Evaluation of the Synovial Effects of Biological and Targeted Synthetic DMARDs in Patients with Psoriatic Arthritis: A Systematic Literature Review and Meta-Analysis

Abstract

The aims of this systematic literature review (SLR) were to identify the effects of approved biological and targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs) on synovial membrane of psoriatic arthritis (PsA) patients, and to determine the existence of histological/molecular biomarkers of response to therapy. A search was conducted on MEDLINE, Embase, Scopus, and Cochrane Library (PROSPERO:CRD42022304986) to retrieve data on longitudinal change of biomarkers in paired synovial biopsies and in vitro studies. A meta-analysis was conducted by adopting the standardized mean difference (SMD) as a measure of the effect. Twenty-two studies were included (19 longitudinal, 3 in vitro). In longitudinal studies, TNF inhibitors were the most used drugs, while, for in vitro studies, JAK inhibitors or adalimumab/secukinumab were assessed. The main technique used was immunohistochemistry (longitudinal studies). The meta-analysis showed a significant reduction in both CD3+ lymphocytes (SMD -0.85 [95% CI -1.23; -0.47]) and CD68+ macrophages (sublining, sl) (SMD -0.74 [-1.16; -0.32]) in synovial biopsies from patients treated for 4-12 weeks with bDMARDs. Reduction in CD3+ mostly correlated with clinical response. Despite heterogeneity among the biomarkers evaluated, the reduction in CD3+/CD68+sl cells during the first 3 months of treatment with TNF inhibitors represents the most consistent variation reported in the literature.

Keywords: biological DMARDs; fibroblast-like synoviocytes; psoriatic arthritis; synovial biopsy; targeted synthetic DMARDs; targeted therapies.

Figure 1

PRISMA Flowchart. Abbreviations: PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2

Forest plot of standardized mean difference of CD3+ lymphocytes in synovial tissue of PsA patients treated with bDMARDs. Negative effect means reduction in CD3+ lymphocyte level. Abbreviations: bDMARD: biological disease-modifying anti-rheumatic drug, SD: standard deviation, SMD: standardized mean difference; 95% CI: 95% confidence interval.

Figure 3

Forest plot of standardized mean difference (SMD) of CD68+ macrophages in sublining synovial tissue of PsA patients treated with bDMARDs (TNFis). Negative effect means reduction in CD68+ macrophage level. Abbreviations: bDMARD: biological disease-modifying anti-rheumatic drug, SD: standard deviation, SMD: standardized mean difference; 95% CI: 95% confidence interval.

Figure 4

Pictorial view of the main synovial effects of approved b/tsDMARDs retrieved in the literature. Abbreviations: PMN: polymorphonuclear cells, PsA: psoriatic arthritis, FLS: fibroblast-like synoviocytes, IL: interleukin; TNFα: tumor necrosis factor alfa; ICAM-1: intercellular adhesion molecule 1, VCAM-1: vascular cell adhesion protein 1, MMP: matrix metalloproteinases, MCP-1: monocyte chemoattractant protein-1, NFKB: nuclear factor kappaB, ERK: extracellular signal-regulated kinases, c-Jun N-terminal kinases, STAT: signal transducer and activator of transcription, ECAR/OCR: extracellular acidification rate/oxygen consumption rate ratio. This image was created with ©BioRender 2021.