Ulcerative Colitis: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

5-ASA – 5-aminosalicylic acid

AZA – azathioprine

Anti-TNF – anti-tumor necrosis factor alpha antibodies

CD – Crohn's disease

BF – biofeedback

IBD – inflammatory bowel disease

GGT – gamma-glutamyl transpeptidase

bDMARD – biologic disease-modifying antirheumatic drug

GCs – glucocorticoids

CI – confidence interval

GI tract – gastrointestinal tract

IPAA – ileal pouch-anal anastomosis

BMI – body mass index

CT – computed tomography

LDH – lactate dehydrogenase

MMX – multimatrix system

MP – mercaptopurine

MRI – magnetic resonance imaging

NSAIDs – nonsteroidal anti-inflammatory and antirheumatic drugs

RCT – randomized controlled trial

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

tsDMARD – targeted synthetic disease-modifying antirheumatic drug

TNF-alpha – tumor necrosis factor-alpha

UC – ulcerative colitis

Terms and Definitions

Ulcerative colitis (UC) – a chronic disease of the colon characterized by immune-mediated inflammation of its mucosa.

UC exacerbation (relapse, flare) – the appearance of typical symptoms of the disease in UC patients in clinical remission, whether spontaneous or medically maintained. In practice, signs of a clinical exacerbation include an increased stool frequency with blood loss and/or characteristic changes detected during endoscopic examination of the colon.

UC remission – disappearance of the main clinical symptoms of the disease [1] and healing of the colonic mucosa ("deep remission") [2].

UC remission, clinical – absence of blood in the stool, absence of tenesmus/false urges with a stool frequency of no more than 3 times per day.

UC remission, endoscopic – absence of visible macroscopic signs of inflammation upon endoscopic examination of the colon.

UC remission, histological – absence of microscopic signs of inflammation.

Steroid resistance – in cases of a severe flare: absence 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 cases of a moderate flare: persistence of disease activity with oral GC intake at a dose equivalent to 1 mg/kg of body weight of prednisolone** for 2 weeks [3,4].

Steroid dependence – an increase in disease activity occurring upon reduction of the GC dose after achieving initial improvement within 3 months from the start of treatment;

Recurrence of the disease within 3 months after completion of GC treatment.

Biologic-naive patient – a patient who has not previously received biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic immunosuppressants (tsDMARDs).

Colectomy – a surgical procedure to remove the cecum and the entire colon from the ileocecal valve to the rectosigmoid junction.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Ulcerative colitis (UC) – a chronic disease of the colon characterized by immune-mediated inflammation of its mucosa.

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

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

The etiology of inflammatory bowel disease (IBD), including UC, is not established. The disease develops as a result of a combination of multiple factors, including genetic predisposition, defects in innate and acquired immunity, alterations in the gut microbiota, and environmental influences. Approximately 100 genetic polymorphisms associated with UC have been described. Genetic determination leads to alterations in the innate immune response, autophagy, impaired microorganism recognition mechanisms, epithelial barrier dysfunction, and, consequently, aberrant adaptive immunity. A key defect predisposing to the development of IBD is impaired recognition of bacterial molecular markers (patterns) by dendritic cells, leading to hyperactivation of pro-inflammatory signaling pathways. Additionally, IBD is characterized by reduced diversity of the intestinal microbiota due to a decrease in the proportion of anaerobic bacteria, predominantly Bacteroidetes and Firmicutes. Against this background, the development of IBD occurs 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 mutual influence of 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, and cell adhesion molecules. As a result of these disorders, inflammatory lymphoplasmacytic infiltration and destruction of the colonic mucosa are formed, with macroscopic changes characteristic of UC.

1.3 Epidemiology of the Disease or Condition

The maximum prevalence of UC in the world currently reaches 505 per 100,000 population (in Europe), and the incidence in different regions ranges from 0.6 to 24.3 per 100,000 population. The highest UC incidence of 24.3 per 100,000 was observed in Europe, and 19.2 per 100,000 in North America [4,5,6,7,8].

Data on the prevalence of UC in the Russian Federation are limited [9,10]. The prevalence of UC is higher in northern latitudes and western regions. The incidence and prevalence of UC in Asia are lower, but are currently increasing. Caucasians suffer from the disease more often than representatives of Negroid and Mongoloid races. The peak incidence falls within the age range of 20–30 years, and a second peak in incidence at 60–70 years has been noted in some countries. The incidence among men and women is approximately equal.

1.4 Features of Coding the Disease or Condition

K51.0 – Ulcerative (chronic) enterocolitis

K51.1 – Ulcerative (chronic) ileocolitis

K51.2 – Ulcerative (chronic) proctitis

K51.3 – Ulcerative (chronic) rectosigmoiditis

K51.4 – Inflammatory polyposis of colon

K51.5 – Mucosal proctocolitis

K51.8 – Other ulcerative colitis

K51.9 – Ulcerative colitis, unspecified

1.5 Classification of the disease or condition

The current classification of UC by extent of involvement, disease course, attack severity, and presence of complications determines the choice of medical therapy, indications and selection of surgical intervention, as well as the frequency of screening for colorectal cancer [11].

To describe the extent of involvement, the Montreal classification is used (Table 1), which evaluates the extent of macroscopic changes during endoscopic examination of the colon.

Table 1. Montreal classification of UC by extent of involvement [12].

It should be specifically noted that proctosigmoiditis is included in the concept of left-sided UC, and extensive colitis also includes subtotal involvement of the colon proximal to the splenic flexure.

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

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

2. Chronic continuous course (duration of remission less than 6 months on adequate therapy);

3. Chronic relapsing course (duration of remission more than 6 months).

To correctly formulate the diagnosis and determine treatment tactics, the severity of the current exacerbation (attack) should be assessed using simple Truelove-Witts criteria, typically used in everyday clinical practice, and the UC activity index (Mayo score; DAI), typically used in clinical trials. However, to assess the prognosis of the disease and determine the patient's social status, including obtaining disability status, preferential drug provision, free sanatorium-resort treatment, and other social benefits, it is necessary to consider the overall severity of the disease, which is determined by the severity of the current attack, the presence of extraintestinal manifestations and complications, refractoriness to treatment, and in particular, the development of steroid dependence and resistance. Mild, moderate, and severe UC attacks are distinguished (Tables 2 and 3).

Table 2. Severity of UC attack according to Truelove-Witts criteria [3,4].

In clinical practice, the so-called "super-severe or fulminant attack" of UC is frequently encountered, characterized by diarrhea more than 10–15 times a day, progressive hemoglobin drop, fever above 38°C, severe hypoproteinemia and electrolyte shifts, and a high level of C-reactive protein (CRP) [13,14,15]. Treatment approaches for such colitis differ from standard ones. In English-language literature, this condition is referred to as "acute severe UC" [16].

Table 3. Attack severity according to the UC activity index (Mayo score).

The Schroeder scale for assessing mucosal appearance used in the Mayo score is presented in Table 4 and is used to evaluate endoscopic UC activity.

Table 4. Classification of UC according to endoscopic activity (by Schroeder) [17].

The classification of UC based on the response to glucocorticosteroids (GCS) facilitates the selection of rational management tactics, since the goal of conservative treatment is to achieve sustained remission with the cessation of GCS therapy. For this purpose, the following are distinguished [3,4]:

1. Steroid resistance:

a. in the case of a severe flare – lack of positive dynamics in clinical and laboratory parameters despite the use of systemic corticosteroids (ATC code H02A) or glucocorticoids (ATC code H02AB) at a dose equivalent to 2 mg/kg of body weight of prednisolone** per day for more than 7 days;

b. in the case of a moderate flare – persistence of disease activity despite oral GCS intake at a dose equivalent to 1 mg/kg of body weight of prednisolone for 2 weeks.

