Difficulties in the Differential Diagnosis of Crohn’s Disease

Abstract

Currently, the main difficulty in the accurate diagnosis of inflammatory bowel disease (IBD) is associated with the high prevalence of infectious, allergic and autoimmune diseases leading to intestinal lesions mimicking IBD. In geographical regions where there is endemicity for certain infections, in particular tuberculosis, timely verification of the diagnoses of ulcerative colitis (UC) and Crohn’s disease (CD) is a serious problem. Some infectious, allergic and autoimmune pathologies can not only imitate the clinical and endoscopic picture of IBD, but also complicate the course of an existing IBD, as a result of which there is resistance to the prescribed basic therapy in patients with UC and CD. Unfortunately, the complexity and limited possibilities of diagnostic methods can often be the reason for the belated establishment of an accurate diagnosis. Thus, in all these diseases, the main fecal markers for verifying the diagnosis of IBD, fecal calprotectin and lactoferrin, often have elevated values.

1. Introduction

At the turn of the twenty-first century, due to a local increase in the incidence of inflammatory bowel diseases, they have become a global medical and social problem. If by the end of 2017 the highest prevalence rates were in Europe (ulcerative colitis 505 per 100,000 in Norway; Crohn’s disease 322 per 100,000 in Germany) and North America (ulcerative colitis 286 per 100,000 in the USA; Crohn’s disease 319 per 100,000 in Canada), by the end of 2019, the prevalence of inflammatory bowel disease exceeded 0.3% of the total population in many other regions of the Earth. As of April 2020, over 2 million people in North America, 3.2 million in Europe, and over 10 million worldwide have IBD. Despite the fact that the incidence in developed Western countries is stabilizing, the burden of costs associated with solving emerging problems remains high [1, 2].

Inflammatory bowel diseases are immune-mediated diseases, due to which “crossovers” with various autoimmune, infectious, proliferative diseases are quite common. Considering the growing incidence of IBD, the high prevalence of opportunistic (including intestinal) infections and “overlap syndromes” with autoimmune, and currently with allergic pathologies, as well as the lack of a single diagnostic “gold” standard, clinicians are faced with a large number of problems.

For the diagnosis of IBD, several world ducts have been adopted today, and in all endoscopy with pathomorphological examination, it is accepted as a mandatory criterion in diagnostic algorithms for verifying the diagnoses of ulcerative colitis, Crohn’s disease, microscopic and undifferentiated colitis.

2. Pathologies, mimicking IBD

2.1 IBD mimics

Infectious		Non-infectious
Small intestine/terminal ileum	Colon	Granulomas present; Sarcoidosis, small vessel vasculitides Hermansky-Pudlak syndrome CVID (common variable immunodeficiency) Ulcer in mouth and small/large intestine; Behcet’s disease Colon inflammation; Diverticulitis SCAD (segmental colitis associated with diverticulosis) Drug induced colitis (NSAIDs, immuno-therapy) Ischemic colitis SRUS (solitary rectal ulcer syndrome) Non-specific mucosal changes without chronic inflammation; IBS (irritable bowel syndrome) Cancer (adenocarcinomas, GL lymphomas, others)
Bacterial; Tuberculosis Yersinia Salmonella Fungal; Histoplazma Coccidioides	Bacterial; C. difficile Salmonella Shigella E. coli Campylobacter Aeromonas Parasitic; Amebiasis (E. histolytica) Viral; CMV

3. Intestinal tuberculosis (ITB)

Diagnosis of IBD in regions where tuberculosis (TB) is common is a major diagnostic challenge. This is especially true for Crohn’s disease, since CD and ITB are chronic granulomatous diseases, quite often with overlapping endoscopic, pathomorphological, radiological, and clinical findings. The similarity in clinical manifestations of these two diseases, as well as the absence of specific laboratory markers of intestinal tuberculosis, may possibly explain the high misdiagnosis rates, which range from 50 to 70% [3]. Misdiagnosis and subsequent treatment can lead to undesirable consequences. For this reason, many clinical studies have examined the role of endoscopy (colonoscopy), pathology, clinical manifestations, quantiferon test (IGRA), polymerase chain reaction (PCR) detection of Mycobacterium tuberculosis, and comprehensive scoring systems in differentiating between ITB and CD.

The symptoms and signs of abdominal tuberculosis are nonspecific and may closely resemble CD and other gastrointestinal pathologies. TB can be confused with cancer of the respective areas. Intestinal TB may be detected in asymptomatic patients who have had a colonoscopy for other reasons. Pain is the most common presentation, in approximately 85% of patients, weight loss in 66%, fever in 35–50%, and diarrhea in 20% of patients. Systemic manifestations (subfebrile temperature, fever in the evening, lethargy, malaise, night sweats and weight loss) can be detected in 30% of patients. This is more often observed with tuberculous ascitic-type peritonitis and ulcerative lesions of the intestine. Abdominal tenderness occurs in most patients, and a mass in the abdomen, usually in the right lower quadrant, in 25 to 50% of patients. Malabsorption is observed in 21–75% of cases [4, 5, 6]. Acute abdomen: In developing countries, extrapulmonary (abdominal) TB can often present as an acute abdominal process during emergency surgery such as perforation and intestinal obstruction [4, 5, 6]. Ascites can be caused by peritoneal tuberculosis or result from hepatic, malignant, cardiac, renal or other infectious diseases [22]. Peritoneal tuberculosis with ascites may occur with less pain and complication than purulent peritonitis with perforation. “Cocoon” of the abdominal cavity–an unusual form of tuberculosis of the abdominal cavity–is characterized by the formation of a fibrous membrane sac around the loops of the small intestine. While conservative treatment with antituberculous therapy (ATT) may suffice for some patients, while other patients who do not respond to treatment require surgical intervention [5, 6]. Anorectal TB may present as a stricture, anal fistula, or anal fissure.

Colonoscopy can be useful for differential diagnosis if it is performed by a doctor who knows the features of these pathologies. A study in Korea in 2006 found that the diagnosis of ITB or CD by colonoscopy was correct in 87.5% of patients (77/88), incorrect in 8.0% of patients (7/88), and was considered indeterminate in 4.5% of patients (4/88) [4]. In another study, including 122 cases of ITB and 130 cases of CD, a mathematical regression equation was developed according to endoscopic parameters: rectal involvement, longitudinal ulcers, transverse ulcers, cobblestone syndrome, fixed open ileocecal valve (Figure 1a and b) [2, 5].

Figure 1.

Endoscopic picture of intestinal lesions in CD and ITB [5]. (a) typical longitudinal ulcers in a patient with CD. (b) typical transverse ulcers in a patient with ITB.

The presence of macroscopic lesions along with microscopic detection of inflammatory infiltration in the terminal ileum often leads the gastroenterologist to the diagnosis of Crohn’s disease (CD).

