Low-dose Methotrexate Therapy Does Not Affect Semen Parameters and Sperm DNA.

BACKGROUND: Methotrexate is widely used in inflammatory diseases during the patients' reproductive years. The effect on male fertility and sperm DNA integrity is largely unknown. We evaluated sperm DNA integrity and basic semen parameters according to the World Health Organization (WHO) in male patients with inflammatory diseases treated with methotrexate. METHODS: Semen samples from 14 patients on low-dose maintenance methotrexate were compared with samples from 40 healthy volunteers. Further, 5 patients delivered samples on and off methotrexate therapy for paired comparison. Sperm DNA fragmentation index (DFI), concentration, motility, and morphology were evaluated. Blood sex hormones and methotrexate levels were measured in blood and semen. RESULTS: DNA fragmentation index in methotrexate-treated patients was comparable with that in healthy volunteers (DFI, 11.5 vs 15.0; P = .06), and DFI did not change significantly on and off methotrexate in the paired samples (DFI, 12.0 vs 14.0; P = 0.35). Sperm concentration, motility, and morphology did not differ between men treated with methotrexate and healthy volunteers. Sperm progressive motility increased off therapy compared with on therapy (65.0% vs 45.0%, P = .04), but all fluctuations in progressive motility were within the WHO reference interval. All methotrexate polyglutamates1-5 were detected in blood, but only methotrexate polyglutamate1 in semen. Serum testosterone was unaffected by methotrexate therapy. CONCLUSIONS: Patients treated with low-dose methotrexate have a sperm quality comparable with that of healthy volunteers, and methotrexate treatment does not increase sperm DNA fragmentation. This study does not support cryopreservation of semen before treatment initiation nor a 3-month methotrexate-free interval prior to conception.

Adalimumab in the treatment of chronic pouchitis. A randomized double-blind, placebo-controlled trial.

BACKGROUND: Pouchitis is a complication of ileal pouch-anal anastomosis and occurs in up to 50% of patients 10 years after IPAA with 10% developing refractory pouchitis. OBJECTIVE: To evaluate the effect of a TNF-α inhibitor (Adalimumab) in the treatment of refractory pouchitis. MATERIALS AND METHODS: A multicenter, randomized double-blind, placebo-controlled trial includes patients with refractory pouchitis for more than 4 weeks despite antibiotic treatment. Patients were randomized to Adalimumab or placebo for 12 weeks. Primary outcome was reduction in clinical pouchitis disease activity index (PDAI) of ≥2 at any time. Secondary endpoints were remission of pouchitis, endoscopic and histologic effect and quality of life. RESULTS: Thirteen patients were included; six patients received active treatment and seven patients received placebo. Nine patients (5/4, Adalimumab/placebo) completed the 12-week program. Reduction in clinical PDAI ≥ 2 was achieved in three patients in each group (50%/43%, Adalimumab/placebo, p > .5). Total PDAI improved in six patients treated with Adalimumab and two patients on placebo (100%/29%, p = .13). There were no differences in secondary endpoints between the groups. CONCLUSIONS: In this randomized controlled trial of treatment with Adalimumab in patients with refractory pouchitis, we were not able to identify any clinical benefit in the primary or secondary endpoints.

Sperm DNA Integrity is Unaffected by Thiopurine Treatment in Men With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Sperm DNA integrity, concentration, and motility are suspected to be altered by thiopurines (azathioprine [AZA] and 6-mercaptopurine [6-MP]). We investigated the impact of thiopurines on semen quality in men with inflammatory bowel disease [IBD], by a comprehensive panel of semen analyses. METHODS: Semen from 40 men with IBD, in remission on AZA/6-MP therapy, was prospectively collected and compared with samples from 40 healthy volunteers. Paired samples [off and on AZA/6-MP] were obtained from a subset of IBD patients, and blood and semen were collected to determine 6-MP transmission to the ejaculate. Sperm DNA fragmentation was evaluated via sperm chromatin structure assay [SCSA] and Comet analysis. Conventional World Health Organization [WHO] parameters, i.e. semen volume and sperm concentration, motility, and morphology, were assessed. Additionally, we measured thioguanine nucleotide [TGN] incorporation in sperm cell DNA. RESULTS: Sperm DNA fragmentation levels did not differ between men with IBD on AZA/6-MP and healthy volunteers when evaluated by SCSA [p = 0.23] and Comet analysis [p = 0.72]. IBD patients on AZA/6-MP had significantly lower total and progressive sperm motility than healthy volunteers [48.5% versus 64.5%, p = 0.0003; 27.4% versus 43.3%, p = 0.0004; respectively], with no differences in concentration, volume, or morphology. The same trend was observed in the 10 paired samples. TGN incorporation was not detectable in sperm DNA, but 6-MP was detected in seminal plasma and correlated to blood levels [rs = 0.79, p = 0.02]. CONCLUSIONS: Thiopurines do not increase sperm DNA fragmentation but may impair sperm motility in this IBD cohort. Our findings support existing epidemiological data that thiopurine therapy is safe during preconception and should not be abandoned.

