Publications by authors named "Taina Sipponen"

57 Publications

Benefit of measuring vedolizumab concentrations in inflammatory bowel disease patients in a real-world setting.

Scand J Gastroenterol 2021 Aug 21;56(8):906-913. Epub 2021 Jun 21.

Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Objectives: We set out to determine the reasons for serum vedolizumab (VDZ) trough concentration (TC) measurements in inflammatory bowel disease (IBD) patients and to evaluate treatment modifications after therapeutic drug measurement (TDM). We also evaluated the effect of increased dosing on patients' response to VDZ therapy.

Methods: We performed a retrospective cohort study of IBD patients who received VDZ therapy at Helsinki University Hospital and whose VDZ levels were measured between June 2014 and December 2018.

Results: Altogether, 90 patients (32 Crohn's disease and 58 ulcerative colitis) and 141 VDZ TC measurements were included. 24.1% of measurements took place during induction and 75.9% during the maintenance phase. During induction, 64.7% reached the target TC >20µg/ml. During maintenance therapy, 82.2% of VDZ TCs were within or exceeded the suggested target range of 5-15µg/ml. Reasons for TDM were: secondary nonresponse (44.0%), assessment of adequate VDZ TC (25.5%), primary nonresponse (12.8%), adverse events (6.4%), and other (11.3%). No treatment changes occurred after 60.3% of VDZ measurements. Increased dose frequency was used after 25.5% of VDZ measurements and 33.3% of these patients experienced improvement. Altogether, 31 (34.4%) patients discontinued the therapy due to inadequate treatment response. No anti-vedolizumab antibodies were detected.

Conclusions: During the maintenance of VDZ therapy, the majority of VDZ TCs were within the suggested range. Measurement of VDZ TC did not lead to any treatment changes in two-thirds of patients. Dose optimization occurred in a quarter of patients and a third of them benefited from it.
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http://dx.doi.org/10.1080/00365521.2021.1938206DOI Listing
August 2021

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn's disease patients in Finland.

Scand J Gastroenterol 2021 Jun 5;56(6):661-670. Epub 2021 Apr 5.

Medical Affairs, Espoo, Finland.

Background: Real-world evidence to support optimal ustekinumab dosing for refractory Crohn's disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland.

Methods: Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017-2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability.

Results: Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period.

Conclusions: Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification.

Trial Registration: EUPAS30920.
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http://dx.doi.org/10.1080/00365521.2021.1906315DOI Listing
June 2021

Intestinal failure in Finland: prevalence and characteristics of an adult patient population.

Eur J Gastroenterol Hepatol 2021 Feb 5. Epub 2021 Feb 5.

Clinical Nutrition Unit, Department of Internal Medicine and Rehabilitation Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Department of Children's Hospital, Pediatric Research Center Department of Gastroenterology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: Details of intestinal failure in the Finnish adult population are unknown. This study aimed to specify the intestinal failure prevalence and to clinically characterize the patient population in Finland.

Methods: All Finnish healthcare units with the potential of providing parenteral support received an electronic survey to report whether they had patient(s) aged ≥18 years on long-term (≥120 days) parenteral support due to intestinal failure. Patient details came from patient records. IBM SPSS v.25 was used to analyze descriptive statistics.

Results: Of the 74 patients, 52 were included after confirming parenteral support indication from the records. The adult intestinal failure prevalence for 2017 was 11.7 per million, 95% confidence interval: 8.9-15.3. Most patients were women (69%), and the median age was 62 (45-72) years. Short bowel syndrome was the most frequent intestinal failure mechanism (73%), and surgical complication the most frequent underlying diagnosis (29%). Of patients, 66% represented the clinical classification category parenteral nutrition 1 or parenteral nutrition 2. Median Charlson Comorbidity Index was one (0-2.8); hypertension (37%) and diabetes (23%) were the most frequent comorbidities. Patients received seven (3.5-7) parenteral support infusions weekly, and eight patients (15%) were on fluids and electrolytes only. The median duration of parenteral support was 27.5 (11.3-57.3) months. Ten patients ceased parenteral support during 2017 after a median of 20.0 (9.0-40.3) parenteral support months. Eight weaned off parenteral support, one ran out of catheter sites, and one died.

Conclusion: Prevalence and patient characteristics of adult intestinal failure in Finland are similar to those in other Western countries.
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http://dx.doi.org/10.1097/MEG.0000000000002082DOI Listing
February 2021

Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease.

J Crohns Colitis 2021 Jun;15(6):1019-1031

Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

Background And Aims: Inflammatory bowel diseases [IBDs], Crohn's disease [CD] and ulcerative colitis [UC], are globally increasing chronic gastro-intestinal inflammatory disorders associated with altered gut microbiota. Infliximab [IFX], a tumour necrosis factor [TNF]-alpha blocker, is used to treat IBD patients successfully, though one-third of the patients do not respond to therapy. No reliable biomarkers are available for prediction of IFX response. Our aims were to investigate the faecal bacterial and fungal communities during IFX therapy and find predictors for IFX treatment response in IBD patients.

Methods: A total of 72 IBD patients [25 CD and 47 UC] started IFX therapy and were followed for 1 year or until IFX treatment was discontinued. An amplicon sequencing approach, targeting the bacterial 16S rRNA gene and fungal ITS 1 region separately, was used to determine the microbiota profiles in faecal samples collected before IFX therapy and 2, 6, and 12 weeks and 1 year after initiation of therapy. The response to IFX was evaluated by colonoscopy and clinically at 12 weeks after initiation.

Results: Both faecal bacterial and fungal profiles differed significantly between response groups before start of IFX treatment. Non-responders had lower abundances of short chain fatty acid producers, particularly of the class Clostridia, and higher abundances of pro-inflammatory bacteria and fungi, such as the genus Candida, compared with responders. This was further indicated by bacterial taxa predicting the response in both CD and UC patients [area under the curve >0.8].

Conclusions: Faecal bacterial and fungal microbiota composition could provide a predictive tool to estimate IFX response in IBD patients.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa252DOI Listing
June 2021

Objectively assessed disease activity and drug persistence during ustekinumab treatment in a nationwide real-world Crohn's disease cohort.

