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INTRODUCTION: Lebrikizumab, a high-affinity IgG4 monoclonal antibody that selectively inhibits interleukin-13 with high binding affinity and slow dissociation rate, prevents the formation of the interleukin-4Rα/interleukin-13Rα1 heterodimer receptor signaling complex. Here we report the impact of lebrikizumab on responses to two non-live vaccines in adult patients with moderate-to-severe atopic dermatitis (AD). METHODS: ADopt-VA (NCT04626297) was a double-blind, placebo-controlled, parallel-group, 16-week, phase 3 randomized study to assess the impact of lebrikizumab treatment on non-live vaccine immune responses, and efficacy and safety of lebrikizumab compared with placebo. Eligible patients included adults from 18 to 55 years of age with moderate-to-severe chronic AD who were randomly assigned 1:1 to lebrikizumab 250 mg every 2 weeks or placebo and stratified according to disease severity. The primary endpoints were the development of a booster response to tetanus toxoid and a positive antibody response to meningococcal conjugate vaccine (MCV), 4 weeks after administration of the corresponding vaccine. RESULTS: At week 16, 73.6% of patients in the lebrikizumab group (n = 78/106) achieved Tdap booster response compared with 73.4% of patients in the placebo group (n = 58/79). MCV vaccine response was observed in 86.9% of patients in the lebrikizumab group (n = 86/99) and 75.0% of patients in the placebo group (n = 60/80). At week 16, IGA 0,1 with ≥ 2-point improvement from baseline was achieved by 40.6% (n = 51/125) of patients treated with lebrikizumab and 18.9% (n = 23/122) of patients who received placebo (p < 0.001). There was a higher proportion of patients achieving EASI 75 at week 16 in the lebrikizumab-treated patients (58.0%, n = 72/125) compared with placebo (32.7%, n = 40/122, p < 0.001). CONCLUSIONS: Treatment with lebrikizumab did not impact response to non-live vaccines Tdap and MCV in this study. Lebrikizumab treatment had a significant degree of efficacy compared to placebo across multiple endpoints. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04626297.
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BACKGROUND: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16 weeks compared to placebo. OBJECTIVES: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment. METHODS: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16 years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep). RESULTS: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders. CONCLUSIONS: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD.ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).
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Dermatite Atópica , Prurido , Qualidade de Vida , Índice de Gravidade de Doença , Humanos , Prurido/tratamento farmacológico , Prurido/etiologia , Dermatite Atópica/tratamento farmacológico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Método Duplo-CegoRESUMO
BACKGROUND: Systemic immunomodulatory agents are indicated in the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. Perioperative use of these medications may increase the risk of surgical site infection (SSI) and complication. OBJECTIVE: To evaluate the risk of SSI and complication in patients with chronic autoimmune inflammatory disease receiving immunomodulatory agents (tumor necrosis factor-alfa [TNF-α] inhibitors, interleukin [IL] 12/23 inhibitor, IL-17 inhibitors, IL-23 inhibitors, cytotoxic T-lymphocyte-associated antigen-4 costimulator, phosphodiesterase-4 inhibitor, Janus kinase inhibitors, tyrosine kinase 2 inhibitor, cyclosporine (CsA), and methotrexate [MTX]) undergoing surgery. METHODS: We performed a search of the MEDLINE PubMed database of patients with chronic autoimmune inflammatory disease on immune therapy undergoing surgery. RESULTS: We examined 48 new or previously unreviewed studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. CONCLUSION: For low-risk procedures, TNF-α inhibitors, IL-17 inhibitors, IL-23 inhibitors, ustekinumab, abatacept, MTX, CsA, and apremilast can safely be continued. For intermediate- and high-risk surgery, MTX, CsA, apremilast, abatacept, IL-17 inhibitors, IL-23 inhibitors, and ustekinumab are likely safe to continue; however, a case-by-case approach is advised. Acitretin can be continued for any surgery. There is insufficient evidence to make firm recommendations on tofacitinib, upadacitinib, and deucravacitinib.
