Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

Association Between Self-Construals, Social Pain Sensitivity, and Gender in Young Adults.

We experience pain in response to negative, unwanted social interaction with others (e.g., social rejection), and this type of pain is termed as social pain in the recent literature. While sensitivity to social pain may be beneficial to increase a chance for survival, social pain sensitivity could also be detrimental to elevate the risk of various health issues. Such opposing natures of social pain sensitivity warrants research to better identify factors that are linked to social pain sensitivity. Self-construals show perspectives on how to view oneself in relations to others, characterized as independent and interdependent self-construals, and may be linked to social pain sensitivity. Additionally, pervious data have indicated gender differences in social pain sensitivity, but it is unclear if self-construals explain gender differences in social pain sensitivity. Therefore, this study examined if self-construals were associated with social pain sensitivity, and gender differences in social pain sensitivity were accounted for by self-construals. The participants were 148 college students who completed several self-report questionnaires to evaluate self-construals and social pain sensitivity. The results indicated that interdependent tendency, which showed higher interdependent self-construal than independent self-construal, was associated with social pain sensitivity. While gender differences in social pain sensitivity were confirmed, gender differences in social pain sensitivity were not accounted for by interdependent tendency. The results suggest that interdependent tendency is associated with social pain sensitivity, but is not involved in gender differences in social pain sensitivity.

Fatal systemic capillary leak syndrome in a patient with a COVID-19 infection.

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with COVID-19.

A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder impacting various organs, notably prevalent in women of reproductive age. This review explores the involvement of a disintegrin and metalloproteinases (ADAMs) in SLE pathogenesis. Despite advancements in understanding SLE through genome and transcriptome studies, the role of ADAMs in post-translational regulations remains insufficiently explored. ADAMs, transmembrane proteins with diverse functions, impact cell adhesion, migration, and inflammation by shedding cell surface proteins, growth factors, and receptors. Notably, ADAM9 is implicated in Th17 cell differentiation, which is crucial in SLE pathology. ADAM10 and ADAM17 play pivotal roles in T-cell biology, influencing immune cell development and differentiation. Elevated soluble ADAM substrates in SLE patients serve as potential biomarkers correlating with disease activity. Targeting ADAMs or their substrates offers promising therapeutic avenues for SLE management and treatment enhancement.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

The double shared epitope: Its impact on clinical features and ultrasound findings in rheumatoid arthritis.

OBJECTIVES: The link between the HLA-DRB1 locus and the risk of rheumatoid arthritis (RA) shown in genome-wide association studies strengthens the shared epitope (SE) hypothesis. We aimed to assess the impact of the double dose of the SE (double SE) on RA and explore its clinical associations, including the response to abatacept. METHODS: We evaluated RA patients treated with csDMARDs or abatacept for HLA-DRB1 typing, clinical characteristics at baseline, and disease activity and ultrasound findings over 12 months. RESULTS: Patients with the double SE (n = 12) had significantly higher anti-citrullinated protein antibody (ACPA) titers, higher total grayscale (GS) score, and power Doppler (PD) score at baseline than patients without the double SE. Patients with the double SE exhibited reduced rates of SDAI remission and pronounced improvements in multiple disease activity between baseline and 12 months, including SDAI, CDAI, total GS score, and total PD score. When focusing on abatacept-treated patients, the decreases in SDAI, CDAI, and total PD score between baseline and 12 months were significantly larger in patients with the double SE. CONCLUSIONS: Patients with the double SE exhibited distinct characteristics, increased disease activity, and improved response to abatacept treatment.

Current Views on Pathophysiology and Potential Therapeutic Targets in Sjögren's Syndrome: A Review from the Perspective of Viral Infections, Toll-like Receptors, and Long-Noncoding RNAs.

Sjögren's syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.

Safety and efficacy of 5-aminolevulinic acid phosphate/iron in mild-to-moderate coronavirus disease 2019: A randomized exploratory phase II trial.

