Azathioprine In Inflammatory Bowel Disease Research Articles

Long-term safety and effectiveness of azathioprine in the management of inflammatory bowel disease: A real-world experience.

Azathioprine (AZA) forms the cornerstone for maintenance of sustained remission in inflammatory bowel disease (IBD). There is apprehension regarding the long-term effectiveness and safety of AZA in IBD. We present our experience with AZA use and outcomes in a cohort of IBD patients followed up over a long period of time. Records of 507 IBD patients under treatment at a single, tertiary care center in south India between 2013 and 2022 were evaluated retrospectively. Long-term compliance, tolerance, clinical outcome at the point of last follow-up, type and duration to the onset of adverse events, and subsequent amendment to treatment with regard to AZA were analyzed. Of 507 patients with IBD, 320 patients (207 Crohn's disease [CD], 113 ulcerative colitis [UC]) who received AZA were included. The median follow-up was 41 months (interquartile range 15.5-77.5). Total duration of exposure was 1359 patient-years with median usage of 33 months. Of the patients, 26.9% received AZA for >5 years. Mean initiation and maximum doses of AZA were 0.97 and 1.72 mg/kg/day. Among the participants, 20.6% experienced side effects, including myelotoxicity (7.2%) and gastrointestinal intolerance (5.6%). Six patients developed malignancy. Among the side effects, 39.4% of side effects were dose-dependent. Among the patients, 38.1% had relapses requiring pulse corticosteroid therapy, and 16.2% had more than one relapse after commencement of AZA. AZA was continued till the last follow-up in 76.5%. Among the patients, 49.7% (UC 51.3, CD 48.8) attained durable remission without biologics, and 5.3% continued to have active disease. AZA is safe and effective in the long-term in IBD. Effectiveness, tolerance, and compliance with AZA are well sustained beyond 5 years of usage and comparable between UC and CD.

Persistently normal blood tests in patients taking methotrexate for RA or azathioprine for IBD: a retrospective cohort study.

BackgroundDisease-modifying anti-rheumatic drugs (DMARDs), including methotrexate and azathioprine, are commonly used to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Blood-test safety monitoring is mainly undertaken in primary care. Normal blood results are common.AimTo determine the frequency and associations of persistently normal blood tests in patients with RA prescribed methotrexate, and patients with IBD prescribed azathioprine.Design and settingTwo-year retrospective study of a cohort taken from an electronic pseudonymised primary care/laboratory database covering >1.4 million patients across Hampshire, UK.MethodPatients with RA and IBD, and associated methotrexate and azathioprine prescriptions, respectively, were identified. Tests and test thresholds recommended by the National Institute for Health and Care Excellence were applied. Persistent normality was defined as no abnormalities of any tests nor alanine aminotransferase (ALT), white blood count (WBC), neutrophils, and estimated glomerular filtration rate (eGFR) individually. Logistic regression was used to identify associations with test normality.ResultsOf 702 265 adults, 7102 had RA and 8597 had IBD. In total, 3001 (42.3%) patients with RA were prescribed methotrexate and 1162 (13.5%) patients with IBD were prescribed azathioprine; persistently normal tests occurred in 1585 (52.8%) and 657 (56.5%) of the populations, respectively. In patients with RA on methotrexate, 585 (19.5%) had eGFR, 219 (7.3%) ALT, 217 (7.2%) WBC, and 202 (6.7%) neutrophil abnormalities. In patients with IBD on azathioprine, 138 (11.9%) had WBC, 88 (7.6%) eGFR, 72 (6.2%) ALT, and 65 (5.6%) neutrophil abnormalities. Those least likely to have persistent test normality were older and/or had comorbidities.ConclusionPersistent test normality is common when monitoring these DMARDs, with few hepatic or haematological abnormalities. More stratified monitoring approaches should be explored.

Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study.

INTRODUCTION:Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A>C is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A>C screening will reduce the risk of azathioprine-induced pancreatitis.METHODS:Participants with IBD were screened for HLADQA1-HLADRB1*07:01A>C, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls.RESULTS:HLADQA1-HLADRB1*07:01A>C screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A>C screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01–0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A>C-screened cohort.DISCUSSION:HLADQA1-HLADRB1*07:01A>C screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A>C-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A>C screening in IBD populations.

