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Wnt-1 inducible signaling pathway protein 2 (WISP-2/CCN5) is a recently identified adipokine that has been described as an important mediator of canonical Wnt activation in adipogenic precursor cells. In osteoarthritis (OA), the most common form of arthritis, chondrocytes exhibit aberrant and increased production of pro-inflammatory mediators and matrix degrading enzymes such as IL-1β and MMP-13. Although recent evidence suggests a role for Wnt signaling in OA physiopathology, little is known about the involvement of WISP-2 in cartilage degradation. In the present study, we determined the expression of WISP-2 in healthy and OA human chondrocytes. WISP-2 expression is modulated along chondrocyte differentiation and downregulated at the onset of hypertrophy by inflammatory mediators. We also investigated the effect of WISP-2 on cartilage catabolism and performed WISP-2 loss-of-function experiments using RNA interference technology in human T/C-28a2 immortalized chondrocytes. We demonstrated that recombinant human WISP-2 protein reduced IL-1β-mediated chondrocyte catabolism, that IL-1β and WNT/b-catenin signaling pathways are involved in rhWISP-2 protein and IL-1β effects in human chondrocytes, and that WISP-2 has a regulatory role in attenuating the catabolic effects of IL-1β in chondrocytes. Gene silencing of WISP-2 increased the induction of the catabolic markers MMP-13 and ADAMTS-5 and the inflammatory mediators IL-6 and IL-8 triggered by IL-1β in human primary OA chondrocytes in a Wnt/β-catenin dependent manner. In conclusion, here we have shown for the first time that WISP-2 may have relevant roles in modulating the turnover of extracellular matrix in the cartilage and that its downregulation may detrimentally alter the inflammatory environment in OA cartilage. We also proved the participation of Wnt/β-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytes. This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA). We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target. We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes. We concluded that mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.

Objetivo: Analizar los efectos de un programa de estimulación motriz de 8 semanas basado en actividades lúdicas, en el nivel de desarrollo motor grueso de varones escolares de tercero y cuarto básico del Instituto Salesiano Valdivia. Método: Participaron 15 alumnos hombres, con una edad de 9.03±0.63 años en un programa de estimulación motriz basado en actividades lúdicas, realizando tres sesiones semanales, por un tiempo de ocho semanas. Se midió el nivel de desarrollo motor grueso antes y después de la intervención, utilizando el Test de Desarrollo Motor Grueso (TGMD-2), el cual determina la edad motriz a través de la evaluación de habilidades manipulativas y locomotoras. Resultados: Los resultados mostraron que hubo una diferencia significativa entre pre y post test en las habilidades locomotoras (p= .0006) manipulativas (p= .0006) y el quociente de los resultados (p= .0006), pasando de un 93% de niños bajo edad, pobre y muy pobre a un 93% de niños en categorías en la edad y sobre la edad. Conclusión: Se concluye que el programa de estimulación motriz basado en actividades lúdicas mejora significativamente los niveles de desarrollo motor en niños. Abstract. Objective: To analyze the effects of an 8-week motor stimulation program based on playful activities, in the level of gross motor development of third and fourth grade school boys from the Salesiano Valdivia Institute. Method: 15 male students, with an age of 9.03±0.63 years, participated in a motor stimulation program based on recreational activities, performing three weekly sessions, for a period of eight weeks. The level of gross motor development was measured before and after the intervention, using the Test Gross Motor Development (TGMD-2), which determines motor age through the evaluation of manipulative and locomotor skills. Results: The results showed that there was a significant difference between the locomotor skills (p= .0006) and manipulative (p= .0006) and the quoient of the results (p= .0006), going from 93% of children low age, poor and very poor even 93% of children in categories in age and over age. Conclusion: It is concluded that the motor stimulation program based on playful activities significantly improves the levels of motor development in children.

[Abstract] Background: One-third of rheumatoid arthritis (RA) patients demonstrate no clinical improvement after receiving tumor necrosis factor inhibitors (TNFi). The presence of serum autoantibodies is a hallmark in RA and may provide information on future response to treatment. The aim of this prospective study was to search for novel serum autoantibodies useful to predict clinical response to TNFi. Methods: The autoantibody repertoire was profiled on RA patients treated with TNFi as a first line of biologic therapy (N = 185), who were recruited in three independent cohorts. The presence and levels of autoantibodies in serum at baseline were analysed in association with the clinical response after 24 weeks follow-up. A multiplex bead array built using antigens selected from an initial untargeted screening was employed to identify the autoantibodies on a discovery cohort (N = 50) and to verify and validate the results on verification (N = 61) and validation (N = 74) cohorts. Non-parametric tests, meta-analysis and Receiver Operating Curves (ROC) were performed in order to assess the clinical relevance of the observed findings. Results: Novel autoantibodies were associated with the clinical response to TNFi, showing different reactivity profiles among the different TNFi. The baseline levels of IgG antibodies against Centromere protein F (CENPF), a protein related to cell proliferation, were significantly (p

