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@#Objective To investigate the mechanism of anti-IL-17A monoclonal antibody(secukinumab) regulating autophagy and inflammation in gout.Methods The peripheral venous blood samples from 57 patients with acute gout(AG),57patients with intermittent gout(IG) and 82 healthy volunteers were collected and measured for the mRNA transcription levels of autophagy-related genes(ATGs) ATG4B,ATG7, A TG16L1,Beclin-1 and LC3B by RT-qPCR.The model of AG inflammation was established by adding monosodium urate(MSU) crystals into the peripheral venous blood samples of healthy volunteers,and the transcription and protein expression of IL-1β were detected by RT-qPCR and ELISA at 0,1,2,4,6 and8 h and different concentrations(0,100,200 and 400 μmol/L) of secukinumab.The peripheral blood samples of healthy volunteers were divided into control(without MSU treatment),MSU(100 μg/mL),MSU+colchicine(100 μg/mL+30 μg/mL) and MSU+secukinumab(100 μg/mL+400 μmol/L) groups,which were detected for the mRNA transcription and protein expression of IL-1 β and ATGs by RT-qPCR and Western blot,and for the expression of IL-1β,IL-12 and IL-35 by ELISA.Results The mRNA expression levels of ATG4B, Beclin-1 and LC3B in AG,IG and healthy control groups were significantly different(F=3.896,11.78 and 3.856,respectively,each P <0.05),among which the mRNA levels in AG were lower than those in IG and HC groups(t=2.692,3.234,2.231 and 2.085,4.795,2.748,respectively,each P <0.05);the expression levels of ATG16L1 mRNA were significantly different in the three groups(F=7.949,P <0.001),and was significantly lower in AG group than HC group(t=3.860,P <0.001).In AG inflammation model,the mRNA and protein expression of IL-1 β reached their peak in 2—4 h,and the anti-inflammation effect of secukinumab was the strongest at the concentration of 400 μmol/L.Compared with MSU group,the mRNA levels of ATG16L1 and LC3B(t=2.343 and 2.916,respectively,each P <0.05) as well as the expression levels of ATG4B,ATG7,Beclin-1,ATG16L1 and LC3B-Ⅱ proteins(t=28.84,11.6,8.402,4.124 and 2.458,respectively,each P <0.05) in MSU+secukinumab group decreased significantly.The expression levels of IL-12 and IL-35 in the control,MSU,MSU+colchicine and MSU+secukinumab groups showed significant difference(F=7.009 and 6.518,respectively,each P <0.01).Compared with MSU group,the expression level of IL-12 significantly decreased(t=2.604,P <0.05)in MSU+secukinumab group,and the expression level of IL-35 also decreased,while with no significant difference(t=1.928,P> 0.05).Conclusion Secukinumab can regulate the mRNA and protein expression of ATGs,reduce the levels of pro-inflammatory cytokines,and inhibit gout inflammation,which provides a reference for the treatment of gout.
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@#Objective To investigate the mechanism of anti-IL-17A monoclonal antibody(secukinumab) regulating autophagy and inflammation in gout.Methods The peripheral venous blood samples from 57 patients with acute gout(AG),57patients with intermittent gout(IG) and 82 healthy volunteers were collected and measured for the mRNA transcription levels of autophagy-related genes(ATGs) ATG4B,ATG7, A TG16L1,Beclin-1 and LC3B by RT-qPCR.The model of AG inflammation was established by adding monosodium urate(MSU) crystals into the peripheral venous blood samples of healthy volunteers,and the transcription and protein expression of IL-1β were detected by RT-qPCR and ELISA at 0,1,2,4,6 and8 h and different concentrations(0,100,200 and 400 μmol/L) of secukinumab.The peripheral blood samples of healthy volunteers were divided into control(without MSU treatment),MSU(100 μg/mL),MSU+colchicine(100 μg/mL+30 μg/mL) and MSU+secukinumab(100 μg/mL+400 μmol/L) groups,which were detected for the mRNA transcription and protein expression of IL-1 β and ATGs by RT-qPCR and Western blot,and for the expression of IL-1β,IL-12 and IL-35 by ELISA.Results The mRNA expression levels of ATG4B, Beclin-1 and LC3B in AG,IG and healthy control groups were significantly different(F=3.896,11.78 and 3.856,respectively,each P <0.05),among which the mRNA levels in AG were lower than those in IG and HC groups(t=2.692,3.234,2.231 and 2.085,4.795,2.748,respectively,each P <0.05);the expression levels of ATG16L1 mRNA were significantly different in the three groups(F=7.949,P <0.001),and was significantly lower in AG group than HC group(t=3.860,P <0.001).In AG inflammation model,the mRNA and protein expression of IL-1 β reached their peak in 2—4 h,and the anti-inflammation effect of secukinumab was the strongest at the concentration of 400 μmol/L.Compared with MSU group,the mRNA levels of ATG16L1 and LC3B(t=2.343 and 2.916,respectively,each P <0.05) as well as the expression levels of ATG4B,ATG7,Beclin-1,ATG16L1 and LC3B-Ⅱ proteins(t=28.84,11.6,8.402,4.124 and 2.458,respectively,each P <0.05) in MSU+secukinumab group decreased significantly.The expression levels of IL-12 and IL-35 in the control,MSU,MSU+colchicine and MSU+secukinumab groups showed significant difference(F=7.009 and 6.518,respectively,each P <0.01).Compared with MSU group,the expression level of IL-12 significantly decreased(t=2.604,P <0.05)in MSU+secukinumab group,and the expression level of IL-35 also decreased,while with no significant difference(t=1.928,P> 0.05).Conclusion Secukinumab can regulate the mRNA and protein expression of ATGs,reduce the levels of pro-inflammatory cytokines,and inhibit gout inflammation,which provides a reference for the treatment of gout.
