Vol 46, No 5 (2018)

The altered gut microbiome (dysbiosis) is involved in the  pathogenesis of most  non-infectious  gastrointestinal diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome, colorectal cancer, celiac disease, hepatic encephalopathy, non-alcoholic  fatty  liver disease,  alcoholic  liver disease, cholelithiasis and  others. The molecular aspects  of the interaction  between dysbiotic microbiota and host immune system are considered in the context of IBD pathogenesis. The authors do provide  original interpretations  of the  concepts of taxonomic (microbiological) and metabolic (functional) dysbiosis. Special attention is paid to the hypothesis  that gut dysbiosis is caused not so much by structural changes  in the microbiome as by alterations  in microbial metabolism. Thus, the metabolome is a greater  predictor  of dysbiosis, than  the  taxonomic  composition  of the  microbiome. It is important to consider dysbiotic changes in the  gut  microbiota  in patients  with ulcerative colitis and  Crohn's  disease,  since  they  may  significantly affect the course and prognosis  of IBD. Factors  hampering  the   microbiota   assessment in  clinical practice  are  discussed  in  detail,  and advanced  dysbiosis tests, including  the  GA-map Dysbiosis  Test  (GA-test) and  the   Colonoflor-16 Test, are described. By means of clinical studies it is demonstrated that  a reduction  in the  genetic capacity of the  microbiome  for butyrate  synthesis, together with an increase in pathobionts and a decrease  in microbial diversity, is an important and necessary feature of dysbiosis in IBD patients. Thus, the butyryl-CoA:acetate CoA-transferase (BCoAT) gene  level can be considered  as a valuable biomarker to assess gut microbiota  function in clinical practice.  In  conclusion,  approaches to correct gut dysbiosis using probiotics, prebiotics, metabiotics  and fecal microbiota  transplantation as an addition to conventional treatment in IBD are critically discussed.

