Azathioprine Group Research Articles

Lymphocyte subsets and Langerhans cells in the skin of kidney transplant recipients under three different immunosuppressive regimens.

Renal transplant recipients (RTRs) are at increased risk of developing skin cancer; however, the role of immunosuppression is not yet fully understood. In this study, we evaluated the immunohistochemical changes in the skin of RTRs under three different immunosuppression regimens: mTOR inhibitors (mTORi), sirolimus or everolimus, mycophenolic acid (MPA) precursors such as mycophenolate sodium or mofetil, or azathioprine (AZA). We evaluated biopsies of sun-exposed and sun-protected skin for immunohistochemical quantification of B lymphocytes (CD20+ ), T lymphocytes (CD3+ , CD4+ , and CD8+ ), and Langerhans cells (LCs) (CD1a+ ) in 30 RTRs and 10 healthy controls. The RTRs were divided into three groups: mTORi (n = 10), MPA (n = 10), and AZA (n = 10). No differences were observed in the number of B lymphocytes. However, a significant decrease in the number of T lymphocytes and LCs was observed in both sun-protected and sun-exposed skin in the AZA and MPA groups, although to a lesser degree in the latter group. The skin of the mTORi group did not differ from that of the control group in terms of the number of B and T lymphocytes and LCs. Patients treated with mTORi exhibit preserved cellular elements related to cutaneous immune surveillance. The use of AZA induced a greater degree of skin immunosuppression than in the control group, as demonstrated by the decrease in T lymphocytes and LCs.

Leflunomide versus azathioprine for maintenance therapy of lupus nephritis: a prospective, multicentre, randomised trial and long-term follow-up

ObjectivesPrevious studies have compared mycophenolate mofetil and azathioprine as maintenance therapy for lupus nephritis (LN). Leflunomide is an immunosuppressant widely used in the treatment of rheumatoid arthritis. The aim of...

Assessment of efficacy of infliximab, Azathioprine, or combination therapy for Crohn's disease

Background: The present study was conducted for assessing the efficacy of Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease.Materials and Methods: A total of 60 patients with confirmed diagnosis of Crohn’s Disease were enrolled. Complete demographic and clinical details of all the subjects was recorded. Random division of all the patients was done into three study groups as follows: Group 1: Azathioprine group, Group 2: Infliximab group and Group 3: Combined therapy. Oral mesalamine was continued at a stable dose. Systemic corticosteroids could be initiated with the dose maintained, increased, or decreased until week 14. The primary efficacy end point was the rate of corticosteroid-free clinical remission at week 26; the rates of corticosteroid-free clinical remission at other time points were secondary efficacy end points. All the results were recorded in Microsoft excel sheet and were analysed by SPSS software.Results: Mean age of the patients of the Azathioprine group, Infliximab group and Combined therapy group was 43.2 years, 40.7 years and 41.6 years respectively. Major proportion of the subjects of all the study groups were males. Patients with corticosteroid free clinical remission was similar in all the three groups. Patients who received systemic corticosteroids during therapy was also similar in all the three groups. Nausea, vomiting, abdominal pain, worsening of disease, fatigue, headache and arthralgia were the commonly encountered adverse events.Conclusion: In Crohn’s disease patients, infliximab monotherapy and combination therapy with infliximab plus azathioprine, in comparison to azathioprine alone, causes enhanced rates of corticosteroid-free clinical remission.

Can visceral adipose tissue and skeletal muscle predict recurrence of newly diagnosed Crohn’s disease in different treatments

Background and aimsIt is crucial to manage the recurrence of Crohn’s disease (CD). This study is aimed to explore whether visceral adipose tissue (VAT) and skeletal muscle (SM) are associated with the recurrence of CD upon different treatments.MethodsAll patients with a definite diagnosis of CD were retrospectively divided into three groups according to distinct treatment regimens: 5-amino salicylic acid group (Group A), steroids + azathioprine (Group B) and biologics (Group C). The pretreatment computerized tomography (CT) images and clinical data were collected. The VAT area, mesenteric fat index (MFI), the ratio of VAT area to fat mass (VAT area/FM) were assessed. The primary end point was the recurrence of CD within 1 year of follow-up.ResultsA total of 171 CD patients were enrolled, including 57 (33.33%) patients in Group A, 70 (40.94%) patients in Group B and 44 (25.73%) patients in Group C. Patients with 1-year recurrence had higher MFI (P = 0.011) and VAT area/FM (P = 0.000). ROC curve demonstrated that patients with the ratio of VAT area/FM and MFI higher than 0.578 and 1.394 tended to have recurrence with the AUC of 0.707 and 0.709. Similar results could be observed in Group A & B but not in Group C.ConclusionsHigh VAT area/FM and MFI are related to recurrence within 1 year for newly diagnosed CD patients treated by 5-amino salicylic or azathioprine + steroids rather than biologics. We could not observe any radiological data associated with the recurrence of CD patients under biological treatment.

