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• W3003571612 abstract "HLA-C*06:02 is the genetic variant that affords the highest susceptibility for psoriasis, increasing the odds for the disease approximately five times (Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 et al., 2010Strange A. Capon F. Spencer C.C. Knight J. Weale M.E. et al.Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.Nat Genet. 2010; 42: 985-990Crossref PubMed Scopus (791) Google Scholar). Its effect may be modified by a number of factors, including smoking (Jin et al., 2009Jin Y. Yang S. Zhang F. Kong Y. Xiao F. Hou Y. et al.Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: a hospital-based case–control study in China.J Eur Acad Dermatol Venereol. 2009; 23: 132-137Crossref PubMed Scopus (49) Google Scholar). Predictors for response to biologic treatment in psoriasis has been deemed a research priority (Majeed-Ariss et al., 2019Majeed-Ariss R. McPhee M. McAteer H. Griffiths C.E.M. Young H. The top ten research priorities for psoriasis in the UK; results of a James Lind Alliance psoriasis priority setting partnership.Br J Dermatol. 2019; 181: 871-873Crossref PubMed Scopus (12) Google Scholar), and a recent meta-analysis found that HLA-C*06:02 was associated with differential response to ustekinumab, albeit with substantial unexplained heterogeneity (van Vugt et al., 2019van Vugt L.J. van den Reek J.M.P.A. Hannink G. Coenen M.J.H. de Jong E.M.G.J. Association of HLA-C*06:02 status with differential response to ustekinumab in patients with psoriasis: a systematic review and meta-analysis.JAMA Dermatol. 2019; 155: 708-715Crossref PubMed Scopus (21) Google Scholar). Given the observed heterogeneity and the interaction between HLA-C*06:02 and smoking on the susceptibility of psoriasis (Jin et al., 2009Jin Y. Yang S. Zhang F. Kong Y. Xiao F. Hou Y. et al.Combined effects of HLA-Cw6 and cigarette smoking in psoriasis vulgaris: a hospital-based case–control study in China.J Eur Acad Dermatol Venereol. 2009; 23: 132-137Crossref PubMed Scopus (49) Google Scholar), we sought to determine if smoking modifies the effect of this genotype on the response to ustekinumab using Swedish registry data. DermaReg is a register collecting data on patients treated with systemics for psoriasis in Stockholm, Sweden (Svedbom and Ståhle, 2019Svedbom A. Ståhle M. Real-world comparative effectiveness of adalimumab, etanercept, and methotrexate: a Swedish register analysis [e-pub ahead of print].J Eur Acad Dermatol Venereol. 2019; (accessed February 19, 2020)https://doi.org/10.1111/jdv.15978Crossref PubMed Scopus (7) Google Scholar). In brief, all patients provide a blood sample and background information at enrollment. Thereafter patients were followed-up prospectively. Data on treatment and clinical outcomes, including PASI, are registered at regular appointments during clinical practice. Genomic DNA was extracted from peripheral blood by standard procedures and HLA-C*06:02 typing was performed as described previously (Nikamo and Ståhle, 2012Nikamo P. Ståhle M. Cost-effective HLA-Cw06: 02 typing in a Caucasian population.Exp Dermatol. 2012; 21: 221-223Crossref PubMed Scopus (13) Google Scholar). Smoking status was reported by patients. Start and end dates of treatment, including reasons for discontinuation, were registered by the treating physician at clinical visits. In chronic symptomatic diseases such as psoriasis, drug survival is a valid marker for real-world effectiveness (Van Den Reek et al., 2015Van Den Reek J.M.P.A. Kievit W. Gniadecki R. Goeman J.J. Zweegers J. Van De Kerkhof P.C.M. et al.Drug survival studies in dermatology: principles, purposes, and pitfalls.J Invest Dermatol. 2015; 135: 1-5Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Drug survival was evaluated in a time-to-event framework. Patients were considered to fail if treatment was discontinued but were censored if the discontinuation was due to remission or reported as being temporary. Patients were also censored 180 days after the latest registered clinic visit, 2 years after treatment initiation, or the date of data extraction (August 27, 2018), whichever came first. Furthermore, we estimated mean PASI during maintenance treatment, defined as treatment from 12 weeks (84 days) after treatment start until patients were no longer on treatment, according to the aforementioned definitions. Drug survival was estimated using the Kaplan-Meier Product Limit Estimator with the Wilcoxon test implemented for comparisons between groups. Cox proportional hazard models were fit to derive estimates of multiplicative and additive interactions between HLA-C*06:02 and smoking, and formal interaction analysis was reported according to recommendations for epidemiologic studies (Knol and VanderWeele, 2012Knol M.J. VanderWeele T.J. Recommendations for presenting analyses of effect modification and interaction.Int J Epidemiol. 