Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling.

OBJECTIVES: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous-only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. METHODS: Genome-wide meta-analyses were conducted separately for 5,065 patients with PsA and 21,286 healthy controls and separately for 4,340 patients with PsA and 6,431 patients with PsC. The heritability of PsA was calculated as a single-nucleotide polymorphism (SNP)-based heritability estimate (h2 SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. RESULTS: We identified a novel genome-wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10-9 ), and key pathways that differentiate PsA from PsC, including NF-κB signaling (adjusted P = 1.4 × 10-45 ) and Wnt signaling (adjusted P = 9.5 × 10-58 ). The heritability of PsA in this cohort was found to be moderate (h2 SNP = 0.63), which was similar to the heritability of PsC (h2 SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. CONCLUSION: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.

Application of information theoretic feature selection and machine learning methods for the development of genetic risk prediction models.

In view of the growth of clinical risk prediction models using genetic data, there is an increasing need for studies that use appropriate methods to select the optimum number of features from a large number of genetic variants with a high degree of redundancy between features due to linkage disequilibrium (LD). Filter feature selection methods based on information theoretic criteria, are well suited to this challenge and will identify a subset of the original variables that should result in more accurate prediction. However, data collected from cohort studies are often high-dimensional genetic data with potential confounders presenting challenges to feature selection and risk prediction machine learning models. Patients with psoriasis are at high risk of developing a chronic arthritis known as psoriatic arthritis (PsA). The prevalence of PsA in this patient group can be up to 30% and the identification of high risk patients represents an important clinical research which would allow early intervention and a reduction of disability. This also provides us with an ideal scenario for the development of clinical risk prediction models and an opportunity to explore the application of information theoretic criteria methods. In this study, we developed the feature selection and psoriatic arthritis (PsA) risk prediction models that were applied to a cross-sectional genetic dataset of 1462 PsA cases and 1132 cutaneous-only psoriasis (PsC) cases using 2-digit HLA alleles imputed using the SNP2HLA algorithm. We also developed stratification method to mitigate the impact of potential confounder features and illustrate that confounding features impact the feature selection. The mitigated dataset was used in training of seven supervised algorithms. 80% of data was randomly used for training of seven supervised machine learning methods using stratified nested cross validation and 20% was selected randomly as a holdout set for internal validation. The risk prediction models were then further validated in UK Biobank dataset containing data on 1187 participants and a set of features overlapping with the training dataset.Performance of these methods has been evaluated using the area under the curve (AUC), accuracy, precision, recall, F1 score and decision curve analysis(net benefit). The best model is selected based on three criteria: the 'lowest number of feature subset' with the 'maximal average AUC over the nested cross validation' and good generalisability to the UK Biobank dataset. In the original dataset, with over 100 different bootstraps and seven feature selection (FS) methods, HLA_C_*06 was selected as the most informative genetic variant. When the dataset is mitigated the single most important genetic features based on rank was identified as HLA_B_*27 by the seven different feature selection methods, consistent with previous analyses of this data using regression based methods. However, the predictive accuracy of these single features in post mitigation was found to be moderate (AUC= 0.54 (internal cross validation), AUC=0.53 (internal hold out set), AUC=0.55(external data set)). Sequentially adding additional HLA features based on rank improved the performance of the Random Forest classification model where 20 2-digit features selected by Interaction Capping (ICAP) demonstrated (AUC= 0.61 (internal cross validation), AUC=0.57 (internal hold out set), AUC=0.58 (external dataset)). The stratification method for mitigation of confounding features and filter information theoretic feature selection can be applied to a high dimensional dataset with the potential confounders.

Composite Measures for Clinical Trials in Psoriatic Arthritis: Testing Pain and Fatigue Modifications in a UK Multicenter Study.

