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The Lancet. Neurology May 2020Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD... (Comparative Study)
Comparative Study Randomized Controlled Trial
Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
BACKGROUND
Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD.
METHODS
We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633.
FINDINGS
Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107-0·518]; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076-0·463]; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related.
INTERPRETATION
Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD.
FUNDING
Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China.
Topics: Adult; Antibodies, Monoclonal, Humanized; Azathioprine; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neuromyelitis Optica; Treatment Outcome
PubMed: 32333897
DOI: 10.1016/S1474-4422(20)30070-3 -
Anais Brasileiros de Dermatologia 2020This is a narrative review of azathioprine. This medication is immunomodulatory and immunosuppressive, and it has been used widely through different medical specialties... (Review)
Review
This is a narrative review of azathioprine. This medication is immunomodulatory and immunosuppressive, and it has been used widely through different medical specialties to modify disease. It has been proven useful for several dermatoses and it has encountered success when used as an off-label indication for other dermatologic diseases. Its mechanism of action is described thoroughly, as well as precautions for monitoring adequate levels in patients using it. Dermatologists should also be aware of the possible adverse events it may present. In dermatology it can be used in bullous and autoimmune diseases, and in other conditions, including intractable pruritus, atopic dermatitis, photodermatoses, psoriasis, and others. Azathioprine offers an alternative as a steroid-sparing agent and this review helps dermatologists prescribe it safely to all patients who require it.
Topics: Azathioprine; Dermatology; Eczema; Humans; Immunosuppressive Agents; Skin Diseases
PubMed: 33250113
DOI: 10.1016/j.abd.2020.05.003 -
Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis.Thorax Dec 2022Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments.
METHODS
We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework.
RESULTS
We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (-88.35 to 411.12)), pirfenidone (2.47% (-0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty).
CONCLUSION AND RELEVANCE
Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.
Topics: Adult; Humans; Idiopathic Pulmonary Fibrosis; Network Meta-Analysis; Sildenafil Citrate; Azathioprine; Acetylcysteine
PubMed: 35145039
DOI: 10.1136/thoraxjnl-2021-217976 -
Dermatologie (Heidelberg, Germany) Dec 2022Pemphigus diseases are a group of organ-specific autoimmune diseases which are characterised by the production of autoantibodies against intra-epidermal adhesion... (Review)
Review
Pemphigus diseases are a group of organ-specific autoimmune diseases which are characterised by the production of autoantibodies against intra-epidermal adhesion molecules and structural proteins of skin and mucosae. Depending on the entity, patients develop blisters and erosions on the skin and/or mucosae. According to the AWMF S2k guidelines for diagnosis and therapy of pemphigus diseases, a systemic therapy is recommended. Initially, high-dose, oral corticosteroids in combination with immunosuppressive drugs as corticosteroid-sparing agent, usually azathioprine or mycophenolate mofetil, can be used. Furthermore, rituximab, a monoclonal antibody directed against CD20 on B cells, was recently approved for pemphigus vulgaris and moderate or severe pemphigus foliaceus.
Topics: Humans; Adrenal Cortex Hormones; Azathioprine; Immunosuppressive Agents; Pemphigus; Rituximab
PubMed: 37902884
DOI: 10.1007/s00105-023-05246-y -
Actas Dermo-sifiliograficas Jun 2020Pemphigus vulgaris (PV) is an uncommon, serious disease that is treated with systemic corticosteroids and corticosteroid-sparing agents.
BACKGROUND
Pemphigus vulgaris (PV) is an uncommon, serious disease that is treated with systemic corticosteroids and corticosteroid-sparing agents.
OBJECTIVES
To describe and analyze the demographic and clinical characteristics of patients with PV.
MATERIAL AND METHODS
Retrospective cohort study of adults diagnosed with PV over a period of 12years.
RESULTS
PV presented with mucosal lesions in 20 of the 32 patients studied (63%); the most common site was the oral mucosa followed by the vulva. Mucosal involvement was more common in women (P=.03). Lesions were found at more than 1 mucosal site in patients whose disease began in the mucosa, independently of age or sex (P=.003). Disease onset before the age of 40years was associated with generalized skin lesions (P=.003), a need for corticosteroid-sparing therapy (P=.05), and refractory PV (P=.02). Azathioprine was the most widely prescribed corticosteroid-sparing agent (in 22 patients). Eight patients (25%) were dependent on corticosteroids and disease recurred in 26 (81%). Complete remission, with or without treatment, was achieved in 15 patients (47%). Patients remained disease-free for a median of 14months, and 2 patients died (6%).
