Azathioprine Monotherapy Research Articles

P0993 Prevention of Postoperative Recurrence of Crohn’s Disease: Comparison of Two Therapeutic Strategies

Abstract Background Postoperative recurrence of Crohn’s disease affects half of patients within 10 years, making prevention crucial. The ECCO recommends immediate postoperative prophylactic treatment for patients with at least one risk factor for recurrence. While this strategy is proven effective for those with multiple risk factors, data on its benefits compared to endoscopy-guided prophylaxis in patients with only one risk factor is lacking. The study aimed to compare immediate postoperative prophylactic treatment with endoscopy-guided prophylaxis in patients with a single risk factor Methods This retrospective bicentric study included patients who underwent ileocolic resection for Crohn’s disease between January 2011 and December 2021, each with one risk factor for postoperative recurrence. Patients were divided into two groups G1 received immediate postoperative prophylactic treatment, while G2 received prophylactic treatment guided by colonoscopy within the first year after surgery. The primary outcome was the frequency of endoscopic recurrence within one year :Rutgeerts score ≥ i2. Secondary outcomes included severe endoscopic recurrence (i4) within 12 months and clinical recurrence at 6 and 24 months. Statistical analysis was conducted using SPSS26 Results This study included 41 patients divided into two groups. Group 1 (24 patients) had an average age of 34 years, with 58.33% being active smokers.Postoperative treatments were as follows: infliximab (4 patients), infliximab-azathioprine combination (3 patients), adalimumab (4 patients), ustekinumab (1 patient), and azathioprine monotherapy (12 patients). A Rutgeerts score of i2 or higher was found in 13 patients after a median of 9 months post-surgery, with an average follow-up of 3 years Group 2 (17 patients) had an average age of 38 years, with 64.7% being active smokers. Postoperative colonoscopy was performed after a median delay of 8 months. A Rutgeerts score of i2 or higher was found in 10 patients. The treatments initiated after colonoscopy were as follows: infliximab (3 patients), infliximab-azathioprine combination (2 patients), adalimumab (7 patients), azathioprine monotherapy (4 patients), and ustekinumab (1 patient). The average follow-up after surgery was 3 years No significant differences were observed between the groups in terms of endoscopic or severe endoscopic recurrence, or clinical recurrence at 6 and 24 months post-surgery Conclusion In our study, early initiation of prophylactic postoperative treatment for patients with a single risk factor did not reduce clinical or endoscopic recurrence rates. This suggests that avoiding such early treatment could help prevent unnecessary exposure to immunosuppressants and biologics, thereby reducing risks of side effects and high costs

Real-world evidence for factors associated with maintenance treatment practices among US adults with autoimmune hepatitis.

While avoidance of long-term corticosteroids is a common objective in the management of autoimmune hepatitis (AIH), prolonged immunosuppression is usually required to prevent disease progression. This study investigates the patient and provider factors associated with treatment patterns in US patients with AIH. A retrospective cohort of adults with the incident and prevalent AIH was identified from Optum's deidentified Clinformatics Data Mart Database. All patients were followed for at least 2 years, with exposures assessed during the first year and treatment patterns during the second. Patient and provider factors associated with corticosteroid-sparing monotherapy and cumulative prednisone use were identified using multivariable logistic and linear regression, respectively.The cohort was 81.2% female, 66.3% White, 11.3% Black, 11.2% Hispanic, and with a median age of 61 years. Among 2203 patients with ≥1 AIH prescription fill, 83.1% received a single regimen for >6 months of the observation year, which included 52.2% azathioprine monotherapy, 16.9% azathioprine/prednisone, and 13.3% prednisone monotherapy. Budesonide use was uncommon (2.1% combination and 1.9% monotherapy). Hispanic ethnicity (aOR: 0.56; p = 0.006), cirrhosis (aOR: 0.73; p = 0.019), osteoporosis (aOR: 0.54; p =0.001), and top quintile of provider AIH experience (aOR: 0.66; p = 0.005) were independently associated with lower use of corticosteroid-sparing monotherapy. Cumulative prednisone use was greater with diabetes (+441mg/y; p = 0.004), osteoporosis (+749mg/y; p < 0.001), and highly experienced providers (+556mg/y; p < 0.001). Long-term prednisone therapy remains common and unexpectedly higher among patients with comorbidities potentially aggravated by corticosteroids. The greater use of corticosteroid-based therapy with highly experienced providers may reflect more treatment-refractory disease.