Background: Epidemiological studies  performed in different countries  have identified a number  of trends  that  allow to predict  the problems  related to the  prevalence  of inflammatory  bowel  diseases  (IBD),  their  severity  and  healthcare resources utilization. Aim:  To  present   comparative   results of two large epidemiological  studies of IBD in the Russian Federation (RF), i.e. ESCApe and ESCApe-2. Materials     and     methods:     Two    multicenter cross-sectional cohort studies with a similar design were performed  at three-year interval. The studies had the common aim: to identify social and demographic and clinical particulars of ulcerative colitis (UC) and Crohn’s disease (CD) in RF, as well as treatment options. Twenty (20) centers of gastroenterology from 17 RF regions participated in the ESCApe (2010–2011) and 8 centers from 7 RF regions in the ESCApe-2 study (2013–2014). Results: The ESCApe study included 1797 patients (1254 UC and 543 CD), whereas   the   ESCApe-2  included   1000  patients (667 UC and 333 CD). Patient demographic and social characteristics: In both  studies, female: male ratio was similar in UC and CD. Patients’ age was almost identical: in UC, median  age was 38 years and 40 years in ESCApe and ESCApe-2, respectively; in CD the  corresponding  values were  36 and 35 years. In ESCApe, the peak UC onset was at the age of 21 to 40 years, whereas in CD it was shifted towards younger age (22.5% of the patients  manifested before 20 years) and the peak incidence was in three age groups (below 20 years, 21 to 30 and 31 to 40 years).  A statistically significant difference between CD and  UC was found  only in the  age group  of 11 to 20 years (22.5% vs. 13.6%, respectively, p < 0.01). In ESCApe-2, median age of disease onset in UC and CD was approximately 30 years. In both  studies, urban:rural ratio for UC and CD was 4:1. In ESCApe, the proportion of current  smokers among  CD patients  was almost  two-fold  higher than  among  those  with  UC (15.6  and  8.8%,  respectively, p < 0.001); the same trend was found in ESCApe-2 (15 and 7.3%, p < 0.001). Socioeconomic characteristics of patients in both studies were similar: 50 to 60% were at work (professional occupation and income levels were not studied); in ESCApe 30.9% of UC patients and 40.9% of CD patients had legal disability due  to various reasons  (including that related to UC and CD in 12,6 and 14.9%, respectively), whereas in ESCApe-2 the respective proportions  were  35.7 and  51.1%.  Clinical characteristics of patients: The time from the  first UC symptoms to diagnosis  was similar in both  studies  (median, 5 months  in ESCApe and 4 months  in ESCApe-2); in CD patients  these parameters were significantly different in both studies (12 vs. 1 month). As for the severity of the disease, the UC patients  in ESCApe had  mild disease  in 16%, moderate in 53%, and severe in 31%, whereas the respective proportions among  the  CD patients  were 21, 44, and  35%. In ESCApe-2, there were no patients  with severe disease;  mild and  moderate UC were  diagnosed  in 51.3 and  46.6% of the  patients, respectively, and mild and moderate CD, in 52.3 and 47.3%. The frequency of left-side UC was similar: 38% in ESCApе and 34% in ESCApе-2. Proctitis was more frequent in the  first study  (33 vs. 11%, p < 0.01), and  total UC was more frequent  in the second  study (29 vs. 55%, p < 0.02). There were no significant differences between ESCApe and ESCApe-2 in the main CD localizations: terminal ileitis was seen  in 31.3 and 35.4% of the  patients,  respectively,  ileocolitis in 33.4 and 37.8%, colitis in 25.6 and 32.1%. The upper gastrointestinal involvement In ESCApе was found 4.4%, and mixed involvement  in 5.3%. In both studies, extra-intestinal  manifestations were more frequent  in CD, than  in UC: in ESCApe, 33.1% and 23% (р < 0.05), and in ESCApe-2 in 41.7 and 29.4%, respectively   (р < 0.05).   Peripheral   arthropathies were  most  frequent. Ankylosing spondylitis  was found in CD only, and primary sclerosing cholangitis, only in UC. Aphthous  stomatitis  was significantly more prevalent in CD in both studies. There were no significant differences in all other extra-intestinal symptoms  (eye and skin involvement). Treatment characteristics: Treatment options before the  study entry, as well as at the  study inclusion visit were analyzed. In ESCApe, the majority of the patients  had not been given any treatment before the study entry (49.1% with UC and 40.5% with CD). Three years later  the  situation  was changing: in ESCApe-2, the  proportion of treatment-naïve patients was 2.5 to 3-fold lower (15.3% with UC and 14.4% with CD), which was most probably related to increasing  awareness  of physicians. Before the study entry, most  patients  (40 to 70%) had  been treated with 5-aminosalicylic acid (5-ASA). Before the  second  study,  the  patients   were  more  frequently  treated with  glucocorticosteroids (GCS), immunosuppressors and  genetically  engineered biological agents  (GEBA),  but  with no significant differences  from the  first study. 5-ASA prevailed also  among  the  agents  that  were  administered during  the  inclusion visits in both  studies  (80 to 90% UC patients  and  about  70% of CD patients). Compared   to  ESCApe,  in  ESCApe-2  there   was a trend  towards  lower rate of GCS administration in UC and CD, but the differences did not reach the significance level. It may be explained  by the absence of severe IBD types in ESCApe-2. In ESCApe, immunosuppressors were rarely used (in 14.4% of the UC patients  and in 26.8% of the CD patients); however, in ESCApe-2 there were administered more  frequently: up to 35.9% of the  UC patients and 55.1% of the CD patients  (р < 0.01 for both cases). It was unknown  if immunosuppressors were used as monotherapy or in combination with GCS. Three years later, the rate of GEBA administration was also higher, but  this increase  was significant only in CD: 28.3%  in ESCApe-2 vs. 9.2% in ESCApe (р < 0.01). According to the results of ESCApe, in the UC patients steroid resistance was seen in 23% and steroid dependency in 21%, whereas in the CD patients these values were 24 and 27%, respectively. In ESCApe-2 these  parameters were not assessed. Conclusion:  Both studies  showed  a  number   of patterns coinciding  with  the  world  trends,  such as age and gender  distribution  of UC and CD patients, age at manifestation, the proportion of urban to rural residents, smoking status, prevalence and types of extra-intestinal  symptoms. Unlike in European countries, moderate and severe forms of UC with extensive involvement are prevalent in RF. Low prevalence  of mild and limited types of IBD is to be explained by underdiagnosis. Of note is the high proportion of patients  with UC and CD treated with 5-ASA, although in CD these  agents  have demonstrated low efficacy. The rates of immunosuppressors  and GEBA administration significantly increased  in the second  study, most likely, due to the  implementation of a  system  of educational measures. Nevertheless, the rate of GEBA use in IBD remains low, which is to be related to their insufficient availability. In total, steroid resistance / steroid dependency rate amount  to almost half of UC and CD cases. In general, some positive changes  in the patient  management are  obvious  in the  second study. However, monitoring  these  changes  over time could only be possible if similar studies would be performed at regular intervals.

