Medical management of Crohn's disease

Introduction: The medical approach to Crohn's disease has been modified in recent years thanks to the introduction of new therapies, like biologics. Also, well-designed studies and systematic reviews have allowed better evaluation of the role of old drugs like steroids and immunosuppressors. This review aims to evaluate the recent evidence on the medical approach to Crohn's disease in the different settings of the disease.

Areas covered: Randomized controlled trials and meta-analyses were included in the review. The research on all the studies discussed was based on the Cochrane Library, Medline and Embase, using the following medical subject headings: Crohn's disease, clinical trial, therapy, 5-aminosalicylicacid, steroid, budesonide, immunosuppressant, anti-meta-analysis TNF and biologics.

Expert opinion: In a mild active inflammatory ileocecal disease, budesonide is considered the best approach. The efficacy of aminosalicylates is limited, but a trial that has recently compared aminosalicylates and budesonide has shown that the two drugs are comparable. In a mild colonic disease, sulfasalazine, antibiotics and steroids are effective but the evidence for antibiotics is less clear. The maintenance of remission in this setting is debatable, but sulfasalazine seems the better choice. In a moderate severe ileal and colonic disease, steroids are the best therapy to induce remission. Once remission is reached, immunosuppressors remain today the better choice to maintain the remission. Anti-TNF therapy is indicated in patients intolerant or not responding to steroids and immunosuppressors and in fistulizing Crohn's disease. Early therapy with biologics may be considered in patients with severe disease.     

Steady-state pharmacokinetics of metronidazole in Crohn's disease

The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day-1. Pharmacokinetic indices were found to be independent of the dose administered. The half-life, volume of distribution and oral clearance of metronidazole were 9.5 +/- 2.1 h, 0.732 +/- 0.094 l kg-1 and 0.921 +/- 0.175 (ml min-1) kg-1 (mean +/- SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 +/- 7.4 to 58.9 +/- 5.2. Both plasma and urine data exhibited very large inter-patient variations. However, intra-patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations as well as cumulative urinary excretion of the drug and its metabolites. It is concluded that in Crohn's disease, the pharmacokinetics of MTZ and its metabolites are linear and that the drug concentrations are dependent on the total body weight.     

Treatment patterns among physician specialties in the management of fibromyalgia: results of a cross-sectional study in the United States

Abstract

Background:

Fibromyalgia (FM) is characterized by persistent and widespread pain and often associated with other symptoms and comorbidities. Thus, FM patients seek care from multiple physician specialties. This study compared prescribing patterns, patient-reported outcomes (PROs), healthcare resource use (HRU), and direct costs related to FM in routine clinical practice across physician specialties.     

An open-label evaluation of rifaximin in the treatment of active Crohn's disease

ABSTRACT

Objective: This open-label study was conducted as a preliminary assessment of rifaximin (200?mg TID for 16 weeks) for the treatment of active Crohn's disease in patients (n = 29) with symptoms for at least 3 months before screening and a Crohn's Disease Activity Index (CDAI) score > 220 and < 400.

Results: At the end of month 4, mean ± SD CDAI score was reduced by 43% compared with baseline in the intent-to-treat population (n = 29; baseline = 278 ± 51; month 4 = 159 ± 102; p < 0.0001 month 4 versus baseline). A similar pattern of results was observed in the per-protocol population (i.e., patients at least 70% compliant with the treatment regimen and having no protocol violations thought to affect efficacy results; n = 16), in which mean CDAI scores at month 4 were reduced by 41% from a baseline of 262.9 ± 38.2 to 155.6 ± 104.5 (?p = 0.0009 month 4 versus baseline). Fifty-nine percent of patients (59%) had a ≥ 70‐point improvement in CDAI score beginning with the first assessment at the end of month 1. By the end of the treatment period, 78% of patients had a ≥ 70‐point improvement in CDAI score. Clinical remission, defined as CDAI score < 150, was observed at the end of treatment months 1, 2, 3, and 4 in 41%, 56%, 56%, and 59% of patients, respectively. Twenty-three (23) patients completed the 4-month course of rifaximin therapy, and 6 prematurely withdrew. The most common adverse events were abdominal pain, fatigue, and headache.