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Artrite Psoriásica , Metotrexato , Psoríase , Humanos , Artrite Psoriásica/tratamento farmacológico , Psoríase/tratamento farmacológico , Psoríase/imunologia , Metotrexato/uso terapêutico , Assistência Perioperatória/métodos , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Talidomida/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/epidemiologia , Piperidinas/uso terapêutico , Ciclosporina/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/efeitos adversos , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Agentes de Imunomodulação/uso terapêutico , Abatacepte/uso terapêutico , Abatacepte/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversosRESUMO
BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).
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Alopecia em Áreas , Antineoplásicos , Triptaminas , Humanos , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/epidemiologia , Carbazóis , Janus Quinase 3 , Inibidores de Proteínas Quinases/efeitos adversos , SARS-CoV-2 , Resultado do TratamentoRESUMO
INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit. METHODS: Adolescent patients (N = 206) (≥ 12 to < 18 years old, weighing ≥ 40 kg) with moderate-to-severe AD received subcutaneous lebrikizumab 500 mg loading doses at baseline and Week 2, followed by 250 mg every 2 weeks (Q2W) thereafter. Safety was monitored using reported AEs, AEs leading to treatment discontinuation, vital signs, growth assessments, and laboratory testing. Efficacy analyses included Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Body Surface Area (BSA), (Children's) Dermatology Life Quality Index ((C)DLQI), and Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, and PROMIS Depression. RESULTS: 172 patients completed the treatment period. Low frequencies of SAEs (n = 5, 2.4%) and AEs leading to treatment discontinuation (n = 5, 2.4%) were reported. Overall, 134 patients (65%) reported at least one treatment-emergent AE (TEAE), most being mild or moderate in severity. In total, 62.6% achieved IGA (0,1) with ≥ 2-point improvement from baseline and 81.9% achieved EASI-75 by Week 52. The EASI mean percentage improvement from baseline to Week 52 was 86.0%. Mean BSA at baseline was 45.4%, decreasing to 8.4% by Week 52. Improvements in mean change from baseline (CFB) to Week 52 were observed in DLQI (baseline 12.3; CFB - 8.9), CDLQI (baseline 10.1; CFB - 6.5), PROMIS Anxiety (baseline 51.5; CFB - 6.3), and PROMIS Depression (baseline 49.3; CFB - 3.4) scores. CONCLUSIONS: Lebrikizumab 250 mg Q2W had a safety profile consistent with previous trials and significantly improved AD symptoms and quality of life, with meaningful responses at Week 16 increasing by Week 52. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04250350.
Atopic dermatitis is a chronic relapsing inflammatory skin disease that affects up to 15% of adolescents worldwide, with up to 50% suffering from moderate-to-severe disease. Signs and symptoms include dry, cracked skin; redness; itching; and painful lesions, which can negatively affect quality of life and lead to complications, including skin infections. Adolescents also report increased rates of anxiety and stress. Lebrikizumab is a novel monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, the key cytokine in atopic dermatitis, blocking the downstream effects of IL-13 with high potency. Lebrikizumab has been shown previously to improve symptoms of atopic dermatitis, including itch, skin clearance, and quality of life in ADvocate1, ADvocate2 and ADhere. The ADore study aimed to evaluate the safety and efficacy of lebrikizumab in adolescents with moderate-to-severe atopic dermatitis. Investigators recruited patients ≥ 12 to < 18 years old, weighing ≥ 40 kg, from Australia, Canada, Poland, and the US who were diagnosed with moderate-to-severe atopic dermatitis. These patients received a loading dose of 500 mg of lebrikizumab at Weeks 0 and 2, followed by 250 mg every 2 weeks for 52 weeks. The safety profile of lebrikizumab was consistent with previously published reports, with mostly mild or moderate adverse events, which did not lead to treatment discontinuation. Lebrikizumab improved skin clearance; 62.6% of patients had clear or almost clear skin by the end of the trial. Lebrikizumab also improved the patients' quality of life. These safety and efficacy results support lebrikizumab's role in treating adolescents with moderate-to-severe atopic dermatitis. Safety and Efficacy of Lebrikizumab in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis: A 52-Week, Open-Label, Phase 3 Study (MP4 44681 KB).
