Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort.

BACKGROUND Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD. METHODS Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. RESULTS The data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30-51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0-25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29-183 mo). CONCLUSIONS In one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD.

Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.

BACKGROUND The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.

Prevalence and Risk Factors for Therapy Escalation in Ulcerative Colitis in the Swiss IBD Cohort Study.

BACKGROUND Physicians traditionally treat ulcerative colitis (UC) using a step-up approach. Given the paucity of data, we aimed to assess the cumulative probability of UC-related need for step-up therapy and to identify escalation-associated risk factors. METHODS Patients with UC enrolled into the Swiss IBD Cohort Study were analyzed. The following steps from the bottom to the top of the therapeutic pyramid were examined: (1) 5-aminosalicylic acid and/or rectal corticosteroids, (2) systemic corticosteroids, (3) immunomodulators (IM) (azathioprine, 6-mercaptopurine, methotrexate), (4) TNF antagonists, (5) calcineurin inhibitors, and (6) colectomy. RESULTS Data on 996 patients with UC with a median disease duration of 9 years were examined. The point estimates of cumulative use of different treatments at years 1, 5, 10, and 20 after UC diagnosis were 91%, 96%, 96%, and 97%, respectively, for 5-ASA and/or rectal corticosteroids, 63%, 69%, 72%, and 79%, respectively, for systemic corticosteroids, 43%, 57%, 59%, and 64%, respectively, for IM, 15%, 28%, and 35% (up to year 10 only), respectively, for TNF antagonists, 5%, 9%, 11%, and 12%, respectively, for calcineurin inhibitors, 1%, 5%, 9%, and 18%, respectively, for colectomy. The presence of extraintestinal manifestations and extended disease location (at least left-sided colitis) were identified as risk factors for step-up in therapy with systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and surgery. Cigarette smoking at diagnosis was protective against surgery. CONCLUSIONS The presence of extraintestinal manifestations, left-sided colitis, and extensive colitis/pancolitis at the time of diagnosis were associated with use of systemic corticosteroids, IM, TNF antagonists, calcineurin inhibitors, and colectomy during the disease course.

Systematic analysis of factors associated with progression and regression of ulcerative colitis in 918 patients.

BACKGROUND Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.

Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study

BACKGROUND Inflammatory bowel diseases (IBD) are systemic conditions that commonly display extraintestinal manifestations. Inflammatory articular disease (IAD: axial or peripheral) is the most common extraintestinal manifestation. The aim of this study was to evaluate the prevalence and the clinical characteristics associated with IAD in patients with IBD. METHODS We analyzed patients enrolled in the Swiss IBD cohort study. IAD was defined as persistent or recurrent joint pain with an inflammatory pattern (night pain, progressive relief during the day, morning stiffness lasting at least 30 minutes) or the presence of arthritis as diagnosed by the physicians. A multivariate logistic regression was performed to analyze which disease characteristics were independently associated with the presence of IAD. RESULTS A total of 2353 patients with IBD, 1359 with Crohn's disease, and 994 with ulcerative colitis (UC) were included. Forty-four percent of patients fulfilled the criteria for IAD, whereas 14.5% presented with other extraintestinal manifestations. IAD was associated with Crohn's disease, with female sex, with older age, and generally in patients with more active intestinal disease. Only in UC, IAD was further associated with tobacco smoking and with increasing body mass index. CONCLUSIONS This population of patients with IBD displays a high prevalence of IAD. IAD was more strongly associated with Crohn's disease than UC. Other risk factors for IAD were female sex, advanced age, active digestive disease, and tobacco consumption in patients with UC, which is interesting given the established association between smoking and other inflammatory arthritides.

[Smoking and digestive tract: a complex relationship. Part 1: Inflammatory bowel disease and cigarette smoking]

Little is known about the effects of smoking on inflammatory bowel diseases (IBD). However the co-occurrence of smoking and IBD often happens in ambulatory care. Smokers have a doubled risk of developing a Crohn's disease with a more active disease course. After quitting, a decrease in risk can be observed after only one year. An inverse relationship is found between smoking and ulcerative colitis. Smoking seems protective for the development of the disease and its course is less active among smokers. Smoking cessation transitorily increases the risk of developing ulcerative colitis. Nevertheless, continuing smoking cannot be justified among those patients given the risks of long-term extra-digestive effects. It is thus important to counsel all smokers with an IBD to quit smoking.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

Quality of Life in Swiss Paediatric Inflammatory Bowel Disease Patients: Do Patients and Their Parents Experience Disease in the Same Way?

