Higher 25-hydroxyvitamin D levels are associated with greater odds of remission with anti-tumour necrosis factor-α medications among patients with inflammatory bowel diseases.

BACKGROUND: Vitamin D has been linked to disease activity among patients with inflammatory bowel diseases (IBD). Prior investigation has also suggested that vitamin D levels may affect duration of therapy with anti-tumour necrosis factor-α (anti-TNF-α) medications among patients with IBD. AIM: To evaluate the relationship between vitamin D levels and odds of reaching remission while on an anti-TNF-α medication. METHODS: A total of 521 IBD patients enrolled in the Brigham and Women's IBD Centre database were eligible for inclusion. Patients treated with anti-TNF-α therapy who had vitamin D levels drawn within 6 months prior or 2 weeks after initiation of anti-TNF-α medication and who had reported remission status at 3 months were included. A logistic regression model adjusting for age, gender, IBD diagnosis, anti-TNF-α medication (infliximab vs. adalimumab) and first or subsequent anti-TNF-α medication was used to identify the effect of vitamin D level on initial response to anti-TNF-α therapy. RESULTS: A total of 173 patients were included in the final analysis. On logistic regression, patients with normal vitamin D levels n = 122 at the time of anti-TNF-α medication initiation had a 2.64 increased odds of remission at 3 months compared to patients with low vitamin D levels n = 51 when controlling for age, gender, diagnosis, type of anti-TNF-α medication and first or subsequent anti-TNF-α medication (OR = 2.64, 95% CI = 1.31-5.32, P = 0.0067). CONCLUSIONS: These findings suggest that vitamin D levels may influence initial response to anti-TNF-α medication and that low vitamin D levels may pre-dispose patients to decreased odds of remission.

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles.

BACKGROUND: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. AIM: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. METHODS: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. RESULTS: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. CONCLUSIONS: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence.

Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease.

BACKGROUND: Recent data suggest that acid suppressive medications may alter factors central to the pathophysiology of inflammatory bowel diseases (IBD), whether through shifts in the intestinal microbiome due to acid suppression or effects on immune function. AIM: To assess the relationship between the use of proton pump inhibitors (PPIs) or histamine2-receptor antagonists (H2Ra) and incidence of 'flares' (hospitalisation/surgery and change in medication). METHODS: We conducted a new user cohort study including individuals diagnosed with IBD in British Columbia using linked healthcare utilisation databases (available from July 1996 through April 2006). Propensity-score matched incidence rates during a 6-month follow-up period and rate ratios (RR) and 95% CI were calculated. RESULTS: Among 16 151 IBD patients, 1307 Crohn's disease (CD) and 996 ulcerative colitis (UC) patients experienced a new use of PPIs, whereas 741 CD and 738 UC used H2Ra. All IBD subgroups were matched separately to an equal number of unexposed IBD patients. H2Ra use in CD doubled the risk of hospitalisation/surgery (RR = 1.94; 95%CI 1.24-3.10) and numerically less so in UC patients (RR = 1.11) with widely overlapping CIs (0.61-2.03). Proton pump inhibitors use was associated with medication change in UC (RR = 1.39; 95%CI 1.20-1.62), but without meaningfully, increased risk of hospitalisation/surgery for UC or CD patients. Extending follow-up showed persistence, but attenuation, of all effects. CONCLUSIONS: Initiation of PPIs or H2Ra may be associated with short-term changes in the course of IBD. Although confounding by indication was adjusted using propensity score matching, residual confounding may persist and findings need to be interpreted cautiously.

Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature.

BACKGROUND Anti-tumour necrosis factor (TNF) antibodies are used to treat both psoriasis and inflammatory bowel disease. The seemingly paradoxical occurrence of psoriasis in patients treated with anti-TNF antibodies is increasingly recognised, but the distinct features associated with inflammatory bowel disease have been incompletely characterised. AIM To identify inflammatory bowel disease patients who developed psoriasis while receiving an anti-TNF antibody at two academic medical centres between 2000 and 2009 and review all published cases of this phenomenon in inflammatory bowel disease. METHODS We identified retrospectively all cases of anti-TNF-induced psoriasis in inflammatory bowel disease patients attending two North American healthcare centres. We analysed these cases alongside the published reports of anti-TNF-induced psoriasis. RESULTS We identified 30 subjects who developed a psoriatic rash while receiving anti-TNF therapy for inflammatory bowel disease. Forty-seven per cent (14/30) responded to topical therapy and 23% (7/30) ultimately discontinued the anti-TNF. The new data were combined with those from 120 published cases of anti-TNF-induced psoriasis in inflammatory bowel disease. Anti-TNF-induced psoriasis in inflammatory bowel disease was more common in women (70%). The most common distributions were palmoplantar (43%) and scalp (42%). Complete follow-up in 148 cases showed that 41% responded to topical therapy but 43% required definitive withdrawal of anti-TNF therapy due to the rash. A second anti-TNF was tried in 27 cases with recurrence or persistence of the rash in 14 (52%). CONCLUSIONS In this analysis, psoriasiform lesions related to anti-TNF therapy in inflammatory bowel disease occurred most commonly in women. Approximately 41% of those who developed psoriasis while on anti-TNFs responded to topical therapy and were able to continue the drug, while 52% of those treated with an alternate anti-TNF had recurrence of the rash.

