TREATMENT OF FISTULIZING CROHN’S DISEASE

Liječenje fistulirajućeg oblika Crohnove bolesti zahtijeva tijesnu suradnju gastroenterologa i kirurga te se temelji na striktnom individualnom pristupu koji uvijek uključuje adekvatnu nutricijsku potporu. Danas još uvijek ne postoje kontrolirane randomizirane studije koje bi adekvatno evaluirale učinkovitostt medikamentne kao niti biološke terapije u liječenju neperianalne fistulirajuće Crohnove bolesti. Retroperitonealne fistule sa slijepim završetkom kao i enterovezikalne fistule apsolutna su indikacija za kiruršku intervenciju. Kirurška intervencija je neophodna i u slučaju gastrokoličnih i duodenokoličnih fistula. U većini slučajeva simptomatske enterovaginalne fistule zahtijevaju kirurški tretman. Imunosupresivna terapija (azatioprin ili merkaptopurin) uz antibiotsku terapiju (ciprofloksacin + metronidazol) u kombinaciji s drenažnim kirurškim postupcima danas je prva medikamentna linija terapije kompleksne perianalne Crohnove bolesti. Svakako treba naglasiti potrebu za dugotrajnom terapijom održavanja kliničke remisije koja u selekcioniranih bolesnika uključuje postavljanje setona uz imunosupresivnu terapiju u razdoblju od najmanje godinu dana. Sukladno dostupnim studijama, anti TNF-terapija (infliksimab ili adalimumab) danas je druga medikamentna terapijska linija u liječenju kompleksnog perianalnog oblika Crohnove bolesti.The treatment of fistulating Crohn’s disease should include a combined medical and surgical approach and should be defined on an individual basis. Asymptomatic enteroenteric fistulas usually require no treatment, but internal fistulas (gastrocolic, duodenocolic, enterovesical) that cause severe or persistent symptoms require surgical intervention. While low asymptomatic analintroital fistula may not need surgical treatment, in case of a symptomatic enterovaginal fistula surgery is usually required. There are no controlled-randomized trials to assess the effect of medical treatment for non-perianal fistulating Crohn’s disease. The incidence of perianal fistulae varies according to the location of the disease, with its occurrence varying between 21-23%. The diagnostic approach should include an examination under anesthesia, endoscopy, and either MRI or EUS before the treatment begins. Asymptomatic simple perianal fistulas require no treatment. The presence of a perianal abscess should be ascertained and if present should be drained urgently. In case of a complex perianal disease, seton placement should also be recommended. Antibiotics (metronidazole and ciprofloxacine) are useful for treating complex perianal disease, however, when discontinued, most of the fistulas relapse. The current consensus suggests that azathioprine/6-mercaptopurine is the first line medical therapy for complex perianal disease, which is always given in combination with surgical therapy (seton, fistulotomy/fistulectomy). Anti TNF-αagents (infliximab and adalimumab) should be used as a second choice medical treatment. In refractory and extensive complex perianal disease a diverting stoma or proctectomy should be performed

Epidemiološka studija varijanti tiopurin-metiltransferaze u skupini hrvatskih bolensika s upalnim bolestima crijeva

Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reactionbased assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers. Study results revealed 434/459 (94.55%) IBD patients and 213/226 (94.25%) healthy subjects to be homozygous for the wild-type allele (TPMT*1/*1). TPMT*1/*2 and TPMT *1/*3C genotypes were found in 4/459 (0.87%) and 7/459 (1.53%) IBD patients, respectively; in healthy volunteers they were not found. TPMT*1/*3A genotype was found in 14/459 (3.05%) IBD patients and 13/226 (5.75%) healthy subjects. Variant genotypes were statistically significantly more common in Crohn’s disease subgroup than in ulcerative colitis subgroup. The prevalence of variant genotypes was 23/338 (6.80%) in Crohn’s disease subgroup as compared with 2/121 (1.65%) in ulcerative colitis subgroup (χ2=4.59; p=0.032). In conclusion, the most frequently occurring nonfunctional TPMT allele in Croatian population is TPMT*3A. The overall frequency of mutant alleles in our population is statistically nonsignificantly lower when compared with other populations of Caucasian origin. The Crohn’s disease group had more mutant alleles than the ulcerative colitis group.Tiopurin S-metiltransferaza (TPMT) je enzim koji sudjeluje u konverziji tiopurinskih lijekova u inaktivne metabolite. Dosad je otkriveno više od 20 varijanti TPMT-kodirajućih alela. Ovi aleli uzrokoju smanjenu enzimatsku aktivnost. Naš cilj je bio istražiti frekvenciju varijantnih alela odnosno genotipova u bolesnika oboljelih od upalnih bolesti crijeva i u zdravih osoba te usporediti dobivene frekvencije s frekvencijama odabranih svjetskih populacija. Najčešći varijantni aleli TPMT*2, TPMT*3A, TPMT*3B i TPMT*3C analizirani su metodama lančane reakcije polimeraze, odnosno alelspecifičnim metodama lančane reakcije polimeraze. U istraživanje je bilo uključeno 685 ispitanika; 459 ispitanika bili su bolesnici s upalnom bolesti crijeva, a 226 bili su zdravi dobrovoljci. Rezultati su pokazali da su 434/459 (94,55%) pacijenata s upalnom bolesti crijeva i 213/226 (94,25%) zdravih osoba homozigoti za divlji tip alela (TPMT*1/*1). Genotipovi TPMT*1/*2 i TPMT*1/*3C nađeni su u 4/459 (0,87%) odnosno 7/459 (1,53%) bolesnika; u zdravih dobrovoljaca nisu nađeni. Genotip TPMT*1/*3A nađen je u 14/459 (3,05%) bolesnika i 13/226 (5,75%) zdravih dobrovoljaca. Varijantni genotipovi bili su statistički značajno češći u podskupini bolesnika s Crohnovom bolešću, s učestalošću od 23/338 (6,80%) u odnosu na podskupinu bolesnika s ulceroznim kolitisom, gdje je učestalost varijantnih genotipova bila 2/121 (1,65%) (χ2=4,46; p=0,035). U zaključku, najčešći nefunkcionalni TPMT alel u Hrvatskoj populaciji je TPMT*3A. Ukupna frekvencija varijantnih alela u našoj je populaciji statistički neznačajno niža u odnosu na druge populacije bjelačkog podrijetla. Bolesnici s Crohnovom bolešću imaju više varijantnih alela u odnosu na podskupinu bolesnika s ulceroznim kolitisom

A Coincidence of HLA-B27 Negative Spondyloarthritis and Paravertebral Non-Hodgkin’s Lymphoma – A Lesson to be Learned from the Past Experience

We reported a case of a 71-year-old woman with progressive low back pain and neurologic symptoms of lower extremities, who in the background had the coexistence of spondyloarthritis (SpA) and non Hodgkin’s lymphoma of the paravertebral location. This example describes a situation where SpA with minimal sacroiliac joints affection has nevertheless led to the overt axial SpA. This situation included undifferentiated or reactive SpA, as well as unusual disease context, presented with late-life disease onset, older age, female gender and no obvious hereditary predisposition. This combination of comorbid factors could allow environmental and disease-specifi c factors to accumulate over time and to, by modifying the primary, low-penetrant genetic background, lead to the development of lymphoma. By achieving better understanding of disease pathophysiology dynamic, we will be able to improve our capabilities to navigate biologic therapy in the future, in order to prevent the development of both, overt SpA and lymphoproliferative disease

