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Inflammatory bowel disease

By Irish Pharmacist - 01st Feb 2024

IBD encompasses two separate diseases — Crohn’s disease and ulcerative colitis — and is a group of autoimmune conditions that are characterised by repeated episodes of gastrointestinal tract inflammation, writes Damien O’Brien

Inflammatory bowel disease (IBD) is a group of autoimmune conditions that are characterised by repeated episodes of gastrointestinal tract inflammation. IBD encompasses two separate diseases, differentiated by the location, and the depth of involvement in the bowel wall. Crohn’s disease (CD), and ulcerative colitis (UC) are the two disorders. Both diseases can be classified by severity (mild, moderate, or severe) and location. Although the two conditions are distinct, they share some common features. Neither of the conditions are curable, they both have a large morbidity burden and both have a genetic predisposition. They also both increase the risk of colorectal cancer. Additionally, both conditions have some extraintestinal manifestations. However, they do differ in certain ways and these differences are outlined in a below paragraph. In approximately 10 per cent of patients, it is not possibly to initially differentiate between CD and UC.

IBD is predominantly diagnosed in or before young adulthood, with approximately 20 per cent diagnosed before 20 years of age. The prevalence of IBD is highest in Europe and North America, with the prevalence estimated at 0.8 per cent of the population. Patients with IBD are more likely to experience several chronic conditions as co-morbidities, including liver disease, psychological disorders, cardiovascular disease, respiratory disease, kidney disease, certain forms of cancer and arthritis.

Aetiology

The exact aetiology of IBD remains unknown but it is known to have a genetic component. Inflammation of the gastrointestinal tract occurs when the immune system has an inappropriate response to intestinal flora. Several possible causes are theorised, but none are present in all patients. The CARD15 gene has a strong link with IBD, but it isn’t possible to determine which part of the gastrointestinal tract will be affected due to its polymorphic features. The genetic component is stronger in CD than UC. Smoking tobacco has a strong link with CD, however it has a protective effect against UC. Smoking should not be encouraged in these patients due to several other health concerns. The role that nutrition plays in IBD remains unclear. A diet high in fat and animal protein may cause an increased risk of IBD. Meanwhile a diet high in fruit and vegetable may decrease the risk of IBD but the scientific evidence isn’t conclusive.

Classification

Crohn’s disease and ulcerative colitis are the two main conditions associated with IBD. They share some similarities but differ in many ways. CD can affect any part of the digestive system, from the mouth to the anus. Symptoms are commonly in the intestine, but the mouth, oesophagus, and stomach can also be affected. Inflammation in CD is non-continuous, with healthy patches often present between lesions. In contrast to CD, UC only affects the colon and rectum. Inflammation in UC is continuous with no healthy areas in between, usually involving the rectum and extending proximally to the colon. Symptoms of CD and UC are mainly characterised by inflammation and include diarrhoea, abdominal pain, rectal bleeding, and weight loss. UC is associated with blood/mucus in the stool, rectal bleeding, and tenesmus, a sensation of incomplete evacuation. Rectal bleeding is not as common in CD, but anal fistula is common. Malnutrition and weight loss are much more common in CD because damage to the small intestine can reduce absorption of nutrients. Fever is a common symptom in CD, while fever in UC is usually associated with severe disease. More than 50 per cent of individuals with CD have a folate and vitamin D deficiency, while more than 50 per cent of those with UC are deficient in iron. Both CD and UC can often have extraintestinal manifestations. These can include arthritis, osteoporosis, uveitis, and ankylosing spondyloarthropathy.

Diagnosis

IBD is diagnosed based on a combination of clinical findings, inflammatory laboratory markers, imaging findings, and endoscopic biopsies. Diagnosis may require ruling out parasitic diseases and tuberculosis. Laboratory blood testing can show elevated erythrocyte sedimentation rates (ESR) and white cell counts, which are associated with intestinal inflammation. A complete blood count can be used to identify anaemia, leukocytosis, and albumin levels. Levels of calprotectin in the faeces can be used as a marker for intestinal inflammation. Imaging techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are also useful in the diagnosis of IBD or to assess for intra-abdomen complications. Endoscopy evaluation is necessary to obtain biopsy to confirm diagnosis of IBD. This technique is effective in diagnosing the disease and differentiating the type of inflammation present.

