Epigenetic scars in regulatory T cells are retained after successful treatment of chronic hepatitis C with direct-acting antivirals.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection results in abnormal immunological alterations, which are not fully normalized after viral elimination by direct-acting antiviral (DAA) treatment. Here we longitudinally examined phenotypic, transcriptomic, and epigenetic alterations in peripheral blood regulatory T (TREG) cells from patients with chronic HCV infection according to DAA treatment. METHODS: Patients with chronic genotype 1b HCV infection who achieved sustained virologic response (SVR) by DAA treatment and age-matched healthy donors were recruited. Phenotypic characteristics of TREG cells were investigated through flow cytometry analysis. Moreover, transcriptomic and epigenetic landscape of TREG cells were analyzed using RNA-seq and ATAC-seq analysis. RESULTS: The TREG cell population-especially the activated TREG cell subpopulation-was expanded in peripheral blood during chronic HCV infection, and this expansion was sustained even after viral clearance. RNA-seq analysis revealed that viral clearance did not abrogate the inflammatory features of these TREG cells, such as TREG activation and TNF signal. Moreover, ATAC-seq analysis showed inflammatory imprinting in the epigenetic landscape of TREG cells from patients, which remained after treatment. These findings were further confirmed by intracellular cytokine staining, demonstrating that TREG cells exhibited inflammatory features and TNF production in chronic HCV infection that were maintained after viral clearance. CONCLUSIONS: Overall, our results showed that during chronic HCV infection, the expanded TREG cell population acquired inflammatory features at phenotypic, transcriptomic, and epigenetic levels, which were maintained even after successful viral elimination by DAA treatment. Further studies are warranted to examine the clinical significance of sustained inflammatory features in the TREG cell population after recovery from chronic HCV infection. IMPACT AND IMPLICATIONS: During chronic HCV infection, several immune components are altered both quantitatively and qualitatively. The recent introduction of DAAs led to a high cure rate of chronic HCV infection. Nevertheless, we have demonstrated that inflammatory features of TREG cells are maintained at phenotypic, transcriptomic, and epigenetic levels even after successful DAA treatment. Further in-depth studies are required to investigate the long-term clinical outcomes of patients who have recovered from chronic HCV infection.

Familial risk of seropositive rheumatoid arthritis and interaction with smoking: a population-based cohort study.

OBJECTIVES: We evaluated the familial risk of seropositive rheumatoid arthritis (RA) and examined interactions between family history and smoking. METHODS: Using the National Health Insurance and Health Screening Program databases, which include information on familial relationships and lifestyle factors, we identified 5 524 403 individuals with first-degree relatives (FDRs) from 2002-2018. We calculated familial risk using hazard ratios (HRs) with 95% CIs which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using the relative excess risk due to interaction (RERI). RESULTS: Individuals with affected FDR had 4.52-fold (95% CI 3.98, 5.12) increased risk of disease compared with those with unaffected FDR. Familial risk adjusted for lifestyle factors decreased slightly (HR 4.49), suggesting that a genetic contribution is the predominant driver in the familial aggregation of RA. Smoking was associated with an increased risk of disease that was more pronounced among heavy (HR 1.92 95% CI 1.70, 2.18) compared with moderate (HR 1.15 95% CI 1.04, 1.28) smoking. In the interaction analysis, the risk associated with the combined effect of smoking and family history was higher than the sum of their individual effects, though statistically non-significant (RERI 1.30 95% CI ‒0.92, 3.51). Heavy smokers with a positive family history showed a prominent interaction (RERI 4.13 95% CI ‒0.88, 9.13) which exceeded moderate smokers (RERI 0.61 95% CI ‒1.90, 3.13), suggesting a dose-response interaction pattern. CONCLUSION: Our findings indicate the possibility of an interaction between RA-associated genes and smoking.

Association between nuclear factor of activated T cells C2 polymorphisms and treatment response in rheumatoid arthritis patients receiving tumor necrosis factor-alpha inhibitors.

