Azathioprine Dose Research Articles

P670 Usefulness of monitoring the concentration of azathioprine metabolites in the children with inflammatory bowel disease and autoimmune hepatitis

Abstract Background Azathioprine (AZA) is an immunosuppressive drug, which is metabolised in the liver and kidneys into 6-thioguanine- the form responsible for the therapeutic effect. Despite its anti-inflammatory, antibacterial and immunomodulating properties, azathioprine has also dose-related side effects, such as bone marrow suppression, liver damage and pancreatitis. The purpose of this study was to assess the usefulness of monitoring the concentration of azathioprine metabolites: 6-tioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in the group of paediatric patients with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). Methods The clinical data of 46 paediatric patients (24 girls) with IBD and AIH, aged 8–17 years, hospitalised in the Department of Gastroenterology, who had undergone a blood examination for AZA metabolites concentration, were analysed. Results Initial mean dose of azathioprine was 1.23 mg/kg/day in IBD and 1.16 mg/kg/day in AIH. In 30% of patients, the concentrations of 6-TG and 6-MMP were within the normal range. Forty-eight per cent of patients required a dose change due to: elevated 6-TG concentration (32.6%) or underdosage (15.4%). After modification the mean dose was 1.16 mg/kg/day in IBD and 0.85 mg/kg/day in AIH. In 10.7 % of patients, the concentrations of 6-TG and 6 MMP were below the proper range, in the same percentage of patients metabolites were undetectable. Conclusion In a significant number of cases monitoring the concentration of AZA metabolites indicated the necessity to reduce the dose of AZA allowing to achieve the therapeutic optimum and prevent serious side effects. Receiving undetectable concentration of metabolites is a sign of non-compliance. The final doses of AZA were found to be lower than the recommended doses. Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels is a good strategy that can be used to optimise IBD and AIH therapeutics.

P501 Thiopurine withdrawal in patients with Crohn’s disease: the SURESTE study

Abstract Background Thiopurine (TP) withdrawal in patients with Crohn’s disease (CD) in clinical remission (CR) is controversial. Our aim was to describe the evolution of CD patients in CR who discontinued TP prescribed to maintain a remission previously achieved with medical treatment, and to detect predictors of reactivation after withdrawal. Methods Multicentric observational retrospective study including CD patients in RC under TP treatment, who electively discontinued TP. Relapse was defined as the need to start any specific treatment for CD, including surgery. Informed consent was obtained from the inclusion in the Eneida database. Results We included 78 patients (52.6% females, age 45(19–77) years) of whom 57 presented an inflammatory, 12 a stricturing and 9 a penetrating behaviour; 31 patients had terminal ileum involvement, 9 colonic, 36 ilecolonic, and 2 ileocolonic plus upper gastrointestinal involvement, whilst 17 also had perianal disease. Mean disease duration was 13.47 (3.02–35.02) years. 48.7% had never smoked whilst 24.4% were active smokers. TP was started to maintain remission previously achieved with medical therapies in 78 patients (100%). Median azathioprine dose was 2.11 (1.3–2.6) mg/kg/d, and of 6-mercaptopurine (6MP) 1.44 (1–2) mg/kg/day. The median duration of TP treatment was 52.79 (3–268) months and of steroid-free remission 49.41 (1–177) months. Reasons for TP withdrawal were: patient choice/request in 20 (25.6%), physician proposal in 28 (25.7%), drug-related adverse events in 19 (24.4%) and miscellaneous in 11 (14.1%). By the time of TP discontinuation, median CRP was 5.08 mg/l (0.1–157.9), fecal calprotectin(FC) 282.38 µg/g (2.4-4430) and a mean 0.45 (0–4) in Harvey–Bradshaw Index (HBI); those who relapsed presented median CRP of 15.31 mg/l (0.1–125.31), fecal calprotectin (FC) 462.22 µg/g (90–1240) and a mean 5.46 (0–15) in HBI. These differences were statistically significant. During a 5.08 (0.12–13.05) years follow-up, 38 (48.1%) patients relapsed, with treatment duration being the only factor associated to risk of relapse (Or = 0.659 IC95 0.43–0.98, p = 0.04) in the multivariant analysis (IMAGE1). Conclusion Thiopurine withdrawal in the context of sustained remission in CD is associated with relapse in almost half of the patients after a median follow-up of 5 years. Thiopurine treatment duration of shorter than 5 years was shown to carry greater risk for relapse.