BACKGROUND: 5-aminolevulinic acid (5-ALA), a natural amino acid that is marketed alongside sodium ferrous citrate (SFC) as a functional food, blocks severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proliferation in vitro and exerts anti-inflammatory effects. In this phase II open-label, prospective, parallel-group, randomized trial, we aimed to evaluate the safety and efficacy of 5-ALA in patients with mild-to-moderate coronavirus disease 2019. METHODS: This trial was conducted in patients receiving 5-ALA/SFC (250/145 mg) orally thrice daily for 7 days, followed by 5-ALA/SFC (150/87 mg) orally thrice daily for 7 days. The primary endpoints were changes in SARS-CoV-2 viral load, clinical symptom scores, and 5-ALA/SFC safety (adverse events [AE] and changes in laboratory values and vital signs). RESULTS: A total of 50 patients were enrolled from 8 institutions in Japan. The change in SARS-CoV-2 viral load from baseline was not significantly different between the 5-ALA/SFC (n = 24) and control (n = 26) groups. The duration to improvement was shorter in the 5-ALA/SFC group than in the control group, although the difference was not significant. The 5-ALA/SFC group exhibited faster improvement rates in "taste abnormality," "cough," "lethargy," and "no appetite" than the control group. Eight AEs were observed in the 5-ALA/SFC group, with 22.7% of patients experiencing gastrointestinal symptoms (decreased appetite, constipation, and vomiting). AEs occurred with 750/435 mg/day in 25.0% of patients in the first phase and with 450/261 mg/day of 5-ALA/SFC in 6.3% of patients in the second phase. CONCLUSION: 5-ALA/SFC improved some symptoms but did not influence the SARS-CoV-2 viral load or clinical symptom scores over 14 days. The safety of 5-ALA/SFC in this study was acceptable. Further evaluation using a larger sample size or modified method is warranted.

The Toll-like Receptor 7-Mediated Ro52 Antigen-Presenting Pathway in the Salivary Gland Epithelial Cells of Sjögren's Syndrome.

OBJECTIVE: To investigate whether stimulation with toll-like receptor (TLR) 7 leads to pathways that proceed to tripartite motif-containing protein 21 (TRIM21) or Ro52/SS-A antigen presentation through major histocompatibility complex (MHC) class I in salivary gland epithelial cells (SGECs) from Sjögren's syndrome (SS) patients. DESIGN AND METHODS: Cultured SGECs from SS patients were stimulated with TLR7 agonist, loxoribine, and interferon-ß. Cell lysates immunoprecipitated by anti-MHC class I antibody were analyzed by Western blotting. The immunofluorescence of salivary gland tissue from SS and non-SS subjects and cultured TLR7-stimulated SGECs was examined. RESULTS: Significantly increased MHC class I expression was observed in SS patients' ducts versus non-SS ducts; no significant difference was detected for ubiquitin. Upregulated MHC class I in the cell membrane and cytoplasm and augmented Ro52 expression were observed in SGECs stimulated with TLR7. The formation of peptide-loading complex (PLC), including tapasin, calreticulin, transporter associated with antigen processing 1, and endoplasmic reticulum-resident protein 57 in labial salivary glands (LSGs) from SS patients, was dominantly observed and colocalized with MHC class I, which was confirmed in TLR7-stimulated SGEC samples. CONCLUSION: These findings suggest that the TLR7 stimulation of SS patients' SGECs advances the process toward the antigen presentation of TRIM21/Ro52-SS-A via MHC class I.

