RESUMEN
Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.
Asunto(s)
Macrófagos , Fagocitosis , Animales , Ratones , Macrófagos/metabolismo , Inflamación/metabolismo , Fagocitos/metabolismo , Proteínas Portadoras/metabolismo , Apoptosis , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
OBJECTIVES: Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. METHODS: Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. RESULTS: MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. CONCLUSIONS: MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.
RESUMEN
BACKGROUND: Despite advances, most patients with multiple myeloma (MM) experience relapse and repeat multiple treatment lines, highlighting an unmet need for patients with relapsed or refractory MM (RRMM). Bispecific antibodies are a new option, but their efficacy and safety in Japanese patients are unknown. METHODS: This was an analysis of Japanese patients receiving elranatamab monotherapy in MagnetisMM-2 (NCT04798586) and MagnetisMM-3 (NCT04649359). Both studies evaluated a priming dose regimen of elranatamab followed by weekly subcutaneous doses, in patients with disease progression while receiving or who were intolerant to ≥3 prior therapies (≥1 proteasome inhibitor, ≥1 immunomodulatory drug and ≥1 anti-CD38 monoclonal antibody). The primary endpoints were dose limiting toxicities (DLTs) in MagnetisMM-2 and confirmed objective response rate (ORR) in MagnetisMM-3. In both, key secondary endpoints included safety, tolerability, duration of response, time to response, progression-free survival and overall survival. RESULTS: In MagnetisMM-2 (N = 4) and MagnetisMM-3 (n = 12), median ages were 68.5 and 66.5 years, respectively. No DLTs were observed in MagnetisMM-2. ORRs were 50.0% (95% CI, 6.8-93.2) and 58.3% (95% CI, 27.7-84.8) in MagnetisMM-2 and MagnetisMM-3, respectively. All patients experienced treatment-emergent adverse events in MagnetisMM-2 (grade 3/4: 75.0%) and MagnetisMM-3 (grade 3/4: 100%); cytokine release syndrome occurred in 100% (grade 3/4: 25.0%) and 58.3% (no grade 3/4) of patients, respectively. Neither study reported immune effector cell-associated neurotoxicity syndrome. CONCLUSIONS: No new safety signals were observed, and ORRs were similar to that of the overall MagnetisMM-3 trial population, supporting further studies of elranatamab in Japanese patients with RRMM. ClinicalTrials.gov identifier: NCT04798586 (MagnetisMM-2), NCT04649359 (MagnetisMM-3).
Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Japón , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Supervivencia sin Progresión , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.
Asunto(s)
Adenina/análogos & derivados , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Sulfonamidas , Adulto , Humanos , Anciano , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Japón , Piperidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.
Asunto(s)
Algoritmos , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Espectrometría de Masas , Fragmentos de Péptidos , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Péptidos beta-Amiloides/sangre , Femenino , Masculino , Proteínas tau/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Fragmentos de Péptidos/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Biomarcadores/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Curva ROCRESUMEN
OBJECTIVES: The aim is to evaluate the treatment and prognosis of coronavirus disease 2019 (COVID-19) according to the time of onset and dominant strain in patients with rheumatic diseases. METHODS: This study analysed a nationwide COVID-19 registry of Japanese patients with rheumatic diseases compiled between June 2020 and December 2022. The primary endpoints of the study were hypoxaemia incidence and mortality. Multivariate logistic regression analysis was performed to assess differences according to the period of onset. RESULTS: A total of 760 patients were compared across four periods. Hypoxaemia rates were 34.9, 27.2, 13.8, and 6.1% and mortality rates were 5.6, 3.5, 1.8, and 0% until June 2021, between July and December 2021, January and June 2022, and July and December 2022, respectively. History of vaccination (odds ratio, 0.39; 95% confidence interval, 0.18-0.84) and onset during the July to December 2022 Omicron BA.5-dominant period (odds ratio, 0.17; 95% confidence interval, 0.07-0.41) were negatively associated with hypoxaemia in the multivariate model, adjusting for age, sex, obesity, glucocorticoid dose, and comorbidities. Over the Omicron-dominant period, antiviral treatment was administered in 30.5% of patients with a low probability of hypoxaemia. CONCLUSIONS: COVID-19 prognosis improved over time in patients with rheumatic diseases, especially in the Omicron BA.5-dominant period. In the future, treatment of mild cases should be optimised.
