Inclusion of Synovial Tissue–Derived Characteristics in a Nomogram for the Prediction of Treatment Response in Treatment‐Naive Rheumatoid Arthritis Patients

Abstract

Objective This study applied a synovitis score obtained during routine care from ultrasound (US)–guided biopsies of synovial tissue (ST) in patients with rheumatoid arthritis (RA) and patients with other inflammatory and noninflammatory joint diseases to identify pretreatment synovial biomarkers associated with disease characteristics, and to integrate the findings into a multiparameter nomogram for use in baseline prediction of diagnosis and treatment response in treatment‐naive rheumatoid arthritis (RA) patients. Methods The study enrolled a total of 1,015 patients with various autoimmune diseases (545 patients with RA, 167 patients with psoriatic arthritis [PsA], 199 patients with undifferentiated peripheral inflammatory arthritis [UPIA], 18 patients with crystal‐induced arthritis, 26 patients with connective tissue diseases, and 60 patients with osteoarthritis [OA] [as part of the SYNGem cohort]). All patients underwent a US‐guided ST biopsy at baseline, and patients were then stratified according to disease phase. The KSS, along with disease characteristics and clinical outcomes, were incorporated into a nomogram for prediction of achievement of clinical remission in RA patients who were previously naive to treatment. In patients in whom a treat‐to‐target strategy was applied, remission was defined as change in the Disease Activity Score in 28 joints (DAS28) at 6 months after treatment initiation. Results The KSS significantly differed among RA patients, as well as PsA patients and UPIA patients, when compared to OA patients. In RA, the KSS directly correlated with the DAS28 and was related to autoantibody positivity in treatment‐naive RA patients. Moreover, at baseline, treatment‐naive RA patients achieving 6‐month remission according to DAS28 had a lower KSS, shorter duration of symptoms (very early RA [VERA]), and lower disease activity than treatment‐naive RA patients not achieving remission according to DAS28. Results of logistic regression analysis identified the following synergistic predictive factors of achievement of DAS28‐based disease remission at 6 months: having a short disease duration (VERA), not having high disease activity, and having a KSS of <5 at baseline. A nomogram integrating these baseline clinical and histologic characteristics in treatment‐naive RA patients yielded an up to 81.7% probability of achieving 6‐month remission according to the DAS28. Conclusion The KSS is a reliable tool for synovitis assessment on US‐guided ST biopsy, contingent on the phase of the disease and the autoimmune profile of each patient. This tool could be integrated within a therapeutic response–predictive nomogram for the prediction of treatment response in RA patients who were previously naive to treatment.

Impact of synovial biopsy procedures and disease-specific aspects on synovial tissue outcome: a systematic literature review informing the EULAR points to consider for the minimal reporting requirements in synovial tissue research in rheumatology

“… 31 Two other studies interrogated ST infiltrate in early naïve versus resistant established RA versus RA in remission. 32 33 In one study, the authors report that the Krenn Synovitis Score (KSS) was higher in patients with early active than established RA and both were higher compared with patients in remission. 32 In addition, established RA resistant to TNFi had higher KSS and higher prevalence of B cell–rich synovitis than early untreated RA.…”

“… 32 33 In one study, the authors report that the Krenn Synovitis Score (KSS) was higher in patients with early active than established RA and both were higher compared with patients in remission. 32 In addition, established RA resistant to TNFi had higher KSS and higher prevalence of B cell–rich synovitis than early untreated RA. 33 It is important to note that the definition of ‘early’ and ‘established’ RA was variable across studies and this might explain the contradictory results observed.…”

“…23 25 As far as cytokine expression (IL-1β, IL-6, TNF-α and MMP-1) by PCR in large joints is concerned, four to seven tissue fragments were deemed necessary in order to detect a twofold change with a 25% sampling error. 24 Impact of the disease stage on the tissue outcomes Fourteen studies assessed the impact of disease stage on histopathological findings in RA, [26][27][28][29][30][31][32][33] osteoarthritis (OA) 34 or transcriptomics aspects in RA, [35][36][37][38] including eight studies with high RoB and seven with unclear RoB. 2 27 31-34 37 Of interest, while contradictory results for lining layer thickness and CD68 +cell infiltrate (lining layer and sublining) in early versus established RA were reported, other cell infiltrates (CD3, CD4, CD8, CD20 or CD22, CD38 and mast cells) and vascularity in sublining appeared to be the same between early and established RA.…”

EULAR points to consider for minimal reporting requirements in synovial tissue research in rheumatology

“…While conducting this work, we realised that the paucity of literature on clinical applications of tissue analysis did not allow the formulation of PtC dedicated to the clinical aspects. Indeed, although recent publications propose encouraging data for the use of SB for diagnosis, outcome prediction or disease management in clinical practice, the task force felt that these aspects should be included in the research agenda 2 4 42–44. One major limitation encountered in the development of these PtC was the scarcity of literature appraising the practical aspects of tissue retrieval, handling and analysis.…”

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis

“…(26) Single Cell-RNA Sequencing of Synovial Tissue Methods for single-cell RNA sequencing (scRNAseq) of synovial tissue have already been described in detail (27). Briefly, synovial tissue biopsies were collected from naive to treatment RA patients (n=4) and from RA patients in sustained clinical and ultrasound remission (n=4) at the SYNGem Biopsy Unit of the Fondazione Policlinico Universitario A. Gemelli IRCCS using US-guided minimally invasive technique (28). High-quality total RNAs (RIN >8) were used to construct Illumina mRNA sequencing libraries.…”