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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. 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. 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. 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). The POCT by ProciseDx (San Diego, CA) demonstrated a good agreement with the in-house ELISA, supporting its use for rapid IFX quantification. [ABSTRACT FROM AUTHOR]

Some studies have suggested a reduced life expectancy in patients with Crohn's disease (CD) compared with the general population. The evidence, however, is inconsistent. Prompted by such studies, we studied survival of CD patients in Örebro county, Sweden. From the medical records, we identified all patients diagnosed with CD during 1963–2010 with follow-up to the end of 2011. We estimated: overall survival, net and crude probabilities of dying from CD, relative survival ratio (RSR), and excess mortality rate ratios (EMRR) at 10-year follow-up. The study included 492 patients (226 males, 266 females). Median age at diagnosis was 32 years (3–87). Net and crude probabilities of dying from CD increased with increasing age and were higher for women. Net survival of patients aged ≥60 at diagnosis was worse for patients diagnosed during 1963–1985 (54%) than for patients diagnosed during 1986–1999 (88%) or 2000–2010 (93%). Overall, CD patients' survival was comparable to that in the general population [RSR = 0.98; 95% CI: (0.95–1.00)]. However, significantly lower than expected survival was suggested for female patients aged ≥60 diagnosed during the 1963–1985 [RSR = 0.47 (0.07–0.95)]. The adjusted model suggested that, compared with diagnostic period 1963–1985, disease-related excess mortality declined during 2000–2010 [EMRR = 0.36 (0.07–1.96)]; and age ≥60 at diagnosis [EMRR = 7.99 (1.64–39.00), reference: age 40–59], female sex [EMRR = 4.16 (0.62–27.85)], colonic localization [EMRR = 4.20 (0.81–21.88), reference: ileal localization], and stricturing/penetrating disease [EMRR = 2.56 (0.52–12.58), reference: inflammatory disease behaviour] were associated with poorer survival. CD-related excess mortality may vary with diagnostic period, age, sex and disease phenotype. There is inconsistent evidence on life expectancy of patients with Crohn's disease Crohn's disease-specific survival improved over time. Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn's disease-related mortality. [ABSTRACT FROM AUTHOR]

Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6–9) at baseline to 1 (0–5) at 52 weeks (p <.01) and the faecal calprotectin decreased from 862 (335–1759) µg/g to 90 (34–169) µg/g (p <.01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis. [ABSTRACT FROM AUTHOR]

Environmental factors are strongly implicated in late-onset of inflammatory bowel disease. Here, we investigate whether high levels of perfluoroalkyl substances are associated with (1) late-onset inflammatory bowel disease, and (2) disturbances of the bile acid pool. We further explore the effect of the specific perfluoroalkyl substance perfluorooctanoic acid on intestinal barrier function in murine tissue. Serum levels of perfluoroalkyl substances and bile acids were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer in matched samples from patients with ulcerative colitis (n = 20) and Crohn's disease (n = 20) diagnosed at the age of ≥55 years. Age and sex-matched blood donors (n = 20), were used as healthy controls. Ex vivo Ussing chamber experiments were performed to assess the effect of perfluorooctanoic acid on ileal and colonic murine tissue (n = 9). The total amount of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls and patients with Crohn's disease (p <.05). Ex vivo exposure to perfluorooctanoic acid induced a significantly altered ileal and colonic barrier function. The distribution of bile acids, as well as the correlation pattern between (1) perfluoroalkyl substances and (2) bile acids, differed between patient and control groups. Our results demonstrate that perfluoroalkyl substances levels are increased in patients with late-onset ulcerative colitis and may contribute to the disease by inducing a dysfunctional intestinal barrier. [ABSTRACT FROM AUTHOR]

To investigate absolute and relative risk of serious infections in adult/elderly inflammatory bowel disease (IBD) diagnosed 2002–2017. Nationwide, register-based cohort study of Swedish patients with IBD compared with general population matched reference individuals with regard to time to first serious infection, equal to hospital admission. Multivariable Cox regression estimated hazard ratios (HRs) for any serious infection. Secondary outcomes included site-specific infections, opportunistic infections and sepsis. We identified 47 798 individuals with IBD. During a follow-up of 329 000 person-years, they had 8752 first serious infections (26.6 per 1000 person-years). This compared with an incidence rate of 10.7 per 1000 person-years in matched reference individuals, corresponding to a 2.53-fold increased hazard of serious infections (95%CI = 2.47–2.59). The HR for serious infection in elderly-onset IBD was 2.01 (95%CI = 1.95–2.08). The relative hazard of serious infection was somewhat higher in Crohn's disease (2.94; 95%CI = 2.81–3.06) than in ulcerative colitis (2.24; 95%CI = 2.17–2.31). The HR for serious infections was high in the first year of follow-up (5.17; 95%CI = 4.93–5.42). Individuals with IBD were at a particularly high relative hazard of gastrointestinal and opportunistic infections. The HR for sepsis was 2.47 (95%CI = 2.32–2.63). The relative rates for serious infections in IBD increased in recent years. Patients with adult-onset IBD are at increased risk of serious infections, particularly gastrointestinal and opportunistic infections. Relative rates were highest just after IBD diagnosis, and seem to have increased in recent years. [ABSTRACT FROM AUTHOR]

Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn's disease (CD) are still limited. To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD. Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey–Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16. Of 114 included patients, 107 (94%) had failed ≥ 1 and 58 (51%) ≥ 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration (N = 65) decreased from 6 to 4 mg/l (p =.006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported. In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option. [ABSTRACT FROM AUTHOR]

It is not known to what extent biologic treatment for IBD is captured in the Swedish Prescribed Drug Register (PDR) and the National Patient Register (NPR). A cross-sectional study from July 2005 until 2017, comparing data on biologic treatment in the PDR and the NPR with medical records. We assessed the proportion of started treatment episodes in the medical records that were found in the PDR/NPR ever, within +/− one year and within +/− three months; for any biologic drug, per specific drug (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab), by calendar period (2005–2008, 2009–2012, and 2013–2017) and by study center. For adalimumab, we assessed the validity of end of treatment episodes. Medical records of 1361 patients and 2323 treatment episodes with any biologic were reviewed and 80.1% (95% CI: 78.4–81.7) were ever captured in the PDR/NPR in. A time window of +/− one year or +/− three months reduced the sensitivity to 63.3% (95% CI: 61.3–65.3) and 52.6% (95% CI: 50.5–54.6), respectively. The sensitivity was high (>85%) for the prescribed injection drugs adalimumab, golimumab, and ustekinumab for all time windows and for adalimumab end of treatment, while considerably lower for the infusion drugs infliximab and vedolizumab. The PDR and the NPR are reliable data sources on treatment with injection biologics in patients with IBD in Sweden. Infliximab and vedolizumab are poorly captured, why PDR/NPR data should only be used after careful consideration of their limitations or complemented by other data sources, e.g., the disease-specific quality register SWIBREG. [ABSTRACT FROM AUTHOR]

Background: Non-invasive markers for predicting relapse would be a useful tool for the management of patients with inflammatory bowel disease. Eosinophil granulocytes and their granule proteins eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) have previously been shown to reflect disease activity in Crohn's disease and ulcerative colitis. Aim: To examine the capacity of faecal ECP and EDN to predict relapse in ulcerative colitis and Crohn's disease, and to compare these proteins with faecal calprotectin. Methods: Patients with Crohn's disease (n = 49) and ulcerative colitis (n = 55) were followed prospectively until relapse or end of the two-year study period. Faecal samples were obtained every third month. The predictive value of ECP and EDN was assessed in Cox regression models. Results: In ulcerative colitis, a doubled EDN or ECP concentration was associated with a 31% and 27% increased risk of relapse, respectively. EDN levels were increased both at relapse and three months prior. By contrast, in Crohn's disease, the concentration of EDN was higher among patients in remission than in those who relapsed. Correlations between faecal calprotectin, ECP and EDN were observed in both diseases. Conclusions: We demonstrate that the risk of relapse in ulcerative colitis can be predicted by consecutively measuring faecal EDN every third month, and suggest EDN as a complementary faecal marker to calprotectin to predict future relapse in ulcerative colitis. Our finding of higher EDN in Crohn's disease-patients staying in remission than in those who relapsed indicates different functions of the protein in ulcerative colitis and Crohn's disease. [ABSTRACT FROM AUTHOR]

Objectives: Crohn's disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity. Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn's disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin. Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = −0.39; p =.009). Changes in C. leptum (R = −0.18, p =.23) and number of copies of the BCoAT gene (R = −0.12; p =.42) did not correlate with f-calprotectin. Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn's disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated. [ABSTRACT FROM AUTHOR]

