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Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab
Journal Pre-proof Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab Jessica Lim, Muhammad B. Hammami, MD, Uma Mahadevan, MD
PII: DOI: Reference:
S0016-5085(20)30012-3 https://doi.org/10.1053/j.gastro.2020.01.002 YGAST 63113
To appear in: Gastroenterology Accepted Date: 2 January 2020 Please cite this article as: Lim J, Hammami MB, Mahadevan U, Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab, Gastroenterology (2020), doi: https://doi.org/10.1053/ j.gastro.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the AGA Institute
TITLE: Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab AUTHOR NAMES: Jessica Lim1, Muhammad B. Hammami, MD 2, 3 Uma Mahadevan, MD1 AUTHOR AFFILIATION: (1) Department of Medicine, Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA. (2) Department of Medicine, University of California, Riverside, Riverside, California, USA (3) Division of Gastroenterology and Hepatology, VA Loma Linda Health Care System, Loma Linda, California, USA Author Contributions: Jessica Lim (acquisition of data, writing of manuscript) Muhammad Bader Hammami MD (writing of manuscript) Uma Mahadevan MD (conceptual design, editing of manuscript) Author Conflict of Interest: Mahadevan – Consultant: Abbvie, Janssen, Genentech, Gilead, Allergan, Takeda Research grant: Pfizer, Celgene
Corresponding Author: Uma Mahadevan MD 1701 Divisadero Street #120 San Francisco, CA 94115 Telephone: 415-502-4444 Facsimile: 415-502-2240 [email protected]
Introduction: Women with IBD are counseled to continue biologic therapy through pregnancy.1 Placental transfer of the drug to the infant can occur with detectable levels for over 6 months from birth.2 The impact of this exposure on immune development is not fully understood. We report the first case of successful infliximab use in a patient initially exposed to the drug in utero. Methods: This was a retrospective chart review of mother and child’s records and direct query of the mother, a healthcare professional. Results: The mother was diagnosed with fistulizing perianal Crohn's Disease at eight years old. Her disease was severe, requiring ileocolonic resection, and was refractory to immunomodulators and biologic therapy. She had no history of tobacco, alcohol or recreational drug use. She had no known family history of inflammatory bowel disease (IBD) or other immune-mediated disorders. She first conceived at age 32 in 2001. She received high dose infliximab (10 mg/kg every 4-5 weeks) throughout pregnancy without interruption. She denies other medications or antibiotics during pregnancy. The pregnancy was uncomplicated, with appropriate weight gain and controlled active perianal disease. One year after delivery, her perianal disease flared and she failed different anti-TNF agents, finally achieving a longstanding endoscopic and clinical remission on standard ustekinumab dosing. Infliximab serum drug concentrations were not standard at the time and were not checked. The child’s father did not have IBD. The child was delivered via caesarean section at 38 weeks gestation due to the mother's active perianal disease. He was healthy with no medical conditions. He was breastfed for six months while the mother was on infliximab, with no maternal antibiotic exposure. As a child, he never traveled overseas and was exposed to a dog at three years of age, both factors that may impact microbiome and immune response.3 He started eating solid food before 6 months of age and ate a plant-based diet with no processed food, no fast food, or sugar-based drinks. He did not attend day care. He had no medical issues until three years of age. Fifty-six months post-delivery, he developed otitis media and was treated with cefprozil. Four weeks later, he developed pharyngitis, treated with cephalexin. Three days later, he developed increased stool frequency and hematochezia. Laboratory tests were normal, and stool cultures including Clostridium
difficile were unremarkable. Dietary changes initially improved his symptoms, but he eventually developed lower abdominal pain and increased loose stools prompting a course of metronidazole. His symptoms worsened, and a month after onset of gastrointestinal symptoms, endoscopy revealed extensive colitis and small duodenal bulb ulcerations. He was diagnosed with indeterminate colitis and started on sulfasalazine 50 mg/kg per day and nightly rectal mesalamine. An inadequate response prompted the addition of prednisone. He was able to taper off prednisone and achieved a brief clinical remission on sulfasalazine 750 mg twice daily with intermittent budesonide. Sulfasalazine was switched to mesalamine due to headaches. At the age of 6 he was started on azathioprine 50 mg daily, increased to 100 mg daily at age 8 and then 150 mg by age 13. He had intermittent flares every 18-24 months treated with rifaximin, budesonide and probiotics. His growth was appropriate. At age fourteen, a second colonoscopy showed moderate to severe pancolitis consistent with ulcerative colitis. Standard infliximab induction therapy (5 mg/kg at weeks zero, 2, and 6) was initiated January 2017 in addition to azathioprine 100 mg daily. Infliximab serum concentration was checked prior to infusion #1 (undetectable), infusion #2 (23.56 mcg/ml) and infusion #3 (12.98 mcg/ml). Suboptimal response and sub-therapeutic drug levels (1.97 mcg/ml) at 12 weeks from initial dose lead to infliximab dose escalation (10 mg/kg at 5-week intervals). Clinical remission was achieved, serum infliximab concentration was 9.46 mcg/ml and azathioprine was self-discontinued. Antibody to infliximab was measured and not detected at any time point. A staging sigmoidoscopy at age 15 revealed a small segment of mild proctitis but otherwise endoscopic remission. At age 17, he remains in sustained clinical remission on infliximab 10 mg/kg every 5 weeks with last infliximab serum concentration in 2018 of 7.2 mcg/ml with no antibody detected. Discussion: This is the first reported case of a child exposed to infliximab in utero successfully receiving the same therapy himself for IBD. While family history is the strongest risk factor for developing IBD,4 antibiotics can be a trigger in genetically susceptible patients5 altering the microbiome and leading to subsequent development of IBD.6 Children of mothers with IBD are therefore at risk.