Vaccine–induced childhood pemphigus vulgaris: A case report in a 5-year-old female child

Pemphigus vulgaris (PV) is an immunobullous disease affecting the skin and mucosa. It is a disease most commonly manifesting in the third–fifth decades of life. Pediatric PV is rare and usually seen at a mean age of 12 years. Early childhood PV is extremely rare with only few cases reported. There are various inducers of PV in children. Diphtheria toxoid (DT) has rarely been reported as an inducer of PV. We report a 5-year-old female child who developed vesiculobullous mucocutaneous lesions after DT vaccination. The diagnosis was confirmed by histopathology and immunofluorescence. She was treated with pulse methylprednisolone therapy and daily dose azathioprine.

Granulomatous hypophysitis causing compression of the internal carotid arteries reversible with azathioprine and rituximab treatment.

Compression of the internal carotid artery (ICA) in the cavernous sinus area is a rare event and is mostly associated with pituitary adenomas and meningiomas. Other causes of ICA compression are less well known. We present a rare case of granulomatous hypophysitis causing compression of the ICA, which was treated successfully with immune-suppressive agents. The electronic database MEDLINE (PubMed) was searched systematically and other cases with ICA compression were identified and analyzed. A female patient with a history of two previous transsphenoidal operations for suspected pituitary adenoma and post-operative complete pituitary insufficiency presented with severe headaches, nausea, fatigue, and diplopia. Pituitary MRI scan suggested relapse of the pituitary lesion with atypical bilateral infiltration of cavernous sinuses and compression of ICAs. After histological reevaluation of her previous pituitary operations, granulomatous hypophysitis was diagnosed. Treatment was started with high doses of prednisolone. With decreasing doses of prednisolone, symptoms recurred, and azathioprine was started, followed by administration of rituximab resulting in clinical recovery and regression of ICA compression. Literature analysis disclosed 36 case reports with ICA compression in the cavernous sinus region (12 pituitary adenoma, 6 meningioma, 7 hypophysitis, 5 other tumors, and 4 other etiologies). Two cases of hypophysitis recovered completely; five cases improved only partly. In the case of ICA compression, clinical signs, onset of symptoms, radiological findings and pituitary insufficiencies should be thoroughly evaluated, and hypophysitis should be considered as a possible cause. In our patient, treatment with azathioprine and, finally, rituximab was successful.

Sporadic Late Onset Nemaline Myopathy with a Monoclonal Gammopathy: Comparative Effectiveness of Immuno- and Chemotherapy