© Copyright Clinical and Experimental Rheumatology 2022., Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Patients with rheumatoid arthritis (RA) show autoantibodies against post-translational protein modifications (PTMs), such as anti-citrullinated protein antibodies. However, the range of recognized PTMs is unknown. Here, we addressed four PTMs: chlorination, non-enzymatic glycation, nitration, and homocysteinylation, identified as targets of atypical RA autoantibodies in studies whose protocols we have followed. The modified antigens included collagen type II, an extract of synovial proteins and a selection of peptides. We interpreted the results according to the optical density (OD) obtained in an enzyme-linked immunosorbent assay ( ELISA) with the modified antigen and the corrected OD obtained after subtracting the reactivity against the unmodified antigen. The results showed evidence of specific antibodies against glycated collagen type II, as the corrected ODs were higher in the 182 patients with RA than in the 164 healthy controls (p = 0.0003). However, the relevance of these antibodies was doubtful because the magnitude of the specific signal was small (median OD = 0.072 vs. 0.027, respectively). There were no specific antibodies against any of the other three PTMs. Therefore, our results showed that the four PTMs are not inducing a significant autoantibody response in patients with RA. These results indicated that the repertoire of PTM autoantigens in RA is restricted.

Objective To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions Our results support the association of the HLA complex with the susceptibility to ASSD.

Objective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. Methods. Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for similar to 8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 x 10(-5). Results. The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 x 10(-7); I-2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. Conclusion. These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.

International audience; Objectives MAXIMISE (Managing AXIal Manifestations in psorIatic arthritis with SEcukinumab) trial was designed to evaluate the efficacy of secukinumab in the management of axial manifestations of psoriatic arthritis (PsA). Methods This phase 3b, double-blind, placebocontrolled, multi-centre 52-week trial included patients (≥18 years) diagnosed with PsA and classified by ClASsification criteria for Psoriatic Arthritis (CASPAR) criteria, with spinal pain Visual Analogue Score ≥40/100 and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥4 despite use of at least two nonsteroidal anti-inflammatory drugs (NSAIDs). Patients were randomised (1:1:1) to secukinumab 300 mg, secukinumab 150 mg or placebo weekly for 4 weeks and every 4 weeks thereafter. At week 12, placebo patients were re-randomised to secukinumab 300/150 mg. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society) response with secukinumab 300 mg at week 12. Results Patients were randomly assigned; 167 to secukinumab 300 mg, 165 to secukinumab 150 mg and 166 to placebo. Secukinumab 300 mg and 150 mg significantly improved ASAS20 response versus placebo at week 12 (63% and 66% vs 31% placebo). The OR (95% CI) comparing secukinumab 300 mg and 150 mg versus placebo, using a logistic regression model after multiple imputation, was 3.8 (2.4 and 6.1) and 4.4 (2.7 and 7.0; p

BackgroundThe impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here we compare the outcomes of a cohort of rheumatic patients with a matched control cohort to identify potential risk factors for severe illness.MethodsIn this comparative cohort study, we identified hospital PCR+ COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or autoimmune/immunomediated diseases (AI/IMID). Non-rheumatic controls were randomly sampled 1:1, and matched by age, sex, and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, ICU admission, or serious complications. We assessed the association between the outcome and potential prognostic variables, adjusted by COVID treatment, using logistic regression.ResultsThe cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 [IQR 53-78] and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and AI/IMID (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular, or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID were increased age (OR 5.31; CI 3.14-8.95), male sex (2.13; CI 1.35-3.36) and having an AI/IMID (OR 1.98; CI 1.15-3.41).ConclusionIn patients with chronic inflammatory rheumatic diseases aging, sex and having an AI/IMID but not IA nor previous immunosuppressive therapies were associated with severe COVID-19.

