Crohn's Disease: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

5-ASA – aminosalicylic acid**

AZA – azathioprine

CD – Crohn's disease

BF – Biofeedback

IBD – inflammatory bowel disease

VTE – venous thromboembolism

gamma-GT – gamma-glutamyl transpeptidase

bDMARD – biological disease-modifying antirheumatic drug (targeted biologic)

GCS – Glucocorticosteroids

CI – confidence interval

GI – gastrointestinal tract

CDAI – Crohn's disease activity index

IPAA – ileal pouch-anal anastomosis

BMI – body mass index

CT – computed tomography

LDH – lactate dehydrogenase

MP – mercaptopurine

MTX – methotrexate

MRI – magnetic resonance imaging

NSAIDs – nonsteroidal anti-inflammatory drugs

LMWH – low-molecular-weight heparin

НФГ – unfractionated heparin

PCR – polymerase chain reaction

RCT – randomized controlled trial

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

TIS – targeted immunosuppressants (L04AA Selective immunosuppressants)

CMV — cytomegalovirus

FC – fecal calprotectin

TNF-alpha – tumor necrosis factor-alpha

US – ultrasound examination

ERUS – endorectal ultrasound

EndoUS – endosonography

UC – ulcerative colitis

SES-CD (Simple Endoscopic Score for Crohn's Disease) – Simple Endoscopic Score for Crohn's Disease

Terms and Definitions

Crohn's disease (CD) is a chronic, relapsing gastrointestinal (GI) tract disease of unknown etiology, characterized by transmural, segmental, granulomatous inflammation with the development of local and systemic complications [1].

CD relapse – recurrence of typical disease manifestations in a patient with an established diagnosis of CD who is in clinical remission (spontaneous, medically maintained, or following surgical treatment), confirmed by objective instrumental and laboratory tests [2].

Early CD relapse – recurrence of typical disease symptoms less than 3 months after achieving clinical remission on prior therapy.

CD clinical response – a decrease in the Harvey-Bradshaw index by 4 or fewer points, or a decrease in the Crohn's Disease Activity Index (CDAI) by more than 100 points.

CD clinical remission – absence of CD symptoms (corresponding to a Harvey-Bradshaw index ≤ 4 or a Crohn's Disease Activity Index (CDAI) <150).

CD endoscopic response – a reduction in endoscopic disease activity by more than 50% from baseline according to the SES-CD score.

Endoscopic mucosal healing – implies not complete endoscopic remission, but the absence of mucosal ulcers on SES-CD in the affected area, with possible persistence of aphthae, hyperemia, and other signs of inflammation.

CD endoscopic remission – a state in which inflammatory activity during endoscopic examination is less than 4 points according to the SES-CD score.

CD transmural healing – normalization (⩽3 mm) of the intestinal wall thickness (on imaging techniques) [3].

Genetically engineered biological drugs (GEBDs) – a group of medicinal products of biological origin, including monoclonal antibodies (chimeric, humanized, fully human) and recombinant proteins (usually including a human IgG Fc fragment) produced using genetic engineering methods, which specifically suppress the immuno-inflammatory process and slow down disease progression [4].

Targeted synthetic immunosuppressants (TSIs) – a group of synthetic anti-inflammatory drugs of chemical origin that, by their mechanism of action, specifically block the functioning of intracellular signaling pathways of "pro-inflammatory" and immunoregulatory cytokines [4].

Biologic-naive patient – a patient who has not previously received genetically engineered biological drugs (GEBDs) or targeted synthetic immunosuppressants (TSIs).

Biosimilars – biological medicinal products containing a version of the active substance of an already authorized original biological medicinal product (reference product).

Steroid resistance

• In the case of a severe CD flare – lack of positive dynamics in clinical and laboratory parameters despite the use of systemic GCS at a dose equivalent to 2 mg/kg of body weight of prednisolone** per day for more than 7 days.

• In the case of a moderately severe CD flare – persistence of disease activity during oral GCS intake at a dose equivalent to 1 mg/kg of body weight of prednisolone** per day for 2 weeks.

Steroid dependence

• An increase in disease activity occurring with a reduction in the GCS dose after achieving initial improvement within 3 months from the start of treatment.

• Occurrence of a disease relapse within 3 months after completion of GCS treatment [2].

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 (GI) tract disease of unknown etiology, characterized by transmural, segmental, granulomatous inflammation with the development of local and systemic complications [1].

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 established. The disease develops as a result of a combination of several factors, including genetic predisposition, defects in innate and acquired immunity, disturbances in the intestinal microflora, and the influence of environmental factors. About 100 genetic polymorphisms associated with CD have been described. Genetic determinism leads to alterations in the innate immune response, autophagy, impaired microorganism recognition mechanisms, epithelial barrier dysfunction, and, as a result, aberrant adaptive immunity. A key defect predisposing to the development of IBD is the impairment of bacterial molecular marker recognition mechanisms by dendritic cells, which leads to hyperactivation of pro-inflammatory signaling pathways. Additionally, IBD is characterized by a decrease in intestinal microflora diversity due to a reduction in the proportion of anaerobic bacteria, predominantly Bacteroidetes and Firmicutes [5, 6]. In the presence of these microbiological, immunological, and genetic alterations, IBD develops under the influence of triggering factors, which include smoking, nervous stress, vitamin D deficiency, a diet low in dietary fiber and high in animal protein, intestinal infections, especially Clostridioides difficile infection and cytomegalovirus infection.

The result of the interaction between genetic and predisposed factors is the activation of various T-lymphocyte subpopulations: T-helper 1, 2, 17 types, and regulatory T-lymphocytes at different stages of inflammation, which leads to overexpression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα), interleukins 1, 12, 23, 17 (IL-1, IL-12, IL-23, IL-17), and others, as well as cell adhesion molecules.

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 GI tract – from the oral cavity to the anus. However, in the vast majority of cases, CD affects the ileocecal region. Unlike UC, CD cannot be cured by either medical or surgical methods [2].

1.3 Epidemiology of the Disease or Condition

The maximum prevalence of CD in the world currently reaches 322/100,000 population (in Europe), and the incidence in various regions ranges from 0.3 to 20.2 per 100,000 population [7, 8, 9, 10]. Data on the prevalence and incidence of CD in the Russian Federation are extremely limited, represented by partial data from regional registries, and differ significantly from each other [11, 12, 13, 14]. The prevalence of CD is higher in northern latitudes and in the West, is constantly increasing, and currently reaches up to 1 in 200 people [9]. The incidence and prevalence of CD in Asia are lower, but are steadily increasing. Caucasians are affected more frequently than representatives of Negroid and Mongoloid races. The peak incidence occurs between 20 and 30 years of age, and a second peak incidence in some countries is described at the age of 60–70 years. The incidence is approximately equal in men and women.

1.4 Features of Coding the Disease or Condition

K50.0 – Crohn's disease of the small intestine

K50.1 – Crohn's disease of the large intestine

K50.8 – Other forms of Crohn's disease

K50.9 – Crohn's disease, unspecified

1.5 Classification of the disease or condition

The Montreal classification is used to classify CD, defining it according to several key categories: localization of the inflammatory process, disease behavior (phenotype), and age at disease onset (Table 1). The need to categorize CD by age is due to differences in clinical manifestations and prognosis across different age groups [15].

Table 1. Montreal classification of CD [15].

According to the extent of lesions, the following are distinguished [10]:

1. Localized CD:

- Lesion extent of less than 30 cm. More common in isolated ileocecal involvement;

- Isolated involvement of a small segment of the colon is possible.

2. Extensive CD:

- Lesion extent greater than 100 cm (sum of all affected segments).

According to the clinical course, the following are distinguished [16]:

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

2. Chronic course (more than 6 months from disease onset).

Assessment of CD severity

To correctly formulate the diagnosis and determine the treatment strategy, the severity of the current exacerbation (relapse) of active CD should be assessed, distinguishing between mild, moderate, and severe exacerbations. Various indices are used for this purpose, including the Harvey-Bradshaw index (Table 2) and the Crohn's Disease Activity Index (CDAI, synonym: Best's index) (Table 3) [17]. It should be noted right away that the CDAI is generally used in clinical trials and is inconvenient for practical use due to the complexity of calculation, whereas for clinical practice, the Harvey-Bradshaw index is simpler and more convenient to use [18]. Simple criteria developed by the All-Russian Association for the Study of IBD and the Association of Coloproctologists of Russia can also be used (Table 4) [19]. The choice of a particular severity assessment system is determined by the routine practice of a specific medical institution.

Table 2. Harvey-Bradshaw Index [18]

https://www.thecalculator.co/health/Harvey-Bradshaw-Index-For-Crohn%E2%80%99s-Disease-Calculator-1036.html (link to the Harvey-Bradshaw index calculator)

Table 3. Crohn's Disease Activity Index (CDAI) [17]

Table 4. Criteria for assessing the severity (clinical activity) of CD exacerbation, Russian Organization for the Study of IBD and Association of Coloproctologists of Russia [19]

However, one should assess not only the severity of the exacerbation, but also take into account the severity of the disease as a whole, which is necessary for evaluating the disease prognosis and determining the patient's social status, including obtaining disability status, preferential drug provision, free sanatorium-resort treatment, and other social benefits. The overall severity of the disease is determined not only by the severity of the current exacerbation, but also by the localization and extent of inflammation, the presence of extraintestinal manifestations and complications (abscesses, strictures, fistulas, etc.), refractoriness to treatment, in particular, the development of steroid dependence and resistance.

The classification of CD according to the response to hormonal therapy corresponds to that of UC. The following are distinguished (see section «Terms and Definitions»):

1. Steroid resistance:

2. Steroid dependence:

When formulating the diagnosis, the following should be reflected:

a) localization of the lesion with enumeration of the affected GI segments;

б) phenotypic variant;

в) severity of the current exacerbation or presence of disease remission;

г) nature of the disease course;

е) presence of steroid dependence or resistance;

ж) presence of extraintestinal and/or intestinal and perianal complications.

If a patient has fistulas and strictures simultaneously or during different periods of the disease, the diagnosis of CD, according to the Montreal classification, is formulated as «penetrating», since this is a more severe complication, but stricture must also necessarily appear in the diagnosis as a complication.

1.6 Clinical presentation of the disease or condition

The clinical presentation of CD includes four clinical syndromes:

Intestinal syndrome. Typical intestinal symptoms include diarrhea (more than 6 weeks), in most cases without blood admixture, and abdominal pain.

Endotoxemia — signs of systemic inflammation caused by high activity of the inflammatory process in the intestine. Endotoxemia to varying degrees accompanies moderate and severe forms of CD. The main symptoms are general intoxication, fever, tachycardia, anemia, increased ESR, leukocytosis, thrombocytosis, and elevated acute-phase proteins: CRP, fibrinogen.

Metabolic disorders are a consequence of toxemia, excessive protein loss in stool due to exudation, and impaired water and electrolyte absorption. Clinical symptoms are typical: weight loss (sometimes to the degree of cachexia), hypoproteinemia, hypoalbuminemia with the development of edema syndrome, hypokalemia and other electrolyte disturbances, hypovitaminosis.

Extraintestinal systemic manifestations (EIMs) (Table 5).

Table 5. Main extraintestinal (systemic) manifestations of CD [14,20,21,22,23].

Autoimmune manifestations associated with the activity of the inflammatory process appear together with the main intestinal symptoms of the exacerbation and disappear with them during treatment. Autoimmune manifestations not associated with disease activity (often referred to in English-language literature as «concomitant autoimmune diseases») tend to progress independently of the phase of the underlying disease (exacerbation or remission) and often determine a negative prognosis of the disease.

