Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

AIM: To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. METHOD: Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. RESULTS: A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). CONCLUSION: Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.

Anti-neutrophil Cytoplasmic Antibody-negative Eosinophilic Granulomatosis with Polyangiitis Complicated with Peripheral Neuropathy that Underwent Remission Induction with Mepolizumab Monotherapy.

A 72-year-old woman was admitted to our hospital with numbness in her lower extremities and hypereosinophilia. She was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). On admission, she was suspected of being complicated with pneumonia and sepsis; therefore, treatment with mepolizumab monotherapy was begun, resulting in partial improvement. After the possibility of a complicating infection was ruled out, corticosteroids were initiated, followed by intravenous gamma globulin therapy. Although the induction of remission of EGPA with mepolizumab monotherapy is not usually recommended, induction with mepolizumab monotherapy may be an option in terms of safety and clinical efficacy in some cases.

Abatacept ameliorates both glandular and extraglandular involvements in patients with Sjögren's syndrome associated with rheumatoid arthritis: Findings from an open-label, multicentre, 1-year, prospective study: The ROSE (Rheumatoid Arthritis with Orencia Trial Toward Sjögren's Syndrome Endocrinopathy) and ROSE II trials.

OBJECTIVE: To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). MATERIALS AND METHODS: We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon's test, Schirmer's test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. RESULTS: 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients. CONCLUSION: Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in SS associated with RA.

Successful Treatment of SARS-CoV-2 Vaccination-related Activation of Rheumatoid Arthritis with Positive Findings for Epstein-Barr Virus.

We herein report a 60-year-old woman who experienced severe flare of rheumatoid arthritis (RA) and Epstein-Barr virus (EBV) positivity following administration of the messenger ribonucleic acid (mRNA)-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Since 40 years old, she had been in long-term remission of anti-citrullinated protein antibody-positive RA. Ten days after SARS-CoV-2 vaccination, she presented with a high fever and polyarthritis, active synovitis on joint ultrasound, a clinical disease activity index of 35, and positivity for anti-early antigen, diffuse type and restricted type (EA DR) IgG and EBV deoxyribonucleic acid (EBV-DNA). Tocilizumab was introduced to treat RA. The RA disease activity disappeared, and anti-EA DR IgG and EBV-DNA became negative.

Successful treatment for eosinophilic granulomatosis with polyangiitis causing severe myocarditis followed by cardiac magnetic resonance.

A 38-year-old woman had a history of asthma for 20 years. Bullous lesions had appeared on her left side of the back. Two months before admission, the biopsy revealed eosinophilic cellulitis. One month later, she experienced numbness in both legs. She was admitted to our hospital for emergency treatment due to chest pain and loss of consciousness. Emergency coronary angiography revealed triple-vessel vasospasm. She had cardiac arrest for 4 min during the examination. We suspected eosinophilic granulomatosis with polyangiitis due to pulmonary infiltrate, eosinophilia, and a history of illness. We, therefore, started methylprednisolone pulse therapy. Although her condition and laboratory findings improved, cardiac magnetic resonance (CMR) imaging performed on day 16 showed myocardial oedema and myocardial fibrosis on late gadolinium enhancement. Coronary angiography on day 35 revealed no spasm, and myocardial biopsy showed the absence of vasculitis. There was no improvement in myocardial oedema. CMR showed enlargement of late gadolinium enhancement and formation of a ventricular aneurysm. As myocarditis did not improve sufficiently, five courses of intravenous cyclophosphamide pulse therapy were administered. CMR on day 152 showed the disappearance of myocardial oedema. We report a unique case of successful treatment of severe myocarditis and the usefulness of follow-up CMR.

Involvement of Epstein-Barr virus in the development and spontaneous regression of methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis.