A nearly fatal primary Epstein-Barr virus infection associated with low NK-cell counts in a patient receiving azathioprine: a case report and review of literature

BackgroundSymptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.Case presentationAn 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine.ConclusionsWe found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.

The Inflammatory Bowel Disease Drug Azathioprine Induces Autophagy via mTORC1 and the Unfolded Protein Response Sensor PERK.

Genetic studies have strongly linked autophagy to Crohn's disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process. Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry. Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy. Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.

PO-212 Morphological heterogeneity of hepatosplenic gamma/delta T-cell lymphoma

IntroductionHepatosplenic gamma/delta T-cell Lymphoma (HSTL) is a systemic extra-nodal lymphoma originating from cytotoxic T-cells expressing the gd receptor. We report clinical, morphologic and phenotypic characteristics of 3 patients with HSTL.Material and methodsAll patients were male and presented at a mean age of 23 years. One was treated with azathioprine for inflammatory bowel disease, the two others had no history of immunosuppression. All patients were admitted to the hospital with high fever and hepatosplenomegaly. Two presented severe abdominal pain and lymphadenopathy.Laboratory studies of the three patients were different:Case 1: thrombopenia and bone marrow infiltration with 69% of large lymphomatous blast cells and minimal peripheral blood infiltration.Case 2: pancytopenia without excess of blasts in the peripheral blood and moderate bone marrow infiltration in cytometry. Morphological and immune-phenotypical studies of the spleen (after splenectomy) showed a massive infiltration by lymphocytic small cells.Case 3: pancytopenia with 25% and 45% of blast cells in the peripheral blood and bone marrow aspirate respectively.Immuno-phenotyping showed a T lymphocytic population double negative (CD3pos CD4neg CD8neg to dim) with gamma-delta expression, CD1a- CD2 +CD5 CD7+CD56+CD57 in all 3 patients.Two patients underwent an initial treatment with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone: the first died after 4 months, and there is no response to treatment in the second patient. Treatment was recently initiated in the third patient.Results and discussionsIn our series, HSTL confirmed a predilection to develop most often in young men with hepatosplenomegaly. Variable degrees of hematologic abnormalities were observed. Thrombocytopenia was the most striking finding in all. Bone marrow involvement is described in approximately two thirds of patients but was observed by immunophenotyping in our 3 cases. We show that immunophenotyping seems to be the best method for the rapid characterisation of the lymphoma cells morphologically heterogeneous and difficult to identify.ConclusionHSTL is an infrequent, rare aggressive tumour. The diagnosis is difficult. There is no treatment consensus and the prognosis remains poor.

P462 Mucosal healing and deep remission rates with azathioprine in inflammatory bowel disease?

P462 Mucosal healing and deep remission rates with azathioprine in inflammatory bowel disease?

Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress.

Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity. A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects. Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione- S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides. Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.

Mercaptopurine and inflammatory bowel disease: the other thiopurine.

Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease. Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease. One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046). In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.

Su1421 Effectiveness and Adverse Events of Azathioprine in Inflammatory Bowel Disease: 9-Year Follow-Up Study

with TPN dependence in 33%, at least one surgical resection in 72%, and fistula in 50% of patients. Failure of at least two anti-TNFs was observed in 89% of patients, methotrexate in 83%, and thiopurines in 89%. Natalizumab had been used in 16.7% of patients prior to ustekinumab. The induction dose ranged from 45mg to 270mg SC at week zero. The most common maintenance dose was 90mg SC every eight weeks. The median duration of followup after initiation of ustekinumab was 9.1 months (5.7-27.8). The cumulative probability of any response was 11.1% at one month, 38.9% at three months, and 44.4% at six months. The cumulative probability of loss of response among patients with partial or complete response was 25% at 1, 3, and 6 months. Of the 15 patients on steroids at the beginning of therapy, 4 (26.7%) were able to taper off successfully. Mucosal healing was observed in 3 of the 8 patients (37.5%) who had a repeat endoscopy. Adverse events (AE) occurred in 10 patients; six month survival free of AE was 50%. Worsening arthralgias was the most common AE in 50% of patients. Serious infections included line-sepsis in one patient receiving TPN, and herpes zoster in another patient. Conclusion: In our clinical experience, patients with moderate to severe Crohn's disease who are refractory to currently approved therapies may benefit from treatment with ustekinumab.

