Association between serum interleukin-17a and clinical response to tofacitinib and etanercept in moderate to severe psoriasis
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1 Original article CED Clinical and Experimental Dermatology Association between serum interleukin-17a and clinical response to tofacitinib and etanercept in moderate to severe psoriasis L. Fitz, 1 W. Zhang, 1 C. Soderstrom, 2 S. Fraser, 2 J. Lee, 1 A. Quazi, 1 R. Wolk, 3 C. A. Mebus, 4 H. Valdez 4 and G. Berstein 5 1 Pfizer Early Clinical Development, Cambridge, MA, USA; 2 Pfizer Early Clinical Development, Groton, CT, USA; 3 Pfizer Global Innovative Pharmaceuticals, Groton, CT, USA; 4 Pfizer Global Innovative Pharmaceuticals, New York, NY, USA; and 5 Pfizer Inflammation and Immunology Research Unit, Cambridge, MA, USA doi:.1111/ced Summary Background. Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-a inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. Aim. To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. Methods. Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 6), tofacitinib 5 mg twice daily (n = 184), tofacitinib mg twice daily (n = 1), or etanercept 5 mg subcutaneously twice weekly (n = 1). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving 75% improvement from baseline PASI (PASI75). Results. Serum levels of IL-17A homodimer at week showed moderate correlation with PASI, with a Spearman correlation coefficient of.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: pg/ml) at week 12 vs. nonresponders ( pg/ml), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders. Conclusions. Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent. Introduction Tofacitinib is an oral Janus kinase (JAK) inhibitor. Tofacitinib inhibits various members of the JAK family, including JAK1, JAK3 and, to a lesser extent, tyrosine Correspondence: Dr Gabriel Berstein, Pfizer Inflammation and Immunology Research Unit, 1 Portland Street, Cambridge, MA, 213, USA gabriel.berstein@pfizer.com Conflict of interest: All authors are employees and shareholders of Pfizer Inc. Accepted for publication 15 September 17 kinase 2, thereby modulating innate and adaptive immune responses. 1 Etanercept is a tumour necrosis factor (TNF)-a inhibitor that is used in the treatment of psoriasis. 2 In a Phase 3 clinical study 3 of patients with psoriasis, 3.5% and 63.6% of patients achieved a clinical response ( 75% improvement from baseline Psoriasis Area and Severity Index; PASI75) after 12 weeks of treatment with tofacitinib 5 mg twice daily and mg twice daily, respectively. Tofacitinib mg twice daily was shown to be noninferior to etanercept 5 mg twice weekly (PASI75 response at ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by 7 Clinical and Experimental Dermatology (18) 43, pp7 77 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
2 week 12: 58.8%), and etanercept and both tofacitinib doses all showed greater efficacy vs. placebo (PASI75 response at week 12: 5.6%) at week 12. Tofacitinib and etanercept target two different inflammatory pathways and have different mechanisms to reduce the inflammatory cascade in plaque psoriasis. Although neither agent directly inhibits interleukin (IL)-17A, both treatments have been shown to produce a reduction of IL-17A signalling in psoriatic skin lesions. 4,5 IL-17A plays a central role in the pathogenesis of plaque psoriasis. It is elevated in psoriatic skin lesions and promotes local production of multiple pro-inflammatory molecules, particularly by keratinocytes. 6 Neutralizing antibodies against IL-17A and its receptor are efficacious in psoriasis. 7 The aim of this study was to investigate the correlation between serum IL-17A and response to treatment in patients with psoriasis treated with tofacitinib or etanercept, using a highly sensitive and specific IL-17 assay. We hypothesized that if IL-17A is critical in psoriasis pathogenesis, it should be reduced after successful therapy in patients achieving a response, regardless of whether or not the primary target of the drug is IL-17A. Methods The study was conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines. All patients provided written informed consent. Patient samples Serum samples were obtained from patients with moderate to severe chronic plaque psoriasis enrolled in a double-blind, placebo-controlled Phase 3 study (NCT124151). 