Clinical Applications of Synovial Biopsy

The synovial tissue is a primary target of multiple diseases characterized by different pathogenic mechanisms, including infective, deposition, neoplastic, and chronic immune-inflammatory pathologies. Synovial biopsy can have a relevant role in differential diagnosis of specific conditions in clinical practice, although its exploitation remains relatively limited. In particular, no validated synovial-tissue-derived biomarkers are currently available in the clinic to aid in the diagnosis and management in most frequent forms of chronic inflammatory arthropathies, namely rheumatoid arthritis (RA) and the spondyloarthritides (SpA). In this brief review, we will discuss the current spectrum of clinical applications of synovial biopsy in routine rheumatologic care and will provide an analysis of the perspectives for its potential exploitation in patients with chronic inflammatory arthritides

Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment

The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30–6.75), 3.69 (2.67–4.62), 2.9 (2.39–4.65) and 3.71 (2.62–5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47–290 IU/ml) to 53 IU/ml (18–106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy

Self-renewal of macrophages: Tumor-released factors and signaling pathways

Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal

The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium

Background: Interleukin (IL)-36α is a recently described member of the IL-1 cytokine family with pro-inflammatory and clearly pathogenic properties in psoriasis. Objective: To determine the IL-36α expression in psoriatic arthritis (PsA) compared to rheumatoid arthritis (RA) and osteoarthritis (OA). Methods: Synovial tissues obtained from arthritis patients were stained for IL-36α, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by immunohistochemistry and immunofluorescence. Lysates were examined for IL-36α by western blot analysis. Synovial fibroblasts (FLS) cultured in the presence of IL-36α were assayed for cytokine expression by quantitative real time PCR and multiplex assay. IL-36α-induced signal transduction in FLS was analysed by immunoblotting. Results: Expression of IL-36R and its ligands IL-36α and IL-36Ra was detected in the synovial lining layer and cellular infiltrates of patients with inflammatory arthritis. IL-36α was expressed significantly higher in PsA and RA than in OA synovium. CD138-positive plasma cells were identified as the main cellular source of IL-36α. No differences were observed for the expression of IL-36R and IL-36Ra between PsA, RA and OA. Functionally, IL-36α induced the expression of IL-6 and IL-8 in FLS through p38/NFkB activation. Conclusions: IL-36α is up-regulated in PsA and RA synovium, expressed by tissue plasma cells and leads to IL-6 and IL-8 production by synovial fibroblasts. Hence, IL-36α links plasma cells to inflammatory cytokine production by FLS and may represent a key link between autoimmunity and the induction of synovitis

Rheumatology training experience across Europe : Analysis of core competences

Publisher Copyright: © 2016 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.Background: The aim of this project was to analyze and compare the educational experience in rheumatology specialty training programs across European countries, with a focus on self-reported ability. Method: An electronic survey was designed to assess the training experience in terms of self-reported ability, existence of formal education, number of patients managed and assessments performed during rheumatology training in 21 core competences including managing specific diseases, generic competences and procedures. The target population consisted of rheumatology trainees and recently certified rheumatologists across Europe. The relationship between the country of training and the self-reported ability or training methods for each competence was analyzed through linear or logistic regression, as appropriate. Results: In total 1079 questionnaires from 41 countries were gathered. Self-reported ability was high for most competences, range 7.5-9.4 (0-10 scale) for clinical competences, 5.8-9.0 for technical procedures and 7.8-8.9 for generic competences. Competences with lower self-reported ability included managing patients with vasculitis, identifying crystals and performing an ultrasound. Between 53 and 91 % of the trainees received formal education and between 7 and 61 % of the trainees reported limited practical experience (managing ≤10 patients) in each competence. Evaluation of each competence was reported by 29-60 % of the respondents. In adjusted multivariable analysis, the country of training was associated with significant differences in self-reported ability for all individual competences. Conclusion: Even though self-reported ability is generally high, there are significant differences amongst European countries, including differences in the learning structure and assessment of competences. This suggests that educational outcomes may also differ. Efforts to promote European harmonization in rheumatology training should be encouraged and supported.publishersversionPeer reviewe

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 r4ra randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

The Clinical Value of Autoantibodies in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a highly heterogeneous syndrome in terms of clinical presentation, progression, and response to therapy. In such a complicated context, the identification of disease-related biomarkers would be undoubtedly helpful in assisting tailored approaches for every patient. Despite remarkable efforts, however, progress in new biomarker development and validation is dramatically slow. At present, none of the candidate genetic, cellular, or molecular biomarker has yet surpassed the clinical value of RA-specific autoantibodies, including rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA). Rather, recent years have witnessed significant advancements in our understanding of the multiple roles that RF and ACPA play in RA pathophysiology. This has helped clarifying the mechanistic basis of the clinical associations of autoantibodies in RA. In this short review, we will briefly summarize the effector functions of RF and ACPA, and analyse how autoantibodies may help subclassifying RA patients in terms of clinical presentation and response to therapy