The spectrum of treatment for inflammatory bowel disease

An expert overview of the pathology, epidemiology, and diagnosis of IBD and the latest treatment and management strategies

The term inflammatory bowel disease (IBD) refers to two main subtypes of disease: Crohn’s disease (CD) and ulcerative colitis (UC), which are immune mediated diseases characterised by chronic inflammation of the gastrointestinal tract.

Pathology and epidemiology

The pathogenesis of both CD and UC is complex and is felt to be secondary to an interplay between genetic susceptibility, environmental factors, and an altered gut microbiota.

CD can affect almost any part of the digestive tract, whereas UC only affects the large intestine, primarily involving the rectum and can extend in a continuous fashion to involve other or all parts of the colon. CD exhibits histologically a thickened submucosa, transmural inflammation, fissuring ulceration, and granulomas, whereas the inflammation in UC is limited to the mucosa and submucosa with cryptitis and crypt abscess formation.

IBD is considered one of the most prevalent gastrointestinal diseases with accelerating incidence in newly-industrialised countries. The highest prevalence of IBD is reported in Europe and North America. The incidence of CD in Ireland is approximately 5.9 per 100,000 population, while the incidence of UC is approximately 14.9 per 100,000 population. The peak of IBD’s occurrence usually happens in the second-to-fourth decades of life with a second, smaller peak during the fifth-to-seventh decades.

Symptoms and diagnosis

The symptoms of IBD vary depending on which part of the intestine is affected and severity of the disease.

The predominant symptom of UC is diarrhoea, which is frequently bloody. Over the course of their lifetime, 15 per cent of patients with UC develop acute severe ulcerative colitis (ASUC), which presents with severe diarrhoea and associated systemic dysfunction, such as fevers or tachycardia requiring hospitalisation.

Active CD can cause diffuse abdominal pain, anorexia, diarrhoea, and weight loss. CD can be sub-classified into inflammatory, stenotic, or fistulating disease and these different forms are often a continuum of disease progression. Perianal disease can occur in a subset of patients with CD, with fistula and abscess formation developing in 21-to-54 per cent of CD patients. If patients have a convincing history, screening tests for IBD including serology and non-invasive stool tests including a faecal calprotectin (FCP) level are performed.

The diagnosis of IBD is based on a combination of a detailed clinical history and examination along with biochemical, endoscopic, and histological findings. European Crohn’s and Colitis Organisation (ECCO) guidelines advise an ileocolonoscopy for all patients with suspected IBD except in the case of ASUC in which sigmoidoscopy is sufficient.

Treatment

Once a diagnosis of IBD is established, treatment is focused around a combination of medication, sometimes surgery, and nutritional optimisation. The overall goal of therapy is to induce remission in the short-term and maintain remission in the long-term. In addition to improving symptoms, mucosal healing is another goal of therapy for all patients with IBD. Mucosal healing is associated with fewer hospitalisations, reduced need for surgery, and lower rates of disease complications.

Medications used for the treatment of UC and CD differ somewhat depending on disease location and severity of disease. Along with medication and/or surgical treatments, all patients with IBD should be encouraged to stop smoking, nutritional deficiencies should be corrected, and appropriate surveillance for vaccinations, osteoporosis, and sun protection should be implemented as per the ECCO guidelines.

Management of UC

Steroids

Steroids are used for induction of remission in patients with UC. For patients with UC with mild/moderate symptoms, a locally-acting steroid, such as Cortiment, can be used. Cortiment contains budesonide as an active ingredient along with multimatrix (MMX) that releases the drug in a controlled manner along the colon and not in the small bowel, therefore Cortiment is used to treat mainly UC or colonic CD.

If a patient develops a severe flare of colitis, a course of prednisolone is the best treatment option and in certain cases patients require hospitalisation for intravenous steroids, especially patients with ASUC.

Steroids only induce remission and patients normally need a maintenance therapy to keep their disease in remission and prevent further flares.

Mild-to-moderate UC

Patients with UC with mild-to-moderate disease may achieve disease remission with 5-aminosalicylate (5-ASA) therapy. 5-ASA therapy can be given as an oral medication or in topical forms, such as enemas or suppositories for more distal disease. For patients with proctitis, treatment with topical 5ASA suppositories is often sufficient to keep a patient’s disease in remission. 5-ASA suppositories taken once-daily are the preferred initial treatment for mildly- or moderately-active proctitis. If patients have mild-to-moderate left-sided colitis or extensive colitis, treatment with a 5-ASA enema, combined with oral mesalamine, is more effective than oral or topical 5-ASA alone.