MO163: Mycophenolate Mofetil Superior to Azathioprine and as Effective as Calcineurin Inhibitors in Lupus Nephritis Maintenance Therapy: Data from a Single Centre Prospective Study

Abstract BACKGROUND AND AIMS Systemic lupus erythematosus is the prototype of a multiorgan, multisystemic autoimmune disease. It has relatively frequent renal involvement (prevalence of 15–60%). A total of 19–25 patients develop end-stage renal disease after 10 years of disease onset. We studied the efficiency of mycophenolate mofetil compared to azathioprine and calcineurin inhibitors as maintenance therapy. We analysed a population of 67 patients with biopsy-proven lupus nephritis. We compared the groups for rates of achievement and maintaining remission at 18 months after the induction therapy, renal flares and rates of ESRD at the end of the study. METHOD We concluded a single-centre longitudinal study to assess the efficacy of mycophenolate mofetil as maintenance therapy in patients with biopsy-proven lupus nephritis: clinical remission rates, renal flares, renal function at the end of the follow-up period. We used SPSS version 16 for the statistics. Clinical data were taken from the electronic health records of the hospital (Hipocrate Informational System). RESULTS We included in the study patients diagnosed with systemic lupus erythematosus, who underwent renal biopsy between January 2008 and December 2018, followed-up until May 2020. Patients were assessed using proteinuria, anti-DNA double-strand antibodies, serum creatinine and eGFR-CKD-EPI measurements, C3, C4 levels and urinary sediment. In our study group, 58 patients were female, 9 were male, with a median age at diagnosis of 29 years, and median duration of the disease of 10 years. Median duration of corticosteroid treatment was 10.1 years. The most frequent classes of lupus nephritis were class IV (47.76%), class III (17.91%) and class V (17.91%) (ISN classification). At the moment of the kidney biopsy, 77.61% patients had nephrotic syndrome, and 22.39% nephritic syndrome. Patients underwent induction therapy with standard regimens (NIH 55.22%, Euro-Lupus 19.4%, mycophenolate 25.37%, CNI 1.49%). Maintenance therapy during the study period was as follows (all patients had corticosteroids in standard dose): 5 had mycophenolate, 27 azathioprine, 26 had both mycophenolate and azathioprine during the study period (treatment switches form one immunosuppressant to another were necessary during the study period due to adverse effects, occurring pregnancies, patient preference, costs of treatment), and 9 had calcineurin inhibitors. Of the 67 patients, at 18 months after the first induction regimen, 3 had no therapeutic response, and required a second course of induction, 25 maintained partial remission and 39 maintained total remission. A total of 21/67 patients had no renal flare, 46/67 patients had renal flares. At the end of the study, 13/67 patients were ESRD and 54/67 were non-ESRD. We obtained the following results (Kruskal–Wallis and Bonferroni tests): maintaining remission at 18 months following induction therapy for mycophenolate mofetil—15.4% complete remission, 2.6% partial remission; in the azathioprine group—52.6% partial remission, 26.9% complete remission; in patients who received both mycophenolate and azathioprine (required a switch in therapy)—36.8% partial remission, 42.3% complete remission; in patients receiving calcineurin inhibitors—7.9% partial remission, 15.4% complete remission (P = .02). Renal flare rates were 7.1% for calcineurin inhibitors, 11.9% for mycophenolate mofetil, 28.6% for azathioprine, 52.4% for azathioprine and mycophenolate (Kruskal–Wallis, P = .002). At the end of the study, the frequency of ESRD was lowest in patients receiving mycophenolate or calcineurin inhibitors: 7.1% mycophenolate, 7.1% calcineurin inhibitors, 14.3% azathioprine, 71.4% mycophenolate and azathioprine (P = .039). CONCLUSION We identified that mycophenolate mofetil therapy led to better renal outcomes compared to azathioprine (higher clinical remission rates and fewer ESRD patients) and proved the same efficiency as calcineurin inhibitors.

Efficacy and safety of azathioprine, mycophenolate mofetil, and reduced dose of rituximab in neuromyelitis optica spectrum disorder.

Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort. Patients with aquaporin 4 (AQP4) antibody-positive NMOSD with AZA (n=167), MMF (n=131), or RTX (n=55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events. The median follow-up time of the 353 patients was 30.3months. The regimen of RTX was 100mg on Day 1 and 500mg on Day 2, followed by 500mg every 6months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR]=4.40, 95% confidence interval [CI]=1.41-13.80, p=0.011) or MMF (HR=5.20, 95% CI = 1.60-16.86, p=0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34-3.66, p=0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%, p<0.001). We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody-positive NMOSD.

Comparative Survival Analysis Between Azathioprine and Mykophenolate in Chagasic Patients Undergoing Heart Transplantation

PurposeChagas' cardiomyopathy is considered an aggressive etiology of heart failure(HF).When evolving to advanced HF, the gold standard treatment is heart transplantation (HT).The immunosuppressive therapy used in HT may facilitate infectious complications, including the reactivation of Chagas disease(CD).Bacal et al demonstrated lower rates of chagasic reactivation with azathioprine compared to mycophenolate. However, studies in HT of non-chagasic patients revealed superiority of mycophenolate in relation to rejection and survival. The present study aims to assess the survival of chagasic patients using mycofenolate compared to azathioprine.MethodsRetrospective observational study that evaluated HT patients due to CD between 2003 and 2020.Patients who died before discharge and who suspended the use of antiproliferatives were excluded. Patients were divided into two groups (Azathioprine x Mycofenolate) based on the most recent immunosuppressive regimen. The difference between groups was tested in quantitative variables using Mann-Whitney test. For categorical variables, the Fisher and Wilcoxon tests were used. Survival were analysed by Kaplan-Mayer and Log-Rank.Results20 patients were evaluated in the Azathioprine group and 54 in the Mycophenolate group. The study population had a median age of 50 years, male predominance(56,7%), white race(60,8%) and all using calcineurin inhibitors,73% using tacrolimus and 27% using cyclosporine. As for the baseline characteristics, there was no difference between the groups. As for the survival analysis, as shown in the Kaplan-Mayer curves, there was no difference between the groups.ConclusionThere was no difference in survival when compared to immunosuppression between Azathioprine X Mykophenolate in chagasic transplant patients, suggesting that there is no preference for an antiproliferative in chagasic transplant patients. Further studies are needed to corroborate this fact. Chagas' cardiomyopathy is considered an aggressive etiology of heart failure(HF).When evolving to advanced HF, the gold standard treatment is heart transplantation (HT).The immunosuppressive therapy used in HT may facilitate infectious complications, including the reactivation of Chagas disease(CD).Bacal et al demonstrated lower rates of chagasic reactivation with azathioprine compared to mycophenolate. However, studies in HT of non-chagasic patients revealed superiority of mycophenolate in relation to rejection and survival. The present study aims to assess the survival of chagasic patients using mycofenolate compared to azathioprine. Retrospective observational study that evaluated HT patients due to CD between 2003 and 2020.Patients who died before discharge and who suspended the use of antiproliferatives were excluded. Patients were divided into two groups (Azathioprine x Mycofenolate) based on the most recent immunosuppressive regimen. The difference between groups was tested in quantitative variables using Mann-Whitney test. For categorical variables, the Fisher and Wilcoxon tests were used. Survival were analysed by Kaplan-Mayer and Log-Rank. 20 patients were evaluated in the Azathioprine group and 54 in the Mycophenolate group. The study population had a median age of 50 years, male predominance(56,7%), white race(60,8%) and all using calcineurin inhibitors,73% using tacrolimus and 27% using cyclosporine. As for the baseline characteristics, there was no difference between the groups. As for the survival analysis, as shown in the Kaplan-Mayer curves, there was no difference between the groups. There was no difference in survival when compared to immunosuppression between Azathioprine X Mykophenolate in chagasic transplant patients, suggesting that there is no preference for an antiproliferative in chagasic transplant patients. Further studies are needed to corroborate this fact.

Mycophenolate mofetil or tacrolimus compared with azathioprine in long-term maintenance treatment for active lupus nephritis.

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.

Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial.

