Scheme of drug therapy for nonspecific ulcerative colitis in children

general description

Ulcerative colitis or nonspecific ulcerative colitis is a chronic inflammatory disease of the mucous membrane of the large intestine, resulting from an imbalance of the immune system (antibodies are released to the own epithelium of the mucous membrane).
Cases of morbidity are registered in 0.3-0.5% of people, which is approximately 3-5 cases per 100 thousand population. The disease occurs in both men and women.

Ulcerative colitis can affect people of any age, most often occurring in the 25-35 and 60-80 age groups.

Scheme of drug therapy for nonspecific ulcerative colitis in children

Nonspecific ulcerative colitis (UC) is a chronic inflammatory bowel disease, the etiology of which remains unknown to date. The frequency of nonspecific ulcerative colitis, according to foreign researchers, is 4–10 per 100 thousand children [1]. Difficulties in selecting therapy for UC are associated with a lack of knowledge about the etiology and some parts of the pathogenesis of the disease [2].

In choosing the most optimal treatment regimen for nonspecific ulcerative colitis, first of all, determining the degree of activity of the inflammatory process and its localization helps. According to the literature, with nonspecific ulcerative colitis, the inflammatory process in 54% of cases is localized in the rectum and sigmoid colon, in 28% of cases there is left-sided damage to the colon, and in 18% of patients pancolitis occurs. In young children (up to three years of age), the right-sided parts of the colon are predominantly affected [3].

The degree of activity of nonspecific ulcerative colitis is determined based on the severity of clinical and laboratory parameters. The most pronounced clinical indicators are: diarrhea, blood in the stool, intensity of abdominal pain, weight loss and fever. Laboratory indicators of nonspecific ulcerative colitis include changes in hemoglobin and albumin levels, and an increase in ESR. Currently, there are three degrees of activity of ulcerative colitis: mild, moderate and high (see Table 1) [4, 5].

Among the main directions in the treatment of nonspecific ulcerative colitis, nutrition correction and diet therapy should be mentioned. The principles of rational nutrition include avoiding fried, fatty, salty, spicy foods, milk and dairy products.

A sick child’s diet should also not include chocolate, legumes, mushrooms, fruits and vegetables that stimulate peristalsis (plums, kiwi, dried apricots, beets). During periods of exacerbation, the consumption of fiber, sweets, and juices is limited [6]. With long-term remission, the diet can be significantly expanded, but milk and dairy products are contraindicated for the patient throughout his life [7].

Drug therapy as the main method of treating ulcerative colitis involves the use of:

• preparations of 5-aminosalicylic acid (5-ASA);
• corticosteroids;
• immunosuppressants (cytostatics).

Symptomatic and antibacterial therapy is prescribed to restore the structure of the mucous membrane, normalize peristalsis, restore digestive processes and eubiosis of the colon, and increase the overall immunoreactivity of the body. If diet therapy and drug therapy are ineffective, surgical treatment is indicated.

5-ASA drugs are basic in the treatment of ulcerative colitis. In 1942, the drug sulfasalazine was first used in patients with combined damage to the intestines and large joints, which gave a pronounced positive effect: arthralgia and hemocolitis were relieved [8]. Sulfasalazine has been used in the treatment of ulcerative colitis to this day. However, its use is limited due to a large number of side effects, such as hemolytic anemia, neutropenia, drug-induced hepatitis, Steven-Johnson syndrome, pericarditis, interstitial nephritis, pancreatitis. The frequency of side effects, according to different authors, ranges from 5 to 55% [9]. Sulfasalazine contains mesalazine (5-aminosalicylic acid), which has an anti-inflammatory effect, and sulfapyridine, which ensures the delivery of mesalazine to the colon,

to the site of localization of the main inflammatory process in nonspecific ulcerative colitis. Sulfapyridine contributes to the development of a large number of side effects [10]. Numerous studies conducted to develop drugs containing mesalazine made it possible in the late 70s and early 80s. create drugs that did not contain sulfapyridine. This has led to a significant reduction in side effects, which in turn has made it possible to use higher doses of mesalazine and, in some cases, eliminate the use of corticosteroids. Mesalazine is active upon local contact with the intestinal mucosa, and its therapeutic efficacy is correlated with the concentration in the intestinal lumen. These features of mesalazine made it possible to develop drugs based on it and successfully use them both in the acute period and for the purpose of local maintenance therapy, such as suppositories and microenemas [11].

