Long-term Use Of Azathioprine Research Articles

Promote the electrocatalytic activity through the assembly of hexagonal SnS2/C sphere nanocomposite for determination of the immunosuppressant drug azathioprine in biological samples

In modernized eras, enhanced growth of transplantation and the use of drugs are high. However, the overuse of immunosuppressant drugs is hazardous to human health. In particular, long-term use of azathioprine (ATN) causes heavy side effects on human health, therefore nanomolar detection and determination of ATN are essential. Herein, an efficient electrocatalyst of hexagonal tin sulfide incorporated carbon sphere (SnS2/C) nanocomposite was prepared by using the temperature and pressure maintained hydrothermal method. The prepared electrocatalyst was successfully characterized by using various spectra and microscopic techniques. The SnS2/C/GCE exhibits the well-resolved ATN reduction peak in the CV experiments, due to the synergetic effect between the hexagonal SnS2 and C sphere. In addition, SnS2/C/GCE exhibits two linear ranges of (0.001 – 104.7 µM and 121.8 – 1275 µM) and the low detection limit of 5.7 nM along with the higher sensitivity (0.4325 µA µM−1 cm−2). In addition to that, the constructed sensor delivers notable repeatability, reproducibility, and superior selectivity with the existence of metal ions, biological molecules, and nitro compounds, enabling the electrochemical detection of ATN. The fabricated, SnS2/C/GCE sensor was successfully applied to the real-time determination of ATN in biological human urine and blood serum samples with good recovery results. Based on this, SnS2/C is a portable electrocatalyst for sensing ATN for biological and clinical purposes.

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

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

O20 A case series of paediatric primary Sjögren’s syndrome: differential diagnoses and multidisciplinary management

O20 A case series of paediatric primary Sjögren’s syndrome: differential diagnoses and multidisciplinary management

Use of azathioprine for non‐thymoma myasthenia and risk of cancer: a nationwide case–control study in Denmark

To evaluate the association between the use of azathioprine and risk of cancer in patients with non-thymoma myasthenia gravis (MG) in a nationwide setting. Case-control study based on population-based registries. Cases were patients with MG with a first time diagnosis of cancer (except non-melanoma skin cancer) registered during 2000-2009, and controls were patients with MG with no history of cancer. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for cancer associated with a high cumulative dose [≥ 1000 defined daily doses (DDD)] or long-term use (≥ 5 years) of azathioprine, compared with never use of the drug and adjusted for potential confounders. We identified 89 cases and 873 controls. The prevalence of ever use of azathioprine was similar among cases (39.3%) and controls (39.4%). We observed a slightly elevated OR for cancer overall associated with long-term use of azathioprine (1.22; 95% CI: 0.62-2.40, P = 0.56). The highest ORs were observed for use of 2000 DDD or more of azathioprine; however, these risk estimates were based on small numbers. Use of azathioprine in patients with non-thymoma MG may be associated with a slightly increased risk of cancer overall. Larger studies are necessary to address the risk of site-specific cancers.

Effect of azathioprine or mesalazine therapy on incidence of re-hospitalization in sub-occlusive ileocecal Crohn’s disease patients

BackgroundAlthough the cost of Crohn’s disease (CD) treatment differs considerably, hospitalization and surgery costs account for most of the total treatment cost. Decreasing hospitalization and surgery rates are pivotal issues in reducing health-care costs.Material/MethodsWe evaluated the effect of azathioprine (AZA) compared with mesalazine on incidence of re-hospitalizations due to all causes and for CD-related surgeries. In this controlled, randomized study, 72 subjects with sub-occlusive ileocecal CD were randomized for AZA (2–3 mg/kg per day) or mesalazine (3.2 g per day) therapy during a 3-year period. The primary end point was the re-hospitalization proportion due to all causes, as well as for surgical procedures during this period evaluated between the groups.ResultsOn an intention-to-treat basis, the proportion of patients re-hospitalized within 36 months due to all causes was lower in patients treated with AZA compared to those on mesalazine (0.39 vs. 0.83, respectively; p=0.035). The AZA group had also significantly lower proportions of re-hospitalization for surgical intervention (0.25 vs. 0.56, respectively; p=0.011). The number of admissions (0.70 vs. 1.41, p=0.001) and the length of re-hospitalization (3.8 vs. 7.7 days; p=0.002) were both lower in AZA patients.ConclusionsPatients with sub-occlusive ileocecal CD treated with AZA had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. The long-term use of AZA in ileocecal CD patients recovering from a sub-occlusion episode can save healthcare costs.

