Cholinergic regulation of vascular endothelial function by human ChAT+ T cells.

Endothelial dysfunction and impaired vasodilation are linked with adverse cardiovascular events. T lymphocytes expressing choline acetyltransferase (ChAT), the enzyme catalyzing biosynthesis of the vasorelaxant acetylcholine (ACh), regulate vasodilation and are integral to the cholinergic antiinflammatory pathway in an inflammatory reflex in mice. Here, we found that human T cell ChAT mRNA expression was induced by T cell activation involving the PI3K signaling cascade. Mechanistically, we identified that ChAT mRNA expression was induced following the attenuation of RE-1 Silencing Transcription factor REST-mediated methylation of the ChAT promoter, and that ChAT mRNA expression levels were up-regulated by GATA3 in human T cells. In functional experiments, T cell-derived ACh increased endothelial nitric oxide-synthase activity, promoted vasorelaxation, and reduced vascular endothelial activation and promoted barrier integrity by a cholinergic mechanism. Further, we observed that survival in a cohort of patients with severe circulatory failure correlated with their relative frequency of ChAT +CD4+ T cells in blood. These findings on ChAT+ human T cells provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.

Comparative study of a point-of-care test and an enzyme-linked immunosorbent assay (ELISA) for infliximab levels.

BACKGROUND: Proactive therapeutic drug monitoring (TDM) is often challenged by long turnaround time when using enzyme-linked immunosorbent assays (ELISAs), especially when analyses are centralised. Point-of-care tests (POCTs) allow rapid assessments, but data on their agreement with existing in-house methodologies are scarce. OBJECTIVE: To examine the agreement between a POCT by ProciseDx (San Diego, CA) and the most frequently used in-house ELISA for infliximab (IFX) quantification in Sweden. METHODS: Serum samples were analysed using the in-house ELISA, Karolinska University Hospital, Stockholm, Sweden and a POCT by ProciseDx (San Diego, CA). Agreement was assessed and differences were examined. RESULTS: Samples from 61 inflammatory bowel disease (IBD) patients were analysed with a median IFX concentration of 7.9 µg/mL (interquartile range (IQR) 5.5-13) for the POCT and 7.9 µg/mL (IQR 5.2-12) for the ELISA (Pearson's correlation coefficient = 0.95 (95% CI 0.92-0.97, p < .01)). A Passing-Bablok regression yielded an intercept of -0.44 and a slope of 1.09. The Bland-Altman plot showed a systemic bias of -0.77 µg/mL (95% CI -0.18 to -1.4) between the methods. The upper limit of agreement was 3.7 (95% CI 2.7-4.8) (µg/mL), whereas the lower limit agreement was -5.3 (95% CI -6.3 to -4.3) (µg/mL). An excellent reliability was observed, intraclass correlation showed = 0.94 (95% CI 0.89-0.96, p < .0001). When defining IFX concentration as subtherapeutic (<3.0 µg/mL), therapeutic (3.0-7.0 µg/mL) or supratherapeutic (>7.0 µg/mL) drug levels, Kappa statistics showed a substantial agreement (0.79). CONCLUSIONS: The POCT by ProciseDx (San Diego, CA) demonstrated a good agreement with the in-house ELISA, supporting its use for rapid IFX quantification.

Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia.

BACKGROUND AND AIMS: Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. METHODS: A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. RESULTS: In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. CONCLUSION: TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

The brain-gut axis, inflammatory bowel disease and bioelectronic medicine.

The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain-gut axis through bioelectronic devices.

Tumour necrosis factor inhibitors in Crohn's disease and the effect on surgery rates.