OBJECTIVES: Conventionally, some patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) undergo spontaneous tumour regression after cessation of MTX. Although the involvement of Epstein-Barr virus (EBV) in the development and spontaneous regression has been suggested, the underlying mechanism remains unknown. In this study, we analysed patients who had developed MTX-LPD to evaluate the association between the development and spontaneous regression of MTX-LPD with EBV. METHODS: We analysed the age, stage, disease activity, MTX dose, lymphocyte count, EBV real-time polymerase chain reaction (PCR) test value, and EBV-encoded small RNA (EBER) positivity rate in patients with MTX-LPD at our hospital. Moreover, we investigated the factors related to spontaneous regression, which is a characteristic of MTX-LPD. RESULTS: Thirty-four patients were enrolled in this study. The MTX dose at LPD onset was 8.3±2.0 mg/week, and the total dose of MTX was 1,530.3±779.2 mg. The EBV load in the peripheral blood was 270.4±431.8 copy/µL, and the pathological tissues of 17 of 34 (50%) patients tested positive for EBER. Twenty-one patients had spontaneous regression after discontinuation of MTX. The factors related to spontaneous regression were examined using a univariate analysis, and the EBV real-time PCR test value in the peripheral blood, EBER in pathological tissues, and improvement rate of lymphocyte count were considered significant factors. The EBV real-time PCR test value in the peripheral blood was defined as an independent factor of spontaneous regression using a multivariate analysis of related factors. CONCLUSIONS: EBV may be involved in the development of MTX-LPD and its spontaneous regression.

Asymptomatic myocardial dysfunction was revealed by feature tracking cardiac magnetic resonance imaging in patients with primary Sjögren's syndrome.

AIM: To evaluate subclinical left ventricular (LV) regional dysfunction in patients with primary Sjögren's syndrome (pSS) using feature tracking cardiac magnetic resonance (FT-CMR) imaging and to identify pSS characteristics independently associated with LV regional dysfunction. METHOD: Fifty patients with pSS and 20 controls without cardiovascular disease underwent non-contrast CMR imaging. Labial gland biopsy was performed in 42 patients (84%). Disease activity was assessed using the European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI). LV global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were measured using FT-CMR. RESULTS: No significant differences in cardiovascular risk factors were found between the pSS group and controls. The pSS group had significantly lower GLS (P = .015) and GCS (P = .008) than the control group. Multiple linear regression analysis indicated that GCS was significantly associated with Raynaud's phenomenon (P = .015), focus score ≥2 (P = .032), and total ESSDAI score ≥8 (P = .029). CONCLUSION: FT-CMR can reveal subclinical LV regional dysfunction in patients with pSS without cardiovascular disease. Furthermore, patients with pSS and Raynaud's phenomenon, a focus score ≥2, or an ESSDAI score ≥8 were considered to be at high risk for myocardial dysfunction.

Successful early introduction of mepolizumab for peripheral neuropathy with a peripheral circulatory disorder in a patient with myeloperoxidase anti-neutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

A 26-year-old woman presented with abdominal pain, diarrhoea, vomiting, fever, and progressive paralysis in the lower limbs. She had a history of bronchial asthma and experienced sinusitis, progressive peripheral neuropathy, polyarthritis, and leukocytosis with prominent eosinophilia. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Abdominal pain was considered to be an ischaemic enteritis associated with EGPA. She was administered 1,000 mg/day of methylprednisolone for 3 days and intravenous immunoglobulin (400 mg/kg/day of γ-globulin for 5 days) followed by 50 mg (1 mg/kg)/day of oral prednisolone due to rapidly progressing peripheral neuropathy. Her symptoms temporarily improved; however, peripheral neuropathy recurred after a week, and the eosinophil count increased. Eighteen days after following the resumed treatment, 300 mg of mepolizumab, a humanised monoclonal antibody, was administered. Subjective symptoms, nerve conduction velocity, and skin perfusion pressure (an index of peripheral circulation in the lower extremities) improved after 4 weeks. Although mepolizumab has been approved for EGPA, there is no evidence of its efficacy against peripheral neuropathy. Early introduction of mepolizumab may contribute to an the early improved progressive peripheral neuropathy with eosinophilia.