Moderate-to-severe UC

Patients who experience frequent disease relapse, are resistant to or dependent on steroids, or those intolerant to 5-ASA may require treatment escalation with immunomodulators or biologic therapy or a combination of both.

Immunomodulators include purine anti-metabolites, such as azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP). Immunomodulators tend to be used in UC for patients with mild/moderate disease activity who have experienced early or frequent relapses while taking 5-ASAs at optimal doses or who are intolerant of 5-ASAs. Patients with low thiopurine S-methyltransferase (TPMP) levels are at increased risk of leukopaenia from immunomodulators and 0.3 per cent of Europeans are TPMT deficient. TPMT levels can be checked prior to commencing immunomodulators, however, even patients with normal levels can develop leukopaenia or hepatotoxicity, therefore, weekly bloods for eight weeks (FBC and liver profile) after commencing thiopurines is required to screen for these side-effects.

Methotrexate or tacrolimus are no longer recommended for management of UC as a monotherapy. Patients with moderate colitis refractory to thiopurines should be treated with an anti-TNF therapy.

Biologic therapies have revolutionised the management of IBD over the past two decades. Before commencing biologic therapy, all patients need a full pre-biologic screen to screen for opportunistic infections, which can be prevented by vaccination or could be re-activated once therapy is commenced. The screen includes testing for HIV, hepatitis B and C, EBV/CMV serology, VZV titres as well as a QuantiFERON test, and chest x-ray to assess for latent TB.

Infliximab was the first biologic therapy approved for the treatment of IBD. Infliximab is an anti-TNF agent, which is given intravenously. It is recommended for the treatment of moderate-to-severe UC and is often used as a rescue therapy for patients admitted with ASUC to help prevent the need for colectomy. There are two other anti-TNF agents approved for the treatment of UC: Adalimumab and golimumab, which are both given subcutaneously. The combination of infliximab with azathioprine is more effective than infliximab aloneand combination therapy of infliximab and an immunomodulator is common practice for patients with moderate-to-severe UC. Similar evidence does not exist for adalimumab in combination with thiopurine therapy in UC. Given the mixed evidence available, ECCO advises that patients who have previously developed anti-drug antibodies (ADA), resulting in loss of response to their first anti-TNF agent, should be given combination therapy with a thiopurine when commencing on a second anti-TNF agent to help prevent formation of ADA.

Other biologic agents used for the treatment of UC include vedolizumab, an anti-integrin inhibitor licensed for moderate-to-severe UC. Vedolizumab blocks trafficking of neutrophils and lymphocytes to sites of inflammation. As vedolizumab is a gut specific anti-integrin, it is associated with less systemic side-effects compared to anti-TNF agents. Recently, ustekinumab, an interleukin inhibitor (IL12/IL23) that blocks the inflammatory response, has been licensed for moderate-to-severe UC and is advised by ECCO guidelines for treatment of moderate-to-severe UC resistant to anti-TNF therapy.

Unfortunately, over time patients treated with biologic therapies can lose response to treatment, with up to 50 per cent of patients developing loss of response to anti-TNF therapy in one study. Loss of response to therapy can often be secondary to the development of antibodies to the drug and serum trough drug levels and specific drug antibodies levels can be tested, called therapeutic drug monitoring (TDM). TDM for symptomatic patients treated with anti-TNF therapyis common in routine clinical practice, with numerous studies showing clinical benefit for patients losing response to therapy. Proactive drug monitoring in asymptomatic patients is not recommended to date. If patients have low levels of a drug and are symptomatic, options include reducing the interval of the biologic medication, or if a patient has developed high antibodies with low drug levels, then an immunomodulator can be introduced to help reduce and overcome these antibodies, thereby increasing available drug levels. Sometimes, despite the above changes, patients do not regain response and often require a switch to an alternative biologic. In cases of treatment failure in UC, a different anti-TNF agent, combined with a thiopurine if patients develop ADA, or vedolizumab or ustekinumab should be considered.

