RESUMEN
BACKGROUND: Remibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, offers fast disease control in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite treatment with second-generation H1 antihistamines. It is currently in phase 3 development for CSU. OBJECTIVE: We sought to evaluate long-term safety and efficacy of remibrutinib in patients with CSU inadequately controlled with H1 antihistamines. METHODS: In this phase 2b extension study, patients who completed the core study and had a weekly Urticaria Activity Score (UAS7) ≥16 at the beginning of the extension study received remibrutinib 100 mg twice daily for 52 weeks. The primary objective was to assess long-term safety and tolerability. Key efficacy end points included change from baseline in UAS7 and proportion of patients with complete response to treatment (UAS7 = 0) and well-controlled disease (UAS7 ≤6) at week 4 and over 52 weeks. RESULTS: Overall, 84.3% (194/230) of patients entered the treatment period and received ≥1 doses of remibrutinib. The overall safety profile of remibrutinib was comparable between the extension and core studies. Most treatment-emergent adverse events were mild to moderate and considered unrelated to remibrutinib by investigators. The 3 most common treatment-emergent adverse events by system organ class were infections (30.9%), skin and subcutaneous tissue (26.8%), and gastrointestinal disorders (16.5%). At week 4 and 52, mean ± SD change from baseline in UAS7 was -17.6 ± 13.40 and -21.8 ± 10.70; UAS7 = 0 (as observed) was achieved in 28.2% and 55.8% and UAS7 ≤6 (as observed) was achieved in 52.7% and 68.0% of patients, respectively. CONCLUSIONS: Remibrutinib demonstrated a consistent favorable safety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU.
Asunto(s)
Antialérgicos , Urticaria Crónica , Pirimidinas , Urticaria , Humanos , Antialérgicos/uso terapéutico , Omalizumab/uso terapéutico , Resultado del Tratamiento , Enfermedad Crónica , Urticaria Crónica/tratamiento farmacológico , Urticaria/tratamiento farmacológico , Urticaria/inducido químicamente , Antagonistas de los Receptores Histamínicos H1/uso terapéuticoRESUMEN
BACKGROUND: Chronic spontaneous urticaria (CSU) is inadequately controlled in many patients and greatly affects quality of life. Remibrutinib, a highly selective, oral, novel covalent Bruton tyrosine kinase inhibitor, might be effective in CSU. OBJECTIVE: This first-in-patient trial aimed to evaluate the efficacy and safety of remibrutinib in CSU treatment and characterize the dose-response. METHODS: This randomized, double-blind, placebo-controlled, phase 2b dose-finding trial evaluated remibrutinib (12 weeks) in patients inadequately controlled with second-generation H1-antihistamines, with at least moderately active CSU, with or without prior anti-IgE treatment (NCT03926611). Patients received remibrutinib 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo (1:1:1:1:1:1:1 ratio). The main end points were weekly Urticaria Activity Score change from baseline at week 4 and safety. RESULTS: Overall, 311 patients were randomized. Reduced symptom score was observed for all remibrutinib doses from week 1 until week 12, with weekly Urticaria Activity Score change from baseline at week 4: -19.1 (10 mg once daily), -19.1 (35 mg once daily), -14.7 (100 mg once daily), -16.0 (10 mg twice daily), -20.0 (25 mg twice daily), -18.1 (100 mg twice daily), and -5.4 for placebo (nominal P < .0001 for all doses vs placebo). Most adverse events were mild or moderate, with no dose-dependent pattern. CONCLUSION: Remibrutinib was highly effective in the treatment of CSU over the entire dose range, with a rapid onset of action and a favorable safety profile.
Asunto(s)
Urticaria Crónica , Inhibidores de Proteínas Quinasas , Humanos , Urticaria Crónica/tratamiento farmacológico , Calidad de Vida , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear. OBJECTIVE: We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). METHODS: Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC. RESULTS: Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects. CONCLUSION: Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.
