JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases

JAK inhibitors; Oral therapies; Small moleculesInhibidors de JAK; Teràpies orals; Molècules petitesInhibidores de JAK; Terapias orales; Moléculas pequeñasInflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients

Sucrosomial Iron Supplementation for the Treatment of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients Refractory to Oral Iron Treatment

Malaltia inflamatòria intestinal; Deficiència de ferro; Suplementació de ferroEnfermedad inflamatoria intestinal; Deficiencia de hierro; Suplementación con hierroInflammatory bowel disease; Iron deficiency; Iron supplementationIron deficiency anemia (IDA) is a common manifestation of Inflammatory Bowel Disease (IBD). Oral iron supplements are the treatment of choice, but are not always well tolerated. Sucrosomial® iron (SI) may represent an alternative. This prospective study assessed the tolerability and effectiveness of SI, and quality of life (QoL) of IDA-IBD patients who were intolerant to oral iron salts. The study included 52 individuals treated with 1 capsule/day for 12 weeks. Tolerability was assessed through a gastrointestinal symptom severity questionnaire. Hemoglobin (Hb) levels and clinical symptoms of IDA were analyzed. QoL was assessed using IBDQ-9 and EuroQoL questionnaires. The percentage of patients with excellent/good health increased from 42.9% to 94.3%. Mean Hb concentration significantly increased at all follow-up visits (p < 0.05). Almost all participants (96.9%) were adherent to the study medication. Patients’ QoL improved (IBDQ-9: from 60.9 to 65.5). Patients also improved in mobility (71.8% to 78.1%), usual activities (51.3% to 68.7%), pain/discomfort (41.0% to 53.1%), and extreme depression/anxiety problems (7.7% to 3.2%); they worsened in self-care (100% to 90.6%), but perceived an enhancement in their global health [EQ-VAS score: 61.9 (±26.1) to 66.9 (±20.3)]. SI was well tolerated and improved IDA symptoms, IBD activity, and patients’ QoL. In conclusion, SI should be considered in IDA–IBD patients.The authors of this manuscript received financial support from ZAMBON S.A.U. for the writing of the manuscript. The sponsor had no role in the design or conduct of the study, data collection and analysis, or preparation of the manuscript

Leishmania infantum asymptomatic infection in inflammatory bowel disease patients under anti-TNF therapy

Background: In recent years anti-TNF therapy has been associated with leishmaniasis in immunocompromised patients from endemic areas. Nevertheless, data on asymptomatic Leishmania infection in such patients is scarce. The aim of this study was to determine the prevalence of asymptomatic infection in inflammatory bowel disease (IBD) patients treated with TNF inhibitors living in an endemic area (Catalonia) and to follow up them to study how the infection evolved. Methods: 192 IBD patients (143 Crohn's disease; 49 ulcerative colitis) from Catalonia (Spain), an area endemic for L. infantum, were recruited. Peripheral blood samples were collected and tested for anti-Leishmania antibodies by Western blotting (WB). Leishmania kinetoplast DNA was detected in peripheral blood mononuclear cells (PBMC) by a quantitative PCR. Results: Serology was positive in 3.1% and Leishmania DNA was found in 8.8%, with a low parasitic load and humoral response. The prevalence was 10.9%, patients being considered infected if they tested positive by at least one of the techniques. Eight out of the 21 patients with asymptomatic leishmaniasis were monitored for 3-8 months after the first test. None of them showed an increased parasitemia or humoral response, or developed leishmaniasis during the follow-up period. Conclusion: The prevalence of Leishmania asymptomatic infection detected in our IBD cohort is similar to that found in healthy population in close endemic areas. Due to the short monitoring period, it is not possible to reach a conclusion about the risk of Leishmania reactivation from this study

Observational study in Ulcerative Colitis to investigate the composition of the intestinal microbiota in patients in long-term remission

La colitis ulcerosa (CU) és una malaltia inflamatòria idiopàtica crònica que afecta l'intestí gros. És un dels dos trastorns principals que engloba el terme Malaltia Inflamatòria Intestinal (MII). L'etiologia de la CU involucra una resposta immune a una microbiota intestinal desequilibrada en individus genèticament susceptibles, després d'esdeveniments desencadenants desconeguts. Els estudis de la microbiota han trobat una menor riquesa i diversitat en la microbiota intestinal en els pacients amb MII que en els controls sans, i aquesta descans de la diversitat es manifesta especialment durant i després dels brots de la malaltia. El microbioma intestinal és essencial per a mantenir la salut; els factors ambientals i de l'hoste influeixen en la composició de la microbiota intestinal. La remissió clínica, endoscòpica i histològica impacta positivament en la història natural de la CU. Aquesta tesi té com a objectiu determinar si els pacients amb CU que aconsegueixen la remissió clínica, endoscòpica i histològica durant un període prolongat presenten una composició de microbiota intestinal significativament diferent a la dels pacients amb CU en períodes de remissió més curts o amb malaltia activa. És a dir si els pacients amb CU en remissió perllongada mostren una microbiota intestinal similar a la dels individus sans. Per a això, hem analitzat mostres fecals de pacients amb CU en remissió llarga, pacients amb CU en remissió curta i pacients amb CU en brot i la hem comparat amb les mostres d'individus sans. Hem utilitzat dos mètodes diferents: seqüenciació del gen 16S ARNr i qPCR per a bacteris específics. També hem explorat els components no bacterians de la microbiota intestinal mitjançant la determinació de la càrrega fúngica mitjançant qPCR. Com es preveia, observem la presència de disbiosis en la CU amb una reducció en la diversitat i riquesa bacterianes, sub-representació de bacteris beneficiosos i l'increment de bacteris potencialment nocius. Aquesta disbiosis és més pronunciada en pacients amb CU en brot de la malaltia, però també és present en pacients amb CU en remissió curta. Els pacients amb CU que van aconseguir una remissió profunda i histològica estable i a llarg termini de la seva malaltia, presenten una composició bacteriana intestinal més pròxima a la dels controls sans, per tant menys "disbiótica". Més enllà del component bacterià, també trobem un vincle entre l'abundància de fongs i l'estat inflamatori en la CU. Els pacients en brot de la malaltia presenten una major abundància de càrrega fúngica que els pacients en remissió, però aquests resultats han d'interpretar-se amb cautela i avaluar-se més a fons en estudis longitudinals més amplis. Creiem que una microbiota en els pacients amb CU semblant a la que trobem en individus "sans", pot ser d'utilitat per a definir amb més precisió la remissió de la malaltia.La colitis ulcerosa (CU) es una enfermedad inflamatoria idiopática crónica que afecta el colon. Es uno de los dos trastornos principales que engloba el término Enfermedad Inflamatoria Intestinal (EII). La etiología de la CU involucra una respuesta inmune a una microbiota intestinal desequilibrada en individuos genéticamente susceptibles, después de eventos desencadenantes desconocidos. Los estudios de la microbiota han encontrado una menor riqueza y diversidad en la microbiota intestinal en los pacientes con EII que en los individuos sanos, y estas diferencias se manifiestan especialmente durante y después de los brotes de la enfermedad. El microbioma intestinal es esencial para mantener la salud; los factores ambientales y del huésped influyen en la composición de la microbiota intestinal. La remisión clínica, endoscópica e histológica impacta positivamente en la historia natural de la CU. Esta tesis tiene como objetivo determinar si los pacientes con CU que alcanzan la remisión clínica, endoscópica e histológica durante un período prolongado de tiempo, presentan una composición de la microbiota intestinal significativamente diferente a la de los pacientes con CU en periodos de remisión más cortos o con enfermedad activa. Para ello, hemos analizado muestras fecales de pacientes con CU en remisión larga, pacientes con CU en remisión corta y pacientes con CU en brote y hemos comparado con las muestras fecales obtenidas de individuos sanos. Hemos utilizado dos métodos diferentes: secuenciación del gen 16S ARNr y qPCR para bacterias específicas. También hemos explorado los componentes no bacterianos de la microbiota intestinal mediante la determinación de la carga fúngica mediante qPCR. Como se preveía, observamos la presencia de disbiosis en la CU con una reducción en la diversidad y riqueza bacterianas, sub-representación de bacterias beneficiosas y el incremento de bacterias potencialmente nocivas. Esta disbiosis es más pronunciada en pacientes con CU en brote de la enfermedad, pero también está presente en pacientes con CU en remisión corta. Los pacientes con CU que lograron una remisión profunda e histológica estable y a largo plazo de su enfermedad, presentan una composición bacteriana intestinal más próxima a la de los controles sanos, por lo tanto menos "disbiótica". Más allá del componente bacteriano, también encontramos un vínculo entre la abundancia de hongos y el estado inflamatorio en la CU. Los pacientes en brote de la enfermedad presentan una mayor abundancia de carga fúngica que los pacientes en remisión, pero estos resultados deben interpretarse con cautela y evaluar más a fondo en estudios longitudinales más amplios. Creemos que una microbiota en los pacientes con CU similar a la que encontramos en individuos "sanos", puede ser de utilidad para definir con mayor precisión la remisión de la enfermedad.Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease that affects the large bowel. It is one of the two major disorders under the broad term of Inflammatory Bowel Disease (IBD). The etiology of UC involves an immune response to an imbalanced gut microbiota in genetically susceptible individuals, following unknown triggering events. Microbiome studies have found a lower microbial richness and diversity in the gut microbiota of IBD patients than healthy controls, and the drop is especially manifested during and after flares of disease. The gut microbiome is essential in maintaining health and mediating illness, and environmental and host factors influence its composition. Clinical, endoscopic, and histological remission positively impacts the natural history of UC. This thesis aimed to determine if UC patients who reach clinical, endoscopic, and histological remission for an extended period would present a different gut microbiota composition than UC patients with shorter remission lengths or active disease. UC patients in long remission will show a gut microbiota that is similar to healthy individuals. For this purpose, we analyzed fecal samples of UC patients in long remission, UC patients in short remission and UC patients in flare and compared it to healthy individuals. We used two different methods: 16S rRNA gene sequencing and qPCR for specific bacteria. We also sought to explore non-bacterial constituents of the gut microbiota by determining the fungal load using qPCR. As expected, we observed dysbiosis in UC with a reduction in diversity and richness, underrepresentation of beneficial bacteria, and the gain of potentially harmful microbes. This dysbiosis was greater in UC patients in disease-flare but was also present in UC patients in short remission. UC patients who were able to achieve a long-term, stable, deep, and histological remission of their disease presented a gut bacterial composition closer to health, thus less dysbiotic. Beyond the bacterial component, we found a link between fungi abundance and inflammatory status in UC. Patients in disease-flare present a greater abundance of the fungal load than patients in remission, but these results must be interpreted cautiously and further evaluated in larger, longitudinal studies. We believe that a 'healthier' gut microbiota in UC patients could potentially be a goal to pursue in order to define disease remission further