Conclusion: These data, which are consistent with the possibility that rifaximin may be useful for active Crohn's disease, warrant confirmation in a randomized, double-blind, placebo-controlled trial.     

Use of atorvastatin as an anti-inflammatory treatment in Crohn's disease

Background and purpose:

Experimental and clinical investigations have revealed that statins can downregulate both acute and chronic inflammatory processes. Whether statins express anti-inflammatory activities in the treatment of Crohn''s disease is unknown.

Experimental approach:

Ten patients were given 80 mg atorvastatin once daily for 13 weeks and then followed up for 8 weeks after the treatment. The anti-inflammatory effects of statin were assessed by measuring levels of plasma C-reactive protein (CRP), soluble (s) CD14, tumour necrosis factor (TNF)-α, sTNFRI and II, CCL2 and 8 and the mucosal inflammation by faecal calprotectin. Circulating monocytes were subgrouped and their chemokine receptor expression of CCR2 and CX₃CR1 were analysed.

Key results:

In 8 of 10 patients, atorvastatin treatment reduced CRP (P=0.008) and sTNFRII (P=0.064). A slight decrease in plasma levels of sCD14, TNF-α and sTNFRI was observed in 7/10 patients and faecal calprotectin was reduced in 8/10 patients. We also observed that the treatment diminished expression of CCR2 and CX₃CR1 on monocyte populations (P=0.014). At the follow-up visit, 8 weeks after the atorvastatin treatment was terminated, CRP levels had returned to those seen before the treatment.

Conclusions and implications:

Our findings imply that atorvastatin therapy reduces inflammation in patients with Crohn''s disease and, therefore, encourage further investigations of statin-mediated protective effects in inflammatory bowel diseases.     

克罗恩病患者疾病活动指数应对方式与抑郁的相关性研究

目的 调查分析克罗恩病患者的疾病活动指数、应对方式与抑郁的相关性,为制订针对性的干预措施提供依据。 方法 以Harvey简化CDAI计算法、抑郁自评量表(SDS) 、应对方式量表(MCMQ)对100例克罗恩病患者进行调查。 结果 62%的克罗恩病患者存在抑郁;克罗恩病患者疾病活动指数与抑郁呈正相关(r=0.556,P< 0.01);面对与抑郁呈负相关(r=-0.578,P< 0.01);回避与抑郁呈正相关(r=0.165,P< 0.05);屈服与抑郁呈正相关(r=0.215,P< 0.01)。 结论 克罗恩病患者多存在抑郁,与疾病程度和应对方式有一定相关性,护理人员应根据患者特点进行心理护理,减少患者抑郁。     

Economic costs of drug abuse: financial, cost of illness, and services

This article examines costs as they relate to the financial costs of providing drug abuse treatment in private and public health plans, costs to society relating to drug abuse, and many smaller costing studies of various stakeholders in the health care system. A bibliography is developed from searches across PubMed, Web of Science, and other bibliographic sources. The review indicates that a wide collection of cost findings is available to policy makers. For example, the financial aspects of health plans have been dominated by considerations of actuarial costs of parity for drug abuse treatment. Cost-of-illness methods have been developed and extended to drug abuse costing to measure the national level of burden and are important to the economic evaluation of interventions at the program level. Costing is done in many small and focused studies, reflecting the interests of different stakeholders in the health care system. For costs in programs and health plans, as well as cost offsets of the impact of substance abuse treatment on medical expenditures, findings are surprisingly important to policy makers. Maintaining ongoing research that is highly policy relevant from the point of view of health services, more is needed on costing concepts and measurement applications.     

