Ju-Yang Jung’s research while affiliated with Ajou University Medical Center and other places

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder primarily targeting joints, significantly impacting patients’ quality of life. The introduction of tumor necrosis factor-alpha (TNF-α) inhibitors has markedly improved RA management by reducing inflammation. However, these medications are associated with adverse skin reactions, which can vary greatly among patients due to genetic differences. Objectives: This study aimed to identify risk factors associated with skin adverse events by TNF-α in RA patients. Methods: A cohort study was conducted, encompassing patients with RA who were prescribed TNF-α inhibitors. This study utilized machine learning algorithms to analyze genetic data and identify markers associated with skin-related adverse events. Various machine learning algorithms were employed to predict skin and subcutaneous tissue-related outcomes, leading to the development of a risk-scoring system. Multivariable logistic regression analysis identified independent risk factors for skin and subcutaneous tissue-related complications. Results: After adjusting for covariates, individuals with the TT genotype of rs12551103, A allele carriers of rs13265933, and C allele carriers of rs73210737 exhibited approximately 20-, 14-, and 10-fold higher incidences of skin adverse events, respectively, compared to those with the C allele, GG genotype, and TT genotype. The machine learning algorithms used for risk prediction showed excellent performance. The risk of skin adverse events among patients receiving TNF-α inhibitors varied based on the risk score: 0 points, 0.6%; 2 points, 3.6%; 3 points, 8.5%; 4 points, 18.9%; 5 points, 36.7%; 6 points, 59.2%; 8 points, 90.0%; 9 points, 95.7%; and 10 points, 98.2%. Conclusions: These findings, emerging from this preliminary study, lay the groundwork for personalized intervention strategies to prevent TNF-α inhibitor-associated skin adverse events. This approach has the potential to improve patient outcomes by minimizing the risk of adverse effects while optimizing therapeutic efficacy.

Background/aims: This study aimed to identify the clinical characteristics of patients with concurrent rheumatoid arthritis (RA) and suspected non-tuberculous mycobacterial (NTM) infections as well as determine their prognostic factors. Methods: We retrospectively reviewed the medical records of 91 patients with RA whose computed tomography (CT) findings suggested NTM infection. Subsequently, we compared the clinical characteristics between patients with and without clinical or radiological exacerbation of NTM-pulmonary disease (PD) and investigated the risk factors for the exacerbation and associated mortality. Results: The mean age of patients with RA and suspected NTM-PD was 65.0 ± 10.2 years. The nodular/bronchiectatic (NB) form of NTM-PD was the predominant radiographic feature (78.0%). During follow-up, 36 patients (41.9%) experienced a radiological or clinical exacerbation of NTM-PD, whereas 12 patients (13.2%) died. Combined interstitial lung disease (ILD), microbiologically confirmed NTM-PD, and NB with the fibrocavitary (FC) form on chest CT were identified as risk factors for the clinical or radiological exacerbation of NTM-PD. Hydroxychloroquine use was identified as a good prognostic factor. Conversely, history of tuberculosis, ILD, smoking, microbiologically confirmed NTM-PD, and NB with the FC form on chest CT were identified as poor prognostic factors for mortality in suspected NTM-PD. Conclusions: ILD and NB with the FC form on chest CT were associated with NTM-PD exacerbation and mortality. Hydroxychloroquine use may lower the risk of NTM-PD exacerbation. Therefore, radiographic features and presence of ILD should be considered when predicting the prognosis of patients with RA and suspected NTM-PD.

Background Seasonal variation and sunlight exposure can impact serum vitamin D levels, potentially influencing lupus symptoms. We investigated seasonal vitamin D levels and their correlation with clinical manifestations and disease activity in systemic lupus erythematosus (SLE). Methods Serum 25(OH) vitamin D3 (25(OH)D3) levels were categorised as deficient (25(OH)D3 < 10 ng/mL), insufficient (10–30 ng/mL) and sufficiency (>30 ng/mL) in participants analysed in winter ( n = 407) and summer ( n = 377). Logistic regression analysis was performed to assess the impact of vitamin D levels on achieving a lupus low disease activity state (LLDAS), stratified by season. Results The mean serum 25(OH)D3 levels differed significantly between the winter and summer measurement groups (22.4 vs. 24.2 ng/mL; p = .018). The prevalences of vitamin D deficiency, insufficiency and sufficiency in the winter group were 12.8%, 66.6% and 20.6%, respectively, compared with 4.5%, 67.9% and 27.6% in the summer group. Achieving LLDAS was highest in the vitamin D sufficiency group (winter: 56.6%, summer: 55%) and lowest in the vitamin D deficiency group (winter: 15.4%, summer: 13.6%), with significant differences (all p < .001). Multivariate analysis identified SLE disease activity index ≤4, normal anti‐double‐stranded DNA and vitamin D sufficiency as significant factors for achieving LLDAS in both seasons. Conclusions Sufficient vitamin D levels are important for achieving LLDAS in patients with SLE during winter and summer. Therefore, physicians should pay attention to the adequacy of vitamin D levels and consider recommending vitamin D supplementation for patients with vitamin D insufficiency.