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BACKGROUND: The IL-17A inhibitor secukinumab has demonstrated consistent efficacy and safety in patients with moderate-to-severe plaque psoriasis, with normalization of molecular and histopathologic psoriasis markers. OBJECTIVE: To investigate treatment effects of secukinumab on clinical signs and psoriatic inflammation markers over 52 weeks in patients with psoriasis. METHODS: In the ObePso-S study (NCT03055494), patients with psoriasis were randomized 2:1 to receive secukinumab 300 mg (n = 54) or placebo (n = 28), stratified by body weight (<90 or ≥90 kg), for 52 weeks. At Week 12, patients receiving placebo were switched to secukinumab. Psoriasis Area and Severity Index improvement of 90% (PASI90) and Investigator's Global Assessment modified 2011 0/1 responses were assessed at Weeks 12 and 52. Immunohistochemistry for keratin 16 (K16) and gene expression profiles were evaluated in lesional and non-lesional skin biopsies collected at baseline, Week 12, and Week 52. RESULTS: Of patients receiving secukinumab, 55.8% and 59.6% achieved PASI90 at Weeks 12 and 52, respectively. K16 was absent in 93.1% of Week 12 PASI90 responders and 93.6% of Week 52 PASI90 responders, which mirrored the down-regulated expression of psoriatic inflammation. Week 52 PASI90 non-responders experienced regression of clinical and inflammatory marker responses toward baseline levels. Lower control of inflammatory gene expression at Week 12 was associated with suboptimal clinical responses at Week 52. CONCLUSION: Sustained clinical responses with secukinumab were associated with rapid and sustained normalization of K16 and inflammatory gene expression in most patients. Molecular anti-inflammatory effects of secukinumab at Week 12 were associated with clinical responses at Week 52.
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Anticorpos Monoclonais , Psoríase , Humanos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Método Duplo-Cego , Resultado do Tratamento , Índice de Gravidade de Doença , Psoríase/patologiaRESUMO
Importance: Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials. Objective: To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD. Design, Setting, and Participants: The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO). Interventions: Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks [Q2W] thereafter) or PBO Q2W in combination with TCS for 16 weeks. Main Outcomes and Measures: Efficacy analyses at week 16 included proportions of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs). Results: The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 [4.8%]), headache (7 [4.8%]), hypertension (4 [2.8%]), injection site reactions (4 [2.8%]), and herpes infection (5 [3.4%]) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%). Conclusions and Relevance: In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04250337.
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Corticosteroides , Dermatite Atópica , Fármacos Dermatológicos , Adolescente , Adulto , Feminino , Humanos , Masculino , Corticosteroides/uso terapêutico , Anticorpos Monoclonais , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Método Duplo-Cego , Imunoglobulina A , Interleucina-13 , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
INTRODUCTION: We evaluated the efficacy of brodalumab in patients with nail or scalp psoriasis in three phase 3 studies (AMAGINE-1/-2/-3). METHODS: In AMAGINE-1, scalp clearance, measured by the psoriasis scalp severity index (PSSI), was reported for patients who received brodalumab 210 mg every 2 weeks (Q2W) or placebo through 12 weeks. In AMAGINE-2/-3, nail clearance, measured by the nail psoriasis severity index (NAPSI), was reported for patients receiving either brodalumab 210 mg Q2W or ustekinumab continuously through 52 weeks. RESULTS: At week 12, significantly more patients receiving brodalumab achieved 75% and 100% improvement rates from baseline PSSI and had lower mean PSSI across 12 weeks compared with placebo, with significant improvement in PSSI evident with brodalumab 210 mg Q2W vs placebo by week 2. Across 52 weeks, patients receiving brodalumab achieved significantly greater complete clearance of nail psoriasis (NAPSI 0), lower mean NAPSI, and higher mean percent improvement rates from baseline NAPSI than patients receiving ustekinumab. At week 52, 63.8% of patients receiving brodalumab achieved NAPSI 0 vs 39.1% of patients receiving ustekinumab. CONCLUSIONS: Brodalumab was associated with clearance of scalp psoriasis through 12 weeks and improvements in nail psoriasis, including complete nail clearance, through 52 weeks.
