Current Therapeutic Apheresis Technologies for Inflammatory Bowel Disease

Abstract: A large number of physicians have indicated that patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) respond to current apheresis technology treatment. However, the mechanism of the apheresis procedure is undefined for patients with IBD. IBD appears to be caused by a complex of interactions from the genes, environment, and the immune system; therefore, the immune system plays a crucial role in the inflammatory responses. In this process, lots of interactions occur simultaneously, and they cross relate with each other. This review paper briefly discusses the etiology and pathogenesis of IBD and attempts to elucidate the mechanism that occurs after apheresis treatment.     

Inflammatory Bowel Disease in Children, an Evolving Problem in Kuwait

Background/Aims:

Inflammatory bowel disease (IBD) was previously thought a rare disease among children in Kuwait since most diarrhea cases were attributed to infections. In the past few years we observed an increase in the number of patients presenting with IBD. In this study we aimed to determine the epidemiology of IBD among children in the State of Kuwait.

Patients and Methods:

The charts of all children with IBD who were referred to the pediatric gastroenterology unit during the period February 1998 to January 2008 were retrospectively reviewed.

Results:

Out of a total of 130 children with IBD, 92 (71%) had Crohn''s disease, 36 (28%) had ulcerative colitis and two (1%) had indeterminate colitis. The estimated annual incidence for IBD was 2.16/10⁵ /year. The age range was nine months-15 years (median: 11 years). Fifty-three percent of all patients were females and 77% were Kuwaiti nationals. Positive family history was found in 23%. The commonest presenting symptoms were abdominal pain (87%) and diarrhea (82%). Failure to thrive was detected in 35% and short stature in 20% at presentation. The ileocolonic region was the most common presentation site affected in Crohn''s patients and pancolitis was the commonest in ulcerative colitis.

Conclusion:

Inflammatory bowel disease is not uncommon in our children. We found no differences regarding disease presentation and clinical features compared to the Western world.     

A Saudi Gastroenterology Association Position Statement on the Use of Tumor Necrosis Factor-alfa Antagonists for the Treatment of Inflammatory Bowel Disease

The objective of this position statement from the Saudi Gastroenterology Association is to guide gastroenterologists on the use of tumor necrosis factor-alfa (TNF-α) antagonists for the treatment of the idiopathic inflammatory bowel diseases, Crohn''s disease, and ulcerative colitis. In this article, we summarize the relevant literature regarding the safety and efficacy of TNF-α antagonists, highlight relevant safety concerns specific to the environment in Saudi Arabia, and provide specific recommendations for the use of these agents.     

Effect of the Coronavirus Disease 2019 Lockdown on Lifestyle Factors in Japanese Patients with Inflammatory Bowel Disease

Objective To examine the effect of the coronavirus disease 2019 (COVID-19) lockdown on lifestyle factors and psychological stress in patients with inflammatory bowel disease (IBD). Methods A retrospective study was conducted on patients with IBD in Japan 2 months after the initiation of the first state of emergency (June 16 to August 21, 2020). A self-reported questionnaire was used to collect data, and lifestyle factors and psychological stress levels before and after the state of emergency were compared. Patients Patients with IBD who were followed up regularly at Osaka City University Hospital from June 16 to August 21, 2020, were included and were classified into elderly (≥65 years old) and non-elderly groups (<65 years old). Results The study sample comprised 451 responders (241, ulcerative colitis; 210, Crohn''s disease; 0, COVID-19). The sleep duration increased, whereas the exercise, working, and walking durations decreased during the COVID-19 lockdown. The proportion of patients with psychological stress due to COVID-19, those with an inability to exercise, and those staying indoors increased significantly during COVID-19 lockdown. Lifestyle factors changed more markedly in non-elderly patients, those who were more stressed due to COVID-19, those with the inability to exercise, and those staying indoors during COVID-19 lockdown. Among elderly patients, no significant changes were identified in stress-causing factors. Conclusion The COVID-19 lockdown affected lifestyle factors and psychological stress in patients with IBD, particularly non-elderly patients. These findings may be helpful in suggesting favorable lifestyle changes for patients with IBD.     