2012; 41: 514-520Crossref PubMed Scopus (617) Google Scholar). Firth type penalization (Firth, 1993Firth D. Bias reduction of maximum likelihood estimates.Biometrika. 1993; 80: 27-38Crossref Scopus (2532) Google Scholar) was implemented in the Cox model given the limited number of events in strata. Furthermore, we estimated the interaction between HLA-C*06:02 and smoking on PASI during maintenance treatment using regression models with random intercepts and robust standard errors (StataCorp, 2013StataCorp L.P. Stata multilevel mixed-effects reference manual. StataCorp LP, College Station, TX2013Google Scholar). Interaction on the additive scale was estimated by fitting a linear model, and interaction on the multiplicative scale was estimated by fitting a mixed model with a log-link. All models included main effects of smoking and HLA-C*06:02, along with an interaction term for the two covariates. The discriminative ability of HLA-C*06:02 and smoking in terms of drug survival to ustekinumab was assessed using bootstrapped c-indices (100 replications) excluding ties on predictor groups 2 years after treatment start. Analyses were conducted in SAS version 9.2 (SAS institute, Cary, NC), STATA version 14.1 (StataCorp LLC, College Station, TX), and R version 3.4.2 (R Core Team, Vienna, Austria). The study was approved by the regional Stockholm Ethics Committee and performed according to the Declaration of Helsinki Principles. Written informed consent was obtained from all participants before enrollment. Given that the data related to this article contain potentially patient identifiable information, in compliance with Swedish law, the datasets related to this article can be obtained from the registry holder (Karolinska University Hospital) upon approval from the Swedish Ethical Review Authority and the registry holder. Among the 167 patients treated with ustekinumab between 2009 and 2019, 45 (27%) were smokers and 61 (37%) were HLA-C*06:02–positive; 23 patients (14%) were both smokers and HLA-C*06:02–positive, whereas 84 patients (50%) were neither. During maintenance treatment, 426 PASI scores were registered (minimum 1; maximum 9; and mean 3 per patient). Patient characteristics are presented in Supplementary Table S1. There was no statistically significant difference in drug survival between HLA-C*06:02–positive and HLA-C*06:02–negative patients (P = 0.11) nor between smokers and nonsmokers (P = 0.55) (Figure 1a and b). When the impact of HLA-C*06:02 on drug survival was stratified by smoking, the genotype was associated with decreased drug survival in smokers (P < 0.001) but not in nonsmokers (P = 0.71) (Figure 1c and d). Drug survival for the four combinations between smoking and HLA-C*06:02 are provided in Supplementary Figure S1. The interaction analysis (Table 1) indicated a positive interaction on both the multiplicative (hazard ratio [HR] 9.4, 95% confidence interval [CI] 2.0–44.4) and the additive scales (2.1, 95% CI 0.6–3.5) for HLA-C*06:02 and smoking.Table 1Interaction between HLA-C*06:02 and Smoking on Drug Survival and Maintenance PASI in Patients Treated with UstekinumabPatientsHLA-C*06:02−HLA-C*06:02+HLA-C*06:02− vs. HLA-C*06:02+ by smokingDrug survivalHazard ratio (95% CI)Hazard ratio (95% CI)Hazard ratio (95% CI)Nonsmokers1.4 (0.5–3.8)2.6 (0.7–9.3)0.8 (0.4–1.7)Smoker7.4 (1.7–29.0)1.0 (ref)7.7 (1.9–30.8)Maintenance PASIBeta coefficient (95% CI)Beta coefficient (95% CI)Beta coefficient (95% CI)Nonsmokers1.5 (0.2–3.0)1.1 (−0.6 to 2.9)0.4 (−1.4 to 2.1)Smoker3.7 (0.5–6.9)0 (ref)3.7 (0.5–6.9)Abbreviation: CI, confidence interval.The second and third columns present effect estimates and associated 95% confidence limits versus the reference groups. The fourth column