Salivary Gland Focus Score Is Associated With Myocardial Fibrosis in Primary Sjögren Syndrome Assessed by a Cardiac Magnetic Resonance Approach.

OBJECTIVE: The risk of clinically manifested major cardiovascular (CV) events in primary Sjögren syndrome (pSS) remains unclear. This study aimed to assess myocardial fibrosis in pSS and investigate the associated disease characteristics by cardiac magnetic resonance imaging (cMRI). METHODS: We performed a cross-sectional study of patients with pSS without cardiac symptoms. Labial gland biopsy was documented in 44 patients (85%). Patients without CV risk factors underwent contrast-enhanced cMRI. Late gadolinium enhancement (LGE) was used to assess myocardial fibrosis. Myocardial edema was assessed using T2-weighted imaging (T2WI). We compared the left ventricular (LV) geometry and function between the groups with and without LGE. Further, we explored the associations of cMRI abnormalities with pSS characteristics. RESULTS: Fifty-two women with pSS (median age 55, IQR 47.0-65.7 yrs) were enrolled in the study. LGE was observed in 10 patients (19%), two of whom showed high intensity on T2WI. High intensity on T2WI was observed in 3 patients (5.8%). LV mass index and LV mass/end-diastolic volume tended to be higher in the LGE-positive group than in the LGE-negative group (P = 0.078 and 0.093, respectively). Salivary gland focus score (FS) ≥ 3 was independently associated with LGE-positive in the multivariable analysis (OR 11.21, 95% CI 1.18-106.80). CONCLUSION: Subclinical myocardial fibrosis, as detected by cMRI, was frequent in patients with pSS without cardiac symptoms. Abnormal cMRI findings were associated with salivary gland FS ≥ 3.

Impact of biological treatment on left ventricular dysfunction determined by global circumferential, longitudinal and radial strain values using cardiac magnetic resonance imaging in patients with rheumatoid arthritis.

AIM: To evaluate left ventricular (LV) dysfunction in patients with rheumatoid arthritis (RA) and to determine the impact of biological treatment on LV function in these patients using global circumferential strain (GCS), global longitudinal strain (GLS) and global radial strain (GRS) values assessed by feature tracking cardiac magnetic resonance (FT-CMR) imaging. METHODS: Eighty patients with RA and 20 controls without cardiovascular disease underwent non-contrast CMR imaging. Patients with RA received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Global strains were calculated in 16 LV segments. RESULTS: No significant differences in cardiovascular risk factors were found between the RA group and controls. GCS was 21% lower in the RA group compared with controls (P < 0.001) and was 14% lower in the csDMARDs group compared with the bDMARDs group (P = 0.002), whereas, there was no significant difference in GLS and GRS between the RA group and the controls. In regard to strain rates, diastolic GCS and GRS rates were significantly lower in the RA group (P < 0.001, 0.011, respectively). In univariate analyses, GCS was significantly associated with the Simplified Disease Activity Index, bDMARDs, swollen joint count, anti-cyclic citrullinated peptides antibodies and matrix metalloproteinase-3, but in multivariable analysis, only bDMARDs was significantly associated with GCS (P = 0.021). CONCLUSION: Global circumferential strain, GLS and GRS assessed by FT-CMR can reveal subclinical LV dysfunction in patients with RA. Furthermore, they can be used to determine the normalization of LV regional dysfunction induced by bDMARDs possibly related to disease activity reduction.

Association of cardiac magnetic resonance-detected myocardial abnormalities with disease characteristics and brain natriuretic peptide levels in systemic sclerosis without cardiac symptoms.

