Inflammatory Bowel Disease PDF

**[INFLAMMATORY BOWEL DISEASE]** Inflammatory bowel disease is an inflammatory disorder of the GI-tract, and this comes in two forms. - Crohn's Disease (CD). - Ulcerative Colitis (UC). Both diseases are chronic in nature with periods of unpredictable relapsing and remission. There are also e...

**[INFLAMMATORY BOWEL DISEASE]** Inflammatory bowel disease is an inflammatory disorder of the GI-tract, and this comes in two forms. - Crohn's Disease (CD). - Ulcerative Colitis (UC). Both diseases are chronic in nature with periods of unpredictable relapsing and remission. There are also extra-gastrointestinal manifestations. In about 10 -- 15% of the cases, it if very difficult to distinguish between the two conditions. +-----------------------------------+-----------------------------------+ | **Crohn's Disease** | **Ulcerative Colitis** | +===================================+===================================+ | This can affect any part of the | Can only affect the colon and | | GI tract ranging from the mouth | rectum. | | through to the rectum | | | | NB: It does not affect the anus | | | but rather starts at the rectum | | | and works its way up. | +-----------------------------------+-----------------------------------+ | The inflammation seen in CD | In terms of UC, it only affects | | extends through all the layers of | the mucosa (and submucosa). | | the GUT wall. This means it can | | | range from the mucosa through to | | | the serosa. This means there is a | | | possibility of causing of a | | | fistula which is a complication | | | of Crohn's disease. | | +-----------------------------------+-----------------------------------+ | The inflammation seen in CD is | In UC, the inflammation is | | patchy in distribution. | diffuse in distribution mainly | | | starting from the rectum and | | Example patch of it will be seen | working its way up into the colon | | in the small intestine and | and it is also continuous. | | another patch seen in the colon | | | etc. | | +-----------------------------------+-----------------------------------+ [Epidemiology]. In terms of Worldwide distribution, IBD is more common in industrialised countries and affects all races and both sexes. It can occur at any age but the incidence in age occurs between 10 -- 40 years. - About 15% of affected people are over the age of 60 years. In the UK, it is estimated that about 1 in 250 individuals have IBD. For some reason which is unknown, there seemed to be a rapid increase in the incidence of IBD between 1955 -- 1975 (post -- war era). It should be known that it has now been stabilised. [Incidence]. +-----------------------------------+-----------------------------------+ | Crohn's Disease | Ulcerative Colitis. | +===================================+===================================+ | Less common when compared to UC. | More common when compared to CD. | | | | | About 5 -- 10 people per 100,000 | About 10 -- 20 people per 100,000 | | per year. | per year. | +-----------------------------------+-----------------------------------+ | Prevalence of 50 -- 100 cases per | Prevalence of 100 -- 200 cases | | 100,000 population. | per 100,000 population. | +-----------------------------------+-----------------------------------+ | Slightly more common in females | Slightly more common in males (M: | | (M: F à 1:1.2). | F à 1.2:1). | +-----------------------------------+-----------------------------------+ | Occurs normally at a younger age | Occurs more common in at an older | | with mean age of onset being at | age with mean age of onset being | | 26 years. | at 34 years. | +-----------------------------------+-----------------------------------+ [Aetiology]. In terms of the aetiology, the causative agent is unknown. However, there are some numerous factors that plays a key role. Environment. - Diet. - Smoking. - Infection. - Drugs. Genetics. There is a genetic cause of the disease as it is known that if a person has some specific genetic characteristics, they may be predisposed to getting the disease. [Environmental factors]. - Diet: Several factors have been associated with IBD. Examples include fat intake, fast food indigestion, milk and fibre consumption, total protein and energy intake and refined carbohydrates. - Smoking: In general, it is thought that smoking worsens the clinical course of the disease. It increases the risk of relapse and the need for surgery. 