Host-Pathogen Interactions in K. pneumoniae Urinary Tract Infections: Investigating Genetic Risk Factors in the Taiwanese Population.

BACKGROUND: Klebsiella pneumoniae (K. pneumoniae) urinary tract infections pose a significant challenge in Taiwan. The significance of this issue arises because of the growing concerns about the antibiotic resistance of K. pneumoniae. Therefore, this study aimed to uncover potential genomic risk factors in Taiwanese patients with K. pneumoniae urinary tract infections through genome-wide association studies (GWAS). METHODS: Genotyping data are obtained from participants with a history of urinary tract infections enrolled at the Tri-Service General Hospital as part of the Taiwan Precision Medicine Initiative (TPMI). A case-control study employing GWAS is designed to detect potential susceptibility single-nucleotide polymorphisms (SNPs) in patients with K. pneumoniae-related urinary tract infections. The associated genes are determined using a genome browser, and their expression profiles are validated via the GTEx database. The GO, Reactome, DisGeNET, and MalaCards databases are also consulted to determine further connections between biological functions, molecular pathways, and associated diseases between these genes. RESULTS: The results identified 11 genetic variants with higher odds ratios compared to controls. These variants are implicated in processes such as adhesion, protein depolymerization, Ca2+-activated potassium channels, SUMOylation, and protein ubiquitination, which could potentially influence the host immune response. CONCLUSIONS: This study implies that certain risk variants may be linked to K. pneumoniae infections by affecting diverse molecular functions that can potentially impact host immunity. Additional research and follow-up studies are necessary to elucidate the influence of these risk variants on infectious diseases and develop targeted interventions for mitigating the spread of K. pneumoniae urinary tract infections.

Anti-citrullinated α-enolase peptide as a highly sensitive autoantigen in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease in Taiwan. Anti-cyclic citrullinated peptide (anti-CCP) assay is widely used for RA diagnosis; however, not all anti-CCPs are detectable in RA-joint lesions. Citrullinated α-enolase peptide (CEP), which has a unique immunodominant epitope, can be detected in synovial fluid. Here, we aimed to evaluate the potential of anti-CEP as a serologic marker for the early diagnosis of RA and a prognostic predictor of joint destruction. We also determined the association of single-nucleotide polymorphisms (SNPs) in genes with the serological status and clinical characteristics of RA. Clinical records of 30 patients with RA were collected, and their serum and DNA samples were evaluated using enzyme-linked immunosorbent assay (ELISA) and SNP cross-reaction analysis. A considerable amount of anti-CEP was detected in patients with RA, a trend similar to that of anti-CCP. Moreover, anti-CEP was considerably associated with the protein-arginine deiminase type-2 SNP rs1005753.

Functional implications of rs9373441 with FOXP3+Treg and Tr1 for the clinical effectiveness of csDMARDs in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by a deficiency in regulatory T cells (Treg), which play a crucial role in immune regulation. While conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are widely used, there remains a challenge as efficacy varies among patients. In this genome-wide association study (GWAS) involving 410 RA patients, rs9373441 emerged as the most significantly linked single-nucleotide polymorphism (SNP) to csDMARDs response. This non-coding variant functions as a cis-acting regulatory element within the UTRN gene, which is associated with cortical erosion and osteoporosis. Particularly, individuals with the TT allele at rs9373441 exhibited a more favorable response, characterized by a significant increase in FOXP3 + Treg and Type 1 regulatory T cells (Tr1) (p = 0.04, 0.02) and a decrease in Effector T helper cells (Effector Th) (p = 0.03). The GATA3-GCM2-PTH and GATA3-FOXO1-FOXP3 pathways were implicated. RNA-sequencing (RNA-seq) analysis revealed increased expression levels of UTRN, PTH2R, FOXO1, and FOXO3 in good and moderate responders (p = 0.01, 0.03, 0.0005, and 0.02). Notably, the change in FOXP3 + Treg and Tr1 was positively correlated with UTRN expression (both p = 0.03). These findings underscore the critical link between rs9373441 and the response to csDMARDs, empowering clinicians to tailor treatments for enhanced outcomes in patients with RA.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

Streptococcus agalactiae pyomyositis in a patient with primary biliary cholangitis: A case report.