In CD, pathomorphological diagnosis is problematic due to the lack of specific microscopic features and discrete lesions. The Singapore study assessed the baseline features of mucosal biopsy in 25 CD patients, 3 patients with ITB, and 2 cases of colitis associated with diverticular disease. Granulomas were observed in 10 of 41 CD biopsies and in all 5 other biopsies. Small, firm, well-circumscribed granulomas are characteristic of CD compared with large coalesced granulomas in tuberculosis. Cellular, pseudopyloric and Paneth’s metaplasia was observed only in CD (2/25) [7]. Due to the low sensitivity of standard biopsy sampling, which is limited to the mucosa only and involves the submucosal layer, it is difficult to make an accurate diagnosis based on the histology of the biopsy. To date, the role of the quantiferon test (IGRA) in differentiating ITB from CD has been sufficiently studied. A systematic review with a meta-analysis of IGRA accuracy was published in 2014 [3]. The sensitivity, specificity, positive predictive value, and negative predictive value of the tests in the 8 studies averaged 81, 85, 78, and 87%, respectively. In conditions of high incidence of tuberculosis, when latent infection is widespread, a positive result of the quantiferon test does not make it possible to distinguish between active and latent tuberculosis [8]. However, in TB endemic regions, this test is necessary to rule out TB in IBD, as evidenced by a high negative predictive value (94.2%) [9]. PCR analysis also helps differentiate TB from CD by detecting M. tuberculosis DNA in biopsy or stool specimens. The reported sensitivity and specificity of TB-PCR mucosal biopsy were 64.1% and 100%, respectively [10]. However, one must be aware of the possibility of false positive or negative results (primer not specific enough or limited amount of tissue available in mucosal biopsy specimens). M. tuberculosis DNA has also been reported to be found in mucus and fecal samples of some CD patients due to the presence of latent tuberculosis [10, 11, 12].

Computed tomography (CT) enterography also plays a role in disease differentiation. Segmental involvement, comb sign, changes in fibro-adipose tissue, moderate wall thickening, and asymmetric distribution are significantly more common in CD patients than in patients with ITB [13]. The combination of CT enterography with endoscopy data increases the accuracy of diagnosing CD and/or ITB from 66.7 to 95.2% [14]. In addition, concurrent active pulmonary tuberculosis detected by computed tomography may add value to the diagnosis of ITB.

Differentiation between CD and ITB is the most difficult, as there are cases of crossover options. In this case, the practitioner needs to remember the differential features of CD and ITB (see Table 1).

Peculiarities	CD	ITB
Clinical:	Specific (disease of the perianal region)
Perianal lesion		Rarely; Peritoneal involvement with ascites (but this is often absent and not very discriminatory)
Blood in stool	Present	Rarely
Endoscopy:	≥ 4 segments	< 4 segments
Lesions
Ulcer shape	Longitudinal ulcers Aphthoid ulceration Cobblestones	Transverse ulcers, nodules, scars, strictures of short segments
Ileocecal valve disease	Rarely; Long segment of the ileum with preservation of the ileocecal valve	Specific; The ileocecal valve is almost always affected - a fixed, patulous ileocecal valve is a very typical finding in ITB
Quantiferon test	Negative PCR and tissue culture for TB	Positive tissue TB PCR and culture; Positive IGRA and/or PPD test result
Active pulmonary TIB (Chest X-ray/CT)	Negative	Specific
CT enterography:	Specific	Less specific
Multisegmental lesion
Sigmoid/rectal lesion	Specific	Less specific
Asymmetric lesions	Specific	Less specific
“Comb” symptom	Specific	Less specific
Fibro-fatty changes	Specific	Less specific
Radiographic features and radiological signs:	long segment strictures, multi-site involvement, ridge sign, perianal disease.	short strictures, deformed ileocecal valve, lymphadenopathy with hypodense centers, thickened peritoneum
Histology of the biopsy	Granulomas (noncaseating, small, losses and infrequent); focally enhanced colitis; loss of mucosal architecture is present even at a distance from granulomas	Granulomas (caseous, large, confluent and many others); architectural mucosal loss only close to granuloma; protruding submucosal inflammation
Focal chronic inflammation	Specific	Less specific
Granuloma	Solitary, <400 μm, noncaseating	Sticky, ≥400 μm, caseous
Features of the course of the disease	Younger age; Relapses and remissions Shorter duration of symptoms; Intestinal fistulas Extraintestinal manifestations of CD (although TB involvement of the joints of the lower extremities, skin, eyes, and liver may mimic extraintestinal CD)	Chronic, continuous course of the disease; High temperature (>38.5 °C) without intra-abdominal abscess (although fever is seen in both CD and ITB)

Table 1.

Clinical, endoscopic, laboratory, radiological, histological features and features of the course of the disease of CD and 1 TB [14, 15, 16, 17, 18].

4. Yersiniosis, histioplasmosis, granulomatous enterocolitis

The presence of macroscopic lesions along with microscopic detection of inflammatory infiltration in the terminal ileum often leads the clinician to the diagnosis of Crohn’s disease. However, some of these cases may actually be Yersinia spp. infection, with or without CD, which can be easily diagnosed. John K. Triantafillidis et al. recommended testing serum antibodies against YOP antigens in all patients with endoscopic and histological evidence of terminal ileitis to identify yersiniosis with or without terminal ileal CD [19, 20].

In recent years, inflammatory lesions of the terminal ileum mucosa have been increasingly recognized due to easy endoscopic access. Moreover, the histological finding of inflammation in symptomatic individuals prompted endoscopists to hastily diagnose Crohn’s disease in the absence of a recent history of drug use or viral infection. However, a number of these cases may actually correspond to Yersinia infection, as tests for serum antibodies against Yersinia outer protein (YOP) antigens are not usually performed. Thus, it is reasonable to assume that some cases characterized as CD, especially those of mild severity, are in fact cases of yersiniosis that resolve spontaneously or are followed by treatment with ciprofloxacin, the antibiotic commonly used by most gastroenterologists worldwide in patients with CD. It is not known whether the coexistence of Yersinia infection and CD in the same patient increases the severity of the underlying enteropathy. In addition, the ability of Yersinia to survive in natural specimens and thrive at low temperatures means that the true contribution of this pathogen to disease may be underestimated.

YE has been isolated from patients in many parts of the world, but appears to be predominantly found in cooler climates, including northern Europe, Scandinavia, and Japan. The prevalence of infection is higher from November to January. In the US, YE infection accounts for 5% of intestinal infections among children under 5 years of age. Isolation of YE in developing countries is rare [21]. YE is transmitted to humans through water, food, soil and animals. YE has also been isolated from flies found in piggeries and farm kitchens, suggesting that arthropod/insect vectors may contribute to animal-to-human transmission of Yersinia [22]. The infection is transmitted mainly by the fecal-oral route. Consumption of pork (especially undercooked) or raw pork products is a cause of yersiniosis. Outbreaks from drinking water contaminated with this pathogen have also been reported. There are reports of cases of transmission from an infected pet and through transfused blood products. It is important to emphasize that infected people can pass YE in their stool for at least 90 days after the symptoms have disappeared.

