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Key Clinical Updates in Inflammatory Bowel Disease

FDA has issued a black box warning for tofacitinib and upadacitinib about an increased risk of thrombosis, including MI, stroke, arterial thrombosis, DVT, PE, and death.

In 2023, a new subcutaneous formulation of infliximab became available.

Buisson A et al. Clin Gastroenterol Hepatol. [PMID: 35987302]

Vedolizumab is approved for administration as both an intravenous and subcutaneous formulation.

Lim SH et al. Inflamm Bowel Dis. [PMID: 37603730]

The term “inflammatory bowel disease” includes ulcerative colitis and Crohn disease. The diagnosis and management of each will be reviewed in the sections below. After a marked (up to 4-fold) increase over the past 40 years in northern European countries and the United States, the incidence in these regions may have stabilized. In the United States, there are approximately 2.4 million people with IBD (0.7%) with an adjusted annual incidence of 10.9 cases/100,000 person-years. The prevalence of ulcerative colitis is slightly higher than Crohn disease. These diseases can occur at any age but most commonly begin in adolescents and adults under age 40 years. The natural history of both varies from mild, often intermittent disease symptoms to severe disease characterized by elevated inflammatory markers and mucosal ulcerations that may lead to intestinal complications (bleeding, strictures, fistulas, surgery), nutritional deficiencies, and impaired quality of life. Both diseases may be associated with several extraintestinal manifestations, including oral ulcers, oligoarticular or polyarticular nondeforming peripheral arthritis, spondylitis or sacroiliitis, episcleritis or uveitis, erythema nodosum, pyoderma gangrenosum, hepatitis and sclerosing cholangitis, and thromboembolic events.

Pharmacologic Therapy

Although ulcerative colitis and Crohn disease appear to be distinct entities, several pharmacologic agents are used to treat both. For many years, the primary therapeutic options were 5-aminosalicylic acid agents, corticosteroids, and immunomodulating drugs (thiopurines and methotrexate). Over the last decade, the therapeutic options have greatly expanded to include other small-molecule agents (JAK inhibitors and sphingosine 1-phosphate receptor modulators) and biologic therapies (TNF antagonists, IL 12/23 antibodies, anti-integrins). See Table 17-13. Biologic Agents for Treatment of Ibd.

A. 5-Aminosalicylic Acid (5-Asa)

5-ASA is a topically active agent that has a variety of anti-inflammatory effects. It is used in the active treatment of ulcerative colitis and Crohn disease and during disease inactivity to maintain remission. It is readily absorbed from the small intestine but demonstrates minimal colonic absorption. Several oral and topical compounds have been designed to target delivery of 5-ASA to the colon or distal small intestine. Commonly used formulations of 5-ASA are sulfasalazine, mesalamine, and azo compounds.

1. Oral formulations- Mesalamine compounds are oral 5-ASA formulations that are either coated in various pH-sensitive resins (Asacol, Apriso, and Lialda) that release 5-ASA throughout the colon or packaged in timed-release capsules (Pentasa) that release 5-ASA in the small intestine and colon. Side effects of these compounds are uncommon but include nausea, rash, diarrhea, pancreatitis, and acute interstitial nephritis. Sulfasalazine and balsalazide are oral formulations that contain 5-ASA linked by an azo bond to another agent (sulfapyridine or an inert peptide, respectively) to prevent small intestine absorption. Following cleavage of the azo bond by colonic bacteria, 5-ASA is released in the colon. The sulfapyridine group is absorbed and may cause side effects in 15-30% of patients, including nausea, oligospermia, leukopenia, agranulocytosis, impaired folate metabolism, and hypersensitivity (fever, rash, hemolytic anemia, pneumonitis). Because of its side effects, sulfasalazine is used less frequently than balsalazide and other 5-ASA agents. It should always be administered in conjunction with folate. Eighty percent of patients intolerant of sulfasalazine can tolerate mesalamine.
2. Topical mesalamine- 5-ASA is provided in the form of suppositories (Canasa; 1000 mg) and enemas (Rowasa; 4 g/60 mL). These formulations can deliver much higher concentrations of 5-ASA to the distal colon than oral compounds. Side effects are uncommon.