OBJECTIVES: Nuclear factor of activated T cells C2 (NFATC2) is known as a member of the transcription family and enhances tumor necrosis factor-alpha (TNF-α) synthesis in human T cells at the gene transcription level. Although NFATC2 has a potential role in rheumatoid arthritis (RA) progression and treatment, no study has investigated the association between NFATC2 gene polymorphisms and response status in RA patients receiving TNF-α inhibitors. This study aimed to examine the effects of polymorphisms in NFATC2, a TNF-α transcription factor, on response to TNF-α inhibitors. METHODS: This prospective observational study was performed in two centers. Seven single nucleotide polymorphisms (SNPs) were investigated. Good responders were defined as patients with disease activity score (DAS)28 ≤3.2 after 6 months of treatment. Logistic regression analyses were used to investigate the association between genetic polymorphisms and response to the treatment. To test the model's goodness of fit, a Hosmer-Lemeshow test was performed. RESULTS: This study included 98 patients, among whom 46 showed favorable responses to the treatment. Patients with hypertension revealed an approximately three-fold lower response to TNF-α inhibitors compared to those without hypertension (23.5 vs. 76.5%; P = 0.049). After adjusting for covariates, C allele carriers of NFATC2 rs3787186 exhibited approximately three-fold lower rates of treatment response compared to those with TT genotype (P = 0.037). The Hosmer-Lemeshow test showed that the fitness of the multivariable analysis model was satisfactory (χ2 = 9.745; 8 degrees of freedom; P = 0.283). CONCLUSION: This study suggested an association between the C allele of rs3787186 and treatment response in RA patients receiving TNF-α inhibitors.

A clinical comparison of an endothelin receptor antagonist and phosphodiesterase type 5 inhibitors for treating digital ulcers of systemic sclerosis.

OBJECTIVES: To assess the efficacy of an endothelin receptor antagonist (ERA) and phosphodiesterase type5 inhibitors (PDE5is) for treating SSc-related digital ulcers (DUs). METHODS: This prospective, multicentre, observational cohort study recruited patients with active SSc-related DUs from 13 medical centres in South Korea. The primary outcome was time to cardinal ulcer (CU) healing. A secondary outcome was time to new DU occurrence. Patients were followed up 4, 8, 12 and 24 weeks after treatment initiation. RESULTS: Sixty-three patients were analysed. Their mean age was 49.9 years (s.d. 11.4) and 49 were female. Twenty-eight had limited SSc. Forty-nine patients received ERA, 11 received a PDE5i (9 sildenafil, 1 udenafil and 1 tadalafil) and 3 received other medication. The hazard ratio (HR) for time to CU healing in the ERA group vs the PDE5i group was 0.75 (95% CI 0.35, 1.64; P = 0.47) in an unadjusted model and 0.80 (95% CI 0.36, 1.78; P = 0.59) in a model adjusted for age, sex, use of calcium channel blockers (CCBs), total DU number and initial CU area. The HR for new DU development in the ERA group vs the PDE5i group was 0.39 (95% CI 0.16, 0.93; P = 0.03) in an unadjusted model and 0.32 (95% CI 0.13, 0.81; P = 0.02) in an adjusted model. No patients receiving CCBs developed new DUs at 24 weeks. CONCLUSION: Time to CU healing is comparable for ERA and PDE5i. ERAs are more effective in reducing new DU occurrence than PDE5is. CCBs may be effective as a background medication.

Clinical Association between Gout and Parkinson's Disease: A Nationwide Population-Based Cohort Study in Korea.

Background and Objectives: This retrospective cohort study aimed to investigate the association between gout and Parkinson's disease (PD) in Korea. Materials and Methods: Overall, 327,160 patients with gout and 327,160 age- and sex-matched controls were selected from the Korean National Health Insurance Service (NHIS) database. PD incidence was evaluated by reviewing NHIS records during the period from 2002 to 2019. Patients with a diagnosis of gout (International Classification of Diseases-10 (ICD-10), M10) who were prescribed medications for gout, including colchicine, allopurinol, febuxostat, and benzbromarone for at least 90 days were selected. Patients with PD who were assigned a diagnosis code (ICD-G20) and were registered in the rare incurable diseases (RID) system were extracted. Results: During follow-up, 912 patients with gout and 929 control participants developed PD. The incidence rate (IR) of overall PD (per 1000 person-years) was not significantly different between both groups (0.35 vs. 0.36 in gout and control groups, respectively). The incidence rate ratio (IRR) was 0.98 (95% CI: 0.89-1.07). The cumulative incidence of PD was not significantly different between the groups. No association between gout and PD was identified in univariate analysis (HR = 1.00, 95% CI: 0.91-1.10, p = 0.935). HR increased significantly with old age (HR = 92.08, 198, and 235.2 for 60-69 years, 70-79 years, and over 80 years, respectively), female sex (HR = 1.21, 95% CI: 1.07-1.37, p = 0.002), stroke (HR = 1.95, 95% CI: 1.76-2.16, p < 0.001), and hypertension (HR = 1.16, 95% CI: 1.01-1.34, p = 0.04). Dyslipidemia exhibited an inverse result for PD (HR = 0.6, 95% CI: 0.52-0.68, p < 0.001). Conclusions: This population-based study did not identify an association between gout and PD. Age, female sex, stroke, and hypertension were identified as independent risk factors for PD, and dyslipidemia demonstrated an inverse result for PD.