The clinical presentation of CD in early stages does not always have clearly defined symptoms, which complicates timely diagnosis. Therefore, in a significant number of patients at the time of diagnosis, the disease already has a complicated course. In some cases, CD manifests with complications, such as intestinal obstruction arising seemingly against the background of complete health. In this regard, upon diagnosis, a significant number of patients present with symptoms associated with CD complications.

Complications of CD:

1. Fistulas of various locations

· external (enterocutaneous)

· internal (enteroenteric, enterovesical, rectovaginal)

2. Abdominal infiltrate

3. Interenteric or intra-abdominal abscesses

4. GI strictures (with or without intestinal obstruction)

5. Anal fissures, paraproctitis (in case of anorectal involvement)

6. Gastrointestinal bleeding (rare).

2. Diagnostics, medical indications and contraindications for diagnostic methods

There are no unambiguous diagnostic criteria for CD; the diagnosis is established based on a combination of anamnesis, clinical presentation, and typical endoscopic and histological findings [2,24,25].

The universally accepted criteria for a definitive diagnosis of CD according to Lennard-Jones include the determination of seven key features of the disease [26]:

1. Localization anywhere in the GI tract from the oral cavity to the anal canal; chronic granulomatous involvement of the lip or cheek mucosa; gastroduodenal involvement, small bowel involvement, chronic perianal involvement.

2. Segmental (discontinuous/skip) lesions.

3. Transmural nature of the lesions: fissure ulcers, abscesses, fistulas.

4. Fibrosis: strictures.

5. Lymphoid infiltration (histology): aphthoid ulcers or transmural focal lymphoid aggregates.

6. Mucus (histology): normal mucus content (preserved secretion) in the area of active colonic mucosal inflammation.

7. Presence of epithelioid granuloma.

A diagnosis of CD is considered definitive in the presence of any 3 features or upon detection of a granuloma combined with any other feature.

The diagnosis must be confirmed by:

· endoscopic and morphological methods and/or endoscopic and radiological diagnostic methods.

Endoscopic criteria for CD:

· Regional (skip) mucosal lesions;

· "Cobblestone" appearance (combination of deep longitudinally and transversely oriented ulcers with protruding hyperplastic mucosa between them);

· Linear ulcers (fissure ulcers);

· Aphthae;

· In some cases, strictures and fistula openings.

Endoscopic indices are used to objectify and quantify the endoscopic picture. The simplest and most convenient to use is the Simple Endoscopic Score for Crohn's Disease (SES-CD) (Table 6) [27]. According to this scale, the endoscopic picture must be assessed in 5 intestinal segments: ileum, ascending colon, transverse colon, descending colon including sigmoid, and rectum. In each segment, the following are determined: presence and size of ulcers, presence of aphthae, ulcerated surface area, affected surface area, and presence and severity of stenoses. Each criterion is scored.

Table 6. Simple Endoscopic Score for Crohn's Disease (SES-CD) [27]

SES-CD allows not only to interpret the new targets formulated in the STRIDE 2 concept [76], but also to monitor the dynamics of inflammatory activity and, accordingly, treatment efficacy. New targets (see the terms section) include concepts such as:

· Endoscopic response – a reduction in endoscopic disease activity by the SES-CD score of more than 50% from baseline

· Mucosal healing – implies not complete endoscopic remission, but the absence of mucosal ulcers in the affected area

· Endoscopic remission – interpreted as inflammatory activity ≤ 4 points

The Rutgeerts score (Table 7) [49] is applicable for assessing activity after postoperative recurrence of CD.

Table 7. Endoscopic scoring system for postoperative recurrence activity of CD (Rutgeerts) [49].

Radiological manifestations of CD:

· Regional involvement;

· Skip lesions;

· Strictures;

· «Cobblestoning»;

· Interintestinal fistulas or intra-abdominal abscesses.

Morphological features of CD:

· Deep cleft-like ulcers penetrating into the submucosa or muscular layer;

· Epithelioid granulomas (clusters of epithelioid histiocytes without necrosis foci and giant cells), which are usually found in the wall of the resected segment and in only 15–36% of cases on mucosal biopsy);

· Focal (discrete) lymphoplasmacytic infiltration of the lamina propria of the mucosa;

· Transmural inflammatory infiltration with lymphoid hyperplasia in all layers of the intestinal wall;

· Involvement of the ileum with structural changes in villi, mucoid or pseudopyloric metaplasia of crypts, and chronic active inflammation [28];

· Skip lesions – alternation of affected and healthy segments of the intestine (when examining a resected intestinal segment).

Unlike UC, crypt abscesses in CD are rare, and mucus secretion remains normal.

2.1 Complaints and Anamnesis

For primary diagnosis, all patients are recommended an appointment (examination, consultation) with a coloproctologist and/or gastroenterologist with mandatory digital rectal examination (in the presence of fistulas and/or perianal manifestations of Crohn's disease, external intestinal fistulas, fistulas with hollow organs, interintestinal fistulas, intestinal strictures), as well as in case of external intestinal fistulas, fistulas with hollow organs, interintestinal fistulas, strictures of the intestine, manifestations, bleeding, an examination/consultation by a coloproctologist or surgeon is recommended [29, 246-251].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

When interviewing the patient, attention should be paid to the frequency and nature of stool, duration of these symptoms, presence of blood impurities, nature of abdominal pain, episodes of fever, appearance of anemia of unknown origin, symptoms of intestinal obstruction, perianal complications (chronic anal fissures recurrent after surgical treatment, paraproctitis, rectal fistulas), and extraintestinal manifestations of the disease [14, 20, 21, 22, 23].

When taking the anamnesis, it is worthwhile to clarify the presence of autoimmune manifestations associated and not associated with the activity of the inflammatory process, as well as symptoms associated with complications of CD. In addition, the nature of the onset of the disease, information about trips to southern countries, food intolerances, medication use (including antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs)), smoking, and family history should be clarified.

2.2 Physical Examination

- examination of the perianal region

- digital rectal examination to identify perianal manifestations of CD [29].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

Comment: physical examination may reveal various manifestations of CD, including fever, malnutrition, presence of an abdominal infiltrate, external intestinal fistulas, perianal manifestations (fissures, fistulas), as well as extraintestinal manifestations.

2.3 Laboratory Diagnostics

Comment: laboratory manifestations of CD are non-specific. A complete blood count may diagnose anemia (iron deficiency, anemia of chronic disease, B12 or folate deficiency), leukocytosis (against the background of chronic inflammation, in the presence of an abscess, or during steroid therapy). Biochemical analysis can reveal electrolyte disturbances and hypoproteinemia (in particular, hypoalbuminemia).

For CD patients, if differential diagnosis of anemia is necessary, it is recommended to test the levels of folic acid, vitamin B12, serum iron, total iron-binding capacity of serum, and ferritin [236].

GRL BLEL 3Recommendation Grade B (Level of Evidence – 3)

Comment: to detect infection in 90% of cases, a minimum of 4 stool samples are required [38, 39, 40]. In severe CD attacks, morphological examination of biopsy specimens and/or PCR testing of colonic mucosal biopsy material (from lesions) for cytomegalovirus infection (CMV) is important [41].

• For patients with suspected CD during primary diagnosis, it is recommended to perform microscopic stool examination for helminths using concentration methods to rule out parasitic infection [29, 42].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

2.4 Instrumental Diagnostics

• For patients with suspected CD for primary diagnosis, it is recommended to perform rectosigmoidoscopy [29].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• For patients with CD to determine the localization, extent, and degree of activity of the inflammatory process, it is recommended to perform a colonoscopy with examination of the terminal ileum and biopsy from the pathological area [45, 46, 48].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

To assess the endoscopic activity of CD, the Simple Endoscopic Score for Crohn's Disease (SES-CD) is recommended for use (see Section 2 "Endoscopic Criteria for CD") (Table 6). To assess activity after postoperative recurrence of CD, the Rutgeerts scale is applicable (Table 7) [49].

• For patients during primary CD diagnosis, suspected disease progression, signs of relapse, and annual monitoring, it is recommended to perform esophagogastroduodenoscopy to rule out/confirm upper GI tract involvement [50, 51, 52].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4)

• For patients with CD, if it is necessary to determine the localization, extent, and degree of activity of the inflammatory process, as well as to detect abdominal infiltrates, interintestinal and inter-organ fistulas, perforations, and strictures, it is recommended to perform magnetic resonance imaging (MRI) and/or computed tomography (CT) with intestinal contrast enhancement [53, 54].

GRL ALEL 1Recommendation Grade A (Level of Evidence – 1)

• For patients with perianal manifestations of CD in the form of rectal fistulas or suspicion thereof, it is recommended to perform pelvic MRI with intravenous contrast enhancement to confirm the diagnosis, determine the localization and extent of the fistulous tract, and the presence/absence of complications [53, 55, 56].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: the primary goal of examination in perianal manifestations of CD is, first of all, to rule out an acute purulent process in the pararectal region requiring urgent surgical treatment. MRI is the main diagnostic method for determining the configuration of fistulous tracts and fluid collections in the pelvic cavity.

• In patients with perianal manifestations of CD or suspected CD, in the absence of cicatricial-inflammatory strictures of the anal canal and the lower ampullary rectum, endorectal ultrasound (ERUS) in both B-mode and with three-dimensional image reconstruction is recommended [57].

GCR CLEL 4Grading of Recommendation - C (Level of Evidence – 4)

Comment: ERUS (with a frequency of 5–16 MHz) allows for detailed visualization of the fistulous tract and its location relative to muscle structures in 86–95% of cases, and identification of internal openings in 62–94% of cases. In the presence of external fistula openings, the injection of hydrogen peroxide into them significantly improves the visualization of the fistulous tract. In the presence of an acute purulent-inflammatory process and severe pain, it is advisable to perform the study under anesthesia. As an additional method when it is impossible to insert the probe into the intestinal lumen, transperineal ultrasound can be used, but its accuracy in diagnosing deeply located abscesses is quite low (47.1%) due to the limited field of view [58,59].

• In patients when CT or MRI is not feasible, after ruling out intestinal obstruction, contrast radiography of the small intestine with a barium suspension is recommended to confirm the localization and extent of the inflammatory process, entero-enteric or inter-organ fistulas, and strictures [43].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• In patients with an acute attack of CD or at initial presentation, biopsy of the intestinal mucosa in the affected area and pathomorphological examination of the biopsy material are recommended to clarify the diagnosis [45,60,61].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• In all patients with CD, transabdominal ultrasound of the abdominal cavity, retroperitoneal space, and pelvis is recommended to rule out complications of the underlying disease and comorbid conditions, as well as to assess intestinal wall thickness, the presence of defects in the affected area, the degree of vascularization, and other signs of inflammation. During the ultrasound, it is advisable to perform bowel wall elastography, especially in stricture zones, to determine its nature using color mapping (fibrosis or inflammatory edema) [62,63,64,65,66].

GCR BLEL 2Grading of Recommendation - B (Level of Evidence – 2)

• In patients with suspected small bowel involvement (in the absence of GI tract luminal narrowing) and insufficient information regarding the localization of the inflammatory focus from MRI, CT, and ultrasound, or when these methods are not feasible, video capsule endoscopy is recommended to confirm the diagnosis, determine the localization and degree of activity of the inflammatory process [67].

GCR BLEL 1Grading of Recommendation - B (Level of Evidence – 1)

Comment: it must be borne in mind that capsule retention in the intestine is observed in 13% of patients [67].

• In patients with CD, video capsule endoscopy is recommended in the absence of strictures according to contrast-enhanced MRI or CT enterography [68,69].

GCR CLEL 4Grading of Recommendation - C (Level of Evidence – 4)

• In patients with CD, when small bowel involvement is suspected and the diagnosis cannot be reliably confirmed by colonoscopy (with examination of the terminal ileum), contrast-enhanced CT and MRI enterography, or when video capsule endoscopy cannot be performed, double-balloon enteroscopy is recommended to confirm the diagnosis, determine the localization and degree of activity of the inflammatory process, and obtain biopsies [70].