克罗恩病肛瘘病人焦虑抑郁发病现状及影响因素分析

目的 调查克罗恩病肛瘘（PFCD）病人的焦虑抑郁发病现状,对其发病的影响因素进行分析,从而为临床身心指导提供理论支撑。方法 选取2020年9月至2021年7月南京中医药大学附属医院肛肠外科住院部就诊的PFCD病人197例,收集病人一般资料及临床表现,采用广泛性焦虑障碍量表（GAD-7）、抑郁症筛查量表（PHQ-9）对病人精神进行评估。结果 在197例PFCD病人中,有66例（33.50%）出现焦虑状态,81例（41.12%）出现抑郁状态。合并并发症[OR=2.25,95%CI:(1.20,4.25)]、肛周手术次数≥2次[OR=2.15,95%CI:(1.17,3.96)]是PFCD病人出现抑郁状态的危险因素;合并并发症[OR=2.27,95%CI:(1.19,4.34)]、疾病处于活动期[OR=2.58,95%CI:(1.04,6.42)]是PFCD病人出现焦虑状态的危险因素。结论 克罗恩病（CD）病人合并肛周瘘管病变发生率高,病程长,治疗难度大,病人由于全身条件和肛周病变往往存在情绪压力,在临床治疗疾病的同时应该关注病人的心理健康。     

Pharmacokinetic and pharmacodynamic model for analysis of adalimumab administered for Crohn's disease

Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has not been analysed theoretically. The present study analysed of sequential changes in the Crohn's disease activity index (CDAI) after repeated administrations of adalimumab using a pharmacokinetic and pharmacodynamic model. In addition, we analysed the validity of the dosage regimen, and the potential efficacy gained by increasing the dose and reducing the interval of administration. The sequential changes in CDAI values obtained with our model were in good agreement with observed CDAI values, which is considered to show the validity of our analysis. We consider that our results showed the importance of a loading dose of adalimumab to obtain remission in an early stage of active CD. In addition, we showed that patients who have an incomplete response to adalimumab can obtain similar efficacy from increasing the dose and reducing the dose interval. In conclusion, our results showed that the present model may be applied to predict the CDAI values of adalimumab for CD. They indicate the validity of the dosage regimen, as well as the efficacy of increasing the dose and reducing the dose interval.     

Recent advances in the medical therapy of Crohn's disease in childhood

Crohn's disease (CrD) is characterised by an ongoing inflammatory response in the gut, in the absence of an obvious trigger. The treatment of CrD in children, during relapse and remission, requires special consideration of growth and development. This review addresses the use of present medical management strategies, including enteral nutrition, corticosteroids, immunosuppression and anti-TNF-α therapies. Anti-inflammatory IL-11 and leukocyte adhesion inhibitors have shown only moderate clinical efficacy in adults. Emerging treatments directed against the inflammatory cascade under investigation include inhibitors of IL-6 and -12, IFN-γ and MAPKs. Probiotics and colony stimulating factors aim to stimulate the innate immune system. Research data from clinical trials are reviewed and summarised in respect of their potential within paediatric practice.     

多排CT小肠成像鉴别小肠结核和克罗恩病的价值

目的 探讨多排CT小肠成像（MDCTE）特征性征象在鉴别诊断肠结核和克罗恩病中的价值。方法 收集安徽医科大学第一附属医院2011年8月至2014年11月经内镜、病理确诊的克罗恩病（CD）22例、结核（ITB）25例患者临床资料。每位患者入院后均行MDCTE检查,记录并分析各种MDCTE征象,寻求鉴别诊断CD和ITB有价值的CT表现。结果 CD和ITB回盲瓣受累分别占54.5%和72.0%,累及降结肠的分别占31.8%和12.0%,累及横结肠分别占18.2%和4.0%;多节段受累患者中,CD组为63.6%,ITB为36.0%;肠系膜侧肠壁增厚在CD中占50.0%,ITB则表现为环形或肠系膜对侧增厚;60.0%的ITB患者和9.1% CD患者有淋巴结中心坏死;36.4%的CD患者出现"梳状征",ITB患者中仅有4.0%,两者差异均有统计学意义（P<0.05）。结论 MDCTE征象中,病变节段数、病变累及部位、"梳状征"和淋巴结坏死情况在鉴别诊断CD和ITB中具有参考价值。     

