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Secukinumab responses vary across the spectrum of congenital ichthyosis in adults

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Abstract

Importance

Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity.

Objective

To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes.

Design

Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively.

Setting

Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York.

Participants

Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma.

Results

IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29–50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels.

Limitations

Small sample size; heterogeneous ichthyosis subsets.

Conclusion

IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses.

ClinicalTrials.gov registration number

NCT03041038; first posted on 02/02/2017.

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Data availability

The minimal dataset that supports the central findings of this study can be requested from the corresponding authors.

Abbreviations

AE:

Adverse event(s)

ARCI:

Autosomal recessive congenital ichthyosis

CIE:

Congenital ichthyosiform erythroderma

DLQI:

Dermatology Life Quality Index

EI:

Epidermolytic ichthyosis

IASI:

Ichthyosis Area Severity Index

IASI-E:

Erythema Subscore of Ichthyosis Area Severity Index

IASI-S:

Scaling Subscore of Ichthyosis Area Severity Index

IRB:

Institutional review board

iQoL-32:

Ichthyosis quality of life-32 items

LI:

Lamellar ichthyosis

LOCF:

Last-observation carried forward

NRS:

Numerical Rating Scale

NS:

Netherton syndrome

PASI:

Psoriasis Area Severity Index

PRO:

Patient-reported outcome

SAE:

Serious adverse event

SD:

Standard deviation

TEWL:

Transepidermal water loss

VIIS:

Visual Index for Ichthyosis Severity

References

  1. AS, Renert-Yuval Y, Suprun M, Esaki H, Oliva M, Huynh TN, et al. (2017) An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol 139:152-165. https://doi.org/10.1016/j.jaci.2016.07.019

  2. Malik K, He H, Huynh TN, Tran G, Mueller K, Doytcheva K et al (2019) Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature. J Allergy Clin Immunol 143:604–618. https://doi.org/10.1016/j.jaci.2018.03.021

    Article  CAS  PubMed  Google Scholar 

  3. Czarnowicki T, He H, Leonard A, Malik K, Magidi S, Rangel S et al (2018) The major orphan forms of ichthyosis are characterized by systemic T-cell activation and Th-17/Tc-17/Th-22/Tc-22 polarization in blood. J Invest Dermatol 138:2157–2167. https://doi.org/10.1016/j.jid.2018.03.1523

    Article  CAS  PubMed  Google Scholar 

  4. Thaçi D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F, Kingo K et al (2015) Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 73:400–409. https://doi.org/10.1016/j.jaad.2015.05.013

    Article  CAS  PubMed  Google Scholar 

  5. Marukian NV, Deng Y, Gan G, Ren I, Thermidor W, Craiglow BG et al (2017) Establishing and validating an ichthyosis severity index. J Invest Dermatol 137:1834–1841. https://doi.org/10.1016/j.jid.2017.04.037

    Article  CAS  PubMed  Google Scholar 

  6. Bodemer C, Bourrat E, Mazereeuw-Hautier J, Boralevi F, Barbarot S, Bessis D, Blanchet-Bardon C et al (2011) Short- and medium-term efficacy of specific hydrotherapy in inherited ichthyosis. Br J Dermatol 165:1087–1094. https://doi.org/10.1111/j.1365-2133.2011.10510

    Article  CAS  PubMed  Google Scholar 

  7. Erickson TR, Murphrey MB, Abu-Zayed H, Wu B, Ibler E, Rangel SM et al (2020) Transepidermal water loss in the orphan forms of ichthyosis. Pediatr Dermatol 37:771–773. https://doi.org/10.1111/pde.14221

    Article  PubMed  Google Scholar 

  8. Elman S, Hynan LS, Gabriel V, Mayo MJ (2009) The 5-D itch scale: a new measure of pruritus. Br J Dermatol 162:587–593. https://doi.org/10.1111/j.1365-2133.2009.09586

    Article  PubMed  PubMed Central  Google Scholar 

  9. Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY (2008) The Dermatology Life Quality Index 1994–2007: a comprehensive review of validation data and clinical results. Br J Dermatol 159:997–1035. https://doi.org/10.1111/j.1365-2133.2008.08832

    Article  CAS  PubMed  Google Scholar 

  10. Dreyfus I, Taïeb C, Barbarot S, Maza A, Galera I, Bourrat E, et al. et al (2013) iQoL-32: a new ichthyosis-specific measure of quality of life. J Am Acad Dermatol 69:82–87. https://doi.org/10.1016/j.jaad.2013.01.022

    Article  PubMed  Google Scholar 

  11. Krueger JG, Wharton KA Jr, Schlitt T, Suprun M, Torene RI, Jiang X et al (2019) IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis. J Allergy Clin Immunol 144:750–763. https://doi.org/10.1016/j.jaci.2019.04.029

    Article  CAS  PubMed  Google Scholar 

  12. Hernández-Martín A, Kennedy-Batalla R, Cañedo E, González-Sarmiento R, Kennedy-Batalla Rebeca, Martínez-Bonet Marta, et al. (2019) Imbalance in T-helper 17 cells and targeted therapy in an infant with SAM-like syndrome. N Engl J Med 381:2176–2178. https://doi.org/10.1056/NEJMc1908531

  13. Paller AS. (2020) Pathogenesis-based therapy with repurposed biologics for monogenic inflammatory skin disorders. JAMA Dermatol 156:839–41. https://doi.org/10.1001/jamadermatol.2020.1018

  14. Luchsinger I, Knöpfel N, Theiler M, Bonnet des Claustres M, Barbieux C, Schwieger-Briel A, et al. (2020) Secukinumab therapy for Netherton syndrome. JAMA Dermatol156:907–11. https://doi.org/10.1001/jamadermatol.2020.1019

  15. Blanchard SK, Prose NS (2020) Successful use of secukinumab in Netherton syndrome. JAAD Case Rep 6:577–578. https://doi.org/10.1016/j.jdcr.2020.04.025

    Article  PubMed  PubMed Central  Google Scholar 

  16. Paller AS, Czarnowicki T, Renert-Yuval Y, Holland K, Huynh T, Sadlier M, et al. (2018) The spectrum of manifestations in desmoplakin gene (DSP) spectrin repeat 6 domain mutations: Immunophenotyping and response to ustekinumab. J Am Acad Dermatol 78:498–505.e2. https://doi.org/10.1016/j.jaad.2017.10.026

  17. Sun Q, Wine Lee L, Hall EK, Choate KA, Elder RW. (2021) Hair and skin predict cardiomyopathies: Carvajal and erythrokeratodermia cardiomyopathy syndromes. Pediatr Dermatol 38:31–38. https://doi.org/10.1111/pde.14478

  18. Frommherz LH, Schempp CM, Has C. (2021) Secukinumab for the treatment of SAM syndrome associated with desmoglein-1 deficiency. Br J Dermatol 184:770–772. https://doi.org/10.1111/bjd.19684

  19. Steinhoff, M, Al-Marri, F, Al Chalabi, R, Gieler, U, Buddenkotte, J. (2021) Recalcitrant erythrodermic ichthyosis with atopic dermatitis successfully treated with dupilumab in combination with guselkumab. Skin Health Dis.e87. https://doi.org/10.1002/ski2.87

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Funding

Investigator-initiated grant from Novartis CAIN457AUS05T (AP, EG); genotyping was supported by NIH R01AR068392 (KC), biosample management through NIH P30AR075049 (Northwestern’s Skin Biology and Disease Resource-based Center/SBDRC) (AP), and regulatory support and some of the clinical statistical analyses through NIH UL1TR001422 (Northwestern University Clinical and Translational Sciences Institute/NUCATS and its Biostatistics Collaboration Center. Dr. Lefferdink received salary funding from a National Psoriasis Foundation fellowship grant.

