The introduction of biologic medications for the treatment of inflammatory bowel disease (IBD) is arguably the most significant advancement to date, leading to a paradigm shift in patient care, says gastroenterologist David T. Rubin, MD, codirector of the Digestive Diseases Center at the University of Chicago. “We can now change the natural history of the disease,” he says. In the pre-biologics era, clinicians were limited to managing IBD symptoms with corticosteroids, immunomodulators and surgery. Today, the availability of an expanded list of biologic medications (as well as one small-molecule therapy) has not only led to superior long-term control of IBD symptoms, but many patients can also achieve healing of damaged mucosal tissue—the combination known as “deep remission.”

All biologic medications approved for treating IBD, which potently reduce chronic inflammation, are associated with other critical benefits for patients, including reduced use of corticosteroids and lower rates of surgery, while evidence suggests that the risk for colon cancer is likely decreased, too, notes Dr. Rubin. However, getting the most from these medications requires a change in philosophy about managing IBD, he adds. “We used to treat active IBD more as an acute illness, but such reactive management is outdated,” says Dr. Rubin, who is lead author of the American College of Gastroenterology (ACG) clinical guidelines on management of ulcerative colitis in adults. “Now it’s appropriate to be proactive. This is a disease that needs a chronic management strategy.”

Here, experts offer suggestions for maximizing treatment with the goal of achieving clinical and symptomatic remission.
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Tailor treatment based on the patient’s history and preferences

Selection of IBD therapy should be based on shared decision-making with the patient, taking into consideration their medical history and preferences, says Kelly Colleen Cushing, MD, a gastroenterologist at the Brighton Center for Specialty Care in Michigan and a clinical lecturer in gastroenterology at the University of Michigan. There are several key factors that may influence selection of a biologic (see box). When deciding on a treatment plan, experts suggest keeping these considerations in mind:

Past use of biologics. If a patient previously achieved therapeutic levels of a biologic with no or inadequate response, it’s unlikely that an alternative biologic within the same class will be effective. “In that case, we would likely go to a different class of medications,” says Dr. Cushing. However, some patients may still respond to the initial biologic therapy. For example, subtherapeutic levels may have occurred as a result of pharmacokinetics or the presence of anti-drug antibodies; in such cases, the patient may respond to drug optimization (a higher dose of drug or a shorter interval between doses). Other options include adding an immunomodulator or trying another drug within the same class.

Delivery method. Patient preference for delivery method should be considered as well when selecting a biologic therapy. Some are administered via intravenous infusion given by a healthcare professional, which may be attractive to patients who prefer fewer injections or do not like the idea of self-injecting. Other patients may prefer the convenience of subcutaneous self-injection at home.

Frailty. Frail patients are vulnerable to serious infections. TNF inhibitors induce systemic immune suppression and are associated with an increased risk for infection, which may make non-TNF inhibitors preferable for frail patients. In one study, vedolizumab (which only targets inflammation in the gut) was associated with a 46% lower risk for serious infections among patients with ulcerative colitis compared with other patients given TNF inhibitors.¹ (There was no difference in infection risk among patients with Crohn’s disease.) Dr. Cushing notes that this rule may not apply to seniors who are in good health, and that patient frailty may be a better determinant than age when electing to avoid systemic immune suppression with a TNF inhibitor.
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Consider combination therapy with an immunomodulator

The ACG and American Gastroenterological Association (AGA) guidelines for managing moderate-to-severe IBD note that combining a biologic with an immunomodulator (thiopurines or methotrexate) has produced superior outcomes when compared with monotherapy in clinical trials.^2,3 “The rationale for combination therapy with biologic agents and immunomodulators is that the latter decrease the risk of immunogenicity, or developing antidrug antibodies, against monoclonal antibodies by about 50%,” says gastroenterologist Siddharth Singh, MD, an assistant professor of medicine at the University of California at San Diego and a coauthor of the AGA clinical practice guidelines on managing moderate-to-severe ulcerative colitis. What’s more, immunomodulators independently suppress the immune system and may have disease-modifying effects, notes Dr. Singh. He adds that combination therapy may be particularly beneficial for patients with severe disease. “However, some patients find it challenging to accept combination therapy up front,” notes Dr. Singh. “In these circumstances, especially if the risk of treatment failure is low or if I’m using a less-immunogenic non-TNF-targeting biologic like vedolizumab or ustekinumab, I may be okay with monotherapy.”
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Address patient concerns