Asunto(s)
COVID-19 , Enfermedades Reumáticas , Humanos , Pronóstico , Japón/epidemiología , COVID-19/epidemiología , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/epidemiología , Sistema de Registros , HipoxiaRESUMEN
OBJECTIVES: Impact of osteoarthritis (OA) on the initial treatment response of rheumatoid arthritis (RA) by treat to target (T2T) practice was compared between the patients with an onset age ≥65 years old (late-onset RA [LORA]) and those with an onset age <65 years old (young-onset RA [YORA]). METHODS: A retrospective study was conducted on the patients with RA, who were referred to our clinic without treatment between January 2021 and July 2022. Patients with grade ≥3 OA according to the Kellgren-Lawrence (K-L) classification either in the knee or hand were classified in the OA(+) group and others were in the OA(-) group. The clinical data were compared at the diagnosis and one year after the initial treatment between the groups for 74 LORA and 59 YORA patients, respectively. RESULTS: One year after starting treatment in the LORA patients, the OA(+) group had poorer disease activity control and greater disability in the several activities of daily living (ADL) than the OA(-) group. In the YORA patients, there were no differences in ADL disability between the groups. CONCLUSIONS: In the initial treatment of the LORA patients, the prevalence of OA was high, and impact of OA on LORA was larger than on YORA.
RESUMEN
OBJECTIVES: This study aimed to understand the status quo of medical treatments of the primary disease and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes. METHODS: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labor, and Welfare for Intractable Vasculitis. RESULTS: This study enrolled 51 cases and 68 pregnancies 2019-2021. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. Enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. TAK relapsed in 4 (6.2%) and 8 (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low birth weight infants were observed, and none had serious postnatal abnormalities. Of the 51 confirmed infants, 42 (82.4%) were exclusively breastfed or mixed with formula. CONCLUSION: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies.
RESUMEN
Several studies have investigated the association between P2Y12 reaction unit (PRU) value and major adverse cardiovascular events (MACEs) in patients with ischemic heart disease, but there is no well-established consensus on the utility of PRU value. Furthermore, the optimal PRU cut-off value varied with studies. One reason may be that the endpoints and observation periods differed, depending on the study. This study aimed to investigate the optimal cut-off and predictive ability of the PRU value for predicting cardiovascular events, while considering different endpoints and observation periods. We surveyed a total of 338 patients receiving P2Y12 inhibitors and measured PRU during cardiac catheterization. Using time-dependent receiver operating characteristic analysis, we evaluated the cut-off and area under curve (AUC) of the PRU value for two MACEs (MACE â : composite of death, myocardial infarction, stent thrombosis, and cerebral infarction; MACE â¡: composite of MACE â and target vessel revascularization) at 6, 12, 24 and 36 months after cardiac catheterization. MACE â occurred in 18 cases and MACE â¡ in 32 cases. The PRU cut-off values at 6, 12, 24, and 36 months were 257, 238, 217, and 216, respectively, for MACE â and 250, 238, 209, and 204, respectively, for MACE â¡. The AUCs at 6, 12, 24, and 36 months were 0.753, 0.832, 0.718, and 0.717, respectively, for MACE â and 0.724, 0.722, 0.664, and 0.682, respectively, for MACE â¡. The optimal cut-off and predictive ability of PRU values for cardiovascular events varied depending on different endpoints and duration of the observation periods. A relatively high PRU value is effective for short-term event suppression, but a low value is required for long-term event suppression.