Retrospective Single Center Study of Granulocyte Monocyte Adsorption Apheresis Treatment in Inflammatory Bowel Disease

Patients with active inflammatory bowel disease (IBD) have elevated and activated myeloid leukocytes, which infiltrate the intestinal mucosa. A significant proportion of IBD patients do not respond adequately to conventional treatment regimes. Studies have suggested that treatment with granulocyte monocyte apheresis (GMA) could be a safe and efficacious alternative for these patients. We evaluated the efficacy and safety of granulocyte/monocyte apheresis in patients with IBD in a retrospective cohort study, conducted from a single center in Stockholm. Clinical details from consecutive apheresis treated patients were retrospectively reviewed from 2004 to 2012. A total of 37 patients were included, 23 patients with ulcerative colitis (UC) and 14 with Crohn's disease (CD). Clinical response was seen in 11 patients (30%) and complete remission in 11 patients (30%). The remission rate was higher in UC patients compared to CD patients, 39% (N = 9) and 14% (N = 2) respectively. A total of 9 patients experienced adverse events. Most frequently reported was headache (N = 4). GMA seems to be a valuable adjuvant treatment regime in the care of patients with refractory IBD.     

Primary Sclerosing Cholangitis and Inflammatory Bowel Disease: A Review

Primary sclerosing cholangitis is a disease affecting around 0.006–0.016% of the population. Of these, around 75% have concomitant inflammatory bowel disease (IBD) according to the most recent epidemiological studies. Several theories have been proposed regarding the pathogenesis of primary sclerosing cholangitis (PSC). These include changes in the function of cholangiocytes, effects of the gut microbiome, association with specific human leukocyte antigen haplotypes and dysregulation of the immune system. However, these do not explain the observed association with IBD. Moreover, there are considerable differences in the frequency and outcomes between patients with PSC and ulcerative colitis compared with PSC and Crohn’s disease. The aim of this review is to appraise the most recent studies that have contributed to the epidemiology, advances in the pathophysiology, and characterization of important clinical aspects of the association of PSC and IBD.     

Emerging Inflammatory Bowel Disease in Saudi Outpatients: A Report of 693 Cases

Background/Aim:

Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology and considered traditionally as a disease of the western world. Recently, rising trends have been observed in countries previously known to have a low prevalence and incidence. The aim of this study is to collect epidemiological data on IBD outpatients and to add data from the Kingdom of Saudi Arabia (KSA) to the available IBD literature.

Patients and Methods:

The medical records of 693 Saudi patients with IBD over a period of 17 years, between 1993 and 2009, were reviewed. The demographic and clinical data and methods of diagnosis were retrieved.

Results:

The total number of patients in this cohort was 693. It constituted 238 (34.3%) ulcerative colitis (UC) and 455 (65.7%) Crohn''s disease (CD) patients. UC was steady throughout the years, whereas only 1.2 CD patients were diagnosed per year in the first 11 years, and 73.7 per year in the last six years. The median age of UC patients was 34 years, ranging from 10 to 80 years with a peak between 21 and 40 years and in CD it was 27 years, ranging from 11 to 73 years with a peak between 11 and 30 years. There was a male preponderance of 1.5:1 and 2:1, respectively. The rest of the data is discussed in this study.

Conclusion:

IBD is no longer a rare disease in KSA. UC is in a steady state, whereas CD is increasing significantly and far outnumbering UC.     

Fecal Microbiota Transplantation in Inflammatory Bowel Disease: A Primer for Internists

Inflammatory bowel disease consists of disorders characterized by chronic idiopathic bowel inflammation. The concept of host–gut–microbiome interaction in the pathogenesis of various complex immune-mediated chronic diseases, including inflammatory bowel disease, has recently generated immense interest. Mounting evidence confirms alteration of intestinal microflora in patients with inflammatory bowel disease. Thus, restoration of normal gut microbiota has become a focus of basic and clinical research in recent years. Fecal microbiota transplantation is being explored as one such therapeutic strategy and has shown encouraging results in the management of patients with inflammatory bowel disease.     