Some patients may be reluctant to accept biologic therapy or may not follow their regimen as prescribed. In such cases, this simple approach can help increase acceptance and adherence:

Demystify biologic therapy. Dr. Rubin finds that a little knowledge can ease the minds of patients who are put off by the term “biologic” or who are frightened by the prospect of an infused or injected medication. “I always make sure people understand that ‘biologic’ simply refers to the fact that the protein is made by living cells,” says Dr. Rubin. “And I explain that biological therapies are proteins that are too big to get absorbed through the lining of your small intestine, so they have to be delivered through an injection or infusion.”

Listen, but be frank. “My approach is to have a very open, back-and-forth conversation with the patient,” says Dr. Cushing. “What’s really important is to not only talk about the risks and benefits of the medication but also what will happen if we don’t do anything. That helps patients understand that the risks are quite negligible compared with the risk of not treating the disease.”
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Use a treat-to-target strategy

Setting specific treatment goals for both symptom improvement and reduction in objective measures of inflammation increases a patient’s odds for achieving deep remission, says Dr. Rubin, who coauthored the 2021 Selecting Therapeutic Targets in IBD (STRIDE-II) initiative produced by the International Organization for the Study of IBD.⁴

The concept is simple: Make a baseline assessment of patient symptoms and objective targets, then routinely monitor them. Targets can be individualized to the patient and your practice. “Not everyone can hit their targets, but with this strategy you don’t waste time on therapies that aren’t working,” says Dr. Rubin. “It also helps strengthen the relationship with patients.” In addition to patient-reported symptoms, these objective measures are most commonly used:

Stool and blood tests. The two most widely used biochemical tests for monitoring IBD are:

• Fecal calprotectin: STRIDE-II suggests a cut-off value of 150 mg/g to identify endoscopic healing. However, lower thresholds (<100 mg/g) may reflect deeper mucosal healing.
• C-reactive protein: Normalization (<0.5 mg/dL) is the goal, though the upper limit of normal (<0.8 mg/dL) is acceptable; however, bear in mind that 20% of the population does not form this inflammatory marker.

Scoping. Biochemical assessment may be adequate but you might also consider colonoscopy or sigmoidoscopy to measure endoscopic healing. Various indices are available depending on the diagnosis:

• Crohn’s disease: Endoscopic remission is indicated by a Simple Endoscopic Score for Crohn’s Disease of ≤2 or Crohn’s Disease Endoscopic Index of Severity of <3 with lack of any ulceration.
• Ulcerative colitis: Complete remission is associated with resolution of symptoms and a Mayo Endoscopic Subscore of 0 or 1.

Other targets. A commercially available serum test (Monitr) that measures 13 biomarkers of mucosal inflammation in Crohn’s disease produces an endoscopic healing index (EHI) from zero to 100; an EHI lower than 20 likely indicates remission. A few institutions in the United States now offer bedside bowel ultrasound as an imaging tool for detecting inflammation.
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Don’t delay considering an alternative agent—but investigate reasons for nonremission

STRIDE-II encourages clinicians to consider changing treatments when targets are not achieved. Time to response to a new agent varies depending on the patient and the medication, but after taking a baseline measurement, Dr. Rubin often repeats stool or blood tests in 6 weeks and repeats scoping in 6 months. However, consider possible explanations for nonremission of symptoms. For example, the patient may have:

• Postinflammatory hypersensitivity, which can result in symptoms despite healing of the bowel. In this scenario, symptomatic therapy with anticholinergic or antidiarrheal medications may be helpful.
• Scar tissue that is causing obstructive symptoms, in which case, a surgical consultation and review is appropriate.
• An infection such as Clostridioides difficile (which is increased and produces worse outcomes in people with IBD) or even COVID-19, which causes gastrointestinal symptoms in 50% of patients with severe disease.
• An undiagnosed coexisting condition such as celiac disease.
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Troubleshoot issues with prior authorization or reimbursement

Many insurers require a patient to fail on an aminosalicylate (5-ASA) drug before they will pay for a biologic agent, says Dr. Singh. He hopes that additional clinical trials and society guidelines will make the case for insurers to curb the requirement of “step-up” therapy for patients who can benefit from earlier use of biologics.

