Diagnosing and managing IBD

The aetiology of IBD is not fully understood, although as with most diseases, there is both an environmental and genetic component

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract (GIT) that usually start in adolescence and adulthood.¹ IBD is split into two categories: Crohn’s disease (CD) and ulcerative colitis (UC). IBD is a debilitating, complex disorder that is caused by multiple factors, including psychological distress, autonomic dysfunction, gut microbiome dysbiosis, genetic predisposition, and immune modulations linked to disease activity.

The aetiology of the disease is not fully understood, although as with most diseases, there is both an environmental and genetic component. In general, there is an immune response in the mucosa that is too easily triggered, and lasts longer than usual.

Genetic studies have shown that there is a 30-fold higher risk of developing IBD if a sibling has it, compared to the general population. Genome-wide association studies (GWAS) have helped identify hundreds of genetic variants that are present in CD and UC.¹ Many of these are associated with genes involved in immune stimulation, or mucosal barrier function. Evidence suggests inverse associations between risk of IBD and determinants for more diverse gut microbiomes in early life, ie, early exposure, pets, larger family size, greater number of siblings, and breastfeeding. There is altered gut microbiota in IBD, but it is still uncertain as to whether this is a cause or a consequence of the disease.

Microfilms formed by bacteria in healthy guts give protection to the intestinal lining: This is often not present to the same extent in IBD. There is also a strong association between diet and disease. Smoking is linked with more severe disease in CD, yet with UC, smoking cessation commonly causes disease relapse. Stress and its effect on the immune system are of relevance to IBD, as in other chronic and complex inflammatory disorders.

In IBD, there is an increased production of pro-inflammatory cytokines (such as TNF alpha, IL-6, IFN-Ɣ). Epithelial barrier damage from this inflammation can lead to increased intestinal permeability and the influx of intestinal lumen microbes and antigens into the underlying layer, worsening symptoms.

Common IBD symptoms caused by intestinal damage that results from the exaggerated inflammatory response include:¹ Diarrhoea, rectal bleeding, intermittent nausea and vomiting, and abdominal pain and tenderness. Complications such as anaemia, malnutrition, obstruction, fistulae, infection, and increased colon cancer risk are associated with IBD. The disease can also have extra-intestinal manifestations such as joint problems, skin conditions, chronic liver disease, and eye conditions (ie, uveitis).

Any chronic disease, including IBD, is associated with a greater burden of psychological distress, depression, anxiety, and altered quality-of-life. These psychiatric comorbidities are more pronounced during active disease, however, there is also evidence to suggest that they can contribute to relapse even in times of remission.

UC occurs when chronic inflammation occurs in the large intestine (the innermost layer of the colon and rectum) with abnormal immune system activation,^1,2 UC can develop at any age, but the peak incidence is between 15-and-25 years of age with a second, smaller peak between 55-and-65 years.³

CD has a variable age of onset and disease location, affecting any part of the GIT from the mouth to the anus, and across all layers of the bowel wall. The lower small intestine (ileum) and colon are most commonly affected.^1,2

Diagnosis and management

There is no treatment for the cause of IBD: Clinical management focuses on treating symptoms – keeping patients in remission, primarily aiming to reduce inflammation levels if symptoms reoccur, and also aiming to prolong the time spent in remission and mucosal healing periods.¹ As many as 85 per cent of patients with IBD do not ingest/absorb adequate nutrition. IBD patients should be encouraged to eat a varied diet that meets their energy, macro, and micronutrient requirements. Supplementation with enteral or parenteral nutrition may be required to achieve this.

Other modifiable factors should be considered, like sleep pattern, side-effects from medication, anaemia, iron deficiency, electrolyte disturbance, thyroid dysfunction, vitamin D and B12 deficiency, and psychological symptoms.² IBD patients with disabling fatigue should be investigated for subclinical disease activity.

Non-pharmacological therapies such as supportive psychotherapy, stress management or graded exercise, may be useful. Patients with functional bowel symptoms only, ie, in remission or with mildly active disease, might find dietary advice, as for irritable bowel syndrome (IBS), useful (ie, low FODMAP diet).