Efficacy of optimised thiopurine therapy in patients with moderate-to-severe ulcerative colitis: retrospective long-term follow-up from two randomised trials

Objective The long-term outcome of thiopurine therapy in patients with ulcerative colitis (UC) enrolled in prospective trials have not been evaluated. We aimed to assess the effects of optimised thiopurine maintenance therapy for UC. Methods Long-term data were obtained from patients from our center enrolled in two randomised, prospective, open-label, controlled studies comprising 66 thiopurine-naïve moderate-to-severe patients with UC consisting of a low dose azathioprine (AZA)/allopurinol combination or AZA monotherapy. Following the randomised trials, treatment was adjusted according to adverse effects and metabolites. Patients requiring optimisation initially on AZA monotherapy treatment were switched to low dose AZA in combination with allopurinol, low dose 6-mercaptopurin in combination with allopurinol, or 6-mercaptopurin treatment alone, and those treated with low dose AZA in combination with allopurinol were switched to low dose 6-mercaptopurin in combination with allopurinol or 6-mercaptopurin alone. Results A total of 62 patients were included in the analysis; 31 were initially treated with AZA monotherapy and 31 with low dose AZA in combination with allopurinol. Initial treatment was tolerated by 67% patients (7 AZA monotherapy and 28 low dose AZA in combination with allopurinol), increasing to 94% (58 patients) post-adjustment. After a median 52-month follow-up period, 38 (93%) out of the 41 primary responding patients-maintained clinical remission without steroids, biologics or surgery. The four intolerant patients and the 17 not responding to optimisation were more likely to require colectomy (odds ratio 16.36; 95% confidence interval 3.08–87.03, p < 0.0001). Conclusion Optimised thiopurine therapy demonstrated effective long-term treatment for patients with ulcerative colitis.

P779 Long term efficacy of azathioprine monotherapy in patients with Inflammatory Bowel Disease

Abstract Background ECCO guidelines recommend monotherapy with azathioprine (AZA) as maintenance therapy of patients with inflammatory bowel disease (IBD) mainly in steroid-dependent disease. However, in the era of the new advanced treatments AZA is not considered as a preferable option, mainly because of the referred side effects and its use is limited in combination with biologic agents. Methods This is a retrospective observational study using data from the longitudinal, prospective IBD registry of University Hospital of Heraklion, Greece. Our aim was to study IBD patients who started on monotherapy with AZA, the profile of adverse effects they developed, the treatment persistence in monotherapy, as well as the possible related factors of treatment success [including age, gender, smoking status, body mass index, disease type, disease phenotype for Crohn’s disease (CD), history of IBD related surgery and the presence of extraintestinal manifestations]. Results Of 168 IBD patients treated with AZA, 89 (53%) were under AZA monotherapy [38 (43%) female, 67 (74%) CD, median age (IQR) 47 (32-56) years, mean (±SD) disease duration 17 (±8.4) years, median (IQR) time receiving AZA 72 (7-120) months]. Thirty (34%) patients continue their treatment till now (23 CD, 7 ulcerative colitis-UC), with a median time (IQR) of 108 (81-132) months. Of these, 18 (60%) (15 with CD and 3 with UC) present endoscopic remission and 11 (36%) (8 with CD, 3 with UC) mild endoscopic activity (based on SES-CD Score for CD and Mayo endoscopic score for UC). Of the 59 who discontinued, 33 (37%) experienced adverse events, 5 (5.5%) developed malignancy, 5 (5.5%) did not respond at baseline, 6 (6.5%) had loss of response (at a median of 91 months), 3 (3%) discontinued due to advanced age, 3 (3%) discontinued their medication on their own and 2 because of treatment de-escalation due to deep remission. Using logistic regression analysis, patients who responded to AZA monotherapy were patients without a history of IBD surgery or any extraintestinal manifestation, P=0.001 and 0.004, respectively. In the multivariate analysis, these associations remained statistically significant (P=0.01 and 0.006 respectively). Conclusion About one third of patients with IBD under AZA monotherapy experience long term response and about two thirds of them prolonged disease remission. Patients without either a history of IBD surgery or extraintestinal manifestations seem to respond better to AZA monotherapy.

