Different Therapeutic Response to Anti-TNF Drugs in Patients with Axial Spondyloarthritis Depending on Their Clinical Profile: An Unsupervised Cluster Analysis.

Background: The objectives were as follows: (a) to identify, among patients with axial spondyloarthritis (axSpA), "clusters" of patients based on the presence of peripheral and extra-musculoskeletal manifestations (EMMs) and (b) to compare the effectiveness of the first anti-TNF drugs across the different clusters after 6 months of follow-up. Methods: An observational and retrospective study of 90 axSpA patients naïve to bDMARDs was conducted. An unsupervised cluster analysis using the "k-means" technique was performed using variables of peripheral and EMMs. Baseline clinical and sociodemographic characteristics were evaluated, and the response to anti-TNF treatment (considering responders as those with an improvement ≥1.1 for the Ankylosing Spondylitis Disease Activity Score (ASDAS) or ≥2.0 for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) was compared across the clusters after 6 months of follow-up. Results: Two clusters were identified: cluster 1 (n = 14), with a higher prevalence of peripheral manifestations, inflammatory bowel disease (IBD), and HLA-B27-positive status, and a lower prevalence of uveitis in comparison with cluster 2 (n = 76). Patients from cluster 1 experienced a more pronounced absolute improvement in ASDAS and BASDAI indices after 6 months. The percentage of responders after 6 months of follow-up was superior in cluster 1 compared to cluster 2 (85.7% vs. 48.7%, p = 0.011). Conclusion: This study suggests the existence of two clinical profiles in axSpA patients according to the peripheral and EMMs, with higher rates of anti-TNF effectiveness after 6 months in those with a greater presence of peripheral features.

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation.

Introduction: Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients. Methods: A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay. Results: R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others. Conclusion: Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.

Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways. Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform. Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels. Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.

Exploring the unifying concept of Spondyloarthritis: a latent class analysis of the REGISPONSER registry.

OBJECTIVES: The aim of our study is to identify the potential distinct phenotypes within a broad Spondyloarthritis (SpA) population. METHODS: We conducted a cross-sectional study using the REGISPONSER registry with data from 31 specialist centres in Spain including patients with SpA who fulfilled the European Spondyloarthropathy Study Group (ESSG) criteria. A latent class analysis (LCA) was performed to identify the latent classes underlying SpA according to a set of predefined clinical and radiographic features, independently of expert opinion. RESULTS: In a population of 2319 SpA patients, a 5 classes LCA model yielded the best fit. Classes named 'axial with spine involvement' and 'axial with isolated SIJ involvement" show a primarily axial SpA phenotype defined by inflammatory back pain and high HLA-B27 prevalence. Patients in class 'axial + peripheral' show similar distribution of manifest variables to previous classes but also have a higher likelihood of peripheral involvement (peripheral arthritis/dactylitis) and enthesitis, therefore representing a mixed (axial and peripheral) subtype. Classes 'Peripheral + psoriasis' and 'Axial + peripheral + psoriasis' are indicative of peripheral SpA (and/or PsA) with high likelihood of psoriasis, peripheral involvement, dactylitis, nail disease, and low HLA-B27 prevalence, while class 'Axial + peripheral + psoriasis' also exhibits increased probability of axial involvement both clinically and radiologically. CONCLUSION: The identification of 5 latent classes in the REGISPONSER registry with significant overlap between axial and peripheral phenotypes is concordant with a unifying concept of SpA. Psoriasis and related features (nail disease and dactylitis) influence the phenotype of both axial and peripheral manifestations.

Diagnostic delay is associated with uveitis and inflammatory bowel disease in AS: a study of extra-musculoskeletal manifestations in SpA.