Eur J Gastroenterol Hepatol 2020 12;32(12):1507-1513

Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki.

Objective: Long-term evidence on ustekinumab treatment response and persistence in patients with Crohn's disease in a real-world setting is scarce. We performed a retrospective nationwide chart review study of long-term clinical outcomes in Crohn's disease patients treated with ustekinumab.

Methods: The study was conducted in 17 Finnish hospitals and included adult Crohn's disease patients who received an initial intravenous dose of ustekinumab during 2017-2018. Disease activity data were collected at baseline, 16 weeks, and 1 year from health records.

Results: The study included 155 patients. The disease was stricturing or penetrating in 69 and 59% had prior Crohn's disease-related surgeries, and 97% had a treatment history of at least one biologic agent. Of 93 patients with ≥1 year of follow-up, 77 (83%) were still on ustekinumab at 1 year. In patients with data available, from baseline to the 1-year follow-up the simple endoscopic score for Crohn's disease (SES-CD) decreased from 10 to 3 (P = 0.033), C-reactive protein from 7  to 5 mg/L, (P < 0.001) and faecal calprotectin from 776 to 305 μg/g (P < 0.001).

Conclusions: Ustekinumab treatment in patients with highly refractory Crohn's disease resulted in high long-term treatment persistence and significantly reduced disease activity, assessed with objective markers for intestinal inflammatory activity.
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http://dx.doi.org/10.1097/MEG.0000000000001831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590962PMC
December 2020

Health-related quality of life and costs of switching originator infliximab to biosimilar one in treatment of inflammatory bowel disease.

Medicine (Baltimore) 2020 Jan;99(2):e18723

University of Helsinki, Helsinki.

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment.In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database.Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX.HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.
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http://dx.doi.org/10.1097/MD.0000000000018723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959900PMC
January 2020

Long-term deep remission during maintenance therapy with biological agents in inflammatory bowel diseases.

Scand J Gastroenterol 2020 Jan 14;55(1):34-40. Epub 2019 Dec 14.

Abdominal Center, Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

A multicentre, retrospective, non-interventional, patient chart review study was conducted to investigate deep (DR) and histological remission rates during maintenance therapy with biological agents in inflammatory bowel disease (IBD). We reviewed clinical, endoscopic, and histological findings, and laboratory markers such as C-reactive protein (CRP) and faecal calprotectin (FC) on average of nine years after the initiation of anti-TNF-therapy. DR was defined as no clinical symptoms (The physicians' global assessment scores; PGA = 0) with endoscopic remission (the Simple Endoscopic Score for Crohn's Disease [SES-CD] ≤ 2 or Mayo endoscopic subscore ≤1). Histological activity was defined as normal if only architectural alterations without cellularity changes occurred. Of 117 IBD patients on maintenance therapy, 72 (62%; CD  = 55 [56%], UC  = 17 [85%]) patients were in DR. Of patients in DR, 76% were also in histological remission. 77% of patients remained on initiated biological treatment. UC patients achieved DR significantly more often than CD patients ( = .016). Both median CRP and FC levels were significantly lower in patients with DR. Reassuringly, almost two thirds of the IBD patients on maintenance therapy with biological agents maintained DR in the long-term, and more than two thirds of patients in DR achieved also histological remission. CD patients in DR had fewer surgical operations due to CD than patients not achieving DR.
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http://dx.doi.org/10.1080/00365521.2019.1701070DOI Listing
January 2020

Ustekinumab for Crohn's disease: a nationwide real-life cohort study from Finland (FINUSTE).

Scand J Gastroenterol 2019 Jun 11;54(6):718-725. Epub 2019 Jun 11.

Gastroenterology, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.

Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, has been approved for treatment of Crohn's Disease (CD) since the end of 2016. This nationwide noninterventional, retrospective chart review explored real-life data in patients receiving UST to provide guidance in UST treatment in the era of increasing prevalence of CD. The study assessed UST treatment patterns such as dosing frequency, concomitant medication and persistence in 48 CD patients commencing UST therapy in 12 Finnish hospitals during 2017. Clinical remission and response rates were explored using a modified Harvey-Bradshaw index (mHBI) and endoscopic response via the simple endoscopic score for Crohn's disease (SES-CD) as proportions of patients at week 16 and at the end of follow-up. Forty patients (83%) continued UST-treatment at the end of follow-up. At week 16, clinical response and endoscopic healing was observed, where data were available; mHBI decreased from 9 to 3 ( = .0001) and SES-CD from 12 to 3 ( = .009). Clinical benefit was achieved by 83% (19/23) at week 16 and by 76% (16/21) at the end of follow-up. The proportion of patients using corticosteroids decreased from 48% to 25% at week 16 and to 13% at the end of the follow-up. UST showed to be effective and persistent, inducing short-term clinical benefit and endoscopic response in this real-life nationwide study of CD patients. Significant corticosteroid tapering in patients with highly treatment refractory and long-standing CD was observed.
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http://dx.doi.org/10.1080/00365521.2019.1624817DOI Listing
June 2019

Fragmented management of long-term parenteral support for adult intestinal failure in Finland.

Scand J Gastroenterol 2019 Apr 27;54(4):414-418. Epub 2019 Mar 27.

c Department of Gastroenterology , Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki , Finland.

Parenteral support (PS) is the first-line therapy for intestinal failure (IF). Optimal patient outcomes require experienced multidisciplinary teams adhering to structured protocols. As practices to provide long-term PS for adult IF patients in Finland are unknown, this cross-sectional nationwide study aimed to evaluate current management of PS for adult IF across the country. An internet-based survey was emailed to all Finnish hospitals and hospital-at-home services with the potential to provide PS for adult IF. The survey included 20 items addressing the provision of long-term PS for adult IF patients (aged ≥18 years). Data were analysed using descriptive statistics. Overall, 52 (47%) of the 111 identified units responded. Of responding units, 38 (73%) had at some point provided long-term (≥120 days) PS for adult IF, and 23 (44%) had done so during the preceding year. Only three units currently managed ≥3 adult patients. Most (65%) of the respondents worked in a hospital and were either physicians (38%) or dietitians (39%). Only 65% of respondents reported that their unit had an assigned physician responsible for PS provision, and 28% reported that a team was responsible for long-term PS. Only 26% of respondents reported having a written protocol to guide PS management. Health care providers with very limited experience and a fragmented approach manage most Finnish adult IF patients. Evidence-based protocols and multidisciplinary teams are scarce. The care for adult IF patients on long-term PS needs to be improved in Finland.
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http://dx.doi.org/10.1080/00365521.2019.1588370DOI Listing
April 2019

Characterization of inflammatory bowel disease management by vedolizumab and concomitant treatments in real-life clinical practice.

