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OBJECTIVE: To report 5-year efficacy and safety of upadacitinib (UPA) in rheumatoid arthritis (RA) from the phase III long-term extension (LTE) of SELECT-NEXT. METHODS: Patients on stable conventional synthetic disease-modifying antirheumatic drugs were randomized to UPA 15 mg once daily (QD), UPA 30 mg QD, or placebo for 12 weeks. Following this, placebo-randomized patients were switched to UPA 15 mg QD or UPA 30 mg QD in the LTE; UPA-randomized patients continued their original dose. Blinding remained until dose switching from UPA 30 mg QD to UPA 15 mg QD because of approval of UPA 15 mg QD; the earliest switch occurred at week 168. Efficacy (as observed) and treatment-emergent adverse events (TEAEs) are reported through 5 years. RESULTS: Overall, 611 (92%) randomized patients entered the LTE; 271 (44%) discontinued the study drug by 5 years, primarily because of adverse events (16%). Clinical outcomes improved or were maintained at 5 years; 51% and 43% of patients achieved Clinical Disease Activity Index remission and 75% and 66% achieved Disease Activity Score in 28 joints based on C-reactive protein < 2.6 among those initially randomized to UPA 15 mg QD and UPA 30 mg QD, respectively. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria responses increased from week 60 through 5 years. Results were similar regardless of initial randomization to UPA or placebo. TEAEs, including TEAEs of special interest, were consistent with earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were reported infrequently. No new safety signals were observed. CONCLUSION: The 5-year benefit-risk profile for UPA in RA remains favorable. (SELECT-NEXT; ClinicalTrials.gov: NCT02675426).
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Antirreumáticos , Artritis Reumatoide , Compuestos Heterocíclicos con 3 Anillos , Humanos , Artritis Reumatoide/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/administración & dosificación , Femenino , Persona de Mediana Edad , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Masculino , Resultado del Tratamiento , Adulto , Anciano , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis (RA). JAK inhibitors have been associated with an increased risk of herpes zoster (HZ) in patients with RA. OBJECTIVES: To evaluate the incidence and risk factors for HZ in UPA-treated patients with RA from the UPA phase III clinical trial programme. METHODS: Exposure-adjusted incidence/event rates for HZ were determined in patients receiving UPA (monotherapy or combination therapy) in six randomised phase III trials (data cut-off on 30 June 2020). HZ incidence and event rates were also determined in patients receiving methotrexate (MTX) monotherapy or adalimumab (ADA) + MTX. Multivariable Cox regression analysis was used to identify HZ risk factors in UPA-treated patients. RESULTS: A total of 5306 patients were included in this analysis. The incidence rate of HZ/100 patient-years (95% CI) was 0.8 (0.3 to 1.9), 1.1 (0.5 to 1.9), 3.0 (2.6 to 3.5) and 5.3 (4.5 to 6.2), in the MTX monotherapy, ADA + MTX, UPA 15 mg and UPA 30 mg groups, respectively. The majority of HZ cases with UPA (71%) involved a single dermatome. Prior history of HZ and Asian region were HZ risk factors in UPA-treated patients. CONCLUSION: In the UPA phase III RA clinical programme, HZ incidence and event rates were higher with UPA versus ADA + MTX or MTX monotherapy, and higher with the 30 mg versus 15 mg dose. Patients from Asia and those with a history of HZ may be at increased risk of HZ while receiving UPA.
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Artritis Reumatoide/tratamiento farmacológico , Herpes Zóster/inducido químicamente , Herpes Zóster/epidemiología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Inhibidores de las Cinasas Janus/efectos adversos , Adulto , Anciano , Antirreumáticos/efectos adversos , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR). METHODS: PROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined. RESULTS: In 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values. CONCLUSION: Among MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone. CLINICAL TRIAL REGISTRATION NUMBER: SELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov.
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Artritis Reumatoide/tratamiento farmacológico , Fatiga/fisiopatología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Calidad de Vida , Actividades Cotidianas , Adulto , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/fisiopatología , Eficiencia , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Dimensión del Dolor , Medición de Resultados Informados por el Paciente , TrabajoRESUMEN
BACKGROUND: Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate. METHODS: SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of of upadacitinib or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951. FINDINGS: Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35-48) in the continued methotrexate group, 147 (68%) of 217 patients (62-74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65-77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14-25) in the continued methotrexate group, 97 (45%) of 217 (38-51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46-60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study. INTERPRETATION: Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies. FUNDING: AbbVie Inc, USA.