40% of CD patients are smokers compared to the 10% seen in UC. NB: An interesting study shows that smoking may help to prevent the onset of UC. This may be attributed to the chemicals in the smoke and its effect on the colonic smooth muscle which is mainly altering the gut motility and the transit time. - Infection: There are some evidences of association of infection in relation to IBD. For instance, there are some evidences that shows that exposure to Mycobacterium paratuberculosis can cause CD. Also, UC is taught to be able to occur after episodes of infective diarrhoea. There is no definite association with a single infective agent. There is an association with measles and mumps as well. - Enteric Microflora: In IBD patients, there is loss of immunological tolerance to the intestinal microflora. NB: this can be manipulated by antibiotics (less frequently), probiotics and prebiotics to balance this favourably. - Drugs: Drugs are known to exacerbate the disease and not cause the disease. - NSAIDS à known to exacerbate IBD as they inhibit the synthesis of cytoprotective prostaglandins. - Antibiotics can change the enteric microflora and therefore precipitate the relapse of the disease. - Oral contraceptives are also known to increase the risk of developing CD which is possibly caused by vascular changes. - Isotretinoin which is used for acne could possibly be a risk factor. It is known that appendectomy has a protective effect in CD and UC. Stress is also implicated as a trigger factor in terms of the relapse of the disease. It activates inflammatory mediators at enteric nerve ending in gut wall. [Genetics]. In terms of genetics, there is a known pattern in relation to the cause of IBD. Genetic factors influence the risk of IBD mainly by causing. - Disruption of epithelial barrier integrity. - Deficits in autophagy. - Deficiencies in innate pattern recognition receptors. - Problems with lymphocyte differentiation especially CD. Here, there is inappropriate response to the immune system in the mucosa of the GI-tract to normal enteric flora. Mutations of the gene CARD15/NOD2 located on chromosome 16. This is associated with small intestine CD in white populations. The genes OCTNI on chromosome 5 and DLG5 on chromosome 10 have also been linked to CD. In UC, there is an autoimmune component. About 70% of UC patients have p-ANCA (anti-neutrophil cytoplasmic antibodies). In CD, there is an autoimmune disease association known as ankylosing spondylitis and HLA-B27. Ethical factors. - Jews are more prone than non-Jews. - IBD incidence is lower on non-white races. Familial factors. - First degree relatives of those with IBD have up to 20-fold increase in developing the disease. - 15 -- fold greater concordance for IBD in identical twins than non-identical twins. [Pathophysiology of IBD]. IBD is a severe, prolonged, and inappropriate inflammatory response to factors that trigger the disease. This leads to alteration of the normal architecture of the GI tract. This could be. - Increased activity of effector lymphocytes and pro-inflammatory cytokines that overrides normal control mechanisms. - Primary failure of regulatory lymphocytes and cytokines. - In CD, T cells are resistant to apoptosis after inactivation. - [Pathophysiology of CD]. Affects any part of the gut. It may involve one area or multiple areas and usually at the terminal ileum and ascending colon. It is discontinuous. Affected areas are thickened, oedematous and narrowed. Here, deep ulcers may also appear. Mucous membrane between fissures has a cobblestone appearance. This can progress to deep fissuring ulcers, fibrosis and strictures. Also, this can lead to bowel obstructions, abscesses and gut perforations. Microscopically, there is non-specific granulomatous inflammation. The inflammation extends throughout all the layers of the bowel (transmural). Inflammatory cells are seen throughout -- lymphocytes and plasma cells. In CD, the inflammation is TH-1 associated. Chronic inflammation in CD may lead to increased risk of cancer. - [Pathophysiology of UC] In UC, it starts in the rectum which is called proctitis. It then diffuses to the sigmoid and descending colon which is called left-sided and then eventually gets to large intestine which is then called universal. At first presentation. - 40% of patients are diagnosed with proctitis which is affecting the rectum. - 40% sigmoid and