Validation of the functional assessment of chronic illness therapy-fatigue (FACIT-F) in patients with inflammatory bowel disease.

BACKGROUND Many patients with ulcerative colitis (UC) and Crohn's disease (CD) complain of significant fatigue. To date, no instrument to measure fatigue has been validated in a US inflammatory bowel disease (IBD) population. AIM To determine the reliability and validity of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale in IBD. METHODS A total of 209 patients with IBD completed the 13 items of the FACIT-F, alongside laboratory testing and disease activity assessment. Internal consistency was measured by Cronbach's alpha; test-retest reliability by the intraclass correlation coefficient (ICC); validity by the correlation of the FACIT-F score with C-reactive protein (CRP) erythrocyte sedimentation rate (ESR), haematocrit (HCT) and disease activity as measured by the Harvey-Bradshaw Index (HBI; CD) and Simple Clinical Colitis Activity Index (SCCAI; UC). RESULTS The mean ± SD FACIT-F score was 38.9 ± 11.0 overall (CD 38.6 ± 11.3; UC 39.4 ± 10.6). Cronbach's alpha was 0.94. The ICC for first and repeat FACIT-F scores assessed within 180 days without change in disease state was 0.81 (CD 0.78; UC 0.87). FACIT-F scores were lower in patients with active symptoms (CD 4.6 points, 95% CI 2.4-6.9, P < 0.001; UC 8.5 points, 95% CI 5.5-11.4, P < 0.001). In UC, FACIT-F scores were correlated with ESR (-0.76, 95% CI -0.89 to -0.50), CRP (-0.72, 95% CI -0.88 to -0.43) and HCT (0.53, 95% CI 0.22-0.74). CONCLUSION The FACIT-F scale is a reliable and valid instrument for measuring fatigue in IBD.

Is Crohn's disease due to defective immunity?

The understanding of the pathophysiology of Crohn's disease is currently undergoing a reassessment. The concept of this disease as a primary T cell disorder is being questioned, with a new emphasis on the role of innate immunity in initiating early events and in perpetuating the inflammatory state. Crohn's disease has been proposed instead to result from impaired innate immunity, encompassing the mucosal barrier and cellular elements including neutrophils and macrophages. Recent advances in genetics, functional studies on innate immunity and therapeutic trials on patients with Crohn's disease have lent support to this evolving hypothesis.

An open-labelled study of granulocyte colony-stimulating factor in the treatment of active Crohn's disease.

BACKGROUND: Immunodeficiency syndromes associated with a Crohn's-like illness suggest innate immune defects may lead to Crohn's disease. Anecdotal cases using haemopoietic colony-stimulating factors report improvement in intestinal disease associated with these syndromes. AIM: To test the safety and efficacy of recombinant human granulocyte colony-stimulating factor in active Crohn's disease. METHODS: In an open-labelled 12-week trial, patients with a Crohn's Disease Activity Index between 220 and 450 were treated with recombinant human granulocyte colony-stimulating factor (filgrastim, Neupogen). Concomitant immunosuppressants were prohibited except prednisone < or =20 mg/day. Patient's received recombinant human granulocyte colony-stimulating factor 300 mcg daily subcutaneously adjusted to achieve an absolute neutrophil count between 25 and 35 x 10(9)/L. RESULTS: Twenty patients were enrolled with a mean initial Crohn's Disease Activity Index of 307 (range: 234-428). Fifteen patients (75%) completed 8 weeks; 13 patients (65%) completed 12 weeks with the mean Crohn's Disease Activity Index for patients continuing through those times of 196 (range: 36-343) and 162 (range: 20-308), respectively. At week 12, 11 patients (55%) demonstrated a decrease of at least 70 points; five (25%) achieved a sustained remission. The mean decrease was statistically significant at each assessment time-point. Three of four patients with fistulae had a positive response. Adverse effects included bone pain, mostly mild resolving with continued treatment. One patient was hospitalized with a viral-like syndrome but it is uncertain if this was treatment related. CONCLUSION: Recombinant human granulocyte colony-stimulating factor is safe and potentially effective therapy for active Crohn's disease.

Analysis of mucosal gene expression in inflammatory bowel disease by parallel oligonucleotide arrays.

