Bindia Jharap

Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8-year intercept cohorts†

Background: Thiopurines have proven efficacy in long‐term maintenance therapy of inflammatory bowel disease (IBD). Limited data are available with regard to factors predicting effectiveness and failure of long‐term thiopurine use in IBD patients. Methods: The data in this retrospective study are based on an 8‐year intercept cohort of previous or present thiopurine‐using IBD patients. Both cohorts are assessed by descriptive and statistical analysis aimed at determining thiopurine effectiveness and the variables that are predictive for failure of thiopurine therapy. Results: In all, 363 IBD patients were included (60% female), 63% with Crohns disease and 33% with ulcerative colitis. Overall, thiopurines were continued in 145/363 (40%) and discontinued in 208/363 (57%) patients. The proportion of patients still using thiopurines at 3, 6, 12, 24, and 60 months was 73%, 69%, 63%, 51%, and 42%, respectively. Patients discontinued thiopurines due to adverse events (39%), refractoriness (16%), and ongoing remission / patients request (4%). 6‐methylmercaptopurine (6‐MMP) concentration and 6‐MMP/6‐thioguanine nucleotides (6‐TGN) ratio were significant higher in the failure group. Prolonged continuation of thiopurines was associated with a decreased risk of discontinuation. Conclusions: Azathioprine and 6‐mercaptopurine were considered effective in ≈40% of IBD patients after 5 years of treatment. A quarter of the patients discontinued thiopurines within 3 months, mostly due to adverse events. A high 6‐MMP concentration or 6‐MMP/6‐TGN ratio was associated with therapeutic failure. If thiopurine use was successfully initiated in the first months, its use was usually extended over many years, as long‐term use was associated with continuation of therapy. (Inflamm Bowel Dis 2010)

Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD

Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5′-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.

Dose-Dependent Influence of 5-Aminosalicylates on Thiopurine Metabolism

INTRODUCTION:Studies indicated that 5-aminosalicylates (5-ASA) may influence the metabolism of thiopurines; however, conclusions were restricted as a result of number of patients or study design.AIM:To determine the influence of 5-ASA on thiopurine metabolism, we performed a prospective multicenter pharmacokinetic interaction study of two different 5-ASA dosages (2 g daily followed by 4 g daily) in 26 inflammatory bowel disease (IBD) patients during steady-state AZA or 6-MP therapy.RESULTS:The 4-wk coadministration of 2 g 5-ASA daily, followed by a 4-wk period of 4 g 5-ASA daily, led to a statistical significant increase of 40% (absolute 84 pmol/8 × 108 RBC) and 70% (absolute 154 pmol/8 × 108 RBC) in 6-thioguaninenucleotide levels (6-TGN), respectively. A rise in 6-TGN levels was observed in 100% of patients after a 4-wk period of 4 g 5-ASA daily. The 6-methylmercaptopurine-ribonucleotide levels did not change. Signs of myelotoxicity were observed in 7.7% of patients (N = 2).CONCLUSIONS:The level of the pharmacologically active 6-TGN significantly increases in a dose-dependent manner during 5-ASA coadministration. IBD patients who are unresponsive or refractory to standard thiopurine therapy may benefit from the coadministration of 5-ASA, leading to an increase in 6-TGN levels.

Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease

Objective Several studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using thiopurines, in order to determine the influence of pregnancy on thiopurine metabolism and to assess intrauterine exposure of the fetus to thiopurines. Design Female patients with IBD receiving steady-state thiopurines and planning a pregnancy were prospectively enrolled. 6-Thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations were determined, combined with routine laboratory tests, before, during and after pregnancy. Thiopurine metabolites were measured in umbilical cord blood immediately after delivery. Results Thirty patients who were using azathioprine (28 patients, median dose 1.93 mg/kg) or mercaptopurine (two patients, doses 1.32 and 0.94 mg/kg) were included. During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except one born with pancytopenia and high alkaline phosphatase activity; the mother of this infant had severe pre-eclampsia. All infants had normal Apgar scores, but 60% had anaemia at birth. No major congenital abnormalities were observed. Conclusions Pregnancy has a major effect on maternal thiopurine metabolism. In utero the unborn child is exposed to 6-TGN, but not to 6-MMP. Sixty per cent of the infants were born with anaemia, which raises the question whether infants should be tested for possible anaemia immediately after birth.

Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management

Tumor necrosis factor-α (TNFα) antagonists have advanced the management of inflammatory bowel diseases patients leading to an improvement of patient’s quality of life with the reduction of number of surgeries and hospitalizations. Despite these advances, many patients do not respond to the induction therapy (primary non-response—PNR) or lose response during the treatment (secondary loss of response—LOR). In this paper we will provide an overview of the definition, epidemiology and risk factors for PNR and LOR, as well as discuss the therapeutic options for managing LOR.

Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease.

Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long‐term development outcome of children exposed to maternal thiopurine therapy are very limited.

Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy

Background and purpose:  5‐aminosalicylate (5‐ASA) raises levels of 6‐thioguanine nucleotides (6‐TGN), the active metabolites of thiopurines such as azathioprine (AZA). Changes in levels of each individual TGN – 6‐thioguanosine mono‐, di‐ and triphosphate (6‐TGMP, 6‐TGDP, 6‐TGTP) – and of 6‐methylmercaptopurine ribonucleotides (6‐MMPR) after 5‐ASA are not known.

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease.

Background:Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. Methods:A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. Results:One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4–64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3–14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%–9%), only one of whom had NRH. There was no clinically overt portal hypertension. Conclusions:The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

Diagnosing nodular regenerative hyperplasia of the liver is thwarted by low interobserver agreement

Background and Aims Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH. Methods Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index. Results After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45). Conclusions The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.

Anal Neoplasia in Inflammatory Bowel Disease Is Associated With HPV and Perianal Disease.

OBJECTIVES:Literature describing the risk factors predisposing inflammatory bowel disease (IBD) patients to anal squamous neoplasia is very scarce. Case reports and small case series have implicated perianal Crohn’s disease (CD), long-standing IBD, human papillomavirus (HPV) infection, and immunosuppressive treatment. In this study, we retrospectively examined the association between HPV infection and anal squamous neoplastic lesions among IBD patients from our center.METHODS:We reviewed the pathology records and slides of IBD patients diagnosed with anal squamous cell carcinomas (SCCs), high-grade squamous intraepithelial lesions (HSILs), and low-grade squamous intraepithelial lesions (LSILs) who presented at our center between 1 March 1994 and 9 September 2014. The HPV status of the neoplasms was assessed histologically, by immunohistochemical staining for p16 overexpression, and by global and type-specific HPV PCR.RESULTS:SCCs, HSILs, LSILs, and small cell carcinoma were identified, respectively, in six, nine, two, and one IBD patients. All six patients with SCC had CD with perianal involvement. HPV-related neoplasia was identified in 3/6 cases of SCC (all HPV-16), 1/1 small cell carcinoma (HPV-18), and 9/9 HSIL (7 HPV-16, 2 not typed); 2/2 LSILs were negative for high-risk HPV.CONCLUSIONS:In our experience, anal squamous neoplastic lesions in IBD are associated with HPV infection and SCC seem to be associated with perianal CD. Prospective studies are needed to confirm these results.