GRL CLEL 4Recommendation Grade C (Level of Evidence – 4)

2.5 Other Procedures

Additional instrumental and laboratory tests are performed primarily for the purpose of differential diagnosis with a number of diseases [71,72,73].

Differential diagnosis of CD is performed with:

• ulcerative colitis

• acute bacterial infectious colitides (dysentery, salmonellosis, campylobacteriosis, yersiniosis, amebiasis)

• viral colitides (primarily cytomegalovirus colitis)

• parasitic infestations

• helminthiases

• Clostridioides difficile-associated intestinal lesions, including antibiotic-induced ones

• intestinal tuberculosis

• systemic vasculitides

• ischemic bowel disease (ischemic colitis, enteritis)

• colorectal cancer

• diverticulitis

• microscopic colitides (collagenous and lymphocytic)

• radiation colitis (usually proctitis)

• primary immunodeficiency states mimicking CD (common variable immunodeficiency, primary IgA deficiency)

• drug-induced intestinal injuries (NSAIDs).

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

3.1 Conservative Treatment

Treatment measures for CD include the prescription of medicinal products, surgical treatment, psychosocial support, and dietary recommendations [74].

Globally, the goals of CD treatment are currently defined by the "Treat-to-target (T2T)" strategy, which means treating to achieve a specific target. This concept aims to achieve long-term treatment efficacy, prevent complications, reduce hospitalization rates, lower the risk of surgery, improve quality of life, and decrease the rate of disability in patients with chronic diseases [75,76].

From the perspective of daily clinical practice, the goals of CD therapy are to achieve and maintain long-term steroid-free clinical and endoscopic remission [2,24,77].

In case of disease progression and/or the development of life-threatening complications, the specific goal is the timely performance of surgical treatment.

Within the framework of the T2T strategy, continuous monitoring of treatment efficacy is provided through regular testing of biological markers (CRP, fecal calprotectin) and the use of endoscopic and imaging methods [76,78].

Treatment options for patients with CD are determined based on the severity of the attack, extent and localization of inflammation in the GI tract, presence of extraintestinal manifestations and intestinal complications (stricture, abscess, phlegmon/infiltrate), disease duration, efficacy and safety of previous therapy, as well as the risk of complications and the presence of risk factors for a negative prognosis of CD course.

Risk factors for a negative prognosis of CD course and development of complications [79, 80]:

• Patient age <40 years at diagnosis (early onset of the disease, pediatric-onset)

• Extensive intestinal involvement (>100 cm in sum of affected segments)

• Need for systemic GCS at baseline

• Presence of perianal lesions

• Deep mucosal ulcers on endoscopy

• Complicated disease phenotype: stricturing or penetrating CD

• Upper GI tract involvement

• Smoking (more aggressive course)

• Presence of concomitant autoimmune diseases or immune-mediated inflammatory diseases

• Presence of granulomas

Since surgical treatment does not lead to a complete cure in patients with CD, even with radical resection of all affected intestinal segments, anti-relapse therapy must be administered, which should be initiated no later than 2 weeks after surgery [81].

Medicinal products prescribed to patients with CD are conventionally subdivided into:

• Agents for induction of remission: systemic (prednisolone** and methylprednisolone**) and topical (budesonide**) GCS, in combination with thiopurines (azathioprine**, #mercaptopurine**, #methotrexate** (MTX)), bDMARDs: tumor necrosis factor alpha (TNF-alpha) inhibitors (infliximab**, adalimumab**, and certolizumab pegol**), interleukin 12/23 inhibitors (ustekinumab**), and selective gut-adhesion integrin α4β7 inhibitors (vedolizumab**), JAK inhibitors (upadacitinib**), as well as antibiotics.

• Agents for maintenance of remission (anti-relapse agents): thiopurines (azathioprine**, #mercaptopurine**), #methotrexate**, bDMARDs (infliximab**, adalimumab**, certolizumab pegol**, ustekinumab**, and vedolizumab**), and JAK inhibitors (upadacitinib**).

• Adjuvant symptomatic agents: drugs for the correction of anemia, drugs for the correction of protein and electrolyte disturbances, agents for the prevention of osteoporosis (calcium and vitamin D supplements), etc.

Below are recommendations for the choice of drugs for induction and maintenance of remission depending on the extent of involvement and severity of the attack.

3.1.1 Mild ileocecal CD

• For this group of patients as first-line therapy, prescribing budesonide** (prolonged-release gastro-resistant capsules, gastro-resistant granules in sachets) is recommended [74,82,83].

GCR BLEL 1Grading of Recommendation - B (Level of Evidence – 1)

Comment: when taking budesonide** capsules, the daily dose is 9 mg once daily or 3 mg 3 times a day for 8 weeks, followed by a taper of 3 mg per week until complete discontinuation. When taking granules, the daily dose is 9 mg once daily for 8 weeks, followed by a taper of 9 mg every other day for two weeks. The therapeutic effect of budesonide** should be evaluated in 2–4 weeks. If there is no therapeutic response to budesonide**, treatment is conducted as for a moderate-to-severe CD flare. Budesonide** is not intended for maintenance therapy, but if necessary, the maximum duration of administration may be up to 16 weeks [24].

Oral mesalazine** has not shown efficacy compared with placebo for the induction of remission and is not recommended for use in CD [24, 61, 84, 85].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 2)

• In this group of patients, early prescription of thiopurines (AZA** 2–2.5 mg/kg per day or #MP** 1.5 mg/kg per day) is recommended as maintenance therapy (simultaneously with budesonide**), and in case of their intolerance or ineffectiveness – #MT** (25 mg/week s.c. or i.m.). The duration of maintenance therapy with thiopurines (AZA**/ #MP**) should be at least 2–4 years at therapeutic doses [24, 61, 86, 87, 88].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

Comment: since AZA** starts acting after 12 weeks, early prescription is necessary so that its onset of action coincides with the discontinuation of GCS.

3.1.2 Moderately severe ileocecal CD

• In this group of patients, topical oral GCS (budesonide** gastro-resistant prolonged-release capsules, gastro-resistant granules in sachets) are recommended for the induction of remission; for the dosing regimen and evaluation timelines, see section 3.1.1 "Mild ileocecal CD" [74, 82, 83].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 1)

• In this group of patients, for the induction of remission of CD, in the absence of response to budesonide, in the presence of an infiltrate, inflammatory stricture, and signs of systemic inflammation, systemic GCS (prednisolone** or equivalent doses of other GCS) are recommended [89] (Table 8).

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

Comment: the dose of prednisolone** for this localization and severity is 1 mg/kg of body weight per day until a clinical response is achieved, followed by a taper of 5 mg every 5–7 days until complete discontinuation, for no more than 12 weeks. The efficacy of GCS is evaluated in 2–4 weeks.

Table 8. Duration of action and equivalent doses of GCS [240, 241].

• In this group of patients, in the presence of signs of systemic inflammation and/or an abdominal cavity infiltrate, it is recommended to combine systemic GCS (glucocorticosteroids) in combination with antibiotics [24, 90].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 1)

• In this group of patients, early prescription of thiopurines (AZA** 2–2.5 mg/kg or #MP** 1.5 mg/kg) is recommended as maintenance therapy (simultaneously with GCS), and in case of their intolerance or ineffectiveness – #MT** (25 mg/week s.c. or i.m.). The duration of maintenance therapy with thiopurines (AZA**/ #MP**) should be at least 2–4 years at therapeutic doses [24, 61, 86, 87].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

• For the group of patients with active CD with steroid resistance, steroid dependence, GCS intolerance, or ineffectiveness/intolerance of immunosuppressants, biologic therapy (bDMARDs) (infliximab**, adalimumab**, certolizumab pegol**, ustekinumab**, vedolizumab**) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (upadacitinib**) is recommended as an induction (initiating) course followed by long-term maintenance treatment [93, 94, 95, 96].

GRL ALEL 1Recommendation Grade A (Level of Evidence – 1)

Comment: Regimens and doses of bDMARDs and tsDMARDs within the induction (initiating) course and maintenance therapy:

• for infliximab**, the induction (initiating) course involves three intravenous administrations at weeks 0, 2, and 6 at a dose of 5 mg/kg of body weight, followed by the same dose for maintenance therapy every 8 weeks;

• for adalimumab**, the induction (initiating) course consists of a first subcutaneous administration at a dose of 160 mg, followed by a second subcutaneous administration 2 weeks later at a dose of 80 mg, and then maintenance therapy at a dose of 40 mg every 2 weeks;

• for certolizumab pegol**, the induction (initiating) course consists of a first subcutaneous administration of 400 mg, a second subcutaneous administration at week 2 at a dose of 400 mg, a third subcutaneous administration of the drug at the same dosage at week 4 of treatment, followed by maintenance therapy at the same dosage subcutaneously every 4 weeks;

• for vedolizumab**, the induction (initiating) course involves three intravenous administrations at weeks 0, 2, and 6 at a dose of 300 mg, followed by maintenance treatment of 300 mg intravenously every 8 weeks;

• for ustekinumab**, the induction (initiating) dose is administered intravenously on the first day, with the dose calculated based on the patient's body weight at the time of administration, followed 8 weeks later by the first subcutaneous maintenance administration at a dose of 90 mg, and thereafter by therapy at a dose of 90 mg subcutaneously every 8 or 12 weeks (depending on the disease course);

• for upadacitinib**, a 12-week induction (initiating) course at a dose of 45 mg in tablets once daily, followed by 30 mg or 15 mg (depending on the disease course) in tablets once daily as maintenance therapy.

All bDMARDs and tsDMARDs are approximately equal in efficacy; therefore, in biologic-naive patients, any of the indicated drugs can be used as first-line therapy. However, the optimal sequence for prescribing bDMARDs and tsDMARDs has not yet been established. To a large extent, the choice of the first drug depends on the patient's individual characteristics and the presence of risk factors for a negative disease prognosis. Nevertheless, it should be kept in mind that all bDMARDs are more effective in the first line in biologic-naive patients. Each additional bDMARD statistically significantly reduces the probability of achieving clinical, endoscopic, and steroid-free remission [97]. Some bDMARDs and tsDMARDs retain efficacy in the 2nd and subsequent lines of therapy (ustekinumab**, upadacitinib**) [98, 99, 100].

In addition, when choosing between different drug classes, it should be taken into account that ustekinumab** and adalimumab** demonstrated comparable efficacy in first-line therapy, but in the adalimumab** group, the discontinuation rate due to adverse events was almost twice as high as in the ustekinumab** group [101].

The absence of a primary response to therapy is determined after the induction course (depending on the drug). In the presence of negative dynamics, the efficacy of the drug is evaluated earlier.

• Patients who have achieved remission with any bDMARD or tsDMARD are recommended to undergo maintenance therapy with the same drug (with or without immunosuppressants) [24, 61, 85, 102].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

• In patients with active CD, combining infliximab** with thiopurines is recommended to increase treatment efficacy [85, 88, 103].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

Comment: for other bDMARDs, the feasibility of such a combination has not been proven. The prescription of combination therapy remains at the discretion of the attending physician.

• In patients with active CD with intolerance/lack of response to thiopurines, the use of infliximab** in combination with #methotrexate** (#MT** 25 mg/week s.c. or i.m.) is recommended [61, 85, 104].

GCR CLEL 4Grade of Clinical Recommendation — C (Level of Evidence Likelihood — 4)

• In patients with primary inefficacy of any anti-TNF agent, switching therapy to vedolizumab**, ustekinumab**, or upadacitinib** is recommended for the induction of remission [253, 254, 255, 256].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

Comment: any of the indicated drugs can be prescribed as 2nd and subsequent lines of therapy with or without GCS. When choosing vedolizumab after anti-TNF, it should be kept in mind that its efficacy as a 2nd-line drug is lower than in the 1st line [105, 106].