Most recently, new targets including Janus kinase (JAK) inhibitors have been approved for medically-refractory UC. Tofacitinib is an oral, non-selective JAK inhibitor that is effective and safe for patients with moderately-to-severely active UC and is approved by the European Medicines Agency (EMA) for management of moderate-to-severe UC refractory to other medical therapies. ECCO guidelines advocate for tofacitinib in patients with moderately-to-severely active UC. Other JAK inhibitors recently approved by the EMA for treatment of UC include filgotinib and upadacitinib.

If patients with UC fail multiple medical therapies, develop ASUC unresponsive to medical therapy, or develop a malignancy or dysplasia in the colon, subtotal colectomy is often necessary with an end ileostomy. The European Collaborative Study Group on Inflammatory Bowel Disease reported a cumulative 10-year colectomy rate of 8.7 per cent for patients with UC. Most patients post-surgery for medically refractory UC have an end ileostomy. If patients are content with an end ileostomy and do not want their stoma reversed, a completion proctectomy is advised as there is still a risk of developing malignancy in the remnant rectum. If patients wish to have their ileostomy reversed, they can subsequently have an ileal pouch-anal anastomosis (IPAA). Occasionally some of these patients develop pouchitis (inflammation of the reconstituted ileal reservoir (pouch)), which responds well to courses of antibiotics or anti-TNF therapy.

Management of Crohn’s disease

Steroids

For CD patients, steroids are often prescribed for induction of remission and for those with an acute disease flare. For patients with CD affecting the ileum and/or ascending colon, locally-active steroids, such as oral Entocort or Budenofalk, are advised for patients with mild/moderate symptoms. Budesonide is the active ingredient in Entocort and Budenofalk. Neither Entocort nor Budenofalk contain MMX and therefore target the small bowel and right colon.

As seen with UC, patients with CD who are having a severe flare of colitis often require a course of prednisolone. Steroids are only a short-term treatment and maintenance treatment is often needed to treat active disease and prevent progression of disease. Steroids should be avoided in patients with CD if there are concerns regarding abscess formation.

Mild CD

Management of mild CD can often be difficult, especially if disease is isolated to a very short segment in the small bowel. The decision to start treatment often depends on the severity of disease and if patients are symptomatic. For patients with persistent or recurrent symptoms, treatment options include an immunomodulator, such as azathioprine or 6-mercaptopurine. As mentioned above, screening for leukopaenia and liver toxicity is essential once thiopurines are commenced.

If patients have very mild disease and are asymptomatic, no treatment is sometimes an option and patients are monitored closely in outpatient clinics. If their disease flares again, then escalation of therapy can be considered. Aminosalicylates are no longer recommended in CD, however, they may be of some benefit to patients with CD isolated to the colon.

Moderate-to-severe CD

The use of thiopurines as monotherapy for the induction of remission of moderate-to-severe luminal CD is contraindicated. Biologic therapies are the most commonly-used medication for moderate-to-severe CD to treat the inflammatory burden and prevent stricture formation.

Anti-TNF therapies used for the treatment of CD are similar to those used in UC. Infliximab and adalimumab are recommended for induction and maintenance of remission in patients with moderate-to-severe CD who do not respond to conventional therapy. Ustekinumab, an interleukin inhibitor (IL12/IL23), is currently licensed for moderate-to-severe CD. Guidelines advise either the use of vedolizumab or ustekinumab for the treatment of moderate-to-severe active luminal CD in patients who have previously failed anti-TNF therapy.

For patients with severe CD with a high inflammatory burden, a combination of infliximab and an immunomodulator can be used to help obtain disease remission and mucosal healing; however, combination therapy is not recommended with adalimumab. Loss of response to biologic therapy is frequently seen in CD also, and monitoring drug levels for symptomatic patients can help improve response by alterations in medication prescribing as described above.

While gastroenterologists and patients often strive to manage disease medically and avoid intestinal resection, surgery is crucial in certain clinical settings in achieving disease control. Surgery is more common in patients with CD than UC. One systematic review found that while rates of surgery have decreased since the introduction of biologic therapies, the risk of surgery five years after diagnosis of CD was 33 per cent, and 47 per cent at 10 years after diagnosis. Early treatment with thiopurines and anti-TNF therapy is associated with reduced risk of surgery. Currently, smoking, penetrating and stricturing disease behaviour, early steroid use, ileal disease, jejunal disease, and young age at diagnosis are risk factors for surgery in CD.

