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BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.
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Artrite Reumatoide , Azetidinas , Inibidores de Janus Quinases , Piperidinas , Purinas , Pirazóis , Sulfonamidas , Humanos , Artrite Reumatoide/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Estudos Retrospectivos , Idoso , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Purinas/uso terapêutico , Purinas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Triazóis/uso terapêutico , Triazóis/efeitos adversos , Fatores de Risco , Adulto , PiridinasRESUMO
BACKGROUND: Caspase-1 is a crucial component in the inflammasome activation cascade. This study evaluated the potential of serum caspase-1 level as an inflammatory biomarker in patients with adult-onset Still's disease (AOSD). METHODS: The study included 51 consecutive patients diagnosed with AOSD based on the Yamaguchi criteria, 66 patients with rheumatoid arthritis (RA) as disease control, and 36 healthy controls (HCs). Serum caspase-1 concentrations were measured using enzyme-linked immunosorbent assay. The serum 69 cytokine levels were analyzed using a multisuspension cytokine array in patients with AOSD, and a cluster analysis of each cytokine was performed to determine specific molecular networks. RESULTS: Patients with AOSD had significantly increased serum caspase-1 levels versus patients with RA (p < 0.001) and HCs (p < 0.001). Additionally, serum caspase-1 demonstrated significant positive correlations with AOSD disease activity score (Pouchot score, r = 0.59, p < 0.001) and serum ferritin (r = 0.54, p < 0.001). Furthermore, among patients with AOSD, significant correlations existed between serum caspase-1 and inflammatory cytokines, including interleukin-18. Immunoblot analysis detected the cleaved form of caspase-1 (p20) in the serum of untreated patients with AOSD, not in those from patients with inactive AOSD receiving immunosuppressive treatments. CONCLUSIONS: Caspase-1 is a useful biomarker for AOSD diagnosis and monitoring. Caspase-1 activation could be correlated with the inflammatory component of AOSD, specifically through proinflammatory cytokine induction via inflammasome activation cascades.
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Biomarcadores , Caspase 1 , Doença de Still de Início Tardio , Humanos , Doença de Still de Início Tardio/sangue , Doença de Still de Início Tardio/diagnóstico , Caspase 1/sangue , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Biomarcadores/sangue , Interleucina-18/sangue , Estudos de Casos e Controles , Citocinas/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnósticoRESUMO
Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHbâ5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.
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Comportamento Alimentar , Habenula , Luz , Animais , Masculino , Camundongos , Habenula/fisiologia , Comportamento Alimentar/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Ingestão de Alimentos/fisiologia , Vias Neurais/fisiologia , Ratos , Neurônios Serotoninérgicos/fisiologia , Rede Nervosa/fisiologia , EscuridãoRESUMO
This study aimed to elucidate the clinical features, outcomes and risk factors of flares in patients with systemic lupus erythematosus (SLE). Data were collected from patients with newly diagnosed SLE at the Fukushima Medical University Hospital between 2011 and 2022. Patients who experienced a flare during the study period constituted the flare group, and their clinical features were compared with those of the no-flare group. The cumulative flare-free survival regarding several clinical items was compared between the two groups using Kaplan-Meier's curves. Among 387 patients with SLE, 83 patients with newly diagnosed SLE were included. Their mean age was 37.9 years, and 29 patients experienced flares during the study period. The general characteristics were similar between the two groups, with the exception of the observation period and anti-SS-A antibody positivity. Regarding therapy, a significantly increased frequency of hydroxychloroquine intake and combination with immunosuppressive agents were observed in the no-flare group. The Kaplan-Meier analysis revealed a significantly higher cumulative flare-free survival in the anti-SS-A negative group and combination immunosuppressive therapy group. In conclusion, anti-SS-A positivity may be a risk factor for SLE flare. In turn, combination immunosuppressive therapy may be beneficial for SLE treatment in daily clinical practice.
