Emerging Research and Future Directions

28.1 Oral IL-23 Pathway Inhibitors

A major area of development is the creation of orally administered IL-23 pathway inhibitors. Icotrokinra (formerly JNJ-77242113) is a first-in-class oral peptide that antagonises the IL-23 receptor, potentially combining the high efficacy of IL-23 inhibition with the convenience of oral dosing. Phase 3 data (ICONIC-LEAD) showed that nearly half of patients achieved completely clear skin (IGA 0) at week 24 with a once-daily pill (see Section 27.6 for full trial details). Zasocitinib, a next-generation oral TYK2 inhibitor, demonstrated biologic-approaching efficacy in Phase 3 trials (Section 27.7). Together, these agents point toward an era where high-efficacy psoriasis treatment may no longer require injections (Childs et al., 2025).

28.2 Targeting Immunological Memory

Given the role of tissue-resident memory T cells (TRM cells) in psoriasis relapse, there is significant interest in developing therapies that target these memory populations. The STEPIn and GUIDE trials (Sections 27.2-27.3) demonstrated that early, aggressive treatment can reverse the epigenetic reprogramming of psoriatic skin and produce “super-responders” who maintain clearance even when treatment is tapered. Successfully depleting or reprogramming TRM cells could theoretically achieve true disease modification, potentially curing psoriasis rather than merely suppressing active inflammation (Sieminska et al., 2024). Research is ongoing into antibodies that target TRM surface markers (CD103, CD69) and strategies to disrupt the local cytokine signals (IL-15, IL-7) that sustain TRM survival in the skin.

28.3 The Microbiome as a Therapeutic Target

Research into the gut-skin axis may yield new therapeutic approaches. Prebiotics, probiotics, and faecal microbiota transplantation are all being investigated for their potential to modulate systemic inflammation in psoriasis. Dietary interventions, particularly Mediterranean, low-calorie, and omega-3-enriched diets, have shown some benefit as adjunctive strategies (Caso et al., 2022). The MEDIPSO trial (Section 19.2) provided the first RCT evidence that a structured Mediterranean diet improves psoriasis independently of weight loss, and further trials investigating specific probiotic strains and dietary fibre supplementation are underway.

28.4 Personalised/Precision Medicine

The integration of genetic data (such as HLA-C06:02 status), transcriptomic profiling of lesional skin, and biomarker-guided treatment selection represents the direction of precision medicine in psoriasis. As genetic risk scores become more refined (the 109-loci GWAS meta-analysis in Section 27.1 provides the most comprehensive foundation to date), they may enable risk prediction for disease onset, disease severity, comorbidity development, and treatment response (Li et al., 2019). The UK PSORT Consortium has already demonstrated that HLA-C06:02 status can predict differential response to adalimumab vs ustekinumab (Section 12.7), and similar pharmacogenomic approaches are being developed for the newer IL-23 and IL-17 inhibitors.

28.5 CAR-T and Engineered Cell Therapies

Chimeric antigen receptor T-cell (CAR-T) therapy, originally developed for haematological malignancies, is now being explored for severe autoimmune diseases. Anti-CD19 CAR-T cells, which comprehensively deplete B lymphocytes, produced sustained drug-free remission in patients with refractory systemic lupus erythematosus. Naive B cell populations reconstituted after approximately 100 days, while autoreactive B cell clones did not return (Mackensen et al., 2022). A subsequent case series of 15 patients with SLE, inflammatory myositis, and systemic sclerosis confirmed these findings, with all participants achieving remission and discontinuing immunosuppressive medications (Muller et al., 2024).

Direct evidence in psoriasis remains limited but provocative. A 2024 case report described a patient with concurrent chronic plaque psoriasis whose skin lesions completely resolved following CD19 CAR-T cell infusion for lymphoma, suggesting that B-cell depletion may disrupt the immunological circuits sustaining psoriatic inflammation (Wang et al., 2024). Beyond broad B-cell depletion, researchers are developing more targeted approaches: chimeric autoantigen receptor (CAAR) T cells that eliminate only autoreactive B cells, and regulatory CAR-T cells engineered to suppress rather than kill. These therapies remain at an early stage. Still, the prospect of achieving lasting drug-free remission through a single cellular infusion would represent a fundamental change in how autoimmune disease is managed.

28.6 Epigenetic Therapies

Unlike the DNA sequence itself, epigenetic modifications (including DNA methylation, histone acetylation, and microRNA expression) are potentially reversible, opening an entirely new avenue for therapeutic intervention. The STEPIn trial demonstrated that early biologic treatment can reverse disease-associated DNA methylation patterns in psoriatic skin (Section 27.2), providing proof of concept that the epigenetic landscape in psoriasis is dynamically responsive to treatment.

