Secukinumab Reduces Psoriasis-associated Pruritus and Regenerates the Cutaneous Nerve Architecture: Results from PSORITUS a Doubleblind, Placebo-controlled, Randomized Withdrawal Phase IIIb Study

Authors

  • Lina Renkhold 1Department of Dermatology, University Hospital Münster, Münster, Germany; Center for Chronic Pruritus, University Hospital Münster, Münster, Germany https://orcid.org/0000-0002-3187-0602
  • Manuel P. Pereira Institute of Allergology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany https://orcid.org/0000-0001-5649-2698
  • Karin Loser Institute of Immunology, University of Oldenburg, Oldenburg, Germany https://orcid.org/0000-0002-0007-0936
  • Dieter Metze Department of Dermatology, University Hospital Münster, Münster, Germany
  • Daniel Baeumer Novartis Pharma GmbH, Nuremberg, Germany https://orcid.org/0000-0003-4236-4438
  • Nima Melzer Novartis Pharma GmbH, Nuremberg, Germany
  • Maximilian Reinhardt Novartis Pharma AG, Basel, Switzerland
  • Athanasios Tsianakas Fachklinik Bad Bentheim, Department of Dermatology, Bad Bentheim, Germany https://orcid.org/0000-0003-1563-7402
  • Thomas Luger Department of Dermatology, University Hospital Münster, Münster, Germany https://orcid.org/0000-0003-1397-1626
  • Christian Mess Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany https://orcid.org/0000-0001-8642-5226
  • Ruth Becker 1Department of Dermatology, University Hospital Münster, Münster, Germany; Center for Chronic Pruritus, University Hospital Münster, Münster, Germany
  • Clara Hambüchen 1Department of Dermatology, University Hospital Münster, Münster, Germany; Center for Chronic Pruritus, University Hospital Münster, Münster, Germany
  • Konstantin Agelopoulos 1Department of Dermatology, University Hospital Münster, Münster, Germany; Center for Chronic Pruritus, University Hospital Münster, Münster, Germany https://orcid.org/0000-0002-5601-9195
  • Sonja Ständer 1Department of Dermatology, University Hospital Münster, Münster, Germany; Center for Chronic Pruritus, University Hospital Münster, Münster, Germany https://orcid.org/0000-0003-3612-7786

DOI:

https://doi.org/10.2340/actadv.v104.40737

Keywords:

Pruritus, Psoriasis, Neuroanatomy, Therapy

Abstract

The occurrence of pruritus in psoriasis was previously underestimated but is a significant burden. Secukinumab (SEC), a monoclonal anti-interleukin-17A antibody, efficiently controls signs of psoriasis, but the effect on pruritus and cutaneous neuroanatomy remained unknown. The primary objective of this study (NCT02362789) was to evaluate the superiority of SEC treatment vs placebo on pruritus intensity (visual analogue scale; VAS). Furthermore, the treatment-dependent course of pruritus in association with absolute Psoriasis Area Severity Index (PASI) score, as well as cutaneous histopathology and neuroanatomy, was assessed. Open-label SEC 300 mg s.c. was administered regularly until week 16. Patients who reached a ≥ 98% PASI reduction (PASI ≥ 98) were randomized to receive either placebo or SEC up to week 32. Punch biopsies were collected from lesional psoriatic (baseline, weeks 16 and 32) and non-lesional (baseline) skin for histopathological and neuroanatomical analyses. VAS scores improved significantly after open-label SEC treatment but relapsed upon placebo (29.92 ± 33.8) compared with SEC (12.30 ± 22.6; p = 0.036). After SEC-dependent improvement in PASI, histopathology, marker expression and neuroanatomy, relapse was observed with treatment discontinuation in all parameters except neuroanatomy. SEC was superior to placebo by efficiently controlling reduced pruritus intensity, clinically normalizing skin lesions, and reversing histopathological abnormalities. The neuroanatomy recovered upon SEC and remained stable even after withdrawal.