Biologicals 2019 Mar 10;58:50-56. Epub 2019 Feb 10.

Department of Internal Medicine, Forssa Hospital, Forssa, Finland.

Limited data is available on vedolizumab combination therapies in real-world clinical practice. Here, we evaluated the concomitant corticosteroid, immunosuppressive, and 5-aminosalicylic acid utilization of inflammatory bowel disease (IBD) patients treated with vedolizumab in a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centres with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) who had at least one vedolizumab infusion since it's availability in Finland were included in the study. Data were collected from medical charts at baseline (vedolizumab treatment initiation), week 14, and month 6. The majority of patients who used corticosteroids at the baseline and persisted on vedolizumab treatment for 6 months were taken off corticosteroid treatment by the 6-month time point (CD, 54.5%; UC, 69.8%). Modest corticosteroid dose reductions were observed among treatment persistent CD patients from the baseline until month 6. Corticosteroid users had less vedolizumab discontinuations due to primary ineffectiveness and more discontinuations due to adverse events than patients not using corticosteroids. Vedolizumab may have a corticosteroid sparing effect in real-world clinical practice. Concomitant corticosteroid use may lead to a lower rate of vedolizumab discontinuation due to primary ineffectiveness, but a higher discontinuation rate due to adverse events.
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http://dx.doi.org/10.1016/j.biologicals.2019.01.007DOI Listing
March 2019

The impact of an adaptation course on health-related quality of life and functional capacity of patients with inflammatory bowel disease.

Scand J Gastroenterol 2018 Sep 2;53(9):1074-1078. Epub 2018 Sep 2.

a Helsinki University Hospital , Helsinki University , Helsinki , Finland.

Background: Inflammatory bowel disease (IBD) has a substantial impact on patients health-related quality of life (HRQoL). In this study, we examined the impact of adaptation courses on HRQoL, psychological well-being, depression and number of sick-leave days of IBD patients.

Methods: The study recruited 142 IBD patients attending an adaptation course of 5-12 days. The courses were specially designed for IBD patients and included multidisciplinary information about IBD, peer support, group activities and encouragement for adequate physical exercise. The participants completed the study questionnaire at the beginning and the end of the course and after six and 12 months of follow-up. HRQoL was assessed with the generic 15-dimensional (15D) tool and depression with Beck's Depression Inventory (BDI). Utilization of health care services and work absenteeism was also assessed. Visual analog scales were used for assessing psychological functioning.

Results: 15D, BDI scores and scores describing psychological well-being were significantly better at the end of the course when compared to baseline (15D 0.82 vs. 0.84, p < .001; BDI 11.8 vs. 8.5, p < .001). Positive results were maintained during follow up. The percentage of patients receiving peer support rose from 32 to 70% and those with peer support had better HRQoL at the 12-month follow-up (p = .01). No significant change in health care utilization or number of sick-leave days was observed.

Conclusion: Adaptation training appears to have a positive impact on the psychological well-being of IBD patients. Peer support appears to be an important factor.
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http://dx.doi.org/10.1080/00365521.2018.1500639DOI Listing
September 2018

Effectiveness and Safety of Vedolizumab in Anti-TNF-Naïve Patients With Inflammatory Bowel Disease-A Multicenter Retrospective European Study.

Inflamm Bowel Dis 2018 10;24(11):2442-2451

Inflammatory Bowel Disease Center, Department of Gastroenterology and Hepatology, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany.

Background: Vedolizumab (VDZ) is effective for treatment of ulcerative colitis (UC) and Crohn's disease (CD). In GEMINI trials, anti-tumor necrosis factor (anti-TNF)-naïve patients had a superior response compared with anti-TNF-exposed patients. In real-world experience (RWE), the number of included anti-TNF-naïve patients was low. We aimed to evaluate the effectiveness and safety of VDZ in anti-TNF-naïve patients in an RWE setting.

Methods: This retrospective multicenter European pooled cohort study included consecutive active anti-TNF-naïve IBD patients treated with VDZ. The primary end point was clinical response at week 14. Patients with follow-up beyond week 14 and those discontinuing VDZ at any time were included for maintenance outcomes analysis.

Results: Since January 2015, 184 anti-TNF-naïve patients from 23 centers initiated VDZ treatment (Crohn's disease [CD], 50; ulcerative colitis [UC], 134). In CD, 42/50 (82%) patients responded by week 14 and 32 (64%) were in clinical remission; 26/50 (52%) achieved corticosteroid-free remission (CSFR). At last follow-up (44 weeks; interquartile range [IQR], 30-52 weeks), 27/35 (77.1%) patients with available data responded to treatment; 24/35 (68.6%) were in clinical remission, 21/35 (60%) were in CSFR. For UC, 116/134 (79.1%) responded to treatment by week 14, including 53 (39.5%) in clinical remission; 49/134 (36.6%) achieved CSFR. At last follow-up (42.5 weeks; IQR, 30-52 weeks), 79/103 (76.7%) patients responded to treatment, 69/103 (67.0%) were in remission, and 61/103 (59.2%) were in CSFR. Adverse effects were reported in 20 (11%) of the patients, leading to treatment discontinuation in 6 (3.3%).

Conclusions: VDZ is similarly effective in ant-TNF-naïve CD and UC patients. The efficacy is higher than reported in anti-TNF-experienced patients and is comparable to that of anti-TNF biologics in this population.
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http://dx.doi.org/10.1093/ibd/izy155DOI Listing
October 2018

Low childhood high density lipoprotein cholesterol levels and subsequent risk for chronic inflammatory bowel disease.