B. Corticosteroids

A variety of intravenous, oral, and topical corticosteroid formulations have been used in IBD. They have utility in the short-term treatment of moderate to severe disease. However, long-term use is associated with serious, potentially irreversible side effects and is to be avoided. The agents, route of administration, duration of use, and tapering regimens used are based more on personal bias and experience than on data from rigorous clinical trials. Oral formulations are prednisone or methylprednisolone. Adverse events commonly occur during short-term systemic corticosteroid therapy, including mood changes, insomnia, dyspepsia, weight gain, edema, elevated serum glucose levels, acne, and moon facies. Side effects of long-term use include osteoporosis, osteonecrosis of the femoral head, myopathy, cataracts, and susceptibility to infections. Calcium and vitamin D supplementation should be administered to all patients receiving long-term corticosteroid therapy. Bone densitometry should be considered in patients with IBD with other risk factors for osteoporosis and in all patients with a lifetime use of corticosteroids for 3 months or more. Budesonide is an oral corticosteroid with high topical anti-inflammatory activity but low systemic activity due to high first-pass hepatic metabolism. It is available as an enteric-coated formulation (Entocort) that targets delivery to the terminal ileum and proximal colon and a multi-matrix, delayed-release formulation (budesonide Multi Matrix [MMX] formulation [Uceris]) that releases budesonide throughout the colon. Budesonide produces less suppression of the hypothalamic-pituitary-adrenal axis and fewer steroid-related side effects than hydrocortisone or prednisone. Topical preparations are provided as hydrocortisone suppositories (25 mg and 30 mg), foam (10%, 80 mg), and enemas (100 mg) and as budesonide foam (2 mg).

C. Immunomodulating Drugs and Other Small Molecules

1. Thiopurines (mercaptopurine and azathioprine)- In current clinical practice, these drugs are mainly used in combination with anti-TNF agents (see section D.1. below) in patients with moderate to severe Crohn disease and ulcerative colitis to reduce antibody formation against the biologic agent and to increase the likelihood of clinical remission through increased anti-TNF drug levels and possible synergistic effects. In some settings, they continue to be used as monotherapy to maintain remission in patients with quiescent disease. Azathioprine is converted in vivo to mercaptopurine. It is believed that the active metabolite of mercaptopurine is 6-thioguanine. Side effects of mercaptopurine and azathioprine, including allergic reactions (fever, rash, or arthralgias) and nonallergic reactions (nausea, vomiting, pancreatitis, hepatotoxicity, bone marrow suppression, infections), occur in 15% of patients. Thiopurines are associated with up to a 2.5-fold increased risk of non-Hodgkin lymphomas (0.5/1000 patient-years). The risk rises after 1-2 years of exposure and is higher in men younger than age 30 years and patients older than age 50 years. Thiopurines also are associated with a risk of HPV-related cervical dysplasia and with an increased risk of non-melanoma skin cancer. Younger patients also are at risk for severe primary Epstein-Barr virus (EBV) infection, if not previously exposed.

Three competing enzymes are involved in the metabolism of mercaptopurine to its active (6-thioguanine) and inactive but potentially toxic metabolites (6-MMP). About 1 person in 300 has a homozygous pathogenic variant of one of the enzymes that metabolizes thiopurine methyltransferase (TPMT), placing them at risk for profound immunosuppression; 1 person in 9 is heterozygous for TPMT, resulting in intermediate enzyme activity. Measurement of TPMT functional activity is recommended prior to initiation of therapy. Treatment should be withheld in patients with absent TPMT activity. The most effective dose of mercaptopurine is 1-1.5 mg/kg and for azathioprine, is 2-3 mg/kg daily. For patients with normal TPMT activity, both drugs may be initiated at the weight-calculated dose. A CBC should be obtained weekly for 4 weeks, biweekly for 4 weeks, and then every 1-3 months for the duration of therapy. Liver biochemical tests should be measured periodically. Some clinicians prefer gradual dose escalation, especially for patients with intermediate TPMT activity or for whom TPMT measurement is not available; both drugs may be started at 25 mg/day and increased by 25 mg every 1-2 weeks while monitoring for myelosuppression until the target dose is reached. If the white blood count falls below 4000/mcL (4.0 × 109 /L) or the platelet count falls below 100,000/mcL (100 × 109 /L), the medication should be held for at least 1 week before reducing the daily dose by 25-50 mg. Measurement of thiopurine metabolites (6-TG and 6-MMP) is of unproved value in most patients but is recommended in patients who have not responded to standard, weight-based dosing or in whom adverse effects develop.

