Inflammatory bowel disease in adults

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are recurrent diseases with periods of remission and are characterized by chronic inflammation of various parts of the gastrointestinal tract that lead to diarrhea and abdominal pain.

Inflammation is the result of a cell-mediated immune response in the mucosa of the gastrointestinal tract. The exact etiology is unknown; some studies suggest that normal intestinal flora elicits an immune response in patients with a multifactorial genetic predisposition (possibly a breach of the epithelial barrier and immune defense of the mucosa). No specific, environmental, nutritional or infectious causes have been identified. The immune response involves the release of inflammatory mediators, including cytokines, interleukins and tumor necrosis factor (TNF).

Although the symptoms of Crohn's disease and ulcerative colitis are similar, they can be differentiated in most cases. Approximately 10% of cases of colitis are considered nonspecific. The term "colitis" is applicable only to inflammatory diseases of the colon (eg, ulcerative, granulomatous, ischemic, radiation, infectious). The term "spastic (mucous) colitis" is sometimes used incorrectly, since it refers not to inflammatory, but to functional bowel diseases.

[1], [2], [3], [4], [5], [6], [7], [8]

Epidemiology of inflammatory bowel disease

Inflammatory bowel disease affects people of all ages, but is usually manifested at the age of 30 with a peak incidence from 14 to 24 years. Ulcerative colitis may have a second, but smaller, incidence rate between 50 and 70 years; however, this later peak incidence may include some cases of ischemic colitis.

Inflammatory bowel diseases in adults are most common in people of northern European and Anglo-Saxon origin and several times more often among Jews. The incidence of inflammatory bowel diseases is lower in central and southern Europe and even lower in South America, Asia and Africa. However, the incidence increases in blacks and Hispanics living in North America. Both sexes are affected equally. In relatives of the first generation of patients with inflammatory bowel disease, the risk of disease increases 4-20 times; the absolute risk of the disease can be above 7%. Family history is much higher with Crohn's disease than with ulcerative colitis.

[9], [10], [11], [12], [13], [14], [15], [16], [17],

What causes inflammatory bowel disease in adults?

A specific gene mutation was identified that determines the high risk of Crohn's disease (but not ulcerative colitis).

Smoking may contribute to the development or exacerbation of Crohn's disease, but reduces the risk of ulcerative colitis. Non-steroidal anti-inflammatory drugs (NSAIDs) can exacerbate inflammatory bowel diseases.

Symptoms of inflammatory bowel disease

Crohn's disease and ulcerative colitis affect, in addition to the intestine, and other organs. Most of the extra-intestinal manifestations are more characteristic of NK and Colitis colitis than of Crohn's disease, limited to the small intestine. Extra-intestinal symptoms of inflammatory bowel diseases are divided into three categories:

1. Disturbances, which usually occur in parallel (ie, increase and decrease), exacerbations of inflammatory bowel diseases. These include peripheral arthritis, episcleritis, aphthous stomatitis, erythema nodosum and pyoderma gangrenosum. Arthritis usually has a migratory, transient nature involving large joints. One or more such concurrent disorders develops in more than one third of patients hospitalized with inflammatory bowel diseases.
2. Disturbances, which are probably a consequence of inflammatory bowel diseases, but appear regardless of the periods of exacerbations of inflammatory bowel diseases. These include ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerosing cholangitis. Ankylosing spondylitis is more common in patients with inflammatory bowel disease and HLA-B27 antigen. The majority of patients with spinal cord injury and iliac-sacral region exhibit signs of uveitis and vice versa. Primary sclerosing cholangitis is a risk factor for biliary tract cancer, which can appear even 20 years after colectomy. Liver diseases (eg, fatty hepatosis, autoimmune hepatitis, perichalangitis, cirrhosis) are observed in 3-5% of patients, although minor changes in functional hepatic tests are more typical. Some of these disorders (eg, primary sclerosing cholangitis) may precede inflammatory bowel disease, and if they are diagnosed, an assessment should be made of the possibility of manifesting inflammatory bowel diseases.
3. Violations that are the result of destructive changes in the gut. They develop mainly in the severe course of Crohn's disease of the small intestine. Malabsorption may be the result of extensive resection of the ileum and cause deficiency of vitamin B ₁₂, and minerals, resulting in anemia, hypocalcemia, hypomagnesemia, coagulation disorders, bone demineralization in children - to stunted growth and development. Other disorders include the formation of kidney stones due to excessive absorption of oxalates, hydroureter and hydronephrosis due to compression of the ureter, inflammatory bowel diseases, cholelithiasis as a result of impaired reabsorption of bile salts in the ileum and amyloidosis as a consequence of the long-running purulent inflammatory process.

In all three groups, thromboembolic disease may develop as a result of the influence of various factors.

Treatment of inflammatory bowel diseases

Several classes of medications are effective in the treatment of inflammatory bowel diseases. Details of their choice and use are discussed for each disease.

