Crohn's Disease: Clinical Guidelines

List of Abbreviations

MP – mercaptopurine**

AZA – azathioprine**

CD – Crohn's disease

GC – glucocorticoids

GI – gastrointestinal tract

IFM – #infliximab**

CT – computed tomography

MR-enterography – magnetic resonance enterography

MRI – magnetic resonance imaging

MT – methotrexate**

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

"Liver" enzymes – determination of the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase in the blood

PCV13 – pneumococcal polysaccharide conjugate vaccine (adsorbed)** and pneumococcal vaccine** (conjugated) (13-valent)

PPS23 – pneumococcal polysaccharide vaccine** (23-valent)

PSC – primary sclerosing cholangitis

EEN – exclusive enteral nutrition

RCT – randomized controlled trial

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

Thiopurines – (L04AX) Other immunosuppressants / (L01BB) Purine analogues

US – ultrasound examination

UC – ulcerative colitis

PCDAI – Pediatric Crohn's Disease Activity Index

Terms and Definitions

Crohn's disease (CD) is a chronic, relapsing multisystem disease of unclear etiology, predominantly affecting the entire gastrointestinal tract, characterized by focal, asymmetric, transmural, segmental, granulomatous inflammation of the wall of the small and/or large intestine or the entire gastrointestinal tract, accompanied by intestinal and extraintestinal complications. Outdated name: regional enteritis.

CD flare (relapse, attack) is the appearance of typical symptoms of the disease for the first time or in patients with CD in clinical remission, whether spontaneous or medically maintained.

CD remission is the disappearance of typical manifestations of the disease.

CD remission, clinical – absence of CD symptoms (corresponds to a Pediatric Crohn's Disease Activity Index (PCDAI) value <10 [1].

CD remission, endoscopic – absence of visible macroscopic signs of inflammation on endoscopic examination [1], corresponding to a Simple Endoscopic Score for Crohn's Disease (SES-CD) <= 3

Non-medical switching (NMS) is the changing of a patient's established therapy to an alternative for reasons unrelated to clinical ineffectiveness, the occurrence of adverse drug reactions (ADRs), or patient intolerance to the therapy [2, 3].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Crohn's disease (CD) is a chronic, relapsing gastrointestinal disease of unclear etiology, characterized by transmural, segmental inflammation of the small and/or large intestine wall or the entire gastrointestinal tract, with the development of local and systemic complications.

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

The etiology of inflammatory bowel diseases (IBD), including CD, has not been precisely established: the disease develops as a result of a combination of several factors, including genetic predisposition, defects in innate and acquired immunity, alterations in the intestinal microbiota, and various environmental factors.

More than 100 genes predisposing to IBD have been discovered, the majority of which control the interaction of the immune system with external antigens; among them, mutations in NOD2, IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 5p13, HERC2, CCNY, and 10q21 are more frequently found in CD. More than 50% of the genes determining susceptibility to IBD are also associated with other inflammatory and autoimmune diseases, which may explain the development of extraintestinal manifestations of IBD [4]. At the same time, no specific genetic features characteristic of children have been identified, with the exception of a group of very early onset pediatric patients.

Changes in the intestinal microbiota are detected in all CD patients and are characterized by a decrease in species diversity, a reduction in the number of tolerogenic species (e.g., Faecalibacterium prausnitzii, Bacteroides thetaiotaomicron), an increase in flagellated bacteria, changes in the virome, increased permeability of the mucus layer, and an elevated number of microbes penetrating the mucosal layer [5].

Chronic inflammation in IBD is a consequence of abnormal and prolonged activation of the intestinal immune system. Numerous studies have demonstrated that abnormalities occur in virtually all links of the immune response [6], ranging from epithelial barrier functions and antigen recognition by pattern-recognition receptors, signal transmission by dendritic cells and signaling molecules, and HLA antigen presentation, down to the effector functions of monocytes-macrophages, T and B lymphocytes. The formation of inflammasomes, activation of caspase-1, and secretion of proinflammatory cytokines (IL-1, IL-17, IL-23, IL-6, TNF-a) drive intestinal inflammation with the development of massive, deep inflammatory infiltration of the bowel. Infantile forms of IBD may be caused by impaired formation of immunological tolerance to the host's own intestinal microbiota due to mutations in specific genes, such as IL-10, FOXP3, XIAP, and others [7].

The cascade of humoral and cellular reactions in CD leads to transmural inflammation of the intestinal wall with the formation of sarcoid granulomas characteristic of CD, consisting of epithelioid histiocytes without areas of necrosis and giant cells.

CD can affect any part of the gastrointestinal tract, from the oral cavity to the anus. However, in the vast majority of children, ileocecal involvement dominates (70%), isolated colonic involvement occurs in 30%, anorectal involvement in 20%, and upper GI tract involvement in 5–15% [8].

1.3 Epidemiology of the Disease or Condition

Worldwide, there is an increase in the incidence of inflammatory bowel disease (IBD) in children, specifically Crohn's disease (CD), the incidence of which ranges from 1.5 to 11.4 per 100,000 [9, 10], with the estimated prevalence of CD being 58 per 100,000. There are no exact data on the prevalence of CD in children in Russia, but individual regional observations indicate a similar trend. For instance, in Saint Petersburg, the incidence of CD has increased more than 10-fold over the past 10 years to reach 5.5 per 100,000, and the prevalence is 20 per 100,000 children and adolescents [8]. Approximately 10% of CD patients first manifest the disease under the age of 17; over the past 10 years, pediatric-onset IBD has increased 3-fold [11].

1.4 Features of Coding the Disease or Condition

K50 Crohn's disease [regional enteritis]

K50.0 Crohn's disease of the small intestine

K50.1 Crohn's disease of the large intestine

K50.8 Other Crohn's disease

K50.9 Crohn's disease, unspecified

K52.3 Indeterminate colitis

K52.9 Noninfective gastroenteritis and colitis, unspecified

1.5 Classification of the disease or condition

To classify CD by lesion localization and phenotypic disease variants with respect to children, it is recommended to use the international Paris classification of Crohn's disease adopted in 2010 (Table 1).

Table 1. Classification of Crohn's disease

Very early-onset IBD (VEO-IBD) – under 6 years of age – and infantile IBD – onset in the first 2 years of life – are now also distinguished [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 and to facilitate the selection of rational treatment tactics—since the goal of conservative management is to achieve sustained remission with discontinuation of GCS therapy—the following are distinguished:

• Steroid resistance (persistence of disease activity despite oral intake of an adequate dose of GCS for 7–14 days);

• Steroid dependence (defined when clinical remission is achieved during glucocorticoid therapy and symptoms recur upon dose reduction or within 3 months after complete cessation, as well as in cases where glucocorticoid therapy cannot be stopped within 14–16 weeks).

The Pediatric Crohn's Disease Activity Index (PCDAI) is also determined to assess the clinical activity of a CD flare (Appendix G1) [10].

1.6 Clinical presentation of the disease or condition

In pediatric age, IBD is characterized by a more aggressive course than in adults; the process is more widespread, tends to progressively increase in severity, is associated with a higher likelihood of developing complications, and requires more intensive therapy, in particular the administration of glucocorticoids, thiopurines, #methotrexate**, and tumor necrosis factor alpha (TNF-alpha) inhibitors (anticytokine drugs) [12, 13]. The probability of complications requiring surgery is also higher in patients with pediatric-onset CD. By the age of 30, their risk of bowel resection is 48 ± 5% compared to 14 ± 2% in those who fell ill as adults [14].

The clinical presentation in the early stages of CD may be mild and the symptoms non-specific, which complicates timely diagnosis. Sometimes CD runs a latent course, manifesting only as delayed physical development of the child, and sometimes the first symptoms may be complications or extraintestinal manifestations (EIMs).

Complications of CD include: external fistulas (enterocutaneous), internal fistulas (enteroenteric, enterovesical, rectovaginal), abdominal infiltrates, interloop or intra-abdominal abscesses, gastrointestinal strictures (with or without intestinal obstruction), anal fissures, paraproctitis (in anorectal involvement), and intestinal bleeding (rare).

More than 40% of children have extraintestinal manifestations of the disease [10] (Table 2). The likelihood of EIM development increases with the duration of CD; they are more common in the colonic form of CD, and EIMs associated with disease activity frequently co-occur. In principle, IBD can affect any organ, but joint, liver, eye, and skin involvement are the most frequent [8].

Table 2 – Extraintestinal manifestations of Crohn's disease

Autoimmune manifestations associated with the activity of the inflammatory process appear alongside the main intestinal symptoms of a flare-up and resolve with them during treatment. Autoimmune manifestations not associated with disease activity (concomitant autoimmune diseases) tend to progress regardless of the phase of the underlying disease (flare-up or remission) and often determine an unfavorable prognosis of the disease.

Timely and accurate diagnosis, and adequate therapy can alter the natural history of CD. The choice of therapy must correspond to the localization of the process and its activity, taking into account the patient's individual characteristics, in particular, age and existing risk factors.

2. Diagnostics, medical indications and contraindications for diagnostic methods

There are no unequivocal diagnostic criteria for CD; the diagnosis is established based on a combination of anamnesis, clinical presentation, and typical endoscopic and pathoanatomical (histological) changes [15,16].

In practice, one may be guided by the Lennard-Jones diagnostic criteria for Crohn's disease which include the definition of seven main features of the disease:

1. Involvement of any part of the GI tract from the oral cavity to the anal canal: chronic granulomatous involvement of the labial or buccal mucosa; gastroduodenal involvement, small bowel involvement, chronic perianal involvement

2. Discontinuous (skip) pattern of GI involvement

3. Transmural nature of involvement: aphthous ulcers, fissuring ulcers, abscesses, fistulas

4. Fibrosis: strictures

5. Lymphoid: transmural inflammation, lymphoid aggregates

6. Mucin: normal mucin content in the area

7. of active inflammation of the colonic mucosa

8. Detection of non-caseating granuloma

CD diagnosis is definitive: 3 features or any 1 feature + granuloma

IBD phenotypes are also distinguished depending on frequency and probable diagnosis depending on the initial phenotype (in an untreated child) [8,17] (Table 3)

Table 3.IBD phenotypes according to frequency and probable diagnosis based on the initial phenotype (in an untreated child)

To verify the disease period (flare-up or remission), assess the severity of the flare-up, and dynamically evaluate the effectiveness of the patient's treatment, the Pediatric Crohn's Disease Activity Index (PCDAI) should be used (Appendix G1) [10].

2.1 Complaints and Anamnesis

The most frequent clinical symptoms of CD in children include [10]:

• prolonged chronic diarrhea (more than 6 weeks), frequently without blood admixture;

• persistent abdominal pain with clear localization;

• weight loss, significant weight deficit, growth retardation;

• prolonged fever of unknown origin;

• anemia, most commonly iron deficiency anemia and/or anemia of chronic disease;

• perianal complications (chronic anal fissures, paraproctitis, rectal fistulas).

Patients with CD and upper GI involvement may present with other gastroenterological complaints. Thus, esophageal involvement is manifested by chest pain, heartburn, and regurgitation (resembling those in gastroesophageal reflux disease), and in more severe cases, dysphagia, odynophagia, vomiting, and weight loss. In CD with gastric and duodenal involvement, patients may complain of pain, heaviness, and fullness in the epigastric region, nausea, and decreased appetite [1,15].

When taking the anamnesis, attention should be paid to information about travel to southern countries, food intolerances, medication use (including systemic antibacterial drugs and nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs)), smoking, and a family history of IBD and other autoimmune diseases.

2.2 Physical Examination

The physical examination of a child should include the assessment of physical and sexual development, a complete examination including inspection of the perianal area. The examination may reveal various manifestations of the disease, including weight loss, growth and pubertal retardation, oral aphthae, an abdominal infiltrate, external intestinal fistulas, perianal changes (fissures, fistulas), as well as extraintestinal manifestations.

2.3 Laboratory Diagnostics

(GQR – A LoE - 1).

Comments: Fecal calprotectin levels are significantly higher in colonic inflammation.

If the fecal calprotectin level is elevated more than 5-fold (250 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, calprotectin levels are always elevated and can normally be up to 2000 mcg/g) [21,22].

For children with an established diagnosis of CD, fecal calprotectin monitoring should be performed on average once a year to monitor the intestinal inflammatory response and timely adjust therapy, or during a flare-up. Fecal calprotectin is a sensitive marker of inflammation and is also used as a method for monitoring disease activity. To increase the sensitivity of fecal calprotectin in monitoring disease activity, it is also recommended to additionally determine CRP and the clinical CD activity index PCDAI [10].

(GQR – C LoE - 3).

Comments: There is no evidence-based data on the required frequency of these laboratory tests. Complete blood count and C-reactive protein parameters should be monitored on average at least 1–2 times a year during disease remission; if necessary (onset, flare-up), parameter monitoring may be more frequent (mandatory upon hospitalization) and is determined by the severity of the patient's condition.

A complete blood count is monitored in patients receiving certain types of immunosuppressive therapy (thiopurines or #methotrexate**) at least once every 1–3 months (Appendix A3.1).

Laboratory changes in CD are nonspecific. The complete blood count may reveal anemia (most commonly iron deficiency anemia or anemia of chronic disease, less commonly vitamin B12 or folate deficiency anemia), leukocytosis (due to chronic inflammation, the presence of an abscess, or steroid therapy), and an elevated ESR.

• Children with suspected CD are recommended to undergo a general routine blood biochemistry panel (total protein, blood albumin/globulin ratio, liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase activities in blood), electrolytes (sodium, potassium, magnesium, chlorine), serum iron level, transferrin, ferritin, total blood bilirubin level, unconjugated and conjugated bilirubin levels in blood, blood glucose level, blood creatinine level, blood urea level) to assess inflammation, liver and kidney function, iron metabolism, and electrolyte balance [19,20,24].

(GQR-C; LoE-5)

Comment: blood biochemistry allows the detection of dysproteinemia (in particular, hypoalbuminemia and elevated a₂- and γ-globulins).

In liver involvement, levels of ALT, AST, GGT, total bilirubin, and the direct bilirubin fraction in cholestatic liver disease may be elevated.

In the future, during follow-up monitoring, general general-health blood chemistry parameters should be controlled. The frequency and choice of parameters are determined individually, depending on the phase of the disease, severity of the course, and clinical manifestations. Dynamically, on average, tests can be performed 1-2 times a year. In patients receiving thiopurines or #methotrexate**, ALT, AST, and GGT are tested on average at least once every 1–3 months (Appendix A3.1).

(RRR - C; LOR - 4)

Comments: a general (clinical) urinalysis should be performed during diagnosis and follow-up monitoring.

(GQR-C; LoE-5)

Comments: tests may also be performed during follow-up monitoring if helminthic infections are suspected.

(GQR-C; LoE-5)

Comment: If intestinal infections are suspected, appropriate tests are performed to detect Salmonella, Shigella, Yersinia, Campylobacter (for example: microbiological (cultural) examination of feces/rectal swab for microorganisms of the genus Salmonella (Salmonella spp.), microbiological (cultural) examination of feces/rectal swab for the causative agent of dysentery (Shigella spp.), microbiological (cultural) examination of feces/rectal swab for Yersinia (Yersinia spp.), microbiological (cultural) examination of feces/rectal swab for the causative agent of yersiniosis (Yersinia enterocolitica), microbiological (cultural) examination of feces/rectal swab for the causative agent of pseudotuberculosis (Yersinia pseudotuberculosis), microbiological (cultural) examination of feces/rectal swab for pathogenic Campylobacter (Campylobacter jejuni/coli)) with determination of sensitivity to antibacterial drugs.

Determination of antibodies to the causative agents of strongyloidiasis (Strongyloides stercoralis), molecular biological examination of feces for the causative agent of strongyloidiasis (Strongyloides stercoralis), determination of Strongyloides stercoralis pathogen DNA in feces by PCR

A 3-fold bacteriological examination of feces for the intestinal group, including Campylobacter, as well as serological blood testing to determine the level of antibodies to intestinal infections, is performed. If antibodies are present in a low titer, the test is repeated; in an intestinal infection, the antibody titer increases. Currently, the capabilities of PCR diagnostics for intestinal infections are expanding, which should also be used [8].

• In children with suspected Crohn's disease, if differential diagnosis with ulcerative colitis is necessary, it is recommended to test the blood for IBD immunological markers: ASCA (determination of class G antibodies (IgG) in the blood to Saccharomyces cerevisiae (ASCA)) and ANCA (determination of markers of ANCA-associated vasculitis: PR3 (c-ANCA), MPO (p-ANCA)) [19, 20].

(RRR - C, LOR - 5).

Comments: The presence of ASCA (antibodies to Saccharomyces cerevisiae) supports the diagnosis of Crohn's disease and is a marker of an adverse phenotype

The absence of ASCA does not rule out the diagnosis, as they are positive in only 20% of patients.

In the Nomenclature of Medical Services (Order of the Ministry of Health of the Russian Federation dated October 13, 2017, No. 804n), the service "Determination of class G antibodies (IgG) in the blood to Saccharomyces cerevisiae (ASCA)" is absent.

(RRR-C; LOR-5)

Comments: preferably in an intestinal biopsy obtained during sigmoidoscopy (determination of Cytomegalovirus DNA in biopsies and punctates from lesions of organs and tissues by PCR, qualitative study; determination of Cytomegalovirus DNA in biopsies and punctates from lesions of organs and tissues by PCR, quantitative study). If the test result is positive, appropriate therapy is required.

• In all children during the diagnosis of Crohn's disease, it is recommended to screen for hepatitis B (determination of hepatitis B virus surface antigen (HBsAg) in the blood) to select patients for immunization against this infection or to prescribe appropriate therapy if the disease is detected [20].

(RRR-C; LOR-5).

(GQR-C; LoE-5)

Comment: An intradermal test with a tuberculosis allergen and/or IGRA tests (Interferon-γ release assays) can be performed—immunological methods based on the stimulation of T-lymphocytes by peptide antigens and the production of interferon-γ secreted by blood cells of an M. tuberculosis-infected person (determination of interferon-gamma level for Mycobacterium tuberculosis complex antigens in the blood).

Intradermal test results should be interpreted with caution, as anergy may occur in inflammatory bowel diseases.

In addition to laboratory tests, history and clinical presentation data, as well as chest radiography and/or chest computed tomography, should be evaluated [26].

(RRR - C, LOR - 5).

Comments: determination of blood thrombin time, fibrinogen, international normalized ratio (INR), blood D-dimer concentration, etc., is possible.

(RRR - C, LOR - 5).

Comments: further investigations and tactics for doubtful results should follow the relevant clinical guidelines. The frequent combination of Crohn's disease and celiac disease should also be taken into account [29, 30].

(RRR - C, LOR - 5).

Comments: The determination of the 25-OH vitamin D level in the blood should be performed in all patients regularly, on average once a year.

(RRR - C, LOR - 5).

Comments: indications and frequency of tests are determined individually, for example: blood 25-OH vitamin D level testing should be performed regularly in all patients, cyanocobalamin is mandatory for monitoring in patients after terminal ileal resection, cyanocobalamin and folic acid in the presence of macrocytic anemia, zinc in patients with profuse diarrhea or high-output fistulas, and vitamins A and E rarely and when feasible.

(LoE - C, GoR - 5)

Comment: The Nomenclature of Medical Services currently lacks a service for microbiological (culture) blood testing for aerobic and facultatively anaerobic microorganisms.

If necessary, rapid tests for pathogen identification and antimicrobial susceptibility testing may be considered.

If a septic state develops or is suspected, patient management should be carried out in accordance with relevant guidelines

2.4 Instrumental Diagnostics

2.4.1 Endoscopic diagnostic methods

• All children with suspected Crohn's disease are recommended to undergo:

• colonoscopy with ileoscopy (colonoscopy, videocolonoscopy, intestinoscopy)

• esophagogastroduodenoscopy

• step-by-step mucosal biopsy of all examined segments [19,20].

(LoE – C; GoR - 5)

Comments: in children, colonoscopy, videocolonoscopy, and intestinoscopy are performed under general anesthesia, while esophagogastroduodenoscopy is performed when indicated.

These studies are also performed during follow-up monitoring – the frequency is set individually (including in relapses, suspected progression, and post-surgical monitoring)

• When small bowel involvement is suspected and the diagnosis cannot be reliably confirmed by colonoscopy (with examination of the terminal ileum), CT, and MRI, or when video capsule endoscopy cannot be performed, it is recommended to selectively perform balloon-assisted enteroscopy (double-balloon intestinoscopy) with biopsy (endoscopic small bowel biopsy) to clarify the diagnosis [33, 34].

(LoE – B; GoR – 3).

Comments: the procedure is performed under general anesthesia

2.4.2 Imaging methods

• When small bowel involvement is suspected in Crohn's disease, it is recommended to perform:

MR enterography (hydro-MRI, (magnetic resonance enterography, contrast-enhanced magnetic resonance enterography)) and/or CT enterography (hydro-CT, (contrast-enhanced computed tomography of the small intestine)) to clarify the diagnosis [20,35]

(LoE – C; GoR - 5)

Comments: MRI may be preferred in children due to the absence of radiation exposure, whereas CT is more suitable in emergency conditions.

When choosing an examination, one should be guided by the patient's condition, age, and the capabilities of the medical organization.

General anesthesia is performed when indicated.

• If MRI or CT cannot be performed, it is recommended to perform a contrast X-ray examination of the small intestine using barium sulfate**-containing radiopaque agents (radiography of the small intestine with contrast) (after excluding signs of obstruction or perforation) [19,20,36, 37].

(LoE – C; GoR - 5)

• Comments: barium sulfate** examinations are contraindicated in patients with known or suspected perforation, as barium peritonitis may develop in such cases. Instead of barium sulfate**, a water-soluble contrast agent group drug should be used.

• In children with suspected IBD, as an alternative to MR enterography (hydro-MRI, (magnetic resonance enterography, contrast-enhanced magnetic resonance enterography)) as well as in case of negative results of this study with a high suspicion of Crohn's disease, it is recommended to selectively perform video capsule endoscopy (small bowel video capsule endoscopy, colon video capsule endoscopy) to clarify the diagnosis and assess local inflammation [19,20,38].

(LoE – C; GoR – 5).

Comment: Video capsule endoscopy (small bowel video capsule endoscopy, colon video capsule endoscopy) is more sensitive in detecting local mucosal changes compared to MR enterography (hydro-MRI, (magnetic resonance enterography, contrast-enhanced magnetic resonance enterography) [38].

A limitation to the use of small bowel video capsule endoscopy and colon video capsule endoscopy is the inability to obtain a biopsy specimen; however, low invasiveness and the lack of need for general anesthesia allow this study to be used, inter alia, during follow-up monitoring of the patient.

In Crohn's disease, before performing video capsule endoscopy, radiological examinations (barium follow-through) [39,40,41] (small bowel radiography with contrast, X-ray control of contrast passage through the stomach, small and colon) or CT enterography (contrast-enhanced computed tomography of the small intestine) or MR enterography (magnetic resonance enterography, contrast-enhanced magnetic resonance enterography) [42] should be performed to exclude/confirm small bowel strictures when such conditions are suspected. Small bowel video capsule endoscopy is performed when small bowel involvement is suspected and strictures are absent [43].

(LoE – C, GoR - 5)

Comment: according to the Order of the Russian Ministry of Health dated October 13, 2017, No. 804n "On Approval of the Nomenclature of Medical Services" – Comprehensive pelvic ultrasound (transvaginal and transabdominal). In clinical practice, transvaginal examination is not performed in children with Crohn's disease.

This method has limited capabilities in diagnosing intestinal lesions. At the same time, the procedure is non-invasive, which determines its widespread use, especially in childhood.

• In perianal lesions, anal fistulas (including those ending blindly in soft tissues), as well as when pararectal tissue involvement is suspected in patients with Crohn's disease, it is recommended to perform transrectal and/or transperineal ultrasound or magnetic resonance imaging of the rectum (transrectal ultrasound of the rectum, magnetic resonance imaging of the colon, contrast-enhanced magnetic resonance imaging of the colon) and pelvic magnetic resonance imaging to visualize fistulous tracts and clarify the degree of inflammation and the extent of rectal and anal canal involvement [35,44, 45].

(LoE – C, GoR - 5)

(LoE – C; GoR - 5)

Comments: if pelvic magnetic resonance imaging with intravenous contrast cannot be performed, contrast-enhanced pelvic CT (contrast-enhanced computed tomography of the pelvis in women, contrast-enhanced computed tomography of the pelvis in men), fistulography (fistulography of rectal and perianal fistulas), or ultrasound with a rectal probe is performed.

General anesthesia when indicated.

• Magnetic resonance cholangiopancreatography is recommended for children with Crohn's disease if there is evidence (suspicion) of liver and/or bile duct involvement [19].

(LoE – C; GoR - 5)

• Patients with suspected Crohn's disease complications, such as intestinal obstruction or intestinal perforation, are recommended to undergo plain abdominal radiography to confirm the condition [19, 47].

(LoE – C, GoR - 5)

(LoE 5, GoR C)

Comments: reduced bone density is observed in 30% of children with IBD. The frequency of the study is determined individually according to clinical guidelines for osteoporosis and reduced bone mineral density [49, 50, 51].

2.5 Other Procedures

Not applicable.

2.5.1 Pathological anatomical examination (histological examination)

• Pathological anatomical examination of biopsy specimens and resected intestinal segments obtained during endoscopy is recommended for diagnosing Crohn's disease and evaluating treatment efficacy [52, 53]. In case of endoscopic signs of esophageal, gastric, and duodenal involvement, pathological anatomical examination of biopsies obtained from these areas is also performed (up to 23% of cases in pediatric practice) [54].

(GoR – C, LoE – 5)

Comments: Pathological anatomical examination of small intestine biopsy (surgical) material, Pathological anatomical examination of small intestine biopsy (surgical) material using immunohistochemical methods, Pathological anatomical examination of small intestine biopsy (surgical) material using histochemical methods.

Pathological anatomical examination of large intestine biopsy (surgical) material, Pathological anatomical examination of large intestine biopsy (surgical) material using immunohistochemical methods, Pathological anatomical examination of large intestine biopsy (surgical) material using histochemical methods, Pathological anatomical examination of rectum biopsy (surgical) material, Pathological anatomical examination of rectum biopsy (surgical) material using histochemical methods, Pathological anatomical examination of rectum biopsy (surgical) material using immunohistochemical methods.

Pathological anatomical examination of esophagus biopsy (surgical) material, Pathological anatomical examination of esophagus biopsy (surgical) material using immunohistochemical methods, Pathological anatomical examination of esophagus biopsy (surgical) material using histochemical methods.

Pathological anatomical examination of stomach biopsy (surgical) material, Pathological anatomical examination of stomach biopsy (surgical) material using immunohistochemical methods, Pathological anatomical examination of stomach biopsy (surgical) material using histochemical methods.

Pathological anatomical examination of duodenal biopsy (surgical) material, Pathological anatomical examination of duodenal biopsy (surgical) material using immunohistochemical methods, Pathological anatomical examination of duodenal biopsy (surgical) material using histochemical methods

(LoE – C, GoR - 5)

Comments: biopsies are usually taken from a single segment that allows the procedure to be performed with minimal complications

It is recommended to take biopsies from both altered and endoscopically normal areas to establish the diagnosis [52, 53].

(GoR – C, LoE – 5)

(LoE – C, GoR - 5)

Comments:

1. Biopsies taken from different parts of the gastrointestinal tract must be placed in a separate labeled vial with buffered formalin.

2. The pathological anatomical (histological) examination report must contain information on the presence or absence of signs of inflammatory bowel disease (chronic inflammation), data on the localization and activity of inflammatory changes, as well as the presence or absence of dysplasia.

3. Signs of chronic inflammation include: basal plasmacytosis, architectural distortion of glands (crypts), pyloric gland metaplasia in the ileum, and non-caseating non-cryptolytic granulomas. The absence of the latter does not rule out Crohn's disease. Signs of active inflammation include: cryptitis, crypt abscesses, erosions, and ulcers.

4. Crohn's disease is characterized by segmental involvement, focal and transmural nature of inflammation, and chronic active inflammation in the small intestine and upper digestive tract.

5. The pathological anatomical (histological) report must include a conclusion on the presence of inflammatory bowel disease and a statement that the most likely diagnosis is Crohn's disease.

2.5.2. Specialist consultations

(LoE – C; GoR - 5)

Comments: diagnosis and management of patients are carried out by a gastroenterologist (или pediatrician with appropriate training); consultations are held, if necessary, with a dietician, pediatric surgeon, clinical pharmacologist, pediatric oncological hematologist, dermatovenereologist, allergist-immunologist, pediatric endocrinologist, exercise therapy doctor, medical psychologist, etc. If indicated, hospitalization in a surgical hospital is required.

2.5.3 Differential diagnosis

• Differential diagnosis is carried out with a number of diseases. These include:

• ulcerative colitis (Table 4),

• acute intestinal infections (dysentery, salmonellosis, campylobacteriosis, yersiniosis, amebiasis, parasitoses),

• C. difficile-associated diarrhea,

• cytomegalovirus colitis,

• intestinal tuberculosis,

• systemic vasculitides,

• neoplasms of the large and small intestine,

• Behcet's disease,

• appendicitis,

• irritable bowel syndrome,

• celiac disease (noting that a diagnosis of celiac disease does not exclude a diagnosis of Crohn's disease, and their combination is frequently described), primary immunodeficiencies, etc. (Table 5) [19, 20].

To rule out/confirm these diseases/conditions, an examination is performed in accordance with the relevant clinical guidelines. Crohn's disease often has to be differentiated from ulcerative colitis. The features of these diseases are presented in Tables 4 and 5.

Table 4. Features of Crohn's disease and ulcerative colitis in children [52, 54].

Table 5. Inflammatory bowel disease: differential diagnosis in children [19]

Primary immunodeficiency states most often debut in children under 2 years of age; attention should be paid to the following signs:

• Family history of primary immunodeficiency;

• Parents or >2 blood relatives in the family with early-onset IBD;

• «Infantile» (<2 years) IBD;

• Severe, treatment-refractory IBD, especially with perianal/rectovaginal involvement/abscesses;

• Recurrent infections (pulmonary infections, skin abscesses) in the absence of immunosuppressive therapy;

• Neutropenia, thrombocytopenia, abnormal immune status (Ig levels) in the absence of immunosuppressive therapy;

• Nail dystrophy and hair disorders (trichorrhexis nodosa);

• Skin disorders (congenital eczema, albinism) [56].