AIM: This study aimed to evaluate the association between myocardial abnormalities and left ventricular (LV) geometry as assessed using cardiac magnetic resonance imaging (CMRI) in systemic sclerosis (SSc) patients without cardiac symptoms. METHODS: SSc patients without cardiac symptoms or cardiovascular risk factors underwent contrast CMRI. CMRI were assessed for structural and functional LV parameters and myocardial fibrosis based on myocardial late gadolinium enhancement (LGE). The correlation between brain natriuretic peptide (BNP) levels and LGE status was evaluated. RESULTS: Among 49 patients, 27 (55%) showed LGE positivity. The most common identified LGE pattern was a linear pattern. LGE was not consistent with coronary artery distribution. There was no difference in ejection fraction between those with and without LGE. LV morphological changes were observed in 29% of SSc patients. An abnormal LV structure was detected in 44% and 14% of patients in the LGE+ and LGE- groups, respectively. The BNP levels were higher by 57% in the LGE+ group than in the LGE-group. Receiver operating characteristic analysis showed that BNP levels reliably detected myocardial abnormalities (area under the curve, 0.72; 95% confidence interval 0.58-0.88). CONCLUSIONS: Myocardial abnormalities were common in SSc patients without cardiac symptoms. We suggest that LV morphological changes may have resulted from myocardial abnormalities. BNP may be useful as a screening tool for the detection of myocardial abnormalities in SSc patients.

How will "democratization of artificial intelligence" change the future of radiologists?

The "democratization of AI" is progressing, and it is becoming an era when anyone can utilize AI. What kind of radiologists are new generation radiologists suitable for the AI era? The first is maintaining a broad perspective regarding healthcare in its entirety. Next, it is necessary to study the basic knowledge and latest information concerning AI and possess the latest knowledge concerning modalities such as CT/MRI and imaging information systems. Finally, it is important for radiologists to not forget the viewpoint of patient-centered healthcare. It is an urgent task to nurture human resources by realizing such a healthcare AI education program to educate radiologists at an early stage. If we can evolve to become radiologists suitable for the AI era, AI will likely be our ally more than ever and healthcare will progress dramatically. As we approach the "democratization of AI," it is becoming an era in which all radiologists must learn AI as they learn statistics.

Heart Rate-corrected QT Interval Duration in Rheumatoid Arthritis and Its Reduction with Treatment with the Interleukin 6 Inhibitor Tocilizumab.

OBJECTIVE: Individuals with rheumatoid arthritis (RA) are at a heightened risk of sudden cardiac death, an outcome increased in those with prolongation of the corrected electrocardiographic QT interval (QTc). We compared QTc between patients with RA and demographically matched controls and studied the change in QTc after treatment with the interleukin 6 inhibitor tocilizumab (TCZ). METHODS: Standard 12-lead electrocardiograms were obtained and QTc was measured in patients with RA at baseline and after 24 weeks of TCZ treatment, then compared with non-RA controls who were frequency-matched on age and sex. Indicators of the baseline QTc and predictors of change in QTc were studied using multivariable linear regression. RESULTS: A total of 94 RA and 42 non-RA controls were studied. The average baseline QTc was 10 ms longer in the RA group vs controls (422 vs 412 ms, respectively; p < 0.001) and decreased to an average of 406 ms with treatment (p < 0.001). Baseline QTc was significantly and independently higher among those with anticyclic citrullinated peptide antibodies seropositivity, higher swollen joint counts, and higher levels of C-reactive protein (CRP) and matrix metalloproteinase 3. Each log unit decrease in CRP with treatment was associated with an average reduction in QTc of 2.9 ms (p = 0.002) after adjusting for age and baseline QTc. Clinical response measures were not associated with the change in QTc. CONCLUSION: The marked normalization of QTc observed with TCZ treatment, and its close parallel with CRP reduction, support the premise that systemic inflammation contributes to cardiac repolarization abnormalities in RA that may be amenable to treatment.

Protein-losing gastroenteropathy in a patient with concomitant systemic lupus erythematosus and Sjögren's syndrome.

