Characteristics of included studies (n=9)
| Study 1st author, year, country, design | Participants’ characteristics | Marker(s) of inflammation | Experimental pain assessment | Statistical analysis | Quality |
| Arendt-Nielsen,42 2014, Denmark, CS | Patients grouped according to experimental pain CPM, knee Most sensitised: n=42 (52% female); mean age 64.57±7.63 years; BMI=28.98±5.64 kg/m2; KL=1.95±0.94 Medium sensitised: n=193 (30% female); mean age 67.71±3.66 years; BMI=27.46±3.93 kg/m2; KL=1.54±0.69 Least sensitised: n=46 (30% female); mean age 63.40±7.32 years; BMI=27.68±4.03 kg/m2; KL=1.82±0.85 TS, knee Most sensitised: n=46 (49% female); mean age 65.37±5.87 years; BMI=26.82±3.75 kg/m2; KL=1.77±0.72 Medium sensitised: n=187 (55% female); mean age 65.80±7.28 years; BMI=28.20±4.64 kg/m2; KL=1.74±0.83 Least sensitised: n=48 (37% female); mean age 63.37±7.95 years; BMI=30.14±4.78 kg/m2; KL=2.04±0.77 OA definition: ACR Symptoms duration: N.R. OA duration: N.R. | Blood samples Serological markers: hsCRP | PPT (8 knee locations, muscle tibialis anterior, muscle extensor carpi radialis) TS (pressure pain) CPM | Repeated measures ANOVA and post-hoc test (t-test with Bonferroni correction) | Good |
| Imamura,43 2015, Brazil, CS | OA group: n=53 (100% female); mean age 71.23±7.62 years; BMI=28.33±5.95 kg/m2 OA definition: ACR, KL grade 2–4 and VAS >4 (averaged daily pain for the past month and lasting ≥3 months) Symptoms duration: at least 24 months; median 96 months (range 36–150) OA duration: N.R. | Blood samples Proinflammatory cytokines: IL-6, IL-8, TNF-α Anti-inflammatory cytokine: IL-10 | PPT over vastus medialis, adductor longus, rectus femoris, vastus lateralis, tibialis anterior, peroneus longus, iliacus, sartorius, gracilis, quadratus lumborum and popliteus PPT over supraspinous ligaments (L1–L2, L2–L3, L3–L4, L4–L5, L5–S1, S1–S2) Hyperalgesia: pinch and roll manoeuvre at the L1, L2, L3, L4, L5, S1 and S2 dermatomes | Spearman correlation Mann-Whitney U | Fair |
| Lee,44 2011, USA, CS | OA group: n=26 (76.9% female); mean age 59±7.5 years; BMI=27.5 (IQR: 24.8–32.6) kg/m2 OA definition: clinically diagnosed knee OA, documented by a physician Symptoms duration: N.R. OA duration: N.R. Controls: n=33 (69.7% female); mean age 57.7±10.3 years; BMI=27.9 (IQR: 24.3–30.0) kg/m2 | Blood samples CRP, IL-6, IL-1β, TNF-α | PPT at the trapezius, 1st metacarpophalangeal joint and quadriceps Heat pain threshold+suprathreshold heat pain ratings on ventral forearm Cold pressor task | General linear mixed models | Fair |
| Li,45 2020, China, CS | n=83 (74.7% female); mean age 63.4±10.4 years; BMI=N.R. OA definition: ACR KL grade 1: 20 2: 48 3: 12 4: 3 Symptoms duration: N.R. OA duration: N.R. | SF samples Inflammatory cytokines: IL-1β, IL-6, TNF-α | painDETECT | Spearman correlation | Fair |
