Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.     

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.     

Maximizing the effect of biologics in inflammatory bowel disease

The chronic course of inflammatory bowel disease (IBD) leads to recurrent episodes of active clinical symptoms, as well as long term complications, including hospitalizations, surgeries, and a decreased quality of life. Biologic agents have been shown to be effective for the induction and maintenance of remission in patients with moderate to severe IBD, and may alter the natural history of disease. Loss of response to biologic therapy is a common problem in clinical practice, the reasons for which are likely multifactorial; antibody development, alterations in drug clearance, and possibly a change to a non-TNF-driven inflammatory mechanism. Several studies have evaluated interventions that may lead to an increased rate of response and an increase in the durability. In this review, we evaluate ways to maximize anti-TNF treatment by administering scheduled therapy, using concomitant immunomodulator therapy, escalating dosage, and switching between biologic agents and classes. Finally, the role of antibody to infliximab (ATI) and infliximab serum trough levels are discussed in the context of optimizing biologic therapy for inflammatory bowel disease.     

Optimizing conventional therapy for inflammatory bowel disease

Recently, conventional therapies for inflammatory bowel disease (IBD) have not received the same amount of attention as biologic therapies, yet they remain the backbone of therapy for IBD because of their efficacy, safety, and relatively low cost. Advances in efficacy and safety continue because of modifications in drug dosing and monitoring. Higher doses of mesalamine per pill, together with once-daily dosing, may help to optimize drug delivery and patient compliance. Budesonide, an effective agent for both induction and short-term remission maintenance in Crohn’s disease, is devoid of many of the toxicities common to corticosteroids. Assessments of thiopurine methyltransferase and metabolite levels are helping to fine-tune dose optimization for the thiopurines azathioprine and 6-mercaptopurine. The oral calcineurin inhibitors tacrolimus and cyclosporine have been shown to have expanded roles in IBD, and methotrexate may be useful in some patients with refractory ulcerative colitis. Probiotics are showing promise for maintenance of remission in Crohn’s disease, ulcerative colitis, and pouchitis.     

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease(IBD),including immunosuppressants and biologics.Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients,as induction and maintainance treatment.Infliximab,as well as cyclosporine,is considered a second line therapy in the case of severe ulcerative colitis,or non-responders to intravenous corticosteroids.An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy.Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines.Evidence for the use of methotrexate in ulcerative colitis is insufficient.The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease,these treatments could be considered in case of failure of all other therapeutic options.In patients with moderately active ulcerative colitis,refractory to thiopurines,the use of tacrolimus is considered an alternative to biologics.An increase of the dose or a decrease in the interval of administration of biologic treatment could be useful in the presence of an incomplete clinical response.In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered.Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients.The final outcome of the treatment should be considered the clinical remission,with mucosa healing,and not the clinical response.The evaluation of serum concentration of thiopurine methyl transferase activity,thiopurine metabolites,biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice.The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.     

Optimizing immunomodulator therapy for inflammatory bowel disease

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) remain the mainstay of immunomodulator therapy for the maintenance of steroid-free remission in patients with inflammatory bowel disease (IBD). Traditional dosing strategies for initiation of thiopurines are often based on weight or empirically chosen. Dosing based on an understanding of an inherited difference in drug disposition and metabolism may provide a safer alternative. The thiopurine methyltransferase (TPMT) enzyme plays a pivotal role in the metabolism of 6-MP and AZA and is critical to the determination of thiopurine toxicity. The therapeutic benefits of thiopurines correlate best with concentration of the active 6-thioguanine (6-TGN) metabolites. Reports suggest that therapeutic response can be maximized when patients achieve therapeutic 6-TGN levels. Pharmacogenetic dosing based on TPMT and pharmacokinetic dosing based on 6-TGN levels may offer a safety and efficacy advantage over traditional dosing strategies and provide a novel mechanism for optimizing immunomodulator therapy in IBD.     

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.     