SummaryBackgroundRetrospective studies suggest that for patients with ulcerative colitis (UC) combination therapy with low-dose azathioprine and allopurinol (L-AZA/ALLO) may result in higher remission rates than monotherapy with azathioprine (AZA). We prospectively investigated the effects of these drugs for remission in patients with moderate-to-severe UC.MethodsOpen-label, unblinded, randomised, controlled, investigator-initiated, multicentre study conducted at eight hospital sites in Denmark. Adult patients with established UC, who were steroid dependent/refractory, thiopurine naïve, had a normal thiopurine methyltransferase, and achieved remission with steroids or infliximab were eligible for inclusion. Patients were randomly assigned by the investigators (1:1) to 52 weeks of treatment with once daily oral AZA (median dose 50 mg) combined with ALLO 100 mg versus AZA monotherapy (median dose 200 mg), using a computer-generated randomisation list with blocks of six. The trial was open without masking. All randomised patients who received at least one dose of study drug were included in primary and safety analyses (intention to treat population). The primary outcome was steroid and infliximab free remission after 52 weeks, defined as a Mayo Score of ≤1 and no rectal bleeding. The trial is completed and is registered in ClinicalTrials.gov (ClinicalTrials.gov NCT03101800).FindingsBetween January 9, 2017 and February 10, 2021, 47 patients were randomised to l-AZA/ALLO and 42 to AZA and received at least one dose of the study drug. After 52 weeks, 20 of 47 (43%) patients in the l-AZA/ALLO group and nine of 42 (21%) patients in the AZA group achieved remission (odds ratio 2·54 [95% CI 1·00 to 6.78, p < 0·048]). Fourteen patients (30%) in the l-AZA/ALLO group and 16 (38%) in the AZA group were withdrawn from the study due to adverse events.InterpretationThis study suggests that after one year l-AZA/ALLO therapy may be associated with a beneficial effect on steroid- and infliximab-free clinical remission in patients with moderate-to-severe UC and should be considered as first line therapy.FundingFunding for AAUC was provided by The Capital Region of Denmark (Regionernes Medicinpulje (6062/16)).

Protective effect of carvacrol against hepato-renal toxicity induced by azathioprine in rats

Background and aims: Azathioprine (AZA) is an immunosuppressant medication that has toxicity to kidneys and liver. This study aimed to investigate the protective activity of carvacrol (CAR) against hepatorenal toxic activity of AZA in male Wistar rats. Methods: All study rats were divided into five groups: control (saline, ip); azathioprine-only (AZA 50 mg/kg, ip), Sily+AZA (Silymarin 50 mg/kg, gavage), CAR+AZA (CAR 10 mg/kg, gavage), and CAR+AZA (CAR 20 mg/kg, gavage) groups. Silymarin was used as the standard hepatoprotective drug. The drugs were administered once daily for 21 days in III-V groups, and a single dose of AZA was injected on the seventh day of the experiment. Results: AZA-intoxicated rats exhibited an elevation in aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) activity in serum, as well as an increase in extent of lipid peroxidation. Activities of enzymatic antioxidants (superoxide dismutase – SOD, catalase - CAT) in the serum, liver, and kidney were decreased as for the AZA group (P&lt;0.05). Co-treatment of CAR (both doses of 10 and 20 mg/kg) lowered the serum transaminases and ALP level, the elevation of endogenous enzymes levels, and the malondialdehyde (MDA) in serum and both tissues (P&lt;0.05). This protective effect was greater in CAR 10 compared to 20 mg/kg doses, which was comparable to silymarin. Conclusion: This study demonstrated that the renal and nephrotoxic activities of AZA could be attributed to the generated increased oxidative stress, as well as to the CAR with antioxidant effect similar to that in silymarin, which protected these tissues against AZA-induced nephrotoxicity hepatotoxicity.

Effective Rituximab Treatment in Patients with Neuromyelitis Optica Spectrum Disorders Compared with Azathioprine and Mycophenolate.