Histone deacetylase (HDAC) inhibitors are among the most studied epigenetic agents in inflammatory skin disease. Remetinostat, a topical HDAC inhibitor designed for skin-restricted activity, has shown promise in preclinical models: it suppressed dendritic cell maturation, inhibited keratinocyte inflammatory signalling, and reduced IL-17A and IL-22 expression. Its metabolically unstable structure ensures rapid systemic inactivation, minimising off-target effects (Yi & McGee, 2021). Bromodomain and extra-terminal domain (BET) inhibitors represent a complementary strategy: BET proteins read acetylated histone marks and recruit transcriptional machinery, and the BET inhibitor JQ-1 suppressed psoriasiform skin inflammation in mice by modulating the RORC/IL-17A pathway, the same axis targeted by licensed anti-IL-17 biologics (Nadeem et al., 2015). These approaches suggest that future therapies may move beyond blocking individual cytokines to reprogramming the aberrant transcriptional landscape that sustains chronic inflammation.

28.7 Artificial Intelligence in Psoriasis Management

Artificial intelligence (AI) is beginning to transform how psoriasis is diagnosed and monitored. The PASI score, long the gold standard for clinical assessment, is notoriously subjective, with substantial inter-rater variability even among experienced dermatologists. Deep learning systems trained on large image databases can now match or exceed specialist performance. A system trained on over 14,000 clinical images and deployed as a smartphone application called SkinTeller outperformed the average scoring of 43 experienced dermatologists by 33% in overall PASI estimation, and has been used over 3,300 times across 18 hospitals in real-world clinical practice (Huang et al., 2023).

Beyond severity assessment, machine learning is being applied to predict treatment response and to differentiate psoriasis from similar conditions. A comprehensive review identified a rapidly expanding landscape of AI applications encompassing lesion detection and segmentation, psoriasis subtype identification, and personalised treatment selection (Goessinger et al., 2024). Significant challenges remain, though. Most training datasets lack diversity in skin phototypes (compounding the diagnostic disparities discussed in Section 21.3), imaging protocols aren’t standardised across centres, and regulatory frameworks for AI-assisted clinical decision-making are still evolving. The integration of AI tools into routine dermatology practice appears increasingly inevitable and may prove particularly valuable where specialist dermatology access is limited.

28.8 The Neuroimmunology of Psoriasis

Psoriatic skin isn’t merely inflamed. It’s hyperinnervated. Compared with healthy skin, psoriatic plaques contain markedly increased densities of sensory nerve fibres, with substance P-positive (SP+) fibres increased approximately sixfold and calcitonin gene-related peptide-positive (CGRP+) fibres roughly doubled. This sensory nerve proliferation is driven largely by elevated nerve growth factor (NGF), which both promotes axonal outgrowth and directly sensitises nociceptors, lowering the threshold for itch and pain perception (Zhang & He, 2020).

These neuropeptides aren’t passive bystanders. They actively drive inflammation. Substance P, acting through the neurokinin-1 receptor (NK1R), promotes vasodilation, mast cell degranulation, and Th17 polarisation. CGRP activates the IL-23/IL-17 axis, the central pathogenic pathway in psoriasis. Together, these neuropeptides establish a bidirectional feedback loop: immune cells release cytokines that sensitise nerve endings and promote further neuropeptide release, which in turn amplifies immune activation. This neuroimmune circuit helps explain several clinical observations, including the well-documented role of psychological stress in triggering flares (Section 8.3), the intense pruritus that many patients experience, and the Koebner phenomenon. Current biologics, while effective at suppressing cutaneous inflammation, have limited impact on neurological symptoms such as itch and pain (see Section 18 for detailed coverage of pain and itch mechanisms). This suggests that the nervous and immune components of psoriasis may require distinct therapeutic approaches.

28.9 Nanomedicine Drug Delivery

Conventional topical therapies for psoriasis face a fundamental limitation: the skin barrier (stratum corneum) efficiently blocks most drug molecules, particularly large, hydrophilic ones. Nanomedicine, the application of nanotechnology to drug delivery, aims to overcome this barrier using engineered nanocarrier systems that enhance skin penetration, provide sustained release, and reduce systemic exposure.

Nanocarrier systems under investigation for psoriasis include (Saleem et al., 2024):

Liposomes and ethosomes: Phospholipid vesicles (50-200 nm) that fuse with the skin’s lipid bilayers, enhancing drug penetration. Ethosomes contain ethanol, which further fluidises the stratum corneum.
Solid lipid nanoparticles (SLNs): Biodegradable lipid particles that provide controlled drug release and protect encapsulated drugs from degradation.
Microneedle arrays: Tiny needles (25-2000 μm) that painlessly create microchannels in the stratum corneum, allowing direct delivery of drugs, including biologics and nucleic acids, into the viable epidermis.
Transferosomes and niosomes: Ultra-deformable vesicles that can squeeze through intercellular spaces in the stratum corneum.
Dendrimers and polymeric micelles: Branched or self-assembling nanostructures that can encapsulate hydrophobic drugs and target them to inflamed skin.

The theoretical advantages are compelling: reduced application frequency, lower total drug doses, fewer local side effects (e.g., steroid atrophy), and the potential to deliver biologic-class molecules (antibodies, siRNAs) topically. None of these systems has yet progressed beyond early clinical development for psoriasis (Li et al., 2025).

Research stage: Experimental. Evidence strength: Low. Extensive preclinical data; Phase I/II clinical trials for some formulations; no approved nanomedicine products for psoriasis.