Zadernowskaya et al. have shown that blue cheese may be a suitable growth medium for YE. Given the fact that YE can grow under cold conditions, they can pose a real threat to human health [23]. In patients diagnosed with TI, an infectious cause can be found in a third of cases; including Yersinia spp., CD can also be demonstrated in 12.1% of patients [24]. Taking into account these two critical conditions, namely Yersinia infection and CD, it can be concluded that TI can occur under three conditions: TI due to Yersinia infection, TI due to CD, and TI due to the coexistence of Yersinia infection with CD. Yersinia species are often found in small amounts in the terminal ileum in both healthy individuals and patients with TI. According to the latest data, Y. infection was detected in CD tissues no more often than in tissues of inflammatory and non-inflammatory control [25]. However, in a study to determine the seroprevalence of anti-Yersinia antibodies in 750 healthy Austrians using the recomBlot Yersinia Western blot kit, an overall seroprevalence of 29.7% was found. Seroprevalence increased significantly with age: from 24.7% in the group of people aged 19 to 24 years to 38.5% in the group of people over 44 years of age. This high seroprevalence contrasts with the small number of reported cases suggesting a subclinical or mild infection [26]. Knösel et al. showed that although several potential pathogens can be detected in tissue samples from CD patients, these pathogens can also be detected in controls, suggesting that many infectious pathogens may be associated with CD, but they are not necessarily cause [27]. In a subsequent study of 44 Crohn’s disease patients tested for Yersinia infection, a significant proportion of patients (39%) were positive [28]. Finally, a German study found an average annual incidence of yersiniosis of 7.2/100,000 population, with a higher incidence found in children under 5 years of age. About 90% of infections occurred within the country. The predominant serotype was O:3 [29]. Intestinal yersiniosis can present with TI, enteritis, mesenteric lymphadenitis, pseudoappendicitis, and septicemia. The incubation period is usually 4 to 6 days (1 to 14 days). Acute infection may result in mucosal ulceration (usually in the terminal ileum and rarely in the ascending colon), necrotic Peyer’s patches, and mesenteric lymph node enlargement. Symptoms include diarrhea or bloody stools, abdominal pain, and fever. The duration of diarrhea in acute yersiniosis can be from 12 to 22 days. The infection usually resolves within a few weeks with or without antibiotics. However, complications such as reactive arthritis can appear 1–4 weeks after infection, with an increased risk if a person tests positive for the MHC HLA-B27 allele [30].

Yersiniosis is difficult to distinguish from other causes of acute diarrhea. Localization of pain in the right hypochondrium can be a diagnostic sign of yersiniosis. Sepsis has been described in patients who are immunocompromised or in a state of iron overload. Acute yersiniosis can also mimic appendicitis (pseudo-appendicitis), which presents with right lower quadrant pain, fever, vomiting, elevated white blood cells, and diarrhea. Emergency surgery demonstrates inflammation of the terminal ileum and mesenteric lymph nodes with a normal appendix [31]. In a study aimed at elucidating the long-term prognosis in patients with TI, it was found that isolated acute TI detected during diagnostic ileocolonoscopy rarely leads to a definitive diagnosis of CD (4.6%) and that only the presence of strictures on a transverse section can predict the development of celiac disease [32]. In patients with Yersinia infection and symptoms suggestive of acute appendicitis, abdominal MRI may show evidence of TI with a normal appendix. Further examination in these cases may reveal Yersinia infection [33]. Yersinia infection can also present with liver or spleen abscesses [34], bacteremia, septic arthritis [35] or aseptic skin abscesses [36].

Yersinia infection may precede the diagnosis of CD. Zippi et al. described a patient with mesenteric adenitis due to yersiniosis who was subsequently diagnosed with CD [37]. Whether the presence of microorganisms is an epiphenomenon or actually a contributing factor to the pathogenesis of CD is currently unknown. Homewood et al. [38] described another case of terminal ileitis caused by YP infection. The patient was subsequently diagnosed with CD [39, 40, 41]. In addition, YE DNA was found in the histology of colonic and mesenteric lymph node resections in a number of CD cases. In a related study, the incidence of inflammatory bowel disease was found to be higher in anti-YE serum antibody-positive patients than in antibody-negative group [42]. The incidence of reactive arthritis following YE infection varies across countries. The knee and ankle joints are most commonly affected. In most cases, two to four joints are involved sequentially and asymmetrically over a period of several days to 2 weeks. In two-thirds of cases, acute arthritis persists for 1 to 4 months. Chronic joint disease or ankylosing spondylitis is rare. Gastrointestinal complications include intestinal perforation, peritonitis, ulcerative ileitis and colitis, intussusception, paralytic ileus, cholangitis, mesenteric vein thrombosis, toxic megacolon, liver and spleen abscesses, liver failure, and small bowel necrosis, and extraintestinal complications include septicemia, renal failure, abscess, osteomyelitis, lung abscess, endocarditis, purulent lymphadenitis, skin infection, fungal aneurysm, myocarditis and glomerulonephritis.

Diagnosis depends on a detailed history, physical examination, laboratory findings, and imaging. The diagnosis can also be confirmed by positive cultures obtained from mesenteric lymph nodes, pharyngeal exudate, peritoneal fluid, or blood. Polymerase chain reaction and immunofluorescent analysis have been developed. Endoscopy and imaging studies (ultrasound or CT) are often required to determine whether a patient has appendicitis or pseudo-appendicitis. Serological tests, including ELISA assays and immunoblotting for the detection of IgG, IgA, and IgM, are used in many countries. The detection of antibodies against YOP has made a significant contribution to the diagnostic arsenal. Antibodies against the microorganism are produced shortly after infection and persist for a long period of time. Antibody levels begin to rise during the first week of illness, peak in the second week, and then return to normal within 3 to 6 months. However, antibodies can remain detectable for several years. Polymerase chain reaction is now suspected in patients with suspected terminal ileitis as culture-based diagnostics of Y. infection are gradually being replaced by molecular tests. DNA microarray for pathogenic organisms, a relatively new technique that is used to identify several genes of various types of pathogens, has been used to diagnose Y. infection. Endoscopy is very useful in identifying mucosal lesions in the terminal ileum and obtaining a biopsy to assess the extent and type of inflammation. Results can vary and in most cases are relatively non-specific. Typically, in patients with YE infection, aphthoid ulcers may be found in the caecum, and small rounded elevations and ulcers may be demonstrated in the terminal ileum, and exudates may be present; the left side of the colon is usually not affected. In one study of eight patients, with fecal isolation of Yersinia and serum anti-Yersinia antibodies, all had terminal ileum involvement followed by involvement of the ileocecal valve and caecum and, to a lesser extent, the ascending colon [43]. The main endoscopic findings were round or oval elevations with or without ulcers in the terminal ileum. However, small ulcers have also been found in the ileocecal valve as well as in the caecum [43]. Interestingly, these endoscopic findings were visible 5 weeks after symptom onset.