2. Steroid dependence:

a. an increase in disease activity occurring when the GCS dose is tapered after achieving initial improvement within 3 months from the start of treatment;

b. recurrence of the disease within 3 months after completion of GCS treatment.

When formulating the diagnosis, it is necessary to reflect the nature of the disease course, the extent of involvement, the severity of the current flare or presence of remission, the presence of steroid dependence or resistance, as well as the presence of extraintestinal manifestations or intestinal complications of UC. Examples of diagnostic formulations are given below:

1. "Ulcerative colitis, chronic relapsing course, proctitis, moderate flare."

2. "Ulcerative colitis, chronic continuous course, left-sided involvement, moderate flare. Steroid dependence. Extraintestinal manifestations (peripheral arthropathy)."

3. "Ulcerative colitis, chronic relapsing course, extensive involvement, severe flare. Steroid resistance. Toxic megacolon."

1.6 Clinical presentation of the disease or condition

The clinical picture of UC includes four clinical syndromes:

Intestinal syndrome. Typical intestinal symptoms include diarrhea, predominantly at night (65% of cases), blood in the stool (95–100% of cases), tenesmus (more common in proctitis and proctosigmoiditis), sometimes tenesmus combined with constipation in distal limited involvement. In proctitis and proctosigmoiditis, diarrhea may be absent, and tenesmus predominates in the clinical picture. Unlike CD, abdominal pain is not typical for UC. Spasmodic abdominal pain of mild to moderate intensity may occur, usually before defecation.

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

Metabolic disorders are a consequence of diarrhea, 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), dehydration, hypoproteinemia, hypoalbuminemia with the development of edema syndrome, hypokalemia and other electrolyte disturbances, hypovitaminosis.

Extraintestinal systemic manifestations (EIMs) occur in 20–25% of UC cases and usually accompany severe forms of the disease [18] (Table 5).

Table 5. Main extraintestinal (systemic) manifestations of ulcerative colitis.

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.

Intestinal complications of UC include gastrointestinal bleeding, toxic dilatation and perforation of the colon, as well as colorectal cancer. Since these complications largely require surgical treatment, they are discussed in detail in Section 3.2 "Surgical Treatment".

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition based on pathognomonic data:

1) anamestic data;

2) physical examination;

3) laboratory tests;

4) instrumental examinations.

There are no unambiguous diagnostic criteria for UC. The diagnosis is established based on a combination of medical history, clinical presentation, and typical endoscopic and histological changes.

2.1 Complaints and Anamnesis

• In all patients with suspected UC, taking a medical history and assessing complaints is recommended to verify the diagnosis [19–22].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• In particular, when taking the medical history, it is recommended to clarify the smoking status to narrow down the diagnostic search and verify the diagnosis [23].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

Comment: attention should be paid to the frequency and consistency of stool (frequent loose stools, tenesmus), the daily stool volume, the duration of these symptoms, the presence of blood in the stool, the nature of abdominal pain, travel to southern countries, medications taken (particularly antibiotics and nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs)), smoking, and a family history of inflammatory bowel disease or colorectal cancer [24,25].

2.2 Physical Examination

• In all patients with suspected UC, a physical examination is strictly recommended to narrow down the diagnostic search and verify the diagnosis:

- inspection of the perianal area;

- digital rectal examination [26].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: physical examination may reveal various manifestations of UC, including fever, peripheral edema, malnutrition, signs of colonic perforation or toxic dilatation, as well as extraintestinal manifestations.

2.3 Laboratory Diagnostics

Comment: the complete blood count may reveal anemia (iron deficiency anemia, anemia of chronic disease, vitamin B₁₂ or folate deficiency anemia), leukocytosis (associated with chronic inflammation or steroid therapy), thrombocytosis, and elevated ESR [27–32].

Comment: biochemical testing can detect electrolyte disturbances, hypoproteinemia (in particular, hypoalbuminemia), and elevated alkaline phosphatase, which is a potential manifestation of UC-associated primary sclerosing cholangitis.

• In all patients with suspected UC, moderate and severe UC flares, steroid resistance, or resistance to biological therapy, it is recommended to perform a pathomorphological examination of biopsy (surgical) material and/or PCR testing of colonic mucosal biopsy specimens (from lesion sites) for cytomegalovirus (CMV) [42,43].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

2.4 Instrumental Diagnostics

Comment: colonoscopy is mandatory to establish the diagnosis of UC, to assess UC activity, and to address the issue of colectomy. Endoscopic examination of the colon is the primary diagnostic method for UC, although specific endoscopic features are absent. The most characteristic findings are diffuse inflammation limited to the mucosa, starting in the rectum and extending proximally with a clear margin of inflammation. Endoscopic activity of UC is best reflected by contact friability (bleeding upon contact with the endoscope), loss of vascular pattern, and the presence of erosions and ulcerations. The detection of a persistent stricture in a patient with UC requires the mandatory exclusion of colorectal cancer.

• All patients with suspected UC at initial diagnosis, or when the diagnosis is uncertain, are recommended to undergo colonic mucosal biopsy to verify the diagnosis [46,47].

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

Comment: in patients with a long-standing history of UC (> 7–10 years), chromoendoscopy with targeted biopsy or step-by-step biopsies (from each colonic segment) is advisable to rule out epithelial dysplasia. The recommended biopsy standard at diagnosis is taking mucosal biopsies from the rectum and at least 4 other sites of the colon, as well as the terminal ileum.

Microscopic features of UC include crypt distortion (branching, multidirectional crypts, variation in crypt diameter, decreased crypt density, shortened crypts that fail to reach the underlying muscularis mucosae layer), "uneven" mucosal surface in the mucosal biopsy specimen, depletion of goblet cells, basal plasmacytosis, lamina propria infiltration by mononuclear cells mixed with segmented leukocytes and eosinophils, crypt abscesses, and basal lymphoid aggregates. The degree of inflammatory infiltration typically decreases with distance from the rectum.

- contrast-enhanced magnetic resonance imaging (MRI) of the colon [51];

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

- contrast-enhanced computed tomography (CT) of the intestine (computed tomography of the colon with retrograde contrast enhancement, computed tomography of the colon with double contrast, computed tomography of the small intestine with contrast enhancement, computed tomography of the small intestine with double contrast) (if expert evaluation is unavailable or MRI cannot be performed) [52,53].

Level of Evidence BGrade of Recommendation 3Level of Clinical Recommendations – B (Level of Evidence – 3)

Comment: patients with suspected UC may also undergo additional examinations depending on the clinical situation.

2.5 Other Procedures

Additional instrumental and laboratory examinations are performed primarily to conduct differential diagnosis with a number of conditions. These include infectious, vascular, drug-induced, toxic, and radiation-induced lesions, as well as diverticulitis, etc. The next stage of differential diagnosis involves verifying the clinical diagnoses of UC and CD, which belong to the IBD group. Thus, the differential diagnosis of UC includes colonic CD, acute intestinal infections (dysentery, salmonellosis, campylobacteriosis, yersiniosis, amebiasis), parasitoses, Cl. difficile-associated intestinal lesions, including antibiotic-induced ones [56], intestinal tuberculosis, systemic vasculitis, colon cancer, diverticulitis, microscopic colitis (collagenous and lymphocytic) [56], and radiation proctitis.