Aim: To study epidemiology and risk factors of Clostridium difficile infection (CDI) and its association with colectomy rates in patients with ulcerative colitis (UC). Materials and methods: We retrospectively analyzed medical files of 1179 patients with inflammatory bowel disease who had been treated from January 1 to December 31, 2017, in the Loginov Moscow Clinical Scientific Center (Moscow, Russia). UC was diagnosed according to the International Classification of Diseases, v. 10 (ICD10: K51). Final analysis included data from 400 UC patients. Depending on the presence of preliminary CDI diagnosis, the patients were divided into two groups: 79 (19.75%) patients with UC had at least one confirmed CDI episode, whereas 321 (80.25%) patients had no history of CDI. Results: CDI prevalence in UC patients was 19.75%, and 88.6% of the infectious episodes were community-acquired, whereas only 5.1% occurred in the inpatients. Mean (± SD) age at CDI occurrence in patients with inflammatory bowel disease was 37.8 ± 12.9 years. Only 13.4% of the patients with UC and associated CDI had the history of antibiotic therapy, and 40.5% had been previously treated with steroids. Prolonged immunosuppressive therapy in UC patients was associated with CDI: 41.8% of those with CDI had been treated with azathioprine/6-mercaptopurin for a long time, while among those without CDI this treatment had been administered only to 14.6% (p < 0.001). CDI prevalence in the UC patients who had been treated with mesenchymal stromal bone marrow cells was significantly lower than in those who had been treated with genetically engineered biological agents, both with and without immunosuppressants (p < 0.05). Surgery (colectomy) was necessary in 3 out of 4 patients with extremely severe UC associated with CDI, and in 2 out of 18 patients with extremely severe UC exacerbation without CDI. Conclusion: Young UC patients are more susceptible to CDI and often do not have any conventional CDI risk factors. In UC patients, other risk factors than in the general population, may have a significant impact on the CDI occurrence. UC patients with CDI more often have a history of salicylate failure, they more frequently require biological treatments, have lower mean albumin levels and higher activity of the inflammation. Extremely severe UC episode associated with CDI significantly increases the risk of colectomy.

Eosinophilic gastrointestinal disorders (EGID) are a kind of pathology which has not been well studied and has a trend to an increase during the last years that raises concern. They may have highly variable clinical manifestations; therefore, their differential diagnosis is not infrequently challenging. The article presents a review of scientific data on EGID and three clinical cases of various eosinophilic lesions of the stomach and gut in children. Clinical manifestations of EGID depend on their location and on the depth of the lesions. The first clinical case presented with repeated gastrointestinal bleedings in a child with hemorrhagic eosinophilic gastritis. The second clinical case was eosinophilic colitis with Crohnlike clinical and endoscopic manifestations, and the third one was eosinophilic ileocolitis with ascites. All these children had a background of sensitization to various food allergens. However, there were no high specific IgE in blood in any of the cases, although IgE were identified in the biopsy sample of intestinal mucosa and in duodenal aspirates. The results of the mast cell degranulation test with corresponding allergens correlated with the efficacy of their elimination. Elimination diet was recommended to all the patients; in two patients it was combined with a short course of glucocorticosteroids and in one case with subsequent montelucast treatment. All three patients achieved complete recovery, confirmed by their follow-up and repeated endoscopic and histological examinations.

Antibiotic-associated diarrhea remains an unresolved problem in current medicine. In the last decade, in addition to idiopathic antibiotic-associated diarrhea, diseases caused by cytotoxin-producing Klebsiella oxytoca strains are becoming increasingly detected. Clinical manifestations of this infection may vary from relatively mild diarrhea without signs of hemocolitis to severe antibiotic-associated hemorrhagic colitis with predominant involvement of the right hemicolon. High prevalence of resistance to ciprofloxacin, tetracycline, gentamicin, amikacyne, and trimethoprim/sulfamethoxazole is associated with the presence of all adhesion genes of K. oxytoca and its greater cytotoxicity. The genes encoding the K. oxytoca cytotoxin (tilivalline) are a part of the pathogenicity island (PAI) and are similar to the clusters responsible for the biosynthesis of pyrrolobenzodiazepine and found in gram-positive bacteria. The most important pathogenicity factor related to the development of K. oxytoca-associated hemorrhagic colitis is a cytotoxin kleboxymycin, which is a tilivalline metabolite. The treatment strategy in K. oxytoca-associated hemorrhagic colitis is to withdraw the trigger antimicrobial agent, to refrain from administration of new antimicrobials, to administer rehydration and rational pathogenetically based therapy. Studies on the development of therapeutic bacteriophages against K. oxytoca are of pilot nature.

