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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. Funding Agencies|Akershus University Hospital

Background Inflammatory bowel disease [IBD] has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear. Methods We identified 41 880 individuals with IBD (Crohn’s disease [CD: n = 12 850]; ulcerative colitis [UC]: n = 29 030]) from Sweden matched with 41 880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios [aHRs] for neoplastic colorectal polyps [tubular, serrated/sessile, advanced and villous] defined by histopathology codes. Results During follow-up, 1648 [3.9%] IBD patients and 1143 [2.7%] reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10 000 person-years, respectively. This correlated to an aHR of 1.23 (95% confidence interval [CI] 1.12–1.35) with the highest HRs seen for sessile serrated polyps [8.50, 95% CI 1.10–65.90] and traditional serrated adenomas [1.72, 95% CI 1.02–2.91]. aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and at 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD [aHRs 1.31 vs 1.06, respectively], with a 20-year cumulative risk difference of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis. Conclusions In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.

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.

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

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.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.Overall, 19%, 31%, and 45% of patients had days with energy intake30,50, and70% of calculated requirement. Older age was associated with a higher number of days with energy intake30,50, and70% of calculated requirement (regression coefficient 0.03, 0.04, 0.06 respectively,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.

Background The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti-inflammatory properties. Aims To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC). Methods A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index. Results We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person-years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time-dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40-2.31) at year 5 and 1.49 (1.14-1.96) at year 10 post-vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94-6.80] for truncal and 2.06 [1.49-2.84] for selective vagotomy) but not UC (1.36 [0.71-2.62] for truncal and 1.25 [0.95-1.63] for selective vagotomy). Conclusions We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.

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....

In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis of those occurring in gastrointestinal organs, lungs and kidneys.

Aim Surgery is an important therapeutic option for Crohns 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 Crohns disease patients irrespective of prior bowel resection is not known. The aim of this work is to compare the incidence of bowel surgery in Crohns 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 Crohns 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 Crohns disease patients with TNFi exposure: 3748 surgery naive 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 Crohns disease patients compared with those who continued TNFi for 12 months or more. Funding Agencies|Bengt Ihre Research Fellowship; Stockholm County Council ALFStockholm County Council [20180565, 20170720, 20190638]; SFO Young Scholar Award at Karolinska Institutet; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-02002]; Swedish Society of Medicine; Bengt Ihre Fellowship; Stockholm County Council postdoctoral fellowship; Bengt Ihre Foundation

We aimed to compare the risk of frailty in older adults with incident inflammatory bowel disease (IBD) and matched non-IBD comparators and assess the association between frailty and future hospitalizations and mortality.In a cohort of patients with incident IBD ≥60 years of age from 2007 to 2016 in Sweden identified using nationwide registers, we defined frailty using Hospital Frailty Risk Score. We compared prevalence of frailty in patients with IBD with age, sex, place of residency- and calendar year-matched population comparators. In the IBD cohort, we used Cox proportional hazards modeling to examine the associations between frailty risk and hospitalizations or mortality.We identified 10,590 patients with IBD, 52% female with a mean age of 71 years of age, matched to 103,398 population-based comparators. Among patients with IBD, 39% had no risk for frailty, 49% had low risk for frailty, and 12% had higher risk for frailty. Mean Hospital Frailty Risk Score was 1.9 in IBD and 0.9 in matched comparators (Plt; .01). Older adults with IBD at higher risk for frailty had a 20% greater risk for mortality at 3 years compared with those who were not frail. Compared with nonfrail older patients with IBD, patients at higher risk for frailty had increased mortality (hazard ratio [HR], 3.22, 95% confidence interval [CI], 2.86-3.61), all-cause hospitalization (HR, 2.42; 95% CI, 2.24-2.61), and IBD-related hospitalization (HR, 1.50; 95% CI, 1.35-1.66). These associations were not attenuated after adjusting for comorbidities.Frailty is more prevalent in older adults with IBD than in matched comparators. Among older patients with IBD, frailty is associated with increased risk for hospitalizations and mortality.