For the purpose of differential diagnosis and therapy selection in extraintestinal manifestations of UC and comorbid conditions, consultation may be required from:

- a psychotherapist or medical psychologist (neurosis, planned surgery involving a stoma, etc.);

- an endocrinologist (steroid-induced diabetes mellitus, adrenal insufficiency in patients on long-term GCS therapy);

- dermatovenerologist (differential diagnosis of erythema nodosum, pyoderma, etc.);

- rheumatologist (arthropathies, sacroiliitis, etc.);

- obstetrician-gynecologist (pregnancy).

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

3.1 Conservative Treatment

3.1.1 Goals and principles of therapy

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

Globally, the treatment goals for UC are currently defined by the "Treat-to-target (T2T)" strategy, which means "Treating to achieve the target." This concept aims to achieve long-term treatment efficacy, prevent complications, reduce hospitalization rates, lower the risk of surgery and colorectal cancer, improve quality of life, and decrease disability rates in patients with chronic diseases [57,58]. From the perspective of daily clinical practice, the goals of UC therapy are to achieve and maintain long-term steroid-free clinical and endoscopic remission (cessation of GCS intake within 12 weeks of therapy initiation) [59].

In accordance with the "T2T" strategy for UC, the primary goal of therapy should be the complete relief of clinical symptoms (absence of blood in the stool and normalization of bowel movements) reported by the patient themselves. Achieving endoscopic remission is mandatory.

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, FC) and endoscopic examination [58].

The choice of conservative or surgical treatment type is determined by the severity of the attack, the extent of colonic involvement, the presence of EIMs, the duration of medical history, the efficacy and safety of previously administered therapy, as well as the risk of UC complications [59,60] and the presence of risk factors for a negative UC prognosis [61-64].

Risk factors for a negative UC prognosis

Predictors of aggressive disease course and predictors of colectomy risk.

· Age at diagnosis ≤ 40 years (associated with a more severe disease course, shorter remission periods, and a higher risk of colectomy);

· age ≥ 65 years at the time of diagnosis (associated with the risk of early colectomy);

· extensive involvement;

· high endoscopic activity (large and/or deep ulcers);

· presence of extraintestinal manifestations;

· early need for systemic GCS (prescribed at disease onset) or the need for at least one course of GCS;

· severe flare according to Truelove-Witts (the number of criteria in addition to bloody stool frequency >6 times/day correlates with prognosis: the rate of colectomy as an outcome of the current flare) [65];

· hyperacute UC attack with diarrhea exceeding 10-15 times per day, progressive anemia, fever above 38°C, hypoalbuminemia ≤ 27 g/L, high CRP levels, and deep extensive colonic mucosal ulcers is associated with a high risk of colectomy in the first days of the flare [13,15];

· elevated levels of inflammatory markers;

· non-smokers and former smokers tend to have a greater extent of inflammation and slower healing. Smokers have been reported to have less frequent relapses and hospitalizations.

Since a complete cure for ulcerative colitis (UC) patients is achieved only by surgical removal of the colon (colectomy), once remission is achieved, the non-operated patient must remain on continuous maintenance (relapse-prevention) therapy. It should be emphasized that systemic corticosteroids cannot be used as maintenance therapy. Below are the guidelines for selecting drugs for the induction and maintenance of remission depending on the extent of the lesion and severity of the attack [26].

3.1.2 Proctitis. Mild and moderate flare

• Patients with mild to moderate proctitis are recommended local treatment with mesalazine** preparations (ATX code A07EC02) [26,66,67].

GCR BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: in this situation, it is advisable to prescribe mesalazine** suppositories (1 g/day, if necessary the dose can be increased to a dose of #mesalazine** of 2 g/day) or mesalazine rectal foam (1 g once/day, if necessary the dose can be increased to a dose of #mesalazine of 2 times/day) [26,66,67,263]. The therapeutic response is evaluated after 2 weeks [66]; if the response is positive, treatment at the specified doses is prolonged up to 6-8 weeks.

Comment: in this situation, it is advisable to prescribe budesonide rectal foam 2 mg per day or prednisolone suppositories 10 mg (extempore) 2 times a day with response evaluation after 2 weeks to achieve remission [26,68,69].

Comment. It is permissible to prescribe sulfasalazine** instead of mesalazine** [74,77].

Comment: in this clinical situation, corticosteroids are prescribed in tablets at a dose equivalent to prednisolone** 0.5-0.75 mg/kg of body weight per day to achieve remission.

For azathioprine** (AZA) - Level of recommendation strength A (level of evidence – 1)

For #mercaptopurine** (MP) - Level of recommendation strength C (level of evidence – 4)

Comment: AZA** is prescribed at 2-2.5 mg/kg, and #MP** at 1.5 mg/kg. Local therapy (budesonide rectal foam 2 mg/day, prednisolone suppositories 10 mg x 1-2 times/day (extempore)) can be continued.

Comment: during the period of treatment with #ganciclovir**, discontinuation of baseline therapy is not required.

3.1.3 Proctitis. Severe course (extremely rare)

• In the case of the first attack of UC, upon achieving remission to maintain it, patients are recommended therapy with local forms of mesalazine** preparations (rectal suppositories, rectal foam) 1 g x 3 times a week as monotherapy or in combination with oral mesalazine** (granules, tablets, gastroresistant prolonged-release film-coated tablets MMX) at a dose of 2-2.4 g – for at least 2 years to maintain remission [26,67,70,71,74,75,76].

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

Comment. It is permissible to prescribe sulfasalazine** 2 g/day instead of mesalazine** [74,77].

For azathioprine** (AZA) - Level of recommendation strength A (level of evidence – 1)

For #mercaptopurine** (MP) - Level of recommendation strength C (level of evidence – 4)

Comment: during the period of treatment with #ganciclovir**, discontinuation of baseline therapy is not required.

3.1.4 Left-sided and total ulcerative colitis. Mild flare

Comment: the therapeutic response is evaluated after 2 weeks. If the clinical picture improves and laboratory dynamics are positive, therapy is continued for up to 6-8 weeks.

Comment: it is advisable to prescribe budesonide rectal foam 2 mg per day or #hydrocortisone acetate + lidocaine suspension 125-250 mg once a day in the form of enemas or rectal drip administration to achieve remission [235, 236,267,268,269 ].

Comment: additional administration of mesalazine** enemas 2 g x 2 times a week ("weekend therapy") increases the likelihood of long-term remission.

Comment: during the period of treatment with #ganciclovir**, discontinuation of baseline therapy is not required.

3.1.5 Left-sided and total ulcerative colitis. Moderate flare

Comment: the therapeutic response is evaluated after 2 weeks. If the clinical picture improves and laboratory dynamics are positive, therapy is continued for up to 6-8 weeks.

Comment: it is permissible to prescribe sulfasalazine** 2 g/day instead of mesalazine** [74,77].

Comment: systemic GCS are prescribed at a dose equivalent to prednisolone** 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 a duration of no more than 12 weeks.

Comment: further GCS tapering should be carried out while continuing mesalazine**, followed by a switch to maintenance therapy with mesalazine** (granules, tablets, gastro-resistant prolonged-release film-coated tablets [MMX]) 2.0–2.4 g per day.

For azathioprine** (AZA) - Recommendation grade A (evidence level – 1)

For #mercaptopurine** (MP) - Level of recommendation strength C (level of evidence – 4)

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

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

· for adalimumab**, the induction (initiating) course consists of an initial subcutaneous injection of 160 mg, followed by a second subcutaneous injection of 80 mg 2 weeks later, and then maintenance therapy at a dose of 40 mg every 2 weeks

· for golimumab**, the induction (initiating) course consists of a first subcutaneous injection of 200 mg, a second subcutaneous injection of 100 mg 2 weeks later, and a third injection of 100 mg or 50 mg based on the patient's body weight, followed by maintenance therapy at the same dosage subcutaneously every 4 weeks

· for vedolizumab**, the induction (initiating) course involves intravenous administration of 300 mg three times at weeks 0, 2, and 6, followed by maintenance treatment with 300 mg intravenously every 8 weeks

· for ustekinumab**, the induction (initiating) dose is administered intravenously on the first day, calculated based on the patient's body weight at the time of administration, followed 8 weeks later by the first subcutaneous maintenance dose of 90 mg, and subsequently by therapy at a dose of 90 mg subcutaneously every 12 or 8 weeks (in case of loss of response).