Effectiveness and safety of ustekinumab in bio-naive Crohn's disease patients: a multicentre observational retrospective study

Background: Clinical trials have demonstrated the efficacy and safety of ustekinumab in Crohn’s disease (CD). However, more data are necessary on the effectiveness of ustekinumab in bio-naïve patients in real-life studies. Objectives: The aim of our study was to evaluate the effectiveness and safety of ustekinumab in patients with CD refractory or intolerant to conventional therapy and without previous exposure to biological drugs. Design: We performed a nationwide, observational, retrospective, multicentre study including patients with CD, in which ustekinumab was used as the first biological drug. Methods: The corticosteroid-free clinical and biological response and remission were analysed at weeks 16, 24, 52 and 72. Clinical remission was defined as Harvey–Bradshaw index⩽4 and biological remission as a faecal calprotectin (FC) <250mg/g and C-reactive protein (CRP) <5mg/L. Moreover, the persistence of the treatment and any adverse events were assessed. Results: In all, 84 patients were included in the study, males and females were equally distributed, with a median age of 63years [interquartile range (IQR): 51–75] and a median disease duration of 6.8years [IQR: 3.6–17.0]. The majority (86.9%) of patients were treated with ustekinumab as monotherapy, without concomitant immunosuppressive medication. The proportion of patients in corticosteroid-free clinical remission or response at weeks 16, 24, 52 and 72 was 93.3% (56/60), 86.8% (46/53), 82.2% (37/45) and 71.4% (30/42), respectively. CRP returned to normal values in 47.6%, 43.2%, 50% and 52.4% of patients at weeks 16, 24, 52 and 72, respectively. Similarly, FC was normalized in 45.5%, 45.5%, 48.6% and 50% of patients at weeks 16, 24, 52 and 72, respectively. The cumulative probability of remaining on ustekinumab treatment was 84.8% (95% confidence interval: 73.3–91.6) after 72weeks. Ustekinumab was discontinued in 10 patients (11.9%) within 72weeks of follow-up. Reasons for discontinuing treatment were lack of response (n=4), adverse events (n=4) and death (n=2). There were no discontinuations because of stable remission. Conclusions: Ustekinumab was effective and safe in Spanish bio-naïve CD patients, showing a quicker and more durable response than obtained in patients with previous biological treatment. In this cohort of bio-naïve patients starting on ustekinumab, the average age was high

Sucrosomial Iron Supplementation for the Treatment of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients Refractory to Oral Iron Treatment

Iron deficiency anemia (IDA) is a common manifestation of Inflammatory Bowel Disease (IBD). Oral iron supplements are the treatment of choice, but are not always well tolerated. Sucrosomial® iron (SI) may represent an alternative. This prospective study assessed the tolerability and effectiveness of SI, and quality of life (QoL) of IDA-IBD patients who were intolerant to oral iron salts. The study included 52 individuals treated with 1 capsule/day for 12 weeks. Tolerability was assessed through a gastrointestinal symptom severity questionnaire. Hemoglobin (Hb) levels and clinical symptoms of IDA were analyzed. QoL was assessed using IBDQ-9 and EuroQoL questionnaires. The percentage of patients with excellent/good health increased from 42.9% to 94.3%. Mean Hb concentration significantly increased at all follow-up visits (p &lt; 0.05). Almost all participants (96.9%) were adherent to the study medication. Patients’ QoL improved (IBDQ-9: from 60.9 to 65.5). Patients also improved in mobility (71.8% to 78.1%), usual activities (51.3% to 68.7%), pain/discomfort (41.0% to 53.1%), and extreme depression/anxiety problems (7.7% to 3.2%); they worsened in self-care (100% to 90.6%), but perceived an enhancement in their global health [EQ-VAS score: 61.9 (±26.1) to 66.9 (±20.3)]. SI was well tolerated and improved IDA symptoms, IBD activity, and patients’ QoL. In conclusion, SI should be considered in IDA–IBD patients