IntroductionAs an autoimmune central nervous system disease characterized by inflammation and demyelination, neuromyelitis optica (NMO) has been extensively investigated. A specific antigenic target, astrocytic water channel aquaporin-4 (AQP4) has already been identified, and it can be recognized explicitly by the autoantibody marker NMO-IgG. Along with the immune attacks, clinical disabilities would gradually accumulate. As there has been no validated and well-recognized therapy for NMO till now, preventing and postponing attack using immunosuppressive therapies is the primary treatment option.MethodsIn the current retrospective study, the effect of immunosuppressive agents was investigated through a long-term follow-up. To assess the long-term effectiveness and safety of rituximab (RTX), azathioprine (AZA), and mycophenolate mofetil (MMF) therapies, all 129 patients with NMO spectrum disorders (NMOSD) who received at least one of these treatments were studied, including 55 seropositive for AQP4-Ab and 74 seronegative for AQP4-Ab.ResultsThe median post-treatment annualized relapse rate (ARR) was lower than the pre-treatment rates in all AQP4+Ab groups (from 1.0 to 0.7 in RTX, from 0.8 to 0.3 in AZA, and from 0.85 to 0.35 in MMF). Meanwhile, the ARR also decreased in all AQP4−Ab groups (from 0.3 to 0.2 in RTX, from 0.9 to 0.5 in AZA, and from 0.9 to 0.4 in MMF). Disability condition improved in the Expanded Disability Status Scale (EDSS) in all AQP4+Ab groups (from 4.0 to 2.75 in RTX, from 3.5 to 2.5 in AZA, and from 3.0 to 2.0 in MMF) and in all AQP4−Ab groups (from 3.0 to 2.5 in RTX, from 3.0 to 2.5 in AZA, and from 3.5 to 2.0 in MMF). There was no statistically significant difference between the post-treatment and pre-treatment changes of EDSS and ARR in the RTX, AZA, and MMF groups (P > 0.05). However, according to Kaplan–Meier survival analysis, RTX-treated patients were more likely to be relapse-free after long-term follow-up than those who received AZA or MMF therapy. Meanwhile, adverse effects were noted in three out of 23 patients with RTX treatment, five of 32 with AZA treatment, and three of 21 with MMF treatment. No serious adverse events were observed in all treatment groups during the study.ConclusionsRTX, AZA, and MMF therapies efficiently lowered the relapse frequency and disability in both of the AQP4-Ab seropositive or seronegative patients with NMO. Furthermore, low dosage of RTX is recommended for the patients with NMO owing to its long-term effectiveness and safety.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00298-5.

Comparative Effectiveness of Azathioprine Versus Cyclosporine as an Initial Treatment for Idiopathic Inflammatory Myopathies: A Population-Based Observational Study.

ObjectiveTo compare the effectiveness of azathioprine (AZA) and cyclosporine (CsA) as initial treatments for patients with idiopathic inflammatory myopathies (IIM).MethodsA retrospective cohort study was conducted using information from the National Health Insurance Service database of Republic of Korea. Patients with IIM who had started AZA or CsA as initial treatment between January 2007 and December 2011 were selected for the study. They were followed from the day of treatment initiation to the occurrence of study outcomes or the end of the study until December 2016. Effectiveness outcomes, defined as switching the drug or adding immunosuppressants, and discontinuation of corticosteroids, were compared between the two groups. The Cox proportional-hazards model was used to calculate the adjusted relative risk (aRR) with 95% confidence interval (CI) between the AZA and CsA groups.ResultsA total of 376 patients with incident IIM who used AZA (n = 288) or CsA (n = 88) were identified. The aRR of switching the drug or adding immunosuppressants (1.45 [95% CI 0.99–2.11]) was not significantly different between the CsA and AZA groups. Among patients who were treated with corticosteroids at baseline, the rate of discontinuation of corticosteroids was not different between the two groups (1.69 [95% CI 0.82–3.47]).ConclusionsThe effectiveness of AZA and CsA as initial treatments for the management of IIM was comparable.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00392-y.

Efficacy of azathioprine, mycophenolate mofetil, and rituximab in the treatment of neuromyelitis optica spectrum disorder and analysis of prognostic factors.

The study aims to compare the efficacies of the immunosuppressants most commonly prescribed for patients with neuromyelitis optica spectrum disorder (NMOSD). The predictors, which might be associated with relapse and disability in NMOSD, were also analyzed. This retrospective study included NMOSD patients treated with azathioprine (AZA), mycophenolate mofetil (MMF), and rituximab (RTX). The annual relapse rate (ARR) and the incidence rates of adverse events were compared. Cox proportional-hazards model calculated the potential predictors of NMOSD relapse and disability. A total of 83 patients were included. The median treatment time of AZA group (n = 34), MMF group (n = 20), and RTX group (n = 29) were 19.5, 15.5, and 12months, respectively. ARR of the three groups reduced significantly after treatment. In the three groups, 55.9%, 50%, and 79.3% of patients, respectively, were free from relapse. However, the difference among the three groups was of no statistical significance, possibly due to the small sample size. During the treatment, 32.4%, 15%, and 24.1% of patients experienced adverse events in the AZA group, MMF group, and RTX group, respectively. Additionally, the multivariate Cox analyses indicated that history of a severe attack and disease duration were associated with the risk of relapse after immunotherapy. Late-onset (≥ 50years old) NMOSD patients were probably more susceptible to motor disability, and those with optic neuritis at onset were more likely to develop visual disability. AZA, MMF, and low-dose RTX were all effective in reducing the relapse rate in NMOSD. The age at onset, disease duration, history of severe attacks, and primary syndromes might be significant prognostic predictors in NMOSD.

Azathioprine pretreatment ameliorates myocardial ischaemia reperfusion injury in diabetic rats by reducing oxidative stress, apoptosis, and inflammation.