P504 Effectiveness and adverse events of azathioprine in inflammatory bowel disease: 9-year follow-up study

P504 Effectiveness and adverse events of azathioprine in inflammatory bowel disease: 9-year follow-up study

Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

Letter: flu-like illness with mercaptopurine and azathioprine in inflammatory bowel disease

Letter: flu-like illness with mercaptopurine and azathioprine in inflammatory bowel disease

P-176 Thiopurine S-methyltransferase Analysis Does Not Correctly Predict the Risk of Toxicity in Hispanic Children with Inflammatory Bowel Disease

Thiopurine S-methyltransferase (TPMT) catalyzes the methlyation of thiopurine compounds, and is measured prior to using medications such as 6-mercaptopurine or Azathioprine. TPMT can be measured as blood enzyme levels or allelic variations (phenotype or genotype assay), both of which are important in distinguishing the possibility of desired clinical effects versus toxicity. The aim of our study was to evaluate the prevalence of variations in TPMT activity in pediatric Hispanic Inflammatory Bowel Disease (IBD) patients in our South Florida based Pediatric Gastroenterology practice, and to evaluate the reliability of TPMT levels in predicting toxicity risk in our studied population. Sixty-four pediatric Hispanic patients treated with either 6-mercaptopurine or Azathioprine for IBD were retrospectively studied. Either a radiochemical method to measure TPMT phenotype or TPMT genotype was analyzed to detect allelic variations and predisposition to myelotoxicity, hepatotoxicity, and pancreatotoxicity. Of the 64 Hispanic patients included (mean age: 16 years): 54.6% with Crohn's disease, 37.5% with Ulcerative Colitis, 4.6% with nonspecific colitis, and 3.1% with other unspecified abdominal complaints. TPMT phenotypes were documented in 50 patients and Genotype analysis was documented in 14 patients. TPMT phenotype was distributed as: Normal level 80% (40/50), Intermediate 18% (9/50), Low 2% (1/50). TPMT genotypic variations were distributed as: Normal 92.8% (13/14), Intermediate 7.1% (1/14), Low 0% (0/14). Toxicity was characterized by leukopenia with or without neutropenia, anemia, pancytopenia, elevated transaminases, or pancreatitis. The percentage of patients with toxicity regardless of normal or abnormal TPMT levels or alleles were 37.5%. This was further evaluated to find that 12.5% had liver toxicity, 15% had bone marrow toxicity, and 10% had both. The percentage of patients with toxicity despite normal TPMT phenotype was 22.5%. The percentage of patients with toxicity despite normal genotype was 23.07%. Our study demonstrates that 17% (11/64) of pediatric Hispanic patients in our practice have either an abnormal phenotype or genotype TPMT enzyme analysis, which is greater than previously documented in other ethnic groups. Additionally, the risk of toxicity despite normal TPMT enzyme levels and alleles was higher in our studied group compared to other previously studied populations, indicating that pediatric Hispanic patients must be monitored carefully at regular intervals to monitor for adverse reactions to thiopurine based medications.

PTU-075 Long Term outcome of Azathioprine Therapy in 353 Consecutive IBD Patients

IntroductionThiopurines are the mainstay of therapy in Inflammatory Bowel Disease (IBD). Azathioprine (AZA) and Mercaptopurine are very effective at maintaining remission but have a wide range of side effects which...

