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Advances in IBD Therapy at Penn GI: Severe Ulcerative Colitis

Virtual image of inflammatory bowel disease.

Penn Medicine is home to a robust and thriving inflammatory bowel disease (IBD) Center comprised of clinical and research faculty (among the nation’s largest based at an academic medical center) who, in collaboration with a team of skilled colorectal surgeons, are committed to the diagnosis and treatment of Crohn’s and ulcerative colitis (UC), and the management of the complications that attend IBD. The IBD team at Penn Gastroenterology includes gastroenterologists Faten Aberra, MD, MSCE; Meenakshi Bewtra, MD, MPH; Anna Buchner, MD, PhD; Jesse A. Green, MD; Nabeel Khan, MD; Jan-Michael A Klapproth, MD; James D. Lewis, MD, MSCE; Gary R. Lichtenstein, MD; Mark Osterman, MD, MSCE; Farzana Rashid, MD; Robert B Stein, MD; Vesselin Tomov, MD, PhD; and Gary D. Wu, MD.  The colorectal surgery team includes Cary Aarons, MD; Joshua Bleier, MD; Najia Mahmoud, MD; Nicole Saur, MD; and Skandan Shanmugan, MD.

Our thanks to Dr. Jesse A. Green, Director of Gastroenterology, Penn Presbyterian Medical Center, for his significant contributions to this article, which concerns a single aspect of IBD therapy as practiced at Penn Medicine's Division of Gastroenterology, the management of severe ulcerative colitis.

Background

Ulcerative colitis (UC) is a chronic condition affecting the colon that is characterized by a relapsing and remitting course and degrees of severity that may progress over many years. In the milder stages of UC, symptoms may include bowel movements up to four times a day, diarrhea, tenesmus and abdominal pain. By contrast, individuals with severe UC have significant bloody diarrhea with mucus greater than six times daily, and prevalent signs of toxicity, including fever, anemia and weight loss. Because there is, as yet, no cure for UC, treatment has the objective of inducing and maintaining remission.

Management of Severe Ulcerative Colitis at Penn Medicine

The treatment of severe UC involves procedures and medications that are unique to this stage of the disease. The first step in treatment, however, is common to any patient with UC. Because infection of any kind can be a cause of flares and morbidity, patients must be free of any infectious agent prior to further therapy.

“When a patient presents with severe ulcerative colitis, we first rule out concomitant infection,” says Jesse Green, MD, Director of Gastroenterology at Penn Presbyterian Medical Center, noting that the presence or absence of infection will influence management. Infection in severe UC can be caused by viruses or parasites, or bacteria. Perhaps the most significant of the latter is Clostridium difficile, a bacterium with a remarkable regenerative capacity in the wake of antibacterial assault, and a known precipitant of relapse in UC.

“The object of treating infection at this time is to improve symptoms,” Dr. Green observes.

In a few patients, treating infection alone is sufficient to resolve symptoms. For patients who continue to be symptomatic in the absence of infection (or for whom infection was not a cause of symptoms) short-term treatment with oral corticosteroids (IV, if the patient is in hospital) may be recommended as a bridge to biologic therapy with the intention of suppressing inflammation and improving symptoms .

Biologic Therapy for Severe UC

“There has been a marked increase in biological options for patients with severe ulcerative colitis in recent years,” Dr Green says. The category now includes anti-TNF agents, anti-integrins and janus kinase inhibitors.

“We typically start with the anti-TNFs,” says Dr. Green. “There are now three, infliximab, adalimumab and golimumab.” Infliximab and golimumab are monoclonal anti-TNF antibody agents; adalimumab is a humanized (not fully human) antibody targeting TNF.

“The dosing and administration for these agents varies, “Dr. Green adds. “Infliximab, for example, is an IV infusion agent that’s given as an induction at zero, two and six weeks, followed every eight weeks thereafter. Although 5 mg/kg dosing is often utilized, we will sometimes initiate 10 mg/kg dosing in severely ill UC patients.” Adalimumab and golimumab are injectable agents with unique dosing schedules.

The Penn IBD team often uses proactive therapeutic drug monitoring (TDM) to guide management. TDM is the clinical practice of measuring and interpreting drug levels at designated intervals to maintain a therapeutic level. TDM is implemented to optimize dosing regimens, determine compliance, and assess response to a particular drug class, among other objectives.

“For patients new to the category, therapeutic drug monitoring helps us make dose adjustments,” Dr. Green says. “For example, a patient with low therapeutic drug levels might receive an increase in dose.” TDM can also be used in patients with known ulcerative colitis already on anti-TNF therapy to determine when changes in therapy might be beneficial.

Recent Additions

A significant percentage of patients on anti-TNF therapy lose their response to these medications over time. [1] Thus, for patients with known ulcerative colitis already on an anti-TNF agent, TDM can also be used to determine changes in therapy. When TDM suggests that a change of anti-TNF might be advantageous, Dr. Green may switch patients to other classes of biologics such as vedolizumab, a gut-specific anti-integrin. The janus kinase inhibitor tofacitinib, expected to be approved for UC soon, might be another option.