This study was presented to observe the therapeutic effects of azathioprine (AZA) pretreatment on myocardial ischaemia reperfusion (I/R) damage in diabetic rats. All rats were randomly separated into control + sham operation; control +I/R; diabetes mellitus (DM) +I/R and DM +I/R + AZA groups. Diabetic rat models were established by intraperitoneally injecting 60 mg/kg streptozotocin (STZ). Diabetic rats were given 3 mg/kg AZA daily by gavage for 5 days. Then, myocardial I/R rat models were constructed. Myocardial infarction size and myocardial damage were respectively detected by TTC and H&E staining. Cardiac injury markers (CK‐MB and MPO) and oxidative stress factors (SOD and MDA) were measured via ELISA. The protein expression of apoptotic markers (Caspase8, Caspase3, BAX and Bcl2), inflammatory factors (TLR4 and TNF‐α) and AKT1/GSK3β in myocardial tissues was measured by western blot, immunohistochemistry or immunofluorescence. Data showed that AZA pretreatment could lessen myocardial infarction size and myocardial damage, and could down‐regulate serum CK‐MB, MPO, SOD and MDA levels in diabetic rats under I/R. Furthermore, AZA pretreatment decreased Caspase8, Caspase3, BAX, TLR4 and TNF‐α expression, and increased Bcl2 expression in myocardial tissues of diabetic rats following I/R. Also, AZA pretreatment lowered AKT1, p‐AKT1, GSK3β and p‐GSK3β expression in diabetic heart after I/R. This study found that AZA may reduce myocardial injury in diabetic rats following I/R via reducing oxidative stress, cardiomyocyte apoptosis, and inflammatory response, which could be related to AKT1/GSK3β pathway inactivation.

Efficacy and safety of modified reduced-dose rituximab in Chinese patients with neuromyelitis optica spectrum disorder: A retrospective cohort study

ObjectiveTo evaluate the long-term efficacy and safety of a modified reduced-dose rituximab (mRTX) regimen compared with azathioprine (AZA) and mycophenolate mofetil (MMF) in Chinese patients with neuromyelitis optica spectrum disorder (NMOSD). MethodsIn this retrospective cohort study, 71 patients with NMOSD were treated with AZA (n = 24), MMF (n = 18), or mRTX (n = 29). The primary outcome was initial relapse after first-line immunosuppressant therapy. The annualized relapse rate (ARR), expanded disability status scale (EDSS) score, activities of daily living (ADL) scale score, and treatment-related adverse events were compared between groups. ResultsSignificant ARR reductions were observed in the three groups, with relapse-free rates of 37.5%, 72.2%, and 79.3% in the AZA, MMF, and RTX groups, respectively. Compared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. Relapse within 1 year before immunosuppressant therapy or ARR before immunosuppressant therapy increased the NMOSD relapse risk. mRTX and MMF were superior to AZA in reducing the EDSS score and increasing the ADL score, but there was no significant difference between the mRTX and MMF groups. Additionally, mRTX-treated patients were less likely to use steroids concurrently than those treated with AZA and MMF. The adverse event rate in the AZA group was relatively higher than that in the MMF and mRTX groups, though no significant difference was noted among the three groups. ConclusionsCompared with AZA, mRTX and MMF significantly reduced the NMOSD relapse risk. mRTX-treated patients presented less concomitant steroid use than those treated with AZA and MMF, fewer adverse events, and better tolerance.

P201 Evaluation of the role of anti-TNF in stabilizing the progression of intestinal lesions in Crohn’s disease using the Lemann Index

