Psoriasis PDF - Lancet 2021

Seminar Psoriasis Christopher E M Griffiths, April W Armstrong, Johann E Gudjonsson, Jonathan N W N Barker Psoriasis is a common, chronic papulosquamou...

Seminar Psoriasis Christopher E M Griffiths, April W Armstrong, Johann E Gudjonsson, Jonathan N W N Barker Psoriasis is a common, chronic papulosquamous skin disease occurring worldwide, presenting at any age, and Lancet 2021; 397: 1301–15 leading to a substantial burden for individuals and society. It is associated with several important medical conditions, Dermatology Centre, Salford including depression, psoriatic arthritis, and cardiometabolic syndrome. Its most common form, chronic plaque or Royal NHS Foundation Trust, University of Manchester, psoriasis vulgaris, is a consequence of genetic susceptibility, particularly in the presence of the HLA-C*06:02 risk Manchester, UK allele, and of environmental triggers such as streptococcal infection, stress, smoking, obesity, and alcohol (Prof C E M Griffiths MD); NIHR consumption. There are several phenotypes and research has separated pustular from chronic plaque forms. Manchester Biomedical Immunological and genetic studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis. Immune Research Centre, Manchester, UK (Prof C E M Griffiths); targeting of these cytokines and of TNFα by biological therapies has revolutionised the care of severe chronic plaque Department of Dermatology, disease. Psoriasis cannot currently be cured, but management should aim to minimise physical and psychological Keck School of Medicine, harm by treating patients early in the disease process, identifying and preventing associated multimorbidity, instilling University of Southern lifestyle modifications, and employing a personalised approach to treatment. California, Los Angeles, CA, USA (Prof A W Armstrong MD); Department of Dermatology, Epidemiology and disease burden soles, and genitalia. Compared with the general popula­ University of Michigan, Psoriasis is an inflammatory skin disease that is tion, patients with psoriasis are more likely to be Ann Arbor, MI, USA associated with many other medical conditions, and depressed (up to 20%) and exhibit suicidal ideation (J E Gudjonsson MD); St John’s Institute of Dermatology, affects over 60 million adults and children worldwide.1 extending to suicidal behaviour.14,15 Faculty of Life Sciences and Establishing the global burden of psoriasis is a key Medicine, King’s College research imperative of WHO. In 2014, the organi­sation Clinical presentation London, London, UK passed a resolution recognising psoriasis as a “chronic, Chronic plaque (Prof J N W N Barker MD) non-communicable, painful, disfiguring, and disabling Psoriasis has different clinical phenotypes, but the most Correspondence to: Prof Christopher E M Griffiths, disease for which there is no cure”.1 Psoriasis occurs frequent and most easily recognised is chronic plaque Dermatology Centre, Salford equally in men and women, with a mean age of onset or psoriasis vulgaris. The classic morphology is that of Royal NHS Foundation Trust, of 33 years. It can present earlier in women, with a well demarcated, salmon-pink plaques covered in silvery University of Manchester, bimodal onset at the age of 16–22 years and 55–60 years, scales in white skin (figure 1A) and of grey plaques in Manchester M6 8HD, UK christopher.griffiths@ associated with two different subtypes based on genetic black skin (figure 1B). Removal of the adherent scales manchester.ac.uk and immunological features: early onset, before the age can result in small bleeding points (known as the of 40 years (75% of cases), and late onset, after the age Auspitz sign). Plaques can have highly variable sizes of 40 years.2 and thicknesses, which can in turn signify active disease The prevalence of psoriasis is known in only 19% of (small plaques) or responsiveness to some therapies countries worldwide and is unequally distributed across (eg, thin plaques are more likely to respond to photo­ geographical regions,3,4 occurring more commonly in therapy).16 An individual plaque is dynamic: its edge white individuals. Overall prevalence ranges from 0·1% moves outwards and is the most active area, which can in east Asia to 1·5% in western Europe, and is highest in lead to a central clearing, showing as lesions with high-income countries. Prevalence and incidence are annu­ lar appearance. Common sites of occurrence lower in children than in adults.5–8 A decrease in the include extensor aspects of the knees and elbows, the incidence of psoriasis, occurring concomitantly with an lumbosacral region, and the scalp, rarely encroaching increase in prevalence over time, is probably due to much beyond the hairline, although any skin surface people with psoriasis living longer but still having can be involved. A characteristic feature is anatomical shorter life spans than that of the general population.9–11 symmetry of plaques (figure 1C). If the disease is very Some evidence suggests a differential effect of latitude on psoriasis prevalence, such as the increased prevalence and incidence in Scotland compared with that of the Search strategy and selection criteria southwest of England.9,12 However, this differential effect We searched PubMed, MEDLINE, and Cochrane Library with has not been observed uniformly across disparate the search term “psoriasis” in combination with terms geographical regions.13 “epidemiology”, “phenotypes”, “genetics”, “pathogenesis”, Most patients with psoriasis have some detriment to “comorbidities”, “therapy”, “management”, their quality of life attributable to the disease, and many “recommendations”, and “guidelines”. We focused on all feel a substantial, negative effect on their psychosocial relevant publications publications in English from the past wellbeing. Indeed, avoidance coping that results from 10 years (May 14, 2010, to May 14, 2020), but did not psoriasis is often the single biggest daily stressor in exclude commonly referenced older publications. patients’ lives.14 A greater psychological effect occurs We identified additional reports from the references in among those with extensive psoriasis or with involvement systematic reviews. of functionally crucial areas such as the face, palms, www.thelancet.com Vol 397 April 3, 2021 1301 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar about half have elevated antistreptolysin O, anti-DNase B, A B or streptozyme titres.18 Whereas most children and young adults with guttate psoriasis have spontaneous resolution after several weeks or months, approximately 40% of C cases progress to chronic plaque disease.19 The role of antibiotics in managing guttate psoriasis is unclear, but tonsillectomy has shown some benefit in recurrent cases associated with tonsillitis.17,20 The factors that dictate permanent resolution or persistence are unknown. Erythroderma is a severe, potentially life-threatening form of psoriasis, although it is more often a complication of flaring disease, affecting approximately 2–3% of adults with the condition (figure 1E).2,21,22 It typically presents D E with confluent erythema, scales, or exfoliation involving more than 75% of