Vasodilation is a cornerstone of inflammation physiology. By regulating vasodilation and tissue entry of T cells, CD4+ T lymphocytes expressing choline acetyltransferase (ChAT), a key enzyme for biosynthesis of the vasorelaxant acetylcholine (ACh), critically link immunity with vascular biology in mice. However, the characterization of primary human ChAT+ T cells remained elusive. Here, we identified human ChAT+ T cells and report that ChAT mRNA was induced by activation. Functional studies demonstrated that T cell-derived ACh increased muscarinic ACh-receptor dependent NO-synthase activity and vasorelaxation. Further, single-cell RNA-sequencing revealed ChAT+CD4+ T cells in blood from patients with severe circulatory failure and a high relative frequency of ChAT+CD4+ T cells correlated with better 30-day survival in this cohort. Our findings provide the first insights into ChAT biology in primary human T cells, linking ChAT+ T cells with vasorelaxation as well as survival in a cohort of critically ill patients.

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.

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.

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 (Crohns 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. Funding Agencies|Janssen Corporation; Swedish Association of Local Authorities and Regions (SALAR; Swedish: SKL)

Exclusive Enteral Nutrition (EEN) is the first-line treatment in children with Crohn&rsquo, s disease (CD) for induction of remission. However, the mode of action remains conjectural. The aim of this study was to investigate whether the effect of EEN is paralleled by changes in the mucosal cytokine profiles (MCP). Twelve children with new onset inflammatory bowel disease (IBD) received induction treatment with a polymeric EEN. We assessed clinical, endoscopic and histologic scoring before and after EEN. Twelve colonic cytokines were analyzed by Polymerase Chain Reaction (PCR) in six of the IBD patients at onset and after EEN as well as in six non-IBD control children at the diagnostic colonoscopy. Twelve children completed 6 weeks of EEN, except from one child who completed 4 weeks. At the control colonoscopy, 83% were in complete clinical remission. Changes were found in the MCPs of individual patients after EEN. In particular, children with IBD showed significantly higher values of Interleukin (IL)-12&beta, (p = 0.008) and IL-23&alpha, (p = 0.02) compared to non-IBD controls at the diagnostic colonoscopy. Furthermore, an overall change in proinflammatory cytokines was noted in the IBD-group after treatment. Further studies are warranted to understand the role of EEN in MCP.

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.

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.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).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).Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of 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.

TNF inhibitors (TNFi) have been shown to reduce the need for surgery in Crohn's disease, but few studies have examined their effect beyond the first year of treatment.To conduct a register-based observational cohort study in Sweden 2006-2014 to investigate the risk of bowel resection in bowel surgery naïve TNFi-treated Crohn's disease patients and whether patients on TNFi ≥12 months are less likely to undergo bowel resection than patients discontinuing treatment before 12 months.We identified all individuals in Sweden with Crohn's disease through the Swedish National Patient Register 1987-2014 and evaluated the incidence of bowel resection after first ever dispensation of adalimumab or infliximab from 2006 and up to 7 years follow-up.We identified 1856 Crohn's disease patients who had received TNFi. Among these patients, 90% treatment retention was observed at 6 months after start of TNFi and 65% remained on the drug after 12 months. The cumulative rates of surgery in Crohn's disease patients exposed to TNFi years 1-7 were 7%, 13%, 17%, 20%, 23%, 25% and 28%. Rates of bowel resection were similar between patients with TNFi survival12 months and ≥12 months respectively (P=.27). No predictors (eg, sex, age, extension or duration of disease) for bowel resection were identified.The risk of bowel resection after start of anti-TNF treatment is higher in regular health care than in published RCTs. Patients on sustained TNFi treatment beyond 12 months have bowel resection rates similar to those who discontinue TNFi treatment earlier.

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.