Dig Liver Dis 2018 Apr 31;50(4):348-352. Epub 2018 Jan 31.

Department of Medicine, University of Turku, Turku, Finland; Division of Medicine, Turku University Hospital, Turku, Finland.

Background And Aims: Several genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents.

Methods: A Finnish study population consisting of 3551 children and adolescents originally evaluated as part of the Cardiovascular Risk in Young Finns study in 1980. At baseline, participant BMI, insulin, lipid, C-reactive protein and blood pressure levels, socioeconomic position, dietary habits, and physical activity, were evaluated. In addition, information was gathered on rural residency, severe infections, breast feeding, parental smoking and birth weight. Subsequent IBD diagnosis status was evaluated based on nationwide registries on hospitalisations and drug imbursement decisions.

Results: Altogether, 49 participants (1.4%) had IBD diagnosed during the 34 years of register follow-up, of which 31 had ulcerative colitis, 12 Crohn's disease and 6 undetermined colitis. In univariate analyses, significant correlations were observed between childhood HDL-cholesterol (risk ratio (95% CI) for 1-SD change (0.58 (0.42-0.79)) and CRP concentrations (1.20 (1.01-1.43)) with IBD. The inverse association between HDL-cholesterol and IBD remained significant (0.57 (0.39-0.82)) in a multivariable model including data on age, sex and CRP. In addition, a weighted genetic z-score of 71 single nucleotide polymorphisms associated with elevated HDL-cholesterol levels was significantly lower in IBD patients, P=0.01).

Conclusion: Low childhood HDL-cholesterol levels are associated with subsequent IBD diagnosis. In addition, a genetic risk score associated with low HDL-cholesterol levels predict later IBD suggesting that HDL-cholesterol metabolism might have a role in the pathogenesis of IBD.
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http://dx.doi.org/10.1016/j.dld.2018.01.121DOI Listing
April 2018

High treatment persistence rate and significant endoscopic healing among real-life patients treated with vedolizumab - a Finnish Nationwide Inflammatory Bowel Disease Cohort Study (FINVEDO).

Scand J Gastroenterol 2018 Feb 19;53(2):158-167. Epub 2017 Dec 19.

b MedEngine Oy , Helsinki , Finland.

Objectives: The efficacy and tolerability of vedolizumab in the treatment of inflammatory bowel diseases (IBD) has been demonstrated in an extensive GEMINI clinical trial programme. Clinical trials represent highly selected patient populations and, therefore, it is important to demonstrate effectiveness in real-life clinical practice. We set out to assess real-world treatment outcomes of vedolizumab in a nationwide cohort of treatment refractory Finnish Crohn's disease (CD) and ulcerative colitis (UC) patients.

Methods: This was a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centers with a diagnosis of UC or CD who had at least one vedolizumab infusion since the availability of the product in Finland, were included in the study. Data were collected retrospectively from medical charts at baseline, week 14, and month 6. The primary outcome measure was treatment persistence 24 weeks post-vedolizumab initiation.

Results: A total of 247 patients were included (108 CD, 139 UC). A total of 75.0% (n = 81) of all CD patients and 66.2% (n = 92) of all UC patients, were persistent on vedolizumab therapy for 6 months post treatment initiation. At month 6, 41.8% (28/67) of the treatment persistent CD patients and 73.3% (63/86) of the treatment persistent UC patients achieved clinical remission. Significant improvement in endoscopic scores were observed among treatment persistent patients (CD, n = 17, ΔSES-CD=-5.5, p = .008; UC, n = 26, ΔMayo endoscopic score =-0.5, p = .003) at month 6.

Conclusions: Vedolizumab provides an effective and well-tolerated treatment option in real-world clinical practice even among treatment refractory IBD patients.
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http://dx.doi.org/10.1080/00365521.2017.1416160DOI Listing
February 2018

Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients.

Scand J Gastroenterol 2017 Dec 24;52(12):1348-1353. Epub 2017 Aug 24.

a Department of Gastroenterology , Helsinki University Hospital, University of Helsinki , Helsinki , Finland.

Background: Clinical use of biosimilar infliximab (CT-P13) in inflammatory bowel diseases (IBDs) is based on extrapolation of indication from clinical studies performed in rheumatological diseases. Only few data exist of behaviour of infliximab trough levels (TLs) and anti-drug antibodies (ADAs) during switching.

Aim: The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one.

Methods: All our IBD patients receiving maintenance infliximab therapy were switched to biosimilar infliximab. TLs and ADAs were measured before the last originator infusion and before the third biosimilar infusion. Laboratory values, disease activity indices (partial Mayo score and Harvey-Bradshaw index) and demographic data were collected from patient records.

Results: A total of 62 patients were included in the final analysis (32 Crohn's disease, 30 ulcerative colitis (UC) or IBD-unclassified). No significant changes in median TLs before (5.5 mg/l) and after switching (5.5 mg/l, p = .05) occurred in the entire study group or in the Crohn's disease (CD) subgroup (5.75 and 6.5 mg/l, p = .68). However, in the subgroup of ulcerative colitis, the change in median TL was significantly different (from 5.2 to 4.25 mg/l, p = .019). Two patients developed ADAs after switching. No changes in disease activity were detected during switching and no safety concerns occurred.

Conclusions: Switching from originator to biosimilar infliximab resulted in statistically significant differences in infliximab TLs in patients with UC but not in patients with Crohn's disease. The clinical significance for this difference is doubtful and in neither group changes in disease activity occurred.
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http://dx.doi.org/10.1080/00365521.2017.1369561DOI Listing
December 2017

Detailed Follow-up Study of Pediatric Orofacial Granulomatosis Patients.

J Pediatr Gastroenterol Nutr 2017 10;65(4):388-393

*Department of Otorhinolaryngology, Head and Neck Surgery †Children's Hospital ‡Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and Helsinki University, Helsinki §Department of Dentistry, Tampere University Hospital and Tampere University, Tampere ||Department of Gastroenterology, Tampere University Hospital and Tampere University, Tampere ¶Department of Gastroenterology, Helsinki University Hospital and Helsinki University, Helsinki, Finland.