· for tofacitinib**, an 8-week induction (initiating) course at a dose of 10 mg twice daily, followed by 5 mg twice daily as maintenance therapy

· for upadacitinib**, an 8-week induction (initiating) course at a dose of 45 mg tablets once daily, followed by 30 mg or 15 mg tablets once daily as maintenance therapy

· for ozanimod, the induction (initiating) course is 7 days with gradual oral dose escalation (starting from 0.23 mg daily up to 0.92 mg daily) according to the instructions for use; on day 8 and thereafter, the full dose is 0.92 mg once daily.

In biologic-naive patients, any of the indicated drugs can be used as first-line therapy [203]. It should be borne in mind that vedolizumab** is more effective than adalimumab** in first-line therapy [210].

Comment: it is permissible to use #MP** 1.5 mg/kg instead of AZA** due to the fact that MP** is a metabolite of AZA**. For other bDMARDs (adalimumab** – (ATX code L04AB04), golimumab** (ATX code L04AB06), selective immunosuppressants – vedolizumab** (ATX code L04AA33), interleukin inhibitors ustekinumab** (ATX code L04AC05) tofacitinib** (ATX code L04AA29), upadacitinib** (ATX code L04AA44), ozanimod (ATX code L04AA38)), the efficacy of combination with immunosuppressants (other immunosuppressants, ATX code L04AX) has not been proven. Co-administration of azathioprine** and tofacitinib** is contraindicated [99,100].

Comment: any of the indicated drugs can be prescribed as 2nd and subsequent lines of therapy with or without GCS. When choosing vedolizumab** after tumor necrosis factor alpha (TNF-alpha) inhibitors, it should be kept in mind that its efficacy as a 2nd-line drug is lower than in the 1st line [211]. Choosing ustekinumab** as a second-line bDMARD when the first tumor necrosis factor alpha (TNF-alpha) inhibitor fails is associated with better outcomes (achievement of clinical response and clinical remission) compared to switching the patient to another tumor necrosis factor alpha (TNF-alpha) inhibitor or vedolizumab** [225,226].

Comment: switching to another tumor necrosis factor alpha (TNF-alpha) inhibitor is possible, but its efficacy is lower than when switching to drugs of other classes (vedolizumab**, tofacitinib**, ustekinumab**, upadacitinib**, or ozanimod).

Comment: the efficacy of tumor necrosis factor alpha (TNF-alpha) inhibitors in 2nd-line therapy after loss of response to vedolizumab** is not reduced compared to their efficacy in 1st-line therapy, i.e., the use of vedolizumab** does not affect the subsequent efficacy of tumor necrosis factor alpha (TNF-alpha) inhibitors [211,212].

Comment: the evidence base regarding the feasibility of switching from tofacitinib** to biologic agents is insufficient. Switching drugs is possible and remains at the discretion of the attending physician. Upon achieving stable clinical and endoscopic steroid-free remission, the duration of biologic therapy is determined by the attending physician. In most countries, treatment is carried out for many years. Early discontinuation of drugs generally leads to a relapse of UC within a short period. If prolonged use of bDMARDs and tsDMARDs is not feasible, maintenance therapy is carried out using immunosuppressants alone (antineoplastic and immunomodulating agents: AZA**, #MP**).

Comment: any of the indicated drugs can be prescribed as the first-line therapy (see Section 3.1.5).

Comment: discontinuation of basic therapy is not required during the period of treatment with #ganciclovir**.

3.1.6 Left-sided and total ulcerative colitis. Severe flare

Comment: it is advisable to use GCs at a dose equivalent to prednisolone** 2 mg/kg of body weight intravenously (for high body weight, prescribing 1.5 mg/kg is possible) for 7 days, or to use hydrocortisone** at an equivalent dose. Dose equivalence and duration of action of GCs are given in Table 6. Response is assessed within an interval of 3 to 7 days. If the condition is stable within three days, therapy is continued up to 7 days. If the patient's condition worsens within three days, the issue of "rescue therapy" or colectomy is raised. If clinical improvement is noted after 7 days, GC therapy can be continued until stable improvement is achieved, and then switched to oral administration with a slow taper of 5 mg every 5-7 days. In the absence of significant clinical improvement after 7 days, the condition is regarded as steroid resistance.

Comment: hypokalemia and hypomagnesemia increase the risk of toxic dilation of the colon.

Comment: total parenteral nutrition and/or temporary restriction of oral intake is inappropriate.

• When signs of systemic inflammation develop in patients, it is recommended to prescribe systemic antibacterial drugs to prevent septic complications:

1st line – #metronidazole** (500 mg IV 3 times a day) + fluoroquinolones (#ciprofloxacin** 500 mg IV 2 times a day, #ciprofloxacin** 400 mg IV 2 times a day) [112, 113, 261, 262, 270];

Comment: If first-line antibacterial therapy is ineffective, a combination of other systemic antibacterial drugs may be used, taking into account the pathogen's susceptibility [113]

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

Table 6. Comparative characteristics of GCs

Comment: the schedule for switching from intravenous GCs to oral forms is considered individually by the attending physician depending on the rate of effect achievement and the severity of the therapeutic response.

Upon the development of steroid resistance, if there is no immediate threat to life or severe complications requiring urgent surgical intervention, "rescue therapy" is indicated against the background of ongoing GC treatment, i.e., intensification of conservative therapy, which is carried out with infliximab** at a dose of 5 mg/kg as part of the induction regimen at weeks 0, 2, and 6, or #ciclosporin** IV at a dose of 2–4 mg/kg for 7 days (with monitoring of renal function parameters and determination of the drug concentration in the blood), or tofacitinib** (20 mg/day as part of the induction regimen for 8 weeks) [103, 206, 207, 208, 256, 260]. The clinical result of such therapy is evaluated after 7 days. Studies have shown that the efficacy of the two regimens (with infliximab** and #ciclosporin**) on day 8 of treatment is identical; therefore, infliximab** is currently used mainly in foreign practice as a safer drug that does not require labor-intensive and expensive concentration determination. In the absence of an effect after 7–8 days, options for surgical treatment are considered. If it is impossible to prescribe infliximab**, the prescription of tofacitinib** is acceptable taking into account the rate of effect achievement [207, 208] (see Section 3.1.5).

Comment: A significant drawback of this treatment regimen is due to the simultaneous use of three immunosuppressive drugs at once, with an increased risk of adverse events.

3.1.7 Fulminant ulcerative colitis of any extent

This form can manifest either as the first attack of UC or as any of the subsequent exacerbations (for characteristics, see the section "Classification of UC"). The patient should be hospitalized in a multidisciplinary (specialized) hospital for conservative treatment, followed by mandatory follow-up by a gastroenterologist and a coloproctologist (surgeon) to resolve the issue of the advisability of performing surgical intervention within 24 hours.

Comment: the efficacy of conservative therapy in a fulminant UC attack does not exceed 50%. Clinical status and laboratory parameters should be evaluated every 24 hours, or more frequently if necessary. If clinical and laboratory parameters deteriorate, colectomy is the only life-saving intervention for patients with a fulminant UC attack. If there is significant positive dynamics in clinical status and laboratory parameters, intravenous GCS therapy may be continued for up to 14 days with due caution. If no improvement is observed within 3 days, this condition is regarded as steroid resistance.

