Pharmacologic Treatment Challenges for IBD

Irritable bowel disease (IBD), which is defined as chronic idiopathic inflammation of the digestive tract, affects 3.1 million adults in the United States.¹ There are 2 forms of IBD: Crohn disease (CD) and ulcerative colitis (UC). CD is characterized by deeper and more erratic inflammation that can occur throughout the entire digestive tract. In UC, inflammation is continuous and widespread and disturbs the superficial mucosal layer of the large intestine or the colon.

There is no known cure for IBD, and symptoms, such as abdominal pain, diarrhea, fatigue, and malabsorption, can severely diminish patients’ quality of life.^2,3 Despite a somewhat low prevalence, with just 1.3% of US adults affected, the economic implications of IBD are enormous. Expensive imaging studies, procedures, and medications contribute to costs of $2 billion annually for CD alone.⁴

The goal of treatment depends on disease activity. For patients experiencing flare-ups or periods of high disease activity with intensification of symptoms, the goal of therapy is to induce remission or induction. For patients in remission or periods of low disease activity with minimal symptoms, the goal is to maintain remission or maintenance.

The 5-aminosalicylates may be used for treatment and maintenance of mild disease in both UC and ileal-to-colonic CD.^4,5 The 5-aminosalicylates include topical mesalamine, sulfasalazine, and balsalazide. Mesalamine can be delivered orally by targeted-release formulations or by alternate routes of administration. Sulfasalazine and balsalazide are prodrugs converted to mesalamine by enzymes present in gastrointestinal bacteria. Many medications used for maintenance therapy can be used to induce remission, but corticosteroids, such as prednisone, are often chosen for acute disease activity in both CD and UC.

Systemic immunomodulators, such as 6-mercaptopurine, azathioprine, cyclosporine, methotrexate, and tacrolimus, can be used for maintaining steroid-induced remission, as adjunctive treatment to steroids or in steroid-refractory cases.

Gram-negative and anaerobic antibiotics, such as ciprofloxacin and metronidazole, play a role in therapy for patients who develop infections as complications from the disease, but they lack strong evidence supporting use for induction and maintenance therapy. Some evidence supports metronidazole’s use in CD for patients failing on 5-aminosalicylates.

Anti—tumor necrosis factor (TNF)-alpha antibodies are reserved for moderate to severe disease refractory to corticosteroids and immunomodulators in both CD and UC. Infliximab and adalimumab carry approvals for both CD and UC, though certolizumab pegol is approved only for CD.

Other monoclonal antibodies approved for IBD are the integrin inhibitors. Vedolizumab, an α4 β7 integrin inhibitor, is approved for both CD and UC, and natalizumab, an α4 integrin inhibitor, is approved for use in CD. These drugs are reserved for patients nonresponsive to conventional therapies, including TNF inhibitors, and carry a risk of progressive multifocal leukoencephalopathy.

Treatment Challenges

Interindividual variability exists in disease location, severity, response to therapy, and associated complications. The heterogeneous nature of the disease presents challenges, particularly those regarding drug delivery, when selecting pharmacologic therapy.

The location of inflammation differs for patients, so pharmacologic treatment options must be able to affect the length of the digestive tract. Systemic therapy accomplishes this but is coupled with risks of increased adverse effects. Targeted delivery systems have been a mainstay of IBD pharmacotherapy and aim to locally treat inflammation. This is done with a variety of pH, temporal, and pressure-sensitive drug delivery systems that deliver the drug directly to the site of inflammation and treat topically rather than systemically.⁶ Alternate routes of administration are also used to deliver medications capable of treating inflammation topically. An overview of available medications, their delivery, and their routes of administration is provided in the Table.

Patient adherence also presents a challenge to the treatment of IBD. Patients can become nonadherent when their disease is controlled, thus triggering a relapse and a loss of remission. Complex dosing regimens, rectal delivery methods, and adverse effects contribute to nonadherence rates as high as 60% in some studies.⁷ Medication nonadherence is associated with increased costs, hospitalization, and relapse.^8,9

The rise and widespread use of monoclonal antibodies to treat disease has brought about new challenges. For starters, prescription costs can present barriers to care. Adalimumab, the top-selling drug in the world, can cost payers up to $50,000 a year per patient.¹⁰ Insurers often require step therapy, which can delay patients’ much needed disease control. Antibody therapeutics have adverse effects that include immunogenicity, risk of infection, and loss of response because of the development of antidrug antibodies.¹¹

Conclusion

Pharmacologic treatment of IBD involves targeted-release dosage forms, different routes of administration, and a strong link between adherence and patient outcomes. This represents an enormous opportunity for pharmacists to make a difference. Pharmacist medication education can save providers time on educating patients about their medications. Pharmacists can counsel on proper administration techniques and provide motivational interviewing to improve compliance. Pharmacists are knowledgeable about toxicities, adverse effects, and the management of adverse effects associated with pharmacotherapy.

Geoffrey Brown is a PharmD candidate at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in New York.

References

• Dahlhamer JM, Zammitti EP, Ward BW, Wheaton AG, Croft JB. Prevalence of inflammatory bowel disease among adults aged ≥ 18 years - United States, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(42):1166-1169. doi: 10.15585/mmwr.mm6542a3.
• Ghosh S, Mitchell R. Impact of inflammatory bowel disease on quality of life: results of the European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA) patient survey. J Crohns Colitis. 2007;1(1):10-20. doi: 10.1016/j.crohns.2007.06.005.
• Moradkhani A, Beckman LJ, Tabibian JH. Health-related quality of life in inflammatory bowel disease: psychosocial, clinical, socioeconomic, and demographic predictors. J Crohns Colitis. 2013;7(6):467-473. doi: 10.1016/j.crohns.2012.07.012.
• Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-483. doi: 10.1038/ajg.2008.168.
• Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523. doi: 10.1038/ajg.2009.727.
• Friend DR. New oral delivery systems for treatment of inflammatory bowel disease. Adv Drug Deliv Rev. 2005;57(2):247-265. doi: 10.1016/j.addr.2004.08.011.
• Lakatos PL. Prevalence, predictors, and clinical consequences of medical adherence in IBD: how to improve it? World J Gastroenterol. 2009;15(34):4234-4239.
• Fukuda T, Naganuma M, Sugimoto S, et al. The risk factor of clinical relapse in ulcerative colitis patients with low dose 5-aminosalicylic acid as maintenance therapy: a report from the IBD registry. PLoS One. 2017;12(11):e0187737. doi: 10.1371/journal.pone.0187737.
• Herman ML, Kane SV. Treatment nonadherence in inflammatory bowel disease: identification, scope, and management strategies. Inflamm Bowel Dis. 2015;21(12):2979-2984. doi: 10.1097/MIB.0000000000000581.
• Japsen B. How Abbvie’s Humira undercuts the drug industry price defense. Forbes. forbes.com/sites/brucejapsen/2016/07/21/how-abbvies- humira-undercuts- the-drug- industry- price-defense/#18134d426821. Published July 21, 2016. Accessed January 16, 2018.
• Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460-1468. doi: 10.1001/jama.2011.406.