Azathioprine Therapy Research Articles

The Nancy Histopathological Index has limited value in predicting clinical outcomes in newly diagnosed pediatric patients with ulcerative colitis.

The Nancy Histological Index (NHI) is used to score histologic disease activity in patients with ulcerative colitis (UC). Our goal was to assess the utility of NHI at diagnosis in predicting clinical outcomes in pediatric patients with UC, in comparison to clinical and endoscopic scores. We retrospectively reviewed data at diagnosis of 106 children with UC (59 [55.7%] females; median age 14.4 [11.2-15.9] years, median Pediatric Ulcerative Colitis Activity Index [PUCAI] 35 [25-55]). During a follow-up of 116 (55-171) weeks, 33 patients (31.1%) required azathioprine therapy, and 32 (30.2%) were escalated to anti-tumor necrosis factor alpha (anti-TNFa). The PUCAI and Mayo endoscopic scores at diagnosis were significantly associated with escalation to anti-TNFa (p = 0.036 and p = 0.02, respectively), but not with initiation of azathioprine or subsequent acute severe colitis (ASC) events. However, the NHI was not associated with subsequent immunomodulators or anti-TNFa therapy (p = 0.42 and p = 0.78, respectively), nor with future ASC events (p = 0.70). In conclusion, the NHI failed to predict clinical outcomes in newly diagnosed pediatric patients with UC.

Contemporary and prospective use of azathioprine (AZA) in viral, rheumatic, and dermatological disorders: a review of pharmacogenomic and nanotechnology applications.

Azathioprine (AZA) has been extensively used for immunomodulatory effects in autoimmune disorders and transplantation. This article is proposed to review the contemporary and prospective use of AZA in viral, rheumatic, and dermatological disorders. The primary objective is to draw attention to possible developments in regards to AZA application in recent years, with an emphasis on the use of pharmacogenomics and nanotechnology to improve its efficacy in practice. This study reveals that AZA, having the active metabolites 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), may be useful in the treatment of systemic lupus erythematosus (SLE), pemphigus vulgaris, and psoriasis. Pharmacogenomic testing of thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) genotypes minimizes the occurrence of myelosuppression. Furthermore, new formulations of AZA using biocompatible polymers and nanoparticles for drug delivery were reported to improve its efficacy and lower systemic toxicity. This paper aims to establish the multifunctional nature of AZA in modern medicine, thus emphasizing its potential for other applications. Through the combination of pharmacogenomic analysis along with nanotechnology application, AZA makes the promise of enhancing patients' treatment efficacy and extending the stock of medical information available. These advancements offer new possibilities for application of precision medicine and improvements in the use of AZA therapy.

CASE REPORT: AUTOIMMUNE HEPATITIS IN A 29-YEAR-OLD FEMALE WITH RECURRENT PREGNANCY LOSS

Autoimmune hepatitis (AIH) is a rare chronic liver disease characterized by a wide spectrum of symptoms ranging from asymptomatic to jaundice, which can be confusing in diagnosis because of their non-specificity and the presence of laboratory changes. This case report presents a 29-year-old woman with AIH and past history of repetitive pregnancy losses. She has been diagnosed with various problems such as two rounds of failed in vitro fertilization, five miscarriages and secondary amenorrhea. A liver biopsy proved AIH, and appropriate prednisolone and azathioprine therapy resulted in a positive change in her liver status. Early diagnosis and right management of AIHresulted in significant clinicalimprovement and normalization of liver function tests.

Systemic lupus erythematous in men with interstitial lung pneumonia: a rare case report

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with unknown etiology and very diverse clinical manifestations, disease course, and prognosis. It is most common in African-American women, the prevalence being 4 per 1000 females. SLE predominantly affects young women, most presenting between 20 and 40 years of age. Male SLE is rare, with only one male patient reported per nine females. Pulmonary involvement in SLE is various. SLE-associated interstitial lung disease (ILD), while rare, is a predictor of poor prognosis. We report a 50-year-old male patient with complaints of shortness of breath, previously diagnosed with systemic lupus erythematous by examination of the antinuclear antibody (ANA) profile. The patient underwent a computed tomography (CT) scan of the thorax and the results showed interstitial lung pneumonia. The patient was given azathioprine and methylprednisolone therapy for Systemic lupus erythematous and ceftriaxone and acetylcysteine ​​for interstitial lung pneumonia.

