Psoriasis: Past, Present, and FuturePsoriasis is a chronic inflammatory disease of the skin, nails, and joints. In the last two decades, there has been enormous progress in our understanding of the genetics, immunology, and associated comorbidities (Figure 1). This has been accompanied by a marked improvement in the number of therapeutic agents and their effectiveness. Much of this progress has been outlined in numerous articles, commentaries and reviews in the Journal of Investigative Dermatology (JID) over the years (Figure 2). This commentary, which is part of the JID Collections, serves to outline how we have arrived at our present state of knowledge on psoriasis and provides an overview of some exciting future directions.
Psoriasis Caught in the NETA report in the June 2019 issue of the Journal of Investigative Dermatology reveals a role of neutrophil extracellular traps (NETs) in the induction of T helper type 17 cell responses and shows the relevance of this pathway in patients with psoriasis carrying a common risk variant in the TRAF3IP2 gene (Lambert et al., 2019). This work provides a new piece to the puzzle that links neutrophils to the T helper type 17–mediated pathogenesis of psoriasis.
IL-17 May Be a Key Cytokine Linking Psoriasis and HyperglycemiaPsoriasis is associated with the metabolic syndrome, an interconnected group of conditions characterized by significant morbidity and mortality, although the causal mechanisms are still under investigation. Ikumi et al. provide evidence of a link—involving IL-17—between psoriasis and hyperglycemia in humans and mice.
Psoriasis Pathogenesis: Keratinocytes Are Back in the SpotlightPsoriasis is a T helper type 17–mediated immune disease. Initial triggers that lead to T helper type 17 production and inflammatory cell recruitment into skin are being delineated. Autoantigens that stimulate T helper type 17 cells are also being identified. A new and important piece of the puzzle indicates that keratinocytes not only amplify inflammation, but that they are essential for a full-blown IL-17–mediated psoriatic phenotype in mice.
Adalimumab in Psoriasis: How Much Is Enough?Biologic therapies targeting tumor necrosis factor have revolutionized treatment of immune-mediated inflammatory diseases such as psoriasis, but optimal dosing and appropriate use of therapeutic drug monitoring are not yet fully understood. Wilkinson et al. explore these questions in a real-world psoriasis cohort on adalimumab monotherapy, defining a therapeutic range and finding value in early measurement for predicting clinical response.
Psoriasis Plays a Wild CARDRare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown. Mellett et al. generated mice harboring the patient-derived gain-of-function Card14ΔE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis.
Saturated Fatty Acids as Possible Key Amplifiers of Psoriatic DermatitisThe association of obesity with psoriasis is well known, but the molecular link between these two entities is incompletely characterized. Herbert et al. report that dietary saturated fatty acids, rather than obesity itself, promote exacerbation of psoriasis in high fat diet-induced obesity. They also suggest that dietary manipulation could improve psoriasis.
IL-17C: A Unique Epithelial Cytokine with Potential for Targeting across the Spectrum of Atopic Dermatitis and PsoriasisBoth atopic dermatitis (AD) and psoriasis are characterized by complex inflammatory circuits that may be regulated through “feed-forward” mechanisms in the epidermis that amplify cellular immune responses through production of keratinocyte-derived cytokines and inflammatory mediators. IL-17C is a unique cytokine that is produced by keratinocytes and that is involved in such synergistic loops that may be responsible for amplifying the inflammation in both diseases. This may ultimately lead to induction of S100As and other molecules that accompany epidermal hyperplasia.
Targeting the Plasticity of PsoriasisPsoriasis is a common inflammatory condition found in 1–2% of the population. The greatest advances in psoriasis treatment have occurred in patients with severe psoriasis, moving from systemic small molecules including methotrexate, cyclosporine, and retinoids to targeted agents against psoriasis-associated cytokines, such as TNF-α, IL-12, IL-23, and IL-17. Although the new biologics do not have the same adverse effects as the systemic drugs, they do predispose to systemic infections (and perhaps cancer), and they are extremely expensive.
Survival of Second-Line Biologics in Psoriasis: The British BADBIR Registry Data Informs Daily PracticePsoriasis is one of the most chronic diseases in dermatology. Only a small percentage of patients ever experience relapse-free survival. The constant presence of plaques and comorbidities that affect the cardiovascular system, joints, and other organs greatly impair patients’ quality of life. In addition, the life expectancy of psoriatic patients is shortened by several years. Hence, long-term and ideally systemic treatment with minimal adverse effects may be warranted.
Back to the Future: Looking at the Skin to Predict Death—A Lesson from PsoriasisNoe et al. have documented that an objective measure of psoriasis severity, the body surface area as assessed at a single time point, could predict the risk of all-cause mortality in psoriatic patients. The results have important implications for disease management. Socioeconomic variables may, in part, confound the association between severe psoriasis and increased mortality.
Pushing the Envelope in Psoriasis: Late Cornified Envelope Proteins Possess Antimicrobial ActivityDeletion of late cornified envelope (LCE) genes LCE3B and LCE3C (LCE3B/C-del) is a psoriasis risk factor linked to the major psoriasis risk gene HLA-C*06. Niehues et al. demonstrate that LCE3B/C-del leads to increased keratinocyte LCE3A expression. They also show that LCE3A/B/C possess antimicrobial activity but do not obviously regulate epidermal barrier integrity. These findings implicate LCE proteins in psoriasis pathogenesis via a new functional role.
