Histologic Remission in Inflammatory Bowel Disease and Female Fertility: A Nationwide Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity. METHODS: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD). RESULTS: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98]). CONCLUSIONS: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD.

Emergency subtotal colectomy rates in relation to anti-TNF therapy in inflammatory bowel disease patients: comparison of retrospective cohorts.

OBJECTIVES: The introduction of anti-TNF therapy has revolutionized the management of inflammatory bowel disease (IBD). This study aimed to investigate the impact of anti-TNF therapy on emergency subtotal colectomy rates in patients with IBD (ulcerative colitis, Crohn's disease or indeterminate colitis) during two time periods. METHODS: IBD patients treated with emergency subtotal colectomy for acute severe colitis at Skåne University Hospital, Sweden, during two six-year windows were included. The two time-windows represented pre- and introductory (2004-2009) versus post-introductory (2012-2017) anti-TNF therapy usage. The two periods were compared in terms of the proportion of patients who received anti-TNF therapy, rates of emergency subtotal colectomy, and local IBD prevalence numbers. RESULTS: In total 91 patients were included, 42 (2004-2009) and 49 (2012-2017) patients, respectively. The proportion of patients that received anti-TNF therapy prior to admission was increased from 29% (2004-2009) to 63% (2012-2017) (p = .001). Despite this no significant difference was found in the emergency subtotal colectomy rates between the time periods considering the population at risk (IBD patients living in Skåne county); 1.44/1000 person years versus 1.37/1000 person years (p = .83). CONCLUSION: Despite an increased proportion of patients with IBD that received anti-TNF therapy prior to admission, no significant decrease in emergency subtotal colectomy rates was noted. Further research is warranted, and a prospective study design would facilitate a better causal understanding.

IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation.

CD103(+)CD11b(+) dendritic cells (DCs) represent the major migratory DC population within the small intestinal lamina propria (SI-LP), but their in vivo function remains unclear. Here we demonstrate that intestinal CD103(+)CD11b(+) DC survival was dependent on interferon regulatory factor 4 (IRF4). Mice with a DC deletion in Irf4 displayed reduced numbers of intestinal interleukin 17 (IL-17)-secreting helper T 17 (Th17) cells and failed to support Th17 cell differentiation in draining mesenteric lymph nodes (MLN) following immunization. The latter was associated with a selective reduction in CD103(+)CD11b(+) MLN DCs and DC derived IL-6. Immunized Il6(-/-) mice failed to support Th17 cell differentiation in MLN in vivo and CD103(+)CD11b(+) MLN DCs supported IL-6-dependent Th17 cell differentiation in vitro. Together, our results suggest a central role for IRF4-dependent, IL-6 producing CD103(+)CD11b(+) DCs in intestinal Th17 cell differentiation.

Short and long-term efficacy of adalimumab in ulcerative colitis: a real-life study.

Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort.Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model.Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0-51.4) were included. Median disease duration was 4.3 years (IQR 2.0-9.0) and follow-up 1.27 years (IQR 0.33-4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years.Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.

Elevated faecal calprotectin is linked to worse disease status in axial spondyloarthritis: results from the SPARTAKUS cohort.

OBJECTIVES: To examine faecal calprotectin (F-calprotectin) levels and presence of anti-Saccharomyces cerevisiae antibodies (ASCA) and their associations with disease subtype and current status in axial SpA (axSpA). METHODS: F-calprotectin and ASCA in serum were compared between consecutive patients with a clinical axSpA diagnosis, classified as non-radiographic axSpA (nr-axSpA; n = 40) or AS (n = 90), and with healthy controls (n = 35). Furthermore, standard axSpA outcome measures were compared between axSpA patients (nr-axSpA and AS combined) with elevated vs normal F-calprotectin, ASCA IgA and IgG, respectively. RESULTS: Elevated F-calprotectin (⩾50 mg/kg) was observed in 27% of nr-axSpA patients, 38% of AS patients and 6% of controls. F-calprotectin was significantly higher in AS vs nr-axSpA [AS: geometric mean 41 (95% CI 32, 54) mg/kg; nr-axSpA: 24 (95% CI 16, 38) mg/kg; P = 0.037], and in each axSpA subtype vs controls. Overall, worse disease activity and physical function scores were observed among axSpA patients with elevated vs normal F-calprotectin levels, with significant differences regarding patient's visual analogue scale for global health, ASDAS using CRP, and BASFI (adjusted for age, sex, NSAID use, anti-rheumatic treatments, and CRP). ASCA titres and seropositivity (⩾10 U/ml) were similar in nr-axSpA (IgA/IgG-seropositivity: 8%/26%) and AS (7%/28%), and clinical outcome measures did not differ between patients with elevated vs normal ASCA IgA or IgG, respectively. Compared with controls (IgA/IgG-seropositivity: 0%/17%), ASCA IgA was significantly higher in both axSpA subtypes, and IgG was significantly higher in the AS group. CONCLUSION: In patients with axSpA, gut inflammation measured by elevated F-calprotectin is associated with worse disease activity and physical function, and may be a marker of more severe disease.