CONCLUSION
Onset before the age of 40 years could be a sign of poor prognosis in patients with PV, as it was significantly associated with a higher risk of generalized skin involvement, a need for corticosteroid-sparing therapy, and refractory disease.
Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Female; Humans; Pemphigus; Retrospective Studies; Skin Diseases
PubMed: 32466985
DOI: 10.1016/j.ad.2019.10.004 -
The Canadian Journal of Cardiology Aug 2023Recurrent pericarditis is a common and troublesome complication that affects 15%-30% of patients with a previous episode of pericarditis. However, the pathogenesis of... (Review)
Review
Recurrent pericarditis is a common and troublesome complication that affects 15%-30% of patients with a previous episode of pericarditis. However, the pathogenesis of these recurrences is not well understood, and most cases remain idiopathic. Recent advances in medical therapy, including the use of colchicine and anti-interleukin-1 agents like anakinra and rilonacept, have suggested an autoinflammatory rather than an autoimmune mechanism for recurrences with an inflammatory phenotype. As a result, a more personalized approach to treatment is now recommended. Patients with an inflammatory phenotype (fever and elevated C-reactive protein level) should receive colchicine and anti-interleukin-1 agents as first-line therapy, whereas those without systemic inflammation should receive low to moderate doses of corticosteroids (eg, prednisone 0.2-0.5 mg/kg/d as an initial dose) and consider azathioprine and intravenous human immunoglobulins in the case of corticosteroid failure. Tapering of corticosteroids should be slow after achieving clinical remission. In this article, we review the new developments in the management of recurrent pericarditis.
Topics: Humans; Pericarditis; Azathioprine; Adrenal Cortex Hormones; Colchicine; Immunoglobulins, Intravenous; Recurrence
PubMed: 37075863
DOI: 10.1016/j.cjca.2023.04.008 -
Obstetrics and Gynecology Apr 2024Pregnant patients are often on immunosuppressant medications, most commonly to manage transplantation or autoimmune disorders. Most immunosuppressant agents, including... (Review)
Review
Pregnant patients are often on immunosuppressant medications, most commonly to manage transplantation or autoimmune disorders. Most immunosuppressant agents, including tacrolimus, corticosteroids, azathioprine, and calcineurin inhibitors, are safe during pregnancy and lactation. However, mycophenolic acid is associated with higher risks of birth defects and should be avoided in pregnancy. Tacrolimus, the commonly used drug in transplantation medicine and autoimmune disorders, requires monitoring of serum levels for dose adjustment, particularly during pregnancy. Although no pregnancy-specific therapeutic range exists, the general target range is 5-15 ng/mL, and pregnant patients may require higher doses to achieve therapeutic levels. Adherence to prescribed immunosuppressive regimens is crucial to prevent graft rejection and autoimmune disorder flare-ups. This review aims to provide essential information about the use of immunosuppressant medications in pregnant individuals. With a rising number of pregnant patients undergoing organ transplantations or having autoimmune disorders, it is important to understand the implications of the use of these medications during pregnancy.
Topics: Pregnancy; Female; Humans; Tacrolimus; Immunosuppressive Agents; Organ Transplantation; Azathioprine; Autoimmune Diseases
PubMed: 38227938
DOI: 10.1097/AOG.0000000000005512 -
Xenobiotica; the Fate of Foreign... Jan 2020The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although... (Review)
Review
The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.
Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines
PubMed: 31682552
DOI: 10.1080/00498254.2019.1688424 -
Journal of Clinical Rheumatology :... Sep 2020
Topics: Azathioprine; Humans; Melanoma; Nail Diseases
PubMed: 30946288
DOI: 10.1097/RHU.0000000000001031 -
Gastroenterology Clinics of North... Dec 2020This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American... (Review)
Review
This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American guidelines, azathioprine, mercaptopurine, and methotrexate monotherapy are not recommended for induction therapy. Thiopurines are recommended in combination with infliximab. Tofacitinib has been shown to be an effective induction agent. Cyclosporine or tacrolimus are calcineurin inhibitors that can be used as induction therapy. Thiopurine monotherapy is suggested or recommended as maintenance therapy for patients who have achieved steroid-induced remission. Methotrexate monotherapy is not recommended. Tofacitinib has been shown to be an effective maintenance agent in moderate to severe disease.
Topics: Azathioprine; Colitis, Ulcerative; Contraindications, Drug; Glucocorticoids; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Meta-Analysis as Topic; Methotrexate; Piperidines; Pyrimidines; Remission Induction
PubMed: 33121692
DOI: 10.1016/j.gtc.2020.07.003