• In patients with loss of response to first-line anti-TNF therapy (relapse of Crohn's disease against the background of previously achieved remission), treatment optimization is recommended by increasing the drug dose (infliximab** 10 mg/kg every 8 weeks, adalimumab 80 mg every 2 weeks) or shortening the intervals between administrations (infliximab** to 4–6 weeks, adalimumab** 40 mg every week), or prescribing drugs with a different mechanism of action: vedolizumab**, ustekinumab**, upadacitinib** to achieve a therapeutic effect [107,108,109].

GOR ALE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: switching to another anti-TNF agent is acceptable, but its efficacy is lower than when switching to drugs of other classes (vedolizumab**, ustekinumab**, upadacitinib**) [107,111]. To increase treatment efficacy when switching to another anti-TNF agent, combination with immunosuppressants is possible [108,109]. When choosing vedolizumab**, it should be borne in mind that its efficacy as a first-line drug is higher than in second and subsequent lines [110].

• In patients with loss of response to vedolizumab** at the standard dose of 300 mg every 8 weeks, treatment optimization is recommended by shortening the intervals between administrations to 4–6 weeks or switching to a drug of another class (anti-TNFs, ustekinumab**, upadacitinib**) [105,110].

GGR CLeL 4Grade of recommendation C (Level of evidence – 4)

Comment: the efficacy of anti-TNFs in 2nd-line therapy after loss of response to vedolizumab** does not decrease compared to their efficacy in the 1st line, i.e., the use of vedolizumab** does not affect the subsequent efficacy of anti-TNFs [110].

• In patients with loss of response to ustekinumab** at the standard administration regimen every 12 weeks, treatment optimization is recommended by shortening the intervals between administrations to 8 weeks or switching to a drug of another class (anti-TNFs, vedolizumab**, upadacitinib**) [85].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

• In case of primary non-response or loss of response to upadacitinib**, treatment optimization with an increase in the maintenance dose from 15 mg to 30 mg or switching to another drug class is recommended [233].

GGR CLeL 4Grade of recommendation C (Level of evidence – 4)

• In patients with active Crohn's disease when conservative therapy is ineffective, surgical treatment is recommended [61].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

3.1.3 Mild to moderate colonic CD

This group of patients is recommended therapy with systemic GCS (prednisolone** or equivalent doses of other GCS) [89,91].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

Comment: the dose of prednisolone** for this localization and severity is 0.75–1 mg/kg of body weight per day until a clinical response is achieved, followed by a taper of 5 mg every 5–7 days until complete discontinuation, over 12 weeks. The efficacy of GCS is evaluated in 2–4 weeks.

• This group of patients is recommended to be prescribed thiopurines (AZA** 2–2.5 mg/kg or #MP** 1.5 mg/kg) simultaneously with systemic GCS, and in case of their intolerance or ineffectiveness – #MTX** (25 mg/week s/c or i/m once a week) [86,87,102].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

• This group of patients, in the presence of signs of active systemic inflammation and/or the presence of an infiltrate, is recommended to add antibiotics to the treatment regimen [61,85,90].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

For therapy with immunosuppressants, bDMARDs, and tsDMARDs, see section 3.1.2 "Crohn's disease of ileocecal localization".

• In patients with active Crohn's disease when conservative therapy is ineffective, surgical treatment is recommended [61].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

3.1.4 Small bowel CD (excluding terminal ileitis)

• Oral mesalazine** has not shown efficacy compared to placebo for inducing remission and is not recommended for use in Crohn's disease [24,61,79,84,85].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 2)

• This group of patients is recommended systemic GCS (prednisolone** or equivalent doses of other GCS) [24,85,89,91].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

Comment: the dose of prednisolone** for this localization and severity is 1 mg/kg of body weight per day until a clinical response is achieved, followed by a taper of 5 mg every 5–7 days until complete discontinuation, for no more than 12 weeks. The efficacy of GCS is evaluated in 2–4 weeks.

• This group of patients is recommended to be prescribed thiopurines (AZA** 2–2.5 mg/kg or #MP** 1.5 mg/kg) simultaneously with systemic GCS, and in case of their intolerance or ineffectiveness – #MTX** (25 mg/week s/c or i/m once a week). The duration of maintenance therapy with thiopurines (AZA**/#MP**) is at least 2–4 years at therapeutic doses [24,61,86,87].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

• This group of patients, in the presence of signs of systemic inflammation and/or the presence of an infiltrate, is recommended antibacterial therapy: #metronidazole 1 g/day + fluoroquinolones 1 g/day parenterally for 10–14 days [24,61,90].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

For therapy with immunosuppressants, bDMARDs, and tsDMARDs, see section 3.1.2 "Crohn's disease of ileocecal localization"

• In patients with active Crohn's disease when conservative therapy is ineffective, surgical treatment is recommended [61].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

3.1.5 Severe active CD of any localization

Severe Crohn's disease is assessed by the Harvey-Bradshaw index as > 16 points (Table 3) (see section 1.5 "Classification of the disease or condition (groups of diseases or conditions)").

Patients with severe Crohn's disease are recommended to start treatment with systemic GCS (prednisolone** or equivalent doses of other GCS) intravenously or orally. Dose equivalence and duration of action of GCS are given in Table 7 (see section 3.1.2 "Moderately severe Crohn's disease of ileocecal localization") [89,91].

GCR ALEL 1Grade of Clinical Recommendation — A (Level of Evidence Likelihood — 1)

Comment: the dose of prednisolone** for this severity is 1.5–2 mg/kg of body weight per day until a clinical response is achieved, followed by a taper of 5 mg every 5–7 days until complete discontinuation, for no more than 12 weeks. The efficacy of GCS is evaluated in 2–4 weeks.

• This group of patients is recommended to be prescribed thiopurines (AZA** 2–2.5 mg/kg or #MP** 1.5 mg/kg) simultaneously with systemic GCS, and in case of their intolerance or ineffectiveness – #MTX** (25 mg/week s/c or i/m once a week). The duration of maintenance therapy with thiopurines (AZA**/#MP**) is at least 2–4 years at therapeutic doses [24,61,86,87].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

• This group of patients, in the presence of signs of systemic inflammation and/or the presence of an infiltrate, is recommended antibacterial therapy: #metronidazole 1 g/day + fluoroquinolones 1 g/day parenterally for 10–14 days [24,61,90,112].

GGR AGrading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of Evidence – 1)

• This group of patients with an early relapse of the disease less than 3 months after achieving clinical remission is recommended to start immediately with bDMARDs or tsDMARDs without re-administering systemic GCS [24,74].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

Comment: Repeated courses of GCS are highly undesirable. GCS are acceptable to use only if bDMARDs or tsDMARDs cannot be used.

For therapy with immunosuppressants, bDMARDs, and tsDMARDs, see section 3.1.2 "Crohn's disease of ileocecal localization"

• Patients with active Crohn's disease when conservative therapy is ineffective are recommended surgical treatment [61].

LoR CLevel of Recommendation - C (Level of Evidence

3.1.6 CD with perianal lesions

Perianal lesions in Crohn's disease often require surgical treatment, which is discussed in Section 3.2.6 "Surgical treatment of perianal Crohn's disease".

• In all patients with perianal involvement in Crohn's disease, in the absence of indications for surgical treatment or after it, it is recommended to prescribe immunosuppressants (AZA**, #MP**, #MTX**) and/or bDMARDs (infliximab**, adalimumab**, certolizumab pegol**, ustekinumab**, vedolizumab**) or tsDMARDs (upadacitinib**) as an induction (initiating) course followed by long-term maintenance treatment [58,113,114,115].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

• Patients with perianal lesions of Crohn's disease for the treatment of a purulent-inflammatory process are recommended the prescription of #metronidazole** 0.75 g/day and/or #ciprofloxacin** 1 g/day [24,116].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 2)

Comment: antibiotics are prescribed for a long time (up to 6 months or until side effects appear). Combination therapy of anti-TNFs (infliximab**, adalimumab**) with antibacterial drugs increases their efficacy [116, 117,118,119,120].

• In patients with perianal manifestations of Crohn's disease, it is recommended to add #metronidazole** suppositories and ointments to the therapy [116, 117].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

• In patients with perianal manifestations of Crohn's disease, in the presence of anal fissures, surgical intervention is not recommended, and preference is given to the local conservative treatment described above [24, 58, 116].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

3.1.7 Monitoring of efficacy and side effects of drug therapy

During GCS therapy, patients need blood glucose monitoring.

During immunosuppressant therapy, follow-up complete blood counts and blood biochemistry tests are necessary, taking into account leukocyte counts and liver enzymes (at the beginning of treatment once every two weeks, then once a month for the first 6 months of therapy, then once every three months).

In addition, before starting bDMARD and tsDMARD therapy and subsequently every 6 months in accordance with the order of the Russian Ministry of Health (No. 124n dated March 21, 2017 "On approval of the procedures and timelines for preventive medical examinations of citizens for the purpose of tuberculosis detection"), a consultation with a phthisiatrician and tuberculosis screening (QuantiFERON test, or if impossible – an intradermal test with a tuberculous allergen: Mantoux test, Diaskintest) are mandatory.

• Before prescribing immunosuppressants, bDMARDs, and tsDMARDs, and during treatment, patients are recommended to undergo testing in the blood for Hepatitis B virus (HBV) surface antigen (HBsAg), Hepatitis C virus antibodies; testing for antibodies to Treponema pallidum in the blood using enzyme immunoassay (EIA) or non-treponemal tests (RPR, VDRL) (qualitative and semi-quantitative assay) in blood serum; testing for Human immunodeficiency virus HIV 1 antibodies (IgM, IgG) in the blood; testing for Human immunodeficiency virus HIV 2 antibodies (IgM, IgG) in the blood [121, 242, 243].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

3.1.8 Biosimilars

Biosimilars are biological medicinal products containing a version of the active substance of an already authorized original biological medicinal product (reference product) [123]. Currently, the biosimilar market is constantly expanding. In the context of IBD, this currently applies to biosimilars based on anti-TNF-alpha monoclonal antibodies. In Europe alone, 21 biosimilars were approved in the last decade, including 14 based on adalimumab and 4 on infliximab [124]. Infliximab and adalimumab biosimilars are also approved in the Russian Federation. The use of biosimilars reduces the economic burden on the healthcare system and thereby significantly expands the availability and accessibility of biological therapy. There is currently sufficient evidence regarding the efficacy and safety of biosimilars, yet clinician prejudice against them as drugs with lower efficacy persists [125]. In 2017, the European Crohn's and Colitis Organisation (ECCO) issued a position statement on the use of biosimilars in IBD, emphasizing that once approved, a biosimilar is considered as effective as the originator product, while large observational studies are required to assess its long-term efficacy and safety [126]. From this perspective, a 2018 systematic review of 90 studies across various immune-mediated inflammatory diseases showed that the vast majority of studies observed no differences in safety, efficacy, or immunogenicity between biosimilars and their corresponding originator products, indicating that a favorable benefit–risk profile is maintained when switching from an originator to a biosimilar [127]. Clinical practice in European countries and the USA demonstrates similar efficacy, safety, and immunogenicity when IBD patients are switched from originator infliximab to its biosimilars [128, 129, 130, 131, 132]. Only one study reported a 9.9% rate of reverse switching from a biosimilar back to the reference product due to adverse skin or gastrointestinal events or loss of response. The vast majority of patients regained response to treatment after reverse switching [130]. A comparison of adalimumab and two of its biosimilars in IBD patients in Italy showed no significant difference in efficacy, safety, and immunogenicity between the drugs following the induction course and after 6 months of maintenance therapy [133]. Results of long-term post-marketing surveillance of the efficacy and safety of monoclonal antibody-based biosimilars over 7 years revealed no biosimilar-specific adverse effects [134]. The ECCO consensus emphasizes that decisions to switch from an originator to a biosimilar for non-medical reasons should be made in accordance with national clinical guidelines, and all information must be communicated and explained to the patient [126].