3 All obtained serum samples were included in this analysis. All patients had been diagnosed with chronic ( 12 months) stable plaque psoriasis, and were required to have a PASI of >12 and a Physician s Global Assessment of moderate or severe. Samples for all measurements were obtained at weeks (baseline), 4 and 12 in patients treated with placebo (n = 6), tofacitinib 5 mg twice daily (n = 184), tofacitinib mg twice daily (n = 1) or etanercept 5 mg twice weekly (n = 1). Clinical response at each time point was defined by patients achieving PASI75. Protein measurements All assays were validated using a fit-for-purpose strategy, including analysis of intra-assay and inter-assay accuracy and precision. Prior to running the study samples, the assays were quality-checked for acceptable performance parameters for accuracy and precision using purchased normal and psoriasis samples. Serum concentrations of IL-17A/A homodimer (IL- 17A) and IL-17A/F heterodimer (IL-17A/F) were measured by validated methods, 8, using commercial kits (Singulex Inc., Alameda, CA, USA) and immunoassays were performed (Erenna â Immunoassay System; Singulex Inc.). Method precision and accuracy were assessed using quality control samples. Intra-assay and inter-assay precision did not exceed 3% of the coefficient of variation, and accuracy for assays was within the prespecified range of 7 13%. Excess IL-17A spiked into control serum samples did not interfere with IL-17A/F measurements, nor did excess IL-17A/F interfere with IL-17A measurement. The lower limit of quantification (LLOQ) was.5 pg/ml and.15 pg/ml for IL-17A and IL-17A/F, respectively. The accuracy (% relative error) for IL-17A ranged from 1.5% to 3.1%, and for IL-17A/F ranged from 2.% to 8.4%. Based on validation data, the allowed differential between sample replicates was set at 25%, or at 3% at the LLOQ. Additional cytokines relevant to psoriasis were determined, including E-selectin, IL-8, interferoninducible protein (IP-, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1b, MIP-3b and thymus- and activationregulated chemokine (TARC), using a custom multiplex assay (Meso Scale Discovery; MSD), and analysis was performed using a plate reader (SECTOR â Imager 6) (both Meso Scale Diagnostics, Rockville, MD, USA). The interassay coefficient of variance (CV) for the analytes measured in the MSD multiplex assay was determined by repeated measurements of the same sample across all assay plates (22 in total) for the study samples. The reproducibility of this control sample for each analyte was: E-selection (.% CV), IL-8 (17.3% CV), IP- (.6% CV), MIG (64.% CV), MIP-1b (11.2% CV), MIP-3b (35.7% CV) and TARC (7.8% CV). Data analysis Data were analysed using a linear mixed model with random coefficients analysis. Treatment, visit and treatment visit interaction were treated as fixed effects, and random intercepts and slopes as random effects. Bootstrap resampling was used to estimate confidence intervals for the median percentage change in IL-17A ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by Clinical and Experimental Dermatology (18) 43, pp
3 and IL-17A/F and the median concentration of IL-17A. R-project software packages ( were used for modelling, data manipulation and graphics. Demographics data such as patient sex, age, body weight and body mass index (BMI) at baseline were also investigated as additional predictors in the linear model to predict clinical endpoints such as change in PASI and PASI75 response at week 12. Results Serum concentrations of interleukin 17 Across pooled treatment groups, serum concentration of IL-17A homodimer at week showed a moderate correlation with disease severity as measured by PASI [correlation coefficient (q) =.43; P <.1] (Fig. 1). The correlation coefficient for the IL-17A/F heterodimer at week was also significant (q =.36; P <.1; data not shown). Correlation with Psoriasis Area and Severity Index Across the treatment groups, including placebo, PASI75 responders showed a larger decrease in circulating IL-17A homodimer than did nonresponders (regression slopes at week 12:. vs..3 in PASI75 responders vs. nonresponders, respectively) (Fig. 2a,b). These differences were observed as early as week 4, with a median percentage decrease from baseline of 44.7% in PASI75 responders vs. an increase of 1.6% for nonresponders (Fig. 2c), while at week 12, both groups had a decrease by 57.1% vs. 15.