the total body surface area.21 This extent of skin involvement can be associated with hypothermia, high-output cardiac failure, electrolyte imbalance, pruritus, and skin pain. Pustular forms of psoriasis are uncommon and morphologically distinct, characterised by sterile pustules and erythema. They are divided into three subgroups based on the involved anatomical location: generalised F G H pustular psoriasis (also known as von Zumbusch disease), palmoplantar pustulosis, and acrodermatitis continua of Hallopeau. Generalised pustular psoriasis (figure 1F) has the hallmarks of an autoinflammatory disease associated with periodic flares, sterile pustules, and pyrexia, and can be life-threatening. It is epide­ miologically distinct from chronic plaque psoriasis and more common in women than in men. Generalised pustular psoriasis can be triggered by rapid tapering of systemic and potent topical corticosteroids, hypo­ I J calcaemia, pregnancy, and infection.23 The second subgroup, palmoplantar pustu­losis (figure 1G), classically presents as sterile yellow pustules on the palms and soles, resolving over several weeks to red or brown macules. Palmoplantar pustulosis occurs predominantly in middle-aged (30–60 years of age) female smokers (current or recent); approximately 20% of patients have concomitant chronic plaque psoriasis.24 Acroder­matitis continua of Hallopeau is a rare disease, characterised Figure 1: Various clinical presentations of psoriasis and its subtypes by pustules on the distal portions of the fingers and (A) A well demarcated, pink plaque on white skin. (B) On black skin, the plaques are grey. (C) Symmetry of plaques is characteristic. (D) Small centripetal papules in guttate psoriasis. (E) Erythroderma. (F) Generalised pustular sometimes toes, which can lead to shedding of the nail psoriasis. (G) Palmoplantar pustulosis. (H) Flexural or inverse psoriasis with absence of scale. (I) Nail pitting and plate; approximately 40% of affected individuals have onycholysis. (J) Psoriatic arthritis with dactylitis and nail changes. concomitant chronic plaque psoriasis.24 Although guttate, erythrodermic, and pustular active, lesions can occur at sites of trauma or pressure forms of psoriasis have distinctive morphologies, other on the skin, such as under a tight waistband (known as psoriasis variants are characterised by location. These Koebner phenomenon). include inverse or flexural psoriasis, palmoplantar psoriasis, sebopsoriasis, and nail psoriasis. Inverse Other subtypes of psoriasis psoriasis involves the skin folds, such as the axillary, Less common forms of psoriasis include guttate, inframammary, inguinal, and intergluteal areas. Due to erythrodermic, and pustular psoriasis. Guttate psoriasis its occluded location, this form is shiny, red, and does constitutes 2% of all cases (figure 1D) and presents as not present the characteristic scaling seen in plaque numerous, small, and scaly papules distributed in a disease (figure 1H). It can be mistaken for candidiasis centripetal pattern.17 Approximately two thirds of patients or another fungal infection. Palmo­ plantar psoriasis have a preceding episode of pharyngitis or tonsillitis, and presents as hyperkeratotic, fissured plaques on the 1302 www.thelancet.com Vol 397 April 3, 2021 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar palms and soles, greatly impairing manual dexterity and Pathophysiology walking. Sebopsoriasis occurs in the scalp, seborrhoeic Histological features regions of the face (eg, eyebrows and nasolabial folds), The histology of psoriasis includes thickening of the and postauricular and presternal areas. There is debate epidermis (acanthosis) with downward elongation of rete as to the taxonomic relationship between seborrhoeic ridges, a thinned or absent granular layer, elongated and dermatitis, dandruff, and sebopsoriasis. Nail psoriasis, dilated capillaries, suprapapillary thinning, an inflam­ which affects about 50% of people with plaque matory infiltrate of T cells in the dermis and epidermis, psoriasis,25 has multiple presentations, ranging from and sometimes clusters of neutrophils in the parakeratotic small pits on one to all 20 nail plates, separation of the scale. When present, neutrophil clustering in pustules nail plate from the nail bed (onycholysis; figure 1I), oil (Kogoj spongiform micropustules), or surrounded by spots (orange-yellow discolouration of the nail bed), or parakeratosis (microabscesses of Munro), can be patho­ even crumbling (dystrophy) of the nail plates. The gnomonic of psoriasis. presence of nail disease, particularly onycholysis, is associated with a doubled risk of psoriatic arthritis Pathogenesis (figure 1J) and with longer disease duration than in In the past 20 years, findings from immunological and patients with psoriasis without nail disease.26 genetic studies have highlighted causal immunological circuits that converge on adaptive immune pathways Diagnostic investigation and differential involving IL-17 and IL-23. We focus on the central diagnoses mecha­nisms of the disease: crosstalk between the innate The diagnosis of psoriasis is usually clinical, on the basis and adaptive immune systems and the so-called feed- of the history, morphology, and distribution of skin forward amplification of psoriasis inflammation; the lesions. Obtaining the patient’s history should help to central role of IL-23 and helper T cells type 17 (Th17) establish if there is a family history of psoriasis, potential responses; the role of TNFα and interferons; and the triggers, the onset of psoriasis symp­toms, and whether link to genetics. there are musculo­ skeletal symptoms suggestive of psoriatic arthritis. A thorough skin examina­tion needs to Genetic contributions include inspection of the nails, scalp, flexures, and Heritability is the main risk determinant for developing intergluteal cleft. Because patients are often embarrassed psoriasis, the risk being two to three times higher in to inform clinicians regarding genital involvement, this monozygotic twins compared with dizygotic twins. Of area should be included as a part of the full skin the many genetic methodologies applied to psoriasis, examination. Very rarely, in cases of erythro­derma, a skin genome-wide association studies have been particularly biopsy might be necessary to help to exclude cutaneous helpful in identifying risk loci across the genome, with T-cell lymphoma. over 80 loci, explaining about 30% of disease heritability, The list of differential diagnoses for psoriasis is long reported to date.27–29 Downstream studies have identified and includes inflammatory, infectious, and neoplastic causative variants at many of these loci30 and shown processes that mimic its papulosquamous presentation. several findings of clinical and therapeutic importance. The following is not an exhaustive list, but examples of Firstly, the major genetic risk factor for early-onset skin diseases that can be mistaken for psoriasis. psoriasis is HLA-C*06:02.31 Late-onset disease, psoriatic Pityriasis rosea is distinguishable from guttate psoriasis arthritis, and pustular forms of psoriasis are not by its collarette scale and by the occurrence