Table 2 presents some of the 5-ASA drugs [12], which can be divided into three groups. The first group includes sulfasalazine and olsalazine, which are released under the influence of intestinal flora and act in the colon. The second group includes mesacol, salofalk, rovaza. The release of these drugs depends on the pH of the environment, and their action is localized in the terminal ileum and colon. The third group includes the drug Pentasa, which is released slowly and acts throughout the intestine.

The mechanism of action of 5-ASA is based on an anti-inflammatory effect, which is realized through inhibition of prostaglandin formation, reduction in the synthesis of cytokines IL-1, IL-2, IL-6, tumor necrosis factor, inhibition of the lipoxygenase pathway of arachidonic acid metabolism, and reduction in the production of free radicals [13, 14, 15].

Indications for the use of 5-ASA drugs.

• Primary therapy for mild UC activity.
• Primary therapy in combination with steroids for moderate to highly active UC.
• Maintenance therapy for UC.

In our country, the most commonly used 5-ASA drugs are sulfasalazine, salofalk and pentasa. As noted earlier, sulfasalazine has been used in the treatment of ulcerative colitis for 60 years. The breakdown of sulfasalazine into mesalazine and sulfapyridine depends on the composition of the intestinal flora and occurs only in the colon [16]. When inflammation is localized in the cecum and ascending colon (in young children), the effectiveness of sulfasalazine is significantly reduced.

Salofalk - the active ingredient in this drug is mesalazine. The drug is a tablet coated that is resistant to gastric juice. Its feature is the absence of a sulfonic component, which reduces the number of side effects. Activation of salofalk occurs when the acidity of the environment changes (over 6). The site of action of salofalk is predominantly the terminal ileum and colon [17].

The drug Pentasa appeared on the Russian market relatively recently. The active ingredient is also mesalazine, enclosed in microgranules that are resistant to the acidic environment of the stomach. Pentasa is released slowly, gradually, along the intestine, starting from the duodenum. At the same time, changes in the level of intraluminal pH and acceleration of transit during diarrhea do not affect the rate of drug release. Thanks to these features, Pentasa provides high therapeutic concentrations throughout the small and large intestines [18, 19].

When treating nonspecific ulcerative colitis, doses of 5-ASA drugs are selected individually. Typically, the dose of sulfasalazine is 50–60 mg/kg/day; the maximum daily dose at which no side effects are observed is up to 6 g/day [20]. The dosage of mesalazine ranges from 20 to 50 mg/kg/day, the maximum daily dose is 4 g/day. At these dosages, the drug can be used from one to three months [21]. Salofalk and Pentasa are used for local therapy in suppositories and microenemas: suppositories - 250-500 mg once or twice a day, microenemas - 2-4 mg once a day. Local therapy is carried out for 14–28 days; if necessary, repeated courses of local therapy can be prescribed. Maintenance doses of 5-ASA for nonspecific ulcerative colitis are half the therapeutic dose: sulfasalazine - 20 mg/kg/day, mesalazine - 10 mg/kg/day. Maintenance therapy is prescribed for a long time, from six months to two years, in the absence of an active inflammatory process [22].

Side effects when using mesalazine are quite rare (1–3%) [23]. In this case, abdominal pain, diarrhea, flatulence, nausea, vomiting, and pancreatitis are noted. Allergic reactions occur in the form of skin itching and allergic rash. Bronchospasm, pericarditis, myocarditis, and interstitial nephritis are extremely rare; their frequency, according to the literature, is 0.1-0.5% [24]. To prevent side effects, it is not recommended to exceed the maximum permissible therapeutic doses of drugs; the condition of peripheral blood should be monitored (complete blood count once every two weeks). Repeated biochemical blood tests are also necessary, including determination of the level of total protein, protein fractions, urea, creatinine, transaminases, alkaline phosphatase, electrolytes, and serum iron.