presents impact of HLA*06:02–negative status on drug survival and PASI stratified by smoking. For drug survival, measures of the interaction between smoking and HLA-C*06:02 on the additive scale and multiplicative scales were 2.1 (95% CI 0.6–3.5) and 9.4 (95% CI 2.0–44.4), respectively. For maintenance PASI, measures of the interaction between smoking and HLA-C*06:02 on the additive scale and multiplicative scales were 4.2 (95% CI 0.1–8.3) and 3.0 (95% CI 1.5–5.9), respectively. Open table in a new tab Abbreviation: CI, confidence interval. The second and third columns present effect estimates and associated 95% confidence limits versus the reference groups. The fourth column presents impact of HLA*06:02–negative status on drug survival and PASI stratified by smoking. For drug survival, measures of the interaction between smoking and HLA-C*06:02 on the additive scale and multiplicative scales were 2.1 (95% CI 0.6–3.5) and 9.4 (95% CI 2.0–44.4), respectively. For maintenance PASI, measures of the interaction between smoking and HLA-C*06:02 on the additive scale and multiplicative scales were 4.2 (95% CI 0.1–8.3) and 3.0 (95% CI 1.5–5.9), respectively. The bootstrap adjusted c-index for the model including the combination of HLA-C*06:02 status and smoking was estimated at 0.724. HLA-C*06:02–negative patients had nonsignificantly higher mean PASI during maintenance treatment compared with patients positive for HLA-C*06:02 (1.4, 95% CI −0.1 to 2.8), whereas no significant difference was observed for smoking (0.4, 95% CI −1.6 to 2.3). The additive interaction derived from the linear model between HLA-C*06:02 and smoking was statistically significant (4.2, 95% CI 0.1–8.3) and was also present on the multiplicative scale (3.0, 95% CI 1.5–5.9). This study indicates the existence of a previously unknown interaction between HLA-C*06:02 and smoking on the response to ustekinumab. This interaction may explain the heterogeneity of the association between HLA-C*06:02 and response to ustekinumab noted in a recent systematic review and meta-analysis (van Vugt et al., 2019van Vugt L.J. van den Reek J.M.P.A. Hannink G. Coenen M.J.H. de Jong E.M.G.J. Association of HLA-C*06:02 status with differential response to ustekinumab in patients with psoriasis: a systematic review and meta-analysis.JAMA Dermatol. 2019; 155: 708-715Crossref PubMed Scopus (21) Google Scholar). The interaction appears to be clinically meaningful. The c-index for a comparison between HLA-C*06:02–negative smokers versus remaining patients in terms of drug survival indicated good discriminatory power, and the point estimate of the interaction term between smoking and HLA-C*06:02 on maintenance PASI exceeded the minimally clinically important difference for PASI estimated at 3.2 (Mattei et al., 2014Mattei P.L. Corey K.C. Kimball A.B. Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI): the correlation between disease severity and psychological burden in patients treated with biological therapies.J Eur Acad Dermatol Venereol. 2014; 28: 333-337Crossref PubMed Scopus (165) Google Scholar). The biological function of HLA-C*06:02 in psoriasis is not well understood (van Vugt et al., 2019van Vugt L.J. van den Reek J.M.P.A. Hannink G. Coenen M.J.H. de Jong E.M.G.J. Association of HLA-C*06:02 status with differential response to ustekinumab in patients with psoriasis: a systematic review and meta-analysis.JAMA Dermatol. 2019; 155: 708-715Crossref PubMed Scopus (21) Google Scholar), and smoking may affect a number of physiological mechanisms that can impact psoriasis (Naldi, 2016Naldi L. Psoriasis and smoking: links and risks.Psoriasis (Auckland, NZ). 2016; 6: 65-71PubMed Google Scholar). Therefore, the biological basis for the observed interaction on the response to ustekinumab is difficult to elucidate. A number of limitations with the study may be noted. First, the study is of limited size and a larger number of patients would have been preferable. Second, response assessment is not ideal; drug survival comprises other aspects than effectiveness, and PASI was not registered at set intervals in the same manner as in a protocol-driven trial. Third, there may be residual confounding; for example, disease severity before treatment initiation may differ systematically between the smoking and HLA-C*06:02 strata. Furthermore, the