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

BACKGROUND 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.AIM To describe the events following AZA cessation.METHODS 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.RESULTS 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.CONCLUSION 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.

Azathioprine-induced fever in autoimmune hepatitis

Underdiagnosis of drug-induced fever leads to extensive investigation and prolongation of hospitalization, and may lead to multiple unnecessary invasive procedures and a wrong diagnosis. Azathioprine is a widely used immunosuppressive drug. We report a case of a 53-year-old female patient diagnosed with autoimmune hepatitis treated with azathioprine, who presented to the emergency room with a 6-wk history of fever and chills without other associated symptoms. Since the patient's fever was of unknown origin, she was hospitalized. All treatment was stopped and an extensive workup to explore the source of fever and chills was performed. Results of chest X-ray, viral, urine, and blood cultures, autoimmune serology, transthoracic and transesophageal echocardiography, and abdominal ultrasound revealed no source of infection. A rechallenge test of azathioprine was performed and the fever and chills returned within a few hours. Azathioprine was established as the definite cause following rechallenge. Fever as an adverse drug reaction is often unrecognized. Azathioprine has been reported to cause druginduced fever in patients with inflammatory bowel disease, rheumatoid arthritis, and sarcoidosis. To the bestof our knowledge there have been no previous reports documenting azathioprine-induced fever in patients with autoimmune hepatitis. The occurrence of fever following the readministration of azathioprine suggests the diagnosis of drug-induced fever, particularly after the exclusion of other causes. A careful rechallenge is recommended to confirm the diagnosis.

Efficacy of additional treatment with azathioprine in a patient with prednisolone-dependent gastric sarcoidosis

Gastric sarcoidosis with noncaseating granuloma is rare. Although corticosteroid produces a dramatic clinical response, it is unknown whether azathioprine show efficacy in prednisolone-dependent cases. Here, we report a case of gastric sarcoidosis in a 25-year-old man with severe epigastlargia. Gastroendoscopy revealed multiple map-like ulcerations. Histological examination showed multiple noncaseating granulomatous lesions in gastric mucosa, which were incompatible with diagnoses of Crohn's disease or tuberculosis. He was started on prednisolone at 30 mg/d, and his symptoms improved within 7-d. The prednisolone was gradually tapered by 5 mg every 2-wk, but oral azathioprine at 50 mg was added after symptoms recurred at tapered dose of 10 mg. Endoscopy 4-wk later showed healing ulcers, and, lymphocytic infiltration was absent. The efficacy of additional azathioprine in gastric sarcoidosis is not well defined. Here, we report a case of prednisolone-dependent gastric sarcoidosis that improved after additional azathioprine, and also review the literature concerning the treatment, especially for prednisolone-dependent cases.

Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease(IBD).In vivo it is active after reaction with reduced glutathione(GSH)and conversion to mercaptopurine.Although this reaction may occur spontaneously,the presence of isoforms M and A of the enzyme glutathione-S-transferase(GST)may increase its speed.Indeed,in pediatric patients with IBD,deletion of GST-M1,which determines reduced enzymatic activity,was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites.In addition to increase the activation of azathioprine to mercaptopurine,GSTs may contribute to azathioprine effects even by modulating GSH consumption,oxidative stress and apoptosis.Therefore,genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.reserved.

Clinical effects of adalimumab treatment with concomitant azathioprine in Japanese Crohn's disease patients

AIM:To assess adalimumab's efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn's disease (CD) patients. METHODS:This retrospective, observational, singlecenter study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn's disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered:160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS:The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION:Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn's disease patients.

Azathioprine does not reduce adenoma formation in a mouse model of sporadic intestinal tumorigenesis

AIM: To investigate if azathioprine could reduce adenoma formation in ApcMin/+, a mouse model of sporadic intestinal tumorigenesis.METHODS:Azathioprine was administered via drinking water(estimated 6-20 mg/kg body weight per day)to ApcMin/+and wildtype mice.Control animals received vehicle only(DMSO)dissolved in drinking water.At 15wk of age all mice were sacrificed and intestines of ApcMin/+were harvested for evaluation of polyp number.Azathioprine induced toxicity was investigated by immunohistochemical analysis on spleens.RESULTS:All azathioprine treated mice showed signs of drug-associated toxicity such as weight loss and development of splenic T-cell lymphomas.Although this suggests that the thiopurine concentration was clearly in the therapeutic range,it did not reduce tumor formation(48±3.1 adenomas vs 59±5.7 adenomas,P=0.148).CONCLUSION:We conclude that in the absence of inflammation,azathioprine does not affect intestinal tumorigenesis.