P.010 Safety and efficacy of inebilizumab in AQP4+ NMOSD participants with history of immunosuppression treatment prior to N-MOmentum study

Background: The long-term outcomes of inebilizumab in participants from the N-MOmentum trial with a history of immunosuppressant therapy as compared to those without was evaluated. Methods: N-MOmentum (NCT02200770) was a 28-week randomized phase 2/3 trial of inebilizumab vs placebo, with an optional Open-Label Period (OLP) (>2 years). In this post hoc analysis, AQP4+ participants who received inebilizumab (through the OLP) were grouped by no history of immunosuppression therapy beyond treatment of acute NMOSD attacks (naïve), or prior azathioprine (AZA) and/or mycophenolate mofetil (MMF) therapy. Results: Among participants who received inebilizumab during the study, 94 received prior AZA/MMF and 103 were immunosuppressant naïve. Annualized relapse rate (95%CI) for participants with prior AZA/MMF was 0.11 (0.07, 0.17), compared to 0.08 (0.05, 0.14) for naïve. The hospitalization rate (annualized rate [95% CI]) for prior AZA/MMF was 0.15 (0.08, 0.27), and 0.12 (0.06, 0.22) for naïve. Participants with ≥1 study drug-related-treatment-emergent-adverse-event (TEAE) was 30.9% (29/94) in prior AZA/MMF and 46.6% (48/103) of naïve. Most adverse events were infection-related for both groups; 72.3% (68/94) for prior AZA/MMF and 77.7% (80/94) for naïve. Conclusions: This post hoc analysis evaluating long-term outcomes of inebilizumab in AQP4+ NMOSD participants treated with prior AZA/MMF therapy demonstrated a similar efficacy and safety profile as participants without prior immunosuppressant therapy.

#2403 Impact of pregnancy on kidney transplant recipients

Abstract Background and Aims Kidney transplantation (KT) provides an opportunity to increase fertility in women with chronic kidney disease and gestational desire. Lack of knowledge about obstetric complications and implications for the graft may lead to discourage pregnancy for these women. Although the incidence of pregnancy is rising in women receiving KT, the impact that it may have on the graft function is unknown. Method We conducted an observational, retrospective, single-centre study of a cohort of kidney transplant recipients (KTR) who became pregnant between 2007 and 2022. Clinical and analytical parameters were evaluated before, during and after pregnancy. The main aim was to assess the long-term impact of pregnancy on the graft by analysing renal function 3 years after pregnancy. Results We included 25 women receiving a KT between 1990 and 2018, among which 72% (n = 18) were transplanted from a deceased donor. 2 women (8%) received a combined liver-kidney transplant and 2 women (8%) a simultaneous pancreas-kidney transplant. Maintenance immunosuppression before conception included teratogenic drugs in 68% of cases [12 of them (48%) received mycophenolate mofetil and 5 of them (20%), mTOR inhibitors]. Planned withdrawal was only applied in 50.0% of pregnancies (n = 15). 30 pregnancies were identified (5 patients had 2 post-transplant pregnancies). Median age at gestation was 35 years [interquartile range (IQR) 33-39]. 5 conceptions required assisted reproductive technology. The main complications were gestational hypertension in 4 KTR (13.3%) and preeclampsia in 7 pregnancies (23.3%). 60% of neonates (n = 18) were preterm births (36 [IQR 34-37] weeks of pregnancy at birth) and 44% (n = 12) had low birth weight (2530 [IQR 2283-2950] grams). No foetal malformations were described. Due to physiological changes, a significant increase in estimated glomerular filtration rate (eGFR) was observed in the first and the second trimester of pregnancy (61 [IQR 50-91] ml/min and 70 [IQR 50-90] ml/min, respectively vs. baseline eGFR 59 [IQR 47-77] ml/min; p 0.001]. However, eGFR was equal to the previous one in the third trimester of pregnancy (60 [IQR 44-69] ml/min vs. 59 [IQR 47-77] ml/min; p 0.322). Median proteinuria remained below 0.5 g/day throughout pregnancy, without significant variation. Immunosuppression regimen during pregnancy was mainly based on a combined therapy of steroids, calcineurin inhibitors and azathioprine (21 KTR, 70%). Tacrolimus dose increase (median 63.6% [IQR 33.3-90.0%]) was necessary to maintain proper drug levels throughout gestation. Kidney graft function showed a decline in the first and second year after pregnancy compared to baseline function (54 [IQR 35-77] ml/min and 55 [IQR 36-75] ml/min vs. 59 [IQR 47-77] ml/min; p 0.018 and p 0.021, respectively]. Nevertheless, by the third year post-pregnancy, eGFR was similar to the baseline function (62 [IQR 43-73] ml/min vs. 59 [IQR 47-77] ml/min; p 0.365]. Likewise, annual eGFR variation was comparable during 3 years before (+1.0 ml/min/year) and 3 years after pregnancy (−0.9 ml/min/year), hence no worsening was observed after gestation (p 0.78). No differences were observed in proteinuria either (baseline proteinuria 0.17 [IQR 0.13-0.3] g/day vs. third-year proteinuria 0.21 [IQR 0.15-0.34] g/day; p 0.938). Only 5 women had a baseline serum creatinine above current recommendations for pregnancy (>1.5 mg/dl) and only 3 women presented baseline proteinuria > 0.5 g/day. In this group (n = 7), pregnancy occurred later after KT (96.0 [IQR 80.9-213.0] vs. 46.0 [IQR 16.0-67.5] months; p 0.024). The only 2 graft losses in the cohort were in this group. Both were attributed to transplant glomerulopathy, and they occurred at years 3 and 5 after pregnancy. On the other side, in this group there were no other baseline differences or obstetrical complications [Table 1]. Conclusion Pregnancy does not normally affect graft function and it stabilises within 3 years after gestation. It is important to increase data on women with suboptimal graft function to determine the direct implications that pregnancy may have on these KTRs.