of a larger associated with HLA-C*06:02. Inheritance of one allele so-called herald patch, a week or two before the main increases the risk of psoriasis by four to five times,32,33 rash. Atopic dermatitis is distinguished by the absence and interac­tion with a risk variant in the ERAP1 gene, of clear demarcation from uninvolved skin, predilection which codes an aminopeptidase that helps to process for flexural areas, and considerable pruritus. Seborrhoeic antigens for HLA class I presentation, markedly dermatitis occurs at sites identical to sebopsoriasis, but increases that risk.32 Ongoing studies indicate that, scales tend to be greasy and adherent. Secondary syphilis although not currently amenable to therapeutic can have an appearance similar to guttate psoriasis, but intervention, HLA-C*06:02 might be useful with its unique features include orange, pink, or violaceous respect to clinical and therapeutic stratification.34 (depending on skin tone) macules on the palms and Secondly, whereas other variants have a minor genetic soles. The early stages of cutaneous T-cell lymphoma effect, they clearly sign­post the central role of innate can be mistaken for psoriasis, although lesions do not and adaptive immunity in disease pathogenesis. Crucial have clear demarcation and thick scales. In many low- pathways include those involving type 1 inter­ ferons income and middle-income countries, the most common and antiviral signalling, NF-κB, IL-23, and IL-17, and cause of misdiagnosis is tinea corporis. Other skin antigen processing and presentation.35 When combined diseases that should be considered are lichen planus, with immunological investigation, a clear explanation subacute cutaneous lupus erythematosus, nummular of psoriasis patho­genesis emerges and, with it, major eczema, and pityriasis rubra pilaris. advances in psoriasis therapy.36 www.thelancet.com Vol 397 April 3, 2021 1303 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar Non-lesional skin Environmental Psoriasis plaque Resolved psoriasis plaque Pathogens, obesity, drugs, smoking, alcohol, stress Tc1 Treatment Triggers Tc17 Neu TRMs Mφ TRMs Tc17 Cessation or interruption LC Th1 LC Tc17 of treatment Tc1 Th1 Genetic Th17 pDCs Th1 Th17 predisposition Th1 DCs Tc17 Th17 ILC3 DC Th1 Tc1 Th22 ILC3 Th17 Mφ Tc17 TRMs Mφ ILC3 Th17 Tc17 Tc1 Th22 Tc17 Tc17 Th1 DCs Th1 Lymph node ILC3 Mφ Figure 2: Immunopathogenesis of psoriasis and resolved psoriasis plaques Progression of non-lesional skin into a fully developed psoriasis lesion or plaque involves complex and not yet completely understood interactions between environmental factors and genetic susceptibility. The best-defined psoriasis triggers include exposure to environmental pathogens (such as streptococcus), obesity, drugs, alcohol consumption, stress, and smoking. In terms of genetic susceptibility, to date, over 80 different genetic risk loci have been shown to predispose to psoriasis. With the right trigger in a genetically susceptible individual, a psoriasis plaque develops, with participation of plasmacytoid dendritic cells and type I interferons, leading to marked thickening (acanthosis) of the epidermis, club shaped elongation of the rete pegs, and growth and dilatation of blood vessels in the dermal papillae. Various immune cell subsets, including IL-17 secreting group 3 innate lymphoid and Th17 and Tc17 cells, IFN-γ secreting Th1 and Tc1 cells, and neutrophils are drawn into the skin, along with activated macrophages and dendritic cells. Through the involvement of skin draining lymph nodes, the initial immune response creates a self-sustaining cycle of inflammation, maintaining disease activity. During treatment-induced remission, resolved psoriasis plaques contain tissue resident memory cells, typically CD8⁺ IL-17-positive or CD8⁺ IFN-γ-positive cells. On cessation or interruption of treatment, these cells become reactivated and drive reoccurrence of skin inflammation at previous sites of involvement. DC=dendritic cell. ILC=innate lymphoid cell. LC=Langerhans cell. Mφ=macrophage. Neu=neutrophil. pDC=plasmacytoid dendritic cell. Tc=cytotoxic T cell. Th=helper T cell. TRM=tissue resident memory T cells. Triggers type 1 (Th1) and Th17 cells,40 creating a self-sustaining Psoriasis expression is dependent on gene–environment cycle of inflam­mation (figure 2). interaction, in that the disease does not manifest unless A subset of T cells, tissue-resident memory T cells, there is an environmental trigger, such as stress, have attracted substantial attention in the last decade. infection (particularly streptococcal), alcohol consump­ These are non-recirculating memory T cells that persist tion, smoking, exposure to drugs such as lithium, long-term in epithelial tissues.41 They evolved to provide antimalarials, and non-steroidal inflammatory agents, rapid protection against pathogens, but when aberrantly and, in some cases, sunlight.2 Weight gain and obesity activated, contribute to immune-mediated diseases are both risk factors and triggers, as well as a possible such as psoriasis.41 This aberrant activation can happen consequence of living with psoriasis.37 in response to autoantigens, such as those presented by HLA-C*06:02. Autoantigens implicated in pso­ Innate and adaptive immune system and feed-forward riasis pathogenesis include the melanocyte antigen amplification ADAMTSL5,42 the cathelicidin antimicrobial peptide The importance of T cells in psoriasis pathogenesis has LL37,43 and KRT17.44 The persistence of tissue-resident been well known since the early 1980s and confirmed by memory T cells in the skin can explain several features clinical trials with ciclosporin,38,39 although many classic of psoriasis, including the sharp demarcation of (including dendritic cells and neutrophils) and non-classic involved skin from clinically healthy skin40 and the immune cells (such as keratinocytes) are involved in characteristic recurrence of psoriasis at previous sites of disease pathogenesis. Communication between these involvement.45 cells happens mainly through cytokines such as TNFα, IFN-γ, IL-17, and IL-22, and through activation of Cytokine circuits in psoriasis: IL-23 and Th17 and beyond keratinocytes, driving epidermal hyperprolifer­ation and IL-23 and Th17 responses are considered important production of antimicrobial proteins, growth factors, and drivers of psoriasis, on the basis of findings from chemokines. These factors promote the characteristic genome-wide association studies32,33,46–48 and clinical changes in psoriasis including angiogenesis, neutrophil trials.49–54 IL-23, composed of p40 and p19 subunits, plays infiltration, and increased numbers of helper T cells a major role in IL-17 biology through maintenance and 1304 www.thelancet.com Vol 397 April 3, 2021 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar expansion of IL-17-producing immune cells.55 IL-23 is the CARD14 gene have also been associated with familial closely related to IL-12, with which it shares the forms of pityriasis rubra pilaris,79 a psoriasis-like disorder. p40 subunit (the therapeutic target of ustekinumab).56,57 The balance between the key cytokine circuits in psoriasis IL-12 promotes Th1 responses, characterised by the might help to explain some of the clinical manifestations of production of IFN-γ, but direct therapeutic targeting of the disease, with IL-23 and IL-17 dominating in plaque this cytokine is ineffective.58 psoriasis,80 interferon responses being most prominent in The IL-17 family of cytokines contains six structurally early, developing plaques of psoriasis,81 and paradoxical related cytokines, IL-17A through IL-17F.55 IL-17A, psoriasis reactions seen in patients on anti-TNFα agents.82 commonly referred to as IL-17, is the most strongly Furthermore, the IL-36 circuit, when active in plaque implicated in psoriasis pathogenesis, but there has been psoriasis,72 tends to be hyperactive in pustular forms.75 less attention on other IL-17 family members, such as These inflammatory circuits amplify each other, with IFN-γ IL-17C and IL-17F, despite these being prominently promoting IL-23 and Th17 responses83 and IL-17 responses expressed in psoriasis.59 The major source of IL-17 in promoting IL-36 expression and activation,72 creating psoriasis plaques is from activated T cells and group 3 complex, interacting, and self-sustaining inflammatory innate lymphoid cells.60 IL-17 in turn leads to upregulation circuits in psoriasis (figure 3). of CCL20, a Th17 chemoattractant, thereby setting up a positive IL-17 response feedback loop.61 Disease associations TNFα is a proinflammatory cytokine produced by Psoriasis is associated with many diseases, most notably immune cells including dendritic cells, macrophages, with psoriatic arthritis,84,85 a seronegative inflammatory and T cells.62 It has a broad range of biological effects arthritis observed in 10–40% of patients with psoriasis through the induction of expression of other proinflam­ (depending on how it is defined), and typically lagging in matory cytokines (by dendritic cells and T cells) and of onset behind the skin disease by 10 years.86 It is generally neutrophil chemoattractants, inducing vascular adhesion asymmetrical and affects the distal interphalangeal joints, molecules facilitating the influx of inflammatory cells, sometimes with axial involvement (figure 1J). Other and amplification of the effects of other cytokines, manifestations of psoriatic arthritis include enthesitis including IL-17.63 and dactylitis. Psoriasis and psoriatic arthritis share IFN-γ, primarily derived from T cells, was one of some pathogenetic and immunological features and the first inflammatory mediators identified in psoriasis therapies frequently overlap, but they are distinct genetic, plaques.64,65 Similar to type I interferons, which are immunological, and therapeutically responsive entities. known to initiate and increase disease activity in Recently, the association of psoriasis with hypertension, psoriasis,66,67 IFN-γ promotes antigen processing68,69 and obesity, type 2 diabetes, dyslipidaemia (sometimes expression of MHC class II molecules (such as HLA-DR) collectively referred to as metabolic syndrome), and on antigen presenting cells.69 In addition, IFN-γ induces cardiovascular disease has received substantial attention. expression of proinflammatory mediators including Myocardial infarction has been more frequently observed the chemoattractants CXCL9 and CXCL10 that attract in patients with psoriasis than in the general population, additional Th1 and cytotoxic T cells type 1 (Tc1) to the site particularly in people with severe psoriasis and at a of inflammation, thereby setting up a positive feedback younger age.87 Similar findings have been reported for the loop involving interferon responses. risk of stroke.88 However, it remains to be determined IL-36 has gained considerable attention in the past whether psoriasis per se is an independent risk factor for decade. It is a member of the IL-1 family of cytokines that cardiovascular disease.89,90 These conditions are commonly includes IL-36α, IL-36β, IL-36γ, and IL-36 receptor regarded as psoriasis comorbidities, but given the doubt antagonist (IL36RN). Mutations in the IL36RN gene are as to the direction of causality as exemplified by associated with pustular forms of psoriasis, particularly Mendelian randomisation studies,91 coexistence of these generalised pustular psoriasis.70,71 IL-36 cytokines are conditions is better described as multimorbidity: the co- primarily expressed by epithelial cells and their expres­ existence of two or more chronic conditions.92 Other sion can be induced by other proinflammatory cytokines, conditions occurring more commonly in patients with including IL-17, TNFα, and IL-36 itself.72 They contribute psoriasis than in the general population include chronic to the so-called feed-forward amplification in psoriasis, obstructive pulmonary disease, asthma, chronic kidney thus promoting progressively increased inflammatory disease, hepatobiliary cancer, and inflammatory bowel activity and influx of other immune cells, particularly disease (in which up to 10% of patients can have neutrophils.73,74 Keratinocytes regulate IL-36 activation psoriasis). Although further work is required to establish through secretion of serine protease inhibitors, such as the true relationship between these conditions, there is members of the serpin A family.75 A rare loss-of-function no doubt that within the population of people with variant in the SERPINA3 gene has been shown to psoriasis, there is a considerable burden of morbidity, predispose to generalised pustular psoriasis.76 Other and it is likely that management directed at lifestyle genes associating with pustular forms of psoriasis are would aid clinical outcomes. For example, strong evidence CARD14, AP1S3,24 and myeloperoxidase.77,78 Mutations in exists that patients with obesity and psoriasis respond www.thelancet.com Vol 397 April 3, 2021 1305 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar A B IL-17 IFN IL-36 IL-36 500X Keratinocytes CXCL1 CXCL2 C Plaque psoriasis Innate CXCL8 (IL-8) Neutrophils CCL20 CXCL9 IL-17F/A IL-17 IFN IL-36 CXCL10 Mast cells IL-17A/A TNF IFNy IFNa IL-17F/F Paradoxical psoriasis Mast cells ILC3 mDC pDC Vascular Vascular IL-17 IFN IL-36 endothelium Tc17 Tc1 endothelium Th17 Th1 Pustular psoriasis Mφ Adaptive IL-23 IL-12 IL-23 IL-12 IL-17 IFN IL-36 Dendritic cells Figure 3: Inflammatory circuits in psoriasis (A) Skin inflammation in psoriasis involves components of both the adaptive and innate immune systems. Three major, interlinked inflammatory circuits are present in psoriasis: Th17 and Tc17 responses driven by a IL-17, IL-23, and CCL20 feedback circuit (red dotted lines), a type I and type II interferon circuit driven by plasmacytoid dendritic cells, IFN-γ secreting T-cells (Th1 and Tc1) through a CXCL9 and CXCL10 feedback circuit (green dotted lines), and an IL-36 (whose activity is about 500 times increased) and neutrophil axis driven by the neutrophil chemokines CXCL1, CXCL2, and CXCL8 (IL-8; blue dotted lines). Neutrophil proteases show in green (cathepsin G), blue (neutrophil elastase), and red (proteinase 3). (B) These three circuits are linked with IL-36 and IFN-γ responses through a positive feedback mechanism, supporting Th17 responses that activate