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1.
Artigo em Inglês | MEDLINE | ID: mdl-31764973

RESUMO

OBJECTIVES: Peficitinib, a novel Janus kinase (JAK) inhibitor, demonstrated promising results in treating RA in phase 3 clinical trials. This in vitro study was undertaken to characterize the pharmacological properties of peficitinib and investigate the involvement of JAK and signal transducer and activator of transcription (STAT) pathways in the pathological processes of SSc, which is also an autoimmune disease. METHODS: Phosphorylation levels of STAT molecules were assessed in peripheral blood mononuclear cells collected from patients with RA or SSc and healthy subjects, and in skin specimens obtained from 19 patients with SSc. In vitro inhibition of STAT phosphorylation and cytokine/chemokine production by peficitinib, tofacitinib and baricitinib were also characterized. RESULTS: Higher spontaneous STAT1 or STAT3 phosphorylation was observed in peripheral T-cells and monocytes from patients with RA and SSc compared with healthy subjects. In skin sections from patients with SSc, phosphorylated STAT3-positive cells were found in almost all cases, irrespective of disease subtype or patient characteristics. Conversely, phosphorylated STAT1-positive cells were observed only in samples from untreated patients with diffuse disease of short duration. Peficitinib inhibited STAT phosphorylation induced by various cytokines, with comparable efficacy to tofacitinib and baricitinib. Peficitinib also suppressed cytokine and chemokine production by peripheral blood mononuclear cells and skin fibroblasts. CONCLUSION: Our results suggest that JAK/STAT pathways are constitutively activated in SSc and RA, and that the JAK inhibitor may represent a novel therapeutic option for SSc.

2.
J Vis Exp ; (151)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31545323

RESUMO

We present a high-performance source of unconditional polarization-entangled photons that have a high-emission rate, a broadband distribution, are degenerated and postselection free. The property of the source is based on the multiple quantum interference effect with a round-trip configuration of a Sagnac interferometer. The quantum interference effects make it possible to use the high generation efficiency of the polarization-entangled photons to process parametric down-conversion, and separate degenerated photon pairs into different optical modes without a postselection requirement. The principle of the optical system was described and experimentally used to measure the fidelity and Bell parameters, and also to characterize the generated polarization-entangled photons from a minimum of six combinations of polarization correlated data. The experimentally obtained fidelity and Bell parameters exceeded the classical local correlation limit and are clear evidence of the generation of unconditional polarization-entangled photons.

3.
Autoimmun Rev ; 18(11): 102394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520797

RESUMO

OBJECTIVES: This study was designed to propose a simple "Fast Track algorithm" for capillaroscopists of any level of experience to differentiate "scleroderma patterns" from "non-scleroderma patterns" on capillaroscopy and to assess its inter-rater reliability. METHODS: Based on existing definitions to categorise capillaroscopic images as "scleroderma patterns" and taking into account the real life variability of capillaroscopic images described standardly according to the European League Against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases, a fast track decision tree, the "Fast Track algorithm" was created by the principal expert (VS) to facilitate swift categorisation of an image as "non-scleroderma pattern (category 1)" or "scleroderma pattern (category 2)". Mean inter-rater reliability between all raters (experts/attendees) of the 8th EULAR course on capillaroscopy in Rheumatic Diseases (Genoa, 2018) and, as external validation, of the 8th European Scleroderma Trials and Research group (EUSTAR) course on systemic sclerosis (SSc) (Nijmegen, 2019) versus the principal expert, as well as reliability between the rater pairs themselves was assessed by mean Cohen's and Light's kappa coefficients. RESULTS: Mean Cohen's kappa was 1/0.96 (95% CI 0.95-0.98) for the 6 experts/135 attendees of the 8th EULAR capillaroscopy course and 1/0.94 (95% CI 0.92-0.96) for the 3 experts/85 attendees of the 8th EUSTAR SSc course. Light's kappa was 1/0.92 at the 8th EULAR capillaroscopy course, and 1/0.87 at the 8th EUSTAR SSc course. CONCLUSION: For the first time, a clinical expert based fast track decision algorithm has been developed to differentiate a "non-scleroderma" from a "scleroderma pattern" on capillaroscopic images, demonstrating excellent reliability when applied by capillaroscopists with varying levels of expertise versus the principal expert and corroborated with external validation.