Despite rather clearly formulated statements regarding biosimilars, there are certain controversies on this issue, according to which the adopted provisions are based on studies with different methodological approaches and an insufficient number of observations, which limits their reliability [234].

Russian publications indicate that the incidence of secondary loss of response and adverse events in IBD patients when switching from originator infliximab to its biosimilar is about 30%, which is significantly higher than in those continuously receiving the originator drug. Furthermore, the incidence of adverse events is significantly higher in patients receiving the drug by INN, which leads to unjustified and unregulated alternation of the originator drug and biosimilars compared to patients receiving drugs by trade name [235].

The provision on biosimilars is being introduced into the Russian clinical guidelines for Crohn's disease for the first time. Since Russian biosimilars are not represented on the foreign market, international data on successful switching experience will have limited applicability for Russia. Therefore, these data should be extrapolated to domestic clinical practice with caution.

Comment: this provision applies equally to the initial prescription of anti-TNF drugs in biologic-naive patients and when switching from the originator drug to a biosimilar and vice versa for non-medical reasons. However, it should be borne in mind that uncontrolled switching from the originator to a biosimilar or different biosimilars and back by INN can lead to a worsening of the disease course, rapid loss of response, and adverse events. Switching from one anti-TNF drug to another within the same class upon loss of response to the first drug is not recommended for either originator drugs or biosimilars. There is currently insufficient evidence base for using biosimilars of other drug classes for the treatment of Crohn's disease.

3.2 Surgical treatment of CD

Most patients with Crohn's disease undergo at least one gastrointestinal surgery in their lifetime. The impossibility of a radical cure for patients with Crohn's disease often leads to repeated resections, increasing the risk of short bowel syndrome. Modern tactics of surgical treatment for Crohn's disease are aimed at performing limited resections and, whenever possible, organ-sparing interventions (strictureplasty, stricture dilation) [135].

Preoperative intake of glucocorticosteroids at a dose of more than 20 mg per day is associated with an increase in postoperative septic complications [136].

In patients with Crohn's disease who have undergone surgery, a history of biological therapy (anti-TNF drugs, vedolizumab**, or ustekinumab**) is not associated with an increase in postoperative septic complications [137, 138, 139, 140, 141, 142].

Discontinuation of these drugs before surgery is not mandatory.

The administration of immunomodulators prior to surgery is not associated with an increased rate of postoperative septic complications [143, 144].

3.2.1 Indications for surgical treatment of CD

Indications for surgery in CD include acute and chronic complications, as well as the failure of medical therapy and growth retardation [135].

Acute complications of CD.

Acute complications of CD include intestinal bleeding, bowel perforation, and toxic megacolon.

• In cases of intestinal bleeding, emergency surgery is recommended if hemodynamic stabilization cannot be achieved despite red blood cell transfusion and intensive hemostatic therapy [145, 146].

GCR CGrade of Recommendation — C (Level of Evidence – 4)

Comment: intestinal bleeding is diagnosed when blood loss exceeds 100 mL/day according to objective laboratory methods (scintigraphy, fecal occult blood test, rapid immunochromatographic fecal occult blood test) or when the volume of stool with visually detectable blood admixture exceeds 800 mL/day. In such cases, resection of the affected bowel segment is performed (with or without anastomosis, and with potential stoma formation) accompanied by mandatory intraoperative entero- or colonoscopy [147].

• In patients with complicated CD, in the event of small/large bowel perforation into the free peritoneal cavity with the development of acute peritonitis, emergency surgery with resection of the affected bowel segment, preferably with the creation of an intestinal stoma, is recommended [148, 149].

GCR CGrade of Recommendation — C (Level of Evidence – 4)

Comment: the creation of an intestinal stoma as an alternative to primary anastomosis in complicated CD with peritoneal contamination resulting from perforation into the free peritoneal cavity helps reduce the risk of septic complications and CD recurrence. In patients with small bowel CD, its perforation into the free peritoneal cavity is a fairly rare complication and typically occurs either distal or proximal to a strictured bowel segment. In emergency surgery, it is recommended to avoid creating an unprotected primary anastomosis without a covering loop ileostomy [150].

• In patients with colonic CD who develop toxic megacolon, subtotal colectomy with end ileostomy is recommended as the surgery of choice [150].

GCR CGrade of Recommendation — C (Level of Evidence – 4)

Comment: toxic dilatation of the colon is a rare complication of CD characterized by non-obstructive colonic dilation of 6.0 cm or more accompanied by signs of systemic toxicity. Risk factors for toxic megacolon include hypokalemia, hypomagnesemia, bowel preparation for colonoscopy using osmotic laxatives, and the use of antidiarrheal medications. The development of toxic megacolon is indicated by a sudden decrease in stool frequency against the background of preexisting diarrhea, abdominal distension, as well as a sudden reduction or disappearance of pain and worsening symptoms of toxicity (increasing tachycardia, drop in blood pressure). If perforation of the colon occurs in patients with a complicated course of CD who are in severe condition and have metabolic disorders, exteriorization of the affected segment is acceptable.

Chronic complications of CD.

Chronic complications include strictures, abdominal mass, internal or external intestinal fistulas, and the presence of neoplasia [151].

Chronic complications should also include growth retardation resulting from inadequate medical therapy, most commonly occurring with upper GI tract involvement.

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

• In a patient presenting with a clinical picture of acute appendicitis, when abdominal exploration reveals a macroscopically normal appendix and terminal ileitis, it is recommended to refrain from performing an appendectomy, as well as bowel resection or ileocecal bowel resection [149, 152].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

Comment: Sometimes the onset of Crohn's disease presenting as terminal ileitis can mimic acute appendicitis, leading to patient admission to a general surgery department and frequently to appendectomy and unjustified resection of the affected ileum [153, 154]. In the 2020 clinical guidelines of the Russian Society of Surgeons, this situation is described as "secondary appendicitis." In such cases, it is strongly recommended to refrain from performing an appendectomy if there are no macroscopic signs of secondary inflammation in the appendix. There are no prospective studies on this topic. In 2021, a systematic review by Quaresma A.B. was published, based on data from 6 retrospective studies, most of which are case reports. As a result of this review, the authors do not recommend performing an appendectomy and primary ileal resection in uncomplicated CD [155]. It is important to note that this recommendation is consistent with the consensus statement of the expert panel of the European Crohn's and Colitis Organisation (ECCO) and the European Society of Coloproctology (ESCP) [152, 156].

• In patients with a penetrating form of CD with intra-abdominal abscess formation, ultrasound- or CT-guided drainage is recommended followed by conservative therapy (antibiotics, corticosteroids, and biologic therapy) as an alternative to surgical resection [149, 152, 157].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: drainage of the intra-abdominal abscess and subsequent conservative therapy serve as a bridge to surgical resection, allowing for a reduction in the extent of surgery due to the decrease in inflammatory changes. It is also important to note that the conservative treatment strategy following drainage reduces the likelihood of entero-enteric anastomotic leakage, external intestinal fistula formation, and the need for intestinal stoma creation after elective bowel resection [158, 159, 160]. Furthermore, a meta-analysis by He X. et al. revealed a significant reduction in the probability of postoperative complications (OR = 0.44; 95% CI 0.23–0.83; p = 0.03) [161]

If primary bowel resection is performed in the presence of an infiltrat and intra-abdominal abscess in CD, the scope of surgery increases, which may subsequently lead to short bowel syndrome [162]. It is important to emphasize that, according to a systematic review by Clancy C. et al., abscess drainage combined with conservative therapy helped avoid surgical resection in more than 30% of patients [157].

• In patients of this group, when an ileal or ileocecal valve stricture develops, ileocecal resection with the formation of an ileoascending anastomosis or stoma is recommended as the operation of choice [163, 164].

Level of Evidence CGrade of Recommendation - C (Level of Evidence – 4)

Comment: approximately 1/3 of all CD patients have this localization, which is frequently complicated by stricture of the ileum or ileocecal valve. At the same time, the presence of intestinal obstruction is the decisive factor against performing a primary anastomosis.

• In patients of this group, if a stricture is identified after the first course of conservative treatment (i.e., corticosteroid therapy), resection of the affected bowel segment is recommended as the first stage of treatment rather than a repeated course of conservative (hormonal) therapy [165].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

• In patients with active CD and intra-abdominal abscess formation, the administration of antibiotics as well as abscess drainage or resection of the affected segment is recommended [157, 161].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: drainage can be performed surgically or, in specialized centers with sufficient expertise, via percutaneous drainage. The latter option can only be used if there is no stricture of the affected bowel segment, which necessitates the resection of the involved section.

• In patients with complicated CD with short strictures of the jejunum or ileum, including anastomotic strictures following previous resection, stricturoplasty (incision of scarring small bowel strictures) is recommended as an alternative to resection, allowing extensive small bowel resections to be avoided [166].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

Comment: this intervention is feasible when the stricture length does not exceed 10 cm. Contraindications to stricturoplasty include the presence of an infiltrate, abscess, malignant tumors in the bowel wall, or active bleeding and severe inflammation of the affected area.

• In the presence of a short stricture (less than 4 cm) of the jejunum or ileum, including anastomotic strictures after prior resection, without infiltrate, purulent cavities, or entero-enteric fistulas and without signs of acute intestinal obstruction, balloon dilation of the stricture zone located within endoscopic reach may be an alternative to resection and stricturoplasty [167].

Level of Evidence CGrade of Recommendation - C (Level of Evidence – 2)

Comment: endoscopic balloon dilation helps avoid surgical resection. Balloon dilation is more effective and safer when diagnosing no more than 4 strictures located in close proximity to each other compared to multiple strictures. Balloon dilation is not recommended in the presence of a long stricture (more than 4 cm), entero-enteric fistulas, purulent cavities, deep ulcers within the strictures, or prestenotic dilation.

• In patients of this group, in the absence of an infiltrate and abscess, laparoscopic small bowel and ileocecal surgery is recommended [168, 169, 170, 171].

Level of Evidence AGrade of Recommendation - A (Level of Evidence – 2)

Comment: simultaneous creation of more than one anastomosis does not increase the rate of postoperative complications or disease recurrence [172]. The preferred technique for small bowel anastomosis is a side-to-side stapled anastomosis, which reduces the likelihood of leakage [173] and subsequent stricture formation.

3.2.3 Surgical treatment of colonic CD

• In patients of this group with localized colonic involvement, resection of the affected segment with bowel anastomosis within healthy tissues is recommended [174, 175].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: patients with localized colonic involvement (less than one-third of the colon) who develop CD complications do not require colectomy. When the lesion is located in the ascending colon, right hemicolectomy (preserving the terminal ileum) is indicated due to anatomical features. When the splenic flexure and/or descending colon is affected, left hemicolectomy with transverse-sigmoid anastomosis or stoma formation is performed. When CD is localized in the sigmoid colon, resection of the affected segment is performed.

• In patients with extensive colonic CD with severe clinical manifestations, subtotal colectomy with end ileostomy is recommended as the operation of choice [74, 176].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: the distal colon may not be resected provided there is no severe inflammation in it, and it can be brought out onto the anterior abdominal wall as a single-barrel sigmoid stoma, or the rectal stump can be closed securely with a purse-string or continuous suture.

