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BackgroundThe prevalence of late-onset psoriatic arthritis (PsA) is increasing in parallel with the progressive aging of the population. The elderly population presents a greater functional deterioration and a greater number of comorbidities than the young people. With this study we aim to find clinically relevant differences to predict the evolution and prognosis of the disease depending on the onset of the symptoms to carry out a more exhaustive follow-up.ObjectivesTo evaluate the association of the age at onset of PsA symptoms with the characteristics and burden of the disease.MethodsObservational study that includes a subgroup of 231 patients with Psoriatic Arthritis (PsA) from the REGISPONSER study (Registry of Spondyloarthritis of Spanish Rheumatology) and the RESPONDIA study (Ibero-American Registry of Spondyloarthropathies). Patients with less than 10 years of disease duration (since the first symptom) were selected so that the sample was homogeneous. Patients were divided into two groups according to the age of PsA onset (early-onset: ≤40 years old and late-onset: ≥60 years old). The characteristics and burden of the disease were compared using the Student’s t-test/Mann-Whitney U test for quantitative variables or using the chi-square/Fisher test for qualitative variables.Results411 patients were included [early-onset 179 (77.5%); late-onset 52 (22.5%)]. There was a higher percentage of men in the late-onset group compared to the early-onset group [94 (62.3%) vs. 38 (86.4%), p = 0.003]. The diagnostic delay was shorter in those whose onset of the disease was late [1.5 (2.7) vs 4 (7.7), p=0.036], as well as the duration of the disease [2.9 (2.4) vs 4.2 (2.7), p= 0.012]. A lower presence of sacroiliitis was found in patients with late-onset PsA [6 (12.2%) vs 58 (32.6%), p=0.005] as well as enthesitis [5 (9.8%) vs 44 (24.6%), p =0.023]. Regarding the comorbidities, there was a higher frequency of heart disease among patients with late-onset PsA [4 (7.8) vs 0 (0), p=0.000]. No statistically significant differences were found between kidney and lung disease. Regarding the outcome measures, the BASFI score was higher in the late-onset group [3.3 (2.5) vs. 2.2 (2.2), p=0.002]. The late-onset group had a lower FSF12 component [34.6 (8.7) vs. 38.7 (10.5), p = 0.001]. The radiographic indices measured by BASRI showed worse results in those patients with late-onset disease both in the spine [2.9 (3) vs 1.6 (2), p=0.020] and in the total BASRI [3.4 (3 .4) vs 1.9 (2.4), p=0.012].ConclusionOur study suggests that the age of onset of PsA was associated with the different characteristics of the disease. Patients with late-onset PsA were more frequently males, showed worse functionality and more structural damage in comparison with early-onset PsA. Sacroiliitis and enthesitis were found less frequently in the late-onset group. Quality of life, disease activity and treatments taken were not associated significantly with age of onset.Table 1.Description of different characteristics across two groups: early and late onsetEarly-onset N=179 n (%)=77.5Late-onset N=52 n (%)=22.5p-valueSex (male)94 (62.3)38 (86.4)0.003Age (SD)38.7 (9.3)71.3 (7.5)0.000Enthesitis44 (24.6)5 (9.8)0.023Dactilytis36 (20.1)9 (17.6)0.695Sacroiliitis58 (32.6)6 (12.2)0.005Diagnostic Delay, mean (SD)4 (7.7)1.5 (2.7)0.036Disease Duration, mean (SD)4.2 (2.7)2.9 (2.4)0.012Arthritis (lower limbs)118 (65.9)33 (64.7)0.872Arthritis (upper limbs)82 (45.8)31 (60.8)0.059BASDAI, mean (SD)3.9 (2.5)3.8 (2.4)0.932BASFI, mean (SD)2.2 (2.2)3.3 (2.5)0.002ASDAS, mean (SD)2.3 (1.1)2.3 (0.9)0.894FSF12, mean (SD)38.7 (10.5)34.6 (8.7)0.001MSF12, mean (SD)47.7 (10.6)49.3 (9.2)0.341BASRI spine1.6 (2)2.9 (3)0.020BASRI total1.9 (2.4)3.4 (3.4)0.012ESR mm/h, mean (SD)17.2 (14.2)23.9 (19.1)0.005csDMARDs (ever)111 (62.7)31 (63.3)0.943bDMARDs (ever)21 (11.9)3 (6)0.234Disclosure of InterestsNone declared