Indications for surgery in CD tend to be secondary to stricture formation resulting in recurrent episodes of bowel obstruction or development of fistulas. Surgery is the preferred option in patients with localised ileo-caecal CD with obstructive symptoms, but no significant evidence of active inflammation. Other indications include failure to respond to medical treatment, or development of dysplastic or malignant changes. The range of surgeries performed for CD is varied and depends on disease location and disease behaviour. These include colectomy, small bowel resection with or without ileostomy, ileo-caecectomy, and fistulotomy.

Management of fistulating perianal disease in CD can be complex, requiring a combination of medical therapies and surgery. Perianal disease can be managed with anti-TNF therapy including infliximab or adalimumab. Monotherapy with thiopurines is not advised for fistulae closure in patients with perianal CD. The aim of medical therapy is to reduce the inflammatory burden in the perianal area allowing the fistula to heal and close up over time. If there are concerns that a patient has developed a perianal abscess, which presents with symptoms including perianal pain, fever or chills, then patients need their immunosuppressive agents held and review by a surgical colleague to examine for an abscess. If patients develop an abscess, this requires incision and drainage prior to re-commencing immunosuppression. For patients with severe fistulating perianal disease, setons can be inserted by colorectal surgeons to assist healing of fistula tracts. If perianal disease cannot be managed by the above treatments, it can ultimately require surgery, which might be a proctectomy and permanent ileostomy to alleviate symptoms.

Biosimilars

Biosimilars are biologic products that are highly similar to previously approved reference biologic drugs in terms of safety, purity, and efficacy, and certain biosimilars are approved for the treatment of IBD. Biosimilars for infliximab and for adalimumab are licensed by the EMA. Biological medicines consistently feature in the ‘top 10’ of drug expenditure reports in secondary care in Ireland. Given this cost, the HSE Acute Hospital Drug Management Programme set a target rate of 50 per cent for biosimilar uptake (Feb 2018) for biological medicines with a biosimilar available. The uptake rates and use of biosimilars vary widely both nationally and within hospital groups, ranging from 0-to-100 per cent for different hospitals.

There is a vast amount of evidence to support switching of reference medicines to biosimilars. The NOR-SWITCH study is one of the largest randomised switch trials to date. NOR-SWITCH results showed that a single switch from reference infliximab (Remicade) to the biosimilar infliximab (Inflectra, Remsima) in inflammatory arthropathies, IBD, and psoriasis was non-inferior in terms of safety, efficacy, and immunogenicity. Although specific to infliximab in certain indications, these data are supportive of the framework and scientific principles applied by the EMA in biosimilar development to ensure no significant difference between reference medicines and their biosimilars.

As per the HSE’s Guidance for Biological Medicines in Acute Hospitals, for a biological medicine with a biosimilar available for the same licensed indication, the best value biological medicine should be prescribed (provided that this is the most clinically-appropriate biological medicine for the patient). It is recommended all treatment-naïve patients should be initiated on the best value biological medicine (whether biosimilar or reference medicine). All non-naïve patients currently on treatment with the reference medicine should be considered for a switch to a biosimilar if the biosimilar is the best value biological medicine.

Before switching a patient’s therapy, it is essential to discuss this with your patient in clinic and explain the reasoning behind this decision. It is important patients are informed that based on evidence from controlled trials and real-world experience in IBD, data supports the use of biosimilars for both treatment initiation and switching as safe, effective, and potentially cheaper alternatives to the originator biologic.

Clinical nutrition in IBD

Dietary management in IBD focuses on maximising nutritional status, maintaining adequate intake, and avoiding foods that can exacerbate symptoms. Malnutrition can occur in UC and CD, but is a considerably greater problem in CD given its capacity to affect any part of the GI tract.

In both UC and CD, malnutrition may be the result of reduced oral intake, increased nutrient requirements, and increased gastrointestinal losses of nutrients. The severity of malnutrition in IBD is influenced by the activity, duration, and extent of the disease, and particularly by the magnitude of the inflammatory response. Patients with CD remain at risk even when their disease appears quiescent, whereas patients with UC generally develop problems only when the disease is active.

There is no IBD diet that can be generally recommended to promote remission in IBD patients with active disease. However, adequate calorie and protein intake and monitoring for malnutrition are recommended. The energy requirements of patients with IBD are similar to those of the healthy population, however, protein requirements are increased in active IBD, and intake should be increased during a flare.

