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(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.

Background: Detecting vertebral structural damage in patients with ankylosing spondylitis (AS) is crucial for understanding disease progression and in research settings. Objectives: This study aimed to use deep learning to score the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) using lateral X-ray images of the cervical and lumbar spine in patients with AS in Asian populations. Design: A deep learning model was developed to automate the scoring of mSASSS based on X-ray images. Methods: We enrolled patients with AS at a tertiary medical center in Taiwan from August 1, 2001 to December 30, 2020. A localization module was used to locate the vertebral bodies in the images of the cervical and lumbar spine. Images were then extracted from these localized points and fed into a classification module to determine whether common lesions of AS were present. The scores of each localized point were calculated based on the presence of these lesions and summed to obtain the total mSASSS score. The performance of the model was evaluated on both validation set and testing set. Results: This study reviewed X-ray image data from 554 patients diagnosed with AS, which were then annotated by 3 medical experts for structural changes. The accuracy for judging various structural changes in the validation set ranged from 0.886 to 0.985, whereas the accuracy for scoring the single vertebral corner in the test set was 0.865. Conclusion: This study demonstrated a well-trained deep learning model of mSASSS scoring for detecting the vertebral structural damage in patients with AS at an accuracy rate of 86.5%. This artificial intelligence model would provide real-time mSASSS assessment for physicians to help better assist in radiographic status evaluation with minimal human errors. Furthermore, it can assist in a research setting by offering a consistent and objective method of scoring, which could enhance the reproducibility and reliability of clinical studies. [ABSTRACT FROM AUTHOR]

Background: Patients with ankylosing spondylitis (AS) suffer from impaired physical activity and are prone to motor vehicle accidents (MVA), but definite instruction regarding the relationship between disease evolvement and MVA and potential risk factors is lacking. Objectives: To explore the risk factors and their impact on recorded MVA with profound injuries in AS patients with prescriptions. Design: Nationwide, population-based, matched retrospective cohort study. Methods: Using Taiwanese administrative healthcare databases, with available claims data from 2003 to 2013, we selected 30,911 newly diagnosed adult AS patients with concurrent prescriptions from 2006 to 2012 as AS patients, along with 309,110 non-AS individuals as the control group, matched in gender, age at index date and year of the index date. The risk of recorded MVA with profound injuries was compared between the two groups in terms of incidence rate ratio (IRR) and log-rank test p -value. Using Cox regression analysis, we studied associations between the risk and AS diagnosis. Results: The risk of recorded MVA with profound injuries in AS patients was significantly higher than in non-AS individuals, specifically 2 years after AS diagnosis (IRR, 2.00; 95% confidence interval (CI), 1.42–2.81). For patients with follow-up periods >2 years, the adjusted risk was positively associated with suburban residence (adjusted hazard ratio (aHR), 2.18; 95% CI, 1.55–3.06), rural residence (aHR, 1.89; 95% CI, 1.27–2.80), lower insured income (aHR, 1.35; 95% CI, 1.01–1.81) and recorded MVA with profound injuries before AS diagnosis (aHR, 6.16; 95% CI, 2.53–14.96). AS diagnosis (aHR, 1.81; 95% CI, 1.27–2.59) and frequency of ambulatory visits (aHR, 1.01; 95% CI, 1.004-–1.02) were specific associated factors for them compared with those with follow-up periods ⩽2 years. Conclusion: For adult AS patients in Taiwan, factors such as AS disease evolution and frequent ambulatory visits for disease control in the second year of the disease course may significantly increase the risk of recorded MVA with profound injuries beyond 2 years after AS diagnosis. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to assess the incidence and risk factors of major adverse cardiovascular events (MACEs) in patients with systemic sclerosis (SSc). Methods We conducted a nationwide, population-based, cohort study using Taiwan's National Health Insurance Research Database. We performed propensity score matching (PSM) using a 1:2 ratio, resulting in inclusion of 1379 patients with SSc and 2758 non-SSc individuals in the analysis. We assessed the association between SSc and MACEs, using the multivariable Cox proportional hazard regression model with adjustment of time-dependent covariates, and investigated risk factors for MACEs in patients with SSc, shown as adjusted hazard ratios (aHRs) with 95% CIs. Results SSc was not significantly associated with the risk of MACEs (aHR 1.04; 95% CI 0.77–1.42). Nevertheless, SSc was associated with increased risk of myocardial infarction [incidence rate ratio (IRR) 1.76; 95% CI 1.08–2.86] and peripheral arterial occlusion disease (IRR 3.67; 95% CI 2.84–4.74) but not of ischaemic stroke (IRR 0.89; 95% CI 0.61–1.29). Factors independently associated with MACEs in SSc patients included age (aHR 1.02), male gender (aHR 2.01), living in a suburban area (aHR 2.09), living in a rural area (aHR 3.00), valvular heart disease (aHR 4.26), RA (aHR 2.14), use of clopidogrel (aHR 26.65), and use of aspirin (aHR 5.31). Conclusions The risk of MACEs was not significantly increased in Taiwanese patients with SSc, and our investigation effectively identified the factors independently associated with MACEs in SSc patients. Additionally, patients with SSc exhibited higher risks of myocardial infarction and peripheral arterial occlusion disease but not of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Objectives: To assess the association between antirheumatic drugs and of the risk of nonalcoholic fatty liver disease (NAFLD) in a nationwide rheumatoid arthritis (RA) cohort. Methods: Using claim data from the 2000–2020 National Health Insurance Research Database, we identified 21 457 incident patients with RA from 2002 to 2020 without prior liver diseases. A time‐varying multivariable Cox regression model was applied to estimate for the association of NAFLD with the use of antirheumatic drugs after adjusting potential confounders, show as adjusted hazard ratios (aHRs) with 95% confidence interval (CIs). Subgroup analyses were conducted based on age‐, sex‐, and obesity‐related comorbidities. Results: Multivariable time‐dependent Cox regression analyses showed that defined daily dose (DDD) of NSAID (aHR, 1.03; 95% CI: 1.02–1.05) and prednisolone equivalent dose >5 mg/day (aHR, 2.39; 95% CI: 1.85–3.09) were risk factors of NAFLD in patients with RA, while prednisolone equivalent dose ≤5 mg/day (aHR of 0.53; 95% CI: 0.40–0.71) and HCQ use (aHR of 0.75; 95% CI: 0.60–0.93) were associated with a decreased risk of NAFLD. In addition, a history of hospitalizations, number of outpatient visits, age, male, and leflunomide use were associated with the development of NAFLD in some subgroups. Conclusion: This study reveals that NSAID use and prednisolone equivalent dose >5 mg/day were associated with an increased risk of NAFLD in patients with RA, while the use of HCQ and prednisolone equivalent dose ≤5 mg/day decreased the risk of NAFLD. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE). Methods: We conducted a systematic literature review of studies focusing on adult patients classified as having SLE‐related PAH by searching the electronic databases Embase, Medline, Medline in‐progress, Wanfang, China National Knowledge Infrastructure, Ichushi Web, Kmbase, and KoreaMed. Based on the findings, we conducted a Delphi survey to build expert consensus on issues related to screening for PAH in patients with SLE and on the importance and feasibility of measuring the identified factors in clinical practice. Results: We included 21 eligible studies for data synthesis. Sixteen factors were associated with an increased risk of SLE‐PAH: pericardial effusion, serositis, longer duration of SLE, arthritis, acute and subacute cutaneous lupus, scleroderma pattern on nailfold capillaroscopy, diffusion capacity of carbon monoxide in the lungs (DLCO) <70% predicted, interstitial lung disease, thrombocytopenia, and seven serological factors. Six factors were associated with a decreased risk of SLE‐PAH: malar/acute rash, hematologic disorder, renal disorder, higher Systemic Lupus Erythematosus Disease Activity Index score, and two serological factors. Among these, there were six risk factors on which the panelists reached strong or general consensus (peak tricuspid regurgitation velocity on echocardiography >2.8 m/s, pericardial effusion, DLCO <70% predicted, scleroderma pattern on nailfold capillaroscopy, brain natriuretic peptide >50 ng/l, and N‐terminal pro–brain natriuretic peptide >300 ng/l). The Delphi panel confirmed the need for a screening tool to identify patients with SLE at high risk of developing PAH and provided consensus on the importance and/or practicality of measuring the identified factors. Conclusion: The risk factors we identified could be used in a screening algorithm to identify patients with SLE with a high risk of developing PAH to facilitate early diagnosis, which could improve prognosis and management of these patients. [ABSTRACT FROM AUTHOR]