Abstract Background The Lemann Index (LI) was developed to assess cumulative digestive tract damage in patients with Crohn’s disease (CD), independently of clinical and biological activity. Recently, therapeutic goals in CD have focused on achieving mucosal healing and deep remission rather than simple symptom control, thus requiring prevention of progression of intestinal damage. The aim of this study was to assess the influence of different treatments on the progression of structural damage, using the LI. Methods we retrospectively included all patients with CD, followed in our center during the period between January 2016 and January 2020. The LI was calculated from the first (LI1) and the last (LI2) clinical consultations. The evolution of (LI1-LI2) or Delta LI (DLI) was recorded. Results 112 patients with CD were collected, of which 53.6% were female. The mean age at diagnosis was 33.29 years [15–63]. Active smoking was found in 34 patients (30.4%). Regarding the localization of CD, it was ileal (L1 according to the Montreal classification), colonic (L2), and ileocolonic (L3) in respectively 16.1%, 42.9% and 41%. The disease phenotype was inflammatory (B1) in 60.7%, stricturing (B2) in 21.42%, and penetrating (B3) in 17.85%. The initial flare was judged to be severe in 33.9% of cases, moderate in 55.4% of cases and mild in 10.7% of cases, with a mean CDAI of 305.21 [115–493]. Regarding maintenance treatment, 51.8% of patients (n = 58) were on Azathioprine, 23.2% (n = 26) were on aminosalicylates, and 25% (n = 28) were on anti-TNF, including 42, 9% under combination therapy. The median follow-up was 36.82 ± 16.83 months, with no difference between the groups. During follow-up, the mean LI increased significantly from 3.34 [0.58–8.82] to 7.82 [0.62–32.6] in the azathioprine group (p = 0.0001), from 2.0 [0.58–6.52] to 3.91 [0.6–14.03] in the Aminosalicylates group (p = 0.001) and from 3.79 [1.05–8.42] to 10.01 [2.58–33.08] in the Anti-TNF group (p = 0.0001). The mean DLI was -4.48 for the Azathioprine group, -1.9 for the Salicylates group and -6.14 for the Anti-TNF group, with no statistically significant difference (p = 0.16). Conclusion In patients with CD, the LI tends to increase over time. In our series, the use of Anti-TNF α does not appear to be able to reduce the progression of intestinal lesions, compared to other therapies.

Comparison of therapeutic effects of combination therapy with prednisolone and tacrolimus or azathioprine on progressive interstitial pneumonia with systemic sclerosis

Objectives We retrospectively compared the therapeutic effects of combination therapy with prednisolone (PSL) and oral tacrolimus (TAC) or azathioprine (AZA) on progressive interstitial pneumonia with systemic sclerosis (SSc-PIP). Methods The effects of PSL (0.2–0.5 mg/kg/day) and TAC (3 mg/day) or AZA (1–2 mg/kg/day) therapies (n = 18) were evaluated for short (12 months) and long (36 months or more) periods. Results In the short period, IP improved in 6 and 5 patients and was stable in 12 and 13 patients in the TAC and AZA groups, respectively. In the long period, 11 patients were followed up in the TAC group and 12 in the AZA group. IP improved in 4 and 2 patients and was stable in seven and nine in the TAC and AZA groups, respectively. The rates of evolution of total fibrosis score, and those corrected by disease duration for the long period, in the TAC group were significantly lower than those in the AZA group (p = .017 and .025, respectively). Conclusion The inhibitory effect of PSL and TAC combination therapy on the progression of fibrosis in SSc-PIP may be superior to that of PSL and AZA in the long period.

Editors' Note: Evaluation of Efficacy and Tolerability of First-Line Therapies in NMOSD

In the article, “Evaluation of Efficacy and Tolerability of First-Line Therapies in NMOSD,” Dr. Poupart et al. compared the efficacy and risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD). Among 136 patients, they found that the use of first-line rituximab seemed more effective than mycophenolate mofetil (MMF) in suppressing clinical activity, independent of the antibody status. In response, Dr. Leite notes that rituximab is currently used as second-line therapy in most countries, but because rituximab and MMF have similar tolerability but rituximab had superior efficacy, an argument could be made for considering rituximab as a first-line therapy. In addition to noting that the apparent similarity in efficacy of rituximab and azathioprine was unexpected and contradicts other studies, Dr. Leite raises a couple of concerns about rituximab, including (1) rituximab-associated hypogammaglobulinemia (assessment of which would require analyses of plasma immunoglobulin levels) and (2) potential differences in the role of rituximab for chronic management between NMOSD patients with aquaporin-4 (AQP4) antibodies vs myelin oligodendrocyte (MOG) antibodies, who were analyzed together in this study. Responding to these comments, the authors note the small sample size of the azathioprine group, which limited statistical power. They also report that 22.7% of 44 patients treated with rituximab who had immunoglobulin results available met their definition of hypogammaglobulinemia, with one such patient having a serious infection. They agree that MOG and AQP4 diseases are different processes but note that they chose to focus on the broader NMOSD phenotype because the optimal management of MOG-positive patients is also uncertain. The authors note that there was no significant difference in therapeutic response based on the antibody status. This exchange highlights the need to further examine the commonly used treatment regimens for NMOSD in controlled trials, both in those that are MOG positive and those that harbor AQP4 antibodies. In the article, “Evaluation of Efficacy and Tolerability of First-Line Therapies in NMOSD,” Dr. Poupart et al. compared the efficacy and risk of severe infectious events of immunosuppressive agents used early as first-line therapy in patients with neuromyelitis optica spectrum disorder (NMOSD). Among 136 patients, they found that the use of first-line rituximab seemed more effective than mycophenolate mofetil (MMF) in suppressing clinical activity, independent of the antibody status. In response, Dr. Leite notes that rituximab is currently used as second-line therapy in most countries, but because rituximab and MMF have similar tolerability but rituximab had superior efficacy, an argument could be made for considering rituximab as a first-line therapy. In addition to noting that the apparent similarity in efficacy of rituximab and azathioprine was unexpected and contradicts other studies, Dr. Leite raises a couple of concerns about rituximab, including (1) rituximab-associated hypogammaglobulinemia (assessment of which would require analyses of plasma immunoglobulin levels) and (2) potential differences in the role of rituximab for chronic management between NMOSD patients with aquaporin-4 (AQP4) antibodies vs myelin oligodendrocyte (MOG) antibodies, who were analyzed together in this study. Responding to these comments, the authors note the small sample size of the azathioprine group, which limited statistical power. They also report that 22.7% of 44 patients treated with rituximab who had immunoglobulin results available met their definition of hypogammaglobulinemia, with one such patient having a serious infection. They agree that MOG and AQP4 diseases are different processes but note that they chose to focus on the broader NMOSD phenotype because the optimal management of MOG-positive patients is also uncertain. The authors note that there was no significant difference in therapeutic response based on the antibody status. This exchange highlights the need to further examine the commonly used treatment regimens for NMOSD in controlled trials, both in those that are MOG positive and those that harbor AQP4 antibodies.