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Aim: Graduate students are exposed to various types of stress. Thus, they are prone to mental health problems, and the most devastating result is suicide. The aim of this paper is to reveal the status of suicide among graduate students in Japan for 20 years. Methods: We analyzed cumulative data on suicide among national university graduate students from annual surveys on causes of non-graduation in Japan for the 2002-2003 through 2021-2022 academic years. We asked all national universities with graduate schools to complete the surveys, and the participation rate was 91.1%. Results: The total number of students in the surveys was 2,383,858, and the number of deaths by suicide was 347 (292 males, 55 females). Chi-squared test results showed significantly higher suicide mortality rates for the following groups: male (p < 0.001), temporary leave (p < 0.001), repeating the same year (p = 0.006), master's level (p = 0.005), and majoring in engineering (p < 0.001). Psychiatric diagnoses were detected among 44 students (12.7%). The largest distribution (27 cases) of International Classification of Diseases, Tenth Revision (ICD-10) codes among those whose diagnoses were evident was F3, mood disorders. Estimated motives for suicide were reported for only 36 students (10.4%), of which the most prevalent was job search failure. The most prevalent suicide method was hanging (151 cases, 43.5%). Conclusion: Our findings indicate that student support facilities should recognize higher-risk groups for suicide among graduate students. Our study adds suggestions for suicide prevention on campus during future pandemics.
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Background: Autoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still's disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD. Methods: We recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks. Results: Significant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p <0.001). There were significant positive correlations between serum Gal-3 levels and AOSD disease activity score (Pouchot score, r=0.66, p <0.001) and serum ferritin levels. However, no significant correlations were observed between serum M2BPGi levels and AOSD disease activity scores (Pouchot score, r = 0.32, p = 0.06) or serum ferritin levels. Furthermore, significant correlations were observed between the serum levels of Gal-3 and various inflammatory cytokines, including interleukin-18, in patients with AOSD. Immunosuppressive treatment in patients with AOSD significantly reduced serum Gal-3 and M2BPGi levels (p = 0.03 and 0.004, respectively). Conclusions: Although both Gal-3 and M2BPGi were elevated in patients with AOSD, only Gal-3 was a useful biomarker for predicting disease activity in AOSD. Our findings suggest that circulating Gal-3 reflects the inflammatory component of AOSD, which corresponds to proinflammatory cytokine induction through inflammasome activation cascades.
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Biomarcadores , Proteínas Sanguíneas , Citocinas , Galectina 3 , Doença de Still de Início Tardio , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Citocinas/sangue , Galectina 3/sangue , Glicosilação , Glicoproteínas de Membrana/sangue , Doença de Still de Início Tardio/sangue , Doença de Still de Início Tardio/diagnóstico , Doença de Still de Início Tardio/imunologiaRESUMO
Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.
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Autoanticorpos , Dermatomiosite , Helicase IFIH1 Induzida por Interferon , Sinovite , Ultrassonografia , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Dermatomiosite/diagnóstico por imagem , Dermatomiosite/complicações , Masculino , Helicase IFIH1 Induzida por Interferon/imunologia , Idoso de 80 Anos ou mais , Sinovite/tratamento farmacológico , Sinovite/diagnóstico por imagem , Sinovite/etiologia , Sinovite/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Corticosteroides/uso terapêutico , Resultado do TratamentoRESUMO
Objective: This study aimed to compare the incidence rates (IRs) of infections, including herpes zoster (HZ), in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) or interleukin-6 inhibitors (IL-6is). Methods: We retrospectively analyzed 444 RA patients treated using IL-6is (n = 283) or JAKis (n = 161). After adjusting for clinical characteristic imbalances by propensity score matching (PSM), we compared the IRs of infections including HZ between the JAKi and IL-6i groups. Results: Observational period: 1423.93 patient years (PY); median observational period: 2.51 years. After PSM, incidence rate ratios comparing JAKi with IL-6i were 3.45 (95% confidence interval [CI]: 1.48-9.04) for serious infections other than HZ indicating that the JAKi-treated group was more likely to develop serious infection than the IL-6i-treated group. Multivariate Cox regression analyses revealed that the use of prednisolone > 5.0 mg/day, coexisting interstitial lung disease (ILD), and diabetes mellitus (DM) were independent risk factors for serious infections. The crude IR for HZ was significantly higher in the JAKi group, but the difference between groups was not significant (IRR: 2.83, 95% CI: 0.87-10.96) in PSM analysis. Unadjusted and PSM analyses performed in our study showed increased IRs of serious infections in patients with RA treated with JAKis compared with those treated with IL-6is. Conclusions: The presence of ILD or DM and the use of prednisolone were found to be independent risk factors for serious infection in RA patients treated using JAKis. Whereas the IRs for HZ after PSM were not significantly different between the JAKi and IL-6i groups.
