Treating IBD

Anti-integrins (biological therapy)

Integrins are a family of cell-surface dimers comprising a single α chain combined with a single β chain³⁰. Integrins play an important role in cellular trafficking, making them an attractive therapeutic target in IBD³⁰.

Anti-lymphocyte trafficking

The process of lymphocyte adhesion and extravasation involves multiple steps including tethering, rolling, activation and adhesion which culminate in the migration of lymphocytes into the intestinal mucosa (Figure 1). This process is facilitated by the formation of low-affinity bonds between integrins located on the surface of lymphocytes and cellular adhesion molecules (CAMs), natural integrin ligands that are expressed on the surface of vascular endothelial cells³¹.

Figure 1. Lymphocyte adhesion and extravasation (Adapted³²). CCL19/21, C-C-chemokine ligand; CCR7, C-C-chemokine receptor; GALT, gut-associated lymphoid tissue; HEV, high endothelial venule; MAdCAM-1, mucosal addressin cell adhesion molecule-1.

The following adhesion molecules all play a role in integrin-dependent homing to the gut³²:

• Intercellular adhesion molecule (ICAM)-1
• Vascular cell adhesion molecule (VCAM)-1
• Mucosal addressin cell adhesion molecule (MAdCAM)-1

ICAM-1 and VCAM-1 are expressed in venules throughout the body, whereas MAdCAM-1 expression is thought to be largely limited to the gut³².

There is growing interest in the development of therapeutic agents that disrupt the interaction between integrins and their ligands and prevent the recruitment of lymphocytes to sites of inflammation in patients with IBD³³.

Natalizumab

Natalizumab is a humanised monoclonal IgG4 antibody that binds with high affinity to α₄-integrins^34,35. The safety and efficacy of natalizumab for the treatment of patients with moderately to severely active Crohn’s disease was investigated in three large phase III clinical trials: ENACT-1, ENACT-2 and ENCORE (Table 1)^36–39.

Table 1. Summary of the results of key clinical trials of natalizumab for the treatment of Crohn’s disease (Adapted^36,37). CDAI, Crohn’s Disease Activity Index.

Though these studies clearly demonstrated the clinical efficacy of natalizumab, they also revealed an association with increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection, caused by the John Cunningham virus, which destroys CNS oligodendrocytes and can lead to severe disability or death^33,36,37,40. This is because natalizumab binds the α4 integrin subunit. As a result, not only does it block the interaction between α4β7 and MAdCAM-1 in the gut, but also that of α4β1 and VCAM-1, which mediates lymphocyte trafficking in the central nervous system (CNS)³³. For this reason, natalizumab is only approved for the treatment of Crohn’s disease in the US and Switzerland, where its use is tightly regulated³¹.

Like natalizumab, some other biological agents, such as TNFα inhibitors are non-selective and are therefore associated with a range of safety issues⁴¹. Potential emerging therapies that address the need for selectivity include etrolizumab, which selectively targets the β7 subunit and PF-00547659 which selectively inhibits MAdCAM-1⁴¹.

Vedolizumab

Vedolizumab is a humanised immunoglobulin (Ig) G1 monoclonal antibody⁴². In contrast to natalizumab, vedolizumab preferentially targets the gut-specific α4β7 integrin, blocking its interaction with MAdCAM-1 on the endothelial cells in the gastrointestinal (GI) tract^42,43. As a result, vedolizumab is not currently thought to be associated with an increased risk of PML (Figure 2)⁴³.

Figure 2. Anti-integrins mechanisms of action. Natalizumab targets both α4β7 and α4β1 integrins, while vedolizumab is gut selective, targeting α4β7 only (Adapted^44,45). MAdCAM-1, mucosal addressin cell adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1.