OBJECTIVES: To examine the prevalence of extra-musculoskeletal manifestations (EMM) and the association between diagnostic delay and their incidence in AS and PsA. METHODS: This was a retrospective, cohort study comprising two single centre cohorts in Europe and one multicentre cohort in Latin America (RESPONDIA). Crude prevalence of EMMs (uveitis, IBD and psoriasis) was calculated across geographic area and adjusted by direct standardization. Cox proportional hazard analysis was performed to assess the association between diagnostic delay and EMM incidence. RESULTS: Of 3553 patients, 2097 had AS and 1456 had PsA. The overall prevalence of uveitis was 22.9% (95% CI: 21.1, 24.8) in AS and 3.8% (95% CI: 2.9, 5.0) in PsA; 8.1% (95% CI: 7.0, 9.4) and 2.1% (1.3, 2.9), respectively, for IBD; and 11.0% (95% CI: 9.7, 12.4) and 94.6% (93.0, 95.9), respectively, for psoriasis. The EMM often presented before the arthritis (uveitis 45.1% and 33.3%, and IBD 37.4% and 70%, in AS and PsA, respectively). In the multivariable model, longer diagnostic delay (≥5 years) associated with more uveitis (hazard ratio [HR] 4.01; 95% CI: 3.23, 4.07) and IBD events (HR 1.85; 95% CI: 1.28, 2.67) in AS. Diagnostic delay was not significantly associated with uveitis (HR 1.57; 95% CI: 0.69, 3.59) or IBD events (HR 1.59; 95% CI: 0.39, 6.37) in PsA. CONCLUSION: EMMs are more prevalent in AS than PsA and often present before the onset of the articular disease. A longer diagnostic delay is associated with the 'de novo' appearance of uveitis and IBD in AS, highlighting the need to enhance diagnostic strategies to shorten the time from first symptom to diagnosis in SpA.

Identification of the first signs or symptoms in different spondyloarthritis subtypes and their association with HLA-B27: data from REGISPONSER and RESPONDIA registries.

OBJECTIVE: To describe and analyse the initial symptoms attributable to patients with spondyloarthritis (SpA) and their association with HLA-B27 status. METHODS: This was an observational, cross-sectional and multicentre study with patients who fulfilled the European Spondyloarthropathy Study Group criteria for SpA from the Registry of Spondyloarthritis of Spanish Rheumatology (REGISPONSER) and Ibero-American Registry of Spondyloarthropathies (RESPONDIA) united registries. Differences in the first sign(s) or symptom(s) were compared across diagnoses and between HLA-B27 status. The diagnostic delay between patients who start the disease with musculoskeletal manifestations (MMs) and extra-MMs (EMMs) was compared. RESULTS: A total of 4067 patients were included (2208 from REGISPONSER and 1859 from RESPONDIA) (ankylosing spondylitis (AS): 68.3%, psoriatic arthritis (PsA): 19.9%, undifferentiated SpA: 11.8%). Overall, 3624 (89.1%) patients initiated the disease with MMs and 443 (10.9%) with EMMs. Low back pain (61.7%) and lower-limb arthritis (38.5%) were the most frequent initial symptoms. In AS patients, the absence of HLA-B27 seems to be related to an increase in the probability of starting the disease with cervical pain and peripheral manifestations. In PsA, the onset of arthritis and psoriasis was more prevalent in HLA-B27-negative patients, while initiation with axial manifestations was more predominant in HLA-B27-positive patients. The diagnostic delay was longer in patients with initial MMs than in those with EMMs (7.2 (34.8) vs 4.5 (7.6) years, respectively). CONCLUSION: In this SpA population, MMs were the most prevalent initial symptoms, with differences across diagnoses and depending on the presence of the HLA-B27 antigen.

Enthesitis indices identify different patients with this characteristic in axial and peripheral spondyloarthritis and also in psoriatic arthritis: ASAS-PerSpA data.

