Diverse pro-inflammatory ability of mutated spike protein derived from variant strains of SARS-CoV-2.

The severity of COVID-19 has been reported to differ among SARS-CoV-2 mutant variants. The overactivation of macrophages is involved in severe COVID-19, yet the effects of SARS-CoV-2 mutations on macrophages remain poorly understood. To clarify the effects, we examined whether mutations of spike proteins (S-proteins) affect macrophage activation. CD14+ monocyte-derived macrophages were stimulated with the recombinant S-protein of the wild-type, Delta, and Omicron strains or live viral particles of individual strains. Regarding IL-6 and TNF-α, Delta or Omicron S-protein had stronger or weaker pro­inflammatory ability, respectively, than the wild-type. Similar trends were observed between S-proteins and viral particles. S-protein mutations could be related to the diversity in macrophage activation and severity rates in COVID-19 caused by various SARS-CoV-2 strains.

Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19.

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.

Factors associated with impaired physical function in elderly rheumatoid arthritis patients who had achieved low disease activity.

OBJECTIVE: We aimed to investigate factors associated with impaired physical function (defined as HAQ Disability Index [HAQ-DI] >0.5) of old-old (aged 75-84) patients with rheumatoid arthritis (RA). METHODS: Data from 15,185 RA patients in the National Database of Rheumatic Disease in Japan were extracted from 2017 to 2018. We enrolled 3,708 patients aged 55-84 in simplified disease activity index (SDAI) ≤11 and Steinbrocker stage I/II. Factors associated with HAQ-DI >0.5 were analyzed by multivariable logistic regression. RESULTS: About half of the old-old patients received methotrexate, which was lower than middle-aged (55-64) and young-old patients (65-74). The proportion of glucocorticoids in the old-old patients was highest among the three groups, and biological disease-modifying anti-rheumatic drugs were similarly used. The prevalence of HAQ-DI >0.5 was significantly higher in old-old patients with low disease activity than in those with remission. The same was true in the middle-aged and young-old patients. Multivariable analysis showed age, higher SDAI, glucocorticoid use, and methotrexate non-use were significantly associated with HAQ-DI >0.5 in the old-old patients. CONCLUSIONS: SDAI remission was an ideal goal for old-old patients in terms of physical function. Glucocorticoids and a low proportion of methotrexate use may influence the physical function of old-old patients.

CD34+THY1+ synovial fibroblast subset in arthritic joints has high osteoblastic and chondrogenic potentials in vitro.

OBJECTIVE: Synovial fibroblasts (SFs) in rheumatoid arthritis (RA) and osteoarthritis (OA) play biphasic roles in joint destruction and regeneration of bone/cartilage as mesenchymal stem cells (MSCs). Although MSCs contribute to joint homeostasis, such function is impaired in arthritic joints. We have identified functionally distinct three SF subsets characterized by the expression of CD34 and THY1 as follows: CD34+THY1+, CD34-THY1-, and CD34-THY1+. The objective of this study was to clarify the differentiation potentials as MSCs in each SF subset since both molecules would be associated with the MSC function. METHODS: SF subsets were isolated from synovial tissues of 70 patients (RA: 18, OA: 52). Expressions of surface markers associated with MSCs (THY1, CD34, CD73, CD271, CD54, CD44, and CD29) were evaluated in fleshly isolated SF subsets by flow cytometry. The differentiation potentials of osteogenesis, chondrogenesis, and adipogenesis were evaluated with histological staining and a quantitative polymerase chain reaction of differentiation marker genes. Small interfering RNA was examined to deplete THY1 in SFs. RESULTS: The expression levels of THY1+, CD73+, and CD271+ were highest and those of CD54+ and CD29+ were lowest in CD34+THY1+ among three subsets. Comparing three subsets, the calcified area, alkaline phosphatase (ALP)-stained area, and cartilage matrix subset were the largest in the CD34+THY1+ subset. Consistently, the expressions of differentiation markers of the osteoblasts (RUNX2, ALPL, and OCN) or chondrocytes (ACAN) were the highest in the CD34+THY1+ subset, indicating that the CD34+THY1+ subset possessed the highest osteogenic and chondrogenic potential among three subsets, while the differentiation potentials to adipocytes were comparable among the subsets regarding lipid droplet formations and the expression of LPL and PPARγ. The knockdown of THY1 in bulk SFs resulted in impaired osteoblast differentiation indicating some functional aspects in this stem-cell marker. CONCLUSION: The CD34+THY1+ SF subset has high osteogenic and chondrogenic potentials. The preferential enhancement of MSC functions in the CD34+THY1+ subset may provide a new treatment strategy for regenerating damaged bone/cartilage in arthritic joints.

A Patient with Necrotizing Vasculitis Related to Sarcoidosis, which Was Diagnosed via Immunohistochemical Methods Using Propionibacterium acnes-specific Monoclonal Antibodies.