Assuntos
Algoritmos , Esclerodermia Localizada/diagnóstico , Escleroderma Sistêmico/diagnóstico , Humanos , Angioscopia Microscópica/métodos , Reprodutibilidade dos Testes
4.
Bone ; 128: 115034, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421252

RESUMO

Diabetes patients are at high risk of bone fracture due to accumulation of advanced glycation end products (AGEs) and low bone turnover. Although AGEs inhibit osteoblast functions, little is known about their roles in regulation of human osteoclast differentiation. The aim of this study was to determine the roles of AGEs in regulation of human osteoclast differentiation. Human CD14+ monocytes collected from healthy individuals were stimulated in vitro with conventional cytokines to induce osteoclast differentiation. Simultaneously, glucose-modified AGEs-BSA (Glu-AGEs-BSA) and glycolaldehyde-modified AGEs-BSA (Glyco-AGEs-BSA) were added to analyze their role in regulation of osteoclast differentiation. Human CD14+ cells expressed endogenous receptor for AGE (RAGE). Stimulation with Glyco-AGEs-BSA, but not Glu-AGEs-BSA, reduced the number of tartrate-resistant acid phosphatase-positive cells in a dose-dependent manner and suppressed mRNA expression of nuclear factor of activated T-cells 1 and cathepsin K. Glyco-AGEs-BSA up-regulated pro-inflammatory cytokines and anti-inflammatory cytokine IL-10. The addition of IL-10-neutralizing antibodies abrogated the suppressive effect of Glyco-AGEs-BSA on osteoclast differentiation. Stimulation of Glyco-AGE-BSA resulted in nuclear factor (NF)-κB phosphorylation, and addition of an inhibitor of κB kinase suppressed IL-10 production. We conclude that Glyco-AGEs-BSA inhibited human osteoclast differentiation through induction of IL-10 expression via NF-κB. It can be assumed that AGE bioaccumulation in diabetic patients increases the risk of bone fracture, through inhibition of osteoclast differentiation, reduction of bone turnover, and disruption of bone remodeling.

5.
Rheumatology (Oxford) ; 58(12): 2273-2283, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31230071

RESUMO

OBJECTIVE: The pathological changes in SSc include immune system dysregulation and microvascular damage. However, the association of immune cell phenotype heterogeneity and microvascular abnormalities is unclear. The aim of this study is to elucidate this association in SSc. METHODS: Peripheral blood mononuclear cells obtained from 150 SSc patients were used for comprehensive flow cytometric analysis based on the Human Immunology Project. Hierarchical cluster analysis was used to classify SSc patients into subgroups and their association with microvascular abnormalities, as assessed by nailfold videocapillaroscopy (i.e. 'early', 'active' and 'late' patterns), was analysed. RESULTS: The proportions of activated CD4+ T cells, T cells re-expressing CD45RA, activated Th1 and Th17 cells and IgD-CD27- B cells were higher in SSc patients than in healthy individuals. Hierarchical cluster analysis stratified SSc patients into three groups: patients with few immune abnormalities (fewer abnormalities group), patients with high proportions of activated T and Treg cells (Treg-dominant group) and patients with high proportions of Tfh and plasmablasts (Tfh-dominant group). Age and disease duration were comparable among the groups. On the other hand, microvascular abnormalities, especially the 'late' nailfold videocapillaroscopy pattern, correlated with internal organ involvement. Among the groups stratified according to immune cell phenotype, the progression to the 'late' nailfold videocapillaroscopy pattern was more frequent in the Tfh-dominant group. CONCLUSION: Our study confirmed the presence of immunophenotypic abnormalities in SSc. Immunological abnormalities were not uniform but rather limited to subpopulations, particularly the Tfh-dominant group, where they were highly associated with microvascular abnormalities and organ involvement.