Su1224 Long Term Outcome of Azathioprine Therapy in 353 Consecutive IBD Patients

Introduction Thiopurines are the mainstay of therapy in Inflammatory Bowel Disease (IBD). Azathioprine (AZA) and Mercaptopurine are very effective at maintaining remission but have a wide range of side effects which can limit their use as long term maintenance therapy. To assess how effective AZA was in IBD, and what its limitations were, the outcome of 353 consecutive IBD patients started on AZA with at least onw year follow up was assessed. Methods Since 2005 all patients started on AZA for IBD have been recorded and monitored. These data were then used to assess the outcomes of patients where there had been at least one year of follow up. Outcomes recorded were whether AZA was still being taken or not. If still being taken information about the disease activity was recorded. If AZA therapy had been discontinued then the reason for this was recorded and subsequent therapeutic interventions noted. Results 353 patients had started AZA and had at least one year of follow up. TPMT status was checked in all patients. Dosing was as follows: low TPMT; 50mg and increased as tolerated. Normal TPMT; 2–2.5mg/kg. Of the 353 patients, 204 had Crohn’s disease (CD), 141 had Ulcerative Colitis and 8 had IBD-unclassified. The male:female ratio was 184:169 (52.1% male). Age range was 16–86 years (mean; 46). 322/353 (91%) remain under follow up. 127 (36%) of patients stopped taking AZA at one year. After six years 152 (43.1%) remained on AZA, 182 (51.6%) had stopped and in 19 (5%) the outcome was unknown. Nausea and myalgia were the main reasons for stopping AZA. 40(11.3%) patients developed hepatitis (ALT rise > 2xULN), 6 (1.7%) developed myelosuppression and 7 (2%) developed pancreatitis (consistent clinical presentation and raised amylase). Of the 182 patients who stopped AZA, 67 (37.8%) had an escalation of therapy – 20 started methotrexate, 18 started biologics and 29 underwent surgery. Of the 152 who continued AZA, 138 (90.8%) were in a clinical remission based on clinical assessment supported by normal C-reactive protein in 126 (91.3%), Harvey Bradshaw Index in those with CD 55 (40%) patients and endoscopic findings in 22 (15.9%). 112 (73.6%) patients had blood monitoring (FBC and LFTs) at least quarterly and 147 (96.7%) at bi-annually. Conclusion For such an important drug in IBD management a significant number of patients stop AZA due to side effects. This study highlights these so that patients can be accurately informed. It also highlights that AZA when tolerated is a very effective maintenance medication. Published data from our own and other units suggest that low-dose AZA in combination with allopurinol reduces side effects and increases tolerability and may make AZA a more effective longterm maintenance agent. Disclosure of Interest None Declared