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References

Amatya B, Wennersten G, Nordlind K. Patients’ perspective of pruritus in chronic plaque psoriasis: a questionnaire-based study. J Eur Acad Dermatol Venereol 2008; 22: 822–826.

https://doi.org/10.1111/J.1468-3083.2008.02591.X DOI: https://doi.org/10.1111/j.1468-3083.2008.02591.x

Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol 2000; 143: 969–973.

https://doi.org/10.1046/J.1365-2133.2000.03829.X DOI: https://doi.org/10.1046/j.1365-2133.2000.03829.x

Reich A, Hrehorow E, Szepietowski JC. Pruritus is an important factor negatively influencing the well-being of psoriatic patients. Acta Derm Venereol 2010; 90: 257–263.

https://doi.org/10.2340/00015555-0851 DOI: https://doi.org/10.2340/00015555-0851

Hawro M, Sahin E, Steć M, Różewicka-Czabańska M, Raducha E, Garanyan L, et al. A comprehensive, tri-national, cross-sectional analysis of characteristics and impact of pruritus in psoriasis. J Eur Acad Dermatol Venereol 2022; 36: 2064–2075.

https://doi.org/10.1111/JDV.18330 DOI: https://doi.org/10.1111/jdv.18330

Korman NJ, Zhao Y, Pike J, Roberts J, Sullivan E. Increased severity of itching, pain, and scaling in psoriasis patients is associated with increased disease severity, reduced quality of life, and reduced work productivity. Dermatol Online J 2015; 21.

https://doi.org/10.5070/d32110028943 DOI: https://doi.org/10.5070/D32110028943

Zhu B, Edson-Heredia E, Guo J, Maeda-Chubachi T, Shen W, Kimball AB. Itching is a significant problem and a mediator between disease severity and quality of life for patients with psoriasis: results from a randomized controlled trial. Br J Dermatol 2014; 171: 1215–1219.

https://doi.org/10.1111/bjd.13065 DOI: https://doi.org/10.1111/bjd.13065

Ständer S, Steinke S, Augustin M, Metze D, Loser K, Baeumer D, et al. Quality of life in psoriasis vulgaris: use of the ItchyQoL questionnaire in a secukinumab phase iii trial in patients with psoriasis vulgaris. Acta Derm Venereol 2019; 99: 1085–1090.

https://doi.org/10.2340/00015555-3275 DOI: https://doi.org/10.2340/00015555-3275

Agelopoulos K, Pereira MP, Wiegmann H, Ständer S. Cutaneous neuroimmune crosstalk in pruritus. Trends Mol Med 2022; 28: 452–462.

https://doi.org/10.1016/J.MOLMED.2022.03.005 DOI: https://doi.org/10.1016/j.molmed.2022.03.005

Komiya E, Tominaga M, Kamata Y, Suga Y, Takamori K. Molecular and cellular mechanisms of itch in psoriasis. Int J Mol Sci 2020; 21: 1–25.

https://doi.org/10.3390/IJMS21218406 DOI: https://doi.org/10.3390/ijms21218406

Ayasse MT, Buddenkotte J, Alam M, Steinhoff M. Role of neuroimmune circuits and pruritus in psoriasis. Exp Dermatol 2020; 29: 414–426.

https://doi.org/10.1111/EXD.14071 DOI: https://doi.org/10.1111/exd.14071

Nattkemper LA, Lipman ZM, Ingrasci G, Maldonado C, Garces JC, Loayza E, et al. Neuroimmune mediators of pruritus in Hispanic scalp psoriatic itch. Acta Derm Venereol 2023; 103: adv4463.

https://doi.org/10.2340/actadv.v103.4463 DOI: https://doi.org/10.2340/actadv.v103.4463

Kodji X, Arkless KL, Kee Z, Cleary SJ, Aubdool AA, Evans E, et al. Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis. FASEB J 2019; 33: 1578–1594.

https://doi.org/10.1096/FJ.201800395RR DOI: https://doi.org/10.1096/fj.201800395RR

Johansson O, Han SW, Enhamre A. Altered cutaneous innervation in psoriatic skin as revealed by PGP 9.5 immunohistochemistry. Arch Dermatol Res 1991; 283: 519–523.

https://doi.org/10.1007/BF00371926 DOI: https://doi.org/10.1007/BF00371926

Tan Y, Ng WJ, Lee SZX, Lee BTK, Nattkemper LA, Yosipovitch G, et al. 3-dimensional optical clearing and imaging of pruritic atopic dermatitis and psoriasis skin reveals downregulation of epidermal innervation. J Invest Dermatol 2019; 139: 1201–1204.

https://doi.org/10.1016/j.jid.2018.11.006 DOI: https://doi.org/10.1016/j.jid.2018.11.006

Taneda K, Tominaga M, Negi O, Tengara S, Kamo A, Ogawa H, et al. Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch. Br J Dermatol 2011; 165: 277–284.

https://doi.org/10.1111/J.1365-2133.2011.10347.X DOI: https://doi.org/10.1111/j.1365-2133.2011.10347.x

Nattkemper LA, Tey HL, Valdes-Rodriguez R, Lee H, Mollanazar NK, Albornoz C, et al. The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch. J Invest Dermatol 2018; 138: 1311–1317.