CROATIAN GUIDELINES FOR USE OF ENTERAL NUTRITION IN CROHN’S DISEASE

Prehrana ima važnu višeznačnu ulogu u liječenju upalnih bolesti crijeva, poglavito u bolesnika koji boluju od Crohnove bolesti. U prvom redu adekvatna nutritivna potpora nužna je u prevenciji i liječenju malnutricije, kao i u prevenciji osteoporoze te u promicanju dobi primjerenog rasta u pedijatrijskih bolesnika. S druge strane, u aktivnoj fazi Crohnove bolesti u pedijatrijskih bolesnika enteralna je prehrana terapija izbora za uvođenje bolesnika u remisiju. Glede vrste enteralnih pripravaka istraživanja upućuju na jednaku učinkovitost elementarnih, oligomernih i polimernih enteralnih pripravaka. Uporaba standardnih polimernih enteralnih pripravaka danas se preporučuje i zbog boljeg okusa, lakšeg prihvaćanja od bolesnika, manje komplikacija te značajno nižih troškova u usporedbi s troškovima primjene ostalih enteralnih pripravaka. Najnovije spoznaje upućuju i na to da neki nutrijenti poput transformirajućeg čimbenika rasta beta (TGF-2), koji se nalaze u modificiranim polimernim enteralnim pripravcima, imaju farmakološki terapijski potencijal u liječenju upalnih bolesti crijeva, potvrđen u nekoliko kliničkih ispitivanja. Radna skupina koju su činili internisti gastroenterolozi i pedijatrijski gastroenterolozi, posebno upućeni u liječenje bolesnika s kroničnim upalnim bolestima crijeva izradila je Hrvatske smjernice za primjenu enteralne prehrane u Crohnovoj bolesti. Izrada smjernica temeljena je na dokazima iz relevantne medicinske literature te kliničkim iskustvima članova radne skupine.Nutrition has an important role in the management of inflammatory bowel disease (IBD), especially in patients with Crohn’s disease (CD). This role includes the prevention and correction of malnutrition, the prevention of osteoporosis and the promotion of optimal growth and development in children. In active Crohn’s disease, nutritional therapy (in the form of enteral feeding) is an effective primary therapy for pediatric patients. Studies have shown that there is no difference in the efficacy of elemental, oligomeric and polymeric enteral formulas. Therefore, the use of polymeric formula is recommended because of higher palatability, better acceptance by patients, lower rate of complications and lower cost when compared with other enteral formulas. Today we have knowledge that some nutrients which are added to modified special enteral formulas have almost pharmacological terapeutic potential in the management of inflammatory bowel disease. Novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta-enriched (TGF-2) enteral feeding, showed beneficial effects in several clinical studies. Croatian guidelines for enteral nutrition in Crohn’s disease have been developed by interdisciplinary expert group of Croatian clinicians involved with inflammatory bowel disease. The guidelines are based on evidence from relevant medical literature and clinical experience of working group