Asunto(s)
Citocinas/inmunología , Vesículas Extracelulares/inmunología , Linfocitos/inmunología , Mastocitos/inmunología , MicroARNs/inmunología , Receptores de IgE/inmunología , Adulto , Anciano , Células Cultivadas , Dermatitis Atópica/inmunología , Eosinófilos/inmunología , Femenino , Humanos , Inmunidad Innata , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: We previously reported upregulation of expression of Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells (MCs) in the skin of patients with severe chronic spontaneous urticaria (CSU). Serum levels of substance P (SP) were reportedly significantly elevated, in correlation with the severity of CSU. Hemokinin-1 (HK-1) reportedly induced histamine release from LAD2 cells via MRGPRX2. We aimed to investigate HK-1's role in CSU. METHODS: The concentrations of HK-1 and SP were measured using ELISAs. Skin- and synovium-derived cultured MCs were generated by culturing dispersed skin and synovial cells, respectively, with stem cell factor. MRGPRX2 expression in the MCs was reduced using a lentiviral shRNA silencing technique. RESULTS: Anti-SP Ab used in the SP ELISA showed 100% cross-reactivity to HK-1, but anti-HK-1 Ab showed 0% cross-reactivity to SP. The serum level of HK-1 was significantly lower in patients with CSU (n = 151) than in non-atopic healthy control (NC) subjects (n = 114). The EC50 of histamine release from MCs induced by HK-1 (5056 nM) was 12-fold higher than by SP (426 nM). Brief pretreatment of MCs with HK-1 at concentrations of 3.0-10 µM significantly reduced histamine release by 0.1 µM SP. However, brief incubation of MCs with HK-1 did not elicit rapid MRGPRX2 internalization. CONCLUSIONS: In NC subjects, high HK-1 concentrations may desensitize MGRPRX2-mediated MC activation, thereby preventing MC degranulation by SP.
Asunto(s)
Urticaria Crónica/sangre , Taquicininas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Urticaria Crónica/inmunología , Femenino , Humanos , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/inmunología , ARN Interferente Pequeño/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología , Receptores de Neuropéptido/genética , Receptores de Neuropéptido/inmunología , Piel/citología , Membrana Sinovial/citología , Taquicininas/inmunología , Adulto JovenAsunto(s)
Hidradenitis Supurativa , Humanos , Hidradenitis Supurativa/diagnóstico , Hidradenitis Supurativa/epidemiología , Estudios Transversales , Japón/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Costo de Enfermedad , Internet , Adulto Joven , Encuestas y Cuestionarios , Anciano , AdolescenteRESUMEN
BACKGROUND: The reported prevalences of IgG autoantibodies (AAbs) to FcεRIα and IgE in sera from patients with chronic spontaneous urticaria (CSU) have varied, and these AAbs are also often observed in healthy control subjects. Regarding the histamine release activity of purified IgG from patients with CSU, the number of examined patients has been small. Thus, we sought to determine the prevalence and FcεRI crosslinking ability of these AAbs in a large number of patients with CSU and non-atopic control (NC) subjects. METHODS: We compared the concentrations of anti-IgE and anti-FcεRIα AAbs and the abilities of these AAbs to cause FcεRI aggregation in patients with CSU (n = 134) and NC subjects (n = 55) using ELISA and an in vitro elicitation test, respectively. RESULTS: The concentration of anti-IgE AAbs was significantly different between the NC subjects and the CSU patients (P < 0.0001, cutoff value: 0.558 µg/mL), whereas the concentration of anti-FcεRIα AAbs was not. A significant difference in the duration of illness was noted between patients with lower and those with higher concentrations of anti-IgE AAbs relative to the cutoff value. The abilities of anti-IgE AAbs, but not anti-FcεRIα AAbs, to induce FcεRI crosslinking were significantly higher in CSU patients than in NC subjects (P = 0.0106). CONCLUSIONS: In the Japanese population of CSU patients studied, the ability of the anti-IgE AAbs to induce FcεRI crosslinking differed significantly between NC subjects and CSU patients, suggesting the involvement of anti-IgE AAbs in the pathogenesis of CSU in the Japanese population.
