therapeutic Drug Monitoring in Postoperative Crohn's Disease. J Crohns Colitis 2018; 12:653-661. [PMID: 29385469 DOI: 10.1093/ecco-jcc/jjy003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 01/13/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. METHODS As part of a study of postoperative Crohn's disease management, some patients undergoing resection received prophylactic postoperative adalimumab. In these patients, serum and fecal adalimumab concentration and serum anti-adalimumab antibodies [AAAs] were measured at 6, 12 and 18 months postoperatively. Levels of Crohn's disease activity index [CDAI], C-reactive protein [CRP] and fecal calprotectin [FC] were assessed at 6 and 18 months postoperatively. Body mass index and smoking status were recorded. A colonoscopy was performed at 6 and/or 18 months. RESULTS Fifty-two patients [32 on monotherapy and 20 on combination therapy with thiopurine] were studied. Adalimumab concentration did not differ significantly between patients in endoscopic remission vs recurrence [Rutgeerts ≥ i2] [9.98µg/mL vs 8.43 µg/mL, p = 0.387]. Patients on adalimumab monotherapy had a significantly lower adalimumab concentration [7.89 µg/mL] than patients on combination therapy [11.725 µg/mL] [p = 0.001], and were significantly more likely to have measurable AAA [31% vs 17%, p = 0.001]. Adalimumab concentrations were lower in patients with detectable AAA compared with those without [3.59 µg/mL vs 12.0 µg/mL, p < 0.001]. Adalimumab was not detected in fecal samples. Adalimumab serum concentrations were lower in obese patients compared with in non-obese patients [p = 0.046]. CONCLUSION Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients.
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Affiliation(s)
- Emily K Wright
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Michael A Kamm
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Peter De Cruz
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Amy L Hamilton
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Fabiyola Selvaraj
- Department of Research and Development, Prometheus Laboratories, Inc., San Diego, California, USA
| | - Fred Princen
- Department of Research and Development, Prometheus Laboratories, Inc., San Diego, California, USA
| | - Alexandra Gorelik
- Melbourne EpiCentre, University of Melbourne and Melbourne Health, Melbourne, Australia
| | - Danny Liew
- Monash University, School of Public Health and Preventative Medicine, Melbourne, Australia
| | - Lani Prideaux
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Fremantle Hospital and The University of Western Australia, Fremantle, Australia
| | - Jane M Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia
| | - Peter A Bampton
- Department of Gastroenterology and Hepatology, Flinders Medical Centre and Flinders University, Adelaide, Australia
| | | | - Timothy H Florin
- Department of Gastroenterology, Mater Health Services, University of Queensland Brisbane, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia
| | - Henry Debinski
- Melbourne Gastrointestinal Investigation Unit, Cabrini Hospital, Melbourne, Australia
| | - Finlay A Macrae
- Department of Colorectal Medicine and Genetics, and Department of Medicine, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia
| | - Douglas Samuel
- Department of Gastroenterology, Bankstown Hospital, Sydney, Australia
| | - Ian Kronborg
- Department of Gastroenterology, Western Hospital, Melbourne, Australia
| | - Graham Radford-Smith
- Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia.,IBD Group Queensland Institute of Medical Research, University of Queensland, Brisbane, Australia
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Warwick Selby
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Sally J Bell
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - Steven J Brown
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
| | - William R Connell
- Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Australia
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Abstract
PURPOSE OF REVIEW The review summarizes our current understanding of how obesity impacts diagnostic studies and therapies used in inflammatory bowel disease (IBD) as well as the safety and efficacy of medical and surgical weight loss therapies in the obese IBD patient. RECENT FINDINGS Many of the diagnostic tools we rely on in the identification and monitoring of IBD can be altered by obesity. Obesity is associated with increased acute phase proteins and fecal calprotectin. It can be more difficult to obtain and interpret cross sectional imaging of obese patients. Recent studies have also shown that common therapies used to treat IBD may be less effective in the obese population and may impact comorbid disease. Our understanding of how best to measure obesity is evolving. In addition to BMI, studies now include measures of visceral adiposity and subcutaneous to visceral adiposity ratios. An emerging area of interest is the safety and efficacy of obesity treatment including bariatric surgery in patients with IBD. A remaining question is how weight loss may alter the course of IBD. SUMMARY The proportion of obese IBD patients is on the rise. Caring for this population requires a better understanding of how obesity impacts diagnostic testing and therapeutic strategies. The approach to weight loss in this population is complex and future studies are needed to determine the safety of medical or surgical weight loss and its impact on the course of disease.