Pyomyositis is an uncommon clinical scenario; it is usually associated with predisposing factors, including poorly controlled diabetes mellitus, trauma history, and immunocompromise. We discuss the case of an elderly woman with a 20-year history of diabetes mellitus and remissive breast cancer after modified radical mastectomy and subsequent chemotherapy 28 years previously. The patient presented with severe shoulder pain and gradual swelling. After examination, pyomyositis was diagnosed and debridement surgery was performed. Culture of the wound samples showed the growth of Streptococcus agalactiae. During hospitalization, primary biliary cholangitis (PBC) was diagnosed incidentally, accompanied by poor glycemic control. After treatment with antibiotics for pyomyositis and ursodeoxycholic acid for PBC, the infection resolved in 8 weeks, and her glycemic control was improved after PBC treatment. It is possible that the long-term untreated PBC worsened insulin resistance and aggravated diabetes mellitus in this patient. To the best of our knowledge, this is the first reported case of pyomyositis caused by an unusual pathogen, S. agalactiae, in a patient with newly diagnosed PBC.

Early urate-lowering therapy in gouty arthritis with acute flares: a double-blind placebo controlled clinical trial.

BACKGROUND: Gouty arthritis (GA) is a chronic systemic disease with recurrent acute monoarthritis. In a previous study, a higher incidence of acute flares was observed during the initial marked decrease in serum urate level. Our study evaluated the effect of early urate-lowering therapy in patients with acute GA flares. METHODS: This study included 40 patients with acute GA; of them, 20 received colchicine 0.5 mg colchicine twice daily, while 20 received probenecid 500 mg and colchicine 0.5 mg twice daily. We evaluated GA severity and laboratory data for 2 weeks after the initial therapy. Medians and interquartile ranges (IQRs) were calculated to evaluate clinical presentations between these two groups. RESULTS: Rapidly decreasing median serum uric acid levels was found in the patients treated with probenecid and colchicine compared with the patients treated with colchicine alone on day 8 (- 1.9 [IQR, - 3.7 to 0] vs 0.8 [IQR, - 0.1-2.2]; P < 0.001). However, the median decrease in visual analog scale score did not differ significantly between the two groups (- 5.5 [IQR, - 8.0 to - 3.0] vs - 3.5 [IQR, - 5.9 to - 2.0]; P = 0.080). CONCLUSION: No significant increase was noted in acute gout flare severity or duration among GA patients treated with early aggressive control of hyperuricemia using probenecid plus colchicine.

Genome-wide association study reveals ethnicity-specific SNPs associated with ankylosing spondylitis in the Taiwanese population.

BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune disease affecting mainly spine and sacroiliac joints and adjacent soft tissues. Genome-wide association studies (GWASs) are used to evaluate genetic associations and to predict genetic risk factors that determine the biological basis of disease susceptibility. We aimed to explore the race-specific SNP susceptibility of AS in Taiwanese individuals and to investigate the association between HLA-B27 and AS susceptibility SNPs in Taiwan. METHODS: Genotyping data were collected from a medical center participating in the Taiwan Precision Medicine Initiative (TPMI) in the northern district of Taiwan. We designed a case-control study to identify AS susceptibility SNPs through GWAS. We searched the genome browser to find the corresponding susceptibility genes and used the GTEx database to confirm the regulation of gene expression. A polygenic risk score approach was also applied to evaluate the genetic variants in the prediction of developing AS. RESULTS: The results showed that the SNPs located on the sixth chromosome were related to higher susceptibility in the AS group. There was no overlap between our results and the susceptibility SNPs found in other races. The 12 tag SNPs located in the MHC region that were found through the linkage disequilibrium method had higher gene expression. Furthermore, Taiwanese people with HLA-B27 positivity had a higher proportion of minor alleles. This might be the reason that the AS prevalence is higher in Taiwan than in other countries. We developed AS polygenic risk score models with six different methods in which those with the top 10% polygenic risk had a fivefold increased risk of developing AS compared to the remaining group with low risk. CONCLUSION: A total of 147 SNPs in the Taiwanese population were found to be statistically significantly associated with AS on the sixth pair of chromosomes and did not overlap with previously published sites in the GWAS Catalog. Whether those genes mapped by AS-associated SNPs are involved in AS and what the pathogenic mechanism of the mapped genes is remain to be further studied.