6.
Arthritis Res Ther ; 21(1): 151, 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31228955

RESUMO

BACKGROUND: Tumor necrosis factor (TNF) inhibitors (TNF-i) are effective in the treatment of entero-Behcet's disease (BD). However, there is no objective tool for assessment of disease activity in entero-BD; therefore, it is not easy to evaluate treatment effectiveness in the clinical setting. In addition, because corticosteroid (CS) is considered for standard therapy, the effectiveness of TNF-i without CS has not been well examined. In this retrospective study, the effectiveness of CS without TNF-i and the effectiveness of TNF-i with or without CS therapy were investigated and compared. METHODS: This study included 71 patients with entero-BD who were followed up for 1 year (CS without TNF-i group: n = 22; TNF-i group: n = 49 [with CS: n = 20, without CS: n = 29]). All patients had active ulcerative lesions. The primary endpoint was the ulcer cure rate evaluated by lower gastrointestinal endoscopy. Secondary endpoints were ulcer improvement rate, disease activity improvement based on the quantitative disease activity index for intestinal Behcet's disease (DAIBD), and CS-sparing effect. RESULTS: Ulcer cure rates were 13.6% in the CS without TNF-i group, 60.0% in the TNF-i with CS group, and 44.8% in the TNF-i without CS group. Ulcer improvement rates were 27.2% in the CS without TNF-i group, 60.0% in the TNF-i with CS group, and 51.7% in the TNF-i without CS group. The multivariate analysis revealed that TNF-i was an independent predictive factor for cure of the ulcerative lesions. The DAIBD and concomitant CS dose were significantly decreased in both the CS without TNF-i group (DAIBD 85.2 → 40.5, CS 32.3 → 18.7 mg/day) and the TNF-i group (DAIBD 64.7 → 21.1. CS 18.7 → 3.88 mg/day). The ulcer cure and improvement rates were significantly higher in the TNF-i group. In addition, the proportion of concomitant CS dose less than 7.5 mg was significantly higher in the TNF-i group (CS without TNF-i group 18.2% vs. TNF-i group 85%, P < 0.01). There were no statistically significant differences between the TNF-i with CS group and the TNF-i without CS group in any of the endpoints. CONCLUSIONS: This study demonstrated that compared to CS alone, TNF-i improve disease activity and possess a higher ulcer healing effect and CS tapering effect with or without concomitant CS.

7.
Plast Reconstr Surg ; 143(6): 1657-1664, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31136481

RESUMO

BACKGROUND: When frostbite thaws, reperfusion injury has a crucial impact on tissue injury, and production of free radicals induces further tissue damage. This study examined whether extract of Ginkgo biloba 761 could ameliorate frostbite injury as a free radical scavenger. METHODS: Seventy-five Fisher 344 rats were divided into five groups of 15, and frostbite injury was created in each animal by sandwiching the left hind foot between a frozen magnet (-78.5°C) and a room-temperature magnet. Group I received saline; groups II, III, and IV received extract of Ginkgo biloba 761 (200, 100, and 50 mg/kg, respectively); and group V received superoxide dismutase (12 mg/kg). All drugs were injected intraperitoneally three times at 24-hour intervals. The wound surface area was measured throughout the wound healing period. Wounds were also harvested at various times to count cells stained by monoclonal antibodies for 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine. RESULTS: Compared to group I, the wound surface area was significantly smaller in groups II and III on days 1 and 3 after wound creation. Histologic examination revealed significantly more 4-hydroxy-2-nonenal-stained cells and 8-hydroxy-2'-deoxyguanosine-stained cells in group I compared to other groups on day 1. However, there was no difference in the total healing period among the groups. A higher dose test of extract of Ginkgo biloba 761 (300 mg/kg daily) induced animal death, probably because of toxicity. CONCLUSION: Extract of Ginkgo biloba 761 demonstrated a protective effect against frostbite in the present model and probably alleviated reperfusion injury by reducing tissue peroxidation.


Assuntos
Congelamento das Extremidades/prevenção & controle , Extratos Vegetais/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Cicatrização/fisiologia , Administração Tópica , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Feminino , Congelamento das Extremidades/tratamento farmacológico , Congelamento das Extremidades/patologia , Imuno-Histoquímica , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/prevenção & controle , Resultado do Tratamento
8.
Semin Arthritis Rheum ; 48(6): 1146-1150, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079846

RESUMO

Systemic lupus erythematosus (SLE) is a representative autoimmune disease characterized by multiple organ manifestations but is molecularly and genetically heterogeneous which makes difficult to manage every case based on one kinetic molecular theory. We, therefore, have tried to obtain a broader perspective on the molecular heterogeneity in SLE by immunophenotyping and found that patients with active SLE can be divided into 3 subgroups based on T cell heterogeneity. Although immunophenotypic features were different even among patients with similar clinical features, patients resistant to treatment were most frequently seen in the follicular helper T cell-dominant group. Because belimumab is only approved targeted therapy for SLE, the concept was encompassed with psoriatic arthritis (PsA) for which multiple biologics are approved. The obtained results suggest the potential for precision medicine via the strategic selection of different biologics based on the phenotypic differences in peripheral helper T cells in individual patients with PsA. Thus, subgrouping heterogeneous diseases could provide good bases for precision medicine, which would encourage treatment strategies of diseases with high clinical and molecular heterogeneity such as SLE.