CD8αß+ γδ T Cells: A Novel T Cell Subset with a Potential Role in Inflammatory Bowel Disease.

γδ T cells have been attributed a wide variety of functions, which in some cases may appear as contradictory. To better understand the enigmatic biology of γδ T cells it is crucial to define the constituting subpopulations. γδ T cells have previously been categorized into two subpopulations: CD8αα+ and CD8- cells. In this study we have defined and characterized a novel subset of human γδ T-cells expressing CD8αß. These CD8αß+ γδ T cells differed from the previously described γδ T cell subsets in several aspects, including the degree of enrichment within the gut mucosa, the activation status in blood, the type of TCRδ variant used in blood, and small but significant differences in their response to IL-2 stimulation. Furthermore, the novel subset expressed cytotoxic mediators and CD69, and produced IFN-γ and TNF-α. In patients with active inflammatory bowel disease the mucosal frequencies of CD8αß+ γδ T cells were significantly lower as compared with healthy controls, correlated negatively with the degree of disease activity, and increased to normal levels as a result of anti-TNF-α therapy. In conclusion, our results demonstrate that CD8αß+ γδ T cells constitute a novel lymphocyte subset, which is strongly enriched within the gut and may play an important role in gut homeostasis and mucosal healing in inflammatory bowel disease.

Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND: Approximately 15-20% of ulcerative colitis patients and 20-40% of those with Crohn's disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action. AIMS: This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action. METHODS: We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy. RESULTS: Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn's disease. CONCLUSIONS: These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.

Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.

Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4ß7 antibody with gut-specific immunosuppressive effects, approved for Crohn's disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.

Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVES: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Multilocus Sequence Analysis of Clinical "Candidatus Neoehrlichia mikurensis" Strains from Europe.

"Candidatus Neoehrlichia mikurensis" is the tick-borne agent of neoehrlichiosis, an infectious disease that primarily affects immunocompromised patients. So far, the genetic variability of "Ca. Neoehrlichia" has been studied only by comparing 16S rRNA genes and groEL operon sequences. We describe the development and use of a multilocus sequence analysis (MLSA) protocol to characterize the genetic diversity of clinical "Ca. Neoehrlichia" strains in Europe and their relatedness to other species within the Anaplasmataceae family. Six genes were selected: ftsZ, clpB, gatB, lipA, groEL, and 16S rRNA. Each MLSA locus was amplified by real-time PCR, and the PCR products were sequenced. Phylogenetic trees of MLSA locus relatedness were constructed from aligned sequences. Blood samples from 12 patients with confirmed "Ca. Neoehrlichia" infection from Sweden (n = 9), the Czech Republic (n = 2), and Germany (n = 1) were analyzed with the MLSA protocol. Three of the Swedish strains exhibited identical lipA sequences, while the lipA sequences of the strains from the other nine patients were identical to each other. One of the Czech strains had one differing nucleotide in the clpB sequence from the sequences of the other 11 strains. All 12 strains had identical sequences for the genes 16S rRNA, ftsZ, gatB, and groEL. According to the MLSA, among the Anaplasmataceae, "Ca. Neoehrlichia" is most closely related to Ehrlichia ruminantium, less so to Anaplasma phagocytophilum, and least to Wolbachia endosymbionts. To conclude, three sequence types of infectious "Ca. Neoehrlichia" were identified: one in the west of Sweden, one in the Czech Republic, and one spread throughout Europe.

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device.

Impairment of intestinal epithelium is a typical feature of inflammatory bowel disease (IBD) that causes leakage of bacteria and antigens from the intestinal lumen and thus results in persistent immune activation. Hence, healing and regeneration of the damaged gut mucosa is a promising therapeutic approach to achieve deep remission in IBD. Currently, available systemic therapies have moderate effects and are often associated with numerous side effects and malignancies. In this study, we aimed to develop a topical therapy by chemically conjugating a temperature-responsive polymer, i.e., poly(N-isopropylacrylamide), along with hyaluronic acid to obtain a sprayable therapeutic formulation that upon colon instillation adheres to the damaged gut mucosa due to its temperature-induced phase transition and mucoadhesive properties. An ex vivo adhesion experiment demonstrates that this therapeutic formulation forms a thin physical coating on the mucosal lining at a physiological temperature within 5 min. Physicochemical characterization of (P(NIPAM-co-NTBAM)-HA) established this formulation to be biocompatible, hemo-compatible, and non-immunogenic. Prednisolone was encapsulated within the polymer formulation to achieve maximum therapeutic efficacy in the case of IBD-like conditions as assessed in a custom-fabricated perfusion-based ex vivo model system. Histological analysis suggests that the prednisolone-encapsulated polymer formulation nearly restored the mucosal architecture after 2,4,6-trinitrobenzenesulfonic acid-induced damage. Furthermore, a significant (p ≤ 0.001) increase in mRNA levels of Muc-2 and ZO-1 in treated groups further confirmed the mucosal epithelial barrier restoration.