Vercirnon for the treatment of Crohn's disease

Introduction: CCR9 antagonism is a promising new therapeutic approach for the treatment of Crohn's disease. CCR9 is expressed on the cell surface of memory/effector CD4⁺ T cells and selectively binds to the small intestinal lymphocyte chemoattractant CCL25 (TECK). Blockade of the CCR9/CCL25 interaction inhibits lymphocyte homing to the intestinal mucosa, thereby limiting inflammation and disease at this site.

Areas covered: This review details the current research on CCR9 antagonism and summarizes available clinical trial data for vercirnon, a selective CCR9 antagonist currently under development.

Expert opinion: If the results of ongoing large-scale clinical trials of vercirnon are in line with preliminary reports, CCR9 antagonism may have comparable efficacy to anti-TNF therapies and a potentially superior safety profile, making it the latest addition to the growing arsenal of immunomodulatory drug therapies available to combat Crohn's disease. Moreover, since vercirnon is an oral drug, its associated costs will likely be much lower than expensive infusion-based anti-TNF therapies, providing further economic benefits.     

Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease

The influence of prednisone(PR), sulfasalazine(SZ), cimetidine(CM), and phenobarbital(PB) on the pharmacokinetics of metronidazole was investigated in six Crohn's patients. Metronidazole was first administered alone (250 mg bid, po) and then with prednisone (10 mg bid, po), sulfasalazine (1 g bid, po), cimetidine (600 mg bid) or phenobarbital (60 mg bid, po). Each regimen was followed for 6 days and sampling of blood and urine was carried out on the 7th day after the first dose of each regimen. Plasma and urine samples were analysed for the drug and its two principal metabolites, hydroxymetronidazole and metronidazole-1-acetic acid, by HPLC. When given alone, metronidazole had a mean volume of distribution of 0.667 +/- 0.15 lkg-1, a half-life of 9.7 +/- 3.1 h and an oral clearance of 0.852 +/- 0.23 (ml-1 min) kg-1. The disposition kinetics of metronidazole and its metabolites was not altered by CM and SZ. Induction of metabolism of metronidazole by PR was made manifest in significant increases in oral clearance of the former and urinary excretion of the hydroxy metabolite, and significant decrease in AUC of the parent compound. PB also induced the metabolism of metronidazole. This induction was reflected in significant increases in the oral clearance of metronidazole and AUC of the hydroxy metabolite as well as significant decreases in AUC, half-life, and urinary excretion of the parent drug.     

Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn's disease

ABSTRACT

Objectives: The long-term effect of infliximab on endoscopic and histologic disease activity and expression of inflammatory markers was assessed in Crohn's disease patients who received infliximab as episodic or scheduled maintenance therapy over 54 weeks (ACCENT I).

Methods: All patients received infliximab 5?mg/kg at week 0 and at week 2 were then randomized as responders or nonresponders to placebo or infliximab (5 or 10?mg/kg). Patients received placebo or infliximab 5?mg/kg at weeks 2 and 6 followed by placebo or infliximab (5 or 10?mg/kg) every 8 weeks or episodically on loss of response. Crohn's Disease Activity Index (CDAI), Crohn's Disease Endoscopic Index of Severity (CDEIS), Inflammatory Bowel Disease Questionnaire (IBDQ), and colonic and ileal Global Histologic Disease Activity (CGHAS and IGHAS) scores were determined at weeks 0, 10, and 54. Tumor necrosis factor-alpha (TNF‐α), gelatinase B, infliximab, tenascin, clusters of differentiation marker 68 (CD68), and intercellular adhesion molecule‐1 (ICAM‐1) were detected in mucosal biopsies by immunohistochemistry.