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Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Inhibidores de las Cinasas Janus/administración & dosificación , Adulto , Anciano , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Proteína C-Reactiva/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Inducción de Remisión , Resultado del TratamientoRESUMEN
BACKGROUND: Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. FINDINGS: Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. INTERPRETATION: Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. FUNDING: AbbVie Inc.
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Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Inhibidores de las Cinasas Janus/administración & dosificación , Adulto , Anciano , Antirreumáticos/administración & dosificación , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Inhibidores de las Cinasas Janus/farmacología , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol, The Evaluation of Choline Fenofibrate (ABT-335) on Carotid Intima-Media Thickness (cIMT) in Subjects with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy (FIRST) trial evaluated the effects of fenofibric acid (FA) treatment on cIMT in patients with mixed dyslipidemia on atorvastatin. APPROACH AND RESULTS: This multicenter, double-blind, placebo-controlled study was performed in patients with mixed dyslipidemia (fasting triglycerides, ≥150 mg/dL; high-density lipoprotein cholesterol, ≤45 [men] or 55 mg/dL [women]; low-density lipoprotein cholesterol, ≤100 mg/dL once and averaging ≤105 mg/dL) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg, if needed) were randomized to FA 135 mg or placebo. The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT, measured by ultrasound. In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy, rate of change in posterior-wall cIMT was similar with FA plus atorvastatin (-0.006 mm/y) versus atorvastatin monotherapy (0.000 mm/y; P=0.22). FA plus atorvastatin was favored (P<0.05) in 5 of 24 prespecified subgroups: age ≥60 years, history of coronary artery disease, cIMT >0.795 mm, triglycerides 170 to 235 mg/dL, and statin use at entry. Adverse events were consistent with the known safety profiles of both drugs; however, FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy (6.5% versus 0.9%). CONCLUSIONS: Compared with atorvastatin monotherapy, FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia.
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Grosor Intima-Media Carotídeo , Dislipidemias/tratamiento farmacológico , Fenofibrato/análogos & derivados , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pirroles/uso terapéutico , Atorvastatina , LDL-Colesterol/sangre , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/patología , Femenino , Fenofibrato/efectos adversos , Fenofibrato/farmacología , Ácidos Heptanoicos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Pirroles/efectos adversos , Triglicéridos/sangreRESUMEN
Patients with vitiligo incur direct and indirect costs associated with their condition; however, data regarding the economic burden of vitiligo are scarce and outdated. In this retrospective cohort analysis of the Merative MarketScan Commercial Database, healthcare costs and healthcare resource utilization (HCRU) were evaluated among United States patients with vitiligo. Patients with vitiligo were matched (1:2) with individuals without vitiligo (controls) between January 2007 and December 2021. Outcomes included all-cause and vitiligo-related costs (2021 dollars) and all-cause HCRU, including mental health-related HCRU, during a 1-year postindex period. Subgroup analyses were completed for patients on vitiligo treatments with systemic effects (such as phototherapy and oral steroids) or a new mental health diagnosis. The analysis was focused solely on direct costs. Baseline demographics were well-balanced between matched vitiligo (49,512) and control (99,024) cohorts. Patients with vitiligo incurred significantly higher all-cause ($15,551 vs $7735) and vitiligo-related ($3490 vs $54) costs than controls (P < .0001). All-cause and mental health-related HCRU were also significantly higher among patients with vitiligo (P < .0001). Differences in all-cause and vitiligo-related healthcare costs remained significantly higher in patients on treatments with systemic effects/mental health diagnoses than in controls (P < .0001). Taken together, healthcare costs and HCRU were significantly higher among patients with vitiligo than among controls.
