Design, outcomes and population of studies included in the manuscript
| RQ | Author and year | Objective | Patients | Procedures | Outcomes |
| RQ 1 | Humby et al 201815 | Comparing across techniques:
| 125 patients:
Follow-up (n=34) | Synovial biopsies (n=159)
| Graded ST fragments/total ST fragments Total mean graded ST area Mean ST area per graded biopsy fragment Total mean graded ST surface Mean synovitis scores Mean semiquantitative scores of synovial infiltration in sublining (SL) of CD20 +B cells; CD3 +T cells; CD68 +macrophages Frequency of synovial pathotype RNA quantity and RIN in small and large joints |
| Just et al 201816 | Comparing across techniques:
| 421 patients
Follow-up (n=103) | Synovial biopsies (n=524)
| VAS: joint pain/joint swelling/stiffness Delta VAS: joint pain/joint swelling/stiffness ‘How does joint feel compared with before biopsy’ Willingness to repeat: 1–5 Likert scale Adverse events | |
| RQ2 | Kraan et al 200217 | Comparing in paired biopsies from small and large joints:
| 9 RA patients | Arthroscopic SB (n=18)
| Cell numbers per mm2 in lining layer (LL) and SL:
IL-6 expression (integrated optical density) |
| Musters et al 201818 | Comparing in paired biopsies from right and left joints:
| 9 RA patients | Arthroscopic SB (n=18)
| Number of TCRβ clones Number of highly expanded clones (HEC) Impact of the HECs on the total repertoire Overlap between the 25 most expanded TCRβ clones (%) Chao-modified Sørensen index | |
| Triaille et al 202019 | Comparing in paired biopsies from small and large joints:
| 10 RA patients | Synovial biopsies (n=20)
| Synovitis scores Mean semiquantitative scores of synovial infiltration of CD20 +B cells, CD3 +T cells and CD68 +macrophages Number of transcripts overexpressed Pathway expression patterns Enriched T-cell clonotypes (ETC) and % of shared ETC | |
| RQ3 | Donlin et al 201820 | Comparing tissue handling methods:
| RA patients | Synovial biopsies (n=19)
| Total cell counts per gram from ST mechanically disaggregated Flow cytometry:
|
| Smeets et al 200321 | Comparing intra-articular variability of:
| 17 RA patients | Arthroscopic biopsies (n=17) Paired SB of 2 different sites of the knee (CPJ and SP recess) | Quantitative analysis of CD3, CD4, CD8, CD22, CD38, CD68, MMP-1 and granzyme B7 by computer-assisted image analysis. Semiquantitative analysis of CD3, CD4, CD8, CD22, CD38, CD68, CD55, mast cells, MMP-1, MMP-3 and MMP-13 | |
| Kirkham et al 199922 | Comparing intra-articular variability of:
| 11 RA patients | Arthroscopic biopsies (n=11) Knee; 4 anatomically different sites: CPJ and SP, lateral and medial recesses | Semiquantitative analysis of CD3, CD8, CD45RO, Mac 387 Cytokine mRNA expression: IL-1β, TNF, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFNγ Weighted kappa coefficient | |
| Musters et al 201818 | Comparing intra-articular variability of T-cell repertoire | 13 RA patients | Arthroscopie biopsies (n=7) Knee; 2 anatomically different sites: SP and IP recesses | Number of TCRβ clones Number of HEC Impact of the HECs on the total repertoire Overlap between the 25 most expanded TCRβ clones (%) Chao-modified Sørensen index | |
| Kennedy et al 198823 | Minimal number of tissue fragments required to limit sampling error in large joints | 11 RA patients | Surgical biopsies (n=11) | H&E, absolute value of cell density par high power field. Number of tissue fragments to analyse to reduce sampling error | |
| Boyle et al 200324 | Minimal number of tissue fragments required to limit sampling error in large joints | 5 RA patients | Surgical biopsies (n=5) Hip or knee | PBMC equivalent (cellular equivalents of expression (CE)) number for synovial samples Relative expression (RE) of mRNA IL-1β, IL-6, TNF-α, MMP-1 CE and GAPDH CE Number of biopsies required to limit sample error to <25% for each IL-1β, IL-6, TNF-α, MMP-1 | |
| Humby et al 201511 | Minimal number of tissue fragments required to limit sampling error in small joints | RA patients
| Synovial biopsies (n=41)
| Semiquantitative analysis of CD20+, CD3 + and CD68+ cells in LL and SL % mean difference for different samples | |