Immunoglobulin G4-associated sclerosing cholangitis (IgG4-SC) can mimic primary sclerosing cholangitis, cholangiocarcinoma, and pancreatic adenocarcinoma. Its proper diagnosis allows for an adequate therapy and an improvement of the outcomes. The article presents a short literature review with an emphasis on the challenging diagnostic and therapeutic aspects, illustrated by a clinical case. The diagnosis of IgG4-SC is based on a combination of biochemical, radiological and histological signs and symptoms, including elevated levels of serum IgG4, intra- and extrahepatic biliary strictures detected by magnetic resonance cholangiography, and multifocal IgG4-lymphoplasmic infiltrations, sclerosing fibrosis of the bile ducts, seen at morphological assessment. Glucocorticoids (GCS) are the first line agents to achieve remission in patients with IgG4-SC. Most patients respond well to the systemic GCS. However, about 20% of patients (mostly those with extensive sclerotic intra- and/or extrahepatic abnormalities and signs of advanced disease / cirrhosis) show an insufficient or no response from the beginning of the treatment. The clinical case illustrates that timely verification of the IgG4-SC diagnosis may have an important prognostic value. The case history of a 62-year old female patient confirms the difficulties of the early diagnosis of the disease: for a relatively long time, the patient had the diagnosis of primary sclerosing cholangitis. Delay with GCS prescription (the treatment was initiated only at the stage of liver cirrhosis) had led to the lack of clinical efficacy and development of complications, such as relapsing cholangitis with advanced biliary strictures. In patients with suspected primary sclerosing cholangitis, timely differential diagnosis with IgG4-SC is relevant, because early GCS administration can slow the progression of the disease.

Crohn's disease is a chronic, recurring gastrointestinal tract disease of unknown etiology with alternating periods of exacerbations and remissions; however, some patients can have a fulminant disease with predominance of fever. In some cases, extraintestinal manifestations of the disease (arthritis, sacroiliitis, aphthous stomatitis) come to the fore. This paper presents a clinical case of a 46 years old patient Z., who was treated in the Republican Clinical Hospital (Kazan, Russia). His past history was remarkable for a painful ulceration of the oral mucosa about 1.5 months ago, after a planned replacement of a removable prosthesis on the lower jaw. The patient was diagnosed with "decubital ulcer of the oral mucosa in the right retro-molar area"; malignancies were excluded, and anti-inflammatory therapy was initiated. Then he had fever of up to 39.5 °C and abdominal pains. The infectious causes of fever were excluded, abdominal ultrasound showed no free fluid in the abdominal cavity, and macroscopic segmental erosive-ulcerative changes of the colon, specific for Crohn's disease were found at colonoscopy. Intravenous prednisolone was initiated, with augmentation of infusions and administration of protein and antibacterials. The next day abdominal pain became more severe, with vomiting, abdominal distension, Blumberg's sign; blood pressure was 90/60 mm Hg and heart rate 120 beats perminute. Abdominal ultrasound showed free fluid in the abdominal cavity; dilated intestine loops with horizontal fluid levels were seen at X-ray. The diagnosis was "advanced peritonitis, hollow organ perforation", and emergency laparotomy was performed that showed multiple perforations of the colon and sigmoid, diffuse fibrinous-purulent fecal peritonitis. Colectomy and end ileostomy were performed. Despite intensive therapy in the intensive care unit, the patient's general condition continued to worsen, and two days after the operation, with deterioration of cardiovascular failure, he died. Based on the histological examination of the colon and the autopsy results, the diagnosis of Crohn's disease was confirmed. Thus, the presence of febrile fever, as the leading syndrome, without any intestinal symptoms, should be included in the differential diagnostic list of symptoms of Crohn's disease.

The differential diagnosis between chronic pancreatitis   (CP) and  pancreatic   cancer  (PC) is a challenging  issue in the clinical practice, taking into account common  risk factors shared by these disorders   (smoking,  obesity,  diabetes   mellitus and insulin resistance), as well as a high risk of PC development  against  the  underlying  CP of 2 to 3 years' duration; this risk would  be  manifold  in hereditary CP. The article presents a clinical case of PC in a 60-year old man at three years after he had been  diagnosed with CP. The disease manifested from an acute  episode  of pancreatitis, which was treated in a hospital. Two years later, the  patient suffered from acute destructive pancreatitis complicated  by portal vein thrombosis and formation   of  pseudocysts.  Subsequently,  there was  a  rupture   of  the   post-necrotic  cyst  with leakage  into the  abdominal  cavity; this required surgical intervention. The differential diagnosis between CP and PC was done  at all steps  of the diagnostic work-up and treatment. However, afterthe inflammation  resolved, there  was a period of apparent well-being,  during  which  the  patient developed PC. This clinical case is intended to draw attention of clinicians, while making  differential diagnosis, to the detailed past history assessment, use of multiaxial computed tomography with intravenous      bolus      contrast      enhancement, and endoscopic  ultrasound examination  with elastography. In difficult cases, regular follow-up of at least every three months would be necessary.

