Association of Tumor Necrosis Factor Inhibitors with the Risk of Nontuberculous Mycobacterial Infection in Patients with Rheumatoid Arthritis: A Nationwide Cohort Study.

Tumor necrosis factor inhibitors (TNFi) are proposed as a risk factor for nontuberculous mycobacteria (NTM) infection. Limited research investigates NTM infection risk in rheumatoid arthritis (RA) patients treated with TNFi compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), considering other concurrent or prior non-TNFi antirheumatic drugs. We aimed to evaluate the NTM infection risk associated with TNFi using a real-world database. Patients with RA treated with TNFi or csDMARDs between 2005 and 2016 were identified utilizing the Korean National Health Insurance Service database. To minimize potential bias, we aligned the initiation year of csDMARDs for both TNFi and csDMARD users and tracked them from their respective treatment start dates. The association of TNFi with NTM infection risk was estimated in a one-to-one matched cohort using a multivariable conditional Cox regression analysis. In the matched cohort (n = 4556), the incidence rates of NTM infection were 2.47 and 3.66 per 1000 person-year in TNFi and csDMARD users. Compared to csDMARDs, TNFi did not increase the risk of NTM infection (adjusted hazard ratio (aHR) 0.517 (95% confidence interval, 0.205-1.301)). The TNFi use in RA patients was not associated with an increased risk of NTM infection compared to csDMARDs. Nevertheless, monitoring during TNFi treatment is crucial.

The risk of newly diagnosed cancer in patients with rheumatoid arthritis by TNF inhibitor use: a nationwide cohort study.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors use in patients with rheumatoid arthritis (RA) has raised safety concerns about cancer risk, but study results remain controversial. This largest nationwide study to date compared cancer risk in TNF inhibitor users to non-biologic disease-modifying anti-rheumatic drug (nbDMARD) users in Korean patients with RA. METHODS: Data on all the eligible patients diagnosed with RA between 2005 and 2016 were retrieved from the Korean National Health Information Database. The one-to-one matched patients consisted of the matched cohort. The risks for developing all-type and site-specific cancers were estimated using incidence and incidence rate (IR) per 1000 person-years. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using a Cox regression model. RESULTS: Of the 22,851 patients in the before matching cohort, 4592 patients were included in the matched cohort. Treatment with TNF inhibitors was consistently associated with a lower risk of cancer than in the nbDMARD cohort (IR per 1000 person-years, 6.5 vs. 15.6; adjusted HR, 0.379; 95% CI, 0.255-0.563). The adjusted HR (95% CI) was significantly lower in the TNF inhibitor cohort than the nbDMARD cohort for gastrointestinal cancer (0.432; 0.235-0.797), breast cancer (0.146; 0.045-0.474), and genitourinary cancer (0.220; 0.059-0.820). CONCLUSIONS: The use of TNF inhibitors was not associated with an increased risk of cancer development, and rather associated with a lower cancer incidence in Korean patients with RA. Cautious interpretation is needed not to oversimplify the study results as cancer-protective effects of TNF inhibitors. A further study linking claims and clinical data is needed to confirm our results.

Cancer risk in Korean patients with gout.

BACKGROUND/AIMS: Using a nationwide cohort, we investigated the cancer risk in Korean patients with gout. METHODS: Data were obtained from the Korean National Health Insurance Service Database. Patients with gout were defined as those aged ≥ 20 years who were diagnosed with gout and received anti-gout medication (allopurinol, colchicine, and benzbromarone) between 2008 and 2010. Patients with nail disorders were randomly assigned to a control group (1:1 ratio) after frequency matching for age and sex. Cancer incidence was then investigated between 2012 and 2018. Cox proportional hazard regression analysis was used to investigate the association between gout and cancer after adjusting for concomitant diseases. RESULTS: This study included 179,930 patients with gout and an equal number of matched controls. The incidence of overall cancer was higher in patients with gout than in controls (incidence rate ratio, 1.08). Cox proportional hazards regression analysis showed that gout was associated with a hazard ratio of 1.053 (95% confidence interval ,1.031 to 1.077) after adjusting for concomitant diseases. CONCLUSION: Gout was associated with a significantly high risk of cancer, especially esophageal, stomach, colon, liver, pancreatic, lung, ovarian, renal, and bladder cancers.

