Urpo Nieminen

Surrogate markers and clinical indices, alone or combined, as indicators for endoscopic remission in anti-TNF-treated luminal Crohn's disease

Abstract Objective. Endoscopically confirmed mucosal healing has become an important therapeutic goal in the treatment of Crohns disease (CD). The role of clinical indices, such as the Crohns disease activity index (CDAI) and the Harvey–Bradshaw index (HBI), and surrogate markers, such as C-reactive protein (CRP) and fecal calprotectin, to indicate remission determined by endoscopy needs to be clarified. We analyzed the role of surrogate markers and clinical indices, separately and in combination, by comparing them with endoscopically scored disease activity in biologically treated CD patients. Material and methods. Prospectively collected data of all patients with inflammatory bowel disease treated with tumor necrosis factor alpha antibodies in a tertiary center between 2007 and 2010. Altogether 210 endoscopies in 64 CD patients were analyzed. The simple endoscopic score for Crohns disease (SES-CD) was used for scoring disease activity and compared with available data on concurrent CDAI, HBI, CRP, and calprotectin. Results. Endoscopic activity demonstrated a stronger correlation with calprotectin and CRP than with the clinical indices. Neither the clinical indices nor CRP was reliable at identifying endoscopic remission. However, calprotectin alone identified endoscopic remission with a sensitivity of 84% and specificity of 74%, but was beaten, although not statistically significantly, by a combined index, based on calprotectin and the HBI. Conclusions. Clinical scores commonly used in the assessment of disease activity are unreliable at differentiating endoscopic remission from active CD. Despite this, a score based on a combination of fecal calprotectin and the HBI is a new promising tool for identifying endoscopic remission.

Esophageal Morbidity and Function in Adults With Repaired Esophageal Atresia With Tracheoesophageal Fistula A Population-Based Long-term Follow-up

Objective:We assessed esophageal morbidity and relationships between surgical complications, symptoms, endoscopic findings, immunohistochemistry, and esophageal motility in adults with repaired esophageal atresia (EA). Summary of Background Data:There exist no previous population-based long-term follow-up studies on EA. Methods:Participants were interviewed, and they underwent esophageal endoscopy and manometry. Matched control subjects (n = 287) served as controls. Results:A total of 101 (42%) individuals representative of the entire study population participated at a mean age of 36 years (range, 21–57). Symptomatic gastroesophageal reflux had occurred in 34% and dysphagia in 85% of the patients and in 8% and 2% of the controls (P < 0.001 for both). Endoscopic findings included hiatal hernia (28%), Barrett′s esophagus (11%), esophagitis (8%), and anastomotic stricture (8%). Immunohistochemistry revealed esophagitis in 25%, and CDX2-positive columnar epithelial metaplasia in 21%, with additional goblet cells and MUC2 positivity in 6%. Gastroesophageal reflux and dysphagia were equally common in individuals with normal histology, esophagitis, or epithelial metaplasia. Manometry demonstrated nonpropagating peristalsis in 80% of the patients, and low distal wave amplitudes of the esophagus in all the changes being significantly worse in those with epithelial metaplasia (P ≤ 0.022 metaplasia vs. esophagitis/normal). Anastomotic complications (odds ratio [OR]: 8.6–24, 95% confidence interval [CI]: 1.7–260, P = 0.011–0.008), age (OR: 20, 95% CI: 1.3–310, P = 0.034), low distal esophageal body pressure (OR: 2.6, 95% CI: 0.7–10, P = 0.002), and defective esophageal peristalsis (OR: 2.2, 95% CI: 0.4–11, P = 0.014) predicted development of epithelial metaplasia. Conclusions:Significant esophageal morbidity associated with EA extends into adulthood. Surgical complications, increasing age, and impaired esophageal motility predict development of epithelial metaplasia after repair of EA.

Does Fecal Calprotectin Predict Short-Term Relapse After Stopping Tnfα-Blocking Agents In Inflammatory Bowel Disease Patients In Deep Remission?

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 Crohns 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.