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D'Agostino MA, Alten R, Mysler E, Le Bars M, Ye J, Murthy B, Heitzmann J, Vadanici R, Ferraccioli G. Body mass index and clinical response to intravenous or subcutaneous abatacept in patients with rheumatoid arthritis. Clin Rheumatol 2017; 36:2655-2665. [PMID: 28822046 PMCID: PMC5681604 DOI: 10.1007/s10067-017-3788-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 07/17/2017] [Accepted: 08/10/2017] [Indexed: 12/31/2022]
Abstract
This post hoc analysis of ACQUIRE (NCT00559585) explored the effect of baseline body mass index (BMI) on the pharmacokinetics of and clinical response to subcutaneous (SC) or intravenous (IV) abatacept in patients with rheumatoid arthritis (RA). ACQUIRE was a phase 3b, 6-month, double-blind, double-dummy study in which patients with RA were randomized (1:1) to SC (fixed - dose; 125 mg/week) or IV (weight-tiered; ~ 10 mg/kg/month) abatacept plus methotrexate. In this analysis, minimum abatacept plasma concentration (Cmin) was measured at 3 and 6 months, and clinical remission over 6 months was assessed by Disease Activity Score 28 (C-reactive protein; DAS28 [CRP], < 2.6), Simplified Disease Activity Index (SDAI, ≤ 3.3), and Clinical Disease Activity Index (CDAI, ≤ 2.8). Data were stratified by baseline BMI (underweight/normal, < 25 kg/m2; overweight, 25 to < 30 kg/m2; obese, ≥ 30 kg/m2) and administration route. Of the 1456/1457 patients for whom baseline BMIs were available, 526 (36%; SC 265, IV 261) patients were underweight/normal, 497 (34%; SC 249, IV 248) were overweight, and 433 (30%; SC 221, IV 212) were obese. Median Cmin abatacept concentration was ≥ 10 μg/mL (efficacy threshold) at 3 and 6 months in > 90% of patients across BMI groups with both administration routes. DAS28 (CRP), SDAI, and CDAI remission rates at 6 months were similar across BMI groups and 95% confidence intervals overlapped at all time points in both separate and pooled SC/IV analyses. Therapeutic concentrations of abatacept and clinical remission rates using stringent criteria were similar across patient BMIs and administration routes.
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Affiliation(s)
- Maria-Antonietta D'Agostino
- Departement de Rhumatologie, AP-HP, Hôpital Ambroise Paré, INSERM U1173, Laboratoire d'Excellence INFLAMEX, UFR Simone Veil, Versailles-Saint-Quentin University, 92100, Boulogne-Billancourt, France.
| | - Rieke Alten
- Schlosspark-Klinik University Medicine, Berlin, Germany
| | - Eduardo Mysler
- Organización Médica de Investigación, Buenos Aires, Argentina
| | | | - June Ye
- Bristol-Myers Squibb, Princeton, NJ, USA
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22
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Nakase H, Motoya S, Matsumoto T, Watanabe K, Hisamatsu T, Yoshimura N, Ishida T, Kato S, Nakagawa T, Esaki M, Nagahori M, Matsui T, Naito Y, Kanai T, Suzuki Y, Nojima M, Watanabe M, Hibi T. Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial. Aliment Pharmacol Ther 2017; 46:873-882. [PMID: 28884856 PMCID: PMC5656923 DOI: 10.1111/apt.14318] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 07/18/2017] [Accepted: 08/18/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/mL vs 5.4 ± 4.3 μg/mL: P <.001). Adalimumab trough level of 5.0 μg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146).