• In cases of steroid resistance, if there is no immediate threat to the patient's life or the development of severe complications requiring emergency surgery, this group of patients is recommended to receive second-line therapy (referred to in English-language literature as "rescue therapy"), which includes the following treatment options:

infliximab** 5 mg/kg (induction infusions at weeks 0, 2, and 6) [118,119]

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

or

#cyclosporine** (preferably intravenous) 2–4 mg/kg for 7 days with monitoring of renal function [120,121]

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

or

Tofacitinib** 20 mg/day as part of an 8-week induction course [103,206,207,208].

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

Comment: other biological agents are not used as "rescue therapy". Surgical treatment is indicated for this group of patients if there is negative dynamics or no response by day 7 of therapy with infliximab**, #cyclosporine**, or tofacitinib** [122].

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) [213]. Currently, the biosimilar market is constantly expanding. Regarding IBD, this currently applies to biosimilars based on monoclonal antibodies to TNF-alpha. In Europe alone, 21 biosimilars have been registered over the last decade, including 14 based on adalimumab and 4 based on infliximab** [214]. In the Russian Federation, biosimilars of infliximab** and adalimumab** are also registered, and analogs of tofacitinib** have recently appeared. The use of biosimilars reduces the economic burden on the healthcare system and thereby significantly expands the possibilities of use and availability of biologic and targeted synthetic DMARDs. There is currently sufficient evidence regarding the efficacy and safety of biosimilars, but a bias remains among clinicians against them as drugs with lower efficacy [215]. The European Crohn's and Colitis Organisation (ECCO) in 2017 declared its position on the use of biosimilars in IBD, emphasizing that once registered, a biosimilar is considered as effective as the original product, and large observational studies are required to assess its long-term efficacy and safety [216]. From this perspective, a 2018 systematic review of 90 studies in various immune-mediated inflammatory diseases showed that in the vast majority of studies, no differences were observed in safety, efficacy, or immunogenicity between biosimilars and their corresponding original drugs, indicating the preservation of a good benefit-risk profile when switching from an original drug to a biosimilar [217]. Real-world clinical practice in European countries and the US demonstrates similar efficacy, safety, and immunogenicity when switching IBD patients from original infliximab** to its biosimilars [218-222]. In only one study, a 9.9% rate of switching back from the biosimilar to the reference product was recorded due to cutaneous or gastrointestinal adverse events or loss of response. In the vast majority of patients, response to treatment was restored after switching back [220]. A comparison of adalimumab and two of its analogs in IBD patients in Italy showed no significant difference in efficacy, safety, and immunogenicity between the drugs after the induction course and after 6 months of maintenance therapy [223]. The results of long-term post-marketing surveillance of the efficacy and safety of monoclonal antibody-based biosimilars for 7 years did not reveal any side effects specific to biosimilars [224]. The ECCO consensus emphasizes that the decision to switch from an original drug 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 [216].

Despite rather clearly formulated statements regarding biosimilars, there are certain controversies on this issue, as the adopted provisions are based on studies with different methodological approaches and an insufficient number of observations, which limits their reliability [227].

Russian publications indicate that the rate 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. In addition, the rate 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 [227, 228].

The provision on biosimilars is being introduced into the Russian Clinical Guidelines for UC for the first time. Since Russian biosimilars are not represented on the foreign market, international data on successful switching experiences 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 tumor necrosis factor-alpha (TNF-alpha) inhibitors in biologic-naive patients and to switching from the originator drug to a biosimilar 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 worsening of the disease course, rapid loss of response, and adverse events [228].

Switching from one tumor necrosis factor-alpha (TNF-alpha) inhibitor to another within the same class upon loss of response to the first drug is not recommended for either originator drugs or biosimilars (see Section 3.1.5). There is currently insufficient evidence base for using biosimilars of other drug classes for the treatment of UC.

3.2 Surgical Treatment

3.2.1 Indications for surgical treatment of UC: ineffectiveness or inability to continue conservative therapy.

Indications for surgical treatment of UC include ineffectiveness of conservative therapy (steroid resistance, ineffectiveness of biological DMARDs) or the inability to continue it (steroid dependence, intolerance, or contraindications to conservative therapy), intestinal complications of UC (toxic dilatation, bowel perforation, gastrointestinal bleeding), as well as colorectal cancer or a high risk of its development.

Signs of ineffectiveness of conservative therapy include (see Section 1.5):

· steroid resistance;

· steroid dependence.

Steroid dependence can be effectively overcome using biological DMARDs and/or immunosuppressants (AZP**, #MP**) in 40-55% of cases [78,116], whereas in steroid resistance, the administration of #cyclosporine** or infliximab** allows remission to be induced in 43-80% of cases [118,119,120]. However, in some patients with a high risk of complications and conservative therapy failure who develop steroid resistance or dependence, surgical treatment may be performed without attempting to use biological DMARDs or antineoplastic agents (immunosuppressants) (Azathioprine** ATC code L04AX01, Mercaptopurine** ATC code L01BB02)

3.2.2 Indications for surgical treatment of UC: intestinal complications of UC

• Patients with UC complications (gastrointestinal bleeding, colonic perforation, toxic dilatation refractory to adequate infusion therapy) are recommended emergency surgery in the scope of subtotal colectomy, total colectomy, or colproctectomy (in case of pronounced inflammation in the rectum) to increase the patient's life expectancy [123,124,125].

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

Comment: toxic colonic dilatation (toxic megacolon) is a non-obstructive dilatation of the colon of 6 cm or more accompanied by signs of systemic toxicity. Risk factors for toxic dilatation include hypokalemia, hypomagnesemia, bowel preparation for colonoscopy using osmotic laxatives, and the use of antidiarrheal drugs. Indirect signs of toxic dilatation include a sudden decrease in stool frequency against the background of existing diarrhea, abdominal distension, as well as a sudden decrease or disappearance of pain and an increase in symptoms of intoxication (increasing tachycardia, dropping blood pressure). Colonic perforation is the most dangerous complication of UC with a mortality rate of nearly 50%.

3.2.3 Indications for surgical treatment of UC: colorectal cancer

Patients with a long-standing history of UC have a significantly increased risk of colorectal cancer, which necessitates regular screening to detect dysplasia in the colonic mucosal epithelium. The likelihood of cancer development is influenced by the following factors:

a) duration of UC history: the risk of colorectal cancer is 2% at 10 years, 8% at 20 years, and 18% at 30 years of disease history [126];

b) onset of the disease in childhood and adolescence, although this factor may merely reflect the disease duration and may not be an independent predictor of colorectal cancer [127];

c) extent of involvement: the risk is highest in patients with total UC, whereas in patients with proctitis the risk does not differ from the general population average;

d) presence of primary sclerosing cholangitis [128];

e) family history of colorectal cancer;

f) severe UC flares in history or continuous UC course. A consequence of high UC activity can be inflammatory polyposis, which is also a risk factor for colorectal cancer [129].

Follow-up colonoscopy should be performed under conditions of good bowel preparation and, preferably, during remission, as active inflammation makes it difficult to detect dysplasia.

To screen for neoplastic mucosal changes, clarifying endoscopic techniques are used: videocolonoscopy with dye chromoendoscopy or virtual (optical) chromoendoscopy with targeted biopsy [130,131,132]. When using clarifying endoscopic techniques, a random mapping biopsy is not required.

The results of screening biopsies influence further treatment and management tactics.