Azathioprine Plus Exclusive Enteral Nutrition Versus Azathioprine Monotherapy for the Prevention of Postoperative Recurrence in Patients with Crohn's Disease: An Open-Label, Single-Centre, Randomized Controlled Trial.

Azathioprine [AZA] effectively prevents postoperative endoscopic recurrence [ER] in Crohn's disease [CD]. However, the efficacy of AZA emerges after 3 months. Exclusive enteral nutrition [EEN] can maintain remission in CD. The present trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. In total, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus 3 months of EEN [AZA + EEN] postoperatively. The primary endpoint was the rate of ER at 12 months. Secondary endpoints included the rate of ER at 3 months, clinical recurrence [CR], CD activity index [CDAI] scores, faecal calprotectin [FC], and C-reactive protein [CRP]. Quality of life was assessed using Short Form-36 [SF-36] and the Inflammatory Bowel Disease Questionnaire [IBDQ]. Patients in the AZA + EEN group exhibited significantly lower rates of ER compared to the AZA group at both 12 months (33.3% [13/39] vs 63.2% [24/38], P = 0.009) and 3 months (8.6% [3/35] vs 28.1% [9/32], P = 0.037) post-surgery. The rates of CR between the two groups at 3 and 12 months were similar. CDAI scores, FC, albumin level, and CRP were all comparable between the two groups. Quality of life was significantly higher in the AZA group than in the AZA + EEN group at 3 months but became comparable from 5 to 12 months postoperatively. In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted. NCT05214430.

Azathioprine in hidradenitis suppurativa with inflammatory phenotype: a case series of 11 patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that negatively impacts the quality of life of patients. It presents as deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. Recently, two phenotypes have been described: a follicular phenotype and an inflammatory phenotype. Numerous medical treatments are available for hidradenitis suppurativa, with particular importance of antitumor necrosis factor antibodies. Due to the association of HS with other conditions with a pro-inflammatory state, particularly Crohn's disease, it has been suggested that azathioprine may have a role in the treatment of HS. To assess the effectiveness of azathioprine monotherapy in patients with moderate-severe HS. We retrospectively studied patients with HS treated with azathioprine in monotherapy. We performed both clinical and ultrasound evaluation at baseline as well as in the follow-up visits. Their baseline score on the iHS4 and DLQI scales and 12-16 weeks after starting the treatment were compared. We also registered the number of patients who achieved HiSCR. Six patients presented significant improvement, reducing their score in iHS4 and DLQI scales and achieving HiSCR. Another patient had clinical improvement, meaning reduction in iHS4 and DLQI, but without achieving HiSCR. Two patients stopped the treatment before week 12 because of adverse events. The remaining two patients presented no improvement. The median (Q3-Q1) baseline iHS4 score was 6 (12-6), and follow-up iHS4 score, 4 (6-2), being these differences statistically significant (P = 0.006). Median (Q3-Q1) baseline DLQI scores and 12-16 weeks after treatment were 17 (23-11) and 14 (18-9), although statistically nonsignificant (P = 0.099). We present a case series of 11 patients treated with azathioprine with good clinical and ultrasonographic response. We suggest that azathioprine may benefit a certain patient profile with the inflammatory phenotype.