Low Molecular Weight Sericin Enhances the In Vitro of Immunological Modulation and Cell Migration.

Sericin, a waste product of the silk textile industry, has favorable physicochemical and biological properties. In this study, we extracted a low molecular weight (MW) sericin (LMW-sericin; below 10 kDa) by a performing high-temperature and high-pressure method and confirmed the MW using matrix-assisted laser desorption ionization-time of flight and liquid chromatography-mass spectrometry. Furthermore, we determined its biological effects on macrophages and human adipose stem cells (hASCs) as cell models to investigate the biocompatibility, immunomodulation behavior, and potential signaling pathway-related wound healing via analyses of gene expression of focal adhesion and human cytokines and chemokines using quantitative real-time polymerase chain reaction and cytokine assay. LMW-sericin showed good biocompatibility both in macrophages and hASCs. Macrophages cultured with 0.1 mg/ml LMW-sericin displayed an improved inflammatory response shown by the upregulation of CXCL9, IL12A, BMP7, and IL10, which developed Th1 and Th2 balance. LMW-sericin also improved the differentiation of macrophages toward the M2 phenotype by significantly enhancing the expression of Arg-1, which is conducive to the repair of the inflammatory environment. Moreover, the gene expression of hASCs showed that LMW-sericin promoted the secretion of beneficial adhesion molecules that potentially activate the gene transcription of differentiation and migration in hASCs, as well as significantly enhanced the levels of PKCß1, RhoA, and RasGFR1 as fruitful molecules in wound healing. These findings provide insights into LMW-sericin application as a potential biomaterial for wound management.

Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population.

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10-25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10-9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10-20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.

Strategy to Estimate Sample Sizes to Justify the Association between MMP1 SNP and Osteoarthritis.

Background: the impact of knee osteoarthritis (OA) poses a formidable challenge to older adults. Studies have reported that genetic factors, such as MMP1, are one of important risk factors for knee OA. Although the relationship between the genetic polymorphism of MMP1 rs1799750 and the risk of knee OA has been explored, conclusions have been nonunanimous and pending due to research sample sizes, one of determinants in studying genetic polymorphisms associated with disease. Objective: to establish a model to assess whether the genetic polymorphism of MMP1 rs1799750 is associated with knee OA based on an estimation of sample sizes. Methods: samples were collected from a case−control and meta-analysis study. In the case−control study, patients who underwent knee X-ray examinations based on the Kellgren−Lawrence Grading System (KL) as diagnostic criteria were recruited at the Health Examination Center of the Tri-Service General Hospital from 2015 to 2019. Gene sequencing was conducted using iPLEX Gold. Those with unsuccessful gene sequencing were excluded. Finally, there were 569 patients in the knee OA group (KL ≥ 2) and 534 participants in the control group (KL < 2). In the meta-analysis, we used the databases PubMed, EMBASE, and Cochrane to search for studies on the relationship between MMP1 rs1799750 and knee OA. Next, we adopted the trial sequential analysis (TSA) method to assess whether sample sizes were sufficient or not to determine the risk of the genetic polymorphism of MMP1 rs1799750 on knee OA in Caucasians and Asians. Results: in Caucasians, the MMP1 rs1799750 was not significantly associated with knee OA with an odds ratios (OR) of 1.10 (95% confidence interval, CI: 0.45−2.68). Some extra 8559 samples were needed to conclude this relationship in Caucasians by the TSA model. In Asians, neither our case−control study results (n = 1103) nor a combination of samples from the case−control and meta-analysis results showed an association between MMP1 rs1799750 and knee OA. The OR (95% CI) was 1.10 (0.81−1.49) in a combination of Asian samples. Some extra 5517 samples were needed to justify this relationship in Asians by the TSA model. Conclusions: this research shows that an extra 8559 and 5517 samples are needed in Caucasians and Asians, respectively, in order to justify the association between MMP1 rs1799750 and knee OA.