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Coronavirus disease 2019 (COVID-19) is a respiratory viral disease, and several cases of autoimmune diseases have been reported after infection. This report presents the case of a 38-year-old Japanese woman who developed systemic lupus erythematosus (SLE) following COVID-19. Clinical manifestations included dermatological complications, joint pain, and positive autoantibodies. The patient met the SLE classification criteria, and renal involvement was observed. Her symptoms improved with immunosuppressive therapy. A literature review identified 10 similar cases, those with lymphopenia and renal involvement. SLE should be considered in patients with persistent nonspecific symptoms after COVID-19 infection, particularly when hematologic and renal involvement are present.
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COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Feminino , Adulto , COVID-19/complicações , COVID-19/diagnóstico , Imunossupressores/uso terapêutico , SARS-CoV-2RESUMO
Solid-state reaction (SSR) is a widely adopted method for functional inorganic material syntheses. Unlike intricate systems emerging from chemically unstable precursor usage, the SSR can proceed from stable precursor couples using simple apparatuses. However, this reaction is associated with high temperatures that overcome solid-state diffusion. Moreover, solid-state syntheses of technologically crucial carbides lead to greenhouse gas emissions. Therefore, exploring an extrinsic component to suppress these challenges is vital to confronting global energy and environmental issues. This study reports that the presence of an ordinary element, vanadium (V), changes the routes of the SSR of niobium carbide (NbC), producing NbC efficiently and cleanly. 1000 °C is far below the temperature required to obtain NbC from a precursor couple of Nb2O5 and C, i.e., approximately 1500 °C is required. However, a carbon substitute, vanadium carbide, completely consumed Nb2O5 before reaching 1000 °C and consummated NbC crystallization for 10 h. Furthermore, NbC crystallites were observed using X-ray diffraction from 770 °C, and their formation was primarily accompanied by VNbO4, rather than being routed through NbO2 produced for the Nb2O5-C combination. The obtained NbC contained V as a dopant in the 15-50% range (NbC:V), and the relative abundance was correlated with the preparation temperature. Mass analyses revealed that the formation of NbC/V is barely associated with greenhouse gas emissions because of the sizable thermodynamic driving force for primarily forming vanadium oxide byproducts. Device performance using NbC/V was also assessed for a standard electrochemical hydrogen evolution reaction.
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Metabolism is one of the vital functions of cells and living organisms, and the systems to sense and respond to the metabolic alterations play pivotal roles in a plethora of biological processes, including cell proliferative activities, immune cell functions, aging processes, and neuronal functions. Recently, we have reported that a transcriptional cofactor, C-terminal binding protein 2 (CtBP2), serves as a critical metabolite sensor in this context. CtBP2 has a structural pocket called Rossmann fold to accommodate metabolites, and it has been reported to be activated upon binding to NADH/NADï¼. Owing to its preferential binding affinity for NADH compared with NADï¼, increased glycolysis activates CtBP2 by regenerating NADH from NADï¼. Furthermore, we recently reported that fatty acyl-CoAs, metabolites accumulated under the condition of lipid overload, as represented by obesity, can inactivate CtBP2. These observations suggest that CtBP2 monitors not only redox state but also energy substrate preference in the maintenance of metabolic homeostasis. In line with these metabolite-sensing capabilities, CtBP2 is activated in healthy subjects to protect against metabolic disturbances, whereas inactivation of CtBP2 in obesity contributes to the pathogeneses of obesity.This metabolic system orchestrated by CtBP2 can provide a novel framework for understanding how cells maintain their homeostasis through coordination of metabolism, and CtBP2 incapacitation can be a critical point of the obesogenic cascade.
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Oxirredutases do Álcool , Proteínas de Ligação a DNA , NAD , Fatores de Transcrição , Humanos , NAD/metabolismo , Proteínas Correpressoras/metabolismo , Fatores de Transcrição/metabolismo , Obesidade , Ligação ProteicaRESUMO
The complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1ß is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1ß secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1ß expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1ß (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1ß in C5a concentration-dependent manner. The protein levels of pro-IL-1ß in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1ß (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1ß (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1ß (p17). C5a induced the production of mature IL-1ß in PBMCs. The IL-1ß production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1ß production mainly in monocytes.
