The renaissance of therapeutic options in dermatology

Megan Lau Joseph Largen Ester Del Duca Helen He Emma Guttman-Yassky Recent breakthroughs in deciphering the immunopathomechanisms underlying dermatologic diseases have fundamentally reshaped the therapeutic landscape of dermatology, marking a transition from broad-spectrum immunosuppression to targeted, mechanism-based interventions.1 A cross-comparison of expression profiles from various skin diseases defined transcriptional modules, including Th1, Th2, Th17, type I IFN, neutrophilic, macrophagic and eosinophilic, and demonstrated how patient-based molecular profiling can support precision dermatology, showing diagnostic utility in clinico-pathologically undetermined cases and improved treatment responses when modules were aligned with therapeutic targets.2 This approach demonstrated the potential of molecular profiling to inform diagnosis and guide the selection of targeted therapies in personalized dermatological treatment.2 Transcriptomic, proteomic and cytokine analysis of skin and blood have identified disease-specific biomarkers, revealed the immune signatures of skin disease, drove the development of systemic therapies and laid the foundation for personalized medicine in inflammatory dermatoses.1 Psoriasis served as an early model for translational medicine in dermatology. Comprehensive molecular profiling has identified Th17/IL-23 as key cytokines in the pathogenesis of psoriasis, paving the way for the development and FDA approval of targeted biologic therapies.3 These include ustekinumab (IL-12/IL-23p40 inhibitor); guselkumab, tildrakizumab and risankizumab (IL-23p19 inhibitors); secukinumab and ixekizumab (IL-17A inhibitors) and brodalumab (IL-17 receptor A inhibitor).4 Approximately 33% of psoriasis patients develop psoriatic arthritis (PsA), with nearly all PsA patients having cutaneous involvement; tofacitinib and upadacitinib are approved for PsA, whereas deucravacitinib, a selective TYK2 inhibitor targeting the JAK–STAT pathway, is approved for plaque psoriasis.5 These targeted therapeutics demonstrate clinical efficacy and molecular disease improvement, establishing a new standard of care for immune-targeted, mechanism-based treatment approaches. This bench-to-bedside paradigm has expanded to atopic dermatitis (AD), where molecular profiling has revealed Th2 and Th22 cytokine upregulation and barrier dysfunction with reduced expression of structural proteins such as filaggrin, loricrin, tight junction proteins, like claudins 1, 8 and 23, and lipids.6 Studies have revealed differences across ethnicities in AD, such as greater Th17 polarization in Asian patients and attenuated Th1/Th17 responses in Black patients.7 Our group has also shown age-specific molecular changes in AD, with younger patients showing dominant greater Th17 polarization and less pronounced filaggrin and loricrin barrier defects, while older patients exhibit additional Th1 skewing and greater barrier impairment.8 These findings accentuate the need for incorporating patient age, ethnicity and immune endotype in guiding treatment plans and demonstrate the impact of molecular characterization in targeted interventions across distinct AD phenotypes. Enhanced understanding of AD immune signatures catalysed the development of targeted therapies that address disease heterogeneity and support personalized treatment approaches.1 Biopsy studies provided clues into skin biomarkers, including upregulation of inflammatory markers (MMP12), Th2 (IL13, CCL17), Th1 (CXCL10), Th17/Th22 (PI3, CCL20, S100A12) in AD skin compared to controls.9 While blood analyses allow some insights, the skin is the primary source of AD biomarkers.10 Implementation of tape-strip transcriptomics and proteomics offered a minimally invasive method to capture immune and barrier signatures in skin conditions.9 These molecular insights drove the development of dupilumab, which acts through IL-4 receptor α blockade to inhibit IL-4/IL-13 signalling.1 Tralokinumab and lebrikizumab, selective IL-13 inhibitors, offer a Th2-specific blockade alternative.1 Nemolizumab, which blocks the