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.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases

Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

Feasibility of Reduced Clinical Monitoring in Patients with Inflammatory Bowel Disease Treated with Thiopurine Therapy

BackgroundOutpatient visits and laboratory assessments are routinely scheduled every 3 to 4 months in thiopurine-treated patients with inflammatory bowel disease (IBD) to timely detect thiopurine-related adverse events (AEs). AEs that require therapy adjustment beyond 12 months of treatment are rare.Aim and MethodsThis single-center prospective cohort study evaluated the safety of a reduced 6-monthly monitoring strategy in steroid-free patients with quiescent IBD on stable dose of azathioprine, mercaptopurine, or thioguanine monotherapy. The primary outcome was thiopurine-related AEs requiring therapy adjustments during a follow-up period of 24 months. Secondary outcomes included all AEs including laboratory toxicity, disease flares until 12 months, and the net monetary benefit from this strategy concerning IBD-related health care use.ResultsWe enrolled 85 patients with IBD (median age 42 years, 61% Crohn’s disease, 62% female), with a median disease duration of 12.5 years and median thiopurine treatment duration of 6.7 years. During follow-up, 3 patients (4%) ceased thiopurines due to AEs: recurrent infections, non-melanoma skin cancer, and gastrointestinal complaints (nausea, vomiting). At 12 months, 25 laboratory toxicities were observed (including 13% myelotoxicity, 17% hepatotoxicity); none required therapy adjustments and all were transient. A reduced monitoring strategy had a net benefit of €136 per patient.ConclusionThree patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.

Remarkable 107-year-old kidney with a 49-year of long-term allograph survival through continuous azathioprine monotherapy

BackgroundThe main goal of kidney allograft transplantation is to improve survival in patients with end-stage kidney failure. Herein, we report a 49-year long-term allograft survival with non-identical human leukocyte antigens (HLA). The purpose of this study was to report the successful clinical outcome of 49 years of transplant survival in a 79-year-old patient with a 107-year-old kidney undergoing continued immunosuppressive monotherapy. Material and methodsThe patient was evaluated clinically and immunologically with HLA typing and anti-HLA antibodies before transplantation. Post-transplant, the patient's clinical and immunological survival were monitored for 49 years. The state of the chimerism was assessed using the polymerase chain reaction to amplify 24 short tandem repeats using a DNA thermocycler and DNA analyzer. ResultsThe patient and donor were haploidentical and the patient was treated with azathioprine monotherapy. Donor-specific antibodies were detected only for the HLA-DPB1* 03:01 mismatch. This patient developed multiple skin tumors 26 years after transplant, which were successfully treated with topical therapy or surgical removal. The patient developed an intestinal adenocarcinoma 43 years after kidney transplantation, which was surgically removal; six years later, adenocarcinoma was diagnosed in a finger, followed by axillar and hepatic metastases. After 49 years of graft survival of a kidney of 107 years old in a patient with 79 years of age, the patient's health worsened with severe dehydration, anemia, and bacterial infection. The patient was hospitalized with a serum creatinine level of 3.45 mg/dL, urea level of 188 mg/dL, and estimated glomerular filtration rate of 22 mL/1.72 m2; septicemia developed and was treated with antibiotics. The patient had poor clinical progress, was intubated, and later died due to septic shock. ConclusionsTo the best of our knowledge, this is the first case of a 107-year-old kidney, transplanted into a recipient who was treated with azathioprine monotherapy for 49 years.

P855 The impact of the severe financial crisis on drug persistence and disease course in IBD patients in Lebanon