Background:The presence of cardiovascular disease in psoriatic arthritis (PsA) is of particular concern, as it is considered the leading cause of mortality in PsA. Thus, it is essential to recognize those appropriate therapies that could target this comorbidity, reducing the risk of cardiovascular disease and metabolic alterations.Objectives:To evaluate the efficacy of methotrexate (MTX) and apremilast as monotherapies or in combination, in the clinical manifestations of the disease and the reduction of cardiovascular risk factors in PsA.Methods:Prospective longitudinal study in 30 PsA patients diagnosed according to CASPAR criteria: 10 patients were treated with MTX (12 ± 2,58 mg/week), 10 patients with apremilast (60 mg/day) and 10 were treated with combined therapy for 6 months, recruited in the routine clinical practice at the Reina Sofia Hospital of Cordoba and University Hospital of Jaen, Spain. Clinical and analytical parameters were collected at baseline and after 6 months of treatment: lipid profile (cholesterol, HDL, LDL, TG, ApoA and ApoB), glucose and insulin, body surface area (BSA) affected by psoriasis, number of tender and swollen joints, DAS28, DAPSA, VAS, CRP and ESR.The presence of cardiometabolic risk factors such as metabolic syndrome (MetSyn) was evaluated according to National Cholesterol Education Program (NCEP) adult treatment panel III (ATP III) criteria, meeting 3 of the following characteristics: abdominal obesity (men (>102 cm); women (>88 cm), TG > 150 mg/dL, HDL (men ( 130/85 mmHg, glucose levels > 110 mg/dL). Insulin resistance (HOMA-IR > 2,5), body mass index (BMI), ApoB/ApoA ratio, atherogenic index (AI) and SCORE (age, gender, cholesterol, HDL, smoking habit and diabetes) were also studied.Results:Apremilast or MTX monotherapies caused a moderate reduction of the clinical inflammatory markers (CRP and ESR) and disease activity (VAS, DAPSA and DAS28) after 6 months of treatment. On the other hand, while apremilast significantly reduced the affected BSA, MTX had no significant effect. All those parameters were more significantly reduced after the combined treatment (MTX+ apremilast).Apremilast monotherapy significantly improved alterations in the lipid profile (reducing cholesterol and LDL levels, ApoB/ApoA ratio and AI), insulin resistance and decreased BMI, thus reducing the number of patients with MetSyn. MTX monotherapy treatment had no positive effect on these parameters. None of the treatments had significant effects on SCORE values.The beneficial effects of apremilast on the lipid profile were mitigated after the combination with MTX. Nevertheless, the number of patients with MetSyn decreased even more after the combined therapy of MTX with apremilast compared to apremilast monotherapy.Conclusion:1) In patients with moderate disease activity, treatment with apremilast monotherapy might have some advantages compared to the MTX monotherapy, since it can decrease the percentage of BSA with psoriasis, the lipid profile alteration, IR and weight, thus improving the cardiovascular risk profile. 2) Combined therapy (MTX+ apremilast) can induce a deeper reduction in the disease activity compared to the monotherapies, maintaining, in turn, the positive effects of apremilast on the cardiovascular risk.Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene., Iván Arias de la Rosa: None declared, Carmen Torres-Granados: None declared, Maria del Carmen Abalos-Aguilera: None declared, Gómez García Ignacio: None declared, Isabel Añón Oñate: None declared, María José Pérez Galán: None declared, Desiree Ruiz: None declared, Alejandra M. Patiño-Trives: None declared, María Luque-Tévar: None declared, Eduardo Collantes Estevez Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene, Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Alejandro Escudero Contreras Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene., María Dolores López Montilla Speakers bureau: Celgene