DNA arrays capable of simultaneously measuring expression of thousands of genes in clinical specimens from affected and normal individuals have the potential to provide information about disease pathogenesis not previously possible. Few studies have applied mRNA profiling to diseases involving complex tissues like the intestinal mucosa, reflecting the unique challenges inherent to this type of analysis. We report the analysis of mucosal gene expression in ulcerative colitis (UC) patients and inflamed and noninflamed control specimens. Genes can be used as markers for cell recruitment, activation, and mucosal synthesis of immunoregulatory molecules. Self-organizing maps were applied to cluster and analyze gene expression patterns and were paired with histopathological scores to identify genes associated with increased disease activity. Clustering was achieved on the basis of differences in expression levels across individual specimens. Several inflammatory mediators were identified as likely determinants of characteristic histological features of active UC. These results provide proof of principle for application of functional genomics to larger inflammatory bowel disease populations for gene discovery, to facilitate identification of disease subgroups on the basis of gene expression signatures, and for prediction of disease behavior or optimal therapeutic intervention.

Liver disease in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal dominant disorder characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations) that affect many organs. Liver involvement in patients with this disease has not been fully characterized. METHODS: We studied the clinical findings and results of hemodynamic, angiographic, and imaging studies in 19 patients with hereditary hemorrhagic telangiectasia and symptomatic liver involvement. RESULTS: We evaluated 14 women and 5 men who ranged in age from 34 to 74 years. All but one of the patients had a hyperdynamic circulation (cardiac index, 4.2 to 7.3 liters per minute per square meter of body-surface area). In eight patients, the clinical findings were consistent with the presence of high-output heart failure. The cardiac index and pulmonary-capillary wedge pressure were elevated in the six patients in whom these measurements were performed. After a median period of 24 months, the condition of three of the eight patients had improved, four were in stable condition with medical therapy, and one had died. Six patients had manifestations of portal hypertension such as ascites or variceal bleeding. The hepatic sinusoidal pressure was elevated in the four patients in whom it was measured. After a median period of 19 months, the condition of two of the six patients had improved, and the other four had died. Five patients had manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging. After a median period of 30 months, the condition of two of the five had improved, the condition of one was unchanged, heart failure had developed in one, and one had died after an unsuccessful attempt at liver transplantation. CONCLUSIONS: In patients with hereditary hemorrhagic telangiectasia and symptomatic liver-involvement, the typical clinical presentations include high-output heart failure, portal hypertension, and biliary disease.

Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease.

The current hypothesis for the etiology of Crohn's disease proposes an excessive immune response, largely T-cell driven, possibly against endogenous bacteria. Standard therapy is therefore directed towards suppression of this immune response. An alternative theory of pathogenesis accounts for epidemiologic and pathophysiologic observations that have been hitherto underemphasized, namely, (1) genetic disorders with deficiencies in neutrophil function can give rise to a clinical and pathologic syndrome indistinguishable from Crohn's; (2) abnormal neutrophil function is well described in Crohn's disease; (3) a group of bacteria implicated in other chronic inflammatory disorders causes impairment of neutrophil function; and (4) 20th century environmental risk factors for Crohn's disease may directly suppress neutrophil function and may have led to a shift in the dominant gut flora with similar effects. We propose that some cases of Crohn's disease result from the interaction of environmental and genetic influences leading to impaired mucosal neutrophil function, resulting in failure to effectively clear intramucosal microbes effectively. While encompassing existing data, this hypothesis proposes a proximate defect in the mucosal immune response. If this paradigm were correct, new therapeutic approaches might involve strategies to alter intestinal flora and stimulate neutrophil function.

Effect of heparin on dextran sulfate sodium-induced colitis.

Heparin has been shown to ameliorate inflammatory bowel disease in several series. In addition to its anticoagulant properties, heparin has numerous other effects that may be beneficial in inflammatory bowel disease. Other sulfated polysaccharides, such as dextran sulfate, cause colitis in mice through unknown mechanisms. We postulate that dextran sulfate and heparin may act via similar pathways with opposite effects. To examine this thesis, the effect of heparin on dextran sulfate-induced colitis was studied. Swiss-Webster mice were given 5% dextran sulfate in their drinking water for five days to induce colitis. Heparin was given both therapeutically after the induction of colitis and prophylactically by subcutaneous injections, with saline injections given in controls. Histologic sections of colon were randomized and graded for colitis. Heparinized animals showed no significant difference in the pattern or severity of colitis when compared to control animals. It is concluded that heparin does not ameliorate the murine colitis induced by dextran sulfate in the doses given.

Nutritional issues and therapy in inflammatory bowel disease.

