Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis

Objectives. To evaluate the association between metastasis-inducing protein S100A4 and disease activity in patients with RA, and to demonstrate the effect of TNF-alpha blocking therapy on plasma levels of S100A4 in these patients. Methods. Plasma levels of the S100A4 protein were analysed in 40 anti-TNF-alpha naive patients with active RA. Of the 40 patients, 25 were treated with adalimumab and monitored over time. The conformational form of S100A4 was analysed using size-exclusion gel chromatography. TNF-alpha mRNA expression and protein synthesis were analysed by RT-PCR and ELISA, respectively. Results. Baseline levels of S100A4 were significantly correlated with disease activity in RA patients (r = 0.41; P < 0.01). After 12 weeks of treatment with adalimumab, there was an obvious shift in the conformations of S100A4 from the multimeric to the dimeric forms, whereas the total levels of the S100A4 protein remained unchanged. This suggests that the bioactive (multimer) S100A4 may decline in response to successful treatment with adalimumab. In addition, we showed significant up-regulation of TNF-alpha mRNA (P < 0.01), and protein release to the cell culture medium of monocytes stimulated with the S100A4 multimer compared with those treated with the dimer and to the unstimulated monocytes (P < 0.001). Conclusions. This is the first study to show that the levels of the S100A4 protein are correlated with RA disease activity. Furthermore, only the bioactive form, but not the total amount of S100A4, decreases after successful TNF-alpha blocking therapy in patients with RA. These data support an important role for the S100A4 multimer in the pathogenesis of R

Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey

Objectives: Patients with difficult-to-treat rheumatoid arthritis (RA) remain symptomatic despite treatment according to current European League Against Rheumatism (EULAR) management recommendations. These focus on early phases of the disease and pharmacological management. We aimed to identify characteristics of difficult-to-treat RA and issues to be addressed in its workup and management that are not covered by current management recommendations. Methods: An international survey was conducted among rheumatologists with multiple-choice questions on disease characteristics of difficult-to-treat RA. Using open questions, additional items to be addressed and items missing in current management recommendations were identified. Results: 410 respondents completed the survey: 50% selected disease activity score assessing 28 joints &gt;3.2 OR presence of signs suggestive of active disease as characteristics of difficult-to-treat RA; 42% selected fatigue; 48% selected failure to ≥2 conventional synthetic disease-modifying antirheumatic drugs (DMARDs) AND ≥2 biological/targeted synthetic DMARDs; 89% selected inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily. Interfering comorbidities, extra-articular manifestations and polypharmacy were identified as important issues missing in current management recommendations. Conclusions: There is wide variation in concepts of difficult-to-treat RA. Several important issues regarding these patients are not addressed by current EULAR recommendations

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

EULAR definition of difficult-to-treat rheumatoid arthritis

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have ‘difficult-to-treat RA’. However, uniform terminology and an appropriate definition are lacking. Objective: The Task Force in charge of the „Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis” aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to treat RA, as the first step. Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: 1) Treatment according to EULAR rec-ommendation and failure of ≥2 b/tsDMARDs (with different mechanisms of action) after failing csDMARD therapy (unless contraindicated); 2) presence of at least one of the follow-ing: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; 3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research

Molecular mechanisms of vaspin action: from adipose tissue to skin and bone, from blood vessels to the brain

Visceral adipose tissue derived serine protease inhibitor (vaspin) or SERPINA12 according to the serpin nomenclature was identified together with other genes and gene products that  were specifically expressed or overexpressed in the intra abdominal or visceral adipose tissue  (AT) of the Otsuka Long-Evans Tokushima fatty rat. These rats spontaneously develop visceral  obesity, insulin resistance, hyperinsulinemia and ‐glycemia, as well as hypertension and thus represent a well suited animal model of obesity and related metabolic disorders such as type  2 diabetes.  The follow-up study reporting the cloning, expression and functional characterization of  vaspin suggested the great and promising potential of this molecule to counteract obesity induced insulin resistance and inflammation and has since initiated over 300 publications, clinical and experimental, that have contributed to uncover the multifaceted functions and molecular mechanisms of vaspin action not only in the adipose, but in many different cells, tissues and organs. This review will give an update on mechanistic and structural aspects of vaspin with a focus on its serpin function, the physiology and regulation of vaspin expression, and will summarize the latest on vaspin function in various tissues such as the different adipose tissue depots as well as the vasculature, skin, bone and the brain