CROATIAN GUIDELINES FOR USE OF ENTERAL NUTRITION IN CROHN’S DISEASE

Prehrana ima važnu višeznačnu ulogu u liječenju upalnih bolesti crijeva, poglavito u bolesnika koji boluju od Crohnove bolesti. U prvom redu adekvatna nutritivna potpora nužna je u prevenciji i liječenju malnutricije, kao i u prevenciji osteoporoze te u promicanju dobi primjerenog rasta u pedijatrijskih bolesnika. S druge strane, u aktivnoj fazi Crohnove bolesti u pedijatrijskih bolesnika enteralna je prehrana terapija izbora za uvođenje bolesnika u remisiju. Glede vrste enteralnih pripravaka istraživanja upućuju na jednaku učinkovitost elementarnih, oligomernih i polimernih enteralnih pripravaka. Uporaba standardnih polimernih enteralnih pripravaka danas se preporučuje i zbog boljeg okusa, lakšeg prihvaćanja od bolesnika, manje komplikacija te značajno nižih troškova u usporedbi s troškovima primjene ostalih enteralnih pripravaka. Najnovije spoznaje upućuju i na to da neki nutrijenti poput transformirajućeg čimbenika rasta beta (TGF-2), koji se nalaze u modificiranim polimernim enteralnim pripravcima, imaju farmakološki terapijski potencijal u liječenju upalnih bolesti crijeva, potvrđen u nekoliko kliničkih ispitivanja. Radna skupina koju su činili internisti gastroenterolozi i pedijatrijski gastroenterolozi, posebno upućeni u liječenje bolesnika s kroničnim upalnim bolestima crijeva izradila je Hrvatske smjernice za primjenu enteralne prehrane u Crohnovoj bolesti. Izrada smjernica temeljena je na dokazima iz relevantne medicinske literature te kliničkim iskustvima članova radne skupine.Nutrition has an important role in the management of inflammatory bowel disease (IBD), especially in patients with Crohn’s disease (CD). This role includes the prevention and correction of malnutrition, the prevention of osteoporosis and the promotion of optimal growth and development in children. In active Crohn’s disease, nutritional therapy (in the form of enteral feeding) is an effective primary therapy for pediatric patients. Studies have shown that there is no difference in the efficacy of elemental, oligomeric and polymeric enteral formulas. Therefore, the use of polymeric formula is recommended because of higher palatability, better acceptance by patients, lower rate of complications and lower cost when compared with other enteral formulas. Today we have knowledge that some nutrients which are added to modified special enteral formulas have almost pharmacological terapeutic potential in the management of inflammatory bowel disease. Novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta-enriched (TGF-2) enteral feeding, showed beneficial effects in several clinical studies. Croatian guidelines for enteral nutrition in Crohn’s disease have been developed by interdisciplinary expert group of Croatian clinicians involved with inflammatory bowel disease. The guidelines are based on evidence from relevant medical literature and clinical experience of working group

CROATIAN CONSENSUS ON THE TREATMENT OF INFLAMMATORY BOWEL DISEASES WITH BIOLOGIC THERAPY

Uvođenje biološke terapije u kliničku praksu je značajan napredak u liječenju kroničnih upalnih bolesti crijeva, prije svega zbog njihove dokazane djelotvornosti te činjenice da su to prvi lijekovi kojima se uspjelo promijeniti prirodni tijek tih bolesti. Radi se, međutim, o vrlo skupim lijekovima s vrlo kompleksnim mehanizmima djelovanja i mogućim nuspojavama, te njihovo korištenje u vrlo kompliciranim bolestima kakve su upalne bolesti crijeva zahtijeva smjernice bazirane na rezultatima dobro kontroliranih studija. Referentni centar Ministarstva zdravlja i Sekcija za upalne bolesti crijeva Hrvatskog gastroenterološkog društva organizirali su stoga konsenzus konferenciju tijekom koje su definirane hrvatske smjernice za liječenje upalnih bolesti crijeva anti-TNF lijekovima. Tekst sa smjernicama uključuje definicije upalnih bolesti crijeva, opće principe liječenja upalnih bolesti crijeva, važnost mukoznog cijeljenja, analizu razloga nedjelotvornosti i gubitka djelotvornosti anti-TNF terapije, daje preporuke o dužini terapije, daje smjernice za probir na oportunističke infekcije prije početka anti-TNF terapije, osvrće se na probleme reprodukcije vezane za anti-TNF terapiju te konačno daje smjernice za liječenje raznih fenotipova upalnih bolesti crijeva i ekstraintestinalnih manifestacija upalnih bolesti crijeva.Introduction of biologic therapy in clinical practice represented significant progress in the treatment of inflammatory bowel diseases (IBD) because of its proven efficacy and due to the fact that biologics are the first drugs used in the treatment of IBD that can change the natural course of this diseases. At the same time, biologics are very expensive drugs with complex mechanism of action and important side effects and their use requires evidence-based clinical guidelines. These were the reasons that Referral Center of the Croatian Ministry of Health for IBD and the IBD Section of the Croatian Society of Gastroenterology organised Croatian consensus conference that defined guidelines for the treatment of IBD with anti-TNF drugs. The text below includes definitions of IBD, general principles of IBD therapy, comments on the importance of mucosal healing, analysis of reasons for nonresponse and loss of response to anti-TNF drugs, recommendation for the duration of anti-TNF therapy, rules of screening for opportunistic infections prior to anti-TNF therapy, comments on the problems with reproduction in IBD and finally guidelines for the treatment of various phenotypes of IBD including extraintestinal manifestations with anti-TNF therapy