Pachydermodactyly is a rare, benign fibromatosis located around the proximal interphalangeal joints. It is often misdiagnosed as juvenile idiopathic arthritis and may cause unnecessary treatments and anxiety in patients. The goal of this paper is to describe this condition through all the existing information in the scientific literature. A systematic review and a descriptive study have been conducted. A systematic research was performed in PubMed, Embase, Cochrane Library and WOS. Pachydermodactyly was four times more frequent in male subjects and usually started in adolescence. Bilateral presentation was more frequent. History of microtrauma in both hands due to digital manipulation was found in almost half of the patients, many of them showed some neuropsychiatric disorder. In women, the onset happened later, unilateral involvement and family history were more frequent. Swelling of soft tissue without joint implication was found in imaging tests. The progression was usually positive and the treatment included stopping the microtrauma, administrating intralesional corticoids and/or surgery. Diagnosis can be established in asymptomatic young patients through a congruent physical exam, regular analytic results and imaging tests that simply show swelling of soft tissue—a biopsy is generally not required for diagnosis. As pachydermodactyly’s course is asymptomatic and benign, knowledge about this condition is limited, which increases the likelihood of its underdiagnosis—it is important that clinicians know of pachydermodactyly in order to avoid misdiagnosis.

Osteoarthritis (OA) is a highly prevalent debilitating and painful pathology derived from progressive degeneration of articular joints. Obesity has long been recognized as a significant and potentially preventable risk factor for OA incidence, progression, and disability. Biomechanical loading, together with metabolic and inflammatory imbalances of the joint, strongly contributes to obesity-induced OA pathophysiology. Adipose-tissue derived cytokines—adipokines—have demonstrated roles in modulating pro/anti-inflammatory and anabolic/catabolic joint balance, with implications in cartilage and bone homeostasis. Mechanical stress may lead to considerable increases in proinflammatory mediators within the joint. Therefore, adipokines emerged as potential candidates to link mechanical, metabolic and inflammatory components of obesity-induced osteoarthritis. Herein we summarize the biology of adipokines in joint tissues, highlighting their implications in the dysregulation of joint homeostasis and, thus OA pathogenesis. Many of the aspects of the adipokine network remain largely unknown and further insights into the intimate mechanisms of adipokines activity will be of great relevance to develop disease-modifying osteoarthritis drugs, especially for obese patients.

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1 , MIP1 , MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.

Background: The impact of chronic inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here we compare the outcomes of a cohort of rheumatic patients with a matched control cohort to identify potential risk factors for severe illness. Methods: In this comparative cohort study, we systematically identified hospital PCR+ COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or autoimmune/immunomediated diseases (AI/IMID). Non-rheumatic controls were randomly sampled 1:1, and matched by age, sex, and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, ICU admission, or serious complications. We assessed the association between the outcome and potential prognostic variables, adjusted by COVID treatment, using logistic regression. Findings: The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 [IQR 53-78] and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and AI/IMID (40%). Patients were on treatment with glucocorticoids (40%), conventional synthetic disease modifying antirheumatic drugs (csDMARD) (57%), targeted synthetic or biological (ts/bDMARD) (23%), or other immunosuppressants (12%). Most patients (74%) had been hospitalised, and the risk of severe COVID was 31·6% in the rheumatic and 28·1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular, or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe were increased age (OR 5·31; CI 3·14-8·95), male sex (2·13; CI 1·35-3·36) and having an AI/IMID (OR 1·98; CI 1·15-3·41). Interpretation: In patients with chronic inflammatory rheumatic diseases aging, sex and having an AI/IMID but not IA nor previous immunosuppressive therapies were associated with severe COVID-19. Funding Statement: The RIER network was supported by Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (RD16/0012 RETICS program) and cofinanced by the European Regional Development Fund. Declaration of Interests: None of the authors have competing interests to declare. Ethics Approval Statement: The study was approved by Comite de Etica de la Investigacion del Hospital Universitario 12 de Octubre, CEIm number: 20/160.

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD, This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), cofunded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10

Magnetic resonance imaging (MRI) is considered the gold standard to reliably diagnose inflammation in the temporomandibular joint (TMJ) of patients with juvenile idiopathic arthritis (JIA). However, even MRI imaging is dependent on the familiarity of the radiologist with the normal appearance of the TMJ; therefore, new approaches are needed. Our purpose here is to improve imaging quality of cone beam computed tomography (CBCT) as a tool to help in the diagnosis of JIA in the TMJ. We have designed and applied a filter (the Stacking Enhancement Filter) over a stock of CBCT images from the TMJs of two patients with JIA. We then made a visual comparison of the results with archival images from MRI of the same patients, to show that the filter substantially improves the visual quality of the image. The work on the image contrast and the increase of the difference of appearance between tissues of different densities (all the anatomical structures that are present within the joint) leads to an improvement of the resulting images of the TMJ without the use of a chemical contrast agent. We conclude that CBCT could be used as a filter tool for the analysis of the TMJs affected by arthritis. Our image processing technique yields images that possible improve the range of use of CBCT.