In addition to 5-ASA drugs, corticosteroids are used in the treatment of ulcerative colitis. The most commonly used are prednisolone, methylprednisolone, and hydrocortisone. The mechanism of action of corticosteroids is based on the anti-inflammatory effect, reducing the formation of prostaglandins, inhibiting the formation and action of cytokines IL-1, IL-2, IL-3, tumor necrosis factor and stabilization of lysosomal membranes [25]. Indications for the use of corticosteroids in nonspecific ulcerative colitis are the lack of effect of mesalazine therapy for mild UC activity (in combination with mesalazine), primary therapy for moderate and high UC activity. Corticosteroid treatment is often complicated by multiple side effects, the most common of which are hypothalamic-pituitary axis suppression, Cushing's syndrome, hypertension, osteoporosis, peptic ulcers, electrolyte disturbances, and steroid-induced diabetes [26]. Side effects are dose-dependent and increase with increasing duration of hormonal therapy. To prevent them, it is necessary to monitor the state of peripheral blood, biochemical parameters, and electrolyte state of the blood.

Doses of glucocorticoids in the treatment of nonspecific ulcerative colitis for oral and/or parenteral administration are: when prescribing prednisolone - 1-2 mg/kg/day, methylprednisolone - 25-30 mg/day. For local therapy, it is possible to use prednisolone in suppositories 20-40 mg 1 time per day and/or in microenemas 20 mg per 60-100 ml of liquid 1 time per day. Hydrocortisone is usually used only for local therapy in microenemas 100 mg per 60–100 ml of water once a day. The duration of therapy for oral administration is 2-3 weeks, then it is necessary to gradually reduce the dosage of the drugs by 10 mg per week to a level of 0.75 mg/kg/day. Further reduction is carried out by 5 mg per week until the drug is completely discontinued. In this case, the dose of 5-ASA should not be lower than 1/2 of the therapeutic dose [27].

Hormonal therapy can lead to the development of hormonal dependence, in which the positive effect is either absent or replaced by reactivation of the inflammatory process due to dose reduction or withdrawal of corticosteroid therapy [28]. There are two forms of hormonal dependence of ulcerative colitis (in relation to steroids): a hormone-resistant form, which is primary, and a hormone-dependent form, which is often secondary. In this case, sensitivity to 5-ASA drugs may remain or be absent [29]. To overcome hormonal dependence, increased doses of glucocorticoids and pulse therapy are used; if these measures are ineffective, immunosuppressive therapy is indicated [19].

Immunosuppressants used in the treatment of ulcerative colitis include azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine. The mechanism of action of these drugs is different. Azathioprine and 6-mercaptopurine affect natural killer cells [30], methotrexate disrupts the synthesis of RNA and DNA of cells [31], cyclosporine inhibits the production of cytotoxic lymphocytes and inhibits interleukins IL-2, as well as their receptors [32].

Indications for the use of immunosuppressants for nonspecific ulcerative colitis are hormone-resistant and hormone-dependent forms.

Doses of immunosuppressants in the treatment of ulcerative colitis, according to different authors, vary greatly. Typically, azathioprine is prescribed at a dose of 1-2 mg/kg/day, 6-mercaptopurine at a dose of 1.5 mg/kg/day. The dosage regimen is set individually. The effect of therapy with these drugs is observed after 3 months. Methotrexate is used at a dose of 2.5 mg/day; the therapeutic effect of methotrexate occurs much earlier than that of azathioprine: after 3-4 weeks. Cyclosporine is usually used in a short course to interrupt the activity of the process, followed by a transition to long-acting immunosuppressants [33].

The toxic effects that occur with the use of antidepressants are very diverse. These include anorexia, nausea, vomiting, suppression of hematopoiesis, skin rash, arthralgia, myalgia, pancreatitis, toxic hepatitis, cholestasis syndrome, opportunistic infections, lymphadenopathy, arterial hypertension, toxic kidney damage, parasthesia, tremor. The severity of side effects of immunosuppressants limits their use in the treatment of ulcerative colitis [34]. To prevent side effects, it is necessary to monitor the functions of hematopoiesis, liver, and kidneys. General blood test, general urine test, biochemical blood test, including determination of the level of total protein, protein fractions, liver enzymes, alkaline phosphatase, urea, creatinine, glucose, acute phase proteins - all these studies must be carried out once a week.

