Table 2.

Common RA models and reported behaviors.

Type	Model (Trigger, Onset of Pathology)	Pros/Cons	Pathological Findings	Behavioral Assay (Pain Response Onset)	Findings	Molecular Pathogenesis Identified
Induced (onset after first immunization)	CIA (CII/adjuvant)	Most common induced model, RA-like pathogenesis. Restricted strains in mice, severe progressive disease.	-Adaptive immune system activation against endogenous joint epitopes. -Inflammation -Immune cell infiltration -Joint destruction and synovial hyperplasia	von Frey (30 d), rotarod (5 d), locomotion (25 d), tail flick (1 wk), Hargreaves (24 d)	Pain response is induced rapidly after induction. Pain response increases in early phase and persists. Most representative methods: von Frey and Hargreaves	Anti-Cat S and FKN attenuate pain in CIA. Gabapentin and buprenorphine attenuate pain in CAIA. Knockout of TLR-4 inhibits pain in K/BxN.
	CAIA (Anti-CII Ab)	Efficient and robust to study the effector phase of RA, diverse susceptible strains. Does not involve full spectrum of immune activation.	-Inflammation -Immune cell infiltration -Joint destruction	von Frey (6 d), hot plate (15 d), locomotion (5 d)
	K/BxN (Serum/Anti-GPI Ab)			von Frey (2 d), Hargreaves (3 d), locomotion (3 d)
	AIA (mBSA/adjuvant)	Local RA-like pathogenesis, localized inflammation. Damage to cartilage less severe than in RA.	-Adaptive immune system activation against exogenous epitopes -Inflammation -Immune cell infiltration -Joint destruction and synovial hyperplasia	von Frey (22 d), Hargreaves (7 d), gait (15 d), incapacitance (17 d)	Pain response is induced rapidly after induction. Pain response increases in early phase and restores in late phase. Most representative methods: von Frey and incapacitance	Anti-IL-17 alleviates pain in AIA. Increase of IL-1RI and pCREB in AIA.
Spontaneous	TNF-Tg (hTNF overexpression)	Useful for studies in effect of excess TNF in RA. Only been identified in mice, does not involve full spectrum of immune activation.	-Inflammation -Immune cell infiltration -Joint destruction and synovial hyperplasia -Pannus formation	von Frey (6 wk), tail flick (10 wk), Hargreaves (6 wk)	Pain response increases in early phase and persists. Most representative methods: von Frey and Hargreaves	Increase of the nociceptive brain activity in TNF-Tg mice.
	IL-1RA−/− (Genetic deficiency of 1L-1Ra)	Useful for studies in effect of IL-1 signaling in RA. Only been identified in mice.		No behavioral data available to date.

CIA, collagen-induced arthritis; CAIA, collagen antibody-induced arthritis; AIA, antigen-induced arthritis; TNF-Tg, tumor necrosis factor transgene; IL-1RA–/–, interleukin-1 receptor antagonist knockout; CII, collagen type II; Ab, antibody; mBSA, methylated bovine serum albumin; GPI, glucose-6-phosphateisomerase; hTNF, human tumor necrosis factor; RA, rheumatoid arthritis; d, day; wk, week(s); Cat S, cathepsin S; FKN, fractalkine; TLR-4, toll-like receptor 4; IL-1RI, interleukin-1 receptor type I; pCREB, phospho-CREB.