Efficacy of anifrolumab in long-term intractable alopecia due to discoid lupus erythematosus.

Alopecia associated with lupus erythematosus is broadly classified into reversible nonscarring alopecia seen in the acute phase, such as worsening of systemic lupus erythematosus (SLE) and cicatricial alopecia seen in chronic cutaneous lupus erythematosus represented by discoid lupus erythematosus (DLE). In DLE-induced alopecia, early therapeutic intervention before developing scarring alopecia is important, but the condition is often resistant to conventional treatment. Anifrolumab (ANI), a novel therapeutic agent for SLE that inhibits type I interferon activity, has been shown to be effective against acute skin lesions, including alopecia, in patients with SLE. However, there are very few reports on the effect of ANI on alopecia due to DLE. We report on a 27-year-old Japanese woman with SLE whose alopecia due to chronic DLE was refractory to topical therapy and systemic therapy with oral glucocorticoid, multiple immunosuppressants and belimumab for approximately 8 years after onset, and whose alopecia improved with ANI. ANI can be considered to be an effective treatment option in lupus patients presenting with alopecia due to DLE, even in the chronic refractory stage.

Implications of Incorporating Plasma Lipoprotein Binding into a Physiologically-Based Pharmacokinetic Model: A Simulation Study with Amiodarone.

Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.

Anticoagulation therapy for endocardial/epicardial ablation of infarct-related ventricular tachycardia in a patient with antithrombin deficiency.

In patients with a history of antithrombin deficiency, a direct thrombin inhibitor may be considered as an alternative to intraprocedural anticoagulation. A 55-year-old woman with antithrombin deficiency and prior myocardial infarction suffered from electrical storm and appropriate defibrillator shocks. Substrate mapping guided left ventricular endocardial and epicardial ablations were successfully performed. The direct thrombin inhibitor, argatroban, was safely used as intraprocedural anticoagulation therapy with no complications. Learning objective: Optimal anticoagulation during endocardial and epicardial catheter ablation is essential to prevent thromboembolic and bleeding complications. Although patients with infarct-related electrical storm and antithrombin deficiency require unusual attention to anticoagulation, argatroban, a direct thrombin inhibitor, was safely used as intraprocedural anticoagulation therapy during catheter ablations, with no complications.

Improved cerebral blood flow and hippocampal blood flow in stroke-free patients after catheter ablation of atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is a risk factor for reduced cerebral blood flow (CBF) and cognitive dysfunction, even in stroke-free patients. We aimed to test the hypothesis that CBF and hippocampal blood flow (HBF), measured with arterial spin labeling magnetic resonance imaging (MRI), improve after catheter ablation of AF to achieve sinus rhythm (SR). METHODS: A total of 84 stroke-free patients (63.1 ± 9.1 years; paroxysmal AF, n = 50; non-paroxysmal AF, n = 34) undergoing AF catheter ablation were included. MRI studies were done before, 3 months, and 12 months after the procedure with CBF and HBF measurements. RESULTS: Baseline CBF and HBF values in 50 paroxysmal AF patients were used as controls. Baseline CBF was higher in patients with paroxysmal AF than with non-paroxysmal AF (100 ± 32% vs. 86 ± 28%, p = .04). Patients with non-paroxysmal AF had increased CBF 3 months after AF ablation (86 ± 28% to 99 ± 34%, p = .03). Differences in CBF and HBF were greater in the group with AF restored to SR (p < .01). Both CBF and HBF levels at 12 months were unchanged from the 3 months level. Successful rhythm control by catheter ablation was an independent predictor of an increase in CBF > 17.5%. The Mini-Mental State Examination score improved after ablation (p = .02). CONCLUSION: SR restoration with catheter ablation was associated with improved CBF and HBF at 3 months, maintenance of blood flow, and improved cognitive function at 12 months.

Prognostic impact of plasma xanthine oxidoreductase activity in patients with heart failure with atrial fibrillation.