% in PASI score at Week log2 (IL-17A concentration [pg/ml]) Figure 1 Psoriasis Area and Severity Index (PASI) plotted against IL-17A concentration, showing that interleukin (IL)-17A at week correlates moderately with disease severity. Each circle represents one patient, and the solid line shows Spearman correlation. PASI75 responders vs. nonresponders, respectively (Fig. 2d). The related cytokine IL-17A/F heterodimer showed a smaller difference between responders and nonresponders both at week 4 (22.% vs. 5.%, respectively) (Fig. 2e) and week 12 (5.% vs. 61.6%, respectively) (Fig. 2f). PASI75 responders showed a strong and rapid reduction of IL-17A homodimer, with comparable concentrations in the tofacitinib and etanercept cohorts at weeks 4 and 12 (Fig. 3). PASI75 responders reached similar low median circulating concentrations of IL-17A at week 12 (range across treatment groups: pg/ml) regardless of treatment and baseline cytokine concentrations. By contrast, nonresponders showed only a minimal decrease in IL-17A by week 12 and did not achieve such low IL-17A homodimer levels ( pg/ml). In addition, patients with little residual clinical disease (PASI < 5) had IL-17A median levels of.24 pg/ml, whereas the levels were twice as high (.55 pg/ml) in patients with PASI > 5(P <.1). Serum levels of other molecules In addition to IL-17, serum levels of a variety of lymphocyte and granulocyte migration molecules were measured at weeks, 4 and 12. No correlation was found between serum concentrations of migration molecules and either disease severity (data not shown) or effect of treatment (Table 1). Patient characteristics Patient demographics such as sex, age, body weight and BMI at baseline were also explored as potential variables that might correlate with response to treatment. None of these demographic variables was predictive (at a significance level of.5) for change in PASI over the treatment period or PASI75 response at week 12 (data not shown). Discussion In the current study, we found that baseline serum IL- 17A moderately correlated with disease severity in a large cohort of 623 patients with psoriasis. Similar correlations have been reported in other independent studies. 17 The association of high serum IL-17A with greater disease severity supports the concept that, although the skin is primarily affected, psoriasis is a systemic disease. Reduction of serum IL-17A following successful psoriasis therapy with TNF-a inhibitors has been 72 Clinical and Experimental Dermatology (18) 43, pp7 77 ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by
4 (a) <PASI75 at Week 12 (b) PASI75 at Week IL-17A (pg/ml) 1.25 IL-17A (pg/ml) Week Week (c) IL-17A percent change between Week and Week 4 1.6% 44.7% (d) IL-17A percent change between Week and Week % 57.1% Percent change 4 6 Percent change <PASI75 at Week 12 PASI75 at Week 12 (e) IL-17A/F percent change between Week and Week 4 8 <PASI75 at Week 12 PASI75 at Week 12 (f) IL-17A/F percent change between Week and Week % 5.% 5.