IL-36 responses as part of a feed-forward amplification. (C) The balance between these three inflammatory circuits can help to explain some of the clinical heterogeneity of psoriasis, with IL-17 responses dominating in plaque psoriasis, a shift towards interferon responses in paradoxical psoriasis, and towards IL-36 responses in pustular psoriasis. IFN=interferon. ILC=innate lymphoid cell. Mφ=macrophage. mDC=myeloid dendritic cell. pDC=plasmacytoid dendritic cell. Th=helper T cell. Tc=cytotoxic T cell. less well to biological therapies (biologics),93 and small helpful in this regard.97 Other studies examining inter­ studies show a beneficial effect of bariatric surgery on ventions involving individual educational sessions psoriasis.94 have also found these to be successful, but their use in resource-limited settings can be challenging.98 Management Overall treatment strategy for plaque psoriasis Treatment goals In general, treatment strategies for plaque psoriasis The definition of moderate-to-severe plaque psoriasis should account for psoriasis severity, presence of varies worldwide. In some European countries, moderate- pso­riatic arthritis, consideration of other associated to-severe psoriasis can be defined by several parameters. medical conditions, and patient preference and satis­ These include psoriasis affecting more than 10% of the faction. For example, if a patient has psoriatic arthritis, body surface area; a psoriasis area severity index equal to the treatment regimen should, if possible, include a or higher than 10, or impairment of quality of life assessed systemic medication that treats this condition in by a dermatology life quality index higher than 10. addition to psoriasis. Psoriasis severity, location, and Moderate-to-severe psoriasis can also be defined in the multimorbidity contribute to the choice of treatment.95,96 presence of one or several of the aforementioned factors: a Education about psoriasis is important, and excellent substantial effect of the disease on physical, social, and information for patients is available from patient psychological wellbeing resulting in depression or anxiety, organisations such as the Psoriasis Association in the or localised psoriasis that cannot be controlled with topical UK and the National Psoriasis Foundation in the USA. therapies and is associated with functional impairment A holistic approach to management is increasingly or considerable distress.99 The treatment framework for being taken, with advice about lifestyle including moderate-to-severe disease has evolved substantially smoking cessation, reduction in alcohol intake, weight internationally.100 The International Psoriasis Council has loss, improvement of sleep, and exercise being deemed published a simplified statement that rejects the mild, as important. The PsoWell programme, which teaches moderate, and severe categories of severity, in favour of a motivational interviewing techniques, is particularly dichotomous definition.101 Patients should be classified as 1306 www.thelancet.com Vol 397 April 3, 2021 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar Maintenance dose in adults Efficacy (PASI 75) Adverse effects and considerations Methotrexate 15–20 mg per week, with folic acid 36% by week 16 Hepatoxicity (cirrhosis) with long-term use; pneumonitis or pulmonary fibrosis; bone marrow suppression; teratogenicity; contraindicated in case of renal insufficiency Apremilast 30 mg twice a day 33% by week 16 Worsening of depression; gastrointestinal disturbance; weight loss; dose adjustment necessary in those with severe renal insufficiency Ciclosporin Up to 5 mg/kg per day to treat so-called 65% clear or almost Hypertension; hypomagnesaemia, hyperkalaemia, and hyperlipidaemia; crisis patients clear by week 8 lymphoma and skin cancer risks; not suitable for long-term use due to irreversible nephrotoxicity Fumarates Maximum 720 mg per day after gradual 37% by week 16 High rate of gastrointestinal intolerance; flushing leading to abandonment titration of treatment by 40% of patients Acitretin 25–50 mg per day 47% by week 16 Contraindicated in women of childbearing age due to teratogenicity; xerosis, sticky skin, and hair loss (more probable with higher doses); hypertriglyceridaemia; hepatoxicity PASI 75=75% reduction in the baseline Psoriasis Area and Severity Index value. Table 1: Oral agents for the treatment of moderate-to-severe plaque psoriasis suitable for topical therapy or suitable for systemic therapy. (anthralin) are used in day treatment centres and in Patients suitable for systemic therapy are defined as dermatology departments that have inpatient beds, meeting at least one of three criteria: more than 10% of body but are being replaced by modern, more cosmetically surface area is affected, psoriasis at special sites (scalp, acceptable, albeit not necessarily more effective, topicals. face, palms and soles, or genitalia), and non-response to A key downside of topical therapies is poor adherence to topical therapy. In some countries, practice guidelines for treatment. moderate-to-severe plaque psoriasis have shifted away from step therapy (ie, starting with phototherapy, then Phototherapy oral agents, then biologics) to concurrently considering Ultraviolet radiation is locally immunosuppressive. It biologics, oral agents, or phototherapies.100 directly affects Langerhans’ cells, inhibits epidermal In the UK, patients are eligible for biologics or the hyper­proliferation and angiogenesis, and causes selec­ newer oral small molecules if they fulfil National tive reduction in cutaneous T cells via apoptosis.109 Institute of Health and Care Excellence guidance of Dif­ferent modalities of phototherapy include narrow­ having had plaque psoriasis for at least 6 months, a band (311–313 nm) ultraviolet B radiation, broadband psoriasis area severity index equal or higher than 10, a (280–320 nm) ultraviolet B radiation, targeted photo­ dermatology life quality index higher than 10 and having therapy, and oral psoralen ultraviolet A (photochemo­ tried, but not responded to or having been found therapy), which is now used less frequently in some unsuitable for conventional systemic therapies such as parts of the world due to the cumulative risk of skin methotrexate.102 cancer.110 Among these, narrowband ultraviolet B Relevant and quantifiable disease endpoints for radiation is the most commonly used phototherapy psoriasis management are emerging, but should take modality, typically administered two or three times into account all of the aforementioned factors. There is an per week, and the use of home units is increasing in increasing global effort to adopt a treat-to-target approach some countries. Narrowband ultraviolet B radiation is to achieve better control of psoriasis and improve patient effective for plaque psoriasis, but side-effects include outcomes.103–105 Thus, an absolute psoriasis area severity burning and a slight potential for photocarcinogenesis index equal to or under 2, or a physician’s global assess­ that is far inferior to that caused by photochemotherapy, ment of clear or almost clear are realistic; these equate to and it is time-consuming.109 In some centres, it is still a 90% reduction of psoriasis area severity index from combined with crude coal tar (Goeckerman regimen) or baseline value (psoriasis area severity index 90) and to a dithranol. dermatology life quality index of less than 5.106 Oral systemic therapies Topical therapy Before the advent of biologics, oral systemic treatments All patients benefit from liberal application of emollients. were for many decades the staple treatment for If psoriasis is limited to a small area (less than 3–5% of moderate-to-severe plaque psoriasis. The mechanisms the body surface), the mainstay of treatment is topical of action, efficacy, and safety profiles of these oral agents agents including corticosteroids, vitamin D3 analogues, differ substantially (table 1).95 As these small molecules calcineurin inhibitors, keratolytics, and combination interact with ubiquitous intracellular targets, their topical agents (eg, corticosteroid with vitamin D3), in actions can be relatively broad compared with those of vehicles such as cream, ointment, foam, or gel.107 Targeted biologics. Commonly used oral agents in psoriasis phototherapy is also used.108 Crude coal tar and dithranol include methotrexate, ciclosporin, acitretin, fumarates, www.thelancet.com Vol 397 April 3, 2021 1307 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar Drug type Biological target Indication Dosing Efficacy Common side-effects Precautions Adalimumab Anti-TNF TNF Psoriasis and 80 mg loading dose, 40 mg PASI 75: 71% Upper respiratory tract History of infections*, psoriatic arthritis 1 week later, then 40 mg every (week 16) infection, injection site malignancies, heart failure, 2 weeks, subcutaneously reactions demyelinating disease, autoimmunity, live-attenuated vaccines Certolizumab pegol Anti-TNF TNF Psoriasis and 400 mg at baseline, 2 weeks, PASI75: 82% Upper respiratory tract History of infections*, psoriatic arthritis and 4 weeks, then 200 mg every (week 16) infection, urinary tract malignancies, heart failure, 2 weeks, subcutaneously infection demyelinating disease, autoimmunity, live-attenuated vaccines Etanercept Anti-TNF TNF Psoriasis and 50 mg twice weekly, PASI 75: 59% Infections, Injection site History of infections*, psoriatic arthritis subcutaneously (week 12) reactions malignancies, heart failure, demyelinating disease, autoimmunity, live-attenuated vaccines Infliximab Anti-TNF TNF Psoriasis and 5–10 mg/kg of bodyweight PASI 75: 80% Upper respiratory tract History of infections*, psoriatic arthritis at weeks 0, 2, and 6, then every (week 10) infection, infusion malignancies, heart failure, 8 weeks, intravenous infusion related reactions demyelinating disease, autoimmunity, live-attenuated vaccines Brodalumab Anti-IL-17 IL-17RA (leading to Psoriasis 210 mg weekly from 0–2 weeks, PASI 75: Injection site reactions, History of infections, inhibition of IL-17A, then every 2 weeks, 86% candida and tinea inflammatory bowel disease, IL-17F, IL-17C, and subcutaneously (week 12) infections live-attenuated vaccines, IL-17E [IL-25]) suicidal ideation and behaviour Ixekizumab Anti-IL-17 IL-17A Psoriasis and 160 mg loading dose, then PASI 75: 90% Injection site reactions, History of infections, psoriatic arthritis 80 mg at weeks 2, 4, 6, 8, 10, (week 12) upper respiratory tract inflammatory bowel disease, and 12, then 80 mg every infection, candida and live-attenuated vaccines 4 weeks, subcutaneously tinea infections Secukinumab Anti-IL-17 IL-17A Psoriasis and 300 mg weekly from 0–4 weeks, PASI 75: 82% Upper respiratory tract History of infections, psoriatic arthritis then monthly, subcutaneously (week 12) infection, candida and inflammatory bowel disease, tinea infections live-attenuated vaccines Guselkumab Anti-IL-23 IL-23 Psoriasis 100 mg at weeks 0 and 4, PASI 90: 73% Upper respiratory tract Infections, live-attenuated then every 8 weeks, (week 16) infection, injection site vaccines subcutaneously51 reactions, tinea infections, herpes simplex infections Risankizumab Anti-IL-23 IL-23 Psoriasis 150 mg at weeks 0 and 4, PASI 90: 75% Upper respiratory tract Infections, live-attenuated then every 12 weeks, (week 16) infection, tinea infections vaccines subcutaneously Tildrakizumab Anti-IL-23 IL-23 Psoriasis 100 mg at weeks 0 and 4, PASI 75: 64% Upper respiratory tract Infections, live-attenuated then every 12 weeks, (week 12) infection, injection site vaccines subcutaneously53 reactions Ustekinumab Anti-IL-12 and IL-12, IL-23 Psoriasis and 45 mg (if bodyweight 100 kg) (week 12) infection live-attenuated vaccines at weeks 0, 4, and 12, then every 12 weeks, subcutaneously PASI 75=75% reduction in baseline Psoriasis Area and Severity Index value. IL=interleukin. PASI 90=90% reduction in baseline Psoriasis Area and Severity Index value. *Especially tuberculosis. Table 2: Efficacy and side-effects of biologics for the treatment of psoriasis and apremilast.95 An oral inhibitor of TYK2 is in methods of surveillance for liver fibrosis include late-phase development for psoriasis.111 serum assay for the amino­ propeptide fragment of Methotrexate has been used for more than 50 years procollagen III, elastography (eg, FibroScan), and for the management of psoriasis and psoriatic algorithm-based risk assessment based on liver arthritis.112 Its mechanism of action is most probably enzymes, platelet count, and age.109,114 Other adverse via 5-aminoimidazole-4-carboxamide ribonucleotide effects of methotrexate include nausea, vomiting, hair transformylase activity and increased adenosine loss, teratogenicity, and pulmo­nary toxicity. To decrease produc­­tion, causing an inhibition of lymphocyte adverse effects of methotrexate on haema­topoiesis and function.113 Oral methotrexate is usually given once the gastrointestinal tract, folic acid supplementation is weekly. The main cause of death caused by methotrexate recommended in most guidelines. toxicity is bone marrow suppression, but patients are Subcutaneous methotrexate is also available and is also at risk of liver fibrosis (cirrhosis). Non-invasive gradually replacing oral administration in many countries. 