Presence of tophi is associated with a rapid decline in the renal function in patients with gout.

We aimed to compare clinical characteristics of patients with and without tophi at the time of the diagnosis of gout and investigate the association of tophi and renal function in gout patients. The patients who were first diagnosed with gout at the Kangwon National University Hospital were retrospectively studied. Patients were divided into 2 groups according to the presence of tophi at the diagnosis. We compared clinical characteristics and the progression of renal dysfunction between the two groups. Of 276 patients, 66 (25.5%) initially presented with tophi. Tophi group was older, had a longer symptom duration, and a higher prevalence of multiple joint involvement than those without tophi. In multivariate logistic regression analysis, prolonged symptom duration and multiple joint involvement were significantly associated with increased risk of formation of tophi. The decline in the eGFR was more prominent in patients with tophi than in those without (- 4.8 ± 14.5 vs. - 0.7 ± 11.9 ml/min/1.73 m2/year, respectively; P = 0.039). The presence of tophi was significantly associated with a rapid decline in the eGFR (ß = - 0.136; P = 0.042). In conclusion, the presence of tophi was associated with a rapid declining renal function. Therefore, an early diagnosis and closely monitoring of renal function might be important in gout patients with tophi.

A Patient With Late-onset Limb-girdle Muscular Dystrophy Type 2B Mimicking Dermatomyositis: A Case Report and Review.

Limb-Girdle Muscular Dystrophy 2B (LGMD2B) presents with proximal and/or distal muscle weakness and markedly high creatine kinase level. It is caused by the loss of dysferlin due to mutations in the DYSF gene. Due to its similar clinical features as inflammatory myopathy, it is often difficult to distinguish between the two. We present a case of a 48-year-old male who developed progressive proximal muscle weakness, papulosquamous lesions on the knuckles, elevated levels of muscle enzymes, and electromyogram abnormalities. Based on the clinical presentation, the initial impression was dermatomyositis, yet it was refractory to immunosuppressive therapy. Subsequently, dysferlin immunostaining and genetic analysis led to the final diagnosis of LGMD2B. This case shows that LGMD2B can present with extramuscular symptoms mimicking inflammatory myopathy in later stages of life. Dysferlin immunostaining and/or genetic analysis of the DYSF gene are essential for its diagnosis.

Patient perspectives on biological treatments for inflammatory arthritis: A multi-center study in Korea.

Objectives: The aim of this study was to evaluate the patient's perception of the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) and provide a basis for physicians to understand the patient's perspective. Patients and methods: Between December 2018 and June 2019, a total of 307 patients (162 males, 145 females; mean age: 48 years; range, 18 to 81 years) were included in this investigator-initiated, multi-center, observational, and cross-sectional study in six rheumatology centers. We asked patients using bDMARDs to treat rheumatoid arthritis (RA) or ankylosing spondylitis (AS) to complete a questionnaire regarding major considerations and satisfaction with bDMARDs, preferred administration route, knowledge about bDMARDs, experiences of adverse events, non-adherence, and expectations of their healthcare provider. The satisfaction of physician and clinical information on the patient's disease and treatment were also collected. Results: Of the patients, 139 had RA and 168 had AS. Median disease duration was six years in RA and five years in AS. A total of 80.1% of the patients and 77.1% of the physicians indicated being satisfied or very satisfied with the therapeutic effect of the current bDMARD. Most patients were open to intravenous or subcutaneous injection, with the most preferred route of administration being subcutaneous (41.3%), followed by intravenous (32.0%), and oral (26.7%). The patients considered therapeutic effect to be more important than cost or convenience while choosing a bDMARD (69.3%), and most were willing to be educated about therapeutic effects (46.1%). Only 35.2% of the patients reported well and/or very well knowledge about the therapeutic effects, side effects, and administration methods of their current bDMARD, and 86.6% cited their physician as the primary source of information about biological treatment. Conclusion: Patients value therapeutic effect more than cost or convenience while selecting a bDMARD, and consider their physicians to be the primary information source. Therefore, it is important for physicians to provide appropriate education and encourage patients to cooperate actively with treatment.