If the mother receives biologic therapy during pregnancy, it is not known how offspring exposed in utero will react to the same therapy later in life. Will they develop tolerance given early exposure or will they develop anti-drug antibodies? Generally, exposure to an anti-TNF can lead to attenuated response or antidrug antibodies if a significant lapse in exposure occurs.7 This patient certainly demonstrated need for accelerated dosing, but thankfully responded to the agent and has been able to maintain response. As more mothers are using biologic therapy during pregnancy, the question of what therapies their offspring will respond to, should they develop IBD themselves, will be asked with increasing frequency. This case provides a reassuring first data point.
References:
1.
2.
3.
4.
5. 6. 7.
Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report From the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology 2019;156:15081524. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:286-92; quiz e24. Cholapranee A, Ananthakrishnan AN. Environmental Hygiene and Risk of Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 2016;22:2191-9. Childers RE, Eluri S, Vazquez C, et al. Family history of inflammatory bowel disease among patients with ulcerative colitis: a systematic review and meta-analysis. J Crohns Colitis 2014;8:1480-97. Theochari NA, Stefanopoulos A, Mylonas KS, et al. Antibiotics exposure and risk of inflammatory bowel disease: a systematic review. Scand J Gastroenterol 2018;53:1-7. Lane ER, Zisman TL, Suskind DL. The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res 2017;10:63-73. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2004;2:542-53.
PII: DOI: Reference:
S0016-5085(20)30012-3 https://doi.org/10.1053/j.gastro.2020.01.002 YGAST 63113
To appear in: Gastroenterology Accepted Date: 2 January 2020 Please cite this article as: Lim J, Hammami MB, Mahadevan U, Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab, Gastroenterology (2020), doi: https://doi.org/10.1053/ j.gastro.2020.01.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the AGA Institute
TITLE: Infliximab Use in a Child with Ulcerative Colitis and Prior in utero Exposure to Infliximab AUTHOR NAMES: Jessica Lim1, Muhammad B. Hammami, MD 2, 3 Uma Mahadevan, MD1 AUTHOR AFFILIATION: (1) Department of Medicine, Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA. (2) Department of Medicine, University of California, Riverside, Riverside, California, USA (3) Division of Gastroenterology and Hepatology, VA Loma Linda Health Care System, Loma Linda, California, USA Author Contributions: Jessica Lim (acquisition of data, writing of manuscript) Muhammad Bader Hammami MD (writing of manuscript) Uma Mahadevan MD (conceptual design, editing of manuscript) Author Conflict of Interest: Mahadevan – Consultant: Abbvie, Janssen, Genentech, Gilead, Allergan, Takeda Research grant: Pfizer, Celgene
Corresponding Author: Uma Mahadevan MD 1701 Divisadero Street #120 San Francisco, CA 94115 Telephone: 415-502-4444 Facsimile: 415-502-2240 [email protected]
Introduction: Women with IBD are counseled to continue biologic therapy through pregnancy.1 Placental transfer of the drug to the infant can occur with detectable levels for over 6 months from birth.2 The impact of this exposure on immune development is not fully understood. We report the first case of successful infliximab use in a patient initially exposed to the drug in utero. Methods: This was a retrospective chart review of mother and child’s records and direct query of the mother, a healthcare professional. Results: The mother was diagnosed with fistulizing perianal Crohn's Disease at eight years old. Her disease was severe, requiring ileocolonic resection, and was refractory to immunomodulators and biologic therapy. She had no history of tobacco, alcohol or recreational drug use. She had no known family history of inflammatory bowel disease (IBD) or other immune-mediated disorders. She first conceived at age 32 in 2001. She received high dose infliximab (10 mg/kg every 4-5 weeks) throughout pregnancy without interruption. She denies other medications or antibiotics during pregnancy. The pregnancy was uncomplicated, with appropriate weight gain and controlled active perianal disease. One year after delivery, her perianal disease flared and she failed different anti-TNF agents, finally achieving a longstanding endoscopic and clinical remission on standard ustekinumab dosing. Infliximab serum drug concentrations were not standard at the time and were not checked. The child’s father did not have IBD. The child was delivered via caesarean section at 38 weeks gestation due to the mother's active perianal disease. He was healthy with no medical conditions. He was breastfed for six months while the mother was on infliximab, with no maternal antibiotic exposure. As a child, he never traveled overseas and was exposed to a dog at three years of age, both factors that may impact microbiome and immune response.3 He started eating solid food before 6 months of age and ate a plant-based diet with no processed food, no fast food, or sugar-based drinks. He did not attend day care. He had no medical issues until three years of age. Fifty-six months post-delivery, he developed otitis media and was treated with cefprozil. Four weeks later, he developed pharyngitis, treated with cephalexin. Three days later, he developed increased stool frequency and hematochezia. Laboratory tests were normal, and stool cultures including Clostridium
