Oral locally active steroids in inflammatory bowel disease

IBD is a chronic and relapsing inflammatory disorder of the gut that demands long-lasting treatment targeting both flare-up periods and maintenance of remission. Oral systemic steroids have been used to induce remission in patients with active IBD for over 50 years due to their potent anti-inflammatory effects. The efficacy of systemic steroids in this setting has been largely demonstrated. However, the wide range of adverse events associated with these drugs has prompted the development of equally effective but less toxic steroid compounds. Currently, topically acting oral steroids are an important therapeutic option for Crohn's disease, ulcerative colitis and microscopic colitis, being oral budesonide and oral beclomethasone established elements of the IBD armamentarium. At present, oral budesonide is the first-line therapy to induce remission in microscopic colitis and mild to moderate ileocaecal CD patients and oral beclomethasone is effective treating mild to moderate UC patients with left-sided or extensive disease. This review aims at evaluating the current role of these compounds in IBD clinical practice.     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

CED: Standards in Diagnostik und Therapie

Over the last few years, German and European guidelines on Crohn’s disease (CD) and ulcerative colitis (UC) were developed. With regard to diagnostics, infectious causes, particularly Clostridium and cytomegalovirus, must be excluded initially and whenever patients do not respond to standard therapy. Acute flare-ups of UC are treated with 5-aminosalicylates (5-ASA) and/or corticosteroids either locally (enema, foam, or suppository), systemically, or both. For CD, oral steroids (e.g. budesonide) are preferred; 5-ASA play only a minor role. For maintenance, smokers with CD are strongly recommended to stop smoking. Steroids have no role in maintenance therapy. 5-ASA and azathioprine are recommended for maintenance of UC, and azathioprine also for CD. Refractory courses require methotrexate and anti-tumor necrosis factor-alpha antibodies, and surgery should always be discussed as alternative treatment in these patients. High-grade dysplasias or malignancy should always lead to proctocolectomy with construction of a pouch.     

Standard treatment of ulcerative colitis

Ulcerative colitis (UC) is an idiopathic, chronic inflammation of the colon which may present with a range of mild to severe symptoms. The disease may be localized to the rectum or can be more extensive and involve the left side of the colon or the whole colon. Treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. The key parameters to be assessed for the most appropriate treatment are the severity and extent of the inflammation. Meta-analyses of published trials have shown that topical treatment with 5-aminosalicylic acid (5-ASA) is the treatment of choice in active distal mild-to-moderate UC. Oral aminosalicylates are effective in both distal and extensive mild-to-moderate disease, but in distal disease, the rates of remission are lower than those obtained with topical 5-ASA. New steroids, such as budesonide and beclomethasone dipropionate (BDP), administered as enemas, constitute an alternative to 5-ASA therapy. In some studies, these have been shown to be as effective as conventional steroids but with significantly lower inhibition of plasma cortisol levels. Patients with unresponsive disease or those with more severe presentation will require oral corticosteroids and sometimes intravenous therapy. Approximately 10% of patients with unresponsive UC have severe attacks requiring hospitalization. Patients with severe disease should be managed jointly by a medical and surgical team, and intensive intravenous treatment should be started with high-dose steroids. Early recognition of failure of therapy will allow the introduction of immunosuppressive therapy with intravenous cyclosporine. Patients who respond are shifted to oral cyclosporine associated with azathioprine/6-mercaptopurine, whereas those who fail will require proctocolectomy. Oral aminosalicylates are the first-line therapy in maintenance of remission. Topical 5-ASA may play a role in distal disease. Patients who are steroid dependent can be started on azathioprine or 6-mercaptopurine although it may take up to 3 months for the treatment to become effective. They may have reversible immediate side effects, such as pancreatitis or bone marrow suppression, which disappear upon discontinuation of therapy. Close monitoring of these hematologic and biochemical parameters will improve safety. The use of biologic therapy with infliximab in more severe disease has not been established.     