Symptomatic therapy for nonspecific ulcerative colitis is indicated for any degree of activity of the inflammatory process. In each special case it is selected individually. Enzyme preparations (Creon, Mezim-Forte) are often prescribed in the presence of malabsorption syndrome and to relieve the load on the pancreas. Choleretic drugs and hepatoprotectors are used if the patient has cholestasis syndrome and toxic hepatitis. To correct vitamin and metabolite deficiency and iron deficiency anemia, multivitamins, iron preparations (for parenteral administration), and a metabolite complex are used. It is advisable to include herbal medicine (galangal, chamomile, burnet, licorice) in the complex of therapeutic effects. Antibacterial therapy is prescribed in the presence of secondary infections, septic complications, and perianal inflammation. Antibiotics, nitrofuran drugs, metronidazole (Trichopol) are used [27].

The treatment regimen for nonspecific ulcerative colitis, developed by the European Association of Pediatric Gastroenterologists, Hepatologists and Nutritionologists (ESPGHAN) and used in the Department of Gastroenterology and Hepatology of the Scientific Center for Disease Control and Prevention of the Russian Academy of Medical Sciences, is based on various degrees of activity and localization of the inflammatory process. For isolated proctitis, the main treatment method is local therapy in the form of suppositories and/or microenemas. With a mild degree of activity, you can limit yourself to using only mesalazine drugs (salofalk, pentasy). Changes in intestinal flora make treatment with sulfasalazine suppositories ineffective. The treatment regimen for nonspecific ulcerative colitis with proctitis is presented in Table 3.

For proctosigmoiditis of moderate and high activity, in addition to local therapy, oral administration of mesalazine or prednisolone in age-specific dosages is indicated. The treatment regimen for proctosigmoiditis is given in Table. 4.

Pancolitis, or total intestinal damage, usually has a moderate or high degree of activity. In the treatment of pancolitis, mesalazine or sulfasalazine orally and prednisolone in large doses orally or parenterally are used; in the presence of rectal damage, local therapy is indicated (see tables 3 and 4). The treatment regimen for pancolitis in nonspecific ulcerative colitis is presented in Table 5. Doses of 5-ASA drugs are given for children over 12 years of age. For children under 12 years of age, the dosage of drugs is calculated based on body weight: sulfasalazine - 60 mg/kg/day, mesalazine - 30-40 mg/kg/day.

The tactics for monitoring children with nonspecific ulcerative colitis in the active stage include conducting control blood tests to determine the level of hemoglobin, ESR, leukocytes, total protein and protein fractions once a week during the active stage and once a month during remission. Colonoscopy and morphological examination are carried out 3 months after the appointment of therapy during exacerbation of the disease, once every 2-3 years - during remission, once a year - when the disease history is more than 8-10 years. Children with inflammatory bowel diseases require long-term medical supervision. In the presence of remission in spring and autumn, preventive courses of 5-ASA drugs in maintenance doses for 3 months are indicated [7].

Thus, treatment of nonspecific ulcerative colitis is based on determining the localization of the inflammatory process and the degree of its activity. With a mild degree of activity, the prescription of mesalazine is indicated; moderate and high degrees of activity require the appointment of corticosteroid therapy. If there is no effect from therapy with 5-ASA drugs and steroids and the development of hormonal dependence, immunosuppressive therapy is used. If drug therapy is ineffective, surgical treatment is indicated.

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E. G. Tsimbalova, Candidate of Medical Sciences A. S. Potapov P. L. Shcherbakov, Doctor of Medical Sciences SCCD RAMS, Moscow

Causes of ulcerative colitis

Until now, the exact cause of ulcerative colitis is unknown.

Several reasons are considered in the scientific literature, but they are not fully understood:

• Genetic predisposition: close relatives have diseases such as Crohn's disease or ulcerative colitis
• Bacterial and viral infections
• Environmental factors (smoking, adherence to diets, long-term use of oral contraceptives)