[New solutions for an old problem : Current developments in oral contrast agents]. / Neue Lösung für ein altes Problem : Aktuelle Entwicklungen bei oralen Kontrastmitteln.

BACKGROUND: Several radiological societies in Europe have so far spoken out in favor of MRI of the small intestine over CT, since MRI is said to provide more detailed image information. Due to the limited availability of MRI machines, long waiting times arise for many patients who clinically require small bowel imaging. OBJECTIVES: These circumstances guided our search for an improved CT technique that would provide scans that mimic the image impression of T1 sequence in MRI, i.e. with IV contrast-enhanced intestinal wall versus low/no signal lumen. MATERIAL AND METHODS: The oral use of fat or oil is poorly tolerated by patients, as is the placement of a naso-duodenal tube for air insufflation. We have now succeeded in creating a foamy drink with 44% air content, which is kept stable by protein together with buffers, and can be easily administered orally. CT with the Lumentin® beverage as bowel filling agent has been tested on healthy adult volunteers; oncology patients; and Crohn's disease patients who, for comparison, also underwent MRI of the small bowel with conventional oral contrast. RESULTS: The results so far with Lumentin® show a very good distribution throughout the entire small intestine with good lumen distension, images with strongly enhanced contrast of the intestinal mucosa, and lesions that are detected at the same or increased frequency as compared with MRI. Side effects were few and mild, and overall fewer than with commonly used oral agents. Lumentin's foamy consistency was unfamiliar to a few patients, but it wasn't difficult to drink. CONCLUSIONS: The new and innovative luminal HU-negative contrast agent Lumentin® improves the diagnostic CT image quality. In addition, Lumentin® experimental MRI tests have provided promising results, which are currently leading to further clinical MRI studies.

Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study.

Background: Real-world data on long-term outcomes of vedolizumab (VDZ) are scarce. Objective: To assess long-term outcomes (up to 3 years) of VDZ in treating inflammatory bowel disease (IBD). Design: A nationwide, prospective multicentre extension of a Swedish observational study on VDZ assessing Effectiveness And Healthcare resource utilization in patients with IBD (SVEAH). Methods: After re-consent, data of patients with Crohn's disease (CD) (n = 68) and ulcerative colitis (UC) (n = 46) treated with VDZ were prospectively recorded using an electronic case report form integrated with the Swedish IBD Register (SWIBREG). The primary outcome was clinical remission (defined as Harvey-Bradshaw Index ⩽4 in CD and partial Mayo score ⩽2 in UC) at 104 and 156 weeks in patients with a response and/or remission 12 weeks after starting VDZ. Secondary outcomes included health-related quality of life (HRQoL) and biochemical outcomes. Results: VDZ continuation rates were high at weeks 104 and 156, 88% and 84%, respectively, for CD and 87% and 78%, respectively, for UC. Of the 53 CD patients with a response/remission at 12 weeks, 40 (75%) patients were in remission at 104 weeks and 42 (79%) patients at 156 weeks. For UC, these numbers were 25/31 (81%) and 22/31 (71%), respectively. Improvements were seen in the Short Health Scale (p < 0.01 for each dimension; CD, n = 51; UC, n = 33) and the EuroQol 5-Dimensions, 5-levels index value (p < 0.01; CD, n = 39; UC, n = 30). Median plasma-C-reactive protein concentrations (mg/L) decreased from 5 at baseline to 4 in CD (p = 0.01, n = 53) and from 5 to 4 in UC (p = 0.03, n = 34) at 156 weeks. Correspondingly, median faecal-calprotectin (µg/g) decreased from 641 to 114 in CD patients (p < 0.01, n = 26) and from 387 to 37 in UC patients (p = 0.02, n = 17). Conclusion: VDZ demonstrated high continuation rates and was associated with improvements in clinical outcomes, HRQoL measures and inflammatory markers at 2 and 3 years after treatment initiation in this prospective national SVEAH extension study. Registration: ENCePP registration number: EUPAS22735.