Rheumatoid arthritis (RA) is a systemic autoimmune disease including synovitis and synovial hyperplasia that contribute to joint destruction. Pivotal pathogenic mechanisms in this process are the dysregulated proliferation and apoptosis of fibroblast-like synoviocytes (FLS). Unfortunately, the mechanisms of FLS dysregulation are not completely elucidated. Here, we explored a new hypothesis based in the potent anti-proliferative and pro-apoptotic activity of retinoids in some types of cancer. Specifically, we investigated the role of retinoids and of the retinoic acid binding proteins, CRABP2 and FABP5, on the proliferation and apoptosis of FLS from RA by adding all-trans retinoic acid (ATRA) or silencing CRABP2 and FABP5. We showed an unconventional behaviour of RA FLS, which were relatively insensitive to ATRA. In effect, ATRA increased the resistance to apoptosis despite the high CRABP2/FABP5 ratio of RA FLS; and CRABP2 suppression sensitized RA FLS to Fas-induced apoptosis. This latter effect was associated with changes in expression of kinases, ASK1 up-regulation and ERK down-regulation, and increased phosphorylation of JNK. In addition, the potentiation of FLS apoptosis by CRABP2 silencing persisted in the presence of pro-inflammatory mediators, TNF e IL1β. Therefore, the results point to CRABP2 as a potential target to decrease synovial hyperplasia in RA.

Obesity has reached epidemic proportions in the Western society and is increasing in the developing world. It is considered as one of the major contributors to the global burden of disability and chronic diseases, including autoimmune, inflammatory and degenerative diseases. Research conducted on obesity and its complications over the last two decades has transformed the outdated concept of white adipose tissue (WAT) merely serving as an energy depot. WAT is now recognized as an active and inflammatory organ capable of producing a wide variety of factors known as adipokines. These molecules participate through endocrine, paracrine, autocrine or juxtacrine crosstalk mechanisms in a great variety of physiological or pathophysiological processes, regulating food intake, insulin sensitivity, immunity and inflammation. Although initially restricted to metabolic activities (regulation of glucose and lipid metabolism), adipokines currently represent a new family of proteins that can be considered key players in the complex network of soluble mediators involved in the pathophysiology of immune/inflammatory diseases. However, the complexity of the adipokine network in the pathogenesis and progression of inflammatory diseases has posed, since the beginning, the important question of whether it may be possible to target the mechanism(s) by which adipokines contribute to disease selectively without suppressing their physiological functions. Here, we explore in depth the most recent findings concerning the involvement of adipokines in inflammation and immune responses, in particular in rheumatic, inflammatory and degenerative diseases. We also highlight several possible strategies for therapeutic development and propose that adipokines and their signalling pathways may represent innovative therapeutic strategies for inflammatory disorders.

Background/Aims: The E74-like factor 3 (ELF3) is an inflammatory mediator that participates in cartilage destruction in osteoarthritis. Leptin and other adipokines negatively impact articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated whether leptin induces ELF3 expression in chondrocytes and the signaling pathway involved in this process. Methods: We determined mRNA and protein levels of ELF3 by RT-qPCR and Western blotting using cultured human primary chondrocytes and the human T/C-28a2 chondrocyte cell line. Further, we measured luciferase activities of different reporter constructs, and we assessed the contribution of leptin to the induction of ELF3 mRNA by knocking down hLEPR gene expression using siRNA technology. Results: Leptin synergizes with IL-1β in inducing ELF3 expression in chondrocytes. We also found that PI3K, p38, and JAK2 signaling pathways are at play in the leptin-driven induction of ELF3. Moreover, we confirm the participation of NFΚB in the leptin/IL-1β synergistic induction of ELF3. Conclusion: Here we show, for the first time, the regulation of ELF3 expression by leptin, suggesting that this transcription factor likely mediates the inflammatory responses triggered by leptin in articular chondrocytes.

