Azathioprine Withdrawal Research Articles

P0625 Impact of TMPT genotype on Azathioprine side effects and durability in a cohort of pediatric patients with Inflammatory Bowel Diasease: a real life study

Abstract Background Genetic variations in the thiopurine S-methyltransferase (TPMT) gene have been associated with adverse events (ADRs) to Azathioprine (AZA). This study aims to investigate the prevalence of TPMT polymorphisms and their correlation with AZA toxicity and treatment durability in a cohort of pediatric patients with inflammatory bowel disease (IBD). Methods A total of 104 IBD patients (47% males, 53% females), of which one had indeterminate colitis, 56 had Crohn ‘s disease and 47 had ulcerative colitis, with a mean age at diagnosis of 11±3.7 years, were genotyped for TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C. Data on AZA related side effects, dosage, and treatment durability were recorded. Results Of the 104 patients, six (5.7%) had TPMT mutations: three carried the TPMT *3A variant, one the TPMT *3B variant, and two the TPMT *3C variant (Figure 1). Among the 104 patients, 94 (90%) started on AZA treatment. Among the 86 patients who started AZA with at least 6 months of follow-up, 18 (20.9%) developed ADRs, primarily pancreatitis (9.3%) and myelotoxicity (8%) (Figure 2). Of the 6 patients with mutations, only one developed ADRs, showing no significant difference from the total population. AZA withdrawal due to ADRs occurred in 18.7% of the population, with no significant differences between the two groups. At the start of therapy and after 12 months, the mean AZA dosage (mg/kg/day) was lower in mutated patients compared to wild-type patients, though this difference did not reach statistical significance (1.35±0.51 vs 1.67±0.4, p=0.12; 12 1.74±0.35 vs 2.1±0.45, p=0.09 respectively). Conclusion In this cohort of IBD subjects, no significant association was observed between TPMT polymorphisms, the occurrence of thiopurine-related ADRs, and the durability of AZA treatment. This suggests that screening for TPMT variants does not impact the likelihood of patients developing ADRs.

Evaluating Kaposi Sarcoma in Kidney Transplant Patients: A Systematic Review and Meta-Analysis.

Kaposi's sarcoma (KS) is a malignancy that commonly appears as lesions on the skin or mucosal surfaces but can also develop in other organs. This cancer is usually caused by the human herpesvirus 8 (HHV-8), recently known as Kaposi's sarcoma-associated herpesvirus (KSHV). KS is rare in the general population but can develop in kidney transplant recipients with varying incidence due to immunocompromised status from immunosuppression. The main aim of the present systematic review was to identify the prevalence and treatment of KS in kidney transplant patients. PubMed, Cochrane Library, and Google Scholar databases were searched for studies until October 2023. Full-text studies with similar research objectives were included, while non-English articles, reviews, case reports, ongoing clinical trials, and studies evaluating KS in HIV patients or after other solid organ transplants were excluded. All studies were observational; therefore, methodological quality was assessed using the Newcastle-Ottawa Scale. The statistical analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Biostat, Inc.Englewood, NJ). The pooled analysis from the 15 studies includedshowed that KS develops in 1.5% of kidney transplant recipients and is more prevalent in African (1.7%) and Middle Eastern (1.7%) recipients than in Western recipients (0.07%). KS was also significantly more prevalent among male recipients than female recipients (OR: 2.36; p < 0.0001). Additionally, cyclosporine-based immunosuppression accounts for most KS incidences (79.6%) compared to azathioprine-based immunosuppression (28.2%). Furthermore, reduction or withdrawal of immunosuppression alone resulted in 47.8% KS complete remissions. Post-kidney transplantation KS is more frequent among males and patients of Middle Eastern and African origin. However, the gender difference may be attributed to most patients undergoing kidney transplants being male. Therefore, if gender balance is considered in future studies, then the difference might be insignificant. Based on our results, we can concur that the mainstay treatment for post-transplant KS is reduction or withdrawal of immunosuppression. However, the patients should be closely monitored to avoid KS recurrence and kidney rejection. Furthermore, there is an increased risk for KS with the use of cyclosporine-based immunosuppression. However, this does not mean that the withdrawal of this immunosuppression agent might result in improved KS outcomes because the withdrawal of azathioprine with or without cyclosporine reduction has also led to improved outcomes.