Differential gene expression orchestrated by transcription factors in osteoporosis: bioinformatics analysis of associated polymorphism elaborating functional relationships.

BACKGROUND: Identification of candidate SNPs from transcription factors (TFs) is a novel concept, while systematic large-scale studies on these SNPs are scarce. PURPOSE: This study aimed to identify the SNPs of six TF binding sites (TFBSs) and examine the association between candidate SNPs and osteoporosis. METHODS: We used the Taiwan BioBank database; University of California, Santa Cruz, reference genome; and a chromatin immunoprecipitation sequencing database to detect 14 SNPs at the potential binding sites of six TFs. Moreover, we performed a case-control study and genotyped 109 patients with osteoporosis (T-score ≤ -2.5 evaluated by dual-energy X-ray absorptiometry) and 262 healthy individuals (T-score ≥ -1) at Tri-Service General Hospital from 2015 to 2019. Furthermore, we used the expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression database to identify downstream gene expression as a criterion for the function of candidate SNPs. RESULTS: Bioinformatic analysis identified 14 SNPs of TFBSs influencing osteoporosis. Of these SNPs, the rs130347 CC + TC genotype had 0.57 times higher risk than the TT genotype (OR = 0.57, p = 0.031). Validation of eQTL analysis revealed that rs130347 T allele influences mRNA expression of downstream A4GALT in whole blood (p = 0.0041) and skeletal tissues (p = 0.011). CONCLUSIONS: We successfully identified the unique osteoporosis locus rs130347 in the Taiwanese and functionally validated this finding. In the future, this strategy can be expanded to other diseases to identify susceptible loci and achieve personalized precision medicine.

Association Between Depression or Anxiety and the Risk of Hepatitis B Flares: A Nationwide Population-Based Cohort Study.

Purpose: Depression and anxiety have been reported to increase the risk of infectious diseases and reactivation of latent infection. We conducted a nationwide population-based retrospective cohort study to determine the relationship between hepatitis B flares and depression or anxiety, utilizing outpatient and inpatient data from the Taiwan National Health Insurance Research database collected from 2000 to 2015. Patients and Methods: A total of 12,992 patients with chronic hepatitis B and newly diagnosed anxiety/depression, without advanced liver disease, were propensity score-matched for age, sex, and comorbidities in a 1:4 ratio to 51,968 controls with chronic hepatitis B without depression/anxiety or advanced liver disease. Both groups were followed-up until December 31, 2015. Cox proportional hazards regression was used to determine the risk factors for hepatitis B flares. The Log rank test and Kaplan-Meier analysis were performed to assess differences in the cumulative incidence of hepatitis B flares according to anxiety/depression status. Results: The incidence of hepatitis B flares was higher in the depression/anxiety cohort than in the control cohort (log-rank; p < 0.001). Patients with depression/anxiety had a significantly higher incidence rate of hepatitis B flares than those without depression/anxiety (3017 per 105 person-years versus 2042 per 105 person-years, p = 0.003). After adjusting for age and comorbidities, anxiety/depression was independently associated with an increased risk of hepatitis B flares (hazard ratio, 1.173; 95% confidence interval, 1.033-1.277; p = 0.003). Conclusion: This analysis suggests that in patients with chronic hepatitis B without advanced liver disease, those with concomitant depression or anxiety may be at higher risk of hepatitis B flares.

KL-6 as a Biomarker of Interstitial Lung Disease Development in Patients with Sjögren Syndrome: A Retrospective Case-Control Study.