Histologic evidence of Yersinia infection is not pathognomonic and usually indicates only acute and/or chronic inflammation. Focal villous atrophy and crypt hyperplasia with mixed acute and chronic inflammation and focal neutrophilic cryptitis, as well as epithelial cell granulomas consisting of histiocytes and small T-lymphocytes and plasma monocytes with suppurative centers have been reported [41, 44]. Whereas small bowel infection caused by yersiniosis results in the formation of necrotizing granulomas, small bowel adenoviral lesions cause marked lymphoid hyperplasia, which in turn can lead to obstructive or intussusception ileus [45]. In biopsy material, because necrotizing granulomas are usually located deep. Adenovirus affects more epithelial cells.

In immunosuppressed patients, a number of other pathogens can be detected, for example, cryptococcal enteritis, histoplasmosis.

Histoplasmosis is the most common endemic pathology [46]. Immunosuppressive status increases the risk of developing severe disease, but gastrointestinal histoplasmosis can occur in immunocompetent patients and mimic Crohn’s disease. Lamps and all [46] studied 56 biopsies stained with silver and H&E from 52 patients. In 43% of patients, the disease manifested itself more with signs of gastrointestinal damage than with signs of lung damage. Grossly, changes in the gastrointestinal tract were represented by ulcers (49%), nodules (21%), bleeding (13%), obstructive growths (6%), and normal mucosa (23%). Microscopic changes included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%) or minimal inflammatory response (15%), and very rarely regular granulomas (8.5%). The most common finding in the liver was lymphohistiocytic infiltration in the region of the portal tracts. Focal granulomas in the liver were observed in less than 20% of cases. In these groups, about half of the patients were immunocompetent, which highlights the need to consider the possibility of developing this pathology before making a diagnosis of Crohn’s disease. The differential diagnosis of granulomatous enterocolitis includes enterocolitis, which develops in a number of diseases accompanied by the formation of granulomas in other organs. Some infectious diseases are relatively specific for the gastrointestinal tract, for example, the above-mentioned yersiniosis, some variants of salmonellosis. The granulomatous process in yersiniosis is centered around Peyer’s patches.

Some forms of immunodeficiency can also lead to the development of granulomatous colitis. Chronic granulomatous disease is a hereditary disorder manifested by immunodeficiency caused by a mutation in any of the genes encoding various subunits of the superoxide-forming phagocytic NADPH oxidase system, which is responsible for an oxidative burst that leads to the death of microorganisms. Chronic granulomatous disease can affect the gastrointestinal tract in about a third of patients and is manifested by a pronounced accumulation of macrophages and eosinophils. Granulomas, if present, are usually irregularly shaped and the macrophages are pigmented. Rare cases of common variable immunodeficiency are also characterized by the formation of granulomas, the hallmark of common variable immunodeficiency is the absence of plasma cells in its own plastic and apoptosis. If other granulomatous lesions are excluded, sarcoidosis, which is rare in the lower gastrointestinal tract, should be considered.

Cytomegalovirus infection in the small intestine has the same manifestations as in any other localization.

Escherichia coli is an exception among infectious colitis, as it leads to ischemic colitis. In such cases, neutrophils with crypt abscesses are detected, often localized in the upper half of the mucous membrane, and pronounced neutrophils in the lamina propria of the mucous membrane. Basal plasmacytosis, detected in inflammatory bowel diseases, is absent, the structure of the glands remains normal. Erosions and edema of the lamina propria are found. The disease stops on its own, its course correlates with what bacteria are found in the fecal masses. As the self-limiting colitis subsides (which often occurs by the time of biopsy), biopsy specimens show reactive epithelial changes, but the shape of the crypts remains unchanged. With regard to specific pathogens affecting the colon, bacterial colitis is often caused by Campylobacter spp. or Aeromonas spp., but bacteriological and cultural examination of feces is required to accurately determine the pathogen. In cases of immunodeficiency, cytomegalovirus and various parasites may be found in the colon. Colon biopsies show schistosome and Strongyloides eggs. In patients with HIV, biopsy specimens show characteristic giant cell colitis.

Colon spirochetosis is a characteristic condition in which the surface of the colon is lined with numerous organisms stained using the Warthin-Starry method. The disease is manifested by abdominal pain, appendicitis, chronic diarrhea, and in some cases rectal bleeding. In most cases, spirochetosis is an incidental finding that is not accompanied by overt clinical manifestations. On endoscopic examination, the mucosa may appear completely normal, or there may be areas of ulceration, erosion, edema, and/or hyperemia of the mucosa. In most cases, the causative agents of spirochetosis are the anaerobic intestinal spirochetes Brachyspira aalborgi and Brachyspira pilosicoli. B. pilosicoli colonizes the intestinal tract of many animals, especially pigs, and is found in the feces of 30% of people in developing countries.

5. Behçet’s disease

Behçet’s disease (BD) is a chronic multisystem inflammatory disease characterized by recurrent oral and/or genital aphthous ulcers and may be complicated by thrombotic and/or inflammatory lesions of the skin, eyes, joints, gastrointestinal tract, and/or CNS. The disease is most common in East Asia and in the countries of the Mediterranean basin. The incidence of gastrointestinal involvement in Behcet’s disease varies and is 2.8% in patients in Turkey, 32% in Taiwan, 37–43% in the United States, and 50–60% in Japan [47].

Intestinal BD and inflammatory bowel disease share a considerable number of genetic backgrounds, pathogenesis, and clinical features. Moreover, current therapeutic strategies for intestinal BD have many similarities to those of IBD. Some experts classify the two diseases as the same category of a single disease or as different spectrums of the same disease; others regard them as totally different diseases (see Table 2) [48].