We report a female in her twenties who developed generalized edema. She was diagnosed as systemic lupus erythematous (SLE) and Sjögren's syndrome (SS) based on her physical manifestations and positive findings for antinuclear antibody and anti-SS-A/SS-B-antibody. Although she manifested hypoproteinemia, a possibility of lupus nephritis was denied due to a lack of significant abnormality in kidney function tests and urinalysis. The nature of hypoproteinemia and related symptoms was identified as protein losing gastroenteropathy (PLGE) based on α 1-antitrypsin clearance and histopathology findings. Physicians should be aware that PLGE may develop as an underlying cause of edema in SLE and SS.

Correction: Soy and fish as features of the Japanese diet and cardiovascular disease risks.

[This corrects the article DOI: 10.1371/journal.pone.0176039.].

Taurine Intake with Magnesium Reduces Cardiometabolic Risks.

WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study revealed the quintile analyses of 24-h urinary (24 U) taurine (T) and magnesium (Mg) excretions were inversely related with cardiometabolic risks (CMR) such as obesity, hypertension and hypercholesterolemia in 50 population samples in the world. To exclude the influence of ethnicity in the study, 24 U T and Mg excretions were analyzed for the association with CMR in one ethnicity, Japanese population.24 U T/creatinine (C) ratios were divided into 5 quintiles and the ratios of Japanese to the total of each quintile were analyzed from CARDIAC Study samples. The highest 24 U T quintile consisted of 60% Japanese, indicating high seafood consumption in Japanese.Over 600 Japanese aged 30-79 were invited to a health examination for blood pressure measurement and for fasting blood and 24 U samplings. Tertile analysis of 24 U T/C ratios in relation to CMR indicated the third tertile had significantly higher HDL cholesterol, 24 U potassium (K) and 24 U salt than the first (lowest) tertile. Tertile analysis of 24 U Mg/C ratios indicated the third tertile had significantly lower body mass index and significantly higher folic acid, 24 U isoflavones, K and salt than the first tertile after age and gender adjustment. The third tertile of both T/C and Mg/C had significantly lower body mass index, LDL/HDL and Na/K ratios, and significantly higher HDL cholesterol and folic acid than the first tertile, indicating seafood eaters taking Mg rich diets had lower risks of obesity, atherosclerosis, hypertension and higher folic acid, beneficial for healthy longevity.

Soy and fish as features of the Japanese diet and cardiovascular disease risks.

In the World Health Organization (WHO)-coordinated Cardiovascular Disease and Alimentary Comparison Study, isoflavones (I; biomarker for dietary soy) and taurine (T; biomarker for dietary fish) in 24-hour-urine (24U) were inversely related to coronary heart disease (CHD) mortality. High levels of these biomarkers are found in Japanese people, whose CHD mortality is lowest among developed countries. We analyzed the association of these biomarkers with cardiovascular disease risk in the Japanese to know their health effects within one ethnic population. First, to compare the Japanese intake of I and T with international intakes, the ratios of 24UI and 24UT to creatinine from the WHO Study were divided into quintiles for analysis. The ratio for the Japanese was the highest in the highest quintiles for both I and T, reaching 88.1%, far higher than the average ratio for the Japanese (26.3%) in the total study population. Second, 553 inhabitants of Hyogo Prefecture, Japan, aged 30 to 79 years underwent 24-U collection and blood analyses. The 24UT and 24UI were divided into tertiles and adjusted for age and sex. The highest T tertile, compared with the lowest tertile, showed significantly higher levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, 24U sodium (Na) and potassium (K). The highest I tertile showed significantly higher folate, 24UNa and 24UK compared with the lowest tertile. The highest tertile of both T and I showed significantly higher HDL-C, folate, and 24UNa and 24UK compared with the lowest tertile. Thus, greater consumption of fish and soy were significantly associated with higher HDL-C and folate levels, possibly a contributor to Japan having the lowest CHD mortality and longest life expectancy among developed countries. As these intakes were also associated with a high intake of salt, a low-salt intake of fish and soy should be recommended for healthy life expectancy.