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ABSTRACT Objective Therefore, this study aimed to evaluate the impact of secukinumab and ustekinumab against moderate-to-severe plaque psoriasis in a Brazilian pediatric population with access to public healthcare. Methods A survey of immunobiological treatments registered for use against pediatric psoriasis at the National Health Surveillance Agency was conducted. These treatments were compared to the list available in the same treatment category in the public health system through the Clinical Protocol and Therapeutic Guidelines for psoriasis. A quantitative analysis of the data of patients treated with immunobiological drugs the previous year in accordance with the Clinical Protocol and Therapeutic Guidelines was performed using data available in the DATASUS portal. Results The public budget impact scenarios analyzed were comparable to the investment already planned for acquiring the only available drug option. Conclusion The incorporation of two therapeutic options in the Clinical Protocol and Therapeutic Guidelines list for moderate-to-severe pediatric psoriasis was feasible in a horizon of 5 years compared to the investment into the single option available to pediatric patients. These findings can facilitate the local analysis of budgetary impact and discussions on the feasibility of this therapeutic incorporation at the state level.
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Interleukin 17 (IL-17) inhibitors are approved for treating psoriasis, psoriatic arthropathy, and ankylosing spondylitis. IL-17 is involved in the pathogenesis of inflammatory bowel disease (IBD); however, paradoxical events have been reported using selective IL-17 inhibitors such as secukinumab, whose pathophysiological mechanisms have not been fully clarified. Although the incidence of IBD in this group of patients is low, the risk could be reduced by carefully assessing risk factors such as family history, gastrointestinal symptoms, and fecal calprotectin before starting treatment.
Los inhibidores de interleucina 17 (IL-17) se encuentran aprobados para el tratamiento de psoriasis, artropatía psoriásica y espondilitis anquilosante. La IL-17 se encuentra involucrada en la patogenia de la enfermedad inflamatoria intestinal (EII); sin embargo, hasta la fecha se han reportado eventos paradójicos con el uso inhibidores selectivos de IL-17 como el secukinumab, cuyos mecanismos fisiopatológicos no han sido del todo aclarados. Aunque la incidencia de EII en este grupo de pacientes es baja, el riesgo podría disminuirse mediante una evaluación cuidadosa de factores de riesgo tales como historia familiar, síntomas gastrointestinales y la realización de calprotectina fecal previo al inicio del tratamiento.
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Objective:To compare the efficacy and safety of different dosages of new drugs in the treatment of PsA by using network meta-analysis.Methods:Three medical databases (PubMed, Web of Science, Cochrane Library) were searched for the studies that compared the efficacy and safety of 4 new drugs (secukinumab, ixekizumab, apremilast, tofacitinib) with different dosages in the treatment of PsA. Data from included studies were analyzed by Stata 15.0.Results:A total of 16 RCTs were included. The results of the network meta-analysis showed that: (1) Among the overall patients, in terms of ACR20 response rate, the larger the surface under the cumulative ranking (SUCRA), the more effective it is. Secukinumab 300 mg Q4W(96.1%) had the best efficacy, followed by ixekizumab 80 mg Q4W(79.0%), ixekizumab 80 mg Q2W(75.1%), secukinumab 150 mg Q4W(73.2%), apremilast 30 mg BID(50.6%), apremilast 20 mg BID(38.6%), tofacitinib 5 mg BID(18.1%), tofacitinib 10 mg BID(17.7%) and placebo(2.0%). (2) In terms of PASI75 response rate, the larger the area under the SUCRA curve, the more effective it is. Ixekizumab 80 mg Q4W(96.1%) had the best efficacy, followed by ixekizumab 80 mg Q2W(88.7%), secukinumab 300 mg Q4W(75.6%), secukinumab 150 mg Q4W(63.3%), apremilast 30 mg BID(44.5%), apremilast 20 mg BID(38.4%), tofacitinib 10 mg BID(30.0%), tofacitinib 5 mg BID(12.5%) and placebo(1.0%). (3) Among the overall patients, in terms of safety, the smaller the area under the SUCRA curve, the higher the safety it is. Secukinumab 300 mg Q4W (17.3%) has the best safety. (4) The results of subgroup analysis showed that in terms of ACR20 response rate, ixekizumab 80 mg Q2W(85.3%) had the best efficacy in bDMARDs-na?ve patients, while in bDMARDs-IR patients, secukinumab 300 mg Q4W(83.9%) had the best efficacy.Conclusion:Among all patients, secukinumab 300 mg Q4W is the best in terms of ACR20 response rate and safety, but ixekizumab 80 mg Q4W is more effective in improving PsA lesions comparing yo other drugs.