• In patients with involvement of the entire colon, as well as severe inflammation in the rectum and severe perianal disease, colectomy with proctectomy (abdomino-anal resection) and end ileostomy is recommended as an alternative procedure [74].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

Comment: this intervention is performed exclusively in patients with marked inflammatory activity in the rectum or severe perianal manifestations, as it makes future restoration of physiological bowel function impossible.

• In patients with severe perianal disease, abdominoperineal resection is not recommended [149].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

Comment: proctectomy is inappropriate due to extremely poor healing capacity and the risk of extensive perineal wounds that subsequently heal slowly by secondary intention, which disables patients and limits their social activity.

• For surgical treatment of colonic CD with a purulent-septic process in the perirectal region and perineum, rectal resection is recommended to be performed in the scope of total mesorectal excision [149, 177].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

Comment: recently, data have accumulated indicating that in CD, the bowel mesentery plays a key role in the pathogenesis of the inflammatory process in the intestinal wall. Thus, according to de Groof et al., mesorectal adipose tissue contains an increased number of activated CD14+ macrophages producing anti-TNF-α, as well as a reduced concentration of the wound healing marker CD206 compared to similar tissue in UC. These fundamental data also have practical significance, since performing a total mesorectal excision, compared to a wall-preserving rectal resection leaving adipose tissue in the pelvic cavity, is accompanied by a lower incidence of postoperative perineal complications, including CD recurrence: 17.6% and 59.5%, p = 0.007 [177]. It is important to note that this refers to CD with prominent perianal manifestations and a purulent-septic process in the perineal region. The decision on the necessity of performing mesorectal excision in other situations remains at the discretion of the operating surgeon.

• In patients with total colonic involvement, in the absence of severe clinical manifestations and minimal activity of inflammatory changes in the rectum, adequate bowel content continence function, and the absence of perianal lesions, colectomy with ileorectal anastomosis is recommended as the operation of choice [91].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

Comment: the feasibility of forming a small bowel reservoir (ileal pouch-anal anastomosis (IPAA)) in colonic CD is controversial due to the high rate of complications and frequent indications for reservoir excision. At the same time, the average life expectancy of patients after IPAA formation without a permanent ileostomy reaches 10 years, which is important for young, able-bodied patients [178]. The main problems threatening a patient with IPAA in the setting of CD are the development of perianal lesions and the development of CD in the ileal reservoir.

• In patients with colonic localization of CD, the formation of an ileostomy (diverting loop stoma) to stop the transit of bowel contents through the colon is recommended only in severely emaciated patients and pregnant women [168].

LoR CLevel of Recommendation - C (Level of Recommendation – 5)

Comment: this type of surgical treatment is temporary. Given that in CD, diverting the passage through the colon is not always effective, the scope of surgical intervention must be discussed again subsequently after performing an accurate differential diagnosis between colonic CD and UC.

All of the listed surgical interventions can be safely performed using laparoscopic technology [174, 180].

• In patients with colonic localization of CD and identification of a short stricture, endoscopic balloon dilation of colonic strictures is recommended [167, 181, 182, 183].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: this procedure is associated with a higher risk of disease recurrence compared to resection of the affected bowel segment.

• In patients with colonic localization of CD, division of fibrous strictures (strictureplasty) is not recommended [165, 184, 185].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 2)

3.2.4 Surgical treatment of CD with upper gastrointestinal tract involvement

• In patients of this group, in the presence of single or multiple short strictures, various options for small bowel strictureplasty are recommended as operations of choice [64, 149, 184, 185, 186].

GGR BGrading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of Evidence – 2)

Comment: involvement of the bowel segment proximal to the terminal ileum in the inflammatory process often leads to the formation of multiple strictures and inter-enteric fistulas, which determines an unfavorable prognosis for CD and requires surgical treatment. In patients of this group, resorting to bypass anastomosis is recommended only in exceptional cases, since there is a high risk of developing small intestinal bacterial overgrowth syndrome in the bypassed part of the small intestine, as well as the potential development of cancer. At the same time, extensive resections lead to the development of short bowel syndrome [149].

• In patients of this group, when a stricture of the gastroduodenal zone (typically the duodenum) is identified, endoscopic balloon dilation or strictureplasty is recommended [186].

GCR CGrade of Recommendation — C (Level of Evidence – 4)

3.2.5 Treatment of CD with perianal manifestations (perianal CD)

The approach to surgical intervention in the perianal region must be individualized for each patient [187, 188].

• In patients with perianal manifestations of CD, in the presence of simple external perianal fistulas, eradication of the fistula by excision (via fistulotomy) [189] or its adequate drainage in the presence of abscesses using seton placement combined with medical therapy is recommended [190, 191].

Level of Evidence CGrade of Recommendation - C (Level of Evidence – 4)

Comment: simple fistulas unaccompanied by any symptoms do not require surgical intervention. Dynamic observation against the background of the aforementioned conservative therapy is recommended. The indication for seton placement in most cases is trans- and extrasphincteric fistulas. In the absence of an inflammatory process in the rectal mucosa, advancement of the mucosal-muscular flap of the rectum with closure of the internal fistula opening can be performed [190].

• In patients with perianal manifestations of CD, in the treatment of complex fistulas, their drainage (placement of latex setons) combined with biological therapy is recommended [58, 191, 192].

Level of Evidence CGrade of Recommendation - C (Level of Evidence – 4)

Comment: drainage latex setons are used as an adjunct to medical therapy for CD to ensure adequate drainage of the fistula tract to prevent recurrent abscess formation and eliminate the local inflammatory response in the surrounding tissues. Often, the placement of a draining seton is a preparatory stage for radical surgery to eliminate the fistula. The advantages of this method are: low cost, the ability to prevent the formation of new fistula tracts and purulent cavities, a reduction in the need for a temporary or permanent intestinal stoma, and a low re-intervention rate (from 10% to 20%). Considering the high efficacy of biological therapy with proper drainage of complex rectal fistulas, its early administration is justified (infliximab**, adalimumab**, certolizumab pegol**, ustekinumab**, vedolizumab**, upadacitinib**). Nevertheless, complex fistulas with fluid collections and pronounced purulent inflammation are frequently an indication for diverting the passage by forming an intestinal stoma.

• In patients with perianal manifestations of CD and a rectovaginal fistula, its excision with closure of the vaginal defect and advancement of a full-thickness rectal flap is recommended [58].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

Comment: rectovaginal fistulas in most cases require surgical intervention. At the same time, surgical treatment is indicated under the cover of an ileostomy. Only in isolated situations, in the presence of a low fistula between the rectum and the vaginal vestibule, is conservative treatment alone recommended. In the presence of active rectal involvement, adequate anti-inflammatory therapy before surgery increases the effectiveness of the intervention [58].

• Patients with perianal manifestations of CD accompanied by evacuation disorders and anal incontinence leading to a significant decrease in quality of life are recommended to undergo abdominoperineal rectal resection [58, 149].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

Comment: the most unfavorable factor increasing the likelihood of a permanent ileostomy or colostomy is the presence of a stricture in the lower ampullary rectum or anal canal stenosis. In isolated situations, in the absence of active inflammation in the upper bowel segments, bougienage of the stricture is possible [58].

• Patients with complex fistulas are recommended staged surgical treatment. As a first stage, opening and drainage of abscesses and purulent cavities is recommended [251].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: adequate opening of the purulent cavity allows immunosuppressive therapy for CD to be administered without the risk of developing a perianal abscess or infection generalization. Drainage of fluid collections is also possible using a draining latex seton, provided there is precise localization of the internal fistula opening.

• In patients with complex fistulas, as the second stage of surgical treatment, excision of the fistula with closure of the internal fistula opening using a mucosomuscular flap from the rectal wall is recommended, provided that purulent collections and proctitis have resolved and there are no pronounced scarring changes in the walls of the anal canal and rectum [193].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: The mobilized flap can be either mucosal-submucosal or mucosomuscular. The advantages of the technique are the absence of impact on the structures of the anal sphincter apparatus and the minimization of the extent of wound defects. At the same time, the healing rate is about 60%, with an incontinence development rate of up to 10%. As a second stage of treatment, procedures such as video-assisted anal fistula treatment (VAAFT) and ligation of theintersphincteric fistula tract (LIFT) can also be performed in a strictly selected group of patients in the absence of fluid collections, signs of proctitis, and absence of signs of incontinence [194,195].

3.2.6 Maintenance therapy to prevent recurrence after surgical treatment of CD

Even with the complete removal of all macroscopically altered segments of the intestine, surgical intervention does not lead to complete recovery: within 5 years, a clinically significant recurrence is observed in 28-45% of patients, and within 10 years – in 36-61%, which dictates the need to prescribe or continue anti-relapse therapy after surgery for CD [196,197].

Factors that reliably increase the risk of postoperative recurrence include: smoking, a history of two or more bowel resections, a history of extensive small bowel resections (>50 cm), perianal lesions, and a penetrating phenotype [198].

Depending on the combination of risk factors, as well as the efficacy of previously administered anti-relapse therapy, patients after surgery should be stratified into groups with different risks of postoperative recurrence.

High risk of postoperative recurrence includes the presence of 2 or more risk factors:

- smoking;

- perianal lesions;

- penetrating CD;

- extensive intestinal resection (more than 50 cm);

- previous surgical intervention;

- early onset of the disease.

• For patients in the low-risk group, in order to prevent recurrence, it is recommended to administer therapy with thiopurines (AZA** 2.0-2.5 mg/kg/day or #MP** 1.5 mg/kg/day) [199,245,252].

GCR BLEL 1Grading of Recommendation - B (Level of Evidence – 1)

• For patients at high risk of CD exacerbation, even before control endoscopic examination, in order to prevent recurrence, it is recommended to prescribe bDMARDs (infliximab**, adalimumab**, certolizumab pegol**, ustekinumab**, vedolizumab**) or tsDMARDs (upadacitinib**) [61,85,200,201,202].

GCR CLOC 3Grade of Recommendation - C (Level of Evidence – 3)

Comment: there is currently still insufficient data on the use of ustekinumab**, vedolizumab**, and upadacitinib** to reliably judge their efficacy as postoperative anti-relapse therapy.

• For patients with CD, anti-relapse therapy is recommended to be initiated within 4 weeks after surgical intervention in the absence of postoperative complications [204].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• 6-12 months after surgery, patients with CD are recommended to undergo a control endoscopic examination, and if necessary, MRI and/or CT with contrast enhancement of the intestine [200,205,206,207].

GCR CLOC 3Grade of Recommendation - C (Level of Evidence – 3)

• For operated patients with CD in whom it is impossible to visualize the anastomosis zone, it is recommended to confirm the presence or absence of recurrence based on a combination of radiological examination data (CT and/or MRI with contrast enhancement of the intestine) and non-invasive inflammatory markers – CRP, FC, etc. [200,206,207,208].

GCR CLOC 3Grade of Recommendation - C (Level of Evidence – 3)

Comment: in case of resection of the terminal ileum or ileocecal resection, it is advisable to use the Rutgeerts endoscopic activity scale for postoperative CD recurrence (see section 2.4 "Instrumental Diagnostic Investigations", Table 7) [49,209].

• In patients with CD without signs of inflammation or with minimal inflammatory changes detected (i1 on the Rutgeerts scale), it is recommended to continue the ongoing therapy [209].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• In the presence of more pronounced inflammatory changes (i2-i4), it is recommended to intensify therapy: adding immunosuppressants in patients who have not previously received them, or administering bDMARDs or tsDMARDs in those receiving maintenance therapy with thiopurines (AZA**/#MP**) or if they cannot be prescribed [210, 211].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

Comment: the presence of more pronounced inflammatory changes (i2-i4) indicates the ineffectiveness of the ongoing therapy.

• Subsequently, in patients with CD, regardless of the disease course and clinical manifestation of CD, it is recommended to perform a control endoscopic examination at least once every 1-3 years [212].