Subsequent Entry Biologics – Opportunities and Challenges

Currently, infliximab and adalimumab are the two antitumour necrosis factor (TNF) agents available in Canada for the treatment of Crohn disease and ulcerative colitis (adalimumab is not yet licensed for use in ulcerative colitis). At least one more anti-TNF monoclonal antibody (golimumab) is awaiting approval. Furthermore, the gut-specific antiadhesion antibody vedolizumab is also on the horizon for inflammatory bowel disease (IBD). Subsequent entry biologics (SEBs), also known as biosimilars, are monoclonal antibodies that are similar but not identical to the reference biologic drug (RBD). With the patents for anti-TNF antibodies, such as infliximab, coming to an end, anti-TNF SEBs have been manufactured and an important overview of this has been provided by Devlin et al (1) (pages 567–571) in the current issue of the Journal. Given the cost of biological drugs, the potential for SEBs to lower cost, both by virtue of lower cost of SEBs and competitive lowering of cost of RBDs, will be welcome. SEBs are already on the market in some geographical jurisdictions, such as South Korea, and are well on the way to approval in Europe. There are, however, certain considerations that may be of clinical relevance to practising gastroenterologists in Canada, which include the following: Are the molecular structures of SEBs and RBDs comparable?: Subtle differences in structure, such as fucosylated forms, may affect antibody-dependent cell-mediated cytotoxicity and binding to FcγR, which may affect drug clearance and serum drug levels. Therefore, SEBs cannot be viewed as a generic RBD (2). It is also not clear whether the ‘molecular drift’ between SEBs and RBDs may widen over time as part of the manufacturing process. Are the pharmacokinetics of SEBs and RBDs comparable?: RBDs are used in combination with methotrexate in rheumatoid arthritis, as monotherapy in ankylosing spondylitis, and often in psoriasis and in combination with azathioprine in IBD. The doses are different for different indications in the case of RBDs. Therefore, comprehensive pharmacokinetic studies at low and high dose levels, as well as single and multiple doses, may be required to ensure the comparability of SEBs and RBDs. Serum drug levels are critical for the efficacy of monoclonal antibodies in immune-mediated inflammatory diseases (3). Are trial designs sufficiently robust to test efficacy comparability of SEBs and RBDs?: Equivalency studies with sufficiently narrow comparability margins to establish efficacy may require very large studies, which are difficult to conduct, and would compete for the same patients who may otherwise enter studies for the development of novel compounds for the treatment of IBD. For logistical reasons, such very large equivalence studies may not be performed. Are the immunogenicities of SEBs and RBDs comparable?: Immunogenicity of biological drugs is an important consideration and depends on the molecular structure of the monoclonal antibody, concomitant drugs such as methotrexate or azathioprine, the nature of the immune-mediated inflammatory disease, as well as the assay platform and test method. The assay methodology should be capable of detecting unique antidrug antibody to SEB; otherwise, the immunogenicity may be underestimated. It will also be important to determine clearly whether the antidrug antibodies cross-react between RBDs and SEBs. Can SEB drugs be extrapolated from one indication to another?: The precise mechanism of action, site of action, dose of monoclonal antibody and safety profile may have subtle differences among different immune-mediated inflammatory diseases. Therefore, extrapolation of efficacy based on clinical trials for one indication, such as rheumatoid arthritis, to another indication, such as ulcerative colitis or Crohn disease, may be difficult. On the other hand, conducting large separate clinical trials in different immune-mediated inflammatory diseases may be extremely expensive. Will the logistical support for administration be similar between RBDs and SEBs?: In Canada, gastroenterologists rely heavily on a support network from the sponsor company for administration of intravenous monoclonal antibodies. The comparability of such support networks between SEBs and RBDs will be important to practising gastroenterologists. Gastroenterologists treating IBD need to watch this rapidly evolving area with interest. Any reduction in cost of treatment with monoclonal antibodies will be welcome. The unique way in which the SEB drugs will have to considered, as described by Devlin et al (1) is, however, alien to gastroenterologists who have previously considered generic 5-aminosalicylates in their practice. A basic understanding of the issues will ensure that gastroenterologists are prepared for SEBs. Switching a well-controlled patient on a biological drug to another biological drug of the same class may be inadvisable based on the experience of the SWITCH study, which switched well-controlled patients on infliximab to adalimumab (4).

Sa1917 Efficacy of Allopurinol Added to 6MP or Azathioprine for Inflammatory Bowel Disease