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Objective:To evaluate clinical efficacy and safety of secukinumab in the treatment of patients with localized pustular psoriasis irresponsive or intolerant to conventional treatment.Methods:Clinical data were collected from 13 patients with refractory localized pustular psoriasis, who received secukinumab treatment in Department of Dermatology, Xijing Hospital from December 2019 to April 2022. Efficacy was evaluated by comparing palmoplantar pustulosis (PPP) area and severity index (PPPASI) score and physician global assessment (PGA) score in PPP patients before and after the treatment, and by comparing clinical global impression (CGI) score in patients with acrodermatitis continua of Hallopeau (ACH). Adverse events were recorded during the treatment.Results:Among the 13 patients with refractory localized pustular psoriasis, 6 were diagnosed with PPP, 3 with ACH, and 4 with PPP complicated by ACH. There were 3 males and 10 females, and their age was 33.2 ± 14.6 years. After 12-week treatment, the PPPASI score decreased from 13.88 ± 3.62 points at baseline to 6.81 ± 2.31 points in 10 patients presenting with PPP lesions, 4 achieved 75% improvement in the PPPASI score (PPPASI75), and 5 achieved PGA0/1; at the same time, 6 of the 7 patients presenting with ACH lesions achieved moderate or marked improvement in the CGI score, and 4 of the 6 patients achieved marked improvement. Two patients with PPP discontinued the treatment after 3- and 5-week treatment respectively due to poor response, and 1 patient with ACH achieved mild improvement in the CGI score after 12-week treatment. No severe adverse events were reported during the treatment. However, inflammatory follicular papules occurred in 1 patient, and eczematoid lesions occurred in another 1 patient, which both regressed after symptomatic treatment.Conclusion:Secukinumab was effective and safe in the treatment of refractory localized pustular psoriasis, and may serve as a new treatment option for refractory PPP and ACH.
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Objective:To summarize and analyze clinical characteristics and possible pathogenesis of atopic dermatitis (AD) -like lesions after treatment with interleukin-17 (IL-17) antagonists in patients with psoriasis, so as to improve the clinical management of these patients.Methods:Four patients with psoriasis, who developed AD-like lesions after the treatment with IL-17 antagonists, were reported. A comprehensive update-search was carried out to analyze and summarize clinical characteristics of and therapeutic strategies for other related cases reported in Chinese and international literature.Results:Among the 4 patients in this study, 2 were males and 2 were females, with a history of psoriasis ranging from 10 to 35 years; after 5-month to 2-year treatment with secukinumab, they developed pruritic erythema and papules with exudation on the trunk, limbs and/or face. All the 4 patients had a history of atopic diseases and elevated serum total IgE levels and/or eosinophil counts. AD-like lesions were controlled in 3 patients after treatment with systemic cyclosporine, glucocorticoids and/or antihistamines, as well as topical glucocorticoids and/or tacrolimus, and secukinumab continued to be administered simultaneously; 1 discontinued secukinumab due to repeated AD-like lesions. Totally, 12 articles in English containing 48 patients were included, and a total of 52 patients including the 4 patients in this study were analyzed. Among them, there were 30 males and 22 females, with the age being 50.1 ± 13.6 years; 37 cases were induced by secukinumab, 14 induced by ixekizumab, and 1 induced by brodalumab; the time from the initiation of biologic therapy to the onset of AD-like lesions ranged from 1 week to 2 years; the lesions manifested as pruritic erythema and papules, accompanied by scales or exudation; the skin lesions were mainly distributed on the limbs (41 cases, 78.8%), followed by the trunk (32 cases, 61.5%) and face (20 cases, 38.5%) ; a personal or family history of atopic diseases was reported in 57.7% patients; peripheral blood eosinophil counts increased in 5 cases, and serum total IgE levels were elevated in 17. Thirty-two (61.5%) patients discontinued IL-17 antagonists, and received single or combination therapies, including systemic treatment with cyclosporine, methotrexate, glucocorticoids, antihistamines, other biologic agents and small-molecule drugs, topical treatment with glucocorticoids and/or tacrolimus, and phototherapy; 20 (38.5%) patients continued the previous treatment with IL-17 antagonists, and additionally received topical treatment with or without oral antihistamines or cyclosporine; after the above treatment, the psoriatic and AD-like lesions were controlled in most patients.Conclusions:AD-like lesions after IL-17 antagonist therapy were not common in patients with psoriasis, and these patients developing AD-like lesions were more likely to have a personal or family history of atopic diseases and elevated levels of serum total IgE; based on the disease condition, the treatment with IL-17 antagonists may be considered to continue during the symptomatic treatment of AD-like lesions.