Nutritional issues in inflammatory bowel disease (IBD) often receive inadequate attention both in regard to therapy and nutritionally related complications of IBD. This article reviews much of the research that has evaluated the role of diet in the causation, primary treatment, and adjunctive therapy of both ulcerative colitis (UC) and Crohn's disease (CD). Benefits have been demonstrated in the use of elemental diets or polymeric diets in CD in both acute flare up or maintenance of IBD. A careful team approach can overcome problems in implementing nutritional therapy. Nutrition also has a critical benefit in postoperative CD and perioperative UC. Numerous easily corrected, nutritional abnormalities are often overlooked in patients with IBD, which may have significant consequences. Nutritional therapy may have a central place in the hierarchy of treatment in IBD and further research is critical in this area to better define the benefits of nutrition in IBD.

A case-control study of maternal knowledge of malnutrition and health-care-seeking attitudes in rural South India.

INTRODUCTION: In India, approximately 20 percent of children under the age of four suffer from severe malnutrition, while half of all the children suffer from undernutrition. The contributions of knowledge and attitudes of nutrition-conscious behaviors of the mothers to childhood malnutrition has been unclear. The purpose of this study was to explore maternal knowledge of the causes of malnutrition, health-care-seeking attitudes and socioeconomic risk factors in relation to children's nutritional status in rural south India. METHODS: A case-controlled study was conducted in a rural area in Tamil Nadu, India. Thirty-four cases and 34 controls were selected from the population of approximately 97,000 by using the local hospital's list of young children. A case was defined as a mother of a severely malnourished child under four years of age. Severe malnutrition was defined as having less than 60 percent of expected median weight-for-age. A control had a well-nourished child and was matched by the location and the age of the child. Interviews obtained: (1) socioeconomic information on the family, (2) knowledge of the cause of malnutrition and (3) health-care-seeking attitudes for common childhood illnesses, including malnutrition. RESULTS: Poor nutritional status was associated with socioeconomic variables such as sex of the child and father's occupation. Female gender (OR = 3.44, p = .02) and father's occupation as a laborer (OR = 2.98, p = .05) were significant risk factors for severe malnutrition. The two groups showed a significant difference in nutrition-related knowledge of mild mixed malnutrition (OR = 2.62, p = .05). No significant difference was apparent in health-care-seeking attitudes. Based on their traditional beliefs, the mothers did not believe that medical care was an appropriate intervention for childhood illnesses such as malnutrition or measles. DISCUSSION: The results suggested that the gender of the child and socioeconomic factors were stronger risk factors for malnutrition than health-care availability and health-care-seeking attitudes. The father's occupation was a more accurate indicator for malnutrition than household income. These results suggest a need for intensive nutritional programs targeted toward poor female children and their mothers.

PIP: The contribution of maternal nutritional knowledge and attitudes to children's nutritional status was investigated in a case-control study conducted in a rural area in Tamil Nadu, India. 34 cases (mothers of a severely malnourished child under 4 years of age) and 34 controls (mothers of a well-nourished age- and location-matched child) were selected from the Christian Medical Center and Hospital registry. The 68 mothers interviewed were predominantly young (mean age, 25 years), poor, and illiterate (67.6%). Severe malnutrition, defined as less than 60% of expected weight-for-age, was significantly associated with female gender (odds ratio (OR), 3.44) and father's occupation as a laborer (OR, 2.98), as opposed to a civil servant or private sector professional. Knowledge of the role of lack of food or nutrition in mild marasmus-kwashiorkor mixed malnutrition was significantly higher among controls (59%) than cases (35%), but there were no significant differences in health-seeking behaviors. In general, mothers from this area did not regard medical care as an appropriate intervention for malnutrition or measles. Only 28% of mothers indicated they would seek medical care for malnutrition. Conversely, medical care was considered indicated for diarrhea, colds, and worms. These findings indicate a need for intensive nutritional programs targeted toward the families of low-income female children.

IBD: A Vascular Disorder? The Case for Heparin Therapy.

SUMMARY: : In recent years, heparin has emerged as a possible therapy for inflammatory bowel disease (IBD). Several recent, strongly positive, open-labeled series of heparin in both ulcerative colitis (UC) and Crohn's disease (CD) reinforce the work of Gaffney and co-workers that suggested a benefit of heparin in UC. Although counterintuitive as a therapy for a disorder characterized by bleeding, heparin is intriguing also for implications with regard to the pathophysiology of UC and CD. Although the thromboembolic complications and hypercoagulable state associating flares of both UC and CD suggest that heparin may produce a benefit by treating microthrombi in the intestinal circulation, recent IBD research suggests that a broader endothelial dysfunction in regulation of coagulation, inflammation, and vascular repair may be important events in the pathogenesis of IBD. Heparin, with its diverse effects targeting the endothelium, may be an ideal agent to reverse these defects and produce significant therapeutic benefits in both UC and CD. Randomized, controlled trials currently in progress will help determine whether heparin and the endothelial cell are but another epiphenomenon in IBD or provide important clues to understanding its pathogenesis.