P368 Safety issues of azathioprine in patients with inflammatory bowel disease: clinical experience from a referral center

Abstract Background Despite the development new agents for inflammatory bowel disease (IBD) therapy, azathioprine (AZA) is widely used as both as monotherapy and as combination therapy for induction and maintenance of remission both Crohn’s disease (CD) and ulcerative colitis (UC). Aim of this study is to investigate the long-term safety of AZA, to document the prevalence of adverse events of AZA in patients with IBD. Methods In this retrospective study, we included, 222 patients with IBD, who were monitored at University hospital of Ioannina from, 2003 to, 2019. The diagnosis of IBD was made based on endoscopic and histologic findings after ileocolonoscopy with biopsies. Inclusion criteria of study were diagnosis of IBD and regular follow-up intervals at least every six month after start of AZA administration. Results The average age of patients was, 46.9 years (Std. Dev., 17,9) at start of AZA administration., 65.6% of IBD patients (146/222) had CD and, 34.4% had UC (76/222). The mean duration of AZA administration was, 51 months (range:, 0–135 months). The most frequent location of CD was ileocolonic (38.4%, 56/146), while the most patients with UC had left sided colitis (54%, 41/76). Furthermore, the main indication for AZA treatment was the maintenance of remission both in UC and CD. The most common dose of AZA was, 100mg/day (range:, 50-200mg). The most common adverse events were gastrointestinal symptoms (8.6%, 18/222), leucopenia (2.7%, 6/222), hepatotoxicity (5.4%, 12/222) and pancreatitis (1.8%, 4/222). Two patients were diagnosed with basal cell cancer. Infections were recorded in, 19 patients (8.6%) of whom, 6 needed hospitalization. Conclusion According to this retrospective observational study, approximately one-third of IBD patients receiving AZA presented clinical significant adverse event during follow-up. Azathioprine withdrawal or dose reduction was needed in, 47 (21%) patients.

P289 Evaluation of the safety and effectiveness of direct-acting antiviral drugs in the treatment of hepatitis C in patients with inflammatory bowel disease: National multicenter study (ENEIDA registry). MIC project

Abstract Background The prevalence of hepatitis C virus infection (HCV) in patients with inflammatory bowel disease (IBD) ranges from 1–6%. Direct-acting antivirals (DAAs), with cure rates &amp;gt;90%, represent a radical change from interferon-based therapies. The ECCO guidelines (Kucharzik JCC 2021) warns about the risk of IBD reactivation due to the effect of DAAs, but HCV management in this situation is uncertain given the lack of evidence. AIMS: To evaluate: 1) Effectiveness and safety of DAAs in IBD; 2) Interaction of DAAs with IBD drugs, particularly immunosuppressants and/or biologics. Methods Multicenter retrospective study of patients with IBD and HCV treated with DAAs identified on the ENEIDA registry (January 2011-February 2021). Variables evaluated: age, gender, location, extent, phenotype and activity of IBD, treatments, anti-HCV and viral load, DAA treatment and duration, fibrosis and hepatic decompensations, adverse effects (AE) and interactions. Results We included 79 patients with IBD and HCV treated with DAAs (47 sofosbuvir, 28 ledipasvir, 7 daclatasvir, 8 velpatasvir, 1 simeprevir, 16 paritaprevir+ritonavir+ombitasvir, 14 dasabuvir, 3 grazoprevir+elbasvir, 13 glecaprevir+pibrentasvir). Clinical and demographic characteristics: mean age (years) 54+/-12.66SD; 62% male, 77.2% genotype 1, 32.6% advanced fibrosis (none Child B-C). A 78.5% (n=62) received IBD treatment (39 salicylates, 20 azathioprine, 1 methotrexate, 4 corticosteroids, 10 antiTNF, 2 vedolizumab, 2 ustekinumab, 1 apheresis). A 17.7% (n=14) had active IBD (64.3% remained unchanged, 21.4% improved and 14.3% worsened) and 82.3% (n=65) were inactive at the onset of ADD. Of these, 9.2% (n=6) developed mild-moderate activity (4 mild and 2 moderate). In 85% (n=67) no treatment changes were made, in 9% (n=7) it was intensified and in 6% (n=5) it was de-intensified. Adherence to DAAs and sustained virologic response was obtained in 96.2% (n=76). A total of 7 (8.9%) AE were notified, of which 5 were possibly/probably related to DAAs (100% mild) and 2 were unrelated (1 azathioprine withdrawal due to pancytopenia). The AE were unrelated with the presence of inflammatory activity, type of IBD, liver fibrosis, use of immunosuppressants, biologics, or with any DAA regimen. Conclusion This is the first reported series of IBD patients infected with HCV and treated with DAAs, we showed that DAA are effective and safe. They do not trigger IBD flare-ups, nor have more AE than in patients without IBD. Moreover, they do not have clinically significant pharmacological interactions with immunosuppressants and/or biologics. Thus, the eradication of HCV with DAA in IBD patients must be the same of the HCV infected patients without IBD, based on EASL recommendations.