If you determine that a patient is a candidate for biologic therapy, choice of initial agent may be dictated by their insurance plan’s formulary. “We make decisions based on what’s best for the patient,” says Dr. Cushing. “But we have to work within the confines of what the insurance will cover.” Often, an insurer will mandate a specific TNF inhibitor as the first-choice biologic therapy. “However, more insurers are becoming open to alternative first-line therapies besides anti-TNFs,” notes Dr. Cushing.

Moreover, says Dr. Cushing, insurers can be receptive to appeals for prior authorization when a non-TNF inhibitor is the best choice for a patient. “For example, if you have a patient undergoing cancer treatment, you may want a more gut-selective therapy rather than a systemic immune suppressive due to the latter’s increased risk for infection,” she says. “In that case, we could go to the insurer and outline the reasons why we think a non-TNF inhibitor would be a better first-line approach.” Another tip: Take advantage of resources at the Crohn’s & Colitis Foundation website (crohnscolitisfoundation.org), which has customizable appeal letters for downloading as well as links to various programs for patients who need financial support to pay for IBD medications.

—by Timothy Gower

While gut symptoms are the hallmark of inflammatory bowel disease (IBD), up to 47% of patients with Crohn’s disease and ulcerative colitis develop extraintestinal manifestations (EIMs), which are related complications that affect other parts of the body. (In some surveys, patients say that EIMs are more bothersome than IBD itself.)^1,2 Meanwhile, the medications used to treat common comorbidities in patients with IBD may also cause problems.

The upshot: Early recognition and management of coexisting conditions are crucial for improving patient outcomes and quality of life. Here, experts discuss the most common complications of IBD and how to manage them.

JOINT PROBLEMS
“Joint pain is the most common extraintestinal manifestation of IBD,” says David T. Rubin, MD, codirector of the Digestive Diseases Center at the University of Chicago. About one third of patients experience joint pain and stiffness, with some research suggesting the figure is even higher, notes Dr. Rubin. Arthritis and arthralgia may affect both younger and older patients. The Crohn’s & Colitis Foundation (CCF) identifies three types of arthritis as commonly afflicting people with IBD:²

Peripheral arthritis, which typically affects joints in the limbs such as the knees, hips, elbows and shoulders, though the fingers may become symptomatic, too. Diagnosis is based on medical history, physical examination and exclusion of other potential causes of joint pain with lab tests and imaging. Severity of joint symptoms generally parallel those of the gastrointestinal tract. Fortunately, no joint destruction occurs and peripheral arthritis usually resolves when underlying IBD is effectively treated. “If you treat the bowel, the joints get better,” says Dr. Rubin. 

Axial arthritis, or spondylitis, which causes pain and stiffness in the lower spine and sacroiliac joints. Symptoms may arise months or years before a patient reports IBD symptoms. “These large joints in your lower back and pelvis can be inflamed independently of IBD disease activity,” says Dr. Rubin. “So you can fix the IBD, but the problems with the large joints will still progress.” Left untreated, inflammation can produce permanent joint damage and vertebral fusion that limits range of motion. Therefore, it’s crucial to coordinate care with a rheumatologist.

Ankylosing spondylitis (AS) is a less common but more severe form of spinal arthritis that’s diagnosed in a small portion (2% to 3%) of IBD patients. AS typically afflicts younger patients, especially males, and those with Crohn’s disease are more at risk than those with ulcerative colitis. As with axial arthritis, successful treatment of IBD will not alter the course of AS. Damage to joints in the lower spine and sacroiliac joints can dramatically limit range of motion. Again, the key to minimizing damage is coordinated care with a rheumatologist.