9.
Expert Rev Clin Immunol ; 15(7): 693-700, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30987474

RESUMO

Introduction: JAK, which constitutively binds to some cytokine receptors, plays an important role in cytokine signaling. While JAK is comprised of JAK1, JAK2, JAK3, and Tyk2, more than 40 types of cytokines transmit signals through JAK. Baricitinib is reported to be highly effective in the treatment of rheumatoid arthritis (RA) and is the second drug launched as a JAK inhibitor for RA. Area covered: We provide an overview of the mechanisms of action of baricitinib and its clinical implications in RA and other autoimmune diseases based on recent reports. This review outlines the mechanisms of action of baricitinib on human immune cells, the results of Phase III trials for RA, and the results of Phase II trials on SLE. Expert opinion: Baricitinib has potential to fine-tune various immune networks through a variety of mechanisms. Precision medicine is required in order to achieve maximum effects of targeted synthetic DMARDs including baricitinib and biological DMARDs in the future.

10.
BMC Surg ; 19(1): 14, 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711000

RESUMO

BACKGROUND: Chest wall necrosis can manifest as a late effect of radiation therapy for breast cancer. Only two cases of fistulas communicating with the respiratory tract as a result of radiation-induced necrosis of the lungs or bronchi have been reported. To the best of our knowledge, we report the first case of a pulmonary cutaneous fistula arising as a late effect of radiation therapy for breast cancer, which was successfully repaired using a free omental graft. CASE PRESENTATION: A 64-year-old woman underwent Halsted surgery and postoperative radiation therapy for breast cancer 25 years earlier. One year before visiting our hospital, she developed a fistula and bleeding in her left clavicular region, which was expanding. On initial examination, a 6-cm-wide skin defect was observed in the left clavicular region and the clavicle appeared sequestrated. Computed tomography revealed part of the first to third left ribs, part of the left clavicle, the subclavian artery, and the brachial plexus to be missing. Several rounds of debridement revealed approximately 10 bronchial stumps on the surface of the collapsed lung, from which exhaled air and sputum were effusing. Surgery was performed to implant a free omental flap with vascular anastomosis and a skin graft in the neck region, and the pulmonary cutaneous fistula was closed. Two years after surgery, emphysema remained inside the omentum, which spontaneously resolved by the 3rd postoperative year. CONCLUSIONS: Various treatment options are conceivable for the repair of pulmonary cutaneous and bronchocutaneous fistulas induced by radiation damage (e.g., free tissue grafts and endoscopic bronchial occlusion); however, these are rarely reported, and the most reliable method thus remains unclear. Positive outcomes in our case indicate that implanting a free omental graft may be effective. Furthermore, spontaneous healing can be expected for the residual emphysema inside the omentum.


Assuntos
Fístula Cutânea/cirurgia , Omento/cirurgia , Retalhos Cirúrgicos , Fístula Cutânea/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Lesões por Radiação/patologia , Lesões por Radiação/cirurgia , Transplante de Pele/métodos , Parede Torácica/cirurgia
11.
Bioorg Med Chem ; 27(6): 1056-1064, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30755348

RESUMO

Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.

12.
Clin Immunol ; 200: 1-9, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30576845

RESUMO

Memory B cells are increased in systemic lupus erythematosus (SLE) cases, but the qualitative abnormalities and induction mechanism of these cells are unclear. Here, we subclassified B cells by their chemokine receptor expression and investigated their induction mechanism. The peripheral blood of patients with SLE showed higher levels of CXCR5- and CXCR3+ B cells. CXCR5-CXCR3+ B cell levels were elevated in patients with active SLE, which decreased with improving disease conditions. Interferon (IFN)-γ stimulation increased CXCR3 expression, whereas IFN-ß stimulation reduced CXCR5 expression in B cells. Furthermore, CXCR5-CXCR3+ B cells were induced by a combination of IFN-ß and IFN-γ stimulation. Renal tissue examination of patients with active lupus nephritis confirmed the presence of CD19+CXCR3+ B cells. Collectively, the results revealed qualitative abnormalities accompanying reduced CXCR5 expression via type I IFN and enhanced CXCR3 expression via type II IFN in SLE, suggesting their involvement in B cell infiltration into tissues and inflammatory pathogenesis.