difficile were unremarkable. Dietary changes initially improved his symptoms, but he eventually developed lower abdominal pain and increased loose stools prompting a course of metronidazole. His symptoms worsened, and a month after onset of gastrointestinal symptoms, endoscopy revealed extensive colitis and small duodenal bulb ulcerations. He was diagnosed with indeterminate colitis and started on sulfasalazine 50 mg/kg per day and nightly rectal mesalamine. An inadequate response prompted the addition of prednisone. He was able to taper off prednisone and achieved a brief clinical remission on sulfasalazine 750 mg twice daily with intermittent budesonide. Sulfasalazine was switched to mesalamine due to headaches. At the age of 6 he was started on azathioprine 50 mg daily, increased to 100 mg daily at age 8 and then 150 mg by age 13. He had intermittent flares every 18-24 months treated with rifaximin, budesonide and probiotics. His growth was appropriate. At age fourteen, a second colonoscopy showed moderate to severe pancolitis consistent with ulcerative colitis. Standard infliximab induction therapy (5 mg/kg at weeks zero, 2, and 6) was initiated January 2017 in addition to azathioprine 100 mg daily. Infliximab serum concentration was checked prior to infusion #1 (undetectable), infusion #2 (23.56 mcg/ml) and infusion #3 (12.98 mcg/ml). Suboptimal response and sub-therapeutic drug levels (1.97 mcg/ml) at 12 weeks from initial dose lead to infliximab dose escalation (10 mg/kg at 5-week intervals). Clinical remission was achieved, serum infliximab concentration was 9.46 mcg/ml and azathioprine was self-discontinued. Antibody to infliximab was measured and not detected at any time point. A staging sigmoidoscopy at age 15 revealed a small segment of mild proctitis but otherwise endoscopic remission. At age 17, he remains in sustained clinical remission on infliximab 10 mg/kg every 5 weeks with last infliximab serum concentration in 2018 of 7.2 mcg/ml with no antibody detected. Discussion: This is the first reported case of a child exposed to infliximab in utero successfully receiving the same therapy himself for IBD. While family history is the strongest risk factor for developing IBD,4 antibiotics can be a trigger in genetically susceptible patients5 altering the microbiome and leading to subsequent development of IBD.6 Children of mothers with IBD are therefore at risk.
If the mother receives biologic therapy during pregnancy, it is not known how offspring exposed in utero will react to the same therapy later in life. Will they develop tolerance given early exposure or will they develop anti-drug antibodies? Generally, exposure to an anti-TNF can lead to attenuated response or antidrug antibodies if a significant lapse in exposure occurs.7 This patient certainly demonstrated need for accelerated dosing, but thankfully responded to the agent and has been able to maintain response. As more mothers are using biologic therapy during pregnancy, the question of what therapies their offspring will respond to, should they develop IBD themselves, will be asked with increasing frequency. This case provides a reassuring first data point.
References:
1.
2.
3.
4.
5. 6. 7.
Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report From the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology 2019;156:15081524. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:286-92; quiz e24. Cholapranee A, Ananthakrishnan AN. Environmental Hygiene and Risk of Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 2016;22:2191-9. Childers RE, Eluri S, Vazquez C, et al. Family history of inflammatory bowel disease among patients with ulcerative colitis: a systematic review and meta-analysis. J Crohns Colitis 2014;8:1480-97. Theochari NA, Stefanopoulos A, Mylonas KS, et al. Antibiotics exposure and risk of inflammatory bowel disease: a systematic review. Scand J Gastroenterol 2018;53:1-7. Lane ER, Zisman TL, Suskind DL. The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res 2017;10:63-73. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2004;2:542-53.