Thiopurine Research Articles

Incidence of thiopurine induced severe myelosuppression in a nationwide cohort of inflammatory bowel disease patients.

There is paucity of data on the incidence of severe thiopurine (TP)-induced myelosuppression (TIM) among inflammatory bowel disease (IBD) patients. Utilizing the Veterans Affairs Healthcare system we identified IBD patients with normal pre-treatment thiopurine S-methyltransferase(TPMT) levels who received TPs for 6 months and developed severe TIM. Among 73,392 IBD patients, 14,760 had received TPs, and 2823 had a normal TPMT level. The incidence rate of severe TIM was 1.25 per 1000 patient-years. The incidence of severe TIM was very low, calling into question the necessity of frequent long-term CBC monitoring among IBD patients on TPs.

ASSESSING THE CLINICAL IMPACTS OF IMMUNOMODULATORY WITHDRAWAL FROM ANTI-TNF COMBINATION THERAPY IN PEDIATRIC INFLAMMTORY BOWEL DISEASE

Abstract INTRODUCTION Combination therapy consists of both a monoclonal antibody against tumor necrosis factor (anti-TNF) (infliximab (IFX) or adalimumab (ADA)) and an immunomodulator (IMM) (thiopurines (TP) or methotrexate (MTX)). Although combination therapy improves clinical outcomes, the IMM may be discontinued to mitigate the risk of IMM-related adverse events. However, it is unknown how de-escalation impacts clinical outcomes in children with IBD. METHODS This is a retrospective review of pediatric patients with IBD (<18 years of age) initiated on combination therapy between January 2014 and December 2019. Demographic and laboratory data were recorded at initiation of combination therapy, prior to IMM discontinuation, and between 6-12 months after de-escalation. The primary objectives were to assess the impacts of de-escalation on clinical remission rates, laboratory markers, and anti-TNF trough levels, and to evaluate factors that predict a poor response to de-escalation. Linear mixed effects models with random intercepts accounting for correlated measures with a patient across time were used to compare differences between study groups (and subgroups). Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation. Hypothesis testing was conducted at an alpha of 0.05. RESULTS We included 152 pediatric patients, of whom 126 patients had CD and 26 patients had UC/IC. The mean age of initiating combination therapy was 13.76 (± 3.1) years, and the mean duration of combination therapy was 106 (± 56) weeks. De-escalation did not increase the risk of worsening disease activity or affect laboratory values, including albumin, hemoglobin, sedimentation rate, and c-reactive protein. In patients with CD on IFX and TP, calprotectin significantly increased from 107 ug/g to 383 ug/g (p<0.05) and anti-TNF trough levels significantly decreased from 19 ug/ml to 14 ug/ml (p<0.05) after de-escalation. Eighteen percent (27 patients) of patients required subsequent escalation in therapy. Amongst these patients, anti-TNF levels were lower and CRP and ESR were higher prior to de-escalation compared to patients who did not require adjustments (p<0.05). DISCUSSION Only patients with CD on IFX who discontinued the TP had a significant increase in fecal calprotectin and decrease in IFX levels, though the drug levels remained within therapeutic range >10 ug/ml, and there was no increased risk of worsening disease. Lower anti-TNF levels and higher inflammatory markers prior to de-escalation may be predictive of patients requiring escalation in therapy after stopping the IMM. De-escalation in children on combination therapy may be safely considered with close attention to clinical symptoms, inflammatory markers, and anti-TNF drug levels, especially in children with CD on IFX and TP combination therapy.

Risk of Cancer in Patients with Inflammatory Bowel Diseases and Keys for Patient Management.

Chronic inflammation in patients with Inflammatory Bowel Disease (IBD) leads to an increased risk of colorectal cancer, small bowel cancer, intestinal lymphoma and cholangiocarcinoma. However, treatments for IBD have also been associated with an increased risk of neoplasms. Patients receiving Thiopurines (TPs) have an increased risk of hematologic malignancies, non-melanoma skin cancer, urinary tract neoplasms and cervical cancer. Anti-TNFs have been associated with a higher risk of neoplasms, mainly lymphomas and melanomas; however, the data are controversial, and some recent studies do not confirm the association. Nevertheless, other biologic agents, such as ustekinumab and vedolizumab, have not shown an increased risk of any neoplasm to date. The risk of malignancies with tofacitinib exists, but its magnitude and relationship with previous treatment with TPs is not defined, so more studies from daily clinical practice are needed. Although biologic therapy seems to be safe for patients with current cancer or a prior history of cancer, as has been demonstrated in other chronic inflammatory conditions, prospective studies in this specific population are needed. Until that time, it is crucial to manage such conditions via the combined clinical expertise of the gastroenterologist and oncologist.