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Objective:To observe the clinical efficacy of secukinumab in the treatment of active psoriatic arthritis (PsA).Methods:Thirty active PsA patients in the out-patient clinic of the First Affiliated Hospital of the PLA Air Force Military Medical University between July 2020 to December 2021 were included in this study. Patients were categorized into one group with axial involvement ( n=17, 57%) and the other group with peripheral joint involvement ( n=13, 43%) according to arthritis subtypes. Patients in both groups received a subcutaneous injection of 300 mg of secukinumab at 0, 1, 2, 3, and 4 weeks, and then every 4 weeks. The CRP, ESR, VAS pain score (VAS-pain, 0~10 cm), physician comprehensive assessment of disease activity by VAS score (VAS-gh, 0~10 cm), psoriasis involvement area and severity index (PASI), skin quality of life index (DLQI), psoriatic arthritis disease activity index (DAPSA), psoriatic arthritis activity score (PASDAS), Bath ankylosing spondylitis activity index (BASDAI) were recorded at week 0, week 12, and week 24. DAP-SA response (score ≤4) and minimum disease activity (MDA) were also used to assess the proportion of overall patients who responded to secukinumab treatment. The measurement data with normal distribution were analyzed by repeated measure analysis of variance. Non-normally distributed data were expressed as median (IQR). Count data were expressed as frequency and percentage (%) and analyzed by Fisher exact probability method. Results:The mean duration of skin disease in both axial involvement and peripheral joint involvement groups was (14±8)years and (12±7)years ( t=0.70, P=0.256), respectively. The mean duration of arthritis symptoms in both groups was (3.2±3.7)years and (1.8±2.1)years ( t=1.17, P=0.125), respectively. All patients completed 24 weeks of secukinumab treatment. At 24 weeks, VAS-pain, VAS-gh, PASI, DLQI, DAPSA, PASDAS and BASDAI were all decreased significantly ( P<0.05). Patients with axial involvement seemed more likely to benefit in CRP [2.4 (1.7, 3.5) mg/L vs 8.0 (5.3, 14.0) mg/L, Z=-2.69, P=0.007] and VAS-pain[1.0 (0, 2.0) vs (5.0, 6.0), Z=-3.47, P<0.001]improvement ( P<0.005). Both groups achieved PASI 100, which meant achieving clearance of skin dis-ease. The DAPSA remission rate and MDA of the patients with axial involvement were 88% and 82%, re-spectively, and the DAPSA remission rate and MDA were 92% and 92%, respectively. Secukinumab was found to be safe and well tolerated with no adverse event reported or observed during 24-week treatment. Conclusion:In real-world observations, secukinumab is proven to be safe and effective for the treatment of PsA, with rapid relieving of skin and joint symptoms and reduction of disease activity. Patients with axial involvement may benefit more notably than patients with peripheral arthritis subtype.
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Abstract Background Secukinumab has shown high efficacy in randomized controlled trials in both ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Here, we investigated its real-life effectiveness and tolerability in a cohort of AS and PsA patients. Methods We retrospectively analyzed medical records of outpatients with AS or PsA treated with secukinumab between December 2017 and December 2019. ASDAS-CRP and DAS28-CRP scores were used to measure axial and peripheral disease activity in AS and PsA, respectively. Data were collected at baseline and after 8, 24, and 52 weeks of treatment. Results Eighty-five adult patients with active disease (29 with AS and 56 with PsA; 23 males and 62 females) were treated. Overall, mean disease duration was 6.7 years and biologic-naïve patients were 85%. Significant reductions in ASDAS-CRP and DAS28-CRP were observed at all time-points. Body weight (in AS) and disease activity status at baseline (particularly in PsA) significantly affected disease activity changes. ASDAS-defined inactive disease and DAS28-defined remission were achieved in comparable proportions between AS and PsA patients, at both 24 weeks (45% and 46%) and 52 weeks (65.5% and 68%, respectively); male sex was found an independent predictor of positive response (OR 5.16, P = 0.027). After 52 weeks, achievement of at least low disease activity and drug retention were observed in 75% of patients. Secukinumab was well-tolerated and only mild injection-site reactions were recorded in 4 patients. Conclusion In a real-world setting, secukinumab confirmed great effectiveness and safety in both AS and PsA patients. The influence of gender on treatment response deserves further attention.