The GEMINI clinical trial programme was designed to investigate the safety and efficacy of vedolizumab in patients with IBD^46–48. The results of GEMINI-I demonstrated superiority of vedolizumab over placebo with respect to all primary and secondary outcomes in patients with moderately-to-severely active ulcerative colitis. At 6 weeks, the results showed a statistically significant difference in the primary endpoint of clinical response rates (47.1% vs. 25.5%, p<0.001) between the vedolizumab and placebo groups in cohort 1 (clinical response was defined as total Mayo score reduced by ≥3 points and by ≥30% from baseline, with rectal bleeding subscale either decreased by ≥1 or absolute score 0 or 1)⁴⁶. After 6 weeks, patients who achieved a clinical response in either of the two cohorts were enrolled in the maintenance trial⁴⁶. These patients received placebo or vedolizumab at 4- or 8-week intervals until Week 52⁴⁶. Rates of clinical remission were higher among those receiving vedolizumab compared to placebo (Q8W 41.8%, p<0.001; Q4W 44.8%, p<0.001; placebo 15.9%), as were steroid-free remission rates (Q8W 31.4, p=0.01; Q4W 45.2%, p<0.001; placebo 13.9%)⁴⁶.

GEMINI II and III included patients with moderately-to-severely active Crohn’s disease, and reported less favourable outcomes in terms of clinical remission at Week 6 than in GEMINI-I^46–48. However, interestingly the therapeutic benefits of vedolizumab were detectable in a proportion of patients at Week 10, suggesting that for patients with Crohn’s disease, particularly those who have previously been exposed to anti-TNFs, vedolizumab’s mode of onset of action may be slower^31,48. Concomitant treatment with faster acting agents, such as steroids, may improve the response and remission rates of these patients^31,48.

The results of GEMINI, which are summarised in Figure 3, led to the approval of vedolizumab for the treatment of adults with moderately to severely active disease.

Figure 3. Summary of phase III GEMINI clinical trials of vedolizumab in patients with moderately to severely active ulcerative colitis (GEMINI-I) and Crohn’s disease (GEMINI II and III) (Adapted^46–48). CDAI Crohn’s disease activity index; CS, corticosteroid.

The most common adverse reactions associated with vedolizumab use include nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritis, sinusitis, oropharyngeal pain, and pain in extremities⁴⁹.

Pooled safety data from six clinical trials do not indicate an association between vedolizumab and increased risk of developing malignancy or serious opportunistic infection. In addition, no cases of PML were reported among the 2,830 patients included in these trials (Figure 4)⁵⁰.

Figure 4. Exposure-adjusted incidence rates of adverse events were lower with vedolizumab compared to placebo. Prolonged exposure to vedolizumab did not increase the frequency of adverse events or serious adverse events, including gastrointestinal serious adverse events or serious infections. GI, gastrointestinal; NEC, not elsewhere classified (Adapted⁵⁰).

Results from the GEMINI 5-year open-label extension study were consistent with these findings, providing further evidence of vedolizumab’s favourable safety profile⁵¹.

The VARSITY trial was a head-to-head study which, for the first time, provided direct comparative data on the superiority of the gut selective biologic vedolizumab and the anti-TNF biologic adalimumab in moderately to severely active ulcerative colitis⁵². 

Sphingosine-1-phosphate (small molecule therapy)

Sphingosine-1-phosphate (S1P) binds to five sub-types of the G-protein-coupled receptor S1P_1–5 . S1P receptors play a role in mediating angiogenesis, vascular tone and permeability, as well as lymphocyte trafficking⁵³.

Therefore, like the monoclonal antibodies vedolizumab and natalizumab, S1P receptor 1 agonists interfere with lymphocyte trafficking. When S1P binds to S1P₁ on lymphocytes in lymph nodes, the lymphocytes are released from the lymph nodes and migrate to inflammatory sites, where they can contribute to immune-mediated pathology^54,55.

When S1P receptor 1 agonists bind the S1P receptor, the receptor is internalised and degraded, and as a result the lymphocytes can no longer leave lymph nodes⁵³.