Tocilizumab Increases Body Weight and Serum Adipokine Levels in Patients with Rheumatoid Arthritis Independently of Their Treatment Response: a Retrospective Cohort Study.

BACKGROUND: Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA). METHODS: In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24-72 weeks). RESULTS: No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, -0.2 kg; P = 0.630), but was observed after 24 weeks of tocilizumab treatment (mean difference, +0.9 kg; P = 0.010). Weight changed regardless of the treatment response in both treatment groups. The leptin-adiponectin ratio (P = 0.015) and levels of adiponectin (P < 0.001), leptin (P < 0.001), and resistin (P = 0.003) increased significantly after 24 weeks of tocilizumab, but not methotrexate treatment. After 24, 48 and 72 weeks of tocilizumab treatment in Cohort II, mean (95% confidence interval [CI]) weight changes from baseline were +0.7 (0.0-1.4), +1.2 (0.4-2.0) and +1.1 (0.2-2.0) kg, respectively, and mean (95% CI) percent weight changes from baseline were +1.3% (0.1%-2.6%), +2.2% (0.7%-3.6%), and +2.0% (0.4%-3.7%) at 24, 48, and 72 weeks, respectively. CONCLUSION: Weight and the leptin-adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients.

Performance of the 2015 American College of Rheumatology/European League against Rheumatism Classification Criteria for Gout in Korean Patients with Acute Arthritis.

BACKGROUND: We aimed to assess the performance of the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for gout in Korean patients with acute arthritis and to compare the performance of the ACR/EULAR criteria to that of other sets of criteria for gout classification. METHODS: Patients with acute arthritis who underwent diagnostic arthrocentesis at one of the four participating rheumatology clinics were consecutively enrolled between February and December 2017. Crystal-proven gout was diagnosed upon confirming the presence of monosodium urate (MSU) crystals in patients with a clinical impression of gout as judged by the rheumatologist. The performance of the ACR/EULAR and other gout classification criteria, including the Rome, New York, American Rheumatism Association (ARA), Mexico, and Netherlands criteria, was analyzed regardless of the presence/absence of MSU crystals. RESULTS: The study enrolled 118 gout patients (all crystal-proven) and 95 non-gout patients. According to the area under the curve, the diagnostic performance was the highest for the ACR/EULAR classification criteria (sensitivity, 80.5%; specificity, 95.8%; area under the curve, 0.966), followed by the Netherlands, Rome, ARA, New York, and Mexico criteria. All six sets of criteria demonstrated lower sensitivity in patients exhibiting the first episode of acute arthritis. CONCLUSION: In Korean patients with acute arthritis, the ACR/EULAR classification criteria outperformed other sets of gout classification criteria even in the absence of information regarding the presence of MSU crystals. However, to enhance diagnostic sensitivity, synovial fluid analysis should be considered in patients with the first episode of acute arthritis.

Association between anti-Porphyromonas gingivalis or anti-α-enolase antibody and severity of periodontitis or rheumatoid arthritis (RA) disease activity in RA.

