Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study.

BACKGROUND: Methotrexate is an immunomodulatory drug for patients with Crohn's disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX's efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn's disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn's disease. METHODS: Adults with Crohn's disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry. RESULTS: Nineteen patients were included, with a median duration of MTX use of 77 months (range 7-202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4-258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3-96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (ß = 0.71) and lower estimated glomerular filtration rate (ß = - 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001). CONCLUSION: MTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn's disease patients.

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: a Prospective Cohort Study.

BACKGROUND AND AIMS: The number of patients with inflammatory bowel disease [IBD], of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD phenotype. METHODS: IBD patients treated in the eight University Medical Centers in The Netherlands [Dutch IBD Biobank] were divided into two groups according to their ethnicity: 1] Caucasian patients of Western and Central European descent [CEU]; and 2] patients of non-Caucasian descent [non-CEU]. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe [non-CEU European born]; or born outside Western-Europe who migrated to The Netherlands [non-CEU non-European born]. Both comparisons were analysed for phenotype differences [by chi-square test]. RESULTS: The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease [CD] patients more often had upper gastro-intestinal disease [16% vs 8%, p = 0.001] and anal stenosis [10% vs 4%, p = 0.002] than CEU CD patients. The use of anti-tumour necrosis factor [TNF] agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients [45% vs 38%, p = 0.042] and [77% vs 66%, p = 0.001], respectively. Non-CEU IBD patients born in Europe [n = 116] were diagnosed at a lower age than non-CEU IBD patients born outside Europe [n = 115] [at 22.7 vs 28.9 years old, p < 0.001]. CONCLUSION: Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.

Smoking is Associated with Higher Disease-related Costs and Lower Health-related Quality of Life in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of inflammatory bowel disease [IBD]. We aimed to study the impact of smoking on IBD-specific costs and health-related quality-of-life [HrQoL] among adults with Crohn's disease [CD] and ulcerative colitis [UC]. METHODS: A large cohort of IBD patients was prospectively followed during 1 year using 3-monthly questionnaires on smoking status, health resources, disease activity and HrQoL. Costs were calculated by multiplying used resources with corresponding unit prices. Healthcare costs, patient costs, productivity losses, disease course items and HrQoL were compared between smokers, never-smokers and ex-smokers, adjusted for potential confounders. RESULTS: In total, 3030 patients [1558 CD, 1054 UC, 418 IBD-unknown] were enrolled; 16% smoked at baseline. In CD, disease course was more severe among smokers. Smoking was associated with > 30% higher annual societal costs in IBD (€7,905 [95% confidence interval €6,234 - €9,864] vs €6,017 [€5,186 - €6,946] in never-smokers and €5,710 [€4,687 - €6,878] in ex-smokers, p = 0.06 and p = 0.04, respectively). In CD, smoking patients generated the highest societal costs, primarily driven by the use of anti-tumour necrosis factor compounds. In UC, societal costs of smoking patients were comparable to those of non-smokers. Societal costs of IBD patients who quitted smoking > 5 years before inclusion were lower than in patients who quitted within the past 5 years (€ 5,135 [95% CI €4,122 - €6,303] vs €9,342 [€6,010 - €12,788], p = 0.01). In both CD and UC, smoking was associated with a lower HrQoL. CONCLUSIONS: Smoking is associated with higher societal costs and lower HrQoL in IBD patients. Smoking cessation may result in considerably lower societal costs.

Illness Perceptions and Outcomes in Patients with Inflammatory Bowel Disease: Is Coping a Mediator?

PURPOSE: Patients with inflammatory bowel disease (IBD) often experience severe impairment in different life domains. Psychological factors, such as illness perceptions and coping, may play a role in the adjustment to IBD as indicated by mental and physical health, activity, and work impairment. The present study aimed at examining the assumption of the Common Sense Model (CSM) that coping mediates the relationship between illness perceptions and adjustment in patients with IBD. METHOD: In a cross-sectional design, 211 IBD patients (73 % Crohn's disease, 40 % male, mean age 42.9 ± 12.9 years) attending an outpatient clinic completed questionnaires assessing illness perceptions (IPQ-R), coping (CORS), mental and physical health (SF-36), as well as activity and work impairment (WPAI). Multiple mediation analyses were applied that allow estimating the total and direct effects of all illness perception dimensions and the indirect effects through all coping strategies on the illness outcomes simultaneously. RESULTS: The analyses yielded significant direct effects of perceptions regarding the cyclical course, the chronic course, the severity of the consequences, the comprehensibility, and the emotional impact of IBD on study outcomes. Additionally, significant indirect effects were found for the perceptions regarding the severity of the consequences, the possibility of personal control, and the comprehensibility of IBD on mental and physical health as well as activity impairment through the use of one specific coping strategy, i.e., reduction of activity. CONCLUSION: The results provide evidence for the assumptions of the CSM and suggest the importance of addressing illness perceptions and activity stimulation in quality health care for IBD patients.

Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD). METHODS: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. RESULTS: In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). CONCLUSIONS: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.

Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study.

BACKGROUND AND AIMS: Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. METHODS: IBD patients with back pain ≥ 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. RESULTS: Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. CONCLUSIONS: In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist.

Chromoendoscopy for Surveillance in Inflammatory Bowel Disease Does Not Increase Neoplasia Detection Compared With Conventional Colonoscopy With Random Biopsies: Results From a Large Retrospective Study.

OBJECTIVES: Randomized trials demonstrated that chromoendoscopy is superior to white light endoscopy with random biopsy sampling (WLE) for the detection of dysplasia in patients with inflammatory bowel disease (IBD). Whether implementing chromoendoscopy can increase the detection of dysplasia in clinical practice is unknown. METHODS: Patients with ulcerative colitis (UC) and Crohn's disease (CD) undergoing colonoscopic surveillance between January 2000 and November 2013 in three referral centers were identified using the patients' medical records. In recent years, the use of high-definition chromoendoscopy was adopted in all three centers using segmental pancolonic spraying of 0.1% methylene blue or 0.3% indigo carmine (chromoendoscopy group). Previously, surveillance was performed employing WLE with random biopsies every 10 cm (WLE group). The percentage of colonoscopies with dysplasia was compared between both groups. RESULTS: A total of 440 colonoscopies in 401 patients were performed using chromoendoscopy and 1,802 colonoscopies in 772 patients using WLE. Except for a higher number of CD patients with extensive disease and more patients with a first-degree relative with colorectal cancer (CRC) in the chromoendoscopy group, the known risk factors for IBD-associated CRC were comparable between both groups. Dysplasia was detected during 48 surveillance procedures (11%) in the chromoendoscopy group as compared with 189 procedures (10%) in the WLE group (P=0.80). Targeted biopsies yielded 59 dysplastic lesions in the chromoendoscopy group, comparable to the 211 dysplastic lesions detected in the WLE group (P=0.30). CONCLUSIONS: Despite compelling evidence from randomized trials, implementation of chromoendoscopy for IBD surveillance did not increase dysplasia detection compared with WLE with targeted and random biopsies.

Magnetic resonance imaging of the hand joints in patients with inflammatory bowel disease and arthralgia: a pilot study.

OBJECTIVES: To assess whether subclinical inflammatory changes are present on magnetic resonance imaging (MRI) in patients with inflammatory bowel disease (IBD) and arthralgia. METHOD: In this pilot study, painful hand joints [metacarpophalangeal (MCP), proximal interphalangeal (PIP), and/or distal interphalangeal (DIP)] of 11 IBD patients (age 18-45 years) with continuous pain for > 6 weeks were scanned on a 1.5-T extremity MRI system. A control group of 11 IBD patients without joint pain who were matched for type and disease duration of IBD, gender, and age was included. All patients were clinically examined by a rheumatologist for the presence of pain and arthritis. Imaging was performed according to a standard arthritis protocol with intravenous contrast administration on the same day. Images (blinded for clinical information) were evaluated by two readers in consensus for the presence of joint fluid, synovitis, tenosynovitis, enthesitis, erosions, cartilage defects, and bone marrow oedema. RESULTS: Enthesitis was seen in three hand joints (MCP 2, MCP 3, PIP 3) of 2/11 (18%) arthralgia patients and in none of the control group (p = 0.48). A small amount of subchondral bone marrow oedema was seen in the metacarpal head of two controls. No other abnormalities were observed. CONCLUSIONS: Several young IBD patients with chronic hand pain had subclinical inflammation on MRI, which invites for further study in a larger group of patients.

Anti-TNF and Crohn's disease: when should we start?

The natural course of Crohn's disease is characterized by the progression from primarily inflammatory disease to a complicated stricturing or penetrating disease. This irreversible complications lead to repeated surgery and considerable disability. It may therefore be argued that a window of opportunity for intensive treatment exists early in the disease course. Healing of the mucosa has been shown to be a strong predictor of improved outcome of Crohn's disease on the long-term, in terms disease control, hospitalizations, and surgery. Anti-tumor necrosis factor (TNF)-alpha therapy has shown to be a strong inducer of mucosal healing and it may be argued that early treatment with anti-TNF's and/or immunomodulators may be the preferable approach in selected patients. The main concern with such strategies is safety, especially the risk of lymphoma's and infections. This paper aims to review the existing data regarding the benefits and disadvantages of inverting the classic step up therapeutic paradigm.

Response to medical treatment in patients with Crohn's disease: the role of NOD2/CRAD15, disease phenotype, and age of diagnosis.

PURPOSE: Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab. METHODS: A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy. RESULTS: CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy. CONCLUSIONS: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

The I1307K APC mutation in a high-risk clinic setting: a follow-up study.