5-aminosalicylic acid

(5-ASA, mesalamine). 5-ASA blocks the production of prostaglandins and leukotrienes and has other beneficial effects on the inflammatory cascade. Since 5-ASA is active only within the intestinal lumen and is rapidly absorbed in the proximal small intestine, this should be taken into account to create conditions for delayed absorption by oral administration. Sulfasalazine, the original drug in this class, delays the absorption of the 5-ASA complex with the sulphopyridine sulfa group. The complex is split by the bacterial flora in terminal sections of the ileum and colon, releasing 5-ASA. The sulfa group, however, causes numerous undesirable effects (eg, nausea, dyspepsia, headache), violates the absorption of folic acid, and sometimes causes severe adverse reactions (eg, hemolytic anemia and agranulocytosis and, rarely, hepatitis or pneumonitis).

A reversible decrease in the sperm of sperm count and their mobility is observed in 80% of men. When using sulfasalazine it must be taken with food, initially in a low dosage (eg, 0.5 g orally 2 times a day) and gradually increase the dose for several days to 1-2 g 2-3 times a day. Patients should additionally take an oral daily 1 mg folate and monitor a general blood test and liver tests every 6-12 months.

More modern preparations consisting of a complex of 5-ASA with other vehicles are also effective, but have less adverse effects. Olsalazine (dimer 5-ASA) and balsalazine (5-ASA conjugated to the inactive component) are cleaved by bacterial azo reductase (like sulfasalazine). These drugs are activated mainly in the large intestine and are less effective in the lesions of the proximal parts of the small intestine. Dosage of olsalazine is 500-1500 mg 2 times a day and balsalazine - 2.25 g 3 times a day. Olsalazine sometimes causes diarrhea, especially in patients with pancolitis. This problem is minimized by a gradual increase in the dose and intake of the drug with food.

Other forms of 5-ASA include coatings for delayed drug release. Asakol (the usual dose of 800-1200 mg 3 times a day) is a 5-ASA coated with an acrylic polymer whose pH solubility delays the yield of the drug to the distal portion of the ileum and large intestine. Pentase (1 g 4 times a day) is a 5-ASA encapsulated in ethyl cellulose microgranules, and only 35% of the drug is released in the small intestine. Secondary acute interstitial nephritis rarely develops due to the use of mesalamine; periodic monitoring of kidney function is desirable, since in most cases, the disorders are reversible with the timely detection of complications.

With proctitis and lesion of the left half of the large intestine, it is possible to use 5-ASA in the form of suppositories (500 mg 2-3 times a day) or as enemas (4 g at bedtime or 2 times a day). Rectal administration of the drug is effective in the acute course of the disease and prolonged use and may be appropriate in combination with oral administration of 5-ASA.

[18], [19], [20], [21], [22], [23], [24], [25], [26]

Glucocorticoids

Glucocorticoids are indicated in the acute cases of most forms of inflammatory bowel disease if 5-ASA preparations are not sufficient, but they are not intended for maintenance treatment. In severe cases intravenous hydrocortisone 300 mg / day or methylprednisolone 60-80 mg / day is continuously administered by drip or divided doses; at an average severity, oral prednisolone or prednisolone 40-60 mg once a day can be used. Treatment of inflammatory bowel disease continues until the symptoms disappear (usually 7-28 days) and the dose decreases gradually from 5 to 10 mg weekly to 20 mg once daily, followed by a decrease from 2.5 to 5 mg weekly with the maintenance of 5-ASA maintenance therapy or immunomodulators. The adverse effects of short-term therapy with glucocorticoids in high doses include hyperglycemia, hypertension, insomnia, increased activity and acute episodes of psychotic disorders.

Enemas with hydrocortisone or irrigation can be used for proctitis and lesion of the left flank of the colon; In the form of an enema, 100 mg of the drug is injected into 60 ml of an isotonic solution 1-2 times a day. This composition should be retained in the gut as long as possible; instillation before bedtime when the patient's position on the left side with the hips brought to the stomach allow prolonging the delay time of the solution and increasing the area of influence. In case of effectiveness, daily treatment should be continued for approximately 2-4 weeks, then every other day for 1-2 weeks, followed by a gradual cancellation for more than 1-2 weeks.

Budesonide is a glucocorticoid with a high (> 90%) metabolism in the liver during the first cycle; Thus, oral administration may have a significant effect on GI disease, but a minimal suppressive effect on the adrenal glands. Oral administration of budesonide has fewer adverse effects than prednisolone, but it is less effective and is usually used in less severe cases of the disease. Its dosage is 9 mg once a day. Its use is also available outside the US, as is the enema. Like other glucocorticoids, budesonide is not recommended for long-term use.