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) may impair quality of life (QoL) in paediatric patients. We aimed to evaluate in a nationwide cohort whether patients experience QoL in a different way when compared with their parents. METHODS Sociodemographic and psychosocial characteristics were prospectively acquired from paediatric patients and their parents included in the Swiss IBD Cohort Study. Disease activity was evaluated by the Paediatric Crohn's Disease Activity Index (PCDAI) and the Paediatric Ulcerative Colitis Activity Index (PUCAI). We assessed QoL using the KIDSCREEN questionnaire. The QoL domains were analysed and compared between children and parents according to type of disease, parents' age, origin, education and marital status. RESULTS We included 110 children and parents (59 Crohn's disease [CD], 45 ulcerative colitis [UC], 6 IBD unclassified [IBDU]). There was no significant difference in QoL between CD and UC/IBDU, whether the disease was active or in remission. Parents perceived overall QoL, as well as 'mood', 'family' and 'friends' domains, lower than the children themselves, independently of their place of birth and education. However, better concordance was found on 'school performance' and 'physical activity' domains. Marital status and age of parents significantly influenced the evaluation of QoL. Mothers and fathers being married or cohabiting perceived significantly lower mood, family and friends domains than their children, whereas mothers living alone had a lower perception of the friends domain; fathers living alone had a lower perception of family and mood subscores. CONCLUSION Parents of Swiss paediatric IBD patients significantly underestimate overall QoL and domains of QoL of their children independently of origin and education.

Risk factors and inflammatory markers in pouchitis

Individuals who do not respond to medical therapy for ulcerative colitis (UC) often undergo proctocolectomy followed by ileal-pouch anal anastomosis (IPAA) in hopes of resolving symptoms associated with UC. Inflammation of the ileal pouch, better known as pouchitis, is the most common complication of the IPAA procedure. The causes and development of pouchitis is not well understood. To better understand pathogenesis of pouchitis, pouch aspirates of patients having undergone IPAA were quantitatively analyzed for fecal IL-8, IL-17, and IL-23 levels. According to published literature IL-8 has been linked to pouchitis whereas IL-17 and IL-23 are associated with intestinal inflammation. The study had 80 participants, 33 patients diagnosed with Crohn's Disease (CD) of the pouch, 19 patients diagnosed with pouchitis, and 28 diagnosed with having normal pouches. Patient characteristics and histopathological findings for all patients were noted and statistically compared in addition to fecal cytokine levels. This study supported previous literature that IL-8 production was associated with pouch inflammation. However, IL-17 and IL-23 levels in both CD of the pouch and pouchitis were not significantly different to the levels noted in normal pouch.^

Network-based genome-wide association study of Crohn's disease

Genome-wide association studies (GWAS) have rapidly become a standard method for disease gene discovery. Many recent GWAS indicate that for most disorders, only a few common variants are implicated and the associated SNPs explain only a small fraction of the genetic risk. The current study incorporated gene network information into gene-based analysis of GWAS data for Crohn's disease (CD). The purpose was to develop statistical models to boost the power of identifying disease-associated genes and gene subnetworks by maximizing the use of existing biological knowledge from multiple sources. The results revealed that Markov random field (MRF) based mixture model incorporating direct neighborhood information from a single gene network is not efficient in identifying CD-related genes based on the GWAS data. The incorporation of solely direct neighborhood information might lead to the low efficiency of these models. Alternative MRF models looking beyond direct neighboring information are necessary to be developed in the future for the purpose of this study.^

Estudo do potencial imunomodulador de Dehidroepiandrosterona (DHEA) na inflamação intestinal experimental