Behçet’s Disease

Neurologic involvement in Behçet's disease (BD) is seen in about 5% to 10% of all BD patients. Clinical and imaging data suggest that neurologic involvement in BD presents in two major forms. The first, central nervous system (CNS) parenchymal involvement with a predilection to brainstem-diencephalic regions, is seen in the majority of patients with neuro-BD (NBD). The second form is cerebral venous sinus thrombosis (CVST), which is seen in up to 20% of cases. BD is very rare in children, but when it does occur, the patterns are reversed: most children with NBD present with CVST. Other syndromes such as spinal cord involvement, arterial CNS involvement, optic neuritis, aseptic meningitis, and peripheral neuropathies may be seen, but are rare. Venous sinus thrombosis in BD has a significantly better neurologic prognosis than parenchymal CNS involvement. There is no Class I evidence regarding treatment of parenchymal CNS involvement or CVST in BD. Current treatment applications are based largely on expert opinion; none are evidence-based. Acute parenchymal CNS involvement should be treated with high-dose intravenous methylprednisolone (IVMP), 1g per day, for 5 to 10days, followed by either a prolonged oral taper or intermittent IVMP pulses with a low oral dose between the pulses, over 6months. After treatment of the acute attack, long-term maintenance with immunosuppressive agents should be considered in patients with parenchymal CNS involvement, as this form may follow a relapsing or secondary progressive course and may result in significant physical and cognitive deficits leading to severe neurologic disability. A number of randomized controlled studies have tested treatments for systemic manifestations of BD. Colchicine was found to be effective for mucocutaneous symptoms, thalidomide was found to be effective in erythema nodosum-like skin lesions, azathioprine and cyclosporine were shown to be effective in BD uveitis, and cyclophosphamide was shown to be effective for major vascular involvement. More recently, interferon alfa and anti-TNF agents were also shown to be effective in BD uveitis. Although randomized controlled studies have not been performed in NBD, the most widely used long-term therapeutic agent is azathioprine. Recent observations suggest that the addition and long-term use of azathioprine in NBD could be associated with a more favorable course. A growing number of case reports in recent years suggest that anti-TNF agents may be an effective alternative in NBD, but current experience with these agents is limited. CVST in BD is also treated with steroids. The addition to glucocorticoids of anticoagulation, including short-term fractionated heparin, is controversial, as these patients have a higher probability of harboring pulmonary or other aneurysms, which may be associated with an increased risk of bleeding. Long-term oral anticoagulation is unnecessary. Interestingly, the prognosis of CVST due to BD seems to be much more favorable than the prognosis of CVST due to other causes, with much less tendency for venous infarcts and seizures. However, as recurrences may occur, long-term treatment with azathioprine is recommended.

Immune Effector Cells Produce Lethal DNA Damage in Cells Treated with a Thiopurine

Azathioprine, a widely used immunosuppressant, is also used in the control of inflammatory disorders. These are characterized by the local accumulation of immune effector cells that produce reactive oxygen species (ROS). The DNA of azathioprine-treated patients contains 6-thioguanine (6-TG), a base analogue that is particularly susceptible to oxidation. Here, we show that 6-TG is vulnerable to ROS produced by chemical oxidants and that cells containing DNA 6-TG are hypersensitive to these oxidants. We also show that 6-TG incorporated into the DNA of macrophages sensitizes them to killing by endogenously produced ROS. ROS generated by macrophages are also a hazard for cocultured nonmacrophage cells containing DNA 6-TG. This bystander vulnerability of cells containing DNA 6-TG to oxidation by ROS generated by immune effector cells has implications for the long-term use of azathioprine in the management of inflammatory disorders.

Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome

Hepatic sinusoidal obstruction syndrome is frequently linked to high-dose chemotherapy/total-body irradiation in recipients of haematopoietic stem cell transplantation, long-term use of azathioprine after organ transplantation and other chemotherapeutic agents. The incidence of hepatic sinusoidal obstruction syndrome varies from 0% to 70%, and is decreasing. Disease risk is higher in patients with malignancies, hepatitis C virus infection, those who present late, when norethisterone is used to prevent menstruation, and when broad-spectrum antibiotics and antifungals are used during and after the conditioning therapy. Hepatic sinusoidal obstruction syndrome presents with tender hepatomegaly, hyperbilirubinaemia and ascites, and diagnosis is mainly clinical (Seattle and Baltimore Criteria). Imaging excludes biliary obstruction and malignancy, but cannot establish accurate diagnosis. Hepatic sinusoidal obstruction syndrome may be prevented by avoiding the highest risk regimens, using non-myelo-ablative regimens, and reducing total-body irradiation dose. Treatment is largely symptomatic and supportive, because 70-80% of patients recover spontaneously. Tissue plasminogen activator plus heparin improves outcome in <30% of cases. Defibrotide, a polydeoxyribonucleotide, is showing encouraging results. Transjugular intrahepatic porto-systemic shunt relieves ascites, but does not improve outcome. Liver transplantation may be an option in the absence of malignancy. Prognosis is variable and depends on disease severity, aetiology and associated conditions. Death is most commonly caused by renal or cardiopulmonary failure.

Azathioprine-induced pure red cell aplasia: Case report and review

The major adverse effect of azathioprine is its myelotoxicity, with leukocytes being affected more commonly than the other bone marrow elements. Although megaloblastic change is frequent, reportedly seen in 16% to 82% of bone marrow aspirates, long-term use of azathioprine rarely causes severe anemia. We report a case of refractory pure red cell aplasia resulting from long-term use of azathioprine in a renal transplant recipient and examine the possible underlying mechanisms. There was no response to dose reduction or to erythropoietin administration. However, there was immediate recovery after complete drug withdrawal. A review of the literature revealed that only ten cases of azathioprine-induced red cell aplasia have so far been described, all in transplant recipients.

Prostatic Involvement of a Testicular Lymphoma in a Patient with Myasthenia Gravis on Long-term Azathioprine

Side effects of long-term use of azathioprine in myasthenia gravis are infrequently reported. We present a patient who developed non-Hodgkin's lymphoma after eight years of azathioprine treatment for myasthenia gravis. He presented unusually with testicular lymphoma spreading to the prostate and the illness followed a particularly aggressive course.

The Long-Term Use of Azathioprine in Patients with Psoriatic Arthritis

Despite the widespread use of methotrexate in the treatment of psoriatic arthritis (PsA), there are patients who are either refractory, develop toxicity to, or refuse to take methotrexate. In search of an alternative, we studied long-term tolerability of and clinical response to azathioprine (AZA) in PsA patients in comparison with matched controls and followed them in a longitudinal clinic. Twenty-eight of 485 patients followed prospectively between 1978 and 1998 took AZA during their clinic follow-ups. Eighteen of the 28 took AZA for 12 months and were included in the study. AZA was well tolerated by most patients, even in the long-term. Although there was no statistically significant difference in the reduction in number of actively inflamed joints between AZA-treated patients and controls, and AZA was no better in preventing progression of damage, AZA was still as good as the other medications. Consequently, AZA was often given to individuals who had not responded to other medications in the past. We provide illustrative case reports in which AZA also controlled psoriasis, and we conclude that, whereas AZA is not superior to other medications in the treatment of PsA, it may be safely used and it provides an alternative therapy for patients with PsA.

Trainees' section: The use of azathioprine in dermatology

Editorial commentDermatology trainees need to be familiar with azathioprine as this drug is an important immunosuppressive agent used in a variety of different dermatological conditions. This article covers both the licensed and unlicensed indications for azathioprine and outlines the metabolic fate of this drug in relation to safety and efficacy. Guidelines concerning pre-treatment counselling of patients, dosage and monitoring for side-effects are included. Trainees should be aware that long-term use of azathioprine has been implicated as a co-factor in the development of skin neoplasia and in non-cutaneous malignancy.