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EASI p-EASI: Predicting Disease Severity in Patients with Atopic Dermatitis Treated with Tralokinumab

Open AccessPublished:July 14, 2022DOI:https://doi.org/10.1016/j.jid.2022.06.008

      Abbreviations:

      AD (atopic dermatitis), EASI (Eczema Area Severity Index), IQR (interquartile range), p-EASI (predicted Eczema Area Severity Index), sIL-2R (soluble IL-2 receptor)
      To The Editor
      Numerous targeted treatments for atopic dermatitis (AD) are currently under investigation in clinical trials. Comparability of the efficacy of new drugs is therefore becoming more and more important. However, this remains challenging given the high intraobserver and interobserver variability of primary endpoints (
      • Flohr C.
      Atopic dermatitis diagnostic criteria and outcome measures for clinical trials: still a mess.
      ). The use of serological biomarkers may overcome this problem. Recent studies have shown that a combination of serum biomarkers, including TARC, IL-22, and sIL-2R (using a formula called predicted Eczema Area Severity Index [EASI] [p-EASI]), predicts disease severity in patients with AD treated with dupilumab, cyclosporine A, and topical corticosteroids (
      • Bakker D.S.
      • Ariens L.F.M.
      • Giovannone B.
      • Hijnen D.
      • Delemarre E.M.
      • Knol E.
      • et al.
      EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with dupilumab using a combination of serum biomarkers.
      ;
      • Thijs J.L.
      • Drylewicz J.
      • Bruijnzeel-Koomen C.A.F.M.
      • Giovannone B.
      • Knol E.F.
      • de Bruin-Weller M.S.
      • et al.
      EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with cyclosporin A.
      ,
      • Thijs J.L.
      • Drylewicz J.
      • Fiechter R.
      • Strickland I.
      • Sleeman M.A.
      • Herath A.
      • et al.
      EASI p-EASI: utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients.
      ). The advantage of the use of serum biomarkers is that they are objective and do not require subjective assessment of disease activity by clinicians (
      • Renert-Yuval Y.
      • Thyssen J.P.
      • Bissonnette R.
      • Bieber T.
      • Kabashima K.
      • Hijnen D.
      • et al.
      Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council.
      ). This study reports on the use of p-EASI in a randomized controlled trial with tralokinumab treatment. The safety and efficacy of tralokinumab in AD have been shown in several clinical trials.
      A total of 198 adult patients with moderate-to-severe AD were randomly included from the total population of the ECZema TRAlokinumab Trial No. 1 trial (N = 802) (NCT03131648). Written informed consent was obtained from all participants, and the trial was approved by the ethics committee of the Medical Faculty at the Ludwig-Maximilian University of Munich (Munich, Germany) (
      • Wollenberg A.
      • Blauvelt A.
      • Guttman-Yassky E.
      • Worm M.
      • Lynde C.
      • Lacour J.P.
      • et al.
      Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).
      ).
      Baseline characteristics were well-balanced across treatment and placebo groups (Supplementary Table S1). A total of 149 patients were treated with subcutaneous 300 mg tralokinumab every other week, and 49 patients received a placebo for 16 weeks. If medically necessary (e.g., intolerable AD symptoms), rescue treatment for AD was provided at the discretion of the investigator. Disease severity was assessed by EASI, and serum was collected before initiation of treatment (time 0) and after 16 weeks of treatment (time 3). Serum TARC, sIL-2R, and IL-22 levels were measured using a multiplex immunoassay, as previously described (
      • Bakker D.S.
      • Ariens L.F.M.
      • Giovannone B.
      • Hijnen D.
      • Delemarre E.M.
      • Knol E.
      • et al.
      EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with dupilumab using a combination of serum biomarkers.
      ;
      • Thijs J.L.
      • Drylewicz J.
      • Bruijnzeel-Koomen C.A.F.M.
      • Giovannone B.
      • Knol E.F.
      • de Bruin-Weller M.S.
      • et al.
      EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with cyclosporin A.
      ,
      • Thijs J.L.
      • Drylewicz J.
      • Fiechter R.
      • Strickland I.
      • Sleeman M.A.
      • Herath A.
      • et al.
      EASI p-EASI: utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients.
      ). Differences between the two time points were tested by Wilcoxon signed-rank tests. All patients provided informed consent.
      Tralokinumab treatment significantly decreased median EASI scores from baseline (30.9, interquartile range [IQR] = 22.5‒42.3) through week 16 (13.5, IQR = 6.6‒22.5, P < 0.0001). At week 16, the median percentage changes from baseline in the levels of TARC measured were significantly larger in the tralokinumab-treated patients than in the placebo-treated group (Figure 1). The largest difference was observed for TARC levels in tralokinumab versus placebo (‒57.01% vs. ‒28.33%, P = 0.0007). The levels of sIL-2R (‒32.28% vs. ‒29.06%, P = 0.33) and IL-22 (‒23.63% vs. ‒24.98, P = 0.94) showed comparable decreases in both groups (Figure 1 and Supplementary Table S2).
      Figure thumbnail gr1
      Figure 1Median percentage (IQR) change from baseline to week 16 in biomarker levels. Significance levels correspond to the following P-value: ∗∗∗P = 0.0007. IQR, interquartile range.
      Serum biomarker levels were used to calculate p-EASI scores at two time points using the formula: b0t + b1t × log (TARC) + b2t × IL-22 + b3t × sIL-2R (
      • Thijs J.L.
      • Drylewicz J.