OBJECTIVE: To test the addition of pain and fatigue to the Composite Psoriatic Arthritis Disease Activity (CPDAI) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) Composite Exercise (GRACE) composite measures of psoriatic arthritis (PsA). METHODS: Clinical and patient-reported outcome measures were assessed in patients with PsA at 3 consecutive follow-up visits over 6 months in a UK multicenter observational study. A pain visual analog scale and Functional Assessment of Chronic Illness Therapy Fatigue scale were added as modifications to the CPDAI and GRACE composite measures. Original and modified versions were tested against the PsA Disease Activity Score (PASDAS) and the Disease Activity Index for PsA (DAPSA). Discrimination between disease states and responsiveness were tested with t-scores, standardized response means (SRMs), and effect sizes. Data were presented to members at the 2020 annual meeting who then voted on the GRAPPA-recommended composite and treatment targets for clinical trials. RESULTS: One hundred forty-one patients were recruited with a mean PsA disease duration of 6.1 years (range 0-41 yrs). The SRMs for the GRACE and modified GRACE (mGRACE) were 0.67 and 0.64, respectively, and 0.54 and 0.46, respectively, for the CPDAI and modified CPDAI (mCPDAI). The t-scores for the GRACE and mGRACE were unchanged at 7.8 for both, and 6.8 and 7.0 for the CPDAI and mCPDAI, respectively. The PASDAS demonstrated the best responsiveness (SRM 0.84) and discrimination (t-scores 8.3). Most members (82%) agreed the composites should not be modified and 77% voted for the PASDAS as the GRAPPA-recommended composite for clinical trials, with 90% minimal disease activity (MDA) as the target. CONCLUSION: Modifying the CPDAI and GRACE with the addition of pain and fatigue does not enhance responsiveness nor the measures' ability to detect disease status in terms of requiring treatment escalation. GRAPPA members voted for the PASDAS as the composite measure in clinical trials and MDA as the target.

Composite Measures for Routine Clinical Practice in Psoriatic Arthritis: Testing of Shortened Versions in a UK Multicenter Study.

OBJECTIVE: To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice. METHODS: Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t-score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice. RESULTS: The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t-score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t-score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. Conclusion. Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets.

Composite Measures for Clinical Trials in Psoriatic Arthritis: Testing Pain and Fatigue Modifications in a UK Multicenter Study.

OBJECTIVE: To test the addition of pain and fatigue to the Composite Psoriatic Arthritis Disease Activity (CPDAI) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) Composite Exercise (GRACE) composite measures of psoriatic arthritis (PsA). METHODS: Clinical and patient-reported outcome measures were assessed in patients with PsA at 3 consecutive follow-up visits over 6 months in a UK multicenter observational study. A pain visual analog scale and Functional Assessment of Chronic Illness Therapy Fatigue scale were added as modifications to the CPDAI and GRACE composite measures. Original and modified versions were tested against the PsA Disease Activity Score (PASDAS) and the Disease Activity Index for PsA (DAPSA). Discrimination between disease states and responsiveness were tested with t-scores, standardized response means (SRMs), and effect sizes. Data were presented to members at the 2020 annual meeting who then voted on the GRAPPArecommended composite and treatment targets for clinical trials. RESULTS: One hundred forty-one patients were recruited with a mean PsA disease duration of 6.1 years (range 0-41 yrs). The SRMs for the GRACE and modified GRACE (mGRACE) were 0.67 and 0.64, respectively, and 0.54 and 0.46, respectively, for the CPDAI and modified CPDAI (mCPDAI). The t-scores for the GRACE and mGRACE were unchanged at 7.8 for both, and 6.8 and 7.0 for the CPDAI and mCPDAI, respectively. The PASDAS demonstrated the best responsiveness (SRM 0.84) and discrimination (t-scores 8.3). Most members (82%) agreed the composites should not be modified and 77% voted for the PASDAS as the GRAPPA-recommended composite for clinical trials, with 90% minimal disease activity (MDA) as the target. CONCLUSION: Modifying the CPDAI and GRACE with the addition of pain and fatigue does not enhance responsiveness nor the measures' ability to detect disease status in terms of requiring treatment escalation. GRAPPA members voted for the PASDAS as the composite measure in clinical trials and MDA as the target.

Composite Measures for Routine Clinical Practice in Psoriatic Arthritis: Testing of Shortened Versions in a UK Multicenter Study.

OBJECTIVE: To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice. METHODS: Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t-score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice. RESULTS: The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t-score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t-score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. CONCLUSION: Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets.

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

BACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS.

Evaluation of the Economic Burden of Psoriatic Arthritis and the Relationship Between Functional Status and Healthcare Costs.