Combination Therapy of Prednisone, Azathioprine, and Hydroxychloroquine in Patient with Dermatomyositis

manifestations of inflammatory myopathy accompanied by cutaneous involvement. In patients with cutaneous DM, for the first line of therapy can be given photoprotection, topical steroids, Hydoroxychloroquin (HCQ) or Chloroquine and Quinacrine, while the gold standard in DM myopathy is systemic corticosteroids. Inadequate therapeutic regimens can result in morbidity or complications, especially calcinosis. Case Presentation: A 29-year-old woman had reddish spots on her face and hands accompanied by pain in her hands, hips, knees and elbows making it difficult for the patient to walk. Found it exists Heliotrop sign, Gottron papule and Gottron sign. The main aim of providing therapy to DM patients is to reduce inflammation, such as minimizing symptoms, especially those related to muscle weakness and improving the patient's quality of life. Glucocorticoids remain the first line therapy option for DM with the choice of oral prednisone 1mg/kgBW/day. Meanwhile, moderate to severe DM specifically should be treated with a combination which contains steroids and immunosuppressants, such as Methotrexate (MTX), Azathioprine (AZA), or Mycophenolate Mofetil (MMF). The therapy regimen must be given appropriately and adequately to minimize the occurrence of complications. Conclusion: A combination of Prednisone, Azathioprine, andHydoroxychloroquin is effective as a therapy for Dermatomyositis. This can be proven by an increase in muscle strength and the red spots disappearing in this patient.

An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis

Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n= 39) or azathioprine plus prednisolone (n= 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p= 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p= 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p= 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p= 0.018). In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. #NCT02900443.

Complex Overlap Syndrome of Rheumatoid Arthritis and Systemic Lupus Erythematosus - A Therapeutic Breakthrough with Azathioprine

