Use of biological molecules in the treatment of inflammatory bowel disease.

The introduction of biological agents (i.e. antitumour necrosis factor-α and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn's disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the 'trough-level strategy' may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient's lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-α agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed.

Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. METHODS: Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7α-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. RESULTS: Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41-138] to 99 pg/mL (IQR: 67-147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54-512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42-79); 90 min: 48 pg/mL [IQR: 37-63); 150 min: 57 pg/mL (48-198)]. Receiver operating characteristics (ROCAUC ) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α-hydroxy-4-cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. CONCLUSIONS: The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.

Chloride-dependent amino acid transport in the small intestine: occurrence and significance.

The unidirectional influx of amino acids, D-glucose and ions across the brush-border membrane of the small intestine of different species has been measured in vitro with emphasis on characterization of topographic and species differences and on chloride dependence. The regional differences in transport along the small intestine are outlined and shown to be caused by variation in transport capacity, while the apparent affinity constants are unchanged. Rabbit small intestine is unique by exhibiting maximal rates of transport in the distal ileum and a very steep decline in the oral direction from where tissues are normally harvested for preparation of brush-border membrane vesicles. Transport in the guinea pig and rat is much more constant throughout the small intestine. Since the capacity of nutrient carriers is regulated by their substrates it is possible that bacterial breakdown of peptides and proteins in rabbit distal ileum increases the concentration of amino acids leading to an upregulation of the carriers. Chloride dependence is a characteristics of the carrier rather than the transported amino acid, and is used to improve the classification of amino acid carriers in rabbit small intestine. In this species the imino acid carrier, the beta-amino acid carrier, and the beta-alanine carrier, which should be renamed the B0,+ carrier, are chloride-dependent. The steady-state mucosal uptake of classical substrates for these carriers in biopsies from the human duodenum is also chloride-dependent. The carrier of beta-amino acids emerges as ubiquitous and chloride-dependent, and evidence of cotransport with both sodium and chloride is reviewed. A sodium:chloride:2-methyl-aminoisobutyric acid coupling stoichiometry of approx. 2:1:1 is suggested by ion activation studies. Direct measurements of coupled ion fluxes in rabbit distal ileum confirm that sodium, chloride and 2-methyl-aminoisobutyric acid are cotransported on the imino acid carrier with an identical influx stoichiometry. Control experiments and reference to the literature on the electrophysiology of the small intestine exclude alterations of the membrane potential as a feasible explanation of the chloride dependence. Thus, it is concluded that chloride is cotransported with both sodium and 2-methyl-aminoisobutyric acid across the brush-border membrane of rabbit distal ileum.

Transport of glycine and lysine on the chloride-dependent beta-alanine (B0,+) carrier in rabbit small intestine.

Transport of glycine, lysine and beta-alanine in rabbit, guinea pig and rat small intestine has been examined by measurements of the unidirectional influx across the brush border membrane of the intact epithelium. In rabbit distal ileum the chloride-dependent fraction of glycine transport, and all sodium- and chloride-dependent lysine transport is carried on the beta-alanine carrier. Lysine eliminates all saturable, sodium-independent transport of glycine. The saturable, sodium-dependent, and lysine resistant influx of glycine is characterized by a K1/2Gly of 60 mM. Glycine transport in the mid intestine of the guinea pig is chloride-independent and in the rat only a minute fraction may be chloride-dependent. These species do not possess an equivalent of the rabbit beta-alanine carrier. In conclusion, glycine transport in rabbit distal ileum is by the sodium-dependent carrier of neutral amino acids, by the sodium-independent lysine carrier, and by the sodium- and chloride-dependent beta-alanine carrier which closely resembles the B0,+ carrier described in mouse blastocysts. All sodium dependent lysine transport in rabbit distal ileum is by the chloride- and sodium-dependent beta-alanine carrier. It is proposed that the beta-alanine carrier in rabbit distal ileum be renamed the B0,+ carrier.

The rabbit jejunal 'imino carrier' and the ileal 'imino acid carrier' describe the same epithelial function.

