EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Comorbidities in Early Psoriatic Arthritis: Data From the Metabolic Disturbances in Psoriatic Arthritis Cohort Study.

OBJECTIVE: The aim of this study was to investigate the prevalence of comorbidities and cardiovascular (CV) risk factors (RFs) in treatment-naive patients with early psoriatic arthritis (ePsA) and to identify factors that contribute to metabolic burden in ePsA. METHODS: This was an observational longitudinal multicenter cohort study. Clinical and demographic characteristics, CV RFs, and comorbidities were compared in patients newly diagnosed with psoriatic arthritis (PsA) and sex- and age-matched controls. In patients with PsA, comorbidities were reevaluated after one year's follow-up because the disease activity changed. RESULTS: Sixty-seven patients with ePsA and 61 healthy volunteers were included. The rate of comorbidities was similar in patients with ePsA and in healthy controls; 82.1% of patients with ePsA had CV RFs at baseline as compared with 62.3% of healthy volunteers (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.14-2.0). Patients with ePsA had higher odds of having multiple (two or more) comorbidities (OR 1.9, 95% CI 1.2-3.0) and multiple CV RFs (OR 2.1, 95% CI 1.3-3.2) than the controls. Comorbidities or CV RFs in patients with ePsA were not influenced by duration of skin psoriasis. Dyslipidemia was the most prevalent comorbidity in the PsA cohort (64.2% vs 39.3% in controls; OR 1.7, 95% CI 1.2-2.5). Patients with ePsA had, on average, above normal body mass index (mean ± SD 28.82 ± 4.5) and a higher rate of obesity (40.3% vs 18.3% in controls; OR 1.9, 95% CI 1.1-3.2). After 1 year, although disease activity scores improved, the proportion of patients with comorbidities and CV RFs did not increase or drop. CONCLUSION: Our data imply that patients with PsA already have higher comorbidities and CV burden at early stages of the disease, suggesting that these are not only a consequence of long-lasting disease and chronic systemic inflammation.

Specific descriptions of axial involvement are associated with radiographic damage development after 2 years in psoriatic arthritis patients.

OBJECTIVES: Investigating the association between different definitions of axial involvement and syndesmophytes development over 2 years in patients with psoriatic arthritis (PsA). METHODS: Patients from a prospective multicentre cohort (Belgian Epidemiological Psoriatic Arthritis Study) involving 17 Belgian rheumatology practices were recruited between December 2012 and July 2014 and included when fulfilling the Classification Criteria for Psoriatic Arthritis. Axial involvement included six clinical and two radiographic oriented definitions.Two calibrated central readers evaluated radiographic damage by assessing the modified Stoke Ankylosing Spondylitis Spinal Score and modified New York criteria. New syndesmophytes after 2 years were described conditional on axial involvement at baseline. Logistic regression analyses were used to investigate the association between syndesmophyte development and axial involvement. All definitions of axial involvement were evaluated separately. RESULTS: From 150 patients, a 2-year follow-up of spinal radiographs was obtained. There are 11 patients with new syndesmophytes after 2 years. For the clinical definitions of axial involvement 'global assessment', 'detailed assessment', 'back pain (BP)' and 'inflammatory BP (IBP)' the probabilities of developing syndesmophytes ranged between 0.06 and 0.08 and were similar for the presence or absence of the definition. When including elevated C reactive protein (CRP) to the definitions the probability of developing syndesmophytes over 2 years increased two times for CBP and seven times for IBP.With radiographic axial involvement a similar trend was seen; radiographic sacroiliitis as definition showed a probability three times higher. When combined with elevated CRP there would be a 14 times higher chance to develop syndesmophytes in 2 years. The ORs varied from 0.83 to 13.80, though none of them were statistically significant. CONCLUSIONS: The likelihood of syndesmophyte formation in PsA is low. The probability of developing syndesmophytes is much higher when axial involvement is determined radiographically rather than clinically, particularly in the context of high CRP.

Osteomodulin downregulation is associated with osteoarthritis development.

Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

Prolonged mechanical muscle loading increases mechanosensor gene and protein levels and causes a moderate fast-to-slow fiber type switch in mice.

