Psoriasis is an inflammatory skin disorder that is inherited as a multifactorial trait. Genetic analyses have repeatedly identified a primary disease susceptibility locus lying within the major ...histocompatibility complex (MHC), on chromosome 6p21. A small number of non-MHC susceptibility loci have also been identified. These regions tend to overlap with susceptibility intervals for Crohn's disease and atopic dermatitis, suggesting the possibility that genetic variants affecting inflammatory pathways may contribute to the pathogenesis of multiple disorders. Here, we report a genetic analysis of the interleukin 23 receptor gene (IL23R), which was recently identified as a susceptibility determinant for Crohn's disease. We initially examined the results of a whole-genome association scan, carried out on 318 cases and 288 controls. We observed a significant increase of a non-synonymous substitution (p.Arg381Gln) among controls (P = 0.00036). We validated this finding by extending our cohort to include a further 519 cases and 528 controls. In the overall sample, the frequency of the 381Gln allele was 3.6% in cases and 7% in controls, yielding a P value of 0.00014. Next, we examined genetic variation at the IL12RB1, IL23A and IL12B genes, respectively, encoding the second subunit of the IL23R receptor and the two subunits of its ligand. This analysis identified independent associations for IL12B SNPs rs10045431 (P value for the extended dataset = 0.0001) and rs3212227 (P = 0.036). Altogether, these findings indicate that genes participating in IL23 signalling play a significant role in the pathogenesis of chronic epithelial inflammation.
Summary
Background
The effectiveness and cost‐effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of ...psoriasis is needed.
Objectives
To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management.
Methods
We applied latent class mixed modelling to identify trajectory‐based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials.
Results
We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA‐C*06:02 between our registry‐identified trajectories.
Conclusions
These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.
What is already known about this topic?
While many patients with psoriasis respond to treatment with biologics, there are those who show little or no response and those who respond initially but then either lose response or suffer from adverse effects.
Better characterization of patients who will, or will not, benefit from biologic therapy will facilitate the understanding of relevant biological mechanisms and explain treatment outcome variation in patient cohorts.
What does this study add?
Using a data‐driven approach, we identified four subgroups of patients with psoriasis defined by global trajectories of response to biologic therapies.
Our results were replicated in a second cohort obtained by pooling data from four clinical trials of biologic therapies for psoriasis.
We further identified potential human leucocyte antigen biomarkers that help to distinguish between the trajectory‐based subgroups.
Linked Comment: L.S. van der Schoot and J.M.P.A. van den Reek. Br J Dermatol 2021; 185:698–699.
Summary
Background
Registry data suggest that people with immune‐mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID‐19) ...outcomes compared with patients receiving no systemic treatments.
Objectives
We used international patient survey data to explore the hypothesis that greater risk‐mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation.
Methods
Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk‐mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed‐effects model.
Results
Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk‐mitigating behaviour (classified here under the umbrella term ‘shielding’). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35–1·97. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23–1·56). Shielding was associated with established risk factors for severe COVID‐19 male sex (OR 1·14, 95% CI 1·05–1·24), obesity (OR 1·37, 95% CI 1·23–1·54), comorbidity burden (OR 1·43, 95% CI 1·15–1·78), a primary indication of RMDs (OR 1·37, 95% CI 1·27–1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36–1·80). Modest differences in the proportion shielding were observed across nations.
Conclusions
Greater risk‐mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID‐19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence‐based patient communication on risk‐mitigation strategies and may help inform updated public health guidelines as the pandemic continues.
What is already known about this topic?
At the beginning of the coronavirus disease 2019 (COVID‐19) pandemic, patients with immune‐mediated inflammatory diseases (IMIDs) on targeted systemic therapies were considered to be at higher risk of severe COVID‐19.
Subsequent clinician‐reported registry data suggest that targeted systemic therapy use is associated with fewer adverse COVID‐19 outcomes compared with no systemic therapy.
What does this study add?
We characterize shielding behaviour in 3720 patients with IMIDs from a global self‐report survey.
Use of targeted systemic therapy associates with increased shielding behaviour, compared with standard systemics or no therapy, as do demographic risk factors for severe COVID‐19 including male sex and obesity.
Greater risk‐mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID‐19 outcomes.
Behaviour variation across treatment groups reinforces the need for clear, evidence‐based patient communication on risk‐mitigation strategies.
These data may help to inform updated public health guidelines as the pandemic continues.
Linked Comment: G. Becher and A.D. Burden. Br J Dermatol 2021; 185:7–8.
Psoriasis Di Meglio, Paola; Villanova, Federica; Nestle, Frank O
Cold Spring Harbor perspectives in medicine,
08/2014, Letnik:
4, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of ...clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life.
The skin provides the first line defense of the human body against injury and infection. By integrating recent findings in cutaneous immunology with fundamental concepts of skin biology, we portray ...the skin as a multitasking organ ensuring body homeostasis. Crosstalk between the skin and its microbial environment is also highlighted as influencing the response to injury, infection, and autoimmunity. The importance of the skin immune network is emphasized by the identification of several skin-resident cell subsets, each with its unique functions. Lessons learned from targeted therapy in inflammatory skin conditions, such as psoriasis, provide further insights into skin immune function. Finally, we look at the skin as an interacting network of immune signaling pathways exemplified by the development of a disease interactome for psoriasis.
Psoriasis is a common immune-mediated disease of the skin, which associates in 20-30% of patients with psoriatic arthritis (PsA). The immunopathogenesis of both conditions is not fully understood as ...it is the result of a complex interaction between genetic, environmental and immunological factors. At present there is no cure for psoriasis and there are no specific markers that can accurately predict disease progression and therapeutic response. Therefore, biomarkers for disease prognosis and response to treatment are urgently needed to help clinicians with objective indications to improve patient management and outcomes. Although many efforts have been made to identify psoriasis/PsA biomarkers none of them has yet been translated into routine clinical practice. In this review we summarise the different classes of possible biomarkers explored in psoriasis and PsA so far and discuss novel strategies for biomarker discovery.
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