Practical Utility of D-dimer Test for Venous Thromboembolism in Systemic Lupus Erythematosus Depends on Disease Activity: a Retrospective Cohort Study.

BACKGROUND: The D-dimer test is a screening tool for venous thromboembolism (VTE); however, its utility for patients with systemic lupus erythematosus (SLE) remains unclear. Here, we examined the utility of the D-dimer test as a screening tool for VTE in SLE patients. METHODS: SLE patients (n = 276) and age- and sex-matched patients with non-rheumatic disease (n = 1,104), all of whom underwent D-dimer testing to screen for VTE, were enrolled. The sensitivity and specificity and receiver operating characteristics curve of the D-dimer test were compared in both groups. Then, subgroup of SLE patients in whom the D-dimer test can be useful was sought. RESULTS: The incidence of VTE was more common in SLE patients than controls (10.9% vs. 4.0%). Although the sensitivity of the D-dimer test was comparable between SLE patients and controls (93.3% vs. 90.9%), the specificity of the test was profoundly lower in SLE patients compared to controls (28.4% vs. 84.4%). The area under the curve (AUC) of the D-dimer for VTE was 0.669 in SLE patients and 0.90 in control group. Multiple linear regression analysis demonstrated that SLE disease activity index-2000 (SLEDAI-2K) was significantly associated with D-dimer levels in SLE patients (ß = 0.155; P = 0.022). Subgroup analysis showed that the AUC is moderate (0.768) with low disease activity, while it is low (0.518) with high SLEDAI-2K. CONCLUSION: The D-dimer test may not be a useful screening tool for VTE in patients with active SLE. D-dimer test for predicting VTE in SLE patients should be differentially applied according to disease activity of SLE.

Predictors of Flares in Patients with Rheumatoid Arthritis Who Exhibit Low Disease Activity: A Nationwide Cohort Study.

Using nationwide cohort data, this study evaluated predictors of flares in patients with rheumatoid arthritis (RA) who exhibit low disease activity (LDA) and the effects of flares on clinical outcomes. The Korean Observational Study Network for Arthritis (KORONA) registry is a nationwide Korean RA-specific cohort registry that collects data annually from 5.077 patients, with RA in 23 centers across South Korea. This study used data from 1.717 patients with RA who exhibited LDA [28-joint disease activity score (DAS28) < 3.2] at enrollment. Flares were defined as an increase in DAS28, compared with the previous value of > 1.2 or > 0.6, if the concurrent DAS28 was ≥ 3.2. Cox regression analysis was used to identify baseline predictors of flares. Of the 1.717 patients with RA, 566 (33.0%) experienced flares during the 2-year study period. An analysis of baseline characteristics of flare and non-flare groups revealed that more women and non-smokers were present in the flare group than in the non-flare group; the flare group also had higher scores on physician's and patient's pain and fatigue visual analogue scales (VAS) and the health assessment questionnaire (HAQ). In a multivariate analysis, physician's VAS score, hemoglobin level, and HAQ score were significant predictors of flares. A high physician's VAS score, low hemoglobin, and high HAQ score at baseline were significant predictors of flares in patients with RA who exhibited LDA.

Combined Use of Febuxostat and Colchicine Does Not Increase Acute Hepatotoxicity in Patients with Gout: A Retrospective Study.

Colchicine has been effectively used to prevent acute flares in patients with gout, but drug-related adverse events have frequently occurred. We investigated whether colchicine therapy with febuxostat is associated with hepatotoxicity in gout patients. Gout patients treated with (n = 121) or without (n = 57) colchicine were enrolled upon initiating febuxostat as a urate-lowering treatment, and clinical and laboratory data at diagnosis were compared. Logistic regression analysis was performed to evaluate the risk factors related to hepatotoxicity. Median age of the with-colchicine and without-colchicine groups was 51.0 (37.0-62.0) and 56.0 (43.5-68.5) years, respectively. During the three months of febuxostat prescription, the prevalence of hepatotoxicity was 13/121 (10.9%) in the with-colchicine group and 4/57 (7.0%) in the without-colchicine group, without statistical significance. The rate of colchicine use was not different between the study subjects with or without hepatotoxicity (76.5% vs. 67.1%, p = 0.587). Pre-existing liver disease was significantly associated with increased risk of hepatotoxicity after febuxostat treatment (odds ratio, 4.083; 95% confidence interval, 1.326-12.577; p = 0.014). Colchicine may be safely used as a prophylactic agent for gout patients with febuxostat. However, upon initiating febuxostat, it is recommended to monitor the development of acute liver injury in gout patients with underlying liver disease.

Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome.

BACKGROUND/AIMS: Myelodysplastic syndrome (MDS) is caused by genetic and epigenetic alteration of hematopoietic precursors and immune dysregulation. Approximately 20% of patients with MDS develop an autoimmune disease (AID). Here, we investigated whether particular genetic mutations are associated with AID in patients with MDS. METHODS: Eighty-eight genetic mutations associated with myeloid malignancy were sequenced in 73 MDS patients. The association between these mutations and AID was then analyzed. RESULTS: The median age of the 73 MDS patients was 70 years (interquartile range, 56 to 75), and 49 (67.1%) were male. AID was observed in 16 of 73 patients (21.9%). Mutations were detected in 57 (78.1%) patients. The percentage (68.8% vs. 80.7%, p = 0.32) and the mean number of mutations (1.8 ± 1.6 vs. 2.2 ± 1.8, p = 0.34) in MDS patients with or without AID were similar. However, the ten-eleven translocation- 2 (TET2) mutation rate was significantly higher in patients with AID than in those without (31.3% vs. 5.3%, respectively; p = 0.001). All TET2 mutations were variants of strong clinical significance. CONCLUSION: Mutation of TET2 in patients with MDS may be associated with increased risk of developing AID.

Health-related quality of life in systemic sclerosis compared with other rheumatic diseases: a cross-sectional study.

BACKGROUND: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and the involvement of multiple internal organs. Previous studies reported poorer health-related quality of life (HRQoL) in patients with SSc compared with the general population. However, very little is known about how HRQoL in SSc patients compares with that in patients with other systemic autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS). Thus, the main aim of this study was to compare HRQoL in SSc patients, patients with other rheumatic diseases, and the general population. METHODS: In this cross-sectional study, patients from the rheumatology clinics of Seoul National University Hospital with SSc, RA, SLE, and SjS were enrolled via a random sampling technique. HRQoL was captured by the Short Form (36) health survey (SF-36), the Short Form Six-Dimensional health index (SF-6D), and the EuroQol Five-Dimensional descriptive system (EQ-5D). Demographic characteristics and standardized disease activity for each disease were also obtained. Previously reported data from 600 healthy Koreans were used for the healthy controls. An ANCOVA test was used to compare the SF-36, SF-6D, and EQ-5D values between study subjects with adjustments for age, sex, disease duration, comorbidities, and disease activity status. RESULTS: One hundred twenty patients were included in each of the SSc, RA, SLE, and SjS cohorts. Patients with rheumatic diseases had significantly lower SF-36, SF-6D, and EQ-5D scores than healthy controls (all P < 0.001). After statistical adjustments, SSc patients reported significantly lower mental component summary (MCS) scores than patients with RA (P < 0.001) or SLE (P = 0.001). Specifically, the mental health and general health domains were significantly lower in SSc patients than reported in RA or SLE patients (P < 0.001 and P = 0.001, respectively, in both domains). In SSc patients, higher modified Rodnan skin scores (mRSS) correlated with lower MCS scores. CONCLUSIONS: SSc patients report poorer HRQoL than patients with RA or SLE. The extent of skin involvement is associated with poorer HRQoL in SSc patients. TRIAL REGISTRATION: NCT03257878 . Registered 22 August 2017.

Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses.