Objectives: Orofacial granulomatosis (OFG) is a chronic inflammatory condition affecting the orofacial area. Its connection to Crohn disease (CD) is debated. Our aim was to describe a cohort of pediatric patients with OFG in detail, study the long-term behavior of OFG, and evaluate factors predicting CD in patients with OFG.

Methods: We invited patients diagnosed with OFG at 2 university hospitals, Finland for a follow-up appointment. Patients (n = 29) were examined by a dentist and an otorhinolaryngologist using a structural schema. Orofacial findings were also recorded using digital photographing. Patients filled in questionnaires about general health and special diets. Patients' nutrition was evaluated from food records. The findings were compared between patients with OFG only and OFG with CD.

Results: Patients with CD had more findings in the orofacial area (total score for orofacial findings median 11) compared to patients with OFG only (total score median 7.5). There was no statistically significant difference in the type of lesions between these groups, except the upper lip was more often affected in patients with CD (n = 11) than in patients with OFG only (n = 0). Most of the patients had normal otorhinolaryngological findings. All patients with elevated anti-Saccharomyces cerevisiae antibody A levels had CD (n = 6) and they presented with more orofacial findings (total score) than patients with normal levels of anti-S cerevisiae antibody A (P = 0.0311).

Conclusions: Long-term follow-up of pediatric-onset patients with OFG shows good prognosis. Patients with OFG do not seem to have otorhinolaryngological comorbidity. Anti-S cerevisiae antibody A may serve as a factor to indicate the possible presence of underlying CD in patients with OFG, but further studies are requested.
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http://dx.doi.org/10.1097/MPG.0000000000001554DOI Listing
October 2017

Long-term outcome of inflammatory bowel disease patients with deep remission after discontinuation of TNFα-blocking agents.

Scand J Gastroenterol 2017 Mar 3;52(3):284-290. Epub 2016 Nov 3.

a Department of Gastroenterology , Helsinki University Central Hospital and University of Helsinki , Helsinki , Finland.

Background: Little data exist on the long-term prognosis of patients with inflammatory bowel disease (IBD) after stopping TNFα-blocking therapy in deep remission. Existing data indicate that approximately 50% of patients on combination therapy who discontinued TNFα-blockers are still in remission 24 months later. The aims of this follow-up analysis were to evaluate the long-term remission rate after cessation of TNFα-blocking therapy, the predicting factors of a relapse and the response to restarting TNFα blockers.

Methods: The first follow-up data of 51 IBD patients (17 Crohn's disease [CD], 30 ulcerative colitis [UC] and four inflammatory bowel disease type unclassified [IBDU]) in deep remission at the time of cessation of TNFα-blocking therapy have been published earlier. The long-term data was collected retrospectively after the first follow-up year to evaluate the remission rate and risk factors for the relapse after a median of 36 months.

Results: After the first relapse-free year, 14 out of the remaining 34 IBD patients relapsed (41%; 5/12 [42%] CD and 9/22 [41%] UC/IBDU). Univariate analysis indicated no associations with any predictive factors. Re-treatment was effective in 90% (26/29) of patients.

Conclusion: Of IBD patients in deep remission at the time of cessation of TNFα-blocking therapy, up to 60% experience a clinical or endoscopic relapse after a median follow-up time of 36 months (95% CI 31-41 months). No individual risk factors predicting relapse could be identified. However, the initial response to a restart of TNFα-blockers seems to be effective and well tolerated.
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http://dx.doi.org/10.1080/00365521.2016.1250942DOI Listing
March 2017

[Exemplary cases of individualization of biological therapy].

Duodecim 2016 ;132(4):387-90

The use of biological drugs consisting of large molecules has in recent years expanded to new indications and new specialties. These drugs are most commonly proteins possessing the structure of an antibody or a receptor, and treatment with them is significantly more expensive than that carried out with conventional small molecule drugs. Determination of drug levels and emerging antibodies form the basis of individualization. They will enable better treatment results with simultaneous avoidance of unnecessary medications, excessive doses--and extra costs. We demonstrate the individualization of TNF-α blocker therapy through patient cases in various situations.
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May 2016

Association Between Fecal Calprotectin Levels and Small-bowel Inflammation Score in Capsule Endoscopy: A Multicenter Retrospective Study.

Dig Dis Sci 2016 07 23;61(7):2033-40. Epub 2016 Mar 23.

Department of Gastroenterology, Skåne University Hospital, Lund University, Malmö, Sweden.

Background: Accurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images.

Goals: Multicenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels.

Study: Five academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3 months.

Results: Overall, correlation between FC and LS was weak (r s: 0.232, P < 0.001). When two clinically significant FC thresholds (100 and 250 μg/g) were examined, the r s between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (P = 0.307). For clinically significant (LS ≥ 135) or negative (LS < 135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76 μg/g with sensitivity 0.59 and specificity 0.41.

Limitations: Retrospective design.

Conclusions: LS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC level ≥ 76 μg/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.
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http://dx.doi.org/10.1007/s10620-016-4104-7DOI Listing
July 2016

Does oral α-galactosidase relieve irritable bowel symptoms?

Scand J Gastroenterol 2016 Jan 2;51(1):16-21. Epub 2015 Jul 2.

a 1 Aava Gastroenterology Clinic , Helsinki, Finland.

Objective: Abdominal bloating is reported by a majority of irritable bowel syndrome (IBS) patients. Excess colonic fermentation may cause gaseous symptoms. Several foodstuffs contain oligosaccharides with an α-galactosidic linkage that is resistant to mammalian hydrolases. Assisted hydrolysis by exogenous α-galactosidase enzyme (AG) could offer a way of controlling IBS symptoms by reducing colonic fermentation and gas production. The aim of this study was to assess the effect of AG on symptom severity and quality of life in IBS patients with abdominal bloating or flatulence.

Methods: A total of 125 subjects with IBS received AG or placebo at meals for 12 weeks. IBS-Symptom Severity Score (IBS-SSS) and quality of life (QoL) were assessed at baseline, during the treatment and at 4-week follow-up.