BACKGROUND: Periodontitis (PD) has been reported to be associated with rheumatoid arthritis (RA). Porphyromonas gingivalis (P. gingivalis) is a gram-negative anaerobic bacterium that is recognized as one of the major pathogenic organisms in PD and is the only bacterium known to express peptidylarginine deiminase (PAD). Antibody against human α-enolase (ENO1) is one of the autoantibodies in RA. ENO1 is a highly conserved protein, and could be a candidate molecule for molecular mimicry between bacterial and human proteins. In the present study, we measured serum antibody against P. gingivalis and human ENO1 in patients with RA and investigated their association with the severity of PD or disease activity of RA. METHODS: Two hundred, forty-eight patients with RA and 85 age- and sex-matched healthy controls were evaluated by rheumatologic and periodontal examinations. The serum levels of anti-P. gingivalis and anti-ENO1 antibodies were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with RA had significantly higher levels of anti-P. gingivalis and anti-ENO1 antibody titers than the controls (p = 0.002 and 0.0001, respectively). Anti-P. gingivalis antibody titers significantly correlated with anti-ENO1 antibody titers in RA patients (r = 0.30, p < 0.0001). There were significant correlations between anti-P. gingivalis antibody titers and the gingival index (GI), probing pocket depth (PPD), bleeding on probing (BOP) and clinical attachment level (CAL) (p = 0.038, 0.004, 0.004 and 0.002, respectively) in RA. Anti-P. gingivalis antibody titers were not correlated with disease activity score 28 (DAS28) or anti-CCP titer. However, anti-ENO1 antibody titers were significantly correlated not only with the periodontal indices, such as PPD, BOP, and CAL (p = 0.013, 0.023 and 0.017, respectively), but also RA clinical characteristics, such as DAS28, anti-CCP titer, and ESR (p = 0.009, 0.015 and 0.001, respectively). CONCLUSION: Anti-P. gingivalis and anti-ENO1 antibody titers were correlated with the severity of PD in RA. Anti-ENO1 antibody titers, but not anti-P. gingivalis antibody titers, were further associated with RA disease activity.

Incidence of malignancy in Takayasu arteritis in Korea.

Cancer is associated with autoimmune diseases. This study aimed to estimate the incidence of cancer in a cohort of patients with Takayasu arteritis (TA) and to compare this incidence with the general population cancer rate in South Korea in a retrospective cohort study. The medical records of TA patients who underwent medical care at our institution between 1979 and 2009 were reviewed. The 2008 National Cancer Registry was used as the reference to calculate the standardized incidence ratio (SIR). The mean age of 180 patients was 48.6 ± 14.3 years, and 87.2 % of the patients were female. During the follow-up of 2,285 person years, 10 females developed cancer. Breast cancer was the most common malignancy with three cases, followed by two endometrial, one gastric, one colon, one pancreatic, one myelodysplastic syndrome (MDS) with refractory anemia with excess blasts, and one multiple myeloma. The SIR of cancer in TA was comparable with that of the general population at 1.3 [95 % confidence interval (CI) 0.6-2.3]; however, the risk of MDS was significantly increased (SIR 51.3; 95 % CI 1.3-285.7). While two patients with hematologic malignancies died, all TA patients with non-hematologic malignancies were still alive during the follow-up period. The overall risk of malignancy is not increased in TA. Further work is needed to determine if TA is associated with an increased risk of certain hematologic malignancies.

Comparison of the efficacy and safety profiles of a pelubiprofen versus celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, phase III, non-inferiority clinical trial.

BACKGROUND: Pelubiprofen is a prodrug of 2-arylpropionic acid with relatively selective effects on cyclooxygenase-2 activity. The aim of this study was to compare the efficacy and safety profiles of pelubiprofen with those of celecoxib in patients with rheumatoid arthritis. METHODS: This was a 6-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, non-inferiority clinical trial. The primary end point was non-inferiority of pain decrease from baseline to week-6 as determined using a 100 mm pain visual analog scale (VAS). Pelubiprofen was considered non-inferior to celecoxib if the lower limit of the 97.5% confidence interval for treatment difference [(pain reduction in pelubiprofen group) - (pain reduction in celecoxib group)] was more than -10 mm. The secondary end points were as follows: non-inferiority of (1) reduction of Korean health assessment questionnaire (KHAQ) score; (2) decreased duration of morning stiffness; and (3) decrease in the frequency and total dose of rescue drugs after 6 weeks of treatment. RESULTS: Seventy-seven patients in the pelubiprofen group and 68 patients in the celecoxib group started the study medication. Pelubiprofen was non-inferior to celecoxib with regard to reduction in VAS pain severity (difference, mean ± SD 5.0 ± 20.1; 97.5% CI, -2.3 to ∞). Pelubiprofen was also non-inferior to celecoxib in terms of the secondary end points, such as, decrease in KHAQ score (0.0 ± 0.5, 97.5% CI -0.2 to ∞), decrease in duration of morning stiffness (median 0.0 minute in both groups), and decrease in the frequency (0.7 ± 3.5, 97.5% CI -0.6 to ∞) and total amount (0.7 ± 3.6, 97.5% CI -0.6 to ∞) of rescue medication uses during the 6 week study period. Safety analysis revealed 31.2% patients in the pelubiprofen group and 20.6% patients in the celecoxib group experienced an adverse drug reaction (ADR). The frequency of gastrointestinal ADRs was 20.8 % and 8.8%, respectively. CONCLUSIONS: Pelubiprofen was found to be as effective as celecoxib at pain reduction and for relieving stiffness in RA patients. However, more patients in the pelubiprofen group experienced ADR and the frequency of gastrointestinal ADRs was higher in the pelubiprofen group. ClinialTrials.gov identifier: NCT01781702.