Asunto(s)
Infarto del Miocardio , Isquemia Miocárdica , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Plaquetas , Estudios Prospectivos , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: In recent years, advances in pharmacotherapy for rheumatoid arthritis (RA) have dramatically improved the control of disease activity. However, a significant number of patients still develop forefoot deformity. The purpose of this study was to investigate the results of more than 20 years' follow-up of metatarsal neck shortening oblique osteotomy (SOO) for forefoot deformity in patients with RA. METHODS: The metatarsal neck SOO was performed on 163 feet in 108 patients between January 1985 and December 1996 in the authors' hospital. For the patients, who met the survey criteria, an observational study was performed clinically and radiologically at the baseline and at more than 20 years after surgery. RESULTS: A retrospective cohort study was conducted on 36 feet in 22 patients, all of whom were female, and the mean age at surgery was 45.6 (35.0-63.0) years old. The follow-up period was 25.1 (21.0-31.0) years. The presence of painful callosities in the surgically treated feet without revised surgeries decreased from 32 feet (100%) to 4 feet (12.5%) at the last follow-up with mild pain that did not cause any footwear problems. Re-osteotomy at the metatarsal of the lessor toe was performed on four feet in two patients. Radiologically, among 128 toes without revised surgeries, 85% were able to have the joint space preserved, and 89% maintained a pain-free condition without any recurrence of deformity. The mean total Japanese Society for Surgery for the Foot (JSSF) RA foot and ankle score was 64.0/100, and the visual analogue scale (VAS) of overall satisfaction was 62 (0: dissatisfied, 100: highly satisfied). The overall satisfaction had a positive correlation with calcaneal pitch and negative correlation with joint space narrowing at the talocrural joint. CONCLUSIONS: Metatarsal neck SOO appeared to be effective for patients with RA. The deformity was corrected and retained for a long time.
Asunto(s)
Artritis Reumatoide , Hallux Valgus , Huesos Metatarsianos , Articulación Metatarsofalángica , Humanos , Femenino , Persona de Mediana Edad , Masculino , Huesos Metatarsianos/diagnóstico por imagen , Huesos Metatarsianos/cirugía , Estudios de Seguimiento , Estudios Retrospectivos , Pie , Articulación Metatarsofalángica/diagnóstico por imagen , Articulación Metatarsofalángica/cirugía , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/cirugía , Osteotomía/métodos , Resultado del Tratamiento , Hallux Valgus/cirugíaRESUMEN
BACKGROUND: In recent years, advances in pharmacotherapy for rheumatoid arthritis have dramatically improved the control of disease activity. However, a significant number of patients still develop hand deformity and require surgical reconstruction. The objective of this study was to evaluate the long-term efficacy and drawbacks of the Swanson metacarpophalangeal joint arthroplasty for patients with rheumatoid arthritis over 10 years. METHODS: Clinical and radiological evaluations were performed for 87 joints of 29 hands in 27 patients who underwent metacarpophalangeal joint arthroplasty using the Swanson implant, and who were followed up for an average of 11.4 (10-14) years. RESULTS: The number of operated tender and swollen metacarpophalangeal joints decreased from 24 (27.6%) and 28 (32.2%) to 1 (1.1%) and 2 (2.3%), respectively. The patients' general health and disease activity score 28-erythrocyte sedimentation rate improved at the last survey. Mild recurrence of ulnar drift was observed, but the deformity was generally well-corrected. Implant fracture was noted in eight joints (9.2%), and revision surgery was performed in two joints (2.3%). The average active range of extension/flexion changed from -46.3°/65.9° to -32.3°/56.6°. While a significant change was not noted in grip or pinch strength, patients were satisfied with the operation especially in terms of pain relief and improved hand appearance. CONCLUSIONS: The long-term results of Swanson metacarpophalangeal joint arthroplasty were good in pain relief and correction of deformity, but some problems remain with regard to implant durability and mobility.