GCR CLOC 4Grade of Recommendation - C (Level of Evidence - 4)

3.2.7 Ileostomy dysfunction after surgical treatment of CD

Ileostomy dysfunction is defined as an increase in the volume of intestinal output via the ileostomy of more than 1000 ml per day. The management of patients with this condition is described in the clinical guidelines "Ulcerative Colitis" [213].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation measures are aimed at preventing complications of conservative therapy and undesirable consequences of surgical treatment.

Mild to moderate degree of functional impairment requires treatment in an outpatient setting. A severe degree of functional impairment, or its absolute impossibility, requires hospitalization in a 24-hour inpatient facility.

Patients who required surgical treatment for CD complications may undergo rehabilitation in three stages.

Stage 1 – early rehabilitation, carried out immediately after surgical treatment from the 2nd to the 14th day. The main objective of stage 1 rehabilitation is to restore normal GI tract function after surgery. It is at this stage that urinary disorders are most often identified and must be corrected. An important role is also assigned to homeostasis control, measures aimed at healing postoperative wounds, relief of postoperative pain syndrome, and patient mobilization. During this period, a complete blood count, biochemical blood test, coagulogram, and urinalysis are monitored.

Stage 2 of rehabilitation begins after 15 days and continues as needed thereafter. It is aimed at the final healing of postoperative wounds with monitoring of the GI tract and other body systems. This stage can be carried out both on an outpatient basis and in a day or 24-hour inpatient setting.

Stage 3 of rehabilitation is carried out in the late rehabilitation period in patients both with a permanent ileostomy and prior to reconstructive surgery. The main objective at this stage is the compensation of GI tract function, and measures aimed at identifying and correcting disorders of the anal sphincter apparatus function.

Anal sphincter insufficiency (ASI) – rehabilitation is possible at stages 2 and 3. Patients after surgery for CD with stoma formation show a decrease in continence function.

• Patients with anal sphincter insufficiency prior to reconstructive treatment are recommended to undergo an examination of the function of the anal sphincter apparatus followed by a consultation with a physical therapist [214].

GRL CLEL 5Recommendation Grade C (Level of Evidence – 5)

• In patients with identified grade 2-3 anal sphincter insufficiency, it is recommended to carry out rehabilitation treatment including a 10-day cycle of biofeedback (BFB) therapy and tibial neuromodulation in a day or 24-hour inpatient setting [214].

GGR CLeE 5Grade of Recommendation C (Level of Evidence – 5)

Comment: According to the literature, biofeedback therapy (BFB therapy) is widely used in the rehabilitation of patients with anal sphincter insufficiency. It aims to improve the contractility of the external sphincter and pelvic floor muscles by increasing both the strength and duration of voluntary contraction [215, 216]. This non-invasive method engages the body's own resources in the rehabilitation process, developing proper skills through the creation of new conditioned reflex pathways. Tibial neuromodulation is also an effective method. Neuromodulation is a process in which an electrical current along certain nerve pathways modulates pre-existing activity in other nerve pathways or centers. Percutaneous electrical stimulation of the posterior tibial nerve (n. tibialis) is used for functional pelvic floor disorders because the posterior tibial nerve contains fibers from the II and III sacral segments of the spinal cord, which play a significant role in the innervation of the rectum, bladder, and their sphincters. It has been proven that the muscle structures of a compromised sphincter apparatus can respond to BFB therapy and tibial neuromodulation by increasing both tone and the strength of voluntary contractions [214, 216]. Tibial nerve stimulation is performed using a transcutaneous stimulation electrode, which allows the patient, after a preliminary training course, to continue treatment independently at home. In such cases, the treatment course with daily stimulation sessions can be extended up to 1-3 months. The effectiveness of BFB therapy is monitored before and after each course of procedures through a comprehensive physiological study of the rectal sphincter function. If there is an improvement in the tone and contractility of the anal sphincters, reconstructive surgery aimed at restoring natural gastrointestinal passage can be considered.

5. Prevention and Dispensary Observation

Crohn's disease (CD) is characterized by progressive bowel damage. At the time of diagnosis, complications (strictures, fistulas) are found in 10-20% of patients, while within 10 years such complications develop in more than 90% of cases. Within 10 years, surgical interventions due to complications and/or failure of conservative therapy are performed in half of the patients with CD, and 35-60% develop disease relapse within 10 years after surgery. Hormone dependency in CD is documented at least once within 10 years in 30% of cases [217].

Due to the progressive nature of the disease, patients suffering from CD must receive continuous (lifelong) therapy and undergo regular (lifelong) monitoring of disease activity. It is important to monitor disease activity not only using instrumental diagnostic methods, but also by studying inflammatory markers—primarily fecal calprotectin (FC) levels, the concentration of which in the stool correlates with the severity of ulcerative lesions in the gastrointestinal tract.

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

- On average, every 6 months — a consultation with a gastroenterologist; every 12 months — a colorectal surgeon examination with mandatory digital transrectal examination to rule out perianal manifestations of CD, external intestinal fistulas, fistulas with hollow organs, inter-intestinal fistulas, and intestinal strictures. Every 6 months — a complete blood count (CBC), C-reactive protein (CRP) level testing, and fecal calprotectin (FC) level determination.

- Routine (annual) endoscopic examination in the absence of clinical indications (doubtful diagnosis, need to exclude comorbid conditions, worsening of clinical manifestations, suspected complications, need for follow-up after surgical treatment) is not performed in most cases

- In case of clinical deterioration and an increase in inflammatory marker levels (C-reactive protein, fecal calprotectin), a colonoscopy should be performed to assess disease activity, followed by an examination by a gastroenterologist and/or colorectal surgeon with a full physical examination.

If it is necessary to determine the localization, extent, and degree of activity of the inflammatory process, and to rule out complications of the underlying disease such as abdominal infiltrates, inter-intestinal or inter-organ fistulas, perforations, and strictures (in the absence of medical contraindications to contrast agents), magnetic resonance imaging (MRI) and/or computed tomography (CT) of the abdominal cavity and pelvic organs with intravenous contrast enhancement should be performed.

• The frequency and scope of follow-up care are determined individually, but for most patients, it is recommended to perform serum C-reactive protein testing and stool calprotectin testing every 3 months [74].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

• In patients receiving immunosuppressants, it is recommended to perform monthly blood tests for red blood cells, white blood cells, platelets, free and conjugated bilirubin, creatinine, urea, and to determine the activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and blood amylase to assess liver function [74].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

• Patients are recommended to undergo annual radiological or MRI examination of the intestine to rule out stricture formation and the development of other complications [74].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

• Patients are recommended to undergo an annual local examination of the perianal region and a digital rectal examination to rule out perianal complications, as well as endoanal ultrasound (EAUS) if necessary [29, 59].

LoR CLevel of Recommendation - C (Level of Evidence – 5)

• In patients with dynamically increasing levels of inflammatory markers (CRP, FC), it is recommended to perform an (ileo)colonoscopy to assess disease activity [208].

Level of Evidence BGrade of Recommendation - B (Level of Evidence – 3)

Comment: Routine (annual) endoscopic examination in the absence of clinical indications (doubtful diagnosis, need to exclude comorbid conditions, worsening of clinical manifestations, suspected complications) is generally not required. In the absence of CD-related indications, the frequency of ileocolonoscopy is determined by clinical guidelines for the early detection of colorectal malignancies.

5.1 Prevention of venous thrombosis

• In patients with CD during hospitalization, as well as in the outpatient setting during an exacerbation, in the presence of other known risk factors for venous thrombosis, it is recommended to carry out prophylaxis of venous thromboembolic events (VTE) [218].

Level of Evidence CGrade of Recommendation C (Level of Evidence – 5)

Comment. Patients with CD have a two-fold or higher increased risk of developing venous thrombosis [219]. The risk of venous thrombosis increases during periods of active disease and during hospitalization for any reason. Post-discharge thromboprophylaxis should be considered only in patients with major risk factors for VTE [218]. To assess the likelihood of their development in hospitalized non-surgical patients, the Padua [220] and IMPROVE VTE scales are recommended; in surgical patients, the Caprini scale [221] is recommended. For thromboprophylaxis in patients with CD, unfractionated heparin (UFH) or low molecular weight heparin (LMWH) (ATCC code B01AB) in prophylactic doses are recommended. In the presence of contraindications to UFH or LMWH and a high risk of hemorrhagic complications according to the HAS-BLED or RIETE scales, mechanical methods of prophylaxis are recommended.

5.2 Vaccination

Strategies for mitigating the risks of acquiring and/mina reactivating various infections in a CD patient include timely diagnosis of infections and their specific prophylaxis, primarily in the form of vaccination [222, 223, 224].

All patients with CD are recommended to undergo vaccination status assessment at the time of diagnosis, followed by regular monitoring during subsequent follow-up consultations. Documented vaccination replaces serological screening for immune response titer, which is performed if there are no documents confirming immunization [223].

(Inactivated) vaccines are used in patients with CD regardless of the ongoing treatment [224]. Immunization with live vaccines should be planned before prescribing immunosuppressive therapy if treatment initiation can be safely delayed, or administered during the period when the dose of the immunosuppressive drug is minimal [223]. If there is a high risk of contracting a vaccine-preventable infection and developing a severe course, both potential threats to the patient's life and health should be weighed, and the possibility of vaccination (including with live vaccines) during ongoing CD therapy should be considered [225].

In addition, family members and close contacts of patients with CD should be vaccinated, which is an important strategy to protect IBD patients from severe vaccine-preventable infections. This approach is known as "cocooning vaccination" [223].

Patients with CD are at the highest risk for severe infections caused by Streptococcus pneumoniae, influenza viruses, hepatitis B virus, measles, rubella, mumps, and varicella-zoster virus, which necessitates prioritized vaccination against these pathogens.

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

Comment: patients not receiving immunosuppressive therapy may receive any vaccines in accordance with the instructions (inactivated and live). For patients receiving immunosuppressive therapy, inactivated vaccines are administered without restrictions, while live vaccines are given with restrictions.

Currently, there is no consensus regarding the optimal interval between the potential administration of live vaccines after the completion of immunosuppressive therapy.

The dose of systemic corticosteroids that induces immunosuppression is defined as prednisolone** 2 mg/kg/day administered for 14 days or more; the administration of live vaccines to such patients is permitted 1 month or more after the end of therapy [Methodological Guidelines MU 3.3.1.1095-02. "Medical Contraindications to Preventive Vaccinations with National Immunization Schedule Preparations"]. The use of such a dose for less than 2 weeks or lower doses for a longer period does not lead to pronounced immunosuppression.

At the same time, other guidelines recommend longer intervals between the administration of live vaccines following the completion of immunosuppressive therapy—no earlier than 1–3 months, and in cases of high-dose glucocorticoid therapy, the interval after treatment completion may be up to 6 months depending on the product labeling [222, 223].

Necessary immunization using vaccines (including live ones) should, if possible, be performed before the initiation of immunosuppressive therapy. Otherwise, immunization may be continued once disease control is established, and if maintenance therapy is required, it can be done concurrently with baseline therapy, provided there is strict adherence to the gastroenterologist's dietary and other recommendations. In this case, immunosuppressive treatment may be initiated no earlier than 3–4 weeks after the administration of live vaccines, and without any interval after non-live vaccines [222, 223].

A number of patients with CD retain a risk of an inadequate immune response following standard vaccination regimens; therefore, it is advisable to consider selective testing for antibody titers no earlier than 1 month after the completion of vaccination (e.g., after vaccination for the prevention of viral hepatitis B** — quantitative determination of antibodies to hepatitis B surface antigen (anti-HBs) in the blood), followed by the administration of a booster dose of the vaccine if protective antibody titers are absent [222, 227].