13.
Intern Med ; 58(7): 1023-1027, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568120

RESUMO

We encountered a 60-year-old female patient who died of cerebral hemorrhage caused by disseminated aspergillosis during massive steroid therapy for overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and performed autopsy. Histologically, necrotizing vasculitis accompanied by Aspergillus hyphae was noted in the arterial wall of the region with cerebral hemorrhage and an abscess containing Aspergillus clumps was present in the lung, therefor we considered the cerebral hemorrhage caused by disseminated aspergillosis. For immunocompromised patients, it is desirable to perform treatment taking the possibility of deep mycosis into consideration, and when it is suspected, early therapeutic intervention may be useful.


Assuntos
Aspergilose/tratamento farmacológico , Hemorragia Cerebral/diagnóstico , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Escleroderma Sistêmico/complicações , Aspergilose/complicações , Aspergilose/diagnóstico , Autopsia , Hemorragia Cerebral/etiologia , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/tratamento farmacológico
14.
Rheumatology (Oxford) ; 58(6): 1120-1121, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544264
15.
Eur J Pharmacol ; 843: 190-198, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30472202

RESUMO

Interleukin (IL)-23 is thought to be critical in the pathogenesis of psoriasis, and anti-IL-23 monoclonal antibodies (mAbs) have been approved for the treatment of psoriasis. We speculated that an anti-IL-23 receptor mAb might have greater efficacy than an anti-IL-23 mAb in the treatment of local inflamed lesions with high IL-23 levels. We previously generated an anti-human IL-23 receptor mAb, AS2762900-00, which potently blocked IL-23-induced cell proliferation, regardless of the concentration of IL-23. Here, we evaluated the therapeutic potential of AS2762900-00 in the treatment of psoriasis. Compared with untreated control, AS2762900-00 significantly reduced the epidermal thickness of lesions in a clinically relevant psoriatic human skin xenograft model. The expression of inflammatory genes including genes downstream of IL-23 signaling in the lesion tended to be lower in the AS2762900-00 group than the untreated group, suggesting that the inhibitory effects of AS2762900-00 in the psoriatic human skin xenograft model might occur via blockade of IL-23 signaling pathways. Further, AS2762900-00 showed an inhibitory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation as a downstream signal of IL-23 receptor activation in whole blood from patients with psoriasis. We also confirmed that AS2762900-00 inhibited IL-23-induced STAT3 phosphorylation in a concentration-dependent manner using whole blood from healthy donors. These data suggest that AS2762900-00 is a promising drug candidate for the treatment of psoriasis. In addition, STAT3 phosphorylation in whole blood may be a useful biomarker for the evaluation of the pharmacodynamic effects of AS2762900-00 in healthy volunteers in clinical development.

16.
J Craniofac Surg ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30439734

RESUMO

Developmental lesions, including benign or malignant tumors, rarely arise in the masseteric region. This retrospective study was performed to evaluate the adequacy of different surgical approaches in a series of patients with lesions in the masseteric region. The surgical methods, postoperative complications, pathological diagnosis, and aesthetic outcome were compared in 4 patients who underwent excision of intramasseteric mass lesions. A flap was elevated in 3 patients and direct incisional resection was performed in 1 patient. Two patients underwent incisional biopsy to exclude malignancy before the total excision was performed. The final diagnosis was hemangioma in 3 patients and schwannoma in 1 patient. All patients were satisfied with the aesthetic results and there were no major complications. In conclusion, surgery with skin flap elevation was concluded to be the best approach based on overall assessment of technical considerations, complications, and the cosmetic outcome. However, the surgeon should not hesitate to perform direct incisional biopsy when malignancy needs to be excluded.

17.
Mod Rheumatol ; : 1-13, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30334637

RESUMO

As stated in the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), IgG4-RD is characterized by elevated serum IgG4 level and pathological findings, characterized by infiltration of IgG4-positive plasma cells. In addition to fibrotic changes, dysregulated activation of lymphocytes is considered as one of major pathogenic events in IgG4-RD. Among lymphocytes, the importance of plasmablast, T follicular helper (Tfh) cells, T type 2 helper (Th2) cells, T regulatory (Treg) cells, and CD4 positive T cells with cytotoxic activity has been reported. Conversely, comprehensive immunophenotyping in patients with IgG4-RD revealed that there are two different axes consisting plasmablast-Tfh cells and Treg cells. There is need for research to seek out molecules associated with these immunocompetent cell interactions. It is believed that this will contribute to the future application to disease-specific treatment for IgG4-RD.

18.
Int J Rheum Dis ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30338639

RESUMO

AIM: The effectiveness and safety of hydroxychloroquine (HCQ) have not been fully validated in Japanese patients with systemic lupus erythematosus (SLE) in the clinical setting. This study evaluated the short-term effectiveness and continuation rate of HCQ therapy in Japanese patients with SLE in the clinical setting for 12 months. METHODS: The primary endpoint was defined as the continuation rate up to 12 months after the introduction of HCQ in 122 patients with SLE. The secondary endpoints included changes in the SLE Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index, and the effect on concomitant corticosteroid (CS) dose reduction. RESULTS: The primary endpoint, continuation rate up to 12 months after the introduction of HCQ, was 79.5%. Of 25 patients who discontinued HCQ, 23 patients terminated the therapy within 2 months. The secondary endpoints (SLEDAI, BILAG index, and concomitant CS dose [mg/day, prednisolone equivalent]) all showed a significant decrease. SLEDAI and BILAG index scores indicated significant improvement during the remission induction phase, maintenance phase, and HCQ monotherapy phase. CONCLUSIONS: The results of this study suggested that, with attention paid to possible adverse events immediately after initiation, HCQ may be initiated as a mainstay of SLE therapy in Japanese patients, either as a concomitant medication in the remission induction phase, as a maintenance therapy, or as a monotherapy.

19.
Front Immunol ; 9: 1957, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210502

RESUMO

Objectives: Aberrant and persistent production of interferon-α (IFN-α) by plasmacytoid dendritic cells (pDCs) is known to play a key role in the pathogenesis of systemic lupus erythematosus (SLE). To assess the precise function of pDCs in SLE patients, we investigated the differential regulation of Toll-like receptor 7 (TLR7) and TLR9 responses during IFN-α production by pDCs. Methods: Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, rheumatoid arthritis patients and heathy controls were stimulated with TLR7 and TLR9 agonists. To investigate the priming effect by cytokines, PBMCs from healthy controls were pre-treated with various cytokines and stimulated with TLR7 and TLR9 agonists. The IFN-α production in pDCs was detected by flow cytometry. Results: TLR7-mediated IFN-α production was up-regulated and correlated positively with disease activity in SLE. Conversely, TLR9-mediated IFN-α production was down-regulated. Differential regulation of TLR7/9 response in SLE was independent of TLR7 and TLR9 expression levels. Furthermore, in vitro experiments indicated that TLR7-mediated IFN-α production was up-regulated by pre-treatment with type I IFN, whereas TLR9-mediated IFN-α production was down-regulated by pre-treatment with type II IFN. Conclusions: Our study indicates the association between up-regulation of TLR7- mediated IFN-α production by pDCs and disease activity and that TLR7 and TLR9 responses were reversely regulated on pDCs in SLE patients. Thus, type I IFN and TLR7-mediated IFN-α production were involved in a vicious cycle, causing hyper production of IFN-α by pDCs during the pathogenic processes of SLE.

20.
Artigo em Inglês | MEDLINE | ID: mdl-30169697

RESUMO

Objective: The aim of this study was to investigate the clinical and immunological significance of nailfold videocapillaroscopy (NVC) abnormalities in patients with idiopathic inflammatory myopathies (IIMs). Methods: Seventy consecutive Japanese patients with untreated IIMs, enrolled between April 2014 and August 2017, were prospectively studied. Clinical features, NVC findings, autoantibody profile by immunoprecipitation and ELISA, and histopathological findings of skin biopsies of DM rash were assessed at baseline and after 1-year of immunosuppressive therapy. Results: NVC abnormalities were found in 55.7% (39/70) of IIM patients, with significantly higher prevalence in DM (65.4%) compared with PM (27.8%) (P = 0.01). In subsets of patients classified by autoantibody specificities, the prevalence of NVC abnormalities was significantly higher in patients with anti-MDA5 (87.5%) and anti-transcriptional intermediary factor 1γ (88.9%) vs anti-aminoacyl-tRNA synthetase (26.9%, P < 0.001). Perivascular lymphocytic infiltration in the upper dermis of skin rash biopsy of DM was more severe in patients with NVC abnormalities (P < 0.05). Unexpectedly, NVC abnormalities disappeared in 75% of IIM patients after 1-year of immunosuppressive therapy in contrast to stable NVC changes seen in scleroderma patients. Conclusion: Nailfold microvascular abnormalities were common in DM patients, associated with anti-MDA5 and transcriptional intermediary factor 1γ antibodies, and perivascular inflammation in skin histology. NVC abnormalities in IIMs may become clinically useful markers for defining subsets of DM and understanding the pathogenesis of the clinical features seen in these patients.

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