Comment: proctocolectomy with a permanent end ileostomy or proctocolectomy with simultaneous ileal pouch formation protected by a loop ileostomy can be performed. The presence of dysplasia in the colorectal mucosa epithelium must be confirmed by a second independent pathologist. The extent of surgical treatment is discussed jointly with the patient, thereby accommodating their preference for preserving anal defecation or forming a permanent ileostomy.

Comment: the scope of surgical treatment is discussed jointly with the patient, thereby taking into account their desire to preserve anal defecation or have a permanent ileostomy formed. The patient has the right to refuse surgery, in which case endoscopic screening is offered.

Comment: in UC patients in remission presenting with large colonic neoplastic lesions and no epithelial dysplasia in the mucosa outside these lesions, mucosectomy or endoscopic submucosal dissection (ESD) may be performed [133,134].

Comment: epithelial dysplasia must be confirmed by a second pathologist, after which the treatment plan should be discussed by a multidisciplinary medical board. If colonoscopy is incomplete due to a stricture, CT with intravenous and luminal contrast is necessary to assess the nature of the bowel wall changes proximal to the stricture [135]. All UC patients with colorectal cancer, following an oncological board review, are indicated for surgery in the scope of total colectomy with abdominoperineal resection of the rectum to eliminate the risk of malignant transformation in the remaining segments of the colon.

3.2.4 Types of surgical interventions

In the majority of UC patients, modern conservative therapy allows for the control of the inflammatory process; however, in 10-30% of patients, medical treatment failure necessitates surgery aimed at removing the colon [123,124]. Until the early 1980s, the standard surgical treatment was proctocolectomy with an end ileostomy, despite occasional formation of an ileorectal anastomosis. Over the last 20 years, restorative plastic surgery—total colectomy with pouch formation (restorative proctocolectomy with ileal pouch-anal anastomosis [IPAA])—has become the new gold standard [136,137] (Table 7). In the absence of complications, this surgery provides the possibility of controlled perianal defecation with a satisfactory quality of life [136]: the defecation frequency after IPAA is 4 to 8 times per day [138-140], and the average daily volume of semi-formed/liquid stool is about 700 mL per day (compared to 200 mL/day in a healthy individual).

Table 7. Surgical treatment methods for UC

In all patients scheduled for surgery (total or subtotal colectomy, or colectomy with abdominoperineal resection of the rectum) due to medical refractory ulcerative colitis, excluding intestinal complications, it is preferable to use laparoscopic techniques to reduce intraoperative and postoperative complication rates, achieve faster recovery, reduce the risk of abdominal adhesion formation, lower the risk of reduced fertility, and improve cosmetic outcomes [141-146].

3.2.5 Selection of surgical treatment type

Performing reconstructive plastic surgery with IPAA, despite its obvious appeal to the patient, is not feasible in all cases, as a number of factors impair the functional outcome of the surgery and increase the risk of complications, leading to pouch excision in 3.5-10% of patients [147-149].

In elderly UC patients, despite a higher rate of comorbidities, the surgery itself with ileal pouch formation is safe [150]. Anal sphincter function, which plays a key role in the normal functioning of IPAA, generally deteriorates in older individuals [151].

Furthermore, complications such as pouchitis and anastomotic stricture are more common in patients older than 60 years [152,153]. At the same time, no specific age threshold for contraindicating IPAA has been established.

The formation of an ileal pouch (IPAA) increases the risk of infertility in women of reproductive age with UC by 30-70% [154-158].

The risk of infertility is associated with pelvic adhesions involving the fallopian tubes. A planned pregnancy and young age are not absolute contraindications to IPAA formation; however, the patient must be warned about the potential risk of infertility. In individual cases, the formation of an ileorectal anastomosis may be considered as an interim stage of surgical treatment (see below).

In all female UC patients with surgical indications, the use of laparoscopic techniques reduces the risk of infertility by 90% [158].

In approximately 10% of patients, even after pathomorphological examination of the surgical specimen following colectomy, it is impossible to differentiate between Crohn's disease (CD) and UC, leading to a diagnosis of unclassified colitis. The decision to form an IPAA in such cases is made individually, and the patient must be warned about the risks of reconstructive surgery failure and other complications associated with CD.

In UC patients with comorbid conditions such as rectal cancer and severe grade 2 or 3 fecal incontinence, the formation of an ileal pouch (IPAA) is impractical.

Comment: in all patients with severe or fulminant ulcerative colitis who have indications for surgery, the surgical intervention must be at least a colectomy with the formation of an end ileostomy, which helps improve the patient's general condition, eliminates metabolic disorders, and allows a pathomorphological examination of the surgical specimen to exclude CD. Colectomy is a relatively safe procedure even in critically ill patients [159-161]. With sufficient surgical expertise, the use of laparoscopic techniques is safe [162,163].

The formation of an ileorectal anastomosis does not cure the patient and does not rule out the possibility of recurrent inflammation in the rectum and the development of cancer [164-166]. This surgery for UC should only be performed in exceptional cases in women planning pregnancy. Prerequisites include the presence of remission in the rectum and the patient's consent for regular rectal examinations with mucosal biopsy [165,167].

3.2.6 Special considerations for surgical intervention involving ileal pouch formation

In patients with UC who have undergone colectomy, reconstructive plastic surgeries with the formation of an ileal pouch (IPAA) are performed in specialized hospitals, since the complication rate and functional outcome of such interventions largely depend on the surgeon's personal experience [165].

Length of the preserved rectum and/or sigmoid colon

In patients with UC undergoing emergency colectomy who are subsequently scheduled for ileal pouch formation, it is advisable to preserve the entire rectum and inferior mesenteric vessels to improve quality of life. It is advisable to transect the rectum at the level of the sacral promontory or additionally preserve the distal sigmoid colon (the decision is made by the operating surgeon). If the distal sigmoid colon is preserved, it is brought out onto the anterior abdominal wall as an end sigmoidostomy. The latter option is safest, as no intestinal stump remains in the abdominal cavity. When the rectum is transected at the promontory level, drainage of the stump through the anus is preferred for several days to prevent suture dehiscence due to mucus accumulation. If the excluded rectum or rectum and sigmoid colon are preserved, secondary inflammatory mucosal changes resembling diversion colitis may develop. Controlled drug trials in patients after colectomy have not been conducted. Empirical treatment consists of topical mesalazine [168], steroids, and irrigation of the excluded rectum with antiseptic solutions.

Anastamosis creation during IPAA formation

In patients with UC scheduled for surgical treatment with ileal pouch formation, to improve functional outcomes, it is advisable to preserve the distal segment of the rectum no more than 2 cm above the dentate line. Preserving an extended segment of the rectum (more than 2 cm above the dentate line) can cause chronic inflammation within it with pouch dysfunction, and also contributes to preserving the risk of dysplasia and (very rarely) cancer [164]. If it is impossible to create a pouch-anal anastomosis using a stapler, an abdominoperineal resection of the rectum and a hand-sewn ileoanal anastomosis should be performed.

Morphological changes in the epithelial lining of the pouch usually develop 12–18 months after ileostomy closure and are characterized by flattening and reduction in the number of villi, often accompanied by the development of colonic metaplasia [169,170], which is potentially associated with the risk of malignant transformation of the pouch mucosa. In addition, stapled IPAA preserves a small area of the rectal mucosa ("cuff"). The risk of pouch cancer is increased in patients operated on for cancer or dysplasia associated with UC (and when dysplasia is found in the surgical specimen), as well as in patients with primary sclerosing cholangitis (PSC). Scientific justification for the frequency of follow-up examinations in patients with IPAA has not been established; however, in patients with the aforementioned risk factors, it is advisable to perform follow-up endoscopic examinations (pouchoscopy) with mucosal biopsy at least once every 2 years.