Anti-cytokines

Anti-p40

The cytokines interleukin (IL)-12 and IL-23 are heterodimeric proteins containing two subunits: the p40 subunit is common to both cytokines while the p35 and p19 subunits are present in IL-12 and IL-23 respectively^54,56. IL-12 and IL-23 are both induced as part of the innate immune response in patients with IBD⁵⁷.

IL-12 and IL-23 can both produce pro-inflammatory responses via JAK signalling ; IL-23 may also act via the IL-17 and interferon gamma pathways^56,58. However, their main effect arises through their induction of T helper (Th) cells⁵⁶. IL-12 induces differentiation of Th1 cells and IL-23 induces differentiation of Th17 resulting in increased production of inflammatory cytokines (Figure 5)^54,56.

Figure 5. The interleukin (IL) 12/23 pathway (Adapted⁵⁹). IFN-γ, interferon-γ; IL, interleukin; JAK, Janus kinase; RORγt, retinoic acid-related orphan receptor gamma T; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor-β; TYK, tyrosine kinase.

Given the actions of IL-12 and IL-23, blocking the activity of these cytokines has emerged as a therapeutic option for patients with IBD^56–58.

The anti-IL-12/IL-23 p40 antibody, ustekinumab, was first approved for the treatment of Crohn’s disease in 2016, based on the results of the UNITI clinical trial programme⁶⁰. This included two phase III induction trials, UNITI-1 and UNITI-2, which both investigated an intravenous induction dose of 130 mg or approximately 6mg/kg body weight ustekinumab versus placebo⁶¹.

The primary endpoint in both induction trials was clinical response (≥ 100-point reduction in Crohn’s disease activity index [CDAI] or a total CDAI score of less than 150) at Week 6. In UNITI-1, response rates were significantly higher in patients receiving either 130 mg ustekinumab (34.3%) or 6mg/kg of bodyweight (33.7%) compared to placebo (21.5%) (p≤0.003 for both comparisons with placebo). In UNITI-2, response rates among patients receiving 130 mg ustekinumab, 6mg/kg of bodyweight and placebo were 51.7%, 55.5% and 28.7% respectively, at Week 6 (p<0.001 for both comparisons with placebo) (Figure 6). These patients responded rapidly to treatment and among responders, there was a notable decrease in faecal calprotectin levels⁶¹. 

Figure 6. Clinical response rates (≥ 100 reduction in Crohn’s disease activity index [CDAI] or a total CDAI score of less than 150) at Week 6 in the UNITI-1 and UNITI-2 induction trials (Adapted⁶¹).

Patients who responded to treatment with ustekinumab in UNITI-1 or UNITI-2 were then enrolled into the IM-UNITI maintenance trial, where they were randomised to receive subcutaneous 90 mg of ustekinumab at either 8- or 12-week intervals or placebo. The primary endpoint of clinical remission was defined as a CDAI score of <150 at Week 44. Remission was achieved in 35.9% of those who received placebo by comparison to 53.1% (p=0.005) of patients on 8-weekly ustekinumab and 48.8% (p=0.04) of those on 12-weekly ustekinumab. Most of these patients also achieved steroid-free remission⁶¹.

Rates of adverse events were similar in the ustekinumab and placebo groups. Rates of severe infection were similar across the three trials and serious adverse events were 9.9%, 12.1% and 15% in UNITI-1, UNITI-2 and IM-UNITI respectively⁶¹.

The results of these three trials, along with those of a long-term, open-label extension of UNITI, suggest that ustekinumab has a favourable safety profile, with similar rates of adverse events, including serious infections, in the ustekinumab and placebo groups^60,61.

More recently, the phase III UNIFI trial led to the approval of ustekinumab as induction and maintenance therapy for patients with moderately to severely active ulcerative colitis^62,63. In this study, it was found that at Week 8 rates of clinical remission were significantly higher in patients receiving ustekinumab at 130 mg (15.6%) or 6 mg/kg (15.5%) compared to placebo (5.3%) (p<0.001 for both)⁶². As in the UNITI clinical trial programme, patients who achieved a clinical response to ustekinumab were enrolled in a 44-week maintenance trial, where they were randomised to receive 90 mg subcutaneous ustekinumab at 8- or 12-week intervals, or placebo^61,62. Higher rates of clinical remission were observed in patients receiving ustekinumab every 12 weeks (38.4%) and every 8 weeks (43.8%) compared to the placebo group (24%) (p=0.002 and p<0.001 respectively)⁶². The incidence of serious adverse events was comparable across the three groups⁶².