Rationale for probiotic treatment strategies in inflammatory bowel disease

Chronic inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are recurrent and aggressive inflammatory disorders that are most likely the result of an overly aggressive immune response to ubiquitous intestinal antigens in a genetically susceptible host. Despite decades of intense research, our knowledge of factors causing IBD remains incomplete and, therefore, conventional therapy to induce and maintain remission works in a symptomatic fashion, merely suppressing the immune response. Probiotic bacteria have long been known to confer health benefits, especially with regard to intestinal disorders. Although there is mounting evidence from in vitro and animal experiments supporting the use of probiotics in IBD, clinical trials have not provided definite evidence for the therapeutic effect of probiotic therapy in IBD to date. This is with the notable exception of pouchitis and the maintenance of remission in ulcerative colitis, whereas Crohn’s disease and active ulcerative colitis do not seem amenable to probiotic intervention. The next 5 years will see more trials targeting specific clinical settings using tailor-made probiotic combinations, taking into account our increasing knowledge of individual probiotic properties and the diversity of these microorganisms.     

Immunomodulatory therapy for inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) have intestinal and extraintestinal symptoms that can greatly impair their quality of life. They must rely on multiple medications with aminosalicylates, corticosteroids, and purine analogues to control these symptoms. Although decades of clinical experience in IBD management has led to optimized approaches for achieving the induction and maintenance of remission, the disease in some patients is still refractory to conventional medical treatment, or the effectiveness of these drugs can be limited by treatment-related side effects. Significant progress in our understanding of the pathogenesis of IBD has yielded several immunomodulatory approaches with novel biological agents or apparatus, such as cyclosporine, cytoprotective agents, infliximab, and leukocytapheresis. Further immunomodulatoy therapy, aiming at the inhibition of molecular and cellular mediators, is anticipated, in parallel with the clarification of im-munoinflammatory pathways in IBD. An additional goal will be to identify factors predictive of response to treatment with each novel immunomodulatory agent or apparatus. This will help provide each patient with optimized and individualized therapy, thereby increasing therapeutic efficacy and reducing possible side effects.     

炎症性肠病治疗目标的演变

炎症性肠病(IBD)目前发病机制未明,可能与环境、遗传、感染、免疫等多种因素有关。IBD的治疗目标最初为临床缓解,随着基础研究进展及新型生物制剂的临床广泛实践,推荐黏膜愈合作为炎症性肠病的重要治疗目标,最近深度缓解作为一个新的治疗目标被提出,在国外已被广泛接受并应用于疾病评估,本文主要介绍炎症性肠病治疗目标的演变及黏膜愈合、深度缓解作为IBD治疗目标的重要意义。     

Infliximab: Use in inflammatory bowel disease

Opinion statement Crohn’s disease (CD) and ulcerative colitis (UC) are chronic and often debilitating inflammatory bowel diseases (IBD) without medical cures. Despite the existence of multiple therapies, the medical treatment of these diseases often has proven insufficient and surgery is frequently required. However, as our understanding of the pathogenesis of these disorders and other immune-mediated inflammatory diseases (eg, rheumatoid arthritis and psoriasis) has grown, new and more specific biologic therapies have been developed that are proving more effective than traditional agents. Infliximab is a genetically engineered monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and represents the first effective biologic therapy for IBD and has largely revolutionized treatment. Infliximab initially was developed to be used in patients with moderate to severe luminal or fistulizing CD who are refractory to standard medical therapy. More and more practitioners now are using infliximab as first-line therapy because of its superior efficacy. Infliximab rapidly induces remission in CD, but when given chronically, it can provide long-term maintenance of remission. In addition, there are some data to support its use as a steroid-sparing agent and treatment for various extraintestinal manifestations of IBD and, although used predominantly to treat CD, recent data suggest that infliximab also may have a role in the management of UC. Overall, infliximab represents a clinically useful, cost-effective therapy that works well, even though careful patient monitoring is required to avoid rare but significant toxicities. The hope is that infliximab, together with other biologic agents that currently are in development, will allow us to modify the course of IBD, avoid complications such as strictures and abscesses, and reduce the need for surgery.     