AIM: Surgery is an important therapeutic option for Crohn's disease. The need for first bowel surgery seems to have decreased with the introduction of tumour necrosis factor inhibitors (TNFi; adalimumab or infliximab). However, the impact of TNFi on the need for intestinal surgery in Crohn's disease patients irrespective of prior bowel resection is not known. The aim of this work is to compare the incidence of bowel surgery in Crohn's disease patients who remain on TNFi treatment versus those who discontinue it. METHOD: We performed a nationwide register-based observational cohort study in Sweden of all incident and prevalent cases of Crohn's disease who started first-line TNFi treatment between 2006 and 2017. Patients were categorized according to TNFi treatment retention less than or beyond 1 year. The study cohort was evaluated with regard to incidence of bowel surgery from 12 months after the first ever TNFi dispensation. RESULTS: We identified 5003 Crohn's disease patients with TNFi exposure: 3748 surgery naïve and 1255 with bowel surgery prior to TNFi initiation. Of these patients, 7% (n = 353) were subjected to abdominal surgery during the first 12 months after the start of TNFi and were subsequently excluded from the main analysis. A majority (62%) continued TNFi for 12 months or more. Treatment with TNFi for less than 12 months was associated with a significantly higher surgery rate compared with patients who continued on TNFi for 12 months or more (hazard ratio 1.26, 95% CI 1.09-1.46; p = 0.002). CONCLUSION: Treatment with TNFi for less than 12 months was associated with a higher risk of bowel surgery in Crohn's disease patients compared with those who continued TNFi for 12 months or more.

Plasma HMGB1 levels and physical performance in ICU survivors.

PURPOSE: Physical impairment after critical illness is recognized as a part of the post-intensive care syndrome (PICS). About one third of intensive care unit (ICU) survivors suffer from long-term physical disability, yet the underlying pathophysiological mechanisms remain poorly understood. The pro-inflammatory alarmin, high mobility group box 1 (HMGB1), promotes muscle dysfunction in experimental models, and HMGB1 stays elevated in some patients after ICU discharge. Accordingly, we investigated the relationship between HMGB1 plasma levels and physical performance in ICU survivors. METHODS: Prospective cohort study of 100 ICU survivors from the general ICU at the Karolinska University Hospital, Sweden. Patients returned for follow up at 3 (58 patients) and 6 months (51 patients) after ICU discharge. Blood samples were collected, and a 6-minute walk test (6-MWT), a handgrip-strength test (HST), and a timed-stands test (TST) were performed. RESULTS: Compared to reference values of the different physical tests, 16% of patients underperformed at all tests at 3 months and 12% at 6 months. All test results, except hand-grip strength left, improved significantly over the follow-up period (P < .05). There was no significant association between plasma HMGB1 levels at 3 and 6 months and scores on the three tests (6-MWT, TST, and HST) (P = .50-0.69). CONCLUSION: In this follow-up study of ICU survivors, we found no significant association between plasma HMGB1 levels and physical performance. Additional follow-up studies of HMGB1 plasma levels and muscle function in ICU survivors are still warranted. EDITORIAL COMMENT: HMGB-1, a marker of cell damage and activation, is known to increase in ICU patients. In study participants at 3- to 6-month post-ICU stay, HMGB-1 levels were still elevated, although no association to the primary outcome, physical performance, was found. Mechanisms for failure to recover physical performance post-ICU remain unclear, and investigations into cause of post-intensive care syndrome need to continue. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier NCT02914756.

Sustained clinical benefit, improved quality of life, and reduced intestinal surgery from maintenance infliximab treatment in inflammatory bowel disease.

Objectives: Anti-TNF treatment is established for patients with severe inflammatory bowel disease (IBD) refractory to conventional medication. However, long-term real-life observations are limited. We have monitored 200 patients with primary response to infliximab (Remicade®).Methods: Patients with either Crohn's disease (CD) or ulcerative colitis (UC) who started IFX and had clinical response at 1 year were prospectively followed. C-reactive protein (CRP), albumin, fecal calprotectin (FCP), Harvey Bradshaw index (HBI) in CD cases, and Quality of Life index were monitored. Concomitant medications, surgery and hospitalisation were assessed.Results: Out of the 200 patients, 164 suffered from CD. Median disease duration was 5.0 (0.2-44.0) years and the observation time was 3.4 (1.0-13.9) years. Steroid use was reduced from 51% to 10%. HBI in CD patients decreased from 8.0 ± 0.40 to 2.7 ± 0.26. Disease activity in UC patients was only assessed by biochemical markers. CRP decreased from 29.0 ± 6.2 to 8.0 ± 7.1 mg/L. FCP showed a decrease from 1918 (1837) to 191 (646) mg/kg. Hospitalization showed similar tendency and quality of life was improved. Twenty-seven percent had been operated before IFX introduction compared to 11% during the observation period. Loss of response was seen in 42 patients, of which 20 patients needed intestinal surgery.Conclusion: Two-thirds of the patients demonstrated stable clinical benefit from maintenance IFX. The results show steroid-sparing efficacy as well as improved quality of life and reduced need for surgery.