      • Fiechter R.
      • Strickland I.
      • Sleeman M.A.
      • Herath A.
      • et al.
      EASI p-EASI: utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients.
      ), a linear combination of biomarkers with coefficients that can vary over the treatment course. p-EASI is an algorithm to evaluate severity on the basis of serum markers rather than a static formula. At time point t, the coefficients are estimated that can vary over the treatment course. Application of this algorithm on datasets with different ranges in EASI and biomarkers (values that are not limited to a certain maximum) will generate different coefficients. In addition, the output of p-EASI is not constrained to the range of EASI (0‒72). Therefore, we proposed a translation factor with the existing data to facilitate its use in clinical practice. Consequently, p-EASI can be compared across different studies by mapping its value into the same range of EASI.
      The EASI and p-EASI scores showed a moderate correlation (Spearman correlation r = 0.59, P < 0.0001). In patients treated with tralokinumab, median EASI and p-EASI decreased from 30.9 (IQR = 22.5‒42.3) and 32.9 (IQR = 25.6‒40.2) to 13.5 (IQR = 6.6‒22.5) and 24.8 (IQR = 20.6‒59.0), respectively, after 16 weeks of treatment. In the placebo group, median EASI and p-EASI were 31.1 (IQR = 22.5‒40.4) and 31.3 (IQR = 25.0‒37.5), respectively, at baseline and 19.0 (IQR = 10.2‒29.1) and 29.2 (IQR = 25.5‒32.5) after 16 weeks of treatment (Figure 2).
      Figure thumbnail gr2
      Figure 2Median EASI and p-EASI scores in 149 patients with AD at baseline (week 0) and after 16 weeks of tralokinumab treatment versus 49 patients with AD receiving placebo. Error bars represent the interquartile range. AD, atopic dermatitis; EASI, Eczema Area Severity; p-EASI, predicted Eczema Area Severity.
      Tralokinumab treatment resulted in a large decrease in serum TARC levels, but the effect on the levels of IL-22 and sIL-2R were similar for both groups. This is in accordance with a previous study that showed significant effects of dupilumab treatment on TARC and IL-22 levels but no significant change in sIL-2R levels (
      • Bakker D.S.
      • Ariens L.F.M.
      • Giovannone B.
      • Hijnen D.
      • Delemarre E.M.
      • Knol E.
      • et al.
      EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with dupilumab using a combination of serum biomarkers.
      ). This suggests that different treatments may have differential effects on the individual components of the p-EASI signature. Although the use of a combination of biomarkers may not be essential for all treatments, an affordable, standardized assay that can be used for all treatments may be preferable over different combinations of biomarkers for specific treatments and therefore contribute to improving the comparability of study outcomes.
      The effects on serum biomarker levels in the placebo group might be explained by the use of rescue therapy (e.g., topical steroids) that was allowed at the discretion of the investigator during the trial. The previous cohort included patients with AD treated with topical corticosteroids once daily and showed significant effects on TARC, sIL-2R, and IL-22 levels (
      • Thijs J.L.
      • Drylewicz J.
      • Fiechter R.
      • Strickland I.
      • Sleeman M.A.
      • Herath A.
      • et al.
      EASI p-EASI: utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients.
      ).
      Patients in the placebo group only showed small changes in p-EASI compared with patients treated with tralokinumab (Figure 2). The effect on EASI scores in patients treated with placebo was higher than the effect on p-EASI. Because p-EASI is a truly objective measure, this suggests that the effect on EASI in the placebo group may be an overestimation of the real biological effect.
      This may be the result of two phenomena that have been reported in clinical trials, including eligibility creep and regression to the mean. Eligibility creep suggests an overestimation of disease severity at inclusion (eligibility screening) (
      • Hick J.
      • Feldman S.R.
      Eligibility creep: a cause for placebo group improvement in controlled trials of psoriasis treatments.
      ;
      • Leshem Y.A.
      • Bissonnette R.
      • Paul C.
      • Silverberg J.I.
      • Irvine A.D.
      • Paller A.S.
      • et al.
      Optimization of placebo use in clinical trials with systemic treatments for atopic dermatitis: an International Eczema Council survey-based position statement.
      ). The outcome measures (e.g., EASI) for assessing disease severity have subjectivity to them. Therefore, when there is a range of scores that are subjectively reasonable, the observer might lean toward the high end of the subjective range at initial visits. Scoring in the middle of the subjective range during subsequent visits would yield an apparent improvement in the placebo group, resulting in regression to the mean.
      Our study was limited by the absence of diversity in ethnicity, and representation of patients with black skin is lacking. In addition, children were not included in this study. Furthermore, the clinical significance of p-EASI remains undefined. Additional research is needed to correlate clinical important outcome measures such as EASI50/EASI75. This study shows that the use of a biomarker signature (p-EASI) reflects disease severity in patients with AD treated with tralokinumab in a clinical trial setting. We suggest that the use of objective biomarker signatures such as p-EASI is essential to objectively assess treatment effects and allow for comparison of new drugs for the treatment of AD.