In 2021, the British Society of Gastroenterology (BSG) Clinical Services and Standards Committee (CSSC) published updated guidelines for the management of IBD in adults. Pharmacological treatment recommendations here are taken both from this² and the UK’s National Institute for Health and Care Excellence (NICE) guidelines, which were most recently updated in 2019.^3,7

For mild-to-moderate UC,^2,3 management with oral mesalamine/5-aminosalicylic acid (5-ASA), 2-3g daily is recommended. In flare-ups, dose escalation of 4-4, 8g daily orally and the use of 5-ASA enemas can improve symptoms. All UC patients should be offered a combination of oral and enema 5-ASA, as oral and topical therapy of 5-ASA can be superior to oral alone; however, there may be practical difficulty for the patient in administering and retaining the enema.² In mild-to-moderate UC where 5-ASA induction therapy fails, oral prednisolone should be used. This is superior to 5-ASA for induction of remission, but due to significant side-effects should not be recommended as the first-line. When a course of corticosteroids is used to treat the disease in any case, a time-limited course of four-to-eight weeks (depending on the steroid) is advised. Topically-acting oral steroids like budesonide multi-matrix formulations, ie, Cortiment, which releases budesonide at a controlled rate throughout the colon, can be used if systemic corticosteroids are not acceptable. Budesonide has a lower rate of systemic adverse effects than conventional corticosteroids (33 per cent vs 55 per cent), and is not associated with adrenal suppression or a significant reduction in bone mineral density.

For severe UC, treatment with prednisolone 40mg daily is recommended, weaning over six-to-eight weeks.² The optimal dose regimen is still unclear, but 40mg is more effective than 20mg daily, and there is no evidence to show benefit with doses higher than 40-to-60mg daily.

Single daily dosing is just as effective as split dosing. About half of patients experience short-term adverse drug reactions (ADRs) such as acne, oedema, sleep, and mood disturbance, glucose intolerance, and dyspepsia.² If there is no response within two weeks, escalation to biologics for treatment, or hospital admission, may be necessary.

In proctitis specifically, topical 5-ASA first-line is recommended, ie, a 1g 5-ASA suppository, with the addition of an oral 5-ASA if necessary.^2,3 The suppository, which delivers the drug to the rectum directly, is more effective in this case than a topical steroid. As with oral 5-ASA, once-daily administration should be sufficient, as studies showed no difference in efficacy between a 1g suppository once-daily compared to a 500mg one-to-three times daily. Using a suppository at bedtime is probably the most practical approach, and it allows the suppository to be retained for the longest possible time.

For patients who respond well to 5-ASA suppositories, maintenance treatment is not required. For patients who do require maintenance proctitis treatment, using a suppository every two or three nights does not seem to significantly reduce the maintenance of remission. UC patients who do not respond or are intolerant to 5-ASA suppositories and oral 5-ASA may be switched to corticosteroid suppositories.² Any UC patients on 5-ASA who need multiple corticosteroid courses per year require treatment escalation with a thiopurine (ie, azathioprine, mercaptopurine).

The main way in which the NICE and BSG guidelines differ for UC treatment is about when it is appropriate to start treatment with biological agents in IBD. NICE⁴ recommends the anti-TNF drugs infliximab, adalimumab or golimumab for treatment of moderate-to-severe UC only where disease has not responded to conventional treatment, or where these are unsuitable.

Vedolizumab is recommended for treating moderately-to-severely active UC.⁵

Tofacitinib is recommended as an option when conventional therapy or a biological agent cannot be tolerated, but is also an option for when response to treatment has been lost.⁶ It is a small molecule, taken orally, which gives it the advantage of less immunogenicity and loss of response over time compared with biological agents.

Whereas NICE guidelines advise use of biologics mainly after conventional treatment is unsuitable, BSG guidelines say that due to the increasing range of biologics with less toxicity than thiopurines, there is strong justification for moving directly to these agents.² Network meta-analyses comparing efficacy of anti-TNF drugs show similar levels of efficacy.

The choice of immunosuppressive therapy depends on a few factors:

• Route of administration.

• Speed of response to induction therapy (need for bridging therapy).

• Potential immunogenicity/need for combination therapy.

• Side-effects.

• Availability of infusion facilities and therapeutic drug monitoring.

Methotrexate is not suitable for maintaining remission in UC: A Cochrane review found it to be no better than placebo.

Colectomy is a treatment option if symptoms are inadequately controlled or if the patient has a poor quality-of-life on conventional therapy.³

Crohn’s disease therapies

Mild-to-moderate ileocaecal CD can be treated with ileal-release budesonide 9mg once daily for eight weeks to induce remission.² One 9mg dose is as effective as 3mg three times daily. This has been found to be as effective as oral prednisolone (40mg daily tapering to 5mg at eight weeks) with fewer side-effects.

Moderate-to-severely active uncomplicated CD should be treated initially with systemic corticosteroids, with patients showing extensive disease being considered for biological therapy.

Active Crohn’s colitis can be treated with an eight-week course of systemic corticosteroids, first-line, to induce remission.

For patients with moderate-to-severe CD responding to prednisolone, BSG guidelines advise early introduction of maintenance therapy with thiopurines or methotrexate to minimise risk of flare as prednisolone is withdrawn, which is common.² Once prednisolone is stopped, azathioprine or mercaptopurine are suitable for monotherapy in the maintenance of remission. Methotrexate may also be used for the maintenance of remission of CD. The BSG-recommended dose is at least 15mg weekly.