2. Methotrexate- Low-dose oral methotrexate (12.5 mg once weekly) is used in combination with anti-TNF agents to prevent immunogenicity. Methotrexate is an analog of dihydrofolic acid. Although at high doses it interferes with cell proliferation through inhibition of nucleic acid metabolism, at low doses it has anti-inflammatory properties, including inhibition of expression of TNF in monocytes and macrophages. Side effects of methotrexate include nausea, vomiting, stomatitis, infections, bone marrow suppression, hepatic fibrosis, and life-threatening pneumonitis. A CBC and liver chemistries should be monitored every 3 months. Folate supplementation (1 mg/day) should be administered. Because methotrexate is teratogenic, it should be discontinued in men and women at least 6 months before conception and during pregnancy.
3. Janus kinase inhibitors- Tofacitinib and upadacitinib are nonbiologic small molecules that inhibit Janus kinase, which is involved through the JAK-STAT pathway in modulation of multiple interleukins. Tofacitinib has greater inhibition of JAK1/3, whereas upadacitinib has greater selectivity for JAK1. Due to an increased risk of herpes zoster (up to 5% of patients), vaccination with inactivated (not live) recombinant zoster (Shingrix) is recommended for all patients. Other adverse events include acne, URIs, non-melanoma skin cancers, lymphoma, and GI perforations. Opportunistic infections, including TB, occur rarely. Laboratory abnormalities include lymphopenia, neutropenia, elevated CK, and elevated lipids. Elevations in both LDL and HDL are seen in 10-15% of patients within 4-8 weeks; however, the LDL/HDL ratio is unaltered. Prescribing guidelines recommend monitoring with a lipid panel within the first 8 weeks of treatment and with routine blood tests (liver tests, CBC) every 3 months. FDA has issued a black box warning for tofacitinib and upadacitinib about an increased risk of thrombosis, including MI, stroke, arterial thrombosis, DVT, PE, and death. They therefore should not be prescribed to patients deemed at higher risk for thrombosis.
4. Sphingosine 1-phosphate receptor modulators- Ozanimod and etrasimod are oral agents that bind to lymphocyte sphingosine 1-phosphate (S1P) receptors (ozanomod: types 1 and 5; etrasimod: types 1,4 and 5), thereby blocking their ability to leave lymph tissue, including the GI tract. They lead to a mean 45% reduction of peripheral lymphocyte count that may last for up to 4 weeks after drug discontinuation. Liver chemistries and CBC should be obtained 3-6 months after drug initiation. Severe lymphopenia less than 200 × 109 /L (less than 0.2 × 109 /L) should prompt drug dosage reduction or discontinuation. Other serious adverse events includes hypertension, liver transaminase elevation, and macular edema. Due to a low risk of bradycardia and AV conduction delays, an ECG should be obtained prior to initiating therapy to exclude conduction abnormalities; a cardiology consultation should be considered for patients with heart or cerebrovascular disease, arrhythmias, or AV block. Herpes simplex reactivation or herpes zoster may occur; inactivated recombinant zoster (Shingrix) vaccination is recommended.

D. Biologic Therapies

1. Anti-TNF therapies- TNF is one of the key proinflammatory cytokines in the TH1 response. TNF exists in two biologically active forms: a soluble form (sTNF), which is enzymatically cleaved from its cell surface, and a membrane-bound precursor (tmTNF). When either form binds to the TNF-receptors on effector cells, they initiate a variety of signaling pathways that lead to inflammatory gene activation. Four monoclonal antibodies to TNF are available for the treatment of IBD: infliximab, adalimumab, golimumab, and certolizumab. All four agents bind and neutralize soluble as well as membrane-bound TNF on macrophages and activated T lymphocytes, thereby preventing TNF stimulation of effector cells. When bound to membrane-associated TNF, all agents except certolizumab induce apoptosis and cell lysis of TNF-producing cells.

Infliximab is a chimeric (75% human/25% mouse) IgG1 antibody that is administered by intravenous infusion. Acute infusion reactions occur in 5-10% of infusions but are uncommon in patients receiving regularly scheduled infusions or concomitant immunomodulators (ie, azathioprine or methotrexate). Most reactions are mild or moderate (nausea; headache; dizziness; urticaria; diaphoresis; or mild cardiopulmonary symptoms that include chest tightness, dyspnea, or palpitations) and can be treated by slowing the infusion rate and administering acetaminophen and diphenhydramine. Severe reactions (hypotension, severe shortness of breath, rigors, severe chest discomfort) occur in less than 1% and may require oxygen, diphenhydramine, hydrocortisone, and epinephrine. Delayed serum sickness-like reactions occur in 1%. With repeated, intermittent intravenous injections, antibodies to infliximab develop in up to 40% of patients, which are associated with a shortened duration or loss of response and increased risk of acute or delayed infusion reactions. Giving infliximab in a regularly scheduled maintenance therapy (eg, every 8 weeks) or in combination with other immunomodulating agents (azathioprine, mercaptopurine, or methotrexate) significantly reduces the development of antibodies to less than 10%.