Other forms of arthritis should also be considered. For example, some studies have suggested that IBD patients have an increased risk for rheumatoid arthritis, yet overall findings have been inconsistent.³

SKIN DISORDERS
Skin disturbances are the second most common EIM of IBD. They include:

Erythema nodosum, which occurs more commonly in Crohn’s disease, affecting about 6% of patients and producing nodules that are painful and tender.⁴ Skin symptoms parallel bowel symptoms, but erythema nodosum “responds well when the bowel is treated,” says Dr. Rubin.

Pyoderma gangrenosum is less common, but produces severe, painful ulcers, often on the legs. Patients with ulcerative colitis have a greater risk for these skin manifestations, which occur independently of disease activity in the bowel. Topical corticosteroids and tacrolimus ointments may be useful, but many patients require oral corticosteroids. Ciclosporin may be added or used as an alternative.⁵

Psoriasis. People with Crohn’s disease and ulcerative colitis are 59% to 65% more likely to develop psoriasis.⁶ The skin changes of psoriasis are unrelated to disease activity in the gut. Psoriasis is associated with comorbidities such as obesity and habits such as smoking, but the increased prevalence is also linked to therapy.

While TNF inhibitors are commonly prescribed for management of psoriasis, in some cases the drugs can have the paradoxical effect of triggering the skin condition. One meta-analysis found that 5.6% of IBD patients treated with a TNF inhibitor developed psoriasis or psoriasiform rashes.⁷ In the event a TNF inhibitor is suspected of triggering psoriasis, consider consulting with a dermatologist to determine if topical therapy is sufficient to control psoriasis activity, says Kelly Colleen Cushing, MD, a gastroenterologist at the Brighton Center for Specialty Care in Michigan. “In cases where topical therapy is not sufficient, the anti-TNF therapy is often discontinued and a new class of therapy is started,” notes Dr. Cushing.

BONE DISEASE
Between 30% and 60% of IBD patients have lower-than-average bone density, according to the CCF, leaving them vulnerable to osteoporosis and related skeletal disorders and their sequelae. For example, people with IBD are 40% more likely than age- and sex-matched control subjects to suffer bone fractures.⁶

Baseline bone density testing is recommended for patients who have suffered a previous fragility-related fracture, postmenopausal women, males over 50 years, hypogonadal males and any IBD patient with more than 3 months of corticosteroid therapy.⁸

In addition, several steps can reduce patients’ risk for bone disorders. First, it’s important to optimize IBD therapy, as chronic inflammation disturbs healthy bone metabolism. However, limit corticosteroids, as the increased threat of osteoporosis and bone fractures is largely linked to long-term use of the drugs. “It’s one of many reasons why we want to limit excessive steroid exposure,” says Dr. Cushing. Also, consider nutritional supplements such as calcium and vitamin D, particularly for patients who have undergone surgery to remove portions of the small bowel and who may not adequately absorb bone-building nutrients. Patients with inadequate dietary intake may benefit from supplementation.

LIVER DISEASE
Having IBD increases the risk for several diseases of the liver, with the most prevalent and worrisome being primary sclerosing cholangitis (PSC), or inflammation of the bile ducts.² In a Canadian population-based study of IBD patients, PSC occurred most often in males with ulcerative colitis (3%).⁶ “Inflammation of the bile ducts in PSC occurs independently of IBD disease activity in the gut,” explains Dr. Cushing, and disturbs the normal flow of bile. Early symptoms are itching and jaundice, which can progress to fatigue. Complications include infection, cirrhosis, colon cancer and cancer of the bile duct (cholangiocarcinoma). “PSC requires continuous monitoring and collaboration with our colleagues in hepatology,” says Dr. Cushing.