Abstract Background Lebanon is currently going through an unprecedented financial crisis (considered as one of the worst in the world in modern times) that has affected all aspects of everyday life. In particular, the economical crash has significantly crippled the Lebanese healthcare sector, resulting in severe shortages of basic drugs and medications, most of which cannot be produced locally. Patients with chronic diseases including those with Inflammatory Bowel Disease (IBD) have been impacted most given their need for costly and chronic treatment including biologics. Methods We collected data using a 12-question web survey disseminated through social media platforms of the patient organization, I Battle Disease. The questions aimed to explore the patients’ ability to acquire the necessary medications, whether they had to alter or completely stop their treatment, and any resulting complications (forced corticosteroid use, hospitalization, or surgery) it had on the course of their disease. Results 102 patients completed the survey. The patients were nearly evenly split between Crohn’s disease (53%) and ulcerative colitis (47%). Adalimumab was the most commonly used medication before the economic crisis (30%), followed by infliximab (18%), vedolizumab (10%), ustekinumab (8%), and tofacitinib (8%). Azathioprine and 5-ASA monotherapy were used by 8% and 19% of patients respectively. All biologics and small molecules used to be covered fully by third party payors including the National Social Security Fund (38%), the Ministry of Public Health (22%), and private insurance (18%). As a result of the crisis, the majority of patients (69%) declared stopping or interrupting their treatment in the past 3 years, with most (46%) having interrupted treatment for &amp;gt;12 months. 22% of patients reported switching to azathioprine due to issue in access to biologics. Additionally, 69% of patients reported worsening of their condition after stopping treatment, resulting in forced steroid use (36%), switching to another medication (36%), or unscheduled hospital admission (15%). Further, 66% of participants confirmed that they had to purchase their medications from abroad or through a local private vendor using out-of-pocket foreign currencies. Finally, 12% of patients reported that they had to immigrate or seek employment abroad due to difficulty with drug access. Conclusion The recent financial and economic events in Lebanon have imposed significant challenges on patients with IBD, affecting their adherence to therapy and consequently the control of their disease. There is an urgent need for action within the public health context to improve IBD medication availability and accessibility for the Lebanese population.

Classical Enteropathy-Associated T-cell Lymphoma (EATL) Complicating A Crohn’s Disease Patient on Thiopurine Monotherapy: A Case Report

Thiopurine exposure from inflammatory bowel disease (IBD) treatment had been associated with a higher risk of lymphoproliferative disorders namely peripheral T-cell lymphoma, as early as 2 years after its initiation. We report a rare case of classical or type 1 enteropathy-associated T-cell lymphoma (EATL) with liver metastasis in a long-standing Crohn’s disease 61-year-old patient treated with azathioprine monotherapy. He presented with acute, severe abdominal pain with cholestatic jaundice and pancytopenia. Colonoscopy showed multiple small, superficial ulcers at the terminal ileum and the biopsy taken was reported as classical EATL, an uncommon gastrointestinal non-Hodgkin’s lymphoma with CD2, CD 3, CD 30, and CD 56 positivity and more than 90% Ki67 proliferative index. Computed tomography (CT) 3-phase liver scan suggested liver metastasis. This case highlights the unusual presentation of classical EATL in non-celiac disease patients and its risk association with thiopurine therapy in IBD.

Evaluation of exclusive enteral nutrition and corticosteroid induction treatment in new-onset moderate-to-severe luminal paediatric Crohn’s disease

To induce remission in luminal paediatric Crohn’s disease (CD), the ESPGHAN/ECCO guideline recommends treatment with exclusive enteral nutrition (EEN) or oral corticosteroids. In newly diagnosed moderate-to-severe paediatric CD patients, we determined the proportion of patients in which EEN or corticosteroids induced remission and maintained remission on azathioprine monotherapy. We included patients from the “TISKids” study assigned to the conventional treatment arm. Patients were aged 3–17 years and had new-onset, untreated luminal CD with weighted paediatric CD activity index (wPCDAI) > 40. Induction treatment consisted of EEN or oral corticosteroids; all received azathioprine maintenance treatment from start of treatment. The primary outcome of this study was endoscopic remission defined as a SES-CD score < 3 without treatment escalation at week 10. Secondary outcomes included proportion of patients without treatment escalation at week 52. In total, 27/47 patients received EEN and 20/47 corticosteroids. At baseline, patient demographics and several inflammation parameters were similar between the two treatment groups. At 10 weeks, clinical remission rates were 7/23 (30%) for EEN and 7/19 (37%) for corticosteroids (p = 0.661). Twenty-nine of 47 consented to endoscopy at 10 weeks, showing endoscopic remission rates without treatment escalation in 2/16 (13%) of EEN-treated patients and in 1/13 (8%) of corticosteroid-treated patients (p = 1.00). At week 52, 23/27 (85%) EEN-treated patients received treatment escalation (median 14 weeks) and 13/20 (65%) corticosteroid-treated patients (median 27 weeks), p = 0.070.Conclusion: In children with moderate-to-severe newly diagnosed CD, induction treatment with EEN or CS regularly is insufficient to achieve endoscopic remission without treatment escalation at week 10. Trial registration number: NCT02517684What is Known:• Endoscopic remission is associated with a low risk of disease progression.• FL-IFX was superior to conventional treatment in achieving and maintaining remission in paediatric patients with moderate-to-severe CD the first year from diagnosis.What is New:• In children with newly diagnosed moderate-to-severe CD, clinical remission rates and endoscopic remission rates without treatment escalation at week 10 were 30% and 13% after EEN and 37% and 8% after corticosteroid induction treatment.• The current treatment target was often not achieved by either EEN or corticosteroid induction treatment after bridging to azathioprine.