Asunto(s)
Autoanticuerpos/inmunología , Inmunoglobulina E/inmunología , Receptores de IgE/inmunología , Urticaria/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Autoanticuerpos/sangre , Basófilos/inmunología , Células Cultivadas , Enfermedad Crónica , Femenino , Liberación de Histamina , Humanos , Inmunoglobulina G/sangre , Recubrimiento Inmunológico , Masculino , Mastocitos/inmunología , Persona de Mediana Edad , Adulto JovenAsunto(s)
Conjuntivitis , Dermatitis Atópica , Anticuerpos Monoclonales Humanizados/efectos adversos , Conjuntivitis/inducido químicamente , Conjuntivitis/diagnóstico , Conjuntivitis/tratamiento farmacológico , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND OBJECTIVES: With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid-containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum (SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid-containing moisturiser and a bed bath to treat senile xerosis. METHODS: We recruited 73 individuals to assess the hydration state of the SC on their flexor forearm by measuring their skin capacitance. To evaluate the efficacy of a heparinoid-containing moisturiser on senile xerosis, we recruited seven inpatients with an inactive daily life (IDL) who had senile xerosis. They were treated with the moisturiser in addition to a bed bath in two different protocols, and we measured the skin capacitance on their flexor forearms on days 0, 7 and 14. RESULTS: There was a weak negative correlation (-0.3854, P < 0.01) between skin capacitance and age. Following the moisturiser treatments, the seven inpatients had increased hydration of both arms on days 7 and 14. The skin capacitance of the right forearm slightly decreased on day 14, even though it was significantly different from day 0 (P < 0.05). CONCLUSIONS: These findings indicate that treatment with a heparinoid-containing moisturiser together with a bed bath is an effective method for treating patients who have senile xerosis and IDL.
Asunto(s)
Emolientes/uso terapéutico , Heparinoides/uso terapéutico , Crema para la Piel/uso terapéutico , Enfermedades de la Piel/tratamiento farmacológico , Factores de Edad , Anciano de 80 o más Años , Baños , Capacidad Eléctrica , Epidermis/química , Femenino , Antebrazo , Humanos , Enfermedades de la Piel/fisiopatología , Agua/análisisRESUMEN
BACKGROUND: Wheal reactions to intradermally injected neuropeptides, such as substance P (SP) and vasoactive intestinal peptide, are significantly larger and longer lasting in patients with chronic urticaria (CU) than in nonatopic control (NC) subjects. Mas-related gene X2 (MrgX2) has been identified as a receptor for basic neuropeptides, such as SP and vasoactive intestinal peptide. Mast cell (MC) responsiveness to eosinophil mediators contributes to the late-phase reaction of allergy. OBJECTIVE: We sought to compare the frequency of MrgX2 expression in skin MCs from patients with CU and NC subjects and to identify the receptor for basic eosinophil granule proteins on human skin MCs. METHODS: MrgX2 expression was investigated by using immunofluorescence in skin tissues from NC subjects and patients with severe CU and on skin-derived cultured MCs. MrgX2 expression in human MCs was reduced by using a lentiviral small hairpin RNA silencing technique. Ca(2+) influx was measured in CHO cells transfected with MrgX2 in response to eosinophil granule proteins. Histamine and prostaglandin D2 levels were measured by using enzyme immunoassays. RESULTS: The number of MrgX2(+) skin MCs and the percentage of MrgX2(+) MCs in all MCs in patients with CU were significantly greater than those in NC subjects. Eosinophil infiltration in urticarial lesions was observed in 7 of 9 patients with CU. SP, major basic protein, and eosinophil peroxidase, but not eosinophil-derived neurotoxin, induced histamine release from human skin MCs through MrgX2. CONCLUSION: MrgX2 might be a new target molecule for the treatment of wheal reactions in patients with severe CU.