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

The goals of CD treatment in children are:

• achieving «complete» or «deep» remission as rapidly as possible, which implies not only clinical but also endoscopic remission. Achieving morphological remission is currently not a therapeutic goal;

• maintaining remission for as long as possible without glucocorticoids;

• prevention of complications;

• preventing surgery, and in case of disease progression and development of life-threatening complications, timely prescription of surgical treatment;

• improving quality of life;

• ensuring normal growth and development rates of the child.

The choice of therapy must be made taking into account risk factors for an unfavorable course of CD. According to ESPGHAN experts [10], these are:

• deep ulceration of the colon on endoscopic examination

• persistent severe disease course despite adequate induction therapy

• extensive involvement (total small bowel involvement)

• significant linear growth deceleration (height Z-score > -2.5)

• severe osteoporosis

• stricturing and/or penetrating disease behavior at disease onset (disease behavior B2 and/or B3)

• severe perianal involvement.

The presence of even one of these factors suggests an unfavorable disease outcome, which should serve as the basis for optimizing ongoing therapy and using drugs known to alter the natural history of the disease, such as thiopurines, #methotrexate*, and tumor necrosis factor-alpha (TNF-alpha) inhibitors (biological agents), and in case of complications, appropriate surgery.

The choice of CD therapy should be made in accordance with its localization, extent, and severity. Insufficient efficacy of induction therapy requires treatment intensification. Once remission is achieved, maintenance therapy is administered.

3.1 Conservative therapy

3.1.1 Induction of remission

The potential impact of CD on growth, sexual and emotional development of patients emphasizes the need for a specific approach to treatment in childhood. The goal of therapy is not only symptom relief, but also ensuring physical development appropriate for age and a satisfactory quality of life [57] Factors that influence the use of specialized enteral nutrition include: patient and parent preference, nature of complications, patient taste preferences, absence of complications from systemic corticosteroids, and potential benefits in terms of improved nutritional status and growth rate of the child

• Exclusive enteral nutrition (EEN) for 6–8 weeks is recommended as a first-line therapy for the induction of remission in children with newly diagnosed CD (except for severe pancolitis, oral or isolated perianal CD) or a flare of the inflammatory phenotype of CD [19,10].

(LoE – C; GoR - 5)

Comments:

1. In the management of children with intestinal involvement, including colonic involvement, EEN should be preferred over systemic corticosteroids (H02) or topical corticosteroids (A07EA in enteric-coated capsules) to achieve mucosal healing, normalization of bone mineral density, and growth. EEN has the same efficacy as GCS in inducing remission in children with active CD. However, reliable data regarding the efficacy of EEN in patients with severe isolated pancolitis in Crohn's disease are lacking. There are also no data on the benefit of EEN in isolated oral or perianal disease.

2. EEN can be reused in case of relapse

3. Enteral nutrition is carried out using liquid polymeric formulas (children's dietary therapeutic nutrition product, enteral nutrition product, dry instant complete balanced formula, specialized enteral nutrition product, dry complete formula) that are better tolerated, have better organoleptic properties and lower cost. Hydrolyzed or amino acid formulas should only be used if there is a specific medical indication for their use (e.g., cow's milk protein allergy). Several studies have demonstrated the advantage of specialized formulas enriched with an anti-inflammatory component – transforming growth factor-beta 2 (TGF β2) (children's dietary therapeutic nutrition product, enteral nutrition product, dry instant complete balanced formula, specialized enteral nutrition product, dry complete formula,.

4. The required daily volume of the formula is calculated according to age-related energy requirements (see Methodological Recommendations MR 2.3.1.2432-08 "Norms of physiological requirements for energy and nutrients for various population groups of the Russian Federation" (approved by the Chief State Sanitary Doctor of the RF on December 18, 2008) and may be increased in children with protein-energy malnutrition. Initially, the formula should be administered orally. A nasogastric tube can be used when adequate oral intake cannot be achieved.

5. EEN is recommended for a duration of at least 8 weeks. If there is no clinical response within the first 2 weeks of EEN, alternative treatment options should be considered.

6. The decision to use EEN or alternative treatments should be made on an individual basis, taking into account the patient's quality of life

7. Evidence regarding the transition to normal diet after completion of EEN is lacking. ESPGHAN experts suggest gradual introduction of regular food alongside a decrease in formula volume every 2–3 days over 2–3 weeks [58,59,60]

(LoE – C; GoR - 5)

Comments: partial enteral nutrition is not used as monotherapy; however, there is evidence showing that it helps prolong the remission achieved when combined with a specialized diet and pharmacotherapy.

Although EEN is recognized as the method of choice for inducing remission in pediatric CD, it often poses compliance challenges: the majority of patients consider EEN unacceptable and about half are unsure of its efficacy. Most patients prefer solid food. In a multicenter direct RCT in children with mild-to-moderate CD, the advantage of a partial enteral nutrition regimen using a polymeric formula enriched with TGF β2 (children's dietary therapeutic nutrition product, enteral nutrition product, dry instant complete balanced formula, specialized enteral nutrition product, dry complete formula plus Crohn’s Disease Exclusion Diet [CDED]) compared to EEN was demonstrated regarding tolerability and maintenance of remission by week 12.

Comments: Foods to avoid in Crohn's disease [62]

Efficacy of Topical and Systemic Corticosteroids

Due to the fact that only a few studies have reported the use of glucocorticoids in pediatric patients with IBD, the treatment strategy in children is largely based on adult data [63]. Two RCTs in children have been conducted [64,65] comparing prednisolone** and #budesonide**, along with one study [66] comparing prednisolone** and a combination of prednisolone** with #mercaptopurine** in newly diagnosed pediatric Crohn's disease (CD). In addition, further data were obtained from pediatric IBD registries and population-based studies. Remission rates within 30 days of treatment initiation for prednisolone** in pediatric studies ranged from 57% [67] to 79% [66] in RCTs and 62% in a population-based study [68]. These studies utilized a glucocorticoid tapering schedule lasting from eight to 12 weeks. In clinical practice, the initiation and tapering of glucocorticoids are not standardized and are based on physician experience. A single daily morning dose reduces potential adverse effects related to growth retardation [69]. Intravenous glucocorticoids are reserved exclusively for severe disease flares.

Glucocorticoids and Mucosal Healing

Clinical response in Crohn's disease does not correlate with endoscopic improvement [70], and the assessment of endoscopic response to glucocorticoid therapy in children with CD has been performed in only two studies: Berni Canani [67] found that endoscopic improvement was observed in 4 out of 10 patients, whereas mucosal healing was not achieved in any patient at 8 weeks after treatment initiation. In a study by Borrelli et al. [71], partial mucosal healing was observed in 6 out of 18 (33%) patients receiving glucocorticoids at week 10. In a one-year maintenance therapy study, complete endoscopic mucosal healing was achieved with #budesonide** monotherapy in 24% of patients and with its combination with azathioprine** in 83% of patients [72].

Treatment Options and Efficacy Based on Disease Localization and Behavior

In patients with mild-to-moderate CD involving the ileum or ascending colon, the use of #budesonide** is preferred [64,65,73]. In a study by Levine et al. [74], higher rates of remission and response at 7 weeks were reported with a 12 mg dose compared to the standard 9 mg dose (66% and 74% vs. 42% and 51%, respectively) at 7 weeks.

Maintenance of remission using glucocorticoids is not recommended; in the event of steroid dependence, switching to alternative therapy (thiopurines, #methotrexate**, or biologic therapy) is mandatory.

Glucocorticoid Safety and Adverse Effects

Adrenal suppression can develop as early as one week after initiating systemic corticosteroid therapy [75]. The risk of adverse effects depends on the dose and duration of treatment [76], although patient susceptibility can vary significantly. Growth retardation is one of the most critical concerns when treating pediatric CD patients with systemic corticosteroids. Therefore, prolonged courses of systemic corticosteroids in children are unacceptable.

• Systemic corticosteroids are recommended for induction of remission in children with moderate-to-severe flares of inflammatory CD during recurrent flares, as well as during the initial attack if exclusive enteral nutrition (EEN) is not feasible [10, 19, 20, 57].

(LoE – C, GoR - 5)

Comments:

• The recommended oral dose of prednisolone** (or equivalent) for a CD flare in most pediatric patients is 1 mg/kg (maximum dose 40 mg/day) once daily in the morning. If response is inadequate, an increase up to 1.5 mg/kg (maximum dose 60 mg/day) may be required [57].

• In the absence of a response to oral systemic corticosteroids, intravenous administration of systemic corticosteroids may be effective in certain patients [57].

• Initial dosing is recommended for 2 weeks, followed by gradual tapering and discontinuation no later than 12 weeks. The prednisolone** tapering schedule is provided in Table 5.

Table 5. Prednisolone** tapering schedule for induction therapy of CD in children (according to The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. / Consensus Advance Access publication Paper. October 7, 2020. Journal of Crohn's and Colitis, 2020, 1–24, doi:10.1093/ecco-jcc/jjaa161) [10]¹.

¹ Since prednisolone** tapering regimens are largely based on empirical recommendations rather than clinical trials, approaches vary somewhat in practice. Reducing each step from 7 to 5 days or any other modification of the tapering schedule may be considered on an individual basis.

• In children with mild-to-moderate ileocecal Crohn's disease, the use of enteric-coated #budesonide** capsules is recommended as an alternative to systemic corticosteroids for the induction of remission [19,20,77, 74.]

(LoE – A, GoR - 2)

Comments: The starting dose of #budesonide** is 9 mg daily for 7 weeks, followed by 6 mg daily for 3 weeks (total treatment course is 10 weeks).

(LoE – C, GoR - 5)

• During treatment with systemic and topical corticosteroids, as well as in deficiency states, it is recommended to prescribe calcium supplements (e.g., calcium gluconate**, calcium glycerophosphate (for children aged 2 years and older), calcium carbonate + calcium lactogluconate (for children aged 3 years and older)) along with cholecalciferol** (for children from early infancy, the drug is used as a powder for oral suspension) and vitamin D and its analogues (cholecalciferol** (for children older than 2 weeks)) to correct deficiency and reduce the risk of osteopenia/osteoporosis, and for the prevention and treatment of hypocalcemia (calcium deficiency) [78].

(LoE – C; GoR – 5)

Comments: in practice, it is more convenient to use combination drugs (e.g., calcium carbonate + cholecalciferol).

(LoE – C, GoR - 5)

Comments:

1. The standard daily dose of #metronidazole** is 30 mg/kg, and of #ciprofloxacin** is 20 mg/kg; rifaximin may be used (according to the instructions, contraindicated under 12 years of age, 400 mg every 8–12 hours) for 14 days [79]. The duration of therapy is at least 8 weeks.

2. If combination therapy is ineffective, the dose of tumor necrosis factor alpha (TNF-alpha) inhibitors should be revised (increase the dose of #infliximab** (see subsection 3.1.2.4: higher doses (up to 10 mg/kg) and/or shorter intervals (up to 4 weeks) for those who do not respond to the drug or when trough levels are low). The dose of #infliximab** should be reduced when the trough level exceeds 8–10 µg/mL and remission is achieved (the best effect is observed with target blood trough levels of the drug >12.7 µg/mL)) [10]

Other drugs may be considered on an individual basis depending on the clinical situation.

• In more severe disease courses complicated by fistulas, systemic antibacterial agents are recommended to be used as adjunctive therapy, for example, prior to initiating immunosuppressive therapy when it cannot be started due to the need for surgical intervention [20]

(LoE – C, GoR - 5)

Comment: systemic antibacterial drugs can be used in a course of up to 14 days (first-line drugs: #metronidazole** 10–20 mg/kg/day orally in three divided doses and #ciprofloxacin** 20 mg/kg/day orally in 2 divided doses [80]

3.1.2 Maintenance therapy

Efficacy of azathioprine** and #mercaptopurine**

In children with Crohn's disease, one placebo-controlled and seven observational studies have evaluated the use of thiopurines for maintaining remission. In a randomized controlled trial by Markowitz [66], the relapse rates were 4% and 9% in the #mercaptopurine** group (n = 27 patients) and 26% and 47% in the placebo group (n = 28 patients) at 6 and 18 months, respectively, following remission induction with prednisolone** in patients with newly diagnosed moderate-to-severe Crohn's disease. In retrospective case series, the use of azathioprine** was associated with a longer period of maintained remission, a lower rate of hospitalization, re-administration of systemic corticosteroids, and surgical interventions [81,82]. The use of azathioprine** at a higher dose of 2.5 mg/kg/day was more effective compared to lower doses of 1.0 or 2.0 mg/kg/day. Observational studies in adults noted a reduction in the need for surgical interventions, as well as a preventive effect regarding perianal disease, particularly with early treatment initiation [83,84], although later studies questioned the efficacy of thiopurines in maintaining remission [85,86]. In the SONIC trial, prospective mucosal healing data were obtained from the largest number of adult Crohn's disease patients to date; out of 115 patients treated with azathioprine**, mucosal healing (ulcer healing) was observed in 16.5% [87]. With azathioprine** at a dose of 3 mg/kg, stabilization or improvement of height deviation (Z-score) was observed in 36% of children with Crohn's disease [88].

Safety and adverse effects of azathioprine** and #mercaptopurine**

Adverse reactions to thiopurines were reported in 15–46% of patients [89,90,91]. In 8%–28% of cases, they led to a dose reduction, and in 18%–43% of cases, treatment was discontinued. The use of azathioprine** at a higher dose of 3 mg/kg/day in children with inflammatory bowel disease leads to drug withdrawal in 30% of patients [88]. Dose-dependent toxicity can manifest from a few weeks to several years after treatment initiation and includes hepatotoxicity and myelosuppression. At standard doses, hematological toxicity is observed in 1.8%–13.7% of patients [89,90,91]. The risk of infections is ~8% [91]; however, data from recent large registries, DEVELOP (children) and TREAT (adults), found that immunosuppressant use was not associated with an increased risk of infections, whereas the use of tumor necrosis factor alpha (TNF-alpha) inhibitors (biologics) more than doubled the risk of infections [92,93].

Dose-independent toxicity typically manifests during the first weeks after treatment initiation. Pancreatitis is among the most frequent hypersensitivity manifestations, occurring in 3–4% of patients. Other dose-independent adverse drug reactions include dyspeptic disorders (5–8%), fever, flu-like symptoms, myalgia, arthralgia, and rash (observed in ~9% of patients). Switching to #mercaptopurine** can be successful in approximately 50% of patients with azathioprine** intolerance, particularly in cases of myalgia or arthralgia, and may also be effective for hepatotoxicity, gastrointestinal symptoms, flu-like manifestations, and rash [90]. The results of a recent small case series suggest that a trial of #mercaptopurine** may be successful and safe in some patients with azathioprine-induced pancreatitis [94]. Approximately 9% of inflammatory bowel disease patients do not respond to thiopurines [95], and patients with high TPMT activity (>14 U/mL of red blood cells) show lower treatment efficacy [96].

Long-term observational studies have established that the risk of lymphoma in IBD patients receiving thiopurines, particularly males, increases approximately fourfold, although the absolute risk in children and adolescents was lower [97,98]. The risk in children was calculated to be 4.5 cases/10,000 patient-years [99], which has been documented in the DEVELOP pediatric registry [100]. Additionally, approximately 40 adolescent and adult IBD patients have been reported to develop fatal hepatosplenic T-cell lymphoma; almost all patients were male, and 50% of the patients developed the tumor before the age of 20 years. Approximately half of these patients received long-term thiopurine monotherapy, and the other half received long-term thiopurines in combination with anti-tumor necrosis factor alpha (anti-TNF-alpha) inhibitors, with the duration of anti-TNF therapy exposure varying significantly [101]. Thiopurine use has also been associated with a 4-to-5-fold increased risk of non-melanoma skin cancer, even in individuals under 50 years of age [102,103]. Interestingly, recent studies have revealed that thiopurine use leads to a reduced risk of colorectal neoplasms in both Crohn's disease (CD) and ulcerative colitis (UC) patients, and this preventive effect appears to be more pronounced than that of 5-aminosalicylic acid** and similar drugs [104]. Thiopurines should be avoided during Epstein-Barr virus (EBV) infection due to the risk of EBV-associated lymphomas.

