Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety.

OBJECTIVE: Antitumour necrosis factor (TNF) during pregnancy in patients with IBD is related to high fetal anti-TNF levels. We evaluated maternal and child safety on discontinuing anti-TNF in the second trimester of pregnancy. DESIGN: Two groups of women with IBD were prospectively followed-up during pregnancy: women in sustained remission stopped anti-TNF before week 25 (stop group) and the remaining group continued anti-TNF beyond week 30 (continue group). Maternal, birth and 1-year child outcomes were compared with children of non-IBD women. RESULTS: Overall, 106 patients with 83 completed pregnancies were included. Relapse rate after week 22 did not differ between the stop (n=51) and continue (n=32) groups (5 (9.8%) versus 5 (15.6%), p=0.14). There was no difference in allergic reactions (p=1.00) or loss of response (p=1.00) postpartum between the two groups. Birth outcomes were comparable. Infants from both groups had lower birth weight (p=0.001), shorter gestational term (p=0.0001), were more often delivered via caesarean section (p=0.0001) and were less often breastfed (p=0.0001) compared with infants from non-IBD controls. Growth, infection rate, allergies, eczema and adverse reactions to vaccines were comparable across the stop and the continue groups as well as the children of anti-TNF-exposed and non-IBD women at 1 year. CONCLUSIONS: To limit anti-TNF exposure in utero, anti-TNF can be stopped safely in the second trimester in women with IBD in sustained remission. In patients not in sustained remission, anti-TNF may be continued without clear additional risks to the fetus. We observed excellent 1-year child outcomes compared with children from non-IBD controls.

A prospective study of the safety of lower gastrointestinal endoscopy during pregnancy in patients with inflammatory bowel disease.

INTRODUCTION: Women with inflammatory bowel disease [IBD] have a higher risk of undergoing gastrointestinal [GI] endoscopy during pregnancy than healthy women. Data on endoscopic procedures during pregnancy in IBD women are limited. The aim of this study was to investigate the safety of lower GI endoscopy during pregnancy in IBD women. METHODS: All consecutive IBD women who underwent endoscopy during pregnancy [cases] from 2008-2014 were prospectively included. Cases were matched 1:1 on age, IBD medication, and disease activity with pregnant IBD patients without endoscopy during pregnancy [controls]. Maternal and neonatal outcomes were compared between the cases and controls. Adverse events [AEs] were assessed for a temporal relation and for an aetiological relation with the endoscopy. RESULTS: In total, 42 pregnant IBD patients [19 Crohn's disease, 23 ulcerative colitis] underwent 47 lower GI endoscopies [12 colonoscopies/35 sigmoidoscopies]. Median maternal age was 30 years [interquartile range: 28-32]. Two spontaneous abortions were temporally and probably related to endoscopy; however, spontaneous abortion did not occur more often in cases than in controls (2 [4.8%] vs 10 [23.8%], p 0.01). Median birthweight was significantly lower in the cases compared with controls [3017g vs 3495g, p 0.01]. There were no significant differences in terms of gestational age at birth, congenital abnormalities, or APGAR scores. CONCLUSION: Although lower GI endoscopy in pregnant IBD women should only be performed when strongly indicated, we report no increased adverse outcomes for the mother or the newborn related to endoscopy in any of the three trimesters of pregnancy compared with controls.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

Adalimumab in Crohn's disease patients: pharmacokinetics in the first 6 months of treatment.

BACKGROUND: Adalimumab is an effective therapy for Crohn's disease patients. However, there is limited knowledge on the pharmacokinetic properties of adalilumab in patients with Crohn's disease. AIM: To assess the pharmacokinetic properties of adalilumab in a retrospective clinical cohort of patients with Crohn's disease, naïve to anti-tumour necrosis factor alpha therapy (anti-TNF). METHODS: In a single tertiary centre, a clinical retrospective cohort was formed out of 76 patients with Crohn's disease who started adalilumab treatment (160/80/40EOW) between July 2007 and September 2010. We serially evaluated adalilumab serum levels at week 0, 12 and 28. RESULTS: Patients were followed for a median time of 201 days (range 120-244) and received a median of 14 adalilumab injections (range 6-25). Adalilumab levels, although divergent between patients, were stable between week 12 and week 28. There was no correlation between adalilumab level and time since last administration (r = -0.061). In a multivariable regression analysis of patient factors influencing week 28 adalilumab levels, the regression model containing CRP at week 28 and BMI at baseline weakly but significantly predicted week 28 adalilumab levels (R(2) = 0.193, P = 0.004). Concomitant use of immunosuppressives was not a significant predictor (P = 0.304). CONCLUSIONS: Intra-individual adalilumab levels seem very stable during the first 28 weeks of treatment, whereas inter-individual levels vary. Adalilumab levels appear stable over a 2-week period, as the time since last adalilumab administration did not affect the adalilumab level. CRP and BMI weakly predict week 28 adalilumab levels, whereas the use of immunosuppressives does not.