TREATMENT OF FISTULIZING CROHN’S DISEASE

Liječenje fistulirajućeg oblika Crohnove bolesti zahtijeva tijesnu suradnju gastroenterologa i kirurga te se temelji na striktnom individualnom pristupu koji uvijek uključuje adekvatnu nutricijsku potporu. Danas još uvijek ne postoje kontrolirane randomizirane studije koje bi adekvatno evaluirale učinkovitostt medikamentne kao niti biološke terapije u liječenju neperianalne fistulirajuće Crohnove bolesti. Retroperitonealne fistule sa slijepim završetkom kao i enterovezikalne fistule apsolutna su indikacija za kiruršku intervenciju. Kirurška intervencija je neophodna i u slučaju gastrokoličnih i duodenokoličnih fistula. U većini slučajeva simptomatske enterovaginalne fistule zahtijevaju kirurški tretman. Imunosupresivna terapija (azatioprin ili merkaptopurin) uz antibiotsku terapiju (ciprofloksacin + metronidazol) u kombinaciji s drenažnim kirurškim postupcima danas je prva medikamentna linija terapije kompleksne perianalne Crohnove bolesti. Svakako treba naglasiti potrebu za dugotrajnom terapijom održavanja kliničke remisije koja u selekcioniranih bolesnika uključuje postavljanje setona uz imunosupresivnu terapiju u razdoblju od najmanje godinu dana. Sukladno dostupnim studijama, anti TNF-terapija (infliksimab ili adalimumab) danas je druga medikamentna terapijska linija u liječenju kompleksnog perianalnog oblika Crohnove bolesti.The treatment of fistulating Crohn’s disease should include a combined medical and surgical approach and should be defined on an individual basis. Asymptomatic enteroenteric fistulas usually require no treatment, but internal fistulas (gastrocolic, duodenocolic, enterovesical) that cause severe or persistent symptoms require surgical intervention. While low asymptomatic analintroital fistula may not need surgical treatment, in case of a symptomatic enterovaginal fistula surgery is usually required. There are no controlled-randomized trials to assess the effect of medical treatment for non-perianal fistulating Crohn’s disease. The incidence of perianal fistulae varies according to the location of the disease, with its occurrence varying between 21-23%. The diagnostic approach should include an examination under anesthesia, endoscopy, and either MRI or EUS before the treatment begins. Asymptomatic simple perianal fistulas require no treatment. The presence of a perianal abscess should be ascertained and if present should be drained urgently. In case of a complex perianal disease, seton placement should also be recommended. Antibiotics (metronidazole and ciprofloxacine) are useful for treating complex perianal disease, however, when discontinued, most of the fistulas relapse. The current consensus suggests that azathioprine/6-mercaptopurine is the first line medical therapy for complex perianal disease, which is always given in combination with surgical therapy (seton, fistulotomy/fistulectomy). Anti TNF-αagents (infliximab and adalimumab) should be used as a second choice medical treatment. In refractory and extensive complex perianal disease a diverting stoma or proctectomy should be performed

Real-World Study on Vedolizumab Serum Concentration, Efficacy, and Safety after the Transition from Intravenous to Subcutaneous Vedolizumab in Inflammatory Bowel Disease Patients: Single-Center Experience