Mucosal healing at 3 months predicts long-term endoscopic remission in anti-TNF-treated luminal Crohn's disease

Abstract Background and aims. Studies performed on patient and disease characteristics predicting the treatment response in tumor necrosis factor alpha antibody (anti-TNF)-treated Crohns disease (CD) have generally been based on clinical data. Only a few studies have assessed the role of endoscopy as a predictor for long-term response for anti-TNF therapy. Our aim was to evaluate the role of early endoscopy in predicting the long-term endoscopic response to anti-TNF in active luminal CD in a clinical setting. Patients and methods. Forty-two patients with active luminal CD, treated for at least 3 months with anti-TNF, either adalimumab (52%) or infliximab (48%), were included in this prospective study. Data on the simple endoscopic score for Crohns disease (SES-CD) at 3 months after therapy commencement, and either data on the SES-CD or surgery after 1 year, were available for all patients. Endoscopic remission was defined as SES-CD 0−2. Results. At 3 months after commencing anti-TNF therapy, 10 patients (24%) were in endoscopic remission. Thirty-three patients continued anti-TNF as maintenance therapy. At 1 year, endoscopic remission (11/33, 33%) was significantly more common in those patients who had been in endoscopic remission at 3 months, compared with those with endoscopically active disease at 3 months (7/10, 70% vs. 4/23, 17%, p = 0.01). The 3-month SES-CD had a sensitivity of 88%, and specificity of 64%, to predict 1-year endoscopic remission in patients who received anti-TNF maintenance therapy. Conclusions. In anti-TNF-treated active luminal CD mucosal healing at 3 months is a strong predictor for long-term endoscopic response.

Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: A case–control observational study based on registry data

Patients with long‐standing inflammatory bowel disease (IBD) have an increased risk for colorectal carcinoma (CRC). Earlier studies suggest that the severity of inflammation is an independent risk factor for CRC in ulcerative colitis (UC). We investigated the role of histological inflammation as a risk factor for colorectal dysplasia or CRC to better target dysplasia surveillance in IBD. By combining our hospital patient registry and pathology database between 1996 and 2008, we identified 183 IBD patients with dysplasia or CRC. The control group was collected from our registry of IBD patients. Histological severe inflammation was present in 41.4% of patients with dysplasia and in 24.1% of patients with CRC, but in only 4.3% of controls. Severe inflammation had an odds ratio (OR) of 31.8 [95% confidence interval (CI): 15.6–64.9] for dysplasia or carcinoma compared to patients with no inflammation. Among patients with mild to moderate inflammation, the OR was 2.6 (95% CI: 1.6–4.1). Disease duration increased the annual risk for dysplasia or CRC by 4.5%. Coexisting primary sclerosing cholangitis (PSC) did not elevate the risk, whereas use of thiopurines (OR = 0.09, 95% CI: 0.02–0.33) and also 5‐aminosalicylic acid (OR 0.17, 95% CI: 0.017–1.01) protected against CRC. As conclusion, degree of inflammation and duration of disease cumulatively increase the risk for dysplasia and CRC. PSC was not identified as a risk factor. We demonstrated that use of thiopurines strongly protects against CRC. These results can be applied to better target dysplasia surveillance in IBD patients.

Increasing incidence of inflammatory bowel diseases between 2000 and 2007: A nationwide register study in Finland

Background: The incidence of inflammatory bowel disease (IBD) is high in Western countries, but during the last decade the figures have stabilized, or only slightly increased; at the same time, an increasing incidence rate has been observed in Eastern Europe and Asia. The purpose of this study was to estimate the incidence of IBD in Finland between 2000 and 2007. Methods: New IBD cases between 2000–2007 were retrieved from the national database of special reimbursements for drugs costs. The register includes virtually all Finnish IBD patients since 1986. The incidence rates were calculated per 100,000 persons assuming a Poisson distribution. Results: In total, 14,214 IBD patients were identified; 10,352 had ulcerative colitis (UC) and 3,862 had Crohns disease (CD). During the whole study period the mean annual incidence of IBD per 100,000 was 34.0: in CD 9.2 and in UC 24.8. The incidence of UC was notably higher in males (27.8) than in females (21.9). In CD the incidence rates did not differ significantly between genders. The incidence of UC increased from 22.1 in 2000–2001 to 27.4 in 2006–2007. The incidence of CD increased only slightly. Conclusion: In Finland, the incidence of IBD is high, and UC is almost three times more common than CD. During the new millennium the incidence rate of UC has increased, while the incidence rate of CD has remained fairly stable. To the best of our knowledge, the incidence of UC in this nationwide register study is one of the highest reported to date. (Inflamm Bowel Dis 2012;)

