. 2023 May 24;9(2):e002945. doi: 10.1136/rmdopen-2022-002945

Table 4.

Associations between inflammatory signs and measures of altered pain perception mechanisms

Study	Associations	Results	Confounders	Level of evidence
Effusion/synovitis and pain sensitivity
Petersen et al⁴⁹	A significant BLOKS group effect in the ANOVA of the PPTs	Site 1 (ANOVA: F₂=3.14, p<0.03) Site 2 (ANOVA: F₂=6.59, p<0.001) Site 3 (ANOVA: F₂=4.04, p<0.01) Site 4 (ANOVA: F₂=3.43, p<0.02) Site 5 (ANOVA: F₂=2.40, p<0.07) Site 6 (ANOVA: F₂=4.49, p<0.006) Site 7 (ANOVA: F₂=1.24, p<0.3)	BMI, sex and age	B
Neogi et al⁵⁰	Hoffa-synovitis (baseline)—PPT patella (baseline)	β=−0.42 (95% CI: −0.67 to −0.18)	Age, sex, BMI, race, study site, KL, presence of patellofemoral OA, depressive symptoms, catastrophising, widespread pain, use of analgesics	A2
	Hoffa-synovitis (baseline)—PPT patella change (follow-up 24 months)	β=−0.30 (95% CI: −0.52 to −0.08)
	Hoffa-synovitis (baseline)—PPT wrist (baseline)	β=−0.19 (95% CI: −0.35 to −0.03)
	Hoffa-synovitis (baseline)—PPT wrist change (follow-up 24 months)	β=−0.10 (95% CI: −0.26 to 0.06)
	Effusion (baseline)—PPT patella (baseline)	β=0.23 (95% CI: −0.03 to 0.49)
	Effusion (baseline)—change PPT patella (follow-up 24 months)	β=−0.04 (95% CI: −0.28 to 0.19)
	Effusion (baseline)—PPT wrist (baseline)	β=−0.24 (95% CI: −0.40 to −0.07)
	Effusion (baseline)—PPT wrist change (follow-up 24 months)	β=−0.24 (95% CI: −0.41 to −0.08)
	Hoffa-synovitis (baseline)—TS patella (baseline) (n=1111)	OR=0.83 (95% CI: 0.63 to 1.08)
	Hoffa-synovitis (baseline)—TS patella incident (n=716)	OR=1.12 (95% CI: 0.75 to 1.66)
	Hoffa-synovitis (baseline)—TS wrist (baseline) (n=1111)	OR=0.84 (95% CI: 0.75 to 1.66)
	Hoffa-synovitis (baseline)—TS wrist incident (n=716)	OR=1.22 (95% CI: 0.85 to 1.75)
	Effusion (baseline)—TS patella (baseline) (n=1111)	OR=0.89 (95% CI: 0.67 to 1.18)
	Effusion (baseline)—TS patella incident (n=716)	OR=1.54 (95% CI: 1.01 to 2.36)
	Effusion (baseline)—TS wrist (baseline) (n=1111)	OR=1.13 (95% CI: 0.85 to 1.51)
	Effusion (baseline)—TS wrist incident (n=716)	OR=0.94 (95% CI: 0.66 to 1.35)
Sofat et al⁴⁷	Synovitis—PPT	r=−0.02, N.S.	N.A.	C
BMLs and pain sensitivity
Neogi et al⁵⁰	BMLs—PPT patella (baseline)	β=0.14 (95% CI: −0.16 to 0.08)	Age, sex, BMI, race, study site, KL, presence of patellofemoral OA, depressive symptoms, catastrophising, widespread pain, use of analgesics	A2
	BMLs—change PPT patella (follow-up 24 months)	β=0.03 (95% CI: −0.25 to 0.31)
	BMLs—PPT wrist (baseline)	β=0.05 (95% CI: −0.14 to 0.25)
	BMLs—PPT wrist change (follow-up 24 months)	β=−0.10 (95% CI: 0.29 to 0.10)
	BMLs sum—PPT patella (baseline)	β=0.03 (95% CI: −0.01 to 0.08)
	BMLs sum—change PPT patella (follow-up 24 months)	β=−0.01 (95% CI: −0.05 to 0.04)
	BMLs sum—PPT wrist (baseline)	β=0.00 (95% CI: −0.03 to 0.03)
	BMLs sum—PPT wrist change (follow-up 24 months)	β=0.00 (95% CI: −0.03 to 0.03)
	BMLs—TS patella (baseline) (n=1111)	OR=0.95 (95% CI: 0.68 to 1.32)
	BMLs—TS patella incident (n=716)	OR=0.92 (95% CI: 0.56 to 1.49)
