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Lupus Science & Medicine Sep 2021Immune dysregulation in SLE and the corresponding immune-modulating and immunosuppressive nature of the treatments may play key roles in infection risk. We compared...
OBJECTIVE
Immune dysregulation in SLE and the corresponding immune-modulating and immunosuppressive nature of the treatments may play key roles in infection risk. We compared serious infection rates among individuals with incident SLE with the general population, and examined the role of treatment initiation in SLE.
METHODS
Newly diagnosed patients with SLE (2006-2013) and general population comparators from the Swedish Lupus Linkage cohort were followed for serious infection through 2016. Adjusted Cox and frailty models estimated the relative risk of first and recurrent infections, respectively. Using a new-user design, rates of serious infections were compared between disease-modifying antirheumatic drugs (DMARDs) and hydroxychloroquine (HCQ) initiators. We then evaluated three DMARDs (azathioprine, mycophenolate mofetil and methotrexate) in multivariable-adjusted models.
RESULTS
Individuals with SLE experienced more infections (22% vs 6%), especially during the first year of follow-up, and recurrent serious infections were also more common (HR=2.22, 95% CI 1.93 to 2.56). DMARDs were associated with a higher rate of serious infection versus HCQ (HR=1.82, 95% CI 1.27 to 2.60), which attenuated after multivariable-adjustment (HR=1.30, 95% CI 0.86 to 1.95). Among DMARDs, azathioprine was associated with infection (HR=2.19, 95% CI 1.14 to 4.21) and mycophenolate mofetil yielded an HR=1.39 (95% CI 0.65 to 2.96) in multivariable-adjusted models compared with methotrexate. Results were comparable across numerous sensitivity analyses.
CONCLUSION
Individuals with incident SLE were 2-4 times more likely to be hospitalised for infection and experienced more recurrent infections than the general population. Among DMARD initiators, azathioprine was associated with the highest rate.
Topics: Antirheumatic Agents; Azathioprine; Hospitalization; Humans; Hydroxychloroquine; Sweden
PubMed: 34526357
DOI: 10.1136/lupus-2021-000510 -
International Journal of Molecular... Jun 2021The electrochemical behavior and the interaction of the immunosuppressive drug azathioprine (AZA) with deoxyribonucleic acid (DNA) were investigated using voltammetric...
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.
Topics: Algorithms; Azathioprine; Biosensing Techniques; Chemical Phenomena; DNA; Macromolecular Substances; Mass Spectrometry; Models, Theoretical; Oxidation-Reduction
PubMed: 34202734
DOI: 10.3390/ijms22136805 -
World Journal of Gastroenterology Jul 2023There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal...
BACKGROUND
There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation.
AIM
To describe the events following AZA cessation.
METHODS
Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups.
RESULTS
A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1 year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years.
CONCLUSION
AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.
Topics: Adult; Humans; Azathioprine; Immunosuppressive Agents; Retrospective Studies; Inflammatory Bowel Diseases; Colitis, Ulcerative; Remission Induction
PubMed: 37545640
DOI: 10.3748/wjg.v29.i27.4334 -
Journal of the American Animal Hospital... Jan 2021Treatment with high corticosteroid dosages for steroid-responsive meningitis-arteritis (SRMA) is correlated with severe adverse effects and worse quality of life. In...
Treatment with high corticosteroid dosages for steroid-responsive meningitis-arteritis (SRMA) is correlated with severe adverse effects and worse quality of life. In order to improve immunosuppression and decrease dosage and duration of glucocorticoid treatment, a second immunosuppressive drug is commonly used in most of the immune-mediated diseases. The objective of this retrospective study was to evaluate the efficacy, tolerability, and occurrence of relapse for the combination of prednisolone and azathioprine. All dogs received azathioprine 2 mg/kg q 24 hr for 1 mo and then 2 mg/kg every other day for 2 mo; prednisolone was started at an immunosuppressive dosage and tapered off gradually during a mean of 3 mo. Twenty-six dogs met inclusion criteria. Twenty-one dogs (81%) were in clinical remission with no relapse observed within the 2 yr follow-up period. Treatment was well tolerated in all dogs and side effects were most of the time mild and self-limiting. The relapse rate (19%) was lower than most published rates. A prednisolone and azathioprine combination appeared to be effective for primary treatment of dogs with SRMA and allows a quicker tapering in prednisolone dosage, a decrease in long-term side effects of steroids, a shorter duration of treatment, and a low relapse rate.