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Caspase 1 , Complemento C5a , Interleucina-1beta , Leucócitos Mononucleares , Humanos , Interleucina-1beta/metabolismo , Caspase 1/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Inflamassomos/metabolismo , Inflamassomos/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Células Cultivadas , Receptores de Lipopolissacarídeos/metabolismo , Ativação EnzimáticaRESUMO
This study evaluated the real-world effectiveness of belimumab (BLM) in the treatment of systemic lupus erythematosus (SLE) patients with moderate to high disease activity. This retrospective cohort study enrolled 129 Japanese patients with moderate to high SLE disease activity who received BLM between January 2013 and March 2023. The clinical outcomes, including the flare-free survival, SLE Disease Activity Index 2000 (SLEDAI-2K) score, and prednisone-equivalent dose, in the BLM and mycophenolate mofetil (MMF) treatment groups were compared before and after treatment. Safety data for BLM were collected. Additionally, we compared the effectiveness of BLM and intravenous cyclophosphamide (IV-CY) treatment using the stabilized inverse probability of treatment weighting (IPTW) method based on the propensity scores. This observational study enrolled 129 patients with moderate/severe SLE: 48 patients received belimumab, 45 received IV-CY, and 36 received MMF and prednisolone for remission induction therapy. The median follow-up for the BLM group was 17.0 months. Among them, 19 received BLM plus MMF. BLM significantly reduced the mean SLEDAI-2K (from mean baseline to 52 weeks: 49.2% reduction from 12.8 to 6.5) and prednisone daily dose (from mean baseline to 52 weeks: 21.9% reduction from 12.8 to 10.0 mg/day). The flare-free survival at 52 weeks was not significantly different between the BLM and MMF groups. There was no significant difference in the flare-free survival rates or reduction rates of the SLEDAI-2K between the patients treated with BLM and those treated with BLM plus MMF. In the propensity score-matched comparative analyses, there was no significant difference in the flare-free survival rates or an estimated decline in the SLEDAI-2K scores between the patients with lupus treated with BLM and IV-CY. BLM may be a promising alternative treatment option for lupus patients with moderate or high disease activity who do not respond to conventional treatments.
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Contrary to partially substituted systems, WO3 molecular sieves that exclusively comprise a d0 transition metal ion and do not possess template ions in the cavity are a new class of materials for photocatalysis owing to their framework structure. Because WO3 thermodynamically lacks proton-reduction capability, exploring diverse synthetic approaches of other materials is desirable for facilitating utilization as H2 evolution and water splitting systems. Herein, we report an efficient approach for the protonation of Ag2Ta4O11 to afford H2Ta4O11 for application as a H2 molecular sieve. Hydrogen reduction of Ag2Ta4O11 at 300 °C and post-treatment using HNO3 afforded H2Ta4O11. Characterizations of H2Ta4O11, coupled with density functional theory (DFT) calculations, reveal that the intrinsic structure of Ag2Ta4O11 is maintained. Moreover, H+ is generated from H2 oxidation and forms OH, and the orientation of OH is parallel to that of the ab plane. Desorption and adsorption of H2 within H2Ta4O11 were achieved by heating H2Ta4O11 to above 90 °C. This is attributed to positive thermal expansion, as confirmed by high-temperature X-ray diffraction. H2Ta4O11 is an active heterogeneous photocatalyst for the half-reactions of water splitting. Moreover, deuteration experiments of H2Ta4O11 in D2O suggest its capability as a H2-D2 conversion catalyst. Furthermore, H2Ta4O11 functions as an active synthetic precursor for new tantalate materials, the direct synthesis of which is challenging.
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The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. To prevent its spread, mRNA-based vaccines made by Pfizer/BioNTech (BNT162b1) and Moderna (mRNA-1273) have been widely used, including in Japan. Various adverse events have been reported following the COVID-19 mRNA vaccination, with differences observed among individuals. However, analyses of the genetic background associated with the susceptibility to side effects have been limited. In the present study, we performed genome-wide association studies (GWAS) for self-reported adverse events of the COVID-19 mRNA vaccination in 4545 Japanese individuals and identified 14 associated loci. Among these, 6p21 was associated with 37.5 °C or higher fever, 38 °C or higher fever, and muscle pain. HLA allele association analysis revealed that various HLA alleles were associated with the adverse effects; HLA-DQA1*03:01 and HLA-A*11:01 were more reliably associated with the adverse effects. Our results may enable the preparation and management of adverse effects by identifying the susceptibility to these adverse events. Furthermore, we obtained valuable data that may lead to a better understanding of the mechanisms of action of the COVID-19 mRNA vaccines.