Use of biosimilars in inflammatory bowel disease: Statements of the Italian Group for Inflammatory Bowel Disease

The introduction of biological therapies, particularly anti-TNFα agents, has revolutionized the management of inflammatory bowel disease in those cases which are refractory to conventional treatment; however these drugs are not risk-free and their use has substantially increased the cost of treatment. As marketing protection expires for original, first-generation biopharmaceuticals, lower-cost “copies” of these drugs produced by competitor companies—referred to as biosimilars—are already entering the market. In September 2013, the European Medicines Agency approved two infliximab biosimilars for treatment of adult and paediatric inflammatory bowel disease patients, a decision based largely on efficacy and safety data generated in studies of patients with ankylosing spondylitis and rheumatoid arthritis. For many clinicians, extrapolation practices and the general question of interchangeability between biosimilars and reference biologics are cause for concern. In the present paper, the Italian Group for inflammatory bowel disease presents its statements on these issues, with emphasis on the peculiar clinical characteristics of inflammatory bowel disease and the importance of providing physicians and patients with adequate information and guarantees on the safety and efficacy of these new drugs in the specific setting of inflammatory bowel disease.     

Risk Factors for Vitamin D Deficiency in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background: To identify risk factors for hypovitaminosis D in inflammatory bowel disease and conduct a comprehensive systematic review with meta-analysis to quantify the impact on vitamin D deficiency.Methods: We conducted a literature search of studies through PubMed, Embase, Cochrane Library, and Web of Science. In addition, relevant articles were searched manually. Studies were included if the odds ratios (OR) and 95% CI of each risk factor were reported or could be calculated. We will use the fixed-effects or random-effects model to estimate the pooled effect.Results: Out of 1018 articles, 25 eligible studies were identified, including 5826 participants. The risk factors associated with hypovitaminosis D were non-Caucasian (OR: 3.79, 95% CI: 2.68-5.34), Crohn’s disease (OR: 1.38, 95% CI: 1.21-1.56), disease activity (OR: 1.85, 95% CI: 1.61-2.13), inflammatory bowel disease-related surgery (OR: 1.61, 95% CI: 1.38-1.89), exposure to steroid (OR: 1.61, 95% CI: 1.28-2.03), and biologics (OR: 1.78, 95% CI: 1.48-2.14). In 30 ng/mL and adjusted OR subgroup, male (OR: 1.84, 95% CI: 1.47-2.31) and winter season (OR: 2.49, 95% CI: 1.69-3.67) also were risk factors, respectively. 5-aminosalicylic acid (OR: 1.10, 95% CI: 0.74-1.63) and smoking (OR: 1.19, 95% CI: 0.98-1.45) were unrelated to vitamin D deficiency.Conclusions: For vitamin D deficiency in inflammatory bowel disease, non-Caucasian, Crohn’s disease, disease activity, surgery, exposure to steroid and biologics, males are risk factors, while 5-aminosalicylic acid and smoking are not. The relationship between body mass index, winter season, exposure to immunomodulators, and vitamin D deficiency remains unclear.     