BACKGROUND: In axial spondyloarthritis (axSpA), peripheral SpA (pSpA) and psoriatic arthritis (PsA), enthesitis is a hallmark clinical feature that can be assessed by the SPARCC index, LEI, MASES and MEI. These indices evaluate different locations, which may identify different numbers of patients with enthesitis among SpA subtypes. Thus, the aim of this study was to evaluate whether the proportion of patients with at least one enthesitis across these three most prevalent SpA subtypes differs according to the index used and to evaluate the level of agreement among indices in detecting patients with enthesitis. METHODS: A total of 4185 patients (2719 axSpA, 433 pSpA and 1033 PsA) from the international and cross-sectional ASAS-PerSpA study were included. The proportion of patients with enthesitis identified by the indices was evaluated across the three diseases. Pairwise agreement between indices was computed using Cohen's kappa. RESULTS: The prevalence rates of patients with at least one enthesitis according to the MEI, MASES, SPARCC index and LEI were 17.2%, 13.5%, 10.7%, and 8.3%, respectively. In axSpA, the indices that identified the most patients with enthesitis were the MEI and MASES (98.7% and 82.4%, respectively); in pSpA and PsA, the indices that identified the most patients with enthesitis were the MEI and SPARCC index (MEI: 100% and SPARCC: 84.6%; MEI: 97.3% and SPARCC: 77%, respectively). In the total population, the MASES vs. MEI showed the strongest agreement (absolute agreement 96.3%; kappa: 0.86); similar results were obtained in axSpA patients (97.3%; 0.90). In pSpA and PsA patients, the SPARCC vs. MEI (97.2%; 0.90 and 95.4%; 0.83, respectively) showed the strongest agreement. CONCLUSIONS: These results suggest that the prevalence of patients with enthesitis across SpA subtypes differs depending on the disease and the index used. The MEI and MASES appeared best for assessing enthesis in SpA and axSpA, while the MEI and SPARCC index appeared best for assessing enthesitis in pSpA and PsA.

Preclinical Characterization of Pharmacologic NAD+ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis.

OBJECTIVE: We analyzed NAD+ metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD+ boosting. METHODS: Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD+ levels and NAD+ -related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti-tumor necrosis factor (anti-TNF) drugs, we evaluated changes in NAD+ levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD+ boosters, such as nicotinamide and nicotinamide riboside. RESULTS: Reduced NAD+ levels were found in RA samples, in line with altered activity and expression of genes involved in NAD+ consumption (sirtuins, poly[ADP-ribose] polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD+ levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD+ levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD+ levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status. CONCLUSION: RA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD+ boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.

Characterization of the inflammatory proteome of synovial fluid from patients with psoriatic arthritis: Potential treatment targets.

Objectives: 1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential to stratify patients according to clinical features. Methods: Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group. Results: Seventy-nine inflammation-related proteins were detected in SF from PsA patients (SF-PsA). Unsupervised analyzes of the molecular proteome profile in SF-PsA identified two specific phenotypes characterized by higher or lower levels of inflammation-related proteins. Clinically, SF-PsA with higher levels of inflammatory proteins also showed increased systemic inflammation and altered glucose and lipid metabolisms. Besides, SF from PsA patients showed 39 out of 79 proteins significantly altered compared to SF-OA specifically related to cell migration and inflammatory response. Among these, molecules such as TNFα, IL-17A, IL-6, IL-10, IL-8, ENRAGE, CCL20, TNFSF-14, OSM, IFNγ, MCP-3, CXCL-11, MCP4, CASP-8, CXCL-6, CD-6, ADA, CXCL-10, TNFß and IL-7 showed the most significantly change. Conclusion: This is the first study that characterizes the inflammatory landscape of synovial fluid of PsA patients by analyzing a panel of 92 inflammatory proteins using PEA technology. Novel SF proteins have been described as potential pathogenic molecules involved in the pathogenesis of PsA. Despite the flare, inflammatory proteome could distinguish two different phenotypes related to systemic inflammation and lipid and glucose alterations.

Differences between early vs. late-onset of psoriatic arthritis: Data from the RESPONDIA and REGISPONSER registries.

