Psoriasis and the new biologic agents: interrupting a T-AP dance.
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ABSTRACT:
SUBMITTER: Walsh SR
PROVIDER: S-EPMC421723 | biostudies-literature | 2004 Jun
REPOSITORIES: biostudies-literature
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Psoriasis and the new biologic agents: interrupting a T-AP dance.
Walsh Scott R A SR Shear Neil H NH
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20040601 13
Psoriasis is an immune-mediated skin disease in which chronic T-cell stimulation by antigen-presenting cells (APC) occurs in the skin. This interplay between the T-cell and APC has been likened to a "T-AP dance" where specific steps must occur in sequence to result in T-cell activation and the disease phenotype; otherwise T-cell anergy would occur. Several novel engineered proteins designed to block specific steps in immune activation (biologic agents) have demonstrated efficacy in the treatment ...[more]
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Project description:Psoriasis is a chronic inflammatory skin disorder, which is associated with a significant negative impact on a patient's quality of life. Traditional therapies for psoriasis are often not able to meet desired treatment goals, and high-dose and/or long-term use is associated with toxicities that can result in end-organ damage. An improved understanding of the involvement of cytokines in the etiology of psoriasis has led to the development of biologic agents targeting tumor necrosis factor (TNF)-? and interleukins (ILs)-12/23. While biologic agents have improved treatment outcomes, they are not effective in all individuals with psoriasis. The combination of biologic agents with traditional therapies may provide improved therapeutic options for patients who inadequately respond to a single drug or when efficacy may be increased with supplementation of another treatment. In addition, combination therapy may reduce safety concerns and cumulative toxicity, as lower doses of individual agents may be efficacious when used together. This article reviews the current evidence available on the efficacy and safety of combining biologic agents with systemic therapies (methotrexate, cyclosporine, or retinoids) or with phototherapy, and the combination of biologic agents themselves. Guidance is provided to help physicians identify situations and the characteristics of patients who would benefit from combination therapy with a biologic agent. Finally, the potential clinical impact of biologic therapies in development (e.g., those targeting IL-17A, IL-17RA, or IL-23 alone) is analyzed.
| S-EPMC4239825 | biostudies-other
Project description:ImportanceFew studies have compared the use of methotrexate and biologics, the most commonly used systemic medications for treatment of moderate to severe psoriasis in children.ObjectiveTo assess the real-world, 6-month reduction in psoriasis severity and long-term drug survival (rate and duration of adherence to a specific drug) of methotrexate vs biologics in plaque psoriasis in children.Design, setting, and participantsA retrospective medical records review was conducted at 20 European and North American centers. Treatment response was based on site-reported Psoriasis Area and Severity Index (PASI) and/or Physician Global Assessment (PGA) scores at baseline and within the first 6 months of treatment. Participants included all 234 consecutively seen children with moderate to severe psoriasis who received at least 3 months of methotrexate or biologics from December 1, 1990, to September 16, 2014, with sufficient data for analysis. Data analysis was performed from December 14, 2015, to September 1, 2016.Main outcomes and measuresPASI, with a range from 0 to 72 (highest score indicating severe psoriasis), and/or PGA, with a scale of 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), and 5 (very severe).ResultsOf 234 pediatric patients (103 boys [44.0%]; 131 girls [56.0%]) treated with methotrexate and/or biologics, 163 patients (69.7%) exclusively received methotrexate, 47 patients (20.1%) exclusively received biologics, and 24 children (10.2%) received methotrexate and biologics sequentially. Of the latter cohort, 23 children were treated initially with methotrexate. Mean (SD) age at initiation was 11.6 (3.7) years for methotrexate and 13.3 (2.9) years for biologics (73.2% for etanercept) (P = .002). Among patients evaluated by a scoring method at 6-month follow-up, 75% or greater improvement in PASI (PASI75) was