This case study explores the complex nature of coexisting autoimmune diseases, which is most effectively demonstrated by the coexistence of rheumatoid Arthritis (RA) and systemic lupus erythematosus (SLE), also referred to as “rhupus syndrome.” A comprehensive evaluation of a 28-year-old woman with joint discomfort, morning stiffness, and increased C-reactive protein (CRP) values was conducted. Anti-cyclic citrullinated peptide (CCP), antinuclear antibodies (ANA), and other pertinent serological indicators were examined in the laboratory. The patient’s medical background, prior therapies, and family history were considered to create an individual therapy strategy. The patient’s symptoms remained despite a long history of disease-modifying anti-rheumatic medication (DMARD) use. Positive outcomes for anti-CCP, anti-ANA, and anti-double-stranded DNA (anti-dsDNA) antibodies provide light on the overlap of multiple autoimmune diseases. The diagnostic difficulty was increased when autoimmune neutropenia was diagnosed with a bone marrow biopsy. Once azathioprine therapy was started, symptoms significantly and quickly improved within a month. Azathioprine was found to be successful in the remission of the disease. Azathioprine therapy’s critical role in treating overlapping autoimmune illnesses emphasizes the necessity for individualized and advanced testing and treatment. Targeted immunosuppressive medicines have the potential to make significant advances and enhance patient care and results.

E58 The rheumatologic masquerader: a case report on SLE-dermatomyositis-systemic scleroderma overlap syndrome

Abstract Introduction Juvenile dermatomyositis is an autoimmune connective tissue disorder characterized by idiopathic inflammatory myopathy primarily affecting the skin and muscles(1, 2). It may occur alone or in overlap syndromes usually with systemic scleroderma, systemic lupus erythematosus (SLE) and mixed connective tissue disease(3, 4). There is need to further describe and characterize cases encountered in different set ups. Objective To describe a case of dermatomyositis-scleroderma overlap in an African male adolescent. Methods We carried out a retrospective chart review to ascertain clinical features and management strategies. Results We present a case of a 17- year old African male patient who presented with a diagnosis of systemic lupus erythematosus made at a peripheral facility in February 2021, and started on azathioprine 50 mg daily, hydroxychloroquine 200 mg daily and prednisolone 5 mg twice daily. He presented on 30th November 2022 with a 2-year history of bilateral elbow, knee, ankle pain and swelling with an 8-month history of bilateral proximal upper and lower limb muscle weakness. Review of systems revealed alopecia, occasional fever and hyperpigmentation over his proximal interphalangeal and metacarpophalangeal joints that has since evolved to hypopigmentation. Positive examination findings included fine sparse hair, heliotrope rash, Gottron's papule, salt and pepper skin rash, hardening of the skin over the arm and thighs with a rodnan score 3/3 over the phalanges, nodular non tender lesions in the abdominal subcutaneous tissue and dactylitis with fixed flexion deformities of both elbows. He had bilateral flexion contractures of both elbows and knees with dactylitic fingers. Laboratory investigations showed an elevated CRP 94 mg/l, elevated lactate dehydrogenase 458 U/l, elevated creatine kinase 492U/l, positive antinuclear antibodies (1:640 titres) with a nuclear coarse and large speckled pattern, positive double stranded DNA antibodies and weak positive anti SM, anti RNP and PCNA antibodies. Myositis panel was positive for MDA5 and OJ. Pelvic MRI showed features of proximal inflammatory myositis. The childhood myositis assessment scale revealed a score of 25/52. ECHO and chest radiograph were normal. Pulmonary function test showed a low FEV 1 and FVC in keeping with a restrictive lung picture. Gastroenterology review revealed gastritis with no other stigmata of autoimmune disease. Management has consisted of monthly therapy with intravenous immunoglobulin. Azathioprine therapy was switched with mycophenolate mofetil 1 gram twelve hourly. He was advised on sunscreen protection. Physiotherapy and occupational therapy has been ongoing. Three months of follow up has led to the resolution of the flexion knee contractures, improved functionality in activities of daily living and a rodnan score of 2/3 over the phalanges. Conclusion SLE-juvenile dermatomyositis and systemic scleroderma can occur as an overlap syndrome and a definitive diagnosis remains elusive to many clinicians. A thorough history and comprehensive physical examination remains key to establishing a correct diagnosis. Early patient referral to paediatric rheumatologist for prompt appropriate treatment can avert debilitating morbidity and mortality.

Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B.wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B.wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B.wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B.wexlerae levels in patients with IBD.