Results: AG showed a trend toward a more prominent decrease in IBS-SSS. The responder rate at week 16 was higher for the AG group. No difference was detected in QoL between AG and placebo groups. A total of 25 patients (18 in AG group and 7 in placebo group, p = 0.016) withdrew from the study. Abdominal pain and diarrhea were more often reported as reason for withdrawal in AG group.

Conclusions: We found no evidence to support the use of AG routinely in IBS patients. Improvement of clinical response at 4-week follow-up may suggest a long-term effect of unknown mechanism, but could also be attributed to non-responder drop out. Gastrointestinal (GI) side effects may be a coincidence in this study, but irritation of GI tract by AG administration cannot be excluded.
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http://dx.doi.org/10.3109/00365521.2015.1063156DOI Listing
January 2016

Fecal calprotectin in diagnosis and clinical assessment of inflammatory bowel disease.

Scand J Gastroenterol 2015 Jan;50(1):74-80

Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital , Helsinki , Finland.

The fecal neutrophil-derived biomarker calprotectin has several features of an ideal noninvasive test for detecting intestinal inflammation: it is simple, reliable, and low in cost. Its utility in differentiating inflammatory bowel diseases (IBDs) from functional conditions such as irritable bowel syndrome is well documented. Fecal calprotectin (FC) correlates closely with endoscopic activity of IBD. Emerging evidence suggest its usefulness in serial monitoring of disease activity and of therapy success in IBD. A low FC concentration predicts persistence of clinical remission especially in non-symptomatic ulcerative colitis and Crohn's colitis. Here, an overview is given to the current role of FC in diagnosis and clinical assessment of IBD.
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http://dx.doi.org/10.3109/00365521.2014.987809DOI Listing
January 2015

Surgical rehabilitation of short and dysmotile intestine in children and adults.

Scand J Gastroenterol 2015 Feb 25;50(2):153-61. Epub 2014 Nov 25.

Pediatric Liver and Gut Research Group, University of Helsinki , Helsinki , Finland.

Aims: This is a descriptive study aiming to compare outcomes of intestinal rehabilitation surgery among pediatric and adult intestinal failure (IF) patients with either primary intestinal motility disorders or short bowel syndrome (SBS) treated by our nationwide program.

Methods: Medical records of IF patients (n = 31, 71% children) having undergone autologous intestinal reconstructions (AIR) (n = 25), intestinal transplantation (ITx) (n = 5), or being listed for ITx (n = 2) between 1994 and 2014 were reviewed.

Results: At surgery, median age was 3.4 (interquartile range, 1.0-22.1) in SBS (n = 22) and 16.5 (3.2-26.7) years in dysmotility patients (n = 9) who received median 60% and 83% of energy requirement parenterally, respectively. Median small bowel length was shorter in SBS than dysmotility patients (34 versus 157 cm, p < 0.001). Following AIR, none of the dysmotility patients achieved permanent intestinal autonomy, whereas 68% of SBS patients weaned off parenteral nutrition (PN) (p = 0.022) and none required listing for ITx. Five dysmotility patients who underwent ITx achieved intestinal autonomy. Regarding both AIR and ITx procedures, no significant difference in PN weaning was observed between the two subgroups. At last follow-up, 3.3 (0.6-8.0) years postoperatively, median plasma bilirubin was 6 (4-16) µmol/l, while liver biopsy showed fibrosis (Metavir stage 1-2) in 50% and cholestasis in 8%. Proportion of PN energy requirement had reduced significantly (p = 0.043) among PN-dependent SBS (n = 7) but not among dysmotility patients (n = 5). Overall survival was 90%.

Conclusion: AIR surgery was beneficial among selected SBS patients, whereas in intestinal dysmotility disorders, permanent PN weaning was only achieved by ITx.
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http://dx.doi.org/10.3109/00365521.2014.962607DOI Listing
February 2015

[New treatment options for inflammatory bowel diseases].

Duodecim 2014 ;130(14):1391-8

Ulcerative colitis and Crohn's disease are incurable diseases sharing common features in pathogenesis but usually presenting a different clinical picture. Current medications are effective for some patients only, and an already achieved response can be lost. Better knowledge of inflammatory mechanisms has enabled the development of new treatments, and new drugs are entering clinical application. Patients unresponsive to TNFalpha blockage continue to be specially challenging, as good and effective treatment options for them are scarce.
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September 2014

Does fecal calprotectin predict short-term relapse after stopping TNFα-blocking agents in inflammatory bowel disease patients in deep remission?

J Crohns Colitis 2015 Jan;9(1):33-40

Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland.

Background And Aims: This prospective multicenter study examined whether elevated fecal calprotec tin (FC) concentrations after stopping TNFα-blocking therapy can predict clinical or endoscopic relapse. In addition, we evaluated the impact of histological remission on the relapse risk.

Methods: We enrolled inflammatory bowel disease (IBD) patients who were in clinical, endoscopic, and FC-based (< 100 μg/g) remission after a minimum 11 months of TNFα-blocking therapy. The patients were followed-up for 12 months after the discontinuation of TNFα-blocking therapy. FC was collected monthly for the first 6 months and thereafter every second month. Ileocolonoscopy was performed at inclusion, at 4 months, at the study end, and at the time of clinical relapse.

Results: Of 52 enrolled patients, 49 (16 Crohn's disease, 33 ulcerative colitis/IBD unclassified) provided the stool samples requested and comprised the study group. During the follow-up, 15/49 (31%) relapsed, whereas 34 (69%) remained in remission. Patients relapsing showed constantly elevated FC levels for a median of 94 (13-317) days before the relapse. Significant increase in median FC levels was seen 2 (p = 0.0014), 4 (p = 0.0056), and 6 (p = 0.0029) months before endoscopic relapse. Constantly normal FC concentrations during the follow-up were highly predictive for clinical and endoscopic remission. Normal FC concentrations in patients with remission were associated with histological remission.

Conclusion: FC seems to increase and remain elevated before clinical or endoscopic relapse, suggesting that it can be used as a surrogate marker for predicting and identifying patients requiring close follow-up in clinical practice.
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http://dx.doi.org/10.1016/j.crohns.2014.06.012DOI Listing
January 2015

Skin reactions during anti-TNFα therapy for pediatric inflammatory bowel disease: a 2-year prospective study.

Inflamm Bowel Dis 2014 Aug;20(8):1309-15

*Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland; †Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; ‡Department of Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; and §Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland.

Background: Although the development of therapy-related skin reactions is common along with an increase in the number of adult patients receiving anti-TNFα, there are few studies on pediatric inflammatory bowel disease; hence, this prospective study focuses on skin reactions related to infliximab therapy.

Methods: All pediatric patients with inflammatory bowel disease undergoing infliximab therapy were prospectively screened for the presence of skin manifestations at the time of each infusion between March 1, 2011 and March 31, 2011 at Children's Hospital, Helsinki, Finland. Blood inflammatory markers and fecal calprotectin levels were measured at the time of infusions.

Results: During the study period, 84 children with inflammatory bowel disease (Crohn's n = 64) received infliximab infusions (the median duration of therapy 12.2 mo). Almost every other patient (n = 40; 47.6%) presented chronic skin reactions, 23% with lesions considered severe. Most commonly, the patient's ear lobes and scalp were affected with psoriasis-like manifestations, followed by their eyelids, perioral and pubic area, trunk, and the extremities. However, an HLA-Cw*0602 genotype associating with psoriasis was rare. Interestingly, most patients with skin reactions had a low degree of intestinal inflammation based on their fecal calprotectin levels (median level, 133 μg/g versus 589 in unaffected patients; P < 0.016). Seven patients (8.3% of all patients but 17% of those with skin lesions) discontinued the given therapy due to a skin reaction.

Conclusions: Skin reactions are common during maintenance therapy with infliximab in pediatric patients. For most patients, skin reactions seem to correlate with a low level of intestinal inflammation. Although potentially harsh, skin lesions mostly allow continuation of infliximab.
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http://dx.doi.org/10.1097/MIB.0000000000000088DOI Listing
August 2014

Outcome after discontinuation of TNFα-blocking therapy in patients with inflammatory bowel disease in deep remission.

Inflamm Bowel Dis 2014 Jun;20(6):1021-8

*Department of Medicine, Division of Gastroenterology, Maria Helsinki City Hospital and University of Helsinki, Helsinki, Finland; †Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland; ‡Division of Gastroenterology, Department of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland; §Department of Medicine, Division of Gastroenterology, Turku University Central Hospital, Turku, Finland; ‖Department of Medicine, Division of Gastroenterology, Oulu University Central Hospital, Oulu, Finland; ¶Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland; **Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland; ††Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Peijas Hospital, Vantaa, Finland; ‡‡Department of Medicine, Hyvinkää Hospital, Hyvinkää, Finland; §§Department of Medicine, Porvoo Hospital, Porvoo, Finland; ‖‖Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland; and ¶¶Department of Surgery, Helsinki University Central Hospital, Biomedicum Helsinki, Finland.

Background: Few data are available on the disease course in patients with inflammatory bowel disease (IBD) in deep remission after discontinuing tumor necrosis factor α (TNFα)-blocking therapy. In this prospective multicenter study, we evaluated the relapse rate, predictive factors, and the response to retreatment after discontinuation of TNFα-blocking therapy in patients with IBD in deep remission.

Methods: We recruited 52 patients (17 Crohn's disease, 30 ulcerative colitis, and 5 IBD unclassified) in clinical, endoscopic, and fecal calprotectin-based (<100 μg/g) remission after at least 1 year of TNFα-blocking therapy. Clinical and endoscopic remission and relapse were defined according to validated indices. After discontinuation of therapy, the patients were followed up with endoscopic assessment at 4 and 12 months. In the event of a clinical relapse with endoscopically active disease or minor clinical symptoms but severe endoscopic relapse, TNFα-blocking therapy was restarted.

Results: After a median follow-up time of 13 (range, 12-15) months, 17/51 (33%) patients relapsed (5/17 Crohn's disease, 12/34 ulcerative colitis/IBD unclassified, 1 patient lost to follow-up at 6 mo). Ten experienced clinical and endoscopic relapse, 5 clinical relapse with mild endoscopic activity, and 2 severe endoscopic relapse. No specific predictive factors were associated with the relapse. Retreatment was effective in 94% of patients.

Conclusions: After cessation of TNFα-blocking therapy in patients with IBD in deep remission, up to 67% remained in clinical remission during the 12-month follow-up. Importantly, 85% of these patients sustained endoscopic remission. The response to restart of TNFα antagonists was effective and well tolerated.
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http://dx.doi.org/10.1097/MIB.0000000000000052DOI Listing
June 2014

The long-term outcome of anti-tumor necrosis factor-α therapy related to fecal calprotectin values during induction therapy in pediatric inflammatory bowel disease.

Scand J Gastroenterol 2014 Apr 6;49(4):434-41. Epub 2014 Mar 6.

Children's Hospital, Helsinki University Central Hospital , Helsinki, FIN-00029 , Finland.

Objective: Monitoring fecal calprotectin (FC) could assist in the assessment of the therapeutic response of inflammatory bowel disease (IBD). There are few studies on long-term prognosis related to the FC value response to infliximab induction therapy, thus providing the aim of this study on pediatric patients.

Methods: FC levels were measured during the induction and maintenance phase of infliximab therapy (5 mg/kg) in 76 pediatric IBD patients introduced to maintenance therapy. The long-term outcomes and clinical disease activity were retrospectively related to the FC response to induction.

Results: The median pretreatment FC level of 817 μg/g stool (range <5-24,000) declined to 372 μg/g (range 5-2430) by week 6, with a low level (<100 μg/g) in 35% (pooled comparable data for ulcerative colitis and Crohn's). Clinical activity indices showed remission in 59% (pediatric Crohn's disease activity index: <10, n = 33; pediatric ulcerative colitis activity index: <10 n = 12). In 49 patients (64%), infliximab therapy was discontinued (inadequate effect/surgery = 27; remission/bridging to azathioprine = 12; adverse effect = 6; antibodies to infliximab n = 4) during the study period with a median follow up of 1.1 years (interquartile range [IQR]: 0.71-4.4). Those who discontinued the therapy within the first year due to an inadequate effect had higher median FC level during induction than the other patients (median 633 µg/g, IQR: 197-819 and median 219 µg/g, IQR: 71-508, respectively; p < 0.025) and were less frequently in clinical remission at week 6 (p < 0.01).