Summary Objective Lipocalin-2 (LCN2) is an adipokine that was first identified in neutrophil granules. In the last years it was recognized as a factor that could impair chondrocyte phenotype, cartilage homeostasis as well as growth plate development. Both pro-inflammatory cytokines and glucocorticoids (GCs) modulate LCN2 expression. Actually, GCs were found to be LCN2 inducers, suggesting that part of the negative actions exerted by these anti-inflammatory drugs at cartilage level could be mediated by this adipokine. So, in this study we wanted to investigate whether corticoids were able to act in synergy with IL-1 in the induction of LCN2 and the signaling pathway involved in this process. Materials and methods For the realization of this work, ATDC5 mouse chondrogenic cell line was used. We determined the mRNA and protein expression of LCN2 by real-time reverse transcription-polymerase chain reaction (RT-qPCR) and western blot respectively, after GC or mineralcorticoid treatment. Different signaling pathways inhibitors were also used. Results GC and mineralcorticoid were able to induce the expression of LCN2 in ATDC5 cells. Interestingly, both corticoids synergized with IL-1 in the induction of LCN2. The effect of these corticoids on the expression of LCN2 occurred through GC or mineralcorticoid receptors and the kinases PI3K, ERK1/2 and JAK2. Conclusions Prolonged use of corticoids may have detrimental effects on cartilage homeostasis. Based on our results, we conclude that corticoids could increase the negative actions exerted by IL-1 by increasing the expression of LCN2.

Osteoarthritis (OA) is a chronic systemic musculoskeletal disorder involving inflammation, immunity, and metabolic alterations. OA is commonly regarded as non-inflammatory disease; still inflammation is recognized as contributing to the symptoms and progression of OA. New evidence suggests that adipokines are involved in the pathophysiology of OA and might modulate the production of inflammatory mediators including in immune cells. However, the role of immune component in osteoarthritis is still poorly investigated. To gain further insights into the interaction of immune cells in OA and the role of adipokines on these cells, we performed experiments aimed to determine the cytokine profile in activated CD4+ T cells from OA patients. For completeness, we also explored the cross talk between T lymphocytes and chondrocytes in OA by co-culturing human primary chondrocytes with activated CD4+ T cells in two ways: the first by incubating the cells by direct contact (D.C.) or by transwell system. Our results show that the exposure of activated CD4+ T cells to adipokines modulates IL-6, IL-8, and CCL-3 production. In addition, the production of key macromolecules of ECM (aggrecan and collagen-2) and matrix metalloproteinase 13 (MMP-13) in co-cultured chondrocytes with activated CD4+ T cells was altered. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1299-1303, 2017.

[Abstract] Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT All-trans retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs. Instituto de Salud Carlos III; PI1701660 Instituto de Salud Carlos III; PI1401153 Instituto de Salud Carlos III (RETICS); RD16/0012/0014

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10–8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10–16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+1+2vs. RF−0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms.

Background: The contribution of cigarette smoking to the risk of rheumatoid arthritis (RA) is larger for seropositive than for seronegative patients. Current pathogenic models explain this difference via the production of anti-citrullinated protein antibodies (ACPA) induced by protein citrullination in the lungs as a consequence of smoking. However, there are inconsistent results with this model including the van Wesemael et al. report, which found an association of smoking with the concurrent presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein antibodies (ACarPA), rather than with ACPA. Objectives: We aimed to explore the relationship between smoking and the presence of FR, ACPA and ACarPA and their combinations in patients with RA. Methods: Six cohorts with 2253 RA patients were obtained to replicate the van Wesemael et al. results. After replication, they were combined with the three cohorts from that study comprising 2238 patients to a total of 4491 patients. The results from the different cohorts were combined by fixed-effects meta-analysis. Most analyses involved comparisons between two levels of smoking exposure, never and ever smokers, considering the RF-/ACPA-/ACarP-patients as the reference. Results: Analysis of the replication set confirmed the predominant association of smoking with the concurrent presence of the three RA autoantibodies (OR = 1.99, P = 2.5 x 10-8), whereas the patients with one or two antibodies were not different from the patients without antibodies (OR = 1.22, p = 0.4 and OR = 1.22, p = 0.3, respectively). The combined meta-analysis with all the cohorts clarified the dominant association of smoking with the triple concordant seropositivity (OR = 2.00, p = 4.4 x 10-16). In contrast, there was no association with the patient bearing one autoantibody (OR = 1.12, p = 0.4), and an in-between association with the concurrent presence of two antibodies (OR = 1.26, p = 0.009). Moreover, the association with the presence of three antibodies was significantly larger than with two antibodies (OR = 1.54, p = 1.4 x 10-6), whereas the association with the presence of two antibodies was not larger than with one autoantibody (OR = 1.11, p = 0.3). In the patients remaining after exclusion of the triple seropositive, the smokers were exclusively associated with the RF+ (OR = 1.28, p = 0.03 and OR = 1.30, p = 0.004 in the double and single positive patients, respectively). This association was independent of the reference, either the triple seronegative (OR = 1.29, p = 0.001) or all the RF-patients (OR = 1.32, p = 0.0002). Conclusion: Smoking increases RA susceptibility by promoting pathways leading to the concurrent presence of the three RA autoantibodies and, in its defect, to the production of RF. These actions are not covered by current pathogenic models and suggest that smoking accelerates epitope spreading. Reference [1] van Wesemael, et al. Arthritis Res Ther. 2016;18:285. Acknowledgement: Supported by grants PI17/01606 and RD16/0012/0014 of the Instituto de Salud Carlos III (Spain) that are partially financed by FEDER. Disclosure of Interests: Cristina Regueiro : None declared, Luis Rodriguez Rodriguez: None declared, Raquel Lopez-Mejias: None declared, Laura Nuno: None declared, Ana Triguero-Martinez: None declared, Eva Perez-Pampin: None declared, Alfonso Corrales: None declared, Alejandro Villalva: None declared, Yolanda Lopez-Golan: None declared, Lydia Abasolo: None declared, Sara Remuzgo Martinez: None declared, Ana Ortiz: None declared, Eva Herranz: None declared, ANA MARTiNEZ-FEITO: None declared, Carmen Conde : None declared, ANTONIO MERA VARELA: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Isidoro Gonzalez-Alvaro: None declared, Miguel A Gonzalez-Gay Grant/research support from: Prof. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD, Jansen and Roche., Speakers bureau: Consultation fees/participation in company sponsored speaker’s bureau from Pfizer, Lilly, Sobi, Celgene, Novartis, Roche and Sanofi., Benjamin Fernandez: None declared, Antonio Gonzalez: None declared

Background Chronic inflammatory immune-mediated diseases, as rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (Ps), ankylosing spondylitis (AS), ulcerative colitis (UC) and Crohn’s disease (CD), have higher risks of morbidity and mortality and a great impact on quality of life of patients1. Drug inhibitors of tumor necrosis factor (TNF inhibitors) have demonstrated an adequate efficacy and security profile in these patients when classical treatments (as disease-modifying antirheumatic drugs) have been failed or patients were intolerant. TNF inhibitors are used to control inflammatory response and to improve quality of life, pain, functional capacity and progression of the disease2. Studies in RA show that smoking habit is related to more articular and extra-articular damage, worse prognosis, higher basal activity and higher risk of seropositive RA. It has been related also to greater number of different treatments and higher doses needed for patients by pharmacokinetic and pharmacodynamic processes. Data published until now suggest that smoking habit decreases efficacy of TNF inhibitors3. Objectives To analyze the smoking habit influence on the efficacy of TNF inhibitors in patients diagnosed of chronic inflammatory immune-mediated diseases (RA, PsA, Ps, AS, UC, CD). Methods It was made a systematic literature search using Cochrane Library, Medline, the Web of Science and Embase databases. Meta-analyses were performed using a random-effects model. Results 37 of 3677 identified articles met the inclusion criteria. No documents with GOL were found. The analysis of all the diseases together gives a significant decrease on the response to TNF inhibitors in smoking patients [OR 0.812 (0.662-0.996), p=0.046]. This response also has a significant decrease in IBD maintained response in smoking patients [OR 0.467 (0.257-0.848), p=0.012]. A non-significant decrease in the treatment response of smoking patients with IBD clinical remission was found, in smoking patients versus ex-smoking and never smoking patients with IBD response, in ex-smoking patients versus never smoking patients with IBD partial response, in current and ex-smoking patients versus never smoking patients with IBD partial response, in current smoking patients versus ex-smoking patients with IBD partial response, in current smoking patients versus never and ex-smoking patients with IBD partial response, in current smoking patients versus never smoking patients with IBD partial response, in patients with AR EULAR and in patients with AR EULAR moderate response. Conclusion Smoking habit is a poor prognosis factor in RA, AS, Ps, PsA, UC and CD. Its leaving will decrease cardiovascular risk, joint and bowel damage, will increase the efficacy of TNF inhibitors and will benefit the health of patients, not only in their particular disease, and it can be the first step on their treatment. References [1] Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med 2008;121(10):9-14. [2] Seymour HE. Anti-TNF agents for rheumatoid arthritis. Br J Clin Pharmacol2001;51(3):201-8. [3] Arnson Y. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun2010;34(3):258-65. Disclosure of Interests None declared