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)).

P546 Minimal risk of lymphoma despite long term use of azathioprine in patients with Inflammatory Bowel Disease: a longitudinal cohort analysis from Northern India

Abstract Background Thiopurines are widely used to maintain remission in both ulcerative colitis (UC) and Crohn’s Disease (CD). Reported effectiveness and tolerability rates have been variable across studies. Moreover, there are only sparse data in the Asian population regarding the long-term efficacy and safety of azathioprine (AZT). Methods Records of 5351 patients followed up at IBD clinic, All India Institute of Medical Sciences, New Delhi from 2004–2020 were evaluated retrospectively. Azathioprine efficacy was defined as no requirement of surgery, hospitalizations, anti TNFs agents, and minimum steroid (≤1 course in 2 years) requirement on follow-up. Safety was evaluated in terms of long-term adverse events and the development of malignancy. Results Of 5351 patients with IBD, 1093 who received AZT for &amp;gt; 3 months (UC=788 [proctitis-1.9%, left-sided colitis-44.9%, pancolitis-53.1%], CD=305 [inflammatory-42.6%, stricturing-46.9%, fistulizing-10.5%]) were included (60.8%-males; mean age at disease onset-31.69±12.34 years) (Table1). Follow-up and treatment duration on AZT were 7(4–12) years and 39.41±40.27 months respectively. Mean initiation and maintenance dose of AZT was 1.09±0.45 mg/kg and 94.82±21.29, respectively. One,3,5, and 10 years relapse free survival was 85%,79%,76%, and 64%; 87%, 82%, 79% and 72%; and 78%, 72%, 68% and 61% in overall cohort, UC and CD patients, respectively (Log-rank P=0.001 between UC and CD). Three hundred fifty-nine [UC:249(31.6%); CD:110(36.07%); P=0.158] patients developed adverse events (AE), commonest was myelosuppression (23.42%) followed by gastrointestinal intolerance (2.97%), flu like illness (1.7%), and arthralgia/myalgia (1.37%) (Table 2). Myelosuppression was the commonest cause of AZT withdrawal. No patient (including 254 patients on AZT for ≥5 years) developed lymphoma or non-melanoma skin cancer. Adverse events free course in entire cohort, and in UC and CD are shown in fig.1 and 2 respectively. Conclusion Long-term Azathioprine monotherapy in patients with IBD is safe with minimal risk of lymphoma and non-melanoma skin cancer.