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Aceptación de la Atención de Salud , Vitíligo , Humanos , Estados Unidos/epidemiología , Estudios Retrospectivos , Vitíligo/epidemiología , Vitíligo/terapia , Estrés Financiero , Costos de la Atención en SaludRESUMEN
INTRODUCTION: There is currently a lack of research regarding disease course and burden as well as treatment patterns and goals in patients with non-segmental vitiligo (NSV). The aim of this analysis was to evaluate disease course, treatment patterns and goals in patients with NSV. METHODS: This analysis used secondary data from the Adelphi Real World Vitiligo Disease Specific Programme™ 2021, specifically, a survey of physicians and their adult and adolescent patients with NSV. Physicians categorized patients by the extent of NSV at time of survey completion as mild, moderate or severe/very severe. Physician-reported patient information included demographics, current/previously prescribed NSV therapies, treatment satisfaction and the Vitiligo Noticeability Scale (VNS). Patients completed a survey on treatment satisfaction and the VNS. Treatment pattern data were stratified by disease extent and Fitzpatrick skin type. RESULTS: At survey completion, physicians reported that 38, 50 and 12% of patients (N = 1865) had improving, stable and deteriorating/progressing disease, respectively. Most patients (96%) with mild disease at treatment initiation still had mild disease at the time of survey completion. More than half of patients with moderate disease (62%) or severe/very severe disease (57%) at treatment initiation still had moderate or severe/very severe disease at survey completion. Topical calcineurin inhibitors (TCIs) were the most common treatment in 40% of patients followed by phototherapy in 30%. Patients hoped for re-pigmentation (mild 56%, moderate 62%, severe/very severe 66%), reduction (mild 50%, moderate 56%, severe/very severe 49%) or cessation of affected areas with vitiligo (mild 48%, moderate 54%, severe/very severe 43%). CONCLUSION: The study findings indicate that a significant proportion of patients with NSV are not improving on current treatments, most commonly TCIs and phototherapy. The results highlight the unmet need for novel and effective therapies to substantially improve re-pigmentation, an important treatment goal for patients with NSV.
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INTRODUCTION: Vitiligo was historically regarded as a cosmetic disorder; however, it is an autoimmune disease. As a visible condition, it affects patient well-being. We assessed the impact of disease severity, lesion location, and body surface area (BSA) affected on patient health-related quality of life (HRQoL). METHODS: Retrospective data were from the Adelphi Real World Vitiligo Disease Specific Programme: a cross-sectional survey of physicians and their patients with vitiligo (10/2021-07/2022). Patient-reported outcomes were assessed by the Vitiligo-Specific Quality of Life Instrument (VitiQoL), Hospital Anxiety and Depression Scale (HADS), and EQ-5D-5L. The Work Productivity and Impairment Questionnaire (WPAI) questionnaire was used to assess disease-related impairment of daily activities. Data were stratified by physician-reported disease severity, presence/absence of vitiligo on the face, and BSA percentage affected. RESULTS: In total, 1388 patients were included. Mean (SD) VitiQoL, HADS depression, and anxiety scores were higher for those with severe disease [40.5 (26.1), 5.2 (4.4), and 6.8 (4.7)] than those with mild [24.8 (18.8), 3.6 (3.8), 4.2 (3.8)] or moderate [27.1 (22.6), 3.8 (4.5), 4.3 (4.4)] disease. Patients with face affected reported higher VitiQoL [30.0 (22.3) versus 23.2 (19.3)], and HADS scores [depression, 4.3 (4.3) versus 3.2 (3.9); anxiety, 5.0 (4.3) versus 3.8 (3.9)] than those without. Patients with ≥ 5% BSA affected had higher VitiQoL, depression and anxiety scores [27.9 (21.8), 4.0 (4.4), and 4.5 (4.2)] than those with 0-5% [24.6 (19.7), 3.4 (3.7), and 4.3 (4.1)]. Patients with severe vitiligo, facial lesions, or ≥ 5% BSA reported higher activity impairment. Mean EQ-5D-5L-utility score was approximately 0.9 regardless of disease severity or total BSA affected. CONCLUSIONS: These data demonstrate the impact disease severity can have on HRQoL and daily activities for patients with vitiligo. Lesions that are more severe, on the face, or covering a greater BSA are more often associated with poorer outcomes and activity impairment. These data also highlight the potential insensitivity of commonly used HRQoL measures and a need for more sensitive disease-specific measures.
Vitiligo is a disorder that causes patches of skin to lose pigment. In this study, we examined medical records of patients who have non-segmental vitiligo (the most common type of vitiligo) to better understand how the following factors affect the quality of life of patients with non-segmental vitiligo: (a) disease severity, (b) whether the face was affected, and (c) how much of the body was affected. Using a variety of measures, we found that patients with non-segmental vitiligo had lower quality of life, more symptoms of anxiety and depression, and higher activity impairment than those who did not. Our research highlights the differences in the measures used to assess the quality of life of patients, as well as the need for new therapies for non-segmental vitiligo.