% 61.6% Percent change 4 6 Percent change <PASI75 at Week 12 PASI75 at Week 12 8 <PASI75 at Week 12 PASI75 at Week 12 Figure 2 Patients with 75% improvement from baseline Psoriasis Area and Severity Index (PASI75) had a significant decrease in serum interleukin (IL)-17A across treatment groups. IL-17A concentrations throughout the study in patients achieving (a) < PASI75 and (b) PASI75 response at week 12, respectively. Coloured lines represent one patient; circles indicate measurements at weeks, 4 and 12; IL-17A concentration is shown in log2 scale; and solid black line represents regression analysis. (c,d) Median percentage decrease in serum IL-17A homodimer between (c) week and week 4, and (d) week and week 12. (e,f) Median percentage decrease in serum IL-17A/F heterodimer between (e) week and week 4, and (f) between week and week 12. Error bars represent 5% confidence intervals. There was no difference in the starting IL-17A or IL-17A/F concentrations between cohorts at week. ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by Clinical and Experimental Dermatology (18) 43, pp
5 (a) <PASI75 at Week 12 (b) PASI75 at Week IL-17A (pg/ml).6 IL-17A (pg/ml) Week Week Tofacitinib mg BID Tofacitinib 5 mg BID Etanercept 5 mg BIW Placebo Figure 3 Time course of serum interleukin (IL)-17A concentration in patients achieving < 75% or 75% improvement from baseline Psoriasis Area and Severity Index (PASI75): (a) < PASI75 or (b) PASI75 at week 12 following various treatments. IL-17A concentration (median and 5% CI) is shown at weeks, 4 and 12. BID, twice daily; BIW, twice weekly. reported previously in small cohorts. 11,18 In this study, we used a highly sensitive measurement for serum IL-17 in a large cohort of patients with psoriasis treated with tofacitinib or etanercept. In PASI75 responders to tofacitinib and etanercept, serum IL-17A concentrations at weeks 4 and 12 decreased to a much larger extent than in nonresponders, and reached low levels that were within the range previously reported in normal subjects ( pg/ml).,1 Although tofacitinib and etanercept do not block IL-17 signalling directly, the association between decreases in IL-17A and clinical response suggests that normalization of circulating IL-17A is required for psoriasis remission regardless of the therapeutic agent. This notion is consistent with the strong decrease in skin IL-17A mrna following successful treatment of psoriasis with tofacitinib 4 and the TNF-a inhibitor, adalimumab. 18 Assessment of serum levels of a variety of lymphocyte and granulocyte migration molecules showed no correlation between these molecules and either disease severity or treatment effect, suggesting that IL-17A is particularly relevant to disease remission. In the current study, the median levels of IL-17A at week were higher in etanercept responders than in tofacitinib responders (.76 vs pg/ml), and the opposite trend was observed in the nonresponder groups (.53 vs pg/ml). Although these differences did not reach statistical significance, the observed trends suggest that baseline IL-17 production might be correlated with clinical response to various treatments depending on their mechanism of action, and warrants further investigation. These differences at week do not reflect a randomization issue, because median baseline IL-17A values in pooled PASI75 responders and nonresponders were essentially the same across treatment groups (tofacitinib 5 mg twice daily,.66 pg/ml; tofacitinib mg twice daily,.61 pg/ml; etanercept 5 mg twice weekly,.68 pg/ml) and also similar between PASI75 responders and nonresponders (.62 and.65 pg/ml, respectively). In contrast to the IL-17A homodimer, the serum IL- 17A/F heterodimer correlated poorly with clinical response, particularly at week 12, with a comparable decrease in IL-17A/F in both responders and nonresponders. These observations suggest that the IL-17A homodimer is more relevant to psoriasis pathogenesis than the IL-17A/F heterodimer. In addition, circulating levels of several cytokines and chemokines that are involved in lymphocyte migration to sites of inflammation were tested, and no correlation with disease severity or response to treatment was observed. While these molecules may play a role in local inflammation in psoriasis, their production molecules might not be sufficiently large to be detected systemically. 74 Clinical and Experimental Dermatology (18) 43, pp7 77 ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by