Introduction A rare subset of sporadic late-onset nemaline myopathy (SLONM) is associated with monoclonal gammopathy of unknown significance (MGUS). The role of monoclonal protein (M-protein) in SLONM is unknown, but SLONM with MGUS (SLONM+MGUS) demonstrates an aggressive disease course with severe muscular weakness, early development of respiratory failure, and is often fatal. Whether SLONM+MGUS represents a malignant or dysimmune disease remains unclear. Currently, two approaches are used to treat SLONM+MGUS: 1) immunosuppression ± plasmapheresis/exchange; or 2) chemotherapy (ChT) ± autologous stem cell transplantation (ASCT). Unfortunately, due to the rare occurrence of the disease, the best treatment modality is unknown. Methods We conducted a literature search to identify previous treatment modalities for patients diagnosed with SLONM+MGUS using PubMed, Elsevier, Medline, and CINAHL databases from 1975 to 2019. All publications were carefully reviewed to remove "duplicate" patients. Overall, 28 reports were included for the final analysis. Results We identified 38 unique patients diagnosed with SLONM+MGUS treated either with immunotherapy (IT) (n=19) or ChT ± ASCT (n=19). The median age was 49 years [range: 26-75] in the IT group and 47 years [range: 24-64] in the ChT group. There was a slight male preponderance in the IT group [n=14 (74%)] than in the ChT group [n=10 (53%)]. Similarly, more cases with kappa light chain restricted M-protein were observed in the IT group [n=12 (67%)] than in the ChT group [n=8 (42%)]. In the IT group, M-protein values were only reported in two patients (mean: 0.42 g/L), while M-protein values were reported for 14 patients in the ChT group (mean: 6.54 g/L). In the IT group 16 patients (84%) received steroids, 5 (26%) plasmapheresis, 10 (53%) steroid-sparing immunosuppressants (low dose cyclophosphamide, azathioprine, cytarabine, and mycophenolate mofetil), 2 (11%) rituximab, and 10 (53%) IVIG. Twelve (63%) patients received oral prednisone (mean dose: 67 mg) and 3 (16%) received pulse methylprednisolone (1 g). Patients received IT modalities sequentially or in parallel. Six patients (32%) received 1 and 13 patients (68%) received 2 or 3 (median = 2) IT types. Neurological improvement was observed in 10 patients, a 53% overall response rate (ORR) with 3 (16%) patients in complete remission (CR), and 7 (37%) patients in partial response (PR). No improvement or progression was observed in 9 (47%) patients (Figure 1). In 2 patients, neurological CR was associated with complete disappearance of M-protein. Mean time to best response was 19 months in a follow-up duration of 23 months. The ChT group included three categories: 1) 10 (53%) patients received ASCT with high dose melphalan (mean: 164 mg/m2); 2) 3 patients (16%) were treated with Cyclophosphamide/Bortezomib/Dexamethasone (CyBorD), cyclophosphamide/Thalidomide/Dexamethasone and Lenalidomide and Dexamethasone (Ld) chemotherapy without ASCT; and 3) 6 (31%) patients underwent induction chemotherapy with CyBorD (n=2) and Ld (n=4), followed by consolidative ASCT. Neurological improvement was achieved in 18 patients, a 94.7% ORR with CR in 14 (73.7%) and PR in 3 (21.0%) patients. Only one patient did not respond to therapy. The best neurological improvement correlated with disappearance of M-protein [complete hematological remission (CHR)]. Mean time to best response was 10 months, which was shorter than the IT group. Follow-up duration was 31 months. Conclusion Based on a comprehensive evaluation of existing treatment modalities for patients with SLOMN+MGUS we conclude that the best course of treatment is through consideration of the disease as a malignancy rather than a dysimmune disease. Our review supports that the best method of treatment entails ChT with or without of consolidative ASCT in the pursuit of eliminating the malignant plasma cell clone. In conjunction with nemaline myopathy presence of M-protein has clinical significance and it may be worth considering reclassifying SLONM+MGUS as SLONM with Monoclonal Gammopathy of Clinical (Neurological) Significance (SLONM+MGCS). Disclosures No relevant conflicts of interest to declare.

797 High Thiopurine Methyltransferase Activity Does Not Affect Concentration of Azathioprine Metabolite 6-Thioguanine Nucleotide in Inflammatory Bowel Disease

