Total elbow arthroplasty for active primary tuberculosis of the elbow: a curious case of misdiagnosis

The incidence of musculoskeletal tuberculosis (TB) is on the rise due to the current Acquired Immunodeficiency Syndrome (AIDS) pandemic. Spine is the most common osseous site, followed by other joints. TB identified in the elbow accounts for 2%–5% of skeletal TB cases, which are secondary to pulmonary TB. Primary elbow TB is rare. We report a case of primary TB of the elbow which had a negative synovial biopsy. A 46-year-old right-hand dominant female patient with chronic pain and disability of the right elbow was diagnosed with chronic non-specific arthritis based on an arthroscopic synovial biopsy. The case was diagnosed retrospectively as active TB from bone cuts post total elbow arthroplasty (TEA). Anti-tuberculosis treatment (ATT) was given postoperatively for 12 months. The patient reported good functional outcomes at 3 years of follow-up. Such atypical presentations of osteoarticular TB are challenging to diagnose. Therefore, particularly in endemic areas, clinicians should be careful before excluding such a diagnosis even after a negative biopsy. Further research should investigate whether active TB of small joints such as the elbow can be treated with ATT, and early arthroplasty should be a focus of this research.

The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How?

In the majority of joint diseases, changes in the organization of the synovial architecture appear early. Synovial tissue analysis might provide useful information for the diagnosis, especially in atypical and rare joint disorders, and might have a value in case of undifferentiated inflammatory arthritis, by improving disease classification. After patient selection, it is crucial to address the dialogue between the clinician and the pathologist for adequately handling the sample, allowing identifying histological patterns depending on the clinical suspicion. Moreover, synovial tissue analysis gives insight into disease progression helping patient stratification, by working as an actionable and mechanistic biomarker. Finally, it contributes to an understanding of joint disease pathogenesis holding promise for identifying new synovial biomarkers and developing new therapeutic strategies. All of the indications mentioned above are not so far from being investigated in everyday clinical practice in tertiary referral hospitals, thanks to the great feasibility and safety of old and more recent techniques such as ultrasound-guided needle biopsy and needle arthroscopy. Thus, even in rheumatology clinical practice, pathobiology might be a key component in the management and treatment decision-making process. This review aims to examine some essential and crucial points regarding why, when, where, and how to perform a synovial biopsy in clinical practice and research settings and what information you might expect after a proper patient selection.

BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study

Background Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. Methods The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. Discussion This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need. Trial registration The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380.

POS1315 USEFULNESS OF SYNOVIAL BIOPSY IN THE DIFFERENTIAL DIAGNOSIS AND AS POSSIBLE PREDICTOR OF RESPONSE TO TREATMENT IN JUVENILE IDIOPATHIC ARTHRITIS