Iron supplementation is recommended in all IBD patients with iron deficiency anaemia. Oral iron should be considered as first-line treatment in patients with mild anaemia and those whose disease is clinically inactive. In IBD patients with active disease and those who are steroid-treated, serum calcium and 25 (OH) vitamin D should be monitored and supplemented if required to help prevent low bone mineral density.

IBD patients with severe diarrhoea or a high output jejunostomy or ileostomy should have fluid output and urine sodium monitored and fluid input adapted accordingly.

In CD patients with intestinal strictures or stenosis in combination with obstructive symptoms, a diet with adapted texture including a low-fibre diet can be considered.

Oral nutrition supplements are the first step when artificial nutrition is indicated in IBD, but generally are a minor supportive therapy used in addition to normal food.

If oral feeding is not sufficient, then tube feeding should be considered as supportive therapy. Parenteral nutrition is indicated in IBD only when oral or tube feeding is not sufficiently possible, (eg, when the GI tract is dysfunctional or in CD patients with short bowel syndrome), when there is an obstructed bowel where there is no possibility of placement of a feeding tube beyond the obstruction, or when other complications occur, such as an anastomotic leak or a high output intestinal fistula.

Novel therapies

Although significant progress has been made in the treatment of IBD, current options achieve remission in only a portion of patients affected. Research continues to unveil novel mechanisms of actions and greater understanding of the multiple overactive signalling pathways of the gut mucosal immune response. Enhanced leukocyte trafficking novel therapies have been developed against several modes of action, including adhesion molecules, sphingosine-1-phospate receptors, cytokines (TL1A, and IL-36), JAK, and phosphodiesterase. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Novel therapies in development offer alternatives to existing therapies for IBD with the hope that in the near future more patients can attain disease remission.

Assessment and monitoring

Any patient with IBD needs to be followed up regularly by a gastroenterologist for monitoring for disease progression and surveillance for colorectal cancer. In many hospitals in Ireland specialised IBD clinics have been established with multidisciplinary teams including gastroenterologists, specialist IBD nurses, colorectal surgeons, dietitians, and psychologists in certain centres.

In patients with UC who clinically respond to medical therapy, mucosal healing should be assessed endoscopically or by FCP three-to-six months after treatment initiation. Clinical and biochemical response to treatment of CD should be determined within 12 weeks following initiation of therapy. Endoscopic or transmural response to therapy should be evaluated within six months following initiation of therapy. For patients with IBD on a combination of both a biologic agent and immunomodulator, withdrawal of the immunomodulator can be considered after 18-to-24 months once a patient is in disease remission confirmed by a normal FCP or normal endoscopy.

For patients in remission, routine endoscopy to monitor disease activity is not required. Serum markers of inflammation including CRP, FBC, and albumin are monitored biannually. If a patient has symptoms of a disease flare, non-invasive surrogate markers of intestinal inflammation in the form of FCP are increasingly used to assess disease activity without the need for endoscopy. Surveillance colonoscopy is recommended after eight-to-10 years to assess disease activity, extent, and to screen for early dysplastic changes and then surveillance is required thereafter every one-to-five years depending on disease-related factors. Patients treated with aminosalicylates should have their renal function checked every three months. Patients treated with immunosuppressive agents should have routine bloods including FBC, renal/liver/bone profile, and CRP every three months. Any patient treated with steroids should have vitamin D levels checked and treated with calcium supplements. All patients diagnosed with IBD should be referred to the IBD clinical nurse specialist for education and be provided with written material regarding their diagnosis.

Conclusion

The aim of treatment in IBD should be to alleviate patients’ symptoms and enable them to achieve a good quality-of-life. Patients should be actively involved in their management plan. Treatment modalities over the past two decades for the management of IBD have become more complex and, overall, in this era patients require a multidisciplinary approach to treating and managing their IBD from gastroenterologists, IBD nurse specialists, colorectal surgeons, dietitians, psychologists, pathologists, and their general physician.

References on request and at www.doctorcpd.ie

Authors: Dr Jayne Doherty, SpR in Gastroenterology; and Prof Garret Cullen, Consultant Gastroenterologist, Centre for Colorectal Disease, St Vincent’s University Hospital, Dublin

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