6 Table 1 Serum concentration of selected cell migration molecules for PASI75 responders and nonresponders in patients with psoriasis treated with placebo, tofacitinib or etanercept Placebo Tofacitinib 5 mg twice daily Tofacitinib mg twice daily Etanercept 5 mg twice weekly Treatment visit Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 IL-17A Nonresponder.53 [.32, 1.14] Responder.36 [.28,.44] IL-17A/F Nonresponder.83 [.61, 2.5] Responder.22 [.15,.3] E-selectin ( 3 ) Nonresponder 4. [27.8, 4.] Responder 2.7 [24.5, 34.8] IL-8 Nonresponder [6, 16] Responder 14 [12, 16] IP- Nonresponder 251 [161, 371] Responder 236 [222, 25] MIG Nonresponder 36 [175, 773] Responder 228 [14, 262] MIP1b Nonresponder 83 [62, 117] Responder 72 [6, 84] MIP3b Nonresponder 132 [82, 18].8 [.38, 1.5].36 [.27,.44] 1.21 [.71, 2.71].43 [.4,.45] 4. [23., 4.] 2573 [26.7, 34.8] 11 [7, 13] 15 [, 15] 358 [241, 441] 38 [235, 355] 1131 [441, 1315] 28 [235, 36] [76, 7] 58 [45, 72] 121 [4, 223].61 [.41, 1.16].24 [.18,.31] 1.2 [.6, 1.86].2 [.23,.34] 3.3 [28.3, 4.] 18.6 [12.4, 24.] [7, 13] 3 [2, 4] 274 [157, 377] 67 [54, 8] 36 [13, 828] 4 [47, 51] 74 [63, 2] 28 [1, 37] 14 [84, 1].77 [.48, 1.3].5 [.32, 1.] 1.14 [.6, 2.56] 1.45 [.73, 3.2] 3.3 [27.3, 4.] 4. [26., 4.] [6, 15] [6, 14] 242 [166, 322] [143, 35] 44 [214, 73] 451 [135, 855] 81 [6, 7] 7 [47, 7] [72, 165].82 [.46, 1.4].36 [.22,.73] 1. [.55, 2.24].7 [.31, 1.61] 32.2 [24.4, 4.] 27.6 [., 4.] [6, 15] 8 [6, 11] 11 [117, 262] 124 [71, 1] 432 [23, 666] 268 [117, 516] 82 [53, 1] 64 [52, 2] 78 [62, 115].6 [.35, 1.5].24 [.13,.41].83 [.4, 1.23].44 [.22,.] 31.7 [.7, 4.] 25.7 [15., 34.1] 8 [5, 12] 8 [5, 13] 173 [7, 262] 137 [8, 26] 36 [127, 53] 315 [145, 538] 71 [48, 2] 66 [46, ] 75 [47, ].65 [.43,.].56 [.37, 1.].8 [.44, 3.55] 1.8 [.54, 2.6] 37.2 [3.6, 4.] 34. [22.6, 4.] [8, 13] [6, 14] 214 [161, 342] 18 [126, 358] 453 [148, 47] 385 [134, 768] 8 [58, 5] 66 [48, 2] 8 [7, 148].6 [.36, 1.17].36 [.23,.72].74 [.42, 1.25].44 [.,.87] 31.3 [21.5, 4.] 25.1 [18.3, 38.5] 12 [8, 18] [7, 15] 15 [2, 218] 13 [7, 1] 373 [233, 672] 38 [113, 612] 82 [56, 7] 63 [47, 88] 6 [4, 85].62 [.36,.83].27 [.18,.4].68 [.3, 1.27].37 [.17, 1.] 34. [25.6, 3.] 25.8 [16., 34.8] [8, 16] [7, 14] 214 [126, 34] 175 [3, 256] 461 [241, 816] 376 [117, 87] 75 [54, 1] 66 [47, 3] 76 [53, 4].53 [.32, 1.42].76 [.3, 1.42].3 [.36, 3.85].88 [.52, 1.85] 38.1 [25., 4.] 33.6 [22.6, 4.] [7, 15] [6, 14] 8 [135, 364] 7 [132, 315] 518 [218, 846] 34 [148, 65] 73 [53, 116] 68 [5, 6] [62, 131].38 [.25,.2].35 [.22,.55].55 [.24,.8].45 [.21,.83] 33.7 [.6, 4.] 26. [16., 36.7] [5, 14] 8 [5, 12] 162 [87, 223] 136 [5, 2] 34 [17, 468] 242 [58, 412] 51 [37, 73] 52 [3, 6] 8 [63, 6].37 [.21,.6].26 [.14,.41].42 [.,.8].34 [.21,.73] 28. [17.4, 4.] 23.4 [14.5, 32.6] 7 [5, 12] 7 [5, 11] 126 [76, 236] 12 [76, 7] 235 [116, 543] 151 [68, 326] 52 [34, 6] 47 [35, 65] 8 [51, ] ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by Clinical and Experimental Dermatology (18) 43, pp
7 Table 1. continued Placebo Tofacitinib 5 mg twice daily Tofacitinib mg twice daily Etanercept 5 mg twice weekly Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 Day 1 Week 4 Week 12 Treatment visit 7 [52, 131] 83 [6, 136] [65, 158] 58 [4, 81] 5 [37, 87] 7 [63, 153] 58 [42, ] 63 [43, 5] 111 [67, 17] 71 [4, 2] 167 [14, 224] Responder 254 [161, 347] 17 [135, 281] 221 [2, 374] 345 [14, 56] 338 [6, 47] 358 [, 587] 353 [234, 633] 211 [131, 445] 274 [165, 612] 314 [188, 65] 275 [181, 55] 26 [233, 638] TARC Nonresponder 377 [227, 646] 147 [87, 257] 5 [7, 344] 326 [217, 684] 15 [2, 338] 15 [, 327] 2 [142, 547] 18 [3, 311] 255 [14, 414] 37 [173, 518] [53, 127] 135 [133, 32] Responder 334 [31, 34] IL, interleukin; IP-, interferon-inducible protein-; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; PASI75, 75% improvement in Psoriasis Area and Severity Index score; TARC, thymus- and activation-regulated chemokine. Units are median pg/ml (25% quartile, 75% quartile). Conclusion Serum IL-17A correlates moderately with psoriasis disease severity, and reduction in circulating IL-17A is required for disease remission upon treatment with tofacitinib and etanercept. Acknowledgements We thank the patients, investigators