P166 Impact of consultation frequency and time to diagnosis on subsequent Inflammatory Bowel Disease outcomes

Abstract Background The impact of length of time between the point of initial contact, at symptom onset, with a health-care provider and diagnosis of inflammatory bowel disease (IBD) on subsequent disease outcomes, is unclear. Diagnosis can be challenging and delay common, with an excess of gastrointestinal (GI) symptoms reported 3 years before the diagnosis of IBD compared to the background population.1 We describe the impact of time to diagnosis and frequency of consultation amongst individuals with GI symptoms who later go on to develop ulcerative colitis (UC) and Crohn’s disease (CD). Methods Using the Clinical Practice Research Datalink, a nationally representative research database, incident cases of IBD were identified between 2003 and 2016. GI symptoms were defined as abdominal pain, diarrhoea, or rectal bleeding. The proportion of individuals consulting for incident GI symptoms within 3 years prior to IBD diagnosis was identified. Using a multivariable regression model we evaluated the association between time to diagnosis from incident consultation and consultation frequency for GI symptoms on disease outcomes (corticosteroid (CS) and thiopurine (TP) use, hospitalisation and major abdominal surgery) 5 years after IBD diagnosis. Results Six thousand nine hundred and sixty-seven incident cases of IBD were identified during the study period. Within 3 years prior to IBD diagnosis, 2,645 (38%) patients had an incident presentation with GI symptoms in primary care (782 CD, 1,863 UC). Presentation with GI symptoms occurred >3 years before IBD diagnosis in 2,842 (41%) of patients. There was no recorded primary care consultation for 1,480 (21%) patients. Time to diagnosis from initial consultation was not associated with worse subsequent disease outcomes. However, amongst patients later diagnosed with UC, ≥3 prior consultations for GI symptoms was associated with an increased subsequent risk of CS use (HR 1.19, 95% CI 1.05 -1.36), CS dependency (HR 1.50, 95% CI 1.10 -2.05), TP use (HR 1.60, 95% CI 1.22 – 2.11) and colectomy (HR 1.91, 95% CI 1.21 – 3.04). Amongst patients with CD, ≥3 prior consultations were associated with an increased subsequent risk of major abdominal surgery (HR 1.75, 95% CI 1.22 -2.5) and hospitalisation (HR 1.58, 95% CI 1.18 -2.11) Conclusion Frequent primary care consultation with GI symptoms, but not symptom duration prior to IBD diagnosis, was associated with worse subsequent disease outcomes. Steps are needed to expedite IBD diagnosis to reduce the risk of adverse disease outcomes. Reference

Incidence of Acute Myeloid Leukemia and Myelodysplastic Syndrome in Patients With Inflammatory Bowel Disease and the Impact of Thiopurines on Their Risk.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are rare myeloid clonal disorders that commonly affect the elderly population and have poor prognosis. There are limited data on the risk of AML/MDS among patients with inflammatory bowel disease (IBD), especially on the impact of thiopurines (TPs). We conducted a retrospective cohort study among patients with IBD from Veteran Affairs data set. The exposure of interest was TP exposure: (i) never exposed to TPs, (ii) past TP use (discontinued >6 months ago), (iii) current TP use with a cumulative exposure of <2 years, and (iv) current TP use with a cumulative exposure of ≥2 years. The outcome of interest was a composite outcome of incident diagnosis of AML and/or MDS. Cox regression was used to estimate the adjusted and unadjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for AML/MDS risk associated with TP use defined as a time-varying exposure. Among 56,314 study patients, 107 developed AML/MDS. The overall incidence of AML/MDS in the IBD population was 18.7 per 100,000 patient-years. The incidences among those never exposed to TPs, past users of TPs, current users of TPs with a cumulative exposure of <2 years, and current users of TPs with a cumulative exposure of ≥2 years were 17.0, 17.7, 30.4, and 30.3 per 100,000 patient-years, respectively. In multivariable Cox regression analysis, compared with never exposed to TPs, current use of TPs was associated with increased risk (adjusted HR 3.05; 95% CI 1.54-6.06, P = 0.0014 for current use of TPs with a cumulative exposure of <2 years and adjusted HR 2.32; 95% CI 1.22-4.41, P = 0.0101 for current use of TPs with a cumulative exposure of ≥2 years), whereas past TP exposure was not. Among patients with IBD, current TP use was associated with an increased risk of AML/MDS, which reverts to baseline after discontinuation of TP use.