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Body mass index influences infliximab post-infusion levels and correlates with prospective loss of response to the drug in a cohort of inflammatory bowel disease patients under maintenance therapy with Infliximab. PLoS One 2017; 12:e0186575. [PMID: 29073159 PMCID: PMC5657978 DOI: 10.1371/journal.pone.0186575] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 10/03/2017] [Indexed: 12/20/2022] Open
Abstract
Introduction Infliximab is an effective treatment for inflammatory bowel disease (IBD). Studies differ regarding the influence of body mass index (BMI) on the response to infliximab, with the majority of studies indicating that increased BMI may be associated with a poorer response to Infliximab. However, the pharmacokinetic mechanisms causing this have not yet been reported. Aims Examine the correlation between BMI/immunosuppressant use with clinical response, trough and post-infusion levels of infliximab, tumour necrosis factor-α(TNF-α) and anti-drug antibodies(ATI), and determine if these factors can predict future response. Methods We collected serum from 24 patients receiving Infliximab before and 30 minutes following infusion. Clinical parameters were collected retrospectively and prospectively. ELISA measurements of infliximab, TNF-α and ATI were performed. Results We confirmed that patients with higher infliximab trough levels have a better response rate and that patients with an elevated BMI display a higher rate of loss of response (20%). Patients with a higher BMI had elevated post-infusion levels of infliximab. Additionally, the ratio of IFX/TNF-α trough levels correlated with clinical response to the following infusion. Conclusion This study confirms that an elevated BMI is associated with a poorer response to infliximab. For the first time, we describe that a higher BMI correlates with higher post-infusion levels, however this does not correlate with a higher rate of response to the drug, suggesting that circulating drug levels do not correlate with tissue levels. Furthermore, in our small cohort of patients, we identified a possible predictive marker of future response to treatment which may be used to guide dose escalation and predict non-response to infliximab.
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The Evolving Evidence for Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Bowel Disease. Curr Gastroenterol Rep 2017; 19:19. [PMID: 28397129 DOI: 10.1007/s11894-017-0559-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PURPOSE OF REVIEW Biological medications are effective in inflammatory bowel disease (IBD) but adverse events, cost, and loss of response make their use challenging. Therapeutic drug monitoring (TDM) allows clinicians to more safely, effectively, and efficiently use medications. The purpose of this article is to review and summarize the most recent literature pertaining to TDM in IBD. RECENT FINDINGS Measurement of biological drug trough levels predicts ongoing patient response and can be used to titrate the medication to be more effective and efficient. Antibodies against the medications predict loss of response and adverse events. Using both parameters can predict response to subsequent biologicals. Newer biologicals show similar characteristics to those more commonly used. Management protocols using drug and antibody levels optimize medication use and may be cost-effective. Recent evidence suggests benefit to TDM of biologicals in IBD.