Adalimumab and golimumab are fully human IgG1 antibodies that are administered by subcutaneous injection. In 2023, a new subcutaneous formulation of infliximab also became available. Certolizumab is a fusion compound in which the Fab1 portion of a chimeric (95% human/5% mouse) TNF-antibody is bound to polyethylene glycol in order to prolong the drug half-life. However, certolizumab is infrequently used due to lower clinical efficacy. Hypersensitivity reactions are rare with subcutaneous anti-TNF therapies. Injection site reactions (burning, pain, redness, itching) are relatively common but usually mild and self-limited. Antibodies to adalimumab or golimumab develop in 5% of patients and to certolizumab in 10%, which may lead to shortened duration or loss of response to the drug.

Serious infections with anti-TNF therapies may occur in 2-5% of patients, including sepsis, pneumonia, abscess, and cellulitis; however, the increased risk is partially attributable to increased severity of disease and concomitant use of corticosteroids or immunomodulators. Patients treated with anti-TNF therapies are at increased risk for the development of opportunistic infections with intracellular bacterial pathogens including tuberculosis, mycoses (candidiasis, histoplasmosis, coccidioidomycosis, nocardiosis), and listeriosis, and with reactivation of viral infections, including hepatitis B, herpes simplex, varicella zoster, and EBV. Prior to use of these agents, patients should be screened for latent tuberculosis with PPD testing and a CXR. ANA and anti-DNA antibodies occur in a large percentage of patients; however, the development of drug-induced lupus is rare. All agents may cause severe hepatic reactions leading to acute hepatic failure; liver biochemical tests should be monitored routinely during therapy. Anti-TNF therapies may increase the risk of skin cancer, hence annual dermatologic examinations are recommended. There may be a small risk of non-Hodgkin lymphoma in patients taking anti-TNF monotherapy; however, the risk is much higher in patients receiving a combination of anti-TNF and a thiopurine. Rare cases of optic neuritis and demyelinating diseases, including multiple sclerosis, have been reported. Anti-TNF therapies may worsen HF in patients with cardiac disease.

In patients with active IBD, monitoring of anti-TNF trough levels and any anti-drug antibodies is useful to optimize drug levels and guide therapy. Maintenance of drug trough levels above specified thresholds is associated with higher clinical response rates and decreased risk of formation of neutralizing antibodies. Therapeutic drug monitoring is indicated in patients who have poor clinical response or who have lost clinical response. Patients with high titers of anti-drug antibodies should be switched to a different anti-TNF agent. Anti-TNF therapy is considered to have failed when patients have a poor response despite adequate anti-TNF trough concentrations; another class of drugs should be tried. Increasingly, experts recommend proactive measurement of drug and antibody concentrations in all patients to optimize clinical response and minimize drug antibody formation (more common at low drug levels). At present, recommended trough concentrations during maintenance therapy are greater than 7 mcg/mL for infliximab, greater than 7-10 mcg/mL for adalimumab, and greater than 1 mcg/mL for golimumab.

2. Anti-integrins- Anti-integrins decrease the trafficking of circulating leukocytes through the vasculature, reducing chronic inflammation. Vedolizumab is an anti-integrin that blocks the alpha4beta7 heterodimer, selectively blocking gut, but not brain, lymphocyte trafficking. It now is approved for administration as both an intravenous and subcutaneous formulation. Vedolizumab is not associated with an increased risk of serious infections or malignancy. Infusion reactions are uncommon. Antibodies develop in 3.7% but may not interfere with drug efficacy. Combination therapy with immunomodulators does not appear to increase rates of clinical response or remission. Therapeutic drug monitoring is of uncertain utility.
3. Anti-IL-12/23 and anti-IL-23 antibodies- Ustekinumab is a human IgG1 monoclonal antibody that binds the p40 subunit of IL-12 and IL-23, interfering with their receptor binding on T cells, NK cells, and antigen presenting cells. Approved in 2023, risankizumab and mirikizumab are IgG monoclonal antibodies that bind to the p19 subunit of IL-23, selectively inhibiting the IL-23 (but not the IL-12) receptor. All three IL antibodies are available as an intravenous formulation for induction therapy and subcutaneous formulations for maintenance therapy. Adverse effects include infusion and site-injection reactions, arthralgias, and an increase risk or URIs and nasopharyngitis. There has been no demonstrated increase in severe infections or malignancy with these agents and other serious events are rare. Antibodies to these agents develop in less than 4% of patients and their impact on treatment efficacy is uncertain. Combination therapy with immunomodulators does not appear to increase rates of clinical response or remission. Therapeutic drug monitoring is of uncertain utility.