Background: This study aims to compare the cost-effectiveness of treatment sequences with available biologics, including adalimumab (ADA), biosimilar infliximab (bsIFX), originator infliximab (IFX) and vedolizumab (VEDO) for luminal Crohn's disease in nine European countries.Methods: A Markov-model was constructed to simulate five-year medical costs and quality-adjusted life years (QALYs). Data on clinical efficacy were obtained from randomised controlled trials. Country-specific unit costs, discount rates and a third-party payer perspective were applied.Results: The bsIFX versus conventional therapy resulted in the most favourable incremental cost-utility ratios (ICURs) ranging from €34,580 (Hungary) to €77,062/QALY (Sweden). Compared to bsIFX, the bsIFX-ADA sequence was more cost-effective than the bsIFX-VEDO sequence with ICURs varying between €70,277 (France) and €162,069/QALY (Germany). The ICURs of the bsIFX-ADA-VEDO sequence versus the bsIFX-ADA strategy were between €206,266 (The Netherlands) and €363,232/QALY (Spain).Conclusion: We are the first to compare cost-effectiveness of multiple biological sequences for luminal Crohn's disease. Based on our findings, bsIFX can be recommended as a first-line treatment in patients unresponsive to conventional treatments. While biological sequences only slightly differ in their associated health gains, their costs vary greatly. The bsIFX-ADA-VEDO seems to be the most cost-effective sequence of the available biologics across Europe. [ABSTRACT FROM AUTHOR]

Objective:With several faecal calprotectin (FC) assays on the market, it has been difficult to define a uniform threshold for discriminating between remission and active disease in patients with inflammatory bowel disease (IBD). We aimed to compare the results of different FC-assays in IBD patients, followed over time. Material and methods:IBD patients provided faecal samples and reported clinical activity every third month prospectively over a two year period. FC was measured with two ELISA – (Bühlmann and Immunodiagnostik) and one automated fluoroimmunoassay (Phadia). Results:In total, 13 patients provided 91 faecal samples. The median (IQR) concentration of FC was higher at active disease than at remission for all assays: Bühlmann 845 (1061–226) μg/g versus 62 (224–39) μg/g, Phadia 369 (975–122) μg/g versus 11 (52–11) μg/g, and Immundiagnostik 135 (302–69) μg/g versus 8 (56–4) μg/g. The Bühlmann assay produced the largest absolute difference but the corresponding relative difference seemed to be more pronounced when analysed by the Phadia – (ratio of means 8.5; 95% CI 3.3–21.9) or the Immundiagnostik assay (ratio of means 7.4; 95% CI 3.1–17.6) than by the Bühlmann assay (ratio of means 5.3; 95% CI 2.7–10.6). Consequently, the specificity for discriminating active disease from remission varied between assays (34–75%) when the cut-off 50 μg/g was used, whereas the differences in sensitivity were less pronounced. Conclusions:Cross-comparisons revealed overall poor agreement between the assays as well as differences in the dynamics of FC. These findings suggest that standardisation of the method is needed to implement FC as a disease monitoring tool at large-scale. [ABSTRACT FROM PUBLISHER]

Objective: Changes in medical therapy and surgery might have influenced the natural history of Crohn’s disease (CD). Our aim was to explore the short-term outcome of CD and to specifically assess trends in disease phenotype, medications and surgery in the first five years from diagnosis.Material and methods: A population-based cohort comprising 472 CD patients diagnosed within the primary catchment area of Örebro University Hospital 1963–2005 were identified retrospectively and described. Data on medication, surgery, progression in disease location and behavior, were extracted from the medical records. Patients were divided into three cohorts based on year of diagnosis.Results: The proportion of patients with complicated disease behavior five years after diagnosis decreased from 54.4% (95%CI, 43.9–65.6) to 33.3% (27.4–40.0) in patients diagnosed 1963–1975 and 1991–2005, respectively (p = 0.002), whereas the proportion of patients progressing to complicated disease behavior was stable among those with non-stricturing, non-penetrating disease at diagnosis (p = 0.435). The proportion of patients undergoing surgery decreased from 65.8% (55.4–76.0) to 34.6% (28.6–41.5) in patients diagnosed 1963–1975 and 1991–2005, respectively (p < 0.001). The reduction in surgery preceded an increased use of immunomodulators and was explained by a decrease in surgery within three months from diagnosis (p = 0.001).Conclusions: We observed a striking decrease in complicated disease behavior and surgery five years after CD diagnosis, the latter largely due to a decrease in early surgery. Our findings suggest that the introduction of new treatments alone does not explain the reduction in surgery rates, the increasing proportion of patients with inflammatory disease at diagnosis also play an important role. [ABSTRACT FROM PUBLISHER]