      Data availability statement

      All data generated or analyzed during this study are included in this published article and its Supplementary Materials and Methods.

      Conflict of Interest

      MAR is an employee of LEO Pharma A/S. JCDR is a former employee of LEO Pharma A/S. DJH is an investigator for AbbVie, Galderma, LEO Pharma, MedImmune/AstraZeneca, Novartis, and Sanofi/Regeneron and is a consultant for Incyte, Janssen, LEO Pharma, Lilly, MedImmune/AstraZeneca, Novartis, and Pfizerand Regeneron/Sanofi. The remaining authors state no conflict of interest.

      Author Contributions

      Conceptualization: JIO, LEMDW, MAR, JCDR, DJH; Data Curation: JIO, LEMDW, MAR, JCDR; Formal Analysis: JIO, MAR, JCDR, DJH; Funding Acquisition: MAR, DJH; Investigation: JIO, LEMDW, WAD, DJH; Methodology: JIO, MAR, JCDR, DJH; Project Administration: JIO, LEMDW, MAR, DJH; Resources: MAD, WAD, DJH; Supervision: MAR, DJH; Validation; JIO, MAR, JCDR, DJH Visualization: JIO, LEMDW, MAR, DJH; Writing – Original Draft Preparation: JIO, LEMDW, DJH; Writing – Review and Editing: JIO, LEMDW, MAR, WAD, JCDR, DJH

      Acknowledgments

      The authors wish to thank Athula Herath for his helpful contributions to the statistical analysis of this manuscript. The study was performed in Rotterdam, The Netherlands. The study was supported by LEO Pharma A/S .