BACKGROUND: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme for uric acid (UA) production and plays an important role in generating reactive oxygen species (ROS). Overproduction of ROS is reported to contribute to the pathophysiology of atrial fibrillation (AF), however, the prognostic impact of plasma XOR activity in patients with heart failure (HF) with AF is undetermined. METHODS: We measured plasma XOR activity in 475 HF patients, including those with sinus rhythm (HF-SR, n = 211), and those with AF (HF-AF, n = 264). The type of AF included paroxysmal (n = 128) and persistent (n = 136) AF. All patients were prospectively followed up for a median period of 804 days. RESULTS: HF-AF patients had significantly higher plasma XOR activity and serum UA levels compared with HF-SR patients. Both plasma XOR activity and serum UA levels were higher in patients with persistent AF than in those with SR and with paroxysmal AF. Multivariate linear regression analysis showed that persistent AF was independently associated with increased XOR activity. During the follow-up period, there were 79 major adverse cardiovascular events (MACEs). HF-AF patients with MACEs had higher plasma XOR activity compared with those without MACEs, while there were no significant differences in serum UA levels. Multivariate Cox proportional analysis showed that high XOR activity was an independent risk factor for MACEs after adjustment for confounding factors. Kaplan-Meier analysis revealed that the high XOR activity group had a higher risk of MACEs than the low XOR activity group. The prediction model was significantly improved by the addition of XOR activity to the basic predictors. CONCLUSIONS: HF-AF patients had significantly higher plasma XOR activity compared with HF-SR patients. Plasma XOR activity proved to be a reliable indicator for MACEs in HF-AF patients.

Contact dermatitis associated with wearable cardioverter-defibrillator.

A 51-year-old man with dilated cardiomyopathy was resuscitated from ventricular fibrillation. Twenty-days after using a wearable cardioverter-defibrillator (WCD) contact dermatitis with itching was evident and consistent with the self-gelling defibrillation electrodes patch on the back. Itching was controlled with clobetasol propionate application. The WCD was continued until catheter ablation and device implantation. The contact dermatitis was completely recovered two weeks after discontinuing the WCD. Among 58 patients using the WCD, three (5.2%) complained about discomfort with the device, and two (3.4%) complained of itching. Only the patient presented here (1.7%) suffered from contact dermatitis with itching. Contact dermatitis is rarely observed in patients wearing a WCD but physicians should be aware of this complication to maintain WCD compliance. .

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins.

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration-to-dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs  = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs  = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high-density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs  = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein-binding and decreased metabolism of amiodarone.

Visualization of persistent superior vena cava isolation by cryoballoon ablation.

A 54-year-old man with paroxysmal atrial fibrillation underwent pulmonary vein (PV) isolation using a 28-mm second-generation cryoballoon catheter. Unexpected electrical superior vena cava (SVC) isolation during cryoballoon application to the right superior PV was observed in the first procedure. Thirteen-months after cryoballoon-based PV isolation, sustained SVC fibrillation was confirmed irrespective of sinus rhythm. Voltage mapping visualized a low voltage area around the SVC was close to that around the right superior PV. SVC isolation was obtained by cryoballoon application to the right superior PV and persisted for over a year. .

Visualization of epicardial lead infection using 18F-FDG-PET/CT imaging.

18 F-FDG-PET/CT is promising tool to visualize not only transvenous lead infection but also epicardial lead infection.

A validation study of the Ursodeoxycholic Acid Response Score in Japanese patients with primary biliary cholangitis.

BACKGROUND/PURPOSE: Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC. METHODS: Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase <1.67 times the upper limit of the normal value after 12 months of UDCA treatment. RESULTS: All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160). CONCLUSION: The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate.

Initial Result of Antrum Pulmonary Vein Isolation Using the Radiofrequency Hot-Balloon Catheter With Single-Shot Technique.

OBJECTIVES: This study sought to determine the feasibility of a novel simplified ablation protocol targeting only the pulmonary vein antrum using the radiofrequency hot-balloon catheter in patients with paroxysmal atrial fibrillation. BACKGROUND: Radiofrequency hot-balloon (RHB) catheter has been recently introduced into clinical practice for pulmonary vein isolation (PVI). The authors hypothesized that a novel simplified ablation protocol targeting only the PV antrum with energy application for a longer time (single-shot technique) could be an alternative approach to achieve PVI, while avoiding unnecessary energy application at the PV ostium. METHODS: A total of 61 consecutive paroxysmal atrial fibrillation patients (age 64.1 ± 10.9 years, 48 male) who underwent antrum RHB-PVI were enrolled. Energy applications were performed following the pre-specified protocol only targeting the PV antrum. If the PVI was not achieved after 2 energy applications using the RHB, a touch-up ablation was performed. RESULTS: Of 241 PV, including 3 left common PV, 194 (80%) were isolated exclusively using the RHB. The target PVI average per group of 15 consecutive procedures improved from 75% (initial 15) to 89% (last 16) of patients. The injected volume was greatest in the right superior PV (13.1 ± 2.0 ml) and the smallest in the left inferior PV (10.8 ± 1.1 ml), and 23 PV (9.5%) required over 15 ml (estimated balloon diameter of 30 mm). Periprocedural complications were noted in 3 patients (4.9%), but phrenic nerve injury was not observed. Sinus rhythm maintenance at 12-month follow-up was achieved in 57 patients (93%). CONCLUSIONS: A novel simplified antrum RHB-PVI appears to be a feasible technique for the treatment of paroxysmal atrial fibrillation.

Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.

Biatrial volume, estimated using magnetic resonance imaging, predicts atrial fibrillation recurrence after ablation.

INTRODUCTION: The predictive value of left atrial volume (LAV) in atrial fibrillation (AF) is known, but the relationship of right atrial volume (RAV) and biatrial volume (BAV) with AF recurrence after pulmonary vein isolation (PVI) is not clear. Cardiac magnetic resonance (CMR) imaging allows us to more precisely quantify atrial volume. We investigated LAV, RAV, and BAV as predictors of AF recurrence following PVI in AF patients. METHODS AND RESULTS: We assessed 100 AF patients (age = 59.8 ± 9.5 years, 74 males, 26 females) who underwent nonenhanced CMR before their first PVI. LAV and RAV were measured using CMR. All patients were in sinus rhythm during CMR. BAV was calculated as the sum of LAV and RAV. During the 8-month follow-up, AF recurrence occurred in 23 patients. LAV, RAV, and BAV were significantly greater in patients with AF recurrence than in those without (LAV, 103.7 ± 25.8 vs 81.8 ± 24.2 mL, P < 0.001; RAV, 109.4 ± 27.0 vs 82.2 ± 19.6 mL, P < 0.001; BAV, 213.1 ± 46.7 vs 164.1 ± 38.7 mL, P < 0.001). Multivariate logistic regression analysis revealed that increased LAV, RAV, and BAV were significantly correlated with AF recurrence. The area under the receiver operation characteristic curve for BAV showed the largest value compared to that of LAV or RAV alone. CONCLUSIONS: LAV, RAV, and BAV were independent predictors of AF recurrence after PVI. Quantifying BAV may additionally improve prognostic stratification compared with LAV or RAV.

Assessment of 2012 EULAR/ACR new classification criteria for polymyalgia rheumatica in Japanese patients diagnosed using Bird's criteria.

AIM: The 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for polymyalgia rheumatica (PMR) were published in 2012. The present study aimed to assess the 2012 EULAR/ACR classification criteria for PMR in Japanese patients diagnosed with PMR using Bird's criteria. METHODS: The study included 75 patients diagnosed using Bird's criteria. The patients were divided into fulfilled and not-fulfilled groups according to whether they met the 2012 EULAR/ACR classification criteria for PMR. The factors in the new criteria were morning stiffness duration > 45 min, hip pain or limited range of motion, absence of rheumatoid factor or anti-citrullinated protein antibody, and absence of other joint involvement. RESULTS: Thirty-two of the patients diagnosed with PMR using Bird's criteria met the new EULAR/ACR classification criteria, while the remaining 43 patients did not meet the new criteria. Among the factors, only morning stiffness duration > 45 min was an independent predictive factor. CONCLUSIONS: A morning stiffness duration > 45 min is the only independent predictive factor for differentiating patients diagnosed according to the new 2012 EULAR/ACR classification criteria for PMR.

Successful Switch to Golimumab for Eosinophilia and Skin Symptoms Related to Multiple Biologics in a Patient with Rheumatoid Arthritis.

Biologics used in the treatment of rheumatoid arthritis (RA) rarely cause eosinophilia. We herein report a patient with RA being treated with infliximab, adalimumab, and tocilizumab who developed eosinophilia with skin symptoms. Interestingly, the marked eosinophilia and skin symptoms did not reappear after the patient's medication was switched to golimumab. In this case, the presence of biologics-specific antibodies suggested that immunogenicity caused the eosinophilia. Therefore, switching to a biologic with a lower immunogenicity was effective. These findings may be helpful for clinicians treating patients with biologics-induced eosinophilia.

Anticentromere antibody-positive primary Sjögren's syndrome: Epitope analysis of a subset of anticentromere antibody-positive patients.