For rabbit jejunal brush border vesicles an 'imino carrier' has been defined as a sodium-dependent, alanine-resistant transporter of cyclic imino acids, while for intact rabbit jejunal and ileal epithelia an 'imino acid carrier' has been defined as a sodium-dependent transporter of both aliphatic and cyclic imino acids. This study on intact rabbit intestine examines whether these two terms describe the same epithelial function. The KPro1/2 and the KProi against JMeAIBmc are identical and so are KMeAIB1/2 and KMeAIBi against JPromc. Likewise, KLeui is the same against the transport of both proline and MeAIB. It is, therefore, concluded that the terms 'imino carrier' and 'imino acid carrier' describe the same epithelial function: A sodium-dependent, relatively high afinity, saturable transporter of both aliphatic and cyclic imino acids. Estimates of the apparent affinity and inhibitory constants for MeAIB, proline and leucine confirm that the jejuno-ileal variation of amino acid transport along the rabbit small intestine is a variation of maximal transport capacity.

Variation in amino acid transport along the rabbit small intestine. Mutual jejunal carriers of leucine and lysine.

The jejuno-ileal variation of amino and imino acid transport across the brush-border membrane of intact rabbit small intestine was studied. For the amino acids tested--beta-alanine, leucine, lysine, MeAIB, proline--and for D-glucose, the rates of transport at constant concentrations increase from very low values in the proximal jejunum to maximum values in the most distal 30 cm of the ileum. The apparent affinity constant for jejunal taurine transport is identical to that of the distal ileum, while the jejunal transport capacity is less than half. In the jejunum, as in the distal ileum, leucine and lysine share both sodium-dependent and sodium-independent carriers. Approx. 50% of the quantitative difference in transport capacity is accounted for by the absence of the beta-alanine carrier in the jejunum. These data indicate that the gradients of transport along the small intestine reflect gradients of transport capacities rather than affinities. In comparison with hamster, man and rat, the rabbit seems unique with respect to the location of transport maximum and the steepness of the gradient along the intestine.

Chloride-dependence of amino acid transport in rabbit ileum.

Chloride-dependence of influx across the brush-border membrane of distal rabbit ileum was examined for beta-alanine, 2-methylaminoisobutyric acid (MeAIB), leucine, lysine, proline and D-glucose. Influx of leucine at 2 mM and of D-glucose at 0.5 mM was chloride-independent indicating that substitution of isethionate for chloride has no unspecific effect on sodium gradient driven transport processes. In contrast influx of beta-alanine and MeAIB was totally dependent on the presence of chloride ions. In the absence of chloride, proline transport was reduced to 20% of its control level. This remaining transport can be accounted for by the function of the carrier of alpha-amino-monocarboxylic acids. Transport of leucine at 0.1 mM was reduced by absence of chloride. This is in accordance with the observation of leucine transport by the beta-alanine carrier. The kinetics of chloride and sodium activation of transport of MeAIB were examined at 1 mM MeAIB. Chloride activation was characterized by a Hill coefficient of 1 and a K1/2 of 23.5 mM, and sodium activation by a Hill coefficient of 2 and a K1/2 of 51 mM. Thus cotransport of chloride with an imino acid would be compatible with the known rheogenic nature of this transport. This study adds the imino acid carrier and the beta-alanine carrier to the group of chloride-dependent, epithelial amino acid transport systems.

Baclofen (beta-p-chlorophenyl-gamma-aminobutyric acid) transport across rat jejunum.

Intestinal transport of baclofen (beta-(p-chlorophenyl)-gamma-aminobutyric acid) in the rat has been examined in vitro. Influx of baclofen across the brush-border membrane (JmcBacl) and steady-state accumulation by everted segments of the intestine were measured. JmcBacl could be accounted for as the sum of a saturable process with a maximum rate of approx. 10-20 nmol cm-2 h-1 and a K1/2Bacl of approx. 0.3 mM and a diffusive contribution with a permeability of 0.073 cm h-1. JmcBacl was Na(+)- and Cl(-)-independent. The steady state distribution ratio between the intracellular space of the everted segments and incubation fluid was 1.0 +/- 0.1 (n = 12). Inhibition tests demonstrated that the Na(+)- and Cl(-)-independent, passive, but saturable fraction of baclofen transport can not be mediated by any of the known amino acid carriers of the rat small intestine. Preliminary results suggests that qualitatively baclofen transport in guinea-pig and rabbit is also by facilitated transport.

beta-Amino acid transport in pig small intestine in vitro by a high-affinity, chloride-dependent carrier.