The anti-TNF antibody infliximab is effective in inducing remission in Crohn's disease as well as in ulcerative colitis and many patients are treated for several years with sustained clinical remission. However, the role of monitoring s-infliximab and antibodies towards infliximab during maintenance treatment remains unclear. Our aim was to correlate serum drug levels and antibodies to clinical activity, CRP, albumin and concomitant immunosuppression in a cohort on maintenance infliximab treatment.We included 79 patients with Crohn's disease or ulcerative colitis who had responded to infliximab and received maintenance treatment (4-69 infusions) in this retrospective study. Infliximab levels and antibodies towards the drug were analyzed with in-house-developed ELISA assays.The mean s-infliximab was significantly higher in patients in remission (4.1μg/mL) as compared with disease flare (mean 1.8μg/mL); p0.001. The s-infliximab showed a significant negative correlation with Harvey-Bradshaw index (r=-0.21; p0.05). Serum-infliximab progressively decreased with the number of accumulated infusions (p0.05). In patients with undetectable trough levels, 55% of the patients with concomitant immunosuppressive were positive for antibodies against infliximab, as compared with 94% of patients on monotherapy. Patients with undetectable serum-infliximab were in clinical remission at 25% of the visits.The trough level 4.1μg/mL may serve as cut-off for clinical remission. Drug trough levels decreased during treatment and almost all patients with undetectable s-infliximab and monotherapy had developed antibodies against the drug.

Inflammation is important for antimicrobial defense and for tissue repair after trauma. The inflammatory response and its resolution are both active processes that must be tightly regulated to maintain homeostasis. Excessive inflammation and nonresolving inflammation cause tissue damage and chronic disease, including autoinflammatory and cardiovascular diseases. An improved understanding of the cellular and molecular mechanisms that regulate inflammation has supported development of novel therapies for several inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. Many of the specific anticytokine therapies carry a risk for excessive immunosuppression and serious side effects. The discovery of the inflammatory reflex and the increasingly detailed understanding of the molecular interactions between homeostatic neural reflexes and the immune system have laid the foundation for bioelectronic medicine in the field of inflammatory diseases. Neural interfaces and nerve stimulators are now being tested in human clinical trials and may, as the technology develops further, have advantages over conventional drugs in terms of better compliance, continuously adaptable control of dosing, better monitoring, and reduced risks for unwanted side effects. Here, we review the current mechanistic understanding of common autoinflammatory conditions, consider available therapies, and discuss the potential use of increasingly capable devices in the treatment of inflammatory 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 β7 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.

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.

In previous studies, adaptive immune responses involving T-helper cells have been shown to play an important role in inflammatory bowel diseases (IBDs).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.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 (p0.01). 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, p0.001). 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.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.

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.

Objective Mesenteric lymph nodes may play a crucial role in the pathogenesis of human inflammatory bowel disease. We have used the sentinel node technique to analyze mesenteric lymph nodes draining inflammatory lesions sentinel nodes and corresponding site of inflamed bowel in patients with ulcerative colitis or Crohn's disease. Methods Thirty-two patients undergoing surgical treatment of inflammatory bowel disease were included. Sentinel nodes were identified intraoperatively. The T cells were harvested from the mesenteric lymph nodes and characterized by flow cytometry. Results The distribution of CD4 + CD62L + (homingmarked) and CD4 + CD69 + (activated) T cells was studied in mesenteric lymph nodes draining inflammation, nodes draining normal intestine, blood, and mucosa. The turnover of T cells was markedly increased in the lymph nodes connected to inflammatory segments. The immunologic activity of the sentinel lymph nodes correlated with the degree of intestinal inflammation. Conclusion Mesenteric sentinel nodes provide important information about locoregional immunology and pathogenesis in inflammatory bowel disease.

Background and Aims: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-alpha. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response. Methods: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column. Results: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score = 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome. Conclusion: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.

OBJECTIVES: It has been demonstrated that circulating monocytes relocate to the intestinal mucosa during intestinal inflammation, but the phenotype and inflammatory mechanisms of these monocytes remain poorly understood. Here, we have investigated blood monocytes expressing high levels of HLA-DR and CCR9 in patients with inflammatory bowel disease (IBD). METHODS: Fifty-one patients with mild to severe ulcerative colitis (UC; n=31; UC-DAI 3–12) or Crohn's disease (CD; n=20; Harvey–Bradshaw indices (HBI) 2–16) were included together with 14 controls, during IBD therapy for four consecutive weeks. The frequency of CD14+HLA-DRhi monocytes was monitored weekly in peripheral blood, using flow cytometry. The surface phenotype and cytokine profile of these monocytes were established using flow cytometry and real-time PCR. Clinical parameters were assessed weekly in all patients. RESULTS: The frequency of circulating CD14+HLA-DRhi monocytes was significantly higher in IBD patients with moderate to severe disease compared with healthy controls (P