• Azathioprine** or #mercaptopurine**) are recommended as maintenance therapy for remission in children requiring systemic corticosteroid therapy and/or #budesonide** gastro-resistant capsules, as well as children at risk for an unfavorable disease outcome [19,20].

(LoE – C; GoR - 5)

Comments:

1. Thiopurines are effective in maintaining CD remission achieved with systemic and/or topical corticosteroids. Achieving the maximum effect of thiopurines may take 8 to 16 weeks, so therapy with them should be initiated while tapering the prednisolone** dose [10].

2. In patients without thiopurine metabolism disorders, it is recommended to use azathioprine** at a dose of 2.0-2.5 mg/kg or #mercaptopurine** at an average dose of 1.5 mg/kg per day orally [10] (the duration of treatment is determined individually and can range on average from 6 months to 18 months [66, 105]; azathioprine** can be used until sustained remission is achieved and maintained for 2 years [106].

3. Testing for thiopurine S-methyltransferase (TPMT) activity before initiating thiopurine therapy (normal range 230-450 U/mL) helps identify patients at high risk of myelosuppression. If this test is not available, a half-dose of thiopurine can be prescribed at the start of treatment with weekly complete blood counts for 2 weeks [11]; if no myelosuppression is observed, a gradual increase in the thiopurine dose to the full dose is recommended. A 2-fold reduction in purine analogue (thiopurine) dose is recommended if blood leukocyte counts drop below 3,000/mm³; thiopurines are contraindicated in rare cases where the absolute leukocyte count drops below 1,500/mm³.

4. During the first month after starting treatment, monitoring of the complete blood count and "liver" enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], and alkaline phosphatase levels in the blood) is mandatory, initially every 1-2 weeks with subsequently decreasing frequency; thereafter, monitoring of these parameters is required every 3 months for all patients throughout thiopurine treatment (regardless of TPMT activity).

6. Pancreatitis can develop independently of the dose in the early stages following the initiation of thiopurines, and its development typically requires drug discontinuation. Special attention must be paid to the differential diagnosis between true thiopurine-induced toxicity and extraintestinal manifestations of IBD presenting as pancreatitis.

7. The decision to switch from azathioprine** (AZA) to #mercaptopurine** (MP) and vice versa may be made in patients experiencing a flu-like syndrome or acute gastrointestinal symptoms.

8. An increase in transaminase activity of more than twice the upper limit of normal may be transient or necessitate a dose reduction or discontinuation of the drug. If TPMT activity and transaminase levels are elevated, a reduction in the thiopurine dose and the addition of #allopurinol** are recommended.

9. When adding #allopurinol** to treatment, the thiopurine dose should be reduced to 25-33% of the initial dose. The standard adult dose of #allopurinol** is 100 mg/day, and the pediatric dose of #allopurinol** should be reduced (50-75 mg depending on body weight) [57].

11. All patients who are currently using or have previously used thiopurines are advised to avoid sun exposure throughout their lives and to undergo regular dermatological examinations due to the increased risk of skin tumors.

Note: Item numbering corresponds to the official text of the source document.

(Level of Evidence - C, Grade of Recommendation - 5)

(Level of Evidence - C, Grade of Recommendation - 5)

Comment: the test helps identify patients at high risk of myelosuppression (normal range 230-450 U/mL). If determination is not feasible, a stepwise increase in the azathioprine** dose should be used [8,17].

(LoE - C, GoR - 5)

Comments:

If determination is not feasible, a stepwise increase in the azathioprine** dose should be used [8,17].

Interpretation of thiopurine metabolite levels

^a Cutoff values are based on the method according to [107]

Higher cutoff values [therapeutic range of 6-TGN from 300 to 600 pmol/8×10⁸ RBC] are required when assessed by the Dervieux and Boulieu method [108].

Efficacy of #methotrexate**

Results obtained in 7 retrospective pediatric cohort studies suggest that the efficacy of #methotrexate** in children who experienced treatment failure or intolerance to thiopurines ranges from 50 to 80% [109,110,111,112,113,114,115], with remission rates at 6 and 12 months being 37–62% and 25–33%, respectively, and the remission rate throughout the entire first year being 15–35%. In two small studies (n=50), no differences were found between #methotrexate** and #mercaptopurine** in maintaining CD remission (OR 2.63; 95% CI 0.74–9.37; P=0.14). Children who responded to treatment showed normalization of linear growth, which may be an indirect sign of effective mucosal inflammation control. The mucosal healing efficacy of #methotrexate** has not been evaluated, except for one adult study in which mucosal healing was achieved in 2 of 11 patients receiving #methotrexate**, 8 of 18 receiving azathioprine** (p = 0.011 vs. #methotrexate**), and 9 of 16 patients receiving infliximab** (p = 0.008 vs. #methotrexate**) [116].

Safety and adverse effects of #methotrexate**

Adverse reactions limit the widespread use of #methotrexate**. These include nausea/vomiting, flu-like symptoms, liver injury, and, much less commonly, myelosuppression. The problem of nausea and vomiting can be particularly distressing and frequently leads to discontinuation of the drug [117]; in a study by Uhlen et al. [110], nausea/vomiting was observed in 7/61 (11%) of patients, whereas in a study by Turner et al. [109], it occurred in 4/17 (24%) of children receiving oral medication and in 6/39 (15%) of patients in the subcutaneous group. The onset of nausea and vomiting can be prevented by prophylactic administration of ondansetron** (contraindicated under 1 month of age per the instructions) [118]. Pulmonary toxicity is a very serious but extremely rare complication of #methotrexate** therapy; no cases of this phenomenon have been reported in children with Crohn's disease. Increased liver enzyme activity may be observed in 30% of patients and usually resolves after temporary discontinuation of #methotrexate** and/or dose reduction.

• #Methotrexate** is recommended as one of the options for maintaining remission in children at high risk of an unfavorable disease outcome, either as a first-line drug for maintaining remission or in case of thiopurine failure or intolerance [20].

(LoE - C, GoR - 5)

Comments:

#Methotrexate** should be prescribed at a dose of 15 mg/m² once a week; the maximum dose is 25 mg.

1. If the patient has persistent complete remission with normal inflammatory marker values for several months, an attempt may be made to reduce the dose to 10 mg/m² once a week (maximum dose is 15 mg).

2. #Methotrexate** is usually administered as subcutaneous injections, the efficacy of which is similar to that of intramuscular injections.

3. During therapy with #methotrexate**, oral administration of #folic acid** is recommended (5 mg 24–72 hours after #methotrexate** administration or 1 mg once daily 5 days a week) [10].

4. Patients with sustained remission require periodic monitoring of complete blood count and ALT activity.

5. #Methotrexate** is strictly contraindicated during pregnancy; furthermore, its use is contraindicated for female sexual partners when planning a pregnancy, and an effective method of contraception should be used if necessary.

6. In case of poor tolerance to #methotrexate** (nausea), ondansetron** (contraindicated under 1 month of age per the instructions) should be prescribed one hour before the injection

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

Comments: the dose (if possible) is adjusted according to blood tacrolimus levels (target levels average 10 and 15 ng/mL) (Therapeutic drug monitoring) [119].

During #tacrolimus** therapy, the following monitoring examinations should be performed: blood creatinine test, blood glucose test, blood electrolyte tests (blood sodium test, blood potassium test, serum total calcium test, serum total magnesium test), blood triglyceride test, peripheral blood pressure measurement, and, if necessary, prevention of P. jirovecii pneumonia in accordance with relevant guidelines.

Efficacy of anti-TNF therapy

Inflammatory phenotype of the disease. The efficacy of infliximab** (indicated for children from 6 years of age per the instructions) for the induction and maintenance of remission in children with Crohn's disease has been proven in several RCTs. In the randomized REACH study [120], children aged 6 to 17 years with active Crohn's disease following previously ineffective glucocorticoid and immunosuppressant therapy received infliximab** at weeks 0, 2, and 6. A response to treatment was achieved in 98 (88%) of 112 patients, and clinical remission was observed in 59% at 10 weeks. Patients who responded to treatment at 10 weeks were randomized to further treatment with infliximab** (5 mg/kg) every 8 weeks or every 12 weeks while continuing treatment with a thiopurine. Administration of the drug at 8-week intervals was more effective. The use of infliximab** in the early stages of the disease may lead to better outcomes in selected high-risk patients [121].

The IMAgINE study was the first double-blind randomized trial [122] that evaluated the efficacy of adalimubab** (indicated for children starting from 6 years of age per the instructions) in 192 children aged 6–17 years with moderately severe to severe active Crohn's disease (PCDAI > 30) despite the use of oral glucocorticoids and/or immunosuppressants. The study included patients who had previously responded to infliximab** treatment but had lost response, as well as patients who were intolerant to the drug. Following an open-label induction phase, children were randomized to receive either a high or low dose of adalimubab**. At 54 weeks, clinical remission was observed in 31/93 children (33.3%) receiving the high dose. In a retrospective multicenter study of 115 pediatric patients with Crohn's disease who received at least 1 dose of adalimubab** (95% of whom had previously received infliximab**), the rate of steroid-free remission at 1 year was 42% [123]. Data obtained in children were comparable to data from adult adalimumab trials.

Penetrating phenotype of the disease. Data supporting the efficacy of infliximab** in children with fistulizing Crohn's disease are scarce. A retrospective analysis of infliximab** efficacy for concomitant perianal disease in 31 patients in the REACH study (28%) found that partial or complete fistula closure was achieved in 41% at 2 weeks after a single infusion of the drug [124]. A recent GETAID case-series study in children [125] found that the response rate to infliximab** at 12 months was 75% (75/101 patients with Crohn's disease), with complete fistula closure observed in 54%.

Data regarding fistula closure in children with Crohn's disease treated with adalimubab** are limited. Subgroup analysis in the IMAgINE study found that fistula closure at 52 weeks was achieved in 23.8% of patients (5/21) in the low-dose group and 40% in the high-dose group. In adults, a significant advantage of infliximab** over placebo was demonstrated (55% of patients with closure of all fistulas compared with 13% in the placebo group) (P = 0.002) [126]. The median time to response with infliximab** was 14 days. Regarding adalimubab**, the fistula closure rate at 12 weeks was 48% in patients naive to tumor necrosis factor-alpha (TNF-alpha) inhibitors and 26% in patients previously treated with infliximab** [127]. At week 24, the fistula closure rate was significantly higher in the TNF-alpha inhibitor-naive group (60% vs. 20%, P < 0.01).

Extraintestinal manifestations of Crohn's disease

In adults, infliximab** has been shown to be effective in treating extraintestinal manifestations of Crohn's disease [129]. The use of infliximab** in children with extraintestinal manifestations has been described in a case-series study of patients with pyoderma gangrenosum, facial and oral lesions, erythema, metastatic skin lesions of the penis and scrotum in Crohn's disease, uveitis, primary lung disease, primary sclerosing cholangitis combined with pancreatitis, and osteomyelitis [130, 131, 132, 133, 134].

Mucosal healing

In a recent study conducted in Poland [135], complete mucosal healing at 10 weeks was observed in 23% of 66 pediatric patients with Crohn's disease treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors. Mucosal healing is associated with an increased rate of linear growth and bone formation. Malik et al. [136] described a cohort of patients in whom 42% of those treated with adalimubab** showed improved linear growth, particularly children who achieved remission. Determination of serum bone formation marker concentrations showed a rapid improvement following treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors in both children and adults with Crohn's disease [137, 138, 139, 140]. The use of tumor necrosis factor-alpha (TNF-alpha) inhibitors reduces the need for surgical interventions [84].

Treatment Optimization (Intensification) with Tumor Necrosis Factor-Alpha (TNF-alpha) Inhibitors

To achieve sustained clinical remission in pediatric gastroenterology clinical practice, optimization (intensification of treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors) is sometimes required. The drug dose is increased (from 5 mg/kg to 10 mg/kg of infliximab**) and/or the intervals between administrations are shortened (transition to administration every 4 weeks for infliximab** and weekly administration for adalimumab**). Optimization is performed in cases of treatment failure or loss of response. It is important to maintain the minimum trough serum concentration of the drug at a detectable level (3–8 mcg/mL) (if determination is available) - Drug blood level testing [141].

Combination Therapy

The question of whether tumor necrosis factor-alpha (TNF-alpha) inhibitors should be used as monotherapy or in combination with an immunosuppressant has been particularly controversial in pediatric practice. The SONIC study in adult patients [87] who were naive to both immunosuppressants and infliximab** demonstrated a modest increase in the efficacy of infliximab** when combined with azathioprine**. However, the SONIC study did not address the benefit of combination therapy over infliximab** monotherapy when prior treatment with azathioprine** had failed. Neither the ACCENT I nor the ACCENT II study revealed any differences in achieving remission and treatment response between patients on infliximab** monotherapy and those on combination therapy [142]. Similar results were obtained for adalimumab** in the CHARM study [143]. However, a slight advantage of combination therapy was identified, particularly during the first 6 months of treatment [144,145]. Higher titers of antibodies to infliximab** and lower trough concentrations of the tumor necrosis factor-alpha (TNF-alpha) inhibitor were observed in patients receiving infliximab** monotherapy, which was accompanied by a higher incidence of infusion reactions and less favorable treatment outcomes. A recent meta-analysis established that combination therapy with azathioprine** yields better clinical outcomes than infliximab** monotherapy, even in the case of a history of non-response to azathioprine**.

A negative aspect of combination therapy with tumor necrosis factor-alpha (TNF-alpha) inhibitors and azathioprine** is the increased risk of lymphoma [146]. Combination with #methotrexate** is more attractive due to the lack of evidence for an increased risk of lymphoma and data demonstrating the benefit of combining #methotrexate** and infliximab** in rheumatological patients. In the COMMIT clinical trial, adult patients with Crohn's disease received induction therapy with infliximab** and systemic corticosteroids combined with #methotrexate** or placebo [147]. No differences in clinical response were identified, but the administration of #methotrexate** was accompanied by higher infliximab** concentrations and a reduced rate of anti-infliximab antibody formation. In a retrospective analysis of the ESPGHAN study involving 70 children with Crohn's disease treated with adalimumab** [148], the rate of achieving remission was higher in patients who concurrently received immunosuppressants (34/46 (74%) vs. 9/24 (37%), p=0.003). Given this, it can be concluded that concurrent use of azathioprine** is permissible during the first 6 months of infliximab** therapy, after which azathioprine** is best discontinued, particularly in boys; however, treatment tactics should be individualized and based on the assessment of prognostic factors. Discontinuation of combination therapy is justified only in patients who have achieved deep remission (mucosal healing). The role of #methotrexate** in combination therapy for children with Crohn's disease needs to be defined in clinical trials.

Comparison of Infliximab** and Adalimumab**

A retrospective cohort study [149] comparing the outcomes of 100 adult patients with Crohn's disease treated with infliximab** and 100 patients treated with adalimumab** revealed no differences in achieving a clinical response; treatment response at 1 and 2 years was observed in 62% and 41% of patients receiving adalimumab** and 65% and 49% of patients receiving infliximab**, respectively.