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INTRODUCTION: The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. METHODS: Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. RESULTS: The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n = 277/309) that initially received ABA. Of patients on UPA15 in the LTE (n = 547), 28.3% (n = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n = 263/303, 86.8%; ABA to UPA15: n = 273/309, 88.3%) showed similar responses to the total population. CONCLUSIONS: The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.
A long-term study looked at a drug named upadacitinib to treat people with rheumatoid arthritis (RA), a disease that causes joint pain and damage. The study included patients whose RA was not improved by other injectable medicines. The study compared upadacitinib with another drug called abatacept. After 24 weeks, patients who were taking abatacept switched to upadacitinib, and patients taking upadacitinib continued on upadacitinib treatment for over 4 years. The researchers looked at how well the treatments worked over the long-term and if there were any side effects. The side effects with upadacitinib treatment in this long-term study were similar to side effects reported in previous studies with upadacitinib. The researchers also found that upadacitinib helped to lessen the symptoms of RA over time and helped patients complete their daily activities and reduced their pain and tiredness. This was true for patients who switched from abatacept to upadacitinib after 24 weeks and for patients who took upadacitinib from the start of the study. Patients who had not responded to other medicines also had similar improvements with upadacitinib. In conclusion, upadacitinib can help people with RA over the long term and no new safety risks were found.
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OBJECTIVE: To evaluate the efficacy and safety of upadacitinib over 5 years among patients with rheumatoid arthritis (RA) in a long-term extension (LTE) of the SELECT-BEYOND phase 3 trial. METHODS: Patients refractory to ≥1 biological disease-modifying antirheumatic drug (DMARD) received upadacitinib 15 mg or 30 mg once daily or placebo, in combination with background conventional synthetic DMARD(s). At week 12, patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg. All patients who completed the week 24 visit could enter the LTE for up to 5 years. Efficacy was analysed as observed and by non-responder imputation through week 260. Treatment-emergent adverse events per 100 patient-years were summarised over 5 years. RESULTS: Of the 498 patients randomised, 418 (84%) completed week 24 and entered the LTE. Of those who remained in the trial (n=80, upadacitinib 15 mg; n=81, upadacitinib 30 mg), 36%/36% and 81%/77% randomised to upadacitinib 15/30 mg were in Clinical Disease Activity Index (CDAI) remission or low disease activity at week 260, respectively (as observed). Approximately 47% of all patients who began in high disease activity demonstrated a CDAI improvement >12 at week 260 with upadacitinib 15/30 mg. Functional and pain-related outcomes also showed comparable improvements with both doses. Numerically higher rates of anaemia, herpes zoster and creatine phosphokinase elevation were observed with upadacitinib 30 mg vs 15 mg. No new safety issues were identified. CONCLUSIONS: Upadacitinib 15/30 mg continued to be effective in treating clinical and functional outcomes in patients with RA. The safety profile observed over 5 years was consistent with earlier study-specific and integrated assessments of upadacitinib treatment.
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Antirreumáticos , Artritis Reumatoide , Compuestos Heterocíclicos con 3 Anillos , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Masculino , Femenino , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/administración & dosificación , Persona de Mediana Edad , Resultado del Tratamiento , Anciano , Adulto , Quimioterapia Combinada , Método Doble CiegoRESUMEN
Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was -7.60 (95% CI -22.18 to 6.97; p = 0.3037) for UPA6, -21.27 (95% CI -36.02 to -6.52; p = 0.0051) for UPA11, and -19.60 (95% CI -35.04 to -4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was -7.45 (95% CI -16.86 to 1.96; p = 0.1198) for UPA6, -10.84 (95% CI -20.37 to -1.32; p = 0.0259) for UPA11 and -14.27 (95% CI -24.24 to -4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. Funding: AbbVie Inc.
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BACKGROUND: To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial. METHODS: Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years. RESULTS: Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses. CONCLUSIONS: Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile. TRIAL REGISTRATION: NCT02706873.