INTRODUCTION: Azathioprine (AZA) is commonly used to treat inflammatory bowel disease (IBD). Thiopurine methyltransferase (TPMT) converts AZA to key active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity is associated with high 6-TGN and side effects. Conversely, low 6-TGN is associated with lack of clinical response and has been associated with high TPMT activity but has not been examined in an IBD population. The aim of this study was to identify the independent effect of normal to high TPMT activity on 6-TGN concentrations in an IBD population. METHODS: We performed a retrospective chart review of patients aged >18 with IBD treated with AZA and with documented TPMT activity and 6-TGN levels from 2010 to 2017. To account for different assays, TPMT activity was normalized against the established low-normal TPMT activity, with low activity defined as less than 1 and high activity defined as above the 75th quantile of TPMT activity in the cohort. Those with low TPMT were excluded. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for potential confounders. Further assessment of the interaction between dose and TPMT activity on 6-TGN was measured through the Average Causal Mediation Effects (ACME). Statistics performed in R v3.6.0 using mediation package. This study was IRB approved. RESULTS: Dosing of AZA in mg/kg, TPMT activity, and 6-TGN concentration were documented in 63 patients, of which 10 had low TPMT activity and were subsequently excluded, leaving 53 patients for analysis. Overall 37% of the cohort had a therapeutic 6-TGN level of >240 pmol/8 × 108 RBC. No patient under 1mg/kg achieved a therapeutic 6-TGN level, whereas 50% of patients taking 2.5 mg/kg did. The median 6-TGN in the normal TPMT range was 191.5 (IQR: 78.8, 296.3) versus 201 (IQR: 45, 312) in the high group (P = 0.57). There was a weak positive correlation between dosing (mg/kg) and 6-TGN (R2 = 0.08), while no correlation was seen between TPMT and 6-TGN (R2 = 0.0). Linear regression to assess the effect of TPMT activity and dose on 6-TGN concentrations including potential confounders of sex, age, smoking status only identified dose (mg/kg) to have a significant effect on 6-TGN concentration (Table 1). CONCLUSION: There was no effect on 6-TGN as TPMT activity increased, although 6-TGN was positively affected by dose. Despite normal TPMT activity, therapeutic 6-TGN concentrations were only found in 50% of those dosed at 2.5 mg/kg.

1023 Early Treatment of Recurrent Hepatitis C Post-Liver Transplant

INTRODUCTION: The rate of hepatitis C virus (HCV) recurrence after liver transplant (LT) is greater than 95% and chronic recurrence is more aggressive in the setting of immunosuppressive therapy (IS) in LT patients. Sustained viral response (SVR) is associated with lower mortality rates related to hepatic and extrahepatic manifestations of HCV including renal disease. Currently, however, there are no clear guidelines for the timing of HCV treatment post LT. The goal of this study is to examine the effects of early HCV treatment post-LT on kidney function, liver function and IS. METHODS: This is a retrospective study of 38 LT patients who received HCV treatment within 1 year between 2015 and 2018. Renal function, hepatic function and immunosuppressive regimens were compared at HCV treatment initiation and when patients achieved SVR post treatment. 86% of patients received a Sofosbuvir based regimen. RESULTS: The study included 38 patients with recurrent HCV post LT. Patients were 79% male, 71% Caucasian, with mean age being 57 [range 33-73]. The mean number of days between LT and HCV treatment initiation was 129 days [range 15-321]. All patients were initiated on treatment within the first year of LT. SVR rate was 100% in patients that were compliant with the regimen. No serious side effects were reported. There was no significant difference in mean pre and post-HCV treatment creatinine or number of patients with GFR < 60-pre/post treatment. There was no significant difference between number of patients on Mycophenolate or Tacrolimus before and after treatment. There was no significant difference in the mean dose of steroids, Azathioprine, Mycophenolate or Tacrolimus before and after HCV treatment. CONCLUSION: In patients completing treatment for recurrent HCV within 1 year of LT as early as 15 days post LT, treatment was well tolerated and effective with 100% SVR rate. There was no significant change in number of patients with Cr < 60 before and after treatment and no significant change in the dose of IS. Further studies will help compare outcomes and effects of HCV treatment within one year post LT vs later particularly on renal function and IS therapy.

2926 The Reiationship of Bone Marrow Suppression and Remission by Immunomodulators in the Patients With Crohn's Disease

INTRODUCTION: Immunomodulator including azathioprine and 6-mercaptopurine has been widely used in the patients with Crohn's disease. Most common adverse event of immunomodulator has been known as bone marrow suppression such as leukopenia. We aim to evaluate the relationship of bone marrow suppression and the remission by immunomodulator in the patients with Crohn's disease. METHODS: We investigated 160 patients with Crohn's disease undertaken immunomodulator and analyzed the relationship of bone marrow suppression and the maintenance of remission and relapse rate by immunomodulator. RESULTS: Among the 160 patients (male:female, 122:38, age of 33 ± 12 years (range, 17-69)), 37 patients (23.1%) developed bone marrow suppression. Initial dose of azathioprine was 43 ± 18 mg (25-150 mg, 0.8 ± 0.3 mg/kg) and 81 ± 33 mg (25-175 mg, 1.3 ± 0.6 mg/kg) during maintenance. Only 2 patients were taken 6-mercaptopurine because of nausea with azathioprine. 5-aminosalicylic acid was most frequently co-administered drug with immunomodulator in patients who developed bone marrow suppression. The maintenance of remission and relapse rate showed no significant difference depending on bone marrow suppression during immunomodulator. CONCLUSION: The rate of bone marrow suppression by immunomodulator was relatively high. However, bone marrow suppression did not seem to be related to the maintenance of remission and relapse rate by immunomodulator in the patients with Crohn's disease.