Propionibacterium acnes (P. acnes) is a commensal bacterium indigenous to the skin. Previous reports have suggested that infection with P. acnes causes sarcoidosis, a systemic granulomatous disease. We present the case of a 63-year-old woman who developed subcutaneous nodules. A skin biopsy revealed necrotizing vasculitis and noncaseating granulomas, which are characteristic of sarcoidosis. Immunohistostaining revealed a P. acnes skin infection, which led to the diagnosis of sarcoidosis. Minocycline treatment resolved the infection and improved the patient's symptoms. We herein report a case in which immunohistochemistry was useful in the diagnosis of sarcoidosis.

Early Detection and Intervention of Coronary Artery Involvement in Immunoglobulin G4-related Disease.

A 59-year-old man with swollen submandibular glands developed an aortic aneurysm requiring aortic prosthesis implantation. Echocardiography performed to evaluate the cardiac function before the surgery incidentally revealed masses around the coronary arteries. The serum IgG4 levels were increased. A post-operational pathological examination of the abdominal aneurysms revealed infiltration of plasma cells, with the ratio of IgG4/IgG-positive cells being >80%. The patient was diagnosed with IgG4-related disease (RD) with coronary artery involvement. He was treated successfully with corticosteroid before any associated cardiovascular events occurred. Given the poor prognosis of IgG4-RD-associated coronary artery involvement, this case emphasizes the importance of the early assessment with echocardiography, even if patients have no cardiovascular symptoms.

Hemophagocytic Syndrome Complicated with Dermatomyositis Controlled Successfully with Infliximab and Conventional Therapies.

A 57-year-old woman was admitted to our hospital because of a high fever, anemia, and hyperferritinemia. Since a bone marrow examination revealed hemophagocytosis, she was diagnosed with hemophagocytic syndrome (HPS). During treatment of HPS, a heliotrope rash and Gottron's sign appeared with elevated levels of serum aldolase. She also developed heart failure. She was diagnosed with dermatomyositis (DM) and associated myocarditis. Although the administration of glucocorticoids, calcineurin inhibitors, intravenous immunoglobulins, and etoposide ameliorated the clinical findings of DM and cytopenia, the fever and hyperferritinemia remained. The addition of infliximab to glucocorticoids and tacrolimus improved the fever and hyperferritinemia and enabled a reduction in the dose of prednisolone without relapse of the diseases.

A dose-escalation regimen of trimethoprim-sulfamethoxazole is tolerable for prophylaxis against Pneumocystis jiroveci pneumonia in rheumatic diseases.

OBJECTIVE: To investigate the safety and efficacy of a dose-escalation regimen of trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jiroveci pneumonia (PCP) in rheumatic diseases. METHODS: Data from 41 patients, who received glucocorticoids with or without immunosuppressive agents and prophylactic use of TMP/SMX, were retrospectively analyzed. Thirteen patients were started on a daily dose of 10% of single-strength (SS) TMP/SMX, which was increased gradually (dose-escalation group), while 28 patients were started on 1 SS tablet daily (routine group). RESULTS: In the dose-escalation group, the retention rate was 100% at 6 months. In the routine group, 5 patients discontinued TMP/SMX; the retention rate was 82.1%. Moreover, the retention rate when taking a daily dose of 50% or more of SS TMP/SMX, or 1 SS tablet thrice-weekly, was significantly higher in the dose-escalation group (100 versus 71.4%, P = 0.032). No PCP was observed in the dose-escalation group; however, 1 patient in the routine group, who had discontinued TMP/SMX, developed PCP. The rate of adverse effects was less, although nonsignificant, in the dose-escalation group (30.8 versus 46.4%, P = 0.344). CONCLUSIONS: In rheumatic diseases, a dose-escalation regimen of TMP/SMX resulted in a higher retention rate and was safer than the routine regimen.

Successful treatment of glucocorticoid and cyclosporine refractory adult-onset Still's disease complicated with hemophagocytic syndrome with plasma exchange therapy and tocilizumab : a case report.

A 35-year-old woman was admitted to a hospital because of fever, sore throat, cervical lymph node swelling, and skin rashes. Laboratory data revealed leukocytosis and elevated C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, and ferritin levels. No antinuclear antibody or rheumatoid factor was found. She was diagnosed as having adult-onset Still's disease (AOSD). Although treatment with high-dose glucocorticoid (GC) and cyclosporine (CsA) was started, her condition did not improve because of complication with severe hemophagocytic syndrome (HPS). Therefore, she was transferred to our hospital. Immediately after admission, GC pulse therapy was started again, and treatment with CsA was replaced with tacrolimus (TAC), in addition, plasma exchange therapy was initiated. After treatment, her condition improved. However, 1 week after plasma exchange was discontinued, her condition deteriorated slightly with a slight fever and elevation of CRP level. This indicated that her condition could not be managed with GC and TAC, therefore, tocilizumab (TCZ) was added to her treatment, which improved her symptoms and enabled reduction in GC and TAC doses. Although many reports have indicated that biological agents are effective for refractory AOSD, their safety and efficacy in cases of AOSD complicated with HPS are controversial as these agents may exacerbate HPS. Our present case indicates that TCZ can be used after control of the disease activity by plasma exchange against refractory AOSD complicated with HPS.