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Bond A, Dodd S, Fisher G, Skouras T, Subramanian S. Concurrent immunomodulator therapy is associated with higher adalimumab trough levels during scheduled maintenance therapy. Scand J Gastroenterol 2017; 52:204-208. [PMID: 27797269 DOI: 10.1080/00365521.2016.1245777] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Combination therapy with infliximab and immunomodulators is superior to monotherapy, resulting in better outcomes and higher trough levels of infliximab. The role of concurrent immunomodulatory therapy on adalimumab trough levels has not been adequately investigated. We evaluated the impact of concomitant immunomodulation on adalimumab trough levels in patients on scheduled maintenance therapy. METHOD We conducted a prospective observational, cross-sectional study of all inflammatory bowel disease patients on maintenance therapy who had adalimumab trough levels measured between January 2013 and January 2016. Drug level and anti-drug antibody measurements were performed on sera using a solid phase assay. Pairwise comparison of means was used to compare trough levels in patients with and without concomitant immune modulator therapy. RESULTS In total, 79 patients were included. Twenty-three patients (29.1%) were on weekly dosing whereas 56 (70.9%) were on alternate weeks. Median adalimumab trough levels were comparable in patients with and without clinical remission (6.8 μg/ml (IQR 5.6-8.1) versus 6.7 μg/ml (IQR 3.9-8.1), respectively. Patients with an elevated faecal calprotectin >250 μg/g had lower adalimumab trough levels (median 6.7, IQR 3.9-8) compared to patients with faecal calprotectin <250 μg/g (median 7.7, IQR 6.1-8.1) though this did not achieve statistical significance (p = .062). Median adalimumab trough levels among patients on concurrent immunomodulators was 7.2 μg/ml (IQR 5.7-8.1) compared to those not on concurrent immunomodulator, 6.1 μg/ml (IQR 2.7-7.7, p = .0297). CONCLUSION Adalimumab trough levels were significantly higher in patients on concurrent immunomodulators during maintenance therapy. There was a trend towards a lower adalimumab trough level in patients with elevated calprotectin.
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Affiliation(s)
- Ashley Bond
- a Department of Gastroenterology , Royal Liverpool and Broadgreen University Hospital Trust , Liverpool , UK
| | - Susanna Dodd
- b Department of Biostatistics , University of Liverpool , Liverpool , UK
| | - Gareth Fisher
- a Department of Gastroenterology , Royal Liverpool and Broadgreen University Hospital Trust , Liverpool , UK
| | - Thomas Skouras
- a Department of Gastroenterology , Royal Liverpool and Broadgreen University Hospital Trust , Liverpool , UK
| | - Sreedhar Subramanian
- a Department of Gastroenterology , Royal Liverpool and Broadgreen University Hospital Trust , Liverpool , UK
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Singh S, Dulai PS, Zarrinpar A, Ramamoorthy S, Sandborn WJ. Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes. Nat Rev Gastroenterol Hepatol 2017; 14:110-121. [PMID: 27899815 PMCID: PMC5550405 DOI: 10.1038/nrgastro.2016.181] [Citation(s) in RCA: 271] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Incidence of IBD is rising in parallel with overweight and obesity. Contrary to conventional belief, about 15-40% of patients with IBD are obese, which might contribute to the development of IBD. Findings from cross-sectional and retrospective cohort studies are conflicting on the effect of obesity on natural history and course of IBD. Most studies are limited by small sample size, low event rates, non-validated assessment of disease activity and lack robust longitudinal follow-up and have incomplete adjustment for confounding factors. The effect of obesity on the efficacy of IBD-related therapy remains to be studied, though data from other autoimmune diseases suggests that obesity results in suboptimal response to therapy, potentially by promoting rapid clearance of biologic agents leading to low trough concentrations. These data provide a rationale for using weight loss interventions as adjunctive therapy in patients with IBD who are obese. Obesity also makes colorectal surgery technically challenging and might increase the risk of perioperative complications. In this Review, we highlight the existing literature on the epidemiology of obesity in IBD, discuss its plausible role in disease pathogenesis and effect on disease course and treatment response, and identify high-priority areas of future research.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, Department of Medicine, University of California San Diego, USA,Division of Biomedical Informatics, Department of Medicine, University of California San Diego, USA
| | - Parambir S. Dulai
- Division of Gastroenterology, Department of Medicine, University of California San Diego, USA
| | - Amir Zarrinpar
- Division of Gastroenterology, Department of Medicine, University of California San Diego, USA
| | - Sonia Ramamoorthy
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92193, USA
| | - William J. Sandborn
- Division of Gastroenterology, Department of Medicine, University of California San Diego, USA
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