Background While the availability of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) has improved outcomes for rheumatoid arthritis (RA) patients, there remains a subset of individuals who fail to achieve low disease activity or remission despite multiple cycles of b/tsDMARDs. This state is referred to as 'difficult-to-treat (D2T)' RA. Methods Data from the Korean College of Rheumatology Biologics registry were utilized to analyze patients with RA who were treated with b/tsDMARDs. Results Among 2,321 RA patients with RA treated with b/tsDMARDs, 271 (11.7%) were diagnosed with D2T RA. Lower age (OR = 0.98, p < 0.001), longer disease duration (OR = 1.06, p < 0.001), lower patient global assessment (OR = 0.89, p = 0.045), higher SDAI (OR = 1.06, p = 0.014) and RAPID3 (OR = 1.06, p = 0.002), lower RF positivity (OR = 0.65, p = 0.04), and lower prior use of methotrexate (OR = 0.44, p = 0.008), sulfasalazine (OR = 0.59, p = 0.003), and leflunomide (OR = 0.67, p = 0.013) were associated with D2T RA. The drug survival rate of b/tsDMARDs did not differ between patients with D2T RA and non-D2T RA (p = 0.35). However, the drug survival of individual b/tsDMARD differed between patients with D2T RA and non-D2T RA after eight years. Patients with D2T RA withdrew from b/tsDMARDs due to inefficacy more frequently than those without D2T RA (p < 0.001). Conclusions D2T RA patients experienced higher disease activity despite maintaining b/tsDMARD therapy. Withdrawal rates due to inefficacy were higher in D2T RA. Effective therapeutic strategies are needed to improve disease control and treatment outcomes in this unique patient population.

Background: This study aimed to compare the occurrence of adverse events (AEs) and disease flares after vaccination against coronavirus disease 2019 (COVID-19) and influenza in patients with autoimmune rheumatic diseases (ARDs). Methods: Between November 2021 and March 2022, a survey was conducted among patients with ARD who received COVID-19 and influenza vaccinations. The questionnaire included 11 mandatory and closed-ended questions, and the following items were collected: medical history, immunization history, type of vaccine, patient-reported AEs, flare-up of the underlying disease after vaccination, and a confirmed diagnosis of COVID-19 or influenza. We compared the occurrence of vaccine-related adverse reactions to the COVID-19 and influenza vaccines based on the survey results. Multivariate logistic regression analysis was used to identify the factors affecting AEs or disease flares and to compare the post-vaccine response to mixed and matched vaccines. Results: We analyzed 601 adults with ARD who received the COVID-19 vaccine, with a mean age of 49.6 years (80.5% female). A total of 255 participants (42.4%) received a complete course of primary vaccination, 342 (56.9%) completed the booster dose, and 132 (38.6%) received a mixed vaccine. The frequencies of AEs (188 [52.2%] vs. 21 [5.8%]; P < 0.001) and disease flares (58 [16.2%] vs. 5 [1.4%]; P < 0.001) after COVID-19 vaccination were significantly higher than those after influenza vaccination. In the risk factor analysis, previous allergic reaction to other vaccines (odds ratio, 1.95; confidence interval, 1.07-3.70; P = 0.034) was the only factor associated with the occurrence of AEs. There was no difference in the post-vaccine responses between the mixed and matched vaccines. Conclusion: The results of the survey of patients with ARD revealed that patient-reported AEs and underlying disease flares after receiving the COVID-19 vaccine were significantly higher than those after the influenza vaccine.