RESUMEN
OBJECTIVES: To assess whether periodontitis severity affects the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) for 1 year in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received corticosteroids, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 1 year of bDMARD therapy in a retrospective study. Rheumatologic conditions were compared between the two periodontitis severity groups according to the periodontal inflamed surface area (PISA) or Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) case definitions. RESULTS: Twenty-eight patients with no or mild periodontitis showed significantly greater decreases in changes in Clinical Disease Activity Index (CDAI) and tender and swollen joint count in comparison to 22 patients with moderate and severe periodontitis (p = .02, p = .01, and p = .03). Both bivariate and multivariate analyses revealed a significantly positive association between the baseline CDC/AAP definitions and CDAI changes (p = .005 and p = .0038). However, rheumatologic conditions were comparable between 25 patients each in the low and high PISA groups. CONCLUSIONS: Baseline periodontitis severity according to the CDC/AAP definitions is associated with the clinical response to bDMARDs for 1 year in RA patients.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Periodontitis , Estados Unidos , Humanos , Antirreumáticos/uso terapéutico , Estudios de Seguimiento , Estudios Retrospectivos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Periodontitis/tratamiento farmacológico , Periodontitis/complicaciones , Productos Biológicos/uso terapéuticoRESUMEN
OBJECTIVES: The aim is to evaluate the relevance of serum immunoglobulin G (IgG) titres against periodontopathic bacteria to predict the clinical response to 1-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after 1-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titres against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements. RESULTS: Twenty-five patients with low anti-P. gingivalis IgG titres showed significantly greater decreases in changes in the Clinical Disease Activity Index and swollen joint count than 25 patients with high anti-P. gingivalis IgG titres (p = .04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titres with Clinical Disease Activity Index changes (p = .02 and p = .002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titre groups. CONCLUSIONS: Baseline serum anti-P. gingivalis IgG titres are predictive of the clinical response to 1-year treatment with bDMARDs in RA patients.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Periodontitis , Humanos , Porphyromonas gingivalis , Periodontitis/tratamiento farmacológico , Estudios Retrospectivos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoglobulina GRESUMEN
OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.
Asunto(s)
Artritis Reumatoide , Conservadores de la Densidad Ósea , Fracturas del Fémur , Humanos , Femenino , Conservadores de la Densidad Ósea/uso terapéutico , Fracturas del Fémur/inducido químicamente , Fracturas del Fémur/tratamiento farmacológico , Fracturas del Fémur/epidemiología , Glucocorticoides/efectos adversos , Difosfonatos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Prednisolona/efectos adversosRESUMEN
Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.
Asunto(s)
Regiones no Traducidas 3'/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Receptor de Muerte Celular Programada 1/genética , Escape del Tumor/genética , Regulación hacia Arriba , Adenocarcinoma/genética , Animales , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Sistemas CRISPR-Cas , Línea Celular Tumoral , Selección Clonal Mediada por Antígenos , Femenino , Marcadores Genéticos/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Linfoma de Células B Grandes Difuso/genética , Ratones , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/biosíntesis , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/genéticaRESUMEN
OBJECTIVES: This study aimed to clarify the epidemiological and clinical features and treatment of patients with polyarteritis nodosa (PAN) in Japan. METHODS: We used the database of the Ministry of Health, Labour and Welfare (MHLW) of Japan in 2013 and 2014. We analysed 121 patients who were antineutrophil cytoplasmic antibodies negative among the patients certified as PAN according to the MHLW diagnostic criteria. RESULTS: The analysis included 60 males and 61 females, with a mean age of 52.9 ± 21.0 years. As a general manifestation, fever was observed in 53.7%. Regarding organ involvement, skin manifestations (82.6%), joint and muscle manifestations (75.2%), and neuropsychiatric manifestations (50.4%) were common. Male patients had a higher proportion of mononeuritis multiplex involving motor neuropathy than female patients. Elderly patients had a higher proportion of general and respiratory manifestations. Glucocorticoids were used for treatment in all patients, and 19.0% underwent methylprednisolone pulse. Concomitant immunosuppressants were used in 25.6%, one-third of whom received cyclophosphamide. Methylprednisolone pulse and cyclophosphamide were mostly used in patients with life-threatening organ involvement. CONCLUSIONS: PAN developed in middle-aged people and led to numerous clinical manifestations. The common manifestations varied with age, and treatment was determined based on the type of organ involvement and disease severity.
Asunto(s)
Poliarteritis Nudosa , Adulto , Anciano , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Japón/epidemiología , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/tratamiento farmacológico , Poliarteritis Nudosa/epidemiologíaRESUMEN
OBJECTIVES: To investigate the outcomes of the modified Thompson-Littler (m-TL) method, a corrective surgical method utilising a dynamic tenodesis, in patients with rheumatoid swan-neck deformity. METHODS: Twenty-seven fingers in 10 patients with rheumatoid arthritis (RA) underwent surgical correction. The mean age at the time of surgery was 60.3 (45-77) years, the mean duration of RA was 19.3 (4-34) years, and the mean postoperative follow-up period was 2.4 (0.5-6) years. RESULTS: The deformity was corrected and the proximal interphalangeal (PIP) joint pain disappeared in all operated fingers. The mean pinch power between the thumb and the operated finger increased. The active extension decreased, the active flexion increased, and the total arc of motion decreased. Comparing the range of motion by Nalebuff's type classification, the postoperative arc of motion decreased as the type advanced. CONCLUSIONS: The m-TL method provided a favourable outcome in cases of Type ≤III rheumatoid swan-neck deformity without severe joint deterioration at the PIP joint. Aesthetic and functional improvements were observed and the patients were satisfied with the operation.