Impact of the growth hormone replacement on bone status in growth hormone deficient adults.

INTRODUCTION: Growth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated. OBJECTIVES: The objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD. PATIENTS AND METHODS: Adult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2 years. Lumbar spine (L1-L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24. RESULTS: In total, 147 GHD patients (age 35.1 years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2 years, respectively; p<0.0001). Bone markers increased during the first 12 months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p=0.02). BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p=0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p=0.004). CONCLUSION: GH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.

Predictors of dose escalation of adalimumab in a prospective cohort of Crohn's disease patients.

BACKGROUND: Adalimumab is effective for the induction and maintenance of remission in Crohn's disease (CD)-patients. AIM: To find predictors for adalimumab dose escalation at initiation of adalimumab. METHODS: Crohn's disease patients in a single tertiary referral centre who started adalimumab between July 2007 and March 2010 at an induction dose (week 0 160 mg subcutaneously (sc), week 2 80 mg sc) and maintenance dose of 40 mg sc thereafter every other week were followed prospectively. Patients on adalimumab for at least 3 months were included. The number of patients needing dose escalation was assessed. Patients that needed dose escalation were compared with patients that did not need dose escalation. RESULTS: Of 199 CD patients treated with adalimumab and followed prospectively, 122 patients (M/F 54/68, median age 35 years, range 18-66 years, median CDAI 164, range 6-468) were treated for 3 months. In total 38% of these patients (46/122) needed a dose escalation within a median time of 21 weeks after adalimumab introduction (range 4-105). Body mass index (BMI) (P < 0.03) and secondary non-response to infliximab (IFX) (P < 0.06) were identified as predictors for dose escalation. Concomitant use of immunomodulators at initiation of adalimumab and the presence of autoantibodies to IFX did not predict dose escalation. CONCLUSIONS: Over one-third adalimumab-treated patients are dose escalated within a median of 5 months. Higher BMI and secondary non-response to IFX treatment are predictive for a dose escalation during adalimumab treatment.

High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy.

BACKGROUND: Typically, inflammatory bowel disease (IBD) patients are in their reproductive years, raising questions about safely using antitumour necrosis factor antibodies like infliximab (IFX) during pregnancy. IgG antibodies naturally cross the placenta, especially during the last trimester. To prevent foetal intra-uterine exposure, stopping IFX treatment at gestational week 30 is recommended. However, whether this limits intra-uterine and early postnatal IFX exposure is unestablished. AIM: To determine the intra-uterine exposure to IFX following maternal treatment with IFX. METHODS: Four pregnant IBD patients intentionally continued IFX during pregnancy. IFX levels were assessed in newborns' cord blood and the mothers' peripheral blood at delivery. The children's development during the first 3-6 months, infections, vaccine reactions and antibody responses to vaccinations against Haemophilus influenzae type b and Pneumococcus were assessed. RESULTS: The patients stopped IFX therapy at gestational week 21, 26, 26 and 30, respectively. In three infants, therapeutic IFX levels were present in cord blood at levels of 5.5-13.7 µg/mL and were two- to three-fold higher than in the peripheral blood of their mothers. During the 3- to 6-month follow-up, the children developed normally without signs of infections or allergic reactions, and had normal antibody titres after routine childhood vaccinations. CONCLUSION: The use of IFX until gestational week 30 leads to foetal intra-uterine exposure to IFX at levels that exceed those in the mothers' peripheral blood. Although no short-term complications were detected, the high IFX levels observed in newborns raise concerns about unknown effects of IFX on the developing immune system.

High therapy adherence but substantial limitations to daily activities amongst members of the Dutch inflammatory bowel disease patients' organization: a patient empowerment study.

BACKGROUND: Adherence is important for successful treatment in inflammatory bowel disease (IBD) patients. Previous studies demonstrated high prevalence of non-adherence. AIM: To assess IBD-patients' perceptions of therapy adherence and disease-related functional status in members of the Dutch patients' association of Crohn's disease and ulcerative colitis (CCUVN). METHODS: Inflammatory bowel disease-patients completed anonymously a survey at the website of the CCUVN. Statistical analysis was performed using principal component analysis, univariate and multivariate logistic regression. RESULTS: The questionnaire was completed by 1067 patients [617 (58%) Crohn's disease (CD) and 450 (42%) ulcerative colitis (UC)]. Mean age was 43 years (s.d. 13.7); women (66%). Of 920 patients currently using medication, 797 (87%) were adherent. Of the patients using 5-ASA, 91% were adherent (527/582), vs. 96% using corticosteroids (316/330) and 97% (414/425) using immunosuppressives. CD patients (OR 1.54; 95% CI 1.05-2.27), patients with duration of disease

Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease.