Pharmacological treatment

There is no pharmacological or surgical cure for IBD. The objective of treatment is to reduce symptoms of the disease and induce remission. Treatment of IBD depends on the severity of the disease, the presence of extraintestinal manifestations and the portion of the gastrointestinal tract affected. A stepwise approach is required for management of IBD, while treatment for flare-ups may also be required. Several pharmacological treatment options are available that can reduce symptoms and induce remission.

Aminosalicylates

Aminosalicylates are often the first step in treating IBD. Mesalazine (also called 5-aminosalicylic acid) and sulfasalazine (which is broken down into 5-aminosalicylic acid in body) are commonly used for treating mild-to-moderate IBD. The exact mechanism of aminosalicylates is not fully understood, but it is thought that it reduces the synthesis of prostaglandin and leukotriene, which modulates the inflammatory response from both the cyclooxygenase and lipooxygenase pathways. These drugs can be administered both orally and rectally. The adverse effects associated with mesalazine and sulfasalazine are generally quite favourable but can include nausea, flatulence, abdominal pain, diarrhoea, and headache. More serious adverse effects can include infertility, haemolytic anaemia, and nephrotoxicity.

Immunomodulators

Immunomodulators can be useful in treating patients with IBD and include thiopurines, methotrexate, and calcineurin inhibitors. These immunomodulators all have different mechanisms of action but generally work by dampening the immune response by inhibiting T lymphocyte proliferation and activation. Azathioprine and 6-mercaptopurine are thiopurines that are effective in treating IBD, but have many adverse effects including bone marrow suppression, liver injury, and gastrointestinal intolerance, which has led to a decline in their use. Studies have shown that methotrexate can be more than 70 per cent effective at achieving clinical remission after three months in CD patients. Methotrexate is not as effective at inducing remission in patients with UC and can have adverse effects including fatigue, rash, nausea, vomiting, diarrhoea, and immunosuppression. Intramuscular injection can reduce systemic adverse effects, compared to oral administration. Calcineurin inhibitors, such as ciclosporine and tacrolimus, can also be effective in patients with IBD but can have a high incidence of adverse effects, including renal function damage, tremor, infection, and hyperkalemia. The adverse effect profile of these drugs is one of the reasons for the move towards biologicals in treating IBD.

Biologicals

Biological drugs are often initiated in patients with moderate-to-severe disease. In recent years, biological therapy is often introduced earlier in high-risk patients and patients with severe disease, with a de-escalation when a clinical response is observed. This approach can improve patient outcomes and reduce complications of disease. Anti-tumour necrosis factor (TNF) therapy and anti-interleukin (IL)-12/23 therapy are the two main categories of biological agents. TNF-? is a cytokine that, when overexpressed, can cause chronic inflammation and tissue damage. Infliximab and adalimumab are two agents that exert their therapeutic effect by inhibiting TNF-?-associated inflammation. The main adverse effects associated with anti-TNF therapy includes increased risk of infection, congestive heart disease, malignancies, drug-induced lupus and skin reactions. IL-12 and IL-23 are pro-inflammatory cytokines present in intestinal inflammation. Studies have shown that both IL-12 and IL-23 are involved in the pathophysiology of IBD and play a role in inducing and maintaining intestinal inflammation. Ustekinumab is a commonly used drug that reduces the activity of IL-12 and IL-23, therefore reducing intestinal inflammation. The most common adverse effects with anti-IL-12/23 therapy include nasopharyngitis, headache, increased risk of infection, cardiovascular events, and malignancies. Patients should be screened for latent tuberculosis before initiating biological therapy. Biological agents have the advantages of reduced toxicity, high selectivity, and high efficiency when compared to other therapeutic options.

Corticosteroids

If other treatment options fail or if a patient has flare-ups, corticosteroids can be a useful therapeutic option. Corticosteroids can be very effective at reducing inflammation and therefore inducing remission when a flare-up occurs. Corticosteroids can also be used both orally and rectally. Systemic oral corticosteroids can result in several adverse effects including infection, diabetes, hypertension, ocular effects, venous thromboembolism, and osteoporosis. Second-generation corticosteroids, such as budesonide, have a better safety profile than conventional corticosteroids. Targeted delivery of corticosteroids to the inflammation site can also reduce systemic adverse effects.

Non-pharmacological treatment

There are a number of non-pharmacological treatment options available, either as monotherapy or in combination with pharmacological treatment. Since the development of biologicals, the rate of surgical intervention is declining, but it is still an important treatment option. The main indications for surgery include heavy bleeding, intestinal perforation, carcinogenesis, and highly suspected carcinogenesis. Other indications can include patients with severe IBD that haven’t responded to medical treatment or can’t tolerate medical treatment.