	Similarities	Distinctions
Genetics	Interleukin (IL)-10 and the IL-23R-IL-12RB2 loci	Human leukocyte antigen-B51 allele MHC class I related gene A
Immunology	Activation of innate and adaptive immune system; Increased Th1, Th17, CD4+ and CD8+ T cell, and γδ + T cell activities; Increased Th1-type cytokines; The rate of anti-Saccharomyces cerevisiae antibodies detection is remarkably higher; Bacterial contribution to the disease development	Serum anti-Herpes simplex virus-1 antibodies in the patients with BD were significantly higher than controls; Heat shock protein (HSP) stimulate γδ + T cells in BD patients because of homology between Streptococcus sanguis and human HSP; Anti-endothelial cell antibody
Clinical findings	Wide variation of abdominal symptoms from mild discomfort to hematochezia Similar extra-intestinal manifestations	Rare anorectal involvement in intestinal BD; Possible ischemic damage from vasculitis
Endoscopic findings	Segmental involvement; Various type of ulcerations are able to seen Grossly normal looking intervening mucosa; Mucosal healing is closely related with favorable clinical course	Fewer number of lesion; Large size of ulceration; Round or oval shaped ulceration; Relatively more discrete and elevated border of ulceration
Histologic findings	Non-specific inflammation (lymphocytic or neutrophilic infiltrations)	Vasculitis can be seen; Absence of non-caseating granuloma
Disease activity index	Concordance with clinical disease activity Discordance with endoscopic disease activity	Highly weighted general condition of patient and abdominal pain; Less concern for laboratory test and diarrhea
Treatment	5-amino-salicylates/sulfasalazine, corticosteroids, thiopurines, thalidomide, and biologic agents are used for intestinal lesion	Concomitant use of medications for systemic BD is frequent
Prognosis	Similar admission, operation, and post-operative recurrence rate	Higher cumulative rate in use of corticosteroids and immunomodulators

Table 2.

Similarities and distinctions of intestinal Behçet’s disease (BD) with Crohn’s disease [48].

In 1990, the International Study Group (ISG) for BD established a set of diagnostic criteria [48]. The ISG criteria for BD are not a perfect tool and cannot replace clinical judgment, but they are helpful for reminding clinicians of the most important diagnostic features of BD [48]. However, the ISG criteria for BD do not include intestinal symptoms.

Based on the ISG criteria, the diagnosis is clinically verifiable and includes recurrent oral aphthae (≥3 recurrences per year) (see Figure 2) plus any 2 of the following: genital aphthae (see Figure 3), ocular lesions, skin lesions and/or a positive pattern test [49].

Figure 2.

Oral lesions in Behçet’s disease (unpublished materials from the authors’ archives (Babayeva G.H.)). (a) the patient is 18 years old (b) the patient is 31 years old.

Figure 3.

Genital lesions in Behcet’s disease (unpublished materials from the authors’ archives (Babayeva G.H.)). (a) 18-year-old patient (b) 31-year-old patient, signs of genital ulcers.

Although the ileocecal region is most commonly affected in intestinal BD, other regions of the GI system may also be involved, including the esophagus, stomach, duodenum, jejunum, and colon (see Table 3) [50].

Anatomie site(s)	Gastrointestinal manifestation(s)
Esophagus	Ulcers,* esophagitis, fistulae, strictures, varices
Stomach, small intestine, colon	Ulcers*
Anal/rectal region	Ulcers,* fistulae, abscesses, proctitis, fissures
Liver	Budd-Chiari syndrome (acute, subacute, or chronic), fatty liver disease, hepatomegaly, congestion, cirrhosis
Spleen	Splenomegaly, congestion
Pancreas	Acute pancreatitis

Table 3.

Gastrointestinal manifestations of Behçet Disease (Adapted from Bayraktar Y, Ozaslan E, Van Thiel DH) [50].

*

Ulcers are typically round, deep, and well demarcated, regardless of their location.

In 2020, the Japanese Society of Gastroenterology published “Evidence-based diagnosis and clinical practice guidelines for intestinal Behcet’s disease 2020 edited by Intractable Diseases, the Health and Labor Sciences Research Grants” [51].

Typically, volcano-shaped ulcers (see Figure 4) around the ileocecal region, right lower abdominal pain, and bloody stool are observed in intestinal BD (see Figure 5). Occasionally, patients experience severe abdominal symptoms as a result of ileus, perforation/penetration, and massive hemorrhage [52]. Intestinal BD is suspected when patients with BD (including suspected BD) present with these symptoms [53]. However, it is sometimes difficult to diagnose patients who have not been diagnosed with BD and do not present these symptoms. Differential diagnosis from other diseases, such as CD, is established while considering the presence/absence of local symptoms of BD, including recurring oral aphthae [52, 53].

Figure 4.

Typical ileocecal ulcer in a patient with Behcet’s disease.

Figure 5.

Algorithm for a definite diagnosis of intestinal BD.

The intestinal phenotype of BD is characterized by gastrointestinal manifestations that include, but are not limited to, chronic abdominal pain, diarrhea, gastrointestinal bleeding, mucosal ulceration, and intestinal perforation. Two forms of intestinal manifestations of Behcet’s disease can be distinguished: mucosal ulcers resulting from neutrophilic infiltrates, which can mimic IBD, and intestinal ischemia and infarcts due to large vessel vasculitis, especially mesenteric [54]. To date, there is no consensus in the world regarding the diagnosis of this phenotype of BD.

In one study, up to 50% of BD patients with intestinal lesions required surgical interventions associated with intestinal perforation, gastrointestinal bleeding, and fistula formation [55]. Any part of the gastrointestinal tract can be involved in the pathological process, most often the terminal ileum and the ileocecal intestine. Three types of ulcers have been described in the colon: volcanic, geographic, and aphthous. Volcanic ulcers have the highest risk of perforation, especially in patients younger than 25 years of age. Rectal and/or anal involvement is rare.

When examining biopsies of the superficial layers of the mucosa, only nonspecific changes are found: signs of chronic active inflammation of the mucosa, changes in architectonics with possible ulceration, resembling inflammatory bowel diseases. The most important diagnostic feature is characteristic vasculitis, which is often only possible to detect when studying the surgical material of the resected intestine.

The intestinal phenotype of BD and IBD has a sufficient number of similarities, in particular: the onset of the disease occurs at a young age, nonspecific gastrointestinal symptoms and similar extraintestinal manifestations, as well as a chronically relapsing course of the disease are noted. The similarity of the two diseases and the lack of reliable diagnostic criteria make differentiation difficult.

One retrospective study showed that extraintestinal systemic manifestations and characteristic endoscopic features such as distribution, size, and type of ulcer may contribute to the differential diagnosis of the intestinal phenotype of BD from CD [56]. Focal lesions, deformity of the ileocecal valve, solitary and large ulcers (ulcer size >2 sm), ulcer tendency to merge around the circumference were more frequent in patients with the intestinal form of BD (Figure 6) [2, 5, 8]. A Korean study proposed a new and simple diagnostic criterion based on two aspects: colonoscopy findings and extraintestinal manifestations [57]. This added additional features, especially in patients with ileocolonic ulcers, who do not fully meet the diagnostic criteria for systemic BD [58]. The clinical and endoscopic features of CD and BD are listed in Table 4, Table 5 and Figure 7.

Figure 6.

Endoscopic image of the lesion of the ileocecal region in Behcet’s disease (single, rounded, large ulcers) [5].

Peculiarities	CD	BD
Clinical:
Abdominal pain	Usually associated with intestinal obstruction	Severe pain without signs of intestinal obstruction
Ulcers in the oral cavity (see Figure 2)	Specific	≥3/year, painful
Ulcers in the genital area (see Figure 3)	Not specific	Present
Endoscopic: (See Figures 4 and 6)	Longitudinal	Round
Ulcer shape
Spreading	Segmental	Focal, solitary
Areas involved	Ileocecal	Ileocecal

Table 4.

