Progressive multifocal leukoencephalopathy associated with systemic lupus erythematosus: longitudinal observation of lymphocytes, JC virus in cerebrospinal fluid, and brain magnetic resonance imaging.

Progressive multifocal leukoencephalopathy (PML) rarely occurs in patients with systemic lupus erythematosus (SLE). This report presents the case of a patient who developed PML due to SLE-associated multiple factors. A 60-year-old woman diagnosed with SLE undergoing multiple immunosuppressive therapies, including azathioprine, presented with cerebral cortical symptoms, lymphocytopenia, and vitamin B12 deficiency and was subsequently diagnosed with SLE-associated PML. We evaluated the cause and disease activity of PML, focusing on the longitudinal assessment of lymphocytopenia, JC virus (JCV) DNA copy number in the cerebrospinal fluid, and magnetic resonance imaging (MRI) findings. Discontinuing azathioprine and initiating alternative immunosuppressive treatments with intramuscular vitamin B12 injections affected lymphocytopenia and disease management. However, despite recovery from lymphopenia and JCV DNA copy number being low, the large hyperintense and punctate lesions observed on the fluid-attenuated inversion recovery (FLAIR) images exhibited varying behaviors, indicating that the balance between contributing factors for PML may have fluctuated after the initial treatment. Clinicians should be meticulous when assessing the underlying pathology of the multifactorial causes of PML due to SLE. The difference in the transition pattern of these lesions on FLAIR images may be one of the characteristics of MRI findings in PML associated with SLE, reflecting fluctuations in disease activity and the progression stage of PML.

Disseminated Mycobacterium abscessus infection with osteoarticular manifestations as an important differential diagnosis of inflammatory arthritis: A case report and literature review.

This case report describes a 52-year-old immunocompromised man diagnosed with disseminated Mycobacterium abscessus complex (MABC) infection. The patient had a history of malignant lymphoma and presented with fever and polyarthritis that lasted 3 weeks. Upon initial evaluation, blood and synovial fluid cultures from the swollen joints were negative. Reactive arthritis or rheumatoid arthritis was suspected as the cause of inflammatory synovitis in multiple joints. Administration of prednisolone followed by an interleukin-6 inhibitor improved the fever, but polyarthritis persisted, and destruction of the left hip joint was observed. Two months later, M. abscessus was detected in a blood culture and right shoulder joint synovium, leading to a final diagnosis of disseminated MABC infection. The joint symptoms resolved with combined antimicrobial therapy using amikacin, azithromycin, and imipenem/cilastatin. To date, 12 cases of disseminated MABC infection with osteoarticular manifestations have been reported. A total of 13 cases, including the present case, were reviewed. Seven patients had bone involvements, five had joint involvement, and the remaining one had bursa involvement. All the cases with joint involvement, except for our case, presented with monoarthritis. MABC infection is diagnosed based on the demonstration of MABC itself. Clinicians should keep disseminated MABC infection in mind as a possible cause of persistent arthritis. As demonstrated in our case, multiple replicate cultures of blood or specimens from the affected sites may be needed to detect it.

Tumor Necrosis Factor and Interleukin-1ß Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) and the auxiliary receptor Neuropilin-1 (NRP1) to enter host cells. NRP1 has another isoform, NRP2, whose function in COVID-19 has seldom been reported. In addition, although patients with severe cases of COVID-19 often exhibit increased levels of proinflammatory cytokines, the relationship between these cytokines and SARS-CoV-2 proliferation remains unknown. The aim of this study is to clarify the roles of proinflammatory cytokines in Neuropilin expressions and in SARS-CoV-2 infection. To identify the expression patterns of NRP under inflamed and noninflamed conditions, next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting were performed using primary cultured fibroblast-like synoviocytes, MH7A (immortalized cell line of human rheumatoid fibroblast-like synoviocytes), immortalized MRC5 (human embryonic lung fibroblast), and synovial tissues. To measure viral proliferative capacity, SARS-CoV-2 infection experiments were also performed. NRP2 was upregulated in inflamed tissues. Cytokine-stimulated human fibroblast cell lines, such as MH7A and immortalized MRC5, revealed that NRP2 expression increased with co-stimulation of tumor necrosis factor α (TNFα) and interleukin-1 beta (IL-1ß) and was suppressed with anti-TNFα antibody alone. TNFα and IL-1ß promoted SARS-CoV-2 proliferation and Spike protein binding. The viral proliferation coincided with the expression of NRP2, which was modulated through plasmid transfections. Our results revealed that proinflammatory cytokines, including TNFα, contribute to NRP2 upregulation and SARS-CoV-2 proliferation in host human cells.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Expression of factor XIII originating from synovial fibroblasts and macrophages induced by interleukin-6 signaling.