achieved in 12 of 30 patients (40.0%) receiving methotrexate and 20 of 28 patients (71.4%) receiving biologics, and PGA was clear/almost clear (PGA 0/1) in 41 of 115 patients (35.6%) receiving methotrexate and 18 of 37 patients (48.6%) receiving biologics. Achieving PASI75 and/or PGA 0/1 between baseline and 6 months was more likely with biologics than methotrexate (PASI75: odds ratio [OR], 4.56; 95% CI, 2.02-10.27; P < .001; and PGA 0/1: OR, 2.00; 95% CI, 0.98-4.00; P = .06). Decreased mean PASI and PGA scores were associated with biologics more than with methotrexate (PASI effect, -3.13; 95% CI, -4.33 to -1.94; P < .001; and PGA effect, -0.31; 95% CI, -0.56 to -0.06; P = .02). After 1, 3, and 5 years of use, overall drug survival rates for methotrexate were 77.5%, 50.3%, and 35.9%, and for biologics, the rates were 83.4%, 64.3%, and 57.1%, respectively. Biologics were associated with a better confounder-corrected drug survival than methotrexate (hazard ratio [HR], 2.23; 95% CI, 1.21-4.10; P = .01). Discontinuation owing to lack of response was comparable (HR, 1.64; 95% CI, 0.80-3.36; P = .18).Conclusions and relevanceMethotrexate and biologics appear to be associated with improvement in pediatric psoriasis, although biologics seem to be associated with greater reduction in psoriasis severity scores and higher drug survival rates than methotrexate in the real-world setting. Additional studies directly comparing these medications should be performed for confirmation.
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Project description:Background and objectives: Psoriasis is a chronic immune-mediated skin disease caused by several complex factors, both environmental and genetic, many of which are still not fully understood. Nowadays, several groups of biological drugs are being used for psoriasis treatment. Although these therapies are very effective, they show significant variability in efficacy among individuals. Therefore, there is a need for biomarkers to predict treatment outcomes in order to guide personalized therapeutic decisions. Pharmacogenetics is the study of variations in DNA sequences related to drug response. Materials and Methods: In this article, we review pharmacogenetics studies on the treatment of moderate-to-severe psoriasis focusing on anti-interleukin (IL) 12/23 (ustekinumab) and anti-IL17 drugs (secukinumab and ixekizumab), as well as recent studies concerning anti-TNF drugs. Results: Several polymorphisms have been studied over the years in reference to anti-TNF drugs; some of the most recent studies included the performance of a genome-wide association study (GWAS) and pharmacogenetics studies focused on the optimization of a treatment regimen. Various polymorphisms in different genes have been related to ustekinumab response; among them, the most commonly studied is the HLA-C*06:02 allele. Conclusions: Although not confirmed in some studies, most studies have shown that patients carrying this allele present a significantly higher response rate to ustekinumab. Some polymorphisms have been studied in patients treated with anti-IL17 drugs, mostly related to secukinumab; however, up to now, no association has been found between any of these polymorphisms and response. Nevertheless, further studies involving larger cohorts are needed in order to confirm these results before the implementation of this biomarker in clinical practice.
| S-EPMC7766592 | biostudies-literature
Project description:Psoriasis is a chronic and debilitating inflammatory immune-mediated skin disorder. Several cytokines including interleukin (IL)-23 were demonstrated to play a central role in the pathogenesis of this disease. Treatment options for psoriasis range from topical to systemic modalities, depending on the extent, anatomical locations involved and functional impairment level. Targeting cytokines or their cognate receptors that are involved in disease pathogenesis such as IL-12/23 (i.e., targeting the IL-12p40 subunit shared by these cytokines), IL-17A, IL-17F, IL-17RA, and TNF-α using biologic agents emerged in recent years as a highly effective therapeutic option for patients with moderate-to-severe disease. This review provides an overview of the important role of IL-23 signaling in the pathogenesis of psoriasis. We describe in detail the available IL-23 inhibitors for chronic plaque psoriasis. The efficacy, pharmacokinetic properties, and the safety profile of one of the most recent IL-23 biologic agents (tildrakizumab) are evaluated and reviewed in depth.