Background:While synovial biopsy is an invasive procedure and is not required for the diagnosis of juvenile idiopathic arthritis (JIA), it may be useful in doubtful cases.Objectives:Aims of the study were i.to verify the role of synovial biopsy in the differential diagnosis of JIA and ii. to review the pathology slides in order to evaluate possible associations of a histologic pattern with response to treatment.Methods:We reviewed data from medical records of patients under the age of 18 years who underwent a synovial biopsy requested by our Pediatric Rheumatology Unit over the last 10 years. We collected information on demographic, clinical, laboratory, radiological, histopathological characteristics, as well as treatment response (in particular, remission at the last visit and number of examination, number of biologic drugs used). Among variables in the histologic score, number of layers in the synovial lining and inflammatory infiltrate (0-5) were compared to clinical status at last visit. Potential differences in variables between responders and non responders were assessed by unpaired t-test or non-parametric Mann-Whitney test, as appropriate.Results:We identified 64 patients (40F, 24M) with a median age at disease onset of 9 years (range 1-15) and a median follow-up time of 161 months (range 8-1160). We recognized two groups of interest: patients with a known JIA diagnosis (28/64) and patients with unknown diagnosis (36/64) at the moment of synovial biopsy. In the group with known JIA, most underwent the procedure during orthopedic surgery, and in all cases the histology was consistent with JIA. Among the unknown diagnosis group, in 19 cases results were consistent with a chronic synovitis, while among the other 17 histology could lead to a diagnosis of other conditions in 6 cases (foreign body and villonodular synovitis n=2 each, sarcoidosis and osteochondromatosis n=1 each). In the remaining 11 the final diagnoses were varied (mostly genetic forms eg skeletal dysplasia, CACP, Thiemann disease).Between the two groups we identified 46 patients with a definite JIA diagnosis. At the last follow-up visit 29 of them were in clinical remission, albeit on medication. The remaining 17 had a severe course of disease, with persistent activity and use of at least two biologic drugs. In 26 cases we could evaluate the correlation between status at last visit and number of layers/inflammatory infiltrate, but no statistical significant correlation was found.Conclusion:Despite its limited use nowadays, synovial biopsy may still be a useful tool in patients whose diagnosis is unclear. In our study, while it confirmed the suspicion in most cases, in other instances it allowed the diagnosis of rare conditions that would have been otherwise missed. No association between disease course and histological features in a small JIA cohort was found. We are currently expanding the study with a larger series.Disclosure of Interests:None declared

POS0452 SYNOVIAL MYELOID-STROMAL PATHOTYPE PREDICTS ONE-YEAR RADIOGRAPHIC PROGRESSION IN ACTIVE RHEUMATOID ARTHRITIS

Background:Rheumatoid arthritis (RA) is a heterogeneous disease with variable prognosis. The cellular composition in synovium is the driving force of joint destruction in RA, and the predictive values of histopathological assessments on the clinical outcomes of RA have been identified. However, current synovial histopathological assessments mainly focus on the infiltrated immunocytes to distinguish RA synovium into different synovial pathotypes. Whether addition of stromal cells improve the accuracy of histopathological assessments remains unknow.Objectives:To distinguish synovial pathotypes of RA based on intercellular connection and explore their predictive value on one-year radiographic progression.Methods:Active RA patients who underwent needle synovial biopsy at baseline were recruited from a real-world prospective cohort. Clinical data were evaluated at baseline and 1, 3, 6, 12 months. Histopathologic assessments included Krenn synovitis score and semiquantitative score of immunohistochemical staining for CD20, CD38, CD4, CD8, CD68, CD31 and CD90. Cluster analysis was used to distinguish synovial pathotypes. The primary outcome was one-year radiographic progression defined as a change in total Sharp/van der Heijde modified score≥0.5 units.Results:1. Among 134 RA patients who received synovial biopsy at baseline and finished one-year follow-up, 105 had qualified synovial tissue. The mean age was 50.2±13.3 years with 77.1% female. The median disease duration was 24 (9-120) months. All patients were active RA, and 64.8%, 26.7% and 8.6% patients in high, moderate and low disease activity, respectively. There were 41 (39%) patients who have never been treated with corticosteroids or disease-modifying anti-rheumatic drugs.2. During one-year follow-up, there were 48.6%, 63.8%, 71.4%, and 69.5% patients achieved CDAI LDA target, and 12.4%, 30.5%, 34.3%, and 32.4% patients achieved CDAI remission after 1, 3, 6, and 12 months, respectively. A total of 33 (31.4%) patients had radiographic progression.3. All patients were divided into three clusters using cluster analysis based on the seven synovial cellular scores. Patients in cluster 1 (n=50, 47.6%) had higher scores of sublining CD68+ macrophages, CD31+ endothelial cells and CD90+ fibroblasts, thus named as myeloid-stromal pathotype. Patients in cluster 2 (n=26, 24.8%) had higher scores of CD20+ B cells, CD38+ plasma cells, CD4+ T cells and CD8+ T cells, thus named as lymphoid pathotype. Patients in cluster 3 (n=29, 27.6%) had lower scores of all seven cell types, thus named as pauci-cellular pathotype (Figure 1).4. RA patients with baseline synovial myeloid-stromal pathotype showed higher rate of one-year radiographic progression versus lymphoid and pauci-cellular pathotypes (48% vs. 16.4%, P<0.001), whereas there was no difference between lymphoid and pauci-cellular pathotypes (11.5% vs. 20.7, P=0.475). Adjusted for confounding factors including age, sex, smoking, disease duration, RF status, ACPA status, CDAI, HAQ-DI and mTSS at baseline, multivariate logistic regression analysis showed that baseline synovial myeloid-stromal pathotype independently predicted one-year radiographic progression (AOR=3.602, 95%CI:1.257-10.324, P=0.017, Table 1).Conclusion:Baseline synovial myeloid-stromal pathotype in RA can predict one-year radiographic progression.Funding:This work was supported by National Natural Science Foundation of China (no. 81971527, 81801606 and 81801605), Guangdong Natural Science Foundation (no. 2018A030313541 and 2018A030313690), Guangdong Medical Scientific Research Foundation (no. A2018062), Guangdong Basic and Applied Basic Research Foundation (no. 2019A1515011928 and 2020A1515110061), and Science and Technology Program of Guangzhou (no. 201904010088).Acknowledgements:We thank all subjects and medical staff who generously contributed to this study.Disclosure of Interests:None declared