descending colon (left sided colitis). - 20% are diagnosed as universal which is affecting the whole colon. In UC, it is only the mucosa and submucosa being affected. It is continuous from the rectum to the whole colon. It forms crypt abscesses and mucosal ulceration. The mucosa looks red, inflamed and bleeds easily leading to bloody diarrhoea. - Purulent and granular with superficial ulceration. - Pseudo polyps in severe inflammation. Microscopically, inflamed cells infiltrate the lamina propria and the crypts. UC is also TH-2 associated, Dysplasia can be seen from biopsies, and this can progress to carcinoma. **[SYMTOMS, COMPLICATIONS AND DIAGNOSIS OF IBD]**. Symptoms of IBD (CD and UC). - Diarrhoea. - Fever. - Abdominal pain. - Nausea and vomiting (more common in CD). - Malaise. - Lethargy. - Weight loss (more common in CD). - Malabsorption. - Growth retardation in children. [Clinical features of CD]. In CD, it tends to be much more disabling than UC. The onset of the disease can be acute and insidious. Other symptoms include. - Pain particularly in the Lower Right Quadrant. - Anaemia. - Palpable masses. - Small bowel obstructions. - Abscesses. - Fistulas. - Gut perforations. [Clinical features of UC]. Symptoms of UC include. - Diarrhoea possibly with blood / mucous. This could be up to 10-20 liquid stools per day in severe cases. - Abdominal pain (cramps) with fever. - Constipation. 50% of UC patients are known to have relapse each year. Severe attacks can be life-threatening. A white background with black text Description automatically generated [Complications of IBD -- 10-20%]. Some of the inflammation in IBD will spill over into other tissues. Some of the key areas where the immune cells attack includes the skin, the eyes, the liver meaning there can be problems associated with these areas. - [In the bones Joints and Bones]: They can lead to arthropathies (arthritis -- like symptoms) and osteopenia. Could be attributed to the release of factors such as osteoclast which attacks the bones and joints.  - [In the skin]: Here it can lead to two things. - Erythema nodosum: Tender, hot, red nodules à Subsides over a few days to leave a brown skin discolouration. A close-up of a person\'s legs Description automatically generated - Pyoderma gangrenosum: pustule which later develops into ulcers.  - In the eyes: It can lead to. - Episcleritis: This is the intense burning and itching of blood vessels. - Uveitis: Headaches, burning red eye and blurred vision. - Sclerosing Cholangitis: It can lead to. - Chronic inflammation of the biliary tree. - Leads to progressive fibrosis and biliary strictures. [Morbidity]. In terms of quality of life, this is generally low in CD when compared to UC. This is because, in CD, when the small intestine is affected, malabsorption may mean the patient may become malnutrienated etc and possibly die from that whereas in UC where it is only affecting the rectum and colon only, removing the large intestine entirely does not affect the food absorption of the body. In both CD and UC, there is increased risk of peritonitis and malignancy. Malnutrition and chronic anaemia are common in long-standing CD. [Diagnosis of IBD]. Diagnosis is confirmed by clinical examination and combination of investigations. - Biochemical. - Endoscopy. - Radiology. - Histological. - Nuclear medicine based. - [History of the disease]: Full history to include, any recent travel, medication, smoking and family history. Details of the symptoms including stool frequency, urgency, rectal bleeding, abdominal pain and fever. - [Examinations]: Here there will be some general physical signs: general well-being of the patient, pulse, blood pressure, temperature, weight loss, abdomen tenderness or distention (Right iliac fossa mass) and anus (oedematous anal tags, fissures or perianal abscesses). - [Initial investigations]: They include. - Blood tests à anaemia is common, deficiency of iron and/or folate also occurs, raised ESR and CRP and a raised WCC, hypoalbuminaemia, LFTs may also be abnormal. - Microbiological testing for infectious diarrhoea. - Serological tests à Saccharomyces cerevisae antibody usually present in CD, p-ANCA antibody only present in UC and not CD. - [Abdominal radiography]: This is essential in the initial assessment of suspected severe IBD. It excludes colonic dilatation and also helps assess the disease extent in UC. It also helps in the