Little is known about how the change from intravenous to subcutaneous vedolizumab in a real-life setting in inflammatory bowel disease patients on stable maintenance therapy affects clinical outcomes. We compared the data on vedolizumab serum trough concentration, efficacy, and safety prior to and six months after the switch from intravenous to subcutaneous vedolizumab. In total, 24 patients, 13 with ulcerative colitis (UC) and 11 with Crohn’s disease (CD), were included. Mean serum trough concentration of intravenous vedolizumab was significantly lower than mean serum trough concentration of subcutaneous vedolizumab (p = 0.002). There was no significant difference between C-reactive protein levels, fecal calprotectin levels or clinical scores (Harvey–Bradshaw index or Partial Mayo score) prior to transition to subcutaneous vedolizumab and after 6 months. In four (16.7%) patients, two CD and two UC, therapy was discontinued during the follow-up period with a median of 5 months (minimum–maximum: 4–6). In all patients, therapy was discontinued due to loss of response. In total, 13 adverse events were reported by 11 patients, and the most common adverse event was COVID-19. No serious adverse events were reported. In conclusion, subcutaneous vedolizumab has shown to be effective and safe in patients on previously established maintenance therapy with intravenous vedolizumab

Real-World Study on Vedolizumab Serum Concentration, Efficacy, and Safety after the Transition from Intravenous to Subcutaneous Vedolizumab in Inflammatory Bowel Disease Patients: Single-Center Experience

Little is known about how the change from intravenous to subcutaneous vedolizumab in a real-life setting in inflammatory bowel disease patients on stable maintenance therapy affects clinical outcomes. We compared the data on vedolizumab serum trough concentration, efficacy, and safety prior to and six months after the switch from intravenous to subcutaneous vedolizumab. In total, 24 patients, 13 with ulcerative colitis (UC) and 11 with Crohn’s disease (CD), were included. Mean serum trough concentration of intravenous vedolizumab was significantly lower than mean serum trough concentration of subcutaneous vedolizumab (p = 0.002). There was no significant difference between C-reactive protein levels, fecal calprotectin levels or clinical scores (Harvey–Bradshaw index or Partial Mayo score) prior to transition to subcutaneous vedolizumab and after 6 months. In four (16.7%) patients, two CD and two UC, therapy was discontinued during the follow-up period with a median of 5 months (minimum–maximum: 4–6). In all patients, therapy was discontinued due to loss of response. In total, 13 adverse events were reported by 11 patients, and the most common adverse event was COVID-19. No serious adverse events were reported. In conclusion, subcutaneous vedolizumab has shown to be effective and safe in patients on previously established maintenance therapy with intravenous vedolizumab

Bispectral Index Monitoring and Observer Rating Scale Correlate with Dreaming during Propofol Anesthesia for Gastrointestinal Endoscopies

Background and objectives: Dreaming is a commonly reported side effect of propofol anesthesia. Materials and Methods: We investigated the inci-dence and character of dreams in patients undergoing intravenous propofol anesthesia and cor-related it with an observer rating scale of facial expression on the seven-point scale from pain to smile. A total of 124 patients undergoing gastrointestinal endoscopy were recruited in the pro-spective observational study. Bispectral index (BIS), blood pressure (BP), and pulse were moni-tored. Upon emergence from anesthesia, the patient’s facial expression was rated numerically. Thereafter, patients were asked whether they had dreams and to rate their dreams as pleasant or unpleasant. The mean age of participants was 53; body mass index, 26.17; duration of procedure, 20 min; and average propofol dose, 265 mg. Results: Dreaming was reported by 43% of patients. Dreams were pleasant in all but one patient. There was a significant correlation of the observer’s rating of facial expression with dreaming (r = 0.260; p = 0.004). Dreamers had higher scores of observer rating of facial expression (1 (0–2) vs. 0.5 (0–1), p = 0.006). Conclusions: BIS values were lower in the dreamers vs. non-dreamers 2 min after the endoscopy started (48 (43–62) vs. 59 (45–71), p = 0.038). Both BIS and observer ratings correlate with dreaming in patients undergoing gastrointestinal endos-copy. Trial registration number: NCT04235894