Older age is a risk factor for inadequate energy intake during acute, severe IBD and is associated with shorter time to relapse.

BACKGROUND: Effects of nutritional intake on inflammatory bowel disease (IBD) flare resolution are unknown. We hypothesised that nutritional factors during hospitalisation for acute severe IBD are associated with risk of subsequent relapse. We also studied risk factors for inadequate energy intake. METHODS: Patients admitted to the Karolinska Hospital Gastroenterology ward with IBD flare during 2015-2016 were retrospectively identified. In total, 91 patients were included. Data on nutrition, disease factors, inflammatory markers, and daily energy requirement were extracted. Requirement of new systemic steroid prescription, intensification of biological therapy, readmission, surgery, and calprotectin level were individually used as proxies for disease relapse. Follow-up was one year after discharge. Adjustments for age and sex were made where appropriate. RESULTS: Overall, 19%, 31%, and 45% of patients had days with energy intake <30, <50, and <70% of calculated requirement. Older age was associated with a higher number of days with energy intake <30, <50, and <70% of calculated requirement (regression coefficient 0.03, 0.04, 0.06 respectively, p = .012, .017, .008). The number of days with energy intake <30 and <70% of the calculated requirement and the length of the hospitalisation were associated with shorter time to new steroid prescription (hazard ratio 1.3, 1.1, 1.04 respectively, p = .016, .034, .011). CRP and calprotectin were not associated with relapse. CONCLUSION: Older age is a predictor of inadequate energy intake during hospitalisation for acute severe IBD. Inadequate energy intake adjusted for age and sex during IBD flare was better predictor of time to the next steroid-requiring relapse than inflammatory markers.

The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.

Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.

Towards improved control of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by activation of both the innate and adaptive immune system in genetically susceptible individuals, resulting in chronic intestinal inflammation. The triggers that initiate and perpetuate this continuous inflammation are the subject of much speculation and research, although the central role of the intestinal microbiota is recognized, and is even a target for treatment in some circumstances. The mainstay of modern IBD treatment is suppression of the immune response towards as yet unspecified antigens, and conventional therapy includes corticosteroids, 5-aminosalicylic acid (5-ASA), thiopurines and methotrexate. Reducing activity of specific mediators has proven efficacious, including adhesion molecules, such as the gut-homing integrin α4 ß7 expressed on the surface of circulating immune cells, and cytokines, such as tumour necrosis factor α (TNF-α). This has been achieved using biologic agents including monoclonal antibodies. Recent discoveries in immunology and neuroscience have revealed that signals in the peripheral nervous system regulate inflammation, including levels of TNF-α. The understanding of the mechanisms of the neuro-immune communication involved in inflammation control in the gut is evolving, but is as yet incomplete. Clinical studies using implanted vagus nerve stimulators for treatment of IBD show encouraging results. Accordingly, the neural reflex control of inflammation is emerging as a potential therapeutic target in treatment of IBD. Here, we review current therapeutic options and neural reflex control of gut immunity in the context of intestinal inflammation.

Swedish Inflammatory Bowel Disease Register (SWIBREG) - a nationwide quality register.

Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory relapsing disease with increasing incidence. IBD research and long-term follow-up of patients have, however, been hampered by lack of detailed data on disease phenotype, patient-reported outcome measures, Physician Global Assessment, disease activity, and hospital-administered drugs. Aim: To review the Swedish IBD quality register (SWIBREG). Methods: Review of SWIBREG including questionnaire data from users and patients. Results: SWIBREG was launched in 2005, and as of April 2019, contains 46,400 patients with IBD (Crohn's disease: n = 15,705, ulcerative colitis: n = 21,540, IBD unclassified and other colitis (including e.g., microscopic colitis): n = 9155). Of these IBD patients, 7778 had been diagnosed in childhood (16.8%). Earlier research has shown that combining SWIBREG and the Swedish National Patient Register (NPR) yields a positive predictive value of 100% (95%CI = 95-100%) for having a diagnosis of IBD. Moreover, out of all patients in the NPR with a diagnosis of IBD plus either IBD-related surgery or immunomodulatory/biological treatment during the past 18 months, SWIBREG covers 59.0%. SWIBREG records not only information on conventional therapies but also on biological treatment, surgery, smoking, disease activity, patient-reported outcome measures (PROMs), and patient-experienced measures (PREMs). Data are presented through a graphical decision support system. Conclusion: SWIBREG benefits patients with IBD, and offers an ideal opportunity for healthcare personnel and researchers to examine disease phenotype and activity, PROMs/PREMs, and hospital-administered drugs in patients with IBD.