3.2.7 Medical therapy during the perioperative surgical period

Effect of medical therapy on the risk of surgical interventions.

Comment: taking prednisolone** at a dose of more than 20 mg for more than 6 weeks increases the rate of postoperative complications [171,172]. Preoperative use of AZA** and #MP** does not worsen surgical outcomes [173], whereas administration of infliximab** and cyclosporine** shortly before surgery may increase the rate of postoperative complications [174,175], although data on infliximab** remain contradictory [176]. Abrupt cessation of GCS therapy may cause withdrawal syndrome (acute adrenal insufficiency, so-called Addisonian crisis), which necessitates temporarily continuing hormonal therapy after surgery until complete withdrawal. Currently, there is no reliable scientific basis to justify any specific schedule for discontinuing hormonal therapy after colectomy for UC. The GCS dose for further oral administration during the withdrawal period is determined by the duration of prior therapy and the doses used. According to the European Crohn's and Colitis Organisation (ECCO) guidelines [26], if hormonal therapy before surgery was administered for no more than a month, GCS intake can be discontinued immediately after surgery.

If the patient received GCSs for more than a month before surgery, it is advisable to switch from the aforementioned high parenteral dose after surgery to oral GCSs at a dose not lower than the upper limit of daily stress cortisol production, i.e., not lower than 20 mg of prednisolone**.

3.2.8 Pouchitis and other complications of surgical treatment during ileal pouch formation

Pouchitis is a nonspecific inflammation of the ileal pouch and the most frequent complication of IPAA. Its incidence ranges widely from 15% to 50% within 10 years after IPAA formation in major specialized centers [177-179]. Such variations may be due to a significantly higher risk of pouchitis in UC, exceeding the incidence of this complication when IPAA is performed for other diseases (in particular, familial adenomatous polyposis) [180,181].

Patients with signs and symptoms characteristic of pouchitis should undergo enteroscopy (pouchoscopy) to assess the severity of mucosal inflammatory changes in the pouch with biopsy sampling.

Pouchitis is accompanied by the formation of abscesses, fistulas, stenosis of the pouch-anal anastomosis, and the risk of cancer development within the pouch. The latter complication is extremely rare and almost always occurs in the presence of high-grade dysplasia or cancer in the colectomy specimen.

Differential diagnosis of suspected pouchitis is carried out with irritable pouch syndrome (IPS), ischemic lesions, CD, and other rare causes of pouch dysfunction, such as collagenous, cytomegalovirus, and Clostridioides difficile-associated pouchitis. The possibility of non-specific ileitis caused by NSAIDs and small intestinal bacterial overgrowth syndrome should be considered.

The main drugs used to treat pouchitis remain antibiotics, which allows pouchitis to be classified as antibiotic-responsive, antibiotic-dependent, and antibiotic-resistant.

Comment: adverse events are significantly more common with metronidazole** intake. In cases of antibiotic-resistant pouchitis, oral #budesonide** (9 mg) can be prescribed for 8 weeks [250].

Inflammation of the mucosa of the preserved rectal stump.

Another potential complication of IPAA is inflammation of the mucosa of the rectum preserved when performing a stapled anastomosis.

3.2.9 Ileostomy dysfunction after UC surgery

Ileostomy dysfunction is defined as an increase in the volume of intestinal output via the ileostomy to more than 1000 mL per day. This condition is also accompanied by rapidly progressive metabolic and water-electrolyte disorders [186, 187].

Comment: in addition to profuse liquid stoma output, the clinical presentation also includes fever up to 39⁰C, flatulence, and rarely complaints of nausea, vomiting, and spastic abdominal pain. Laboratory findings include anemia, hypoproteinemia, hypoalbuminemia, hypokalemia, elevated CRP levels, and rarely an increase in creatinine concentration.

Comment: the mild form of the disease is characterized by an increase in the volume of intestinal output via the ileostomy without signs of systemic inflammation.

Comment: moderately severe form is characterized by an increase in the volume of intestinal output via the ileostomy, fever, and changes in laboratory parameters: if blood leukocyte count exceeds 15 × 10⁹/L, serum creatinine is above 115 µmol/L, body temperature rises above 38⁰C, and albumin level drops below 25 g/L, patients must receive inpatient care in a round-the-clock hospital setting. If clostridial infection is confirmed, #vancomycin** is indicated at a dose of 1000 mg orally per day for 10 days.

Comment: severe ileostomy dysfunction, in addition to increased intestinal output via the ileostomy, manifests as spastic abdominal pain, fever up to hectic values, leukocytosis, and hypoalbuminemia. If oral administration is not feasible, #vancomycin** is prescribed intra-intestinally: in this case, 500 mg of the drug is diluted in 500 mL of 0.9% sodium chloride solution and administered into the intestinal lumen four times a day. Clinical deterioration with hypotension, hyperthermia above 38.5 °C, stool retention, pronounced abdominal distension, altered mental status, leukocytosis above 15 × 10⁹ or leukopenia below 2 × 10⁹, serum lactate levels above 2.2 mmol/L, or the development of multiple organ dysfunction syndrome requires transferring the patient to the intensive care unit for further management.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific rehabilitation measures for ulcerative colitis.

Since UC therapy involves the use of immunosuppressants in some cases, the main method of rehabilitation is the prevention of opportunistic infections described in Section 5.

Patients who required surgical treatment for ulcerative colitis can undergo rehabilitation in three stages.

Stage 1 – early rehabilitation, carried out immediately after surgical treatment from days 2 to 14. The main objective of Stage 1 rehabilitation is to restore normal gastrointestinal function following surgery. It is at this stage that urinary disorders are most frequently identified and must be corrected. An important role is also assigned to homeostasis monitoring, measures aimed at surgical wound healing, relief of postoperative pain, and patient mobilization. During this period, laboratory parameters are monitored by ordering a complete blood count, blood chemistry panel, coagulation profile, and urinalysis.

Stage 2 of rehabilitation begins after day 15 and is aimed at the final healing of surgical wounds with monitoring of gastrointestinal function and other body systems. This stage can be carried out both on an outpatient basis and in a day or round-the-clock hospital setting.

Stage 3 of rehabilitation is carried out in the late postoperative period in patients with either a permanent ileostomy or prior to reconstructive surgery. The main objective at this stage is to normalize gastrointestinal function and implement measures aimed at identifying and correcting disorders of the rectal sphincter apparatus.

Anal sphincter insufficiency

Rehabilitation is possible at stages 2 and 3. Some patients who underwent surgery for UC resulting in the formation of an ileal pouch experience decreased continence function.

It is advisable for UC patients with anal sphincter insufficiency to undergo an evaluation of the rectal sphincter apparatus function (sphincterometry, profilometry, pudendal nerve terminal motor latency testing) prior to reconstructive surgery, followed by a consultation with a physical therapist to receive treatment aimed at improving continence function [192].

• When grade 2–3 anal sphincter insufficiency is detected in UC patients, it is recommended to consider a 10-day cycle of electrical stimulation, biofeedback (BFB) therapy, and tibial neuromodulation in a day or round-the-clock hospital setting, aimed at improving the contractility of the external sphincter and pelvic floor muscles by increasing both the strength and duration of voluntary contraction [192, 193].