Azathioprine with Allopurinol Is a Promising First-Line Therapy for Inflammatory Bowel Diseases

BackgroundBeneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce.AimRetrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring.MethodsClinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events.ResultsIn total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200–300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity.ConclusionsOur poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

6-thioguanine nucleotide monitoring in azathioprine and mercaptopurine monotherapy for the treatment of inflammatory bowel disease

6-thioguanine nucleotide monitoring in azathioprine and mercaptopurine monotherapy for the treatment of inflammatory bowel disease

S2900 Autoimmune Hepatitis Presenting as Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic Lymphohistiocytosis (HLH) is rare syndrome characterized by a systemic macrophagocytic process triggered by excessive cytokine and immune activation. We present a case of fulminant autoimmune hepatitis leading to HLH. Case Description/Methods: A 30 year old African American woman was admitted with nausea, vomiting, low grade fevers, and abdominal pain for 4 days. Home medications included 3 days of amoxicillin with acetaminophen 2 g daily for dental infection. She denied heavy alcohol use, illicit drug use, and herbal supplementation. Comprehensive laboratory investigation shown on Table 1. Hepatitis A, B, C, E , CMV, EBV, COVID-19, and pan cultures were negative. Hepatospleenomegaly present. After 3 days of IV NAC, aminotransfereases downtrended to a persistent 400-500's range, however total bilirubin and INR worsened despite Vitamin K administration. Due to clinical suspicion for autoimmune hepatitis, she was started on prednisone 60mg daily. Liver biopsy showed portal and lobular interface hepatitis with focally prominent plasma cells with periportal fibrosis as well as extensive histocyte/macrophage infiltration and activation. Additional labs showed: ferritin 4,014 mg/mL, fibrinogen 94 mg/dL, LDH 1100 U/L, normal triglycerides, elevated IL-2 receptor (6300), and normal NK cell activity. With concern for HLH, a bone marrow biopsy confirmed hypercellular bone marrow with active trilineage hematopoiesis and foci of hemophagocytocytosis. She later developed grade 2-3 hepatic encephalopathy requiring closer monitoring in ICU. Liver transplant evaluation was initiated, but fortunately her clinical status improved with continued steroid use. Azathioprine 50 mg was subsequently started with steroid taper. Her current hepatic function panel remains normal with azathioprine monotherapy. Discussion: HLH has a wide range of clinical presentations, making it difficult to diagnose promptly. The disease has a quick progression and carries a high mortality. HLH subtypes are classified into genetic and acquired etiologies. HLH can be triggered by infections, autoimmune processes, malignancy, and organ transplant with immunosuppressant use. She met 6 of 8 diagnostic criteria, based on the HLH 2004 trial. Although liver failure can be a manifestation of HLH, autoimmune hepatitis likely incited her macrophage activation syndrome. HLH should remain on the differential for patients with unexplained pancytopenia, hepatospleenomegaly, hyperferritinemia, and fevers. (Figure Presented).

Azathioprine Monotherapy for the Cases of Immunoglobulin G4-Related Disease With Contraindications to Glucocorticoids.

Noda, Seiji MD; Honda, Suguru MD; Hirota, Yuka MD, PhD; Ito, Takashi MD, PhD; Hasegawa, Hisanori MD, PhD; Kimura, Naoki MD, PhD; Matsuo, Yusuke MD, PhD; Iwai, Hideyuki MD, PhD; Kohsaka, Hitoshi MD, PhD; Yasuda, Shinsuke MD, PhDAuthor Information

