Laurence Feldmeyer1, Alessio Mylonas2, Olivier Demaria2, Anna Mennella2, Nikhil Yawalkar3, Emmanuel Laffitte4, Daniel Hohl2, Michel Gilliet2, Curdin Conrad2. 1. Department of Dermatology and Venereology, University Hospital of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland2Department of Dermatology and Venereology, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland. 2. Department of Dermatology and Venereology, University Hospital of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 3. Department of Dermatology and Venereology, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland. 4. Department of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland.
Abstract
IMPORTANCE: Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP. OBJECTIVE: To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP. DESIGN, SETTING, AND PARTICIPANTS: In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months. INTERVENTION: Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines. RESULTS: In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1β. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration. CONCLUSIONS AND RELEVANCE: In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP.
IMPORTANCE: Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP. OBJECTIVE: To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP. DESIGN, SETTING, AND PARTICIPANTS: In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months. INTERVENTION: Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines. RESULTS: In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1β. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration. CONCLUSIONS AND RELEVANCE: In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP.
Authors: Cindy P Frare; Alli J Blumstein; Amy S Paller; Lia Pieretti; Keith A Choate; Anne M Bowcock; Margarita Larralde Journal: Pediatr Dermatol Date: 2021-08-26 Impact factor: 1.997
Authors: Dylan Haynes; Jennifer L Strunck; Christina A Topham; Alex G Ortega-Loayza; Gail Kent; Pamela B Cassidy; Ronghua Hu; Keith Choate; Zhiping Wang; Yuangang Liu; Teri M Greiling Journal: JAMA Dermatol Date: 2020-06-01 Impact factor: 10.282
Authors: Brittany G Craiglow; Lynn M Boyden; Ronghua Hu; Marie Virtanen; John Su; Gabriela Rodriguez; Catherine McCarthy; Paula Luna; Margarita Larralde; Stephen Humphrey; Kristen E Holland; Marcia Hogeling; Benjamin Hidalgo-Matlock; Bruno Ferrari; Esteban Fernandez-Faith; Beth Drolet; Kelly M Cordoro; Anne M Bowcock; Richard J Antaya; Kurt Ashack; Richard J Ashack; Richard P Lifton; Leonard M Milstone; Amy S Paller; Keith A Choate Journal: J Am Acad Dermatol Date: 2018-03-01 Impact factor: 11.527