Anti-TNFs

TNFα is one of the main pro-inflammatory cytokines in IBD, with a key role in pathogenesis and blocking its activity is a well-established therapeutic approach^58,64,65. Indeed, for many years anti-TNF agents were the only biologic agents approved for the treatment of IBD and are still widely considered a mainstay of treatment for moderate-to-severe Crohn’s disease and ulcerative colitis³¹. The first anti-TNF antibody, infliximab, became available for the treatment of IBD in the late 1990s³¹. Today, there are a range of different anti-TNF agents on the market, including adalimumab, certolizumab pegol and golimumab (Table 2)³¹.

Table 2. Summary of anti-TNF inhibitors available for the treatment of inflammatory bowel diseases (Adapted⁶⁶) CD, Crohn’s disease; TNF, tumour necrosis factor; UC, ulcerative colitis.

The efficacy of anti-TNF agents in the induction and maintenance of inflammatory bowel diseases has been consistent across numerous clinical trials³¹. In addition to helping patients achieve mucosal healing and providing symptomatic relief, these drugs are also associated with reduced hospital admissions and improvements in patient quality of life³¹.

However, despite the success of these agents, around 30% of patients do not respond to initial treatment (primary responders) with anti-TNFs⁶⁷. Furthermore, 40% of patients who respond initially ultimately lose response (secondary responders) to anti-TNF therapy⁶⁷. These drugs are also associated with a range of serious, albeit uncommon, adverse effects including increased risk of infection, immune reactions and certain cancers^67,68.

JAK inhibitors

The Janus kinase (JAK) enzymes (JAK1, JAK2, JAK3 and TYK2) are a family of tyrosine kinases that, together with signal transducers and activators of transcription (STAT), make up the JAK/STAT pathway⁶⁹. Activation of the JAK/STAT pathway is involved in the signalling of more than 50 different cytokines, including those relevant to IBD pathogenesis, such as IFN-γ, IL-2, IL-6, IL-12 and IL-23^69,70. This has made inhibition of JAK pathways an attractive therapeutic target in IBD.

The pan-JAK inhibitor, tofacitinib, is the first oral medication to receive approval for the treatment of moderate-to-severe ulcerative colitis^71,72. Though tofacitinib inhibits all JAK pathways relevant to the pathogenesis of IBD, it is a particularly potent inhibitor of JAK1 and JAK3^73,74.

The efficacy of tofacitinib for the treatment of moderately to severely active ulcerative colitis was established in the OCTAVE clinical trial programme, which consisted of three phase III, randomised, double-blind, placebo-controlled trials⁷⁴. The induction trials, OCTAVE 1 and 2, both reported significantly higher remission rates in the tofacitinib groups compared to placebo⁷⁴. Patients who responded to tofacitinib in the induction trials were then enrolled in a 52-week maintenance trial, OCTAVE Sustain⁷⁴. These patients were assigned to receive tofacitinib at 5 mg or 10 mg twice daily or a placebo. Rates of remission were significantly higher in both tofacitinib groups compared with placebo (Table 3)⁷⁴.

Table 3. Summary of the OCTAVE clinical trial programme investigating tofacitinib for the treatment of moderate-to-severe ulcerative colitis (Adapted⁷⁴).

Though the results of these studies suggest that tofacitinib is effective for the induction and maintenance of remission in patients with moderately to severely active ulcerative colitis, tofacitinib has proved less successful in the treatment of Crohn’s disease and is not approved for patients with this condition^74–76. Tofacitinib is associated with some safety issues and has an FDA black box warning for pulmonary embolism and mortality and is used only in patients who have previously failed to respond to treatment with biologics or immunosuppressants^77,78.