Topics: Animals; Arteritis; Azathioprine; Dog Diseases; Dogs; Female; Glucocorticoids; Immunosuppressive Agents; Male; Meningitis; Prednisolone; Quality of Life; Retrospective Studies
PubMed: 33260200
DOI: 10.5326/JAAHA-MS-7019 -
The Lancet. Neurology Mar 2024Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression,...
BACKGROUND
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment.
METHODS
We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539).
FINDINGS
Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths.
INTERPRETATION
More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis.
FUNDING
Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.
Topics: Adolescent; Adult; Humans; Azathioprine; Immunosuppressive Agents; Myasthenia Gravis; Mycophenolic Acid; Prospective Studies; Quality of Life
PubMed: 38365379
DOI: 10.1016/S1474-4422(24)00028-0 -
Indian Journal of Ophthalmology Apr 2023Immunosuppression in aqueous-deficient dry eye disease (ADDE) is required not only to improve the symptoms and signs but also to prevent further progression of the... (Review)
Review
Immunosuppression in aqueous-deficient dry eye disease (ADDE) is required not only to improve the symptoms and signs but also to prevent further progression of the disease and its sight-threatening sequelae. This immunomodulation can be achieved through topical and/or systemic medications, and the choice of one drug over the other is determined by the underlying systemic disease. These immunosuppressive agents require a minimum of 6-8 weeks to achieve their beneficial effect, and during this time, the patient is usually placed on topical corticosteroids. Antimetabolites such as methotrexate, azathioprine, and mycophenolate mofetil, along with calcineurin inhibitors, are commonly used as first-line medications. The latter have a pivotal role in immunomodulation since T cells contribute significantly to the pathogenesis of ocular surface inflammation in dry eye disease. Alkylating agents are largely limited to controlling acute exacerbations with pulse doses of cyclophosphamide. Biologic agents, such as rituximab, are particularly useful in patients with refractory disease. Each group of drugs has its own side-effect profiles and requires a stringent monitoring schedule that must be followed to prevent systemic morbidity. A customized combination of topical and systemic medications is usually required to achieve adequate control, and this review aims to help the clinician choose the most appropriate modality and monitoring regimen for a given case of ADDE.
Topics: Humans; Azathioprine; Dry Eye Syndromes; Immunosuppression Therapy; Immunosuppressive Agents; Inflammation; Methotrexate
PubMed: 37026249
DOI: 10.4103/IJO.IJO_2818_22 -
Respiratory Medicine Jan 2024Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting...
BACKGROUND
Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD.
METHODS
Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models.
RESULTS
Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD.
CONCLUSION
Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup.
Topics: Humans; Male; Female; Azathioprine; Lung Diseases, Interstitial; Lung; Connective Tissue Diseases; Immunosuppressive Agents; Risk Factors
PubMed: 38142756
DOI: 10.1016/j.rmed.2023.107500 -
World Journal of Gastroenterology Oct 2021Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the...
Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of , , and genes, in addition to and as possible biomarkers for thiopurine-related gastrointestinal toxicity.
Topics: Azathioprine; Biomarkers; Humans; Immunologic Factors; Mercaptopurine; Methyltransferases; Pyrophosphatases
PubMed: 34720526
DOI: 10.3748/wjg.v27.i38.6348 -
Clinical Rheumatology Jan 2021Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide... (Review)
Review
Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.
Topics: Azathioprine; Humans; Immunosuppressive Agents; Pharmacogenetics; Precision Medicine; Rheumatologists
PubMed: 32617765
DOI: 10.1007/s10067-020-05258-2 -
The Journal of Allergy and Clinical... Jan 2023Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts...
BACKGROUND
Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy.
OBJECTIVE
We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use.
METHODS
Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients.
RESULTS
Azathioprine therapy selectively induced pronounced CD56CD16 natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical T1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort.
CONCLUSION
Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.
Topics: Humans; Azathioprine; Killer Cells, Natural; Interferon-gamma; Herpesviridae; Myasthenia Gravis
PubMed: 36122787
DOI: 10.1016/j.jaci.2022.09.010