| S-EPMC8383205 | biostudies-literature
Project description:BackgroundThe risk of developing cutaneous T cell lymphoma (CTCL) in patients using psoriasis biologics has not been well characterized. The goals of this review were to investigate the incidence of CTCL in patients with psoriasis receiving biologic therapy in clinical trials and psoriasis registries, and to review cases of CTCL and biologic use reported in scientific publications.MethodsThe US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. The incidence of CTCL in these trials was examined and summarized. To examine the incidence of CTCL in psoriasis registries, a Medline search was conducted. Finally, we performed a systematic review of CTCL cases reported in the literature.ResultsOnly two cases of CTCL were reported in 35,801 subjects with psoriasis receiving a biologic agent in the active arm of 108 psoriasis phase 3 clinical trials. One of these CTCL cases was determined by the investigator to be CTCL misdiagnosed as psoriasis prior to randomization. No cases of CTCL were reported in 5440 subjects with psoriasis in 34 phase 4 clinical trials. Only one case of CTCL was identified in 34,111 registry subjects. In the literature, tumor necrosis factor (TNF) inhibitors had the highest number of reported cases of CTCL (34 cases), followed by interleukin (IL)-17 inhibitors (7 cases), and IL-12/23 inhibitors (6 cases). No cases of CTCL were found to be reported with IL-23 inhibitors.ConclusionOur findings indicate that the development of CTCL is rare in the setting of psoriasis biologic use. Of the limited number of cases of CTCL found, most were in the setting of TNF inhibitor use and no cases of CTCL were reported in the setting of IL-23 inhibitor use.
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Project description:Drug survival studies have been utilized to evaluate the real-world effectiveness of biologics used in psoriasis. However, the increasing volume of drug survival data suffers from large variability due to regional differences in drug availability, patient selection and biologic reimbursement. The objective of this study was to conduct a meta-analysis of biologic drug survival to determine comparative effectiveness of the biologics in a real-world setting. Studies reporting drug survival for biologic therapy in psoriasis were identified by a systematic literature search. Hazard ratio data for drug discontinuation were estimated directly from published Kaplan-Meier estimator curves at year 1, 2, and 5 of treatment and compared pairwise for the following biologics: ustekinumab, adalimumab, etanercept, infliximab, secukinumab, and ixekizumab. This pooled hazard ratios were used to estimate 2- and 5-year overall drug survival rates. Ustekinumab had the longest persistence at 2 and 5 years among all biologics included in this meta-analysis. Adalimumab was superior to etanercept and infliximab at 5 years. Pooled 5-year drug survival rates for adalimumab, etanercept, and infliximab were 46.3, 35.9, and 34.7%, respectively. Two- and five-year data were not available for anti-IL-17 drugs, but at 1-year ustekinumab outperformed secukinumab, the latter being equal to anti-TNFs. In conclusion, ustekinumab is characterized by longer drug survival than TNF inhibitors and IL-17 inhibitors. Estimated pooled 2- and 5-year drug survival rates may serve as a useful tool for patient communication and clinical decision-making.
| S-EPMC8012481 | biostudies-literature
Project description:As biologic therapies become first line treatments for many inflammatory disorders, it becomes increasingly important for the practicing physician to be familiar with how these drugs function at the molecular level. This information is useful in making therapeutic decisions and helping patients understand their treatment options. It is critical to patient safety and clinical response that the molecular differences between these drugs inform prescribing practices. To this end, we present and analyze the available structural biology information about the biologics used in the treatment of psoriasis including inhibitors of tumor necrosis factor alpha (TNF?), interleukin-17 (IL-17), and interleukin-23 (IL-23). We describe and analyze the molecular surface character of known binding epitopes for medications in these classes, showing that significant differences exist in epitope location, hydrophobicity, and charge. Some of these differences can be correlated with clinical data, but our analysis ultimately points to the need for more structural information to allow for a better understanding of the structure-function relationship of biologic therapies.