Clinical and endoscopic features of Crohn’s disease and Behçet’s disease.

	Behçet’s Disease	Crohn’s Disease
Gender (M/F)	49–0.57	2.9–0.76
Symptoms onset age (yr)	20.8–40	15–29
Average age at diagnosis (yr)	24.7–35.7	29.5–31
Oral aphtous ulcers (%)	Approximately 100	< 10
Uveitis (%)	57–69	< 10
Skin lesions (%)	61–87	< 10
Arthritis (%)	30–57	2–24.7
Gastrointestinal involvement (%)
Ileocecal area	50–94	40–83
Colon	10–15	32–50
Upper GI	1–3	4
Perianal	1–2	10–15
Intestinal complications (%)
Perforation	12.7	8.7
Fistula	7.6	24.7
Stricture	7.2	38.3
Abscess	3.3	19.6
Endoscopic Morphology	Round-oval shape	Longitudinal ulcers with a cobblestone appearance
	Focal, solitary	segmental and diffuse distribution
	Volcano-shaped
	Deep ulcers
Mucosal Biopsy	Vasculitis	Granuloma
	Neutrophilic infiltration	Focal cryptitis
	Fibrinopurulent exudates	Nerve fiberhyperplasia
	Necrotic debris	Lymphoid aggregates

Table 5.

Distribution of similarities and differences in the differential diagnosis of Behçet’s disease and Crohn’s disease [2, 3, 7, 9, 10, 15, 57, 58, 59, 61, 67, 80].

Figure 7.

Similar and different characteristics of Behçet’s disease and Crohn’s disease [60]. F: Female; M: Male; ASCA: Anti-Saccharomyces cerevisiae antibodies; ANCA: Anti-Saccharomyces cerevisiae antibodies; ANCA: Anti-neutrophil cytoplasmic antibodies.

6. Infectious colitis

Infectious colitis usually presents with sudden onset of symptoms (characterized as acute self-limited colitis). In developing countries, infectious colitis remains one of the most common causes of diarrhea that can mimic IBD. Colitis can be caused by bacterial and parasitic infections, ileitis can be the result of yersiniosis and salmonella infections, and ileocolonic ulcers can be seen with amebiasis. Symptoms of acute infectious colitis are sudden onset, early fever and diarrhea (more than 6 times a day), which can also be in the acute course (fulminant course) of CD. Extraintestinal symptoms and signs such as arthropathy, ophthalmic, and skin symptoms may also be present in acute self-limited colitis but are more common in CD. Stool examinations play an important role in confirming the diagnosis of infectious colitis. In such situations, endoscopy (sigmoidoscopy or total colonoscopy) with the collection of biopsies from the mucous membrane can be very informative.

Histological examination of the biopsy specimen in acute infectious colitis showed that the structure of the crypt was normal, the inflammation of the mucous membrane was predominantly acute; there is no increase in plasma cells or lymphoid aggregates at the base of the crypts. Histological examination of IBD biopsy samples, even in the early course, often reveals crypt deformity, basal plasmacytosis and basal lymphoid aggregates, as well as an increase in the number of cells in the lamina propria in the stages of acute and chronic inflammation [59]. But with the chronicity of the infectious process or with an inadequate choice of antimicrobial therapy, the histological picture begins to change with elements of the lesion characteristic of the complicated course of IBD, in particular, the complicated course of Crohn’s disease combined with an infectious agent. Сhronic schistosomatous colitis may mimic a complicated course of Crohn’s disease with concomitant infection (see Figure 8) [2, 5, 9, 60].

Figure 8.

Endoscopic image of chronic schistosomatous colitis (histologically verified) [5].

Enterohemorrhagic E. coli, which in most cases leads to the onset of ischemic colitis, can mimic an IBD-like lesion, and also occur with overlap syndromes in patients with СD, which makes diagnosis extremely difficult, since due to disturbances in the hemodynamic flow in patients with СD, it is quite ischemic bowel disease is common. The defeat of E. coli is characterized by the appearance of a neutrophilic cryptal abscess, more often localized in the upper half of the mucous membrane, and pronounced neutrophils in the lamina propria of the mucous membrane. Basal plasmacytosis, characteristic of IBD, is absent, the structure of the glands is normal, erosion and edema of the lamina propria of the mucous membrane are found (see Figures 8 and 9). The disease can stop on its own; its course correlates with what bacteria are found in the fecal masses. As the colitis subsides (which is quite common by the time a biopsy is taken), reactive changes in the epithelium are found in the biopsy specimens, but the shape of the crypts remains unchanged.

Figure 9.

Morphological image of the biopsy material of the intestine (unpublished date from the archives of the authors (Musayev C.S.)). (a) Crohn’s disease (biopsy fragment taken from the area of the mucous membrane of the caecum): formed granulomas in the lamina propria with accumulation of lymphocytes and histiocytes (stain: Hematoxylin and Eosin; magnification: x200). (b) infectious colitis (E. Coli O157:H7): diffuse hemorrhages, swelling, erosion, lymphocytic and neutrophilic infiltration of the colon mucosa (stain: Hematoxylin and Eosin; magnification: x200).

Intestinal amebiasis should be included in the differential diagnosis of CD and UC, not only in endemic countries. Some endoscopic and histological features may be useful for differential diagnosis, for example, at endoscopy in patients with amebiasis, discrete small ulcers 2 mm or less in diameter are most often detected in the caecum or rectosigmoid region. With regard to histology, amebic trophozoites are most often localized in necrotic material, mucin, proteinaceous material, and intestinal mucosa [61].

Necrotizing epithelioid granulomatous inflammation may occur in Yersinia pseudotuberculosis infections; in infection with Yersinia enterocolitica, accumulations of macrophages may be found. It is the formation of granulomas that creates difficulties for the morphologist in terms of determining their specificity for Crohn’s disease. It is necessary to take into account the fact that with yersiniosis the granulomas are larger than with Crohn’s disease. Morphological changes in pseudomembranous colitis are also similar to changes characteristic of CD. More Lamps et al. in 2000 pointed to the propensity of histioplasmosis of the gastrointestinal tract to cause changes similar to those in CD. These two pathologies are quite often manifested by common symptoms: fever, weakness, gastrointestinal bleeding, diarrhea, nausea, vomiting, ulcers and cracks, perforation, and due to the presence of granulomas and inflammatory changes that capture the entire thickness of the intestinal wall, they are quite often mistaken for Crohn’s disease.

Lymphogranuloma venereum is a disease caused by three unique strains of Chlamydia trachomatis and characterized by small, often asymptomatic skin lesions accompanied by localized enlargement of the lymph nodes in the groin or pelvis. If infection occurred due to anal sex, then it can manifest itself in the form of severe proctitis. Venereal lymphogranuloma occurs in three stages.