Predictors of azathioprine toxicity in children with autoimmune hepatitis

Aim of the studyAzathioprine (AZA) is an important steroid-sparing drug in the management of autoimmune hepatitis (AIH). Avoidance of its adverse events that could be severe and carry a risk of mortality in a few cases is important, preferably with cheap and easy assessments that could be feasible in developing countries with the unavailability of molecular assays. Assessment of thiopurine methyltransferase (TPMT), the key enzyme for the inactivation of AZA, as a predictor of AZA toxicity had been a matter of conflict. This work aimed to study the role of TPMT serum level assessment and other host-, disease-, and treatment-related factors in predicting AZA toxicity.Material and methodsSixty-six children with AIH, divided into two groups, were recruited. Group 1 included twelve children with AZA toxicity and group 2 included fifty-four children without AZA toxicities. Both groups were compared for demographic, clinical, laboratory, histopathological, and treatment-related factors, and serum TPMT level, measured by ELISA.ResultsTPMT serum level was comparable in both groups (p = 0.363). Duration of treatment until enzyme normalization and duration of AZA therapy were significantly associated with AZA toxicity (p = 0.007 and p = 0.01, respectively). At the first follow-up treatment with AZA, total leucocyte count (TLC) and neutrophil counts were significantly lower in group 1 (p = 0.005 and p = 0.002, respectively). Moreover, the percentage reduction of TLC and neutrophil counts were significantly higher in group 1 (p < 0.001, for both).ConclusionsMonitoring for AZA adverse events in those with the defined predictors of AZA-related adverse events is more important than TPMT assessment.

Infliximab plus azathioprine is more effective than azathioprine alone in achieving mucosal healing in pediatric patients with Crohn's disease.

Over the past few years, mucosal healing (MH) has emerged as a promising goal in the treatment of pediatric patients with Crohn's disease (CD). We aimed to assess whether combination therapy with infliximab (IFX) + azathioprine (AZA) was more effective than AZA therapy alone in achieving mucosal healing in pediatric patients with CD. Newly diagnosed pediatric patients with CD at the Department of Pediatrics in University Hospital in Hradec Králové were retrospectively recruited (2000-2014). The patients were divided into two groups according to the therapy: (a) IFX + AZA ± corticosteroids ± 5-aminosalicylic acid (5-ASA) (n = 16); and (b) AZA ± corticosteroids ± 5-ASA (n = 40). The patients were also divided into two groups: "MH" and "no MH," according to their MH status. MH was defined as the complete endoscopic disappearance of all mucosal ulcerations (including aphthous ulcerations) and the absence of any sign of mucosal inflammation in the terminal ileum and the large bowel. Of 56 patients, MH was observed in 56% (9/16) treated with combined therapy in comparison with 15% (6/40) of patients in the AZA group (P = 0.006). The median dose of AZA in both groups was 2.1 mg/kg per day. We observed eight adverse events in seven patients from the IFX + AZA group. Adverse effects were less common in the AZA group (P = 0.002). Combined therapy (IFX + AZA) was more effective in achieving MH in pediatric CD than treatment with AZA alone.