OBJECTIVE: This analysis aimed to evaluate the economic burden of patients with psoriatic arthritis (PsA) on the UK healthcare system and estimate the relationship between functional status and direct healthcare costs. METHODS: Functional status [measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI)], demographics, disease history, and healthcare resource use data were extracted from a cohort of patients at the Royal National Hospital for Rheumatic Diseases, Bath, UK. Each resource use item per patient was then allocated a unit cost. Linear regression models were used to predict costs as a function of HAQ-DI. Medication costs were not included in the primary analysis, which was carried out from the UK National Health Service perspective. RESULTS: Data were available for 101 patients. Mean HAQ-DI score was 0.84 (SD 0.75) and mean age at HAQ-DI measurement was 57.8 (SD 10.7). Total annual healthcare costs per patient, excluding medication costs, ranged between £174 and £8854, with a mean of £1586 (SD £1639). A 1-point increase in HAQ-DI score was associated with an increase in total costs of £547.49 (standard error £224), with secondary care consultations appearing to be the primary factor. Subgroup analyses suggested higher cost increases in patients with HAQ-DI scores of 2-3 and with a disease duration > 10 years. CONCLUSION: Patients with PsA place a significant economic burden on the healthcare system. Functional status is highly correlated with costs and appears to be driven mainly by the cost of secondary care consultations. Results were similar to previous studies in rheumatoid arthritis populations.

Psoriatic Nail Dystrophy Is Associated with Erosive Disease in the Distal Interphalangeal Joints in Psoriatic Arthritis: A Retrospective Cohort Study.

OBJECTIVE: To assess whether the association between psoriatic nail dystrophy and radiographic damage in the hands of patients with psoriatic arthritis (PsA) is specific to the distal interphalangeal (DIP) joints. METHODS: A convenience sample of patients was collated from the Bath longitudinal PsA cohort. All patients had PsA according to the ClASsification for Psoriatic ARthritis criteria (CASPAR) criteria, scored radiographs of their hands, and documented nail scores as measured by the Psoriatic Nail Severity Score. Chi-square tests were performed to examine for association between features of nail dystrophy and radiographic damage in the DIP joints, and proximal interphalangeal or metacarpophalangeal (non-DIP) joints of the corresponding digits. RESULTS: There were 134 patients included, with a median age of 53 years (interquartile range; IQR 44-61) and disease duration of 7 years (IQR 3-17). The presence of any form of psoriatic nail dystrophy was associated with erosion at the DIP joints of the corresponding digit (OR 1.9, 95% CI 1.23-2.83; p < 0.004) and this association was primarily driven by the presence of nail onycholysis (OR 1.72; 95% CI 1.12-2.62; p = 0.02). Nail subungual hyperkeratosis was more strongly associated with joint space narrowing, erosions, and osteoproliferation at the corresponding DIP joint compared to non-DIP joints (p < 0.001). Nail pitting was not associated with erosions or osteoproliferation. CONCLUSION: The presence of psoriatic nail dystrophy, particularly onycholysis, is associated with erosive disease at the DIP joints. Subungual hyperkeratosis is more strongly associated with erosive damage at the DIP than non-DIP joints. These findings support the anatomical and pathological link between nail and DIP joint disease.

Trajectory of radiographic change over a decade: the effect of transition from conventional synthetic disease-modifying antirheumatic drugs to anti-tumour necrosis factor in patients with psoriatic arthritis.

Objectives: To describe the trajectory of radiographic progression among patients with PsA who transitioned from conventional synthetic DMARDs to anti-TNF-α inhibitors in routine care. Methods: A retrospective sample of patients with PsA (ClASsification criteria for Psoriatic ARthritis) was taken from the Bath longitudinal cohort. All patients had radiographs of the hands and feet taken: 5 years before (T0), at the time of (T1) and 5 years after (T2) commencing anti-TNF treatment. Radiographs were scored blinded using the PsA-modified Sharp-van der Heijde score (mSvdHS) and for osteoproliferation (Psoriatic Arthritis Ratingen Score) by A.Allard, A.Antony and W.T. This sample size was calculated to ensure 90% power to determine the smallest detectable difference of the mSvdHS to a 5% significance level. Cumulative probability plots were used to determine the probability of radiographic progression pre- (T0-T1) and post- (T1-T2) anti-TNF treatment. Results: Eighty-four radiographs from 28 patients were selected for inclusion. The median [interquartile range (IQR)] disease duration at baseline (T0) was 8.5 (0-19.5) years. The interval between T0-T1 and T1-T2 was 4.2 years (3.34-6.65) and 4.9 years (4.25-5.87), respectively. The median mSvdHS at baseline (T0) was 8.5 (IQR 1.75-27.5). The median (IQR) rate of change in mSvdHS per year reduced after commencing anti-TNF, from 2.1 (0.88-3.92) between T0-T1 to 1.0 (IQR 0.05-2.35) between T1-T2 (P = 0.012). Conclusion: The trajectory of damage accumulation over a 10-year period in this observational clinical cohort is low overall. The rate of radiographic damage as measured by the mSvdHS slows following commencement of anti-TNF.

Validation of the Psoriatic Arthritis Impact of Disease (PsAID) Questionnaire and its potential as a single-item outcome measure in clinical practice.

OBJECTIVES: The Psoriatic Arthritis Impact of Disease (PsAID) Questionnaire is a recently developed patient-reported outcome measure (PROM) of disease impact in psoriatic arthritis (PsA). We set out to assess the validity in an independent cohort of patients, estimate the minimally important difference for improvement and explore the potential of individual components of the PsAID in clinical practice. METHODS: Data were collected prospectively for a single-centre cohort of patients with PsA. Construct validity was assessed by Spearman correlation with other PROMs and reliability by intraclass correlation coefficient (ICC) at 1 week. Sensitivity to change at 3 months was determined by the standardised response mean (SRM) in those patients with active disease requiring a change in treatment. RESULTS: A total of 129 patients (mean ±SD age 52.1±13.3, 57% women, disease duration 10.2±8 years) completed the baseline questionnaires and assessments. The mean baseline PsAID12 score was 3.92±2.26 with an ICC of 0.91 (95%CI 0.87 to 0.94). The SE of measurement was 0.51 and the minimal detectable change was 1.41. There was strong correlation (r≥0.70) with most of the PROMs studied and moderate correlation with clinical outcomes (r=0.40-0.57). The SRM of the PsAID12 was 0.74 (95%CI 0.45 to 0.97). There was strong correlation with individual PsAID items and their corresponding PROM questionnaires (r≥0.67). CONCLUSION: The PsAID is a reliable, feasible and discriminative measure in patients with PsA. The good responsiveness of the PsAID and strong correlation of individual items with other PROMS represent an opportunity to reduce questionnaire burden for patients in studies and clinical practice.

Serum bone-turnover biomarkers are associated with the occurrence of peripheral and axial arthritis in psoriatic disease: a prospective cross-sectional comparative study.

BACKGROUND: A recent systematic review identified four candidate serum-soluble bone-turnover biomarkers (dickkopf-1, Dkk-1; macrophage-colony stimulating factor, M-CSF; matrix metalloproteinase-3, MMP-3; osteoprotegerin, OPG) showing possible association with psoriatic arthritis (PsA). We aimed to: (i) confirm and determine if these four biomarkers are associated with PsA; (ii) differentiate psoriasis cases with and without arthritis; and (iii) differentiate PsA cases with and without axial arthritis. METHODS: A prospective cross-sectional comparative two-centre study recruited 200 patients with psoriasis without arthritis (PsC), 127 with PsA without axial arthritis (pPsA), 117 with PsA with axial arthritis (psoriatic spondyloarthritis, PsSpA), 157 with ankylosing spondylitis (AS) without psoriasis, and 50 matched healthy controls (HC). Serum biomarker concentrations were measured using ELISA. Multivariable regression and receiver operating characteristic analyses were performed. RESULTS: MMP-3 concentrations were significantly higher and M-CSF significantly lower in each arthritis disease group compared with HC (p ≤ 0.02). MMP-3 concentrations were significantly higher (adjusted odds ratio, ORadj 1.02 per ng/ml increase in concentration; p = 0.0004) and M-CSF significantly lower (ORadj 0.44 per ng/ml increase; p = 0.01) in PsA (pPsA and PsSpA combined) compared with PsC. Dkk-1 concentrations were significantly higher (ORadj 1.22 per ng/mL increase; p = 0.01), and OPG concentrations significantly lower (ORadj 0.20 per ng/mL increase; p = 0.02) in patients with axial arthritis (PsSpA and AS combined) than in those without (pPsA). Furthermore, Dkk-1 concentrations were significantly higher along a spectrum of increasing axial arthritis; Dkk-1 concentrations were higher in AS compared with PsSpA (ORadj 1.18 per ng/mL increase; p = 0.02). Receiver operating characteristic analysis showed MMP-3 to be the best single biomarker for differentiating PsA from PsC (AUC 0.70 for a cut-off of 14.51 ng/mL; sensitivity 0.76, specificity 0.60). CONCLUSIONS: MMP-3 and M-CSF are biomarkers for the presence of arthritis in psoriatic disease, and could therefore be used to screen for PsA in psoriasis cohorts. Dkk-1 and OPG are biomarkers of axial arthritis; they could therefore be used to screen for the presence of axial disease in PsA cases, and help differentiate PsSpA from AS. High concentrations of Dkk-1 in AS and PsSpA compared with HC, support previous reports that Dkk-1 is dysfunctional in the spondyloarthritides.

Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC). METHODS: 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations. RESULTS: HLA-C*06:02 was protective of PsA compared to PsC (p=9.57×10-66, OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10-59). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10-9) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles. CONCLUSIONS: By controlling for the age of psoriasis onset, we show, for the first time, that HLA-C*06:02 is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies.

A rare coding allele in IFIH1 is protective for psoriatic arthritis.

OBJECTIVES: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. While many common risk alleles have been reported for association with PsA as well as psoriasis, few rare coding alleles have yet been identified. METHODS: To identify rare coding variation associated with PsA risk or protection, we genotyped 41 267 variants with the exome chip and investigated association within an initial cohort of 1980 PsA cases and 5913 controls. Genotype data for an independent cohort of 2234 PsA cases and 5708 controls was also made available, allowing for a meta-analysis to be performed with the discovery dataset. RESULTS: We identified an association with the rare variant rs35667974 (p=2.39x10-6, OR=0.47), encoding an Ile923Val amino acid change in the IFIH1 gene protein product. The association was reproduced in our independent cohort, which reached a high level of significance on meta-analysis with the discovery and replication datasets (p=4.67x10-10). We identified a strong association with IFIH1 when performing multiple-variant analysis (p=6.77x10-6), and found evidence of independent effects between the rare allele and the common PsA variant at the same locus. CONCLUSION: For the first time, we report a rare coding allele in IFIH1 to be protective for PsA. This rare allele has also been identified to have the same direction of effect on type I diabetes and psoriasis. While this association further supports existing evidence for IFIH1 as a causal gene for PsA, mechanistic studies will need to be pursued to confirm that IFIH1 is indeed causal.

Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis.

OBJECTIVES: To compare the prevalence, clinical and radiographic characteristics of psoriatic spondyloarthritis (PsSpA) in psoriatic arthritis (PsA), with ankylosing spondylitis (AS). METHODS: A prospective single-centre cross-sectional observational study recruited consecutive PsA and AS cases. Participants completed outcome measures, and underwent clinical examination, axial radiographic scoring and HLA-sequencing. Multivariable analyses are presented. RESULTS: The 402 enrolled cases (201 PsA, 201 AS; fulfilling classification criteria for respective conditions) were reclassified based upon radiographic axial disease and psoriasis, as: 118 PsSpA, 127 peripheral-only PsA (pPsA), and 157 AS without psoriasis (AS) cases. A significant proportion of patients with radiographic axial disease had PsSpA (118/275; 42.91%), and often had symptomatically silent axial disease (30/118; 25.42%). Modified New York criteria for AS were fulfilled by 48/201 (23.88%) PsA cases, and Classification of Psoriatic Arthritis criteria by 49/201 (24.38%) AS cases. pPsA compared with PsSpA cases had a lower frequency of HLA-B*27 (OR 0.12; 95% CI 0.05 to 0.25). Disease activity, metrology and disability were comparable in PsSpA and AS. A significant proportion of PsSpA cases had spondylitis without sacroiliitis (39/118; 33.05%); they less frequently carried HLA-B*27 (OR 0.11; 95% CI 0.04 to 0.33). Sacroiliac joint complete ankylosis (adjusted OR, ORadj 2.96; 95% CI 1.42 to 6.15) and bridging syndesmophytes (ORadj 2.78; 95% CI 1.49 to 5.18) were more likely in AS than PsSpA. Radiographic axial disease was more severe in AS than PsSpA (Psoriatic Arthritis Spondylitis Radiology Index Score: adjusted incidence risk ratio 1.13; 95% CI 1.09 to 1.19). CONCLUSIONS: In a combined cohort of patients with either PsA or AS from a single centre, 24% fulfilled classification criteria for both conditions. The pattern of axial disease was influenced significantly by the presence of skin psoriasis and HLA-B*27.