Other JAK inhibitors currently under investigation for the treatment of IBD include filgotinib and upadacitinib and TD-1473^79–83.

Surgery

Ulcerative colitis

Surgery can be curative in patients with ulcerative colitis⁸⁴.

Despite the growing number of pharmacological treatments available to patients with ulcerative colitis, surgery remains necessary in a significant proportion of cases⁸⁵. This can be as a result of an inadequate response to long-term pharmacological treatment, emergencies such as serious acute symptoms and toxic megacolon, or cancer of the large bowel⁸⁶.

The most common surgical procedure carried out in patients with ulcerative colitis is proctocolectomy with ileal pouch-anal anastomosis (IPAA)⁸⁷. This involves complete removal of the colon and rectum, followed by the creation of an ileal pouch which is anastomosed to the anal canal⁸⁸. The pouch is most commonly J-shaped but may also be shaped like an S or W⁸⁸. Proctocolectomy with IPAA is widely preferred over other surgical options because it preserves bowel function with no need for a permanent stoma⁸⁹.

Complications that may arise in patients who have undergone IPAA include acute or chronic pouchitis, ileoanal separation, anal stricture, pelvic sepsis, and small bowel obstruction⁹⁰.

A total proctocolectomy with end ileostomy may be performed in patients for who IPAA is unsuitable⁹¹. This procedure involves the removal of colon, rectum, anal canal and anus⁹². Complications of ileostomy include high ileal effluent output leading to dehydration and loss of electrolytes, while complications of stoma include skin problems, retraction, stenosis and peristomal infections⁹³.

Crohn’s disease

Almost half of all patients with Crohn’s disease will require surgery within 10 years of initial diagnosis⁹⁴. This is often as a result of various complications associated with Crohn’s disease such as stenosis, abscesses, fistulae and perforation⁹⁵. Stenotic sections of bowel are removed along with any fistulae that are present^96,97. Unfortunately, unlike in ulcerative colitis, surgery for Crohn’s disease is not considered curative and recurrence of stenoses commonly occurs at the anastomotic site of the previous bowel resection, necessitating further surgery^96,98.

Almost half of all patients with Crohn’s disease require surgery after 10 years⁹⁴.

Common surgical procedures for patients with Crohn’s disease include⁹⁹:

• Stricturoplasty
• Bowel resection
• Proctocolectomy
• Colectomy

Guidelines

Various evidence-based guidelines have been developed to support clinical decision making in IBD. Below is a selection of key guidelines published by the American Gastroenterological Association (AGA) and the European Crohn’s and Colitis Organisation (ECCO).

American Gastroenterological Association (AGA)

AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis

Though 5-aminoalisylates are the most common treatment option for the induction and maintenance of remission in patients with mild-to-moderate ulcerative colitis, some may require immunomodulation or biologic therapy to achieve adequate control over their disease. This guideline highlights the importance of identifying patients who may benefit from earlier treatment escalation and the need for further optimisation of dosing regimens¹⁰⁰.

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AGA Clinical Practice Guidelines on the Management of Moderate-to-Severe Ulcerative Colitis

Published in 2020, this clinical guideline comprises 11 evidence-based recommendations for the management of adult outpatients with moderate-to-severe ulcerative colitis (Table 4) and those hospitalised with acute severe ulcerative colitis (ASUC). In particular, the guideline focuses on the roles of immunomodulators, biologics and small molecule therapies in the induction and maintenance of remission and reducing risk of surgery. These recommendations are informed by the results of recent clinical trials such as the UNIFI and VARSITY¹⁰¹.

Table 4. Summary of the American Gastroenterological Association (AGA) guidelines for the management of adult outpatients with moderate-to-severe ulcerative colitis (Adapted¹⁰¹).