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Antirreumáticos , Artritis Reumatoide , Compuestos Heterocíclicos con 3 Anillos , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Metotrexato/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Masculino , Femenino , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Persona de Mediana Edad , Resultado del Tratamiento , Adulto , Anciano , Método Doble CiegoRESUMEN
INTRODUCTION: Vitiligo is often associated with comorbid conditions that may increase economic burden and affect patients' health-related quality of life. No large-scale study has been published to date using claims databases to evaluate the burden of comorbidities among patients with vitiligo. Herein, we evaluate the comorbidity burden among patients diagnosed with vitiligo from the US. METHODS: This retrospective cohort analysis used the Merative MarketScan Commercial Database. Eligible patients were diagnosed with vitiligo between January 2008 and December 2020 and matched 1:4 (vitiligo:control) with control subjects with no diagnosis of vitiligo between January 2007 and December 2021. Study outcomes were the incidence of comorbidities after matching, adjusted hazard ratios of comorbidity incidence among patients with vitiligo relative to matched control subjects, and time to comorbidity diagnosis or incidence. RESULTS: Baseline demographics were well balanced between matched vitiligo (n = 13,687) and control cohorts (n = 54,748). Incidence rates of comorbidities were higher among patients compared with control subjects (psychiatric, 28.4% vs 22.8%; autoimmune, 13.4% vs 5.1%; and non-autoimmune, 10.0% vs 7.0%). The most common psychiatric and autoimmune comorbidities in patients with vitiligo compared with control subjects included anxiety (14.3% vs 11.0%, respectively), sleep disturbance (9.1% vs 7.1%), depression (8.0% vs 6.3%), atopic dermatitis (3.1% vs 1.1%), psoriasis (2.7% vs 0.6%), and linear morphea (1.5% vs 0.1%). The risk of developing any psychiatric (hazard ratio 1.31; P < 0.01), autoimmune (hazard ratio 2.77; P < 0.01), or non-autoimmune (hazard ratio 1.45; P < 0.01) comorbidity was significantly higher among patients with vitiligo. Time to diagnosis of most vitiligo comorbidities was 1-3 years, although linear morphea was diagnosed at < 1 year. CONCLUSION: Results of this retrospective analysis demonstrated that patients were much more likely to be diagnosed with autoimmune or psychiatric comorbidities following a vitiligo diagnosis, which likely contributed to increased economic burden and lower quality of life.
Vitiligo, a long-lasting disorder in which patches of the skin lose color, is often associated with other medical conditions that may lower a patients' quality of life and increase the cost of caring for patients with the disorder. No large-scale studies are currently available that look at how other medical conditions affect patients with vitiligo. In this study, we determine the occurrence and timing of other medical conditions among patients from the US who have vitiligo. We used the Merative MarketScan Commercial Database, which captures medical and prescription drug data for 145.5 million people in the US. Patients in this study had vitiligo diagnosed between January 2008 and December 2020 and were matched with subjects who did not have vitiligo between January 2007 and December 2021. We looked at the occurrence of other medical conditions among patients with vitiligo compared with subjects without vitiligo and the time it took for another medical condition associated with vitiligo to happen. The authors found that among 13,687 patients with vitiligo and 54,748 subjects without vitiligo, patients with vitiligo were much more likely to have an autoimmune (disorders in which the body's immune system attacks healthy tissue) or psychiatric (mental, emotional, or behavioral) disorder, which likely contributed to the amount of money needed to care for the condition and reduced quality of life.
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AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Pironas/química , Pironas/uso terapéutico , Tiofenos/química , Tiofenos/uso terapéutico , Proteínas Quinasas Activadas por AMP , Animales , Compuestos de Bifenilo , Línea Celular , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Activadores de Enzimas/farmacología , Ácido Graso Sintasas/efectos de los fármacos , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Glucosa-6-Fosfatasa/efectos de los fármacos , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Síndrome Metabólico/metabolismo , Metformina/química , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Ratones Obesos , Peso Molecular , Complejos Multienzimáticos/efectos de los fármacos , Fosfoenolpiruvato Carboxiquinasa (GTP)/efectos de los fármacos , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Pironas/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Tiofenos/farmacologíaRESUMEN
This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin Cmax and AUCinf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The Cmax and AUCinf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib Cmax or area under the plasma concentration-time curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.