OBJECTIVES: The objective was to evaluate the association between the age at onset of psoriatic arthritis (PsA) symptoms with the characteristics and burden of the disease. METHODS: This was an observational and cross-sectional study that included a subgroup of 231 patients with PsA with < 10 years of disease duration from the REGISPONSER and RESPONDIA registries. Patients were divided into two groups according to the age of PsA symptom onset (early onset: ≤ 40-years-old and late onset: ≥ 60-years-old). The characteristics and burden of the disease were compared between the two groups, and multivariate logistic regression was performed to determine the factors independently associated with late-onset PsA. RESULTS: Patients from the early-onset group showed a significantly lower prevalence of males [94 (62.3%) vs. 38 (86.4%)] and a higher prevalence of enthesitis [44 (24.6%) vs. 5 (9.8%)] and sacroiliitis [30 (16.8%) vs. 4 (7.7%)]. Additionally, the early-onset group showed lower scores on the BASFI [2.2 (2.2) vs. 3.3 (2.5)] and minor structural damage (BASRI) in both the spine [1.6 (2) vs. 2.9 (3)] and whole axial skeleton (total BASRI) [1.9 (2.4) vs. 3.4 (3.4)]. In contrast, no statistically significant differences were found between the groups in disease activity evaluated by the BASDAI and ASDAS. Logistic regression analysis showed that late-onset PsA was independently associated with being male (OR 4.4, 95% CI: 1.3, 16.3), greater structural damage (total BASRI) (OR 3.3, 95% CI: 1.3, 8.1), a higher frequency of arthritis in the upper limbs (OR 2.8, 95% CI: 1, 7.7), and greater loss of function (BASFI) (OR 1.3, 95% CI: 1, 1.6). CONCLUSIONS: Patients with late-onset PsA showed different clinical characteristics and greater disease severity than those with early-onset PsA.

Patients with Axial Spondyloarthritis are Great Consumers of Healthcare Resources, Especially Young and Women: Results from the Spanish Atlas.

INTRODUCTION: This study aimed to assess high healthcare utilization over 1 year in patients with axial spondyloarthritis (axSpA) and factors associated with increased healthcare utilization. METHODS: A total of 530 unselected patients with axSpA from the Atlas of Axial Spondyloarthritis in Spain-who had used at least one healthcare resource-were included in the present study. Total health care utilization was obtained from the total number of healthcare visits, medical tests, hospital admissions and emergency visits, during the 12 months prior to the survey. Linear regression was used to analyse possible factors associated with higher healthcare utilization. RESULTS: A total of 530 patients with axSpA participated in this study: mean age was 45.3 years and 51.1% were female. In the previous 12 months, 77.9% (n = 530) used at least one healthcare resource, with the median healthcare utilization at 25. In the multiple linear regression, the only categorical factor associated with higher healthcare utilization was female gender (ß = 12.854), while the continuous factors associated with higher healthcare utilization were higher disease activity (ß = 3.378), longer diagnostic delay (ß = 0.959), younger age (ß = - 0.737) and greater functional limitation (ß = 0.576). CONCLUSION: Half of patients with axSpA used 25 or more healthcare resources during 1 year. Higher healthcare utilization was associated with younger age, female gender, greater disease activity, higher functional limitation and longer diagnostic delay. Optimal monitoring of patients with axSpA may help to reduce their healthcare utilization.

Achilles enthesitis on physical examination leads to worse outcomes after 2 years of follow up in patients with ankylosing spondylitis from REGISPONSER-AS registry.

BACKGROUND: Enthesitis represents one of the most important peripheral musculoskeletal manifestations in patients with axial spondyloarthritis (axSpA). However, studies specifically evaluating Achilles tendon enthesitis and its impact over time are scarce. The objectives of this study were to evaluate the impact of Achilles' tendon enthesitis found at baseline during physical examination on the outcome measures after 2 years of follow-up in patients with ankylosing spondylitis (AS). METHODS: This was an observational and prospective study conducted during 2 years of follow-up in the REGISPONSER-AS registry. Linear regression models adjusted for age, body mass index (BMI), and anti-TNF intake were conducted to evaluate the association between the presence of Achilles enthesitis at baseline and the patient-reported outcome (PRO) scores at baseline. The impact of this feature on PROs over 2 years of follow-up was evaluated using mixed models for repeated measures adjusted for age, BMI, and anti-TNF intake. RESULTS: Among the 749 patients included, 46 patients (6.1%) showed Achilles' tendon enthesitis during physical examination at the baseline study visit. Patients with Achilles enthesitis had an increase in the global VAS score, BASDAI, mBASDAI, ASDAS-CRP, and BASFI scores in comparison with patients without this feature. In addition, the mean global VAS, BASDAI, and ASDAS-CRP scores were significantly higher among patients with Achilles enthesitis over the 2 years of follow-up after adjusting for age, BMI, and current anti-TNF intake. The percentage of patients achieving ASDAS low disease activity (ASDAS < 2.1) after 2 years of follow-up was 15.9% and 31.5% for patients with and without Achilles enthesitis, respectively (p = 0.030). CONCLUSIONS: In patients with AS, the presence of Achilles' tendon enthesitis was associated with worse scores on the outcome measures after 2 years of follow-up, leading to a lower probability of achieving low disease activity.