Determination of Thiopurine S-methyltransferase Activity using Reverse-Phase High-Performance Liquid Chromatography Assay with Ultraviolet Detection: Reference Values for the Indian Population

Objective: To determine thiopurine S-methyltransferase (TPMT) activity and the range of TPMT activity values for the Indian population. Methods: An isocratic reversed-phase high-performance liquid chromatography method with ultraviolet detection for the determination of TPMT activity in red blood cells was developed and validated. TPMT activity (nmol of 6-methylmercaptopurine [6-MMP]/h/ml erythrocytes) was measured based on the conversion of 6-mercaptopurine to 6-MMP with S-adenosyl-l-methionine. The stability of erythrocyte lysate at −20°C and the whole-blood specimens for TPMT activity were determined at 4°C. TPMT enzyme activity was measured in 150 patients who were not on azathioprine (AZA), and population difference in TPMT enzyme activity was evaluated. Results: The assay was linear from 1.0 to 60.14 nmol 6-MMP concentrations. The chromatogram peaks obtained were baseline separated for 6-MMP and the internal standard. The bias and precision of low-, medium-, and high-quality controls (QC) were within acceptable limits. Stock and lysate specimens were found to be stable in −20°C. The Indian populations have a considerable number of patients with low- and intermediate-TPMT activity. The wide range of TPMT activity in the study population (3.85–35.68 nmol/h/ml erythrocytes) is suggestive of high inter-individual variability in the formation of 6-thioguanine nucleotide formation, and therefore clinical efficacy and safety of AZA. Conclusion: A simple isocratic method was developed and validated for measuring TPMT activity in erythrocytes. Measuring TPMT activity before initiating AZA may help to decide the initial dose of AZA in patient management.

Insulin Resistance in Nonobese Renal Allograft Recipients on Maintenance Doses of Cyclosporine or Tacrolimus

PurposeIn comparison to cyclosporine (CsA), tacrolimus (Tac) seems to be more diabetogenic in renal transplant recipients, and post-transplant diabetes mellitus is more common in patients using Tac, especially during the first year after transplantation. However, at maintenance doses, there are no comparative data of insulin resistance (IR) in patients using Tac or CsA. The purpose of this study was to investigate the IR indexes in patients on maintenance doses of CsA or Tac. MethodsForty-five nondiabetic and nonobese renal transplant recipients participated in the study (M:F, 30:15; age, 36 ± 9 years); 27 patients were on CsA, and 18 were on Tac. All had stable graft function, were transplanted at least 6 months previously, and were receiving maintenance doses of steroids (5.0 mg/d), azathioprine or mycophenolate mofetil, and calcineurin inhibitors (CsA [2.14 ± 0.46 mg/kg/d] or Tac [0.06 ± 0.03 mg/kg/d]). IR was evaluated by the homeostasis model assessment (HOMA) index and composite body insulin sensitivity index. ResultsWe did not determine any significant difference in the HOMA and composite body insulin sensitivity index levels among patients using CsA or Tac (1.5 ± 1.3 vs 1.5 ± 1.1, P > .05, and 9.9 ± 5.8 vs 14.6 ± 11.7, P > .05, respectively). There was a significant correlation between creatinine and HOMA values. ConclusionThere was no difference in IR indexes in renal transplant recipients receiving maintenance doses of either CsA or Tac.

