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 mu g/mL (interquartile range (IQR) 5.5-13) for the POCT and 7.9 mu g/mL (IQR 5.2-12) for the ELISA (Pearsons 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 mu g/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) (mu g/mL), whereas the lower limit agreement was -5.3 (95% CI -6.3 to -4.3) (mu g/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 mu g/mL), therapeutic (3.0-7.0 mu g/mL) or supratherapeutic (>7.0 mu g/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.

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.

Background and Aims Crohns disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the inflammatory reflex, has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial.Methods A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety.Results There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean +/- SD: -86.2 +/- 92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 +/- 4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 +/- 1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-gamma [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation.Conclusions Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life. Graphical Abstract

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.

Crohns disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean +/- SEM) sham: 124 +/- 14 mm(2), VNS: 62 +/- 14 mm(2), p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

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.

Immunterapi med immunkontrollpunktshämmare har revolutionerat den onkologiska behandlingen under detsenaste årtiondet

Immunrelaterade biverkningar är vanliga och kan uppstå i så gott som alla kroppens organ. Biverkningarnakan vara allvarliga, och de skiljer sig mycket från dem som förekommer vid traditionella onkologiska behandlingar.

På relativt kort tid har vården fått ställa om för att kunna ta hand om immunterapibehandlade patienter på bästa sätt.

I två artiklar ges en översikt över de vanligast förekommande immunrelaterade biverkningarna. I denna,den första delen, är fokus på biverkningar som kan uppstå i mag–tarmkanalen, lungor och njurar.

Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohns disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.

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.