Porous graphitic carbon based chromatography hyphenated with mass spectrometry: A new strategy for profiling thiopurine nucleotides in patients with inflammatory bowel diseases

Thiopurine (TP) treatment is discontinued in up to 30% of patients suffering from inflammatory bowel diseases (IBD) due to various adverse effects. Therapeutic drug monitoring of biologically active TP metabolites, i.e. thiopurine nucleotides (TPN), can help to optimize the efficacy and safety of the TP treatment. In our work, a novel strategy for TPN profiling, based on a porous graphitic carbon (PGC) chromatography, was developed. The validated PGC-MS method was compared with ion-exchange LC-MS, a currently leading analytical approach established for the determination of TPN. The innovative approach enabled an enhancement of several key performance parameters demanded in a clinical routine use, namely (i) selectivity (time- and mass-recognition of all 12 TPN in one run), (ii) sensitivity (2-5-fold increase in intensities of the analytical signals), (iii) sample throughput (25% shorter analysis time). Application of the novel TPN profiling strategy to a pilot clinical study (12 patients) revealed significantly higher levels of 6-methylthioguanine 5′-diphosphate (MeTGDP) in non-responsive IDB patients treated with azathioprine. Some other TPN are very close to the critical level (p = 0.05) and they will need larger groups of IBD patients to confirm definitively their relevance. In conclusion, the developed PGC-MS method represents a significant improvement to currently available methods for detailed profiling of TPN and its use in bigger clinical studies should lead to a better understanding of the relationship between TPN profiles and therapeutic outcome.

Repeated Occurrences of Basal Cell Cancer in Patients With Inflammatory Bowel Disease Treated With Immunosuppressive Medications

There are limited data on repeated basal cell cancer (BCC) occurrences among patients with inflammatory bowel disease (IBD), especially the impact of continuing immunosuppressive medications. We conducted a retrospective cohort study of 54,919 patients with IBD followed in the Veterans Affairs Healthcare System. We identified patients who had an incident BCC after their IBD diagnosis. We defined patients' exposure based on their IBD medications use as follows: (i) only aminosalicylate (5-ASA) use, (ii) only active thiopurine (TP) use, (iii) past TP use (discontinued >6 months ago) and no antitumor necrosis factor (TNF) use, (iv) anti-TNF use after previous TP use, (v) only anti-TNF use, and (vi) active anti-TNF and TP use. The outcome of interest was the repeated occurrence of BCC. Adjusted and unadjusted hazard ratios with 95% confidence intervals were used to estimate the risk of repeated BCC occurrence. A total of 518 patients developed BCC after their IBD diagnosis. The numbers of repeated BCC occurrences per 100 person-years were 12.8 (5-ASA use only), 34.5 (active TP use), 19.3 (past TP use and no anti-TNF use), 25.4 (anti-TNF use after previous TP use), 17.8 (only anti-TNF use), and 22.4 (active anti-TNF and TP use). Compared with 5-ASA use alone, only active TP use was associated with an increased risk for repeated BCC occurrence (adjusted hazard ratio 1.65, 95% confidence interval 1.24-2.19; P = 0.0005). However, the increased risk was no longer present for other exposure categories. Among IBD patients who developed an incident BCC while taking a TP and continued it, there was an increased risk of repeated BCC occurrences.

The Use of Thiopurine Derivatives in the Treatment of Inflammatory Bowel Disease.

The Use of Thiopurine Derivatives in the Treatment of Inflammatory Bowel Disease.

Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients.

Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort. Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire. A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61years old versus less than 30years old (OR 6.76; 95% CI 2.38-19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6-6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4-10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9-16.0). Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.