BACKGROUND: Blood coagulation factor XIII (FXIII) promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. However, its expression in cells or tissues and function, particularly factor XIII subunit B (FXIII-B), remains controversial. Hemorrhagic FXIII deficiency following anti-interleukin-6 (IL-6) receptor antibody treatment has been reported in patients with rheumatoid arthritis (RA). Patients receiving this biologics have reduced FXIII activity when compared to the activity in those treated with other biologics. The relationship between pro-inflammatory cytokines and FXIII expression remains unknown. METHODS: To investigate the expression pattern of FXIII in synovial tissues, immunohistochemistry, RT-qPCR, and western blotting were performed. FXIII-A expressed monocyte-derived macrophages were treated with recombinant IL-6 and anti-IL-6 receptor antibody. RNA sequencing of FXIII-B-overexpressing cells was performed to clarify the function of FXIII-B. RESULTS: The immunohistochemical analysis of synovial tissues revealed that factor XIII subunit A (FXIII-A) was expressed in M2 macrophages, and FXIII-B was expressed in fibroblast-like synoviocytes. IL-6 stimulation upregulated FXIII-A expression in IL-4-induced monocyte-derived macrophages, and the anti-IL-6 receptor antibody suppressed FXIII-A expression. FXIII-B was more abundantly secreted in the supernatant of fibroblast-like synoviocytes compared with that of other cells. RNA sequencing showed that FXIII-B elevated the expression of genes associated with anti-apoptotic molecules and chemokines. CONCLUSIONS: Our findings highlight that synovial tissue is one of the sources of FXIII production. We also have demonstrated IL-6-dependent FXIII-A expression and the novel potential functions of FXIII-B.

Fluorodeoxyglucose-positron emission tomography/computed tomography-positive ear lesions responsive to immunosuppressive therapy in a patient with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis.

A 74-year-old woman presented with vertigo, left-beating nystagmus, and auditory disturbance 4 months prior, in whom a former physician suspected Meniere's disease. Her signs and symptoms mildly improved with a moderate dose of glucocorticoids, which was eventually tapered. Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) was performed 12 days prior to routine examination. Remarkable FDG uptake was observed in the surrounding areas of the bilateral Eustachian tubes and left middle ear, which was only partially detected on magnetic resonance imaging. The patient also tested positive for myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA). She was admitted to our hospital and diagnosed with otitis media with ANCA-associated vasculitis (OMAAV) based on the classification criteria. Four months after immunosuppressive therapy, the abnormal ear findings were not observed on follow-up FDG-PET/CT. The clinical course of this case suggests that FDG-PET/CT can detect occult ear involvement better than do other modalities in patients with OMAAV. In addition, FDG-PET/CT-positive ear lesions responded to immunosuppressive therapy. Therefore, FDG-PET/CT can help distinguish OMAAV from other ear diseases with non-inflammatory aetiologies and detect occult treatment-responsive OMAAV lesions in the clinical setting.

Portal Vein Thrombosis as a Cause of Undetermined Thrombocytopenia with Liver Dysfunction in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

We herein report a 20-year-old woman who developed eosinophilic granulomatosis with polyangiitis (EGPA) and portal vein thrombosis (PVT). EGPA was diagnosed based on the patient's history of asthma, hypereosinophilia, and mononeuritis complex. Thrombocytopenia and liver dysfunction were observed, necessitating contrast-enhanced computed tomography (CECT), which revealed PVT. Her symptoms soon improved with glucocorticoids and anticoagulation therapy. As patients with EGPA often suffer from asthma, they can be hesitant to undergo CECT. However, if patients with EGPA show uncertain thrombocytopenia with liver dysfunction, a further evaluation using CECT is warranted to detect PVT.

Appearance of anti-MDA5 antibody-positive dermatomyositis after COVID-19 vaccination.

The direct causes of dermatomyositis, a common autoimmune disease, have not yet been accurately identified, but several studies have linked this condition to various patient-associated and environmental factors, such as viral infections and area of residence. In the present report, we describe our experience with a patient presenting with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis, which developed after vaccination against coronavirus disease 2019 (COVID-19). This patient was simultaneously diagnosed with anti-glutamic acid decarboxylase antibody-positive slowly progressive insulin-dependent diabetes (SPIDDM); her human leucocyte antigen test revealed that she expressed the DRB1*04:05 allele. This is important as this genotype is known to increase susceptibility to both anti-MDA5 antibody-positive dermatomyositis and type I diabetes. To the best of our knowledge, this is the first case of dermatomyositis complicated by SPIDDM identified after COVID-19 vaccination against COVID-19 and presenting with an underlying susceptible genotype. The patient's genetic predisposition may also be important for the development of autoimmune disease after COVID-19 vaccination.

Safe Introduction of Hydroxychloroquine Focusing on Early Intolerance Due to Adverse Drug Reactions in Patients with Systemic Lupus Erythematosus.

Objective This study explored the predictors of hydroxychloroquine intolerance and propose appropriate methods to initiate hydroxychloroquine in patients with systemic lupus erythematosus. Methods This retrospective study registered consecutive patients who were diagnosed with systemic lupus erythematosus and started treatment with hydroxychloroquine between 2015 and 2021. Any adverse events that required dose reduction or cessation of hydroxychloroquine, indicating intolerance to the drug, were recorded for up to 26 weeks after initiation of hydroxychloroquine. Results A total of 130 patients were included. Hydroxychloroquine intolerance due to adverse drug reactions was observed in 28 patients (21.5%), including gastrointestinal symptoms in 15 (11.5%) and cutaneous reactions in 7 (5.4%). Furthermore, the intolerance was observed more frequently in the maintenance group (patients treated daily with <20 mg prednisolone) than in the induction group (7.1% vs. 25.5%, p=0.04), and none of the patients in the induction group developed cutaneous reactions. The initial dose of hydroxychloroquine per ideal body weight was associated with hydroxychloroquine intolerance in a dose-dependent manner. Multivariable analyses revealed that the hydroxychloroquine dose per ideal body weight and higher levels of C4 predicted hydroxychloroquine intolerance. In particular, C4 levels were positively correlated with cutaneous reactions, whereas the dose of prednisolone was negatively correlated with gastrointestinal reactions. Conclusion Low-dose hydroxychloroquine may be optimal for induction in patients with systemic lupus erythematosus who have high C4 levels or are taking low doses of steroids.

Cryoglobulinemic Vasculitis Associated with Monoclonal Gammopathy of Undetermined Significance Developed after Sustained Virologic Response of Hepatitis C.

A 72-year-old woman had a history of chronic hepatitis C virus (HCV) infection previously treated with interferon to achieve a sustained virologic response. Thereafter, she developed polyarthritis and purpura of the lower extremities as well as progressive renal dysfunction with hypertension and proteinuria that had occurred in the last three months. Laboratory investigations revealed seropositivity for cryoglobulin but negative findings for HCV RNA. She was ultimately diagnosed with cryoglobulinemic glomerulonephritis complicated by monoclonal gammopathy of undetermined significance (MGUS) based on the pathological findings of the kidney and bone marrow, indicating that MGUS-induced cryoglobulinemic vasculitis may occur even after HCV elimination.

Importance of anti-centromere antibodies in the diagnosis of Sjögren's syndrome.

