Ulcerative Colitis: Clinical Guidelines

List of Abbreviations

AZA** – azathioprine**

CD – Crohn's disease

IBD – inflammatory bowel disease

EIM – extraintestinal manifestations

GC – glucocorticoids

DEXA – dual-energy X-ray absorptiometry (lumbar spine densitometry)

GI – gastrointestinal tract

IFX** – infliximab**

CT – computed tomography

BMG – bone mineral gain

BMD – bone mineral density

MRI – magnetic resonance imaging

MTX** – methotrexate**

VEO-IBD – very early onset IBD (under 6 years of age)

PSC – primary sclerosing cholangitis

RCT – randomized controlled trial

CRP – C-reactive protein

GR – grade of recommendations

ESR – erythrocyte sedimentation rate

Thiopurines – Other immunosuppressants / Purine analogues.

LE – level of evidence

US – ultrasound examination

ERCP – endoscopic retrograde cholangiopancreatography

UC – ulcerative colitis

PUCAI – Pediatric Ulcerative Colitis Activity Index

Aminosalicylic acid and similar agents – aminosalicylates, 5-ASA

Terms and Definitions

Ulcerative colitis – a chronic relapsing inflammatory disease of the large intestine characterized by continuous inflammation spreading proximally from the rectum.

Flare (relapse, attack) of UC – the appearance of typical disease symptoms in UC patients in clinical remission, whether spontaneous or medically maintained. In practice, signs of a clinical flare include an increased frequency of defecation with blood loss and/or characteristic changes detected during endoscopic examination of the colon. An early relapse is defined as a relapse occurring less than 3 months after medically induced remission.

UC remission – disappearance of the main clinical symptoms of the disease and healing of the colonic mucosa ("deep remission").

Clinical remission of UC – absence of blood in the stool, absence of urgency/tenesmus with a defecation frequency of no more than 3 times per day;

Endoscopic remission of UC – absence of visible macroscopic signs of inflammation upon endoscopic examination of the large intestine;

Histological remission of UC – absence of microscopic signs of inflammation;

Rectal sparing – lesser severity of inflammation in the rectum compared to proximal segments in young children and during topical treatment (suppositories)

Non-medical switching (NMS) – changing a patient's current therapy to an alternative one for reasons unrelated to clinical ineffectiveness, occurrence of adverse drug reactions (ADRs), or patient intolerance to therapy [1]

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Ulcerative colitis (UC) – a chronic relapsing inflammatory disease of the large intestine characterized by continuous inflammation spreading proximally from the rectum.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of inflammatory bowel diseases (IBD), including UC, remains unknown: the disease develops as a result of a combination of multiple factors, including genetic predisposition, innate and adaptive immune defects, altered intestinal microflora, and various environmental factors. The genetic background predisposes to alterations in the innate immune response, autophagy, microbial recognition mechanisms, endoplasmic reticulum stress, epithelial barrier function, and the adaptive immune response. A key immune defect leading to the development of IBD is impaired recognition of bacterial molecular markers by dendritic cells, resulting in hyperactivation of pro-inflammatory signaling pathways. Additionally, IBD is characterized by decreased diversity of the intestinal microbiota due to a reduction in the proportion of anaerobic bacteria, predominantly Bacteroidetes and Firmicutes, and an increase in aggressive taxa (Proteobacteria, Fusobacteria). Trigger factors include nervous stress, vitamin D deficiency, antibiotic therapy, smoking, a diet low in dietary fiber and high in animal protein, and intestinal infections, especially C. difficile infection [2].

The interplay of these risk factors results in the activation of Th2 cells, overexpression of pro-inflammatory cytokines—primarily tumor necrosis factor-alpha—and cell adhesion molecules. Deficient immune regulation leads to uncontrolled responses to tissue damage and the development of local inflammation. These reactions result in lymphoplasmacytic infiltration of the colonic mucosa, leading to characteristic macroscopic changes and symptoms of UC.

In UC, only the large intestine is affected (except for backwash ileitis), the rectum is invariably involved, and the inflammation is typically restricted to the mucosa (except for acute severe colitis) and is diffuse in nature.

1.3 Epidemiology of the Disease or Condition

The incidence of UC in children ranges from 1 to 4 cases per 100,000 population in North America and Europe [3, 4, 5], which accounts for approximately 15-20% of UC patients of all ages. Data on the prevalence of UC in the Russian Federation are limited. The prevalence of UC is higher in northern latitudes and Western Europe. The incidence and prevalence of UC in Asia are lower, but increasing. Caucasians are affected more frequently than individuals of Black or Asian descent. The peak incidence occurs between 20 and 30 years of age, and a second peak is described at 60-70 years of age. The incidence is approximately equal in men and women.

1.4 Features of Coding the Disease or Condition

K51.0 – Ulcerative (chronic) pancolitis

K51.2 – Ulcerative (chronic) proctitis

K51.3 – Ulcerative (chronic) rectosigmoiditis

K51.4 – Inflammatory polyps

K51.5 – Left-sided colitis

K51.8 – Other ulcerative colitis

K51.9 – Ulcerative colitis, unspecified

1.5 Classification of the disease or condition

To classify UC by lesion localization and phenotypic disease course, it is recommended to use the international classification adopted in Paris in 2010 (Table 1 [6]) and the updated ESPGHAN Porto criteria [7].

Table 1. Paris classification of ulcerative colitis [6].

Very early-onset IBD (VEO-IBD) – diagnosed under 6 years of age, and infantile IBD – onset within the first 2 years of life, are now also distinguished [2, 8].

By the pattern of the disease course, the following are distinguished:

1. Acute course (less than 6 months from disease onset);

2. Chronic continuous course (absence of remission periods exceeding 6 months against the background of adequate therapy);

3. Chronic relapsing course (presence of remission periods exceeding 6 months).

Depending on the response to corticosteroid therapy, the following are distinguished:

– steroid resistance (persistence of disease activity despite oral administration of an adequate dose of systemic corticosteroids for 7-14 days).

– steroid dependence (defined as achieving clinical remission on systemic corticosteroid therapy and recurrence of symptoms upon dose reduction or within 3 months of complete discontinuation, as well as cases where systemic corticosteroid therapy cannot be stopped within 14-16 weeks).

To determine the severity of the current flare (attack), the Pediatric Ulcerative Colitis Activity Index (PUCAI) is used. Mild, moderate, and severe UC flares are distinguished (Appendix G1) [9].

Phases of the disease course:

Clinical remission – absence of clinical symptoms of disease and inflammatory activity according to blood laboratory tests (PUCAI <10 points).

Clinical-endoscopic (or complete) remission – presence of clinical remission and complete mucosal healing according to endoscopy.

Exacerbation

The appearance of typical symptoms of the disease in UC patients in clinical remission, either spontaneous or medically maintained.

The disease phenotype and the risk of colectomy are determined by: the extent and topography of inflammatory changes, severity of the current exacerbation, history of a severe attack, development of hormone dependence, treatment resistance, and the presence of extraintestinal manifestations and complications [10, 11, 12, 13].

According to the updated ESPGHAN Porto criteria [7], UC in children can present with typical and atypical phenotypes.

The typical phenotype is characterized by continuous chronic active inflammation without granulomas, beginning in the rectum and potentially extending proximally up to the cecum, without involving the small intestine. In cases of total colitis (E4) involving the cecum, the structure of typical UC may include backwash ileitis (erythema and edema in the distal ileum in the absence of aphthae, erosions, and ulcers).

Atypical UC can present in 5 variants:

1. typical involvement of the proximal colon in the absence of inflammatory changes in the rectum;

2. inflammatory changes may be focal in the absence of morphological signs of chronic inflammation (in children with recent symptom onset);

3. left-sided UC with skip lesions in the cecum;

4. presence of diffuse or focal gastritis (without linear and serpentine ulcers);

5. severe colitis with transmural inflammation or deep ulcers [7].

A special phenotype is unclassified IBD. The diagnosis is made if, with isolated colonic involvement, examination results do not allow differentiation between UC and Crohn's disease [7, 14].

1.6 Clinical presentation of the disease or condition

Intestinal manifestations of the disease: chronic (≥4 weeks) or recurrent (≥2 episodes within 6 months) bloody diarrhea, predominantly at night (65% of cases); blood in the stool; tenesmus, sometimes combined with constipation (in distal involvement), in no more than 15% of patients, only with an acute onset in 86% of children having nocturnal stool); spasmodic abdominal pain;

Toxemia manifestations and metabolic disorders: fever, general weakness, weight loss, growth and/or pubertal delay.

Extraintestinal manifestations: lesions of the skin, mucous membranes, joints, liver, eyes, etc.

Extraintestinal manifestations of the disease (EIMs)

EIMs are observed in 30% of pediatric patients with UC. In IBD, any organ can be affected, but joint, liver, eye, and skin involvements are most common. Some EIMs are clearly associated with intestinal disease activity (erythema nodosum, peripheral arthritis), while others occur independently (pyoderma gangrenosum, uveitis, ankylosing spondylitis, and primary sclerosing cholangitis (PSC) [15]. Data from 2 pediatric registries in the USA [16, 17] and Europe [15] show that >1 EIM is present at diagnosis in 6%-17% of pediatric UC patients, especially in children older than 5 years, with an increase of nearly 50% as the disease evolves [18, 19, 20, 21]. EIMs are more likely in patients with extensive colitis [17].

Primary sclerosing cholangitis (PSC) occurs 3 times more frequently in ulcerative colitis (UC) than in Crohn's disease (CD) [17] and is associated with older children [17]. PSC may precede the onset of IBD symptoms by many years, but it can also develop in patients with UC after colectomy. The cumulative incidence of PSC in pediatric IBD increases by 1.6% within 10 years of diagnosis [16]. Although extraintestinal manifestations of ulcerative colitis are generally associated with a more severe disease course, this is not true for PSC [17]. Due to the technical difficulty of performing ERCP, especially in young children, magnetic resonance cholangiopancreatography (MRCP) can demonstrate a characteristic pattern of irregular bile ducts with alternating strictures and dilatations [22]. PSC can progress to liver cirrhosis and ultimately require liver transplantation. Patients with PSC and UC have an increased risk of malignancies, such as colorectal cancer and cholangiocarcinoma (8%–30% of patients with UC and long-standing PSC) [23, 24]. Patients diagnosed with PSC in childhood may experience a more severe disease course [24]. In adults with PSC, ursodeoxycholic acid** has been reported to improve abnormal liver function tests [25] and may improve outcomes. Studies on the treatment of PSC in children are lacking. Magnetic resonance cholangiopancreatography is the first-line imaging modality for PSC in children, though interpretation in young children can be challenging.

The intestinal complications of UC include intestinal bleeding, toxic dilatation and perforation of the colon, as well as colorectal cancer.

Toxic colonic dilatation (toxic megacolon) is a rare complication in children and represents a non-obstructive colonic dilatation (transverse colon diameter in adolescents and adults >60 mm, in children under 10 years >40 mm, over 11 years >55 mm) against the background of intoxication symptoms. Risk factors for toxic dilatation include hypokalemia, hypomagnesemia, use of antidiarrheal, intestinal anti-inflammatory and antimicrobial drugs (loperamide**), anticholinergics, opioids, and antidepressants, as well as cytomegalovirus and clostridial infection [3, 8]. The development of toxic dilatation is indicated by a sudden decrease in stool frequency against the background of existing diarrhea, abdominal distension, as well as a sudden decrease or disappearance of pain and an increase in intoxication symptoms (including tachycardia and decreased blood pressure). Plain upright abdominal radiography is a reliable confirmation of the diagnosis [90, 159].

Intestinal bleeding is indirectly indicated by a progressive decrease in hemoglobin levels during intensive therapy [112]. Objective criteria (against the background of comprehensive adequate conservative treatment) for deciding in favor of emergency surgical treatment include: a tendency to hypotension despite adequate infusion therapy; signs of hemic hypoxia; changes in coagulogram parameters (signs of disseminated intravascular coagulation (DIC), increasing hypocoagulation); progressive anemia despite replacement therapy.

Colonic perforation into the free peritoneal cavity in acute fulminant/severe UC may be the first manifestation of the disease and is the most dangerous complication with nearly 50% mortality.

Clinical practice may encounter the so-called "fulminant or extremely severe attack" of UC ("acute severe colitis" in English-language literature), characterized by diarrhea more than 10-15 times per day, progressive decrease in hemoglobin levels, fever above 38°C, severe hypoproteinemia and electrolyte shifts, and high CRP levels. Treatment approaches for such colitis differ from standard ones [32].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of UC in children should be established based on a combination of medical history, physical examination, andintestinoscopy and colonoscopy with multiple biopsies.

There is no single criterion for establishing a diagnosis of UC. As a rule, UC should be suspected in a child with chronic (≥4 weeks) or recurrent (≥2 episodes within 6 months) bloody diarrhea, tenesmus, abdominal pain after ruling out infectious and other causes, and in severe cases with weight loss, general weakness, and vomiting. Particularly alarming findings regarding IBD in a child include concomitant growth and/or pubertal delay, a family history of IBD, elevated inflammatory markers, or the presence of anemia.

Ulcerative colitis debuting in childhood is total in 60-80% of all cases, i.e., twice as often as in adults [26]. Since it is proven that the extent of the lesion correlates with greater disease activity, the disease course is more severe during the first attack in childhood, leading to colectomy in 30-40% of children within 10 years, compared to 20% in adults [26, 27].