1308 www.thelancet.com Vol 397 April 3, 2021 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar It might have greater efficacy, a more predictable bio­ Inhibition Mφ availability, and fewer gastrointestinal side-effects.115 Effect Keratinocytes Dendritic cells Methotrexate can be used in combination with anti-TNFα biologics to mitigate the development of antidrug anti­ IL-17F/F ILC3 T cell bodies,116 more so in rheumatology than in dermatology. Ciclosporin is a systemic calcineurin inhibitor used for Bimekizumab* IL-17F/A IL-23 short-term treatment of patients with severe plaque Th17 p40 p19 Adalimumab psoriasis or who are in crisis, and as a bridge therapy IL-17A/A Golimumab† to long-term therapies such as biologics or other oral Infliximab Ixekizumab TNF Ustekinumab medications. Its action is fast and its efficacy robust.117 It Secukinumab IL-17C Etanercept Guselkumab should not be used for more than 1 year due to the risk Mirikizumab Certolizumab of irreversible nephro­toxicity.117 Other adverse effects of Risankizumab pegol IL-17RC IL-17RA IL-17RE Tildrakizumab TNFR ciclosporin include hypertension, increased risk of infec­ tion, nausea, hirsutism, gingival hyperplasia, drug–drug interactions, and electrolyte disturbances. Acitretin is a systemic synthetic retinoid that can be used to treat severe plaque psoriasis. It normalises Brodalumab keratinocyte proliferation and exerts immunomodulatory Keratinocyte IL-17 and TNF synergism effects to decrease proinflammatory cytokines, such as IL-6 and IFN-γ.118 It is sometimes used to treat pustular Figure 4: Biologics for the treatment of psoriasis and their targets forms of psoriasis and palmoplantar psoriasis. Now used Currently, 11 biologics are approved for the treatment of psoriasis: four anti-TNF agents (adalimumab, infliximab, less often for plaque psoriasis, it should be avoided etanercept, and certolizumab pegol; a fifth, golimumab, is currently only approved for treatment of psoriatic arthritis), a single agent targeting the p40 subunit of IL-12 and IL-23 (ustekinumab), three biologics targeting the altogether in women of child-bearing age. p19 subunit of IL-23 (guselkumab, risankizumab, tildrakizumab), two anti-IL17A agents (ixekizumab and Fumaric acid esters are small molecules that inhibit secukinumab), and one biologic targeting the anti-IL17 receptor A (brodalumab). Two biologics are currently in maturation of dendritic cells, induce T cell apoptosis, and late-phase clinical trials, including the p19 inhibitor mirikizumab and the bispecific anti-IL-17A and IL-17F agent interfere with leucocyte extravasation.119 In Germany, for bimekizumab. The figure shows the source of the key cytokine targets of biologics and their corresponding cytokine receptors. ILC=innate lymphoid cell. Mφ=macrophage. IL-17RC=IL-17 receptor C. Th17=helper T cells type 17. example, fumaric acid esters are among the most used TNFR=TNF receptor. *Bimekizumab, the bispecific anti-IL-17A and IL-17F agent, and mirikizumab, the p19 inhibitor, treatments for moderate-to-severe plaque psoriasis. are not yet approved and are in phase 3 clinical trials. †Golimumab is currently only approved for treatment of Dimethyl fumarate, a new single ester version, has also psoriatic arthritis. been licensed by the European Medicines Agency for the treatment of psoriasis.120 Typically, the dose is increased these drugs that, for example, has relevance for iden­ gradually because of substantial side-effects, including tifying patients at risk of infection. flushing and diarrhoea, which appear in up to 40% of With the exception of infliximab, all biologics used for patients. A lymphocytopenia of 0·7 K/μL or under is a psoriasis are administered by subcutaneous injection trigger to reduce the dose because of risk of progressive (table 2). There are 11 biologics in four different classes multifocal leukoencephalopathy at counts lower than (anti-TNFα, anti-IL17, anti-IL-12p40 or IL-23p40, and this value. anti-IL-23p19) currently in use for the treatment of Apremilast is a phosphodiesterase-4 inhibitor licensed moderate-to-severe psoriasis (figure 4). for the management of moderate-to-severe psoriasis and Four anti-TNFα agents are currently in use for psoriatic arthritis. It exerts immunomodulatory effects psoriasis: adalimumab, certolizumab pegol, etanercept, to decrease proinflammatory cytokines (such as TNFα, and infliximab.122 Etanercept is a fusion protein of tumour IL-2, and IL-12) and increase anti-inflammatory cytokines necrosis factor receptor 2 (TNFRSF1B) with the Fc end (such as IL-10).121 Adverse effects can include nausea, of IgG1.123 Certolizumab pegol is a polyethylene-glycol diarrhoea, and weight loss. conjugated monoclonal antibody fragment.124 Pegylation decreases its immunogenicity and increases its half-life,125 Biologics and certolizumab, unlike other biological agents, does Over the last 20 years, biologics have drastically changed not cross the placental barrier.126 Adalimumab is a fully our ability to treat psoriasis and psoriatic arthritis. They human antibody, and infliximab is a chimeric anti­ are mostly recombinant monoclonal antibodies or body.127 A fifth anti-TNFα agent, golimumab, is currently receptor fusion proteins, either fully human, humanised, approved for the treatment of psoriatic arthritis but not or human–mouse chimeric, and target specific inflam­ of psoriasis. matory mediators. Although currently classed as immu­ Three anti-IL-17 agents are approved: secukinumab, no­suppressants, it is becoming increasingly apparent ixekizumab, and brodalumab. Both secukinumab and that drugs targeting highly specific pathways within ixekizumab128 specifically target IL-17A and brodalumab the immune system cannot be simply classified as targets the IL-17 receptor A unit (IL-17RA), inhibiting suppressant or stimulatory. Hence, there is need for a IL-17A, IL-17F, and two other members of the IL-17 new nomenclature to describe the modulatory actions of cytokine family (IL-17C and IL-17E or IL-25). Bimekizumab, www.thelancet.com Vol 397 April 3, 2021 1309 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar targeting both IL-17A and IL-17F, is in a phase 3 clinical cancer risk if the necessary pretreatment and annual trial for psoriasis.129 screening procedures are performed. There are currently four agents that target IL-23 in clinical use for psoriasis: ustekinumab, which blocks the SARS-CoV-2 and psoriasis common p40 subunit of IL-12 and IL-23, and guselkumab, The COVID-19 pandemic has created substantial chal­ risankizumab, and tildrakizumab, which target the lenges to the management of psoriasis. Although there is p19 subunit of IL-23. A fourth anti-IL-23p19 biologic, currently no direct evidence that psoriasis is itself a risk mirikizumab, is currently in phase 3 clinical studies factor for COVID-19 infection or worse disease outcomes, (NCT03482011 and NCT03535194). IL-23 has a key role in theoretically, people with severe disease could potentially maintaining and amplifying Th17 and cytotoxic T cells be at higher risk, given that they have comorbidities such type 17 (Tc17) responses.130 This inhibition of IL-17 as obesity and diabetes. Furthermore, there is some responses is thought to be the main mechanism behind evidence that people with immune-mediated inflam­ the therapeutic efficacy of these drugs.131 matory diseases are at greater risk than is the general The highly specific targeting of inflammatory mediators population,143 although whether this risk is a consequence by biologics might enable immune responses to circumvent of the disease or of its treatment remains to be clarified. the blockade leading to worsening disease accompanied by With the exception of acitretin, all systemic therapies a shift in its clinical and immunological characteristics. (including small molecules and biologics) for psoriasis The best characterised of these so-called paradoxical are labelled by regulators as immunosuppressants. This reactions is new onset or worsening of psoriasis during labelling has led to these therapies being declared as anti-TNFα therapy,82 or with anti-IL-6 treatment.132 These risk factors, even though the mode of action of several reactions are more common in women82 and often present of