Random spot urine protein to creatinine ratio is a reliable measure of proteinuria in lupus nephritis in Koreans.

OBJECTIVES: The accurate assessment of proteinuria is critical for the management of lupus nephritis. Measuring the protein to creatinine (P/C) ratio in random spot urine (RSU) samples has been introduced as an alternative to the 24-hour (24h) urine collection method. However, it remains unclear as to whether the RSU P/C ratio is reliable for assessing lupus nephritis (LN) in routine clinical practice. METHODS: In total, 275 pairs of 24h urine and RSU samples from 102 patients with biopsy-proven LN were analysed. The correlation and concordance between the P/C ratios in the two sample types were assessed by Pearson or Spearman correlation and intra-class correlation coefficient (ICC) using mixed models for repeated measurements, respectively. RESULTS: The mean 24h urine P/C ratio was 3.2 ± 4.9. Overall, RSU P/C ratio correlated strongly with the 24h urine P/C ratio (r=0.944, p<0.001) with an excellent agreement (ICC=0.949, 95% confidence interval [CI]: 0.69-1.00). Subgroup analyses revealed that the correlation remained high in class II, III, IV, and V LN (rho=0.868, p<0.001; rho=0.649, p=0.007; r=0.945, p<0.001; and rho=0.900, p=0.001, respectively). The correlation between the 24h urine and RSU P/C ratio in the range of 0.5 to 3 was good (r=0.720, p<0.001) with ICC of 0.659 (95%CI 0.554-0.812). RSU P/C ratio ≥0.5 could predict 24h PCR ≥0.5 with 91.7% sensitivity and 70.2% specificity, whereas RSU P/C ratio ≥1.0 increased specificity up to 94.7%. CONCLUSIONS: The RSU P/C ratio is an excellent alternative to the 24 hour P/C ratio for assessing the presence of clinically significant proteinuria in LN. RSU P/C ratio >1.0 may prompt directly to a renal biopsy, whereas RSU P/C ratio between 0.5-1.0 should be followed by a confirmatory 24h urine collection.

Tofacitinib prevents radiographic progression in rheumatoid arthritis.

Tofacitinib, a novel Janus kinase inhibitor, may prevent structural damage in rheumatoid arthritis (RA). In this cohort study, we compared radiographic progression of hand joints between 21 RA patients who took tofacitinb for 18 months in a phase IIb and its extension study and 42 patients who took conventional disease modifying antirheumatic drugs (DMARDs), using simple erosion narrowing score. For tofacitinib group, changes before and after the treatment were also compared. The changes of erosion and sum scores were significantly less in tofacitinib than DMARDs group (for erosion, -0.60 ± 1.83 vs 0.51 ± 1.77, P = 0.038; for sum, -0.50 ± 1.72 vs 1.57 ± 4.13, P = 0.012). Joint space narrowing score (JSN) was also less in tofacitinib group (0.095 ± 0.58 vs 1.06 ± 2.60, P = 0.055). In tofacitinib group, yearly rates of both erosion and JSN were significantly decreased after administration of tofacitinib (For erosion, 0.62 ± 0.93 to -0.14 ± 0.48, P = 0.009; for JSN, 0.47 ± 0.64 to 0.03 ± 0.40, P = 0.032), as was change of sum score (1.09 ± 1.27 to -0.10 ± 0.63, P < 0.001). In conclusion, tofacitinib may prevent structural damage caused by RA.