Current therapy of pediatric Crohn’s disease

Inflammatory bowel diseases(IBD), including Crohn's disease(CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate,antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor(TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy- induction and maintenance of remission while improving the patient's growth and overall well-being.     

重视炎症性肠病的规范化治疗

炎症性肠病（IBD）的治疗是一个长期、复杂的过程,规范化治疗对于IBD的疾病缓解、减少并发症、预防复发、提高生活质量非常重要。IBD的规范化治疗需建立在正确的疾病诊断和全面的病情评估和充分的知情同意的基础上,主要包括早期积极个体化的治疗力争黏膜愈合,继以长期维持治疗缓解病情并预防复发。     

Immunomodulator therapy in inflammatory bowel disease

The introduction of immunomodulator therapy in the treatment of patients with inflammatory bowel disease (IBD) has provided an important tool in modifying the mucosal immune system thought to be important in the pathogenesis of IBD. Currently available immunomodulating agents include azathioprine, 6-mercaptopurine, cyclosporin, and methotrexate. Recent clinical trials have demonstrated that these agents have an important therapeutic role in the treatment of patients who are either refractory or intolerant to traditional medical therapy. They are useful in the induction and maintenance of remission for both ulcerative colitis and Crohn's disease. However, these agents have significant toxicities and limited efficacy. In addition, potential risks of malignancy and infection limit their indiscriminate use. Thus, with the better understanding of the molecular basis of mucosal immunity, innovative immune-modifying therapies, such as antagonists of cytokines and inhibitors of T-cell activation, are being developed. It is likely that these exciting developments will soon result in specific immune modulating therapy with improved efficacy and reduced toxicity in the treatment of patients with IBD.     

Effect of infliximab on inflammatory bowel disease with Takayasu arteritis: case series and review of the literature

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are chronic inflammatory disorders. The mechanisms underlying these diseases are not precisely known, but tumor necrosis factor alpha (TNF-α) is considered to have an important role in the pathophysiology of both TA and IBD. Simultaneous occurrence of both TA and IBD is rare. Our first case was a 42-year-old woman with TA and inflammatory bowel disease unclassified. The patient was refractory to treatment with an immunomodulator, and infliximab (IFX) was started. After starting IFX, clinical remission was achieved and maintained for 2 years. The second case was a 34-year-old woman with TA accompanied by Crohn’s disease. Because her abdominal symptoms relapsed despite treatment with an immunomodulator, IFX was started. Both diseases were well controlled for 2 years by scheduled maintenance therapy with IFX. Relapse of the TA required increased doses of IFX at shorter intervals, which relieved her symptoms. Overall, we identified nine cases for which IFX was effective, including our 2 cases. They may demonstrate the efficacy of IFX for IBD with TA and emphasize the role of TNF-α in the pathophysiology.     

From bench to bedside: Fecal calprotectin in inflammatory bowel diseases clinical setting

Fecal calprotectin(FC) has emerged as one of the most useful tools for clinical management of inflammatory bowel diseases(IBD). Many different methods of assessment have been developed and different cutoffs have been suggested for different clinical settings. We carried out a comprehensive literature review of the most relevant FC-related topics: the role of FC in discriminating between IBD and irritable bowel syndrome(IBS) and its use in managing IBD patients In patients with intestinal symptoms, due to the high negative predictive value a normal FC level reliably rules out active IBD. In IBD patients a correlation with both mucosal healing and histology was found, and there is increasing evidence that FC assessment can be helpful in monitoring disease activity and response to therapy as well as in predicting relapse, post-operative recurrence or pouchitis. Recently, its use in the context of a treat-to-target approach led to a better outcome than clinically-based therapy adjustment in patients with early Crohn's disease. In conclusion, FC measurement represents a cheap, safe and reliable test, easy to perform and with a good reproducibility. The main concerns are still related to the choice of the optimal cut-off, both for differentiating IBD from IBS, and for the management of IBD patients.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD). METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800 mg) per month. RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d). CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD

Background and aimsDeep remission, meaning clinical remission with mucosal healing (MH), with anti-tumor necrosis factor-alpha (TNF-α) agents is a new target for therapy in inflammatory bowel disease (IBD). Our aim was to study how often patients on TNF-α blocking therapy actually achieve deep remission.MethodsThe total of 252 IBD patients retrospectively included (183 Crohn's disease (CD), 62 ulcerative colitis (CU) or 7 inflammatory bowel disease unclassified-type colitis (IBDU)) received TNFα-antagonists (177 infliximab, 75 adalimumab) for at least 11 months and underwent ileocolonoscopy. We reviewed endoscopic and histological findings, clinical symptoms, C-reactive protein (CRP), and fecal calprotectin (FC) levels, and data on TNF-α blocking therapy. Defining deep remission as no clinical symptoms with endoscopic remission (the simple endoscopic score for Crohn's disease, SES-CD 0–2 or Mayo endoscopic subscore 0–1).ResultsOf the 252 patients, 168 (67%) were in clinical remission and 122 (48%) in deep remission after a median of 23 months of maintenance therapy. Of the 183 CD patients, 117 (64%) reached clinical remission and 79 (43%) deep remission. Of the UC patients, 52 (75%) were in clinical remission and 43 (62%) in deep remission. The majority of patients in deep remission (n = 99, 81%) also had histologically inactive disease. Both median CRP and FC levels were significantly lower in patients with deep remission.ConclusionReassuringly, half of the IBD patients on the TNFα-blocking maintenance therapy achieved deep remission. The majority of patients in deep remission also achieved histological remission.     

Pulse cyclophosphamide therapy for inflammatory bowel disease

AIM: To assess the efficacy of intravenous cyclophosphamide pulse therapy for refractory inflammatory bowel disease (IBD).METHODS: We included in our cohort eight patients with (moderate/severe) steroid refractory IBD (4 with ulcerative colitis and 4 with Crohn's disease). They all received 6 cycles of intravenous cyclophosphamide (800mg) per month.RESULTS: Patients entered into remission after the second/third cyclophosphamide pulse. Disease activity decreased. There were no side effects and toxicity. All the patients went into long lasting remission. All Crohn's disease patients and 3 of 4 ulcerative colitis patients achieved complete remission. One patient with ulcerative colitis showed an impressive clinical response but did not enter into remission. For the maintenance, patients with Crohn's disease were treated with methotrexate (15 mg/wk) and patients with ulcerative colitis were treated with azathioprine (2.5 mg/kg body weight/d).CONCLUSION: Remission was maintained in all patients for 6 mo on the average. The drug was well tolerated. These findings suggest that aggressive immunosuppressive therapy may be useful in some refractory patients and further controlled study should be considered in order to fully evaluate this type of treatment as a potential therapy for IBD.     

Impact of disease and treatments on growth and puberty of pediatric patients with inflammatory bowel disease

Growth retardation, associated with delayed puberty, is a frequent feature in pediatric patients with inflammatory bowel disease (IBD), especially with Crohn's disease. It is mainly induced by malnutrition and the effects of the inflammatory process on the growth hormone/insulin-like growth factor-1 axis or on the growth plate. Therefore, control of disease activity and mucosal healing are paramount to promote growth and adequate pubertal onset. Current therapeutic strategies for maintenance in IBD include anti-inflammatory drugs, immunosuppressives, and, more recently, biologic agents. Although these treatments are efficient in minimizing inflammation and inducing prolonged remission, their long-term effects on growth and final height remain controversial. Furthermore, glucocorticoid therapy, even though very efficient in inducing remission, clearly shows deleterious effects on growth, which is not the case for exclusive enteral nutrition showing comparable results regarding induction of remission. Thus regular assessment of weight, height and pubertal stage is essential in children and adolescents with chronic disease, namely IBD.