Smoking and alcohol consumption are associated with peripheral musculoskeletal involvement in patients with spondyloarthritis (including psoriatic arthritis). Results from the ASAS-PerSpA study.

BACKGROUND: An inverse association between alcohol consumption and disease activity and functional impairment has been observed in patients with spondyloarthritis (SpA). However, neither this association nor the influence of smoking has been investigated in peripheral manifestations of SpA. OBJECTIVES: The objective of this study was to analyze the association between smoking and alcohol consumption and the presence of peripheral musculoskeletal manifestations (arthritis, enthesitis or dactylitis) and to determine the specific location of these manifestations. METHODS: Patients from the worldwide cross-sectional ASAS-PerSpA study with a diagnosis of axial SpA (axSpA), peripheral SpA (pSpA) or psoriatic arthritis (PsA) according to their rheumatologist were included. Generalised linear mixed models used peripheral manifestation (or location) as a dependent variable, smoking status and alcohol consumption as fixed effects and country as a random effect. The interaction between smoking and alcohol was tested. Analyses were performed for each diagnosis (axSpA, pSpA and PsA). RESULTS: A total of 4181 patients were included. In axSpA patients, smoking was associated with a lower prevalence of any peripheral manifestation, and current alcohol consumption was associated with a lower prevalence of both current arthritis and current enthesitis. In pSpA patients, current alcohol consumption was associated with a lower prevalence of current arthritis or enthesitis. In PsA patients, a significant association was found for arthritis with smoking and for enthesitis with alcohol consumption, and current alcohol consumption was associated with a lower prevalence of current arthritis or enthesitis. CONCLUSION: Taking into account the country, smoking and alcohol are associated with a lower prevalence of peripheral manifestations.

Nonalcoholic fatty liver disease in inflammatory arthritis: Relationship with cardiovascular risk.

Liver disease is one of the most important causes of morbidity and mortality worldwide whose prevalence is dramatically increasing. The first sign of hepatic damage is inflammation which could be accompanied by the accumulation of fat called non-alcoholic fatty liver disease (NAFLD), causing damage in the hepatocytes. This stage can progress to fibrosis where the accumulation of fibrotic tissue replaces healthy tissue reducing liver function. The next stage is cirrhosis, a late phase of fibrosis where a high percentage of liver tissue has been replaced by fibrotic tissue and liver functionality is substantially impaired. There is a close interplay of cardiovascular disease (CVD) and hepatic alterations, where different mechanisms mediating this relation between the liver and systemic vasculature have been described. In chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which the CVD risk is high, hepatic alterations seem to be more prevalent compared to the general population and other rheumatic disorders. The pathogenic mechanisms involved in the development of this comorbidity are still unraveled, although chronic inflammation, autoimmunity, treatments, and metabolic deregulation seem to have an important role. In this review, we will discuss the involvement of liver disease in the cardiovascular risk associated with inflammatory arthritis, the pathogenic mechanisms, and the recognized factors involved. Likewise, monitoring of the liver disease risk in routine clinical practice through both, classical and novel techniques and indexes will be exposed. Finally, we will examine the latest controversies that have been raised about the effects of the current therapies used to control the inflammation in RA and PsA, in the liver damage of those patients, such as methotrexate, leflunomide or biologics.

Relationship between onset of psoriasis and spondyloarthritis symptoms with clinical phenotype and diagnosis: data from REGISPONSER registry.