While the I1307K APC mutation clearly confers an increased lifetime risk for colorectal cancer, there is a paucity of data on the natural history of colonic neoplasia in symptomatic and asymptomatic mutation carriers. In this study, 51 Jewish I1307K APC mutation carriers were identified in a high-risk familial cancer clinic over a 4-year period, of whom 29 (56.8%) (four males and 25 females) were successfully telephone interviewed for 0.5-5 years (mean 2.4 +/- 1.4) after initial genetic testing. Of these 29 cases, one individual was diagnosed with colon cancer at the age of 45 years, five had adenomatous polyps (mean number of polyps = 1.8), 11 had breast cancer (mean age at diagnosis 49.5 +/- 10.5 years), and 12 were asymptomatic, at the time of the testing. During the follow-up period, new colonic polyps were diagnosed in three mutation carriers, two with previously diagnosed colon cancer and polyps and only one of the asymptomatic mutation carriers, and two additional previously affected patients had new cancer diagnoses: gastric cancer and melanoma. From this descriptive study, it seems that the short-term risk for colonic polyps in I1307K APC mutation is low, primarily affecting patients with previously diagnosed colon tumors.

Risk factors for mortality in patients undergoing percutaneous endoscopic gastrostomy.

BACKGROUND AND STUDY AIMS: Percutaneous endoscopic gastrostomy (PEG) is a method used for feeding patients who are unable to eat. High early mortality rates among hospitalized patients have been reported. The aim of this study was to shed light on the risk factors for early mortality after PEG tube insertion. PATIENTS AND METHODS: Outpatients from nursing homes and hospitalized patients who underwent PEG between July 1995 and July 2001 were compared. Survival analysis was used to assess mortality after PEG. In a logistic regression analysis, mortality within 30 days among hospitalized patients was chosen as the outcome variable and the predictor variables were demographic characteristics, co-morbid conditions, and indication for PEG. RESULTS: A total of 502 PEG tubes were inserted in 419 hospitalized and 83 nursing-home patients. The prevalence of co-morbid conditions was similar in the two groups. Both the 30- and 60-day mortality rates were around six times higher in the hospitalized patient group than in the nursing-home patient group (30-day mortality rate 8 % vs. 1.2 %, P = 0.034; 60-day mortality rate 12 % vs. 2.4 %, P = 0.016). Risk factors for 30-day mortality among hospitalized patients were: serum albumin < 3 g/dl (odds ratio 2.82, 95 % CI 1.34 - 5.96), chronic obstructive pulmonary disease (odds ratio 2.79, 95 % CI 1.26 - 6.14), and diabetes mellitus (odds ratio 2.44, 95 % CI 1.20 - 4.97). CONCLUSIONS: Compared with nursing-home patients, hospitalized patients are at higher risk for early mortality after PEG. The presence of diabetes, chronic obstructive pulmonary disease, and a low serum albumin level each increase the 30-day mortality risk among hospitalized patients threefold.

Genotype-phenotype correlations in Peutz-Jeghers syndrome.

BACKGROUND AND AIMS: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated. METHODS: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. RESULTS: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. CONCLUSION: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

The I1307K APC polymorphism: prevalence in non-Ashkenazi Jews and evidence for a founder effect.

A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some non-Ashkenazi individuals led us to hypothesize that within the Jewish people, the I1307K polymorphism may reflect a founder mutation, and that the mutation is not restricted to ethnic Ashkenazis. To test that notion, and to establish the occurrence rate of the I1307K polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and Moroccan Jews and consecutive Jewish CRC patients and performed haplotype analysis with APC-linked markers in two I1307K carrier families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148 Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi). The mutation detection scheme included PCR followed by denaturing gradient gel electrophoresis (DGGE) or modified restriction analysis (MRA). Haplotypes were assessed using three intragenic and three flanking markers. The I1307K polymorphism was detected in 29/227 Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2 individuals each (approximately 1%) within the Moroccan and Iraqi populations. Allelic pattern analysis in all our I1307K carriers, revealed a common haplotype for the three intragenic markers tested, in all mutation carriers, regardless of ethnic origin. The I1307K polymorphism, therefore, exists in all ethnic Jewish populations: Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K mutation carriers share a common allelic pattern with APC-linked markers. This strongly supports the notion of a founder mutation for I1307K.

The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients.

It is presently unclear whether carriers of BRCA1 mutations have an increased risk for colorectal cancer (CRC). To gain insight into this issue, 225 unselected Ashkenazi Jewish CRC patients were tested for the presence of the three common Jewish BRCA1/2 germline mutations: 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2). A total of four carriers was found (4/225, 1.78%). This frequency is similar to the estimated normal Ashkenazi population frequency, thus suggesting that these specific mutations do not contribute to CRC predisposition.

Positive antineutrophil cytoplasmic antibodies-associated vasculitis presenting with hemoptysis and a mediastinal mass.

A patient with end-stage renal failure, due to IgA nephropathy, was found to have a mediastinal mass. Biopsy specimen of the mass showed a necrotizing vasculitis. Antineutrophil antibodies to myeloperoxidase were strongly positive. To our knowledge, no case of a mediastinal mass due vasculitis has been reported in the literature, and our observation should lead to broadening of the spectrum of clinical manifestations of vasculitis.