these does not relate to antiviral pathways.144 Conse­ as palmoplantar pustulosis. Another phenotypic shift is the quently, it is crucial that we accumulate data of patients transformation of psoriasis into atopic dermatitis on with psoriasis who develop COVID-19 from registries For PsoProtect see http:// morphology, presence of pruritus, and eosinophilia. This such as PsoProtect to determine risk of the disease and www.PsoProtect.org shift is seen with all biologics but appears prominent with its treatments.145 Early data are encouraging in that no the anti-IL-17 and anti-IL23p19 classes.133 increased risk either of COVID-19 infection or severity Although many biologics are highly effective, not all has been identified and, interestingly, patients on patients respond in the same manner. Some people might biologic therapy are less likely to be hospitalised.145 not respond at all (primary treatment failure) or, far more Patients with psoriasis who do not have a contraindication commonly, have an initial response that is subsequently or a known allergy to a vaccine component should be lost over periods of months to years (secondary failure). recommended to receive one of the SARS-CoV-2 vaccines Time to discontinuation is variable between different based on local availability and guidance from local public biologics and, strikingly, the risk of treatment failure is health bodies. increased with the number of biologics a patient has received previously.134 The underlying causes of primary Unresolved questions, new developments, and and secondary failure are not clear. However, several unmet medical needs fasctors have been implicated, including non-adherence,135 Translational medicine has epitomised psoriasis research low blood concentrations of biologics (probably due to the for the past 25 years, transforming the lives of many development of antidrug antibodies136,137), high body-mass patients in the process, but unanswered questions index, and sex differences, with men being more likely remain. The contribution of genetics to disease expres­ than women to achieve a better initial response and less sion is undoubted, yet the mechanisms underlying likely to lose therapeutic effect over time.138,139 environmental triggers are elusive. The role of the The development of low-cost biosimilars after biologics microbiome might be a key player in this interaction have come off patents has made access to this class of between genetic susceptibility and environ­ mental drug more affordable. Many biosimilar versions of triggers, as are the contributions of stress and infection; infliximab, etanercept, and adalimumab are available, the COVID-19 pandemic will teach clinicians much which, in addition to cost-saving in high-income countries, about the relevance of viral infection to the psoriasis might allow patients in low-income and medium-income phenotype. The application of preventive, predictive, countries to have the opportunity to be treated. personalised, and participatory medicine to personalise The true safety, and to a lesser extent efficacy, of biologics treatment pathways instils a systems medicine, proactive for psoriasis can only be derived from real-world evidence approach to the management of psoriasis that will aim to provided by long-term pharmacovigilance registries, such prevent severe disease and disabling comorbidities, such as the British Association of Dermatologists Biologics as psoriatic arthritis and cardio­vascular disease. Evidence and Immunomodulators Register in the UK, PsoBest in indicates that IL-17 and IL-23 are key drivers of disease Germany, and BIOBADADERM in Spain.140–142 The data expression, but the search will continue for other relevant thus far are reassuring as to the safety profile for biologics cytokines and canonical intracellular signalling path­ in general, and show no major concerns for infection or ways that are druggable for immediate and long-term 1310 www.thelancet.com Vol 397 April 3, 2021 Downloaded for Anonymous User (n/a) at The Aga Khan University from ClinicalKey.in by Elsevier on June 28, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  Seminar management. A stratified approach to treatment might fundamental actionable differences, whether they are emerge from the application of predictive algorithms immunological, genetic, or environmental. based on integrated omics leveraged from clinical, genetic, and immune bio­markers. This approach would Conclusion allow prediction of response to medication: the drug The intricacies of psoriasis are slowly being uncovered. response endotype that facilitates the accurate drug There is widespread agreement that psoriasis is genet­ targeting with the minimum possible dose for an ically predetermined, its expression partly determined by individual. The UK Medical Research Council funded immune factors and environmental exposures, and that academic-industrial stratified medicine consortium it will eventually be reclassified into several taxonomically Psoriasis Stratification to Optimise Relevant Therapy distinct endotypes. Consensus is also emerging that it is working to produce such an algorithm scalable for has various systemic consequences. This realisation clinical use.146 A rapidly emerging concept is that of mandates a holistic and proactive approach to psoriasis early inter­vention: managing patients as soon as pos­sible care, factoring in lifestyle management, identification of after diagnosis not only allows for screening for multi­ risk factors for many important medical conditions, and morbidity, education about psoriasis and behaviour early introduction of therapies targeted to the indivi­ change, and purposeful alignment of treatment path­ dual. The global burden of psoriasis is immense; an ways, but also for early intervention with systemic understanding of this burden and the removal of barriers therapy. Such intervention could modify the disease or to accessing the best care locally is imperative. Progress potentially even halt it by preventing accumulation of will continue to be made by a concerted effort involving tissue-resident memory T cells in the skin. The systemic clinicians, scientists, patients, and the industry. A cure inflammatory nature of psoriasis needs to be fully for psoriasis, or even a preventive strategy, is unlikely explored, particularly the role of adipose inflammation to be delivered in the near future, but an approach and the putative role of biologics in preventing that allows matching the best treatment plan to each cardiovascular disease. individual is achievable. The taxonomy of psoriasis is being rewritten as Contributors molecular and genomic insights add to clinical pheno­ All authors contributed equally to this work. type, exemplified by the separation of pustular forms Declaration of interests from plaque psoriasis and the recognition that within a CEMG reports grants from AbbVie, Almirall, Amgen, Janssen, LEO defined clinical endotype (eg, plaque psoriasis), there can Pharma, Novartis, Eli Lilly, UCB, and Sandoz, and personal fees from AbbVie, Bristol Myers Squibb, Janssen, Novartis, Eli Lilly, and UCB, be different immunogenetic mechanisms at play.