Background: The relationship of psoriasis and spondyloarthritis (SpA) is well-known, and the age of appearance of different manifestations has been described as a determinant of SpA phenotype. However, differences between Spa with psoriasis and psoriatic arthritis (PsA) are still controversial. Objectives: To evaluate whether the time of onset of psoriasis relative to the appearance of rheumatic symptoms in patients with SpA is associated with a clinical phenotype, a rheumatologist's diagnosis and the evolution of the disease. Design: This was a cross-sectional study with data extracted from the REGISPONSER (Spondyloarthritis Registry of the Spanish Rheumatology Society) registry. Methods: All patients had data available for both psoriasis and SpA dates of onset. Patients were classified into two groups depending on the time of appearance of psoriasis: psoriasis before or after rheumatic symptoms. The clinical characteristics, disease activity, radiographic damage, functional ability and received treatments were compared between the two groups. Moreover, the rheumatologists' diagnoses were compared between the two groups. Univariate and multivariate logistic regressions were conducted to evaluate the factors associated with each group. Results: A total of 433/2367 (18.3%) patients included in the REGISPONSER database had psoriasis: 330 (76.2%) patients had psoriasis before rheumatic symptoms, and 103 (23.8%) had psoriasis after rheumatic symptoms. Patients with psoriasis before rheumatic symptoms had a shorter disease duration and a lower body mass index, a lower prevalence of both HLA-B27 antigens and anterior uveitis, a higher prevalence of dactylitis and an increase in levels of the erythrocyte sedimentation rate (ESR). Furthermore, a higher prevalence of PsA diagnoses (78.1% versus 56.4%) and a more frequent fulfilment of the CASPAR criteria (57.5% versus 42.2%) were found in these patients. The use of DMARDs was not significantly different between the two groups. Conclusion: The time of appearance of psoriasis is associated with the clinical phenotype of SpA and could determine a diagnosis of PsA by rheumatologists.

Pathogenic mechanisms involving the interplay between adipose tissue and auto-antibodies in rheumatoid arthritis.

We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals.

Similarities and differences between non-radiographic and radiographic axial spondyloarthritis: The patient perspective from the Spanish atlas.

AIM: Although non-radiographic axial spondyloarthritis (EspAax-nr) is well understood within health institutions, being considered along with radiographic EspAax (EspAax-r) as part of the same disease spectrum, patient understanding is unknown. The aim is to describe the patient's knowledge of the EspAax-nr entity. METHODS: Atlas 2017, promoted by the Spanish Federation of Spondylarthritis Associations (CEADE), aims to comprehensively understand the reality of EspAax patients from a holistic approach. A cross-sectional on-line survey of unselected patients with self-reported EspAax diagnosis from Spain was conducted. Participants were asked to report their diagnosis. Socio-demographic, disease characteristics and patient-reported outcomes (PROs) were compared between those patients self-reporting as EspAax-nr and EspAax-r. RESULTS: 634 EspAax patients participated. Mean age 45.7±10.9 years, 50.9% female and 36.1% university-educated. 35 (5.2%) self-reported as EspAax-nr. Compared to EspAax-r patients, those with EspAax-nr were more frequently women (48.6% vs 91.4%, p<0.001), had longer diagnostic delay (10.1±8.9 vs 8.5±7.6 years), higher psychological distress (GHQ-12: 7.5±4.9 vs 5.6±4.4) and similar degree of disease activity (BASDAI: 5.7±2.1 vs 5.7±2.0), and unemployment rates (20.0% vs 21.6%). 20.0% of EspAax-nr received biologics vs 36.9% of EspAax-r, p=0.043. Visits to the rheumatologist in the past year were similar in both groups (3.8±4.5 vs 3.2±3.8), while GP visits were much higher within EspAax-nr (8.0±10.7 vs 4.9±13.3 p=0.003). CONCLUSION: For the first time, EspAax-nr characteristics and PROs have been analyzed from the patient's perspective. Both groups reported similar trends with the exception of EspAax-nr being more frequently women, younger, having longer diagnostic delay and lower use of biologic therapy.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

OBJECTIVES: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. METHODS: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. RESULTS: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. CONCLUSIONS: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules.