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 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.

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.

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.

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.

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.

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.

Subclinical Atherosclerosis Measure by Carotid Ultrasound and Inflammatory Activity in Patients with Rheumatoid Arthritis and Spondylarthritis.

OBJECTIVE: To compare the effect of inflammation on subclinical atherosclerosis using carotid ultrasound in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: Cross-sectional study including 347 participants (148 RA, 159 SpA, and 40 controls). We measured the carotid intima media thickness (cIMT) and detection of atheromatous plaques using carotid ultrasound. We recorded disease activity (DAS28-CRP/ASDAS-CRP) and traditional cardiovascular risk factors. We performed descriptive, bivariate, and linear multivariate analyses (dependent variable: cIMT) to evaluate the influence of diagnosis on cIMT in all patients. Two additional multivariate analyses were performed by stratifying patients according to their inflammatory activity. RESULTS: cIMT correlated with the mean CRP during the previous 5 years in RA, but not with CRP at the cut-off date. We did not find such differences in patients with SpA. The first multivariate model revealed that increased cIMT was more common in patients with RA than in those with SpA (ß coefficient, 0.045; 95% confidence interval (95% CI), 0.0002-0.09; p = 0.048) after adjusting for age, sex, disease course, and differential cardiovascular risk factors (arterial hypertension, smoking, statins, and corticosteroids). The second model revealed no differences in cIMT between the 2 groups of patients classified as remission-low activity (ß coefficient, 0.020; 95% CI, -0.03 to 0.080; p = 0.500). However, when only patients with moderate-high disease activity were analysed, the cIMT was 0.112 mm greater in those with RA (95% CI, 0.013-0.212; p = 0.026) than in those with SpA after adjusting for the same variables. CONCLUSIONS: Subclinical atherosclerosis measured by carotid ultrasound in patients with RA and SpA is comparable when the disease is well controlled. However, when patients have moderate-high disease activity, cIMT is greater in patients with RA than in those with SpA after adjusting for age, sex, disease course, and cardiovascular risk factors. Our results point to greater involvement of disease activity in subclinical atherosclerosis in patients with RA than in those with SpA.

Impact of the number of comorbidities on the outcome measures and on the retention rate of the first anti-TNF in patients with Ankylosing Spondylitis. Two-year follow-up in REGISPONSER-AS.

OBJECTIVES: To evaluate the impact of the number of comorbidities on the outcome measures after two years of follow-up in patients with Ankylosing Spondylitis (AS) and to determine whether the number of comorbidities influences the retention rate of the first anti-TNF. METHODS: This was an observational and prospective study conducted during 2 years of follow-up in the REGISPONSER-AS registry. The patients were divided into three groups according to the number of comorbidities at baseline (0, 1 or ≥2). Linear regression models adjusted for disease duration, age, sex and smoking were constructed to evaluate the association between the number of comorbidities and the Patient Reported Outcomes (PRO) scores. The impact of the number of comorbidities on PROs over two years of follow-up was evaluated using mixed models for repeated measures adjusted for disease duration, age, sex and smoking. Finally, the retention rate of the first anti-TNF antibody across the three groups was evaluated using a log-rank test. RESULTS: Patients with two or more comorbidities showed higher scores at baseline and during the two years of follow-up for the Global VAS, BASDAI, ASDAS, and BASFI and worse scores for the physical component of the SF12. A higher probability of discontinuation of the first anti-TNF was found in patients with 2 or more comorbidities compared with the patients in the other groups (38.2% vs. 26.6% vs. 25.4% for ≥2 comorbidities, 0 and 1 comorbidity, respectively), although these differences were not significant (log-rank test: p-value = 0.180). CONCLUSION: In patients with AS, the presence of 2 or more comorbidities was associated with worse scores on the outcome measures test after two years of follow-up and a greater tendency of discontinuation for the first anti-TNF.

Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy.

OBJECTIVES: To characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response. METHODS: Leucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed. RESULTS: An altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts. CONCLUSIONS: Overall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy.

Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis.

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients. Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions. Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort. Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.

ASAS Health Index in patients with spondyloarthritis and its association with disease activity and disease burden including fibromyalgia.

OBJECTIVES: To evaluate the association of the Assessment of Spondyloarthritis international Society Health Index (ASAS-HI) with disease activity and disease burden in patients with spondyloarthritis (SpA). METHODS: Observational, cross-sectional and single-centre study from the Córdoba AxSpA Task force, Registry and Outcomes (CASTRO). Scores related to disease activity (BASDAI and ASDAS), functionality (BASFI), structural damage, mobility, health and the presence of concomitant fibromyalgia (FM) were obtained from all patients. ASAS-HI score was considered the main outcome. Pearson's r statistic, Student's t test, and univariate and multivariate linear regressions were performed to assess the association between the ASAS-HI score and the studied covariates. RESULTS: A total of 126 SpA patients were included. The mean ASAS-HI score was 4.6±3.9, showing a "strong" positive linear correlation (r>0.60) with the BASDAI and BASFI and a "moderate" positive linear correlation (r=0.40 to 0.60) with the global VAS and ASDAS. Patients with FM showed a significantly higher ASAS-HI score than patients without FM (9.5±3.2 vs. 3.7±3.4, respectively, p<0.01). Multiple linear regression showed that 57.4% of the ASAS-HI variability (R2=0.574) was explained by the presence of concomitant FM (ß=2.23, 95% CI 0.73 to 3.80, p=0.004), higher scores on the BASDAI (ß=0.62, 95% CI 0.25 to 0.97, p=0.001) and BASFI (ß=0.57, 95% CI 0.26 to 0.88, p=0.001). CONCLUSIONS: The impairment of health in patients with SpA was mainly associated with high disease activity, worsening functionality and with the presence of a possible concomitant FM. Therefore, in patients with high ASAS-HI scores we must evaluate the presence of concomitant FM.

Axial and peripheral spondyloarthritis: does psoriasis influence the clinical expression and disease burden? Data from REGISPONSER registry.

OBJECTIVE: To evaluate whether the presence of psoriasis influences the clinical expression, disease activity and disease burden in both axial and peripheral phenotypes of spondyloarthritis (SpA). METHODS: Patients from the Spanish REGISPONSER registry classified as having SpA according to the ESSG criteria were included. Patients were classified as psoriatic or non-psoriatic depending on the presence of cutaneous or nail psoriasis; thereafter, they were classified as having either axial [presence of radiographic sacroiliitis OR inflammatory back pain (IBP)] or peripheral phenotype (absence of radiographic sacroiliitis AND absence of IBP AND presence of peripheral involvement). Pair-wise univariate and multivariate analyses among the four groups (psoriatic/non-psoriatic axial phenotypes and psoriatic/non-psoriatic peripheral phenotypes) were performed with adjustment for treatment intake. RESULTS: A total of 2296 patients were included in the analysis. Among patients with axial phenotype, psoriasis was independently associated (P < 0.05) with HLA-B27+ [odds ratio (OR) 0.27], uveitis (OR 0.46), synovitis (ever) (OR 2.59), dactylitis (OR 2.78) and the use of conventional synthetic DMARDs (csDMARDs) (OR 1.47) in comparison with non-psoriatic patients. Among patients with peripheral phenotype and adjusting for csDMARD intake, psoriasis was independently associated with higher age at disease onset (OR 1.05), HLA-B27+ (OR 0.14) and heel enthesitis (OR 0.22). Higher scores for patient-reported outcomes and greater use of treatment at the time of the study visit were observed in psoriatic patients with either axial or peripheral phenotype. CONCLUSION: These findings suggest that, among all patients with SpA, psoriasis is associated with differences in clinical expression of SpA, a greater disease burden and increased use of drugs.