Increase in the number of new cases of ANCA-associated vasculitis in the COVID-19 vaccine era.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune vasculitis characterized by the production of antibodies against ANCA, with unclear pathogenesis. With the ongoing COVID-19 pandemic, COVID-19 mRNA vaccination has been available in Japan since February 2021. Although autoimmune symptoms have been reported after COVID-19 vaccinations, there have been no clinical investigations regarding the relationship between COVID-19 mRNA vaccines and the pathogenesis of AAV. Thus, the present study aimed to investigate whether the administration of COVID-19 mRNA vaccines affects the development of AAV. The study identified patients with new-onset AAV who were MPO-ANCA or PR3-ANCA positive and met the entry criteria of the AAV EMA classification algorithm. The study compared the number of new AAV cases per year before and after the start of the COVID-19 mRNA vaccine program in Japan. The study found that the annual number of new cases of AAV in Japan's Nagasaki Prefecture increased by approximately 1.5-fold since the COVID-19 vaccine program was initiated, suggesting a possible link between the COVID-19 mRNA vaccines and the development of AAV. Although the study provides insight into the clinical evaluation and management of autoimmune symptoms following COVID-19 vaccination, further investigation of the possible association between COVID-19 mRNA vaccines and the pathogenesis of AAV is required.

Food insecurity and academic function among college students during the COVID-19 pandemic: A moderating role of the first-generation college student status.

OBJECTIVE: To examine food insecurity (FI) prevalence among college students during the COVID-19 pandemic (April 2021) using cross-sectional design, and the moderating role of the first-generation student status in the relationship between FI and grade point average (GPA). PARTICIPANTS: Three-hundred sixty students recruited mostly from upper-level kinesiology courses. METHODS: General linear model was used to predict GPA based on food security status, psychological health, and bodily pain, with subgroup analysis performed by first-generation student status. RESULTS: Approximately 19% were classified as having FI. Those with FI showed lower GPA and poor health compared to those without FI. The link between FI and GPA was moderated by first-generation student status, with the negative impact of FI on GPA more clearly observed among non-first-generation students. CONCLUSION: First-generation student status could play a role in determining the impact of FI on academic performance.

Chest pain and Raynaud's phenomenon after COVID-19 vaccination in a patient previously diagnosed with systemic lupus erythematosus: a case report.

Background: Cardiovascular events, including pericarditis, myocarditis, and myocardial ischaemia, have been reported as complications following COVID-19 vaccination. Case summary: A 28-year-old Japanese woman diagnosed 10 years earlier with systemic lupus erythematosus and antiphospholipid syndrome was admitted to our hospital because of chest pain and Raynaud's phenomenon. She had received a second dose of the COVID-19 BNT162b2 mRNA vaccine 28 days earlier. 123I-ß-methyl iodophenyl pentadecanoic acid (BMIPP) and 201thallium dual myocardial single-photon emission computed tomography demonstrated mildly reduced perfusion of BMIPP in the mid-anterior wall of the left ventricle. Coronary angiography revealed normal coronary arteries; additionally, an endomyocardial biopsy was performed. Histopathological evaluation revealed a normal myocardium without cell infiltration. However, immunostaining for the severe acute respiratory coronavirus (SARS-CoV)/severe acute respiratory coronavirus 2 (SARS-CoV-2) spike protein was positive in the small intramural coronary arteries. The administration of azathioprine (50 mg/day) and amlodipine (5 mg/day) and increases in her prednisolone (10 mg/day) and aspirin doses led to improvements in the symptoms of the patient. Discussion: Our data lead us to speculate that two events in the timeline of the patient, namely, receiving COVID-19 vaccination and the presence of SARS-CoV/SARS-CoV-2 spike protein in small intramural coronary arteries, may be related to the myocardial microangiopathy observed in this patient.

Exploring the sex differences in conditioned pain modulation and its biobehavioral determinants in healthy adults.