OBJECTIVES: Anticentromere antibody (ACA) is generally considered to be a serological marker for systemic sclerosis (SSc). ACA-positive patients with primary Sjögren's syndrome (pSS) have also been reported. ACA often recognizes centromere proteins (CENPs): CENP-A, CENP-B, and CENP-C, and sometimes reacts to heterochromatin protein 1 (HP1)α. We compared the reactivity against six different epitopes for three ACA-positive clinical subgroups: 29 patients with pSS, 36 SSc patients with sicca symptoms, and 28 SSc patients without sicca symptoms. METHODS: We utilized enzyme-linked immunosorbent assays (ELISAs) with recombinant proteins covering six different epitope regions of ACA (the amino terminus (Nt) of CENP-A, CENP-B, and CENP-C, the carboxyl terminus (Ct) of CENP-B and CENP-C, and HP1α). RESULTS: The patients with pSS were found to have IgG-class autoantibodies against CENP-C-Nt and HP1α, and IgA-class autoantibodies against CENP-C-Ct with significantly higher frequencies than the SSc patients with or without sicca symptoms. The positive predictive value and the negative predictive value of the combination of these three autoantibodies for pSS were 73% and 82%, respectively, for pSS. CONCLUSIONS: Based on the result that reactivities against CENP-C and HP1α in patients with pSS differ from those in patients with SSc, we propose ACA-positive pSS as a clinical subset of SS that is independent of SSc.

The Neutrophil-to-Lymphocyte Ratio Predicts All-Cause Mortality in Patients with Implantable Cardioverter Defibrillators.

BACKGROUND: The relationship between the neutrophil-to-lymphocyte ratio (NLR) and outcome in patients with implantable cardioverter-defibrillators (ICDs) is unclear. METHODS AND RESULTS: Consecutive patients with cardiomyopathy who had received an ICD (n = 120, mean age 64 ± 11 years) were prospectively enrolled. Blood samples were obtained on the morning of the day of implantation. Patients were followed for a median period of 61.2 months, to an endpoint of all-cause mortality or appropriate ICD shock, which occurred in 35 (29%) and 28 (23%) patients, respectively. Multivariate Cox analysis revealed that secondary prevention was only associated with appropriate ICD shocks. The NLR, brain natriuretic peptide level, and estimated glomerular filtration rate were independent predictors of all-cause mortality but not of appropriate ICD shocks. Subgroup analysis revealed that a high NLR (≥2.1) was valuable for anticipating all-cause mortality among patients who had received ICDs for primary or secondary prevention. A high NLR was also associated with death prior to appropriate ICD shock. CONCLUSION: Evaluating the NLR may be useful for predicting outcomes in patients with cardiomyopathy who have received ICDs.

The association between defibrillation shock energy and acute cardiac damage in patients with implantable cardioverter defibrillators.

BACKGROUND: The aim of this study was to establish a minimally invasive defibrillation testing (DT) protocol for patients with implantable cardioverter defibrillators (ICDs). METHODS: Two different energy DTs were performed, immediately after (15 J-DT) and 7 days after (≤10 J-DT) device implantation, in 20 consecutive ICD implantation patients. Cardiac-troponin T (c-TNT) and heart-type fatty acid binding protein (H-FABP) levels were measured before implantation, 2 h after implantation, and 1 day after each DT. For an additional 122 patients with ICD, we retrospectively analyzed 203 DTs immediately and 7 days after device implantation. RESULTS: Serum c-TNT levels were significantly elevated 2 h after 15 J-DT [0.008 (0.004-0.019) vs. 0.053 (0.037-0.068) ng/mL, p<0.001], but not ≤10 J-DT [0.007 (0.004-0.018) ng/mL]. Similarly, serum H-FABP levels were significantly elevated 2 h after 15 J-DT (2.9±1.5 vs. 6.4±3.4 ng/mL, p<0.001), but not ≤10 J-DT (2.7±1.5 ng/mL). The changes in c-TNT and H-FABP levels between baseline and 2 h after DT were significantly greater for 15 J-DT compared with ≤10 J-DT [c-TnT: 0.039 (0.029-0.060) vs. 0 (0-0.003) ng/mL, p<0.001; H-FABP: 3.6±2.8 vs. -0.16±1.1 ng/mL, p<0.001]. The success rates of the initial shocks delivered for ventricular fibrillation were no different between ≤10 J-DT (85% [78/92]) and ≥15 J-DT (92% [103/111]). CONCLUSIONS: Elevated levels of myocardial damage markers such as c-TNT and H-FABP were not found after ≤10 J-DT. In addition, an acceptable success rate was confirmed in ≤10 J-DT.