EYE DISORDERS
Uveitis, or inflammation of the uvea (the middle layer of the eye) and associated tissues, affects about 10% of IBD patients, according to the CCF. Symptoms include redness, pain and sensitivity to light. The patient may also complain of blurred vision and headaches. Untreated uveitis can result in glaucoma and vision loss, so refer a patient with this eye condition to an ophthalmologist.⁹

Unchecked inflammation may also cause episcleritis, which affects the outer coating of the white of the eye, causing redness and pain. However, episcleritis is usually self-limiting and often clears up when gut symptoms are adequately treated.²

CANCER
IBD and its treatment are linked to an increased risk for certain cancers, including:

Colorectal cancer, which is a significant cause of death in IBD patients, accounting for 10% to 15% of mortality,¹⁰ though rates appear to be declining, notes Dr. Rubin. “We know that colon cancer risk is reduced because our prevention strategies and our therapies are working,” he says. Unchecked inflammation in the intestinal tract is the likely explanation for the heightened risk for colorectal cancer in IBD. The American Cancer Society recommends that an IBD patient undergo a colonoscopy within 8 years of diagnosis and suggests follow-up colonoscopies every 1 to 3 years, depending on the initial findings and the patient’s other risk factors.^11,12

Lymphoma. IBD patients as a group have a modestly increased risk for lymphoma. “That has been predominantly driven by one of our older therapies, the thiopurines,” says Dr. Rubin. (TNF inhibitors carry a warning about reports of lymphoma and other malignancies in patients treated with the medications, which primarily occurred in adolescents and young males who received combination therapy with azathioprine or 6-mercaptopurine.) If a patient is a candidate for combination therapy, discuss the risks and benefits of thiopurines.

Skin cancer. Patients with IBD have a four- to seven-fold increased risk for skin cancer, primarily basal cell carcinoma.¹³ The American College of Gastroenterology (ACG) calls for IBD patients receiving immunosuppression to wear sunscreen and sun-protective clothing when outdoors and to undergo evaluation by a dermatologist, with subsequent surveillance determined on a case-by-case basis.¹⁴

Cervical cancer. While data regarding an increased risk for cervical cancer in women with IBD are conflicting, there is consistent evidence linking chronic immunosuppression to the malignancy. Therefore, the ACG recommends annual cervical cancer screening for women with IBD who are on immunosuppressive therapy. ¹⁴  

CARDIOVASCULAR DISEASE
People with IBD have an increased risk for cardiovascular disease (CVD).¹⁵ What’s more, the prevalence of venous thromboembolism (VTE) is at least three times higher among IBD patients than in the general population, with the risk significantly increased during hospitalization, surgery and periods of high disease activity.¹⁶ (In 2019, The Food and Drug Administration required the makers of tofacitinib to caution users about an increased risk of pulmonary thromboembolism and death with a dosage of 10 mg twice daily.¹⁷) The presence of some forms of CVD may influence choice of therapy. “For example, we avoid prescribing anti-TNF medication in patients with significant heart failure, out of concern that it could make their condition worse,” says Dr. Cushing.

DEPRESSION AND ANXIETY
A study of 19,011 adults with IBD found that 17.5% of patients with Crohn’s disease and 14.2% of patients with ulcerative colitis had depressive disorder, which are both modestly higher than rates among matched controls. Patients with Crohn’s disease had a slightly increased rate of anxiety versus matched controls.¹⁸ The ACG clinical guidelines on management of ulcerative colitis and Crohn’s disease note that stress, depression and anxiety can contribute to poor adherence to provider recommendations and decreased health-related quality of life. Patients with IBD should be screened for these coexistent mental health conditions and, when appropriate, referred to a mental health professional and other resources such as an IBD support group (visit crohnscolitisfoundation.org).^11,19

FATIGUE
Two thirds of patients with IBD report fatigue, according to a study in Inflammatory Bowel Disease.²⁰ The authors identified sleep disturbances, disease activity and depression and anxiety as the strongest predictors of persistent fatigue among 2,429 patients with Crohn’s disease or ulcerative colitis followed over a 6-month period. Referral to a sleep specialist, psychological counseling and regular exercise may provide some relief, though sufficient data are lacking. And while findings are inconsistent, some evidence suggests that curbing inflammation may help improve fatigue: One study found that patients who were started on a biologic and achieved clinical remission were less likely to have persistent fatigue after 1 year of treatment.²¹

—by Timothy Gower

Special thanks to our medical reviewer:

Julius M. Wilder, MD, PhD, Assistant Professor of Medicine at Duke University School of Medicine and chair of its Diversity, Equity, Inclusion, and Antiracism committee

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