A Thiopurine with Infliximab Might Improve Efficacy in Crohn Disease

Prospective randomized data show that addition of a thiopurine to infliximab results in better outcomes than infliximab alone in the treatment of Crohn

Efficacy of Thiopurines in Achieving Steroid-Free Remission in a Nationwide Cohort of Ulcerative Colitis Patients

Introduction: Thiopurine (TP) medications i.e. Azathioprine (AZA) and 6-Mercaptopurine (6-MP), are integral components in the management of ulcerative colitis (UC). However, there is limited data on long term effectiveness of TP among UC patients. Our aim was to determine steroid free remission after starting TP in a nationwide cohort of UC patients. Methods: We conducted a retrospective cohort study using the Veterans Affairs (VA) database, which is the largest integrated healthcare system in the United States. We used an internally validated algorithm to identify patients with UC. The cohort study period was from January 1, 2000 to June 30, 2016. The follow-up (FU) began at the date of first thiopurine prescription in the VA pharmacy records and ended if the patient died, had a UC related colectomy or last recorded date in the VAHS if it was not the end of study period. Our outcome of interest was steroid free clinical remission. Results: Our cohort included a total of 5931 UC patients who had utilized thiopurines for management of their disease. The majority of these patients were males (93.86%) and Caucasians (85.25%). A total of 3771 patients (63.58%) had received AZA for their UC and the remaining were on 6-MP. (Table 1) We found that almost 71% of patients continued TP beyond 6 months. At the end of 4 years of the original cohort 36% were still on the drug. Of the patients who continued TP beyond 4 years, almost a third required oral prednisone at some point in their follow up and 4.2 % used IV prednisone. (Table 2) Conclusion: The largest drop off of TP usage occurs in the first 6 months. Almost a third of the patients continued the drug beyond 4 years and of those, the majority remained in steroid free remission.665_A Figure 1. Demographics of our cohort665_B Figure 2. Comparison between thiopurine and steroid usage

Analytical and Sample Preparation Protocol for Therapeutic Drug Monitoring of 12 Thiopurine Metabolites Related to Clinical Treatment of Inflammatory Bowel Disease.

Thiopurines (TP) represent an important therapeutic tool for the treatment of inflammatory bowel diseases (IBD) in the current situation of rising incidence and health care costs. The results of multiple clinical studies aimed at finding correlations between levels of TP metabolites and response of IBD patients to the treatment are, however, often controversial due to variability in analytical and sample preparation procedures among these studies. In this work, therefore, an updated analytical and sample preparation procedure for therapeutic drug monitoring (TDM) of TP metabolites in blood samples obtained from patients with IBD was proposed to establish a unified protocol. An advanced analytical method based on ion-exchange liquid chromatography hyphenated with tandem mass spectrometry (IEC-ESI-MS/MS) was used for the determination of the profiles of 12 individual TP metabolites in the particular steps of sample preparation procedure including blood collection, red blood cells (RBC) isolation, lysis, and storage. Favorable performance parameters of the IEC-ESI-MS/MS method (LLOQs 1–10 nmol/L, accuracy 95–105%, intra-day and inter-day precision < 10%, selectivity demonstrated via no sample matrix interferences) and acceptable stability (peak area fluctuations < 15%) of clinical samples under the proposed sample preparation conditions {(i) EDTA anticoagulant tube for the blood collection; (ii) 4 °C and 4 h between the sample collection and RBC isolation; (iii) phosphate-buffered saline for RBC washing and re-suspendation; (iv) −20 °C for RBC lysis and short-term storage; (v) 50 mmol/L phosphate buffer, pH 7.4, 10 mmol/L DTT as a stabilizing medium for TPN in RBC lysates} demonstrated the suitability of such protocol for a well-defined and reliable routine use in studies on thiopurines TDM.

Utility of proactive infliximab levels in paediatric Crohn’s disease

ObjectiveInfliximab (IFX) has an established role in Crohn’s disease (CD), with serum trough levels of IFX (TLI) increasingly used to optimise dosing. We report the utility of routine, proactive TLI...

Thiopurines Seem Efficacious in the Long-Term Treatment of Ulcerative Colitis

When patients with ulcerative colitis fail or are intolerant to mesalamine products, or require repeated courses of corticosteroids, biologics now

Thiopurines prevented surgical recurrence in patients with Crohn's disease after intestinal resection: Strategy based on risk stratification.

Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR. This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors. A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P=0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P=0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P=0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P<0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P=0.08) in low-risk group (n=46). However, in high risk group (n=200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P<0.001). Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

Recurrence of Non-melanoma Skin Cancer in Inflammatory Bowel Disease Patients Who Continue Thiopurines After Developing Incident Non-melanoma Skin Cancer While on a Thiopurine

Introduction: The use of thiopurines (TP) in patients with inflammatory bowel disease (IBD) is associated with an increased risk of developing non-melanoma skin cancer (NMSC). There is however, paucity of data on the recurrence rate of NMSC if TP are continued after the incident NMSC. Our aim was to determine the rate, number and complications of such recurrences if TP were continued. Methods: We conducted a retrospective study on nationwide data obtained from Veterans Affairs (VA) healthcare system. Veterans who were seen and followed up in the VA healthcare system from January 01, 2001 to June 30, 2016 were identified using the International Classification of Diseases (ICD-9 and ICD-10 codes) for IBD and NMSC. The exposure of interest was patients with IBD who were on TP, developed NMSC while on therapy and continued TP after the development of NMSC. The outcome of interest was one or more recurrence of NMSC. The patients were followed up until the last date of TP use, death or lost to follow up. Our definition of NMSC was based on pathology, diagnostic and surgical treatment codes. A manual chart review was performed by two individual reviewers to ascertain the NMSC diagnosis based on the surgical pathological reports. All recurrences were confirmed by surgical pathology reports.Figure: Time to first recurrence of NMSC.Figure: Number of recurrences.Table: Table. Death due to NMSC complicationsResults: A total of 263 patients had NMSC while on a TP. Median age of the population was 67 (IQR 62-73) years at time of first recurrence of NMSC with majority of population being male (98.1%) and Caucasian (97.7%). Amongst them, 257 (97.7%) patients continued TP medication after NMSC diagnosis. Median duration of follow up was 3.24 years (IQR 1.72-5.83). At least one NMSC recurrence was present in 149 (56.6%) patients, while 125 (47.5%) had two or more recurrences with a median number of recurrences being 3 (IQR 2-5). The median dose of azathioprine (AZA) at the first and the last recurrence was 1.44 (IQR 1.09- 1.82) mg/kg/day and 1.42mg/kg/day (IQR 0.94-1.77) respectively. The median dose of 6-mercaptopurine at the first and the last recurrence was 1 (IQR 0.67-1.28) mg/kg/day and 0.91mg/kg/day (IQR 0.31-2.29) respectively. A total of 66 (25.1 %) patients died during the follow up out of which 8 (3%) died due to NMSC complications. Conclusion: In patients who developed NMSC while on TP therapy there was a high rate of recurrence with continuation of therapy. More importantly the majority of patients who recurred had multiple recurrences and 3% of the patients died of complications of the recurrence.

40 Correlation of relationship between infliximab and adalimumab trough and antibody levels with clinical response rates at completion of induction therapy

Background Anti-TNFa therapies have improved response rates in inflammatory bowel disease. However primary loss of response is problematic. Aim Aim of this study was to explore relationship between infliximab (IFX) and adalimumab (ADA) trough and antibody levels with clinical response. Method This was a prospective, single centre study. Patients were recruited from July 2015-August 2016. Inclusion criteria were patients older than 17 years with IBD who started treatment with anti-TNFa drugs (infliximab/adalimumab) Patient demographics, clinical history were collected from electronic records. Clinical disease activity indexes were performed (Harvey-Bradshaw Index for Crohn’s disease (CD), and partial Mayo scores for Ulcerative colitis (UC)). Clinical response defined as reduction in HBI≤3 or reduction in partial Mayo score ≤4 and Results 35 patients were recruited; 23 CD, 12 UC. 18 patients treated with ADA, 17 IFX. Mean age 40.3 years, 62.9% female, 34.3% thiopurines, 25.7% prior anti-TNFa exposure. Response rate 51.4%, 33.3% for ADA, 70.6% for IFX. Overall trough levels were 12.5 ug/ml for IFX, 4.4 ug/ml for ADA. There was clear link between higher anti-TNFa trough levels at induction with clinical response. For infliximab, mean trough levels in responders were 16.4 ug/ml (IQR 8.4-22.7) versus 5.3 ug/ml(IQR 0.5–8.8) for non-responders (p value 0.02 95% CI: 1.5 to 20.7). Similarly there was a link between higher ADA levels with clinical response, though not statistically significant. Responders mean trough 6.6 ug/ml versus non-responders 3.0 ug/ml (p value 0.14). Antibody formation occurred in 28.5%. Conclusions Higher anti-TNFa trough levels at induction are associated with improved clinical response.