Subcutaneous administration has better bioavailability than oral, particularly at doses above 15mg weekly. Methotrexate should be given with folic acid to reduce gastrointestinal and liver toxicity, 5mg weekly (traditionally one-to-two days after the methotrexate dose).

For patients first presenting or with a single exacerbation of CD in one year, NICE guidance⁷ advises monotherapy with a glucocorticosteroid to induce remission. Budesonide can be used if this is not suitable, but it may be less effective, even though it has fewer side-effects. ASA treatment is a third option, but is not as effective as the steroidal options. If there are two or more exacerbations per year, NICE recommends azathioprine or mercaptopurine as an add-on treatment to steroid options to induce remission.

Patients refractory to conventional therapy should be considered for biological therapy.² Infliximab and adalimumab are options for adults with severe active CD who haven’t responded to immunosuppressive/corticosteroid treatments.⁷ NICE guidelines advise informing the person that there is uncertainty around the efficacy and long-term ADRs of monotherapy with infliximab/adalimumab vs combination therapy with an immunosuppressant. However, the more recent BSG guidelines state that combination therapy of infliximab with a thiopurine should be used in preference to infliximab monotherapy, because this has been shown to be more effective than monotherapy infliximab in CD.² Immunomodulator use also reduces the risk of immunogenicity. Although there is evidence that there are clinical benefits of combination therapy with an immunomodulator in the case of adalimumab, the importance of this is not as strong in studies of adalimumab as it is for infliximab.

Ustekinumab is an option for treating moderately-to-severely active CD for adults who have not responded, or lost response to, a TNF alpha inhibitor.⁸ Vedolizumab is an option for treating moderately-to-severely active CD if a TNF alpha inhibitor has failed or cannot be tolerated.⁹

Mild oesophageal or gastroduodenal CD may be treated with PPIs. For moderate or severe disease, treatment with corticosteroids may also be required, and other immunosuppressive or biological therapies, as for CD elsewhere in the gut.

Surgery for the majority of patients with CD is not curative, with high rates of disease recurrence by one year. People with CD who do not wish to be on maintenance treatment should be advised of the importance of not smoking, and to plan a follow-up promptly if they experience any exacerbations of symptoms. People who do opt for maintenance treatment can be offered azathioprine or mercaptopurine.

In patient surveys, it has been established that adherence can be an issue; therefore, once-daily dosing to simplify the dosing regimen should be considered where possible for each patient.

Colorectal cancer risk is related to inflammation, therefore mucosal healing should be the primary goal of colorectal cancer prevention, regardless of the treatment used. 5-ASA is a safe and effective long-term treatment, and while there is no clear evidence that continuing 5-ASA in particular reduces colorectal cancer risk, if subsequent assessment after stopping 5-ASA shows mucosal inflammation, 5-ASA should be restarted.

Monitoring on pharmacotherapy

Any IBD patients commencing immunomodulators or biologics treatment should undergo screening for hepatitis B (HBV), hepatitis C (HCV), and HIV, and varicella-zoster virus (VZV) if no history of chickenpox, shingles or varicella vaccination.² Live vaccines are contraindicated if the patient is on immunosuppression. These include BCG, oral influenza vaccine, MMR, polio, rotavirus, oral typhoid, VZV, and yellow fever. Annual influenza vaccination (injection) is recommended for all immunosuppressed patients.

5-ASA

Patients treated with 5-ASA should have renal function monitored at baseline, after two-to-three months, and then annually. Renal disease is not only linked with 5-ASA therapy, but can also be a complication of the disease itself.²

Corticosteroids

Patients receiving prolonged courses of corticosteroids should have a tapering course when stopping to avoid adrenal suppression. They should be warned about possible steroid withdrawal syndrome, which can present as weakness, fatigue, loss of appetite, weight loss, nausea and vomiting, diarrhoea and abdominal pain, and so can mimic the underlying disease. It is estimated to occur in about half of patients tested immediately after withdrawal of medium-/high-dose prednisolone used for long periods.²

Prolonged corticosteroid use should be minimised: They are effective to induce remission, but have no role in preventing relapse. All patients on corticosteroids for a disease flare should also take 800-to-1,000mg/day calcium and 800IU/day vitamin D. Factors that have a negative impact on bone mineral density should be addressed, ie, smoking, alcohol intake and the positive impact of muscle-building/weight-bearing exercise. Patients starting corticosteroids should be assessed for risk of osteoporosis. Those at high-risk should be started on bisphosphonate therapy.^2,8 Patients on prolonged courses should have blood pressure, glycaemic control, and serum potassium monitored.²

Thiopurines

BSG guidelines recommend that azathioprine and mercaptopurine should be started at the full dose, because there is no evidence that starting at low doses and then gradually increasing up to target improves safety or tolerance, and low-dose initiation may delay achieving the correct target dose.