study was conducted in Sweden; therefore, the findings may be difficult to generalize to other populations. In conclusion, this study reveals a previously unknown interaction between HLA-C*06:02 and smoking on the response to ustekinumab. The interaction appears to be clinically meaningful and has the potential to improve decision making in clinical practice. However, it is important to validate this interaction in larger cohorts. Axel Svedbom: https://orcid.org/0000-0003-2596-1679 Pernilla Nikamo: https://orcid.org/0000-0001-5028-7466 Mona Ståhle: https://orcid.org/0000-0002-3916-9343 AS is an employee of ICON plc, a contract research organization. MS has received honoraria for serving as an advisor and for participating in symposia arranged by Abbvie, Novartis, Pfizer, Eli Lilly, and Janssen-Cilag. The authors thank the individuals who volunteered to participate in Dermareg. The authors would also like to thank Helena Griehsel and Maria Lundqvist for data collection and registry administration. This study was funded by Stockholm County Council, the Swedish Medical Research Council, Hudfonden, and the Swedish Psoriasis Association. Financial support for administrative costs to develop and maintain the registry is acknowledged from Janssen-Cilag, Abbvie, Novartis, and Eli Lilly. The funders had no role in the study design, data collection, data analysis, data interpretation, drafting of the manuscript, or the decision to submit the manuscript for publication. Conceptualization: MS, AS; Data Curation: AS, MS, PN; Formal Analysis: AS, MS, PN; Funding Acquisition: MS; Investigation: MS; Methodology: AS, MS, PN; Project Administration: MS, AS; Resources: MS, AS; Software: AS, MS; Supervision: MS; Validation: AS, MS; Visualization: AS, MS, PN; Writing - Original Draft Preparation: AS, MS; Writing - Review and Editing: AS, MS, PN Supplementary Table S1Patient Characteristic by HLA-C*06:02 and Smoking in Patients Starting Treatment with UstekinumabCharacteristicsHLA-C*06:02+ smokersHLA-C*06:02+ nonsmokersHLA-C*06:02− nonsmokersHLA-C*06:02− smokersP-valuePatients23388422Age, mean (SD)45.5 (15.0)41.8 (12.7)51.4 (16.7)56.3 (14.4)0.001Male, n12 (52%)23 (61%)50 (60%)8 (36%)0.23Age at onset, n Under 10 years5 (22%)6 (16%)13 (15%)1 (5%)0.010 11 to 20 years9 (39%)21 (55%)25 (30%)4 (19%) 21 to 50 years8 (35%)11 (29%)39 (46%)11 (52%) Over 50 years1 (4%)0 (0%)7 (8%)5 (24%)BMI median (IQR)27.7 (23.1, 32.0)28.0 (22.8, 31.5)27.4 (23.7, 31.4)1Data missing for one patient.30.9 (26.9, 33.7)1Data missing for one patient.0.17PASI at start, mean (SD) [n]11.8 (6.4) [17]11.1 (4.9) [27]10.6 (5.9) [69]13.4 (6.2) [15]0.39Psoriatic arthritis, n9 (39%)11 (29%)38 (45%)8 (36%)0.39Nail lesions14 (61%)23 (61%)54 (64%)18 (82%)0.35Discontinued treatment, n (%)2 (9%)12 (32%)22 (26%)12 (55%)0.007Reasons for discontinuation Ineffective2 (100%)7 (59%)14 (63%)7 (58%)0.85 Adverse event0 (0%)3 (25%)3 (14%)0 (0%) Patient decision0 (0%)0 (0%)1 (5%)1 (8%) Other0 (0%)1 (9%)3 (14%)2 (17%) Unknown0 (0%)1 (9%)1 (5%)2 (17%)Abbreviations: BMI, body mass index; IQR, interquartile range.Age, sex, and PASI were measured at start of treatment. BMI was measured at enrollment. Presence of nail lesions and psoriatic arthritis were evaluated over the entire follow-up period in the register. F-test used to test for difference among groups for continuous variables; Chi-square tests used to test for differences among groups for categorical variables except for reasons for discontinuation for which Fisher’s exact test was implemented.1 Data missing for one patient. Open table in a new tab Abbreviations: BMI, body mass index; IQR, interquartile range. Age, sex, and PASI were measured at start of treatment. BMI was measured at enrollment. Presence of nail lesions and psoriatic arthritis were evaluated over the entire follow-up period in the register. F-test used to test for difference among groups for continuous variables; Chi-square tests used to test for differences among groups for categorical variables except for reasons for discontinuation for which Fisher’s exact test was implemented." @default.
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• W3003571612 title "Interaction between Smoking and HLA-C*06:02 on the Response to Ustekinumab in Psoriasis" @default.
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