How will insights from genetics translate to clinical practice in inflammatory bowel disease?

Inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies.     

影响硫嘌呤类药物个体化应用的主要代谢酶遗传多态性的研究进展

硫嘌呤类药物作为一类常用的免疫抑制药,广泛应用于临床。然而其治疗窗窄,药动学个体差异大一直是困扰该类药物临床应用的难题。许多因素可影响硫嘌呤类药物的代谢及药理效应,但其代谢过程中涉及的代谢酶所具有的遗传药理学方面的个体差异被认为是主要因素。近年来各主要代谢酶的遗传多态性对硫嘌呤类药物药动学和药效学的影响也逐渐成为了关注的焦点。因此本文就相关代谢酶(TPMT,ITPA,GST,HPRT,XO,IMPDH及GMPS)的遗传多态性与硫嘌呤类药物疗效和不良反应的相关性进行综述,以期为临床硫嘌呤类药物个体化应用提供指导。     

Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease

BACKGROUND/AIMS: 6-Mercaptopurine and its prodrug azathioprine are effective for the treatment of inflammatory bowel disease. Thiopurine methyltransferase is important for the metabolism of thiopurines. However, there is controversy as to the clinical utility of measuring thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels. Our aim was to determine if thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide level monitoring would predict response to therapy with thiopurines in patients with inflammatory bowel disease. METHODS: Baseline thiopurine methyltransferase enzyme activity prior to initiation of therapy with either 6-mercaptopurine or azathioprine was determined in 39 patients with inflammatory bowel disease. The association between clinical response and thiopurine methyltransferase activity and 6-thioguanine nucleotide levels singly or in combination were analysed. RESULTS: Seventeen of 39 patients (44%) responded to 6-mercaptopurine or azathioprine therapy. Thiopurine methyltransferase enzyme activity below the mean of 30.5 U was significantly associated with clinical response. The thiopurine methyltransferase low phenotype was associated with response in 65% vs. 29% in individuals with thiopurine methyltransferase enzyme activity above 30.5 U (p = 0.05). There was no correlation between thiopurine methyltransferase activity and 6-thioguanine nucleotide levels. The maximal 6-thioguanine nucleotide levels did not predict clinical response. When combining thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels, the combination of thiopurine methyltransferase low/6-thioguanine nucleotide high was associated with response in 7/7 (100%) vs. only 2/8 (25%) with the combination of thiopurine methyltransferase high/6-thioguanine nucleotide low (p=0.01). CONCLUSIONS: Thiopurine methyltransferase activity inversely correlated with clinical response to thiopurine treatment in inflammatory bowel disease. Thiopurine methyltransferase enzyme activity below 30.5 U combined with a post-treatment 6-thioguanine nucleotide level > 230 pmol/8 x 10(8) erythrocytes was the best predictor of response.     

Experiencia en práctica clínica de optimización de tiopurinas mediante determinación de sus metabolitos en la enfermedad inflamatoria intestinal

Introduction

Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites.

Solid extraintestinal malignancies in patients with inflammatory bowel disease

Malignancies constitute the second cause of death in patients with inflammatory bowel diseases (IBD), after cardiovascular diseases. Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population, lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance, while the incidence of extraintestinal cancers (EICs) is increasing. This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments. It seems that the overall risk of EICs is higher for Crohn’s disease patients and it is mainly driven by skin cancers, and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis. The aims of this review were first to evaluate the prevalence, characteristics, and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis, better prognosis and survival, especially in the era of new IBD treatments that are on the way.     

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. Similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.     

Immunosuppressive and immunomodulatory therapy-associated lymphoproliferative disorders

A variety of therapeutic agents may increase the risk of lymphoproliferative disorders/neoplasms. These include those agents used to treat other malignancies (i.e., cytotoxic chemotherapy) and those used to treat or prevent certain diseases (or graft rejection) that alter the immune system. This review is restricted to the secondary lymphoid disorders that are unrelated to primary DNA damage by cytotoxic chemotherapy, and thus will include discussions regarding post-transplant lymphoproliferative disorders and those lymphoproliferations associated with the therapy of autoimmune and other immune-mediated diseases. Three drugs, or classes of drugs, used in the treatment of autoimmune and other immune-mediated diseases are discussed in some detail. These include methotrexate, anti-metabolites (including thiopurines and mycophenolate mofetil), and immunomodulators. The appropriate recognition of these disorders is important in order to correctly classify and institute appropriate therapy, recognizing that reduced immunosuppression or withdrawal of therapy may be necessary, rather than treating as a malignant lymphoma.     

6-Mercaptopurine: high-dose 24-h infusions in goats

Summary In vitro investigations have indicated the need for both prolonged exposure to 6-mercaptopurine (6MP) and the use of high concentrations to achieve maximal cell kill. After the customary oral administration the bioavailability of 6MP appeared to be low, and i.v. bolus injections resulted in short-live high concentrations of 6MP, so prolonged infusions seemed rational. To test the feasibility of this approach 24-h infusions were given to goats. We used our improved HPLC method to quantitate 6MP and 6MP riboside (6MPR) in plasma, CSF, and urine. The concentrations of 6MPR were in excess of those of 6MP. Since 6MPR can easily be converted to 6MP, 6MPR acts as a depot for 6MP. Penetration of both 6MP and 6MPR into CSF was excellent. Of the total dose administered, 38% to 68% could be accounted for in the urine, with about equal amounts of 6MP and 6MPR. At doses of 20 and 10 mg kg^-1 h^-1 total concentrations of 6MP and 6MPR in excess of 100 M were reached during 24-h infusions. However, all three experimental animals died due to toxicity. A dose of 2 mg kg^-1 h^-1 was tolerated; the total steady state concentration of 6MP and 6MPR in two experiments was about 10 M. We conclude that the prolonged infusion of 6MP is feasible, and in view of the excellent penetration of 6MP and 6MPR into CSF, studies using prolonged infusions of thiopurines are warranted in man.Abbreviations 6MP(R) 6-mercaptopurine (riboside) - 6TG(R) 6-thioguanine (riboside) - CSF cerebrospinal fluid - DTT dithiothreitol Supported by the Queen Wilhelmina Fund (Dutch Cancer Society), Grant NUKC Kg 81-2     

Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis

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