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Psoríase , Couro Cabeludo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Humanos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Baricitinib previously demonstrated improvements in itch and sleep disturbance versus placebo in adults with moderate-to-severe atopic dermatitis (AD). OBJECTIVES: Examine if itch and sleep improvements are associated with better quality of life (QoL) and productivity in patients with AD. METHODS: Data were drawn from BREEZE-AD5 (NCT03435081). Itch and sleep improvement at Week 16 were defined using ≥4-point improvements in the Itch Numeric Rating Scale and ≥1.5 decreases in the number of nighttime awakenings since baseline, respectively. Patients with and without improvements were compared on Dermatology Life Quality Index (DLQI) and Work Productivity and Activity Impairment-AD scores. Changes from baseline were analyzed using ANCOVA with last observation carried forward. Proportions were analyzed using logistic regression with non-responder imputation. RESULTS: Greater proportions of patients with versus without itch improvement indicated no impact of AD on QoL (37.7 vs. 1.8%). Patients with itch improvement had greater decreases in work time impaired (-29.3 vs. -5.6%). More patients with versus without sleep improvement reported no effect of AD on QoL (25.5 vs. 1.1%); patients with better sleep experienced larger reductions in work time spent impaired (-33.3 vs. -6.1%). CONCLUSIONS: Patients with AD who experienced itch and sleep improvement had significantly better QoL and productivity.
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Dermatite Atópica , Qualidade de Vida , Adulto , Azetidinas , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Humanos , Medidas de Resultados Relatados pelo Paciente , Prurido/tratamento farmacológico , Prurido/etiologia , Purinas , Pirazóis , Índice de Gravidade de Doença , Sono , SulfonamidasRESUMO
BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).
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Anti-Inflamatórios não Esteroides/administração & dosagem , Psoríase/tratamento farmacológico , Resorcinóis/administração & dosagem , Estilbenos/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Dermatite de Contato/etiologia , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Psoríase/complicações , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Resorcinóis/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/administração & dosagem , Estilbenos/efeitos adversosRESUMO
BACKGROUND: Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment. METHODS: A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores. RESULTS: Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate. LIMITATIONS: Larger prospective studies are required to confirm the reported analyses. CONCLUSIONS: Tapinarof is a potential important advance in topical medicine development for AD.