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Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Inhibidores de las Cinasas Janus/farmacología , Rosuvastatina Cálcica/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/efectos de los fármacos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adulto , Femenino , Voluntarios Sanos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/efectos de los fármacos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Adulto JovenRESUMEN
The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARgamma plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARgamma activation in muscle cells. We found that pharmacological activation of PPARgamma in primary cultured myocytes, and genetic activation of muscle PPARgamma in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARgamma activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARgamma activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARgamma-dependent manner. We propose that activation of PPARgamma in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.
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Resistencia a la Insulina/fisiología , Músculo Esquelético/fisiología , PPAR gamma/genética , PPAR gamma/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animales , Comunicación Autocrina/fisiología , Glucemia/metabolismo , Células Cultivadas , Grasas de la Dieta/farmacología , Expresión Génica/fisiología , Homeostasis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/fisiología , Mutagénesis Sitio-Dirigida , Miocitos Cardíacos/citología , Miocitos Cardíacos/fisiología , Fenotipo , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/fisiologíaRESUMEN
Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed for treatment of rheumatoid arthritis. This study characterizes the relationships between upadacitinib exposure and interleukin (IL)-6-induced signal transducer and activator of transcription proteins 3 (STAT3) phosphorylation (pSTAT3) and IL-7-induced STAT5 phosphorylation (pSTAT5) in the ex vivo setting as measures for JAK1 and JAK1/JAK3 inhibition, respectively, with comparison to tofacitinib. Drug plasma concentrations and ex vivo IL-6-induced pSTAT3 and IL-7-induced pSTAT5 in blood from subjects evaluated in 2 phase 1 studies who received immediate-release 1 mg to 48 mg upadacitinib, 5 mg twice daily (BID) tofacitinib, or placebo were determined. Exposure-response models were developed, and the effects of different upadacitinib doses on ex vivo biomarker responses were simulated and compared to tofacitinib. Upadacitinib (and tofacitinib) reversibly inhibited IL-6-induced pSTAT3 and IL-7-induced pSTAT5 in a concentration-dependent manner. Model-estimated values of 50% of the maximum effect were 60.7 nM for upadacitinib and 119 nM for tofacitinib for IL-6-induced pSTAT3 inhibition, and 125 nM for upadacitinib and 79.1 nM for tofacitinib for IL-7-induced pSTAT5 inhibition. Tofacitinib 5 mg BID is estimated to have a similar magnitude of effect on IL-6-induced pSTAT3 to â¼3 mg BID of upadacitinib (immediate-release formulation), whereas a 4-fold higher dose of upadacitinib (â¼12 mg BID), is estimated to show a similar magnitude of inhibition on IL-7-induced pSTAT5 as tofacitinb 5 mg BID. This study confirms that in humans, upadacitinib has greater selectivity for JAK1 vs JAK3 relative to the rheumatoid arthritis approved dose of tofacitinib, and results from these analyses informed the selection of upadacitinib IR doses evaluated in phase 2.
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Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piperidinas/farmacología , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Adolescente , Adulto , Ensayos Clínicos Fase I como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Voluntarios Sanos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Modelos Biológicos , Fosforilación/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Factor de Transcripción STAT3/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/efectos de los fármacos , Factor de Transcripción STAT5/metabolismo , Adulto JovenRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
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Abnormal elevation of 11beta-HSD1 activities in tissues, such as fat and brain, may contribute to the development of the abdominal obesity and Alzheimer disease, and the inhibition of 11beta-HSD1 might be beneficial to the management of these diseases. To assess the effects of pharmacologic inhibitors of 11beta-HSD1, we developed a fast LC/MS/MS method to quantify corticosteroids in minced tissue samples in the presence of 11beta-HSD substrates. The novel on-line SPE-LC/MS/MS method was developed with dual binary gradient and a throughput of 4.5 min/sample. A total of six corticosteroids (cortisol, cortisone, corticosterone, dehydrocorticosterone, dexamethasone, and dehydrodexamethasone) were studied. The lower limit of quantitation from 0.40 to 11.4 fmol and 4.5 orders magnitude of dynamic range were obtained for these six compounds. Three novel enzymatic bi-products, all isomers of cortisol, were observed in the liver or fat samples. Two of them were identified by matching the HPLC retention times and MS/MS spectra with authentic compounds. The potential interferences of these isomers and their removal are discussed.