Summary Inflammatory bowel disease (IBD) can be treated effectively by anti-tumour necrosis factor (TNF) therapy. We set out to investigate the unclear immunoregulatory mechanisms of the treatment. Thirty-four patients with IBD treated with anti-TNF were included. Lymphocytes from peripheral blood and intestinal biopsies were analysed by flow cytometry. Regulation of antigen-stimulated proliferation was analysed by blocking of interleukin (IL)-10, transforming growth factor (TGF)-β or depletion of CD25+ cells in peripheral blood mononuclear cell cultures. No changes in CD4+CD25+, CD25+TNF-RII+ or CD4+CD25+forkhead box protein 3 (FoxP3+) T cells could be observed in peripheral blood after, in comparison to before, 6 weeks of treatment. The suppressive ability of CD4+CD25+ cells did not change. There was an initial decrease of CD4+CD25+ cells in intestinal mucosa after 2 weeks of treatment, followed by an increase of these cells from weeks 2 to 6 of treatment (P

Summary Patients with active inflammatory bowel disease (IBD) have elevated and activated myeloid leucocytes which infiltrate the colonic mucosa in vast numbers. Myeloid leucocytes such as the CD14+CD16+ monocytes are major sources of tumour necrosis factor (TNF)-α, and therefore selective granulocyte/monocyte (GM) adsorption (GMA) should promote remission or enhance efficacy of pharmacological therapy. However, studies in IBD have reported both impressive as well as disappointing efficacy outcomes, indicating that patients' demographic factors might determine responders or non-responders to GMA. Nonetheless, this non-drug intervention has an excellent safety profile, and therapeutic GMA is expected to expand. In this review, attempts have been made to compile an update on the mode of actions (MoA) of the Adacolumn GMA. The MoA of GMA appears to be more than adsorption of excess neutrophils and TNF-producing CD14+CD16+ monocytes per se. Adsorbed GMs release interleukin (IL)-1 receptor antagonist, hepatocyte growth factor and soluble TNF receptors, which are anti-inflammatory. Additionally, a sustained increase in lymphocytes including the regulatory CD4+CD25+ T cells (lymphocyte sparing) is seen post-GMA. The impact of GMA on the immune system is potentially very interesting in the context of treating immune-related diseases. Future studies are expected to add intriguing insights to the MoA of GMA.

Background Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn®) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity. Methods Fifteen patients with ulcerative colitis and 25 patients with Crohn's disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months. Results Clinical response was seen in 85% and complete remission in 65% of the patients. Ten patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months. Fourteen patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of seven patients were successfully re-treated for the third time, all of three patients for the fourth time and one for a fifth time. Conclusions IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.

The immunosurveillance theory argues that the immune system recognizes tumour-specific antigens expressed by transformed cells, which results in the destruction of cancer precursors before they become clinically manifest. As a model for the development of cancer, we set out to study premalignant lesions and immune responses in sentinel lymph nodes from patients with long-standing ulcerative colitis and progression of mucosal dysplasia. Mesenteric lymph nodes draining dysplastic and normal intestinal segments were identified by sentinel node technique during surgery in 13 patients with ulcerative colitis who were subjected to colectomy because of intestinal dysplasia. T cells were extracted from the lymph nodes and analysed by flow cytometry, and lymphocyte proliferation assays were set up in the presence of extracts from dysplastic and normal intestinal mucosa. Increase in CD4/CD8 ratio was observed in sentinel lymph nodes draining dysplastic epithelium compared to normal mucosa. The increase in CD4(+) T cells in relation to CD8(+) T cells correlated with the degree of dysplasia reflected by a significant increase in the ratio against low-grade dysplasia compared to indefinite dysplastic lesions. The T-cell response was specific to antigens from dysplastic epithelial lining as seen in proliferation assays. The observation suggests an important surveillance role for the immune system against premalignant intestinal lesions in patients with long-standing ulcerative colitis.