Safety of Tumor Necrosis Factor-Alpha (TNF-alpha) Inhibitors and Adverse Effects

The formation of antibodies against tumor necrosis factor-alpha (TNF-alpha) inhibitors can lead to acute infusion reactions, delayed hypersensitivity reactions, decreased serum drug concentrations, and loss of treatment response [150,151,152]. Irregular drug administration may lead to an increased risk of antibody formation [152]. In three small studies conducted in children, antibodies to infliximab** were detected in one-third of patients with Crohn's disease [151,152,153]. A meta-analysis of 18 studies (including 3326 adult patients with Crohn's disease treated with infliximab**) [154] established that the incidence of anti-infliximab antibody formation was 45.8% with episodic infusions and 12.4% with regular maintenance therapy. In the IMAgINE study, antibodies to adalimumab** were detected in only 2.3% of patients in the high-dose group and 4.4% of patients in the low-dose group.

The most common symptoms of an acute infusion reaction include dyspnea, flushing, nausea, headache, hypoxemia, and tachycardia. An analysis of 18 studies in children showed that acute infusion reactions were reported in 168 of 1100 patients treated with infliximab** (15%) [10]. Most reactions were mild, with a rapid response to treatment consisting of temporary cessation of the drug infusion or a reduction in the infusion rate. The use of premedication (systemic antihistamines, other analgesics and antipyretics, or glucocorticoids) does not appear to prevent the development of acute infusion reactions [155,156,157,158]. The incidence of infusion reactions in children was similar to that in adults [142,159]. Severe infusion reactions manifesting as hypoxia, hypotension, or respiratory distress are a contraindication to the continued use of infliximab**.

Delayed hypersensitivity reactions may occur at least a day after drug infusion and are characterized by the development of arthralgia and joint swelling, which may be accompanied by fever and/or rash. The incidence of these reactions in children receiving infliximab** reaches 8% [120], and a similar situation is observed in adults [142,159]. Antinuclear antibodies (ANAs) were detected in 20–29% of children in this context. The clinical significance of positive ANAs following treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors remains unclear.

Serious infections such as sepsis, meningitis, pneumonia, abscesses, shingles or varicella-zoster virus infection, Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis, dermatomycosis, and opportunistic fungal infections were reported in 49 of 1483 patients treated with infliximab** (3.3%) [160]. In children with Crohn's disease treated with adalimumab** from the BSPGHN cohort, the reported incidence of serious adverse events was 6%, including two deaths from sepsis in patients who were also receiving immunosuppressants and home parenteral nutrition [148].

The risk of opportunistic infections (invasive fungal infections, reactivation of latent tuberculosis) is increased in patients receiving combination therapy with immunosuppressants, as well as in malnourished patients [161]. If a patient has not had chickenpox and lacks antibodies to the virus, varicella vaccination is advisable if the initiation of treatment can be delayed (as a 4–6-week interval is required between immunization and the start of immunosuppressive therapy).

When studying the long-term safety of treatment regimens involving tumor necrosis factor alpha (TNF-alpha) inhibitors, an increased risk of neoplasms was identified: hepatosplenic T-cell lymphoma in 30 patients suffering from IBD who received treatment with tumor necrosis factor alpha (TNF-alpha) inhibitors in combination with thiopurines [162], which suggests that the development of lymphoma is associated with the use of thiopurines, while the combination with infliximab** acts as a catalyst [146]. According to FDA data as of April 2008, 48 cases of malignancies, including lymphoma and skin malignancies such as melanoma, were reported in children receiving tumor necrosis factor alpha (TNF-alpha) inhibitors (biological drugs), including 31 cases after the use of infliximab**, 2 cases after adalimumab**, and 15 cases after #etanercept** (approved by the instructions from 12 years of age) [163].

The appearance of dermatological symptoms, such as eczema or psoriasis-like lesions, has been reported in 20% of adult patients with IBD [159], and their frequency is also increasing in children with IBD. Infliximab**-induced psoriasis was observed in 8% (6/73) of pediatric patients with IBD [164].

Loss of response to treatment

Primary non-response to treatment is the absence of a response to the induction course within the first 6 months after starting treatment. Loss of response to treatment is a situation where a patient who previously responded to tumor necrosis factor alpha (TNF-alpha) inhibitors (a biological drug) experiences worsening disease course or relapse despite regular administration of tumor necrosis factor alpha (TNF-alpha) inhibitors (the biological drug), which is accompanied by a shortened duration of remission after infusion. Determining the trough level of the drug can help clarify the cause of the loss of response and guide further management if the loss of response persists.

Non-immune factors leading to loss of response to treatment include increased inflammation, the emergence of inflammatory processes unresponsive to the administered drugs, and disease complications (stricture or penetration). Issues related to adherence, suboptimal treatment regimens, and a decrease in drug concentration or its metabolites are also possible. Factors unrelated to IBD, such as opportunistic and other infections or non-inflammatory irritable bowel syndrome, are common. Therefore, it is always necessary to re-evaluate the patient in case of loss of treatment efficacy and ensure that symptoms are indeed driven by disease activity. Currently, the strategy used to treat patients with a loss of response is dose escalation, which involves doubling the dose or shortening the interval between infusions/injections; this may be effective in children with low trough drug levels even in the presence of antibodies in low titers. Retrospective studies in Israel [165] and Belgium [166] showed no advantages of using a double dose of infliximab** compared to shortening the interval between administrations, but for reasons related to treatment costs and patient convenience, dose doubling is initially preferred. Overall, 47% of patients achieved a sustained response within 1 year after dose escalation or interval shortening [165]. In ten patients with antibodies to infliximab**, a more intensive treatment regimen was used, with a clinical response observed in 6 (60%) patients. Following the intensive regimen, antibody concentrations against infliximab** decreased in five patients.

Recently, evidence has emerged suggesting that adding thiopurines or #methotrexate** to the treatment regimen of patients who received infliximab** as monotherapy and lost response due to anti-infliximab antibodies can lead to antibody disappearance, restoration of trough levels, and clinical response [167]. Upon detection of significant anti-infliximab antibody titers, either a more intensive regimen can be prescribed or an immunosuppressant can be added. If intensive therapy and combination therapy fail, or if antibody titers to infliximab** are high, a switch to another tumor necrosis factor alpha (TNF-alpha) inhibitor may be decided. Karmiris et al. [168] analyzed 168 patients who started adalimumab** due to loss of response caused by anti-infliximab antibodies. A clinical response was achieved in 93% of patients and was sustained in 62%; the median follow-up period was 20 months. This strategy will not succeed in patients with active disease and adequate blood drug concentrations; in this case, switching to a biological therapy of another class is indicated.

• Infliximab** (from 6 years) or adalimumab** (from 6 years) are recommended for induction and maintenance of remission in children with the inflammatory phenotype of Crohn's disease in case of persistent activity despite prior optimized immunosuppressive therapy [10]. The drug is approved by the instructions for children from 6 years of age; if necessary, #infliximab is prescribed at a younger age (according to studies, from 2.4 years at a dose of 5 mg/kg IV at weeks 0-2-6 and then every 8 weeks [the dosing regimen corresponds to that for children from 6 years according to the instructions]; there are no data on use under 2.4 years of age) [169, 170, 171].

(LoE – C, GoR - 5)

Comments: Intravenous administration of #infliximab** is typically 5 mg/kg with three induction doses over 6 weeks [Weeks 0-2-6], followed by maintenance therapy of 5 mg/kg every 8 weeks.

However, there is sufficient evidence that children <30 kg and those with extensive disease and low serum albumin levels require higher induction doses of #infliximab** up to 10 mg/kg, shorter dosing intervals, or both, to achieve target trough levels [9].

• #Infliximab** or adalimumab** are recommended for induction of remission in children with active Crohn's disease with steroid resistance [10].

(LoE – C, GoR - 5)

Comments: for #infliximab** doses – see above

• #Infliximab** or adalimumab** are recommended as first-line drugs for induction and maintenance of remission in active Crohn's disease in children with perianal fistulas (along with appropriate surgical management) [19,20,10].

(LoE – C, GoR - 5)

Comments: for #infliximab** doses – see above

• #Infliximab** or adalimumab** for the maintenance of remission in patients who responded to induction therapy with tumor necrosis factor alpha (TNF-alpha) inhibitors are recommended to be administered on a scheduled, regular basis rather than episodically [10].

(LoE – C, GoR - 5)

Comments: for #infliximab** doses – see above

1. The decision to use tumor necrosis factor alpha (TNF-alpha) inhibitors as a first-line drug for induction of remission can be made in individual pediatric patients with risk factors for an unfavorable disease outcome (see above).

3. The decision to initiate early treatment with tumor necrosis factor alpha (TNF-alpha) inhibitors should be made in patients with severe extraintestinal manifestations of the disease (e.g., severe arthritis, pyoderma gangrenosum).

4. Evaluation of the initial efficacy of tumor necrosis factor alpha (TNF-alpha) inhibitors should be carried out after the second or third dose, and in the absence of a significant effect, the drug should be discontinued (primary treatment failure).

5. In patients naive to tumor necrosis factor alpha (TNF-alpha) inhibitors (anti-TNF naive), #infliximab** and adalimumab** have equivalent efficacy and adverse reaction profiles. The choice of drug is made according to availability, preferred route of administration, patient preference, cost, and local regulatory requirements.

6. Data are insufficient to assess the risk/benefit ratio of combination therapy versus monotherapy in children with Crohn's disease. Combination therapy during the first 6 months may reduce antibody formation and the resulting loss of response. However, this benefit must be weighed against the increasing long-term risk of lymphoma associated with thiopurines, so this issue should be decided on an individual basis (taking into account poor prognostic factors of the disease). Concomitant use of low-dose #methotrexate** may be safer than thiopurines, but this combination has a lower evidence base.

7. Routine premedication with paracetamol**, systemic corticosteroids, or systemic antihistamines (antiallergic agents – H1-histamine receptor blockers) before the administration of tumor necrosis factor alpha (TNF-alpha) inhibitors is not indicated.

8. Before initiating therapy with tumor necrosis factor alpha (TNF-alpha) inhibitors, screening for tuberculosis is mandatory: chest radiography, tuberculin skin test with purified protein derivative, and/or IGRA tests (Interferon-γ release assays) – immunological methods based on the stimulation of T-lymphocytes by peptide antigens and the production of interferon-γ secreted by blood cells of an M. tuberculosis-infected human (blood test for interferon-gamma level in response to Mycobacterium tuberculosis complex antigens).

It is also necessary to update immunization records, specifically vaccination and antibody titers against hepatitis B, chickenpox, and measles [172].

9. For the induction of remission, #infliximab** is prescribed at a dose of 5 mg/kg, 3 doses over 6 weeks (weeks 0-2-6), followed by maintenance therapy with a drug administration of 5 mg/kg every 8 weeks. In patients who experience a decrease in drug efficacy or have low drug concentrations, higher doses of up to 10 mg/kg and/or a shortened dosing interval of up to 4 weeks may be required. However, there is sufficient evidence that children <30 kg and those with extensive disease and low serum albumin levels require higher induction doses up to 10 mg/kg, shorter dosing intervals, or both to achieve target trough levels [14]. Dose reduction of #infliximab** is indicated if its residual concentration exceeds 8–10 µg/mL.

10. For the induction of remission, #adalimumab** is prescribed to children with a body weight >40 kg at a dose of 2.4 mg/kg (maximum dose 160 mg) for the first injection, 1.2 mg/kg (maximum dose 80 mg) after 2 weeks, followed by drug administration at a dose of 0.6 mg/kg (maximum dose 40 mg) every 2 weeks. In patients with a body weight up to 40 kg: 80 mg for the first injection, 40 mg after 2 weeks, 20 mg once every 2 weeks (40 mg for children with a body weight >40 kg, 20 mg for children with a body weight <40 kg). For children with a body weight >40 kg, a dose of 80 mg once every 2 weeks may be prescribed in this situation. Weekly administration is indicated in cases of decreased efficacy and low residual drug concentration [173].

11. In case of an inadequate response or decreased treatment efficacy, determining the residual concentration of #infliximab** and #adalimumab**, as well as antibodies against them in blood serum, is advisable to identify the cause.

• In the absence of efficacy from optimized anti-TNF therapy, it is recommended to selectively use #ustekinumab** or #vedolizumab** [10].

(GoR – C, LoE – 5)

Comment:

Both drugs can be prescribed off-label – in accordance with indications (characteristics) not specified in their package leaflet (instructions for use).

• #Ustekinumab** consists of human monoclonal antibodies that block the activity of interleukins 12 and 23, preventing the binding of the p40 subunit to the IL-12Rβ1 receptor on the surface of immune cells. A systematic review and meta-analysis including 1,947 adult patients with Crohn's disease demonstrated the efficacy of #ustekinumab** in inducing remission compared to placebo (RR: 0.91; 95% CI: 0.86–0.95) [174]. Data regarding the efficacy of #ustekinumab** in children are derived from small studies. Administration of #ustekinumab** (without glucocorticoids) achieved remission by week 52 in 39–40% of children with Crohn's disease [174].

• For the induction of remission, #ustekinumab** is administered intravenously at a dose of 6 mg/kg, rounded to 130 mg (maximum dose – 520 mg). The efficacy of ustekinumab is evaluated after 8 weeks. The maintenance dose is administered subcutaneously every 8 weeks (in adults – 90 mg; in children – proportionally to body surface area, based on a standard adult body surface area of 1.73 m²) [10].

• #Vedolizumab** consists of humanized monoclonal antibodies (IgG₁) that bind to α₄β₇-integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), preventing the migration of Th cells into the intestinal wall [175]. Administration of #vedolizumab** allows achieving remission by week 14 in an average of 40 children with Crohn's disease [176, 177].

• The probability of achieving remission with #vedolizumab** is higher in children with Crohn's colitis and in anti-TNF-naive patients [176].

• The administration of #vedolizumab** is not associated with an increased risk of opportunistic infections and malignancy [178].

• For the induction of remission in patients weighing more than 40 kg, #vedolizumab** is administered intravenously three times at a dose of 300 mg (weeks 0-2-6). Subsequently, the drug is administered at a dose of 300 mg every 8 weeks.

• In children weighing less than 40 kg, the drug is administered at a dose of 6 mg/kg (maximum single dose – 300 mg) or proportionally to body surface area, based on a standard adult body surface area of 1.73 m² [10].

• Achieving remission may take up to 14 weeks. Therefore, "bridge" therapy with glucocorticoids may be used [10].

(Level of Reliability of Evidence – C, Level of Convincingness of Evidence – 4)

Currently, biosimilars of tumor necrosis factor alpha (TNF-alpha) inhibitors (anti-TNF drugs) are registered, which are structurally equivalent to them, and some of them have demonstrated efficacy in clinical trials similar to that of the original drugs [183], although such studies have not been conducted for all biosimilars.

• Switching from the original drug to a biosimilar is recommended to be considered only after achieving remission (no earlier than after the administration of 3 doses of the original #infliximab**) and after discussing the switch with the patient and/or legal representative in order to achieve the maximum possible therapeutic effect and accurately assess its outcomes [183].

(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, provided there are relevant indications and if its cost is lower than that of the original 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 original 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 the patient's categorization into special populations (children, pregnant women, elderly, etc.) and must be agreed upon with the patient in accordance with global practices.

