Table 1 Evidence for the role of synovitis

Clinical

Effusion, joint swelling or palpable synovitis

Thomas et al. [2], Sellam et al. [5], de Lange-Brokaar [39]

Sudden increase in pain

Night pain and morning stiffness

Histological

Synovial hypertrophy and hyperplasia

Goldenberg et al. [3], Prieto-Potin et al. [8], Klein-Wieringa et al. [9], Deligne et al. [10], de Lange-Brokaar et al. [11], Goldring [13]

Infiltration of mononuclear cells (monocytes/macrophages, activated B cells and T cells)

Adaptive immune T-cell and B-cell responses to fragments of extracellular matrix

Macrophages cluster and form multinucleated giant cells for improved phagocytosis

Increased angiogenesis

Synovitis close to degenerative cartilage

Molecular

Production and/or release of pro-inflammatory cytokines (TNF, IL-1β, IL-6, IL-8, IL-15, IL-17, IL-18, IL-21)

Sokolove and Lepus [12], Wojdasiewicz et al. [16], Larsson et al. [61], Pustjens et al. [18]

Increased production of PGE2 and nitric oxide

Increased expression of adhesion molecules (ICAM-1, VCAM-1) in the synovium

Increased activity of MMPs (MMP-1, MMP-3, MMP-9, MMP-13) and ADAMTS

Production of adipokines (visfatin, leptin, adiponectin)

Release of EGF and VEGF

Involvement of macrophages in osteophyte formation via BMPs

Insufficient release of anti-inflammatory cytokines (IL-4, IL-10, IL-13, IL-1Ra)

Release of pro-inflammatory and pain neurotransmitters (substance P, NGF)

Imaging

Gadolinium-enhanced synovium and increased synovial volume detected by MRI

de Lange-Brokaar et al. [21], Loeuille et al. [22], Sarmanova et al. [27], Mathiessen et al. [29], Haugen et al. [26], Kortekaas et al. [30], Yusuf et al. [35], de Lange-Brokaar et al. [39], Felson et al. [41], Damman et al. [49]

MRI correlates with histological observations and joint volume by arthrocentesis

High prevalence of synovial hypertrophy and effusion using ultrasound

Association between MRI-detected and ultrasound-detected synovitis and clinical symptoms of synovitis

MRI-detected and ultrasound-detected synovitis predicts incident radiographic OA, progression and cartilage degradation

Interventions

High dose of IA corticosteroid injection may have short-term effects on clinical symptoms and synovial tissue volume

Zhang et al. [53], O’Neill et al. [50], Keen et al. [56], Wenham et al. [58], Wenham et al. [59]

Methotrexate may have an analgesic effect

Biological response modifiers have potentially structural-modifying effects