In addition, when treating children, age-related features must be taken into account, such as growth, sexual development, nutrition, and bone mineral density (BMD) accrual in adolescence, age restrictions on the use of drugs, as well as specific features of psychosocial behavior and development [28, 29, 30].

To formulate a diagnosis and determine treatment tactics, the severity of the current exacerbation (attack) should be determined using the Pediatric Ulcerative Colitis Activity Index (PUCAI) (Appendix G1). Mild, moderate, and severe UC attacks are distinguished [9].

2.1 Complaints and Anamnesis

When collecting complaints and history, typical clinical symptoms of the disease should be assessed: stool frequency and consistency, abdominal pain, blood in the stool (see clinical presentation).

2.2 Physical Examination

Physical examination may reveal various manifestations of UC, including fever, peripheral edema, malnutrition, growth and pubertal delay, signs of perforation or toxic megacolon, as well as extraintestinal manifestations.

Physical examination should include an inspection of the perianal area and a digital rectal examination [29, 30, 31].

To clarify the localization and extent of the lesion, attention should be paid to the following symptoms:

1. The presence of proctitis or proctosigmoiditis is indicated by:

– daily stool 1–2 times a day, which may be normally formed or spastic in consistency, blood located on the fecal masses as a rectal "spit" or smear, increased frequency of nocturnal defecations, frequent tenesmus;

– abdominal pain localized in the left abdomen, preceding defecation;

– weight loss develops rarely.

2. The presence of left-sided colitis or total colitis is indicated by:

– frequent stools up to 20–50 times a day, a large amount of blood mixed with fecal masses;

– abdominal pain localized throughout the abdomen, preceding defecation;

– nocturnal urges;

– weight loss [29, 30, 31].

2.3 Laboratory Diagnostics

• All patients at initial diagnosis and subsequently during follow-up are recommended to undergo a complete blood count (CBC) with differential (including hematocrit and erythrocyte sedimentation rate (ESR)) to assess the inflammatory response, detect anemia, and/or monitor therapy [29, 30, 32, 33].

(UBR – C, LOR – 5)

Comments: A complete blood count can diagnose anemia (iron deficiency anemia, anemia of chronic disease), leukocytosis (due to chronic inflammation or steroid therapy), and thrombocytosis.

The frequency of monitoring tests during follow-up depends on clinical necessity, on average at least once a year, or more frequently as indicated (during immunosuppressive therapy – on average every 3 months; during thiopurine therapy

– every 1–2 weeks in the first month of treatment, then monthly up to 3 months of therapy, and thereafter every 3 months).

(UBR – C, LOR – 5)

Comments: Laboratory manifestations of UC are nonspecific. A general biochemical blood test can reveal electrolyte disorders, hypoproteinemia (particularly hypoalbuminemia), and elevated alkaline phosphatase activity, which is a possible manifestation of UC-associated primary sclerosing cholangitis.

The level of inflammatory markers in children with active colitis may be normal, especially when disease activity is low.

The frequency of monitoring tests during follow-up depends on clinical necessity, on average at least 1–2 times a year, or more frequently as indicated (during immunosuppressive therapy, on average every 3 months).

Serum C-reactive protein levels can be monitored upon hospitalization as part of a comprehensive assessment of disease activity.

(UBR – C, LOR – 5)                                    

Comment: The frequency of monitoring tests during follow-up depends on clinical necessity, on average at least 1–2 times a year.

• In UC patients with anemia, it is recommended to assess iron metabolism (serum transferrin and ferritin levels) to evaluate the inflammatory response and iron deficiency [35].

(UBR – C, LOR – 5)

Comment: the test is performed at initial diagnosis and subsequently during follow-up as needed, depending on the severity of the disease course and clinical manifestations.

• In patients with suspected UC, it is recommended to use serological markers (antineutrophil cytoplasmic antibodies) (detection of markers of ANCA-associated vasculitis: PR3 (c-ANCA), MPO (p-ANCA)) for the differential diagnosis between UC, CD, and other diseases [30, 31].

(UBR – C, LOR – 5)

Comments: The absence of serological markers, especially in young children, is not a reason to rule out or revise the diagnosis of UC.

Serological markers are used as an additional method for differential diagnosis in ambiguous cases.

• In the acute course of UC (both during the first attack of the disease and in case of a relapse), it is recommended to perform bacteriological and microscopic stool examinations (microbiological (cultural) examination of feces/rectal swab for Shigella spp. and/or Salmonella typhi and/or Yersinia enterocolitica and/or Campylobacter jejuni/coli with susceptibility testing to antibacterial drugs) and/or microscopic examination of feces for helminth eggs and larvae and/or microscopic examination of feces for helminths using concentration methods, microscopic examination of feces for protozoa (Strongyloides, Amoeba (according to epidemiological indications)) and/or molecular biological examination of feces for whipworm (Trichuris trichiura) and/or microscopic examination of feces for protozoa using concentration methods and/or examination of biological objects found in feces to determine their biological species) to rule out acute intestinal infection [32, 33, 160].

(UBR – C, LOR – 5)

• Both at disease onset and during relapses, it is recommended to test stool for Clostridium difficile toxin using rapid immunochromatographic stool tests for C. difficile toxins A and B. PCR (molecular biological examination of feces for Clostridium difficile / detection of Clostridium difficile DNA in stool samples by PCR) has the highest sensitivity and specificity (especially after a recent course of antibiotic therapy or hospitalization). This test is also recommended in severe disease and the development of resistance to ongoing therapy [36].

(UBR – C, LOR – 4)

Comments: The drug of choice for the treatment of C. difficile-associated colitis in ulcerative colitis is oral vancomycin** [32].

Treatment of colitis caused by other pathogens is carried out in accordance with the relevant clinical guidelines.

(UBR – C, LOR – 5)

Comments: According to some data, at the time of onset, the concentration of inflammatory markers tends to be higher in CD than in UC [37, 38]. In newly diagnosed UC, 54% of patients with a mild attack may have results for the 4 most commonly used markers (hemoglobin, albumin, platelets, and ESR) within the normal range, whereas in a mild CD attack, the proportion of normal results is 21% [37]. In the 2018 international consensus on pediatric ulcerative colitis, fecal calprotectin is given greater importance than in earlier documents. If the fecal calprotectin level is elevated more than 5-fold (212 mg/g or higher, depending on age), the child should be referred to a gastroenterology department for a comprehensive evaluation. It should be noted that in infants and toddlers, calprotectin levels are always elevated and may normally reach up to 2000 µg/g [39, 40].

To increase the sensitivity of fecal calprotectin in monitoring disease activity, it is also recommended to additionally test serum C-reactive protein levels and use the PUCAI clinical activity index for UC [41.

• In patients with UC in the active phase of the disease and during systemic corticosteroid therapy, it is recommended to test total serum calcium, blood ionized calcium, and vitamin D (determination of 25-OH vitamin D levels in the blood) for the prevention of osteoporosis and the timely diagnosis of vitamin D and calcium deficiency [35].

(UBR – C, LOR – 5)

Comment: Diagnosis, follow-up monitoring, and treatment of osteoporosis are carried out in accordance with relevant clinical guidelines.

(Level of reliability of evidence – C, level of trustworthiness of evidence – 5).

Comments: indications and frequency of tests are determined individually. Testing for vitamin A and E levels is performed rarely and when available.

2.4 Instrumental Diagnostics

Diagnosis of UC is predominantly based on instrumental diagnostic methods. The following procedures are required to confirm the diagnosis.

(UBR – C, LOR – 5)

Comments: endoscopic examination of the colon is the primary method for diagnosing UC; however, specific endoscopic signs are absent. The most characteristic features are continuous mucosal-limited inflammation starting in the rectum and extending proximally with a clear demarcation of inflammation. UC endoscopic activity is best reflected by the presence or absence of erosions and ulcers, contact friability (bleeding upon contact with the endoscope), and loss of vascular pattern.

Endoscopic evaluation should be performed to establish the diagnosis, when making significant changes to the treatment regimen, and when there are difficulties in assessing clinical symptoms. Endoscopic examination in children should not be performed routinely during mild exacerbations or in remission, if there is no suspicion of colorectal cancer development [44]. During mild relapses, colonoscopy and enteroscopy are generally not indicated; the procedure is performed when calprotectin levels are high (greater than 250 mg/g).

In patients with acute severe colitis, diagnostic sigmoidoscopy can be used as the initial assessment procedure; however, a follow-up colonoscopy should be performed subsequently.

(GR — C, LE — 5)

Comment: Since individual macroscopic findings may not be specific to UC, it is essential in the diagnosis of IBD in children to perform enteroscopy, colonoscopy, and esophagogastroduodenoscopy with serial biopsies (endoscopic esophageal biopsy and/or endoscopic gastric biopsy, and/or endoscopic duodenal biopsy, and/or endoscopic small bowel biopsy, and/or endoscopic colonic biopsy, and/or sigmoidoscopic biopsy using video-endoscopic techniques, and/or rectal biopsy using video-endoscopic techniques).

(LoE – C; GoR – 5)

• Patients are recommended to undergo endoscopic colonic biopsy, sigmoidoscopic biopsy using video-endoscopic techniques, and colonic biopsy during laparoscopy:

  • at initial diagnosis

  • to assess the dynamics of the condition during therapy

  • when there are doubts about the accuracy of a previously established diagnosis

  • in case of a long-standing history of ulcerative colitis (more than 7–10 years) to rule out epithelial dysplasia

    [28, 30, 47].

(LoE – C; GoR – 5)

(ORR – C; LE – 5)

Comments:

Biopsy specimens should be taken from both altered and endoscopically unchanged areas, placing the biopsy specimens in separate containers with appropriate labeling [48].

Pathological-anatomical (histological) diagnosis of ulcerative colitis consists of the following stages [45, 49, 50]:

1. Confirmation of the presence of inflammatory bowel disease: detection of signs ofchronicinflammation (basal plasmacytosisidisruption of crypt architecture(branching and multidirectionality of crypts, appearance of crypts of varying diameters, diffuse crypt atrophy),presence of Paneth cells in the left colon).

2. Differential diagnosis with Crohn's disease: ulcerative colitis is characterized by the presence ofuniformchanges in biopsy specimens taken from different areas of the colon with endoscopic signs of inflammation,irregular mucosal surface, decrease in the number of goblet cellsiand mucin, and absence of granulomas.

3. Assessment of inflammation activity: presence of cryptitis (infiltration of neutrophils into the crypt epithelium) and crypt abscesses (accumulation of neutrophils in the crypt lumen). Acute infectious colitis is characterized by active inflammation in the absence of signs of chronic inflammation.

According to clinical guidelines for UC in adults, in patients with a long history of UC (more than 7–10 years), chromoendoscopy, contrast gastrointestinal examination with targeted biopsy, or step biopsies (from each colonic segment) are advisable to rule out epithelial dysplasia.

[32].

(ORR – C; LE – 5)

Comments: biopsy specimen examination is performed using hematoxylin-eosin staining (Pathological examination of biopsy (surgical) material of the colon, Pathological examination of biopsy (surgical) material of the rectum) and immunohistochemical examination (Pathological examination of biopsy (surgical) material of the colon using immunohistochemical methods, Pathological examination of biopsy (surgical) material of the rectum using immunohistochemical methods).

A positive PCR-test result (Qualitative determination of Cytomegalovirus DNA in biopsy and puncture samples from lesion sites of organs and tissues by PCR, Quantitative determination of Cytomegalovirus DNA in biopsy and puncture samples from lesion sites of organs and tissues by PCR) in the absence of inclusion bodies or a positive smear is not informative.

(Level of Evidence – C; Grade of Recommendation – 4)

Comment: rectal sparing (sparing of the rectum), focal macroscopic changes, and normal or minimally altered crypt architecture at disease onset are more common in younger children [52, 53]. Such features are characteristic of children aged 10 years and younger [54]. Mild non-erosive ileitis in the presence of severe pancolitis may be the result of retrograde ileitis associated with UC and may manifest microscopically as villous atrophy, increased mononuclear cell count, and unclustered crypt abscesses [55]. In 1 out of 13 patients with colitis, a diagnosis of Crohn's disease can be established based on findings from upper GI endoscopy [53].

• If persistent bowel stricture is detected in the setting of UC, it is recommended to rule out colorectal cancer in order to ensure timely diagnosis and initiation of therapy [51, 56].

(LoE – C; GoR – 5)

Comments: colorectal cancer is extremely rarely detected in children with UC because it requires a long disease duration. However, vigilance regarding colorectal cancer should be maintained, especially in children with IBD-associated PSC [161]: The incidence of CRC/dysplasia at UC onset in pediatric age is 2.8 cases per 1,000 person-years.

(LoE – C; GoR – 5)

(UBR – C, LOR – 5)

Comments: Criteria for suspected toxic megacolon [57]:

Criteria for suspected toxic megacolon [57]:

A) Transverse colon diameter (according to plain radiography) >40 mm in children under 10 years of age, >56 mm in children over 10 years of age, >60 mm in adolescents and adults

+ B) Symptoms of intoxication (body temperature >38.8 °C, tachycardia (heart rate >2 standard deviations for age), dehydration, electrolyte disturbances, impaired consciousness or coma, hypotension or shock.