Mechanosensing and subsequent mechanotransduction are indispensable for muscle plasticity. Nevertheless, a scarcity of literature exists regarding an all-encompassing understanding of the muscle mechanosensing machinery's response to prolonged loading, especially in conditions that resemble a natural physiological state of skeletal muscle. This study aimed to comprehensively explore the effects of prolonged mechanical loading on mechanosensitive components, skeletal muscle characteristics, and metabolism-related gene clusters. Twenty male C57BL/6J mice were randomly divided into two groups: control and prolonged mechanical loading. To induce prolonged mechanical loading on the triceps brachii (TRI) and biceps brachii (BIC) muscles, a 14-day period of tail suspension was implemented. In TRI only, prolonged mechanical loading caused a mild fast-to-slow fiber type shift together with increased mechanosensor gene and protein levels. It also increased transcription factors associated with slow muscle fibers while decreasing those related to fast-type muscle gene expression. Succinate dehydrogenase activity, a marker of muscle oxidative capacity, and genes involved in oxidative and mitochondrial turnover increased, whereas glycolytic-related genes decreased. Moreover, prolonged mechanical loading stimulated markers of muscle protein synthesis. Taken together, our data show a collective muscle-specific increase in mechanosensor gene and protein levels upon a period of prolonged mechanical loading in conditions that reflect a more natural physiological state of skeletal muscle in mice. We provide additional proof-of-concept that prolonged tail suspension-induced loading of the forelimbs triggers a muscle-specific fast-to-slow fiber type switch, and this coincides with increased protein synthesis-related signaling.NEW & NOTEWORTHY This study provides a comprehensive overview of the effects of prolonged loading on mechanosensitive components in conditions that better reflect the natural physiological state of skeletal muscle. Although the muscle mechanosensing machinery has been widely acknowledged for its responsiveness to altered loading, an inclusive understanding of its response to prolonged loading remains scarce. Our results show a fast-to-slow fiber type shift and an upregulation of mechanosensor gene and protein levels following prolonged loading.

Triple jump for the optimal management of psoriatic arthritis: diet, sleep and exercise - a review.

Psoriatic arthritis (PsA) is a complex, multiform and chronic inflammatory disease characterised by the association of arthritis and psoriasis combined with other related conditions and comorbidities. Treatment of PsA has rapidly evolved by the introduction of new biological drugs and small molecules which allow to achieve disease remission or low disease activity in most of the patients. However, unmet treatment needs still persist for those patients with persistent disease activity or symptoms, impaired function, reduced quality of life or comorbidities. In this context, non-pharmacological approaches, including diet modifications, an adequate sleep quality and physical activity could provide additional benefits. In recent years, diet modifications, improvement of sleep quality and physical activity became an area of interest for researchers and some studies showed how a holistic non-pharmacological approach may ameliorate the quality of life of patients with PsA.The aim of this manuscript was to review the current evidence on the intriguing link and potential effects of diet, sleep and exercise in PsA patients. In particular, we reviewed the literature focusing on the possible benefits of a holistic approach to PsA patients considering lifestyle modifications.

A Narrative Review of the Neurological Manifestations of Human Adenosine Deaminase 2 Deficiency.

Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet's disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood.

Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis.

OBJECTIVES: As more has become known of the pathophysiology of osteoarthritis (OA), evidence that inflammation plays a critical role in its development and progression has accumulated. Here, we aim to review current knowledge of the complex inflammatory network in the OA joint. DESIGN: This narrative review is presented in three main sections: local inflammation, systemic inflammation, and therapeutic implications. We focused on inflammatory mediators and their link to OA structural changes in the joint. RESULTS: OA is characterized by chronic and low-grade inflammation mediated mostly by the innate immune system, which results in cartilage degradation, bone remodeling and synovial changes. Synovitis is regarded as an OA characteristic and associated with increased severity of symptoms and joint dysfunction. However, the articular cartilage and the subchondral bone also produce several pro-inflammatory mediators thus establishing a complex interplay between the different tissues of the joint. In addition, systemic low-grade inflammation induced by aging, obesity and metabolic syndrome can contribute to OA development and progression. The main inflammatory mediators associated with OA include cytokines, chemokines, growth factors, adipokines, and neuropeptides. CONCLUSIONS: Future research is needed to deeper understand the molecular pathways mediating the inflammation in OA to provide new therapeutics that target these pathways, or to repurpose existing drugs.

Extent of axial damage in psoriatic arthritis and spondyloarthritis: comparative data from the BEPAS and (Be-)GIANT multicentre cohorts.

BACKGROUND: To examine radiographic axial damage of the sacroiliac joints and spine in patients with psoriatic arthritis (PsA) and spondyloarthritis (SpA) in private and academic Belgian practices. METHODS: Patients with PsA with clinical diagnosis of PsA and fulfilling the Classification Criteria for Psoriatic Arthritis from the prospective Belgian Epidemiological Psoriatic Arthritis Study and patients with SpA fulfilling the Assessment of SpondyloArthritis international Society classification criteria for SpA originate from the Ghent and BelGian Inflammatory Arthritis and spoNdylitis cohorTs were included in this study. Baseline pelvic and spinal radiographs were analysed by two calibrated readers. Blinded for the origin of the cohort or clinical data readers assessed the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and modified New York criteria on spinal and pelvic radiographs, respectively. Data were compared between both patient groups. RESULTS: Of the 525 patients included (312 PsA and 213 SpA), most patients showed normal spinal radiographs: 87.5% of the patients with PsA and 92.0% of the patients with SpA. Patients with SpA with spinal damage show higher mSASSS than the patients with PsA (p<0.05). In patients with PsA, cervical spine is more often affected; 24/33 patients (72.7%) compared with lumbar spine 11/33 (33.3%). While in patients with SpA, syndesmophyte location was more evenly distributed; cervical 9/14 (64.3%) and lumbar 10/14 (71.4%). CONCLUSION: Minimal radiographic spinal damage was observed in Belgian patients with PsA or SpA. Patients with SpA tend to have higher mSASSS values and more syndesmophytes compared with PsA. Syndesmophytes were more often located in the cervical spine of patients with PsA, while the location was equally distributed in axSpA.

Innovation in Targeted Intra-articular Therapies for Osteoarthritis.

Osteoarthritis is the most common chronic joint disease characterized by progressive damage to the joints, leading to pain and loss of function. There is currently no cure or disease-modifying therapy for osteoarthritis. Hence, the increasing disease prevalence linked with ageing and obesity represents a substantial socio-economic burden. Intra-articular therapy by injection of drugs into affected joints can optimize local drug bioavailability, while reducing risks of systemic toxicity, a concern in an ageing patient population. In this review, we investigate the current landscape of intra-articular drug therapies for osteoarthritis, including established approaches and those in clinical development. We performed a literature review using PubMed, complemented with a search for clinical trials using the ClinicalTrials.gov repository. Additionally, conference abstracts and presentations were identified and systematic snowballing was applied. Identified drugs were divided into several groups by main mechanism of action, and include drugs that reduce inflammation (anti-inflammatory), drugs aiming to prevent or reverse structural damage (structure modifying), drugs that aim to reduce the pain, and other drugs with a specific target. Most studies have been performed for osteoarthritis of the knee, a joint that is easily accessible for intra-articular treatments. Optimal therapy would provide symptomatic relief, while preventing further damage to the joint. The field of intra-articular drug therapies for osteoarthritis is rapidly evolving with clear challenges identified: definition of relevant outcome measures, optimization of clinical trial set-ups, and dealing with placebo responses. While many uncertainties persist, it appears that the innovation in drug development and improved clinical trial set-up may finally deliver successful therapies for this important disease.

Anterior Tibiotalar Fat Pad Involvement in Ankle Osteoarthritis: MRI Features in Patients 1 Year After a Lateral Ankle Sprain.

OBJECTIVE: To investigate the characteristics of the anterior tibiotalar fat pad (ATFP) in the ankle joint in a population of patients 1 year after an ankle sprain and its correlation with systemic factors and local articular pathology. DESIGN: The study is a secondary analysis of an observational case-control study. We included 206 patients who were followed 6-12 months after ankle sprain. T1 MRI scans were assessed for signal intensity and area of ATFP by mapping the fat pad using dedicated imaging software (Mimics 18.0). Quantitative values of intensity and area were generated. Linear regression analysis was used to examine the association between both local and systemic factors and the ATFP. Variables with a P value <0.2 were entered in 5 stepwise multivariate models: (1) age-sex-body mass index (BMI); (2) anamnesis; (3) physical examination; (4) radiographic findings; and (5) MRI findings. Predictors in these separate models were entered in the final model. RESULTS: The final multivariate model showed a significant positive association between age (P = 0.04; 95% confidence interval [CI] = 1.13 ± 1.06), BMI (P = 0.05; 95% CI = 3.61 ± 3.53), and sex (P < 0.01; 95% CI = -49.26 ± 30.04) with T1 intensity. The final model also showed a significant negative association between age (P < 0.01; 95% CI = -0.57 ± 0.34), diffuse cartilage loss in the lateral talus (P = 0.03; 95% CI = -0.71 ± 0.63), and Kellgren and Lawrence score in the tibiotalar joint (P < 0.01; 95%CI = -21.61 ± 7.24) and ATFP area. A positive association was found between BMI (P < 0.01; 95% CI = 2.25 ± 1.15) and ATFP area. CONCLUSION: This study demonstrates a correlation between ATFP and both systemic factors and local pathology in the ankle joint.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis.

OBJECTIVES: In osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis. METHODS: We determined histone demethylase expression in human non-osteoarthritis and osteoarthritis cartilage using qPCR. The role of histone demethylase families and subfamilies on H3K79me was interrogated by treatment of human C28/I2 chondrocytes with pharmacological inhibitors, followed by western blot and immunofluorescence. We performed C28/I2 micromasses to evaluate effects on glycosaminoglycans by Alcian blue staining. Changes in H3K79me after destabilisation of the medial meniscus (DMM) in mice were determined by immunohistochemistry. Daminozide, a KDM2/7 subfamily inhibitor, was intra-articularly injected in mice upon DMM. Histone demethylases targeted by daminozide were individually silenced in chondrocytes to dissect their role on H3K79me and osteoarthritis. RESULTS: We documented the expression signature of histone demethylases in human non-osteoarthritis and osteoarthritis articular cartilage. Inhibition of Jumonji-C demethylase family increased H3K79me in human chondrocytes. Blockade of KDM2/7 histone demethylases with daminozide increased H3K79me and glycosaminoglycans. In mouse articular cartilage, H3K79me decayed rapidly upon induction of joint injury. Early and sustained intra-articular treatment with daminozide enhanced H3K79me and exerted protective effects in mice upon DMM. Individual silencing of KDM7A/B demethylases in human chondrocytes demonstrated that KDM7A/B mediate protective effects of daminozide on H3K79me and osteoarthritis. CONCLUSION: Targeting KDM7A/B histone demethylases could be an attractive strategy to protect joints against osteoarthritis.

Cardiovascular comorbidities in psoriatic arthritis: epidemiology and risk factors in two different European populations.

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory disease, frequently associated with cardiovascular (CV) comorbidities. Our aim was to compare the prevalence of CV comorbidities between two groups of PsA patients from different European countries: Belgium and Italy. METHODS: This is a cross-sectional analysis of two longitudinal cohorts in which 803 PsA patients were enrolled (463 from Belgium and 340 from Italy). All enrolled patients were ≥18 years old and fulfilled the ClASsification criteria for Psoriatic Arthritis (CASPAR criteria). For each patient, demographics, clinical assessments, smoking habits, the presence of arterial hypertension (AH), obesity (BMI ≥30), type 2 diabetes (T2D), CV diseases (acute myocardial infarction, stroke or transient ischaemic attack), dyslipidaemia (Italy only) and hypercholesterolaemia (Belgium only) were collected. RESULTS: The most prevalent comorbidities among Italian patients with PsA were: AH (45.1%), dyslipidaemia (38.6%) and obesity (30.8%), and among Belgian patients were: hypercholesterolaemia (30.9%), obesity (27%) and AH (26.4%). Moreover, the prevalence of T2D and CV diseases was respectively 14.2% and 7.1% among Italian patients and 7.6% and 3.5% among Belgian patients. When comparing the two groups, AH, T2D and CV diseases were significantly more prevalent in Italian PsA patients. After controlling for different confounders, Italian patients, regardless of age, sex, smoking habits, PsA duration, other CV comorbidities, therapy, disease activity and function, had a higher risk to be hypertensive (OR 2.00, p=0.007). Instead of the country in which patients lived was not a predictor for the risk of T2D and CV diseases. Obesity prevalence was not different between the two groups. The lipid profile was unfavourable in both populations (even if not comparable between the two groups, due to the different way of collection), as is often the case in PsA. CONCLUSIONS: The prevalence of AH, T2D and CV diseases were higher in Italian patients rather than Belgians. Moreover, among patients with PsA, the risk of AH was higher in the Italian cohort compared to the Belgian cohort. These results suggest that further research is needed to evaluate potential extrinsic factors (geography and sociocultural aspects) that may contribute to CV risk.

Unconfined Compression Experimental Protocol for Cartilage Explants and Hydrogel Constructs: From Sample Preparation to Mechanical Characterization.