This study describes unidirectional influx of amino acids and D-glucose across the small intestinal brush-border membrane of fully weaned eight week old pigs. Influx is minimal in the duodenum and maximal in the distal and/or mid small intestine. Influx of beta-alanine, taurine and N-methyl-aminoisobutyric acid is chloride-dependent. The activation stoichiometry for taurine influx is 1.0 +/- 0.2 chloride/2.4 +/- 0.3 sodium/1 taurine. Influx of D-glucose, lysine, glycine and glutamate is chloride-independent. An ABC test demonstrates a common beta-amino acid carrier: (a) the apparent affinity constant K1/2Taurine is 44 +/- 13 microM (means +/- S.D.) and the inhibitory constant (KiTaurine) against beta-alanine influx is 41 +/- 5 microM (means +/- S.E.). (b) K1/2beta-alanine is 97 +/- 23 microM and Kibeta-alanine against taurine influx is 160 +/- 22 microM. (c) KiHypotaurine against taurine and beta-alanine influx is 43 +/- 4 (n = 7) and 22 +/- 5 microM (n = 7), respectively. In conclusion, a high affinity, low capacity, sodium- and chloride-dependent carrier of beta-amino acids is present in pig small intestine.

Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year.

INTRODUCTION: Azathioprine is effective for maintenance of remission in Crohn's disease, however, duration of efficacy and the dose response relationship has not been fully evaluated. AIMS: To investigate whether patients kept in remission by azathioprine treatment for >2 years benefit from further treatment, and to explore dose-response relationship. PATIENTS AND METHODS: In an open 12-month trial, patients with inactive Crohn's disease after >2 years (median 37 months) of azathioprine treatment were randomized to azathioprine withdrawal or continued treatment. Primary end point was relapse defined as: (i) Crohn's disease activity index rise >/= 75, and Crohn's disease activity index >150 or (ii) disease activity requiring intervention. RESULTS: Of 29 patients, 28 completed the observation period or relapsed. Eleven of 13 patients (85%) continuing azathioprine remained in remission compared with seven of 15 (47%) observed without azathioprine (P = 0.043). In patients who had been treated with azathioprine >1.60 mg/kg/day the difference was even more pronounced, eight of nine (89%) vs. four of 12 (33%) respectively (P = 0.017). CONCLUSIONS: Patients with Crohn's disease in remission after >2 years of continuous azathioprine treatment will benefit from further continued treatment. Further controlled studies with azathioprine doses <2.0 mg/kg/day are needed.

High mortality by natural and unnatural causes: a 10 year follow up study of patients admitted to a poisoning treatment centre after suicide attempts.

OBJECTIVE: To describe mortality by suicide and other causes of death in a group of patients who attempted suicide, and to identify predictive factors. DESIGN: 10 year follow up study based on records of suicide attempters in 1980. SETTING: Poisoning treatment centre at a general hospital. SUBJECTS: 974 patients aged 15 and over referred to the poisoning treatment centre after deliberate self poisoning. MAIN OUTCOME MEASURES: Death by different causes registered in the Danish death cause register. RESULTS: In 10 years of follow up 306 patients died: 103 by suicide, 131 from natural causes, and 31 by accident; five were murdered, and in 36 cases the cause of death was uncertain. The standard mortality ratio was 550. Cause specific standardised mortality rates were 2960 for suicide, 236 for natural causes, 1256 for accidents, and 5459 for uncertain causes. In a Cox regression analysis, high risk factors for subsequent suicide were: more than one previous suicide attempt (relative risk 2.25), living alone (2.28), and age (1.03 per year). Predictors of death by natural causes were receiving a pension (1.69), drug misuse (2.72), more than one previous suicide attempt (2.25), age (1.06 per year), and male sex (2.49). The group of patients fulfilling at least one high risk criterion for later suicide differed significantly from the rest of the patient group in incidence of suicide, but both sensitivity and specificity were low. CONCLUSIONS: Most patients who attempted suicide were at high risk of succeeding because the risk factors, though significant, are not very specific. A strategy to prevent suicide must be directed toward the majority of those who attempt suicide.