identification of proximal constipation and gives an impression of right iliac fossa mass in CD. It can also show evidence of small bowel dilation. [Investigations]. - [Sigmoidoscopy]: This examines only the lower third of the colon. It uses sigmoidoscope. This is used for all patients presenting with diarrhoea. Used to confirm diagnosis of UC. A diagram of the intestine Description automatically generated - [Rectal Biopsy]: Detects non-specific histological changes in the mucosa. - [Colonoscopy]: Internal examination of the colon (entire length) using a colonoscope. Used for mild or moderate disease to assess the extent of the disease. Biopsy can also be performed. Other investigations.  **[IBD PATHOGENESIS]**. [The Gut's defence against pathogens. ] The gut is mostly the first point of contact when it comes to pathogens. The gut consists of the mouth, oesophagus, stomach, small intestine and large intestine all the way to the anus. When a pathogen finds its way into the gut by entering the mouth, it can get to the mucosa and submucosa of the oesophagus but most of them will be killed by the extremely acid area of the gut, however some of the pathogens find their way to the small intestine. In a healthy gut, the goblet cells release a lot of mucus which serves as a first point of defence against the pathogens. Also, there are Paneth cells near the stem cells (they replenish the gut cells) found in the mucosa of the gut that secrete antimicrobial peptides such as alpha defensins that fight against these pathogens. Furthermore, the lumen of the gut is known to have a lot of IgA antibodies that can also help fight against the pathogens. There are specialised cells known as M cells which is found just on the peyes patch can sample antigens and pass Lumenal antigens to immune cells found in the peyes patch. Inside the peyes patch thetre is a mixture of immune cells like dendritic cells, T cells, B cells and macrophages. There is a peyes patch and this is where majority of the immune cells can be found in the mucosa of the gut. Also, there is a secondary lymphatic system where a lot of immune cells are again found. The dendritic cells can also use its dendrites that protrude into the lumen of gut and samples antigens. If these antigens are self, then the dendritic cells activate naïve t cells and make them Treg cells which can pass through the lymphatic system to the lamina propria layer of the mucosa where they release IL-10 to calm down the inflammation in the gut. However, if the antigens are not self but rather pathogens then the dendritic cells can release cytokines like IL-6 and activate the naïve T cells to T helper cells, TH1 and Th2 and Th17 lymphocytes. Thet can also take on entertropic CD4+ memory T cells in the systemic circulation. Also, the activate T cells can get into the gut and exert their immune response.  [In IBD.] [IBD DRUGS]. The IBD drugs are corticosteroids, azathioprine, 5-ASA (mesalazine), ciclosporin and methotrexate. Corticosteroids.  Azathioprine.  5 Amino salicylates (5-ASA). Ciclosporin.  Methotrexate.  **[IBD THERAPEUTICS]**. [ULCERATIVE COLITIS CLINICAL THERAPEUTICS]. Ulcerative colitis is characterised by mucosal inflammation in the colon presenting typical as superficial damage which initiates in the rectum and extend throughout the colon in a continuous fashion. It is a chronic relapsing and remission disease characterised by urgency to pass stool, blood and mucous stool, anaemia, cramping and general characteristics such reduced weight, reduced appetite. In addition to these, there are some extraintestinal features some of which indicate severe disease and need imperative treatment. Treatment of UC requires a multi-disciplinary approach. [Aim of therapy]. The aim of therapy is to reduce symptoms and maintain the quality of life of the patient. To do this, is important to induce remission as well as maintain remission as well as minimising toxicity related to drugs (short and long term). Treatment of UC can be grouped into two forms: Acute and maintenance therapy. Acute therapy is what is used upon first presentation of the disease or in the advent of disease flare up. This is what is called inducing remission of the disease. Maintenance therapy is that used to maintain remission/prevent the relapse of the disease. [Target of therapy (definition of remission)]. There is no evidence to define the remission of the disease. When UC is