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

Comment: Biofeedback (BFB) therapy is a non-invasive method that engages the body's own resources in the rehabilitation process by developing proper skills at the level of creating new conditioned reflex connections. Tibial neuromodulation is also an effective method. Neuromodulation is a process in which an electric current along certain nerve pathways modulates pre-existing activity in other nerve pathways or centers. Percutaneous electrical stimulation of the posterior tibial nerve is used for functional pelvic floor disorders, since fibers from the II and III sacral segments of the spinal cord run within the posterior tibial nerve, playing a significant role in the innervation of the rectum, urinary bladder, and their sphincters. It has been proven that the muscular structures of a deconditioned sphincter apparatus can respond to the therapy by increasing both tone and voluntary contraction strength [192,193]. Tibial nerve stimulation is performed using a cutaneous stimulating electrode, which allows the patient, after a preliminary training course, to continue treatment independently at home. In this case, the course of treatment with daily stimulation sessions can be extended up to 1–3 months. The effectiveness of therapy is monitored before and after each course of procedures through a comprehensive physiological study of the rectal sphincter apparatus function. When parameters of tone and contractility of the anal sphincters improve, the feasibility of reconstructive surgery aimed at restoring natural gastrointestinal transit can be considered.

5. Prevention and Dispensary Observation

Ulcerative colitis is characterized by a chronic relapsing course. Dispensary follow-up for UC is carried out for life. The primary goal of dispensary follow-up is the prevention of colorectal cancer.

For some patients, the frequency of dispensary follow-up with colonoscopy may vary. Specifics of monitoring patients receiving immunosuppressants and/or biologic agents include the prevention of opportunistic infections. Risk factors for opportunistic infections include: taking prednisolone** at a dose of 20 mg/day or more for 2 weeks, taking immunosuppressants (ATX code L04AX other immunosuppressants. AZA**,#MT**, ATX code L01BB02#MP**,) and biologic agents, age over 50 years, and comorbid conditions (chronic lung diseases, alcoholism, organic brain diseases, diabetes mellitus).

Patients should be informed of the necessity for continuous medication intake, since adherence to therapy significantly (2–2.5 times) reduces the frequency of exacerbations, and the therapy itself serves as a chemopreventive method against colorectal cancer.

• viral hepatitis B vaccine**;

• pneumococcal infection vaccine**;

• influenza vaccine [inactivated]**;

• for women under 26 years of age, vaccination against human papillomavirus is recommended if the virus is absent at the time of screening.

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

• Patients receiving GCS therapy are recommended to monitor glycemic levels (blood glucose testing) to prevent side effects of glucocorticoids [273,274].

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

• Female patients with UC are recommended to have an annual appointment (examination, consultation) with an obstetrician-gynecologist and undergo cervical cancer screening (Pap smear with cytological examination of the cervical canal smear) to diagnose cervical intraepithelial neoplasia [209].

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

1) For markers of viral hepatitis (determining antibodies to hepatitis C virus in the blood; determining antibodies to hepatitis B surface antigen (HBsAg) in the blood) [194].

2) For human immunodeficiency (determining antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 in the blood; determining antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 in the blood) [194].

3) For syphilis (determining antibodies to Treponema pallidum in non-treponemal tests (RPR, VDRL) (qualitative and semi-quantitative test) in blood serum).

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

Comment: from the perspective of the long-term prognosis of UC, it is advisable to regularly assess the presence of endoscopic remission (mucosal healing).

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 28, 2022) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", and Government Decree of the Russian Federation No. 1968 dated 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'", is organized and provided:

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 for patients with UC is provided by a gastroenterologist, coloproctologist, and other specialist physicians in medical organizations licensed for the relevant types of medical activities.

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

A gastroenterologist or coloproctologist at a medical organization that includes a gastroenterologist's or coloproctologist's office, outpatient gastroenterology center (department), outpatient coloproctology center (department), or inflammatory bowel disease diagnosis and treatment center shall organize timely and qualified examination and treatment of the patient, including determining the severity of the inflammatory process, the extent of the lesion, the presence of intestinal and extraintestinal manifestations, including obtaining biopsy material.

If inpatient treatment and an in-depth examination are necessary, 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 specialties of "gastroenterology" or "coloproctology".

If ulcerative colitis is suspected and/or diagnosed in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care in the fields of gastroenterology or coloproctology to determine management tactics and the need for additional specialized treatment methods, including targeted biological therapy.

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

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

Indications for admission to an inpatient or day hospital setting of a medical organization providing specialized, including high-tech, medical care for ulcerative colitis are determined by a gastroenterologist and/or coloproctologist, with a multidisciplinary team consultation conducted if necessary.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) presence of complications of ulcerative colitis requiring emergency or urgent specialized medical care;

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

Indications for hospitalization in a medical organization in a planned form 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 treatment of ulcerative colitis (surgical intervention, hormonal and cytostatic therapy, biological and targeted therapy) requiring monitoring in an inpatient or day-care setting.

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

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

7. Additional Information

The lifetime risk of a severe UC exacerbation is 15%, with the probability of a severe attack being higher in patients with total colonic involvement. With adequate maintenance therapy, relapses are avoided in half of the patients within 5 years, and in 20% of patients within 10 years. During the first year after diagnosis, the probability of colectomy is 4–9% (around 50% in severe attacks), and thereafter the risk of colectomy increases by 1% each year of the disease. Risk factors for an aggressive UC course include the progression of lesions from distal (proctitis) to total, primary sclerosing cholangitis, and pediatric and adolescent age at disease onset. Pregnancy planning should be carried out during IBD remission, which helps improve pregnancy outcomes. The use of most IBD medications during pregnancy is associated with a low risk of adverse effects on the fetus, with the exception of methotrexate** and 5-ASA preparations (ATC code: A07EC Aminosalicylic acid and similar agents (ATC code A07EC02 Mesalazine)) containing dibutyl phthalate. Discontinuation of tumor necrosis factor alpha (TNF-alpha) inhibitors or a switch to monotherapy is possible only in a limited number of patients with a low risk of IBD reactivation. Treatment with genetically engineered biologic agents not contraindicated during pregnancy (see instructions for use) may be continued if the benefit to the mother outweighs the potential risks to the fetus.

Reduction of risks associated with GCS prescription is achieved by strict adherence to the principles of hormonal therapy. GCS cannot be used as maintenance therapy.

When prescribing hormone therapy, the following must be considered:

• gradual tapering of the steroid dose until complete discontinuation is strictly mandatory;

• the total duration of hormone therapy must not exceed 12 weeks;

• concurrent intake of calcium preparations in combination with vitamin D and/or other agents is mandatory;

• regular blood glucose monitoring is required during the treatment period.

Patients who have undergone surgical formation of an intestinal stoma may require consultation and follow-up by a stoma care rehabilitation specialist.

Criteria for Evaluating the Quality of Medical Care

Quality evaluation criteria for primary health care in adults with ulcerative colitis

Quality evaluation criteria for specialized medical care in adults with ulcerative colitis

Clinical guidelines for the diagnosis and treatment of ulcerative colitis were discussed at the meeting of the specialized commission on the specialty «Coloproctology» on October 8, 2022, within the framework of the All-Russian Scientific and Practical Conference with International Participation «Congress of Coloproctologists of Russia», and at the meeting of the commission on surgical sciences of the Scientific Council of the Russian Academy of Medical Sciences on November 25, 2022, within the framework of the XVI All-Russian Conference with International Participation «Levitan Readings».

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. Rating scale for levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

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

Order of the Ministry of Health of the Russian Federation No. 206n dated April 2, 2010 (as amended on February 21, 2020) "On approval of the Procedure for providing medical care to the population with diseases of the colon, anal canal, and perineum in coloproctology";

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

Order of the Ministry of Health of the Russian Federation No. 1144n dated December 14, 2021 "On approval of the standard of medical care for adults with ulcerative colitis (diagnosis and treatment)"

Appendix B. Physician Action Algorithms

Figure 1. Algorithm of diagnostic and therapeutic tactics in ulcerative colitis

Appendix C. Patient Information

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

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

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

No