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Inflammatory Bowel Disease Learning Zone

Treating IBD

Read time: 60 mins
Last updated:14th Oct 2021
Published:14th Oct 2021

The treatment landscape for inflammatory bowel disease is rapidly evolving.

  • Familiarise yourself with the pharmacological treatment options for IBD
  • Visualise the results of clinical trials with our key results figures
  • Develop your understanding of guideline recommendations for IBD management

Conventional therapy

Aminosalicylates

Aminosalicylates are a family of anti-inflammatory drugs indicated for the induction and maintenance of clinical remission in patients with mildly to moderately active ulcerative colitis1,2. Though the precise mode of action of aminosalicylates remains elusive, the beneficial effects of these drugs in patients with ulcerative colitis and Crohn’s disease have been attributed to their ability to scavenge free radicals, inhibit nuclear factor kappa B (NFκB) activity, decrease the synthesis of leukotriene, prostaglandin and proinflammatory cytokines, and to protect T84 cells against peroxynitrite3. They can be administered orally or topically depending on disease location and include sulphasalazine and mesalazine 4:

Aminosalicylates are prescribed to 88–97% of patients with ulcerative colitis within one year of their initial diagnosis, with 60–87% of these patients continuing to receive aminosalicylate therapy at 10 years1. It is therefore unsurprising that aminosalicylate use is associated with substantial healthcare costs1.

There is little evidence that aminosalicylates benefit patients with Crohn’s disease and many guidelines recommend against their use for the management of this form of IBD1,5. Nevertheless, it is reported that almost one third of patients with Crohn’s disease receive long-term treatment with aminosalicylates1.

Corticosteroids

IBD flare-ups involve the reappearance of disease symptoms following a period of respite and represent a major source of concern among patients6. In addition to the subjective worsening of symptoms, objective measures of disease activity, such as serum inflammatory markers and faecal calprotectin can be used to confirm that a patient is experiencing a flare-up and help establish an appropriate course of action7.

By binding to glucocorticoid receptors, which are expressed by nearly all cells throughout the body, corticosteroids regulate a numerous metabolic, developmental, cognitive and immune processes8. As a result, these drugs inhibit multiple inflammatory pathways and are used to treat a wide range of inflammatory disorders8.

Oral corticosteroids are commonly used as “rescue” therapy to treat flare-ups of both ulcerative colitis and Crohn’s disease9. These include10:

  • prednisolone
  • prednisone
  • hydrocortisone
  • methylprednisolone
  • beclometasone dipropionate
  • budesonide
  • budesonide-MMX
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Anti-integrins (biological therapy)

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.

T4 IBD Treatment - Jan2021.Fig1.png

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-integrins34,35. 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 (Adapted36,37). CDAI, Crohn’s Disease Activity Index.

*Clinical response was defined as a ≥70 point decrease in CDAI score at Week 10 and clinical remission as a CDAI score of <150 points. † Sustained clinical response was defined as a ≥70 point decrease in CDAI score at Week 36 and sustained clinical remission as a CDAI score <150 points. ‡ Sustained clinical response was defined as a ≥70 point decrease in CDAI score at Week 12 and sustained clinical remission as a CDAI score of <150 points.
Trial Treatment arms Clinical Response Clinical Remission
ENACT-1
(2005)*
Natalizumab (300 mg) at Weeks 0, 4 and 8  56% 37%
  Placebo at Weeks 0, 4 and 8 49% 30%
ENACT-2 
(2005)†
Natalizumab (300 mg) every 4 weeks from Week 12–56  61% 44%
  Placebo every 4 weeks from Week 12–56  28% 26%
ENCORE
(2007)‡
Natalizumab (300 mg) at Weeks 0, 4 and 8  48% 26%
  Placebo at Weeks 0, 4 and 8  32% 16%

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 death33,36,37,40. 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) tract42,43. As a result, vedolizumab is not currently thought to be associated with an increased risk of PML (Figure 2)43.

T4 IBD Treatment - Jan2021.Fig5.png

Figure 2. Anti-integrins mechanisms of action. Natalizumab targets both α4β7 and α4β1 integrins, while vedolizumab is gut selective, targeting α4β7 only (Adapted44,45). 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 IBD46–48. 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-I46–48. 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 slower31,48. Concomitant treatment with faster acting agents, such as steroids, may improve the response and remission rates of these patients31,48.

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.

T4 IBD Treatment - Jan2021.Fig3.png

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) (Adapted46–48). 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.

T4 IBD Treatment - Jan2021.Fig4.png

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 S1P1–5 . 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 pathology54,55.

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 respectively54,56. 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 pathways56,58. 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.

T4 IBD Treatment - Jan2021.Fig6.png

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 IBD56–58.

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

T4 IBD Treatment - Jan2021.Fig7.png

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 groups60,61.

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 colitis62,63. 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 placebo61,62. 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 approach58,64,65. 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.

* administered intravenously; † administered subcutaneously
TNF inhibitor Structure Indication Induction dose Maintenance dose
Infliximab* Chimeric mouse (25%)
and human (75%) monoclonal antibody
UC
CD
5 mg/kg at weeks 0, 2, and 6 5 mg/kg every 8 weeks
Adalimumab Fully human monoclonal antibody UC
CD
Week 0:
160 mg
Week 2:
80 mg
Week 4:
40 mg
40 mg every other week
Certolizumab pegol Recombinant antigen binding Fab fragment
conjugated to polyethylene glycol
CD 400 mg at
weeks 0, 2, and 4
400 mg every 4 weeks
Golimumab Fully human monoclonal antibody UC Week 0:
200 mg
Week 2:
100 mg
<80 kg
50 mg every 4 weeks

>80 kg
100 mg every 4 weeks

US-based dosing
100 mg every 4 weeks

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 cancers67,68.

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-2369,70. This has made inhibition of JAK pathways an attractive therapeutic target in IBD.

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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.

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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).

+++, strong recommendation; ++, conditional recommendation; +, no recommendation 
Patient type  Recommendation
All patients Infliximab, adalimumab, golimumab, tofacitinib, vedolizumab or ustekinumab in preference to no treatment (+++)
   Against use of methotrexate monotherapy for induction or maintenance of remission (++) 
   Biologic monotherapy or tofacitinib over thiopurine monotherapy for induction of remission (++) 
  Combination therapy over biologic or thiopurine monotherapy (++)  
  Early biologics with/without immunomodulator therapy over gradual step-up following failure of 5-aminosalycylic acid (++) 
Biologic-naïve Infliximab or vedolizumab over adalimumab for induction of remission (++) 
  Tofacitinib only in the setting of a clinical trial or registry study (+) 
Anti-TNFα-exposed Ustekinumab or tofacitinib over vedolizumab or adalimumab for induction of remission (++) 

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AGA Drug Therapy for Crohn’s Disease
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References

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