5-ASA在炎症性肠病相关结直肠癌中的化学预防作用

癌变是溃疡性结肠炎(ulcerative colitis,UC)最严重的并发症,其预防手段包括内镜监测、分子生物标志物、手术治疗及化学预防。5-氨基水杨酸盐(5-aminosalicylic acid,5-ASA)是轻-中度UC患者的一线用药,其对炎症性肠病(inflammatory bowel disease,IBD)相关结直肠癌的化学预防作用及机制尚不十分明确。本文较全面地阐述5-ASA的化学预防作用及机制研究进展,旨在为临床实践中预防IBD相关癌变用药方案提供更多依据。     

Asian perspectives in the management of inflammatory bowel disease: Findings from a recent survey

Background and Aim:  The prevalence and incidence of inflammatory bowel disease (IBD) differs worldwide. While the prevalence of IBD has stabilized in Europe, the USA and Japan, an increasing trend has been observed in Asia. However, there are no data on the current clinical practice for the management of IBD in the region. The present study aims to investigate the number of existing and new cases of IBD and to understand the current practice of diagnosis and treatment of IBD in different Asian countries.
Methods:  A self-administered questionnaire, designed according to European and US guidelines, was distributed to IBD specialists throughout Asia. The questionnaire estimated the annual incidence of existing and new IBD cases in physicians' clinical practices and evaluated their procedures of diagnosis and preference for therapeutic treatment and maintenance treatment.
Results:  Eighty-seven questionnaires were received out of the 107 distributed. In the clinical practices of these 87 respondents, there were 502 existing and 73 new cases per year for ulcerative colitis (UC) and 202 existing and 32 new cases per year for Crohn's disease (CD). Colonoscopy and histology were the most commonly used methods for the diagnosis of UC and CD, but clinical practice regarding the diagnosis of IBD varied. The treatment of choice for mild-to-moderate UC and CD was 5-aminosalicylic acid (5-ASA), which is also the preferred choice for the maintenance treatment of UC and CD.
Conclusion:  Clinical practice with regards to IBD diagnosis and management varies within Asia.5-ASA is the preferred treatment and maintenance therapy for mild-to-moderate IBD.     

Topical therapy is underused in patients with ulcerative colitis

The availability of new topical preparations for the treatment of left sided ulcerative colitis offers a therapy optimization for many patients. Rectal application of steroids and 5-aminosalicylic acid (5-ASA) is associated with fewer side effects and has a higher therapeutic efficacy in left-sided colitis as compared to a systemic therapy. Therefore, we were interested in the use of topical therapy in patients with ulcerative colitis. The key question was whether topical treatment is more frequently used than oral therapy in patients with proctitis and left sided colitis. Data of 800 patients of the Swiss IBD cohort study were analyzed.Sixteen percent of patients of the cohort had proctitis, 21% proctosigmoiditis and 41% pancolitis. Topical therapy with 5-ASA or corticosteroids was given in 26% of patients with proctitis, a combined systemic and topical treatment was given in 13%, whereas systemic treatment with 5-ASA without topical treatment was given in 29%. Proportion of topical drug use decreased with respect to disease extension from 39% for proctitis to 13.1% for pancolitis (P = 0.001). Patients with severe colitis received a significantly higher dose of topical 5-ASA than patients in remission.Side effects of topical or systemic 5-ASA or budesonide treatment were less frequently seen compared to other medications. Topical treatment was frequently stopped over time. The quality of life was the same in patients with limited disease compared to patients with pancolitis.Topical treatment in proctitis patients was underused in Switzerland. Since topical treatment is safe and effective it should be used to a larger extend.     

Drug therapy for ulcerative colitis

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole.Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn‘s ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfafree 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds,systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.)are potent and fast-acting drugs for treating UC, Crohn‘s ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC.Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP,methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.     

Inflammatory bowel disease: current therapeutic options

Medical management of inflammatory bowel diseases (IBD) includes two treatment strategies: induction and maintenance of remission. 5-Aminosalicylates are mostly used for mild active IBD and for maintenance treatment in ulcerative colitis (UC). Glucocorticoids remain, despite their frequent (and occasionally severe) side effects, as the mainstay for induction of remission in moderate to severe active IBD, both UC and Crohn's disease (CD). Cyclosporine and infliximab have emerged as the main, rapid-acting, alternatives in steroid-refractory UC and CD, respectively. Thiopurines (azathioprine and 6-mercaptopurine) are the most efficient and used immunomodulators in IBD; steroid refractoriness, steroid dependency, and long-term maintenance of remission for both UC and CD are their main indications. Methotrexate and infliximab may be used in the same clinical settings as thiopurines in CD, but not in UC; however, these drugs are a second-line treatment because of safety profile and economic costs.     