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Anti-Inflamatórios não Esteroides/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Resorcinóis/administração & dosagem , Creme para a Pele/administração & dosagem , Estilbenos/administração & dosagem , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Criança , Dermatite Atópica/diagnóstico , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Resorcinóis/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/efeitos adversos , Estilbenos/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Importance: Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics. Objective: To assess the association of secukinumab with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. Design, Setting, and Participants: This pooled cohort study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018. Main Outcomes and Measures: Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years). Results: A total of 12â¯319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men [67.2%]; mean [SD] age, of 44.9 [13.5] years), 2523 had psoriatic arthritis (20.5%; 1323 women [52.4%]; mean [SD] age, 48.8 [12.1] years), and 977 had ankylosing spondylitis (7.3%; 658 men [67.3%]; mean [SD] age, 42.3 [11.9] years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12â¯319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported. Conclusions and Relevance: This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Psoriásica/tratamento farmacológico , Tuberculose Latente/epidemiologia , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Artrite Psoriásica/imunologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Incidência , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologiaRESUMO
Background: BI 695501 is an approved biosimilar to Humira® reference product (RP). Research design and methods: In this randomized Phase III trial (VOLTAIRE-PSO), patients with moderate-to-severe chronic plaque psoriasis received BI 695501 or adalimumab RP (24-week treatment). Primary efficacy endpoint: the proportion of patients with ≥75% reduction in Psoriasis Area and Severity Index (PASI 75) response at week 16 (±18% equivalence limits for two-sided 95% confidence interval between treatment groups). Safety, pharmacokinetics, and immunogenicity were also assessed. Results: Baseline characteristics were balanced between treated groups (BI 695501, n = 159; adalimumab RP, n = 158). PASI 75 response rates (full analysis set, n = 158; n = 157) were 68.2% (BI 695501) and 70.4% (adalimumab RP) at week 16 (95% CI: -14.4%, 8.7%), and 75.3% and 72.4%, at week 24, respectively. At week 24, 41.5% (BI 695501) and 44.9% (adalimumab RP) of treated patients had treatment-emergent adverse events (AEs), 3.1% and 4.4% had serious AEs, and 0.0% and 1.9% had AEs of special interest. Of treated patients, 75.3% (BI 695501) and 77.9% (adalimumab RP) were anti-drug antibody-positive. Conclusion: These data demonstrate equivalent efficacy and highly similar safety and immunogenicity between BI 695501 and adalimumab RP in patients with chronic plaque psoriasis. Study identifier: NCT02850965.
Assuntos
Medicamentos Biossimilares , Psoríase , Adalimumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Método Duplo-Cego , Humanos , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The interleukin-17 (IL-17) pathway plays a crucial role in the development of psoriasis. Briefly, naive T cells differentiate into helper T (Th17) cells through interaction with activated dendritic cells in the presence of IL-23, Th17 cells produce IL-17 cytokines, and keratinocytes stimulated by IL-17 ligands lead to aberrant differentiation and proliferation that promote production of proinflammatory chemokines and further recruitment of inflammatory cells, setting up a positive feedback loop. Currently, 3 US Food and Drug Administrationapproved agents to treat psoriasis affect the IL-17 pathway: brodalumab, secukinumab, and ixekizumab. Brodalumab is a fully human IL-17 receptor A antagonist that blocks signaling of multiple downstream inflammatory cytokines involved in psoriasis. Secukinumab and ixekizumab selectively bind to and neutralize only IL-17A. Pharmacologic effects in patients with psoriasis include decreased keratinocyte hyperproliferation, reduced epidermal thickening, decreased inflammatory markers, and resolution of histologic and genomic features of psoriasis. In clinical trials, therapeutic doses of brodalumab, secukinumab, and ixekizumab have demonstrated skin clearance efficacy by psoriasis area and severity index and static physician's global assessment scores at 12 weeks. The immunomodulation of these agents is associated with a favorable safety profile. Overall, the clinical improvement and normalization of genetic hallmarks of psoriasis provide a strong case for the unique role of IL-17 receptor blocking as a therapeutic mechanism of action to treat psoriasis. Understanding the unique mechanisms by which treatments interact with the IL-17 pathway to inhibit downstream proinflammatory signal cascade can help physicians make informed treatment decisions when selecting the appropriate medication for patients. J Drugs Dermatol. 2020;19(2)138-143. doi:10.36849/JDD.2020.4645
Assuntos
Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Receptores de Interleucina-17/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Transdução de Sinais/efeitos dos fármacosAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Dor/tratamento farmacológico , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Humanos , Dor/diagnóstico , Dor/psicologia , Prurido/diagnóstico , Prurido/psicologia , Psoríase/diagnóstico , Psoríase/psicologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Potent topical corticosteroids (TCSs) are the mainstay of psoriasis treatment. Safety concerns have limited use to 2 to 4 weeks. The objective of our study was to investigate the safety and efficacy of once-daily halobetasol propionate (HP) lotion 0.01% in moderate to severe plaque psoriasis through 2 multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N=430). Participants were randomized (2:1) to HP lotion 0.01% or vehicle once daily for 8 weeks, followed by 4 weeks of follow-up. The primary efficacy assessment was treatment success (at least a 2-grade improvement in baseline investigator global assessment [IGA] score and a score of 0 [clear] or 1 [almost clear]). Additional assessments included improvement in psoriasis signs and symptoms, body surface area (BSA), and a composite score of IGA×BSA. Safety and treatment-emergent adverse events (AEs) were evaluated throughout. We found that HP lotion 0.01% demonstrated statistically significant superiority over vehicle as early as week 2 and also was superior in reducing psoriasis signs and symptoms and BSA involvement.