compared to CD, there is no substantial evidence to indicate that continuous inflammation seen in UC can lead to permanent bowel damage. However, there is data that suggest that UC is continuous and as such Treat to target is required to manage the disease appropriately. There are several clinical tools used to define the severity of the disease and they include. - [Montreal classification]: Describe the extent and severity of the disease. In terms of the extent of the disease; E1 = proctitis, E2 = left sided. E3 = Extensive. In terms of the severity of the disease; This describes the symptoms the patient has. S0 = clinical remission which basically mean the patient is asymptomatic, S1 = mild which means the 4 or less stools plus or minus blood, no systemic illness, normal inflammatory markers. S2 = moderate which means greater than 4 stools but minimal signs of systemic toxicity. S3 = severe which means at least 6 stools a day, pulse rate of at least 90 beats per minute, increase temperature of about 37.5, low haemoglobin and high ESR. - True love and Witts\'s severity index. - [Mayo score]: Encompasses stool frequency, rectal bleeding, endoscopic score, and physician score. In addition to these there are several clinical tools that may be used. Montreal classification and True love and Witts\'s severity index may be preferred more as it is less invasive however, there are some patients who may be asymptomatic butc may still show inflammation on endoscopy. [Choice of therapy]. The choice of therapy is dependent on. - Disease severity. - Disease extent. - Disease location. - Previous response to therapy. - Presence of complications: Risk factors for progression and complications, patient characteristics, risk: benefit, cost. In term of NICE, it is much more dependent on the location of the disease. 30 -- 60% will have proctitis, 16 -- 45% will have left sided and 14 -- 35% have extensive pancolitis. [NICE 130 Guideline and recommendations for management]. - Inducing remission - Mild to moderate UC. [Proctitis]: Specifically affecting the rectum. A large intestine with a small intestine Description automatically generated First line treatment is topical aminosalicylate. Suppositories is preferred over enemas as it can release the drug effectively in the rectum compared to enemas which basically release drugs in the sigmoid section of the colon which is not needed. Suppositories work faster when compared to oral therapy as it provides high concentration inside the colon and can release the drug much faster. If remission is not achieved in 4 weeks, then consideration of adding in an oral aminosalicylate. The use of both oral and topical aminosalicylate has proven to show better response. If further treatment is needed, then consideration of adding topical and oral corticosteroid for a limited time. Although other steroid can be used, oral prednisolone 40mg daily to be used for 8 weeks is recommended. In terms of the topical corticosteroid, prednisolone 5 mg suppositories can be used. - For patients that decline topical treatment, consider oral aminosalicylate but is supposed to be remembered is not as effective. In terms of topical treatment, adherence is important to ensure the effectiveness of the treatment. - For patients that cannot tolerate aminosalicylates, consider time limited oral or topical corticosteroid. [Proctosigmoiditis and left sided (distal colitis)]. First line is topical aminosalicylates. The condition having moved to the distal colon, the use of enemas is better. If remission is not achieved in 4 weeks, the adding high-dose oral aminosalicylate is used. OR switching to high-dose oral aminosalicylate and time limited topical corticosteroid. If further treatment is needed, them stop the topical treatment and offer oral aminosalicylate and time limited oral corticosteroid. If patients cannot tolerate aminosalicylates, then consider time limited topical or oral corticosteroids. [Extensive]. With the increased area of disease tissue, the starting therapy is stepped up. First line is topical aminosalicylate and a high dose aminosalicylate. If remission is not achieved in 4 weeks, then stop topical treatment and offer a time-limited course of oral corticosteroids. For people who do not tolerate aminosalicylate, consider a time limited oral corticosteroid. - Inducing remission -- Moderate -- severe. The main stay of treatment is oral corticosteroid is used example oral prednisolone. Always time limited meaning they are used for short period of time and then stopped. There are other medicines that may be used as well. They include the Biologics and Janus Kinases.  - Inducing remission -- Acute severe. Here, the patients are supposed to be hospitalised. 15 -- 25% of patient with UC will require hospitalisation. The patient may have greater than 6 bloody stools per day, systemic toxicity with at least one of the following, high temperature of 37 degrees, a pulse rate of at least 90 beats per minute, heamoglobin \< 5 mg/L or CRP \> 30mg/L. These patients require a Multidisiplinary approach. Mainstay of treatment is IV corticosteroids: They include methylprednisolone 60 mg per day OR hydrocortisone 100 mg QDS. Some benefits are expected to be seen by day 3. Alternatively, patients who are intolerant/decline/CI corticosteroids then consideration of adding IV cyclosporin. OR if symptoms worsen or little/no improvement within 72 hours on IV corticosteroids, then IV ciclosporin may be added to IV corticosteroids. If ciclosporin is CI/clinically inappropriate, then infliximab is an option. [Maintenance therapy]. A close-up of a list of words Description automatically generated  A close-up of a white background Description automatically generated [CROHN'S DISEASE CLINICAL THERAPEUTICS]. [Aim of therapy]. The aim of therapy is to reduce symptoms and maintain the quality of life of the patient. To do this, is important to induce remission as well as maintain remission as well as minimising toxicity related to drugs (short and long term). Treatment of UC can be grouped into two forms: Acute and maintenance therapy. Acute therapy is what is used upon first presentation of the disease or in the advent of disease flare up. This is what is called inducing remission of the disease. Maintenance therapy is that used to maintain remission/prevent the relapse of the disease. - Unfortunately, it is a little bit complicated than this. Inducing symptomatic remission and maintenance alone does not tackle the natural course of the disease. This leads to poor outcomes which are associated with untreated inflammation. New hypothesis such as tight control and treat to target are being investigated. - Tight control: Achievement of clinical and endoscopic remission. - Treat to target: Adjustment to therapy based on assessment. Is important to monitor the disease at regular intervals to include CRP, faecal calprotectin, and endoscopy etc. [Choice of therapy]. a. [Disease location]: Since Crohn's disease affects any part of the GUT. Ileocecal Crohn's disease is the most common form where patients mostly complain of right sided pain in the lower abdomen especially after eating and patient may experience weight loss etc. Patients may also have terminal ileocecal disease, Crohn's colitis etc. b. [Disease activity and severity]: Crohn's Disease Activity Index (CDAI) clinical tool. A value less than 150 indicates remission and a value greater than 300 indicates severe disease. The Harvey Bradel index (HBI), a value of less than 4 indicates remission and a value of greater than 8 indicates severity of the disease. Other clinical assessment tool such as PROMs. c. Previous responses to therapy. d. [The presence of complications]: Risk factors for progression and complications, patient characteristics and drug characteristics considering risk, benefit, and cost. Patient's previous use of corticosteroids. - The British society of Gastroenterology states that, for mild to moderate ileocolonic disease (proximal disease), ileal release of Budesonide 9 m at 8 week is as activity as prednisolone 40 mg. The final recommendation for NICE for patients in first presentation or single exacerbation, the use of aminosalicylates if the patient is CI to steroids or decline the use. - Inducing remission -- Add on therapy. Mainly for patients with 2 or more inflammatory exacerbations in 12 months or if glucocorticoid dose cannot be tapered. Consider Azathioprine or Mercaptopurine: Azathioprine dose of between 2 - 2.5 mg/kg per day or mercaptopurine dose of 1 -- 1.5 mg/kg is used. Have slow onset of action. Methotrexate may be used if Azathioprine and mercaptopurine is CI.  A close-up of a medical document Description automatically generated [Maintaining Remission].  Maintaining remission after surgery. 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