Endoscopic monitoring of infliximab therapy in Crohn's disease†

Background: So far, infliximab (IFX) therapy for the treatment of Crohns disease (CD) has generally been guided by clinical symptoms. Data on treatment response as ascertained by endoscopy in IFX therapy are scarce. The aims of this study were to measure the endoscopic response rate during IFX induction and maintenance therapy in luminal CD, and also evaluate the role of endoscopy in monitoring IFX therapy. Methods: Data obtained from 71 patients with active luminal CD and treated with IFX were analyzed retrospectively. The endoscopy findings were scored according to mucosal activity as: 0 (remission), 1–2 (mild), 3–4 (moderate), and 5–6 (severe). A positive endoscopic response was determined by a decrease in score of at least two points and mucosal healing was assigned a score of between 0–2. Results: At baseline all patients presented with moderate or severe luminal inflammation. A positive endoscopic response occurred in 73% of patients at 3 months and when IFX was continued, the endoscopic response was maintained in 77% of these patients at 12 months. Mucosal healing at first follow‐up endoscopy was documented in 45% of patients and was highly predictive for its persistence at 12 months, maintained in 90% of patients, when IFX was continued. Conclusions: Endoscopy at 3 months from the start of IFX therapy helps to predict responders to IFX for maintenance therapy in active luminal CD. (Inflamm Bowel Dis 2011)

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.

Human herpesvirus 6 and cytomegalovirus in ileocolonic mucosa in inflammatory bowel disease

Abstract Objectives. Reactivation of a latent cytomegalovirus (CMV) may occur in inflammatory bowel disease (IBD). Data of human herpesvirus 6 (HHV-6)—a close relative to CMV—in active IBD are scarce. The aim of this study was to detect HHV-6 and CMV antigens in the mucosa of active and inactive IBD. Material and Methods. 79 IBD patients (47 ulcerative colitis (UC) and 32 Crohns disease (CD)) were recruited and endoscopic and histological disease activity was scored. Control group consisted of 15 non-IBD patients with normal colonoscopy. Immunohistochemical stainings for HHV-6B and CMV antigens were performed on biopsy specimens from the ileum and colorectum. The intensity of HHV-6B and CMV expression was graded as negative, mild, moderate, or intense. Results. HHV-6B antigen was positive in 35 (44%) and CMV in 64 (81%). Of controls, 6 (40%) were mildly positive for HHV-6 and 6 (40%) for CMV. In IBD, both CMV and HHV-6B intensity correlated with endoscopic disease severity (CMV p = 0.010 and HHV-6 p = 0.048). Simultaneous HHV-6B and CMV antigen expression occurred in 29 (37%) and associated with endoscopic activity (p = 0.006) and to a number of immunosuppressives (p = 0.033). A significant difference in HHV-6B positivity was found between endoscopically active and inactive UC (p = 0.040). Both CMV and HHV-6B intensity correlated with histological severity in the rectal biopsy specimens (for CMV p = 0.040 and for HHV-6B p = 0.027). Conclusions. Both viruses occurred ubiquitously in the IBD mucosa. Coexistence of viruses was common and associated with disease activity and use of immunosuppressives. HHV-6B intensity correlated with endoscopic severity in UC.

Effect of steatosis and inflammation on liver fibrosis in chronic hepatitis C

Background/Aims: The role of liver biopsy has been questioned in the management of patients with hepatitis C viral (HCV) infection. The aims of this study were to determine the impact of clinical parameters and degree of inflammation and steatosis on liver fibrosis.