Stage 1 begins after an incubation period of approximately 3 days with a small skin lesion at the site of contact. This can cause cracks (ulceration) to appear on the top layer of the skin, but they heal so quickly that it may go unnoticed.

Stage 2 usually begins in men after about 2 to 4 weeks, with enlargement of the inguinal lymph nodes on one or both sides and the formation of large, painful, sometimes fluctuating masses (buboes). The buboes penetrate deeper tissues and make the top layer of the skin inflamed, sometimes accompanied by fever and malaise. In women, low back or pelvic pain is common; the initial lesions may be on the cervix or upper part of the vagina, leading to enlargement and deeper inflammation of the perirectal and pelvic lymph nodes. Multiple drainage fistulas may appear, through which pus or blood comes out.

In stage 3, lesions heal with scarring, but fistula cavities may remain or reappear. The persistent inflammation from an untreated infection clogs the lymphatic vessels, causing skin sores and swelling.

People who practice anal sex in a passive role at the 1st stage may suffer from severe proctitis or proctocolitis with bloody-purulent rectal discharge. In the chronic stages, colitis mimicking Crohn’s disease can cause tenesmus and strictures in the rectum or pain due to inflamed inguinal lymph nodes. Proctoscopy may reveal diffuse inflammation, polyps and masses, or mucopurulent exudate, symptoms that closely resemble inflammatory bowel disease.

A similar clinical, endoscopic and morphological picture with rectal CD is characteristic of sexually transmitted infections (see Table 6).

Gonorrheal proctitis	Clinically: Pain in the rectum and anus, purulent, mucous, spotting, tenesmus, imperative urge to defecate are possible; Endoscopically: picture of non-specific ulcerative lesions; Histologically: corresponds to acute nonspecific proctitis
Chlamydial proctitis	Clinically: Pain in the rectum and anus, purulent, mucous, spotting, tenesmus, imperative urge to defecate are possible; Endoscopically: ulcer picture; Histologically: it resembles Crohn’s disease (the predominance of lymphohistiocytic and plasmacytic infiltration of the submucosa, muscular and serous membranes with hyperplasia of the elements of the submucosal and muscular-intestinal plexuses is characteristic, excessive thickening and fibrosis of the intestinal wall can be detected, spreading only within the rectum, specific in surface biopsy changes may not be
Proctitis syphilis	Clinically: Pain in the rectum and anus, purulent, mucous, spotting, tenesmus, imperative urge to defecate are possible; Endoscopically: granularity, slight vulnerability, hyperemia, thickening or ulceration of the mucous membrane; Histologically: neutrophilic cryptitis with ulceration, granulation tissue and marked lymphoplasmacytic infiltration of the adjacent mucosa and submucosa, immature granulomas may be found

Table 6.

Clinical, endoscopic and histological signs of infectious proctitis caused by pathogens of sexually transmitted infections.

Infections not only mimic CD, but can also worsen the course and outcome of CD treatment. Thorough screening for infections is always necessary before making a diagnosis of IBD and initiating immunosuppressive treatment in these patients.

7. Diseases of the vascular system mimicking IBD

Various diseases based on damage to the vascular system can mimic IBD.

Systemic vasculitis is a heterogeneous group of diseases and is classified depending on the type and size of vessels involved in the pathological process, which, in turn, determines the area and type of ischemic damage [62, 63]. Depending on the type of vasculitis, intestinal involvement ranges from widespread intestinal infarcts in large vessel vasculitis to focal, segmental ischemia and ulceration due to intramural artery involvement in small vessel vasculitis [62, 64]. Clinically, the intestinal manifestations of vasculitis range from mild abdominal pain to serious and potentially life-threatening complications such as peritonitis and intestinal perforation. The frequency and type of these intestinal manifestations depends on the type of systemic vasculitis. The most common intestinal manifestations of systemic vasculitis are given in Table 7.

Vasculitis	Intestinal manifestations and their frequency
Vasculitis of large vessels
Arteritis Takayasu; (non-specific aortoarteritis)	Vascular murmurs (14%) [65]; diffuse ischemia of the gastrointestinal tract (4%) [65]; stenotic or occlusive lesions in the abdominal aorta and/or superior mesenteric arteries (25%) [66].
Giant cell arteritis	Mesenteric ischemia [67].
Medium vessel vasculitis
Polyarteritis nodosa	Abdominal pain (up to 95%) [68, 69]; intestinal ulcers (5–6%) [68, 69]; narrowed cone-shaped and/or saccular arteries, fusiform microaneurysms in the mesenteric arteries (85%) [70]; occlusions and stenosis of the superior mesenteric arteries, infarcts and thickening of the intestinal wall [71].
Kawasaki disease	paralytic ileus, appendicular vasculitis and hemorrhagic duodenitis (5–20%) [72, 73].
Vasculitis of small vessels
ANCA-associated vasculitis	Mucosal ulcers, intestinal infarction, ischemia, perforation or occlusion (20–50%) [68]; MPA: ischemic colon ulcers, peritonitis and intestinal perforation [68, 74]; GPA and EGPA: granulomatous ulceration of the colon (may mimic IBD) [68].
IgA vasculitis (Schonlein-Henoch purpura)	Mucous purpura (20–50%) with gastrointestinal bleeding (18–52%) [75, 76]; swelling of the intestinal mucosa, infarction, diffuse hyperemia of the mucous membrane, hemorrhagic erosions, perforation or invagination (3–5%) [75, 76].
Cryoglobulinemic vasculitis	Intestinal ischemia (80%) [68, 77].
Behçet’s disease	Ileocecal ulcers [47]

Table 7.

Intestinal manifestations of systemic vasculitis.

Notes: ANCA, anti-neutrophil cytoplasmic antibodies; IBD, inflammatory bowel disease; MPA, microscopic polyangiitis; EGPA, eosinophilic granulomotosis with polyangiitis; GPA - granulomatosis with polyangiities.

Clinical symptoms of intestinal damage may be detected at the initial manifestation of the disease or occur during a relapse; may be the only manifestation of the disease.

Diagnosis of intestinal involvement within systemic vasculitis can be quite challenging for the clinician. Patients with GI involvement associated with systemic vasculitis usually present with a range of nonspecific complaints: fever, abdominal pain, nausea, vomiting, diarrhea, and gastrointestinal bleeding. For diagnosis, the most informative are instrumental research methods. So, for example, catheter angiography of blood vessels is the “gold standard” for diagnosis in case of suspected damage to the mesenteric vessels. Computed tomography and magnetic resonance angiography can also be useful for diagnosing gastrointestinal vascular lesions in vasculitis [78].