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AGA Drug Therapy for Crohn’s Disease

This guideline provides recommendations on the medical management of Crohn’s disease, including information on the use of thiopurines, methotrexate, and anti-TNFs for the induction and maintenance of remission in these patients. It consists of 10 evidence-based recommendations designed to support clinical decision making (Table 5)¹⁰².

Table 5. Summary of the American Gastroenterological Association (AGA) guidelines for the pharmacological management of Crohn’s disease (Adapted¹⁰²).

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AGA Institute Guideline on Inflammatory Bowel Disease (IBD) in Pregnancy

The AGA Institute Guideline on Inflammatory Bowel Disease (IBD) in Pregnancy reports that treatment cessation during pregnancy and lactation is common among IBD patients. It highlights the potential risks of allowing disease activity to worsen in pregnant women, including risk of adverse pregnancy outcomes, and offers practical advice on managing patients from pre-conception all the way though to post-partum¹⁰³.

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AGA Institute Guideline on the Management of Crohn’s Disease after Surgical Resection

This guideline includes a total of six recommendations specific to the management of patients who have undergone surgery for the treatment of Crohn’s disease. This includes recommendations on the prophylactic use of thiopurine and/or anti-TNF therapy for the prevention of recurrence and highlights the lack of a validated means of determining which patients are most at risk for developing postoperative recurrence⁹⁴.

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European Crohn’s and Colitis Organisation (ECCO)

ECCO-ESGAR Guideline for Diagnostic Assessment in IBD

This condensed guideline combines ECCO and the formerly separate ECCO-ESGAR imaging and ECCO Endoscopy guidelines. It includes recommendations on diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients already known to have IBD, diagnostics facilitating the detection of complications, IBD scores and information on laboratory parameters and diagnostic tools^104,105.

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ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment

Separate guidelines for the medical and surgical treatment of Crohn’s disease were published by ECCO in 2019. These updated guidelines were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and provide evidence-based recommendations on surgical and pharmacological interventions for Crohn’s disease^106,107. The medical treatment guidelines cover induction and maintenance of remission in patients with mild to severe disease and lists immunosuppressants and biologic agents as the most effective drugs for maintenance of treatment-induced remission in moderate to severe Crohn’s disease patients (Table 6). Meanwhile, long-term management of patients in remission is identified as an area requiring further research¹⁰⁶.

Table 6. Summary of the European Crohn’s and Colitis Organisation (ECCO) guidelines on the medical treatment of adult outpatients with moderate-to-severe Crohn’s disease (Adapted¹⁰⁶).

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ECCO Guidelines on Therapeutics in Crohn’s Disease: Surgical treatment

Surgical guidelines for Crohn’s disease offer advice on the management of patients who require surgery and include information on approaches to drug management prior to surgery and surgical techniques. Recommendations cover surgical therapy for perianal disease, for abdominal Crohn’s disease and small bowel obstruction. It also highlights the importance of an interdisciplinary approach in the surgical management of patients with Crohn’s Disease¹⁰⁷.

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The Third European Evidence-based Consensus of the Diagnosis and Management of Ulcerative Colitis Part 1

The Third European Evidence-based Consensus of the Diagnosis and Management of Ulcerative Colitis was published as two separate papers, the first of which covers the definitions, classification, diagnosis, imaging, histopathology, and disease management in special situations. It highlights that disease extent, severity and location influences choice of therapy and outlines how these can be assessed in clinical practice¹⁰⁸.

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The Third European Evidence-based Consensus of the Diagnosis and Management of Ulcerative Colitis Part 2

The second part of this guideline covers current management strategies for adults with ulcerative colitis. This includes information on the appropriate use of conventional and advanced therapies depending on disease location and activity (Table 7)^4,108. New guidelines for the treatment of ulcerative colitis (including surgery) are currently under development using the GRADE approach and are expected in 2021¹⁰⁹.

Table 7. Summary of the European Crohn’s and Colitis Organisation (ECCO) guidelines on the medical treatment of moderate-to-severe ulcerative colitis (Adapted⁴).

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The IBD therapies listed here may not be approved in some countries. Please refer to your local prescribing information.