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Secukinumab, a fully human monoclonal antibody, is a biological agent that targets interleukin-17A. Secukinumab is used in the management of the common dermatological entity - plaque-type psoriasis and its various types, namely psoriatic arthritis, hypertrophic palmoplantar psoriasis and generalized pustular psoriasis. Other less common indications of this popular interleukin -17A inhibitor, secukinumab include ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, Familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). This review article was written by referring to various review articles, original articles, and some books related to highly regarded databases, such as the Web of Science, PubMed, and Scopus. The keywords explored during review of literature consisted of combinations of the following words: human monoclonal antibody, IL-17A, and biologicals. The authors with this in-depth review hope to explore the working of this versatile biological, Secukinumab, especially as a silver lining in dermatology
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Objetivo: Os agentes biológicos representam um grande avanço no tratamento da psoríase em placas moderada a grave. No entanto, variações de eficácia, segurança e custos dos tratamentos podem dificultar a escolha do agente terapêutico. Este estudo teve como objetivo atualizar o custo por resposta dos agentes biológicos disponíveis para psoríase no ROL de Procedimentos e Eventos em Saúde (ROL) da Agência Nacional de Saúde Suplementar (ANS). Métodos: Uma análise de custo por resposta foi utilizada para avaliar a razão de custo pelo desfecho Índice de Gravidade e Área da Psoríase (PASI) 90. Os resultados foram apresentados para o primeiro ano (ano I), que compreende a fase de indução e a fase manutenção até completar 52 semanas e foi realizada uma análise da efetividade do tratamento num cenário de orçamento fixo. Os custos dos tratamentos foram calculados com base nos preços de fábrica (PF18%) da Tabela da Câmara de Regulação do Mercado de Medicamentos de junho de 2021. Resultados: Para o ano I, o guselcumabe apresentou melhor resultado para custo por resposta (R$ 130.467) PASI 90, seguido por ixequizumabe, ustequinumabe, secuquinumabe, adalimumabe, infliximabe e etanercepte. No cenário com orçamento fixo, o guselcumabe demonstrou ser o agente capaz de tratar com sucesso (PASI 90) o maior número de pacientes. Atualização do custo-efetividade por resposta para psoríase em placas moderada a grave. Conclusão: Sob a perspectiva do Sistema de Saúde Suplementar do Brasil, o guselcumabe apresentou o melhor custo por resposta PASI 90, sendo, assim, a terapia com melhor custo-efetividade no tratamento da psoríase em placas moderada a grave disponível no ROL.
Objective: Biological agents represent a major advance in the treatment of moderate-to-severe plaque psoriasis. However, variations of efficiency, safety and costs of treatments make it difficult to select the drug. This study aims to update the cost per response of biological agents available in the Health Procedures and Events Roll (ROL) of the National Supplementary Health Agency (ANS). Methods: A cost-per-response analysis was used to assess the cost per outcome of Psoriasis Area and Severity Index (PASI) 90. Results were presented for the first year (I), which comprises induction and maintenance for 52 weeks and a fixed budget scenario analysis. Treatment costs were calculated based on the prices of the 2021 Medicines Market Regulation Chamber Table. Results: Analysis of year I, guselkumab showed the best result for cost per cost (R$ 130,467) PASI 90, followed by ixekizumab, ustekinumab, secukinumab, adalimumab, infliximab, and etanercept. In the fixedbudget analysis, guselkumab is the therapy capable of successfully treating (PASI 90) the largest number of patients. Conclusion: From the perspective of the Supplementary Health System in Brazil, guselkumab showed the best cost per response PASI 90, thus being the most cost-effective therapy in the treatment of moderate to severe plaque psoriasis available in the Brazilian ROL.
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Psoriasis , Supplemental Health , Cost-Effectiveness AnalysisABSTRACT
Objective:To evaluate clinical efficacy and safety of secukinumab in the treatment of erythrodermic psoriasis.Methods:From July 2019 to August 2021, 7 patients with erythrodermic psoriasis, who received subcutaneous injection of secukinumab at a dose of 300 mg once a week from week 0 to 4 followed by every-4-week dosing in Wuhan Hospital of Integrated Traditional Chinese and Western Medicine, were collected. At weeks 0, 4, 8 and 12, the psoriasis area and severity index (PASI) was recorded, and adverse drug reactions were observed.Results:All 7 patients were treated for at least 12 weeks. After 4-week treatment, 4 patients achieved PASI50; after 12-week treatment, 5 achieved PASI75, and 2 achieved PASI90. No serious adverse drug reactions occurred. One patient developed fever during the treatment, but the body temperature returned to normal after management; another 1 developed cough and expectoration, and the symptoms were relieved after oral administration of a Chinese herbal preparation named pharyngitis mixture.Conclusion:Secukinumab is effective in the treatment of erythrodermic psoriasis, with fewer adverse reactions, which provides a new option for the treatment of erythrodermic psoriasis.
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The appropriate dosing regimens of secukinumab for psoriatic arthritis (PsA) are not well defined. We performed a meta-analysis to evaluate the efficacy and safety of different dosing regimens of secukinumab in the treatment of PsA. A systematic search was conducted using major electronic databases to identify relevant randomized controlled trials (RCTs) comparing secukinumab 300 mg versus secukinumab 150 mg in patients with PsA. Meta-analysis was performed using Review Manager software (version 5.3). Six studies with a total of 1141 patients were included. At week 24, secukinumab 300 mg was associated with a higher American College of Rheumatology 20% response (ACR 20), ACR 50, PASI 75 response rate, and dactylitis resolution rate than secukinumab 150 mg, especially in the anti-TNF-IR subgroup. At week 52, secukinumab 300 mg was associated with a higher psoriasis area and severity index (PASI) 75 and PASI 90 response rate than secukinumab 150 mg. There was no significant difference between secukinumab 300 mg and secukinumab 150 mg in the risk of any adverse events (AEs) and serious AEs at either week 24 or week 52. Secukinumab 300 mg was significantly more effective than 150 mg, especially for patients with PsA who have failed TNF therapy, and it was well tolerated.
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Humans , Psoriasis , Arthritis, Psoriatic/drug therapy , Severity of Illness Index , Treatment Outcome , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal/adverse effectsABSTRACT
OBJECTIVE:To evaluate therapeutic e fficacy and safety of differen t doses of Secukinumab in the treatment of medium and severe ankylosing spondylitis (AS), and to provide evidence-based reference for clinical treatment of AS. METHODS: Retrieved from Medline , PubMed, Cochrane Library, Embase, VIP, CJFD, Wanfang database andpu- ClinicalTrials.gov, during the inception to March 2020, xiaofeng1205@outlook.com randomized controlled trials (RCTs)about different doses of secukinumab (75, 150, 300 mg) versus placebo in the treatment of medium and severe AS were collected. After data extraction of clinical studies met the inclusion criteria ,quality evaluation with Cochrane risk bias evaluation tool 5.1.0,Rev Man 5.3 statistical software was used for Meta-analysis of therapeutic efficacy [in the international society for the evaluation of spondyloarthritis scale ,the proportion of 20% patients improved (ASAS20);ASAS40;among 6 routine clinical areas related to AS,the scores of at least 5 areas improved by at least 20%,and there was no patients receiving treatment due to deterioration in other areas (ASAS 5/6);remission value of Bath ankylosing spondylitis disease activity index (BASDAI)from baseline to 16th week,the proportion of the patients with the international society for the evaluation of ankylosing spondyloarthritis (ASAS PR ) score no higher than 2 in the 4 ASAS fields within the specified time] and safety [the incidence of withdrawal from treatment due to ADR,the incidence of serious ADR ,the incidence of general ADR (nasopharyngitis,headache,diarrhea)]. RESULTS :A total of 5 RCTs were included ,involving 1 624 patients. Meta-analysis showed that ASAS 20 [total:OR=2.62,95%CI(2.14,3.20),P< 0.000 01;75 mg:OR=2.63,95%CI(1.28,5.40),P=0.008;150 mg:OR=2.58,95%CI(2.01,3.32),P<0.000 01;300 mg:OR=2.63,95%CI(1.37,5.06),P=0.004],ASAS40 [total:OR=2.82,95%CI(2.13,3.74),P<0.000 01;75 mg:OR= 3.14,95%CI(1.86,5.31),P<0.000 1;150 mg:OR=2.79,95%CI(1.85,4.20),P<0.000 01;300 mg:OR=2.73,95%CI (1.33,5.58),P=0.006],ASAS5/6 [total:OR=3.82,95%CI(2.61,5.59),P<0.000 01;75 mg:OR=5.59,95%CI(3.29, 9.49),P<0.000 01;150 mg:OR=3.45,95%CI(2.08,5.70),P<0.000 01;300 mg:OR=3.85,95%CI(1.75,8.47),P= 0.000 8],ASAS PR [total :OR=4.69,95%CI(3.07,7.16),P<0.000 01;75 mg:OR=5.48,95%CI(2.50,11.99),P<0.000 1; 150 mg:OR=3.71,95%CI(2.19,6.29),P<0.000 01;300 mg:OR=20.0,95%CI(2.58,155.14),P=0.004] in trial group was significantly higher than control group ;BASDAI improvement [total :WMD=-1.15,95%CI(-1.50,-0.79),P<0.000 01; 75 mg:WMD=-1.40,95%CI(-2.08,-0.72),P<0.000 1;150 mg:WMD=-1.03,95%CI(-1.52,-0.54),P< 0.000 1;300 mg:WMD=-1.20,95%CI(-2.03,-0.37),P=0.005] of trial group were significantly higher than those of control group ,with statistical significance. The total incidence of nasopharyngitis in trial group [OR =1.77,95%CI(1.22,2.57), P=0.003] and 150 mg dose subgroup [OR =1.84,95%CI(1.18,2.86),P=0.007] was significantly higher than control group , without significant difference in other safety indexes among total and different dose subgroups (P>0.05). CONCLUSIONS :75 mg,150 mg and 300 mg of secukinumab are all effective and well tolerated for medium and severe AS patients ,and 150 mg of secukinumab may increase the incidence of nasopharyngitis.