[High mortality from both natural and unnatural causes. A 10-year follow-up of patients admitted to a center for poisoning treatment after attempted suicide]. / Høj dødelighed af naturlige og unaturlige årsager. En tiårs-opfølgningsundersøgelse af patienter indlagt på en forgiftningscentral efter selvmordsforsøg.

While it is well known that suicide rates for suicide attempters are high, mortality rates for all causes needed to be more thoroughly investigated. A Danish 10-year follow-up study of patients who in 1980 were admitted to a poisoning treatment centre after attempted suicide was carried out with the purpose of describing mortality by suicide and other causes of death, and to identify predictive factors. A total of 974 patients aged 15 and over referred to a poisoning treatment centre after deliberate self-poisoning were included in the study. Death by different causes registered in the Danish Death Cause Register was the outcome measure. Over a 10-year follow-up period 306 patients had died; 103 by suicide, 131 from natural causes, 31 by accidents, five were murdered and in 36 cases the cause of death was uncertain. The Standard Mortality Rate (SMR) was 550. The cause-specific SMRs were for suicide 2960, for natural causes 236, for accidents 1256 and for uncertain causes 5459. In Cox-regression analysis high-risk factors for later suicide were more than one previous suicide attempt (relative risk (RR) 2.25), living alone (RR 2.28) and age (RR 1.03 per year). Predictors of death by natural causes were pension (RR 1.69), drug abuse (RR 2.72), more than one previous suicide attempt (RR 2.25), age (RR 1.06 per year) and male sex (RR 2.49). The group of patients fulfilling at least one high-risk criteria for later suicide differed significantly from the rest of the patient group regarding frequency of suicide, but both sensitivity and specificity remain low.(ABSTRACT TRUNCATED AT 250 WORDS)

[Joint charts in drug handling. Toward increased drug safety]. / Enstrenget medicinhåndtering. På vej mod øget sikkerhed.

INTRODUCTION: Medication errors contribute to 8% of all hospital admissions. Minimalization of the number of information transferrals and improvement in communication may increase the quality of drug treatment. MATERIAL AND METHODS: The effect of introducing joint charts for prescription and administration on the quality of drug handling in a hospital setting is reported. RESULTS: When separate charts were used the prescriptions in the case records and the nurses' charts for administration did not tally for any of 20 patients. One year after introducing the joint charts, prescriptions for the regular medication and medication on demand were correct and signed for 88% and 48%, respectively, on a patient basis. Ninety-five per cent of the regular administrations were correct and signed. Potential interactions were identified in 15% of the prescriptions. Discharge medication was stated in 65% of the discharge letters to the family doctors. Complete agreement on admission medication between the patient and family doctor was found in 39%. DISCUSSION: Joint charts for prescription and administration represent a significant step towards safe and rational medical treatment. It is more time-consuming. Improvement in communication between all parties involved in the treatment of the same patient represents an important potential for further improving the quality of care, including drug treatment.

Azathioprine and mercaptopurine in the management of patients with chronic, active microscopic colitis.

BACKGROUND: Microscopic colitis (MC) is a common chronic diarrhoeal disease, and remission can be induced with budesonide. However, diarrhoea relapses frequently when budesonide is tapered and a few patients become budesonide intolerant. AIM: To examine retrospectively the effect of azathioprine (AZA) and mercaptopurine (MP) in patients with chronic, active MC. METHODS/PATIENTS: Data on all MC patients who received AZA or MP in the years 1997-2011 at three centres representing three countries were pooled for analysis. The indications for thiopurine therapy were frequent relapses after short-term treatment (N = 26), budesonide dependency on 6 mg (N = 15) and budesonide intolerance (N = 5). The response to thiopurine treatment was defined as clinical remission, intolerance or nonresponse. RESULTS: Forty-six MC patients (32 CC and 14 LC), 32 female; median age 59 years (range: 36-83) with a median disease duration of 3 years (range: 0.5-18) were included. Thirteen patients (28%) achieved long-term clinical remission on AZA therapy. AZA failed in 31 patients (67%) due to intolerance and in 2 patients (4%) because of nonresponse. Thirteen of 31 AZA-intolerant patients were switched to MP and 6 patients (46%) obtained clinical remission. Thus, the overall response rate to thiopurines was 19/46 (41%). The main side effects were nausea/vomiting and abnormally elevated liver enzymes. CONCLUSIONS: In this retrospective case series, the majority of chronic, active MC patients were intolerant to AZA leading to cessation of treatment. However, further studies are needed to explore the efficacy, acceptance, tolerance and safety of MP in patients with chronic, active MC refractory to budesonide.