Psoriasis, psoriatic arthritis (PsA) and inflammatory bowel disease (IBD) are multifactorial chronic immunoinflammatory disorders  with  characteristic common  genetic markers that determine their common  pathophysiology and similar immune abnormalities. In particular, IL12/23 signaling pathway of the  immune  pathogenesis of the  above mentioned diseases  is related  to the  IL23R gene polymorphism. Common  pathophysiological features, in their turn, produce  a high risk and prevalence   of  comorbidity.  Clinicians' unawareness of these  particulars  of the  immunoinflammatory disorders  might  lead  to the  absence  of interdisciplinary collaboration, late  diagnosis  of one  of these  disorders and polypharmacy, because  each specialist (i.e., a dermatologist, a rheumatologist, a  gastroenterologist) would  administer  his/hers treatments  independently.  In  this  context,  the issues  of the  multidisciplinary  approach   to  this problem  are becoming  highly relevant  for earlier diagnosis  and  adequate treatment choice that  is optimal  for all disorders  which contribute to the pathological   process, taking  into  account  common mechanism  of their development. Therefore, there  is the  necessity  to  establish  an  interdisciplinary working group  consisting  of the  leading specialists of the  Russian Federation  in rheumatology,  dermatology,  and  gastroenterology,  with a purpose  to elaborate a consensus  on the immunoinflammatory  comorbidities. At the  discretion of the Russian Association of Rheumatologists (RAR), Russian Society of Dermatovenerologists and  Cosmetologists  (RSDVC),  Russian IBD  Study Society (RIBDS),  such  a group  has  been  formed of 11 experts corresponding to their scientific expertise in the area. The main aim of the Working Group was to develop  a universal interdisciplinary questionnaire for detection of the  signs and symptoms  of the immunoinflammatory disorders (psoriasis,  PsA,  IBD),  as  well as  development  of a draft project  of the  interdisciplinary guidelines on  the  early diagnosis, methods of activity assessment  and indications to the use of genetically engineered biological agents  in patients  with comorbid immunoinflammatory comorbidities (psoriasis, PsA, IBD). Procedure of the interdisciplinary guidelines elaboration. The Working Group elaborated a draft project  of the  up-to-date evidence-based guidelines and proposed a multidisciplinary questionnaire. An interdisciplinary expert council of specialists in dermatology, rheumatology and gastroenterology discussed  each position of the  proposed guidelines  and  was adopted by a simple majority of votes through an open votingat the Second Russian Debates “Dermatology, Rheumatology, Gastroenterology: focus on the interdisciplinary interaction” (Moscow, December 12–13, 2017). Results: 1. A universal interdisciplinary questionnaire to detect  clinical signs of immunoinflammatory  disorders (psoriasis, PsA, IBD) hasbeen  created. It contains  the main questions  the answers to which are needed for a specialist physician (a dermatologist, a rheumatologist or a gastroenterologist)  to  suspect   comorbidity  and  to refer the patient to a corresponding specialist. The questionnaire has three  parts, each of them  with questions  to the  patient  aimed  at the  detection of the symptoms  of psoriasis, PsA, and IBD. 2. An algorithm for interaction between dermatologists, rheumatologists   and    gastroenterologists   has been  developed  aimed  at optimal  management of patients  with comorbid  immunoinflammatory disorders. 3. Goals of treatment of immunoinflammatory disorders  (psoriasis, PsA, Crohn's disease) have been  formulated  according  to the “treat-to-target”  (Т2Т) concept.  4. Criteria for assessment of activity and severity of the  immunoinflammatory disorders (psoriasis, PsA, and Crohn's disease) have been  formulated. 5. The draft describes  the indications  for the  administration of genetically engineered biological agents (GEBA), factors influencing  the  choice of treatment, criteria for GEBA efficacy assessment,  indications  to  a  change  of a GEBA in primary or secondary treatment failure. Conclusion: In accordance  with the results of discussion  with  specialists  from various  regions  of the  Russian  Federation  and  with the  decision  ofthe  Expert  Council,  it  is  planned  to  validate  thequestionnaire, with subsequent inclusion  of the position of the draft project into the clinical guidelines on the management of patients  with psoriasis, PsA, and Crohn's disease.