      Supplementary Materials

      Supplementary Table S1Baseline Characteristics
      CharacteristicsPlacebo (n = 49)Tralokinumab Q2W (n = 149)
      Female sex, n (%)12 (24.5)49 (32.9)
      Age, median (IQR)37 (27‒46)35 (27‒46)
      Race, n (%)
      White32 (65.3)112 (75.2)
      Black1 (2.0)1 (0.7)
      Asian16 (32.7)34 (22.8)
      Other0 (—)2 (1.3)
      Missing0 (—)0 (—)
      EASI, median (IQR)31.1 (22.5‒40.4)30.9 (22.5‒42.3)
      IGA score of 4, n (%)26 (53.1)81 (54.5)
      SCORAD score, median (IQR)69.8 (64.3‒83.5)70.7 (63.2‒79.7)
      POEM score, median (IQR)24.0 (22.0‒26.0)
      n = 1 missing value.
      24.0 (19.0‒27.0)
      n = 3 missing values.
      Abbreviations: EASI, Eczema Area Severity Index; IGA, Investigator Global Assessment; IQR, interquartile range; POEM, Patient-Oriented Eczema Measure; Q2W, every 2 weeks; SCORAD, SCORing Atopic Dermatitis.
      1 n = 1 missing value.
      2 n = 3 missing values.
      Supplementary Table S2Serum TARC, sIL-2R, and IL-22 Levels at Baseline and after 16 Weeks of Treaptment
      Serum biomarkersValuesTralokinumab Q2W (n = 149)Placebo (n = 49)
      Serum TARC (pg/ml)Baseline median value (IQR)1,289.10 (411.94‒3,175.18)1,123.92 (358.78‒2,923.83)
      Median value at 16 weeks (IQR)347.46 (154.49‒982.75)653.36 (346.94‒1,285.39)
      Median change from baseline (IQR)579.94
      n = 1 missing value.
      (129.09‒1,959.50)
      130.00
      n = 1 missing value.
      (‒89.32 to 1,205.99)
      Median percentage change from baseline (IQR)‒57.01
      n = 1 missing value.
      (‒80.49 to ‒34.59)
      ‒28.33
      n = 1 missing value.
      (‒66.74 to 6.40)
      Serum IL-22 (pg/ml)Baseline median value (IQR)65.78 (23.06‒137.82)58.48 (14.95‒182.67)
      Median value at 16 weeks (IQR)41.78 (11.39‒100.01)26.26 (9.70‒99.30)
      Median change from baseline (IQR)11.69
      n = 1 missing value.
      (‒1.01 to 63.29)
      10.27
      n = 1 missing value.
      (0.00‒58.68)
      Median percentage change from baseline (IQR)‒23.63
      n = 1 missing value.
      (‒56.26 to 1.03)
      ‒24.98
      n = 1 missing value.
      (‒62.03 to 0.00)
      Serum sIL-2R (pg/ml)Baseline median value (IQR)770.33 (375.05‒1,682.31)754.87 (421.23‒1,328.48)
      Median value at 16 weeks (IQR)465.29 (195.00‒929.44)556.00 (263.56‒898.79)
      Median change from baseline (IQR)280.77
      n = 1 missing value.
      (0.00‒660.34)
      152.00
      n = 1 missing value.
      (0.00‒389.28)
      Median percentage change from baseline (IQR)‒32.28
      n = 1 missing value.
      (‒60.31 to 0.00)
      ‒29.06
      n = 1 missing value.
      (‒50.72 to 0.00)
      Abbreviations: IQR, interquartile range; Q2W, every 2 weeks; sIL-2R, soluble IL-2 receptor.
      1 n = 1 missing value.

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