Background Secukinumab (SEC) has provided significant and sustained improvement in the signs and symptoms of active psoriatic arthritis (PsA) and ankylosing spondylitis 1. Evidence on the efficacy of biologics in the treatment of PsA patients (pts) with axial manifestations affecting 30–70% of PsA pts is limited2, particularly as validated classification criteria for this subtype of PsA are not yet available; an effort to develop criteria is being undertaken by ASAS/GRAPPA. MAXIMISE is an ongoing study evaluating the efficacy and safety of secukinumab 300 or 150mg in managing axial manifestations in PsA pts Objectives To report the primary analysis results at Week (Wk) 12 from MAXIMISE (NCT02721966) trial Methods This phase 3b, double blind, placebo (PBO)-controlled, multicentre 52-wk trial included 498 pts (aged ≥18 years) with PsA (CASPAR criteria), clinician-diagnosed axial involvements, spinal pain VAS >40/100 and BASDAI >4 despite trial of at least two NSAIDs. Pts were randomised to subcutaneous (SC) SEC (300/150 mg) or PBO weekly for 4 wks and every 4 wks thereafter. At Wk 12, PBO pts were re-randomised to SC SEC 300/150 mg. The primary endpoint was proportion of pts achieving ASAS20 response with SEC 300 mg at Wk 12. The key secondary endpoint was ASAS20 response with SEC 150 mg at Wk 12 after superiority of 300 mg was established. Analyses used multiple imputation Results Demographic and baseline (BL) disease characteristics were comparable across groups (Table). Primary and key secondary endpoints were met; ASAS20 response rates at Wk 12 were 63.1% (SEC 300 mg; P Conclusion MAXIMISE is the first randomised controlled trial evaluating the efficacy of a biologic in the management of the axial manifestations of PsA. SEC 300 and 150 mg provided rapid and significant improvement in ASAS20 responses through Wk 12 in PsA pts with axial manifestations and inadequate responses to NSAIDs References [1] Lubrano E and Perrotta FM. Ther Clin Risk Manag. 2016;12:1587-92 [2] Feld J, et al. Rheum Rev.2018;14:363 M, number of pts with available HLA-B27 status Disclosure of Interests Xenofon Baraliakos Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer Inc, Roche and UCB, Grant/research support from: AbbVie, Pfizer, Merck Sharp & Dohme, UCB Pharma, Novartis, Consultant for: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Biologics, Novartis, Pfizer, UCB Pharma, Galapagos, Speakers bureau: AbbVie, Chugai, Janssen, Novartis, Pfizer, UCB Pharma, Laura C Coates Grant/research support from: AbbVie, Celgene, Lilly, Novartis and Pfizer, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead Sciences Inc., Janssen, Lilly, Novartis, Pfizer, Prothena Corp and UCB, Laure Gossec Grant/research support from: AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Sanofi, and UCB, Consultant for: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, MSD, Nordic Pharma, Novartis-Sandoz, Pfizer, Roche, Sanofi, and UCB, Consultant for: L Gossec has received honoraria from Celgene as investigator for this study, Slawomir Jeka: None declared, ANTONIO MERA VARELA: None declared, Barbara Schulz Employee of: Novartis, Michael Rissler Employee of: Novartis, Ayan Das Gupta Employee of: Novartis, Chiara Perella Employee of: Novartis, Effie Pournara Shareholder of: Novartis, Employee of: Novartis

