Table 1.

Evidence for the role of synovitis

Level of evidence	Observation	References
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

Adapted from [5] with permission from Macmillan Publishers Ltd

ADAMTS a disintegrin and metalloproteinase with thrombospondin motifs, BMP bone morphogenetic protein, EGF endothelial growth factor, IA intraarticular, ICAM-1 intercellular adhesion molecule 1, IL interleukin, IL-1Ra interleukin 1 receptor antagonist, MMP matrix metalloproteinase, MRI magnetic resonance imaging, NGF nerve growth factor, OA osteoarthritis, PGE2 prostaglandin E2, TNF tumour necrosis factor, VCAM-1 vascular cell adhesion molecule 1, VEGF vascular endothelial growth factor