Carcinoma Camouflage

Question: A 74-year-old woman with compensated Child-Pugh A cirrhosis (Model for End-Stage Liver Disease score of 8) secondary to autoimmune hepatitis on azathioprine monotherapy was evaluated for abdominal bloating and intermittent right upper quadrant abdominal pain. She endorsed a 5-lb unintentional weight loss over the past 4 months associated with anorexia. On physical examination, she was well-appearing with a soft abdomen and no abdominal tenderness, distension, or ascites. The pertinent serology revealed an aspartate aminotransferase of 76 U/L, a total protein of 8.3 g/dL, albumin of 3.4 g/dL, hemoglobin of 12.2 g/dL, white blood cells of 3.1 × 109/L, platelets of 96,000, lactate dehydrogenase of 290 U/L, and alpha fetoprotein of 4.25 ng/mL. An abdominal ultrasound examination revealed a new hypoechoic lesion measuring 2.5 cm × 2 cm × 1.5 cm with minimal flow by Doppler. Triple phase magnetic resonance imaging (MRI) of the liver revealed a lobular 3.5 cm × 3.0 cm mass in hepatic segments 2 and 3 (Figures A and B, red arrows) as well as a 3.9 cm × 3.1 cm mass in segment 7, each T1 hypointense and T2 hyperintense with peripheral enhancement and washout including marked diffusion restriction favoring multifocal hepatocellular carcinoma with an atypical enhancement pattern. Imaging was negative for extrahepatic disease. Outside of the Milan criteria, the patient was referred to surgical oncology for further evaluation and management. The mass in segment 3 seemed to be larger via intraoperative ultrasound examination (5 cm) and was therefore resected. The mass in segment 7 underwent microwave ablation to preserve the liver parenchyma. Pathology revealed a sheetlike proliferation of large, pleomorphic, atypical vesicular lymphoid cells (Figure C) with mitotic figures and apoptotic bodies (Figure D). Immunohistologic staining was diffusely and strongly positive for CD20 (Figure E), CD10, and BCL6. Workup for viral serologies was negative (hepatitis B virus, hepatitis C virus, HIV, and Epstein–Barr virus stain from liver tissue). What is the next step in evaluation and management? What is the most likely diagnosis? Look on page 1942 for the answer and see the Gastroenterology website (www.gastrojournal.org/) for more information on submitting your favorite image to Clinical Challenges and images in GI. A referral to hematology/oncology was made for the initiation of rituximab-based chemotherapy. This patient has diffuse large B-cell lymphoma (DLBCL), germinal center B-cell type. The pathology from the resected liver segments revealed DLBCL, germinal center B-cell subtype, without double or triple-hit features after fluorescence in situ hybridization analysis. Positron emission tomography with computed tomography scans confirmed no evidence of active disease and final staging was deemed to be stage IEA with a National Comprehensive Cancer Network International Prognostic Index score of 4 (high to intermediate) secondary to age, extranodal disease, and elevated lactate dehydrogenase. Three short cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was recommended. Echocardiogram revealed a normal ejection fraction. Unfortunately, she developed neutropenic fever during cycle 1 with extended spectrum beta lactamase urinary tract infection, urinary retention, and anasarca requiring granulocyte colony stimulating factor, antibiotics, and adjustment of diuretics. Additional chemotherapy was not advised, and she will follow-up with positron emission tomography with computed tomography scans in 2 months. DLBCL is the most common aggressive non-Hodgkin lymphoma (NHL).1Shibata J. Kurahashi S. Naito T. et al.Diffuse large B cell lymphoma primarily presenting as acute liver failure in a surviving patient.J Community Hosp Intern Med Perspect. 2019; 9: 135-139Crossref PubMed Google Scholar DLBCL may manifest as a primary hepatic lymphoma (PHL) in the late stage of disease. PHL is exceedingly rare, estimated to be present in 0.4% of extranodal NHL and 0.016% of all NHL cases.2Zhang K.J. Chen S. Chen J.L. et al.Complete response to comprehensive treatment of a primary hepatic diffuse large b cell lymphoma: a case report.Oncol Lett. 2015; 9: 1557-1660Crossref PubMed Scopus (3) Google Scholar Contributing factors include chronic viral infections (hepatitis B and C, Epstein–Barr virus, HIV), cirrhosis, autoimmune disease, and chronic use of immunosuppressants. R-CHOP is the gold standard of therapy. Chronic azathioprine use increases the risk of lymphoma; however, the association with PHL has not been reported. Imaging characteristics suggestive of PHL on MRI may consist of signal restriction in the diffusion-weighted imaging and a lower apparent diffusion coefficient.3Colagrande S. Calistri L. Grazzini G. et al.MRI features of primary hepatic lymphoma.Abdom Radiol. 2018; 43: 2277-2287Crossref PubMed Scopus (17) Google Scholar Clinicians should consider hepatic lymphoma in cirrhotic patients if there is a history of autoimmune disease, immunosuppressant use such as azathioprine, atypical enhancement pattern on MRI, and a normal alpha fetoprotein.