Bone marrow inhibition induced by azathioprine in a patient without mutation in the thiopurine S-methyltransferase pathogenic site:A case report

BACKGROUND Azathioprine(AZA)and its close analog 6-mercaptopurine are thiopurines widely used in the treatment of patients with cancer,organ transplantation,and autoimmune or inflammatory diseases,including systemic lupus erythematosus.Bone marrow inhibition is a common side effect of AZA,and severe bone marrow inhibition is related to decreased thiopurine S-methyltransferase(TPMT)activity.CASE SUMMARY We herein report a patient with proliferative lupus nephritis who was using AZA for maintenance therapy,had no common TPMT pathogenic site mutations,and exhibited severe bone marrow inhibition on the 15th day after oral administration.CONCLUSION This report alerts physicians to the fact that even though the TPMT gene has no common pathogenic site mutation,severe myelosuppression may also occur.

Azathioprine induced liver cirrhosis: An unusual side effect

In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG), has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn’s disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative factor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.

The Thermodynamic Dissociation Constants of Azathioprine by the Nonlinear Regression and Factor Analysis of Multiwavelength Spectrophotometric pH-Titration Data

The mixed dissociation constant of azathioprine—chemically 6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H- purine at various ionic strengths I of range 0.01-0.2, and at temperatures of 25℃ and 37℃, was determined with the use of two different multiwavelength and multivariate treatments of spectral data, SPECFIT32 and SQUAD(84) nonlinear regression analyses and INDICES factor analysis according to a general rule. First, the number of components is determined, and then the spectral responses and concentrations of the components are calculated. Concurrently, the experimental determination of the thermodynamic dissociation constant was in agreement with its computational prediction of the PALLAS programme based on knowledge of the chemical structures of the drug. The factor analysis in the INDICES programme predicts the correct number of two light-absorbing species L- and HL. The thermodynamic dissociation constant of azathioprine was estimated by nonlinear regression of {pKa, I} data, = 8.07(1) at 25℃ and 7.84(1) at 37℃, where the figure in brackets is the standard deviation in last significant digits. The reliability of the dissociation constants of azathioprine was proven with goodness-of-fit tests of the multiwavelength spectrophotometric pH-titration data.

Azathioprine-induced pancytopenia:A case report

Azathioprine(AZA)is commonly used as immunosuppressive therapy for autoimmune diseases,including systemic lupus erythematosus(SLE).Myelosuppression is a common side effect of AZA.Here we report a case of severe myelosuppression following AZA therapy in a 15-year-old girl despite a normal thiopurine methyltransferase(TPMT)level.She had been receiving AZA for SLE and presented with neutropenic fever and pancytopenia.AZA was stopped.After stopping AZA,her blood counts steadily improved.When TPMT genotyping results were normal,AZA was reintroduced.Pancytopenia reappeared after starting AZA,despite normal TPMT genotype.AZA was replaced with mycophenolate mofetil which consequently resulted in improvement of blood counts.It is essential to understand the temporal relationship between AZA use and pancytopenia onset in patients with normal TPMT activity.This case illustrates that regular monitoring of blood cell counts should be routine practice after starting AZA regardless of TPMT activity.

Comparison of TPMT and NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease

AIM To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine(AZA)-induced leukopenia in inflammatory bowel disease(IBD).METHODS This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.RESULTS There were 219 patients with IBD(160 men and 59 women), including 39 who were confirmed with ulcerative colitis(UC), 176 with Crohn's disease(CD) and 4 with undetermined IBD(UIBD). There were 44 patients(20.1%) with mutant genotype of NUDT15(C/T); among them, 16 received AZA, and 8(50%) developed leukopenia. There were 175 patients(79.7%) with wild genotype of NUDT15(C/C); among them, 64 received AZA, and 11(17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C(P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G(1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients(98.6%) were found to bear the wild genotype of TPMT(A/A); among them, 79 patients received AZA, and 18(22.8%) developed leukopenia, and there was no significant difference from those with A/G(P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1%(P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.CONCLUSION Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.

Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.

Management of difficult inflammatory bowel disease:where are we now?

INTRODUCTION Medical care of patients with inflammatory bowel disease(IBD) comprise general measures and specific pharmacological,nutritional,endoscopic and surgical

Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review

BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.

Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study

AIM To analyze 1-year liver injury burden in inflammatory bowel disease(IBD) patients. METHODS During a 6-mo inclusion period, consecutive IBD cases having a control visit at IBD center were included. Basic demographics, IBD phenotype and IBD treatment were recorded on entry. Aminotransferase(AT) activities of ALT, AST, ALP and gamma-glutamyl transpeptidase(GGT) were measured at baseline, 3 mo prior to study entry and prospectively every 3 mo for 1 year. Liver injury patterns were predefined as: Grade 1 in ALT 1-3 × upper limit of normal(ULN), grade 2 in ALT > 3 × ULN, hepatocellular injury in ALT > 2 × ULN, cholestatic injury in simultaneous GGT and ALP elevation > ULN.Persisting injury was reported when AT elevations were found on > 1 measurement. Risk factors for the patterns of liver injury were identified among demographic parameters, disease phenotype and IBD treatment in univariate and multivariate analysis. Finally, implications for the change in IBD management were evaluated in cases with persisting hepatocellular or cholestatic injury.RESULTS Two hundred and fifty-one patients were included having 917 ALT and 895 ALP and GGT measurements. Over one year, grade 1 injury was found in 66(26.3%), grade 2 in 5(2%) and hepatocellular injury in 16 patients(6.4%). Persisting hepatocellular injury was found in 4 cases. Cholestasis appeared in 11 cases(4.4%) and persisted throughout the entire study period in 1 case. In multivariate analysis, hepatocellular injury was associated with BMI(OR = 1.13, 1.02-1.26), liver steatosis(OR = 10.61, 2.22-50.7), IBD duration(1.07, 1.00-1.15) and solo infliximab(OR = 4.57, 1.33-15.7). Cholestatic liver injury was associated with prior intestinal resection(OR = 32.7, 3.18-335), higher CRP(OR = 1.04, 1.00-1.08) and solo azathioprine(OR = 10.27, 1.46-72.3). In one case with transient hepatocellular injury azathioprine dose was decreased. In 4 cases with persisting hepatocellular injury, fatty liver or alcohol were most likely causes and IBD treatment was pursued without change. In the case with persisting cholestatic injury, no signs of portal hypertension were identified and treatment with infliximab continued.CONCLUSION Liver injury was frequent, mostly transient and rarely changed management. Infliximab or azathioprine were confirmed as its risk factors indicating the need for regular AT monitoring.

Autoimmune hepatitis:Appraisal of current treatment guidelines

Autoimmune hepatitis affects patients of all ages and gender, across all geographic regions. Although still rare, its incidence and prevalence are increasing. Genetic predisposition conveyed by human leucocyte antigen is a strong risk factor for the disease and may be responsible in part for the wide variation in presentation in different geographic regions. Our understanding of the underlying pathogenic mechanisms is evolving and may lead to development of more targeted immunotherapies. Diagnosis is based on elevated levels of serum aminotransferases, gamma globulins, autoantibodies and characteristic findings on histology. Exclusion of other causes of chronic hepatitis is important.Although undiagnosed disease is associated with poor outcomes, it is readily treatable with timely immunosuppressive therapy in the majority of patients.International guidelines are available to guide management but there exists a disparity in the standard treatment regimens. This minireview aims to review the available guidelines and summarize the key recommendations involved in management of this complex autoimmune disease.

Thiopurines in inflammatory bowel disease revisited

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far,a definite cure of the disease is still out of scope.An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy.Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine,are widely used in the therapy of chronic active inflammatory bowel disease(IBD).Their steroid sparing potential and efficacy in remission maintenance are out of doubt.Unfortunately,untoward adverse events are frequently observed and may preclude further administration or be life threatening.This review will focus on new aspects of thiopurine therapy in IBD,its efficacy and safety.

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

甲氨蝶呤联合雷公藤多甙对类风湿性关节炎干预的整体疗效研究

目的 研究甲氨蝶呤联合雷公藤多甙对类风湿关节炎临床干预的整体疗效。方法 选择浙江省长兴县人民医院治疗的96例类风湿性关节炎患者作为研究对象,随机分为对照组与研究组,每组48例。在2组患者均予以基础治疗的前提下,对照组给予甲氨蝶呤治疗,研究组予以甲氨蝶呤联合雷公藤多甙治疗。治疗3个月后,评估2组患者的临床症状、实验室指标、医生与患者对疾病活动性总体评价,同时观察用药的安全性。结果 对比2组治疗前,各项临床症状、实验室指标以及医生、患者对疾病活动性总体评价等均无显著差异,治疗后各组指标均显著好转（P〈0.05）,试验组各项指标均显著优于对照组（P〈0.05）。对照组与研究组分别有4例（8.3%）、6例（12.5%）出现胃肠道反应,组间差异无统计学意义。结论 甲氨蝶呤联合雷公藤多甙对类风湿性关节炎进行临床干预,可获得较为满意的整体疗效,患者的关节疼痛、肿胀等症状以及炎症指标改善显著,且安全性较高,值得临床应用。