28.10 Gene Therapy and CRISPR

The most conceptually ambitious approach to psoriasis treatment involves directly editing or silencing the genes that drive disease. CRISPR-Cas9 gene editing, delivered via lipid nanoparticles (LNPs), can target psoriasis-related genes, including IL-17A, IL-22, IL-23, TNF-α, and NF-κB, directly in keratinocytes via topical application (Li et al., 2025).

Additional nucleic acid approaches under investigation include:

RNA interference (RNAi): Small interfering RNAs (siRNAs) that degrade specific mRNA transcripts, effectively silencing gene expression. siRNAs targeting TNF-α and IL-17A have shown efficacy in psoriasis mouse models.
Antisense oligonucleotides (ASOs): Short synthetic DNA/RNA strands that bind to and block specific mRNA, preventing protein production.
mRNA therapeutics: Building on the success of COVID-19 mRNA vaccines, LNP-encapsulated mRNA encoding anti-inflammatory proteins could theoretically be delivered to the skin.

These approaches are highly experimental and face formidable challenges: achieving efficient delivery to target cells in human skin, ensuring specificity (avoiding off-target gene editing), managing immune responses to delivery vehicles, and demonstrating long-term safety. They do, however, represent a shift from managing symptoms to potentially correcting the underlying molecular defects.

Research stage: Experimental. Evidence strength: Very Low. Preclinical proof-of-concept in mouse models; no human clinical trials for gene therapy in psoriasis.

28.11 Mesenchymal Stem Cell Therapy

Mesenchymal stem cells (MSCs), multipotent stromal cells that can be isolated from bone marrow, adipose tissue, or umbilical cord, have potent immunomodulatory properties. In psoriasis models, MSCs ameliorate inflammation by reducing type I interferon (IFN-I) production by plasmacytoid dendritic cells, the same cells that initiate the psoriatic cascade (Section 6.2) (Li et al., 2025).

A 2025 case series reported MSCs as a rescue therapy in biologic-refractory psoriasis (patients who had failed multiple biologic classes) with significant improvement in PASI scores (Li et al., 2025). An expert consensus on MSC application in psoriasis clinical trials has been published, standardising cell source, dose, and outcome measures (Aging and Disease, 2024).

Next-generation approaches include CRISPR-engineered MSCs with enhanced immunomodulatory functions, for example, MSCs modified to overexpress IL-10 or PD-L1 for more potent and targeted immunosuppression.

Research stage: Experimental. Evidence strength: Low. Case series and preclinical models; expert consensus published but no Phase 3 RCTs.

28.12 Cryotherapy

Cryotherapy, the application of extreme cold to the skin, has been explored as both a localised and whole-body treatment for psoriasis.

Localised cryotherapy using liquid nitrogen or cryoprobe application directly to psoriatic plaques was evaluated in a 2024 study of 128 lesions: 49% achieved G5 (complete or near-complete) improvement. Palmoplantar psoriasis responded better, with 73% achieving G5 improvement (Kumar et al., 2024).

Whole-body cryotherapy (WBC), brief (2-3 minute) exposure to extreme cold (−100°C to −140°C) in a cryochamber, increases anti-inflammatory interleukins (IL-10, IL-4) and decreases pro-inflammatory molecules. Small studies suggest benefit for psoriasis symptoms, though evidence is limited by small sample sizes and lack of blinded controls (He et al., 2025).

Cryotherapy is best considered as a potential adjunctive treatment for localised, refractory plaques rather than a systemic therapy. It doesn’t address the underlying immune dysregulation.

Research stage: Experimental. Evidence strength: Low. Small studies with mixed results; no RCTs; mechanism of action partially understood.

28.13 Phage Therapy and Engineered Microbiome Treatments

Given the gut and skin microbiome alterations in psoriasis (Section 6.6), several novel approaches aim to directly modify microbial communities:

Bacteriophage (phage) therapy: Phages are viruses that specifically infect and kill bacteria. Unlike broad-spectrum antibiotics, phages offer strain-specific treatment that targets pathogenic bacteria while preserving beneficial flora. Personalised phage cocktails based on individual patient skin swabs are being explored for dermatological conditions, though no psoriasis-specific trials have been conducted (Natarelli et al., 2023).
Engineered commensals: Genetically modified bacteria designed to produce anti-inflammatory molecules (e.g., IL-10, antimicrobial peptides) directly at the skin surface or in the gut.
Topical probiotics and postbiotics: Direct application of beneficial bacteria or their metabolic products (postbiotics, including SCFAs and bacteriocins) to psoriatic skin, aiming to restore microbial balance.
Faecal microbiota transplantation (FMT): Transfer of healthy donor stool into the patient’s gut to restore microbial diversity. FMT has shown efficacy in recurrent Clostridioides difficile infection and is being explored in autoimmune conditions, though no published data exist for psoriasis.

Research stage: Experimental. Evidence strength: Very Low. Theoretical basis is strong (supported by microbiome dysbiosis data); clinical applications are at the earliest stages of development.