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Defining a Minimal Effective Serum Trough Concentration of Secukinumab in Psoriasis: A Step toward Personalized Therapy

Open AccessPublished:May 05, 2019DOI:https://doi.org/10.1016/j.jid.2019.04.012

      Abbreviations:

      CI (confidence interval), Ctrough (trough concentration), PASI (Psoriasis Area and Severity Index)
      To the Editor
      The armamentarium of psoriasis treatments has been reinforced by the introduction of biologics that target IL-17A (
      European Medicines Agency
      Cosentyx: EPAR - summary for the public.
      ,
      • Frieder J.
      • Kivelevitch D.
      • Menter A.
      Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis.
      ), and at present, achieving complete skin clearance has become a realistic goal. However, in clinical practice, physicians encounter various levels of responses, including insufficient response or loss of response with anti–IL-17A treatment. This has led to physicians exploring off-label intensification regimens through trial and error, either by increasing the dose or by shortening the administration intervals (
      • Beecker J.
      • Joo J.
      Treatment of moderate to severe psoriasis with high dose (450-mg) secukinumab: case reports of off-label use.
      ,
      • Phung M.
      • Georgakopoulos J.R.
      • Ighani A.
      • Giroux L.
      • Yeung J.
      Secukinumab dose optimization in adult psoriasis patients: a retrospective, multicenter case series.
      ). Thus, there is a current need to target the most optimal therapeutic response in an individual patient to use these highly effective and expensive drugs in a manner as cost-effective as possible. Therapeutic drug monitoring, in which dose adjustments are based on a definable relationship between measurable serum drug concentrations, often taken at trough (Ctrough), and a clinical observable response can be used to reach this goal (
      • Toro-Montecinos M.
      • Ballescá F.
      • Ferrandiz C.
      • Teniente-Serra A.
      • Martinez-Caceres E.
      • Carrascosa J.M.
      Usefulness and correlation with clinical response of serum ustekinumab levels measured at 6 weeks versus 12 weeks.
      ,
      • Wilkinson N.
      • Tsakok T.
      • Dand N.
      • Bloem K.
      • Duckworth M.
      • Baudry D.
      • et al.
      Defining the therapeutic range for adalimumab and predicting response in psoriasis: a multicenter prospective observational cohort study.
      ). Nevertheless, to implement therapeutic drug monitoring, it is crucial to define the optimal therapeutic window for a given biologic in psoriasis (
      • Hoseyni H.
      • Xu Y.
      • Zhou H.
      Therapeutic drug monitoring of biologics for inflammatory bowel disease: an answer to optimized treatment?.
      ).
      In this pilot study, we studied secukinumab, a fully human anti–IL-17A monoclonal antibody, Ctroughs in 40 patients with moderate to severe psoriasis, who administered secukinumab monthly during maintenance, using an in-house–developed, sandwich-type enzyme-linked immunosorbent assay. The medical ethics committee from the Ghent University Hospital, Belgium, approved this study (B670201835652), and written informed consent was obtained from all patients before any study procedure was performed. The Psoriasis Area and Severity Index (PASI) was assessed by a dermatologist before sample collection, and clinical response was established by comparing the percentage of PASI improvement with baseline (ΔPASI). Patients were classified as optimal responders (PASI ≤ 2) or suboptimal responders (PASI > 2), as an absolute PASI cut-off of 2 is associated with the ΔPASI 90 response (
      • Reich K.
      • Bachhuber T.
      • Melzer N.
      • Sieder C.
      • Sticherling M.
      From relative to absolute treatment outcomes—correlation of PASI 90 and PASI ≤ 2 in three clinical trials with secukinumab.
      ).
      In our patient cohort (see Supplementary Table S1 online), we found a significant correlation between secukinumab Ctrough and absolute PASI (ρ = –0.442; P = 0.004; Figure 1a) as well as between Ctrough and relative ΔPASI (ρ = 0.325; P = 0.041). In addition, a significant difference in Ctrough was observed between optimal responders and suboptimal responders (P = 0.004; Figure 1b), with a median Ctrough of 40.2 μg/ml and 29.1 μg/ml, respectively. This correlation suggests a therapeutic window of secukinumab in patients with psoriasis.
      Figure thumbnail gr1
      Figure 1Comparison between secukinumab Ctrough in optimal and suboptimal responders and visualization of a therapeutic window of secukinumab. (a) Correlation between Ctrough and clinical response; Spearman rank test (ρ = –0.442; P = 0.004). (b) Ctrough was compared between suboptimal (PASI > 2; n = 17) and optimal (PASI ≤ 2; n = 23) responders. (c) ROC analysis of secukinumab Ctrough. Optimal cut-off point was selected by using the index of union (