Background The standard treatment of lupus nephritis is based on immunosuppressive therapy using mycophenolate mofetil or cyclophosphamide and with glucocorticoids, however, these treatments are not consistently effective. Tacrolimus (TAC), a novel calcineurin inhibitor with immunosuppressive effects, has recently become increasingly interested in its role as a potential therapeutic agent in SLE. We aimed to evaluate the efficacy of TAC as a treatment for LN. Methods A total 170 patients with biopsy proven LN were enrolled by reviewing the medical records of patients with LN in Ajou Lupus cohort. The clinical response of TAC treatment was evaluated by proteinuria, estimated glomerular filtration rate (eGFR), anti-double-stranded DNA (anti-dsDNA) antibody, complement 3 (C3), complement 4 (C4), and renal SLE disease activity index (SLEDAI). Complete renal response was defined as urine protein to creatinine ratio <0.5, normal serum creatinine or, if normal at baseline, not increased by ≥15%, and partial renal response was defined as a normal or near-normal GFR with a ≥50% reduction in proteinuria to sub-nephrotic levels. The definition of poor outcomes was determined by end stage renal disease or death. Results The baseline clinical manifestations between 92 TAC group and 87 non-TAC group showed no significant differences. Most of TAC group received multi-target therapy with other immunosuppressants, while the non-TAC group usually used monotherapy. After 5 years, there were no statistically significant differences in proteinuria, eGFR levels, anti-dsDNA, serum C3/C4, and renal SLEDAI. The overall (complete and partial) renal response rate was not significantly different (TAC group versus non-TAC group=72.9% versus 85.5%; p=0.1). The poor outcomes were similar in both groups (log-rank p=0.837). Conclusions TAC is an effective maintenance therapy for LN, and may be a reasonable option for patients with refractive LN or LN who have not reached remission. In conclusion, TAC can help patients with LN achieve a renal response and slow progression.

Background In recent years, many studies have demonstrated an important role of gut microbiota in the development of various illnesses including autoimmune diseases. A number of evidence have also been found that alterations of gut microbiota affect the host immune system, resulting in changes in autoimmunity, which contributes significantly to the development of systemic lupus erythematosus (SLE). Therefore, we aimed to elucidate discover the gut microbiotas influential to SLE and investigate their association with disease activities. Methods Fecal samples were provided in the same protocol from 38 patients with SLE in Ajou Lupus Cohort and 52 age and sex-matched healthy controls (HCs). The components of the gut microbiota in feces were investigated via 16S rRNA next-generation sequencing, and alpha and beta diversities were evaluated. Clinical, laboratory, and medication data of SLE patients were obtained through medical records, and the correlation between disease activity and gut microbiota was also analyzed. Results The gut microbiota of SLE group exhibited a significant decrease in species richness in the beta diversity analysis by NMDS plots compared to controls. Taxonomic composition differences between the two groups were also found at phylum, genus, species levels. At the species level, the relative abundance of 7 kind of bacteria was significantly higher and another 7 bacterial taxa were significantly lower in the SLE group compared with HCs, suggesting that reduction in Faecalibacterium prausnitzii and Prevotella copri (p=0.001 and p=0.001, respectively) played an important role in SLE. In clinical correlation analysis, there was a significant positive correlation between complement 3/4 and Faecalibacterium prausnitzii (r=0.44 and r=0.49, respectively), and total lymphocytes and Prevotella copri (r=0.45). Conclusions The composition of gut microbiota was different between SLE patients and HCs in Korean population. Among them, Faecalibacterium prausnitzii and Prevotella copri, which are significantly reduced in SLE patients, are expected to provide potential targets for new treatment.