The purpose of the present study was to indicate that patients with anti-centromere antibodies (ACA) also experience ocular/oral dryness like patients with anti-Ro/SSA and/or anti-La/SSB antibodies (anti-SSA/SSB). A total of 80 patients with subjective ocular and/or oral dryness were classified into two groups, namely, anti-SSA/SSB-positive (anti-SSA/SSB [+]) group and ACA-positive (ACA [+]) group. The degree of ocular and oral dryness in ACA (+) patients is similar to that in anti-SSA/SSB (+) patients. On histopathological examination of the labial glands, the area of fibrosis was significantly larger in the ACA (+) group than in the anti-SSA/SSB (+) group. Thus, ACA (+) patients should be examined for Sjögren's syndrome.

C-reactive protein and ground-glass opacity as predictors for intractable interstitial lung disease in patients with systemic sclerosis under cyclophosphamide treatment regardless of concomitant glucocorticoids.

OBJECTIVES: Cyclophosphamide (CYC) has been proposed as a standard induction regimen for interstitial lung disease (ILD) associated with systemic sclerosis (SSc). However, there remain patients with SSc-ILD who are intractable to the therapy. This study aimed to identify factors associated with inadequate response to CYC and investigate how to treat SSc-ILD, especially in the need for glucocorticoids (GCs) combined with CYC. METHODS: This retrospective study included consecutive patients diagnosed with SSc-ILD and treated with CYC between 2009 and 2020. Logistic regression models were used to determine the prognostic factors indicating significant progression of ILD (SP-ILD). The clinical findings of patients treated with vs. without GCs were compared. RESULTS: Nineteen patients were registered, with a median age of 61.0 years. Fifteen were females, and five were classified into SP-ILD. Baseline high C-reactive protein (CRP) levels and non-widespread or localized ground-glass opacities (GGOs) predicted SP-ILD in multivariable analyses, and the cut-off level of CRP was 0.41 mg/dL. In clinical courses, SSc-ILD with high inflammation temporarily responded to CYC, regardless of the combined use of GCs; however, the therapeutic effects deteriorated soon after stopping CYC. CONCLUSION: High CRP levels with non-widespread GGO predicted progressive ILD in patients with SSc treated with CYC.

Nailfold capillaries and myositis-specific antibodies in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: This study aimed to quantify nailfold capillary (NFC) abnormalities in anti-melanoma differentiation-associated gene 5 (MDA5) -positive DM patients and to evaluate the association with clinical parameters, including serum biomarkers. In addition, we aimed to clarify the period leading to remission of NFC abnormalities during immunosuppressive treatment in patients with DM. METHODS: A prospective observational study was conducted including patients (n = 10) who first visited Hiroshima University Hospital and were diagnosed with DM or clinically amyopathic DM with anti-MDA5 antibodies. We compared the NFC abnormalities detected by nailfold-video capillaroscopy (NVC), physical findings, blood tests, respiratory function tests, and vascular-related growth factors measured using a LEGENDplexTM Multi-Analyte Flow Assay Kit. RESULTS: NFC abnormalities improved in all patients from 2 to 17 weeks after the initiation of immunosuppressive treatment. The NVC scores were inversely correlated with anti-MDA5 antibody titres at baseline. NVC scores and forced vital capacity were positively correlated. Baseline values of M-CSF and stem cell factor were correlated with anti-MDA-5 titres. CONCLUSION: Our study suggested that NVC scores and disease activity were inversely correlated before treatment. Vascular-related growth factors, such as M-CSF and stem cell factor, may be associated with the disease mechanism in patients with anti-MDA5 antibody-positive DM.

The Efficacy of Amenamevir for the Treatment of Disseminated Herpes Zoster Complicated with Probable Varicella-zoster Pneumonia in an Immunocompromised Patient.

We herein report the case of a 78-year-old woman who was diagnosed as having disseminated herpes zoster (DHZ) complicated with probable varicella-zoster pneumonia during maintenance therapy for microscopic polyangiitis. Because the patient had severe renal dysfunction, amenamevir administration was started to avoid any neurotoxicity of acyclovir, which is suggested to be optimal for treatment. It ameliorated her symptoms without any adverse events. This is the first report suggesting the efficacy of amenamevir in the treatment of severe herpes zoster infection with coexisting DHZ and probable varicella-zoster pneumonia. Amenamevir could thus be a treatment option for severe varicella zoster virus infections.