Discontinuation of Azathioprine could be considered in pediatric patients with Crohn\u2019s disease who have sustained clinical and deep remission

Few studies have demonstrated treatment strategies about the duration and cessation of medications in patients with Crohn’s disease (CD). We investigated factors affecting clinical relapse after infliximab (IFX) or azathioprine (AZA) withdrawal in pediatric patients with CD on combination therapy. Pediatric patients with moderate-to-severe CD receiving combination therapy were analyzed retrospectively and factors associated with clinical relapse were investigated. Discontinuation of IFX or AZA was performed in patients who sustained clinical remission (CR) for at least two years and achieved deep remission. A total of 75 patients were included. Forty-four patients (58.7%) continued with combination therapy and 31 patients (41.3%) discontinued AZA or IFX (AZA withdrawal 10, IFX withdrawal 15, both withdrawal 6). Cox proportional-hazards regression and statistical internal validation identified three factors associated with clinical relapse: IFX cessation (hazard ratio; HR 2.982, P = 0.0081), IFX TLs during maintenance therapy (HR 0.581, P = 0.003), 6-thioguanine nucleotide (6-TGN) level (HR 0.978, P < 0.001). However, AZA cessation was not associated with clinical relapse (P = 0.9021). Even when applied in pediatric patients who met stringent criteria, IFX cessation increased the relapse risk. However, withdrawal of AZA could be contemplated in pediatric patients with CD who have sustained CR for at least 2 years and achieved deep remission.

P-106 COVID-19 PRESENTATION AND OUTCOMES IN 33 PATIENTS WITH AUTOIMMUNE HEPATITIS

Background and AimsClinical course of Covid-19 is not yet established in autoimmune hepatitis (AIH). About 25% of our 400 AIH-outpatients from various states in Brazil are using hydrochloroquine (HCQ) for maintenance or treatment with corticosteroids and immunosuppressants (IS). The aim is to describe the clinical features and outcomes of COVID-19 in patients with AIH.MethodsThe diagnosis of COVID was confirmed by positive PCR of nasal swab and/or by serological tests. The diagnosis and treatment of COVID was not always made in our service.Results33 patients, 85% female, 41±13yr; 88% AIH-1; 54.6% with advanced fibrosis (F3/F4); 81.8% with comorbidities (17 overweight/obesity [BMI 31.8±5.4], 10 arterial hypertension, 8 diabetes, 2 systemic lupus erythematosus [SLE, with renal failure], 1 celiac disease and malnutrition). The most frequent symptoms were cough (20), headache (19), anosmia and myalgia (18), diarrhea (17) and dyspnea (11). IS at infection was 14 azathioprine(AZA)+prednisone(PD), 2 AZA+PD+cyclosporine, 3 Mycophenolate+PD. HCQ was used for maintenance (6) or as a complement of IS (5). Five hospitalized patients received oxygen supplementation (1 endotracheal intubation); 1 was pregnant and 1 received methylprednisolone pulse+immunoglobulin to treat SLE immediately before COVID; 3 were under double IS and 2 HCQ. 23 received antibiotics (19 azithromycin). In 10 patients (9 with normal liver enzymes before COVID) there were IS adjustments: IS withdrawal and increase of PD dosage (6), increase PD dosage (2), IS withdrawal and HCQ prescription (1), AZA withdrawal+decrease PD dose (1). Six of the 10 patients had slight increase of liver enzymes, none liver decompensation. One patient died, with celiac disease who acquired COVID during hospitalization for lymphoma investigation.ConclusionsIt appears that patients under IS for AIH and COVID-19 show outcomes similar to that of non-immunosuppressed population. HCQ does not appear to have a positive impact on preventing or progressing the disease.

Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission

There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn's disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission. A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated. Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5-19) and were followed up for median 50 months (range, 25-85). Twenty-six patients (18/31 UC, 8/26 CD; P= .003) relapsed, within a median 15 months (range, 2-37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2-10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4-12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD. More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.

P709 Is azathioprine safe as long-term treatment in paediatric patients with inflammatory bowel disease?