NUDT15 Haplotypes and Diplotypes Predict Thiopurine-Induced Leukopenia and the Influence of Prolonged Exposure to Azathioprine on Hematologic Indices in Patients with Inflammatory Bowel Diseases

Background. NUDT15 gene polymorphisms have been identified to predispose Asian patients with an inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study predicted the influence of NUDT15 haplotypes and diplotypes on azathioprine (AZA)-induced leukopenia as well as the long-term influence of AZA on hematologic parameters in IBD. Methods. 194 IBD patients were tested for NUDT15 genotypes. We collected clinical data of 80 patients with AZA treatment including adverse events, dosage, white blood cell (WBC) count, platelet (PLT) count, and mean corpuscular volume (MCV) after AZA initiation. Patients without adverse events and drug withdrawal were followed up for at least one year. The relationship between NUDT15 haplotypes and diplotypes and leukopenia was analyzed. Results. The haplotypes NUDT15 c.415C > T and c.36_37insGGAGTC as well as the diplotypes NUDT15 ∗ 1/ ∗ 2, ∗ 3/ ∗ 3, and ∗ 3/ ∗ 5 were significantly associated with AZA-induced leukopenia. Only one patient with NUDT15 c.52G > A experienced leukopenia. NUDT15 ∗ 1/ ∗ 3 was not associated with leukopenia. After AZA initiation, the WBC count showed a downward trend in both wild types and mutants. The mean of WBC count in the mutant group at 1st month after AZA initiation was lower than that in the wild-type group ( P = 0.006 ). The MCV increased gradually in mutant cases ( P = 0.039 ), and the differences were obvious at 6th and 12th months compared with the baseline ( P = 0.014 a n d P = 0.042 , respectively). The PLT count showed a decreasing trend in the mutant group, but there was no difference until 11 months after initiating treatment ( P = 0.023 ). The final dose of AZA in the NUDT15 mutant group was significantly lower than that in the wild-type group ( P = 0.006 ). Conclusion. NUDT15 polymorphisms may be an appropriate predictor of AZA abnormal hematologic indices in IBD patients. It is necessary for IBD patients to monitor hematological indices and optimize AZA therapy.

Azathioprine monotherapy withdrawal in inflammatory bowel diseases: A retrospective mono-centric study.

There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation. To describe the events following AZA cessation. Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups. A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1st year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years. AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.

Safety and Efficacy of Inebilizumab in AQP4+ NMOSD Participants with History of Immunosuppression Treatment Prior to N-MOmentum Study (P13-5.003)

Safety and Efficacy of Inebilizumab in AQP4+ NMOSD Participants with History of Immunosuppression Treatment Prior to N-MOmentum Study (P13-5.003)

Risk factors for cancer in patients with primary biliary cholangitis and autoimmune hepatitis and primary biliary cholangitis overlap syndrome

Introduction and objectivesPrimary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. Materials and methodsThe Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. ResultsAmong the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk. ConclusionsThe prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.

Meta-analysis of the effectiveness of relapse prevention therapy for myelin-oligodendrocyte glycoprotein antibody-associated disease.

Approximately 40% of adults and 30% of children with Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) experience a relapsing course, but the optimal relapse prevention therapy remains unclear. A meta- analysis was conducted to investigate the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), maintenance intravenous immunoglobulin (IVIG), and tocilizumab (TCZ) in prevention of attacks in MOGAD. English and Chinese-language articles published from January 2010 to May 2022 were searched in PubMed, Embase, Web of Science, Cochrane, Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (CQVIP). Studies with fewer than three cases were excluded. Meta-analysis of the relapse-free rate, the change of annualized relapse rate (ARR)and Expanded Disability Status Scale (EDSS) scores before and after treatment, and an age subgroup analysis was performed. A total of 41 studies were included. Three were prospective cohort studies, one was an ambispective cohort study, and 37 were retrospective cohort studies or case series. Eleven, eighteen, eighteen, eight, and two studies were included in the meta-analysis for relapse-free probability after AZA, MMF, RTX, IVIG, and TCZ therapy, respectively. The proportions of patients without relapse after AZA, MMF, RTX, IVIG, and TCZ were 65% [95% confidence interval (CI):49%-82%]), 73% (95%CI:62%-84%), 66% (95%CI:55%-77%), 79% (95%CI:66%-91%), and 93% (95%CI:54%-100%), respectively. The relapse-free rate did not significantly differ between the children and adults treated with each medication. Six, nine, ten, and three studies were included in the meta-analysis for the change of ARR before and after AZA, MMF, RTX, and IVIG therapy, respectively. ARR was significantly decreased after AZA, MMF, RTX, and IVIG therapy with a mean reduction of 1.58 (95%CI: [-2.29--0.87]), 1.32 (95%CI: [-1.57--1.07]), 1.01 (95%CI: [-1.34--0.67]), and 1.84 (95%CI: [-2.66--1.02]), respectively. The change in ARR did not significantly differ between children and adults. AZA, MMF, RTX, maintenance IVIG, and TCZ all reduce the risk of relapse in both pediatric and adult patients with MOGAD. The literatures included in the meta-analysis were mainly retrospective studies, so large randomized prospective clinical trials are needed to compare the efficacy of different treatments.

