Limited clinical utility of HLA-Cw6 genotyping for outcome prediction in psoriasis patients under ustekinumab therapy: a monocentric, retrospective analysis.
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ABSTRACT:
SUBMITTER: Anzengruber F
PROVIDER: S-EPMC5919162 | biostudies-other | 2017
REPOSITORIES: biostudies-other
Publications
Limited clinical utility of HLA-Cw6 genotyping for outcome prediction in psoriasis patients under ustekinumab therapy: a monocentric, retrospective analysis.
Anzengruber Florian F Ghosh Adhideb A Maul Julia-Tatjana JT Drach Mathias M Navarini Alexander A AA
Psoriasis (Auckland, N.Z.) 20170101
<h4>Purpose</h4>Several studies have suggested that an HLA-Cw6+ allele can predict an improved outcome of treatment in psoriasis patients. The aim of the study was to assess whether the published association between HLA-Cw6 allele carriers and response to ustekinumab has the potential to impact treatment decisions.<h4>Patients and methods</h4>Differences in Psoriasis Activity and Severity Index 50, 75, and 90; Nail Psoriasis Severity Index; and Dermatology Life Quality Index at 16 weeks were eva ...[more]
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Project description:The introduction of anti-tumor necrosis factor (TNF) therapy marked an important milestone in the management of moderate-to-severe Crohn's disease (CD). However, there remains a pressing demand for alternative therapeutic options for patients with primary nonresponse, secondary loss of response, or intolerable side effects to conventional treatment and TNF antagonists. Ustekinumab (UST) is a fully human IgG1? monoclonal antibody that inhibits the p40 subunit shared by the proinflammatory cytokines, the interleukin (IL)-12 and -23. This blockade leads to dampening of the inflammatory cascade and differentiation of inflammatory T cells. The clinical development program for UST in CD includes dose finding Phase II (Crohn's Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction [CERTIFI]) and the pivotal Phase III (UNITI) trials that demonstrated both the clinical efficacy and safety in anti-TNF-naive and anti-TNF-exposed patients. Real-world evidence has further defined the role of UST in CD management. In this review, we discuss the mechanism of action of UST, describe the results of the randomized controlled trials with this agent, and review the real-world efficacy and safety data from observational cohorts. Finally, we identify areas of future research in the IL-12/23 inflammatory pathway and discuss the positioning of this novel therapeutic option in CD treatment algorithms.
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Project description:PurposeTo determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS.Experimental designPatients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1-specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility.ResultsA total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995-3.813; P = 0.052]. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting.ConclusionsTargeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.
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Project description:Biologics have revolutionized the therapy of the psoriatic disease spectrum. These new classes of drugs also allow deeper insight into the pathogenesis of the disease and highlight the existence of distinct "molecular" disease subgroups as evidenced by the spectrum of clinical response seen. Molecules associated with both the interleukin (IL)-17 and interferon (IFN)? pathways have important functions in psoriatic inflammation, and both are targeted by drugs acting on the p40 subunit shared by IL-12 and IL-23. These IL-12 family members are upstream of pathways characterized by the production of IFN? and IL-17 related molecules, including IL-17, IL-22, and CCL20. We here summarize the mode of action and clinical studies of the p40 inhibitor ustekinumab with focus on both psoriasis and psoriatic arthritis.
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Project description:ImportancePrevious research showed a differential response to ustekinumab therapy based on HLA-C*06:02 status in patients with psoriasis but consisted mostly of small (and sometimes inconclusive) cohort studies.ObjectiveTo assess whether HLA-C*06:02 status is associated with a differential response to ustekinumab therapy in patients with psoriasis through a systematic review and a meta-analysis of available data.Data sourcesA comprehensive search was conducted using MEDLINE, Embase, the Cochrane Library, Web of Science, and gray literature sources. Databases were searched from January 1, 2000, to May 14, 2018. Search strategies included terms and synonyms for psoriasis, HLA-C, and ustekinumab. Languages were restricted to English, French, German, and Dutch.Study selectionStudies were included if they reported the association between HLA-C*06:02 status and 75% improvement in Psoriasis Area and Severity Index (PASI75) response to ustekinumab therapy in patients with plaque psoriasis after 6 and/or 3 months of treatment. Randomized clinical trials and observational studies were included. Screening and selection were performed independently by 2 reviewers.Data extraction and synthesisHLA-C*06:02 genotype status and PASI75 response rates were extracted by 2 reviewers. Data were pooled using random-effects models. Heterogeneity was assessed using the τ2 and I2 statistic. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed.Main outcome and measureThe primary outcome was the risk difference of achieving PASI75 after 6 months of ustekinumab therapy between HLA-C*06:02-positive and HLA-C*06:02-negative patients.ResultsA total of 8 studies were reviewed; 1048 patients were included for meta-analyses, and 937 patients were included for the primary analysis of PASI75 response after 6 months of treatment. Random-effects meta-analysis showed a risk difference of 0.24 (95% CI, 0.14-0.35; P < .001) in favor of HLA-C*06:02-positive patients. The median PASI75 response rate in the HLA-C*06:02-positive group was 92% (pooled, 89%; range, 62%-98%). For HLA-C*06:02-negative patients, the median response rate was 67% (pooled, 62%; range, 40%-84%). Substantial heterogeneity may have been present, with an I2 of 82%.Conclusions and relevanceThe meta-analysis showed a differential response to ustekinumab therapy based on HLA-C*06:02 status in patients with psoriasis. Although HLA-C*06:02-positive patients had high PASI75 response rates after 6 months, the PASI75 response rate was also high in the HLA-C*06:02-negative group. There appears to be no rationale for excluding patients from ustekinumab treatment based on a negative HLA-C*06:02 status.
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Project description:ImportanceHigh-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab.ObjectiveTo evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis.Design, setting, and participantsA prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria.ExposureSerum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay.Main outcomes and measuresDisease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less.ResultsA total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5).Conclusions and relevanceThis real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.
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