The significance of synovial biopsy in the diagnostic workup of the low-grade periprosthetic joint infection of shoulder arthroplasty

Introduction A common reason for painful shoulder arthroplasties and revision surgery is a low-grade periprosthetic joint infection (PJI). Diagnosing a low-grade infection is, however, a major diagnostic challenge. This applies even more to the shoulder, which differs from other large joints in terms of clinical features and microbiological spectrum. Aim of this study was to evaluate the diagnostic value of the synovial biopsy in the diagnostic workup of low-grade PJI of the shoulder. Materials and methods A retrospective evaluation was conducted on 56 patients receiving revision surgery on their shoulder arthroplasty. A standardized preoperative workup was performed comprising CRP value, leukocyte blood count, synovial fluid microbiological analyses and leukocyte count from joint aspiration, and five synovial biopsy samples for bacteriologic and histologic analysis obtained through an arthroscopic approach. During revision surgery, five samples of periprosthetic tissue were harvested for bacteriologic and histologic analyses. The MSIS-Criteria 2014 were used to evaluate the diagnostic results. Results In total, 15 of 56 revised prostheses turned out as PJI (27%). When applying our diagnostic workup, we obtained a sensitivity of 67% with a specificity of 95%. When performing a subgroup analysis on those patients that had received diagnostic biopsy, a sensitivity of 100% and a specificity of 83% could be achieved. With a sensitivity and specificity of 90% and 83%, respectively, the biopsy is the single method with the highest diagnostic value. Conclusions The sensitivity of only 67% of our standard workup emphasizes the difficulty to adequately diagnose low-grade infections after shoulder arthroplasty. The excellent specificity of 95% ensures, however, that non-infected prostheses are not incorrectly explanted. This study highlights that synovial biopsy has a high diagnostic value and should be done prior to complex revision surgeries to raise sensitivity in diagnosing a PJI.

Ultrasound-Guided Synovial Biopsy: A Review

Ultrasound-guided synovial biopsy is a safe, well-tolerated, and effective method to collect good-quality synovial tissue from all types of joints for clinical and research purposes. Although synovial biopsy cannot be used to distinguish between types of inflammatory rheumatic disease, analysis of synovial tissue has led to remarkable advances in the understanding of the pathobiology of rheumatoid arthritis and other inflammatory rheumatic diseases. Synovitis is the hallmark of these diseases; hence, accessing the core of the pathological process, synovial tissue, provides an opportunity to gather information with potential diagnostic and prognostic utility.

Synovial biopsies in clinical practice and research: current developments and perspectives

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•This review provides an overview of synovial biopsy techinques and applications especially in clinical and translational research.