• If differential diagnosis is necessary or if complete enteroscopy and colonoscopy (ileocolonoscopy) cannot be performed, it is recommended to use confirmatory imaging modalities:

– Magnetic resonance enterography with contrast enhancement, Magnetic resonance imaging of the abdominal organs with intravenous contrast enhancement (preferred) or

– Computed tomography enterography with contrast enhancement, Computed tomography of the colon with double contrast, Computed tomography of the abdominal organs with intravenous bolus contrast enhancement [30, 31, 47].

(LoE – C; GoR – 5)

Comment: anesthesiological management (including early postoperative care) is performed according to indications.

• If MRI (Magnetic resonance imaging of the small intestine with contrast) or CT (Computed tomography of the small intestine with contrast) cannot be performed, double-contrast barium enema is recommended (to assess the extent of colonic involvement, clarify the presence of masses, strictures, etc.) [162].

(ORR – C; LE – 5)

2.5 Other Procedures

• If the clinical picture is unclear, selective additional examinations are recommended [30, 31, 47].

(LoE – C; GoR – 5)

Comments: depending on the clinical picture and laboratory-instrumental data, the following may be performed:

o Small bowel ultrasound

o Large bowel ultrasound, ultrasound of the sigmoid and rectum (Transabdominal ultrasound scanning of the ileocolon and sigmoid colon) to assess disease activity and for follow-up;

o Transrectal ultrasound of the rectum to assess disease activity and to detect/rule out perirectal abscesses;

o Esophagogastroduodenoscopy to detect lesions in the upper gastrointestinal tract;

o Video capsule endoscopy (Small bowel video capsule endoscopy, colonic video capsule endoscopy) (in the absence of intestinal strictures) and/or enteroscopy or double-balloon enteroscopy to establish an alternative diagnosis if ulcerative colitis is excluded or unlikely;

• In super-severe UC presenting as a first attack or as a disease relapse during maintenance therapy, the following diagnostic procedures are recommended: plain abdominal radiography (to rule out toxic dilatation or colonic perforation); endoscopic examination of the distal colon (Rectosigmoidoscopy (in the absence of intestinal strictures)) (to assess the required volume of conservative treatment) [31, 46].

(Level of Recommendations – C; Level of Evidence – 5)

Comments: for the definition of a "super-severe or extremely severe attack" of UC, see the "Clinical Presentation" section

Additional instrumental and laboratory examinations are primarily performed for differential diagnosis with a number of conditions. These include infectious, vascular, drug-induced, toxic, and radiation-induced lesions, as well as diverticulitis, etc. At the next stage of differential diagnosis, clinical diagnoses of UC and CD belonging to the IBD group are verified. Thus, the differential diagnosis of UC is carried out with Crohn's disease of the colon, acute intestinal infections (dysentery, salmonellosis, campylobacteriosis, yersiniosis, amebiasis), parasitoses, antibiotic-associated intestinal lesions (pseudomembranous colitis caused by C. difficile) [59], intestinal tuberculosis, systemic vasculitis, colon cancer, diverticulitis, microscopic colitis (collagenous and lymphocytic) [60], and radiation proctitis. Appendix A3.2 lists the main diseases with which differential diagnosis of UC should be performed in children.

• To assess bone mineral density (BMD), especially in children receiving long-term glucocorticoids and suffering from malnutrition, dual-energy X-ray absorptiometry (DEXA) of the lumbar spine (X-ray densitometry of the lumbar spine) is recommended [193, 194].

(LoE – C; GoR – 5)

Comment: children with UC may be at an increased risk of fractures, particularly vertebral fractures [195]. Risk factors for low BMD in pediatric UC patients include growth impairment or low weight for age at initial diagnosis, whereas a higher cumulative glucocorticoid dose is a risk factor during follow-up after diagnosis verification [196]. DEXA should be performed in newly diagnosed UC, especially in children and adolescents with growth disorders.

• For the purpose of differential diagnosis and selection of therapy for extraintestinal manifestations of UC and comorbid conditions, it is recommended to conduct consultations, if necessary::

  • psychotherapist (initial consultation, examination, and assessment by a psychotherapist) and/or medical psychologist (initial consultation, testing, and assessment by a medical psychologist) (neurosis, planned surgery involving an ostomy, etc.);

  • initial consultation with an endocrinologist / pediatric endocrinologist (steroid-induced diabetes mellitus, adrenal insufficiency in patients on long-term hormone therapy);

  • initial consultation with a dermatologist-venereologist (differential diagnosis of erythema nodosum, pyoderma, psoriasis, etc.);

  • initial consultation with a rheumatologist (arthropathies, etc.) [30, 31].

(LoE – C; GoR – 5)

• In children under 2 years of age with clinical signs of UC, it is recommended to selectively conduct a consultation with an allergist-immunologist and immunological testing to rule out colitis associated with primary immunodeficiency [30, 32, 33].

(LoE – C; GoR – 5)

Comments: immunological testing includes the study of lymphocyte populations (peripheral blood immunophenotyping to determine the subpopulation composition of lymphocytes (main), peripheral blood immunophenotyping to determine the subpopulation composition of lymphocytes (minor)), determination of blood immunoglobulin A, M, G levels, total blood immunoglobulin E levels, as well as, if necessary, functional assays of lymphocyte response to antigens/mitogens and neutrophils, including testing for chronic granulomatous disease (CGD) (determination of the peroxidase-hydrogen peroxide system activity in peripheral blood neutrophils, nitroblue tetrazolium (NBT) reduction test) and others, depending on the clinical situation.

• When clinical signs of UC are present in children under 2 years of age, it is recommended to perform an allergological workup to rule out/confirm colitis of allergic etiology [163].

(LoE – C; GoR – 5)

Comments: Large bowel inflammation in children under 2 years of age (especially under 1 year) may be a manifestation of allergic colitis or immunodeficiency, even if it is the only symptom. In this case, to rule out/confirm the diagnosis of allergic colitis, the child should undergo an allergological workup (determination of total blood immunoglobulin E levels, determination of blood antibodies to plant, animal, and chemical antigens (selection of antigens and scope of testing depend on the clinical situation; in young children, manifestations of colitis are often associated with cow's milk protein allergy) and/or a diagnostic elimination diet (avoidance of certain foods) [61]. If symptoms develop in early childhood, classical or concealed immunodeficiency states should be ruled out [62, 63, 64].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment measures for UC include drug prescription, surgical treatment, psychosocial support, and dietary recommendations.

The choice of conservative or surgical treatment is determined by the severity of the attack, extent of large bowel involvement, presence of extraintestinal manifestations, disease duration, efficacy and safety of previous therapy, and the risk of UC complications [65, 66].

The goal of therapy is to achieve clinical, endoscopic, and (ideally) histological remission [50, 67]. Once remission is achieved, the non-operated patient must remain on continuous maintenance (relapse-prevention) therapy.

3.1. Conservative management

3.1.1 Diet Therapy

• Nutritional status and growth in children with UC are recommended to be assessed regularly; if necessary, it is recommended to use nutritional support to maintain an adequate nutritional status [30].

(LoE – C; GoR – 5)

Comment: frequency of growth and weight assessment in children with UC: performed at each hospital admission or outpatient visit

(LoE – C; GoR – 5)

• Special diets or dietary supplements are ineffective and are not recommended for use in inducing and maintaining remission in children with UC, and in some cases may contribute to nutrient deficiencies [30].

(LoE – C; GoR – 5)

(LoE – C; GoR – 5)

Comments: Various strategies for prescribing vitamin D and analogues are possible, for example, daily administration (>2000 IU/day) or 50,000 IU colecalciferol** oral drops (indicated for use in children from 4 weeks of life) orally once a week for 2-3 months. For the prevention and treatment of vitamin D deficiency / determination of the child's daily requirement for vitamin D and the method of its administration must be established by a physician individually and adjusted each time during periodic examinations, especially in the first months of life. Blood and urine calcium concentrations must be monitored. There is a publication on the efficacy and safety of a single high dose of #colecalciferol** 300,000-500,000 IU [33].

Therapy for osteopenia and osteoporosis is carried out in accordance with the relevant clinical guidelines

3.1.2 Drug therapy

3.1.2.1 Therapy with Oral and Rectal 5-Aminosalicylic Acid Preparations and Analogous Preparations (5-ASA))

(LoE – C; GoR – 5)

Comments: mesalazine** – in tablets per instructions – for children from 3 years of age: initial dose 30-50 mg/kg/day, divided into multiple doses, maximum dose 75 mg/kg/day. The total daily dose must not exceed the maximum daily dose for adults. For relapse prevention, the dose is selected individually. The initial dose is 15-30 mg/kg/day, divided into multiple doses. The total daily dose must not exceed the recommended daily dose for adults. The general recommendation is that up to 40 kg of body weight, ½ of the adult daily dose is used; over 40 kg of body weight, the adult daily dose is used,

– in granules – per instructions – for children from 6 years of age during the acute period, the dose is selected individually: the initial dose is 30-50 mg/kg/day, divided into multiple doses, maximum dose is 75 mg/kg/day (not >4 g). The maintenance dose is selected individually: 15-30 mg/kg/day, divided into multiple doses. Maximum daily dose – not >2 g. For children with body weight <40 kg – start with ½ of the adult dose; for children with body weight >40 kg – adult dosages.

For children of any age oral #mesalazine** may be prescribed at a dose of 60 to 75 mg/kg (not more than 4 g/day) and, if necessary, >75 to 80 mg/kg per day (not more than 4.8 g/day) in 2 divided doses [8].

To enhance the efficacy of therapy in distal large bowel involvement, rectal forms of #mesalazine** are used at a dose of 25 mg/kg once daily [8].

Sulfasalazine** is used in the form available in the Russian Federation.

Sulfasalazine** – in tablets per instructions: for children aged 16 to 18 years: on day 1, 500 mg 4 times a day; on day 2, 1 g 4 times a day; on day 3 and subsequent days, 1.5-2 g 4 times a day. After achieving remission, children aged 16 to 18 years and/or with a body weight of more than 65 kg are prescribed a maintenance dose of 500 mg 3-4 times a day for several months. For children aged 10 to 16 years and/or with a body weight from 35 kg to 50 kg: 500 mg 4 times a day. Maintenance therapy for children under 16 years of age and/or with a body weight of less than 65 kg is not recommended. The maximum daily dose for children aged 10 to 16 years is 2 g.

If it is necessary to use at a younger age (under 10 years) #sulfasalazine** is generally prescribed at an initial dose of 25 mg/kg/day, divided into two or three doses, and increased over one week to 40-80 mg/kg/day, divided into two or three doses (up to a maximum dose of 4 g per day). In larger children, the dose of #sulfasalazine** may be titrated up to 4-6 g/day, divided into three to four doses.

All patients taking #sulfasalazine** should be prescribed supplemental #folic acid** (1 mg/day) [8, 68].

The maximum dose of oral and rectal agents (#mesalazine** and #sulfasalazine**) typically does not exceed the standard oral dose by more than 50% or 6.4 g/day in adults. Gradual dose escalation of #sulfasalazine** over 7-14 days can reduce the risk of dose-dependent adverse events, such as headaches, gastrointestinal (GI) disorders, hepatopancreatotoxicity, and myelosuppression.

Once-daily administration of aminosalicylic acid preparations and similar drugs is possible, as reported in a number of studies demonstrating equal efficacy of once-daily and twice-daily dosing regimens.

Acute intolerance to aminosalicylic acid preparations and similar drugs may mimic a colitis flare. Clinical improvement after their withdrawal and symptom recurrence upon re-administration helps verify the cause of the condition and serves as a contraindication to the prescription of any aminosalicylic acid preparations and similar drugs.

(LoE – C; GoR – 5)

Comments: rectal aminosalicylic acid preparations and similar drugs (#mesalazine**) are prescribed at a dose of 25 mg/kg (up to 1 g/day) [8].

(LoE – C; GoR – 5)

Comments: children should be offered rectal therapy, but it should not be forced. Once-daily administration of rectal forms can improve treatment adherence without reducing clinical efficacy.

Effective local treatment requires optimal treatment adherence, which entails support and education of the child and parents, reassurance, and addressing their concerns.

#Mesalazine** rectal suppositories are contraindicated in children under 18 years of age according to the instructions; rectal foam is contraindicated in children under 18 years of age, and its use in children is off-label at a dose of 25 mg/kg (up to 1 g/day) [8].

Rectal suppositories are useful in limited proctitis (0.5 g/day for 3-6 weeks), while foam and liquid enemas with #mesalazine** are also effective in left-sided colitis [8].

• In patients with mild ulcerative colitis, provided there is good tolerance, maintenance therapy with aminosalicylic acid preparations and similar drugs (5-ASA) is recommended for an indefinitely long period. The maintenance dose should equal the dose used for induction of remission, although a lower dose may be used (mesalazine** tablets, granules – according to the instructions, contraindicated under 6 years of age – at least 40 mg/kg or 2.4 g/day; the minimum effective dose in adults is 1.2 g/day) after achieving sustained remission [30, 47, 73, 75].

(LoE – C; GoR – 5)

• If there is no response to oral mesalazine** (tablets, granules – according to the instructions, contraindicated under 6 years of age) within 2 weeks, it is recommended to prescribe alternative treatment, such as adding topical therapy (if not already administered) or prescribing systemic corticosteroids (oral formulations) [30, 47, 73].

(LoE – C; GoR – 5)

3.1.2.2 Systemic corticosteroids

• Systemic corticosteroids (oral) are recommended for induction of remission, but not for its maintenance, in pediatric ulcerative colitis [30, 71].