The specific mechanism of IBD remains unclear but it may be related to an imbalance in beneficial and harmful bacteria in the gastrointestinal tract. Improving the intestinal microecology by using probiotics, prebiotics, postbiotics, synbiotics, and faecal microbiota transplantation (FMT) are all potential treatment options. Synbiotics are a synergistic combination of probiotics and prebiotics. Probiotics, prebiotics or synbiotics can be used in combination with conventional drugs and may be more effective than conventional drugs alone. FMT is a new therapy that involves transplanting the functioning microbiota from the faeces of a healthy individual into the gastrointestinal tract of the patient to reconstruct the intestinal microecology. These treatment options can be effective, as well as being safe and well tolerated.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is characterised by the presence of abdominal pain or discomfort, accompanied by altered bowel habits. It is one of most diagnosed gastrointestinal diseases. The prevalence of IBS is estimated at 10-15 per cent of the population, although a large percentage of these may not seek medical treatment. IBS is more commonly diagnosed in females than males, with a decrease in prevalence observed with age. IBS can be classified into three main categories: IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), and IBS with mixed bowel patterns (IBS-M). The aetiology of IBS is not clearly understood. Brain-gut interaction, visceral sensation, motility, psychosocial distress are all potential causes, with at least one often observed in IBS patients. Intestinal and colonic microbiome may also have an association with IBS. Environmental factors that may contribute to IBS include life stress, enteric infections, food intolerance, and antibiotic use.

The main symptoms of IBS typically include abdominal pain or discomfort, constipation, diarrhoea, and altered bowel habits. Other symptoms can include bloating and distention. Warning signs that may need further referral include severe or worsening symptoms, unexplained weight loss, rectal bleeding, anaemia, onset after the age of 50 years or a family history of other gastrointestinal disorders such as IBD, coeliac disease, and colorectal cancer.

The Rome IV criteria is a tool used to aid in the diagnosis of IBS. Diagnosis criteria requires at least three days per month in the last three months associated with at least two of the following:

  • Improvement in abdominal pain or discomfort with defecation;
  • Onset associated with a change in frequency of stool;
  • Onset accompanied by a change in appearance of stool.

The differential diagnosis of IBS can be broad and difficult. If symptoms are typical of IBS and no warning symptoms are present, routine diagnostic testing may not be required. If the patient has symptoms of IBS-D, differentials include lactose intolerance, alcohol or caffeine intake, IBD, medication-induced diarrhoea, coeliac disease, colorectal cancer, hyperthyroidism, and gastrointestinal infections. If the patient has symptoms of IBS-C, differentials can include inadequate fibre intake, immobility, Parkinson’s disease, multiple sclerosis, hypothyroidism, hypercalcemia, medication-induced constipation, and bowel obstruction. If a patient’s symptoms or history indicate any of these, then appropriate investigations should be performed.

Due to the fact that IBS is a symptom-based disorder, the treatment objectives are aimed at relieving symptoms of pain, cramping, diarrhoea, and constipation. A wide range of fibre supplements and laxatives are available both over the counter (OTC) and on prescription for treating constipation. In patients with diarrhoea, loperamide is available OTC and a product called Lomotil, which contains 2.5mg of diphenoxylate hydrochloride and 0.025mg of atropine sulphate, is available on prescription. Mebeverine hydrochloride and alverine citrate are both available on prescription and can be used for the relief of gastrointestinal spasm in IBS, while hyoscine butylbromide is available OTC for this purpose. Peppermint oil is generally safe and can be an effective treatment option for symptoms of discomfort, distension, and abdominal colic.

Patients with chronic symptoms may respond to low dose tricyclic antidepressants or selective serotonin reuptake inhibitors. Rifaximin has also been shown to be effective in treating IBS. Rifaximin is a broad-spectrum antibiotic that is not well absorbed, which allows it to work locally in the gut. The effectiveness of rifaximin gives support to the theory that bacterial overgrowth plays a role in the aetiology of IBS. Lifestyle modifications can also be effective in improving symptoms. Physical activity can increase colonic transit time and provide symptom relief. Diet modifications can also improve symptoms for some individuals, depending on what symptoms they are experiencing – a food diary can be useful in this regard for some patients. l

References upon request

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