5.2.1 Vaccination against priority infections

• Vaccination against pneumococcal infection in patients with CD for prophylactic purposes is recommended to be performed sequentially, starting with a single dose of pneumococcal conjugate vaccine** (PCV13 or another vaccine with the broadest valence) followed by the administration of a pneumococcal polysaccharide vaccine** (e.g., PPSV23) with a minimum interval of 8 weeks. Revaccination with pneumococcal polysaccharide vaccine (PPSV23) is also indicated after 5 years [223].

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

Comments: vaccination is carried out in accordance with the manufacturer's instructions.

For patients with IBD, vaccination against the novel coronavirus infection COVID-19 using a combined vector vaccine** is recommended with caution to prevent or reduce the likelihood of a severe (complicated) course of infection, taking into account the activity and type of therapy for the underlying disease [229].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

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

There are no data indicating worsening of the underlying disease course due to vaccination [230, 231, 232].

It should be noted that decisions regarding SARS-CoV-2 vaccination currently need to be made individually and with caution, considering the benefit-risk ratio. This is due to the changing nature of the infection, rapid viral mutation, and the lack of updated vaccines, as the vaccines currently available in the Russian Federation were developed against the initial viral strains.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical approbation, is organized and provided in accordance with:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized federal executive body;

2) in accordance with the regulations for the provision of care in the profiles "gastroenterology" and "coloproctology", which are mandatory for implementation across the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a gastroenterologist, coloproctologist, and other medical specialists in medical organizations licensed to perform the corresponding types of medical activities.

When CD is suspected or diagnosed, general practitioners, district general practitioners, family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to a medical organization that includes a gastroenterologist's office, coloproctologist's office, outpatient gastroenterology center (department), outpatient coloproctology center (department), or inflammatory bowel disease diagnosis and treatment center (if functionally organized within the region) for primary specialized health care. The consultation in these structural units of the medical organization must be conducted no later than 14 working days from the date of the referral issuance, and in cases of severe forms of CD, no later than 3 working days from the date of referral issuance.

The gastroenterologist or coloproctologist of a medical organization that includes a gastroenterologist's office, coloproctologist's office, outpatient gastroenterology center (department), outpatient coloproctology center (department), or inflammatory bowel disease diagnosis and treatment center shall organize diagnostic tests necessary to establish the diagnosis, including determining the severity of the inflammatory process, extent of the lesion, presence of intestinal and extraintestinal manifestations, including obtaining biopsy material.

If it is impossible to perform diagnostic tests necessary to establish the diagnosis, including determining the severity of the inflammatory process, the extent of the lesion, the presence of intestinal and extraintestinal manifestations, including the collection of biopsy material, as well as in the presence of indications for inpatient medical care, the attending physician shall refer the patient to a gastroenterology department, coloproctology department, inflammatory bowel disease diagnosis and treatment center, or another medical organization providing inpatient medical care in the fields of "gastroenterology" and "coloproctology".

When CD is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care in the specialties of "gastroenterology" or "coloproctology" to determine management tactics and the need for additional specialized treatment methods, including targeted biologic therapy.

A gastroenterologist or coloproctologist of a medical organization that includes an outpatient gastroenterology or coloproctology office, outpatient gastroenterology or coloproctology center (department), or an inflammatory bowel disease diagnostic and treatment center, refers the patient to medical organizations that provide inpatient medical care including a gastroenterology department and/or coloproctology department, and/or an inflammatory bowel disease diagnostic and treatment center to clarify the diagnosis (if the diagnosis cannot be established during the provision of primary specialized health care) and to provide specialized, including high-tech, medical care. The timeframe for initiating specialized, excluding high-tech, medical care is determined by the decision of the patient selection committee for hospitalization, depending on the severity of CD, the nature of the course, and the extent of the inflammatory process. The timeframe must not exceed 30 calendar days from the date of issuance of the referral for hospitalization.

Specialized, including high-tech, medical care for CD is provided by gastroenterologists and coloproctologists in medical organizations that include a gastroenterology department and/or coloproctology department, and/or an inflammatory bowel disease diagnostic and treatment center, possessing a license, the necessary material and technical base, and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of CD requiring special methods and complex unique medical technologies, as well as medical rehabilitation.

If there is a need for treatment methods not performed in medical organizations operating in the compulsory medical insurance sector within the territorial compulsory medical insurance program, a need for additional examination in diagnostically complex cases and/or cases of complex preoperative preparation in patients with complicated forms of the disease and/or comorbid conditions for subsequent treatment, as well as a need for re-hospitalization upon the recommendation of a federal medical organization, the patient is referred to a federal medical organization providing inpatient medical care to patients in the specialties of "gastroenterology" and "coloproctology" for the provision of high-tech medical care in accordance with the procedure for organizing high-tech medical care using the Unified State Health Information System.

Indications for hospitalization in an inpatient or day-hospital unit of a medical organization providing specialized, including high-tech, medical care for CD are determined by a concilium of gastroenterologists and coloproctologists, involving other medical specialists if necessary.

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

1) presence of CD complications requiring the provision of emergency and urgent specialized medical care;

2) presence of complications from CD treatment (surgical intervention, biologic therapy, hormonal and cytostatic therapy, etc.).

Indications for elective hospitalization in a medical organization are:

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

2) presence of indications for specialized CD treatment (surgical intervention, hormonal and cytostatic therapy, biologic and targeted therapy) requiring monitoring in an inpatient or day-hospital setting.

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-hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2) refusal of the patient or their legal representative to receive specialized, including high-tech, medical care in an inpatient or day-hospital setting determined by the concilium of the medical organization providing CD treatment, provided there are no complications of the underlying disease and/or treatment complications requiring drug correction and/or inpatient medical interventions;

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

7. Additional Information

Prognostically unfavorable factors in CD include smoking, disease onset in childhood, perianal lesions, a penetrating disease phenotype, and extensive small bowel involvement. A patient who smokes must be counseled on the necessity of quitting smoking.

Pregnancy planning should be carried out during a period of IBD remission, which improves pregnancy outcomes. The use of most IBD medications by pregnant women is associated with a low risk of adverse effects on the fetus, with the exception of #MT**. Discontinuation of anti-TNF agents is possible only in a limited number of patients with a low risk of CD reactivation. Treatment with targeted biologic therapies that are not contraindicated during pregnancy (see instructions for use) may be continued if the benefit to the mother outweighs the potential risks to the fetus.

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care in adults with Crohn's disease

Quality assessment criteria for specialized medical care in adults with Crohn's disease

Clinical guidelines for the diagnosis and treatment of Crohn's disease (K50, adults) were discussed on March 31, 2023, at a joint meeting of the Commissions on Surgical and Therapeutic Sciences of the Scientific Council of the Department of Medical Sciences of the Russian Academy of Sciences (RAS), as well as at open meetings of the Board of the All-Russian Public Organization "Association of Coloproctologists of Russia" and a meeting of the specialized commission in the specialty "Coloproctology"

References

Appendix A1. Working Group Composition

All listed authors declare no conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Gastroenterologists

2. Coloproctologists

3. Surgeons

4. General practitioners

5. General practitioners / Family physicians

6. Endoscopists

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table P1. Levels of Evidence (LE) Rating Scale for Diagnostic Methods (Diagnostic Interventions)

Table P2. Levels of Evidence (LE) Rating Scale for Prevention, Treatment, and Rehabilitation Methods (Preventive, Therapeutic, and Rehabilitative Interventions)

Table P3. Grades of Recommendation (GR) Rating Scale for Prevention, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, and Rehabilitative Interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

Medical care, with the exception of medical care within the framework of clinical approbation, is organized and provided in accordance with:

Federal Law No. 323-FZ of November 21, 2011 (as amended on June 13, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"

Decree of the Government of the Russian Federation No. 1968 of November 17, 2021, "On Approval of the Rules for the Phased Transition of Medical Organizations to the Provision of Medical Care Based on Clinical Guidelines Developed and Approved in Accordance with Parts 3, 4, 6–9, and 11 of Article 37 of the Federal Law 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation'"

Order of the Ministry of Health of the Russian Federation No. 206n of April 2, 2010 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to the Population with Colorectal, Anal Canal, and Perineal Diseases in Coloproctology"

Order of the Ministry of Health of the Russian Federation No. 906n of November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Gastroenterology'"

Order of the Ministry of Health of the Russian Federation No. 76n of February 14, 2022, "On Approval of the Standard of Medical Care for Adults with Crohn's Disease (Diagnosis and Treatment)"

Order of the Ministry of Health of the Russian Federation No. 168n of March 15, 2022, "On Approval of the Procedure for Dispensary Observation of Adults"

Order of the Ministry of Health of the Russian Federation No. 1363n of December 23, 2020, "On Approval of the Procedure for Referring Insured Persons to Medical Organizations, the Functions and Powers of Founders in Respect of Which Are Exercised by the Government of the Russian Federation or Federal Executive Bodies, to Provide Medical Care in Accordance with the Unified Requirements of the Basic Compulsory Medical Insurance Program"

Order of the Ministry of Health of the Russian Federation No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care"

These clinical guidelines were developed taking into account the following regulatory legal documents:

• Article 76 of Federal Law of the Russian Federation No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation," regarding the development and approval of clinical guidelines (treatment protocols) on the provision of medical care by medical professional non-profit organizations

• Decree of the Government of the Russian Federation No. 2497 of December 29, 2022, "On the Program of State Guarantees of Free Medical Care to Citizens for 2023 and for the Planning Period of 2024 and 2025"

• Order of the Ministry of Health of the Russian Federation No. 206n of April 2, 2010 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to the Population with Colorectal, Anal Canal, and Perineal Diseases in Coloproctology"

• Order of the Ministry of Health of the Russian Federation No. 906n of November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Gastroenterology'"

• Order of the Ministry of Health of the Russian Federation No. 168n of March 15, 2022, "On Approval of the Procedure for Dispensary Observation of Adults"

• Order of the Ministry of Health of the Russian Federation No. 76n of February 14, 2022, "On Approval of the Standard of Medical Care for Adults with Crohn's Disease (Diagnosis and Treatment)"

• Order of the Ministry of Health of the Russian Federation No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care"

• Order of the Ministry of Health of the Russian Federation No. 1363n of December 23, 2020, "On Approval of the Procedure for Referring Insured Persons to Medical Organizations, the Functions and Powers of Founders in Respect of Which Are Exercised by the Government of the Russian Federation or Federal Executive Bodies, to Provide Medical Care in Accordance with the Unified Requirements of the Basic Compulsory Medical Insurance Program".

Appendix B. Physician Action Algorithms

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 mouth to the anus. Currently, there is no cure for this disease, so CD management mostly involves continuous therapy with various medications to suppress and limit the spread of inflammation, as well as to prevent complications. CD is characterized by alternating periods of disease exacerbation (relapses) and periods of improved well-being (remission). In a very small percentage of patients, remission can persist without treatment; however, in the vast majority of cases, failure to receive continuous therapy leads to frequent flare-ups and, crucially, progressive irreversible damage to the intestinal wall. Over time, this leads to complications that include bowel narrowing (stricture), fistulas (purulent tracts from the intestine to the skin, vagina, bladder, or another intestinal loop), anal lesions, general bodily wasting (cachexia), and even cancer. These complications can be life-threatening and often require surgery involving resection of part of the intestine, frequently with the formation of an intestinal stoma.

Since CD is a relatively rare disease, individuals with this condition should, whenever possible, be followed by a physician specializing in the treatment of this specific pathology and strictly adhere to their recommendations regarding long-term, often lifelong, drug therapy. You can also alleviate the course of the disease by quitting smoking if you smoke. Neither the level of physical activity nor the intake of specific foods affects the risk of CD flares to the extent that irregular medication use and delayed consultation with a specialist do.

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

No