(LoE – C; GoR – 5)

• Systemic corticosteroids are recommended for moderate attacks with systemic manifestations and in selected pediatric patients with severe attacks without systemic manifestations, or in patients who fail to achieve remission on optimal doses of aminosalicylic acid preparations and similar drugs (5-ASA). In severe attacks, intravenous steroid therapy is performed [30].

(LoE – C; GoR – 5)

• The dose of prednisolone^** (tablets – according to the instructions, contraindicated under 3 years of age) is 1 mg/kg and it is not recommended to exceed it; in most children, it is 40 mg daily administered once or in 3 divided doses [30]

(LoE – C; GoR – 5)

Comments: To minimize the potential risk of growth suppression, a single morning dose is recommended. An exemplary regimen for systemic corticosteroids in children is presented in Table 1.

Table 1 – Prednisolone tapering schedule** for children with ulcerative colitis (in mg/day)

First 2–3 weeks: initiation of prednisolone** therapy (tablets – per instructions, contraindicated under 3 years of age) at a dose of 1 mg/kg (up to 60 mg) once daily (*for induction of remission in severe ulcerative colitis, an oral dose of up to 60 mg/day may be used, as well as intravenous administration up to 3–5 mg/kg). In the absence of significant clinical improvement in patients with moderate to severe colitis (PUCAI decrease by <20 points) after 7–14 days of therapy, or if PUCAI increases by ≥20 points at any stage of treatment, escalation of therapy should be considered after ruling out other causes of steroid-refractory disease course.

After the first 2–3 weeks of therapy: with a PUCAI of 15 to 30, continue oral prednisolone** (per instructions, contraindicated under 3 years of age) at the same dose (extending the total duration of intake by 1 week); PUCAI >35: increase the dose to that used in stages 1–2 of treatment for one week, then begin tapering at a slower rate; PUCAI >60 or an increase in PUCAI by at least 20 points at any stage of treatment: consider therapy escalation. In any situation, hormone dependency should be avoided by intensifying maintenance therapy.

The risk of relapse is lower when using a prednisolone** tablet dose (per instructions, contraindicated under 3 years of age) >20 mg, however, the frequency of adverse events increases with high doses. Therefore, dose reduction should be initiated as early as possible, with a more rapid taper at the beginning of the systemic corticosteroid course and a slower reduction rate thereafter. In some cases, each treatment stage may be shortened from 7 to 5 days. Once a low dose is reached, an alternate-day dosing schedule can be used to reduce the risk of adverse events. It is important to remember the possibility of adrenal insufficiency even many months after discontinuing systemic corticosteroids.

Mucosal healing with steroid therapy in UC is achieved more frequently than in CD, though it lags behind clinical improvement [44]. In children, it is particularly important to assess response at the earliest possible stage to rapidly initiate dose tapering and reduce treatment duration. Curtailing unjustified systemic corticosteroid use is mandatory to minimize growth retardation and other systemic corticosteroid-associated adverse events. Hormone therapy may decrease calprotectin levels as disease activity subsides, but normalization of its level is uncommon [74]. An elevated calprotectin level does not warrant continuation of hormone therapy if the patient is in clinical remission.

Dividing the total daily dose into multiple intakes is not superior in efficacy to a single daily dose [75]. In children with UC compared to adults, the frequency of steroid therapy complications, including osteoporosis, glaucoma, and cataracts, may be higher even when doses are calculated by body weight [76]. In most cases, in the absence of clinical symptoms, antacids are not required. They should be prescribed for upper gastrointestinal tract lesions or when using nonsteroidal anti-inflammatory and antirheumatic drugs.

Methods for preventing hormone dependence include dose optimization of 5-aminosalicylic acid (5-ASA) preparations and similar agents, adjunctive therapy with enemas, and intensification of baseline therapy by adding tumor necrosis factor alpha (TNF-alpha) inhibitors and thiopurines, or infliximab** (contraindicated under 6 years of age according to the instructions), or other medications. It is necessary to ensure adherence to medical prescriptions, especially in adolescents. If hormone dependence cannot be overcome by conservative means, the possibility of colectomy should be considered (see section 3.2).

3.1.2.3 Adjuvant therapy

• Systemic antibacterial drugs for ulcerative colitis in children are not recommended for induction or maintenance of remission in outpatient practice due to ineffectiveness [30].

(LoE – C; GoR – 5)

Comments: antibacterial therapy is used in case of complications or as an adjunct to standard therapy during the acute period.

3.1.2.4 Immunosuppressants and antimetabolites (azathioprine**, #mercaptopurine**, #cyclosporine**, #tacrolimus**)

• An immunosuppressant (azathioprine^**) or antimetabolite (#mercaptopurine^**) (traditional name: thiopurines; ATC classification: other immunosuppressants/purine analogues) is recommended to be prescribed for maintaining remission in children with intolerance to aminosalicylic acid preparations and similar agents, or in patients with a frequently relapsing course (2-3 exacerbations per year) or the development of a hormone-dependent form of the disease while receiving therapy with aminosalicylic acid preparations and similar agents at maximum doses [30, 32, 33].

(LoE – C; GoR – 5)

Comments: the therapeutic effect of thiopurines is achieved 10-14 weeks after the start of treatment. The dose can be adjusted to approximately 2.5 mg/kg for azathioprine** or 1-1.5 mg/kg for #mercaptopurine** and taken once daily [30].

Azathioprine** is superior to placebo for maintaining ulcerative colitis remission [30], with an efficacy of approximately 60% [77, 78]. Retrospective studies in children have confirmed the efficacy of thiopurines in maintaining remission and overcoming steroid dependence [79, 80, 81]. The average time to achieve a stable serum thiopurine level is 55 days [82].

Taking into account the efficacy and safety of aminosalicylic acid preparations and similar agents for maintaining remission, the use of thiopurines is limited to the following indications: intolerance to aminosalicylic acid preparations and similar agents, and a severe attack of ulcerative colitis in children, i.e., in cases of an increased risk of an aggressive disease course. Considering the favorable safety profile and high efficacy of aminosalicylic acid preparations and similar agents, including for the prevention of colorectal cancer, the expediency of combined use of aminosalicylic acid preparations and similar agents with thiopurines cannot be ruled out. At the same time, an increased pill burden may reduce children's adherence to treatment.

Dose-independent side effects of thiopurines include fever, pancreatitis, arthralgia, nausea, vomiting, and diarrhea, alongside dose-dependent toxic reactions (leukopenia, thrombocytopenia, infections, and hepatitis) [83]. Pancreatitis is the most frequently observed hypersensitivity reaction, reported in 3-4% of patients and almost always developing within the first few weeks of treatment. Infections represent the greatest risk for children receiving immunosuppressants (other immunosuppressants, purine analogues) [84, 85], although severe infections occur rarely.

• Thiopurines (#mercaptopurine** [at a dose of 1 to 1.5 mg/kg once daily] or azathioprine**) are recommended for maintenance therapy in acute severe colitis after induction of remission with systemic corticosteroids [30, 8].

(LoE – C; GoR – 5)

Comments: they are usually prescribed starting from the 2nd week of systemic corticosteroid treatment.

Thiopurine therapy must be discontinued in the event of clinically significant myelosuppression or pancreatitis. Re-initiating thiopurines after leukopenia should be done at a lower dose, following a careful risk-benefit assessment of the treatment. Switching from azathioprine** to #mercaptopurine** (1-1.5 mg/kg/day, maximum dose for children from 1 year of age: 2.5 mg/kg/day) and vice versa [166, 8] can be effective in cases of acute flu-like and gastrointestinal side effects.

Continuing 5-ASA therapy after initiating thiopurines may offer several advantages.

Thiopurines may also be used concurrently with systemic corticosteroids [165].

• Therapy with #cyclosporine^** initiated for an acute severe attack of ulcerative colitis is recommended to be discontinued after 4 months with a transition to thiopurines [29].

(LoE – C; GoR – 5)

Comment: it is usually prescribed at a starting dose of 2 mg/kg/day [32] (or 2-4 mg/day) [8, 87] (as a continuous intravenous infusion). The target blood concentration of #cyclosporine** during induction is 150-300 ng/mL and 100-200 ng/mL upon achieving remission [32].

Among thiopurines, #mercaptopurine** (at a dose of 1 to 1.5 mg/kg once daily) or azathioprine** are used [8].

Comments: patients receiving systemic corticosteroids and calcineurin inhibitors require pneumocystis pneumonia prophylaxis.

Monitoring is also required for creatinine (Blood creatinine testing), glucose (Blood glucose testing), electrolytes (including magnesium) (Blood sodium testing, blood potassium testing, blood chloride testing), lipid levels (Biochemical blood test for lipid metabolism disorders), blood pressure, and, if possible, calcineurin inhibitor levels (Cyclosporine A level testing, blood drug level testing).

• Routine use of #methotrexate** in pediatric UC is currently not recommended; the drug is prescribed only in cases of thiopurine intolerance when alternative treatment is not feasible [32, 33].

(LoE – C; GoR – 5)

Comments: #methotrexate** doses in children with ulcerative colitis have only been studied in cohort studies. The drug may be used at a dose of 15 mg/m² of body surface area [88]. The use of #methotrexate** must be accompanied by #folic acid** supplementation at 1 mg/day or 5 mg/week [89].

3.1.2.5 #Infliximab**, adalimumab**, #golimumab**, #vedolizumab**, #tofacitinib**, #upadacitinib**

• In patients with a chronic continuous or hormone-dependent course of UC refractory to the "Aminosalicylic acid and similar agents" (5-ASA) group and thiopurines, or in a severe attack of UC (as second-line therapy), selective use of #infliximab^** is recommended [33].

(LoE – C; GoR – 5)

Comments: in children with UC, tumor necrosis factor alpha (TNF-alpha) inhibitors (#infliximab^**) are currently recommended as the first-line biological therapy at a dose of 5 mg/kg (3 induction doses at weeks 0, 2, and 6, followed by 5 mg/kg every 8 weeks as maintenance therapy). Individual dose titration may be required. According to the instructions, the drug is approved for children starting from 6 years of age; if necessary, it is prescribed at a younger age (starting from 3 years at a dose of 5 mg/kg at weeks 0, 2, 6 and every 8 weeks thereafter [the dosing regimen corresponds to the pediatric regimen for children aged 6 years and older according to the instructions]; there are no data on use under 3 years of age) [166, 167].

There is a lack of reliable evidence regarding the necessity of combining tumor necrosis factor-alpha (TNF-alpha) inhibitors (#infliximab**) with thiopurines (other immunosuppressants) in children with ulcerative colitis who have failed therapy with thiopurines (other immunosuppressants, purine analogues) alone. However, the use of biological agents (tumor necrosis factor-alpha (TNF-alpha) inhibitors) in combination with thiopurines (other immunosuppressants, purine analogues) for 4–8 months of therapy may be possible, even if the child has not responded to prior thiopurine therapy (other immunosuppressants, purine analogues). Further careful benefit-risk assessment is required during combined treatment.

Considering the potential beneficial effect (including possible prevention of colorectal cancer) and high safety profile of aminosalicylic acid and similar preparations, it appears rational to administer them in combination therapy with biological agents (tumor necrosis factor-alpha (TNF-alpha) inhibitors).

Infliximab** has been shown to be effective in inducing clinical remission, promoting mucosal healing, and reducing the need for colectomy in patients with active ulcerative colitis who have failed standard therapy [90, 91]. According to the ACT-1 and ACT-2 randomized double-blind placebo-controlled trials, infliximab** is effective for inducing and maintaining remission in adult patients with moderate-to-severe ulcerative colitis [92]. Comparable results were obtained in the pediatric RCT T-72: after 8 weeks of treatment with infliximab** (5 mg/kg intravenously at weeks 0, 2, and 6), 73% of patients responded and 40% achieved clinical remission; 68% of patients showed mucosal healing on endoscopy. With continued therapy for one year on a regular infusion regimen of 5 mg/kg every 8 weeks, sustained corticosteroid-free clinical remission was observed in nearly 40% of patients [93, 94, 95]. Results from other pediatric studies also support the use of infliximab** in children with ulcerative colitis. A meta-analysis showed that the cumulative long-term efficacy of infliximab** in acute severe colitis is 64% [90]. Colectomy was avoided within 2 years in 61% of patients.

• Infliximab^** (approved by the instructions for children aged 6 years and older) is recommended for the hormone-refractory form of the disease (resistance to both oral and intravenous administration). If infliximab** was prescribed for an acute flare in a patient who had not previously received thiopurines, biologic therapy can be used as a bridging therapy to transition to thiopurine therapy (other immunosuppressants, purine analogues). In this case, infliximab** therapy can be discontinued after 4–8 months [32, 33].

(LoE – C; GoR – 5)

Comments: The SUCCESS study [96] in adult patients with ulcerative colitis demonstrated that the combination of infliximab** with azathioprine** is superior in efficacy to monotherapy with either drug alone. Combination therapy should be prescribed taking into account the risk of potential adverse events, including the risk of lymphoma, as well as the fact that the efficacy of the drug combination in case of thiopurine failure (other immunosuppressants, purine analogues) has not yet been reliably proven. Although thiopurines (other immunosuppressants, purine analogues) reduce the rate of infusion reactions and the immunogenicity of infliximab**, they do not affect the clinical outcome of therapy or its pharmacokinetics [97]. Similar results showing no benefit of combination therapy were obtained in a study of infliximab** efficacy in children (T-72) [93]. The probability of colectomy during long-term follow-up of 52 children with ulcerative colitis receiving infliximab** did not differ between the monotherapy and combination treatment groups [95]. In children with steroid resistance who have not previously received thiopurines (other immunosuppressants, purine analogues), infliximab** (contraindicated under 6 years of age according to the instructions) can be used to transition to thiopurine therapy (other immunosuppressants, purine analogues). In this case, combination therapy is usually continued for 4–8 months [29].

