Immunosuppressant therapy of inflammatory bowel disease. Pharmacologic and clinical aspects

The history of immunosuppressant drug use, both azathioprine (Aza) and 6-mercaptopurine (6-MP), in inflammatory bowel disease (IBD) over the past 20 years is briefly reviewed. The two drugs appear identical in their pharmacologic and biologic effects. Azathioprine is converted to 6-MP while in the body. Conflicting reports on the effectiveness of Aza have been published. The major National Cooperative Crohn's Disease Study (NCCDS) has found no advantage in Aza over placebo. In contrast, 6-MP was found to be effective in a large randomized trial. The shortcomings of the NCCDS reports are discussed with possible explanations for their negative findings. Our own studies, dating from 1968, are reviewed with 38 patients having been treated for up to 18 years, always in combination with small doses of steroids. Our results with Aza are similar to those of Present and Korelitz with 6-MP; about 70% of previously intractable patients improved substantially. Both Aza and 6-MP bring about healing and closure of most fistulas. Side effects can be serious but are usually manageable and, to some extent, preventable by appropriate dosage schedules. Since Aza has been approved for another benign, presumably autoimmune disease--rheumatoid arthritis--and because of its extensive use in other autoimmune diseases, we prefer to use Aza in selected patients with Crohn's disease who have failed to respond to more conventional modes of therapy. The use of immunosuppressants in ulcerative colitis is less clearly indicated.     

Occupational mortality of inflammatory bowel disease

A characteristic pattern in the occupational distribution of idiopathic inflammatory bowel disease (IBD) could help to focus research with regard to its etiology or reveal the nature of possible environmental risk factors. The present study analyses occupational mortality from Crohn's disease and ulcerative colitis in England and Wales during 8 consecutive years. Mortality of various occupations was expressed as proportional mortality ratio (PMR) or standardized mortality ratio (SMR). From 1979 to 1986, 321 men aged 16-74 years died from Crohn's disease, and 406 men died from ulcerative colitis. The respective number in women were 561 and 429. In men, there was a correlation between PMR and SMR among various occupations, with r = 0.80 and 0.65 for Crohn's disease and ulcerative colitis, respectively. A relatively low occurrence of male IBD was found in occupations associated with physical work, lower social status, and farming. By contrast, high mortality from IBD tended to be associated with physically less demanding work, sedentary occupations, and type of work which is done indoors.     

Hospitalizations and in-hospital mortality for inflammatory bowel disease in Brazil

BACKGROUND Inflammatory bowel disease(IBD)is associated with complications,frequent hospitalizations,surgery and death.The introduction of biologic drugs into the therapeutic arsenal in the last two decades,combined with an expansion of immunosuppressant therapy,has changed IBD management and may have altered the profile of hospitalizations and in-hospital mortality(IHM)due to IBD.AIM To describe hospitalizations from 2008 to 2018 and to analyze IHM from 1998 to 2017 for IBD in Brazil.METHODS This observational,retrospective,ecological study used secondary data on hospitalizations for IBD in Brazil for 2008-2018 to describe hospitalizations and for 1998-2017 to analyze IHM.Hospitalization data were obtained from the Hospital Information System of the Brazilian Unified Health System and population data from demographic censuses.The following variables were analyzed:Number of deaths and hospitalizations,length of hospital stay,financial costs of hospitalization,sex,age,ethnicity and type of hospital admission.RESULTS There was a reduction in the number of IBD hospitalizations,from 6975 admissions in 1998 to 4113 in 2017(trend:y=-0.1682x+342.8;R²=0.8197;P<0.0001).The hospitalization rate also decreased,from 3.60/100000 in 2000 to 2.17 in 2010.IHM rates varied during the 20-year period,between 2.06 in 2017 and 3.64 in 2007,and did not follow a linear trend(y=-0.0005049x+2.617;R²=0,00006;P=0.9741).IHM rates also varied between regions,increasing in all but the southeast,which showed a decreasing trend(y=-0.1122x+4.427;R²=0,728;P<0.0001).The Southeast region accounted for 44.29%of all hospitalizations.The Northeast region had the highest IHM rate(2.86 deaths/100 admissions),with an increasing trend(y=0.1105x+1.110;R²=0.6265;P<0.0001),but the lowest hospitalization rate(1.15).The Midwest and South regions had the highest hospitalization rates(3.27 and 3.17,respectively).A higher IHM rate was observed for nonelective admissions(2.88),which accounted for 81%of IBD hospitalizations.The total cost of IBD hospitalizations in 2017 exhibited an increase of 37.5%compared to 2008.CONCLUSION There has been a notable reduction in the number of hospitalizations for IBD in Brazil over 20 years.IHM rates varied and did not follow a linear trend.     

Geographic variation in the incidence of and mortality from inflammatory bowel disease

The geographic and temporal variations in mortality from Crohn's disease and ulcerative colitis were investigated. The validity of mortality data as indicators of morbidity was tested by comparing the death rates and incidences among different countries. Death rates from Crohn's disease and ulcerative colitis were high in England, Germany, and the Scandinavian countries, and low in the Mediterranean countries. There was a significant correlation between the incidence and mortality of both diseases among different countries. In addition, the incidence and mortality of Crohn's disease were correlated with those of ulcerative colitis. In countries with a low mortality rate from Crohn's disease, the death rates in men tended to be higher than those in women. In contrast, countries with high death rates from Crohn's disease showed female predominance. No such relationship existed for ulcerative colitis. The overall change in mortality rates during the last 20 to 30 years was characterized by a rise of Crohn's disease and a marked fall of ulcerative colitis. In countries with a high mortality rate from Crohn's disease, the death rates started to fall in recent times. The significant correlations between incidence and mortality show that the death rates from both diseases represent reliable indicators of the morbidity and that the severity of the two diseases is similar in different countries. The marked temporal and geographic variations in both incidence and mortality suggest that environmental factors play an important role in the etiology of both diseases. Supported by grant number So 172/1-1 from the Deutsche Forschungsgemeinschaft.     

Similar geographic variations in mortality from peptic ulcer and inflammatory bowel disease

BACKGROUND: The epidemiology of peptic ulcer and inflammatory bowel disease shows many similar patterns. The aim of the present study was to compare the geographic distribution of mortality from peptic ulcer with that from inflammatory bowel disease. METHODS: Mortality data from 27 countries between 1991 and 2004 were analyzed. The relationships between the geographic distributions of mortality from gastric ulcer, duodenal ulcer, Crohn's disease, and ulcerative colitis were compared using least-squares linear regression analyses. RESULTS: The study revealed a 20- to 30-fold variation in mortality from peptic ulcer and a 60-fold variation in mortality from inflammatory bowel disease among different countries. Mortality from peptic ulcer and inflammatory bowel disease tended to be more common in northern European countries and rare in most countries in Asia and South America. The similar variations of all 4 diseases resulted in the correlations among their geographic distributions being statistically significant. CONCLUSIONS: The similarities in the geographic distributions of gastric ulcer, duodenal ulcer, Crohn's disease, and ulcerative colitis indicate that all 4 diseases may share a common set of risk factors.     

Period and generation effects on mortality from idiopathic inflammatory bowel disease

To test the hypothesis that environmental factors play a role in idiopathic inflammatory bowel disease (IBD), age, period, and generation (cohort) effects on IBD mortality in the United Kingdom and the United States were examined. The crude death rate of ulcerative colitis has declined since 1930. Plotted versus the year of birth, its age-specific death rates showed an initial rise in successive generations born between 1850 and 1900, followed by a fall in all later generations. The crude death rate of Crohn's disease increased from 1950 to 1974 and then declined. When the age-specific death rates for Crohn's disease and ulcerative colitis were superimposed, the mortality from Crohn's disease in each age group or sex began to decline at a different time, but always upon reaching the level of mortality from ulcerative colitis. It appears as if the gradual disappearance of an ulcerative colitis-associated factor in a birth-cohort fashion prevented a further rise in mortality from Crohn's disease after 1974.This study was supported by grant So 172/1-1 from the Deutsche Forschungsgemeinschaft. Part of this work was presented at the 89th meeting of the American Gastroenterological Association in New Orleans, May 16, 1988 (1).     

Small bowel length in inflammatory bowel disease

Small intestinal length has a particular significance in patients with inflammatory bowel disease (IBD). A determination of intestinal length by a standardised and simple technique is of interest for surgical decision making in primary and recurrent disease and in the evaluation and management of postoperative malabsorption. The aim of the present investigation was to analyse intestinal length in patients with IBD and define a standard method for this measurement. Material and methods: Two consecutive series of patients, Crohn's disease (n = 279) and ulcerative colitis (n = 315) and a control group (n = 77) underwent standardised intra-operative small intestinal length measurement. Results: Small intestinal length correlated to weight and height and was less in women than in men (P < 0.001) in both IBD groups and the controls. The small bowel in patients with Crohn's disease was significantly shorter than in patients with ulcerative colitis and in controls, P < 0.001. Also in Ulcerative Colitis small bowel length was significantly less than in controls, P < 0.001. In CD patients there was no difference in bowel length with regards to the anatomical extent of the disease. Original small bowel length in patients with CD and one or two bowel resections (n = 67) was not different from that in patients with three or more resections (n = 88). Conclusion: Small bowel length correlated to weight, height and sex. Patients with CD had a significantly shorter small intestine at first laparotomy, compared with U.C. patients and controls. In CD-patients there was no difference between the anatomical subgroups.

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Résumé. La longueur de l'intestin grêle a une signification tout à fait particulière chez les patients atteints de maladie inflammatoire de l'intestin (IBD). Une détermination de la longueur de l'intestin au moyen d'une technique standardisée et simple est utile lors d'une prise de décision chirurgicale chez des patients atteints de manière primaire ou récurrente de la maladie et dans l'évaluation et le management des troubles d'absorption postopératoire. Le but de la présente étude est d'analyser la longueur de l'intestin chez des patients atteints d'IBD et de définir une méthode standard de mesure. Materiel et methode: Deux séries consécutives de patients atteints de maladie de Crohn (n = 279) et de colite ulcéreuse (n = 315) ainsi qu'un groupe-contr?le (n = 77) ont fait l'objet d'une mesure standardisée per-opératoire de la longueur de l'intestin. Resultats: La longueur de l'intestin est corrélée au poids et à la taille et est plus petite chez les femmes que chez les hommes (P < 0,001) dans les deux groupes de maladie inflammatoire et dans le groupe-contr?le. L'intestin grêle des patients atteints de maladie de Crohn est significativement plus court que celui des patients atteints de colite ulcéreuse et que celui du groupe-contr?le (P < 0,001). De même que l'intestin grêle des patients atteints de colite ulcéreuse est significativement plus court que celui des groupes-contr?le (P < 0,001). Chez des patients atteints de maladie de Crohn, il n'y a pas de différence dans la longueur de l'intestin en relation avec l'étendue de la maladie anatomique. La longuer initiale de l'intestin chez les patients atteints de maladie de Crohn ayant fait l'objet d'une ou de deux résections segmentaires (n = 67) n'est pas significativement différente de celle mesurée chez les patients faisant l'objet de 3 ou plus résections (n = 88). Conclusion: La longueur de l'intestin grêle est corrélée au poids, à la taille et au sexe. Les patients porteurs d'une maladie de Crohn ont un intestin grêle significativement plus court à la première laparotomie que ceux atteints de colite ulcéreuse ou que les sujets-contr?le. Chez les patients porteurs de maladie de Crohn, il n'y a pas de différence significative entre les différents sous-groupes anatomiques.