Background: Fibroblast-like synoviocytes (FLS) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). These cells acquire an aggressive and invasive phenotype and secrete inflammatory mediators, metalloproteases and cathepsins that perpetuate inflammation and lead to cartilage and bone damage. Given the importance of FLS in the pathogenesis of RA, there is a growing interest in developing new therapies aimed to revert their aggressive phenotype. To this end, a better knowledgement of molecular mechanisms involved in FLS behavior is needed. Recently, the role of non-canonical Wnt pathway has been highlighted in several processes as migration, invasion and inflammatory responses. The non-canonical Wnt signaling pathway included the planar cell polarity (PCP), with the activation of Rho and Rac GTPases, and the Wnt/Ca2+ pathways. We have previously demonstrated that Wnt5a contributes to the aggressive phenotype of FLS by increasing their migration and invasion ability, and by stimulating the inflammatory response. Objectives: To analyse the molecular mechanisms involved in the enhancing effects of non-canonical Wnt5a pathway on the aggressive phenotype of rheumatoid synoviocytes. Methods: The expression of receptors of non-canonical Wnt5a pathway was assessed in FLS from six RA patients by real-time PCR. Expression of these receptors was suppressed by siRNA transfection (Dharmacon) and the antibody (anti-RYK, Abgent). Pharmacological inhibitors were used to identify the signaling pathways. Thus, an inhibitor of ROCK pathway (Y-27632, Selleckchem) was used and a calcium chelator (BAPTA-AM, Enzo) for the inhibition of the PKC pathway. The expression of MAPKs was analyzed by western blot. Migration after stimulation with recombinant Wnt5a protein was analyzed by the wound healing assay using Ibidi inserts. The occupation area was determined by Image J software. Results: We analyzed the expression of Wnt5a receptors, FZD1, FZD2, FZD4, FZD5, FZD7, ROR1, ROR2 and RYK of RA FLS. Although all receptors were expressed in theses cells, whereas ROR2 was weakly expressed, RYK showed the highest expression. Migration assays after receptor suppression by siRNA transfection or blocking antibodies showed the involvement of RYK on Wnt5a signaling in RA FLS. In effect, Wnt5a-induced migration was reduced by more than 25% in FLS treated with the anti-RYK antibody. In addition, Wnt5a-induced migration in FLS treated with ROCK inhibitor (Y-27632) was 32% lower than in FLS not treated. No change in spontaneous migration was observed in FLS treated with Y-27632. However, the treatment with the calcium chelator, BAPTA-AM, did not show any differential effect between the spontaneous or the Wnt5a-induced migration. In addition, we found the activation of MAP kinases, ERK and P38, as well as, AKT and GSK3β in FLS treated with rWnt5a. Nevertheless rWnt5a did not activate JNK. These effects were reversed after treatment with the ROCK inhibitor or after blocking the RYK receptor. Conclusion: These results indicate that Wnt5a contributes to the aggressive phenotype of RA FLS by binding to RYK receptor, through Rho-ROCK pathway and the activation of MAPKs, ERK and P38, as well as the activation of AKT and GSK3β. Acknowledgement: Supported by grant of the ISCIII/PI17/01660/RETICS Program, RD16/0012/0014/Cofinanced FEDER Disclosure of Interests: None declared

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

CIRCULATING AUTOANTIBODIES AS INDICATORS TO PREDICT THE CLINICAL RESPONSE TO INFLIXIMAB IN RHEUMATOID ARTHRITIS

Background Patients with rheumatoid arthritis (RA) present increased oxidative stress that leads to lipid peroxidation and the formation of malondialdehyde (MDA) and acetaldehyde (AA). These two compounds under oxidative stress form malondialdehyde-acetaldehyde (MAA) adducts with proteins, which are highly immunogenic. Recently, Thiele et al.1 described the presence of antibodies against human albumin MAA adducts in patients with established RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Of particular relevance was the reported presence of IgG anti-MAA antibodies in 92% of the patients, including 88% of the anti-CCP negative patients. These results suggest MAA adducts could contribute to the pathogenesis of RA and the anti-MAA antibodies could drastically reduce the number of patients with seronegative RA. Objectives To replicate the association of anti-MAA antibodies with RA and explore their value as biomarkers. Methods Sera from 515 Spanish patients with established RA that fulfilled the 1987 ACR classification criteria and from 274 healthy controls were included. Available information included history of smoking, anti-CCP status, and genotype of HLA-DRB1 and PTPN22 rs2476601. Human serum albumin MAA adducts and hexyl-MAA standard were chemically synthesised. Anti-MAA antibodies against the albumin MAA adducts were determined by indirect ELISA using isotype-specific secondary antibodies for IgG, IgM and IgA. Results Anti-MAA antibodies were detected in a small fraction of the RA patients, who had slightly increased antibody titers compared to healthy controls, 6.4% were positive for IgG, 15.7% for IgM and 8.0% for IgA. The low prevalence of anti-MAA antibodies persisted in spite of multiple variations in the ELISA protocols including the use of different albumin sources, albumin MAA adducts produced in two different laboratories, and various secondary antibodies. IgM anti-MAA antibody titers were increased in smokers compared to non-smokers. Moreover, the presence of IgM and of IgA anti-MAA antibodies were associated with anti-CCP and RF positivity. Conclusions Anti-MAA antibodies were detected in a small fraction of the Spanish RA patients, but their low sensitivity questions the value of these antibodies as biomarkers of RA. Due to the contradictory findings, additional studies should be performed that will need to address also the role of MAA adducts on RA pathogenesis. Reference [1] Thiele GM, et al. Arthritis Rheumatol2015;67(3):645–55. Acknowledgements Supported by grants PI14/01651 and RD16/0012/0014 of the Instituto de Salud Carlos III (Spain) that are partially financed by the ERDF Disclosure of Interest None declared