Automatic substitution of the original 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 [184].

(LoE – C; GoR – 5)

• The use of aminosalicylic acid preparations and their derivatives as monotherapy is recommended only in selected patients with mild disease due to insufficient efficacy [20].

(Level of Reliability of Evidence – C; Level of Convincingness of Evidence – 5)

Comments:

• There is no evidence that the use of aminosalicylic acid and its derivatives (mesalazine** prolonged-release oral granules / gastroresistant prolonged-release film-coated tablets / prolonged-release tablets [for children aged 6 years and older according to the instructions]; mesalazine** gastroresistant film-coated tablets for children aged 3 years and older [according to the instructions]) induces mucosal healing; therefore, these drugs should be considered as adjunctive therapy. If a drug from the aminosalicylic acid and its derivatives group is used as a single medication for the treatment of mild forms in the absence of deep ulcerations, confirmation of complete remission requires careful monitoring of indicators such as CRP levels, ESR, and fecal calprotectin concentration, and a low threshold should be established for the need to intensify therapy.

• The efficacy of aminosalicylic acid and its derivatives (aminosalicylates) for maintaining remission is low (no greater than 5% compared to placebo).

(LoE – C, GoR - 5)

Comment: Available evidence suggests that antidiarrheal microorganisms (probiotics) may be effective in reducing inflammation in experimental models of colitis and may have a beneficial effect in certain clinical situations, such as pouchitis and UC. A meta-analysis of the results of 7 small studies in CD patients—which varied regarding the studied antidiarrheal microorganism (probiotic), methodological quality, and administration regimen—did not reveal a statistically significant benefit of using antidiarrheal microorganisms (probiotics) in reducing the risk of relapse compared to standard maintenance therapy [10].

3.2 Surgical treatment of Crohn's disease in children

A progressive disease course leads to the development of intestinal complications in every second patient over a ten-year follow-up period; furthermore, up to 90% of CD patients undergo one or more surgeries during their lifetime [187]. The impossibility of radical cure for CD often leads to repeated interventions, increasing the risk of short bowel syndrome [188].

The modern surgical treatment strategy for CD is aimed at performing conservative bowel resections, utilizing minimally invasive techniques, and organ-sparing interventions [189]. Surgical intervention can alter the course of the disease in children with CD who are growing physically and intellectually; therefore, the decision on surgical treatment must be made after careful consideration of indications and assessment of the appropriateness of surgery [10].

3.2.1 Indications for surgical treatment of CD in children

• Indications for surgical treatment include acute and chronic intestinal complications of CD, as well as the failure of conservative therapy resulting in growth retardation [10,190,191,192,193].

(Level of Evidence – C, Grade of Recommendation - 4)

(Level of Evidence – C, Grade of Recommendation - 5)

Comments: Failure of conservative therapy is evidenced by the presence of hormone dependence and resistance; in addition, growth retardation may also be a manifestation of inadequate drug therapy [10, 1, 195]. In children with severe CD and failure of conservative treatment, especially in the prepubertal or pubertal period, or with growth retardation and localized bowel involvement, bowel resection may be useful to ensure a virtually healthy interval of 2–3 years [196], and in such cases, primary bowel anastomosis is usually safe [197].

Acute complications of CD.

These include intestinal bleeding, bowel perforation, and toxic megacolon.

(Level of Evidence – C, Grade of Recommendation - 5)

Comments:

• In cases of intestinal bleeding, emergency surgery is indicated for massive blood loss despite adequate medical therapy for CD, in the event of clinical deterioration or lack of positive dynamics within 24–48 hours despite intensive hemostatic therapy and red blood cell replacement transfusions (important criteria for ongoing intestinal bleeding in children include stool with blood mixed in more than 6 times a day, blood in the stool exceeding 10–15% of the circulating blood volume, tachycardia, and hemoglobin drop below 80 g/L) [199].

• In the event of intestinal bleeding in CD, small bowel resection for interposition with entero-enteroanastomosis is performed, or resection of the affected intestinal segment and stoma formation (including ileostomy), conservative bowel resection with anastomosis and/or intestinal stoma formation; in addition, to identify additional bleeding sources, intraoperative esophagogastroduodenoscopy and videocolonoscopy are desirable [200].

• Small bowel perforation into the free abdominal cavity is a fairly rare complication and usually occurs in the area of a pathological bowel segment with a stricture [201].

• When clinical and radiological signs of peritonitis are present (abdominal pain syndrome, positive peritoneal irritation signs, free gas in the abdominal cavity according to plain abdominal radiography), emergency surgery is indicated, which in this situation may be limited to resection of the affected bowel segment with stoma or anastomosis formation. In the case of emergency surgery, it is recommended to avoid forming a primary intestinal anastomosis without creating a diverting intestinal stoma.

• Large bowel perforation in CD is extremely rare; the operation of choice is colonic resection with stoma formation [202].

(Level of Evidence – C, Grade of Recommendation - 5).

Comment: Toxic dilation of the colon (toxic megacolon) is a rare complication of colonic CD, representing non-obstructive bowel dilation accompanied by symptoms of intoxication [204]. Plain abdominal radiographs show an increased transverse colon diameter: in adult patients greater than 60 mm in diameter, in children older than 11 years greater than 55 mm, and younger than 11 years greater than 40 mm. Risk factors for toxic dilation include hypokalemia, hypomagnesemia, bowel preparation for colonoscopy using osmotic laxatives, and the use of antidiarrheal, intestinal anti-inflammatory, and antimicrobial agents (antidiarrheal drugs). The development of toxic megacolon is evidenced by abdominal distension, a sharp reduction in stool frequency against the background of prior diarrhea, as well as a sudden decrease or disappearance of abdominal pain with escalating symptoms of intoxication (appearance of tachycardia, arterial hypotension, febrile fever) [203].

Chronic intestinal complications.

Chronic complications of CD include bowel strictures, intra-abdominal infiltrates and abscesses, internal or external intestinal fistulas, and high-grade epithelial dysplasia/neoplasia [1,194,205].

3.2.2 Surgical treatment of CD in the form of terminal ileitis or ileocolitis

Childhood-onset CD often presents with more severe, complicated forms than in adults, with an unpredictable prognosis, and frequently leads to irreversible changes resulting not only from the natural course of the disease but also from previous surgical interventions [32,206,207]. The probability of repeated bowel resection in children with CD is up to 29% within 10 years after the first intervention [208].

Factors that reliably increase the need for surgical treatment of CD include: smoking; penetrating and stricturing CD phenotype; early use of hormone therapy; ileal and jejunal involvement, and early onset of the disease [209].

(LE – C, LOE - 4)

• Surgical treatment is recommended as the preferred option for patients with localized ileocecal Crohn's disease presenting with symptoms of intestinal obstruction, but without significantly prominent active inflammation [210].

(GoR – C, LoE – 5)

(LE – C; LE - 5)

Comment: In the stricturing phenotype of ileocecal Crohn's disease, a stricture forms in the terminal ileum or ileocecal region [212]. Suprastenotic ileal dilation exceeding 3 cm in diameter identified in children with Crohn's disease is significantly associated with irreversible fibrotic bowel changes and may serve as an indication for surgery [213, 214.]. The preferred technique for creating an entero-colonic anastomosis is an end-to-end anastomosis or a stapled side-to-side anastomosis, which reduces the likelihood of leakage and subsequent anastomotic stricture formation [215].

• Laparoscopic approach is recommended as the preferred option for performing ileocecal resections in children with Crohn's disease, as a minimally invasive intervention associated with good cosmetic outcomes, earlier postoperative recovery, and a shorter hospital stay [216, 217, 218].

(LE – C, LOE - 3).

• In more complex cases of Crohn's disease (with interbowel fistulas, intra-abdominal abscess, proximal bowel stricture) or upon repeat bowel resection, a laparoscopic approach as the first-line method may be recommended only in centers where surgeons have sufficient expertise in performing such operations [219].

(Level of Evidence – C, Grade of Recommendation - 5)

Comment: in the absence of an inflammatory mass and abscess, performing small bowel and ileocecal surgery laparoscopically is preferred [220, 221, 222]. Laparoscopic procedures have become widespread over the last decade in pediatric and adult patients with Crohn's disease as a minimally invasive approach with good cosmetic results, earlier postoperative recovery, and a short hospital stay [216, 223]. Complications such as adhesive obstruction and wound infection occur less frequently following laparoscopic surgery, whereas the rate of postoperative Crohn's disease recurrence is comparable to that of open surgery [224, 225, 226, 227].

(LE – B, LOE - 3)

Comment: for short strictures no more than 6–7 cm in length, the most widely accepted technique is Heineke-Mikulicz stricturoplasty (longitudinal incision of the bowel at the stricture site with transverse closure), for strictures 10–25 cm in length, the Finney technique is used (creation of a wide side-to-side anastomosis on a bowel loop containing the stricture), and in cases of more extensive involvement, the Michelassi operation (transection of the bowel proximal to the stricture and creation of an isoperistaltic side-to-side stricturoplasty along the entire length of the affected segment) [230]. Contraindications to stricturoplasty include inflammatory masses, abscesses, malignant bowel neoplasms, or active bleeding and severe inflammation in the affected area [228].

(LE C, LOE - 4)

Comments: procedure names: incision and drainage of phlegmon (abscess), small bowel resection for interposition, creation of an entero-enteral anastomosis, ileostomy, enterostomy).

In Crohn's disease complicated by the formation of an intra-abdominal abscess, administration of antibiotic therapy is required, along with abscess drainage or resection of the affected bowel segment [232, 233]; in addition to systemic antimicrobials and abscess drainage, specific anti-inflammatory therapy for Crohn's disease must be intensified, the dose of systemic corticosteroids reduced (and consideration given to discontinuing topical glucocorticoids (ATX group A07EA) in the preoperative period), and enteral nutrition optimized. Intra-abdominal abscesses in children with Crohn's disease can be successfully drained percutaneously in 90% of cases [32, 234]. In patients with abscesses that cannot be drained (less than 2 cm in diameter), maximum doses of systemic antibiotics should be used. Radical surgery is indicated for intra-abdominal abscesses refractory to a combination of antimicrobial and specific Crohn's disease therapy when drainage is unfeasible [235].

(Level of Evidence – C, Grade of Recommendation - 5)

Comment: When interbowel or enterovesical fistulas are identified in patients with Crohn's disease, the main objective is fistula division with limited resection of the fistula-bearing intestinal segment while preserving bowel length [189]. Surgical intervention should be considered in patients with interbowel fistulas if they are combined with an intra-abdominal abscess and/or intestinal stricture, and if the patient exhibits pronounced diarrhea and malabsorption syndrome [32, 188, 237]

(LE – C, LOE - 3)

Comment: onset of Crohn's disease manifesting as terminal ileitis may mimic acute appendicitis, leading to patient admission to a general surgery department and frequently resulting in appendectomy and unwarranted resection of the affected ileal segment [239].

3.2.3. Surgical treatment of colonic CD

(LE – A, LOE - 2).

Comments: in patients with lesions in two distinct segments of the colon, two segmental colonic resections (e.g., laparoscopic colectomy) are performed at the physician's discretion based on the clinical situation.

(LE – C, LOE - 2).

Comments: Limited colonic involvement in Crohn's disease (less than one-third of the colon) does not require colectomy [217]. If a stricture of the ascending colon is identified, right hemicolectomy with creation of an ileocolic anastomosis may be performed. When the transverse or descending colon is involved, resection of the affected colonic segment with transverse-sigmoid anastomosis is performed. For left-sided involvement, left hemicolectomy is performed with colorectal anastomosis formation. When a short colonic stricture is identified, endoscopic stricture dilation may be performed [241], although this procedure is associated with a higher risk of disease recurrence compared to resection of the affected bowel segment [242].

(Strong Recommendation Level – C, Low Quality of Evidence – 4).

Comments: The "defunctioning" surgery to divert the intestinal contents from the colon by forming an ileostomy is indicated only in severely malnourished patients with severe active colitis [220]. This type of surgical treatment is temporary [244]. Surgical intervention can be safely performed using laparoscopic techniques [221, 245].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

Comment: When the entire colon is involved in the pathological process, with minimal activity of inflammatory changes in the rectum, adequate anal sphincter function, and absence of perianal lesions, formation of an ileorectal anastomosis is possible [206]. Performing a colectomy during puberty improves the physical development of adolescents with severe refractory colonic CD [246]. The feasibility of forming an ileal pouch-anal anastomosis in colonic CD remains controversial given the high risk of complications and the frequent need for pouch excision due to the development of perianal disease and pouchitis [247].

3.2.4 Surgical treatment of CD with upper gastrointestinal tract involvement

Upper gastrointestinal tract involvement in children with CD occurs more frequently than in adults (up to 30%), is a well-known phenotypic feature of childhood [17, 248], and leads to a poor prognosis, especially in the stricturing phenotype [194].

Upper GI tract involvement in CD is more common in children than in adults, but the need for surgical intervention is not increased.

• As surgical treatment for CD with upper GI tract involvement, it is recommended to perform endoscopic balloon dilation of the stricture or small bowel bypass anastomosis (if the stricture is localized in the duodenum), scar strictureotomy (strictureplasty) or resection of the affected area (if the stricture is located in the small intestine) [194, 249, 250].

(GoR – C, LoE – 5)

Comment: resorting to isolated loop small bowel bypass anastomosis should only be done in exceptional cases (e.g., duodenal strictures) due to the high risk of small intestinal bacterial overgrowth syndrome in the excluded segment of the small intestine and malignant transformation [251]. Gastroduodenal strictures (usually duodenal) are amenable to balloon dilation [250]. Strictureplasty is also effective for short small bowel strictures less than 10 cm in length [230, 252]. Extensive resections contribute to short bowel syndrome [253].

3.2.5 Treatment of CD with perianal lesions

Perianal lesions develop in 13–67% of children, can occur with any localization of CD [284], and present as hypertrophied skin tags (inflamed anal tags), anal fissures, perirectal abscesses and fistulas, and anal and rectal stenoses [285]. In 10–12% of children with CD, perianal lesions are the initial manifestations of the disease [286].

To date, there is no consensus on the classification of perianal fistulas in CD. In clinical practice, most experts use a simplified classification of perianal fistulas dividing them into simple or complex.

In recent years, the treatment strategy for patients with perianal lesions in CD has been modified to align with new goals:

1. to use simple, effective procedures;

2. to minimize pain;

3. to prioritize palliative care over aggressive surgical intervention [285].

In clinical practice, most surgeons use a simplified classification of perianal fistulas in patients with Crohn's disease, dividing them into simple or complex, depending on the location of the fistula tract relative to the sphincter and the presence of multiple tracts and perianal fluid collections and cavities. In 2022, an expert consensus was published on a modified classification of perianal fistulizing CD in adults, which identifies four patient groups stratified according to disease severity and postoperative outcome. In addition, a proposed treatment and clinical trial strategy is attached to each specific class [287].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

Comment: given the high efficacy of biological therapy with proper drainage of complex fistulas, early initiation of anti-TNF therapy is justified [10, 288].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

Comments: the approach to perianal surgery must be individualized for each patient [292, 293, 294].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

Comments: conservative treatment is an option in the presence of a low fistula between the rectum and the vaginal vestibule [295]. Spontaneous closure of rectovestibular fistulas does not occur. If clinical symptoms are present, surgical treatment may be performed with or without a diverting stoma [296].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

Comments: many clinical guidelines for the management of perianal CD highlight the important role of manual perineal examination under anesthesia ("exam under anesthesia"), which is not only a valuable diagnostic procedure (the so-called "gold standard" in the hands of an experienced surgeon) but may also be accompanied by surgical intervention—opening and draining of a paraproctitis, with placement of a draining non-cutting ligature, the so-called seton drain [276, 298, 299].