Role of transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of retroperitoneal fibrosis (Ormond's disease).

Retroperitoneal fibrosis (RPF), often referred to as Ormond's disease when it is of idiopathic origin, is a rare disease characterized by the presence of inflammatory infiltrates and periaortic masses in the retroperitoneum. For a definite diagnosis, a biopsy and subsequent pathological examination is required. Currently accepted methods for retroperitoneal biopsy include open, laparoscopic, or CT-guided approaches. However, transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of RPF has attracted only little attention in the literature. We report two male patient cases who presented with leukocytosis, elevated C-reactive protein, and a suspicious retroperitoneal mass of unknown origin on computed tomography. One patient also reported left lower quadrant pain, whereas the other patient suffered from back pain and weight loss. In both patients, idiopathic RPF was successfully diagnosed by using transduodenal EUS-FNA/FNB with 22- and 20-gauge aspiration needles. Histopathology revealed dense lymphocytic infiltrates and fibrosis. The procedures lasted approximately 25 and 20 minutes, respectively, and in both patients no serious adverse events occurred. Treatment included steroid therapy and administration of Azathioprine. We demonstrate that using EUS-FNA/FNB to diagnose RPF is a feasible, fast, and safe method, which should always be considered as a first-line diagnostic modality. Hence, this case report emphasizes that gastrointestinal endoscopists are likely to play an important role in the setting of suspected RPF.

Development and validation of a novel HPLC-UV method for simultaneous determination of azathioprine metabolites in human red blood cells

A rapid, specific and accurate high-performance liquid chromatography with tunable ultraviolet detection method was developed to simultaneously determine azathioprine metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine riboside (6-MMPr) in human red blood cells. Erythrocyte lysate sample was precipitated by perchloric acid under the protection of dithiothreitol, with 6-TGN and 6-MMPr being acid hydrolyzed to produce 6-thioguanine (6-TG) and 6-methymercaptopurine (6-MMP). A Waters Cortecs C18 column (2.1 × 150 mm, 2.7 μm) was used for chromatographic separation with a water (containing 0.01 mol/L ammonium acetate and 0.2% acetic acid)/methanol linear gradient at a flow rate of 0.45 mL/min in a 5.5 min. UV detection wavelengths were 340 nm for 6-TG, 303 nm for 6-MMP and the IS (5-bromouracil). The calibration curves fitted a least squares model (weighed 1/x2) from 0.15 to 15 μmol/L for 6-TG (r2 = 0.9999) and from 1 to 100 μmol/L for 6-MMP (r2 = 0.9998). This method was validated according to the FDA bioanalytical method validation guidance and ICH M10 bioanalytical method validation and study sample analysis guidance for industry, and successfully utilized in ten IBD patients receiving azathioprine therapy.

P401 Concomitant azathioprine treatment effects vedolizumab treatment persistence in Crohn’s Disease but not in Ulcerative Colitis