Semen Quality and Sperm DNA Integrity in Patients With Severe Active Inflammatory Bowel Disease and Effects of Tumour Necrosis Factor-alpha Inhibitors.

BACKGROUND AND AIMS: The impact of severe inflammation on semen quality, including sperm DNA integrity, in men with inflammatory bowel disease [IBD] is unknown, as are the potential effects of anti-tumour necrosis factor-alpha [TNF-alpha] therapy. We investigated the influence of severe active IBD and anti-TNF-alpha treatment on semen quality. METHODS: We prospectively included 20 patients admitted with severe active IBD. Further, 19 patients who initiated and 17 who stopped anti-TNF-alpha therapy were included. Semen samples were obtained during active disease, and on/off treatment. For paired comparisons, samples were collected not less than 3 months after achieving remission, after treatment initiation, or after treatment cessation. Sperm DNA Fragmentation Index [DFI], concentration, morphology, and motility were evaluated. Sex hormones and seminal plasma anti-TNF-alpha drug levels were measured. RESULTS: In patients with severe disease, progressive sperm motility was impaired and increased significantly [from 28.4% to 37.4%, p = 0.045] during remission. There was no difference in DFI [12.5% versus 12.0%, p = 0.55], concentration [55.0 mill/ml versus 70.0 mill/ml, p = 0.39], or normal morphology [4.7% versus 5.1%, p = 0.51] in these patients. During active disease, testosterone was decreased, and normalised after obtaining remission. Patients who started anti-TNF-alpha therapy had a statistically significant, but clinically irrelevant, reduction in DFI after treatment initiation [12.8% versus 10.0%, p = 0.02]. All other semen parameters were unaffected by therapy. Anti-TNF-alpha drugs were excreted in negligible amounts in semen. CONCLUSIONS: Severe active IBD reduces progressive sperm motility and testosterone levels, but sperm DNA integrity is unaffected by active disease. Anti-TNF-alpha therapy does not impair sperm quality.

Adherence and quality of care in IBD.

OBJECTIVE: In inflammatory bowel disease (IBD), adherence to both medical treatment and other aspects of care has a substantial impact on the course of the disease. Most studies of medical adherence have reported that 30-45% of patients with IBD were non-adherent. Our study aimed to investigate the different aspects of adherence and to identify predictors of non-adherence, including the quality of care, for outpatients with IBD. MATERIALS AND METHODS: An anonymous electronic questionnaire was used to investigate different aspects of adherence, the quality of care, patient involvement and shared decision making among 377 IBD outpatients. RESULTS: Three hundred (80%) filled in the questionnaire. The overall adherence rate was 93%. Young age (< 35 years old) and smoking were significantly associated with non-adherence (prevalence odds ratio (POR) 2.98, 95% CI 1.04-8.52, p < 0.05 and POR 3.88, 95% CI 1.36-11.05, p < 0.05, respectively). The lowest medical adherence rates were found for 5-ASA and topical treatments among patients with inactive disease. A large majority of patients stated that treatment strategies were agreed upon as a shared decision between the patient and the health care professionals. CONCLUSIONS: Predictors for non-adherence were young age and smoking. High adherence rates could be explained by a high patient satisfaction and a high degree of shared decision making.

Self-reported adherence to medical treatment, breastfeeding behaviour, and disease activity during the postpartum period in women with Crohn's disease.

OBJECTIVES: Adherence to medical treatment among women with Crohn's disease (CD) in the postpartum period has never been examined. The impact of breast-feeding on disease activity remains controversial. We aimed to assess rates of non-adherence to medical treatment among women with CD in the postpartum period. Further, to assess breast-feeding rates and the impact of breast-feeding on the risk of relapse. METHODS: Within a population of 1.6 million, we identified 154 women with CD who had given birth within a 6-year period. We combined questionnaire data, data from medical records and public register data. We used logistic regression to estimate prevalence odds ratios (POR) for non-adherence, relapse and breast-feeding according to different predictors. RESULTS: Among 105 (80%) respondents, 59 (56%) reported taking medication. Of these, 66.1% reported to be adherent to medical treatment. Fear of medication transmission to the breast milk was stated as the reason for non-adherence in 60%. Those who received counselling regarding medical treatment were less likely to be non-adherent (POR 0.55, 95% confidence interval [CI] 0.1-2.5). In total, 87.6% were breast-feeding. Breast-feeding rates did not vary by medical treatment. Predictors for relapse in CD were smoking (POR 1.85, 95% CI 0.62-5.54) and non-adherence among medical treated (POR 1.25, 95% CI 0.26-6.00). Breast-feeding seemed protective against relapse (POR 0.33, 95% CI 0.10-1.26). CONCLUSIONS: Adherence to medical treatment in the postpartum period was high, and counselling seemed to increase adherence. Relapse may be explained by non-adherence or smoking while breast-feeding seemed protective.

Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn's disease.

OBJECTIVE. Little is known about predictors for adverse pregnancy outcomes among women with Crohn's disease (CD). In this population-based study, we examined pregnancy outcomes in CD stratified by medical treatment and smoking status while accounting for disease activity. METHODS. In two Danish regions with a population of 1.6 million, we identified 154 CD women who had given birth within a 6-year period. We combined questionnaire data, prescription data, data from medical records and population-based medical databases. We used logistic regression to estimate prevalence odds ratios (POR) for adverse pregnancy outcomes by different predictors. RESULTS. Among 105 (80%) respondents, 55 (52%) reported taking medication during pregnancy. The majority (95%) were in disease remission. The children's mean birth weight did not differ by maternal medical treatment. As expected, smoking was a predictor of low birth weight. Mean birth weight in children of smokers in medical treatment was significantly reduced by 274 g compared with children of non-smokers who received medical treatment. In children of women without medical treatment, this difference was 126 g between smokers and non-smokers. Women in medical treatment did not have an increased risk of preterm delivery (POR 0.71; 95% confidence interval (CI) 0.18-2.79), congenital malformations (POR 0.60; 0.10-3.76) or cesarean section (POR 1.40; 0.63-3.08). CONCLUSIon. In CD, smoking was negatively associated with child birth weight. This association was most pronounced among women who received medical treatment. Maternal medical treatment for CD did not seem to be a risk factor for adverse pregnancy outcomes.

Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial.

OBJECTIVE: Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. DESIGN: Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohn's Disease Activity Index (CDAI) decrease ≥ 70, or ≥ 50% reduction in active fistulas) and accumulated costs related to treatment of Crohn's disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. RESULTS: Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: € 6038 vs € 9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (-19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€ 4062 vs € 9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference -5% (-33% to 22%)). CONCLUSIONS: Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. TRIAL REGISTRATION NO: NCT00851565.

Active Crohn's disease is associated with low vitamin D levels.

BACKGROUND AND AIMS: Crohn's disease prevalence increases with increasing latitude. Because most vitamin D comes from sunlight exposure and murine models of intestinal inflammation have demonstrated beneficial effects of 1,25-(OH)2 vitamin D treatment, we hypothesised that Crohn's disease activity is associated with low vitamin D levels. METHODS: In a cross-sectional study of 182 CD patients and 62 healthy controls, we measured serum 25-OH vitamin D. Stratified analysis was used to compare 25-OH vitamin D levels with Crohn's disease activity index, C-reactive protein, smoking status, intake of oral vitamin D supplements and seasonal variation in CD patients and healthy controls. RESULTS: Serum 25-OH vitamin D was inversely associated with disease activity: Median 25-OH vitamin D levels of Crohn's disease in remission, mildly, and moderately active diseases evaluated by Crohn's disease activity index were 64, 49, and 21 nmol/l (p<0.01) and by CRP 68, 76, and 35 nmol/l (p<0.05), respectively. Patients who took oral vitamin D supplementation had lower Crohn's disease activity index (p<0.05) and C-reactive protein (p=0.07) than non-users. Crohn's disease patients who smoked had lower vitamin D levels (51 nmol/l) than patients who did not smoke (76 nmol/l), p<0.01. Overall, Crohn's disease patients did not differ from healthy controls regarding 25-OH vitamin D levels. CONCLUSIONS: Active Crohn's disease was associated with low serum 25-OH vitamin D. Patients who smoked had lower 25-OH vitamin D levels than patients who did not smoke, independently of disease activity.

First-time urea breath tests performed at home by 36,629 patients: a study of Helicobacter pylori prevalence in primary care.

BACKGROUND: The aim of the current study was (1) to describe the use of a (13) C-urea breath test (UBT) that was performed by patients at their homes as a part of a test-and-treat strategy in primary care and (2) to investigate the prevalence of Helicobacter pylori in patients taking a first-time UBT. MATERIAL AND METHODS: The patients performed UBTs at home based on the discretion of the general practitioner and mailed the breath bags to a central laboratory for analysis. Each patient was identified by a unique civil registration number. The study was population-based, and the background population was approximately 700,000 people. RESULTS: From 2003 to 2009, 44,487 UBTs were performed. Of these, 36,629 were first-time UBTs. In total, 726 of 45,213 breath bags received (1.6%) were unable to be analyzed because of errors with the bags. For both women and men who were ≤ 45 years of age, positive H. pylori declined over the time course of the study (women: 19.6% in 2003 to 17.6% in 2009, p < .01; men: 20.7% in 2003 to 16.9% in 2009, p < .001). Patients who were older than 45 years had significantly higher positive H. pylori results than younger patients. CONCLUSIONS: A test-and-treat system was possible to implement that allowed patients to perform UBTs at their homes. The results of the first-time UBTs demonstrated that approximately one of five patients who presented with dyspepsia in the clinical setting of Danish primary care was infected with H. pylori.

Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis.

BACKGROUND: Adherence to medical treatment among women with ulcerative colitis (UC) prior to and during pregnancy has never been investigated. The aim was to examine predictors for and prevalence rates of nonadherence to maintenance treatment among women with UC prior to and during pregnancy. METHODS: We identified 115 women with UC having given birth during 2000-2005 within a population of 1.6 million. They received a questionnaire about predictors and adherence and relapses were registered. We retrieved information on medical treatment from prescription databases and used logistic regression to estimate prevalence odds ratios (POR) for nonadherence by different predictors. RESULTS: Among 93 (81%) respondents, 63 (68%) reported taking medication, 53 of whom had filled prescriptions for relevant medication, yielding a positive predictive value of self-reported use of medical treatment of 84.1% (95% confidence interval [CI] 72.7-92.1). Approximately 60% reported adhering to medical treatment. Those who received counseling regarding medical treatment were less likely to be nonadherent compared with no counseling, especially during pregnancy (POR 0.2, 95% CI 0.04-0.94). Of those who were nonadherent, fear of a negative effect on fertility/fetus was stated as the reason by 23% prior to and by 50% during pregnancy. Notably, 40.3% reported an episode of relapse during the pregnancy period, compared with 13.6% in the period 6 months prior to pregnancy. CONCLUSIONS: Adherence was high despite fear of a negative effect on fertility or the fetus. Counseling predicted higher adherence. This may be important because our study suggests an increase in UC activity during pregnancy.

Treatment of acute ulcerative colitis with infliximab, a retrospective study from three Danish hospitals.

BACKGROUND: In acute steroid-refractory ulcerative colitis, rescue therapy with infliximab has become a therapeutic option in patients facing colectomy. Data on efficacy and safety in this setting are sparse. METHODS: Patients with ulcerative colitis and acute and severe steroid-refractory disease, who were given infliximab as rescue therapy, were identified by a review of patients' records and databases of infliximab-treated patients. Data on patient background, concomitant medication, endoscopic and laboratory results, clinical activity and adverse events were collected. RESULTS: Fifty-six patients, all admitted because of high disease activity of short duration, and failing high-dose glucocorticoid treatment, received infliximab treatment and were followed up for a median of 538 days (range 2-1769). Colectomy was avoided in 61% of cases. No fatalities were observed. Concomitant medication at the end of follow-up indicated a low number of relapses in patients without colectomies. CONCLUSIONS: Our results show a lasting benefit of infliximab rescue therapy in 61% of patients with acute, steroid-refractory ulcerative colitis, a low incidence of late colectomies, and low frequency of steroid use in patients who avoided colectomy. High levels of C-reactive protein on admittance and at the first infliximab infusion were associated with colectomy. Our study adds to the growing experience of infliximab treatment of patients with acute, steroid-refractory ulcerative colitis.

Discrete changes in circulating regulatory T cells during infliximab treatment of Crohn's disease.

Deficiency of CD4+CD25+ regulatory T cells (Tregs) may be involved in Crohn's disease (CD) pathogenesis. In rheumatoid arthritis (RA), the anti-TNF-alpha antibody infliximab increases circulating Treg numbers. We aimed to evaluate circulating Tregs in CD before and after infliximab therapy. In 20 patients with active CD, blood samples were obtained before infusion of infliximab 5 mg/kg and 1, 7, and 42 days after therapy. Clinical, biochemical, and fecal markers of inflammation were obtained. Nine healthy volunteers served as controls. We applied a novel Treg marker, the absence of CD127 expression, to identify Tregs by whole-blood flow cytometry. Treg percentages were similar among CD patients [median 7.7%, interquartile range (IQR) 5.3-10.1%] and healthy volunteers (median 7.6% IQR 6.3-8.9%) with discrete changes (median 7.3%, IQR 4.5-10.1%) throughout the study period, irrespective of the significant clinical effect of infliximab. Unlike in RA, we found no arising population of CD62L - Tregs; however, we observed a rapid recruitment of lymphocytes and upregulation of the intestinal homing marker alpha4beta7 integrin on CD4+T cells. In conclusion, our results do not support the hypothesis that the clinical effect of infliximab is mediated by a reinforcement of defective, circulating Tregs in CD.