Objective: Krebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays. Methods: Patients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA). Results: Of the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15-4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937-2242) and 764.5 U/mL (IQR 503.25-1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235-619) and 245 U/mL (IQR 215.25-291) in the ILD group and the non-ILD group, respectively (p = 0.074). Conclusion: Serum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.

Association between Clinical Use of Colchicine and Risk of Type 2 Diabetes Mellitus among Gouty Patients: A Nationwide Cohort Study.

BACKGROUND: Gout is the most common form of inflammatory arthritis in adults. Even though a link between gouty arthritis and type 2 diabetes mellitus (T2DM) has been reported, there is a limited understanding of the association between the anti-inflammatory agent colchicine and the risk of T2DM. This aim of this study was to assess the association between the use of colchicine and the risk of T2DM in an Asian cohort. METHODS: A retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan from 2000 to 2013. The study cohorts comprised 3841 gouty patients using colchicine (the exposed cohort) and 7682 gouty patients not using colchicine (the unexposed -cohort). The primary outcome was incident DM. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from a Cox proportional regression model were used to assess the association between colchicine use and the risk of diabetes. RESULTS: The cumulative incidence of T2DM was significantly lower in the exposed cohort (18.8%) than in the unexposed cohort (25.0%). The risk of T2DM was significantly lower in colchicine users than in non-users (adjusted HR, 0.74; 95% CI, 0.36-0.87). The inverse relationship between colchicine use and diabetes risk remained consistent across sex and age groups. CONCLUSIONS: This cohort study provides longitudinal evidence that the use of colchicine is associated with a reduced risk of T2DM. This conclusion, however, needs to be interpreted cautiously given the lack of body mass index data in the NHIRD. Further studies are needed to determine the clinical implications of this study.

A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Corticosteroid-Induced Liver Injury in Adult-Onset Still's Disease.

Background and Objectives: Adult-onset Still's disease (AOSD) is a rheumatic disease characterized by systemic inflammatory symptoms, including intermittent spiking fever, polyarthritis and a distinctive salmon-colored rash. Corticosteroids are the first-line treatment for AOSD. However, corticosteroids are potentially hepatotoxic in certain cases and may complicate the course of the disease. Materials and Methods: A 29-year-old female suffering from fever of unknown origin for two weeks was diagnosed with AOSD according to Yamaguchi's criteria. She received corticosteroids as the first-line treatment for AOSD and developed acute severe hepatitis. A diagnostic protocol has been performed. Results: Corticosteroid-induced liver injury was confirmed by clinical observation and rechallenge of the drug in this case. The result of liver biopsy also supported the diagnosis. Mycophenolic acid, a disease-modifying antirheumatic drug (DMARD) was chosen as an alternative treatment. AOSD remission was achieved under this treatment after three months. Conclusions: Severe acute hepatitis induced by corticosteroids, although very rare, may be observed in patients with AOSD. Drug-induced liver injury needs to be kept in mind when unexpected acute hepatitis is found. Mycophenolic acid could be a proper substitute medication in these cases.

Thymoma-Related Paraneoplastic Syndrome Mimicking Reactive Arthritis.

Background and Objectives: Thymomas are associated with a high frequency of paraneoplastic manifestations. Paraneoplastic syndrome (PNS) with thymoma presents a challenge to clinicians because of the need to decipher the association between the presenting symptoms and the underlying tumor. The condition most commonly noted in patients with PNS with thymoma is myasthenia gravis. Other common autoimmune diseases that may present as PNS include systemic lupus erythematosus, pure red cell aplasia, and Good syndrome. Seventy-six percent of patients with PNS-associated thymoma experience resolution of PNS after curing thymoma. Materials and Methods: A 37-year-old man with a two-month fever accompanied by polyarthritis accidently found thymoma after contrast computed tomography scans of his chest. He accepted Video assisted thoracoscopic surgery with resection of thymoma. Results: Fever and polyarthritis resolved after operation but recurred in five days due to cytomegalovirus viremia, which might be predisposed by previous antibiotics treatment before the diagnosis of thymoma. Conclusion: Patients with a thymoma also have a high frequency of PNS, and the most frequent condition found in patients with PNS-associated thymoma is myasthenia gravis. Fever with polyarthritis has been rarely reported as a symptom of PNS-associated thymoma. Here we reported an unusual case of PNS mimicking reactive arthritis with thymoma, as diagnosed based on the patient's clinical progression, imaging examination, and laboratory tests. The patient died of his comorbidities, and his death may have been related to long-term antibiotic use and consequent intestinal dysbiosis. This challenging case may help to inform clinicians of the need for detailed work-up of fever with unknown origin in the presence of chronic polyarthritis to prevent the overdiagnosis of inflammatory arthritis or rheumatic disease and avoid further comorbidities. Detailed work-up should include the patient's history of infections, inflammation, and malignant or nonmalignant tumors.