Significance and application of individualized detection of thiopurine S-methyltransferase in patients with chronic actinic dermatitis

Objective To investigate correlations of thiopurine S-methyltransferase (TPMT) activity (phenotype) and genotype with adverse reactions after oral azathioprine treatment in patients with chronic actinic dermatitis, and to explore optimal azathioprine dose for the treatment of chronic actinic dermatitis. Methods Totally, 70 patients with chronic actinic dermatitis treated with oral azathioprine were enrolled into this study and served as patient group, of whom, 12 had adverse reactions to azathioprine. In addition, 50 health checkup examinees were enrolled as the control group. EDTA-anticoagulated blood samples were collected from the patients and controls, and erythrocytes lysates were prepared. High performance liquid chromatography (HPLC) was performed to evaluate the activity of TPMT. Genome-wide DNA was extracted from the blood samples, and TPMT genotypes were detected by allele-specific PCR and PCR-restriction fragment length polymorphism (RFLP) analysis. Results There was no significant difference in the TPMT activity between the patient group and control group ([25.80 ± 8.34]U/ml vs. [23.58 ± 5.70]U/ml, t= 0.782, P > 0.05) . However, the TPMT activity was significantly lower in patients with adverse reactions than those without ([18.86 ± 9.22]U/ml vs.[27.27 ± 6.72]U/ml, t= 3.437, P < 0.05) . TPMT genotypes were detected among 120 samples, and a heterozygous mutation TPMT*3C (A719G) was found in the TPMT gene in 7 samples, including 5 in the patient group and 2 in the control group. The frequencies of the mutant genotype and allele were 5.8% (7/120) and 2.9% respectively. No significant difference in the frequency of TPMT*3C mutation was observed between the patient group and control group (χ2= 0.108, P= 0.742) . The TPMT*3C mutation was found in 3 of the 12 patients with adverse reactions, as well as in 2 of 58 patients without adverse reactions. Additionally, the frequency of TPMT*3C mutation was significantly higher in patients with adverse reactions than in those without (χ2= 40.093, P < 0.05) . Conclusion Adverse reactions after oral azathioprine treatment are associated with TPMT mutations and decreased TPMT activity in patients with chronic actinic dermatitis, so appropriately adjusting the azathioprine dose in patients with low-activity and mutant-type TPMT can facilitate safe treatment. Key words: Dermatitis, photoallergic; Azathioprine; Drug toxicity; DNA mutational analysis; Thiopurine methyltransferase

Methotrexate for Refractory Crohnʼs Disease Compared with Thiopurines

This study assessed the efficacy and safety of methotrexate (MTX) compared with thiopurines (TPs) for refractory Crohn's disease. Fifty-one consecutive patients who were refractory or intolerant to TPs and steroid-dependent were retrospectively analyzed. MTX (20 mg/wk, subcutaneous) was adopted for inducing and maintaining clinical remission (CR). Fifty-seven patients who were naive to immunosuppressant and prescribed azathioprine (2 mg·kg·d) or mercaptopurine (1 mg·kg·d) were simultaneously recruited. By week 16, the CR rate was 68.6% and 78.9% in the MTX and TPs groups, respectively (P = 0.222). Patients with disease duration ≤3 years were more likely to achieve CR with MTX (odds ratio = 7.667, P = 0.019). By week 64, the CR rate of patients achieved remission at week 16 was 45.7% and 44.4% in the MTX and TPs groups, respectively (P = 0.910). Normalization of high-sensitivity C-reactive protein level (relative risk = 11.221, P = 0.003) and platelet count (relative risk = 9.672, P = 0.004) at week 16 predicted the efficacy of maintaining remission with MTX. Among patients with remission at week 16, the mucosal healing rates at week 36 were 47.4% with MTX and 47.1% with TPs (P ≈ 1.000). Fifteen (29.4%) patients on MTX and 25 (43.9%) on TPs experienced adverse events (P = 0.121). MTX is effective in inducing and maintaining CR and achieving mucosal healing in patients with refractory Crohn's disease, and its efficacy is comparable to that of TPs for naive patients. The side effects of MTX were mild and tolerable.

Safety of Tumor Necrosis Factor Blockers in Pediatric Inflammatory Bowel Disease

Recent data in adults suggest that thiopurines are associated with a threefold to fourfold increased risk for lymphoma when used to treat inflammatory