IL-31 receptor, may be beneficial in severe itch conditions, as it directly targets itch-related neural signalling.1 Small molecules, such as the JAK inhibitors, offer broader immunomodulation, inhibiting cytokine pathways across the Th1, Th2, Th17 and Th22 axes and may be utilized in recalcitrant disease, in phenotypes involving multiple immune axes or when managing coexisting inflammatory comorbidities.1 Novel agents targeting OX40/OX40L are under investigation and aim to modulate memory T-cell survival, which may provide a potential for disease modification, as memory T cells are responsible for repopulation of lesions once treatments are stopped.1 Treatments targeting epidermal barrier dysfunction with IL22/IL22R may offer an alternative for refractory disease phenotype or significant barrier disruption.1 Novel therapeutic approaches are advancing with rezpegaldesleukin, the first regulatory T-cell proliferator that targets the IL-2 pathway to improve immune dysregulation by promoting T regulatory cell expansion and restoring immune balance.11 The translational framework has also extended to other dermatologic conditions and contributed to the growing treatment repertoire of targeted biologics, systemic immunomodulators and small-molecule inhibitors. In alopecia areata (AA), molecular characterization has shown Th1, Th2, IL-9/Th9 and IL-23 cytokine activation and led to the FDA approval of JAK inhibitors, baricitinib (JAK1/2 inhibitor) and ritlecitinib (JAK3/TEC kinase inhibitor), that target pathogenic T cell–mediated IFN-γ signalling with demonstrated efficacy in moderate-to-severe AA.1, 12 Dupilumab is also being evaluated as a potential treatment in AA atopy associated subsets with elevated IgE and Th2 skewing, further supporting a biomarker-driven approach.1 Similar immune mapping has revealed distinct molecular signatures such as Th1-driven inflammation in lichen planus, type I IFN activation in lupus erythematosus, Th2, Th1, Th17/Th22 and JAK3 skewing in keloids, Th17 skewing and cytotoxic T-cell activity against melanocytes in vitiligo, and fibrotic/innate signatures in hidradenitis suppurativa.13, 14 This paves the way for a new paradigm of translational medicine across diverse skin diseases, with the implementation of biologics for hidradenitis suppurativa, adalimumab (anti-TNF-α mAb), secukinumab (anti-IL-17A mAb) and bimekizumab (anti-IL-17A/F mAb), and by the approval of ruxolitinib cream, a topical JAK inhibitor, as the first treatment for repigmentation in non-segmental vitiligo.15 Dermatology is undergoing a translational renaissance with a therapeutic shift towards mechanism-based, personalized treatment, improving outcomes across inflammatory skin diseases. None. Emma Guttman-Yassky is an employee of Mount Sinai and has received research grants from and/or is a consultant for AbbVie, Arcutis, Almirall, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics Limited, Artax Biopharma Inc., Aslan, Astria, Bristol Meyers Squibb, Boerhinger-Ingelhiem, Calliditas, Cara Therapeutics, Celldex, Centrexion Therapeutics Corporation, Concert, Connect Biopharm, Coty, DBV Technologies, Eli Lilly, Enveda Biosciences, Escient Pharmaceuticals, Inc., Fairmount Funds Management LLC, FL2022-001, Inc., Galderma, Gate Bio, Google Ventures (GV), GSK Immunology, Incyte, Inmagene, Janssen Biotech, Jasper Therapeutics, Kymera Therapeutics, Kyowa Kirin, Leo Pharma, Matchpoint Therapeutics, Merck, Nektar Therapeutics, Novartis Pharmaceuticals, NUMAB Therapeutics AG, Nuvig, OrbiMed Advisors LLC, OTSUKA, Pfizer, Pharmaxis Ltd., Pioneering Medicine VII, Inc., Proteologix US Inc., Q32Bio, RAPT, RayThera, Inc., Regeneron Pharmaceuticals, RibonTherapeutics, Inc., Rocatinlimab, SAGIMET Bioscieces, Sanofi, SATO, Schrödinger, Inc., Sitryx, Sun Pharma Advanced Research Company (SPARC), Takeda, Teva Branded Pharmaceutical Products R&D, Inc., TRex, UCB, Ventyx Biosyences. The rest of the authors declare that they have no relevant conflicts of interest. IRB approval not required. Not applicable. Data sharing is not applicable to this article as no new data were created or analysed in this study.