Asunto(s)
Mastocitos/inmunología , Proteínas del Tejido Nervioso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Piel/metabolismo , Urticaria/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Enfermedad Crónica , Proteínas en los Gránulos del Eosinófilo/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Proteínas del Tejido Nervioso/genética , Unión Proteica , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropéptido/genética , Piel/patología , Pruebas Cutáneas , Sustancia P/administración & dosificación , Sustancia P/efectos adversos , Regulación hacia Arriba , Urticaria/inmunología , Péptido Intestinal Vasoactivo/administración & dosificación , Péptido Intestinal Vasoactivo/efectos adversos , Adulto JovenAsunto(s)
Ciclosporina/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Urticaria/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Enfermedad Crónica , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Pruebas Cutáneas , Resultado del Tratamiento , Urticaria/sangre , Adulto JovenRESUMEN
OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndromes Periódicos Asociados a Criopirina , Humanos , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Síndromes Periódicos Asociados a Criopirina/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Japón , Femenino , Masculino , Estudios Retrospectivos , Niño , Preescolar , Adulto , Adolescente , Adulto Joven , Resultado del Tratamiento , Persona de Mediana Edad , Lactante , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Mutación , Inducción de RemisiónRESUMEN
BACKGROUND: Chronic urticaria (CU) appears to be of autoimmune origin in about half of all patients, since several autoreactive immunoglobulin Gs (IgGs), such as anti-FcεRIα and anti-IgE, are detected in the sera of such patients. However, whether autoreactive IgE is associated with CU remains unclear. In this study, we attempted to identify autoreactive IgE antibodies in sera from patients with CU. METHODS: Sera were collected from 67 normal subjects, 85 patients with CU and 28 patients with atopic dermatitis (AD). An autologous serum skin test (ASST) was performed on 27 of the CU patients. Autoreactive IgE and IgG levels against self-antigens were measured using enzyme-linked immunosorbent assays. The basophils were activated with dsDNA, and the CD63 expression level was examined using a fluorescence-activated cell sorter. RESULTS: The anti-dsDNA IgE levels were significantly higher in patients with CU and AD than in normal subjects, but no differences in the anti-dsDNA IgG levels were seen. The levels of thioredoxin-, peroxiredoxin- and thyroglobulin-reactive IgE and IgG were not significantly higher in the CU patients than in the other 2 groups. There was no significant difference in the levels of anti-dsDNA IgE between ASST-positive and ASST-negative patients. The basophils from 2 out of 9 CU patients exhibited degranulation in response to dsDNA. CONCLUSIONS: Our data suggest that anti-dsDNA IgE is involved in the pathogenesis of some cases of CU.
Asunto(s)
Basófilos/inmunología , Degranulación de la Célula/inmunología , ADN/inmunología , Inmunoglobulina E/inmunología , Urticaria/inmunología , Adulto , Enfermedad Crónica , Dermatitis Atópica/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana EdadRESUMEN
Of those patients diagnosed with generalized pustular psoriasis (GPP) in Japan, approximately 30% have a prior psoriasis vulgaris (PsV) diagnosis. Therefore, understanding factors associated with a GPP diagnosis is essential for early diagnosis of GPP in patients with PsV. This retrospective cohort study was conducted to identify associated factors for GPP diagnosis in patients with PsV. Eligible patients with two confirmed diagnoses of PsV with/without a confirmed GPP diagnosis (International Classification of Disease 10th revision codes L40.0 and L40.1, respectively) were identified from the Japanese Medical Data Center database (JMDC) (July 1, 2005-January 31, 2019). Weighted logistic regression was used to identify associated factors (based on recorded comorbidities) between the PsV only and PsV with GPP cohorts. Odds ratios (ORs) of ≥1.5, associated with a high probability of a GPP diagnosis, were reported for factors with ≥5 patients/cohort. The time from event to GPP diagnosis was evaluated. The highest associated factor for GPP diagnosis was psoriatic arthritis (OR 20.2, 95% confidence interval [CI] 17.06-23.92, P < 0.0001), which also had the shortest time from event to GPP diagnosis (median 119 days). Other comorbidities associated with GPP diagnosis were other psoriasis, tonsillitis, and sinusitis. Treatments associated with GPP diagnosis included systemic corticosteroids (OR 2.19, 95% CI 1.98-2.43, P < 0.0001; median time from treatment initiation to GPP diagnosis 180 days). Other associated treatments (other immunosuppressants, interleukin [IL]-17 or IL-23 inhibitors, and phototherapy) had a delay of ≥1 year from treatment initiation to GPP diagnosis. Back pain, headache, and fever were also identified as associated with a GPP diagnosis. Patients with PsV requiring systemic therapies are more likely to receive a GPP diagnosis than those not requiring systemic treatment. These data will help identify patients with PsV at high risk of developing GPP and potentially support early GPP diagnosis.