Effect of anti-TNF and conventional synthetic disease-modifying anti-rheumatic drug treatment on work disability and clinical outcome in a multicentre observational cohort study of psoriatic arthritis.

Objectives: To determine the effect of medical treatment on work disability in patients with active PsA in a real-world setting. Methods: Four hundred patients with active PsA commencing or switching to anti-TNF or conventional synthetic DMARD (csDMARD) were recruited to a multicentre UK prospective observational cohort study. Work disability was measured using the work productivity and activity-specific health problem instrument and peripheral joint activity was measured with the disease activity in PsA composite measure. Results: Four hundred patients were recruited, of whom 229 (57.25%) were working (of any age). Sixty-two patients of working age (24%) were unemployed. At 6 months there was a 10% improvement in presenteeism ( P = 0.007) and a 15% improvement in work productivity ( P = 0.001) among working patients commenced on csDMARDs ( n = 164) vs a larger and more rapid 30% improvement in presenteeism ( P < 0.001) and 40% improvement in work productivity ( P < 0.001) among those commenced on anti-TNF therapy ( n = 65). Clinical response was poor among patients commenced on a csDMARD ( n = 272), with an 8.4 point improvement in disease activity in PsA ( P < 0.001) vs those commenced on anti-TNF therapy ( n = 121), who had a 36.8 point improvement ( P < 0.001). Conclusion: We report significant and clinically meaningful improvements in both work disability and clinical outcomes after commencement of anti-TNF therapy in a real-world setting. Improvements in all outcomes among those commencing csDMARDs were slower and of a smaller magnitude.

Novel Composite Radiographic Score for Longitudinal Observational Studies of Psoriatic Arthritis: A Proof-of-concept Study.

OBJECTIVE: To devise a feasible composite radiographic score for use in observational studies of psoriatic arthritis (PsA). METHODS: Radiographs from 50 patients with PsA were evaluated with the PsA-modified Sharp, Sharp/van der Heijde (SvdH), and Ratingen scores. Data reductions were made to devise a concise score. RESULTS: The Reductive X-ray Score for Psoriatic Arthritis (ReXSPA) required the assessment of only 22 joints (117 points), including erosion, joint space narrowing, and osteoproliferation in the hands and feet. The ReXSPA accounted for 80% of change detected with the SvdH score. CONCLUSION: We report a proof-of-concept radiographic score for observational studies derived though data reduction.

Psoriatic Arthritis Mutilans: Characteristics and Natural Radiographic History.

OBJECTIVE: (1) To compare clinical characteristics of patients with psoriatic arthritis (PsA) with PsA mutilans (PAM) and without PAM, and (2) to determine the rate of PAM radiographic progression. METHODS: A retrospective cohort study was conducted of all patients with PsA attending a teaching hospital. The most recent hand and feet radiographs were screened for PAM. Serial radiographs (earliest to most recent) were quantitatively scored for osteolysis, erosion, joint space narrowing, and osteoproliferation. RESULTS: Out of the 610 cases, 36 PsA cases had PAM (5.9%). PAM cases were younger at diagnosis of PsA than non-PAM cases (p = 0.04), had more prevalent psoriatic nail dystrophy (OR 5.43, p < 0.001), and worse health assessment questionnaire score (1.25 vs 0.63, p < 0.04). Radiographic axial disease (OR 2.31, adjusted p = 0.03) and especially radiographic sacroiliitis (OR 2.99, adjusted p = 0.01) were more prevalent in PAM. PAM were more likely than non-PAM cases to have used a disease-modifying antirheumatic drug (DMARD; OR 16.36, p < 0.001). Out of 33 cases, 29 PAM cases had initiated a synthetic DMARD and 4/13 had initiated anti-tumor necrosis factor (anti-TNF) prior to first demonstration of PAM. A median 5 radiographs were scored for each PAM case (interquartile range 3-7). PAM progressed from monoarticular (60%) to polyarticular (80%) involvement. Osteolysis was initially rapid and progressive in the hands and feet, tapering later during disease course. Nail dystrophy predicted more severe osteolysis (p = 0.03). CONCLUSION: Compared with non-PAM cases, PAM cases have earlier age at PsA diagnosis, poorer function, more prevalent nail dystrophy, and more radiographic axial disease/sacroiliitis. The rate of osteolysis is higher in earlier disease, and more severe in those with nail dystrophy. DMARD and anti-TNF therapy appear not to prevent PAM occurrence.