The Quest for Psoriasis Autoantigens: Genetics Meets Immunology in the MelanocyteIn a 1979 study of the effects of cyclosporin A on rheumatoid arthritis, Mueller and Herrmann (1979) reported profound improvements in the skin lesions of “control” subjects with psoriatic arthritis. This key observation focused attention on the potential role of T cells in psoriasis, because lymphocytes are relatively specific targets of cyclosporin A (Schreiber and Crabtree, 1992). Although the role of T cells in the pathogenesis of psoriasis is now widely accepted based on a wide array of genetic, immunologic, and pharmacological evidence (Greb et al., 2016), the mechanism by which the immune system is triggered in psoriasis has remained a puzzle.
Cutaneous Glucocorticoidogenesis and Cortisol Signaling Are Defective in PsoriasisHannen et al. report that cutaneous glucocorticoidogenesis and expression of glucocorticoid receptors are inhibited in psoriatic skin. These findings substantiate the previous concept that deficient feedback of local proopiomelanocortin and glucocorticoids on cutaneous immunity contributes to inflammatory and autoimmune dermatoses. Restoration of efficient endogenous glucocorticoid signaling represents a realistic goal in treating psoriasis.
Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities?Psoriasis has been associated with an increase in myocardial infarctions. Several registries have shown reductions in major adverse cardiovascular events in psoriasis patients and rheumatoid arthritis patients treated with tumor necrosis factor-α antagonists. Many assume that the reduction in cardiovascular events can be attributed to the anti-inflammatory effect of tumor necrosis factor blockers, but a 52-week study conducted by Bissonnette and coworkers failed to show a reduction in cardiovascular inflammation in psoriasis patients treated with adalimumab.
Act1: A Psoriasis Susceptibility Gene Playing its Part in KeratinocytesUnchecked inflammation, impaired keratinocyte differentiation, and heightened host defense responses typify psoriasis. Lambert et al. make clever use of psoriasis patient genetics and whole transcriptome RNA-Seq analysis to implicate Act1 in these seemingly variegated processes by keeping IL-17 receptor signaling in check while supporting differentiation and limiting innate immune responses in human keratinocytes.
IL-6 Differs from TNF-α: Unpredicted Clinical Effects Caused by IL-6 Blockade in PsoriasisIL-6 is a pleiotropic proinflammatory cytokine that is elevated in serum and skin lesions of patients with psoriasis. Anti-IL-6 therapies, however, which are effective for rheumatoid arthritis, are either ineffective for psoriasis or can induce new-onset psoriasis-like disease. Fritz et al. provide a potential explanation for these clinical observations by examining IL-17C-driven psoriasis-like disease in mice with an IL-6-deficient genetic background. These mice displayed slower onset skin disease initially, but then worsened over time, suggesting that a lack of IL-6 led to compensatory proinflammatory effects by other cytokines, which eventually worsened the psoriatic inflammation.
Infections and Psoriasis Treatment: More “Real-World” Data Needed with Critical AppraisalData from the Spanish registry BIOBADADERM suggest that the risks of any infectious episode in patients treated with biologics are limited, not exceeding the risks observed with a conventional treatment such as cyclosporine. The registry lacked enough statistical power to analyze risks for severe infections. These should be the focus of further research, although the difficulties of “real-world” data analysis should not be trivialized.
Deregulation of Adenosine Receptors in Psoriatic Epidermis: An Option for Therapeutic TreatmentPurinergic signaling is involved in psoriasis, a chronic skin disease characterized by increased epidermis cell growth. In particular, Andrés et al. focus on the keratinocyte biology modulated by adenosine receptors providing evidence that the A2B subtype plays a prominent role in the reduction of keratinocyte proliferation whereas A2A and A2B agonists have antiinflammatory effects independent of adenosine receptors. The authors report that psoriatic epidermis presents a deregulated adenosine receptor expression profile with reduced A2B and increased A2A.
ACKR2: Nature’s Decoy Receptor Lures Unsuspecting Chemokines in PsoriasisWhile we know much about the processes mediated by the Th17 inflammatory pathway that is crucial in psoriasis, we actually know little about the processes by which most psoriatic patients maintain what grossly looks like non-inflamed, normal skin in the face of massive inflammatory changes in nearby affected skin. Other molecular regulators that defend the skin from global inflammation are likely to be involved, including molecules such as ACKR2, an atypical chemokine receptor whose role in psoriasiform dermatitis is explored by Shams et al.
Psoriasis Therapy: Breakthroughs in Pharmacogenomics or in Pharmacology?As the cost of psoriasis therapies skyrockets, it becomes increasingly important to find biomarkers that predict which patients will respond to expensive medications. The ability to predict response to a specific therapy is particularly important for medications that are effective in only a small portion of the population. As we develop medications that clear most patients, the need for a predictive biomarker diminishes. Nevertheless, the importance of pharmacogenomics is likely to increase as the cost of drugs continues to rise.
In the Red: Deficits in Immune Regulation Underlie Psoriasis SeverityIL-17–driven pathways are active in the skin of patients with psoriasis. Kim et al. examined lesions from mild and moderate to severe psoriasis and found that differences in cutaneous disease severity may be the outcome of lapses in immunoregulatory mechanisms; because as much, if not more, T helper type 17–induced inflammation was seen in mild psoriasis, these patients may also benefit from anti-IL-17–targeted biologics.
Expanding the List of Dysregulated Immunosuppressive Cells in PsoriasisTraditionally, myeloid-derived suppressor cells (MDSC) have been studied in regard to their increased numbers of circulating cells in cancer patients. Recent research efforts have also increased awareness of MDSC in non-malignant inflammatory diseases, including asthma, inflammatory bowel disease, and arthritis. Psoriasis can now be added to the growing list of inflammatory disorders with an MDSC component. Cao et al. report increased numbers of monocytic myeloid-derived suppressor cells (Mo-MDSC) in psoriasis patients and examine the implication of dysregulated Mo-MDSC function.