Patients with a loss of response during maintenance therapy may require dose optimization (increasing the dose of #infliximab** to 10 mg/kg or shortening the interval between infusions to 4–6 weeks – according to the instructions, in children older than 6 years) [93, 98]. According to most clinical studies, the most significant risk is that of infusion and allergic reactions, whereas the probability of other side effects is low.

• Adalimumab^** (approved by the instructions for patients with ulcerative colitis from 5 years of age) is recommended to be used only in patients with a loss of response to infliximab** or with infliximab** intolerance [32, 33, 99].

(CRG – B; LE – 2)

Comments: adalimumab** therapy is indicated according to the following schedule: induction dose at weeks 0 and 2 of 160 mg and 80 mg for body weight ≥40 kg or 80 mg and 40 mg for body weight <40 kg, followed by maintenance therapy for patients with body weight ≥40 kg of 80 mg every 2 weeks or 40 mg weekly, and for children with body weight <40 kg of 40 mg every 2 weeks or 20 mg weekly [100]. The drug is administered subcutaneously. Individual dose adjustment may be required.

Another drug of this pharmacotherapeutic group of targeted biological agents (tumor necrosis factor-alpha (TNF-alpha) inhibitors) is #golimumab**, but its prescription to children after failed therapy with infliximab** and adalimumab** is inappropriate.

(LoE – C; GoR – 5)

Comment: As a rule, response to treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors may appear as early as 1–4 weeks and peaks at 12–16 weeks of treatment.

During induction, a trough level >15 µg/mL at week 6 best predicted the likelihood of near-term mucosal healing.

Recommended optimal levels during maintenance therapy to improve clinical outcomes are currently under debate: for example, in a number of studies, >4 µg/mL for infliximab** and >5 µg/mL for adalimumab**. The American Gastroenterological Association recommends threshold values of >5 µg/mL for infliximab** and >7.5 µg/mL for adalimumab**.

• Measurement of blood levels of tumor necrosis factor-alpha (TNF-alpha) inhibitors (therapeutic drug monitoring in blood) is recommended to be used selectively (if possible) in patients with an unsatisfactory response to tumor necrosis factor-alpha (TNF-alpha) inhibitors to decide on a dose increase or a switch to another biological agent [33].

(LoE – C; GoR – 5)

Comment: Factors predictive of lower drug levels (and thus potentially dictating a higher dosage) include a higher body mass index, low body weight <30 kg, male sex, high inflammatory burden (extent and severity of the disease), hypoalbuminemia, presence of anti-drug antibodies, and absence of immunosuppressant therapy.

Persistent symptoms despite adequate drug levels indicate the need to switch therapy to another class of biological agents. A high antibody titer indicates that a dose increase will be ineffective.

• #Vedolizumab^** is recommended to be used only in patients with a loss of response or intolerance to tumor necrosis factor-alpha (TNF-alpha) inhibitors (infliximab**, adalimumab**) (for doses, see Comments) [73, 101, 102, 168, 169, 170].

(LoE – C; GoR – 5)

Comments: the doses of #vedolizumab** in children have not been definitively established; treatment is administered according to the following schedule: starting dose of 5 mg/kg (subsequent doses of 6–10 mg/kg are typically used) [32, 87, 168, 169, 170], up to 300 mg at weeks 0, 2, and 6, and then every 8 weeks (shorter intervals (4 weeks) may be needed in case of incomplete effect) (children <30 kg require higher doses – calculated as 10 mg/kg per administration).

Calculation based on body surface area – 177 mg/m² may be more preferable [8, 32, 103].

the use of #vedolizumab** in children with ulcerative colitis is off-label, i.e., outside the indications approved in the drug's instructions.

(Level of Evidence – C; Grade of Recommendation – 4)

Comments: from 6 years of age, at an initial dose of 5 mg twice daily or 10 mg twice daily, switching to a maintenance dose of 5 mg twice daily once remission is achieved (on average, after 8–16 weeks) or, in the absence of response, the maintenance dose may remain at 10 mg twice daily [171, 172]. According to published data, the follow-up duration ranged from 24 months [171, 172].

#Tofacitinib** can also be used as part of "dual therapy", in addition to infliximab**, adalimumab**, #golimumab**, #vedolizumab** [172].

When using #tofacitinib**, laboratory parameters are monitored according to the Instructions.

Comment: from the age of 8 years in children with therapy-refractory variants of UC, at an initial dose of 45 mg/day for 8–12 weeks, followed by a maintenance dose of 15 mg daily [174, 175], or — after an initial dose of 45 mg/kg for 12 weeks — continuing at 30 mg/day, and upon normalization of calprotectin levels, switching to a maintenance dose of 15 mg daily [175, 176].

3.1.2.5.1 Non-medical switching

Currently, biosimilars of tumor necrosis factor alpha (TNF-alpha) inhibitors (anti-TNF drugs) have been registered, which are equivalent in structure, and some of them have demonstrated efficacy similar to the originator drugs in clinical trials [104], although such studies have not been conducted for all biosimilars.

• Switching from the originator drug to a biosimilar in patients with UC is recommended only after achieving remission (no earlier than after the administration of 3 doses of originator infliximab** — according to the instructions, it is contraindicated under 6 years of age) and after discussing the switch with the patient and/or legal representative in order to achieve maximum therapeutic effect and the possibility of accurately assessing its outcome [104].

(LoE – C; GoR – 5)

Comments:

When using both original drugs and biosimilars, careful monitoring is required with timely submission of information to the Drug Safety and Efficacy Monitoring System of Roszdravnadzor (https://roszdravnadzor.gov.ru/drugs/monitoringlp).

The All-Russian Public Organization "Association of Coloproctologists of Russia" and the "All-Russian Society for the Study of Inflammatory Bowel Diseases" issued the following resolution regarding non-medical switching of biologic therapy in inflammatory bowel diseases at the National Summit on the Treatment of Inflammatory Bowel Diseases on June 22, 2019:

A biosimilar may be prescribed to patients who have not previously received tumor necrosis factor alpha (TNF-alpha) inhibitors, if there are appropriate indications and provided its cost is lower than that of the originator tumor necrosis factor alpha (TNF-alpha) inhibitor, supported by a joint decision of the patient and the physician.

The decision on the feasibility of replacing the originator tumor necrosis factor alpha (TNF-alpha) inhibitor with its biosimilar must be made by the physician based on the individual characteristics of the IBD course, as well as taking into account whether the patient belongs to special populations (children, pregnant women, elderly, etc.), and must be agreed upon with the patient in accordance with global practices.

Automatic substitution of the originator drug with a biosimilar and/or switching from one biosimilar to another is unacceptable due to the current lack of sufficient data on their safety and efficacy [105].

(LoE – C; GoR – 5)

3.1.2.6 Conservative therapy for intestinal hemorrhage

(LoE – C; GoR – 5)

Comments: in the absence of effect within 24–48 hours and in case of massive blood loss, emergency surgery is necessary (a progressive decrease in hemoglobin levels during intensive therapy indirectly indicates ongoing intestinal hemorrhage).

3.1.2.7 Conservative therapy for toxic megacolon

• If toxic megacolon is diagnosed, it is recommended to initiate intensive infusion and antibacterial therapy, anti-inflammatory treatment (systemic corticosteroids), and intestinal decompression (abdominal decompression) (with nasogastric and rectal intubation) [108, 109].

(LoE – C; GoR – 5)

Comment: If conservative measures are ineffective within 24–72 hours, emergency surgery is indicated.

3.1.2.8 Conservative therapy for severe/fulminant UC attack

(LoE – C; GoR – 5)

Comment: The algorithm adopted by ESPGHAN in 2018 should be followed. The key criteria determining treatment tactics are PUCAI and the level of inflammatory markers determined upon admission, on days 3 and 5 of treatment for a severe attack [12, 13, 110].

Upon admission, it is necessary to calculate PUCAI, exclude infectious causes of a severe attack (stool culture for pathogenic bacteria, viruses, C. difficile toxins (A, B)) ((Microbiological (cultural) examination of feces/rectal swab for the causative agent of dysentery (Shigella spp.), Microbiological (cultural) examination of feces for the causative agents of typhoid fever and paratyphoid fevers (Salmonella typhi), Microbiological (cultural) examination of feces/rectal swab for the causative agent of yersiniosis (Yersinia enterocolitica), Microbiological (cultural) examination of feces/rectal swab for pathogenic campylobacters (Campylobacter jejuni/coli) with determination of susceptibility to antibacterial drugs, Microbiological (cultural) examination of feces/rectal swab for the causative agent of Clostridium difficile infection), evaluate the complete blood count, ESR, general clinical blood biochemistry study (Study of blood chloride level, Study of blood sodium level, Study of blood potassium level, Study of blood albumin level, Determination of aspartate aminotransferase activity in blood, Determination of alanine aminotransferase activity in blood, Study of C-reactive protein level in blood serum), perform blood culture (microbiological (cultural) blood test for sterility, if necessary: determination of microorganism susceptibility to antimicrobial chemotherapeutic drugs) (in the presence of febrile fever). In the presence of intoxication symptoms, severe pain syndrome, abdominal distension, and tenderness upon palpation, a plain abdominal X-ray should be performed to exclude toxic megacolon [32].

(CRG – B; LE – 2)

• After excluding infection in a severe/fulminant UC attack, it is recommended to initiate intravenous administration of systemic corticosteroids (GCS). The optimal approach is the administration of methylprednisolone** at a daily dose of 1 mg/kg once daily (up to 40 mg/day). In a fulminant attack, methylprednisolone** may be administered at a daily dose of 1–1.5 mg/kg, either at once or divided into 2 doses (maximum 60 mg/day) [38, 87, 32].

(LoE – C; GoR – 5)

Comments: A decrease in PUCAI to 45 points or lower on the 3rd day of treatment indicates a good response to intravenous systemic corticosteroids (GCS). In this case, therapy should be continued for another 2 days. An attempt to switch to oral forms of systemic corticosteroids (GCS) can be made if PUCAI is less than 35 points [32].

If on the 3rd day of treatment with intravenous systemic corticosteroids, PUCAI is >45 points, planning for 2nd-line therapy should begin over the next 3–5 days. Preparation for 2nd-line therapy includes sigmoidoscopy (to take biopsies for excluding CMV infection, the presence of granulomas, and assessing the severity of inflammation), consultation with a surgeon, screening for tuberculosis, hepatitis B and C. On days 3 and 5, it is necessary to repeat the following tests: complete blood count with ESR, general clinical blood biochemistry study (CRP, albumin, electrolytes) [12, 32].

If on the 5th day of treatment with intravenous systemic corticosteroids, PUCAI is 35–65 points, intravenous administration of systemic corticosteroids should be continued for another 2–5 days and then the algorithm should be followed depending on the PUCAI [32].

If PUCAI is >65 points on the 5th day of systemic corticosteroid treatment, either second-line (EL2) therapy should be initiated or colectomy should be performed.

(LoE – C; GoR – 5)

Comments: may be combined with systemic corticosteroids

(LoE – C; GoR – 5)

Comments: before starting #cyclosporine** therapy, the following should be performed: blood creatinine test, blood glucose test, blood electrolyte tests (blood sodium test, blood potassium test, total blood calcium test, total blood serum magnesium test), blood cholesterol test.

During #cyclosporine** or #tacrolimus** therapy, the following follow-up tests should be performed: blood creatinine test, blood glucose test, blood electrolyte tests (blood sodium test, blood potassium test, total blood calcium test, total blood serum magnesium test, blood triglycerides test, peripheral blood pressure measurement, and prevention of P. jirovecii pneumonia [32].

• Due to the increased clearance of infliximab** (contraindicated under 6 years of age according to the instructions) in children with severe UC attack, it is recommended to #increase the dose to 10 mg/kg and shorten the dosing intervals (e.g., weeks 0-1-4 (5)) [12, 32, 90].

(LoE – C; GoR – 5)

(LoE – C; GoR – 5)

(LoE – C; GoR – 5)

• To prevent immunosuppression when prescribing second-line therapy, as well as prior to colectomy, it is recommended to start tapering systemic corticosteroids [32, 33].

(LoE – C; GoR – 5)

• When hemoglobin levels drop below 80 g/L, it is recommended to perform a blood transfusion (packed red blood cells) to correct anemia [32].

(LoE – C; GoR – 5)

• Adolescents at risk for thromboembolic events (smoking, systemic hormonal contraceptives, complete immobilization, central venous catheter, obesity, concomitant severe infection, history of thrombosis and thromboembolism, burdened family history) are recommended to receive thromboprophylactic agents [113].

(Evidence level – B; Grade of recommendation – 3)

Comment: For this purpose, heparin group drugs (low molecular weight heparins) are used, for example, #enoxaparin sodium** at a dose of 1 mg/kg subcutaneously once daily [114, 115].

• Systemic antibacterial drugs are generally not recommended for children with severe UC upon hospital admission [32].