Background Bisphosphonates (oral alendronate and risedronate, and intravenous zoledronate) are effective agents for glucocorticoid-induced osteoporosis (GIOP). Zoledronate is a convenient and highly compliant treatment compared to other bisphosphonates. In this study, we aimed to compare the efficacy, patient satisfaction, and preference of zoledronate with other bisphosphonates. Methods We included 50 patients diagnosed with GIOP during treatment for autoimmune diseases including systemic lupus erythematosus (SLE). All patients had new fractures or persistent osteoporosis in follow-up bone densitometry after taking oral bisphosphonates for at least 1 year. After 1 year of treatment with zoledronate, a face-to-face survey was conducted on patients’ preference and satisfaction. The treatment efficacy was analyzed by comparing the changes in bone density and fractures with patients maintaining oral bisphosphonates as controls. Results Patients with SLE and rheumatoid arthritis were included, with a mean age of 64.1 years (96% were female), and the mean duration of GIOP of 5.5 years. There was no difference in the cumulative glucocorticoid doses of the two groups. There were no significant differences in the treatment efficacy between zoledronate and oral bisphosphonate; annualized percentage change in bone density in the lumbar spine (1.9±3.91g/cm2 vs. 1±5.3g/cm2, p=0.355), femur neck (-0.91±6.31g/cm2 vs. 0.41±5.07g/cm2, p=0.264), and hip (0.29±2.91g/cm2 vs. 0.41±5.07g/cm2, p=0.888). The incidence of new fractures was two in each of the two groups, showing no difference. As a result of the survey, 39 patients (78%) preferred intravenous zoledronate over oral bisphosphonates and had higher satisfaction, and the most common reasons were administration interval and convenient regimen. The infusion-related adverse events of zoledronate were only 2 patients (4%). Conclusions The patient reported preference and satisfaction of zoledronate were significantly higher than that of oral bisphosphonates, and the treatment efficacy for osteoporosis was similar. Therefore, zoledronate is recommended as a proper treatment for GIOP in patients with autoimmune disease including SLE.

Background Sphingolipids involved in regulating signal pathways in cell growth, differentiation, and apoptosis are increasingly recognized as playing an important role in the pathophysiology of chronic inflammatory diseases. This study aimed to evaluate the serum profile of sphingolipids in systemic lupus erythematosus (SLE) and to investigate the association between serum sphingolipids and disease activity. Methods Levels of sphingolipids in plasma of women with SLE were assessed by liquid chromatography tandem mass spectrometry. The diagnostic value of plasma sphingolipids was analyzed using the area under the receiver operating characteristic curve (ROC). Pearson’s correlation coefficient was used to analyze the relationship with disease activity markers. Results Serum samples were collected from 38 women with SLE, including 11 lupus nephritis, and 30 controls. There were increases in concentration ceramide (Cer) and Cer to sphingosine-1-phosphate (S1P) ratio subspecies in patients with SLE, while the levels of sphingomyelins were decreased compared to the controls. The ratio of Cer16:0 to S1P showed a particularly strong increase in patients with lupus nephritis, with an area under the curve 0.739 (95% confidence interval, 0.581–0.898) to discriminate lupus nephritis in the control group. Furthermore, Cer16/S1P levels were correlated with disease duration, anti-double stranded DNA antibody, SLE disease activity index 2000, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Conclusions Our data indicate that serum sphingolipids can be a good candidate for SLE diagnostic markers. In particular, we identified that Cer16 to S1P could be useful for diagnosing lupus nephritis.

Background Recently, vitamin D has been shown to play an important role in the immune responses, increasing evidence that it can contribute to the pathogenesis of systemic lupus erythematosus (SLE) as well as affect disease course and activity. Therefore, this study aims to determine whether there is a correlation between seasonal vitamin D levels and clinical manifestations or disease activity. Methods Seasonal measurements of serum 25(OH)D3 were performed in December to February in winter time and in July to September in summer time. We included patients with SLE who measured serum 25(OH)D3 from 2013 to 2016, with 407 patients measured during winter and 375 patients measured during summer. Vitamin D-deficient groups were classified based on 20ng/ml, 25ng/ml, and 30ng/ml for each summer and winter. The relationship between vitamin D concentrations and clinical manifestations or disease activity was analyzed using logistic regression analysis. Results There were seasonal differences in the reference concentration of vitamin D, which affects disease activity or clinical manifestations, and the values were 20ng/ml and 30ng/ml in winter and summer, respectively. In the winter vitamin D-deficient group (less than 20ng/ml), the erythrocyte sedimentation rate was 23.9mm/hr, which was marginally higher than that in the vitamin D-sufficient group (22.4mm/hr, p = 0.08). In addition, oral ulcer was significantly less frequent in winter vitamin D-sufficient group (Odds ratio [OR] 0.530, p = 0.047). In summer, oral ulcer (OR 0.278, p = 0.019) and skin rash (OR 0.221, p= 0.015) were significantly less common in vitamin D-sufficient group with cut off of 30ng/ml. Conclusions In conclusion, this study suggests that seasonal variations in serum vitamin D may affect the clinical manifestations of SLE, and that vitamin D-deficiency leads to increased oral ulcer, skin rash, and inflammatory marker.