| Scire et al 200725 | Minimal number of biopsies required to limit sampling error in small joints | RA patients
| Synovial biopsies (n=18)
| Quantitative analysis of CD20+, CD3 + and CD68+ cells in LL and SL % mean difference for different samples or cutting levels | |
| RQ5 | Baeten et al 200026 | Comparing in early vs established RA:
| 30 RA patients
| Arthroscopic biopsies (n=30) | H&E maximal LL thickness, mean LL thickness, vascularity, cell infiltrate Semiquantitative Integrines alphaVBeta3 and 5 |
| Tak et al 199727 | Comparing in early vs established RA:
| 67 RA patients
| Blind NB (n=67) | H&E LL thickness, vascularity, cell infiltrate immunohistochemistry (IHC):
| |
| Katrib et al 200140 | Comparing in early vs established RA:
| 44 RA patients
| Blind NB (n=44) | Quantitative CD68 +cells IHC: quantitative analysis of MCP-1, MIP-1alpha, MMP-1, MMP-3, TIMP-1, TIMP-2 by IHC | |
| Ospelt et al 200829REF34 | Comparing in early vs established RA:
| 21 RA patients
| Synovial biopsies n=44
| IGC: semiquantitative expression of TLR2, 3 and 4 | |
| Dubikov and Kalinichenko 201030 | Comparing in early vs established RA:
| 78 RA patients
| Arthroscopic and surgical biopsies (n=78) | Apoptosis (LL and SL) Quantitative DNA fragmentation staining positive cells p53 +cells and Bcl2 +cells | |
| Tak et al 199928 | Comparing in early vs established RA:
| 27 RA patients
| Blind NB (n=27) | Semiquantitative evaluation of % of p53 +cells Western blot p53 | |
| Alivernini et al 201731 | Comparing in early vs remission and LDA in RA:
| 85 RA patients
| US-NB (n=85) | Semiquantitative CD68+, CD3+, CD20 + and CD21+ cell infiltrate | |
| Rivellese et al 202033 | Comparing in early naïve RA and established TNF inhibitors resistant RA:
| 329 RA patients
| Synovial biopsies (n=329)
| Semiquantitative scoring method (scale of 0–4) and digital image analysis (CD20 +area fraction) histologic B-cell scores | |
| Alivernini et al 202132 | Comparing in early vs remission and low disease activity vs established RA:
| 545 RA patients
| US-NB (n=545) | Krenn Synovitis Score (lining layer thickness, stromal activation and cell infiltrate) | |
| Ostojic et al 201734 | Comparing in early vs advanced stage osteoarthritis (OA):
| 20 OA patients
| Synovial biopsies (n=20)
| Krenn Synovitis Score (lining layer thickness, stromal activation and cell infiltrate) Quantitative iNOS and NF-kB +cells per mm2 | |
| Guo et al 201836 | Examine PD-1 pathway at various stages of RA development | 152 RA patients
| Synovial biopsies (n=152)
| PDCD1, CD274 and PDCD1LG2 expression PD-1-PD-L1 pathway activity | |
| Guo et al 201736 | Examine CD-40-CD40-L pathway in various stages of RA progression | 152 RA patients Early RA <1 year (n=57) Established RA >1 year (n=95) | Synovial biopsies (n=152) Early RA: US-NB (n=57) Established RA: arthroscopic biopsies (n=95) | CD40LG and CD40 expression CD40–CD40L pathway activity | |
| Lequerré et al 200938 | Comparing in early vs established RA:
| 8 RA patients
| Arthroscopic biopsies (n=15) | Inflammatory pathways gene clusters and molecular signatures | |
| Alivernini et al 202037 | Compare in early vs established RA vs remission:
| 112 RA patients
| US-NB (n=112) | ST macrophage clusters tracked in ST using single-cell RNAseq across disease activity and stage |
Bcl2, B-cell lymphoma 2; CD, cluster of differentiation; CPJ, cartilage-pannus junction; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GM-CSF, granulocyte-macrophage colony stimulating factor; IHC, immunohistochemistry; IL, interleukine; iNOS, inducible nitric oxide synthase; IP, infra-patellar responses; JIA, juvenile idiopathic arthritis; LL, lining layer; MCP, metacarpophalangeal joint; MMP, matrix metallo-proteinases; NB, needle biopsy; OA, osteoarthritis; PBMC, peripheral blood mononuclear cell; P&F, portal and forceps; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RIN, RNA integrity number; RQ, research question; SB, synovial biopsy; SL, sublining; SP, supra-patellar recess; SpA, spondyloarthritis; ST, synovial tissue; TCR, T-cell repertoire; TNF, tumour necrosis factor; UA, undifferenciated arthritis; US, ultrasound; VAS, visual analogic scale.