Abstract Background The toxicity of azathioprine (AZA) includes myelosuppression, infections, pancreatitis, photosensitivity, and hepatotoxicity. The aim of this study was to describe the adverse effects profile of azathioprine as long-term treatment in paediatric inflammatory bowel disease (IBD). Methods An observational, descriptive and retrospective study was performed in the paediatric IBD Unit of a tertiary care hospital from September 2008 to December 2018. It was included patients under 18 diagnosed with IBD who were treated with AZA during their follow-up. We recorded epidemiological data, thiopurine methyltransferase (TPMT) enzyme activity, AZA side effects, and the dosage the patients were receiving when these effects took place. Bone marrow suppression (BMS) was defined as leukopenia, thrombocytopenia and/or anaemia. Acute pancreatitis (AP) induced by azathioprine was considered when two of these criteria (Atlanta 2012) were met: lipase increase (&amp;gt; 3 times normal value), congruent signs and symptoms and/or echographic findings, without other possible aetiology and with complete recovery after AZA withdrawal. Results We included 52 patients, being 31 men (59.6%). They were diagnosed with Crohn′s disease (CD) (73%), ulcerative colitis (UC) (21%) and IBD-unclassified (6%). The median TPMT activity was 17 U/ml (14.2–19.2). Up to 63.5% developed adverse effects by AZA with a median time from the beginning of treatment of 11.4 months (2.6–26.4) and a median dosage of 2 mg/kg/day (1.7–2.3). The most frequent side effect was BMS (52%). These patients had a median TPMT activity of 16.9 U/ml (14.2–18.9), the median duration of treatment was 14 months (3.9–27.7), and the median dosage was 2 mg/kg/d (1.8–2.5). BMS was more frequent in patients with UC (p 0.04) and longer treatment (p 0.08). No differences were found according to age, sex or TPMT activity. Up to 11.5% developed AP, the median duration of treatment until its appearance was 1.5 months (0.7–43.3) and the median dosage was 2 mg/kg/d (1.5–2.5). No differences were found related to age, sex, diagnosis or dosage. Other side effects were: 3 flu-like symptoms, 3 opportunistic infections, 2 hypertransaminasemia, and 1 patient with elevated pancreatic enzymes and hyperbilirubinemia. AZA was discontinued in 14 patients (43.8%): in 6 due to AP, in 4 due to severe lymphopenia, in 2 because of Epstein-Barr virus infection, in 1 due to flu-like symptoms and in 1 with several adverse effects. Conclusion More than half of the patients treated with AZA presented side effects, mainly BMS, although most of them were mild and temporary, and the withdrawal of the drug was not necessary. It seems that TPMT activity is not useful to predict BMS, but this adverse effect could be related to a longer treatment.

Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in inflammatory bowel disease.

Combination treatment with azathioprine for 6-12months is the preferred strategy for starting infliximab due to improved pharmacokinetics. However, optimised infliximab monotherapy with proactive dose escalations in case of low trough levels is a safer but under-studied alternative. To compare the clinical success and infliximab consumption of combination vs optimised monotherapy strategies. We studied the clinical success and infliximab consumption of both strategies in 149 patients (94 Crohn's disease; 55 ulcerative colitis) starting infliximab and undergoing intensive drug monitoring assisted treatment optimisation. The drug retention rates were similar for optimised monotherapy and combination treatment after induction (96% vs 97%, P=0.73), after the first year (90% vs 83%, P=0.23) and at the end of follow-up (74% vs 75%, P=0.968). Similarly, no differences were observed for steroid use at year 1 (5% vs 14%, P=0.08) or mucosal healing at the end of follow-up (64% vs 67%, P=0.8). Higher infliximab consumption (7.6mg/kg q8 weeks [interquartile range (IQR): 5.9-10.3] vs 6.4mg/kg q8 weeks [IQR: 5.2-8.0], P=0.019) combined with lower trough levels (1.7µg/mL [IQR: 0.3-6.6] vs 5.0µg/mL [2.5-8.7], P=0.012) resulted in almost 3-fold higher drug-to-trough ratio (3.9 vs 1.5) in monotherapy compared to combination strategy at year 1. At the end of follow-up, when azathioprine had been discontinued for a median of 14 [IQR: 3-33] months, these differences disappeared. In this study, optimised infliximab monotherapy was as clinically effective as combination therapy but was associated with significantly higher infliximab consumption. The infliximab-sparing effect disappeared after azathioprine withdrawal.