بررسی کارآیی آزاتیوپریه با دوزهای پاییه در کاهش عود و وابستگی به کورتیکواستروئید در بیماران مبتال به کولیتاولسراتیو

بررسی کارآیی آزاتیوپریه با دوزهای پاییه در کاهش عود و وابستگی به کورتیکواستروئید در بیماران مبتال به کولیتاولسراتیو

Positive pharmacokinetic effect of azathioprine co-medication on infliximab trough levels is dose-dependent

BackgroundThiopurines seem to have positive effect on the pharmacokinetics of anti-tumor necrosis factor biologics. It has been suggested that a reduced dose of thiopurines is sufficient to achieve this synergism. AimsTo assess the differences of infliximab (IFX) trough levels according to the dose of concomitantly used azathioprine (AZA). Patients & methodsAll IBD patients treated with IFX (Remicade®) in two IBD centres between November 2015 and April 2017 were eligible. Infliximab trough levels were assessed by ELISA (Ridascreen®, R-Biopharm). The differences in IFX trough levels according to AZA dose were analyzed statistically. ResultsIn total, 125 patients were included, 42 pts (33.6%) on infliximab monotherapy, 83 pts (66.4%) using combined immune suppression.The respective median IFX levels according to AZA dose were as follows: group 1 (no concomitant AZA) 2.83 μg/ml (range 0–12); group 2 (AZA dose less than 1 mg/kg) 4.91 μg/ml (range 0.09–15.36); group 3 (AZA dose 1 < 2 mg/kg) 5.67 (range 0.16–16.97); group 4 (AZA dose above 2 mg/kg) 7.53 μg/ml (range 1.15–8.73). The differences in IFX trough levels between the respective groups according to AZA dose were statistically significant (p = 0.0159). ConclusionThe positive effect of azathioprine on infliximab levels seems to be dependent on the dose of concomitantly used azathioprine.

NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis.

The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase (TPMT) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT∗3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg−1 ⋅ d−1 and 0.96 (0.83, 1.19) mg ⋅ kg−1 ⋅ d−1, respectively (P = 0.028). In contrast, no significant association was observed for TPMT∗3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg−1 ⋅ d−1. Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants.

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio (LME p = 0.041) and 30% decrease in clinical efficacy (LME p = 0.0031). GSTA1 variant (12.8% of patients) showed a trend (p = 0.046, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.

A Retrospective Study of Systemic Treatment of Severe Atopic Dermatitis With Azathioprine: Effectiveness and Tolerance in 11 Pediatric Patients

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients’ quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease. ObjectiveTo evaluate the effectiveness and tolerance of AZA in children with severe AD. Patients and methodsWe performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017. ResultsWe reviewed the cases of 11 patients (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment. ConclusionIn our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment.

Frequency of serious adverse events of thiopurine treatment in normal thiopurine S-methyltransferase genotype children with inflammatory bowel disease

Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases. To evaluate the frequency of severe side effects, such as myelosuppression and hepatotoxicity, at standard or decreased azathioprine doses in children with inflammatory bowel disease who do not exhibit any of the four most common variant alleles. Retrospective analysis of children with inflammatory bowel disease treated with azathioprine at a single tertiary referral center. 51 patients were identified (44: Crohn's disease, 7: ulcerative colitis; male ratio: 28/51; mean age at diagnosis: 12.4 years). Two patients discontinued azathioprine arbitrarily whereas in one patient it was stopped due to serious pancreatitis and in another one because of severe flu-like symptoms. None of the remaining 47 patients exhibited hepatotoxicity suggesting abnormally high thiopurine S-methyltransferase activity. Four patients (8.5%) had profound myelosuppression on less than 1 mg/kg/day azathioprine requiring discontinuation of the drug, and all of them showed complete bone marrow recovery subsequently. No myelosuppression occurred in the remaining 43 patients on 2.17 ± 0.31 mg/kg/day (mean ± SD) azathioprine treatment. Regular blood tests are necessary on thiopurine therapy despite normal thiopurine S-methyltransferase genotype because of the risk of myelosuppression. The four most common variant alleles were identified in routine genotyping only, therefore most likely rare variant allele(s) or polymorphism of other enzymes involved in thiopurine metabolism account for the aforementioned four cases with profound bone marrow suppression. Thiopurine metabolite monitoring is the key for individualized treatment when optimal dosing can be achieved with the least side effects. Orv Hetil. 2019; 160(5): 179-185.