BACKGROUND: Females are at greater risk of chronic pain, and exhibit higher pain sensitivity compared to males. However, sex differences in conditioned pain modulation (CPM), a neurophysiological risk factor of chronic pain, are unclear. CPM is influenced by many factors, some of which are sex-dependent. This study explored the sex differences in CPM and its biobehavioral determinants, such as blood pressure responses, physical activity levels, pain catastrophizing scores, and conditioning stimulus intensity, in young, healthy, physically active males and females. METHODS: Twenty-six males and 24 females completed the CPM test using an electrical pain stimulus and a cold pain stimulus induced via 2 min of cold pressor test. Blood pressure was assessed at baseline and during cold pressor test, whereas cold pain ratings were obtained during cold pressor test to monitor the conditioning stimulus intensity. Physical activity was evaluated via questionnaires and accelerometer, whereas pain catastrophizing was evaluated via a questionnaire. RESULTS: Both males and females exhibited CPM, without sex differences in the magnitude of CPM. The males showed higher resting blood pressure, higher physical activity levels, and lower pain catastrophizing scores than the females, without sex differences observed in cold pain ratings and proportion of those who met the physical activity guidelines. No correlations were observed between CPM and its determinants. CONCLUSIONS: The results suggest the complexity of mechanisms underlying the sex differences in CPM. The sex differences in CPM, along with its determinants, may need to be examined in individuals with some risk factors for chronic pain.

A Patient with Severe Fever with Thrombocytopenia Syndrome, Activated Partial Thromboplastin Time Prolongation, and Transient Antiphospholipid Antibodies.

A prolonged activated partial thromboplastin time (APTT) is observed in patients with severe fever with thrombocytopenia syndrome (SFTS) and is one of the risk factors for severe disease. The mechanism underlying a prolonged APTT is largely unknown. The presence of antiphospholipid (aPL) antibodies in various viral infections has been documented but never reported in a patient with SFTS. We herein report the first SFTS patient with APTT prolongation and concurrent transiently positive aPL antibodies (lupus anticoagulants and anticardiolipin antibodies) with no coagulation factor deficiency.

Prediction of radiographic progression during a treat-to-target strategy by the sequential application of MRI-proven bone marrow oedema and power-Doppler grade ≥2 articular synovitis in rheumatoid arthritis: Retrospective observational study.

OBJECTIVES: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA). METHODS: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered. RESULTS: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year. CONCLUSION: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Immunoglobulin G4-related Disease with Marked Eosinophilia: A Case Report and Literature Review.

We encountered a 78-year-old Japanese man with IgG4-related sialoadenitis complicated with marked eosinophilia. We diagnosed him with IgG4-RD (related disease) with a submandibular gland tumor, serum IgG4 elevation, IgG4-positive plasma cell infiltration, and storiform fibrosis. During follow-up after total incision of the submandibular gland, the peripheral eosinophil count was markedly elevated to 29,480/µL. The differential diagnosis of severe eosinophilia without IgG4-RD was excluded. The patient exhibited a prompt response to corticosteroid therapy. His peripheral blood eosinophil count was the highest ever reported among similar cases. We also review previous cases of IgG4-RD with severe eosinophilia.

Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.

Mediating role of physical activity in the relationship between exercise-induced muscle pain and symptom severity in women with fibromyalgia.

BACKGROUND: Individuals with fibromyalgia (FM) exhibit generalized hyperalgesia to pain stimuli, and physical activity (PA) is critical to manage FM symptoms. PURPOSE: This study examined the relationship between exercise-induced muscle pain, symptom severity, and PA in 28 women with FM. METHODS: Muscle pain rating (MPR) was assessed during 3 minutes of submaximal isometric handgrip exercise, whereas PA and symptom severity were evaluated via self-report questionnaires. The analysis examined the relationship between the variables, with the specific interest in the mediating role of PA in the relationship between exercise-induced muscle pain and symptom severity. RESULTS: MPR was positively associated with symptom severity (b = 1.89; 95% CI = 0.01, 3.76; P = .048) and inversely associated with PA levels (b = -0.16; 95% CI = -0.30, -0.03; P = .021). PA levels were inversely associated with symptom severity (b = -7.94; 95% CI = -12.46, -3.42; P = .001). After statistically controlling for PA levels, the relationship between MPR and symptom severity was no longer significant (b = 0.60; Wald 95% CI = -1.05, 2.25; P = .474). CONCLUSION: Results show the link between the variables, and specifically demonstrate that PA mediates the relationship between exercise-induced muscle pain and symptom severity.