Author information

Author notes

  1. Rachel Lefferdink and Stephanie M. Rangel are co-first authors.

  2. Emma Guttman-Yassky and Amy S. Paller: equal contribution.

Authors and Affiliations

  1. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Rachel Lefferdink, Stephanie M. Rangel, Erin Ibler, Benedict Wu, Hajar Abu-Zayed & Amy S. Paller

  2. Department of Dermatology, The Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai Medical Center, New York, NY, USA

    Margot Chima, Ana B. Pavel, HeeJin Kim, Jianni Wu, Giselle Singer & Emma Guttman-Yassky

  3. Department of Biomedical Engineering, University of Mississippi, University, Oxford, MS, USA

    Ana B. Pavel

  4. Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Kathryn Jackson

  5. Departments of Dermatology, Genetics, and Pathology, Yale University School of Medicine, New Haven, CT, USA

    Keith A. Choate

Authors
  1. Rachel Lefferdink
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  2. Stephanie M. Rangel
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  4. Erin Ibler
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  12. Keith A. Choate
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Contributions

Study conception and design were performed by Erin Ibler, EG-Y, and ASP. Material preparation, data collection and analysis were performed by RL, SMR, MC, EI, ABP, HK, BW, HA-Z, JW, KJ, GS, KAC, EG-Y and ASP. The first draft of the manuscript was written by RL, SMR, EG-Y and ASP, and all authors read and approved the final manuscript.

Corresponding authors

Correspondence to Emma Guttman-Yassky or Amy S. Paller.

Ethics declarations

Conflict of interest

Drs. Lefferdink, Chima, Ibler, Pavel, Kim, Wu, and Rangel, and Ms. Abu-Zayed, Wu, Jackson, and Singer declare no conflicts. Dr. Choate has been an investigator for Alderya, Mayne, Galderma, and Regeneron and consultant with honorarium for AbbVie, Eli Lilly, Janssen, KrystalBio, Lifemax, Mayne, and Timber. Dr. Guttman-Yassky has been a researcher/consultant for AbbVie, Anacor, AnaptysBio, Asana Biosciences, Botanix, Celgene, DBV, Dermira, DS Biopharma, Escalier, Galderma, Glenmark, Innovaderm, Janssen, Kyowa Kirin, Leo Pharma, Lilly, MedImmune/AstraZeneca, Mitsubishi Tanabe, Novan, Novartis, Pfizer, Promius, Ralexar, Regeneron, Sanofi-Aventis, Stiefel/GlaxoSmithKline (GSK), UCB, and Vitae. Dr. Paller has been an investigator for AbbVie, AnaptysBio, Eli Lilly, Incyte, Janssen, KrystalBio, Novartis, Regeneron, and UCB and a consultant with honorarium for Abbvie, Abeona, Alcimed, Almirall, Amagma, Anaptysbio, Arena, Azitra, BiomX, Boehringer Ingelheim, Castle Biosciences, Catawba, Dermira, Eli Lilly, Exicure, Forte, Kamari, Leo, Lifemax, NAOS, Novartis, Pfizer, Phoenix, Pierre Fabre, Regeneron, Sanofi/Genzyme, Seanergy, Trifecta, and UCB. She has served on Data Safety Monitoring Boards for AbbVie, Bausch, Galderma, and Novan.

Ethics approval

This study was reviewed and approved by the institutional review boards of Northwestern University and Icahn School of Medicine at Mount Sinai Medical Center. IRB #: STU00202656/STU00202022 (NU); 17–00126 (MS).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Lefferdink, R., Rangel, S.M., Chima, M. et al. Secukinumab responses vary across the spectrum of congenital ichthyosis in adults. Arch Dermatol Res 315, 305–315 (2023). https://doi.org/10.1007/s00403-022-02325-3

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