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Monoclonal antibodies (mAbs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-hIL-17A antibody. From a large naïve phage-displayed library, we isolated the anti-IL-17A mAb 7H9 that can neutralize the effects of recombinant human IL-17A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. affinity optimization was then used to generate 8D3 by using yeast-displayed random mutagenesis libraries. This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions (CDRs) of 8D3 were further grafted onto the stable framework of the huFv 4D5 to improve thermostability. The resulting hybrid antibody 9NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma cell-based assays and analyses in mice indicated that the anti-IL-17A antibody 9NT/S efficiently inhibited the secretion of IL-17A-induced proinflammatory cytokines. Therefore, this lead anti-IL-17A mAb might be used as a potential best-in-class candidate for treating IL-17A related diseases.
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BACKGROUND: Secukinumab, a fully human monoclonal antibody that targets interleukin (IL)-17A, which is a central cytokine in the pathogenesis of psoriasis, has emerged as a promising treatment for moderate to severe psoriasis. However, to date, there are no real-world data for secukinumab in Korean patients with psoriasis. OBJECTIVE: To assess the clinical efficacy and safety of secukinumab in Korean patients with psoriasis. METHODS: Prospective data were gathered during follow-up from 28 consecutive patients with chronic plaque-type psoriasis treated with secukinumab for minimum of 12 weeks at a single referral center. Patient demographics, Psoriasis Area Severity Index (PASI) score, Physicians' Global Assessment (PGA), Dermatologic Life Quality Index (DLQI), and adverse events were investigated. RESULTS: The mean PASI score was significantly decreased after the induction period of secukinumab treatment (paired t-test, p<0.05). Of the 28 patients, 17 (60.7%) had obtained near complete clearance (PASI 90) at the last follow-up visit. No unexpected adverse events, other than nasopharyngitis, were observed. CONCLUSION: Secukinumab can be of benefit for the treatment of Korean patients with psoriasis, as the treatment was associated with a rapid and satisfactory response and safety profile.
Subject(s)
Humans , Demography , Follow-Up Studies , Interleukins , Korea , Nasopharyngitis , Prospective Studies , Psoriasis , Quality of Life , Referral and Consultation , Treatment OutcomeABSTRACT
O OBJETIVO: deste estudo é avaliar o custo por resposta das terapias biológicas disponíveis no Brasil para o tratamento da psoríase em placas moderada a grave na perspectiva do Sistema de Saúde Suplementar. MÉTODOS: A resposta PASI 90 foi o desfecho avaliado neste estudo. Dados clíni-cos foram calculados com base na razão de risco de uma metanálise em rede, comparando adalimu-mabe, etanercepte, infliximabe, ixequizumabe, secuquinumabe e ustequinumabe a guselcumabe, cujo dado foi obtido no estudo clínico. Foram considerados apenas os custos de medicamentos. O caso-base avaliou o custo por resposta do ano de indução do tratamento. Além disso, conduziu-se uma análise de orçamento fixo. Em um cenário alternativo, analisou-se o custo por resposta do ano de manutenção. Uma análise de sensibilidade avaliou incertezas dos dados clínicos. RESULTADOS: O menor custo por resposta foi de guselcumabe (R$ 98.643), seguido de ixequizumabe (R$ 112.549), ustequinumabe (R$ 124.078), secuquinumabe (R$ 160.930), infliximabe (R$ 208.039), adalimumabe (R$ 208.686) e etanercepte (R$ 639.124). Resultados similares foram observados no cenário alterna-tivo, considerando os custos no ano de manutenção. Guselcumabe demonstrou ser a terapia que tratou mais pacientes com sucesso, considerando um cenário de orçamento fixo. Conclusão: O presente estudo demonstrou que, na perspectiva do Sistema de Saúde Suplementar brasileiro, gu-selcumabe possui o menor custo por resposta entre as terapias biológicas para psoríase em placas moderada a grave, além de tratar com sucesso mais pacientes em um cenário de orçamento fixo.