BuchnerAMet al. Biosimilars in inflammatory bowel disease. Am J Gastroenterol. 2021;116:45. [PMID: 33110013]

BuissonAet al. Effectiveness of switching from intravenous to subcutaneous infliximab in patients with inflammatory bowel disease: the REMSWITCH study. Clin Gastroenterol Hepatol. 2023;21:2338. [PMID: 35987302]

HuAet al. Combination therapy does not improve rate of clinical or endoscopic remission in patients with inflammatory bowel diseases treated with vedolizumab or ustekinumab. Clin Gastroenterol Hepatol. 2021;19:1366. [PMID: 32668338]

LarsenLet al. Has the incidence of inflammatory bowel disease peaked? Evidence from the population-based NorIGD cohort 198-2020. Am J Gastroenterol. 2023;118:501. [PMID: 36728238]

LimSHet al. Safety, effectiveness, and treatment persistence of subcutaneous vedolizumab in IBD: a multicenter study from the United Kingdom. Inflamm Bowel Dis. 2023 Aug 21. [Epub ahead of print] [PMID: 37603730]

ShuklaRet al. Therapeutic drug monitoring of non-anti-tumor necrosis factor biologics. Clin Gastroenterol Hepatol. 2021;19:1108. [PMID: 335563]

SolitanoVet al. Comparative risk of serious infections with biologic agents and small molecules in inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023;21:907. [PMID: 35944832]

YarurAet al. Combination therapy with immunomodulators improves the pharmacokinetics of infliximab but not vedolizumab or ustekinumab. Clin Gastroenterol Hepatol. 2023;21:2908. [PMID: 36280102]

Immunizations

Due to increased risk of vaccine-preventable infections, vaccination status should be confirmed in all patients with IBD. Inactivated vaccines-hepatitis A and B, recombinant herpes zoster (Shingrix), influenza, and DTaP (tetanus, diphtheria, pertussis) vaccines-may be safely administered in patients receiving immunosuppressive agents; however, efficacy may be attenuated. Pneumococcal vaccine is recommended for patients who are over age 65 or who are receiving immunosuppressive agents. Live virus vaccines (varicella; MMR) should considered before initiating immunosuppressives for previously unvaccinated patients who lack serologic evidence of prior infection. Live virus vaccines should not be administered to patients taking immunosuppressive agents.

BenchimolEIet al. Canadian Association for Gastroenterology clinical practice guideline for immunizations in patients with inflammatory bowel disease-Part 1: live vaccines. Gastroenterology. 2021;161:669. [PMID: 33617891]

JonesJLet al. Canadian Association of Gastroenterology clinical practice guideline for immunizations in patients with inflammatory bowel disease-Part 2: inactivated vaccines. Gastroenterology. 2021;161:681. [PMID: 34476339]

Lifestyle & Social Support for Patients

IBD is a lifelong illness that can have profound physical, psychological, and social impacts on the individual and their family. A therapeutic relationship between the patient and clinician that involves trust, open communication, and shared decision-making is critical to achieving optimal outcomes. Adherence to a healthy lifestyle is associated with improved outcomes, including reduced mortality. Patients may be encouraged to stop or avoid smoking, limit to no or only light alcohol consumption, and engage in moderate to vigorous physical activity. Diets that are low in saturated fats and red meats and high in fruits and vegetables (eg, the Mediterranean diet) may be encouraged in patients without intestinal strictures. Patients should be screened for anxiety and depression, and psychological support (including cognitive behavioral therapy) offered when appropriate. Patients should be encouraged to become involved in the Crohn's and Colitis Foundation of America (CCFA) for patient-centered educational materials and local support groups (http://www.crohnscolitisfoundation.org/).

KhanNet al. Efficacy of recombinant Zoster vaccine in patient with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2022;20:1670. [PMID: 34274513]

LimketkaiBNet al. Dietary interventions for the treatment of inflammatory bowel diseases: an updated systematic review and meta-analysis. Clin Gastroenterol. 2023;21:2508. [PMID: 36470529]

LewisJDet al. A randomized trial comparing the specific carbohydrate diet to a Mediterranean diet in adults with Crohn's disease. Gastroenterology. 2021;161:837. [PMID: 34052278]

LoCHet al. Healthy lifestyle is associated with reduced mortality in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2021;19:87. [PMID: 32142939]

NarulaNet al. Does a high-inflammatory diet increase the risk of inflammatory bowel disease? Results from the Prospective Urban Rural Epidemiology (PURE) study: a prospective cohort study. Gastroenterology. 2021;161:1333. [PMID: 34118227]

Authors ⬆