A set of serum markers detecting systemic inflammation in psoriatic skin, entheseal, and joint disease in the absence of C-reactive protein and its link to clinical disease manifestations.
ABSTRACT: BACKGROUND:C-reactive protein (CRP) is often normal in patients with psoriatic disease. Herein, we aimed to define markers of systemic inflammation in patients with monomorphic and polymorphic psoriatic skin, entheseal, and joint disease. METHODS:Three-step approach: (i) selection of serum markers elevated in psoriatic arthritis compared healthy controls from a panel of 10 different markers reflecting the pathophysiology of psoriatic disease; (ii) testing of these selected markers as well as C-reactive protein (CRP) in a larger cohort of 210 individuals- 105 healthy controls and 105 patients with psoriatic disease with either monomorphic skin (S), entheseal (E) or joint (A) involvement or polymorphic disease with various combinations of skin, entheseal and joint disease (SE, SA, EA, SEA); (iii) testing whether tumor necrosis factor (TNF) and interleukin (IL)-17 inhibitor therapy normalizes these markers. RESULTS:CRP was not elevated or was rarely elevated in the subgroups (S 0%, E 0%, A 20%, SE 7%, SA 33%, EA 27%, SEA 33%) despite active psoriatic disease. In sharp contrast, beta-defensin 2 and lipocalin-2 levels were elevated in the majority of patients with monomorphic skin (93% and 73%) and entheseal (both 53%), but not joint disease (27% and 20%). Conversely, elevations of calprotectin and IL-8 were found in the majority of patients with monomorphic joint disease (both 73%). IL-22 was elevated in all three monomorphic disease manifestations (S 60%, E 46%; A 60%). Furthermore, the vast majority of patients with polymorphic psoriatic disease (SE, SA, EA, SEA) showed widespread marker elevation. IL-17- and TNF inhibitor treatment significantly lowered all 5 markers of inflammation in PsA patients. CONCLUSIONS:Systemic inflammation is detectable in the majority of patients with psoriatic disease, even if CRP is normal. The respective marker pattern depends on the manifestation of psoriatic disease with respect to skin, entheseal, and joint involvement.
Project description:Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptor 1 (PAR1) and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from patients with psoriasis. Beyond defining a critical role for KLK6/PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6/PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.
Project description:Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from psoriasis patients. Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis. Overall design: RNA-seq was performed to identify genes with altered expression in skin from Klk6+ transgenic mice (n = 3 males, n = 2 females) as compared to WT mice (n = 3 males, n = 2 females).
Project description:The perceived bother of skin and joint-related manifestations of psoriatic disease may differ among patients, rheumatologists, and dermatologists. This study identified and compared the patient and dermatologist/rheumatologist-perceived bother of psoriatic disease manifestations.Online surveys were administered to patients with both psoriasis and psoriatic arthritis and to dermatologists and rheumatologists. Object-case best-worst scaling was used to identify the most and least bothersome items from a set of five items in a series of questions. Each item set was drawn from 20 items describing psoriatic disease skin and joint symptoms and impacts on daily activities. Survey responses were analyzed using random-parameters logit models for each surveyed group, yielding a relative-bother weight (RBW) for each item compared with joint pain, soreness, or tenderness.Surveys were completed by 200 patients, 150 dermatologists, and 150 rheumatologists. Patients and physicians agreed that joint pain, soreness, and tenderness are among the most bothersome manifestations of psoriatic disease (RBW 1.00). For patients, painful, inflamed, or broken skin (RBW 1.03) was more bothersome, while both rheumatologists and dermatologists considered painful skin much less bothersome (RBW 0.17 and 0.22, respectively) than joint pain. Relative to joint pain, rheumatologists were more likely to perceive other joint symptoms as bothersome, while dermatologists were more likely to perceive other skin symptoms as bothersome.This study has identified important areas of discordance both between patients and physicians and between rheumatologists and dermatologists about the relative bother of a comprehensive set of psoriatic disease symptoms and functional impacts. Both physician specialists should ask patients which manifestations of psoriatic disease are most bothersome to them, as these discussions may have important implications for drug and other patient management options.
Project description:There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort.First, the CRP levels were compared between baseline samples of 266 SSc patients enrolled in the Genetics Versus Environment in Scleroderma Outcome Study cohort and 97 unaffected matched controls. Subsequently, the correlation between CRP levels and concomitantly obtained markers of disease severity was assessed. Serially obtained % predicted forced vital capacity (FVC) was used to examine the long-term ILD progression. The predictive significance of CRP level was investigated by a joint analysis of longitudinal measurements (serial FVCs up to 13 years) and survival data. This approach allowed inclusion of all 1,016 FVC measurements and accounted for survival dependency.We confirmed that baseline CRP levels were higher in SSc patients than controls. CRP levels were associated with absence of anticentromere antibodies and correlated with the concomitant severity of lung, skin, and joint involvement. More importantly, higher baseline CRP levels were associated with shorter survival (P < 0.001) and predicted the long-term decline in FVC independent of potential confounders (age at baseline, sex, ethnicity, disease type, current smoking, body mass index, topoisomerase status, and treatment with immunosuppressive agents) in the multivariable model (P = 0.006).Baseline CRP levels are predictive of long-term ILD progression. CRP level might aid clinicians in identifying patients that require more intensive monitoring and treatment.
Project description:Psoriasis is an immune-mediated skin disease which affects 2-4% of the worldwide population. Approximately 20-30% of patients with psoriasis develop psoriatic arthritis (PsA), a frequently destructive and disabling condition. As skin manifestations precede joint symptoms in nearly all patients with PsA, identification of biomarkers for early prediction of joint damage is an important clinical need. Because not all patients with PsA respond to treatment in the same fashion, identification of biomarkers capable of predicting therapeutic response is also imperative. Here, we review existing literature and discuss current investigations to identify potential biomarkers for PsA disease activity, with particular emphasis on microRNAs as novel markers of interest. Serum (soluble) biomarkers, peripheral osteoclast precursor as cellular biomarkers, and genetic loci associated with skin and joint disease are also reviewed.
Project description:INTRODUCTION:Psoriatic arthritis (PsA) is a chronic, systemic, inflammatory disease where disease burden and quality of life (QoL) are affected by both joint and skin manifestations. METHODS:Patient and physician reported data were collected about 3200 patients in a cross-sectional survey of patients from nine countries. Patient-reported outcomes (PROs) included perceptions of symptom importance, EuroQol questionnaire (EQ-5D), Psoriatic Arthritis Impact of Disease (PsAID12), and Work Productivity and Activity Impairment (WPAI) Index. Outcomes were compared in patients with 'joint-only' and 'joint and skin' disease symptoms. RESULTS:Of the 3200 patients, 2703 had complete information for 'joint-only' or 'joint and skin' involvement and were included in the analysis. Patients had a mean age of 49.2 years, 45.2% were female, and 64.5% had 'joint and skin' involvement. Patients with 'joint and skin' involvement had higher mean tender and swollen joint counts (5.2 and 4.8) than patients who were 'joint-only' (2.0 and 1.5). Significantly more patients with active 'joint and skin' symptoms experienced a flare (currently or within the last 12 months) compared with 'joint-only' patients (34.9 vs. 23.2%, p?<?0.001). When asked to prioritize the burden of symptoms, 61.6% of patients prioritized joints, 38.4% prioritized skin. Anxiety/depression was experienced by 41.4% of patients, 62.4% of whom indicated that both joint and skin symptoms were the cause. Patients with 'joint and skin' involvement reported significantly worse QoL, work productivity and activity impairment than 'joint-only' patients (EQ-5D index 0.79 vs. 0.85, p?<?0.001; EQ-5D VAS 71.98 vs. 77.68, p?<?0.001; PsAID12 2.91 vs. 1.66, p?<?0.001; WPAI overall work impairment 25.61 vs. 16.32, p?<?0.001). CONCLUSIONS:PsA patients who experience 'joint and skin' symptoms had significantly worse clinical outcomes, health-related QoL, and work productivity compared with patients with 'joint-only' symptoms.
Project description:OBJECTIVE:To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3Cstopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. METHODS:We characterized a novel murine model of Th17-driven cutaneous and synovio-entheseal disease directed by T cell-specific expression of a hyperactive Stat3 allele. By crossing R26Stat3Cstopfl/fl CD4Cre mice onto an interleukin-22 (IL-22)-knockout background or treating the mice with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. RESULTS:R26Stat3Cstopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell-specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL-producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL-17 or IL-22 improved both the skin and bone phenotype in R26Stat3Cstopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. CONCLUSION:Perturbation of the IL-23/Th17 axis instigates Th17-mediated inflammation in R26Stat3Cstopfl/fl CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL-17A and IL-22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA.