      • Unal I.
      Defining an optimal cut-point value in ROC analysis: an alternative approach.
      ). The minimal effective Ctrough was set at 33.2 μg/ml. (d) Four equal-sized groups (n = 10) were formed based on ascending Ctrough and correlated with the median ΔPASI per group. Each black dot represents the median Ctrough, with correlating median ΔPASI for one group. Alongside each ΔPASI, the IQR is illustrated. The dashed vertical line represents the minimal effective secukinumab Ctrough of 33.2 μg/ml. AUC, area under the curve; Ctrough, trough concentration; IQR, interquartile range; PASI, Psoriasis Area and Severity Index; ΔPASI, percentage of PASI improvement with baseline; ROC, receiver operating characteristic.
      Next, we sought the minimal effective threshold of the therapeutic window by using a receiver operator characteristic analysis and found a minimal effective maintenance secukinumab Ctrough of 33.2 μg/ml with an area under the curve of 0.76 (95% confidence interval [CI] = 0.61–0.92; P = 0.005), sensitivity 78.3% (95% CI = 56.3–92.5), and specificity 76.5% (95% CI = 50.1–93.2), which was associated with a positive and negative predictive value of 0.82 (95% CI = 0.59–0.94) and 0.72 (95% CI = 0.46–0.89), respectively (Figure 1c) (
      • Unal I.
      Defining an optimal cut-point value in ROC analysis: an alternative approach.
      ). This Ctrough indicative of the minimal desirable effect implies that a secukinumab Ctrough of 33.2 μg/ml can distinguish optimal responders (PASI ≤ 2) from suboptimal responders (PASI > 2).
      In addition, we created a concentration-effect curve to elucidate whether the Ctrough, indicating the maximum clinical effect, could be determined. Although relative ΔPASI increased with increasing secukinumab Ctrough, no plateau was observed, and thus, no upper Ctrough threshold could be deduced in this cohort (Figure 1d).
      To explore potential confounding factors of Ctrough and/or clinical response, several correlations were tested. These results showed that obesity, active smoking, long treatment duration, and/or previous treatment with biologics were associated with lower secukinumab Ctrough, which also resulted in lower clinical responses.
      A limitation of our study is the small sample size that hampers a multivariate analysis. In addition, using the receiver operator characteristic analysis, the discrimination between optimal and suboptimal responders was only fair and may not be useful for clinical practice. Therefore, these findings need to be confirmed in a larger cohort as it is not unlikely that some patients may have an increased clearance of therapeutic antibodies or IgG in general.
      Based on these results, we propose a treatment algorithm by combining clinical evaluation (PASI) and the minimal effective Ctrough to adequately monitor patients with psoriasis who are treated with secukinumab during the maintenance phase (Figure 2). This algorithm highlights the potential added value of Ctrough measurement in the clinic because it enables the physicians to make guided decisions instead of the current trial-and-error dose adaptations. In suboptimal responders with subtherapeutic Ctrough, we suggest a dose escalation, which will inevitably lead to an increased cost. Nevertheless, measuring the secukinumab Ctrough allows to select a priori those suboptimal responders in whom it is justified to dose escalate, defining an appropriate extra cost.
      Figure thumbnail gr2
      Figure 2Proposed monitoring algorithm for patients with psoriasis treated with secukinumab during maintenance phase. Before measuring Ctrough, patient’s adherence needs to be checked. If correct, the combination of clinical evaluation (PASI) and the minimal effective Ctrough provide an algorithm to adequately monitor patients with psoriasis treated with secukinumab during maintenance phase (minimal 24 weeks). (a, b) In optimal responders, secukinumab treatment can be continued, but it is recommended to check Ctrough when loss of response occurs. (c) In suboptimal responders with subtherapeutic Ctrough, a dose escalation is recommended. (d) In suboptimal responders with therapeutic Ctrough, it is recommended to switch to another biologic. The dashed horizontal and vertical line represent the absolute PASI 2 and Ctrough threshold level (33.2 μg/ml), respectively. Ctrough, trough concentration; PASI, Psoriasis Area and Severity Index; TDM, therapeutic drug monitoring.
      In summary and to our knowledge previously unreported, we describe a minimal effective secukinumab Ctrough of 33.2 μg/ml and consequently unveil a potential role of therapeutic drug monitoring in patients with psoriasis who are treated with secukinumab. Our results suggest that patients with psoriasis with a suboptimal response and a Ctrough below 33.2 μg/ml during the maintenance phase are potentially undertreated and could benefit from dose intensification.