Immunomodulating drugs

Azathioprine and its metabolite 6-mercaptopurine inhibit the function of T cells. They are effective for long-term use and can reduce the need for glucocorticoids and maintain remission for many years. To achieve a clinical effect, it is often necessary to use these drugs for 1-3 months, so glucocorticoids can not be excluded from treatment for at least 2 months. The usual dosage of azathioprine is 2.5-3.0 mg / kg orally 1 time per day and 6-mercaptopurine 1.5-2.5 mg / kg orally 1 time per day, but the dosage can individually vary depending on the metabolism. Signs of bone marrow suppression should be regularly monitored by counting leukocytes (every two weeks in the 1st month, then every 1-2 months). Pancreatitis or high fever is observed in about 3-5% of patients; any of them is an absolute contraindication to repeated use. Hepatotoxicity develops more rarely and can be controlled by biochemical blood tests every 6-12 months.

In a number of patients who are insensitive to glucocorticoids, methotrexate may be administered orally, intramuscularly or subcutaneously at a dose of 15-25 mg, and even in patients who are insensitive to azathioprine or 6-mercaptopurine. Characteristic nausea, vomiting and asymptomatic changes in functional liver tests. Oral administration of folate 1 mg once daily can reduce some of the adverse effects. The use of alcohol, obesity and diabetes are risk factors for the development of hepatotoxicity. Patients with these risk factors need to perform a liver biopsy after a full dose of 1.5 g.

Cyclosporine, which blocks the activation of lymphocytes, can be effective in patients with severe ulcerative colitis, insensitive to glucocorticoids and requiring colectomy. Its use is absolutely indicated in patients with Crohn's disease and non-treatable fistula or pyoderma.

The initial dose is 4 mg / kg intravenously once a day; with the effectiveness of patients transferred to oral intake of 6-8 mg / kg 1 time per day and then quickly transferred to azathioprine or 6-mercaptopurine. Numerous adverse effects (eg, renal toxicity, epileptic seizures, opportunistic infections) are a contraindication to prolonged use of the drug (> 6 months). In general, patients are not offered ciclosporin treatment if there is no reason to avoid a safer method of treatment than colectomy. When using the drug, its blood levels should be kept between 200-400 ng / ml and thus be considered as a prophylaxis of Pneumocystis jiroveci (formerly called P. Carinii). Tacrolimus, an immunosuppressant used in transplantology, is as effective as cyclosporine.

Anticytokine preparations

Infliximab, CDP571, CDP870 and adalimumab are anti-TNF antibodies. Natalizumab is an antibody against the molecule of leukocyte adhesion. These substances can be effective in Crohn's disease, but their efficacy with YaK is unknown.

Infliximab is administered in a separate intravenous infusion at a dose of 5 mg / kg for 2 hours. Some clinicians start treatment with the parallel assignment of 6-mercaptopurine, using infliximab as a maintenance drug, until the effectiveness of the primary drug reaches its highest activity. A smooth decrease in the glucocorticoid dose can begin after 2 weeks. If necessary, repeated injections of infliximab can be repeated every 8 weeks. Adverse effects include delayed hypersensitivity reactions, headache and nausea. Several patients died from sepsis after using infliximab, so a generalized bacterial infection is a contraindication to the use of the drug. In addition, against the background of the use of this drug reactivated tuberculosis; therefore, before prescribing the drug, it is necessary to perform a tuberculin test with PPD and chest X-ray.

Thalidomide reduces the production of aTNF and interleukin 12 and to some extent inhibits angiogenesis. The drug can be effective in Crohn's disease, but teratogenicity and other adverse effects (eg, rash, hypertension, neurotoxicity) limit its use so far only by scientific research. The effectiveness of other anticytokines, antineutrin antibodies and growth factors is being studied.

[27], [28], [29], [30], [31], [32], [33], [34], [35]

Antibiotics and probiotics

Antibiotics are effective in Crohn's disease, but their use is limited in ulcerative colitis. Metronidazole at a dose of 500-750 mg orally 3 times a day for 4-8 weeks, reverses manifestations of the disease at an average severity level and is quite effective in fistula development. However, adverse effects (especially neurotoxicity) may interfere with the complete course of treatment. Ciprofloxacin in a dose of 500-750 mg orally 2 times a day is less toxic. Some experts recommend the combined use of metronidazole and ciprofloxacin.

Various non-pathogenic microorganisms (eg, commensal Escherichia coli, Lactobacillus species, Saccharomyces) are used daily as probiotics and can be effective in the prevention of inflammation of the pyoictic syndrome (pouchitis syndrom), but other role in the treatment .

[36], [37], [38], [39], [40], [41], [42], [43],

Substitution therapy

Most patients and their families are concerned about the diet and the impact of stress. Although there are isolated reports of the clinical effect of certain diets, including one with a severe restriction of carbohydrates, control studies have not shown any efficacy. Eliminating stressful overloads can be effective.