Assuntos
Clobetasol/análogos & derivados , Fármacos Dermatológicos/administração & dosagem , Glucocorticoides/administração & dosagem , Psoríase/tratamento farmacológico , Administração Cutânea , Adulto , Idoso , Clobetasol/administração & dosagem , Clobetasol/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Purpose: Apremilast, an oral phosphodiesterase 4 inhibitor, was effective in clinical trials in patients with moderate plaque psoriasis (affected body surface area [BSA] 5% to 10%). However, findings from real-world clinical practice are limited. Materials and methods: An online survey and chart review was conducted among US dermatologists during October 2015 to identify clinical characteristics and 6-month treatment outcomes among patients with moderate psoriasis treated with apremilast. Results: A total of 83 dermatologists provided patient chart information at the initial and 6-month follow-up time points for 70 patients with moderate plaque psoriasis initially receiving apremilast, of whom 65 were receiving it as their primary therapy (mean age: 47.3 years; 45% were men). Among apremilast-treated patients, 91% (64 of 70) remained on apremilast and 54% were rated as having improved to mild psoriasis at follow-up; mean BSA decreased from 9.9% at initial chart review to 4.9%. There were 8 of 66 (12%) patients who experienced ≥1 side effect, including diarrhea (7.6%), nausea (4.5%), headache (1.5%), and abdominal pain (4.5%). Most dermatologists (68%) stated that apremilast exceeded or met their expectations. Conclusions: Most patients with moderate psoriasis receiving apremilast had improved at 6-month follow-up. Safety and tolerability were consistent with the safety profile of apremilast.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Psoríase/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Dermatologistas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/uso terapêutico , Estudos Prospectivos , Inquéritos e Questionários , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Patients with moderate plaque psoriasis are often undertreated and may experience unsatisfactory clinical outcomes. Undertreatment may stem partly from a lack of consensus on the definition of moderate psoriasis and appropriate treatments for patients with moderate disease severity. MATERIALS AND METHODS: An online survey was conducted during October 2015 to determine how US dermatologists in the clinical setting define and treat moderate psoriasis. RESULTS: A total of 150 dermatologists responded to the survey (mean time in practice: 13.5 years). On average, they saw 72 patients with psoriasis per month; 40% of these patients were considered to have moderate psoriasis. Most (95%) reported assessing disease severity based on the percentage of psoriasis-affected body surface area (BSA); 59% also considered location of the affected area. BSA cutoffs used to define moderate psoriasis varied widely (median low and high cutoffs: 5-10%; range: 1-70%). Similarly, wide variation in cutoff ranges was observed for the Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA), and Dermatology Life Quality Index (DLQI). Primary therapy comprised biologics (47%), prescription topicals (28%), and oral systemics (18%). CONCLUSIONS: The current findings indicate lack of consensus surrounding the definition of moderate psoriasis among US dermatologists.
Assuntos
Dermatologistas/psicologia , Psoríase/patologia , Administração Tópica , Adulto , Produtos Biológicos/uso terapêutico , Superfície Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fototerapia , Psoríase/tratamento farmacológico , Psoríase/terapia , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.