	BMLs—TS wrist (baseline) (n=1111)	OR=1.04 (95% CI: 0.74 to 1.45)
	BMLs—TS wrist incident (n=716)	OR=1.05 (95% CI: 0.68 to 1.62)
	BMLs sum—TS patella (baseline) (n=1111)	OR=0.98 (95% CI: 0.93 to 1.03)
	BMLs sum—TS patella incident (n=716)	OR=1.00 (95% CI: 0.92 to 1.07)
	BMLs sum—TS wrist (baseline) (n=1111)	OR=0.98 (95% CI: 0.93 to 1.04)
	BMLs sum—TS wrist incident (n=716)	OR=1.00 (95% CI: 0.94 to 1.07)
Sofat et al⁴⁷	BML_load—PPT	r=−0.069, N.S.	N.A.	C
Sofat et al⁴⁷	nBML—PPT	r=−0.114, N.S.	N.A.	C
Inflammatory cytokines and pain sensitivity
Imamura et al⁴³	IL-6—PPT	N.S.	/	C
	IL-10—PPT	N.S.
	TNF-α—PPT	Significantly associated with the majority of PPT measures of the muscular, ligamentous or subcutaneous sources (p<0.05)
Lee et al⁴⁴	Log IL-6—PPT quadriceps	F=0.98, p=N .S.	BMI	C
	Log IL-6—(PPT quadriceps)²	N.S.
	Log IL-6—PPT thumb	F=0.02, N.S.
	Log IL-6—(PPT thumb)²	N.S.
	Log IL-6—PPT trapezius	F=0.97, N.S.
	Log IL-6—(PPT trapezius)²	N.S.
	Log IL-6—HPT	F=0.27, N.S.
	Log IL-6—HPR at 49°C	F=4.51, p=0.04
	Log IL-6—(HPR at 49°C)²	F=4.27, p=0.05
	Log IL-6—HPR at 51°C	F=5.79, p=0.02
	Log IL-6—(HPR at 51°C)²	F=5.26, p=0.03
	Log IL-6—CPR	F=0.03, p=N .S.
	Log IL-6—CPR²	N.S.
	Log IL-6—CPT	F=5.96, p=0.02
	Log IL-6—CPT²	F=6.57, p=0.02
	IL-1β—pain measures	N.S., data N.R.
	TNF-α—pain measures	N.S., data N.R.
C reactive protein and pain sensitivity
Arendt-Nielsen et al⁴²	hsCRP—local/spreading sensitisation/TS	Association sign, data N.R.	Unadjusted	B
Lee et al⁴⁴	Log CRP—PPT quadriceps	F=8.13, p=0.009	Unadjusted	C
	Log CRP—(PPT quadriceps)²	F=6.58, p=0.02
	Log CRP—PPT thumb	F=7.44, p=0.01
	Log CRP—(PPT thumb)²	N.S.
	Log CRP—PPT trapezius	F=9.99, p=0.004
	Log CRP—(PPT trapezius)²	F=9.36, p=0.006
	Log CRP—HPT	F=0.55, p=N .S.
	Log CRP—HPR at 49°C	F=1.17, N.S.
	Log CRP—(HPR at 49°C)²	N.S.
	Log CRP—HPR at 51°C	F=1.96, N.S.
	Log CRP—(HPR at 51°C)²	N.S.
	Log CRP—CPR	F=5.20, p=0.03
	Log CRP—CPR²	F=5.11, p=0.03
	Log CRP—CPT	F=0.74, N.S.
	Log CRP—CPT²	N.S.
Effusion/synovitis and neuropathic-like pain
Radojčić et al⁴⁶	11-point synovitis—NPQ	r=0.25, p=0.011	BMI, sex and age	C
Inflammatory cytokines and neuropathic-like pain
Li et al⁴⁵	IL-1β—painDETECT	r=−0.019, N.S.	N.A.	C
	IL-6—painDETECT	r=−0.034, N.S.
	TNF-α—painDETECT	r=−0.115, N.S.
Radojčić et al⁴⁶	Plasma IL-6—NPQ	β=4.029 (95% CI: −0.032 to 0.838)	BMI, sex and age	C
Radojčić et al⁴⁶	Synovial fluid IL-6—NPQ	β=0.043 (95% CI: 0.005 to 0.082)	BMI, sex and age	C
Tchetina et al⁴⁸	TNF-α—DN4	r=0.330, p=0.02	N.A.	C
	IL-1β—DN4	r=0.496, p<0.01
	IL-1β—painDETECT	r=0.313, p=0.04

ANOVA, analysis of variance; BLOKS, Boston-Leeds Osteoarthritis Knee Score; BMI, body mass index; BMLs, bone marrow lesions; CPR, cold pain rating; CPT, cold pain tolerance; DN4, Douleur Neuropathique-4 Questions; HPR, heat pain rating; HPT, heat pain threshold; (hs)CRP, (high-sensitivity) C reactive protein; IL, interleukin; KL, Kellgren-Lawrence score; N.A., not applicable; NPQ, Neuropathic Pain Questionnaire; N.S., not significant; OA, osteoarthritis; PPT, pressure pain threshold; TNF-α, tumour necrosis factor-α; TS, temporal summation.