Efficacy of a Novel Granulocyte Monocyte Apheresis Adsorber Device in the Treatment of Inflammatory Bowel Diseases: A Pilot Study

Granulocyte monocyte apheresis (GMA) is a non‐pharmacological treatment for inflammatory bowel disease. In our study, we tested a novel GMA adsorber device in terms of clinical efficacy and safety in patients’ non‐response to pharmacological therapy. Secondary outcomes were the evaluation of adsorber's technical performance, the reduction of inflammatory markers and the improvement of patients' life quality. The prospective study included 18 patients enrolled from 2011 to 2012 with a monitoring of 48 weeks. All patients with Crohn's disease achieved a clinical remission after GMA treatments, sustained until the end of follow up, while 80% of ulcerative colitis patients obtained a clinical benefit, maintained after 48 weeks of monitoring. Leukocytes, neutrophils, monocytes and platelets, compared to erythrocytes and lymphocytes, were effectively removed from peripheral blood. There was no statistically significant result about serological markers of inflammation. A consistent improvement of the patients' quality of life was observed up to the end of follow up. No significant side‐effects were recorded. Our study underlines the efficacy and the safety of this novel GMA adsorber device; a prospective randomized clinical trial with adequate sample size should be performed.     

Turner's Syndrome Associated with Chronic Inflammatory Bowel Disease. A Case Report and Review of the Literature

A 26-year-old woman with Turner's syndrome (45,X/46,X,i(Xq)) and Crohn's disease is reported. The inflammatory bowel disease was aggressive with development of intestinal fistulas. Total proctocolectomy was performed, and the patient recovered remarkably well postoperatively. The association of Turner's syndrome and inflammatory bowel disease is reviewed, with special reference to karyotype, severity, mortality and treatment.     

Advances in the Diagnosis and Management of Inflammatory Bowel Disease: Challenges and Uncertainties

Over the past two decades, several advances have been made in the management of patients with inflammatory bowel disease (IBD) from both evaluative and therapeutic perspectives. This review discusses the medical advancements that have recently been made as the standard of care for managing patients with ulcerative colitis (UC) and Crohn''s Disease (CD) and to identify the challenges associated with implementing their use in clinical practice. A comprehensive literature search of the major databases (PubMed and Embase) was conducted for all recent scientific papers (1990–2013) giving the recent updates on the management of IBD and the data were extracted. The reported advancements in managing IBD range from diagnostic and evaluative tools, such as genetic tests, biochemical surrogate markers of activity, endoscopic techniques, and radiological modalities, to therapeutic advances, which encompass medical, endoscopic, and surgical interventions. There are limited studies addressing the cost-effectiveness and the impact that these advances have had on medical practice. The majority of the advances developed for managing IBD, while considered instrumental by some IBD experts in improving patient care, have questionable applications due to constraints of cost, lack of availability, and most importantly, insufficient evidence that supports their role in improving important long-term health-related outcomes.     

Atopy in Inflammatory Bowel Disease

Thirty-nine patients with ulcerative colitis and 35 with Crohn's disease have been investigated for evidence of reaginic hypersensitivity and compared with control subjects. There was no difference in the frequency of a personal or family history of atopy or in serum IgE levels. Similarly, no overall difference was noted in prick test responses to 21 allergens. However, further analysis of prick test responses showed that patients with inflammatory bowel disease responded more frequently to food allergens. This was highly significant when compared with healthy controls (p < 0.001). The relevance of this finding to the aetiology of inflammatory bowel disease is discussed.     

The Role of Tacrolimus in Inflammatory Bowel Disease: A Systematic Review

Therapeutic management of inflammatory bowel disease remains beyond the limits of conventional therapy in many cases. Novel therapies used include tacrolimus, a new powerful immunosuppressive drug, employed in some case reports and a few studies that have tried to evaluate its effectiveness in Crohn’s disease and ulcerative colitis with promising results, but its role in the management of inflammatory bowel disease remains controversial. We performed a systematic review that analyzed a total of 23 reported experiences in 286 patients with inflammatory bowel disease treated with tacrolimus. Although most of the published studies are uncontrolled, short, and heterogeneous, promising results have been obtained in fistulizing disease, unresponsive cases of both ulcerative colitis and Crohn’s disease, and even extraintestinal manifestations. The overall outcome was good enough to consider tacrolimus as a rationale therapeutic option. However, comparative studies with standard therapeutic options like infliximab are needed to assess the correct role that tacrolimus may play in these patients.     

Review of Fecal Biomarkers in Inflammatory Bowel Disease

Purpose  We reviewed potential fecal biomarkers of inflammatory bowel disease and assessed their utility in a range of clinical applications. Methods  A literature search using PubMed, MEDLINE, and Embase database was performed, locating all language articles on fecal biomarkers, including calprotectin and lactoferrin. The references of these papers were searched manually for further references. Results  A wide range of fecal biomarkers have been evaluated in the research setting. Only fecal calprotectin and lactoferrin have translated into useful clinical tools. These biomarkers have demonstrated high sensitivity for organic intestinal disease and good correlation with other measures of disease activity in inflammatory bowel disease. Conclusions  Fecal calprotectin and lactoferrin are useful triage tools to differentiate organic intestinal disorders from functional disorders. They also have a role in monitoring inflammatory bowel disease activity and predicting relapse. Reprints are not available.     

Smoking Habits in Patients with Inflammatory Bowel Disease: A Case-Control Study

In a case-control study there were significantly fewer smokers among patients with ulcerative colitis both at disease onset and at interview, the relative risk compared with non-smokers being 0.33 and 0.12, respectively. Among female patients with Crohn's disease there were significantly more smokers, the relative risk being 2.70 and 2.33, respectively. Of the ex-smokers with ulcerative colitis, two-thirds became ill after they stopped smoking, and most of these during the first years after stopping. Neither in ulcerative colitis nor in Crohn's disease could any relation be found between the localization of disease and smoking habits at the time of diagnosis. The findings in the present study support the hypothesis that smoking may influence the course of inflammatory bowel disease.     

Potential of Measurements of Unsaturated Vitamin B12-Binding Capacity in Serial Colonoscopic Biopsy Specimens for Global and Regional Assessments of Disease Severity in Inflammatory Bowel Disease

We investigated whether measurements of unsaturated vitamin B|₂-binding capacity (UBBC), in homo-genates of serial colonoscopic biopsy specimens, could be used as objective measures of disease severity in ulcerative colitis (UC) and Crohn's disease (CD). On a regional basis UBBC activity correlated with and showed good agreement with endoscopic and histologic activity scores (r = 0.8 and 0.6, respectively, for UC, and r = 0.7 and 0.7, respectively, for CD). For global assessment aggregate UBBC, endoscopic and histologic scores were compared with standard clinical activity scores. In UC, correlations with the van Hees index were r = 0.7, 0.8, and 0.7, respectively, and UBBC assays accurately reflected both regional and global disease activity. In CD, correlations with the CDAI were -0.1, 0.7, and 0.6, respectively. Thus, aggregate UBBC scores failed to reflect disease activity in CD, in which focal deep ulcers may produce high symptom scores but in which adjacent specimens may show no accute inflammation.     

Association between CTLA-4 Gene Promoter (49 A/G) in Exon 1 Polymorphisms and Inflammatory Bowel Disease in the Tunisian Population

Background/Aim:

To investigate the possible association between the polymorphism of the CTLA-4 exon 1 +49 A/G and susceptibility to Crohn''s disease (CD) and ulcerative colitis (UC) in the Tunisian population.

Methods:

The +49 A/G dimorphism was analyzed in 119 patients with CD, 65 patients with UC, and 100 controls by the polymerase chain reaction–restriction fragment length polymorphism method.

Results:

Significantly higher frequencies of the CTLA-4 +49A allele and A/A homozygous individuals were observed in patients with CD when compared with controls (pc = 0.0023 and pc = 0.0003, respectively). Analysis of CTLA-4 A/G polymorphism with respect to sex in CD showed a significant difference in A/A genotypes between female patients and controls (pc = 0.0001 and pc = 0.038, respectively). There were no differences in the subgroups of patients with CD.

Conclusions:

Forty-nine A alleles and AA genotype are associated with CD susceptibility in Tunisians. Other genes involved in the T-cell regulation remain strong candidates for IBD susceptibility and require further investigation.