A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis - 02/03/16

Doi : 10.1016/j.jaci.2015.12.1323

Patrick M. Brunner, MD ^a,^{^{∗
These authors contributed equally to this work.}}, Saakshi Khattri, MD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Sandra Garcet, PhD ^a, Robert Finney, MD ^c, Margeaux Oliva, BA ^a,^b, Riana Dutt, ScB ^a,^b, Judilyn Fuentes-Duculan, MD ^a, Xiuzhong Zheng, MSc ^a, Xuan Li, BA ^a, Kathleen M. Bonifacio, MD ^a, Norma Kunjravia, MD ^a, Israel Coats, BA ^a, Inna Cueto, MSc ^a, Patricia Gilleaudeau, NP ^a, Mary Sullivan-Whalen, NP ^a, Mayte Suárez-Fariñas, PhD ^a,^b,^d,^e, James G. Krueger, MD, PhD ^a, Emma Guttman-Yassky, MD, PhD ^a,^b,^⁎
^a Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
^b Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
^c Department of Dermatology, Jefferson Medical College, Philadelphia, Pa
^d Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
^e Icahn Institute for Genomics and Multiscale Biology at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY

^∗Corresponding author: Emma Guttman-Yassky, MD, PhD, Department of Dermatology, Icahn School of Medicine at Mount Sinai Medical Center, 5 E 98th St, New York, NY 10029.Department of DermatologyIcahn School of Medicine at Mount Sinai Medical Center5 E 98th StNew YorkNY10029

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Abstract

Background

Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking.

Objective

We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers.

Methods

The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD.

Results

At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment.

Conclusion

Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.

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Key words : Atopic dermatitis, triamcinolone acetonide, topical glucocorticosteroids, immune, epidermal

Abbreviations used : AD, DC, FCH, IHC, K16, PI3, qRT-PCR, SCORAD50

Plan

Methods

Patients' characteristics and skin samples

Immunohistochemistry

Quantitative real-time PCR and gene array analysis

Statistical analysis

Results

Profoundly different tissue responses in histologic glucocorticosteroid responders and nonresponders

Differential expression of key immune genes in glucocorticosteroid responders and nonresponders

Suppression of inflammatory cell infiltrates in glucocorticosteroid responders

Significant decreases in T cell–defining cytokine and chemokine levels were only prominent in responders, as assessed by using qRT-PCR

Discussion

P.M.B. and M.S.-F. were supported in part by grant UL1 TR00043 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program.

Disclosure of potential conflict of interest: M. Suárez-Fariñas has received grants from Pfizer and Quorum Consulting. J. G. Krueger has received personal fees and/or payment to his institution from Novartis, Pfizer, Amgen, Lilly, Merck, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, Biogen Idec, Janssen, Delenex, Abbvie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. E. Guttman-Yassky has board memberships with Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, Leo Pharma, AnaptysBio, Celsus, Dermira, Galderma, Novartis, Pfizer, and Vitae; has consultant arrangements with Regeneron, Sanofi Aventis, MedImmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, Drais, AbbVie, Anacor, AnaptysBio, Dermira, Galderma, Leo Pharma, Novartis, Pfizer, Vitae, Mitsubishi Tanabe, and Eli Lilly; and has received grants from Regeneron, Celgene, BMS, Janssen, Dermira, Leo Pharma, Merck, and Novartis. The rest of the authors declare that they have no relevant conflicts of interest.