Objective: This study aims to evaluate the cost per response of the biologic therapies available for moderate to severe plaque psoriasis treatment in Brazil from a private payer perspective Methods: Treatment response evaluated in this study was the achievement of PASI 90. Clinical data was calculated based on the risk ratio of a network meta-analysis comparing adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab to guselkumab, which data was extracted from clinical trials. Only drug acquisition cost were considered. Base case analysis evaluated the first year of treatment cost per response Besides that, a fixed budget analysis was conducted. An alternative scenario analysis considered the maintenance year cost per response. A sensitivity analysis evaluated the clinical data uncertainties. Results: The lowest cost per response was obtained with guselkumab (R$98.643), followed by ixekizumab (R$ 112.549), ustekinumab (R$ 124.078), secukinumab (R$ 160.930), infliximab (R$ 208.039), adalimumab (R$ 208.686), and etanercept (R$ 639.124). Similar results were found in the alternative scenario, with maintenance year costs. Guselkumab demonstrated to be the therapy which successfully treats more patients with a fixed budget. Conclusion: In conclusion, this study demonstrated that, from the Brazilian private payer perspective, guselkumab presents the lowest cost per response among the avail-able biologic therapies for moderate to severe plaque psoriasis, and is able to successfully treat more patients in a limited budget scenario.
Subject(s)
Humans , Psoriasis , Biological Therapy , Costs and Cost Analysis , Supplemental HealthABSTRACT
INTRODUCCIÓN: Los tratamientos biológicos han aparecido como principal alternativa para el manejo de los pacientes con psoriasis en placa que no responden a tratamiento convencional, resultando necesario evaluar su real efectividad y seguridad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos 21 revisiones sistemáticas que en conjunto incluyeron diez estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que secukinumab logra mejoría clínica en pacientes con psoriasis en placa, aunque probablemente se asocia a efectos adversos graves.
INTRODUCTION: Biological treatments have appeared as the main alternative for the management of patients with plaque psoriasis that do not respond to conventional treatment. So, evaluating its actual efficacy and safety is needed. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified 21 systematic reviews including ten studies overall, of which all were randomized trials. We concluded secukinumab achieves clinical improvement in patients with plaque psoriasis, although it is probably associated with serious adverse effects.
Subject(s)
Humans , Psoriasis/drug therapy , Dermatologic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Psoriasis/pathology , Randomized Controlled Trials as Topic , Databases, Factual , Treatment Outcome , Dermatologic Agents/adverse effects , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal/adverse effectsABSTRACT
OBJECTIVE: This study assessed the efficacy and safety of secukinumab and adalimumab in patients with active ankylosing spondylitis (AS). METHODS: A Bayesian network meta-analysis was performed with direct and indirect data collected from randomized controlled trials (RCTs) of efficacy and safety of secukinumab 75 mg, 150 mg and adalimumab 40 mg in patients with active AS. RESULTS: Five RCTs (1,483 patients) met the inclusion criteria. The Assessment in Spondyloarthritis International Society response criteria of ≥20% (ASAS20) response rate was significantly higher in the adalimumab 40 mg (Odds ratio [OR], 4.26; 95% credible interval [CrI], 2.09~8.08), secukinumab 150 mg (OR, 3.35; 95% CrI, 1.73~6.56), and 75 mg dose (OR, 2.44; 95% CrI, 1.06~5.05) than with placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that adalimumab 40 mg had the highest probability of being the best treatment for achieving an ASAS20 response (SUCRA=0.8753), followed by secukinumab 150 mg (SUCRA=0.7051), secukinumab 75 mg (SUCRA=0.4113), and placebo (SUCRA=0.0083). The ASAS40 response rate distribution pattern was similar to the ASAS20 response rate. However, the number of serious adverse events did not differ significantly among the treatment options. CONCLUSION: Secukinumab and adalimumab were effective for the treatment of active AS without causing a significant risk of serious adverse events.
Subject(s)
Humans , Adalimumab , Spondylitis, AnkylosingABSTRACT
Th17 cells, a CD4+ T‑cell subset, produce interleukin (IL)‑17, a pro‑inflammatory cytokine that has been shown to be involved in several forms of infectious and noninfectious uveitis. Here, we explore the roles of this IL in uveitic disorders as well as in experimental autoimmune uveitis, the possible pathogenic implications of several cytokines associated with IL‑17 and analyze the current outcomes and goals for drugs aiming for the IL‑17 pathway.