| S-EPMC7087057 | biostudies-literature
Project description:IntroductionBiologic treatments for psoriasis are commonly switched. Treatment persistence represents an important parameter related to long-term therapeutic performance. The objective of the study was to analyse the real-world persistence with biologics over time in the treatment of psoriasis.MethodsA retrospective observational study of adults with psoriasis was conducted based on Swedish national registry data from 2010 to 2018. Patients included were treated with a biologic between 2010 and 2018. Treatment episodes were identified from the drug's date of dispensation recorded in the Prescribed Drug Register to the end of supply of the drug. Median persistence was estimated by Kaplan-Meier survival curves for patients who received adalimumab, etanercept, secukinumab, ustekinumab and ixekizumab. Descriptive analysis of change in persistence over time for 3-year running cohorts was also carried out.ResultsA total of 2292 patients were analysed. Patients who received ustekinumab had the longest median persistence [49.3 months, 95% confidence interval (CI) 38.0-59.1] and etanercept the shortest (16.3 months, 95% CI 14.5-19.0). Median persistence was longer in biologic-naive than biologic-exposed patients. Persistence for ustekinumab decreased by almost 50% over the study period, from a median of 62.3 (95% CI 45.6-∞) months in 2010-2011 to 32.7 (21.2-49.3) months in 2014-2016.ConclusionsPersistence with biologics was, on average, relatively low, given the chronic nature of psoriasis. Changes in persistence over time seemed to be attributable to changes in the therapeutic landscape, providing patients with more options to switch biologic treatments if their current management was considered suboptimal.
| S-EPMC8611161 | biostudies-literature
Project description:IntroductionReal-world data are limited comparing Asian and White patients with psoriasis using biologic therapy. This study compared the 6-month effectiveness of biologic therapy between Asian and White plaque patients with psoriasis in the CorEvitas Psoriasis Registry.MethodsAnalyses included biologic initiations and 6-month follow-up visits from self-identified Asian (n = 293) and White (n = 2314) patients in the USA/Canada (4/2015-4/2020). Outcomes included: Psoriasis Area Severity Index (PASI) 75, disease activity measures [body surface area (BSA) ≤ 1, BSA ≤ 3, PASI90, PASI100, Investigator's Global Assessment (IGA) 0/1], and patient-reported outcomes [Dermatology Life Quality Index (DLQI) 0/1, itch, fatigue, skin pain, EuroQoL visual analog scale (EQ-VAS), patient global assessment, Work Productivity Activity and Impairment (WPAI) domains]. Unadjusted regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for achievement of binary outcomes and difference in mean change in continuous outcomes (β, 95% CI) at 6 months, followed by adjustment for age, sex, body mass index, alcohol, smoking, health insurance, education, comorbidities, scalp psoriasis morphology, psoriatic arthritis, biologic class, previous biologics, and baseline outcome value.ResultsAsians had lower proportions of women (32.8% versus 49.1%) and obesity (27.3% versus 54.5%), and higher proportions on Medicaid (19.9% versus 8.8%), graduated college (50.9% versus 40.1%) and never smoked (67.1% versus 44.1%). In unadjusted analyses, Asians had 52% higher odds of achieving PASI75 versus White patients (OR 1.52; 95% CI 1.15, 2.02). After adjustment, the association was attenuated (OR 1.11; 0.81, 1.52). Secondary outcomes experienced similar patterns except for DLQI: Asians had 33% lower odds of achieving DLQI 0/1 in both the unadjusted (OR 0.67; 0.50, 0.90) and adjusted (OR 0.67; 0.49, 0.92) models.ConclusionUnadjusted differences in biologic therapy effectiveness between Asians compared with White patients were likely explained by differences in demographic, lifestyle, and psoriatic disease characteristics between groups. However, Asians still experienced lesser improvements in skin-related quality of life, even after adjustment.
| S-EPMC9823174 | biostudies-literature