Impact of Clinical Association Between Gout and Dementia: A Nationwide Population-Based Cohort Study in Korea.

OBJECTIVE: Hyperuricemia might have neuroprotective or neurodegenerative effects on dementia via oxidative stress or inflammatory response regulation. Few studies have explored the association of hyperuricemia or gout with dementia. This retrospective cohort study aimed to investigate the association between gout and dementia in Korea. METHODS: Altogether, 5,052 gout patients and 25,260 age- and sex-matched controls were selected from the National Health Insurance Service (NHIS)-National Sample Cohort database. The incidence and risk of dementia were evaluated by reviewing the NHIS record. We also performed a subgroup analysis according to age group (age <65 or ≥65 years) using the standard age of 65 years for elderly and nonelderly groups and sex. RESULTS: During follow-up, 81 and 558 participants in the gout and control cohorts developed dementia, respectively. The mean follow-up duration was 4.38 years in gout patients and 4.94 years in controls. Gout patients had a hazard ratio (HR) of 0.79 for overall dementia (95% confidence interval [95% CI] 0.62-1.00) and significantly lower Alzheimer's disease risk (HR 0.73 [95% CI 0.54-0.98]) after adjusting for age, sex, household income, and comorbidities. In subgroup analysis stratified by age and sex, the inverse association between gout and the risk of overall dementia (HR 0.71 [95% CI 0.52-0.97]) and Alzheimer's disease (HR 0.67 [95% CI 0.46-0.97]) were observed in the elderly male group. On the other hand, age- and sex-adjusted analysis showed that the HR for vascular dementia of gout patients was 2.31 (95% CI 1.02-5.25) in the nonelderly male group. CONCLUSION: Gout decreased the risk of incident Alzheimer's disease-type dementia, especially in elderly patients. The association between gout and dementia risk may differ according to age and disease duration.

Pembrolizumab-induced psoriatic arthritis treated with disease-modifying anti-rheumatic drugs in a patient with gastric cancer: A case report.

BACKGROUND: Immune checkpoint inhibitor (ICI)-induced rheumatic immune-related adverse events (irAEs) have been infrequently reported, and the treatment of severe or refractory arthritis as irAEs has not been established yet. CASE SUMMARY: The patient was a 67-year-old man with a history of well-controlled foot psoriasis who presented with polyarthralgia. He had received pembrolizumab for metastatic gastric adenocarcinoma 2 mo previously. Physical examination revealed erythematous swelling in the distal interphalangeal joints, left shoulder, and both knees. He had plaque psoriasis with psoriatic nail dystrophy and dactylitis in the distal joints of the fingers and toes. Inflammatory markers including C-reactive protein and erythrocyte sedimentation rate were elevated but rheumatoid factor and anticyclic citrullinated peptide antibody were negative. The patient was diagnosed with psoriatic arthritis (PsA) and started on methylprednisolone 1 mg/kg/day after pembrolizumab discontinuation. However, despite 1 wk of methylprednisolone treatment, PsA worsened; hence, leflunomide and methotrexate were started. After 4 wk of steroid treatment, PsA worsened and improved repeatedly with steroid tapering. Therefore, the therapy was intensified to include etanercept, a tumor necrosis factor inhibitor, which ultimately resulted in adequate PsA control. CONCLUSION: This is the first report of ICI-induced PsA in a gastric cancer patient. Some rheumatic irAEs with refractory severe arthritis may require disease-modifying anti-rheumatic drugs and long-term management.

Familial Risk of Gout and Interaction With Obesity and Alcohol Consumption: A Population-Based Cohort Study in Korea.