Withdrawal of Azathioprine in Inflammatory Bowel Disease Patients Who Sustain Remission: New Risk Factors for Relapse.

The benefits of immunosuppressants for sustaining remission and preventing flares of IBD are well known. However, optimal timing for withdrawal has not been determined. The objective of this study was to calculate the risk of relapse and predictors after withdrawal of azathioprine (AZA) monotherapy in patients who sustain deep remission. This was a multicenter observational study of patients with IBD in remission whose immunosuppressant had been withdrawn. We recorded demographic variables, disease data, laboratory values, and the results of imaging tests performed at withdrawal and, in patients who relapsed, time to relapse and the efficacy of reintroducing the drug. Ninety-five patients were included (35 UC and 60 CD). The mean duration of AZA treatment was 87 and 77months for UC and CD, respectively. Endoscopic remission was evaluated in 23 patients with UC and 35 with CD. After AZA withdrawal, 91% patients with UC and 67% with CD received high doses of salicylates. A total of 26 patients relapsed. The cumulative relapse rate at 5years was 46% for CD and UC. AZA was reintroduced in 19 patients, of whom 14 responded. Predictors of relapse were corticosteroid dependence, early introduction of AZA (CD), and late introduction of AZA (UC). Almost half of the patients in whom AZA was withdrawn were in remission at 5years. The candidates for withdrawal could be better identified based on corticosteroid dependence, previous surgery, timing of initiation, and indication for AZA.

Sweet syndrome: a rare feature of ANCA-associated vasculitis or unusual consequence of azathioprine-induced treatment

BackgroundSweet syndrome is a rare skin condition characterised by fever, neutrophilia, and tender erythematous skin lesions and has been reported to occur in association with anti-neutrophil cytoplasmic antibodies (ANCA) as well as complicate treatment with azathioprine therapy. Azathioprine, a relatively safe immunosuppressive, is frequently used to maintain disease remission in the treatment of ANCA-associated vasculitis. The occurrence of Sweet syndrome in a patient with ANCA-positive vasculitis and following treatment with azathioprine prompted us to present this clinical case and share this unusually rare occurrence. In doing so, we also wish to discuss current understanding of the disease and plausible associations.Case presentationHerein, we discuss the case of a 54-year old white male, who presented with features of ANCA vasculitis with haemoptysis, arthralgia, abnormal kidney function with active urine sediment and a positive p-ANCA titre. Standard immunosuppressive treatment with corticosteroids and intravenous rituximab resulted in disease remission. Due to significant steroid side effects, his steroid treatment was gradually tapered and switched to azathioprine over a 6-month period. Two weeks following initiation of azathioprine, he developed a painful maculo-papular erythematous skin rash and fever. A skin biopsy confirmed classical features consistent with Sweet syndrome. Withdrawal of azathioprine and treatment with oral corticosteroids and colchicine therapy resulted in complete resolution of the rash, although he continued to have high titres of MPO positive ANCA.ConclusionSweet syndrome is a rare adverse reaction to azathioprine but has also been reported to occur in association with ANCA vasculitis. The temporal association with azathioprine in our case and the relatively rapid resolution of the skin vasculitis upon its withdrawal suggested a primarily drug-induced reaction rather than an associated feature of ANCA vasculitis.

Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease.

Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease.

Azathioprine-induced myelosuppression in a pemphigus patient with a heterozygous mutation in the NUDT15 gene

A 49-year-old male patient presented with repeated oral erosions for 1 year, as well as cutaneous erythema and blisters for 1 month. According to histopathological examination and detection of specific antibodies of pemphigus, the patient was diagnosed with pemphigus vulgaris. After the treatment with oral prednisone and azathioprine for 1 month, the white blood cell count and segmented neutrophilic granulocyte count both decreased. After withdrawal of azathioprine, the patient was subcutaneously injected with 150 μg recombinant human granulocyte colony-stimulating factor for 1 session. Then, the white blood cell count became normal. Genotyping test revealed that the patient carried a heterozygous mutation in the NUDT15 gene (JZ274) , and was homozygous for wild-type TPMT*2, TPMT*3C and ITPA genes. The patient was diagnosed with azathioprine-induced myelosuppression. Key words: Azathioprine; Pemphigus; Heterozygote; Bone marrow; NUDT15

P473 How to monitor the withdrawal of maintenance treatment with azathioprine in IBD patients with deep remission: results from a prospective study on multiple non invasive tests

Background: There is uncertainty regarding the optimal duration of maintenance treatment with azathioprine (AZA) in Crohn's disease (CD) and ulcerative colitis (UC), with some studies suggesting durations up to 4–5 years and others supporting long-term indefinite use. More recent guidelines state that for patients in long term remission, cessation of treatment may be considered in the absence of objective signs of inflammation, but no data are available on how to monitor these patients after AZA withdrawal. Methods: A prospective observational study was performed on consecutive patients with CD or UC who stopped their maintenance treatment with AZA while being in steroid-free, deep remission, defined as normal clinical and endoscopic indexes, normal C-reactive protein (CRP) and normal fecal calprotectin. After AZA withdrawal, all patients received maintenance treatment with salicylates. Every 3 months, blood samples were collected for standard biochemical tests (including CRP, full blood count and protein electrophoresis), as well as stool samples for fecal calprotectin dosage. Bowel ultrasonography and ileocolonoscopy were performed every 6 and 12 months, respectively, as well as in case of clinical relapse. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. Results: 41 patients (23 males, median age 45 years) who stopped AZA after median 7 years (range 5–14) were enrolled. After a mean follow-up of 24 months (range 5–48), 19 patients (46%; 7/19 CD, 12/22 UC) relapsed, within median 13 months (range 2–35). Predictors of clinical relapse at the time of AZA withdrawal were female gender (p=0.045) and age ≤45 years (p=0.035) only for UC. Fecal calprotectin was the only predictor of clinical relapse during the non invasive monitoring performed after AZA withdrawal, both in UC (p=0.019) and in CD (p=0.017). Moreover, fecal calprotectin was positive in all patients with UC and in 57% of CD patients at the time of relapse. Conclusions: Up to half of patients with IBD relapses after AZA withdrawal at different times. Fecal calprotectin can predict subsequent clinical relapse after AZA withdrawal. This can be useful in the non invasive monitoring of patients to detect preclinical relapse and to early correct our therapeutic strategy after AZA withdrawal. Prospective randomized studies are needed to validate such strategy.

Azathioprine for refractory ulcerative proctitis: A retrospective multicenter study

BackgroundEfficacy of azathioprine (AZA) in refractory ulcerative proctitis (UP) is unknown. MethodsAll patients treated with AZA for refractory UP in three referral centers between 2002 and 2012 were included. “Treatment success” in the long-term was defined as the absence of colectomy during follow-up, no need for anti-TNF during follow-up, no ongoing systemic steroids use, no adverse event leading to AZA withdrawal, and clinically quiescent disease at last follow-up. ResultsOf the 1279 adult patients with ulcerative colitis, 25 patients were treated with AZA for refractory UP (median disease duration 4.9 years). Of these, 4 had no short-term clinical assessment. Of the remaining 21, 4 were primary non responders to AZA, 7 discontinued AZA for adverse events and 10 showed clinical improvement. At the long-term assessment at last follow up after a median of 46 months, 5 patients had treatment success and were still on AZA treatment, the remaining 20 were treatment failures. Of these, 5 discontinued AZA for adverse events and 15 were treated with infliximab (clinical response in 11 patients, primary non-response in one patient, and 3 underwent colectomy). ConclusionAZA may be efficacious in maintaining clinical response in one-fifth of patients with refractory UP in a real-life setting.

Azathioprine Induced Sweetʼs Syndrome in Crohnʼs Disease: An Important Distinction: 2016 ACG Presidential Poster Award

Sweet's syndrome (SS), or acute febrile neutrophilic dermatosis, is an inflammatory skin disease that has been described in three distinct clinical scenarios. Classical SS either follows infection or occurs during pregnancy. SS also occurs with inflammatory bowel disease (IBD). Lastly, SS can be an atypical drug reaction. We describe a case of Azathioprine induced Sweet's Syndrome (AISS) in a young male with Crohn's disease. A 35-year-old man with ileo-colonic Crohn's disease presented to the emergency department with rash and fever two weeks after starting azathioprine. Within 48 hours of starting this medication the patient noted a left hand purulent lesion that was drained and treated with cephalexin, without resolution. On admission, physical examination revealed multiple papules and nodules that were not painful. The differential diagnosis included pyoderma gangrenosum, drug reaction, and Crohn's related SS. Skin biopsy revealed a predominantly neutrophilic septal and lobular panniculitis. One week after withdrawal of the medication, the patient defervesced and the skin lesions healed without additional treatment. The non-tender character of the lesions, the onset following introduction of azathioprine, and the rapid resolution with azathioprine withdrawal made AISS the most likely etiology. SS is a neutrophilic dermatosis characterized by the acute eruption of erythematous papules, nodules or plaques which may progress to pustules, bullae or ulcers, with systemic symptoms including fever and leukocytosis. The pathogenesis of the condition is unknown, but thought to involve a local or systemic dysregulation of cytokine secretion. SS can be associated with infection, IBD, pregnancy, malignancy, or certain medications and may necessitate treatment with systemic corticosteroid therapy. The treatment of AISS is unique in that withdrawal of the medication alone leads to resolution of symptoms. Clinicians treating patients with IBD should look for signs of AISS in patients who have recently started azathioprine or 6MP. The syndrome can be misinterpreted as an IBD-associated skin eruption or as infection. It is important to make the diagnosis early, as discontinuation of the drug is the necessary treatment. Re-challenge with azathioprine is not recommended. TPMT status is not thought to be related to the incidence of AISS. Therefore, testing for the genetic polymorphism will not help predict likelihood of this atypical reaction.Figure 1Figure 2

Efficacy and tolerance of methotrexate in maintenance of remission in 49 patients with Crohn′s disease

Objective To analyze the efficacy and tolerance of methotrexate(MTX) in remission maintenance of Crohn′s disease (CD). Methods From June 2012 to August 2015, 49 CD patients who received MTX as mainly treatment medication to maintain remission were enrolled. The pre-medication history, efficacy, dosage and side effects of MTX were analyzed. The effects of inducing strategy on disease recurrence were analyzed. Chi-square test and t test were used for statistical analysis. Results Among the 49 patients, 34 (69.4%) received steroids for remission inducing, nine (18.4%) received infliximab for remission inducing and six (12.2%) achieved remission after operation. In the 44 patients treated with azathioprine (AZA) before, the median treatment time was one month and the dosage for withdrawal of AZA was (42.0±14.8) mg/d. The most common reason was leucopenia (81.8%, 36/44). Till the time point of follow-up, 46 of the 49 CD patients still took MTX orally with a median treatment time of 16 months, and the weekly dosage was (12.7±2.0) mg. Thirty-one cases (67.4%) achieved clinical stability, while 15 cases (32.6%) underwent clinical recurrence. The median Crohn′s disease activity index (CDAI) was 123.5±66.6. The weekly dosage of clinical stability group was (12.5±2.1) mg, and that of clinical recurrence group was (13.0±1.7) mg, there was no statistically significant difference between the two groups (t=0.802, P=0.426). The recurrence rate of steroids-induced remission group was 41.2% (14/34), which was higher than that of infliximab and surgery-induced remission group (1/15), and the differnce was statistically significant (χ2 =5.177, P=0.023). The common side effects were gastrointestinal reaction (26.5%, 13/49), impaired liver function (20.4%, 10/49) and leukopenia (12.2%, 6/49). Only three cases could not tolerate the side effects and underwent medication withdrawal. Conclusions As a second-line immunosuppressant for maintanence remission in CD, MTX is effective and well-tolerated in patients. So it can be an important option during the long course of CD. Key words: Methotrexate; Crohn disease; Maintenance of remission; Efficacy; Tolerability

Treatment of recalcitrant adult alopecia areata universalis with oral azathioprine