Project description:This study correlated assessment tools for evaluating the severity of skin, nail, and joint symptoms in patients with psoriasis (Pso) and psoriatic arthritis (PsA). Adults with plaque Pso (with or without PsA) were enrolled from four U.S. institutions. Patients were evaluated using a novel 10-area Linear Psoriasis Area and Severity Index (XL-PASI), Psoriatic Arthritis Assessment (PsAA), Psoriatic Arthritis Screening and Evaluation Questionnaire (PASE), Nail Assessment (NA) and Joint Assessment (JA) tools, Psoriasis Weighted Extent and Severity Index (PWESI), and Lattice Physician Global Assessment (LS-PGA). Correlations between assessment tools and individual items in the assessment tools were performed. Data from 180 patients (55 with PsA) were analyzed. Highest correlations between tools (r?=?0.77-0.88) were between the XL-PASI, PWESI and LS-PGA. Individual items in the XL-PASI correlated with items in the PWESI for extent skin symptoms, but not for all body areas. Overall, correlations were seen between hands and feet, between face and scalp, and between buttocks, chest, and back. Only low correlation was seen between items assessing joint symptoms with items assessing skin symptoms. These data support the notion that the complex phenotype of psoriatic disease requires instruments that assess the severity of skin, nails, and joints separately.
Project description:In a subset of psoriasis (PsO) and psoriatic arthritis (PsA) patients, the skin and/or joint lesions appear to generate biologically significant systemic inflammation. Red cell distribution width (RDW) and mean platelet volume (MPV) are readily available clinical tests that reflect responses of the bone marrow and/or plasma thrombogenicity (e.g., inflammation), and can be markers for major adverse cardiac events (MACE). We aimed to evaluate if RDW and MPV may be employed as inexpensive, routinely obtained biomarkers in predicting myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) in psoriatic and psoriatic arthritis patients. The study was divided into two parts: (a) case control study employing big data (Explorys) to assess MPV and RDW in psoriasis, psoriatic arthritis and control cohorts; (b) a clinical observational study to validate the predictive value of RDW and to evaluate RDW response to anti-psoriatic therapies. We used Explorys, an aggregate electronic database, to identify psoriatic patients with available MPV and RDW data and compared them to gender and age matched controls. The incidence of myocardial infarction (MI), atrial fibrillation (AF), and chronic heart failure (CHF) was highest among patients with both elevated RDW and MPV, followed by patients with high RDW and normal MPV. RDW elevation among PsA patients was associated with an increased risk of MI, AF, and CHF. In a local clinical cohort, high RDWs were concentrated in a subset of patients who also had elevated circulating resistin levels. Among a small subset of participants who were treated with various systemic and biologic therapies, and observed over a year, and in whom RDW was elevated at baseline, a sustained response to therapy was associated with a decrease in RDW. RDW and MPV, tests commonly contained within routine complete blood count (CBC), may be a cost-effective manner to identify PsO and PsA patients at increased risk of MACE.
Project description:<h4>Objective</h4>To compare, "in a real world," the performance of the most common composite activity indices in a cohort of PsA patients.<h4>Methods</h4>A total of 171 PsA patients were involved. The following variables were evaluated: peripheral joint assessment, patient reported of pain, physician and patient assessments of disease activity, patient general health status, dactylitis digit count, Leeds Enthesitis Index, Health Assessment Questionnaire (HAQ), physical and mental component summary score of the Medical Outcome Survey (SF-36), Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). To measure the disease activity, the Disease Activity Score (DAS28-ESR and DAS28-CRP), Simple Disease Activity Index (SDAI), Composite Psoriatic Disease Activity Index (CPDAI), disease activity in psoriatic arthritis (DAPSA), and Psoriatic Arthritis Disease Activity Score (PASDAS) have been calculated. The criteria for minimal disease activity (MDA) and remission were applied as external criterion.<h4>Results</h4>The ROC were similar in all the composite measures. Only the CPDAI showed less discriminative ability. There was a high degree of correlation between all the indices (P < 0.0001). The highest correlations were between DAPSA and SDAI (rho = 0.996) and between DAPSA and DAS28-CRP (rho = 0.957). CPDAI, DAPSA, and PASDAS had the most stringent definitions of remission and MDA category. DAS28-ESR and DAS28-CRP had the highest proportions in remission and MDA.<h4>Conclusions</h4>Although a good concurrent validity and discriminant capacity of six disease activity indices were observed, the proportions of patients classified in the disease activity levels differed. In particular, the rate of patients in remission was clearly different among the respective indices.