Taina Sipponen

IL-23/IL-17 Immunity as a Hallmark of Crohn's Disease

Background: We studied the balance between ileal T‐effector cells versus T‐regulatory cells in active and inactive Crohns disease (CD). Methods: We compared effector and regulatory T‐cell‐related markers such as interleukin (IL)–17, interferon (IFN)‐&ggr;, IL‐4, and Foxp3 transforming growth factor (TGF)–&bgr; CTLA‐4 and markers for innate immune activation such as IL‐6, IL‐10, IL‐18, IL‐23, tumor necrosis factor (TNF)–&agr;, and IL‐12p70, studied with immunohistochemistry and RT‐PCR in ileal biopsies from patients with active or inactive CD and from control subjects. IL‐17 in fecal samples was detected by ELISA. The effect of IL‐17 on IL‐8 and TNF‐&agr; mRNA expression in epithelial cell line Caco‐2 was studied. Results: The numbers of IL‐4‐, IL‐17‐, and IL‐23(p19)‐positive cells in the lamina propria were higher in patients with CD, both active and inactive, than in the controls. mRNA expression of IL‐17A, IL‐6, and Foxp3 was increased in the biopsies both from patients with active disease and those in remission, whereas mRNA expression of IL‐23 was increased only in active disease. Fecal IL‐17 concentration was increased in patients with active disease. IL‐17 enhanced the IL‐8 and TNF‐&agr; response of the epithelial cell line to lipopolysaccharide (LPS) in vitro. Conclusions: Our findings suggest that activation of the IL‐23/IL‐17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS.

Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels.

AIM To study the response to infliximab in pediatric inflammatory bowel disease (IBD), as reflected in fecal calprotectin levels. METHODS Thirty-six pediatric patients with IBD [23 Crohns disease (CD), 13 ulcerative colitis (UC); median age 14 years] were treated with infliximab. Fecal calprotectin was measured at baseline, and 2 and 6 wk after therapy, and compared to blood inflammatory markers. Maintenance medication was unaltered until the third infusion but glucocorticoids were tapered off if the patient was doing well. RESULTS At introduction of infliximab, median fecal calprotectin level was 1150 μg/g (range 54-6032 μg/g). By week 2, the fecal calprotectin level had declined to a median 261 μg/g (P < 0.001). In 37% of the patients, fecal calprotectin was normal (< 100 μg/g) at 2 wk. By week 6, there was no additional improvement in the fecal calprotectin level (median 345 μg/g). In 22% of the patients, fecal calprotectin levels increased by week 6 to pretreatment levels or above, suggesting no response (or a loss of early response). Thus, in CD, the proportion of non-responsive patients by week 6 seemed lower, because only 9% showed no improvement in their fecal calprotectin level when compared to the respective figure of 46% of the UC patients (P < 0.05). CONCLUSION When treated with infliximab, fecal calprotectin levels reflecting intestinal inflammation normalized rapidly in one third of pediatric patients suggesting complete mucosal healing.

Capsule endoscopy in pediatric patients: Technique and results in our first 100 consecutive children

Abstract Objective. Capsule endoscopy (CE) offers noninvasive methods to assess small bowel pathology but only limited data are available on the feasibility, safety, and findings in children. In this study, we report our results of 100 consecutive CE in children. Material and methods. Single center retrospective study. All pediatric patients (mean age 119 months, range from 8 to 188 months) undergoing CE were included until 100 investigations were completed. The indications for CE were: suspicion or evaluation of Crohns disease (n = 35) or ulcerative colitis (n = 24), gastrointestinal bleeding (n = 18), and miscellaneous (n = 23). Results. The youngest patients able to swallow the capsule were 84 months old. When the patient was unable to swallow the capsule (n = 51), it was guided into the duodenum with endoscope. In two patients, the capsule remained in the stomach during the 8 h of recording and in 23 cases the capsule failed to reach the cecum. The capsule was expelled naturally in all except one patient. In 39% of the patients, CE revealed a significant finding (multiple ulcers, bleeding, tumors, strictures). In patients examined for bleeding or for a suspicion of Crohns disease, the respective proportions were 50% and 60%. Conclusions. This study shows that CE is a feasible diagnostic method to study the small intestine in pediatric patients and that CE can be done in children as young as 8 months old. The diagnostic yield is highest in cases with bleeding or a high suspicion of Crohns disease.

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

Background:Few data are available on the disease course in patients with inflammatory bowel disease (IBD) in deep remission after discontinuing tumor necrosis factor &agr; (TNF&agr;)–blocking therapy. In this prospective multicenter study, we evaluated the relapse rate, predictive factors, and the response to retreatment after discontinuation of TNF&agr;-blocking therapy in patients with IBD in deep remission. Methods:We recruited 52 patients (17 Crohns disease, 30 ulcerative colitis, and 5 IBD unclassified) in clinical, endoscopic, and fecal calprotectin-based (<100 &mgr;g/g) remission after at least 1 year of TNF&agr;-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, TNF&agr;-blocking therapy was restarted. Results:After a median follow-up time of 13 (range, 12–15) months, 17/51 (33%) patients relapsed (5/17 Crohns 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 TNF&agr;-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 TNF&agr; antagonists was effective and well tolerated.

Three-generation Familial Visceral Myopathy With α-actin-positive Inclusion Bodies in Intestinal Smooth Muscle

We report the clinical and histopathologic findings of a family with 7 affected members in 3 generations suffering from autosomal dominant visceral myopathy. All patients presented with chronic intestinal pseudo-obstruction affecting especially the entire small bowel. Histologic abnormalities involved intestinal smooth muscle, with degeneration and fibrosis of the muscularis propria. In addition, the inner circular layer of the muscularis propria contained α-smooth muscle actin-positive and, in more advanced disease, also periodic acid-Schiff–positive inclusion bodies. The inclusions were invisible in routine hematoxylin-eosin–stained sections, but were visible in immunohistochemical stainings for α-smooth muscle actin. No abnormality was evident in muscularis mucosae or in blood vessels, and the findings remained unidentified in mucosal biopsy specimens. To our knowledge, this is the first reported α-actin–positive inclusion body finding in familial visceral myopathy.

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

Abstract 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.

In Crohn's Disease, Anti-TNF-α Treatment Changes the Balance between Mucosal IL-17, FOXP3, and CD4 Cells.

Aim. In Crohns disease (CD), anti-TNF-α treatment is a potent medication. We aimed to characterize the effect of anti-TNF-α treatment on T effector and regulatory cells. Material and Methods. We studied T-effector and regulatory cells on cellular and mRNA levels in intestinal biopsy samples from 13 Crohns disease patient. Biopsies were obtained at baseline and 3 months after anti-TNF-α treatment, and from 14 inflammation-free control subjects. Results. Patients had higher numbers of ileal IL-17+ and forkhead box P3 (FOXP3)+ cells than did control subjects, both before ( P ≤ 0.001 and P ≤ 0.05, resp.) and after the anti-TNF-α treatment (P ≤ 0.01, P ≤ 0.01). Intestinal interferon-γ and IL-17 mRNA expression was higher in Crohns disease and remained elevated after anti-TNF-α treatment. The ratio of IL-17+ cells to CD4+ cells decreased (P ≤ 0.05) and compared to baseline the ratio of IL-17+ cells to FOXP3+ was lower after treatment (P ≤ 0.05). Conclusions. TNF-α-blocking agents improved intestinal balance between IL-17+ T-effector and regulatory T cells, although intestinal IL-17 upregulation remained elevated.

Does oral α-galactosidase relieve irritable bowel symptoms?

Abstract 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.

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

Abstract 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.

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

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 Crohns 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.