      Data availability statement

      The data set related to this article can be found at https://osf.io/sbxpj/, hosted at Open Science Framework, and access can be obtained upon request.

      Conflict of Interest

      JL has received grants from Janssen, AbbVie, and Pfizer; had paid consultancies from Pfizer, Novartis, AbbVie, Janssen-Cilag, and Leo Pharma; and carried out clinical trials for Janssen-Cilag, Merck Serono, Amgen, Pfizer, AbbVie, Celgene, Regeneron, and Novartis. AG served as a speaker for MSD, Janssen Biologicals, Abbvie, Pfizer, Takeda, and Novartis and as a consultant for UCB and Takeda, and KU Leuven–licensed (anti-) infliximab, (anti-) adalimumab, vedolizumab, golimumab and ustekinumab ELISA to apDia, and infliximab and adalimumab lateral flow to R-Biopharm AG. The remaining authors state no conflict of interest.

      Acknowledgments

      We would like to express our gratitude to all patients participating in this study. This study was made possible through funding by FWO-TBM ( T003716N and T003218N ).

      Author Contributions

      Conceptualization: JL, LG, AG; Formal Analysis: RSo, EM, LG, RSp; Investigation: EM, RSo, NVdB, EB; Project Administration: RSo, LG; Resources: JL, AG, LT, SL; Supervision: AG, JL, LG; Validation: LG; Writing - Original Draft Preparation: RSo; Writing - Review and Editing: RSo, NVdB, LG, AG, JL

      Supplementary Material

      Supplementary Table S1Baseline Characteristics of Patients with Psoriasis Treated with Secukinumab
      CharacteristicTotal Patients (n = 40)
      Age, y, median (IQR)46.5 (36.3–53.0)
      Male sex, n (%)27 (67.5)
      BMI, kg/m2 (mean ± SD)27.9 ± 3.8
       Normal (<25), n (%)8 (20.0)
       Overweight (25–30), n (%)21(52.5)
       Obese (≥30), n (%)11 (27.5)
      Smoking, n (%)
       Current smoker9 (22.5)
      PsA, n (%)6 (15.0)
      Disease duration, y, median (IQR)19.0 (12.0–31.0)
      Treatment duration, wk, median (IQR)55.9 (45.0–103.7)
      PASI score before secukinumab treatment, median (IQR)12.4 (10.3–18.5)
      PASI score at trough, median (IQR)1.4 (0.0–3.6)
      Secukinumab Ctrough, μg/ml, median (IQR)34.6 (28.2–43.0)
      Concomitant medication, n (%)
       No co-medication23 (57.5)
       Topical corticosteroids15 (37.5)
       Methotrexate1 (2.5)
       Methotrexate and topical corticosteroids1 (2.5)
      Previous biologic treatment, n (%)21 (52.5)
       Adalimumab10 (25.0)
       Ustekinumab12 (30.0)
       Etanercept7 (17.5)
       Ixekizumab1 (2.5)
       Brodalumab2 (5.0)
      Abbreviations: BMI, body mass index; Ctrough, secukinumab serum trough concentration; IQR, interquartile range; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; SD, standard deviation; wk, week; y, year.

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