(LoE – C; GoR – 5)

Comment: if there is a high probability of infection (including C. difficile), empirical antibiotic therapy may be administered before stool test results are available [32].

3.2 Surgical Treatment

3.2.1. Surgical treatment for urgent surgical complications

(LoE – C; GoR – 5)

Comments: when performing emergency colectomy, there is no need to perform a low rectal resection, as this complicates the procedure and lengthens the operative time in critically ill patients. The rectum is transected at the level of the sacral promontory (rectosigmoid junction) with stump closure. Linear staplers are preferred to reduce operative time [117]. Also, within 3–5 days after colectomy, it is recommended to drain the rectal stump using a PVC catheter (Nelaton catheter, PVC catheter) inserted transanally to prevent suture dehiscence caused by the accumulation of mucus and blood in the rectum [118]. Colectomy with ileostomy relieves intoxication symptoms caused by severe colitis, improves the patient's general condition, and the pathological (histological) examination of the surgical specimen helps refine the diagnosis and rule out Crohn's disease of the colon, which in children can phenotypically mimic UC (Crohn's colitis) [119].

(Level of Evidence – C; Grade of Recommendation – 4)

Comment: when performed by a highly skilled and experienced specialist, laparoscopic colectomy is a relatively safe surgical option even in severely ill patients with UC operated on an emergency basis [178].

(Level of Evidence – C; Grade of Recommendation – 4)

Comments: the reconstructive phase includes rectal resection with the formation of a pouch-like supranal ileorectal/ileoanal anastomosis. In children (especially younger patients), a straight ileorectal (ileoanal) intestinal anastomosis is also acceptable [121]. The operation is completed by forming a defunctioning loop Turnbull ileostomy.

The third stage of surgical treatment—closure of the defunctioning ileostomy—can be performed if an adequately formed small bowel pouch is present, with no stenosis or inflammatory mucosal changes in the area of the pouch anastomosis. Reconstructive surgery to restore gastrointestinal transit is possible 1–2 months after the main reconstructive stage [118].

3.2.2 Elective surgical treatment

(LoE – C; GoR – 5)

Comments: services according to the current Nomenclature of Medical Services: Total colectomy/Subtotal colectomy/Colectomy with ileorectal anastomosis/Formation of small bowel anastomosis/Laparoscopically-assisted colectomy with abdominoperineal resection of the rectum/Laparoscopic colectomy with abdominoperineal resection of the rectum/Colectomy with abdominoperineal resection of the rectum/Laparoscopically-assisted colectomy with ileorectal anastomosis/Laparoscopic colectomy with ileorectal anastomosis.

Medical therapy failure includes the development of steroid resistance and/or steroid dependence, or biological therapy failure. The inability to continue therapy occurs with steroid dependency, intolerance, or contraindications to medical treatment (biological and/or immunosuppressive therapy). Physical growth retardation may be observed in children with treatment failure.

(ORR – C; LE – 5)

Comment: When mild dysplasia is detected in patients with UC (in biopsy specimens of unchanged mucosa), the decision to perform surgical treatment is made collectively with the participation of the patient and/or the patient's parents/legal representatives.

• Follow-up with regular pathomorphological (histological) examination of colonic mucosal biopsies (Pathological examination of rectal biopsy (surgical) material, Pathological examination of rectal biopsy (surgical) material using histochemical methods) (every 3 months) is recommended as an alternative to early surgery in certain patients [127].

(ORR – C; LE – 5)

Comment: The need for surgical intervention is decided collectively with the participation of a gastroenterologist, pediatric surgeon, clinical laboratory diagnostician/pathologist, in compliance with an interdisciplinary approach [126].

(Let – B; LDD – 3)

Comment: In hospitals where fewer than 10 patients are operated on per year (with the formation of small bowel reservoirs), it is permissible to perform surgery in the volume of colectomy with resection of the rectal mucosa, pull-through of the ileum through the seromuscular cylinder, and formation of a straight ileoanal anastomosis of the Soave type [120, 121, 131].

Elective surgical intervention in children with UC is technically feasible in two stages – with colectomy, ileoanal anastomosis formation, and protective ileostomy, followed by ileostomy closure, or in a single stage – without ileostomy creation [132].

In patients with early-onset UC (with monogenic forms of IBD/primary immunodeficiency), surgical treatment is considered the only option to achieve stabilization of the condition [133, 134].

Risk factors for postoperative complications that determine the choice of surgical scope include high-dose systemic corticosteroid therapy, acute severe colitis, severe weight loss, and indeterminate colitis, which does not allow the exclusion of Crohn's disease of the colon [132]. The influence of drug therapy on the rate of surgical complications has been noted. Thus, the use of prednisolone** at a dose of more than 20 mg for more than 6 weeks increases the risk of surgical complications [152]. Preoperative use of azathioprine** does not worsen the outcome of surgical treatment [153, 154], while the administration of infliximab** (approved for children from 6 years of age) and #cyclosporine** shortly before surgery may increase the rate of postoperative complications, although data on infliximab** remain contradictory [155, 156]. Hypoalbuminemia, preoperative weight loss, as well as systemic corticosteroid therapy, increase the risk of postoperative complications [157, 158].

Elective surgical intervention in children with UC is technically feasible in two stages – with colproctectomy, ileoanal anastomosis formation, and protective ileostomy, followed by ileostomy closure [180], or even in a single stage – without the creation of a protective ileostomy [132, 181].

3.2.3. Complications of surgical treatment of UC

In the postoperative period, both general surgical complications – purulent-septic infections, adhesive intestinal obstruction [148], and complications associated with the specific course of the immune disease – pouchitis and cuffitis [149, 150, 182] are possible. Postoperative complications due to the technique of reservoir formation – leakage of the reservoir-anal anastomosis or reservoir, or the formation of strictures or fistulas, as well as infertility in women as a result of pelvic adhesions [151, 183, 184] are also possible.

• In the event of pouchitis in children with UC, it is recommended to prescribe conservative therapy – systemic antibacterial drugs for a course of up to 14 days (first-line drugs #metronidazole** 20-30 mg/kg/day in three divided doses (maximum dose 500 mg) and #ciprofloxacin** 30 mg/kg/day in 2 divided doses (maximum dose 1 g), as well as topical glucocorticoids: #budesonide (enteric-coated granules) 9 mg daily to relieve inflammation [30, 135].

(LoE – C; GoR – 5)

Comments: The most frequent complication of colectomy with small bowel reservoir formation is nonspecific inflammation of the reservoir (pouchitis), which can occur within 10 years after surgery, and even in large specialized centers, the incidence of pouchitis ranges from 15 to 75% [11, 185]. Symptoms of pouchitis include increased stool frequency, spasmodic abdominal pain, and tenesmus [136].

(Level of Evidence – C; Grade of Recommendation – 4)

Comments: "Cuffitis" can be the cause of blood in the stool or increased stool frequency [186].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific rehabilitation measures for patients with UC. Medical rehabilitation measures are aimed at preventing complications of conservative therapy

(LoE – C; GoR – 5)

• In children and adolescents, especially with an unstable course of the disease, it is recommended to take into account potential non-adherence to medical prescriptions [139].

(Level of Evidence – C; Grade of Recommendation – 4)

Comments: Lack of adherence to IBD therapy is an important and frequent problem, observed in 50%-66% of children [139, 140], especially in adolescence. Non-adherence is associated with increased disease activity in adolescents [140]. Individual studies among adolescents with IBD have reported problems identical to those existing in adults, as well as specific pediatric problems: fear of drug side effects, belief that the disease is inactive, belief that treatment does not work, >1 daily medication [139], forgetfulness, interference of other activities, difficulty swallowing pills [141], lack of motivation, and conflicts between parents and the child [142].

Adherence can be assessed through interviews with the adolescent and parents, and drug monitoring (e.g., Testing for drug levels and their metabolites in urine (thiopurine)).

Adherence to therapy can be improved by providing comprehensive information regarding prescribed medications, keeping the medication burden as low as possible, and once-daily dosing whenever possible.

5. Prevention and Dispensary Observation

5.1. Prevention

Ulcerative colitis is characterized by a chronic relapsing course. The goal of follow-up monitoring is, first of all, early detection of disease relapses, as well as the prevention of colorectal cancer. Features of monitoring patients receiving various immunosuppressive and biological therapies should be taken into account (see section 5.3). The patient should be informed about the necessity of continuous medication intake, since compliance with therapy prescriptions significantly (by 2–2.5 times) reduces the frequency of exacerbations, and the therapy itself is a method of chemoprevention of colorectal cancer.

5.2. Vaccination

Inflammatory bowel diseases are conditions characterized by an increased risk of acquiring and/or reactivating various infections; patients on immunosuppressive therapy, those with chronic comorbidities (e.g., diabetes, chronic kidney disease, HIV infection, primary immunodeficiency), as well as those with impaired nutritional status are particularly at risk.

Timely diagnosis of infections and vaccination are recognized as strategies to mitigate risks for the patient [187, 188, 189].

Comments: it should also be clarified whether the patient has previously had vaccine-preventable infections (e.g., measles, rubella, chickenpox, mumps, etc.). Subsequently, during follow-up and treatment, the patient's vaccination status should be regularly monitored.

Comment: patients not receiving immunosuppressive therapy (Table 1) may receive any vaccines in accordance with the instructions (inactivated and live). Live vaccines are contraindicated in patients receiving immunosuppressive therapy.

There are currently no definitive data on the optimal interval before live vaccines can be administered after the completion of immunosuppressive therapy.

According to [Methodological Guidelines MU 3.3.1.1095-02 "Medical Contraindications to Preventive Vaccinations with National Immunization Schedule Preparations"], the systemic corticosteroid dose that induces immunosuppression is prednisolone** at 2 mg/kg/day taken for 14 days or more; administration of live vaccines to these patients is permitted 1 month or more after the end of therapy. The use of such a dose for less than 2 weeks or lower doses for a longer period does not lead to pronounced immunosuppression, so live vaccines can be administered immediately after finishing the treatment course. The use of maintenance doses of glucocorticoids, as well as their inhalation, topical, or intra-articular administration, is not a contraindication to the administration of any vaccines.

Live vaccines may be administered no earlier than 1–3 months after the completion of immunosuppressive therapy [187, 188, 190]. In cases where high doses of glucocorticoids are used, the interval between the end of treatment and the potential administration of live vaccines may be up to 6 months, depending on the drug manufacturer's instructions [187].

Whenever possible, necessary immunization with live vaccines should be performed before initiating immunosuppressive therapy. Otherwise, immunization may be resumed once disease control is established; if maintenance therapy is required, it should be given concurrently with baseline therapy, and with strict adherence to dietary and other recommendations provided by the gastroenterologist. Immunosuppressive treatment may be initiated no earlier than 3–4 weeks after the administration of live vaccines [187, 188].

Some patients with inflammatory bowel disease retain a risk of an inadequate immune response following standard vaccination regimens; therefore, selective and targeted monitoring of humoral immunity may be performed no earlier than 1 month after completing vaccination (e.g., following vaccination for the prevention of viral hepatitis B** – quantitative determination of antibodies to hepatitis B surface antigen [anti-HBs] in the blood), followed by the administration of a booster vaccine dose if protective antibody titers are absent [187].

Table 1

List of medications used in the treatment of IBD, categorized by the presence of immunosuppressive activity

Note: ¹ Vedolizumab is not included in the list of drugs with immunosuppressive activity because its action is selectively targeted to the intestine; however, according to the instructions, infectious complications may occur in very rare cases

Patients with IBD are at a particularly high risk for severe courses of infections caused by Streptococcus pneumoniae, influenza viruses, hepatitis B, measles, rubella, mumps, and varicella-zoster virus.

• For prophylactic purposes, it is recommended that patients with ulcerative colitis receive sequential vaccination against pneumococcal infection, starting with a single dose of the broadest-valence adsorbed polysaccharide conjugated pneumococcal vaccine (PCV13), followed by the administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23) with a minimum interval of 8 weeks. Revaccination with the 23-valent pneumococcal polysaccharide vaccine is scheduled after 5 years [188].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: vaccination is carried out in accordance with the instructions

Comment: The frequency of vaccination is determined by regulatory documents of the Russian Ministry of Health.

There is evidence that patients with IBD mount an immune response, though it may be attenuated, particularly in those receiving immunosuppressive therapy [192].

There is no evidence that vaccination worsens the course of the underlying disease [192].

5.3 Clinical follow-up (dispensary observation)

Due to the progressive nature of the disease, patients with UC must receive continuous (lifelong) therapy and undergo regular (lifelong) monitoring of disease activity. Disease activity is monitored using not only instrumental diagnostic methods but also laboratory inflammatory markers—primarily fecal calprotectin, the concentration of which in stool correlates with the severity of intestinal inflammation.

The frequency and scope of follow-up care are determined individually, but for most patients, it is advisable to adhere to the following:

Comments: if the child is being managed in an inpatient setting, examinations and tests are not duplicated.

• In the event of clinical deterioration or a rise in inflammatory markers (C-reactive protein, fecal calprotectin), children with UC are recommended to undergo (ileo)colonoscopy to assess disease activity [2].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: performed in an inpatient setting (see Section 2).