Mechanical characterization of articular cartilage and cell-seeded hydrogel constructs is a challenging task due to the complex biphasic behavior of these materials. Here we describe a step-by-step unconfined compression testing protocol for inverse mechanical characterization of these materials from sample preparation to parameter identification. Examples from our ongoing experiments on alginate hydrogel constructs and preserved and damaged cartilage explants obtained from human hip samples are presented.

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis.

The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in ~30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.

Levelling the playing field of RMD research across Europe to address patients' needs: the emerging EULAR Research Centre.

Herein, we describe the Research Centre launched by the European Alliance of Associations for Rheumatology (EULAR) in 2020. The Centre aims to facilitate collaborative research on rheumatic and musculoskeletal diseases (RMD) across Europe. RMDs disable millions of people in Europe and worldwide. Despite progress with improved therapeutics and strategic interventions in several RMDs, there are no cures, and their collective impact remains substantial. Access to RMD-related care, policies prioritizing RMDs, and related research, education, training, and funding differ significantly across European countries. Building a new equipoise in opportunity and capacity across Europe will facilitate optimal understanding of those different factors that influence the epidemiology, pathogenesis, treatment, and outcomes in RMDs. The EULAR Research Centre aims to address the significant barriers to accelerating RMD research across Europe. It provides an RMD research roadmap of unmet needs, expert services, infrastructures, networks, research resources, training, education, and mentoring. It will place RMD research in the ideal position to benefit from forthcoming remarkable advances in digital, biological, and social science anticipated in the coming decades.

Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism.

BACKGROUND: Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism. METHODS: We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes. RESULTS: Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model. CONCLUSIONS: Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.

Inhibiting thyroid activation in aged human explants prevents mechanical induced detrimental signalling by mitigating metabolic processes.

OBJECTIVES: To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both repeated dosing and slow release of IOP. METHODS: Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP encapsulated in poly lactic-co-glycolic acid-polyethylene glycol nanoparticles (NP-IOP). Changes to cartilage integrity and signalling were determined by Mankin scoring of histology, sulphated glycosaminoglycan (sGAG) release and expression levels of catabolic, anabolic and hypertrophic markers. Subsequently, on a subgroup of samples, RNA sequencing was performed on 65%MS (n = 14) and 65%MS+IOP (n = 7) treated cartilage to identify IOP's mode of action. RESULTS: Damage from injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, and consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, NP-IOP treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and NP-IOP reduced cartilage surface damage induced by 65%MS, while only IOP reduced sGAG release from explants subjected to 65%MS. Lastly, differential expression analysis identified 12 genes in IOP's mode of action to be mainly involved in reducing metabolic processes (INSIG1, DHCR7, FADS1 and ACAT2) and proliferation and differentiation (CTGF, BMP5 and FOXM1). CONCLUSION: Treatment with the deiodinase inhibitor IOP reduced detrimental changes of injurious mechanical stress. In addition, we identified that its mode of action was likely on metabolic processes, cell proliferation and differentiation.

Systematic review of the use of CRP in clinical trials for psoriatic arthritis: a concern for clinical practice?

BACKGROUND: C reactive protein (CRP) levels are suggested as serum biomarkers in the diagnosis and prognosis of psoriatic arthritis (PsA). However, increased CRP levels are found in less than 50% of PsA patients even in the presence of active disease. OBJECTIVES: To evaluate the role of CRP levels in interventional clinical trials in PsA patients to better understand the trial generalisability, relationship with disease activity and predictive value for treatment response and decision making. METHODS: A systematic review was conducted via PubMed, Cochrane and Embase. We focused on phase III trials in PsA. RESULTS: Eight of 22 studies applied minimum baseline CRP levels for inclusion. Baseline CRP levels were wide-ranging (0.1-238 mg/L) and lower in studies without CRP in the enrolment criteria. All 22 studies used the American College of Rheumatology (ACR20) response and other endpoints that integrated CRP levels. One of seven studies that evaluated individual ACR-score components revealed a decrease in CRP levels along with improvement of other endpoints. Subanalyses show conflicting evidence on CRP levels as predictor of disease course. CONCLUSION: CRP levels were inconsistently used as inclusion criterion in clinical trials, often limiting generalisability of the data. The use of composite scores such as ACR20 or Disease Activity Score-28-CRP is also limited since baseline levels of CRP affects their sensitivity to change. High CRP levels may be an individual predictor for disease progression and response to treatment, but the current conflicting findings and selective patient trial inclusions, do not allow CRP to play a very prominent role in treatment decision making.