Background:Psoriatic Arthritis (PsA) displays increased traditional cardiovascular (CV) risk factors, such as insulin resistance (IR), metabolic syndrome or obesity. Thus, it is an urgent need to treat and manage these cardiometabolic comorbidities associated. Some evidence points out that methotrexate could improve CV risk due to its anti-inflammatory properties, however the effect of PDE4 inhibitor treatment on CV risk have not been elucidated yet.Objectives:1) To evaluate the effect of conventional therapy and PDE4 inhibitor in PsA patients with high prevalence of cardiometabolic comorbidities. 2) To identify a molecular patient profile susceptible of being benefit from each therapy regarding disease activity and CV risk.Methods:Thirty biological-naïve patients with PsA were treated with the PDE4 inhibitor (Apremilast), Methotrexate or combined therapy (Apremilast and Methotrexate) following the clinical routine practice for 6 months. A cohort of 30 age and sex-matched healthy donors (HDs) was included. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of patients and HDs. Different parameters related to the cardiometabolic risk were analyzed, including: atherogenic index, ratio apolipoprotein B (apo B)/apolipoprotein A (apo A), insulin resistance (IR), metabolic syndrome, obesity, arterial hypertension, and the SCORE. Clinical and analytical parameters were collected: lipid profile (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, apo A and apo B), glucose and insulin, body surface area (BSA) affected by psoriasis, number of tender and swollen joints, DAPSA, C-reactive protein and erythrocyte sedimentation rate. A panel of 92 proteins involved in cardiovascular disease (cardiovascular panel II, Olink) and an adipocytokine profile was measured in plasma and PBMCs. Hard cluster analysis was carried out in order to identify two distinctive molecular phenotypes depending on the treatment response related to the reduction of CV risk.Results:Among the 92 CV-related proteins, the higher levels of two molecules, CD163 and FABP4 observed in PsA patients compared to HDs, were strongly associated with elevated rates of CV risk factors such as apolipoprotein B/A and atherogenic risks, metabolic syndrome, obesity, IR, arterial hypertension and smoking. Thus, we could identify two clinical profiles of patients according to the plasma levels of these molecules: cluster 1 defined by 20 patients with low levels of CD163 and FABP4 and low prevalence of CV comorbidities and cluster 2 defined by 10 patients with high levels of CD163 and FABP4 and high prevalence of CVD comorbidities. Regarding cluster 2, those patients that were treated with Apremilast or combined therapy had a significant reduction of CD163 and FABP4 associated with a drop in total cholesterol, apo B, IR state and body mass index. In addition, both PDE4 inhibitor and combined treatment reduced activity disease. However, Methotrexate in monotherapy did not show a beneficial effect in PsA patients displaying higher levels of CD163, FABP4, total cholesterol and no changes in disease activity after treatment. In regard to cluster 1, the three therapy strategies reduced disease activity after 6 months. Even with low rates of comorbidities, those patients treated with Apremilast had reduced levels of total cholesterol and apolipoprotein B and body mass index after 6 months of therapy. However, no changes were observed in the treatment with Methotrexate or Methotrexate combined with Apremilast.Conclusion:1- CD163 and FABP4 could be considered as potential biomarkers of treatment efficacy regarding cardiometabolic comorbidities. 2- Apremilast might target metabolic alterations in PsA modulating lipid profile, insulin resistance and body mass index, decreasing the levels of surrogate CV-related molecules. 3- Apremilast treatment should be considered in PsA patients with higher rates of cardiometabolic comorbidities.Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:None declared.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with an increased prevalence of cardiovascular (CV) events. Traditional CV risk factors do not account for the increased CV disease mortality in PsA. Inflammation seems to have a key role in the development of this comorbidity, however the specific molecular mechanisms involved are not defined yet.Objectives:To evaluate clinical CV risk factors and surrogate markers and their relationship with inflammation, disease activity and metabolic comorbidities in PsA patientsMethods:This is a cross-sectional study including 100 PsA patients without CV disease recruited in the routine clinical practice at the Rheumatology Department, Reina Sofia Hospital of Cordoba and 100 age-matched healthy donors (HDs). Different parameters related to the cardiometabolic risk were analyzed. Clinical and analytical parameters were collected: lipid profile (cholesterol, HDL, LDL, TG, ApoA and ApoB), glucose and insulin, body surface area (BSA) affected by psoriasis, number of tender and swollen joints, DAPSA, VAS, CRP and ESR. To measure the persistence of inflammation, CRP levels were recorded retrospectively once, twice, or three times during the 5 years prior to study and at the moment of the study. Increased levels of CRP in at least 50% of the determinations was considered as persistent inflammation. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of patients and HDs. A panel of 92 proteins involved in CV disease and an adipocytokine profile was measured in plasma and PBMCs. In addition, activation of 18 intracellular pathways involved in cell activation was also measured in PBMCs. In vitro experiments in adipocytes treated with serum from PsA patients were also carried out.Results:Traditional CV risk factors including atherogenic risk, insulin resistance (IR), metabolic syndrome, smoking, obesity, arterial hypertension, apolipoprotein B/A risk, type 2 diabetes mellitus and the levels of SCORE were significantly increased in PsA patients. The presence of IR was associated with disease activity markers (DAPSA, ESR and CRP). In fact, the HOMA-IR index was related to the CRP persistence. PsA patients with obesity had significantly increased the number of tender and swollen joints, the levels of DAPSA and CRP. Twenty-eight proteins involved in CV disease and six adipocytokines were significantly elevated in the plasma of PsA patients. Several of these cardiovascular molecules were associated with higher levels of DAPSA (CTSD, GAL3, CD163, FABP4, IL6 and IL1RT2), acute phase reactants (GAL3, TNFα, Adiponectin, TNFR1 and IL6), affected body surface area (IL2RA, GAL3, CCL15, TRAP, CSTB, CD163, OPG and CNTN1) and onychopaty (TRAP, VWF, MCP-1, GAL3, LTBR, TFPI, CHI3L1, CTSZ and JAM-A). In addition, the mRNA expression of most of those 28 CV molecules were significantly increased in PBMCs from PsA patients. At intracellular level, the activation of 11 kinases (ERK1/2, AKT, S6 Ribosomal, mTOR, HSP27, Bad, p70 S6 kinase, PRAS40, p53 and caspase-3) involved in insulin signaling, inflammation, cell survival and apoptosis were altered in PBMCs. Finally, serum from PsA patients was able to modify the expression of these molecules in adipocytes.Conclusion:1) Disease activity and inflammatory burden are closely associated with the presence of metabolic alterations, specifically obesity and IR in patients with PsA. 2) The development of IR is extremely related to the persistence of CRP levels in the previous 5 years. 3) Inflammation is closely associated to the adipose tissue dysfunction in PsA and 4) FABP4, CD163 and GAL3 are surrogate CV markers commonly associated with clinical features of PsA, suggesting the role of these molecules linking CVD and PsA pathogenesis.Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:None declared.

Background:Cardiovascular risk factors are increased in Psoriatic Arthritis (PsA). In fact, around 60% out of PsA patients display insulin resistance (IR), a hallmark of metabolic syndrome, which might significantly contribute to the cardiovascular disease. Latest studies suggested that inflammatory and metabolic disorders may be under epigenetic control, including DNA methylation. DNA methylation is an unexplored area in the field of PsA.Objectives:To study the alterations in the genome-wide DNA methylation profile of CD4+T cells from PsA patients and its relationship with its pathology and the risk of cardiovascular comorbidity.Methods:Twenty healthy controls (HC) and 20 PsA patients were included in the study. PsA patients were classified into insulin resistant and non-insulin resistant according to HOMA-IR index. CD4+T lymphocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs (TSS1500, TSS200, 5UTR, 3UTR, first exon, gene body). Beta values (β) estimating methylation levels were obtained at each CpG site, and differentially methylated genes (DMG) between PsA and HC were identified. Functional classification of these genes was carried out through gene ontology analysis (PANTHER database). Gene expression analysis of the selected genes was also evaluated by RT-PCR. Vascular parameters including carotid intima-media thickness (cIMT) and endothelial function was analyzed by ecodoppler and periflux respectively.Results:The genome-wide methylation analysis identified 112 DMGs including 41 hypomethylated and 71 hypermethylated. These differentially methylated genes were enriched with several signaling pathways and disease categories including immune response, metabolic processes, oxidative stress, vascular and inflammatory pathways. The altered gene expression of selected genes with altered methylation levels in PsA was also validated. Correlation and association analysis of these DMGs with clinical and analytical variables, cardiovascular risk factors and endothelial microvascular function revealed that the degree of methylation of these genes was significantly associated with cIMT (IGF1R, NDRG3, SMYD3, HLA-DRB1, WDR70), arterial pressure (METT5D1, NRDG3, ADAM17, SMYD3, WNK1, CBX1), insulin resistance (AKAP13, SEMA6D, PLCB1), altered lipid profile and atherogenic index (MYBL1, METT5D1, MAN2A1, SLC1A7, SEMA6D, PLCB1, TLK1, SDK1, CBX1), inflammation (MYBL1, NDUFA5, METT5D1, SEMA6D, PLCB1, TLK1), and endothelial dysfunction (ADAMST10, GPCPD1, CCDC88A). In addition, this analysis also identified 435 DMGs including 280 hypomethylated and 155 hypermethylated in CD4+T cells from IR-PsA vs non IR-PsA patients. Between these two groups of PsA patients, CHUK, SERINC1, RUNX1, TTYH2, TXNDC11, FAF1, BICD1, SCD5, PDE5A, FAS, NFIA and GRP75 displayed the most significantly altered methylation, suggesting the role of these genes in the metabolic complications associated with PsA.Conclusion:These findings help our understanding of the pathogenesis of PsA and advance epigenetic studies in regards to this disease and the cardiometabolic comorbidities associated. Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Iván Arias de la Rosa: None declared, María Dolores López Montilla Speakers bureau: Celgene, Javier Rodríguez: None declared, Esteban Ballester: None declared, Carmen Torres-Granados: None declared, Carlos Perez-Sanchez: None declared, Maria del Carmen Abalos-Aguilera: None declared, Gómez García Ignacio: None declared, Desiree Ruiz: None declared, Alejandra M. Patiño-Trives: None declared, María Luque-Tévar: None declared, Eduardo Collantes-Estévez Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Alejandro Escudero Contreras Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene.

The aim of this work is to compare the clinical and radiological manifestations of patients presenting late onset psoriatic arthritis (PsA) with early onset PsA. An overall of 96 consecutive PsA patients were studied over an 8-month-period. Clinical, laboratory and radiographic signs were assessed. Of the 96 patients studied, 84 had their earliest symptoms before the age of 60 (Group I) and 12 after it (Group II). In Group II the mean age was 65.7 years (range 60-73), the sex ratio (male/female) was 9/3. All patients were HLA-B27 negative; the clinical forms observed were: polyarticular (6 patients; 50%), oligoarticular (4 patients; 33%) and spondyloarthropathy (SpA) (2 patients; 17%). Only two patients had asymmetric sacroiliitis and three had history of dactylitis episodes. In conclusion, we found distinct clinical manifestations in late onset PsA. Peripheral affection was found predominant. The male/female ratio was higher than other age groups.