MRI contributes to accurate and early diagnosis of non-radiographic HLA-B27 negative axial spondyloarthritis.

BACKGROUND: Nonradiographic axial spondyloarthropathies (nr-axSpA) are diagnosed by the absence of radiographic sacroiliitis and the presence of bone marrow edema (BME) on magnetic resonance imaging (MRI). According to the classification criteria of the international Assessment of Spondyloarthritis Society (ASAS), structural changes to sacroiliac joints (SIJs) on MRI cannot be used as criteria in the absence of BME. However, less than half the Asian patients with clinically active axSpA show BME. The incidence of human leukocyte antigen (HLA)-B27 is low in Asian populations, which makes it more difficult to identify nr-axSpA. We used MRI to evaluate the structural damage to SIJs in patients with nr-axSpA with and without BME with the aim of identifying the best methodology for accurate diagnosis, especially in populations with less common BME and HLA-B27. METHODS: One hundred three patients with inflammatory back pain were included in this prospective study. No patient's radiograph met the definition of positive modified New York criteria. BME and structural damage to SIJ including sclerosis and erosion were assessed independently on coronal and axial short-tau inversion recovery and T1-weighted spin echo MRI scans by two well-trained musculoskeletal radiologists using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Demographics of patients were collected. Disease characteristics and structural damage were analyzed in patients with and without BME on SIJ MRI. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of structural damage. RESULTS: All individuals in the cohort had at least one abnormal finding on SIJ MRI, including BME or structural damage; 36 of 103 patients had BME. We identified a significant positive correlation between SPARCC scores and severe erosion assessed by focal joint space widening (fJSW) (p = 0.001) in these 36 patients. Fifty-eight of the 103 enrolled patients fulfilled the ASAS criteria for nr-axSpA in the either absence or presence of BME. Of these 58 patients, 57 and 19 had erosions or fJSW, respectively, and the presence of BME was significantly correlated with fJSW (phi score of 0.319 and p = 0.015). We demonstrated a significant positive correlation between fJSW and either the presence or the severity of BME in patients with nr-axSpA who met the ASAS definition. There was a positive correlation between BME and fJSW across the whole study cohort (phi score of 0.389; p < 0.001). The area under the ROC curve (AUC) for fJSW on SIJ MRI was 0.736, p < 0.001. In both HLA-B27-positive and -negative groups, BME was more common in the presence of fJSW (phi scores of 0.370 and 0.377, p = 0.018 and 0.003, respectively) and SPARCC scores were higher in patients with fJSW (p < 0.001 and p = 0.005). We also identified a positive correlation between fJSW and BME in patients with nr-axSpA and normal serum levels of C-reactive protein (phi score of 0.362 and p = 0.001). CONCLUSION: Structural damage detected on SIJ MRI, sclerosis, erosions and fJSW may be present in patients without detectable inflammation on SIJ MRI. However, fJSW is significantly correlated with the severity of inflammation seen on SIJ MRI, which contributes to the accurate diagnosis of nr-axSpA, and it could be used as an alternative diagnostic test for nr-axSpA in the general population, especially for those who do not carry the HLA-B27 gene, Asian patients without BME, or patients with normal serum inflammatory biomarkers.