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update.

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).

Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

BackgroundAzathioprine is widely used for the maintenance of remission in children with inflammatory bowel disease (IBD). Measuring thiopurine metabolites 6-thioguanine (6-TGN) and 6-methyl-mercaptopurine (6-MMP) can aid in optimizing treatment and preventing toxicity. We report a proactive approach combining early metabolite measurements with IBD activity index to achieve optimal azathioprine dosing.MethodsThe reporting of azathioprine dosing, IBD activity indexes and thiopurine metabolites was evaluated retrospectively in 40 children with IBD. Additional treatments and the effect of azathioprine on blood counts were also examined.ResultsForty children (40% female) with IBD (26 Crohn’s disease, 12 ulcerative colitis, and 2 unclassified IBD), mean age 12.2±3.4 years, were included in the study. The mean azathioprine dose was 1.3±0.4 mg/kg; mean 6-TGN level was 280±151 pmol/8 × 108 red blood cells (RBC) and mean 6-MMP level 1022±1007 pmol/8 × 108 RBC. Disease activity index (Crohn’s and ulcerative colitis, pediatric specific) at the time of metabolite measurement was 6.5±8. Twenty-eight children did not require azathioprine dose adjustment, while it was increased in 12. Data from children with azathioprine monotherapy were analyzed separately and the results were similar.ConclusionTimely measurement of thiopurine metabolites and clinical assessment can provide a powerful tool to optimize azathioprine dosing and reduce serious adverse effects in children with IBD.

Complete urological evaluation including sperm DNA fragmentation in male systemic lupus erythematosus patients.

To evaluate sperm DNA fragmentation analysis in non-azoospermic male systemic lupus erythematosus (SLE) patients. Twenty-eight consecutive male SLE patients (American College of Rheumatology criteria) and 34 healthy controls were evaluated for demographic/exposures data, urological evaluation, hormone profile and sperm analysis (including sperm DNA fragmentation). Clinical features, disease activity/damage scores and treatment were also evaluated. The median age (33 (20-52) vs. 36.5 (25-54) years, P = 0.329) and frequency of varicocele (25% vs. 32%, P = 0.183) were similar in SLE patients and healthy controls. Sperm DNA fragmentation showed significantly higher levels of cells class III (44 (9-88) vs. 16.5 (0-80)%, P = 0.001) and cell class IV (10.5 (3-86) vs. 7 (0-36)%, P = 0.039) in SLE. The sperm DNA fragmentation index was also significantly higher in SLE patients (62 (31-97) vs. 25.5 (0-100)%, P < 0.001). Conventional sperm parameters (including sperm count, motility and morphology) were similar in both groups. In SLE patients no correlations were observed between sperm DNA fragmentation index and age, disease duration, Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index scores, and cumulative dose of prednisone, hydroxychloroquine, intravenous cyclophosphamide, methotrexate, azathioprine and mycophenolate mofetil ( P > 0.05). Further analysis of SLE patients treated with and without intravenous cyclophosphamide showed that total sperm motility was significantly lower in the former group (64% (15-83) vs. 72% (57-86), P = 0.024). The sperm DNA fragmentation index was alike in both groups (52.5 (31-95) vs. 67.5 (34-97)%, P = 0.185). To our knowledge, this is the first demonstration that male non-azoospermic SLE patients have increased sperm DNA fragmentation without evident gonadal dysfunction. Intravenous cyclophosphamide does not seem to be a major determinant for this abnormality. Future prospective study is necessary to determine the impact of this alteration in these patients' fertility.

Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients’ quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease. ObjectiveTo evaluate the effectiveness and tolerance of AZA in children with severe AD. Patients and methodsWe performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017. ResultsWe reviewed the cases of 11 patients (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment. ConclusionIn our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment.