Synovial biopsy techniques have developed and widely expanded over the past few years, in particular due to the development of ultrasound-guided procedures. This article reviews the different ...techniques, clinical applications, and the latest advances in translational research as well as current challenges and perspectives. The first part focuses on different techniques available for biopsy, along with their feasibility, success rate, tolerance, and training requirements. In the second part, clinical applications are described. Data on diagnostic performances are reported, especially regarding septic arthritis. Translational research applications are described and explained in the final part, from the early histological studies and the first description of pathotype to more recent technologies involving -omics. Latest developments involving single-cell RNA sequence analysis have allowed the discovery of new cell subpopulations with remarkable roles in RA pathophysiology. These studies pave the ground for the discovery of new therapeutic targets and the implementation of personalized therapy in RA.
Key Point
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This review provides an overview of synovial biopsy techinques and applications especially in clinical and translational research.
Perform a systematic literature review (SLR) on risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in patients with rheumatic and musculoskeletal diseases (RMDs).
...Literature was searched up to 31 May 2021, including (randomised) controlled trials and observational studies with patients with RMD. Pending quality assessment, data extraction was performed and risk of bias (RoB) was assessed. Quality assessment required provision of (1) an appropriate COVID-19 case definition, and (2a) a base incidence (for incidence data) or (2b) a comparator, >10 cases with the outcome and risk estimates minimally adjusted for age, sex and comorbidities (for risk factor data).
Of 5165 records, 208 were included, of which 90 passed quality assessment and data were extracted for incidence (n=42), risk factor (n=42) or vaccination (n=14). Most studies had unclear/high RoB. Generally, patients with RMDs do not face more risk of contracting SARS-CoV-2 (n=26 studies) or worse prognosis of COVID-19 (n=14) than individuals without RMDs. No consistent differences in risk of developing (severe) COVID-19 were found between different RMDs (n=19). Disease activity is associated with worse COVID-19 prognosis (n=2), possibly explaining the increased risk seen for glucocorticoid use (n=13). Rituximab is associated with worse COVID-19 prognosis (n=7) and possibly Janus kinase inhibitors (n=3). Vaccination is generally immunogenic, though antibody responses are lower than in controls. Vaccine immunogenicity is negatively associated with older age, rituximab and mycophenolate.
This SLR informed the July 2021 update of the European Alliance of Associations for Rheumatology recommendations for the management of RMDs in the context of SARS-CoV-2.
Abstract
IL-23 is a cytokine member of the IL-12 superfamily. These heterodimeric cytokines offer broad immune regulatory activity with potential effector function in inflammatory arthritis. IL-23 is ...a pro-inflammatory cytokine secreted by dendritic cells and macrophages. It plays a key role in both innate and adaptive immunity. By promoting and maintaining T cell differentiation into Th17 T cells, IL-23 is a key player in the pathogenesis of rheumatic diseases. Data from pre-clinical IL-23 knockout models show the major importance of IL-23 in development of arthritis. The induction and maintenance of type 17 cells, which secrete IL-17A and other pro-inflammatory cytokines, contributes to local synovial inflammation and skin inflammation in PsA, and perhaps in RA. Commensurate with this, therapeutic strategies targeting IL-23 have proven efficient in PsA in several studies, albeit not yet in RA.
BMC Musculoskeletal Disorders launched a Collection on digital health to get a sense of where the wind is blowing, and what impact these technologies are and will have on musculoskeletal medicine. ...This editorial summarizes findings and focuses on some key topics, which are valuable as digital health establishes itself in patient care. Elements discussed are digital tools for the diagnosis, prognosis and evaluation of rheumatic and musculoskeletal diseases, coupled together with advances in methodologies to analyse health records and imaging. Moreover, the acceptability and validity of these digital advances is discussed. In sum, this editorial and the papers presented in this article collection on Digital health in musculoskeletal care will give the interested reader both a glance towards which future we are heading, and which new challenges these advances bring.
Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have ...exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.
Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.
Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.
This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.
As part of a European League Against Rheumatism (EULAR) taskforce, a systematic ...literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.
Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.
Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.
The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying ...Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = <0.001, r = 0.68, p = <0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response.
To improve the reliability of the quantitative scorings of the synovial biopsies, we evaluate whether diameter of arthroscopic forceps influences histological quality of synovial tissue and/or ...histological scores and we compare the intra- and inter-observer performances of the main histological scoring systems. Synovial biopsies were retrieved in the same part of the joint using 1, 2 and 4 mm diameters grasping forceps. After standard staining and immunohistochemistry with anti-CD68 antibody, slides were scored blindly by 2 independent experienced operators for tissue quality and with Krenn score, de Bois-Tak score and CD68 semi-quantitative score. Four samples did not pass quality control. No difference other than a higher number of vessels in the 4 mm versus 2 mm forceps (p = 0.01) was found among the 3 groups. CD68 score was significantly higher in the 2 versus 4 mm forceps (p = 0.009). So we concluded that only vessels quantification and CD68 semi-quantitative score seemed affected by the forceps size. The intra-reader agreement was variable across observers and features: 0.78 (0.66-0.87) for the Krenn scoring system, 0.89 (0.78-0.97) for the de Bois-Tak score and 0.93 (0.81-1.00) for the CD68 score. Interobserver reliabilities of Krenn score, de Bois-Tak score and CD68 scores were satisfactory: 0.95 (0.92-0.99) for Krenn, 0.98 (0.96-0.99) for de Bois-Tak and 0.80 (0.71-0.89) for CD68.
Objective
We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA‐17‐5p (miR‐17).
Methods
...A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA‐17 lipoplex was delivered intraarticularly in the murine collagen‐induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In‐depth studies of the mechanisms of action of miR‐17 were performed in primary RA fibroblast‐like synoviocytes (FLS) isolated from synovial tissue.
Results
Fifty‐five miRNAs including miR‐17 were reduced in erosive RA. The miR‐17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate‐resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin‐6 (IL‐6) family and IL‐1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA‐17 directly targeted the 3′‐untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR‐17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035).
Conclusion
We demonstrate an antiinflammatory and antierosive role of miR‐17 in vivo. This effect involves the suppression of the IL‐6 family autocrine‐amplifying loop through the direct targeting of JAK1 and STAT3.
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