• A comprehensive evaluation—including endoscopic, pathomorphological (histological), and laboratory assessments—is required when an adolescent with UC transitions to adult care for further follow-up [2].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: performed in an inpatient setting

5.4. Monitoring of patients receiving immunosuppressive therapy.

• When prescribing immunosuppressive and biological therapy, it is recommended to perform a preliminary screening for tuberculosis infection (tuberculin skin test, blood test for interferon-gamma release assay [IGRA] using Mycobacterium tuberculosis complex antigens, chest computed tomography), strictly adhere to dosing schedules and administration intervals, and provide regular monitoring [31].

(LoE – C; GoR – 5)

Comments:

1. Prior to initiating biological therapy, a consultation with a phthisiatrician (initial clinical examination and consultation by a phthisiatrician) for tuberculosis screening is required (see relevant guidelines);

2. Biological therapy requires strict adherence to dosages and administration schedules (irregular administration increases the risk of infusion reactions and treatment failure);

3. During immunosuppressive therapy, mandatory monitoring includes white blood cell counts, platelets, red blood cells, and hemoglobin (monthly complete blood count [CBC] with differential), general clinical blood chemistry (liver function tests [determination of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase activities, and total bilirubin in the blood], serum creatinine, pancreatic amylase, and lipase levels), and tuberculosis screening (see relevant guidelines).

• To minimize the risks associated with systemic corticosteroid therapy, it is recommended to strictly adhere to the principles of hormone therapy in IBD [30].

(LoE – C; GoR – 5)

Comments: systemic corticosteroids cannot be used as maintenance therapy. When prescribing hormone therapy, the following must be considered:

1. A gradual tapering of systemic corticosteroid doses down to complete discontinuation is strictly mandatory;

2. The total duration of hormone therapy must not exceed 12 weeks;

3. Concurrent intake of calcium supplements, vitamin D and its analogues, and proton pump inhibitors is mandatory;

4. Regular blood glucose monitoring is required during the treatment period.

6. Organization of Medical Care

Patients with ulcerative colitis may receive any type, conditions, and forms of medical care provided for by the legislation of the Russian Federation, as clinically indicated.

Diagnosis, dynamic follow-up, and the selection and adjustment of therapy are performed by a gastroenterologist (or a pediatrician experienced in providing medical care to such patients); additionally, the involvement of a pediatrician, general practitioner (family doctor), infectious disease specialist, rheumatologist, allergist-immunologist, medical psychologist, and other specialists may be required at all stages (based on clinical necessity)

Indications for emergency or urgent hospitalization to a medical organization:

1) presence of complications of ulcerative colitis requiring specialized emergency and urgent medical care.

2) presence of treatment complications (surgical intervention, biological therapy, hormonal and cytostatic therapy, etc.) of ulcerative colitis.

Indications for planned hospitalization in a medical organization:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) presence of indications for specialized treatment of ulcerative colitis (surgical intervention, hormonal and cytostatic therapy, biological and targeted therapy) requiring monitoring in an inpatient or day-care setting.

Indications for patient discharge from a medical organization:

1) completion of the course of treatment, or one of the stages of specialized, including high-tech, medical care in an inpatient or day-hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting established by a medical board of the medical organization providing treatment for ulcerative colitis, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) need to transfer the patient to another medical organization in the relevant medical specialty. The conclusion on the feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on provided medical documents and/or a preliminary examination of the patient by medical specialists of the target medical organization.

7. Additional Information

The lifetime risk of a severe UC flare is 15%, with the probability of a severe attack being higher in patients with total colonic involvement. With adequate maintenance therapy, relapses can be avoided in half of the patients within 5 years, and in 20% of patients within 10 years. During the first year after diagnosis, the probability of colectomy is 4–9% (about 50% in severe attacks), and thereafter the risk of colectomy increases by 1% each year of the disease. Risk factors for an aggressive course of UC include childhood and adolescence at disease onset, progression of lesions from distal (proctitis) to total, and primary sclerosing cholangitis.

Chronic intestinal complications of UC include high-grade epithelial dysplasia and colorectal cancer. Patients with a long-standing history of UC have a significantly increased risk of colorectal cancer, which necessitates regular screening to detect colonic epithelial dysplasia. The probability of cancer development is influenced by the following factors:

1) duration of UC history: the risk of colorectal cancer is 2% with a 10-year history, 8% with a 20-year history, and 18% with a 30-year history [126];

2) onset of the disease in childhood and adolescence, although this factor may merely reflect the duration of the history and may not be an independent predictor of colorectal cancer [145];

3) presence of primary sclerosing cholangitis [146];

4) family history of colorectal cancer;

5) history of severe UC flares or continuous UC course. A consequence of high UC activity can be "inflammatory polyposis," which is also a risk factor for the development of colorectal cancer [147].

Postoperative complications

In the postoperative period, both general surgical complications—purulent-septic infections, adhesive intestinal obstruction [148]—and complications associated with the specific course of an immune-mediated disease, such as pouchitis and cuffitis [149, 150], are possible. In the postoperative period, complications related to the technique of pouch creation—leakage of the ileal pouch-anal anastomosis or pouch, or the formation of strictures or fistulas—as well as female infertility as a result of pelvic adhesions, may occur [151].

High-risk factors for postoperative complications that determine the extent of surgery include high-dose systemic corticosteroid therapy, acute severe colitis, severe weight loss, and indeterminate colitis that does not allow Crohn's disease of the colon to be ruled out [132]. The impact of drug therapy on the rate of surgical complications has been noted. Thus, prednisolone** at a dose >20 mg for >6 weeks increases the risk of surgical complications [152]. Preoperative azathioprine** does not worsen surgical outcomes [153, 154], whereas administration of infliximab** (approved for children from 6 years of age) and #cyclosporine** shortly before surgery may increase the frequency of postoperative complications, although data on infliximab** remain contradictory [155, 156]. Hypoalbuminemia, preoperative weight loss, as well as systemic corticosteroid therapy, increase the risk of postoperative complications [157, 158].

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of specialized medical care for children with ulcerative colitis (ICD-10 codes: K51)

References

Appendix A1. Working Group Composition

1. Baranov A.A., Academician of the RAS, Professor, D.Sc. (Medicine); Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief Freelancer Pediatrician of the Russian Ministry of Health

2. Namazova-Baranova L.S., Academician of the RAS, Professor, D.Sc. (Medicine), President of the Union of Pediatricians of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Head of the Department of Faculty Pediatrics, Faculty of Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Chief Freelancer Pediatric Specialist in Preventive Medicine of the Russian Ministry of Health

3. Razumovsky A.Yu., Corresponding Member of the RAS, D.Sc. (Medicine), Professor, Head of the Department of Pediatric Surgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health, President of the Russian Association of Pediatric Surgeons

4. Khavkin A.I., D.Sc. (Medicine), Professor, Chief Researcher at the Gastroenterology Department of the Research Clinical Institute of Childhood, Head of the Mazurin Department of Gastroenterology and Dietetics, Head of the Moscow Regional Center of Pediatric Gastroenterology and Hepatology at the Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Oblast; Professor at the Department of Pediatrics with a Course of Pediatric Surgical Diseases, Medical Institute, Belgorod State National Research University, Chairman of the Society of Pediatric Gastroenterologists, Hepatologists, and Nutritionists of Russia, Member of the Union of Pediatricians of Russia.

5. Averkina N.A., Ph.D. (Medicine), Chief Specialist at the Central Research Institute for Health Information and Informatization of the Russian Ministry of Health, Gastroenterologist, Pediatrician at the Pediatric Consultative and Diagnostic Department of the Shumakov National Medical Research Center of Transplantology and Artificial Organs, Member of the Union of Pediatricians of Russia

6. Akselrov M.A., D.Sc. (Medicine), Associate Professor, Head of the Department of Pediatric Surgery, Tyumen State Medical University, Head of Pediatric Surgery Department No. 1, Regional Clinical Hospital No. 2, Tyumen, Chief Pediatric Surgeon of the Tyumen Oblast, Member of the Russian Association of Pediatric Surgeons.

7. Belmer S.V., Professor, D.Sc. (Medicine), Professor at the Department of Hospital Pediatrics No. 2, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Co-Chairman of the Society of Pediatric Gastroenterologists, Hepatologists, and Nutritionists, Member of the Union of Pediatricians of Russia

8. Borovik T.Э., D.Sc. (Medicine), Professor, Head of the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation; Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University), Member of the Union of Pediatricians of Russia

9. Vishnyova Elena Aleksandrovna, D.Sc. (Medicine), Professor of the RAS, Deputy Head of the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

10. Volynets G.V., D.Sc. (Medicine), Chief Researcher at the Gastroenterology Department of the Veltischev Research Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health

11. Gabrusskaya T.V., Ph.D. (Medicine), Member of the Union of Pediatricians of Russia (participation in the initial version of the document)

12. Gorelov A.V., Academician of the RAS, Professor, Deputy Director for Science, Central Research Institute of Epidemiology of Rospotrebnadzor, D.Sc. (Medicine), Professor at the Department of Children's Diseases, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University)

13. Goryacheva O.A., Ph.D. (Medicine), Pediatrician, Gastroenterologist, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, Department of Propaedeutics of Children's Diseases, Pediatric Faculty, Pirogov Russian National Research Medical University

14. Gundobina O.S., Ph.D. (Medicine), Leading Researcher, Gastroenterologist at the Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Member of the Union of Pediatricians of Russia

15. Gurova M.M., D.Sc. (Medicine), Leading Researcher at the Laboratory of Medical and Social Problems in Pediatrics, Research Center of Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Professor at the Department of Propaedeutics of Children's Diseases with a Course in General Nursing, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia, Member of the Society of Pediatric Gastroenterologists, Hepatologists, and Nutritionists, Deputy Chief Medical Officer for Medical Affairs, Saint Petersburg Consultative and Diagnostic Center for Children.

16. Zakharova I.N., D.Sc. (Medicine), Professor, Member of the Union of Pediatricians of Russia (participation in the initial version of the document)

17. Zokirov N.Z., D.Sc. (Medicine), Head of the Department, Academy of Postgraduate Education, Federal Research and Clinical Center of the Federal Medical-Biological Agency, Federal Research and Clinical Center of Children and Adolescents of the Federal Medical-Biological Agency, Member of the Union of Pediatricians of Russia

18. Kamalova A.A., D.Sc. (Medicine), Associate Professor, Member of the Union of Pediatricians of Russia (participation in the initial version of the document)

19. Kaitukova E.V., Ph.D. (Medicine), Deputy Head for Medical Operations, Head of the Consultative and Diagnostic Center for Children, Gastroenterologist, Leading Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Associate Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia

20. Karavaeva S.A., D.Sc. (Medicine), Professor, Head of the Department of Pediatric Surgery, North-Western State Medical University named after I.I. Mechnikov, Professor at the Department of Pediatric Surgery with a Course in Anesthesiology and Intensive Care, Saint Petersburg State Pediatric Medical University named after Academician I.P. Pavlov, Leading Surgeon of the Neonatal Surgery Service, Children's City Multidisciplinary Clinical Specialized Center for High Medical Technologies (Children's City Hospital No. 1, Saint Petersburg), Member of the Russian Association of Pediatric Surgeons.

21. Komarova E.V., Deputy Head for Expertise of Innovative Treatment and Rehabilitation Methods, Gastroenterologist, Chief Researcher at the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health of the Petrovsky National Research Center of Surgery, Professor at the Department of Faculty Pediatrics, Faculty of Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia

22. Kornienko E.A., D.Sc. (Medicine), Professor, Head of the Department of Gastroenterology, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University (SPbGPMU), Chief Pediatric Gastroenterologist and Endoscopist of Saint Petersburg

23. Kotin A.N., Ph.D. (Medicine), Associate Professor at the Department of Pediatric Surgery, Saint Petersburg State Pediatric Medical University named after I.P. Pavlov, Pediatric Surgeon at the Children's City Multidisciplinary Clinical Specialized Center for High Medical Technologies (Children's City Hospital No. 1, Saint Petersburg), Member of the Russian Association of Pediatric Surgeons.

24. Lokhmatov M.M., D.Sc. (Medicine), Head of the Endoscopic Diagnostics Department, National Medical Research Center for Children's Health of the Russian Ministry of Health, Professor at the Department of Pediatric Surgery, Urology, and Uroandrology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Union of Pediatricians of Russia

25. Mokrushina O.G., D.Sc. (Medicine), Professor at the Department of Pediatric Surgery named after Yu.F. Isakov, Pirogov Russian National Research Medical University, Deputy Chief Medical Officer for Surgical Care, Children's City Clinical Hospital No. 13 named after N.F. Filatov, Member of the Association of Coloproctologists of Russia, Member of the Russian Association of Pediatric Surgeons.

26. Morozov D.A., D.Sc. (Medicine), Professor, Chief Freelance Pediatric Surgeon of the Russian Ministry of Health, Director of the Veltischev Research Clinical Institute, Head of the Department of Pediatric Surgery and Urology-Andrology named after Prof. L.P. Alexandrov, Sechenov First Moscow State Medical University (Sechenov University), Member of the Russian Association of Pediatric Surgeons.

27. Novikova V.P., D.Sc. (Medicine), Professor, Head of the Department of Propaedeutics of Children's Diseases, Head of the Laboratory of Medical and Social Problems in Pediatrics, Research Center of Saint Petersburg State Pediatric Medical University

28. Novozhilov V.A., MD, PhD, Associate Professor, Head of the Department of Pediatric Surgery, Irkutsk State Medical University; Professor at the Department of Pediatric Surgery, Irkutsk State Medical Academy of Postgraduate Education (a branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health); Chief Medical Officer of the City Yвано-Matrenin Children's Clinical Hospital, Irkutsk; Member of the Association of Coloproctologists of Russia, Member of the Russian Association of Pediatric Surgeons (RAPS).