https://doi.org/10.1016/J.JID.2017.12.029 DOI: https://doi.org/10.1016/j.jid.2017.12.029

Pogatzki-Zahn EM, Pereira MP, Cremer A, Zeidler C, Dreyer T, Riepe C, et al. Peripheral sensitization and loss of descending inhibition is a hallmark of chronic pruritus. J Invest Dermatol 2020; 140: 203–211.e4.

https://doi.org/10.1016/J.JID.2019.05.029 DOI: https://doi.org/10.1016/j.jid.2019.05.029

Renkhold L, Wiegmann H, Pfleiderer B, Süer A, Zeidler C, Pereira MP, et al. Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus. Front Mol Neurosci 2023; 16: 1260345.

https://doi.org/10.3389/fnmol.2023.1260345 DOI: https://doi.org/10.3389/fnmol.2023.1260345

Feldman SR, Green L, Kimball AB, Siu K, Zhao Y, Herrera V, et al. Secukinumab improves scalp pain, itching, scaling and quality of life in patients with moderate-to-severe scalp psoriasis. J Dermatolog Treat 2017; 28: 716–721.

https://doi.org/10.1080/09546634.2017.1329502 DOI: https://doi.org/10.1080/09546634.2017.1329502

Lacour JP, Paul C, Jazayeri S, Papanastasiou P, Xu C, Nyirady J, et al. Secukinumab administration by autoinjector maintains reduction of plaque psoriasis severity over 52 weeks: results of the randomized controlled JUNCTURE trial. J Eur Acad Dermatol Venereol 2017; 31: 847–856.

https://doi.org/10.1111/JDV.14073 DOI: https://doi.org/10.1111/jdv.14073

Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 2008; 128: 1207–1211.

https://doi.org/10.1038/sj.jid.5701213 DOI: https://doi.org/10.1038/sj.jid.5701213

Moynes DM, Vanner SJ, Lomax AE. Participation of interleukin 17A in neuroimmune interactions. Brain Behav Immun 2014; 41: 1–9.

https://doi.org/10.1016/j.bbi.2014.03.004 DOI: https://doi.org/10.1016/j.bbi.2014.03.004

Bobko S, Zeidler C, Osada N, Riepe C, Pfleiderer B, Pogatzki-Zahn E, et al. Intraepidermal nerve fibre density is decreased in lesional and inter-lesional prurigo nodularis and reconstitutes on healing of lesions. Acta Derm Venereol 2016; 96: 404–406.

https://doi.org/10.2340/00015555-2232 DOI: https://doi.org/10.2340/00015555-2232

Sage D, Donati L, Soulez F, Fortun D, Schmit G, Seitz A, et al. DeconvolutionLab2: an open-source software for deconvolution microscopy. Methods 2017; 115: 28–41.

https://doi.org/10.1016/J.YMETH.2016.12.015 DOI: https://doi.org/10.1016/j.ymeth.2016.12.015

Markram H. The blue brain project. Nat Rev Neurosci 2006; 7: 153–160.

https://doi.org/10.1038/NRN1848 DOI: https://doi.org/10.1038/nrn1848

Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CEM, Papp K, et al. Secukinumab in plaque psoriasis: results of two phase 3 trials. N Engl J Med 2014; 371: 326–338.

https://doi.org/10.1056/NEJMOA1314258 DOI: https://doi.org/10.1056/NEJMoa1314258

Frieder J, Kivelevitch D, Menter A. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis 2018; 9: 5–21.

https://doi.org/10.1177/2040622317738910 DOI: https://doi.org/10.1177/2040622317738910

Simopoulou T, Tsiogkas SG, Zafiriou E, Bogdanos DP. Secukinumab, ixekizumab, bimekizumab and brodalumab for psoriasis and psoriatic arthritis. Drugs Today (Barc) 2023; 59: 135–167.

https://doi.org/10.1358/dot.2023.59.3.3419557 DOI: https://doi.org/10.1358/dot.2023.59.3.3419557

Lessard JC, Piña-Paz S, Rotty JD, Hickerson RP, Kaspar RL, Balmain A, et al. Keratin 16 regulates innate immunity in response to epidermal barrier breach. Proc Natl Acad Sci U S A 2013; 110: 19537– 19542.

https://doi.org/10.1073/PNAS.1309576110 DOI: https://doi.org/10.1073/pnas.1309576110

Granata M, Skarmoutsou E, Mazzarino MC, D’Amico F. S100A7 in psoriasis: immunodetection and activation by CRISPR technology. Methods Mol Biol 2019; 1929: 729–738.

https://doi.org/10.1007/978-1-4939-9030-6_45 DOI: https://doi.org/10.1007/978-1-4939-9030-6_45