Endoscopic examination in patients with suspected bowel involvement as part of systemic vasculitis is a less informative diagnostic method. Due to the increased risk of perforation in ischemic conditions inherent in systemic vasculitis, endoscopy should be performed with extreme caution. Video capsule endoscopy can be useful for visualizing lesions of the small intestine, areas of which are not accessible to conventional endoscopy, but the lack of a biopsy significantly reduces the information content of the method [62, 64]. Colonoscopic symptoms in the acute period often include edematous friable mucosa, erythema, and disseminated pale areas. More severe disease is characterized by mucosal cyanosis, diffuse hemorrhagic erosions, and/or linear ulceration [62, 64]. In the chronic phase of intestinal ischemia, mucosal atrophy and areas of granulation tissue can be detected.

Biopsies taken from affected areas may show nonspecific changes such as hemorrhage, ruptured crypts, capillary thrombosis, tissue granulation with abscesses, and pseudopolyps [62, 64]. Biopsy material taken from the area of post-ischemic stricture is characterized by extensive transmural fibrosis and mucosal atrophy.

At the moment, there is no single highly informative diagnostic laboratory test for vasculitis. Basic laboratory tests are most often used to determine the extent of organ damage and the extent of organ involvement. More specific serological tests, including antineutrophil cytoplasmic antibodies (ANCA), can also additionally help in the diagnosis of systemic vasculitis, but given the fact that in 60–70% of patients with UC, the ANCA test may be positive, then again the question differential diagnosis becomes debatable. The scientific literature presents an association of Takayasu’s arteritis with inflammatory bowel disease, suggesting a possible link between the two entities. In a North American cohort of 160 patients with Takayasu’s arteritis, 8 patients (5%) were diagnosed with IBD compared with a 0.2% prevalence of Crohn’s disease in the general population [79]. There is evidence of a genetic overlap between Takayasu’s arteritis and ulcerative colitis: the presence of HLA B52:01 as a common genetic determinant [80]. The diagnosis of IBD usually precedes the development of Takayasu’s arteritis (on average by 4 years) [62, 79].

It should be noted that the coexistence of these two diseases does not imply a worse prognosis for either IBD or Takayasu’s arteritis.

Granulomatosis with polyangiitis (GPA) is the most common primary systemic vasculitis. This is an autoimmune granulomatous inflammation of the walls of blood vessels, involving small and medium-sized blood vessels: capillaries, venules, arterioles, and arteries, with involvement of the upper respiratory tract, eyes, kidneys, lungs, and other organs [41, 62]. GPA is commonly associated with PR3-ANCA. Gastrointestinal symptoms occur in 5–11% of patients with GPA [81, 82]. Autopsy studies revealed histopathological evidence of gastrointestinal vasculitis in 24% of GPA cases. Any part of the gastrointestinal tract can be involved in the pathological process, but the most common are lesions of the small and large intestine. Symptoms range from transient abdominal pain and ulcers (oral, esophageal, and peptic) to bloody diarrhea and intestinal perforation [83]. Gastrointestinal imaging findings are generally nonspecific, ranging from multifocal or diffuse bowel wall thickening to mesenteric vascular stasis and ascites [70].

Endoscopy may reveal ulceration, sometimes described as granulomatous and ischemic changes. Compared with Crohn’s disease, the ulcers seen in GPA are more often shallow and transversely oriented, but making a differential diagnosis is difficult, as cases of concomitant Crohn’s disease (or ulcerative colitis) in GPA (or other autoimmune-associated vasculitis) have been described [79, 83, 84]. Standard endoscopic biopsy of colon ulcers has a low sensitivity (∼ 30–40%), but if the material is taken from deep layers, the specificity of the study increases. However, taking deep biopsies has a high risk of perforation in patients with vasculitis [62, 64].

In the scientific literature, there are also indications of the frequent coexistence of EGPA and IBD [79].

The main clinical manifestations in most patients with eosinophilic granulomatosis with polyangiitis (EGPA) are late-onset asthma, eosinophilia, cutaneous vasculitis (purpura), and/or multifocal mononeuritis. Serum MPO-ANCA is found in 30–40% of patients with EGPA. Cardiac involvement, more common in ANCA-negative patients, is a major risk factor for mortality [62, 63, 85]. In the study by Tsurikisawa et al. (2015) studied the pathology of the gastrointestinal tract and the role of T-helpers 17(Th17) in the pathogenesis of gastrointestinal manifestations in patients with EGPA. They had elevated levels of Th17 and serum intercellular adhesion molecule 1 (ICAM-1), colonic eosinophilia, and submucosal edema, which decreased in remission [86]. Similar changes are observed in IBD. Intestinal symptoms occur in 30–50% of patients with EGPA and are nonspecific and include abdominal pain (91%), diarrhea (45%), melena or hematochezia (19–36%), nausea and vomiting (18%), and acute stomach (6–36%).

Mesenteric artery vasculitis is the most common explanation for these manifestations and can lead to intestinal infarction and perforation, especially in the small intestine. Infiltration of the intestinal mucosa by eosinophils can also cause pain, dysmotility, obstructive symptoms, and diarrhea with the development of eosinophilic colitis. Granulomatous and eosinophilic mucosal ulcers have been described as potential sources of bleeding in the jejunum and/or, less commonly, the colon [68, 87].

8. Conclusion

As can be seen from the above material, the diagnosis of IBD continues to be a serious problem. We have considered only the most common pathologies that mimic the clinical picture of IBD. At the same time, one should not forget about drug-induced damage to the intestines (sodium phosphate, non-steroidal anti-inflammatory drugs, proton pump inhibitors, mycophenolate mofetil, chemotherapy drugs for oncological diseases, etc.).

For this reason, only a detailed collection of the patient’s history and a precisely adjusted examination plan can provide enough material to establish the correct diagnosis.

Lack of physician awareness of immune-inflammatory diseases, iatrogenesis, opportunistic infections, and, in certain cases, limited availability of some expensive diagnostic methods, as well as the lack of a state program for the prevention, diagnosis, treatment and rehabilitation of IBD, can lead to diagnostic errors. The incidence of IBD has increased over the past two decades and is expected to continue to rise in the next decade. To date, there are several global recommendations for the diagnosis and treatment of IBD in the world, which help to make the diagnosis accurate and the treatment standardized. Given the high prevalence of infectious enteritis/colitis, tuberculosis, Behçet’s disease, and systemic vasculitis, careful differentiation is always necessary before a diagnosis of IBD is made.

The realities of the status quo underscore the need for innovation in the healthcare system:

1. Based on the data obtained after conducting population studies, it is necessary to develop a National Health Care Program by creating an adapted National Guideline and the Center for the Study of IBD;

2. Improve the program of continuing medical education, incl. as part of a multidisciplinary approach for doctors of related specialties.

3. These measures will reduce the time to establish an accurate diagnosis, and due to the involvement of specialists in related pathologies in conditions overlapping with IBD, timely prescribe adequate therapy and achieve a decrease in disability and death rates in this category of patients.

Conflict of interest

The authors declare no conflict of interest.