Abstract Background Vedolizumab is a monoclonal antibody against integrin α4β7 that is being used for the treatment of moderate to severe Ulcerative Colitis (UC) and Crohn’s Disease (CD). Recent studies have shown conflicting results for the effect of concomitant azathioprine use with vedolizumab monotherapy. In this single center cohort study, we investigated the effect of concomitant azathioprine treatment on vedolizumab drug persistence in UC and CD treatment. Methods We performed a retrospective review of all adult (≥18 years) UC and CD patients started on VDZ at our infusion center. Data collection included baseline demographics, concomitant azathioprine therapy, VDZ therapy and disease activity scores using the partial Mayo score and Harvey Bradshaw Score. Data were obtained from the digital medical record. The primary outcome measure was VDZ persistence, represented in Kaplan-Meier analysis. This analysis assessed persistence on every 8 week dose regimen. Results This single center cohort included 142 VDZ treated UC (n=64) and CD (n=78) patients. All patients had a history of at least one anti-TNF treatment: Mean age 38.9±12.5 years and male gender 84 (59.2%). Median disease duration was 6±1.6 years. 6 Patients were excluded from the analysis since VDZ therapy has been stopped due to side effects. Mean duration of VDZ treatment in Crohn’s disease was 96.5±69.2 weeks and in UC was 72.1±60.5 weeks. Concomitant azathioprine therapy in CD increased VDZ persistence rate. However, in UC concomitant azathioprine therapy did not effect VDZ persistence rate. Conclusion The real-world data collected in this study demonstrate that concomitant azathioprine treatment increase the VDZ persistence rate in Crohn’s disease. However, concomitant azathioprine treatment does not effect the VDZ persistence rate in UC patients.

P729 Evaluation of hepatobiliary pathologies using transient elastography in patients with inflammatory bowel disease: What about the effect of drugs?

Abstract Background In this study, we evaluated hepatobiliary involvement in inflammatory bowel disease (IBD) with FibroScan® (transient elastography) and examined drug effects on liver fibrosis and steatosis. We particularly focused on the effect of azathioprine (AZT) on spleen stiffness (SS). Methods A total of 352 subjects were included in this study, including 298 IBD patients and 54 healthy controls. LSM (liver stiffness measurement), SS, and CAP™ (controlled attenuation parameter) scores were measured by FibroScan®. In addition to disease and patient characteristics; laboratory tests, and effect of the drugs were evaluated and compared within the groups. Results The patient and control groups were similar in terms of age and gender. The characteristics of the groups are shown in Table 1. Mean LSM (5.2±3.1kPa vs 4.5±1,1kPa), mean SS (22.69±13,10kPa vs 17.96±7,44kPa), CAP™ score (hepatosteatosis) (233±56dB/m vs 224±47dB/m) were significantly higher in the patients with IBD than in the control group (p&amp;lt;0.05). Liver fibrosis and steatosis grades are shown in Figure 1. A positive correlation was found between CAP™ score and male gender, hypertension, diabetes, BMI, smoking, penetrating disease, GGT, triglyceride, LSM, and SS (p&amp;lt;0.05). LSM (5.7±3,1kPa vs 5.0±3,1kPa) was significantly higher in patients with extraintestinal involvement (p&amp;lt;0.05). In patients with significant liver fibrosis (F2-3-4), the frequency of anti-TNF treatment was lower (44,4% vs 69,5%; p=0,008) (Figure 2). In patients who use alcohol regularly compared to nondrinkers (25.54±14,83kPa vs 21.05±11,24kPa) SS was significantly higher (p&amp;lt;0.05). Additionally, in patients using AZT≥100 mg/day compared to those using AZT&amp;lt;100 mg/day (23.48±14,61kPa vs 19.99±11,84kPa; p&amp;lt;0,05) SS was significantly higher (Figure 3). AZT dose was positively correlated with SS (Spearman analysis; r=0.182 and p=0.013); however, no correlation was found with the duration or cumulative dose of AZT. The mean level of platelets was significantly higher in patients with IBD than in controls (300±104x10³/µL vs 251±52x10³/µL, p=0,001); however, there was no correlation between SS and trombosit level (p&amp;gt;0,05). 83% of patients were in clinical remission (Mayo score≤2/CDAI&amp;lt;150). No positive correlation was found between disease activity and SS in IBD patients. AZT-associated non-cirrhotic portal hypertension was detected in only one patient. Conclusion In this study, fatty liver, liver fibrosis, and SS were found to be significantly higher in IBD patients than in healthy controls. Although there is no relationship with the duration of AZT therapy, AZT dose was positively correlated with SS. We recommend that spleen stiffness should be evaluated in patients who use high doses of AZT (≥100 mg/day).