RESUMEN
OBJECTIVE: The aim of the present study was to evaluate the association between the periodontal and serological parameters and the disease activity of rheumatoid arthritis (RA) and between the anti-agalactosyl immunoglobulin G (IgG) titer and periodontitis severity. The objective was also to assess the effect of supragingival scaling on the serological parameters in patients with RA. BACKGROUND: The periodontal and serological parameters in relation to the autoimmune inflammatory response have been linked to RA disease activity. However, the association of the anti-agalactosyl IgG titer with RA disease activity and periodontitis severity has not been elucidated. METHODS: The periodontal, rheumatologic, and serological data were collected from 127 patients with RA in a retrospective cohort study. Of the 127 patients, 21 had been randomly assigned to receive oral hygiene instruction and supragingival scaling. The anti-agalactosyl IgG titer was determined by an electrochemiluminescence immunoassay. RESULTS: The patients with a moderate to high RA disease activity showed significantly higher levels of probing depth (PD), clinical attachment level, anti-cyclic citrullinated peptide IgG, and anti-agalactosyl IgG titer and greater mean percentages of severe periodontitis than those with a low RA disease activity (p < .05 for all). Both univariate and multivariate analyses revealed a significantly positive correlation between the PD and RA disease activity (p = .009 and p = .001), between the anti-agalactosyl IgG titer and RA disease activity (p = .002 and p < .001), and between the anti-agalactosyl IgG titer and PD (p < .001 for both). Supragingival scaling significantly decreased the anti-agalactosyl IgG titer (p = 0.03). CONCLUSION: The PD and anti-agalactosyl IgG titer are positively interrelated, both of which are correlated positively with RA disease activity and influenced by supragingival scaling in patients with RA.
Asunto(s)
Artritis Reumatoide , Periodontitis , Autoanticuerpos , Humanos , Inmunoglobulina G , Estudios RetrospectivosRESUMEN
Acquired factor V deficiency (AFVD) is a rare autoimmune bleeding disorder. Unlike acquired hemophilia, bypass therapies with recombinant activated factor VII and activated prothrombin complex concentrates are ineffective for severe bleeding due to AFVD. Although several treatment strategies have been attempted, a standard of care for severe hemorrhage induced by AFVD is lacking. Herein, we report a case of AFVD with severe bleeding that responded to plasma exchange (PE) combined with immunosuppression. We also reviewed previously reported AFVD cases with severe hemorrhage and suggest that PE may be an effective initial treatment for AFVD-induced severe hemorrhage.
Asunto(s)
Deficiencia del Factor V/complicaciones , Hemorragia/etiología , Hemorragia/terapia , Intercambio Plasmático , Autoinmunidad , Biomarcadores , Pruebas de Coagulación Sanguínea , Deficiencia del Factor V/diagnóstico , Deficiencia del Factor V/etiología , Hemorragia/sangre , Hemorragia/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Intercambio Plasmático/efectos adversos , Intercambio Plasmático/métodos , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
This paper proposes a theoretical model of the control and perception mechanism in human balance. Human balance perception is evaluated by the subjective upright posture, the posture at which a person does not feel he/she is at an incline. Our balance experiments in the seated posture showed that the subjective upright posture changed after the balancing task where the participants needed to incline to maintain their balance. This paper aimed to explain this adaptive phenomenon by reproducing the experimental results using computer simulations. Hypothesizing that "humans gradually come to recognize the posture they need to take to maintain their balance as being upright," an adaptation rule for subjective upright posture is defined, so that it approaches the averaged posture in the period of the balancing task. For the balance control, center of pressure feedback is adopted. As a result, the similar changes in subjective upright posture are simulated with a two-link model with a base link, implying that our hypothesis is one possible explanation on the mechanism for human balance control and perception.