Clinical aspects of ulcerative colitis in mainland China

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is reported to be increasing in incidence and prevalence in provinces and cities in mainland China. This article specifically reviews clinical features, extra-intestinal manifestations, complications, diagnosis and differential diagnosis, and medical treatment of UC. Compared to patients in Western countries, more mild to moderate and left-sided colitis cases were observed in a nation-wide study in China. Complications included anal fistula, anal abscess, anal fissure, severe bleeding, intestinal perforation, intestinal obstruction and colonic carcinoma. The extra-intestinal manifestations were arthritis/arthralgia, eye and skin disorders and oral ulcers. The high specificity of antineutrophil cytoplasmic antibody may useful for distinguishing UC from infectious colitis; in addition, serum levels of anti-saccharomyces cerevisiae antibody may be helpful for distinguishing between UC and CD. Oral sulfasalazine and 5-aminosalicylic acid (ASA) remain the mainstays for the management of mild to moderate UC in China. Corticosteroids and immunosuppressive agents are also widely used in severe or refractory UC.     

The role of aminosalicylates in the treatment of ulcerative colitis

Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the treatment of ulcerative colitis (UC). For acute treatment of mild to moderate flares and in maintenance treatment, their efficacy has been established. Since ulcerative colitis is limited to the distal colon in two thirds of the patients, topical therapy also plays an important role. In mild/moderate active disease 5-ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to 4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally well tolerated. The risk of colorectal tumours is increased in patients with longstanding ulcerative colitis and epidemiological evidence indicates that chronic 5-ASA treatment reduces this risk. However, at present there is insufficient evidence to maintain patients on life-long 5-ASA maintenance treatment for this indication.     

Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review

BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.     

The state of the art in the management of inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as inflammatory bowel disease (IBD), afflict an estimated one million Americans and produce symptoms that impair quality of life and ability to function. Progress in IBD management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. Although surgery is indicated to treat refractory disease or specific complications, pharmacotherapy is the cornerstone of IBD management. The efficacy of aminosalicylates for induction of remission in mild to moderate UC and CD is well established, as is their role for maintenance of remission in UC. The sulfa-free mesalamine formulation offers an adverse effect profile similar to that of placebo, enabling the administration of higher, more effective doses. Although corticosteroids provide potent anti-inflammatory effects, their benefits are countermanded by the risk of intolerable and serious adverse effects, and they are ineffective for maintenance therapy. Other agents effective in inducing or maintaining remission are azathioprine, 6-mercaptopurine, infliximab, cyclosporine, methotrexate, and antibiotics. Ongoing clinical trials of experimental therapies will generate new tools for IBD treatment. Currently, a broad range of options allows physicians to tailor treatment to each patient's needs and preferences. Such considerations are essential for maximizing adherence to therapy.     

The role of Budesonide-MMX in active ulcerative colitis

Traditional corticosteroids represent a well-established and effective treatment for active ulcerative colitis (UC). However, the severity of their systemic side effects, led in recent years to look for new steroid molecules that could reduce them, maximizing the anti-inflammatory activity. Budesonide has been one of the most studied steroid compounds and it has been approved for the treatment of mild to moderate active Crohn's disease (CD). In order to extend the release until the distally located inflammation, budesonide has been coupled with a controlled delivery system, called Multi-Matrix system (MMX^®), already successfully tested with oral mesalazine for the treatment of distal UC. After in vitro and in vivo models, the efficacy of Budesonide-MMX has been investigated in active UC with a first small phase II study, and partially encouraging results. This article will review the evidences on the use of budesonide in inflammatory bowel diseases and will discuss the role of Budesonide-MMX in active UC nowadays.     

Microproteinuria in patients with inflammatory bowel disease:TS it associated with the disease activity or the treatment with 5-aminosalicylic acid?

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA).METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study.Forty-six patients received 5-ASA for a period of 28.8months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins β2-microglobulin (β2mGLB) and β-N-acetyl-D-glucosamidase (β-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-α(TNF-α) serum levels were also measured.RESULTS: A totalof 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for β2mGLB, and 11.3% and 8.4% for β-NAG,respectively. mALB was not associated with IBD activity.β2mGLB and β-NAG urine levels were correlated to UC activity (UCAI:P＜0.01; UCEI: P＜0.005). mALB in UC patients and β-NAG urine levels in CD patients were related to TNF-a serum levels. An association was noticed between microproteinuria and smoking habit.Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance.CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

Microproteinuria in patients with inflammatory bowel disease： Is it associated with the disease activity or the treatment with 5-aminosalicylic acid？

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA). METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study. Forty-six patients received 5-ASA for a period of 28.8 months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins beta2-microglobulin (beta2mGLB) and beta-N-acetyl-D-glucosamidase (beta-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-alpha (TNF-alpha) serum levels were also measured. RESULTS: A total of 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for beta2mGLB, and 11.3% and 8.4% for beta-NAG, respectively. mALB was not associated with IBD activity. Beta2mGLB and beta-NAG urine levels were correlated to UC activity (UCAI: P<0.01; UCEI: P<0.005). mALB in UC patients and beta-NAG urine levels in CD patients were related to TNF-alpha serum levels. An association was noticed between microproteinuria and smoking habit. Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance. CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

炎症性肠病858例临床分析

目的总结分析炎症性肠病（IBD）的临床特点,探讨诊治策略。方法对1998年1月至2009年7月354例炎症性肠病住院患者和2003年1月至2009年7月504例炎症性肠病门诊患者资料进行回顾性分析。结果本组资料显示我院近12年来IBD发病呈逐年上升趋势,溃疡性结肠炎（UC）明显多于克罗恩病（CD）。本组IBD患者中男女之比为1.28∶1。IBD平均发病年龄（41.07±16.07）岁。UC发病高峰年龄为30～49岁,CD发病高峰年龄为20～39岁。本组住院患者中UC和CD两组民族构成比较无统计学差异。肠镜检查中UC以直肠和乙状结肠病变为主,CD以回盲部及回肠末端病变为主。本组患者IBD病理组织学检出率为41.5%,UC误诊率为17.0%,CD误诊率为25.0%。治疗以氨基水杨酸类及类固醇激素为主。结论炎症性肠发病数呈逐年上升趋势;IBD诊断主要依靠内镜及病理。IBD呈慢性复发性发作过程,应长期维持治疗。     

5-氨基水杨酸在炎症性肠病及其相关性结直肠癌中的作用新机制

炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD）,5-氨基水杨酸（5-ASA）是IBD治疗中最经典的抗炎剂。IBD患者结直肠癌（CRC）的发病率较正常人群明显增高,长期使用5-ASA可减少IBD患者发生CRC的风险。5-ASA传统的抗炎机制是通过影响抑制前列腺素合成、调节各种细胞因子的产生而发挥抗炎作用的,新近研究发现5-ASA可能通过氧化物酶体增殖物激活受体（PPAR）-γ途径发挥抗炎和抗瘤作用。本文就5-ASA的作用新机制作一简要概述。     

Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

INTRODUCTIONUlcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel diseases (IBD) of the intestine. UC and CD are both debilitating chronic disorders that afflict millions of individuals throughout the world…     

Antibiotics and probiotics in treatment of inflammatory bowel disease

Many experimental and clinical observations suggest that intestinal microflora plays a potential role in the pathogenesis of inflammatory bowel disease (IBD). Manipulation of the luminal content using antibiotics or probiotics represents a potentially effective therapeutic option. The available studies do not support the use of antibiotics in ulcerative colitis (UC). Antibiotics are effective in treating septic complications of Crohn's disease (CD) but their use as a primary therapy is more controversial, although this approach is frequently and successfully adopted in clinical practice. There is evidence that probiotic therapy may be effective in the prevention and treatment of mild to moderate UC. In contrast, a lack of successful study data at present precludes the widespread use of probiotics in the treatment of CD. Both antibiotics and probiotics appear to play a beneficial role in the treatment and prevention of pouchitis and further trials are warranted to fully quantify their clinical efficacy.