As Doenças inflamatórias intestinais (DII) são multifatoriais e sua etiologia envolve susceptibilidade genética, fatores ambientais, disbiose e ativação exacerbada do sistema imunológico no intestino. Essas doenças também tem sido relacionadas a baixos níveis de dehidroepiandrosterona (DHEA), um hormônio precursor de diversos esteroides e relacionado à modulação das respostas imunes. Porém, os mecanismos precisos que relacionam as ações deste hormônio com a proteção ou susceptibilidade à doença de Crohn ou colite ulcerativa ainda não são totalmente conhecidos. Sendo assim, este projeto buscou entender o papel imunomodulador do DHEA exógeno in vitro e in vivo durante a inflamação intestinal experimental induzida por dextran sulfato de sódio (DSS) em camundongos C57BL/6. Inicialmente, in vitro, DHEA inibiu a proliferação de células do baço de forma dose dependente nas concentrações de 5?M, 50?M ou 100?M, com diminuição da produção de IFN-?. Este hormônio não foi tóxico para células de linhagem mieloide, embora tenha causado necrose em leucócitos nas doses mais elevada (50 ?M e 100?M), o que pode ter influenciado a diminuição das citocinas in vitro. Nos ensaios in vivo, os camundongos tratados com DHEA (40 mg/Kg) foram avaliados na fase de indução da doença (dia 6) e durante o reparo tecidual, quando os animais expostos ao DSS e ao DHEA por 9 dias foram mantidos na ausência destas drogas até o dia 15. Houve diminuição do escore pós-morte, melhora no peso e nos sinais clínicos da inflamação intestinal, com redução de monócitos no sangue periférico com 6 dias e aumento de neutrófilos circulantes na fase de reparo tecidual (15 dias). Ainda, a suplementação com DHEA levou à redução da celularidade da lâmina própria (LP) e ao restabelecimento do comprimento normal do intestino. O uso deste hormônio também diminuiu a expressão do RNAm de IL-6 e TGF-?, enquanto aumentou a expressão de IL-13 no colón dos animais durante a fase de indução da doença, o que provavelmente ajudou na atenuação da inflamação intestinal. Além disso, houve acúmulo de linfócitos CD4+ e CD8+ no baço e diminuição apenas de linfócitos CD4+ nos linfonodos mesentéricos (LNM), indicando retenção das células CD4+ no baço após uso do DHEA. O tratamento foi também capaz de aumentar a frequência de células CD4 produtoras de IL-4 e diminuir CD4+IFN-?+ no baço, além de reduzir a frequência de CD4+IL-17+ nos LNM, sugerindo efeito do DHEA no balanço das respostas Th1/Th2/Th17 relacionadas à colite. Em adição, as células de baço dos animais tratados com DHEA e expostos ao DSS se tornaram hiporresponsivas, como visto pela diminuição da proliferação após re-estímulos in vitro. Finalmente, DHEA foi capaz de atuar no metabolismo dos camundongos tratados, levando à diminuição de colesterol total e da fração LDL no soro durante a fase de indução da doença, sem gerar quaisquer disfunções hepáticas. Com isso, podemos concluir que o DHEA atua por meio do balanço das respostas imunes exacerbadas, minimizando os danos locais e sistêmicos causados pela inflamação intestinal induzida por DSS.

Enfermedad de Crohn: experiencias de vivir con una cronicidad

Objetivo. Explorar las experiencias de personas con enfermedad de Crohn (EC), aquellos acontecimientos que modificaron sus vidas, el impacto y las estrategias utilizadas para sobrellevar la enfermedad. Material y métodos. Estudio cualitativo. Se realizaron 10 entrevistas a profundidad a afectados de la provincia de Alicante (España). La recolección de datos, procesamiento y análisis de los mismos se realizó a través de algunos elementos que recoge la fenomenología. Resultados. Las experiencias de los afectados se pueden clasificar en cuatro grandes temas: reconocimiento de enfermar, consecuencias percibidas por los afectados por EC de la propia enfermedad, gestión de la enfermedad y búsqueda de apoyo. Conclusiones. El conocimiento de la experiencia de vida de las personas afectadas por EC parece una herramienta indispensable para conseguir una gestión eficaz del proceso de cronicidad al momento de planificar programas sanitarios específicos de tratamiento.

Étude sur le rôle de SIGIRR chez les cas pédiatriques dans la maladie de Crohn

Il est admis que la maladie de Crohn (MC) résulte de facteurs immunologiques, environnementaux et génétiques. SIGIRR, un récepteur anti-inflammatoire, n’a jamais été étudié dans le contexte de la MC, et de nombreuses découvertes à son sujet ont mené plusieurs à s’intéresser quant à son utilité dans l’atténuation de maladies inflammatoires. Récemment, l’IL-37 a été identifié comme ligand d’un complexe formé de SIGIRR-IL-18Rα. SIGIRR et l’IL-37 pourraient alors être des acteurs de la dérégulation de l’inflammation retrouvée chez la MC. Nous les avons étudiés dans le contexte de la MC pédiatrique, afin d’y caractériser leurs effets. Nous avons identifié une diminution de l’expression de SIGIRR sur certains types de cellules immunitaires. De plus, les personnes atteintes de la MC ont des concentrations de protéines altérées, soit SIGIRR soluble, l’IL-37, l’IL-18BP, et l’IL-18, et tendent à revenir à la normale lorsque l’inflammation est contrôlée par médication. De plus, la concentration de l’IL-18 libre suit le même patron. Par analyse de régression linéaire de SIGIRR soluble et l’IL-37, de l’IL-18BP et l’IL-18, ainsi que l’IL-37 et l’IL-18, des tendances divergentes ont été identifiées entre les patients non traités aux contrôles et patients traités. Nos résultats suggèrent que le système IL-37-SIGIRR est compromis chez les patients de la MC. Étant donné que ce système est un facteur crucial dans la régulation négative de l’inflammation, il sera intéressant de déterminer si SIGIRR et l’IL-37 peuvent constituer des cibles thérapeutiques importantes dans l’atténuation et la résolution de l’inflammation chez les patients atteints de la MC.