Symptomatic simple perianal fistulas require treatment. Placement of a draining seton combined with antibiotics (#metronidazole** 10–20 mg/kg/day orally in 3 doses and #ciprofloxacin** 20 mg/kg/day orally in 2 doses [80]) is the preferred strategy [300].

• If a child has complex perianal CD, after adequate surgical drainage, it is recommended to use #infliximab** or adalimumab** (#adalimumab**) (for detailed dosages, see section 3.1.2.4) as first-line therapy. The combination of #ciprofloxacin** 20 mg/kg/day orally in 2 doses [80] and tumor necrosis factor-alpha (TNF-alpha) inhibitors improves short-term outcomes. To enhance the effect in the comprehensive management of complex perianal CD, a combination of TNF-alpha inhibitors with thiopurines can be used [57].

(Strong Recommendation Level – C, Very Low Quality of Evidence – 5).

(Strong Recommendation Level – C, Low Quality of Evidence – 4).

Comments: cessation of intestinal transit does not lead to fistula healing (it only reduces symptoms), but it allows for successful surgery in the setting of a "defunctioned" colon.

(Strong Recommendation Level – C, Low Quality of Evidence – 4).

Comment: indications are considered individually, depending on the clinical situation.

(GDR – C, LE – 4).

Comments: the presence of a stricture of the lower ampullary rectum or anal canal is the most unfavorable factor increasing the likelihood of permanent intestinal stoma formation [306, 307]. Permanent stoma formation was required in 10% of children with perianal lesions according to a retrospective combined review from two centers [308]. In most cases, these complications require rectal resection [309]. In certain situations, in the absence of active inflammation in the proximal bowel, it is possible to use minimally invasive methods for correcting distal strictures, including injections of systemic corticosteroids and tumor necrosis factor alpha (TNF-alpha) inhibitors into the stricture area, balloon dilation, stricture bougienage with Hegar dilators (for anal canal stricture up to the dentate line), up to more traumatic surgical methods such as strictureplasty (the service is not available in the current Nomenclature) or rectal resection [285, 310].

3.2.6. Medical and nutritional support in the perioperative period

Prednisolone** administration at a daily dose of more than 20 mg for more than six weeks prior to surgery is a major risk factor for surgical complications [254, 255].

Comments: the impact of preoperative conservative CD therapy on postoperative surgical complications has been extensively studied [256]. In contrast, thiopurines can be safely used in the perioperative period, and discontinuation of the drug before surgery is not required [257, 258]. While preoperative treatment with tumor necrosis factor alpha (TNF-alpha) inhibitors may increase the rate of postoperative complications. Recent studies and meta-analyses have shown an increased risk of postoperative sepsis, wound infections, intra-abdominal abscesses, and anastomotic leakage in CD patients [259, 260, 261, 262, 263]. The combination of systemic corticosteroid therapy and tumor necrosis factor alpha (TNF-alpha) inhibitors increases the risk of postoperative complications [254].

(GDR – C, LE – 5).

Comments: Malnutrition is a major risk factor for postoperative complications, including anastomotic leakage, as adequate nutrition provides tissue trophic properties to aid wound healing [265]. A weight loss of 10% or more over a 6-month period is considered severe weight deficit and is accompanied by growth retardation. Serum albumin level is not a primary marker of nutritional status impairment, as albumin levels can depend on multiple factors, including acute or chronic sepsis; other indicators and instrumental assessments should be used in addition to the albumin level [266, 267].

3.2.7 Antirecurrent therapy after surgical treatment of CD.

The risk of symptom recurrence reaches 20–37% at 1 year after surgical treatment, and 43–86% at 3 years after resection [268, 269, 270]

Risk factors for postoperative recurrence in CD patients include smoking, prior bowel resection, genetic markers, perforating CD phenotype, extent of involvement (>40 cm of small bowel), perianal lesions, two or more prior bowel resections, and short disease duration before the first surgery [224, 271, 272].

Endoscopic markers of recurrence appear earlier than symptoms of exacerbation [273].

(GDR – C; LE – 5)

Comment: The presence of severe endoscopic signs of inflammation (i2–4) indicates a high risk of reoperation and is the basis for therapy escalation [274, 275].

• To determine the management strategy for a patient who has undergone surgery when the anastomosis zone cannot be visualized, it is recommended to establish the presence or absence of recurrence based on a combination of instrumental methods (MR enterography, video capsule endoscopy, bowel ultrasound (small bowel, colon, sigmoid, and rectum)) and non-invasive inflammatory markers—serum C-reactive protein level testing, fecal calprotectin level testing, etc. [276, 277, 278].

(GDR – A; LE – 1)

(GoR – C, LoE – 5)

(GoR – C, LoE – 5)

Comments:

• #Infliximab** or adalimumab** (for dosages and regimens see section 3.1.2.4) have approximately equal efficacy [279].

• Patients who have not previously received anti-TNF therapy may be prescribed thiopurines to prevent postoperative recurrence.

• If the patient received anti-TNF therapy prior to surgery, it may be continued postoperatively.

• If endoscopic signs of recurrence (i2–4) are detected in patients receiving thiopurines, therapy escalation is required (prescribing tumor necrosis factor alpha (TNF-alpha) inhibitors

• The administration of mesalazine** (according to the instructions, the use of enteric-coated tablets is limited in children under 3 years of age, and the granule formulation is indicated for children starting from 6 years of age) and systemic antibacterial agents slightly reduces the risk of recurrence after surgical treatment [280, 281, 282].

• Subsequently, regardless of the disease course and clinical manifestation of CD, a follow-up endoscopic examination should be performed at least once every 1–3 years, following the same algorithm for selecting antirecurrent therapy [283].

3.4 Other treatment methods

(LE – C, GDR – 4)

Comment: there is also data on the likely positive effect of physical activity on bone mineral density in children with IBD [312].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Children with Crohn's disease generally require social and psychological rehabilitation, as well as nutritional support in case of protein-energy malnutrition.

Currently, there is insufficient evidence to choose a rehabilitation method for fatigue and tiredness typical of CD patients [314].

Crohn's disease in childhood is a contraindication for health resort (sanatorium) treatment.

5. Prevention and Dispensary Observation

5.1. Prevention

5.1.1 Disease prevention

Does not exist

5.1.2 Vaccination of children with CD

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 [315, 316, 317].

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 2) may receive any vaccines in accordance with the instructions (inactivated and live). Patients receiving immunosuppressive therapy must not be administered live vaccines.

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 [315, 316, 320]. In the case of high-dose glucocorticoid therapy, the interval between the end of treatment and the potential administration of live vaccines may be up to 6 months, depending on the product labeling [315].

Necessary immunization using live vaccines should, whenever possible, be performed before starting immunosuppressive therapy. Otherwise, immunization may be resumed once disease control is established, and if maintenance is required, against the background of baseline therapy, strictly following the gastroenterologist's dietary and other recommendations. Immunosuppressive treatment may be initiated no earlier than 3–4 weeks after the administration of live vaccines [315, 316].

A number of patients with inflammatory bowel disease remain at risk of an inadequate immune response following standard vaccination regimens; therefore, selective monitoring of immunity levels may be considered no earlier than 1 month after completed vaccination (e.g., after hepatitis B virus vaccination** — quantitative determination of antibodies to hepatitis B surface antigen (anti-HBs) in blood), followed by administration of a booster dose of the vaccine in the absence of protective antibody titers [315, 316, 321].

Table 2 List of medicinal products used in the treatment of IBD, classified by the presence of immunosuppressive action

Note: ¹ Vedolizumab is not included in the list of drugs with immunosuppressive action because it has a selective effect on the intestine; nevertheless, 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.

• Vaccination against pneumococcal infection in patients with Crohn's disease is recommended for prophylactic purposes sequentially, starting with a single dose of PCV13 of the broadest valency, followed by PPV23 with a minimum interval of 8 weeks. Revaccination with PPV23 is scheduled 5 years later [316].

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

Comments: vaccination is carried out in accordance with the instructions

5.2 Dispensary monitoring

Due to the progressive nature of the disease, patients suffering from Crohn's disease must receive continuous (lifelong) therapy and undergo regular (lifelong) monitoring of disease activity. Disease activity is monitored not only by instrumental methods but also by laboratory assays of inflammatory markers, primarily fecal calprotectin, the concentration of which in stool correlates with the degree of intestinal inflammatory activity.

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 monitored in an inpatient setting, examinations and tests are not duplicated. In the absence of

• In case of clinical deterioration or an increase in inflammatory markers (C-reactive protein, fecal calprotectin), children with Crohn's disease are recommended to undergo (ileo)colonoscopy to assess disease activity [8].

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

Comments: performed in an inpatient setting

• A complete evaluation, including endoscopic, pathomorphological (histological), and laboratory examinations, is necessary when an adolescent with Crohn's disease transitions to adult healthcare for further follow-up [8].

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

Comments: performed in an inpatient setting

6. Organization of Medical Care

Patients with Crohn's disease may be provided with any type, condition, and form of medical care as stipulated by the legislation of the Russian Federation, depending on their needs.

Primary specialized health care is provided by a gastroenterologist, coloproctologist/pediatric surgeon, and other specialist physicians.

For the diagnosis of Crohn's disease, the patient is referred to an inpatient facility in most cases.

If Crohn's disease is suspected and/or detected during the provision of emergency medical care, such patients are transferred or referred to an inpatient facility to determine management tactics and the need for additional specialized treatment methods, including targeted biologic therapy and surgical treatment.

Specialized, including high-tech, medical care for Crohn's disease is provided by gastroenterologists, coloproctologists/pediatric surgeons.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care for Crohn's disease are determined by a gastroenterologist and/or coloproctologist (pediatric surgeon) and/or infectious disease specialist, etc.

Indications for emergency or urgent hospitalization of a patient to a medical organization are:

1. presence of complications of Crohn's disease requiring specialized medical care in an emergency or urgent setting;

2. presence of complications related to Crohn's disease treatment (surgical intervention, biologic therapy, hormonal and cytostatic therapy, etc.).

Indications for elective hospitalization in a medical organization are:

1. the need for complex invasive diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-care setting;

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

The organization of clinical nutrition for patients during inpatient treatment in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health dated September 23, 2020, No. 1008n "On Approval of the Procedure for Providing Patients with Therapeutic Nutrition".

Indications for discharging a patient from a medical organization are:

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

2. refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting;

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

7. Additional Information

7.1 Outcomes and prognosis

Stigmatizing and prognostically unfavorable factors in CD include smoking, pediatric onset, perianal lesions, a penetrating phenotype, and extensive small bowel involvement. A preventive discussion about the harms of tobacco smoking should be conducted with the child/legal representatives. A patient who smokes must be counseled on the necessity of quitting tobacco smoking, including electronic cigarettes.

Early diagnosis, adequate management, and treatment of patients improve outcomes and prognosis in pediatric CD.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of specialized medical care for children with Crohn's disease (ICD-10 codes: K50)

References

Appendix A1. Working Group Composition

Baranov Aleksandr Aleksandrovich - Academician of the RAS, Professor, Doctor of Medical Sciences; Honorary President of the Union of Pediatricians of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology of the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatric specialist of the Ministry of Health of Russia

Namazova-Baranova Leila Seymurovna - Academician of the RAS, Professor, Doctor of Medical Sciences, 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 National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics of the Pediatric Faculty of the Institute of Motherhood and Childhood of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia

Razumovsky Aleksandr Yuryevich - Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Head of the Department of Pediatric Surgery of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Head of the Russian Association of Pediatric Surgeons

Khavkin Anatoly Ilyich - Doctor of Medical Sciences, Professor, Head of the A.V. Mazurin Department of Gastroenterology and Dietetics, Head of the Moscow Regional Center for Pediatric Gastroenterology and Hepatology of the Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Region; Professor of the Department of Pediatrics with a Course of Pediatric Surgical Diseases of the Medical Institute of the 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

Averkina Natalya Anatolyevna - Candidate of Medical Sciences, Chief Specialist at the Central Research Institute of Organization and Informatization of Healthcare of the Ministry of Health of Russia, 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

Akselrov Mikhail Aleksandrovich, Doctor of Medical Sciences, Associate Professor, Head of the Department of Pediatric Surgery at Tyumen State Medical University, Head of Pediatric Surgery Department No. 1 at Regional Clinical Hospital No. 2, Tyumen, Chief Pediatric Surgeon of the Tyumen Region, Member of the Russian Association of Pediatric Surgeons

Belmer Sergey Viktorovich - Professor, Doctor of Medical Sciences, Professor of the Department of Hospital Pediatrics No. 2 of the Pediatric Faculty of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Co-Chairman of the Society of Pediatric Gastroenterologists, Hepatologists, and Nutritionists, Member of the Union of Pediatricians of Russia

Borovik Tatyana Eduardovna - Doctor of Medical Sciences, Professor, Head of the Laboratory of Nutrition for Healthy and Sick Children at the National Medical Research Center for Children's Health of the Ministry of Health of the Russian Federation; Professor of the Department of Pediatrics and Pediatric Rheumatology at the Sechenov First Moscow State Medical University (Sechenov University)

Vishnyova Elena Aleksandrovna - Doctor of Medical Sciences, Professor of the RAS, Deputy Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Faculty Pediatrics of the Pediatric Faculty of the Institute of Motherhood and Childhood of the Pirogov Russian National Research Medical University (Pirogov University) of the Ministry of Health of Russia, Member of the Union of Pediatricians of Russia

Volynets Galina Vasilyevna - Doctor of Medical Sciences, Chief Researcher of the Department of Gastroenterology of the Veltischev Research Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia

Gabrusskaya Tatyana Viktorovna - Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

Gorelov Aleksandr Vasilyevich - Academician of the RAS, Professor, Deputy Director for Scientific Work at the Central Research Institute of Epidemiology of Rospotrebnadzor, Doctor of Medical Sciences, Professor of the Department of Children's Diseases at the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

Goryacheva Olga Aleksandrovna - Candidate of Medical Sciences, Pediatrician, Gastroenterologist, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department, Department of Propaedeutics of Children's Diseases of the Pediatric Faculty of the Pirogov Russian National Research Medical University

Gurova Margarita Mikhaylovna - Doctor of Medical Sciences, Leading Researcher at the Laboratory of Medical and Social Problems in Pediatrics of the Research Center of the Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, Professor of the Department of Propaedeutics of Children's Diseases with a Course of General Nursing of the Saint Petersburg State Pediatric Medical University of the Ministry of Health of Russia, 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 of the Saint Petersburg Consultative and Diagnostic Center for Children

Zakharova Irina Nikolayevna - Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics of the Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia, Member of the Union_of Pediatricians of Russia (participation in the original version of the document)

Zokirov Nurali Zoirovich - Doctor of Medical Sciences, Head of the Department of the Academy of Postgraduate Education of the 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

Kaytukova Elena Vladimirovna - Candidate of Medical Sciences, Deputy Head for Medical Activities - Head of the Consultative and Diagnostic Center for Children, Gastroenterologist, Leading Researcher of the Department of Orphan Diseases and Prevention of Disabling Conditions at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Associate Professor of the Department of Faculty Pediatrics of the Pediatric Faculty of the Institute of Motherhood and Childhood of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatricians of Russia