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Accepted: 11 March 1997     

Joint disease in inflammatory bowel disease

The joint disorders taxonomically included in the group of seronegative spondyloarthropathies under the generic name of enteropathic arthropathy represent the most frequent extra-intestinal manifestation of inflammatory bowel disease (IBD), affecting 33% of patients. Their frequency is similar to that of ulcerative colitis and Crohn's disease. Enteropathic arthropathy consists of two main joint alterations, peripheral and axial arthritis, as well as a variable group of other peri-articular disorders. Type 1, or pauciarticular, peripheral arthritis generally coincides with IBD exacerbations, while type 2, or polyarticular, peripheral arthritis follows an independent course from IBD. Axial involvement precedes and follows an independent course from IBD and can behave as ankylosing spondylitis or asymptomatic sacroiliitis. The treatment of these rheumatologic disorders is based on the application of general measures and the use of nonsteroidal anti-inflammatory agents; intraarticular corticosteroid administration may eventually become necessary. Sulphasalazine and/or infliximab, which are indicated when the previously mentioned measures fail, can be used to treat both the articular and intestinal diseases simultaneously.     

Hepatobiliary disease in inflammatory bowel disease

Many hepatobiliary diseases are seen in IBD. PSC is the most common, occurring in 7.5% of patients with UC. The cause of PSC is not well understood, but PSC seems to be associated with genetic susceptibility, sharing some immunologic abnormalities with UC. A characteristic cholangiogram in a patient with abnormal liver function tests usually establishes the diagnosis. Liver biopsy is not essential but can help make the diagnosis of small duct PSC in patients with a normal cholangiogram. There are no medications that treat PSC effectively. Endoscopic dilation of dominant strictures reduces the frequency of cholangitis and may improve survival. OLT remains the only proven treatment of advanced PSC. Cholangiocarcinoma is a feared complication of PSC that is difficult to diagnose. Cholelithiasis, PBC, portal vein thrombosis, and hepatic abscess are hepatobiliary disorders that occur less frequently in IBD patients.     

Functional bowel disorders in inflammatory bowel disease

Patients with IBD in remission often have ongoing gastrointestinal symptoms that are related to active inflammation. It is now apparent that functional gastrointestinal disorders may overlap with IBD and increase morbidity and diminish the quality of life of patients. Recognition and treatment of functional symptoms that may be the result of IBD are crucial in the appropriate medical management of these patients.     

肠易激综合征与炎症性肠病

近年发现,炎症性肠病(IBD)患者发病早期或缓解期时常表现为肠易激综合征(IBs)症状,且IBD与IBS的临床表现具有一定的相似性。因而IBS与IBD的相关性受到广泛的重视。此文就IBS与IBD的发病机制及临床相关性予以阐述,以期为临床个体化治疗提供借鉴。     

Hyperamylasemia in inflammatory bowel disease

We determined the prevalance and significance of hyperamylasemia in 180 patients with idiopathic inflammatory bowel disease (IBD) (83 with ulcerative colitis, and 97 with Crohn's disease). Serum total amylase and pancreatic and salivary isoamylase activity were measured in all patients. In all patients with hyperamylasemia, we measured isoamylase activity by cellulose acetate electrophoresis and lipase activity, assayed for the presence of macroamylase, and carried out pancreatic ultrasound examination and barium studies of the upper gastrointestinal tract. Eight of 97 patients with Crohn's disease (8%) had hyperamylasemia; 4 of them had an elevated pancreatic isoamylase and 2 a raised lipase activity. All patients with hyperamylasemia had normal ultrasonographic scans of the pancreas and no evidence of duodenal involvement on barium meal. None had macroamylasemia. We found no relationship of hyperamylasemia to disease site, activity, and duration or therapy and no patient developed clinical evidence of pancreatitis. We conclude that a small but important number of patients with Crohn's disease have hyperamylasemia not associated with overt pancreatitis. In the absence of appropriate indications, it requires no investigation.     

Cancer in inflammatory bowel disease

Patients with long-standing inflammatory bowel disease （IBD） have an increased risk of developing colorectal cancer （CRC）. Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeox, ycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn＇s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal- anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.     

Nutrition in inflammatory bowel disease

The nutritional impact of inflammatory bowel disease is notable, both in Crohn’s disease and ulcerative colitis. The causes of malnutrition include decreased intake, maldigestion, malabsorption, accelerated nutrient losses, increased requirements, and drug-nutrient interactions. Inflammatory bowel disease causes alterations in body composition and, because of these changes, affects energy expenditure. Various approaches have been most effective in correcting malnutrition, supporting growth, and managing short-bowel syndrome, but the success of primary therapy has been limited.     

Gallstones in inflammatory bowel disease

Chronic disease of the terminal ileum is associated with a high prevalence of gallstones. To decide whether the ileal location of the disease is responsible for this finding, we determined the prevalence of gallstones in 189 patients with all types of inflammatory bowel disease. The prevalence of gallstones in patients with disease involving the terminal ileum (regional enteritis and granulomatous ileocolitis) was 28.2% compared to a prevalcolon (ulcerative colitis and granulomatous colitis),P<.001. The prevalence of gallstones in a hospital comparison population, age and sex matched to the regional enteritis-granulomatous ileocolitis group, was 11.7%,P<.01. In patients with disease of the ileum, the presence of gallstones was correlated with the length of ileum involved (P<.001), ileal resection (P<.02), and duration of disease (P<.001). The data suggest that the ileal location of the disease is of major importance.     

Chemokines in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively termed inflammatory bowel diseases (IBD), represent chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract that are charcterized by leukocytic infiltration of the intestinal mucosa and submucosa. In CD, the inflammation is transmural and frequently associated with granuloma formation. Chemokines have emerged as the most important regulators of leukocyte trafficking during infection or inflammation and, therefore, have been implicated in the pathogenesis of IBD. In this review, recent advances on the role of chemokines and their receptors in mucosal immunity and inflammation are discussed, and the potential use of chemokine/chemokine-receptor antagonists as novel therapeutic targets for the treatment of human IBD is highlighted.     

Nutrition in inflammatory bowel disease

Nutrition has an important role in the management of inflammatory bowel disease. This role includes the prevention and correction of malnutrition, the prevention of osteoporosis and in children the promotion of optimal growth and development. In active Crohn's disease nutritional therapy (in the form of enteral feeding) is an effective primary therapy for many patients. Corticosteroids, however, are more effective than enteral diet therapy in adults. Enteral diets should be considered as primary therapy in pediatric Crohn's disease, especially in children with poor nutritional status or growth impairment. Enteral nutrition does not have a proven primary therapeutic role in ulcerative colitis. There are many theories that suggest that diet may be implicated in the aetiology of inflammatory bowel disease, however, there are, as yet, no dietary approaches proven to reduce the risk of developing IBD.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

Anemia in inflammatory bowel disease

Anemia is a frequent extraenteric complication of inflammatory bowel disease (IBD, Crohn's disease and ulcerative colitis). A systematic review of the literature shows that the overall prevalence of anemia ranges from 8.8% to 73.7% but differs whether in a setting of Crohn's disease or ulcerative colitis. A disabling complication of IBD, anemia worsens the patient's general condition and quality of life, and increases hospitalization rates. Different factors, including vitamin B12 and folic acid deficiency, bone marrow suppression secondary to drug therapy, autoimmune hemolytic anemia and the coexistence of myelodysplastic syndromes are involved in the pathogenesis of anemia in IBD. The main types of anemia in IBD are iron deficiency anemia and anemia accompanying chronic diseases. Correct diagnostic definition of anemia is a fundamental step in guiding the choice of therapeutic options, since the co-presence of different pathogenetic factors may sometimes require a more complex treatment plan. A review of anemia in IBD, its pathogenetic features, epidemiology, diagnosis and therapy based on evidence from recent studies is the focus of this article.