Results: At baseline, CDEIS significantly correlated with CGHAS only. Further at baseline, both CDEIS and the worst CGHAS or IGHAS, were significantly correlated with CD68, ICAM‐1, and gelatinase B expression. At week 10, improvement in CGHAS only, correlated significantly with better CDAI, CDEIS, and IBDQ scores. Improvements in CDEIS and GHAS at week 10 correlated with reductions in gelatinase B and CD68, whereas only GHAS improvement correlated with decreased TNF‐α expression. At week 54, decreased gelatinase B expression continued to correlate with improved CDEIS and GHAS while decreased CD68 and TNF-α expression correlated with GHAS and CDEIS improvement, respectively.

Conclusions: Endoscopic and histologic evidence of mucosal healing was associated with a sustained reduction in the expression of inflammatory markers. Infliximab-induced improvement in the clinical signs and symptoms of Crohn's disease was associated with endoscopic and histologic evidence of sustained mucosal healing.     

Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity

AIM

Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn''s disease (CD), a disease for which the disease severity can be readily ranked.

METHODS

We administered 80 mg verapamil orally to (i) healthy control subjects (n = 9), (ii) patients with clinically quiescent CD (n = 22) and (iii) patients with clinically active CD (n = 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index.

RESULTS

CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r = 0.86, P < 0.0006),

CONCLUSIONS

CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.     

Apomorphine therapy in Parkinson's disease: a review

Motor fluctuations are common and distressing for patients with advanced Parkinson's disease. Subcutaneous apomorphine injections can be an extremely valuable adjunctive therapy. In this review, the authors discuss the history, pharmacology, efficacy, safety and proper administration of apomorphine for treating ‘off’ states in Parkinson's disease, with a focus on intermittent subcutaneous administration.     

Development and validation of an optical biosensor for rapid monitoring of adalimumab in serum of patients with Crohn's disease

Therapeutic drug monitoring of adalimumab is recommended to improve therapeutic outcome in patients with Crohn's disease. Performing an ELISA requires a rather long time‐to‐result and the necessity of collecting multiple samples to decrease the cost per adalimumab determination. In this study, we aim to develop and validate a rapid assay suitable for measuring a single adalimumab serum sample using a fiber‐optic surface plasmon resonance (FO‐SPR) based sensor. Therefore, we have immobilized MA‐ADM28B8 as capture antibody on an FO‐probe and conjugated MA‐ADM40D8 as detecting antibody to gold nanoparticles. A dose–response curve ranging from 2.5 to 40 ng/mL adalimumab was obtained in 1/400 diluted serum. Serum samples of patients with adalimumab concentrations between 1 and 16 μg/mL were measured whereas the negative control, a sample spiked with infliximab at a concentration of 16 μg/mL, showed no significant signal. Using a pre‐functionalized FO‐probe, the technology requires less than 45 minutes for measuring a single sample. Comparison of measurements between the biosensor and the ELISA revealed an excellent agreement with a Pearson r coefficient of 0.99 and an intra‐class coefficient of 0.99. The reduced assay time and the possibility of measuring a single sample are major advantages compared to the ELISA. The developed and validated optical adalimumab biosensor could be a valuable point‐of‐care diagnostic tool for adalimumab quantification in patients with Crohn's disease.     

炎症性肠病的药物治疗现状

炎症性肠病（inflammatory bowel disease,IBD）目前是消化系统疾病的研究热点之一,主要包括溃疡性结肠炎（ulcerative colitis,UC）和克罗恩病（Crohn''s disease,CD）,其发病机制尚未完全阐明,也尚无针对IBD的有效治疗药物。随着对IBD发病机制的深入研究,出现了一些新型药物和制剂。笔者就IBD及其药物治疗的研究现状作一简要综述。