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Vacinas contra COVID-19 , COVID-19 , Cromossomos Humanos Par 6 , População do Leste Asiático , Antígenos de Histocompatibilidade , Vacinação , Humanos , Vacina BNT162 , Cromossomos Humanos Par 6/genética , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , População do Leste Asiático/genética , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade/genética , Internet , RNA Mensageiro/genética , Vacinação/efeitos adversos , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genéticaRESUMO
Background: To investigate the clinical features of Japanese patients with Familial Mediterranean Fever (FMF), we evaluated the frequency of attacks, treatment responses, and adverse effects in 27 patients with FMF treated with colchicine or canakinumab in a real-world clinical setting. Methods: We retrospectively reviewed 27 Japanese patients with FMF treated at our institute between April 2012 and June 2023. All patients were diagnosed with FMF according to the Tel-Hashomer criteria. We performed genetic analyses of the MEFV gene using targeted next-generation sequencing. The clinical response was monitored through the number of attacks, and inflammatory markers were monitored through the C-reactive protein (CRP), and serum amyloid A (SAA) concentrations. Colchicine resistance was defined as the presence of at least one attack/month despite administration of the maximum tolerated dose of colchicine for at least 6 months, and C-reactive protein and serum amyloid A levels above the normal range between attacks. Results: A total of 27 patients diagnosed with FMF were enrolled in this study and the median follow-up period was 36.4 months. The median attack frequency was 1.0 (interquartile range: 0.33-1.0) every 3 months before treatment initiation. All the patients (n = 27) were treated with colchicine. Among the 27 patients, 20 (71.8%) showed a clinical response and 7 (25.9%) showed an incomplete response with sufficient doses of colchicine (n = 5) and non-sufficient doses (n = 2). Two patients on non-sufficient doses were unable to increase colchicine to the maximum dose due to diarrhea and liver dysfunction. All seven patients achieved a reduction in attack frequency after the initiation of canakinumab. No serious adverse events associated with canakinumab treatment were observed. In these seven patients with colchicine-resistant FMF (crFMF), the MEFV exon 10 variant was not detected, and the absence ratio of the MEFV variant was significantly higher compared to those without crFMF. Conclusions: Colchicine was effective in 71.8% (20/27) of Japanese patients with FMF; however, the remaining patients (7/27) had crFMF. Canakinumab effectively controlled febrile attacks in crFMF, even in the absence of pathogenic MEFV exon 10 variants.
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Background: The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. Methods: We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. Results: After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). Conclusion: The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.
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Antirreumáticos , Artrite Reumatoide , Inibidores de Interleucina-6 , Inibidores de Janus Quinases , Neoplasias , Humanos , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Inibidores de Interleucina-6/efeitos adversos , Inibidores de Interleucina-6/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Neoplasias/induzido quimicamente , Estudos RetrospectivosRESUMO
The articular involvement in patients with familial Mediterranean fever (FMF) represents a clinical characteristic of acute monoarthritis with pain and hydrarthrosis, which always resolves spontaneously. Colchicine prevents painful arthritis attacks in most FMF cases. Spondyloarthritis is rarely associated with Japanese patients with FMF. Here, we report a Japanese male patient with FMF-related axial joint involvement. A 43-year-old male Japanese patient who presented with recurrent febrile episodes with hip joint and back pain was referred to our hospital. He carried heterozygous variants in exon 2 (L110P/E148Q) of the MEFV gene. FMF was suspected, and oral administration of colchicine (1 mg/day) was initiated. Colchicine treatment improved his febrile attack with hip joint pain. He was diagnosed as having FMF based on the Tel-Hashomer diagnostic criteria for FMF since he fulfilled one major criterion (repeated febrile attack accompanied by hip joint pain) and one minor criterion (improvement with colchicine treatment). Although the human leucocyte antigen-B27 allele was not detected, sacroiliitis-related symptoms progressed despite the ongoing colchicine treatment. Salazosulphapyridine and methotrexate were administered in addition to colchicine; however, these treatments were not effective. Canakinumab treatment successfully resolved this unique aspect of sacroiliitis, and the patient was finally diagnosed with FMF-associated axial joint involvement.
Assuntos
Febre Familiar do Mediterrâneo , Sacroileíte , Humanos , Masculino , Adulto , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Colchicina/uso terapêutico , Sacroileíte/diagnóstico , Sacroileíte/tratamento farmacológico , Sacroileíte/etiologia , Japão , Febre , Artralgia , Pirina/genéticaRESUMO
The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of ß cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured ß cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic ß cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of ß cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches.