Mycophenolate and azathioprine efficacy in interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVES: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD. DESIGN: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded. DATA SYNTHESIS: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design. RESULTS: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I2=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence. CONCLUSIONS: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD. PROSPERO REGISTRATION NUMBER: CRD42023423223.

Evaluation of the mTORC activity in the presence of Toxoplasma gondii and azathioprine in human monocyte cell line.

BACKGROUND: Autophagy is an important part of pathogenesis of IBD. Thiopurines such as azathioprine (AZA) are approved drugs for clinical practices in IBD patients. Besides, as an escape strategy, Toxoplasma gondii can use the mTORC1 complex to inactivate autophagy. METHODS: In this study, we investigated whether T. gondii tachyzoites may modulate autophagy and interfere the effects of azathioprine in IBD treatment. PMA-activated human monocyte cell line (THP-1) was infected with fresh T. gondii RH tachyzoites. After 5 h of infection, the cells were treated with AZA for 6 h. The expression of atg5, atg7, atg12, lc3b, and ß-actin (BACT) genes was evaluated using quantitative real-time PCR. To analyze the phosphorylation of ribosomal protein S6 (rpS6), western blot using specific primary antibodies was performed. RESULTS: The results of real-time PCR revealed that AZA, T. gondii tachyzoites, and a combination of AZA and T. gondii tachyzoites upregulated atg5 gene for 4.297-fold (P-value = 0.014), 2.49-fold (P-value = 0.006), and 4.76-fold (P-value = 0.001), respectively. The atg7 gene showed significant upregulation (2.272-fold; P-value = 0.014) and (1.51-fold; P-value = 0.020) in AZA and AZA / T. gondii, respectively. The expression of atg12 gene was significantly downregulated in AZA and T. gondii tachyzoites for (8.85-fold; P-value = 0.004) and (2.005-fold; P-value = 0.038), respectively, but upregulated in T. gondii/AZA (1.52-fold; P-value = 0.037). In addition, the lc3b gene was only significantly changed in AZA / T. gondii (3.028-fold; P-value = 0.001). Western blot analysis showed that T. gondii tachyzoites significantly phosphorylated rpS6, and tachyzoites did not interfere the effects of AZA to phosphorylate the rpS6. CONCLUSION: Taken together, although AZA and T. gondii similarly affects the expression levels of atg5, atg7, and atg12, but T. gondii does not seem to modulate the effects of AZA via mTORC functions.

Complete Structure Assignment of Azathioprine as a Proton-Deficient Nucleic Acid Analogue Using 1H-13C Long-Range Heteronuclear Single Quantum Multiple Bond Correlation.

In this Note, the successful structural assignment of a proton-deficient nucleic acid analogue using the 1H-13C long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) technique is described. LR-HSQMBC is a 2D NMR technique for the sensitive detection of weak C-H spin couplings. The immunosuppressant drug, azathioprine, served as the target compound. The LR-HSQMBC measurements revealed the existence of covalent bonds between the purine and imidazole rings based on observations of 5JCH and 6JCH with good sensitivity.

Impact of gervital against histopathological, ultrastructural, and biochemical alterations caused by methotrexate or azathioprine in albino rat testis.

Methotrexate (MTX) and azathioprine (AZA) are chemotherapeutic, immunosuppressive, cytotoxic drugs with reported adverse effects, including oxidative damage to testis. This study aims to evaluate the potential effect of grape seed extract (GSE; gervital) to prevent testicular damage caused by MTX and AZA. Male albino rats were separated into six groups: group I, normal control group; group II, GSE (150 mg/kg/day); group III, MTX (8 mg/kg/week); group IV, AZA (15 mg/kg/day); group V, GSE (150 mg/kg/day) + MTX (8 mg/kg/week); group VI, GSE (150 mg/kg/day) + AZA (15 mg/kg/day). All rats were sacrificed, blood samples were obtained for testosterone analysis, and testis was removed for histological and ultrastructural studies and oxidation measurements. A reduction in relative body and testis weight, along with a significant decrease in testosterone levels, was observed. Histopathological and ultrastructural alterations induced by MTX or AZA included reduced spermatozoa, sloughing, marked reduction of spermatogenic cells, and pyknosis of some nuclei. Significant oxidative stress manifested as reduced glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities, as well as increased malondialdehyde (MDA) levels. GSE administration showed an ameliorative effect on testosterone levels and histopathological and ultrastructural changes. GSE treatment also suppressed the increases in MDA levels and the decreases in GSH levels and CAT and SOD activities. In conclusion, these findings confirm that GSE is an effective antioxidant that protects testis from histopathological and ultrastructural damage induced by MTX and AZA. Therefore, GSE is a promising candidate for future use to minimize and alleviate MTX and AZA risks.

Influence of the Photodegradation of Azathioprine on DNA and Cells.

Azathioprine (AZA) is a pharmacologic immunosuppressive agent administrated in various conditions such as autoimmune disease or to prevent the rejection of organ transplantation. The mechanism of action is based on its biologically active metabolite 6-mercaptopurine (6-MP), which is converted, among others, into thioguanine nucleotides capable of incorporating into replicating DNA, which may act as a strong UV chromophore and trigger DNA oxidation. The interaction between azathioprine and DNA, before and after exposure to solar simulator radiation, was investigated using UV-vis spectrometry and differential pulse voltammetry at a glassy carbon electrode. The results indicated that the interaction of AZA with UV radiation was pH-dependent and occurred with the formation of several metabolites, which induced oxidative damage in DNA, and the formation of DNA-metabolite adducts. Moreover, the viability assays obtained for the L929 cell culture showed that both azathioprine and degraded azathioprine induced a decrease in cell proliferation.

Complex assessment of immunosuppression effects in prevention and treatment of adhesive disease, an experiment.

The cause of all small bowel obstruction in 60-75% of cases is adhesive development. The first and main method for adhesion prevention is undoubtedly the surgical technique, but the prevention of adhesive development is still actual. We aimed to study macroscopic and microscopic peculiarities of the intestine, peritoneum, and scars of the anterolateral abdominal wall. Also, immunological blood changes were observed in rats with the experimental created adhesive disease on the background of azathioprine introduction. The experiment was conducted on 40 rats divided into 2 subgroups: 20 animals as an experimental group (EG1) and 20 as a control group (CG1). Animals from EG received azathioprine (Moshimerampreparaty named by N.A. Semashko, Russia) in a dosage of 1 mg/100g of weight once a day for the first 3 days (starting from the day of surgery). The control group did not receive any drugs. All 40 rats survived the postoperative period. Rats were removed from the experiment on the 7th day after the operation. There were significant statistical differences in most indicators between the experimental and control groups. Phagocytic index (PI) was reduced by 4.55 due to the natural reaction of the rat organism to the surgery. Indicators of EG were a slight decrease in leukocytes and lymphocytes by 0.3 and 0.9, respectively, a moderate decrease in T-lymphocytes by no more than 2.0, and a decrease in phagocytic activity by 5.8. Immunosuppression with azathioprine significantly reduced the frequency and severity of the adhesive process of the abdominal cavity. Used in the recommended dose does not significantly inhibit important indicators of immunity and does not affect wound healing processes.

The Thiopurine Tale: An Unexpected Journey.

Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

Rac1/pSTAT3 expression: A pharmacodynamic marker panel as a first step toward optimization of thiopurine therapy in inflammatory bowel disease patients.

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.

Comparative study between the efficacies of azathioprine and mesalazine in the treatment of severe alopecia areata.

BACKGROUND: Various systemic agents have been assessed for treatment of alopecia areata; however, there is a paucity of comparative studies. AIM: To compare the efficacy of azathioprine versus mesalazine in the treatment of severe alopecia areata. METHODS: Our study was carried out in 30 patients with severe alopecia areata divided into two groups, group A: fifteen patients were treated by azathioprine in an oral dose of 1-2 mg/kg/day and group B: fifteen patients were treated by mesalazine in an oral dose of 15-30 mg/kg/day in two divided doses. The treatment was considered effective if percentage regrowth of hair was determined by change in SALT score >50 from base line after 6 months of treatment. The treatment was continued for 3-6 months after complete remission to minimize the risk of relapse. The dose was gradually tapered during this time. RESULTS: The study found that there is statistically significant difference between mean SALT scores before treatment and after 6 months of treatment in both groups. In group A, SALT score at base line was 84.42 ± 17.41, after 6 months it was 35.95 ± 35.79 (p value 0.04). In group B, SALT score at base line was 73.06 ± 22.10, after 6 months it was 23.04± 12.27 (p value 0.037). Changes in SALT score after 6 months were -27.74 ± 20.66 in group A and -60.42±38.41 in group B (p value 0.055). CONCLUSION: Mesalazine may be considered as effective as azathioprine with lesser side effects. Azathioprine is also considered safe. However, a large group study should be performed to confirm these findings.

Anti-angiogenic activity of azathioprine.

Azathioprine (AZA) is the main drug used in immunomodulatory therapy in post-transplant patients or with autoimmune diseases. However, no study has evaluated the AZA angiogenic response. Therefore, this study investigated the effects of AZA on the angiogenic process through macroscopic, histological, and immunohistochemical analyses in chick embryo chorioallantoic membrane (CAM). Our results showed potent anti-angiogenic activity of AZA at the higher concentrations tested in the CAM assay. The histological analysis of CAM confirmed this effect, since AZA induced a significant reduction in all parameters evaluated. In addition, immunohistochemical evaluation of CAM revealed that AZA decreased TGF-ß and VEGF levels, important cytokines involved in the angiogenic process. Therefore, the AZA anti-angiogenic effect identified in our study provides new information for the possible application of this drug in anticancer treatment.

A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica.

OBJECTIVE: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used. METHODS: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors. RESULTS: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA. INTERPRETATION: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX.

Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies.

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19+ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.

Redox Mechanism of Azathioprine and Its Interaction with DNA.

The electrochemical behavior and the interaction of the immunosuppressive drug azathioprine (AZA) with deoxyribonucleic acid (DNA) were investigated using voltammetric techniques, mass spectrometry (MS), and scanning electron microscopy (SEM). The redox mechanism of AZA on glassy carbon (GC) was investigated using cyclic and differential pulse (DP) voltammetry. It was proven that the electroactive center of AZA is the nitro group and its reduction mechanism is a diffusion-controlled process, which occurs in consecutive steps with formation of electroactive products and involves the transfer of electrons and protons. A redox mechanism was proposed and the interaction of AZA with DNA was also investigated. Morphological characterization of the DNA film on the electrode surface before and after interaction with AZA was performed using scanning electron microscopy. An electrochemical DNA biosensor was employed to study the interactions between AZA and DNA with different concentrations, incubation times, and applied potential values. It was shown that the reduction of AZA molecules bound to the DNA layer induces structural changes of the DNA double strands and oxidative damage, which were recognized through the occurrence of the 8-oxo-deoxyguanosine oxidation peak. Mass spectrometry investigation of the DNA film before and after interaction with AZA also demonstrated the formation of AZA adducts with purine bases.

Xanthine oxidase activity in thiopurine curative Chinese inflammatory bowel disease patients.

Xanthine oxidase (XO) competes with thiopurine S-methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6-mercaptopurine (6-MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine-induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6-MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu-like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu-like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine-induced toxicity.

Clinical experience with biologic treatment in resistant eosinophilic fasciitis: Case reports and review of the literature.

RATIONALE: Eosinophilic fasciitis (EF) is an uncommon connective tissue disorder characterized by limb and trunk erythema, with symmetrical thickening of the skin. Its pathogenesis is poorly understood. Treatment consists mainly of glucocorticoids. Yet, no randomized trials have evaluated therapies for this rare disease and the optimal treatment modality remains unclear. Although most patients show partial or complete response to glucocorticoids, many relapse upon drug tapering, while others either do not respond at all or fail to sustain prolonged remission. Second-line therapy for this rare disorder includes mainly methotrexate (MTX), azathioprine, cyclosporine and hydroxychloroquine. Recently, several attempts using rituximab and intravenous immunoglobulins (IVIG) have shown good clinical results. PATIENT CONCERNS: The three patients had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. Adding methotrexate in all patients and azathioprine to patient 3 did not lead to remission. DIAGNOSES: EF was diagnosed in all patients based on clinical presentation accompanied by fascia biopsy that demonstrated eosinophilic fasciitis. INTERVENTIONS: The patients were successfully treated with rituximab or IVIG, achieving sustained remission. OUTCOMES: The three cases had good clinical response to glucocorticoid treatment, followed by disease flare when the drug dose was tapered. The patients were then successfully treated with rituximab or IVIG, achieving sustained remission. LESSONS: This review of three cases of EF supports the results of previous reports, suggesting addition of rituximab and IVIG is an effective treatment for patients with refractory disease.

Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.

Azathioprine as a Neuroprotective Agent in Experimental Traumatic Spinal Cord Injury.

AIM: To evaluate the protective effects of azathioprine, a macrophage-inhibiting agent, on secondary injury in spinal cord trauma. MATERIAL AND METHODS: A total of 40 Wistar rats were randomly divided into 4 groups. All the animals had undergone T8-10 laminectomy. Except in group I (control), all the animals were exposed to spinal cord trauma at the T9 level. Animals in group II (trauma) received no treatment following trauma. Animals in group 3 (treatment) and group IV (vehicle) were given intraperitoneal azathioprine 4 mg/kg and saline 2 ml, respectively, 30 minutes after the trauma. Half of the animals in each group were sacrificed 24 hours after injury and specimens were used for biochemical and immunohistochemical evaluations. The rest of the animals were followed-up for 4 weeks in terms of neurological functions and were also sacrificed to perform the histopathological analysis. RESULTS: Significant decrease in apoptotic cells and improved neurological function were observed in the animals treated with azathioprine. Biological and immunohistochemical analysis also showed less oxidative stress in this group compared to those without treatment. CONCLUSION: Azathioprine, a potent macrophage-inhibiting agent, has been shown to decrease the extent of secondary injury following spinal cord trauma.

Sustained clinical response to infliximab in refractory Cronkhite-Canada syndrome.

A 59-year-old man with refractory Cronkhite-Canada syndrome (CCS) had poor clinical response to high-dose intravenous steroids, azathioprine, total parenteral nutrition and best supportive care. He remained highly symptomatic with abdominal pain, diarrhoea, recurrent sepsis and profound weight loss. Infliximab induction was given as rescue therapy, with marked clinical improvement observed within 3 weeks. This allowed steroid taper. Within 12 months of infliximab therapy, he achieved complete clinical remission and returned to his baseline weight and a full oral diet. Sequential endoscopies observed significant regression of previous marked gastrointestinal polyposis, including histological remission on colonic biopsies at 3.5 and 5 years of treatment. He currently remains in remission following 6 years of combination therapy with 5 mg/kg 8 weekly infliximab and azathioprine, and there is ongoing discussion with regard to the benefits and risks of therapy de-escalation. This case demonstrates the effectiveness of infliximab in inducing and maintaining remission in refractory CCS.

Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT.

Chronic inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.