Vedolizumab blocks activated T cells from exiting small blood vessels and reaching the site of inflammation, thereby lessening the inflammatory cascade. Previously approved for the treatment of psoriasis (and available in the US as of March 2018 ), tofacitinib interferes with the inflammatory cascade at another point by blocking cytokine signaling.

IBD specialists at Penn and elsewhere are now combining biologic agents with immunomodulators, including the thiopurines (6-mercaptopurine and azathioprine) and low dose methotrexate. Although occasionally started at the same time as biologics, the immunomodulators are often added  later in the course of therapy, based upon clinical factors, including TDM.

Newer agents are on the horizon.

“One potential new medication for UC under investigation is ozanimod,”  Dr. Green says. A sphingosine-1-phosphate receptor (S1-P1) agonist, ozanimod works by preventing activated lymphocytes from exiting lymph nodes and so blocks them from being recruited by cytokines to the site of inflammation.

Surgery

A patient who’s failing biologic therapy and other medical options and who has severe symptoms may benefit from moving to a surgical approach. “These are patients who are having more than 10 to 15 bowel movements per day with bloody diarrhea and significant anemia or poor nutritional indicators, such as low albumin or pre-albumin, despite medical therapy” Dr. Green explains.

Penn Medicine offers several options  for surgery in severe UC, including total proctocolectomy with J-pouch (ileal pouch, anal anastomosis, IPAA) done in a two- or three-step fashion depending upon severity of colitis at the time of surgery.

“The vast majority of our younger, active patients choose this option, which appeals to patients concerned with cosmesis,” Dr. Green says. There are concerns that patients must be aware of prior to surgery with IPAA, however, including the possible development of pouchitis.

Total proctocolectomy with end ileostomy offers another option. “It may not be as appealing from the perspective of cosmesis because it results in a permanent ileostomy stoma with a bag attached,” says Dr. Green. “But total proctocolectomy with end ileostomy has the advantage of being a one-step procedure with a shorter overall duration of surgery , and avoids the pouchitis issue.” Select patients may be candidates for variations on these surgeries at Penn Medicine, as well, per the surgeon’s clinical judgment.

“In this respect, we’re fortunate to have excellent colorectal surgeons at each of our hospitals,” Dr. Green says. Skandan Shanmugan, MD, practices primarily at Penn Presbyterian Medical Center with some office hours at Penn Medicine Radnor; Joshua Bleier, MD, practices at Pennsylvania Hospital and joins Carey Aarons, MD, and Najjia Mahmoud, MD, at the Penn Colon and Rectal Surgery Program at the Perelman Center for Advanced Medicine.

“What you should remember  about the treatment of severe ulcerative colitis is that from the beginning, it’s an effort that involves collaboration,” says Dr. Green. “Between primary care and referring gastroenterologists in the community and clinicians here at Penn Medicine, including not only our faculty at Penn GI, but pathologists, infectious disease specialists, imaging experts and surgeons. It’s a team effort. It just couldn’t work otherwise.”

*Image courtesy of Dr Dalia Ibrahim, Radiopaedia.org, rID: 29959.

2017 Clinical Publications in Ulcerative Colitis and Crohn’s Disease from the IBD Program at Penn Gastroenterology.

In 2017, the faculty of the Penn Gastroenterology IBD Program published more than 50 journal articles on the subject of inflammatory bowel disease and its environment, including the following:

Carr RM, Patel A, Bownik H, et al. Intestinal inflammation does not predict non-alcoholic fatty liver disease severity in inflammatory bowel disease patients. Dig Dis Sci. 2017;62:1354-1361.

Khan N, Patel D, Shah Y, et al. Albumin as a prognostic marker for ulcerative colitis. World J Gastroenterol. 2017 7;23:8008-8016.

Lewis JD, Abreu MT. Diet as a trigger or therapy for inflammatory bowel diseases. Gastroenterology. 2017;152:398-414.

Long AG, Lundsmith ET, Hamilton KE .Inflammation and Colorectal Cancer. Curr Colorectal Cancer Rep. 2017;13:341-351.

Ni J, Wu GD, Albenberg L, et al. Gut microbiota and IBD: causation or correlation? Nat Rev Gastroenterol Hepatol. 2017;14:573-584.

Rahman H, Kim M, Leung G, et al. Drug-herb interactions in the elderly patient with IBD: a growing concern. Curr Treat Options Gastroenterol. 2017;15:618-636.

Rubin DT, Cohen RD, Sandborn WJ, et al. Budesonide multimatrix is efficacious for mesalamine-refractory, mild to moderate ulcerative colitis: A randomised, placebo-controlled trial. J Crohns Colitis. 2017;11:785-791.

Vajravelu RK, Osterman MT, Aberra FN, et al. Indeterminate QuantiFERON-TB gold increases likelihood of inflammatory bowel disease treatment delay and hospitalization. Inflamm Bowel Dis. 2017;24:217-226.

About this Blog

The Penn GI News Update reports on recent advances in gastroenterological disease diagnosis, treatment and research at the Penn Division of Gastroenterology and Hepatology.

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