Psoriasis Griffiths, Christopher E M; Armstrong, April W; Gudjonsson, Johann E ...
The Lancet (British edition),
04/2021, Letnik:
397, Številka:
10281
Journal Article
Recenzirano
Psoriasis is a common, chronic papulosquamous skin disease occurring worldwide, presenting at any age, and leading to a substantial burden for individuals and society. It is associated with several ...important medical conditions, including depression, psoriatic arthritis, and cardiometabolic syndrome. Its most common form, chronic plaque or psoriasis vulgaris, is a consequence of genetic susceptibility, particularly in the presence of the HLA-C*06:02 risk allele, and of environmental triggers such as streptococcal infection, stress, smoking, obesity, and alcohol consumption. There are several phenotypes and research has separated pustular from chronic plaque forms. Immunological and genetic studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis. Immune targeting of these cytokines and of TNFα by biological therapies has revolutionised the care of severe chronic plaque disease. Psoriasis cannot currently be cured, but management should aim to minimise physical and psychological harm by treating patients early in the disease process, identifying and preventing associated multimorbidity, instilling lifestyle modifications, and employing a personalised approach to treatment.
Background Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. ...Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted , causing a matted hair phenotype. Objective We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. Methods A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. Results The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt ft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. Conclusion In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the ...relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
Patients with psoriasis enrolled in clinical trials of biologics may not be representative of the real-world population. There is evidence that patients ineligible for such trials have a greater risk ...of serious adverse events (SAEs), but the effect on drug discontinuation and effectiveness are unknown.
To determine whether (1) drug discontinuation, (2) effectiveness, and (3) rates of SAEs differ in patients with psoriasis categorized as eligible or ineligible for clinical trials.
An observational study using 157 dermatology centers in the United Kingdom and Republic of Ireland was carried out wherein we applied the eligibility criteria of clinical trials of biologic therapies for psoriasis to patients who were being followed up in the British Association of Dermatologists Biologic Interventions Register (BADBIR) and being prescribed biologics as part of standard clinical care. Patients with psoriasis registered to BADBIR who were taking etanercept (enbrel only; n = 1509), adalimumab (n = 4000), and ustekinumab (n = 1627) with at least 1 follow-up visit. Eligibility criteria were extracted from phase 3 licensing trials for etanercept, adalimumab, and ustekinumab for the treatment of moderate to severe psoriasis. Patients in BADBIR with a missing baseline Psoriasis Area and Severity Index (PASI) or baseline PASI value less than 10 (etanercept) or less than 12 (adalimumab; ustekinumab) but who would otherwise be eligible were investigated separately. Eligibility categories applied to BADBIR included: eligible, ineligible, insufficient baseline PASI only, and missing baseline PASI only.
(1) Drug discontinuation: cumulative incidence at 12 months by stop reason per eligibility category and drug; (2) effectiveness: linear regression of absolute change in PASI from baseline to 6 and 12 months; and (3) SAEs: incidence rate ratio (IRR) at 12 months between eligibility categories per drug.
The mean (SD) age of the 7136 patients included in the analysis was 45 (13) years and 2924 (41%) were women and 4212 (59%) were men. Of 7136 patients, 839 (56%) etanercept, 2219 (56%) adalimumab, and 754 (46%) ustekinumab registrations were categorized as eligible. The most common reasons for ineligibility were diabetes (etanercept, 143 9%; ustekinumab, 201 12%) and nonchronic plaque psoriasis (adalimumab, 157 4%). Patients categorized as ineligible (etanercept, 367 24%; adalimumab, 282 7%; ustekinumab, 394 24%) achieved a smaller absolute change in PASI after 6 and 12 months (adalimumab, ustekinumab), and had significantly higher rates of SAEs compared with the eligible category (etanercept: IRR, 1.9; 95% CI, 1.4-2.6; adalimumab: IRR, 2.0; 95% CI, 1.5-2.6; ustekinumab: IRR, 2.8; 95% CI, 2.1-3.8). No significant differences in drug discontinuation were observed between categories.
Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.
Psoriasis: a brief overview Raharja, Antony; Mahil, Satveer K; Barker, Jonathan N
Clinical medicine,
20/May , Letnik:
21, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Psoriasis is a clinically heterogeneous lifelong skin disease that presents in multiple forms such as plaque, flexural, guttate, pustular or erythrodermic. An estimated 60 million people have ...psoriasis worldwide, with 1.52% of the general population affected in the UK. An immune-mediated inflammatory disease, psoriasis has a major genetic component. Its association with psoriatic arthritis and increased rates of cardiometabolic, hepatic and psychological comorbidity requires a holistic and multidisciplinary care approach. Psoriasis treatments include topical agents (vitamin D analogues and corticosteroids), phototherapy (narrowband ultraviolet B radiation (NB-UVB) and psoralen and ultraviolet A radiation (PUVA)), standard systemic (methotrexate, ciclosporin and acitretin), biologic (tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors) or small molecule inhibitor (dimethyl fumarate and apremilast) therapies. Advances in the understanding of its pathophysiology have led to development of highly effective and targeted treatments.
Over recent years, significant progress has been made in characterisation of the underlying pathogenic mechanisms in psoriasis, a common cutaneous disease that is associated with major systemic ...co-morbidity and reduced life expectancy. Basic science discoveries have informed the design of novel therapeutic approaches, many of which are now under evaluation in late-stage clinical trials. Here we describe the complex interplay between immune cell types and cytokine networks that acts within self-perpetuating feedback loops to drive cutaneous inflammation in psoriasis. Genetic studies have been pivotal in the construction of the disease model and more recently have uncovered a distinct aetiology for rare, pustular variants of psoriasis. The translation of mechanistic insights into potential advancements in clinical care will also be described, including several treatments that target the interleukin-23 (IL-23)/T17 immune axis.
Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed ...meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10−8) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, prs1250544 = 3.53 × 10−8, 11q13 near PRDX5, prs694739 = 3.71 × 10−09, 22q11 at YDJC, prs181359 = 8.02 × 10−10). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, prs4780355 = 4.99 × 10−8). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.
If a patient appears to have been cleared of psoriasis by systemic therapy, there is no reliable way to ascertain whether control is absolute other than reducing the dose of, or withdrawing, ...therapy.\n83 Studies have shown reliably that psoriasis produces a decrease in quality of life at least equal to and often greater than that of conditions such as diabetes, ischaemic heart disease, and chronic obstructive pulmonary disease.84 The dermatology life quality index is a questionnaire used increasingly to assess improvements in quality of life resulting from therapeutic intervention.83 The stress caused by living with psoriasis can manifest as avoidance behaviours; for example, unwillingness to attend local swimming pools for fear of the ignominy of being asked to leave by a member of the public with unwarranted concerns about the contagiousness of the condition. Objective studies have emphasised the role of automatic vigilance86 for threat in patients with psoriasis, and indeed their coping behaviours are similar to those used by patients with cancer or chronic pain.87 Concerns about chronicity of disease and the absence of a cure are an important undercurrent: even patients in whom systemic therapy causes remission maintain high levels of anxiety because of the fear of relapse.88 Psychological sequelae of the disease can impair response to treatment: patients with pathological levels of anxiety are less likely to respond to photochemotherapy.89 Even patients' partners and dose relatives are less attuned to the psychosocial sequelae of the disease than might be expected.90 Doctors experienced in the management of psoriasis remain fairly poor at identifying and subsequently addressing depression and anxiety in their patients.91 An understanding of the psychosocial difficulties encountered by patients with psoriasis and other chronic skin diseases, and how a biopsychosocial model could be used in the management of such conditions, are unmet needs.
Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic ...basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.
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