OBJECTIVE: Population-based studies of the familial aggregation of gout are scarce, and gene/environment interactions are not well studied. This study was undertaken to evaluate the familial aggregation of gout as well as assess interactions between family history and obesity or alcohol consumption on the development of gout. METHODS: Using the Korean National Health Insurance database, which includes information regarding familial relationships and risk factor data, we identified 5,524,403 individuals from 2002 to 2018. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare the risk in individuals with and those without affected first-degree relatives. Interactions between family history and obesity/alcohol consumption were assessed on an additive scale using the relative excess risk due to interaction (RERI). RESULTS: Individuals with a gout-affected first-degree relative had a 2.42-fold (95% CI 2.39, 2.46) increased risk of disease compared to those with unaffected first-degree relatives. Having both a family history of gout and being either overweight or having moderate alcohol consumption was associated with a markedly increased risk of disease, with HRs of 4.39 (95% CI 4.29, 4.49) and 2.28 (95% CI 2.22, 2.35), respectively, which exceeded the sum of their individual risks but was only statistically significant in overweight individuals (RERI 0.96 [95% CI 0.85, 1.06]). Obese individuals (RERI 1.88 [95% CI 1.61, 2.16]) and heavy drinkers (RERI 0.36 [95% CI 0.20, 0.52]) had a more prominent interaction compared to overweight individuals and moderate drinkers, suggesting a dose-response interaction pattern. CONCLUSION: Our findings indicate the possibility of an interaction between gout-associated genetic factors and obesity/alcohol consumption.

Association between SYVN1 and SEL1 genetic polymorphisms and remission in rheumatoid arthritis patients treated with TNF-α inhibitors: a machine learning approach.

Rheumatoid arthritis (RA) is a severe chronic inflammatory condition that affects joint synovium. Suppressor/enhancer of lin-12-like (SEL1L)-Synoviolin 1 (SYVN1)-mediated endoplasmic reticulum-associated degradation (ERAD) is highly associated with RA development. Although targeting SEL1L-SYVN1-mediated ERAD can be beneficial, studies that evaluate the association between polymorphisms in their genes and remission from the disease in RA patients taking tumor necrosis factor (TNF)-α inhibitors have yet to be carried out. Hence, the purpose of this study was to investigate the association between SYVN1 and SEL1L polymorphisms and TNF-α inhibitor response using various machine learning models. A total of 12 single-nucleotide polymorphisms (SNPs), including 5 SNPs in SYVN1 and 7 SNPs of SEL1L were investigated. Logistic regression analysis was used to examine the relationship between genetic polymorphisms and response to treatment. Various machine learning methods were employed to evaluate factors associated with remission in patients receiving TNF-α inhibitors. After adjusting for covariates, we found that sulfasalazine and rs2025214 in SEL1L increase the remission rates by approximately 3.3 and 2.8 times, respectively (95% confidence intervals 1.126-9.695 and 1.074-7.358, respectively). Machine learning approaches showed acceptable prediction estimates for remission in RA patients receiving TNF-α inhibitors, with the area under the receiver-operating curve (AUROC) values ranging from 0.60 to 0.65. A polymorphism of the SEL1L gene (rs2025214) and sulfasalazine were found to be associated with treatment response in RA patients receiving TNF-α inhibitors. These preliminary data could be used to tailor treatment for RA patients using TNF-α inhibitors.

Cardiovascular Risks in Korean Patients with Gout: Analysis Using a National Health Insurance Service Database.

Although several epidemiologic studies have shown the association between gout and cardiovascular outcomes, specific risk factors for developing cardiovascular diseases in Asian patients with gout are undisclosed. Thus, the purpose of this study was to investigate risks of cardiovascular outcomes and its related factors in Korean patients with gout. This retrospective clinical study used sampled cohort data from the National Health Insurance Service in Korea. Patients with gout were defined as subjects enlisted with an ICD-10 code (M10). Control patients were selected by frequency matching for age, sex, and index year. Primary outcomes included ischemic heart disease (IHD), congestive heart failure, cerebrovascular disease (CVD), or transient ischemic attack. We calculated the hazard ratio (HR) using Cox regression, adjusting potential confounders including age, sex, lifestyle habits, laboratory results, and medication. We identified 3306 patients with gout and an equal number of matched controls. Multivariate Cox regression analysis showed that gout patients had increased risks of IHD (HR: 1.860, 95% CI: 1.446-2.392), acute myocardial infarction (HR: 3.246, 95% CI: 1.460-7.217), and CVD (HR: 1.552, 95% CI: 1.177-2.036). Old age, current smoking, frequent alcohol intake, high low-density lipoprotein, and diabetes mellitus increased the risk of cardiovascular outcomes, yet hypouricemic agents decreased the risk of cerebrovascular diseases. Our data corroborate that it is crucial to identify and manage traditional cardiovascular risk factors alongside lowering urate levels in patients with gout.

Gout as a risk factor for osteoporosis: A Korean population-based study.

Uric acid acts as both an antioxidant and a pre-oxidant that induces oxidative stress; thus, it plays a paradoxical role in inflammation. However, the effect of gout, a hallmark of hyperuricemia, on osteoporosis remains unclear. Therefore, this study aimed to investigate the association between gout and osteoporosis. This retrospective cohort study used data from the Korean National Health Insurance Service Database. In total, 628,565 participants who were diagnosed with gout and prescribed medications for gout for at least 90 days were selected. The control cohort included patients with no history of gout or use of gout medication. Age and sex 1:1 propensity score matching and Cox proportional hazards models were used to investigate risk factors for osteoporosis. In total, 305,810 patients with gout met the inclusion criteria. Compared with the control group, both men and women with gout showed an increased incidence rate ratio of osteoporosis. In the stratified analysis by age, patients with gout showed an increased incidence rate ratio for osteoporosis in all age groups, except for those over 80 years of age (P < .001). Gout showed an increased hazard ratio of 1.48 (95% CI: 1.45-1.51, P < .001). The female sex has also been identified as a risk factor for osteoporosis. Patients in their 70s had the highest HR. Gout is significantly associated with the risk of osteoporosis. In particular, the results of this study showed that the incidence of osteoporosis increased up to four times in male patients in their 20s with gout compared to without gout.

Recurrent pulmonary arteriovenous malformation in a patient with Sjögren syndrome: A case report.

RATIONALE: Pulmonary manifestations of Sjögren syndrome (SS) are variable and may involve the airway or lung parenchyma and increase the risk of vascular and malignant disease. However, to date, only one case of pulmonary arteriovenous malformation (AVM) has been reported in a patient with SS. Here, we report a rare case of recurrent pulmonary AVMs with aggravating multiple cysts in a patient with SS during a period of 14 years. PATIENT CONCERNS: A 45-year-old woman was diagnosed with SS and pulmonary AVM in the right lung. Her AVMs were embolized successfully and she was followed up annually for 14 years. Eleven years after the initial treatment, her chest computed tomography showed new pulmonary AVMs in the left lung with aggravating multiple cysts. DIAGNOSIS: We diagnosed her with SS according to the American-European consensus group criteria of 2010. Chest computed tomography and angiographic findings confirmed the recurrence of pulmonary AVMs. INTERVENTIONS: The patient's recurrent pulmonary AVMs were successfully treated by embolization. OUTCOMES: Although her multiple cystic lung lesions had been aggravating during 14 years, she received embolization for the pulmonary AVMs twice and developed no complication related to these procedures. Currently, the patient is 56 years old and still alive with good performance state. LESSONS: To date, only one case of pulmonary AVM has been reported in a patient with SS. The patient died 2.5 years after the diagnosis without recurrence of AVM. Here, we present a rare case of recurrent pulmonary AVMs associated with aggravating multiple cysts in both lungs, which were observed during long-term follow-up, in a patient with SS.

Expression levels and association of gelatinases MMP-2 and MMP-9 and collagenases MMP-1 and MMP-13 with VEGF in synovial fluid of patients with arthritis.

This study was performed to provide evidence, albeit indirectly, as to which matrix metalloproteinases (MMPs), among the gelatinases MMP-2 and MMP-9 and the collagenases MMP-1 and MMP-13, play a more proactive role in the angiogenic process in arthritic joint. Joint fluid was collected from 33 patients with rhuematoid arthritis (RA) and osteoarthritis (OA), and protein (MMPs and vascular endothelial growth factor (VEGF)) levels were measured by ELISA, and the association of MMPs with VEGF was evaluated in joint fluid of patients with RA or OA. The levels of collagenases (total MMP-1 and total MMP-13) and gelatinases (total MMP-2 and total MMP-9) in RA joint fluid were significantly higher than those in OA fluid. Total MMP-9 levels were significantly associated with VEGF levels in RA fluids, but not in OA fluid, while total MMP-13 levels were strongly associated with VEGF levels in both RA and OA fluid. However, total MMP-2 and total MMP-1 levels were not associated with VEGF levels in either RA or OA joint fluid. Our results indirectly suggest that in RA and OA, MMP-9 and MMP-13 may play a more important role in angiogenesis than MMP-2 and MMP-1.