29. Panfilova V.N., MD, PhD, Associate Professor, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

30. Petryaikina E.E., MD, PhD, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University; Professor at the Department of Evidence-Based Medicine, Medical Institute, RUDN University; Chief Freelance Pediatric Endocrinologist of the Moscow Healthcare Department.

31. Pechkurov D.V., MD, PhD, Professor, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

32. Poddubny I.V., MD, PhD, Professor, Head of the Department of Pediatric Surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry,

33. Podkamenev A.V., MD, PhD, St. Petersburg State Pediatric Medical University, Associate Professor/Professor at the Department of Pediatric Surgical Diseases named after Academician G.A. Bairov,

34. Potapov A.S., MD, PhD, Professor, Head of the Center for Inflammatory Bowel Diseases in Children, Head of the Gastroenterology Department, National Medical Research Center for Children's Health of the Russian Ministry of Health; Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Member of the Union of Pediatricians of Russia

35. Revnova M.O., MD, PhD, Professor, Member of the Union of Pediatricians of Russia

36. Roslavtseva E.A., Candidate of Medical Sciences, Senior Researcher, Laboratory of Healthy and Sick Child Nutrition, National Medical Research Center for Children's Health of the Russian Ministry of Health

37. Svarich Vyacheslav Gavrilovich, MD, PhD, Associate Professor, Professor at the Department of Pediatric Surgical Diseases named after G.A. Bairov, Saint Petersburg State Pediatric Medical University, Member of RAPS.

38. Sitnikova E.P., MD, PhD, Professor, Member of the Union of Pediatricians of Russia

39. Sichinava I.V., MD, PhD, Associate Professor, Professor at the Department of Children's Diseases, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Union of Pediatricians of Russia

40. Skvortsova T.A., Candidate of Medical Sciences, Chief Freelance Pediatric Gastroenterologist of the Moscow Healthcare Department, Head of the Center for Pediatric Gastroenterology and IBD Center, Head of the Gastroenterology Department, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

41. Surkov A.N., MD, PhD, Head of the Pediatric Gastroenterology Department (Inpatient Unit for Children), Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology, and Metabolic Disorders, Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia, Association of Coloproctologists of Russia

42. Stepanova N.M., Candidate of Medical Sciences, Associate Professor at the Department of Pediatric Surgery, Irkutsk State Medical University; Head of the Center for Correction of Anorectal Anomalies and Pediatric Colorectal Surgery, City Yвано-Matrenin Children's Clinical Hospital, Irkutsk; Member of the Association of Coloproctologists of Russia, Member of RAPS.

43. Sytkov V.V., Candidate of Medical Sciences, Associate Professor at the Department of Pediatric Surgery, N.A. Semashko Scientific Research Institute of Clinical Medicine, Russian University of Medicine of the Russian Ministry of Health; Coloproctologist and Pediatric Surgeon, Surgical Department, Federal Research and Clinical Center for Children and Adolescents of the Federal Medical-Biological Agency; Member of the Union of Pediatricians of Russia, Russian Association of Pediatric Surgeons, Russian Society of Colorectal Surgeons

44. Tkachenko M.A., Candidate of Medical Sciences, Pediatrician, Gastroenterologist, Chief Freelance Gastroenterologist of the Healthcare Committee of Leningrad Region, Associate Professor at the Department of Outpatient Pediatrics named after Academician A.F. Tur, Saint Petersburg State Pediatric Medical University.

45. Filippov D.V., Candidate of Medical Sciences, Saint Petersburg State Pediatric Medical University, Associate Professor at the Department of Pediatric Surgical Diseases named after Academician G.A. Bairov)

46. Fedoseenko M.V., Candidate of Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician at the Research Institute of Pediatrics and Children's Health, Petrovsky National Research Centre of Surgery; Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University); Member of the Union of Pediatricians of Russia

47. Fedulova E.N., MD, PhD, Professor, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

48. Tsymbalova E.G., Candidate of Medical Sciences, Head of the Gastroenterology Department, Russian Children's Clinical Hospital (branch of Pirogov Russian National Research Medical University); Head of the Gastroenterology Center, Russian Children's Clinical Hospital (branch of Pirogov Russian National Research Medical University); Coordinator of the Pediatric Group, Russian Children's Clinical Hospital (branch of Pirogov Russian National Research Medical University); Member of the Union of Pediatricians of Russia, Member of the Pediatric Group of the Russian Society for the Study of IBD, Member of the European Crohn's and Colitis Organisation (ECCO)

49. Shumilov P.V., MD, PhD, Professor, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

50. Shcherbakova O.V., MD, PhD, Head of the Surgical Department, Federal Research and Clinical Center for Children and Adolescents of the FMBA of Russia

51. Shchigoleva N.E., Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

52. Yablokova E.A., Candidate of Medical Sciences, Associate Professor at the Department of Children's Diseases, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Union of Pediatricians of Russia

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatricians

2. Gastroenterologists

3. Pediatric surgeons

4. Endoscopists

5. Radiologists

6. Pathologists

7. General practitioners (family physicians)

8. Infectious disease specialists

9. Allergists-immunologists

10. Medical students, residents, and postgraduate students

These guidelines are based on literature data and the European evidence-based consensus on the diagnosis and management of ulcerative colitis presented by the European Crohn's and Colitis Organisation.

Clinical guidelines reflect expert opinion on key issues. Clinical situations may arise that fall outside the scope of these recommendations; therefore, the final decision on the management tactics for each patient must be made by the attending physician, who bears the responsibility for their treatment.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1) Standard of specialized medical care for children with ulcerative (chronic) ileocolitis (ulcerative colitis) (Order of the Russian Ministry of Health No. 649n dated 07.11.2012).

2) On approval of the procedure for providing pediatric care (Order of the Ministry of Health of the Russian Federation No. 366n dated April 16, 2012).

3) Drug information: https://grls.rosminzdrav.ru/.

Main regulatory and legal acts governing the provision of

palliative medical care

1. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

2. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'".

Other regulatory and legal documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers."

4. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

5. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Public Health Protection in the Russian Federation' regarding Clinical Guidelines".

6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

7. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

8. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, "On Classifications and Criteria Used in Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise" (comes into force on January 1, 2020);

9. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Forms for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting, and Storage"

10. Order of the Ministry of Health and Social Development of the Russian Federation "On the procedure for the use of medicinal products in patients for vital indications" No. 494 dated August 9, 2005

11. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

12. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 (as amended on May 25, 2022) "On approval of sanitary rules and norms SanPiN 3.3686-21 'Sanitary and epidemiological requirements for the prevention of infectious diseases'"

Examples of diagnosis formulations:

• Ulcerative colitis, proctitis (E1), mild attack (PUCAI – 30 points). No history of severe attack (S0).

• Ulcerative colitis, left-sided involvement (E2), moderate attack (PUCAI – 50 points). History of severe attack present (S1). Exacerbation. Extraintestinal manifestations (primary sclerosing cholangitis).

• Ulcerative colitis, left-sided involvement (E2), atypical phenotype (skip lesion of the cecum), moderate attack (PUCAI – 50 points), no history of severe attack (S0).

• Ulcerative colitis, pancolitis (E4), severe attack (PUCAI – 80 points) (S1). Corticosteroid resistance. Toxic megacolon.

• Unclassified inflammatory bowel disease, severe attack (PUCAI – 80 points) (S1). Corticosteroid resistance.

• Ulcerative colitis, pancolitis (E4). No history of severe attack (S0). Clinical and endoscopic remission.

Appendix A3.1 Explanation of Notes

** – a medicinal product included in the Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on June 9, 2023) "On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care"

# – The use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use (off-label) is carried out in accordance with Federal Law No. 323-FZ dated November 21, 2011, as amended.

Appendix A3.2 Main diseases requiring differential diagnosis with ulcerative colitis in children

Appendix B. Physician Action Algorithms

Algorithm for the diagnosis and treatment of children with UC

Notes: Medical treatments for UC should be divided into medications for inducing remission (aminosalicylic acid and similar preparations [5-ASA], systemic corticosteroids, tumor necrosis factor-alpha inhibitors [anti-TNF], calcineurin inhibitors) and maintaining remission (aminosalicylic acid and similar preparations [5-ASA], thiopurines, tumor necrosis factor-alpha inhibitors [anti-TNF]).

¹ Regardless of the severity of active disease, the following conditions should be ruled out: infectious colitis (including cytomegalovirus [CMV] and Cl. difficile), 5-ASA-associated colitis, lactose intolerance, irritable bowel syndrome, misdiagnosis, celiac disease, and similar conditions.

² Unlike in adults, endoscopic evaluation of the rectal mucosa in children is considered more invasive for routine monitoring of disease activity and treatment response. Therefore, assessing disease status is preferentially based on non-invasive indirect markers of colitis activity.

³ Aminosalicylic acid and similar preparations (5-ASA) are prescribed at a dose of 60–80 mg/kg/day up to 4.8 g/day [8]. Recent data indicate that a once-daily dose of 3 g of aminosalicylic acid and similar preparations (5-ASA) is no less effective than dividing this dose into 2 administrations.

⁴ Enemas with aminosalicylic acid and similar preparations (5-ASA) (25 mg/kg, up to 1 g) are more effective than enemas with systemic corticosteroids [8].

⁵ If there is no improvement (i.e., a decrease in PUCAI of less than 20 points) after 7–10 days, or if the PUCAI increases by ≥20 points at any stage of treatment, the use of intravenous systemic corticosteroids or the administration of tumor necrosis factor-alpha inhibitors (less commonly – #tacrolimus**) should be considered. In case of corticosteroid dependence, maintenance therapy should be intensified.

⁶ Turner D et al 2011 [29].

⁷ Response is defined as a decrease in PUCAI of at least 20 points; at the same time, the goal of induction therapy is to achieve complete clinical remission (PUCAI <10).

⁸ If infliximab** was prescribed to a patient who had not previously received thiopurines (other immunosuppressants), they may be added to the therapy after achieving complete remission, followed by the discontinuation of infliximab** after 4–8 months. In individual cases, after prolonged sustained remission, a gradual transition to therapy with aminosalicylic acid and similar preparations (5-ASA) is possible, provided that aminosalicylic acid and similar preparations (5-ASA) was not previously shown to be ineffective.

⁹ Currently, there are no data to recommend adding thiopurines (other immunosuppressants) to infliximab** therapy in children in whom thiopurines (other immunosuppressants) were previously ineffective. Discontinuation of thiopurine therapy (other immunosuppressants) is indicated after 4–8 months of combination therapy, especially in boys.

Algorithm for the diagnosis and treatment of severe ulcerative colitis flare

Appendix C. Patient Information

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by recurrent acute flares followed by periods of remission. Numerous studies show that without treatment, patients with UC experience a significant decrease in quality of life, an increased risk of colorectal cancer, and higher mortality. Untimely and inadequate treatment can lead to disease progression and not only worsening symptoms (bloody diarrhea, abdominal pain) but also systemic manifestations: weight loss, fever, anemia. A severe flare of ulcerative colitis is life-threatening due to the risk of intestinal perforation and peritonitis. Most importantly, even with mild or absent symptoms, inflammation may persist in the intestine. With inadequate treatment, this constant inflammation leads to the development of colorectal cancer, which is particularly aggressive in UC. Only regular anti-inflammatory therapy can reduce the likelihood of tumor development.

Ulcerative colitis is a relatively rare disease; patients with this condition should ideally be monitored by a physician specializing specifically in this pathology and strictly follow their recommendations for long-term, often lifelong, drug therapy. Neither the level of physical activity nor the intake of specific foods affects the risk of a UC flare as much as irregular medication use and untimely consultation with a specialist do.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Pediatric Ulcerative Colitis Activity Index

Original name: Pediatric Ulcerative Colitis Activity Index: PUCAI

Source: [32]

Type: rating scale

Purpose: assessment of ulcerative colitis activity

Content (template):

Key (interpretation):

PUCAI criteria:

• Remission – up to 10 points (sensitivity 89%, specificity 89%)

• Minimal activity (mild flare) – 10–34 points (sensitivity 95%, specificity 95%)

• Moderate activity (moderate flare) – 35–64 points (sensitivity 92%, specificity 94%)

• High activity (severe flare) – more than 65 points

• Clinically meaningful response corresponds to a decrease in PUCAI of at least 20 points.

Appendix G2. Endoscopic index of ulcerative colitis severity (UCEIS) [42]

Original name: Ulcerative Colitis Endoscopic Index of Severity (UCEIS)

Source: [42]

Type: rating scale

Purpose: endoscopic assessment of ulcerative colitis activity

Key (interpretation): remission – 0-1 points, minimal activity – 2-4 points, moderate activity – 5-6 points, 7-8 points – high activity.

Appendix G3. Mayo Endoscopy Score (MES) for ulcerative colitis (with mucosal assessment according to Schroeder) [43]

Original title: Mayo Endoscopy Score (MES)

Source: [43]

Type: rating scale

Purpose: endoscopic assessment of ulcerative colitis activity

Key (interpretation): inactive disease (0 points), mild activity (1 point), moderate activity (2 points), and severe (high) activity (3 points).