Lack of clinically relevant correlation between subjective and objective cognitive function in ICU survivors: a prospective 12-month follow-up study.

BACKGROUND: Cognitive impairment and psychological distress are common in intensive care unit (ICU) survivors. Early identification of affected individuals is important, so intervention and treatment can be utilized at an early stage. Cognitive Failures Questionnaire (CFQ) is commonly used to screen for subjective cognitive function, but it is unclear whether CFQ scores correlate to objective cognitive function in this population. METHODS: Between 2014 and 2018, 100 ICU survivors aged 18-70 years from the general ICU at the Karolinska University Hospital, Solna, were included in the study. Out of these, 58 patients completed follow-up at 3 months after ICU discharge, 51 at 6 months, and 45 at 12 months. Follow-up included objective cognitive function testing using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and subjective cognitive function testing with the self-rating Cognitive Failures Questionnaire (CFQ), as well as psychological self-rating with the Post-Traumatic Stress Symptoms Scale-10 (PTSS-10) and Hospital Anxiety and Depression Scale (HADS). RESULTS: The prevalence of cognitive impairment as measured by four selected CANTAB tests was 34% at 3 months after discharge, 18% at 6 months, and 16% at 12 months. There was a lack of significant correlation between CANTAB scores and CFQ scores at 3 months (r = - 0.134-0.207, p > 0.05), at 6 months (r = - 0.106-0.257, p > 0.05), and at 12 months after discharge (r = - 0.070-0.109, p > 0.05). Correlations between CFQ and PTSS-10 scores and HADS scores, respectively, were significant over the follow-up period (r = 0.372-0.710, p ≤ 0.001-0.023). In contrast, CANTAB test scores showed a weak correlation with PTSS-10 and HADS scores, respectively, at 3 months only (r = - 0.319-0.348, p = 0.008-0.015). CONCLUSION: We found no clinically relevant correlation between subjective and objective cognitive function in this cohort of ICU survivors, while subjective cognitive function correlated significantly with psychological symptoms throughout the follow-up period. Treatment and evaluation of ICU survivors' recovery need to consider both subjective and objective aspects of cognitive impairment, and subjective reports must be interpreted with caution as an indicator of objective cognitive function.

Granulocyte and Monocyte Apheresis for Induction of Remission in Children With New-Onset Inflammatory Bowel Colitis.

OBJECTIVE: The aim of the study was to analyze the effect of granulocyte and monocyte apheresis (GMA) with mesalazine for induction of remission in pediatric patients with newly onset chronic inflammatory bowel disease (IBD) colitis. METHODS: Thirteen pediatric patients with newly onset extensive IBD colitis were investigated per the ECCO/ESPGHAN IBD protocol. Of these 13, 12 received 10 treatments with Adacolumn (ADA) during a median of 6.25 weeks in combination with low-to-moderate doses of mesalazine, which was continued after apheresis. A control colonoscopy was performed 12 to 16 weeks after GMA treatment. Primary outcomes were mucosal healing (Mayo endoscopic score) and histopathologic grading of biopsies. A secondary outcome was disease activity as measured by the Pediatric Ulcerative Colitis Activity Index. RESULTS: Twelve children (6 girls) with a median age of 14.6 years and a median duration of symptoms at diagnosis of 3.2 months received all planned 10 treatment sessions with ADA. Ten of 12 patients had pancolitis and 2 of 12 extensive colitis. A final diagnosis, however, indicated ulcerative colitis in 10 children and Crohn disease in 2 children. At control colonoscopy, 8 of 12 children were in clinical remission and the Mayo endoscopic score showed significant improvement in 9 of 12 patients (P = 0.006). Complete microscopic remission, according to the Geboes score, was observed in 2 patients. CONCLUSIONS: In this small study GMA for induction of remission of newly onset pediatric IBD colitis was effective in 8 of 12 patients. Further controlled studies are warranted to confirm the efficacy of this treatment model.