Komarova Elena Vladimirovna - Doctor of Medical Sciences, Deputy Head for Expertise of Innovative Treatment and Rehabilitation Methods, Gastroenterologist, Chief Researcher of the Department of Orphan Diseases and Prevention of Disabling Conditions at the Research Institute of Pediatrics and Child Health of the National Medical Research Center No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Faculty Pediatrics of the Pediatric Faculty of the Institute of Motherhood and Childhood of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia (Pirogov University), Member of the Union of Pediatricians of Russia

Kamalova Aelita Askhatovna - Doctor of Medical Sciences, Associate Professor, Member of the Union of Pediatricians of Russia (participation in the original version of the document)

Karavayeva Svetlana Aleksandrovna, Doctor of Medical Sciences, Professor, Head of the Department of Pediatric Surgery at the Mechnikov North-Western State Medical University, Professor of the Department of Pediatric Surgery with a Course of Anesthesiology and Reanimation at the Saint Petersburg State Pediatric Medical University, Leading Surgeon of the Neonatal Surgery Service of the City Children's Multidisciplinary Clinical Specialized Center for High Medical Technologies (Children's City Hospital No. 1 of Saint Petersburg), Member of the Russian Association of Pediatric Surgeons

Kornienko Elena Aleksandrovna - Doctor of Medical Sciences, Professor, Head of the Department of Gastroenterology of the Faculty of Postgraduate and Additional Professional Education of the Saint Petersburg State Pediatric Medical University (SPbGPMU), Chief Pediatric Gastroenterologist and Endoscopist of Saint Petersburg

Kotin Aleksey Nikolayevich, Candidate of Medical Sciences, Associate Professor of the Department of Pediatric Surgery of the Saint Petersburg State Pediatric Medical University, Pediatric Surgeon of the City Children's Multidisciplinary Clinical Specialized Center for High Medical Technologies (Children's City Hospital No. 1 of Saint Petersburg), Member of the Russian Association of Pediatric Surgeons

Lokhmatov Maksim Mikhaylovich - Doctor of Medical Sciences, Head of the Endoscopic Diagnostics Department of the National Medical Research Center for Children's Health of the Ministry of Health of Russia, Professor of the Department of Pediatric Surgery, Urology, and Uroandrology of the Sechenov First Moscow State Medical University, Member of the Union of Pediatricians of Russia

Mokrushina Olga Gennadyevna, Doctor of Medical Sciences, Professor of the Yu.F. Isakov Department of Pediatric Surgery of the Pirogov Russian National Research Medical University, Deputy Chief Medical Officer for Surgical Care of the N.F. Filatov Children's City Clinical Hospital No. 13, Member of the Association of Coloproctologists of Russia, Member of the Russian Association of Pediatric Surgeons.

Morozov Dmitry Anatolyevich, Doctor of Medical Sciences, Professor, Chief Freelance Pediatric Surgeon of the Ministry of Health of Russia, Director of the Veltischev Research Clinical Institute of Pediatrics, Head of the Department of Pediatric Surgery and Urology-Andrology named after Prof. L.P. Alexandrov of the Sechenov First Moscow State Medical University (Sechenov University), Member of the Russian Association of Pediatric Surgeons.

Valeria P. Novikova – MD, PhD, Professor, Head of the Department of Propaedeutics of Childhood Diseases, Head of the Laboratory of Medical and Social Problems in Pediatrics at the Research Center of the Saint Petersburg State Pediatric Medical University

Vladimir A. Novozhilov, MD, PhD, Associate Professor – Head of the Department of Pediatric Surgery at the Irkutsk State Medical University, Professor at the Department of Pediatric Surgery of the 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 Ivano-Matreninskaya Children's Clinical Hospital of Irkutsk, Member of the Association of Coloproctologists of Russia, Member of the Russian Association of Pediatric Surgeons.

Victoria N. Panfilova – MD, PhD, Associate Professor, Member of the Union of Pediatricians of Russia (contributed to the original version of the document)

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

Dmitry V. Pechkurov – MD, PhD, Professor, Member of the Union of Pediatricians of Russia (contributed to the original version of the document)

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

Aleksey V. Podkamenev – MD, PhD, Saint Petersburg State Pediatric Medical University, Associate Professor / Professor of the Department of Pediatric Surgical Diseases named after Academician G.A. Bairov, Chief Freelance Pediatric Surgeon of the Russian Ministry of Health

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

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

Liliya R. Selimzyanova, Head of the Department of Standardization and Study of Evidence-Based Medicine Foundations at the Research Institute of Pediatrics and Child Health of the Academician B.V. Petrovsky National Research Center of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology at the Sechenov First Moscow State Medical University (Sechenov University), Associate Professor at the Department of Faculty Pediatrics of the Pediatric Faculty of the Institute of Motherhood and Childhood at the Pirogov Russian National Research Medical University of the Russian Ministry of Health (Pirogov University), Member of the Union of Pediatricians of Russia

Irina V. Sichinava – MD, PhD, Associate Professor, Professor at the Department of Childhood Diseases at the Sechenov First Moscow State Medical University (Sechenov University), Member of the Union of Pediatricians of Russia

Tamara A. Skvortsova, 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 at the Morozovskaya Children's City Clinical Hospital of the Moscow Healthcare Department

Natalia M. Stepanova, Candidate of Medical Sciences, Associate Professor of the Department of Pediatric Surgery at the Irkutsk State Medical University, Head of the Center for the Correction of Anorectal Malformations and Pediatric Colorectal Surgery at the City Ivano-Matreninskaya Children's Clinical Hospital of Irkutsk, Member of the Association of Coloproctologists of Russia, Member of the Russian Association of Pediatric Surgeons.

Andrey N. Surkov, MD, PhD, Head of the Pediatric Gastroenterology Department of the Pediatric Inpatient Hospital, Head of the Department of Scientific Foundations of Pediatric Gastroenterology, Hepatology and Metabolic Disorders at the Research Institute of Pediatrics and Child Health of the Academician B.V. Petrovsky National Research Center of Surgery, Professor at the Department of Faculty Pediatrics of the Institute of Motherhood and Childhood at the 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

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

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

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

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

Elvira N. Fedulova – MD, PhD, Professor, Member of the Union of Pediatricians of Russia (contributed to the original version of the document)

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

Ekaterina G. Tsymbalova – Candidate of Medical Sciences, Head of the Gastroenterology Department at the Russian Children's Clinical Hospital (branch of the Pirogov Russian National Research Medical University), Head of the Gastroenterology Center at the Russian Children's Clinical Hospital (branch of the Pirogov Russian National Research Medical University), Coordinator of the Pediatric Group at the Russian Children's Clinical Hospital (branch of the 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)

Petr V. Shumilov – MD, PhD, Professor, Member of the Union of Pediatricians of Russia (contributed to the original version of the document)

Olga V. Shcherbakova – MD, PhD, Head of the Surgical Department at the Federal Scientific and Clinical Center for Children and Adolescents of the Federal Medical-Biological Agency

Natalia E. Shchigoleva – Candidate of Medical Sciences, Member of the Union of Pediatricians of Russia (contributed to the original version of the document)

Ekaterina A. Yablokova – Candidate of Medical Sciences, Associate Professor at the Department of Childhood Diseases at the Sechenov First Moscow State Medical University (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. General practitioners (family physicians)

3. Gastroenterologists providing medical care to children

4. Coloproctologists

5. Pediatric surgeons

6. Endoscopists

7. Mid-level medical personnel

8. Healthcare organizers

9. Expert physicians of medical insurance organizations (including when conducting medical and economic reviews).

The recommendations are based on literature data, the European evidence-based consensus on the diagnosis and management of Crohn's disease in children [9] presented jointly by the European Crohn's and Colitis Organisation and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2014, British [322] and North American [46] guidelines, as well as the World Health Organization evidence-based consensus on the treatment of IBD [11] and the management of perianal Crohn's disease [285]; clinical guidelines for the management of adult patients with Crohn's disease – European [194, 253] and Russian clinical guidelines for the diagnosis and treatment of Crohn's disease in adult patients by the Russian Associations of Coloproctologists and Gastroenterologists [1].

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.Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) 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. 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)

2. "On approval of the procedure for providing medical care to the population with diseases of the colon, anal canal, and perineum in coloproctology" Order No. 206n of the Ministry of Health and Social Development of the Russian Federation dated April 2, 2010;

3. "On approval of the Procedure for providing medical care to the population in the profile 'gastroenterology'"; Order of the Russian Ministry of Health No. 906n dated November 12, 2012

4. "On approval of the Procedure for providing medical care in the profile 'pediatric surgery'"; Order of the Russian Ministry of Health No. 562n dated October 31, 2012

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."

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. 04.12.2023) "On approval of the Nomenclature of positions of medical workers and pharmaceutical workers" (Registered with the Russian Ministry of Justice on 01.06.2023 No. 73664).

4. Order of the Ministry of Health and Social Development of Russia No. 541n dated July 23, 2010 (as amended on April 9, 2018) "On approval of the Unified Qualification Reference Book of Positions of Managers, Specialists, and Employees, section 'Qualification characteristics of positions of workers in the healthcare sector'" (Registered with the Ministry of Justice of Russia on August 25, 2010 No. 18247).

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 Russian Ministry of Health 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 the implementation of 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 Russian Ministry of Health No. 1094n dated November 24, 2021, "On approval of the Procedure for prescribing medicinal products, prescription forms for medicinal products, the Procedure for issuing these forms, their accounting and storage, forms of prescriptions containing appointments of narcotic drugs or psychotropic substances, the Procedure for their manufacture, distribution, registration, accounting and storage, as well as the Rules for issuing prescription forms, including in the form of electronic documents" (Registered with the Ministry of Justice of Russia on November 30, 2021 No. 66124)

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 its trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

12. Decree of the Government of the Russian Federation No. 965 dated June 30, 2020, "On introducing amendments to the Rules for the formation of the list of medicinal products the procurement of which is carried out in accordance with their trade names, and on the use of medicinal products with specific trade names"

13. Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition"

Diagnosis examples

When formulating a diagnosis, it is necessary to reflect the extent of the lesion, the nature of the disease course, the severity of the current attack or the presence of remission, the presence of hormone dependence or resistance, as well as the presence of CD complications and growth status. Examples of diagnosis formulations are given below:

• Crohn's disease: involvement of the duodenum, jejunum, and ileum (L4a, L4b, L1), stenosing phenotype (B2) (stricture of the jejunum with intestinal obstruction), chronic continuous course, hormone resistance, severe attack, growth retardation (G1)

Appendix A3.1 Investigations recommended before prescribing immunosuppressants and tumor necrosis factor alpha (TNF-alpha) inhibitors

[20].

¹For females only.

²Consider the need for screening for histoplasmosis, depending on the region of residence

³Recommend appropriate vaccination.

Appendix A3.2 Explanation of notes

• …** – a medicinal product included in the List of Vital and Essential Drugs for medical use for 2021 (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, No. 3073-r dated November 23, 2020)

• # - off-label use – outside the indications registered in the drug instructions, carried out in accordance with Federal Law No. 323-FZ dated November 21, 2011, as amended;

• *** - a medical device implanted into the human body during the provision of medical care within the framework of the state guarantee program of free medical care to citizens.

Examples of diagnosis formulation

• Crohn's disease: ileocolitis with involvement of the terminal ileum, cecum, and ascending colon (L3), penetrating phenotype complicated by an abdominal infiltrate, external intestinal fistula, and perianal lesions (anterior and posterior anal fissures) (B3p), moderate attack, chronic relapsing course, without growth restriction (G0)

• Crohn's disease: terminal ileitis (L1), stenosing phenotype (stricture of the terminal ileum without intestinal obstruction) (B2), chronic relapsing course, remission, without growth restriction (G0).

• Crohn's disease: colitis with involvement of the ascending colon, sigmoid colon, and rectum (L2), inflammatory phenotype (B1p), chronic continuous course, severe attack. Perianal manifestations in the form of an anal fissure. Hormone dependence, without growth restriction (G0).

• Crohn's disease: colitis with involvement of the rectum, sigmoid colon, and descending colon (L2), chronic relapsing course, minimal activity, complicated by a sigmoid stricture with suprastenotic dilation (B2), without growth restriction (G0).

Appendix B. Physician Action Algorithms

Appendix B1. CD treatment algorithm

[10]

Appendix C. Patient Information

CD is a chronic inflammatory disease of the gastrointestinal tract that can affect any part of the GI tract, from the oral cavity to the anus and perianal region.

Currently, there is no cure for this disease; therefore, in most cases, CD requires ongoing treatment with various medications to suppress and limit the spread of inflammation, as well as to prevent the development of complications.

CD is characterized by alternating periods of disease exacerbation (relapses) and periods of improved well-being (remission).

In a very small proportion of patients, remission can persist without treatment; however, in the vast majority of cases, frequent relapses develop without continuous therapy and, most importantly, irreversible damage to the intestinal wall progresses. Over time, this leads to complications that include strictures, fistulas (suppurative tracts from the intestine to the skin, vagina, urinary bladder, or another intestinal loop), perianal lesions, general bodily wasting (cachexia), and even cancer. These complications can be life-threatening and often require surgery with resection of a part of the intestine, sometimes with the formation of an intestinal stoma.

Since CD is a relatively rare disease, a child with this condition needs regular follow-up by a physician specializing specifically in this pathology and must strictly follow their recommendations for long-term, often lifelong, drug therapy.

Smoking, including passive smoking, should be avoided as it negatively affects the course of the disease. Neither physical activity levels nor the intake of specific foods affects the risk of a CD flare-up to the extent that irregular medication use and untimely consultation with a specialist do.

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

Appendix G1. Pediatric Crohn's Disease Activity Index (PCDAI)

Russian title: Pediatric Crohn's Disease Activity Index (PCDAI)

Original title: PCDAI (Pediatric Crohn’s Disease Activity Index)

Source (official developer website, validation

publication): [323,324]

Type: index

Purpose: determining Crohn's disease activity in children

Content (template):

• Key (interpretation) of PCDAI:

  • <10       :  inactive disease (remission)

  • 11-30    :  mild to moderate

  • 30-100  :  severe

• Clinical response to treatment:

  • Decrease in PCDAI index ≥ 15 points from baseline;

  • total PCDAI index ≤ 30 points

• Clinical remission:

  • PCDAI ≤ 10 points

• Loss of response to treatment:

  • Increase in PCDAI ≥ 15 points or PCDAI > 30 points

Notes: none.

Appendix G2. Macro- and microscopic features of CD in small intestinal biopsies in accordance with the revised Porto criteria

Original title (if applicable): ESPGHAN revised Porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents

Source (official developer website, validated publication): Levine A., Koletzko S., Turner D., et al. ESPGHAN revised Porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents – J. Pediatric Gastroenterol Nutr., 2014, v.58 (6), p.795-806 [17]

Type:

other (specify): criteria

Purpose: diagnosis of Crohn's disease

Content (template):

Key (interpretation):

Macro- and microscopic signs of Crohn's disease in children

Notes: none.

Appendix G3. Rutgeerts endoscopic activity score for postoperative recurrence of Crohn's disease

Original title: Rutgeerts scoring system for endoscopic recurrence of Crohn’s Disease

Source (official developer website, validation publication): [37,274,280,325]

Type: rating scale

Purpose: assessment of endoscopic activity in postoperative recurrence of Crohn's disease

Content:

Key (interpretation):

Comments: none.