Real-world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Vedolizumab is a gut-selective treatment approved for Crohn's disease (CD) and ulcerative colitis (UC). Recently, a subcutaneous formulation of vedolizumab was approved. The aims of this study were to evaluate efficacy, safety, pharmacokinetics, patient experience and costs following a switch from intravenous to subcutaneous vedolizumab treatment. METHODS: Patients were switched from intravenous to subcutaneous vedolizumab maintenance treatment and followed prospectively for 6 months and a subgroup for 12 months. The primary endpoint was change in faecal calprotectin levels. Furthermore, we evaluated clinical disease activity, remission rates, plasma CRP, drug persistence, adverse events, local injection reactions, serum drug concentrations, patient satisfaction, quality-of-life and treatment costs. RESULTS: Eighty-nine patients were included (48 CD; 41 UC). Faecal calprotectin decreased significantly in CD but not in UC. Clinical indices, remission rates, plasma CRP levels and quality-of-life scores remained unchanged. Patients that had been on standard compared to optimised IV vedolizumab dosing displayed similar outcomes on standard SC dosing. Drug persistence at 6 and 12 months was 95.5% and 88.5%, respectively. Frequencies of adverse events were similar before and after the switch. No serious adverse events occurred. Transient severe local injection reactions were experienced by 1.2% of patients. Median vedolizumab trough levels were 2.3 times higher on subcutaneous compared to intravenous treatment. Patient satisfaction was generally high. Annualised treatment costs were reduced by 15% following the switch. CONCLUSIONS: The switch from intravenous to subcutaneous vedolizumab could be done with preserved therapeutic effectiveness, safety, high patient satisfaction and low discontinuation rate, at a reduced cost.

Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations.

Background and aim: Alkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system. Methods: We quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (Tregs), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis. Results: The numbers of both small and large intestinal CD3ε+, CD4+, and CD8α+ T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas Treg numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε+ and CD4+ T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes. Conclusion: NPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.

Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease.

Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both "step-up" and "top-down" approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.

Histological remission in inflammatory bowel disease and risk of adverse pregnancy outcomes: A nationwide study.

Background: Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity. Methods: We performed a nationwide study of Swedish women diagnosed with IBD 1990-2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation (1223 and 630 births, respectively). We also examined pregnancy outcomes in 2007-2016 of women with vs. without clinically active IBD (i.e., IBD-related hospitalization, surgery, or medication escalation) <12 months before pregnancy (2110 and 4993 births, respectively). Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth (<37 gestational weeks) and small-for-gestational age (SGA, <10th percentile weight for age). Findings: Of infants to women with vs. without histological inflammation, 9.6% (n = 117) and 6.5% (n = 41) were preterm, respectively (aRR = 1.46; 95%CI = 1.03-2.06). Histological inflammation was associated with preterm birth in ulcerative colitis (UC) (aRR = 1.64; 95%CI = 1.07-2.52), especially extensive colitis (aRR = 2.37; 95%CI = 1.12-5.02), but not in Crohn's disease (aRR = 0.99; 95%CI = 0.55-1.78). Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA (aRR = 1.09; 95%CI = 0.81-1.47). Clinically active disease before pregnancy was linked to preterm birth (aRR = 1.42; 95%CI = 1.20-1.69), but not to SGA birth (aRR = 1.13; 95%CI = 0.96-1.32). Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth (aRR = 1.20; 95%CI = 0.68-2.13). Interpretation: Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity. Funding: The Swedish Society of Medicine.

A novel food-based negative oral contrast agent compared with two conventional oral contrast agents in abdominal CT: a three-arm parallel blinded randomised controlled single-centre trial.

BACKGROUND: A negative oral contrast agent (OCA) has been long sought for, to better delineate the bowel and visualise surrounding structures. Lumentin® 44 (L44) is a new OCA formulated to fill the entire small bowel. The aim of this study was to compare L44 with positive and neutral conventional OCA in abdominal computed tomography (CT). METHODS: Forty-five oncologic patients were randomised to receive either L44 or one of the two comparators (MoviPrep® or diluted Omnipaque®). Abdominal CT examinations with intravenous contrast agent were acquired according to standard protocols. The studies were read independently by two senior radiologists. RESULTS: The mean intraluminal Hounsfield units (HU)-values of regions-of-interest (ROIs) for each subsegment of small bowel and treatment group were -404.0 HU for L44, 166.1 HU for Omnipaque®, and 16.7 HU for MoviPrep® (L44 versus Omnipaque, p < 0.001: L44 versus MoviPrep p < 0.001; Omnipaque versus MoviPrep, p = 0.003). Adverse events, only mild, using L44 were numerically fewer than for using conventional oral contrast agents. Visualisation of abdominal structures beyond the small bowel was similar to the comparators. CONCLUSIONS: L44 is a negative OCA with luminal radiodensity at approximately -400 HU creating a unique small bowel appearance on CT scans. The high bowel wall-to-lumen contrast may enable improved visualisation in a range of pathologic conditions. L44 showed a good safety profile and was well accepted by patients studied. TRIAL REGISTRATION: EudraCT (2017-002368-42) and in ClinicalTrials.gov (NCT03326518).