Outcomes in novel hospital-at-home model for patients with COVID-19: a multicentre retrospective cohort study.

BACKGROUND: Hospital-at-home (HaH) care has been proposed as an alternative to inpatient care for patients with coronavirus disease (COVID-19). Previous reports were hospital-led and involved patients triaged at the hospitals. To reduce the burden on hospitals, we constructed a novel HaH care model organized by a team of local primary care clinics. METHODS: We conducted a multicentre retrospective cohort study of the COVID-19 patients who received our HaH care from 1 January to 31 March 2022. Patients who were not able to be triaged for the need for hospitalization by the Health Center solely responsible for the management of COVID-19 patients in Osaka city were included. The primary outcome was receiving medical care beyond the HaH care defined as a composite outcome of any medical consultation, hospitalization, or death within 30 days from the initial treatment. RESULTS: Of 382 eligible patients, 34 (9%) were triaged for hospitalization immediately after the initial visit. Of the remaining 348 patients followed up, 37 (11%) developed the primary outcome, while none died. Obesity, fever, and gastrointestinal symptoms at baseline were independently associated with an increased risk of needing medical care beyond the HaH care. A further 129 (37%) patients were managed online alone without home visit, and 170 (50%) required only 1 home visit in addition to online treatment. CONCLUSIONS: The HaH care model with a team of primary care clinics was able to triage patients with COVID-19 who needed immediate hospitalization without involving hospitals, and treated most of the remaining patients at home.

Invasive pulmonary aspergillosis due to Aspergillus lentulus in an adult patient: A case report and literature review.

Aspergillus fumigatus is the commonest cause of pulmonary aspergillosis; however, a recently developed molecular genetic technique identified A. lentulus as a sibling species. Most of the isolates were found in solid organ recipients, often associated with a fatal outcome. Moreover, there is concern that A. lentulus has low susceptibility to multiple antifungal agents. Herein, we report an adult immunocompromised patient with proven invasive pulmonary aspergillosis (IPA) caused by A. lentulus, which was identified through molecular genetic analysis. The patient was diagnosed with IPA by bronchoscopy 3 weeks after initiating systemic corticosteroid therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. The clinical course of IPA due to A. lentulus showed improvement after treatment with the antifungal agent voriconazole. In summary, we report an adult immunocompromised patient without a history of transplantation who was diagnosed with IPA due to A. lentulus successfully treated with voriconazole, and we also report the findings of a literature review on IPA caused by A. lentulus.

Tocilizumab-induced psoriasis-like eruption resolved by shortening the dose interval in a patient with rheumatoid arthritis: a case-based review.

Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption.

Increased circulating CD14brightCD16+ intermediate monocytes are regulated by TNF-α and IL-6 axis in accordance with disease activity in patients with rheumatoid arthritis.

OBJECTIVES: Although circulating CD14brightCD16+ monocyte subsets are increased in inflammatory disease, the pathogenesis of the increase in the inflammatory condition of the cells is still unclear and the relationship to cytokines is unknown particularly in rheumatoid arthritis (RA). The purpose of this study was to investigate the influence anti-cytokine treatment has on CD14brightCD16+ monocytes in patients with RA. METHODS: Thirty-two RA patients and 14 healthy volunteers (HV) were enrolled in this study. All the patients had never been treated with methotrexate (MTX) or biological agents. Peripheral blood samples and clinical information of the patients were obtained at the time of 0, 12 and 24 weeks of treatment. Peripheral blood samples were also obtained from the HV. The expression levels of CD14 and CD16 on monocytes were measured by flow cytometry (FCM). RESULTS: Eight patients received anti-interleukin (IL)-6 receptor antibody, tocilizumab (TCZ) treatment alone, 12 patients received anti-tumour necrosis factor (TNF)-α antibody, adalimumab (ADA) with MTX treatment and the others received only MTX treatment. FCM analysis revealed that the proportion of CD14brightCD16+ monocytes significantly increased in patients at baseline compared with HV. The proportion of CD14brightCD16+ monocytes significantly decreased after TCZ, and ADA with MTX treatment. The proportion of intermediate monocytes was significantly and positively correlated with disease activity and it improved in accordance with the proportion of CD14brightCD16+ monocytes after inhibition of signal transduction of inflammatory cytokines. CONCLUSIONS: We showed that the population of CD14brightCD16+ monocytes significantly decreased with the change of disease activity by key cytokines, IL-6 or TNF-α signal blockade in RA. This result indicates that the proportion of those monocytes is important for reflecting disease activity in RA.

Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis.

OBJECTIVES: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis. METHODS: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients' charts. RESULTS: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01). CONCLUSIONS: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.

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.

Aseptic meningitis followed by mononeuritis multiplex in a patient with primary Sjögren's syndrome.

A 38-year-old woman was admitted to hospital because of fever and headache. Increased cerebrospinal cell count and protein without evidence of infection led to a diagnosis of aseptic meningitis. Although she improved with acyclovir and glyceol, she experienced left forearm pain and sensory disturbance with drop fingers. Poor derivation of compound muscle action potentials in the left radial nerve was observed, leading to a diagnosis of mononeuritis multiplex with sensorimotor neuropathy. Because the patient had primary Sjögren's syndrome with anti-Ro/SS-A antibody and salivary gland hypofunction, treatment with methylprednisolone, intravenous immunoglobulin, and intravenous cyclophosphamide was followed by oral glucocorticoid therapy. After these intensive therapies, her drop fingers gradually improved, although sensory disturbance remained. In conclusion, we report a case of aseptic meningitis and subsequent mononeuritis multiplex that was successfully treated with intensive immunotherapy in a patient with primary Sjögren's syndrome.

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.

Does HTLV-1 Infection Show Phenotypes Found in Sjögren's Syndrome?

Viruses are a possible cause for Sjögren's syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS.

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.

Value of labial salivary gland histopathology for diagnosis of Sjögren's syndrome in patients with anti-centromere antibody positivity.

AIM/INTRODUCTION: Although anti-centromere antibody (ACA)+ Sjögren's syndrome (SS) is considered a subtype of SS, it was not included in the recent American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) SS classification criteria. ACA+ patients without anti-SS-A/Ro antibodies require salivary gland histopathology to fulfill the ACR/EULAR criteria for diagnosis of SS. We reviewed salivary gland histology among ACA+ patients referred for the diagnosis of SS using the ACR/EULAR and Japanese criteria which does not require biopsy. METHOD: Data from 147 ACA+ patients with dry eyes and/or mouth who visited our department were retrospectively analyzed. Clinical, immunological, and histological data were collected and statistically analyzed. RESULT: Sixty-five patients (44%) had undergone labial salivary gland biopsy. The frequency of dry mouth was higher in ACA+ patients who had undergone labial salivary gland biopsy than in those who had not (P = .046), while there were no differences in biopsy rates between patients with and without sclerodactyly (P = .51). According to the current ACR/EULAR classification criteria, Greenspan grade of 3 or 4 for labial salivary gland histopathology is required in patients without anti-SS-A/Ro antibody for the diagnosis of SS. Four patients with Greenspan grades <3 and anti-SS-A/Ro antibody met the criteria for SS. In 54 patients in which the ACR/EULAR criteria were met, 53 patients were diagnosed with SS using the Japanese criteria. CONCLUSION: In ACA+/anti-SS-A/Ro- antibody patients, agreement between ACR/EULAR and Japanese criteria sets was excellent. For easily classifying ACA+ patients as SS cases, salivary gland biopsy should be performed in ACA+ patients with dry symptoms to identify ACA+ patients.

Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement.

Central nervous system (CNS) involvement, including encephalopathy, encephalitis, leptomeningitis, and pachymeningitis, in rheumatoid arthritis (RA) is rather rare. We report the case of a 61-year-old female with a history of RA in remission for 7 years, who presented with numbness, weakness of the left upper limb, dysarthria, and headache. Magnetic resonance imaging (MRI) of the brain showed meningeal enhancement in the frontal, parietal, and temporal lobes. Cerebrospinal fluid (CSF) examination detected high levels of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA), with a high ACPA-immunoglobulin G index (> 2.0). She was diagnosed with rheumatoid meningitis. Following combined therapy with oral prednisolone and intravenous infusion of cyclophosphamide, her symptoms promptly improved. After treatment, RF and ACPA levels in the CSF were reduced, and MRI showed improvement of the meningeal structures. This case, along with existing literature, suggests that the ACPA level in the CSF may serve as a useful marker for diagnosing of CNS involvement in RA, as well as an index of effectiveness of the associated treatment.

Correction to: Anti-cyclic citrullinated peptide antibody in the cerebrospinal fluid in patients with rheumatoid arthritis who have central nervous system involvement.

The authors regret that the original published version of the above article contained errors. The authors requested that these be noted.

Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits.

Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the stratum lucidum, followed by a mild increase in the stratum radiatum adjacent to the stratum lucidum, but not in the distal area of stratum radiatum. The Zn2+ increase was insensitive to a non-N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring stratum radiatum. Electrophysiological analyses revealed that NMDA receptor-mediated synaptic responses in CA3 proximal stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.

Initial presentation determines clinical entity in patients with anti-centromere antibody positivity.

AIM: Anti-centromere antibody (ACA) is often detected in patients with autoimmune diseases, including limited cutaneous systemic sclerosis (SSc), Sjögren's syndrome (SS), and primary biliary cholangitis (PBC). The association between autoimmune disease and ACA positivity remains unclear. We sought to clarify the clinical features of ACA-positive patients and their association with autoantibodies. METHOD: A total of 309 cases of a discrete-speckled pattern anti-nuclear antibody (ANA) test and/or positive ACA who visited our department were retrospectively enrolled. Clinical and immunological data were collected and statistically analyzed. RESULT: A proportion of second and/or third ANA patterns were speckled (16%), homogenous (7%), cytoplasmic (3%) and/or nucleolar (3%). Of the 309 patients, 186 had Raynaud's phenomenon, 149 had sclerodactyly, and 162 had oral and/or ocular dryness. A total of 214 patients were classified into 17 autoimmune diseases based on their symptoms at the initial visit, while the other 95 patients did not meet any criteria. Most of the 214 patients were diagnosed with SSc and/or SS; 25 and 22 additional patients were diagnosed with rheumatoid arthritis and PBC, respectively. Higher titers of immunoglobulins were observed in patients diagnosed with autoimmune disease compared to patients without a diagnosis. The mean observation period was 80 months. Three additional patients received interim diagnoses based on new symptoms or organ involvement. In the other patients, the diagnosis made at the first visit was not changed over the observation period. CONCLUSION: Our study confirmed that many ACA-positive cases can be classified into an autoimmune disease type on presentation.

Ten-year observation of patients with primary Sjögren's syndrome: Initial presenting characteristics and the associated outcomes.

AIM/INTRODUCTION: Primary Sjögren's syndrome (pSS) is a prototypical systemic autoimmune disease that manifests with various signs and symptoms. Although some studies have examined these manifestations over the long-term course of the disease, the association between initial clinical and immunological factors and subsequent long-term manifestations has not been fully elucidated. The aim of this study is to identify initial clinical and immunological factors associated with subsequent manifestations in patients with pSS. METHOD: A retrospective review was performed in pSS patients who were followed up over a 10-year period in our department. Clinical and immunological data, including serum immunoglobulin (Ig) and autoantibody levels, were collected and statistically analyzed. RESULT: We analyzed 91 patients who were followed up in our department. The proportion of patients with extraglandular involvement decreased from 90% to 73%, while eight patients developed extraglandular organ involvement. Extraglandular involvement at 10 years more frequently occurred in patients with hyper-IgG than those without hyper-IgG at initial testing (P < 0.01). Extraglandular organ involvement at 10 years more frequently occurred in rheumatoid factor (RF)-positive patients at the time of SS diagnosis (P < 0.05). Malignancy occurred in 9% of patients. Age, lower CH50 and thrombocytopenia were significantly associated with malignancy. Extraglandular organ involvement was associated with the presence of hyper-IgG and RF positivity (P < 0.01 and P < 0.05). CONCLUSION: Our study identified important initial clinical and immunological factors associated with subsequent manifestations in patients with pSS over a long follow-up period. pSS patients with RF and hyper-IgG at diagnosis may have a higher risk of subsequent extraglandular involvement.

Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjögren's Syndrome.

INTRODUCTION: Anti-centromere antibody (ACA)-positive Sjögren's syndrome (SS) is considered a subtype of SS. ACA-positive SS patients display several features, such as Raynaud's phenomenon, sclerodactyly, and extraglandular dysfunction. However, information on the features of ACA-positive SS is insufficient and the clinical significance of ACA in SS has not been fully established. The aim of this study was to clarify the features of ACA-positive SS. METHODS: All patients with primary SS who visited our hospital were enrolled. Clinical information and immunological tests were collected and statistically analyzed. RESULTS: A total of 585 patients were classified as having primary SS. They were divided into four groups by serum ACA and anti-SS-A antibody status as follows: 22 had ACA only (ACA alone), 464 had anti-SS-A antibodies only (SS-A alone), 26 had both ACA and anti-SS-A antibodies (double-positive), and 73 had neither ACA nor anti-SS-A antibodies (seronegative). The proportion of patients with dryness did not differ between the four groups. The proportion of patients with Raynaud's phenomenon or sclerodactyly was higher in the ACA alone and double-positive groups. The proportion of patients with increased serum IgG or IgA was 0 and 5% in the ACA alone group, 61 and 20% in the SS-A alone group, 52 and 28% in the double-positive group, and 20 and 4% in the seronegative group (p < 0.01 and p < 0.01), respectively. The proportion of patients with leukocytopenia was significantly lower in the SS-A-negative group than in the other groups. CONCLUSIONS: Our study identified characteristics of ACA-positive SS patients that differ from those of anti-SS-A antibody-positive SS patients.

CD14brightCD16+ intermediate monocytes are induced by interleukin-10 and positively correlate with disease activity in rheumatoid arthritis.

BACKGROUND: Three different subsets of circulating human monocytes, CD14brightCD16- (classical), CD14brightCD16+ (intermediate), and CD14dimCD16+ (non-classical) have been recently identified. It has been reported that CD14brightCD16+ monocytes are increased in rheumatoid arthritis (RA). However, the role of each monocyte subset in the pathogenesis of RA is still unclear. The purpose of this study was to investigate the association of CD14brightCD16+ monocytes with RA. METHODS: The study enrolled 35 patients with RA and 14 healthy volunteers. The three subsets of peripheral blood monocytes were analyzed by flow cytometry. Serum cytokines were measured at baseline in patients with RA and in healthy volunteers. CD14brightCD16- monocytes were isolated and cultured in vitro with different cytokines for 14 hours, and CD16 induction was assessed. RESULTS: The proportion of CD14brightCD16+ monocytes, and serum interleukin (IL)-6, IL-8, and IL-10 were increased in patients with RA compared to healthy controls. The proportion of CD14brightCD16+ monocytes correlated with the disease activity of RA positively, whereas the proportion of CD14brightCD16- monocytes correlated negatively. When isolated CD14brightCD16- monocytes were stimulated with IL-6, IL-8, and IL-10, the only cytokine that significantly induced CD16 expression on the cells was IL-10. CONCLUSIONS: The proportion of CD16brightCD14+ monocytes was positively correlated with RA disease activity. The expression of CD16 in monocytes was induced by IL-10 but not IL-6, and IL-8 was enhanced in the sera of patients with RA. Our results suggest that CD16brightCD14+ monocytes are involved in the pathogenesis of RA and that IL-10 is a key cytokine that regulates CD16 expression in monocytes.

Integrative spike dynamics of rat CA1 neurons: a multineuronal imaging study.

The brain operates through a coordinated interplay of numerous neurons, yet little is known about the collective behaviour of individual neurons embedded in a huge network. We used large-scale optical recordings to address synaptic integration in hundreds of neurons. In hippocampal slice cultures bolus-loaded with Ca2+ fluorophores, we stimulated the Schaffer collaterals and monitored the aggregate presynaptic activity from the stratum radiatum and individual postsynaptic spikes from the CA1 stratum pyramidale. Single neurons responded to varying synaptic inputs with unreliable spikes, but at the population level, the networks stably output a linear sum of synaptic inputs. Nonetheless, the network activity, even though given constant stimuli, varied from trial to trial. This variation emerged through time-varying recruitment of different neuron subsets, which were shaped by correlated background noise. We also mapped the input-frequency preference in spiking activity and found that the majority of CA1 neurons fired in response to a limited range of presynaptic firing rates (20-40 Hz), acting like a band-pass filter, although a few neurons had high pass-like or low pass-like characteristics. This frequency selectivity depended on phasic inhibitory transmission. Thus, our imaging approach enables the linking of single-cell behaviours to their communal dynamics, and we discovered that, even in a relatively simple CA1 circuit, neurons could be engaged in concordant information processing.