and study teams involved in this study. Editorial assistance, under direction from the authors, was provided by Dr A. MacLachlan of Complete Medical Communications and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc. What s already known about this topic? IL-17A plays a central role in psoriasis skin lesions, and serum IL-17A levels are moderately correlated with disease severity. Tofacitinib is an oral JAK inhibitor that has shown efficacy in psoriasis clinical studies. Etanercept is a TNFa inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17A directly, but both treatments produce a reduction in IL-17A signalling. What does this study add? In a large Phase 3 study of tofacitinib and etanercept for psoriasis, circulating IL-17A levels were significantly reduced at week 12 by 57.1% in PASI75 responders vs. a 15.% decrease in nonresponders. Normalization of IL-17A was observed at week 12 in both tofacitinib- and etanercept-treated PASI75 responders. Serum levels of IL-17A/F heterodimer and several inflammatory cell migration molecules did not correlate with clinical response. References 1 Hodge JA, Kawabata TT, Krishnaswami S et al. The mechanism of action of tofacitinib an oral Janus kinase 76 Clinical and Experimental Dermatology (18) 43, pp7 77 ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by
8 inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 16; 34: Kivelevitch D, Mansouri B, Menter A. Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis. Biologics 14; 8: Bachelez H, van de Kerkhof PC, Strohal R et al. Tofacitinib versus etanercept or placebo in moderate-tosevere chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 15; 386: Krueger J, Clark JD, Suarez-Fari~nas M et al. Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study. J Allergy Clin Immunol 16; 137: 7. 5 Zaba LC, Suarez-Fari~nas M, Fuentes-Duculan J et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol ; 124: Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin 15; 33: Campa M, Mansouri B, Warren R, Menter A. A review of biologic therapies targeting IL-23 and IL-17 for use in moderate-to-severe plaque psoriasis. Dermatol Ther (Heidelb) 16; 6: Lee JW, Devanarayan V, Barrett YC et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res 6; 23: Soderstrom C, Berstein G, Zhang W et al. Ultra-sensitive measurement of IL-17A and IL-17F in psoriasis patient serum and skin. AAPS J 17; 1: Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL- 18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 5; 5: Caproni M, Antiga E, Melani L et al. Serum levels of IL- 17 and IL-22 are reduced by etanercept, but not by acitretin, in patients with psoriasis: a randomizedcontrolled trial. J Clin Immunol ; 2: Choe YB, Hwang YJ, Hahn HJ et al. A comparison of serum inflammatory cytokines according to phenotype in patients with psoriasis. Br J Dermatol 12; 167: Kolbinger F, Loesche C, Valentin MA et al. beta-defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis. J Allergy Clin Immunol 17; 13: Suarez-Fari~nas M, Li K, Fuentes-Duculan J et al. Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis. J Invest Dermatol 12; 132: Takahashi H, Tsuji H, Hashimoto Y et al. Serum cytokines and growth factor levels in Japanese patients with psoriasis. Clin Exp Dermatol ; 35: Yilmaz SB, Cicek N, Coskun M et al. Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. Arch Dermatol Res 12; 34: Yoo IS, Lee JH, Song ST et al. T-helper 17 cells: the driving force of psoriasis and psoriatic arthritis. Int J Rheum Dis 12; 15: Balato A, Schiattarella M, Di Caprio R et al. Effects of adalimumab therapy in adult subjects with moderate-tosevere psoriasis on Th17 pathway. J Eur Acad Dermatol Venereol 14; 28: Todd J, Simpson P, Estis J et al. Reference range and short- and long-term biological variation of interleukin (IL)-6, IL-17A and tissue necrosis factor-alpha using high sensitivity assays. Cytokine 13; 64: ª 18 Pfizer, Inc. Clinical and Experimental Dermatology published by Clinical and Experimental Dermatology (18) 43, pp
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