INTRODUCTION Azathioprine (AZA) and 6-mercaptopurine (6MP) are indicated for the induction and maintenance of remission in patients with IBD. A drawback is their narrow therapeutic window. Therapeutic levels of the metabolite 6-thioguanine (6TGN) are associated with clinical remission. Adverse effects of 6-methylmercaptopurine ribonucleotide (6MMPN) include hepatotoxicity. Patients who selectively metabolize 6MP to 6MMPN can be identified and co-treated with allopurinol (allo), which shifts metabolism to 6TGN. The use of these measurements remains controversial as some experts maintain that outcomes are unchanged from standard therapy. We retrospectively reviewed charts of patients with toxic levels of 6MMPN who were treated with allo to determine if goals of therapy were achieved. METHODS A list of all patients who had 6MP/AZA metabolites measured in the last 4 years was obtained from Prometheus laboratory. The list included 32 patients, 14 met our criteria. Data was collected regarding age, sex, diagnosis, ESR, CRP, 6MMPN and 6TGN levels and need for anti-TNF therapy before and after initiation of allo, subjective improvement of patient's symptoms. RESULTS 14 patients were treated with allo due to toxic levels of 6MMPN (mean 11175 pmol/8X10^8RBC range 5936-22398). The average age was 49 yrs (range 22-90). 7(50%) were men. 8(57%) had Crohn's, 5(35%) had UC, and 1(7.1%) had indeterminate colitis. Following initiation of allo, all patients had normalization of 6MMPN levels (mean 996.5 range 979-1014). 4(25%) patients had therapeutic 6TGN levels prior to initiating allo. Following allo, 11(79%) reached therapeutic 6TGN levels, 1 achieved near therapeutic level (223) and 2 did not have follow up data. The average levels before and after therapy with allo was 191(range 117-355) and 330.1 pmol/8X10^8RBC (range 223-498), respectively. The average ESR before and after the initiation of allo was 24.7(range 1-111) and 18.7(range 1-76), respectively with an average decrease of 6 mm/ hr. 50% of the patients had a greater than 30% decrease in ESR. The average CRP before and after allo was 3.2 mg/L (range 0.1-18.6) and 0.56(range 0.1-2.4), respectively with an average decrease of 2.66. 57% of the patients had a greater than 40% decrease in CRP. 12 (86%) reported improvement in global symptoms following initiation of allo. 2 of the 3 patients who were on anti-TNF therapy prior to initiation of allo were able to discontinue it, 1 patient had to be switched to biologics due to pancytopenia and 1 required biologics due to lack of response to 6MP/allo . CONCLUSION Our study shows that initiation of allo in patients with elevated 6MMPN level results in normalization of 6MMPN level, achieves therapeutic levels of 6TGN, improvement of subjective symptoms, lab parameters used to assess inflammatory activity(ESR, CRP) and decrease in need for anti-TNF therapy.

6-Thioguanine Measurement Allows Optimisation in Management of IBD Patients on Azathioprine

Introduction Azathioprine is widely used in the management of Inflammatory Bowel Disease (IBD). The ideal dose for a patient is usually calculated by weight, but the rate of metabolism of azathioprine to its active metabolite 6-thioguanine (6TGN) varies between individuals. In addition, therapy may be limited by non-compliance, side effects or relapse of disease while on treatment. This retrospective study evaluates whether measuring 6TGN levels alters the management of patients on azathioprine for IBD. Methods A search of laboratory records identified a cohort of 41 patients with IBD that had been tested for 6TGN levels. 48 tests had been performed as 7 patients were tested twice. Electronic and, when required, paper records were reviewed to record demographics and diagnosis. The reason for checking 6TGN level and how this altered management was evaluated. Results The cohort was mainly young adults, with an age range of 18–73 years (median 36 years), and a slight female predominance (22 F:19 M). 66% of patients had Crohn9s disease, the remainder Ulcerative Colitis (UC). Tests were performed because patients were symptomatic, suspected of non-compliance, had abnormal liver biochemistry or to confirm a therapeutic dose. Of the 48 tests performed, 12 (25%) identified low 6TGN levels. Compliance was addressed in 3 cases. Dose of azathioprine was increased in 6 cases and management was altered in 2 cases. 20 tests (42%) were within the therapeutic range and azathioprine dose was only increased following 3 of these tests. 4 patients required escalation of treatment to alternative medication or surgery. 16 tests (33%) were above the recommended level of 6TGN, despite all the patients receiving 29 (60%) of all tests were performed on symptomatic patients to confirm adequate dosing before declaring a treatment failure. By weight calculation, 11 of these patients were receiving subtherapeutic doses of azathioprine. However, contrary to expectation, only 5 of 11 had low levels of 6TGN. Conclusion Calculation of azathioprine dose by weight does not address individual variation in metabolism to the active component, 6TGN. In this retrospective study, management was altered in 51% of patients as a result of measuring 6TGN, with either alteration of dose, or change of therapy. The cost of the assay (£29) limits its use, and currently we would recommend the use of 6TGN as a useful adjunct to established measures for azathioprine dose adjustment, such as clinical response and haematological indices.

W1197 Effectiveness and Adverse Effects of Azathioprine in Inflammatory Bowel Disease: 5-Year Follow-up Study

W1197 Effectiveness and Adverse Effects of Azathioprine in Inflammatory Bowel Disease: 5-Year Follow-up Study