Conclusions: The long-term prognosis of infliximab therapy is related to the response to induction therapy in pediatric IBD and reflected in low FC values between weeks 2 and 6 and clinical remission.
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http://dx.doi.org/10.3109/00365521.2014.886719DOI Listing
April 2014

Diagnostics and prognostics of inflammatory bowel disease with fecal neutrophil-derived biomarkers calprotectin and lactoferrin.

Authors:
Taina Sipponen

Dig Dis 2013 14;31(3-4):336-44. Epub 2013 Nov 14.

Department of Medicine, Clinic of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland.

Crohn's disease (CD), ulcerative colitis (UC), and colitis unclassified, collectively defined as inflammatory bowel disease (IBD), are the consequence of chronic inflammatory reactions in the gastrointestinal tissue. Endoscopy with biopsies is the mainstay in the diagnosis of this inflammation and is also important in the assessment of disease activity and monitoring of treatment. Furthermore, mucosal healing is increasingly becoming a therapeutic target for treatment of IBD and the golden standard of assessing it is endoscopy. However, due to the costs, invasiveness, and to limited endoscopic capacity, the need is strong for reliable surrogate markers of intestinal inflammation. Bowel contents, being in close contact with intestinal mucosa, can take up molecules that are measurable from stool samples and thus can serve as markers of inflammation. The fecal neutrophil-derived biomarkers, especially calprotectin and lactoferrin, have several features of an ideal test for detecting intestinal inflammation: they are noninvasive, simple, and low in cost. The utility of these biomarkers in distinguishing IBD from noninflammatory conditions such as irritable bowel syndrome is well documented. They correlate closely with endoscopic activity both in CD and UC. They allow serial monitoring of disease activity and of treatment success, and can even serve in predicting clinical relapse in unsymptomatic patients or sustained remission after induction with TNF-α-blocking agents. In this review an overview will be given to the role of fecal neutrophil-derived biomarkers calprotectin and lactoferrin in diagnostics and prognostics of IBD.
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http://dx.doi.org/10.1159/000354689DOI Listing
June 2014

Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease.

Int J Colorectal Dis 2014 Jan;29(1):43-50

Purpose: Fecal MMP-9 and human beta-defensin-2 (HBD-2)levels, potential markers of intestinal inflammation, are in sufficiently explored in pediatric inflammatory bowel disease(IBD). The aim was to study fecal MMP-9 and HBD-2 in pediatric IBD to compare their performance to calprotectin and to study whether they would provide additional value in categorizing patients according to their disease subtype.

Methods: Fecal calprotectin, MMP-9, and HBD-2 levels were measured with ELISA in 110 pediatric patients with IBD(Crohn’s disease, n = 68; ulcerative colitis (UC), n = 27; unclassified, n = 15; median age, 14). To compare the performance of the fecal markers, the area under the receiver operating characteristics curve (±95 % CI) was used. In addition,the best cut-off values of each measure to differentiate IBD patients and controls (n = 27 presenting with diarrhea, abdominal pain, and/or anemia) were derived by maximizing sensitivity and specificity.

Results: Of the fecal markers studied, calprotectin performed best for separation of IBD and non-IBD patients with the are a under curve (AUC) of 0.944 (95 % CI, 0.907 to 0.981). For MMP-9, AUC was 0.837 (95% CI, 0.766 to 0.909), the levels being significantly higher in active IBD and in UC compared with Crohn’s disease (p = 0.0013), but categorization of these patient groups did not take place. HBD-2 did not categorize any of the studied groups.

Conclusions: Calprotectin was the best fecal marker in pediatric IBD, but MMP-9 showed almost comparable performance in UC, suggesting applicability as a surrogate marker of inflammation. Fecal HBD-2 did not bring information to the disease characteristics of pediatric IBD patients.
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http://dx.doi.org/10.1007/s00384-013-1775-9DOI Listing
January 2014

Dendritic cells from Crohn's disease patients show aberrant STAT1 and STAT3 signaling.

PLoS One 2013 7;8(8):e70738. Epub 2013 Aug 7.

Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.

Abnormalities of dendritic cells (DCs) and STAT proteins have been reported in Crohn's disease (CD). Studies on JAK/STAT signaling in DCs are, however, lacking in CD. We applied a flowcytometric single-cell-based phosphoepitope assay to evaluate STAT1 and STAT3 pathways in DC subsets from CD patients. In addition, circulating DC counts were determined, together with the activation-related immunophenotype. We found that IL-6- and IFN-α-induced STAT3 phosphorylation and IFN-α-induced STAT1 phosphorylation were impaired in plasmacytoid DCs (pDCs) from CD patients (P = 0.005, P = 0.013, and P = 0.006, respectively). In myeloid DCs (mDCs), IFN-α-induced STAT1 and STAT3 phosphorylation were attenuated (P<0.001 and P = 0.048, respectively), but IL-10-induced STAT3 phosphorylation was enhanced (P = 0.026). IFN-γ-induced STAT1 signaling was intact in both DC subtypes. Elevated plasma IL-6 levels were detected in CD (P = 0.004), which strongly correlated with disease activity (ρ = 0.690, P<0.001) but not with IL-6-induced STAT3 phosphorylation. The numbers of pDCs and BDCA3+ mDCs were decreased, and CD40 expression on CD1c+ mDCs was increased in CD. When elucidating the effect of IL-6 signaling on pDC function, we observed that IL-6 treatment of healthy donor pDCs affected the maturation of and modified the T-cell priming by pDCs, favoring Th2 over Th1 type of response and the expression of IL-10 in T cells. Our results implicate DC signaling in human CD. Reduced IL-6 responsiveness in pDCs, together with the attenuated IFN-α-induced signaling in both DC subtypes, may contribute to the immunological dysregulation in CD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070738PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737363PMC
August 2014
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