Amino acids (AAs) are necessary nutrients which act not only as building blocks in protein synthesis but also in crucial anabolic cellular signaling pathways. It has been demonstrated that SLC7A5 is a critical transporter that mediates uptake of several essential amino acids in highly proliferative tumors and activated T cells. However, the dynamics and relevance of SLC7A5 activity in monocytes/macrophages is still poorly understood. We provide evidence that SLC7A5-mediated leucine influx contributes to pro-inflammatory cytokine production via mTOR complex 1 (mTORC1)-induced glycolytic reprograming in activated human monocytes/macrophages. Moreover, expression of SLC7A5 is significantly elevated in monocytes derived from patients with rheumatoid arthritis (RA), a chronic inflammatory disease, and was also markedly induced by LPS stimulation of both monocytes and macrophages from healthy individuals. Further, pharmacological blockade or silencing of SLC7A5 led to a significant reduction of IL-1ß downstream of leucine-mediated mTORC1 activation. Inhibition of SLC7A5-mediated leucine influx was linked to downregulation of glycolytic metabolism as evidenced by the decreased extracellular acidification rate, suggesting a regulatory role for this molecule in glycolytic reprograming. Furthermore, the expression of SLC7A5 on circulating monocytes from RA patients positively correlated with clinical parameters, suggesting that SLC7A5-mediated AA influx is related to inflammatory conditions.

Birmingham vasculitis activity score at diagnosis is a significant predictor of relapse of polyarteritis nodosa.

The objective of this study was to investigate whether clinical and laboratory data, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis could predict relapse in 30 patients with polyarteritis nodosa (PAN) having the follow-up duration for over 12 months. We reviewed the medical charts of 30 patients with PAN. We obtained clinical and laboratory data at diagnosis, and we compared them between the two groups based on relapse. The optimal cut-off values of BVAS and FFS (1996) at diagnosis to predict relapse were extrapolated. The mean age of patients (15 men) was 50.8 years, and the mean follow-up duration was 64.1 months. Nine patients (30.0%) had experience relapse after remission. Patients having relapse showed the higher frequency of weight loss and ocular symptoms and the less frequency of diastolic hypertension than those having not (p < 0.005 for all). On multivariate logistic regression analysis, weight loss was the only independent predictor of relapse, but on Cox Hazard model analysis, its statistical significance disappeared. The mean initial BVAS and FFS (1996) of patients in relapse group were higher than those of patients in no relapse group (p < 0.005 for all). Patients having initial BVAS over 13.5 and FFS (1996) over 1 exhibited significantly higher risk of relapse than those having not (RR 40.0 and RR 7.0, respectively). However, initial BVAS over 13.5 only remained significant in Kaplan-Meier survival analysis. In conclusion, BVAS over 13.5 at diagnosis was the only independent predictor of relapse of PAN.

Chest and renal involvements, Birmingham vascular activity score more than 13.5 and five factor score (1996) more than 1 at diagnosis are significant predictors of relapse of microscopic polyangiitis.

OBJECTIVES: We investigated whether specified organ involvements, antineutrophil cytoplasmic antibody (ANCA) positivity, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis could predict relapse of microscopic polyangiitis (MPA). METHODS: We reviewed the medical records of 90 patients with MPA. We collected clinical and prognostic data, (MPO)-ANCA and proteinase 3 (PR3)-ANCA, BVAS and FFS at diagnosis, and we compared them between the two groups. The optimal cut-off values of BVAS and FFS (1996) for predicting relapse were extrapolated. RESULTS: The mean age of patients (63 women) was 62.3 years and the mean follow-up duration was 41.7 months. At diagnosis, the mean BVAS, FFS (1996) and FFS (2009) of patients in no remission group were higher than those of patients in remission group (p<0.005 for all). Patients in relapse group exhibited chest and renal manifestations more frequently than those in no relapse group and the mean BVAS and FFS (1996) of patients in relapse group were significantly higher than those of patients in remission group (p<0.005 for all). There were no differences in MPO-ANCA and PR3-ANCA between the two groups. On multivariate logistic regression analysis, chest and renal manifestations were all independent predictors of relapse (OR 2.013 and OR 3.517). Patients who had BVAS ≥13.5 and FFS ≥ 1 exhibited a significantly increased risk of relapse than those who did not (RR 4.408 and RR 3.030). CONCLUSIONS: Chest and renal involvements, BVAS ≥13.5 and FFS ≥1 at diagnosis were independent predictors of relapse of MPA.