Mucosal Cytokine Profiles After Induction Therapy With Granulocyte/Monocyte Apheresis in New-onset Inflammatory Colitis.

Granulocyte/monocyte apheresis (GMA) selectively removes circulating granulocytes and monocytes; important producers of proinflammatory cytokines. Seven children with new-onset inflammatory bowel disease (IBD) colitis were treated with GMA together with mesalazine, and had significant decreases in Pediatric UC Activity Index (P = 0.018) and Mayo endoscopic score (P = 0.013). We investigated the colonic mucosal cytokine profiles (analyzed with real-time polymerase chain reaction), before and after induction treatment, and in 6 non-IBD controls. Significant decreases were seen in Colony Stimulating Factor 2 (P = 0.018), tumor necrosis factor-α (P = 0.028), interleukin (IL)-23α (P = 0.043), IL-1ß (P = 0.028), IL-36γ (P = 0.018), IL-10 (P = 0.028), and transforming growth factor beta 1 (P = 0.043) after treatment. In 6 non-IBD controls there were significantly lower levels of IL-12ß (P = 0.023) and IL-23α (P = 0.046) compared to the patients with IBD at onset, and IL-22 (P = 0.088) and IL-36γ (P = 0.062) showed lower values without reaching significant differences. We speculate that the decreases in colonic mucosal cytokine profiles after treatment may explain the observed clinical efficacy in the GMA-treated children with IBD.

Safety and Immunogenicity of Inactivated Varicella-Zoster Virus Vaccine in Adults With Autoimmune Disease: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Immunogenicity and safety of inactivated zoster vaccine (ZVIN) were evaluated in adults with autoimmune disease. METHODS: Adults with autoimmune disease treated with immunosuppressive therapy (biologic or nonbiologic) were randomized to receive 4 doses of ZVIN, ZVIN containing a higher quantity of antigen, or placebo. To measure varicella-zoster virus (VZV)-specific immune responses using glycoprotein enzyme-linked immunosorbent assay (gpELISA) and interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT), blood samples were collected at baseline, post-doses 2, 3, and 4. The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses, measured by gpELISA or ELISPOT, at approximately 28 days post-dose 4. Safety and tolerability was assessed through 28 days post-dose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response approximately 28 days post-dose 4, measured by gpELISA (estimated geometric mean fold rise from baseline [GMFR] = 1.6 [95% confidence interval [CI], 1.4,1.7], P value < .0001) and IFN-γ ELISPOT (estimated GMFR = 2.0 [95% CI, 1.6,2.6], P value < .0001); both results met the prespecified success criterion. Overall, 57% (164/289) of all ZVIN and 21% (13/62) of placebo recipients reported ≥1 injection-site adverse events (AEs), and 52% (149/289) and 47% (29/62) reported ≥1 systemic AEs, respectively. Eight ZVIN and 1 placebo recipients experienced serious AEs, including 2 events (ZVIN group) determined by the investigator to be vaccine related (keratitis; amnesia). Overall frequency of AEs decreased with subsequent doses of vaccine. CONCLUSIONS: In adults with autoimmune disease, ZVIN was well tolerated and elicited statistically significant VZV-specific immune responses approximately 28 days post-dose 4, measured by gpELISA and IFN-γ ELISPOT. CLINICAL TRIALS REGISTRATION: NCT01527383.

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.

Serum-Infliximab Trough Levels in 45 Children with Inflammatory Bowel Disease on Maintenance Treatment.

The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in a pediatric inflammatory bowel disease (IBD) cohort. We investigated the s-IFX trough levels in pediatric IBD patients (n = 45) on maintenance IFX treatment. Ninety-three blood samples were collected and demographics, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin were recorded. The mean s-IFX trough level was 5.2 µg/mL. The mean trough s-IFX level was significantly higher in the samples taken during remission (7.2 µg/mL) compared to active disease (4.5 µg/mL, p < 0.05). The trough s-IFX levels correlated with ESR, CRP, and albumin. S-IFX was undetectable in eight of the patients, all with positive ATI and active disease. Surprisingly, clinical and biochemical remission was observed at only 26 of the 93 visits. The correlation between dose variations and changes in trough s-IFX was not evident. In line with studies in adults, the s-IFX trough levels correlated with response to infliximab.