Systematic review: are lymphocytic colitis and collagenous colitis two subtypes of the same disease - microscopic colitis?

BACKGROUND: Despite similar clinical symptoms, collagenous colitis (CC) and lymphocytic colitis (LC) are considered two distinct disease entities. AIM: To compare pathoanatomical findings, clinical presentations, risk factors, course of diseases and response to treatment in CC and LC to establish whether they could be subtypes of the same disease, microscopic colitis (MC). METHODS: The MEDLINE was searched for CC, LC and MC, and clinical studies of >20 patients were included. Pooled results with 95% confidence intervals were calculated based on the number of patients. RESULTS: An abnormal number of intraepithelial lymphocytes are found in 45% (40-50%) with CC, and an abnormal subepithelial collagen band in 16% (13-20%) with LC suggesting a histological overlap. The incidence of CC and LC has increased in parallel. Mean age (CC 63 years; LC 60 years) and clinical presentation are indistinguishable, and females are predominant in CC (77%; 75-79%) as well as LC (68%; 66-70%). Risk factors such as nonsteroid anti-inflammatory drugs consumption CC 39% (36-42%); LC 32% (29-35%) are similar and prevalence of concomitant autoimmune diseases such as coeliac disease (CC 5%; CI: 4-6% and LC 7%; CI: 6-9%) do not differ. Bile acid diarrhoea is highly prevalent in CC (41%; 37-45%) and LC (29%; 24-34%). The effect of budesonide is identical. CONCLUSIONS: CC and LC could be considered histological subtypes of the same disease, MC. To facilitate recruitment to clinical trials, all MC patients could be included in future trials and stratified for subtypes.

Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group.

Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials.

Microscopic colitis: clinical findings, topography and persistence of histopathological subgroups.

BACKGROUND: Uncertainty remains on topography and persistence of histological subgroups of microscopic colitis (MC). AIM: To assess longitudinal clinical, endoscopic, histological, and therapeutic description of MC subgroups including patients with incomplete findings of MC (MCi). METHODS: Retrospective review of a consecutive cohort with MC and histological reassessment of MCi. RESULTS: Clinical characteristics of 168 patients with lymphocytic colitis (LC), 270 with collagenous colitis (CC) and 101 with MCi were similar. At colonoscopy 95% (95% CI: 91-98%) of CC and 98% (93-100%) of LC cases had diagnostic histopathology of MC in both left and right colon. Eight and three patients had characteristics of MC only in the left and right colon, respectively. Histology findings resembling coexistence of the other MC subtype was present in 48% (40-55%) with CC and 24% (18-31%) with LC. A first diagnosis of MC was made in 49 (30%) of 164 patients only at repeat endoscopy. Another 34 of 115 (30%) with MC in the first endoscopy did not fulfil the MC criteria at repeat endoscopy. Only seven cases had a primary endoscopy without histopathological abnormalities. Fifteen percentage of MCi were reclassified as MC. Ileal inflammation was present in 33 of 81 patients. Budesonide was efficacious in all MC subgroups irrespective of bile acid malabsorption. CONCLUSIONS: Clinical characteristics of microscopic colitis subgroups are indistinguishable. Biopsies from the left colon suffice to exclude microscopic colitis, and the histological diagnosis of microscopic colitis is inconsistent over time. Ileal inflammation is common. The term microscopic colitis should perhaps be considered one clinical entity and include lymphocytic colitis, collagenous colitis, and incomplete findings of microscopic colitis.