Werner B, Bresch M, Brenner FM, Lima HC. Comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after treatment with acitretin. J Cutan Pathol 2008; 35: 302–310.

https://doi.org/10.1111/J.1600-0560.2007.00800.X DOI: https://doi.org/10.1111/j.1600-0560.2007.00800.x

Fernandes AR, Martins-Gomes C, Santini A, Silva AM, Souto EB. Psoriasis vulgaris: pathophysiology of the disease and its classical treatment versus new drug delivery systems. In: Grumezescu AM, editor. Design of nanostructures for versatile therapeutic applications. Norwich, NY: William Andrew Publishing; 2018: p. 379–406.

https://doi.org/10.1016/B978-0-12-813667-6.00009-7 DOI: https://doi.org/10.1016/B978-0-12-813667-6.00009-7

Blauvelt A, Pariser DM, Tyring S, Bagel J, Alexis AF, Soung J, et al. Psoriasis improvements and inflammatory biomarker normalization with secukinumab: the randomized ObePso-S study. J Dermatol Sci 2023; 109: 12–21.

https://doi.org/10.1016/J.JDERMSCI.2023.01.003 DOI: https://doi.org/10.1016/j.jdermsci.2023.01.003

Gauglitz GG, Bureik D, Zwicker S, Ruzicka T, Wolf R. The antimicrobial peptides psoriasin (S100A7) and koebnerisin (S100A15) suppress extracellular matrix production and proliferation of human fibroblasts. Skin Pharmacol Physiol 2015; 28: 115–123.

https://doi.org/10.1159/000363579 DOI: https://doi.org/10.1159/000363579

Kim TW, Shim WH, Kim JM, Mun JH, Song M, Kim HS, et al. Clinical characteristics of pruritus in patients with scalp psoriasis and their relation with intraepidermal nerve fiber density. Ann Dermatol 2014; 26: 727–732.

https://doi.org/10.5021/ad.2014.26.6.727 DOI: https://doi.org/10.5021/ad.2014.26.6.727

Cui S, Xiao T, Wang Y, Lu H, Wang Y, Gao XH, et al. Morphological relationship between nerve fibers and Langerhans cells in the epidermis of psoriasis vulgaris and lichen simplex chronicus. J Dermatol Sci 2009; 56: 132–134.

https://doi.org/10.1016/J.JDERMSCI.2009.07.009 DOI: https://doi.org/10.1016/j.jdermsci.2009.07.009

Choi JE, Di Nardo A. Skin neurogenic inflammation. Semin Immunopathol 2018; 40: 249–259.

https://doi.org/10.1007/s00281-018-0675-z DOI: https://doi.org/10.1007/s00281-018-0675-z

Nemmer JM, Kuchner M, Datsi A, Oláh P, Julia V, Raap U, et al. Interleukin-31 signaling bridges the gap between immune cells, the nervous system and epithelial tissues. Front Med (Lausanne) 2021; 8: 639097.

https://doi.org/10.3389/fmed.2021.639097 DOI: https://doi.org/10.3389/fmed.2021.639097

Oleszycka E, Kwiecien K, Kwiecinska P, Morytko A, Pocalun N, Camacho M, et al. Soluble mediators in the function of the epidermal-immune-neuro unit in the skin. Front Immunol 2022; 13: 1003970.

https://doi.org/10.3389/fimmu.2022.1003970 DOI: https://doi.org/10.3389/fimmu.2022.1003970

Gu D, Xia Y, Ding Z, Qian J, Gu X, Bai H, et al. Inflammation in the peripheral nervous system after injury. Biomedicines 2024; 12: 1256.

https://doi.org/10.3390/biomedicines12061256 DOI: https://doi.org/10.3390/biomedicines12061256

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2024-11-20

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Renkhold, L., Pereira, M. P., Loser, K., Metze, D., Baeumer, D., Melzer, N., … Ständer, S. (2024). Secukinumab Reduces Psoriasis-associated Pruritus and Regenerates the Cutaneous Nerve Architecture: Results from PSORITUS a Doubleblind, Placebo-controlled, Randomized Withdrawal Phase IIIb Study. Acta Dermato-Venereologica, 104, adv40737. https://doi.org/10.2340/actadv.v104.40737

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Vol. 104 (2024)

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Copyright (c) 2024 Lina Renkhold, Manuel P. Pereira, Karin Loser, Dieter Metze, Daniel Baeumer, Nima Melzer, Maximilian Reinhardt, Athanasios Tsianakas, Thomas Luger, Christian Mess, Ruth Becker, Clara Hambüchen, Konstantin Agelopoulos, Sonja Ständer

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