Naïve T cells correlate with mucosal healing in patients with inflammatory bowel disease.

BACKGROUND: In previous studies, adaptive immune responses involving T-helper cells have been shown to play an important role in inflammatory bowel diseases (IBDs). METHODS: The aim of this study was to investigate any correlation between the degree of mucosal inflammation and the phenotype of gut-infiltrating T-helper cells. Biopsies from intestinal mucosa were obtained and intestinal T cells were analyzed with regard to activity and maturation markers. Patients with active colitis (39 with Crohn's disease and 47 with ulcerative colitis) were included and treated with corticosteroids, biologicals or leukocytapheresis. Flow cytometry was used to analyze activation marker expression on gut-infiltrating T-helper cells. RESULTS: Mucosal healing was reflected by almost 100% increase of CD62L expression in mucosal T cells in patients in remission compared to those with active inflammation (p < 0.01). The frequency of mucosal-naïve CD4(+)CD45RA(+) T cells was reduced by 50% in mucosa displaying remission (5.3% compared to 12% of the total amount and CD4(+) T cells, p < 0.001). Surprisingly, the proportion of early activated T-helper cells (CD4(+)CD69(+)) did not differ between mucosa in remission and non-remission (43% and 42%, respectively). Moreover, no change in memory T-helper cells (CD4(+)CD45RO(+)) was observed (64% compared to 66%). The findings were independent of diagnosis (Crohn's disease or ulcerative colitis) or mode of treatment. CONCLUSION: This study suggests that a reduced recruitment of naïve T-helper cells and increased frequency of T-helper cells with lymph node homing marker expression reflect mucosal healing in IBD. Surprisingly, the degree of activation of mucosal T-helper cells did not correlate with disease remission.

Treatment of inflammatory bowel disease by chemokine receptor-targeted leukapheresis.

Leukapheresis removes circulating leukocytes en route to the target organ. Hitherto unspecific matrixes have been used to remove leukocytes in inflammatory bowel disease (IBD). This report describes a novel selective leukapheresis column based on chemokine-chemokine receptor interaction. We found an increased expression of the gut homing chemokine receptor CCR9 on CD14(+) monocytes and on CD3(+) T lymphocytes from IBD patients. Biologically active CCL25 was coupled to a Sepharose matrix and demonstrated to selectively remove CCR9-expressing cells leaving other cell populations largely unaffected. A patient with active ulcerative colitis, was subjected to CCL25-column leukapheresis. Four days after treatment, he experienced clinical improvement and stable disease improvement ensued. The study illustrates that specific cells can be targeted using high affinity interactions, i.e., CCL25-CCR9 interactions to remove pathogenic gut-homing cells. Leukapheresis using the bCCL25 column should be investigated in a clinical phase I trial of patients with inflammatory bowel disease.

Profiling of CD4+ T cells with epigenetic immune lineage analysis.

Proper transcriptional control of pro- and anti-inflammatory responses of the immune system is important for a fine-tuned balance between protection and tolerance. Emerging evidence suggests a key role for epigenetic regulation in governing the Th cell differentiation, where effector cytokines direct the overall immune response. In this study, we describe a method to pinpoint the location of isolated human CD4(+) T cells on any T cell effector axis based on specific CpG methylation of cytokine and transcription factor loci. We apply the method on CD4(+) cells obtained from rheumatoid arthritis and multiple sclerosis patients and show that synovial fluid infiltrating CD4(+) T cells are committed toward both Th1 and regulatory T cell phenotype, whereas the Th2 response is suppressed. Furthermore, we show that the IL-17A gene is regulated by promoter methylation and that Th17 commitment is not a common feature in the inflamed joints of rheumatoid arthritis patients. We conclude that the method described in this paper allows for accurate profiling of Th lineage commitment in ex vivo-isolated CD4(+) T cells.