IBD patients in prolonged remission on thiopurines, and who have mucosal healing, may stop the drug after discussion of risks and benefits and considering patient preference. Reintroduction if relapse occurs is usually successful.²

Before starting, the following are recommended:

• Baseline FBC, urea and electrolytes (U&E), and LFT measurement.

• If available, test NUDT¹⁵ genotype, as some genetic variants in NUDT¹⁵ are associated with thiopurine-related myelosuppression.

• Screen for HCV, HBV, HIV, refer if positive, consider HBV vaccination.

• Check VZV immunity and vaccinate if low.

• Vaccinate for influenza and pneumococcal vaccine.

• Check cervical screening is up-to-date (studies have found an increased risk of cervical dysplasia among women with IBD).

• Check thiopurine methyltransferase (TPMT, the enzyme that metabolises thiopurines) and start at target dose once the result is available. If very low: Avoid thiopurine.

• Monitoring: FBC, U&E, and LFT at least at weeks two, four, eight, and 12, and then at least three-monthly.

Methotrexate

Methotrexate has comparable safety to thiopurines. IBD patients initiating methotrexate therapy should have baseline FBC, U&E, and LFT measurement, with monitoring of these bloods at least at weeks two, four, eight, and 12, and then at least three-monthly, with monitoring for side-effects.² Risk of cirrhosis is much lower than previously thought. Due to teratogenic and embryotoxic effects of methotrexate, prior to conception, women should discontinue methotrexate for six months.

Immunomodulators or biologics

IBD patients receiving immunomodulators or biologics should have an annual review of treatment, including consideration of response and treatment continuation, optimisation or cessation. Pre-treatment screening and blood monitoring of therapy on vedolizumab and ustekinumab should at present follow recommendations for anti-TNF drugs due to insufficient long-term safety data at this time to recommend an alternative algorithm.

Treatment options for failure of initial anti-TNF therapy include increasing dose, shortening dosage interval, switching to alternative anti-TNF, or switching to a different drug class. Secondary loss of response to anti-TNF therapy can occur as a consequence of immune-mediated neutralising antibodies to the drug (although there are likely to be other mechanisms, including non-neutralising, drug-clearing antibodies, or non-immune-mediated mechanisms).²

UC can develop at any age, but the peak incidence
is between 15-and-25 years of age with
a second, smaller peak between 55-and-65 years

Treatments: Mechanism of action

5-ASA

5-ASA medicines interfere with the metabolism of arachidonic acid to prostaglandins and leukotrienes, scavenge reactive oxygen species, and effect leukocyte function and production of cytokines.¹⁰ Recent research has also shown that 5-ASA medicines may act by activating a class of nuclear receptors involved in the control of inflammation, cell proliferation, apoptosis, and metabolic function, the gamma form of peroxisome proliferator-activated receptors.¹¹ These receptors are expressed at high levels in colon epithelial cells, and regulated at least in part stimulated by gut bacteria.

Thiopurines

Azathioprine is a product of 6-mercaptopurine that is metabolised in the liver and gut. Both drugs are slow acting, which is why they are not suitable choices for induction of remission. The mode of action of these drugs includes inhibition of several pathways in nucleic acid biosynthesis. This prevents proliferation of cells involved in the determination and amplification of the immune response,¹² ie, damaging DNA is through the incorporation of thiopurine analogues.

Methotrexate

Methotrexate is a competitive antagonist of folic acid, which has a cytotoxic and antiproliferative effect due to inhibition of dihydrofolate reductase. This blocks DNA and RNA synthesis.¹³

Corticosteroids

Prednisolone decreases inflammation by suppressing leukocyte migration and reversing increased capillary permeability. After attachment to cellular glucocorticoid receptors, prednisolone enters the nucleus, binds, and activates specific nuclear receptors, resulting in altered gene expression and inhibition of pro-inflammatory cytokine production.¹⁴

TNF alpha inhibitors

Adalimumab, golimumab, and infliximab are monoclonal antibodies that inhibit the pro-inflammatory cytokine, TNF alpha.⁴

Integrin receptor antagonists

Vedolizumab is a humanised monoclonal antibody. It targets α4β7 integrin, which is expressed in certain white blood cells that are found in the gut.⁵ α4β7 integrin is responsible for recruiting these inflammatory cells to inflamed bowel tissue. Vedolizumab, therefore, specifically targets the gut.

Janus kinase inhibitors

Tofacitinib is a selective and specific inhibitor of pro-inflammatory receptor signalling: It inhibits the process of intracellular signalling from the receptor to the cellular nucleus and inhibits the inflammation process via a new pathway, inhibition of the Janus kinases (JAK).⁶

Cytokine inhibitors

Ustekinumab is a human monoclonal antibody that acts as a cytokine inhibitor by targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), which activate certain T-cells in the inflammatory cascade.⁸