To the Editor: Treatment of alopecia areata universalis (AAU) is challenging, and systemic and even immunosuppressive drugs are often required. Therapy with topical immunotherapy with diphencyprone (DFCP) and oral corticosteroids are the most used treatments in adult patients with AAU. Some patients are resistant to multiple therapies.1Alkhalifah A. Alsantali A. Wang E. McElwee K.J. Shapiro J. Alopecia areata update: part II. Treatment.J Am Acad Dermatol. 2010; 62 (quiz 203-204): 191-202Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 2Spano F. Donovan J.C. Alopecia areata: Part 2: treatment.Can Fam physician Médecin Fam Can. 2015; 61: 757-761Google Scholar The objective of this study was to evaluate the efficacy and safety of oral azathioprine for adult patients with recalcitrant AAU. A prospective study including adult patients with recalcitrant AAU (non-responders to oral corticosteroids and DFCP) between 2010 and 2015 was designed. Treatment with azathioprine at a dosage of 2.5 mg/kg/day (adjusted based thiopurine methyltransferase [TPMT] level) was administered. Therapeutic response was assessed as no response (no regrowth), partial response (regrowth of <75% of scalp), and complete response (regrowth of 75% or more of scalp). Persistent response was defined as the maintenance of >75% of regrowth after 6 months of the withdrawal of therapy. Overall, 14 patients (8 females [57%] and 6 males [43%]) with a mean age of 37.7 years (range, 23-59 years) were included. The mean time since onset of AAU was 24.5 months (range, 8-72 months). The mean dosage of azathioprine used was 142 mg daily. Therapeutic response was observed in 6 of 14 patients (43%), all of them achieving complete response, also including regrowth of body hair (Fig 1). There were no identifiable prognostic factors statistically associated with better response. The mean time until response was 4.7 months (range, 4-6 months), while the mean duration of therapy was 9.8 months (range, 1-36 months). Two patients (14.3%) presented with relapses after a mean time of 2.5 months after the withdrawal of azathioprine. On the other hand, persistent response was observed in 4 patients (29%), with a mean follow-up time of 18 months (range, 6-30 months). Adverse effects were detected in 5 patients (35%): diarrhea (2 patients) and elevation of liver enzymes, pancreatitis, and bone marrow suppression (1 patient each). In 4 cases (28%), treatment had to be discontinued. Azathioprine is a purine antimetabolite drug widely used in dermatologic conditions.3Wise M. Callen J.P. Azathioprine: a guide for the management of dermatology patients.Dermatol Ther. 2007; 20: 206-215Crossref Scopus (40) Google Scholar, 4Sidbury R. Davis D.M. Cohen D.E. et al.Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.J Am Acad Dermatol. 2014; 71: 327-349Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar However, the reports of the usefulness of this drug in AA are anecdotal. Farshi et al5Farshi S. Mansouri P. Safar F. Khiabanloo S.R. Could azathioprine be considered as a therapeutic alternative in the treatment of alopecia areata? A pilot study.Int J Dermatol. 2010; 49: 1188-1193Crossref PubMed Scopus (50) Google Scholar reported a series of 20 AA patients (5 with AAU) treated with oral azathioprine. The mean global regrowth percentage was 52.3%, although response to azathioprine was assessed based on the change in the percentage of hair regrowth, so a direct comparison with our study cannot be performed. Adverse effects appeared in 4 patients (20%), which is inferior to our study. The effectiveness of azathioprine in our study was acceptable (43% of patients), taking into account that patients presented recalcitrant AAU. In addition, 2 out of 3 responders presented a persistent response. Nevertheless, the rate of adverse effects was higher than previous reports,5Farshi S. Mansouri P. Safar F. Khiabanloo S.R. Could azathioprine be considered as a therapeutic alternative in the treatment of alopecia areata? A pilot study.Int J Dermatol. 2010; 49: 1188-1193Crossref PubMed Scopus (50) Google Scholar including 2 patients with serious adverse effects: pancreatitis and bone marrow suppression, both in patients with normal TPMT. In conclusion, oral azathioprine may be an interesting therapeutic option for adult patients with recalcitrant AAU. However, adverse effects may appear, so a strict follow-up with frequent blood tests is encouraged.

Azathioprine withdrawal

Azathioprine withdrawal

Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn's disease.

Many patients with quiescent Crohn's disease are maintained on long-term treatment with azathioprine (AZA), but controlled data are limited. We aimed to evaluate the efficacy of AZA therapy for more than 4 years to maintain clinical remission. We performed a randomized double-blind placebo-controlled AZA withdrawal trial with a follow-up period of 24 months. Patients had to have continuous AZA therapy ≥ 4 years without exacerbation of disease during the 12 months before enrollment, and a Crohn's disease activity index < 150 at baseline. Patients were randomized to continue on AZA or switch to placebo. The primary endpoint was time to clinical relapse during follow-up. After inclusion of 52 patients, the trial was stopped prematurely due to slow recruitment. During the 2-year follow-up, clinical relapse occurred in 4 of 26 (15 %) patients on continued AZA and in 8 of 26 (31 %) patients on placebo. Time to clinical relapse averaged 22.3 months (95 % CI 20.6-24.0) on AZA and 19.2 months (95 % CI 16.4-22.1) on placebo (p = 0.20). According to life-table analysis, the proportion of patients in remission after 12 and 24 months was 96 ± 4 and 86 ± 7 % in patients receiving AZA versus 76 ± 8 and 68 ± 9 % in patients receiving placebo (month 12, p = 0.035; month 24, p = 0.30). A higher AZA dose at enrollment was an independent predictor for relapse (p < 0.05). AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.