BACKGROUND: Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance. AIM: To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab. METHODS: A retrospective study was performed. Patients with active Crohn's disease and who had lost response or were intolerant to infliximab were treated with adalimumab. Clinical response and side effects were assessed as were serum ATAs and antibodies to infliximab (ATIs). RESULTS: In total 30 patients [M/F (7/23)], median age 36 years (range 21-73) were treated with adalimumab for 318 days (median range 83-632). Clinical response was 77% (23/30), a dose escalation was necessary in eight (27%) patients and side effects were observed in 47% (14/30). In five patients (17%) ATAs were detected; of these patients, four were nonresponders. The presence of ATAs was related to nonresponse to adalimumab (P = 0.006). ATIs were positive in 57% of patients (17/30) and serum levels were significantly increased in adalimumab nonresponders (P = 0.01). CONCLUSION: Immunogenicity plays a role in adalimumab treatment because of the development of ATAs.

Occurrence of 3-MCPD fatty acid esters in human breast milk.

A series of twelve breast milk samples were analysed by gas chromatography-mass spectrometry (GC/MS) operated in selected ion monitoring mode for 3-chloropropane-1,2-diol (3-MCPD). Whilst none of the samples contained 3-MCPD above the limit of detection of 3 microg kg(-1) milk, all contained high amounts of 3-MCPD esterified with higher fatty acids. The levels of 3-MCPD released by hydrolysis of these esters (bound 3-MCPD) ranged from the limit of detection (300 microg kg(-1), expressed on a fat basis) to 2195 microg kg(-1); with a mean level of bound 3-MCPD of 1014 microg kg(-1), which corresponded to 35.5 microg kg(-1) milk. The presence of bound 3-MCPD was confirmed using orthogonal gas chromatography coupled with high-speed time-of-flight mass spectrometry analysis for four randomly selected breast milk samples. Six breast milks collected from one of the nursing mothers 14-76 days after childbirth contained bound 3-MCPD within the range of 328-2078 microg kg(-1) fat (mean 930 microg kg(-1) fat). The calculated bound 3-MCPD content of these samples was within the range of 6 and 19 microg kg(-1) milk (mean of 12 microg kg(-1) milk). The major types of 3-MCPD esters were the symmetric diesters with lauric, palmitic, and oleic acids, and asymmetric diesters with palmitic acid/oleic acid among which 3-chloro-1,2-propanediol 1,2-dioleate prevailed.

Fatty acid esters of 3-chloropropane-1,2-diol in edible oils.

A series of 25 virgin and refined edible oils, obtained from retailers, was analyzed for levels of free 3-chloropropane-1,2-diol (3-MCPD) and 3-MCPD released from esters with higher fatty acids (bound 3-MCPD). Oils containing free 3-MCPD ranging from <3 microg kg-1 (LOD) to 24 microg kg-1. Surprisingly, bound 3-MCPD levels were much higher and varied between <100 (LOD) and 2462 microg kg-1. On average, virgin oils had relatively low levels of bound 3-MCPD, ranging from <100 (LOD) to <300 microg kg-1 (LOQ). Higher levels of bound 3-MCPD were found in oils from roasted oilseeds (337 microg kg-1) and in the majority of refined oils (<300-2462 microg kg-1), including refined olive oils. In general, it appears that the formation of bound 3-MCPD in oils is linked to preliminary heat treatment of oilseeds and to the process of oil refining. Analysis of unrefined, de-gummed, bleached, and deodorized rapeseed oil showed that the level of bound MCPD decreased during the refining process. However, additional heating of seed oils for 30 min at temperatures ranging from 100 to 280 degrees C, and heating at 230 degrees C (260 degrees C) for up to 8 h, led to an increase in bound 3-MCPD levels. On the other hand, heating of olive oil resulted in a decrease in bound 3-MCPD levels. For comparison, fat isolated from salami was analyzed for intact fatty acid esters of 3-MCPD. This fat contained bound 3-MCPD at a level of 1670 microg kg-1 and the fatty acid esters of 3-MCPD mainly consisted of 3-MCPD diesters; monoesters of 3-MCPD were present in smaller amounts. The major types of 3-MCPD diesters (about 85%) were mixed diesters of palmitic acid with C18 fatty acids (stearic, oleic, linoleic acids). These diesters were followed by 3-MCPD distearate (11%) and 3-MCPD dipalmitate (4%). Generally, very little 3-MCPD existed as the free compound (31 microg kg-1).

Volatile degradation products of l-dehydroascorbic acid.

Volatile degradation products were isolated from a solution of L-dehydroascorbic acid in phosphate buffer solution of pH 2,4,6 and 8 heated under reflux for 3 h or left at 25 degrees C for 200 h. The products were identified by comparison of their gas chromatographic retention data, infra-red and mass spectra with those of authentic compounds. Fifteen products were identified, among which 12 had not yet been reported as degradation products of L-dehydroascorbic acid. Concentrations of 5 main degradation products, i.e. 3-hydroxy-2-pyrone, 2-furancarboxylic acid, 2-furaldehyde, acetic acid and 2-acetylfuran depended on the pH values and temperature; the presence of oxygen had no pronounced effect.