| Neogi,50 2016, USA, cohort | n=1111 with knee OA or at risk (62% female), mean age 66.9±7.5 years; BMI=29.7±4.8 kg/m2; 38% with radiographic knee OA Subjects free of TS at baseline n=716 (61% female); mean age 66.3±7.4 years; BMI=29.7±4.8; 37% with radiographic knee OA OA definition: sample from MOST Study KL grade 0–3 and frequent knee pain in the past 30 days or no frequent pain, but with at least one risk factor (history of knee injury/operation, overweight/obese) Symptoms duration: N.R. OA duration: N.R. | Non-CE-MRI Hoffa-synovitis (0–3) (WORMS) Effusion (0–3) (WORMS) BMLs (0–3) (WORMS) | PPT knee (peripheral sensitisation) PPT wrist (central sensitisation) TS mechanical (central sensitisation) | Linear regression Logistic regression Conditional logistic regression | Good |
| Petersen,49 2016, Denmark, CC | Patients with KOA BLOKS 0 n=16 (75% female), mean age 67.9±5.75 years; BMI=30.5±3.0 kg/m2; KL grade: 3.9 (95% CI: 3.7 to 4.0) OA duration: 11.5 years (95% CI: 4.2 to 18.8) Symptoms duration: N.R. BLOKS 1 n=24 (46% female), mean age 67.5±4.9 years; BMI=30.7±2.65 kg/m2; KL grade: 4 (95% CI: 4.0 to 4.0) OA duration: 13.5 years (95% CI: 8.8 to 18.1) Symptoms duration: N.R. BLOKS 2 and 3 n=21 (57% female), mean age 69.1±4.1 years; BMI=29.1±2.7 kg/m2; KL grade: 3.9 (95% CI: 3.7 to 4.0) OA duration: 15.3 years (95% CI: 10.0 to 20.6) Symptoms duration: N.R. OA definition: patients with KOA scheduled for TKA Controls VAS <10 mm, KL <2, no long-lasting pain problems in the past year n=33 (55% female), mean age 66.3±1.8 years; BMI=27.0±1.4 k g/m2 | Non-CE-MRI Degrees of synovitis: no (BLOKS 0), low (BLOKS 1), moderate (BLOKS 2) or severe (BLOKS 3) | PPT (7 sites in the peripatellar region) | ANOVA | Fair |
| Radojčić,46 2017, Denmark, CS | n=104 (62% female); mean age 66.78±7.24 years; BMI=30.4±5.21 kg/m2 OA definition: ACR (clinical and radiological); patients scheduled for TKA Symptoms duration: ≥6 months before enrolment OA duration: N.R. | non-CE-MRI Synovitis (MOAKS) Effusion/synovitis (MOAKS) CE-MRI Synovitis (11-point score on CE images) Blood and SF Plasma IL-6 SF IL-6 | NPQ | Spearman correlation Linear regression Logistic regression | Good |
| Sofat,47 2019, UK, CS | Patients with OA (n=120) Advanced OA n=78 (64% female); mean age 68.9±7.7 years; BMI=32.3±5.6 kg/m2 Mild OA n=42 (71% female); mean age 64.1±9.6; BMI=29.2±4.7 kg/m2 OA definition: ACR; KL grade ≥2 Symptoms duration: N.R. OA duration: N.R. | Non-CE-MRI Synovitis (MOAKS) BML load (MOAKS) | PPT
| Pearson correlation | Good |
| Tchetina,48 2020, Russia, CS | n=50 (74% female); mean age 67.6±7.5 years; BMI=30.5±9.05 kg/m2 KL 3: 37 4: 13 OA definition: ACR, KL Symptoms duration: permanent pain during the last 3 months before enrolment OA duration: 9.9 years (range 3–30) | Blood samples TNF-α, IL-1β gene expression | DN4 painDETECT | Spearman correlation | Fair |
ACR, American College of Rheumatology; ANOVA, analysis of variance; BLOKS, Boston-Leeds Osteoarthritis Knee Score; BMI, body mass index; BML, bone marrow lesion; CC, case–control; CE-MRI, contrast-enhanced MRI; CPM, conditioned pain modulation; CS, cross-sectional; DN4, Douleur Neuropathique-4 Questions; hsCRP, high-sensitivity C reactive protein; IL, interleukin; KL, Kellgren-Lawrence score; KOA, knee osteoarthritis; MOAKS, MRI Osteoarthritis Knee Score; NPQ, Neuropathic Pain Questionnaire; N.R., not reported; OA, osteoarthritis; PPT, pressure pain threshold; SF, synovial fluid; TKA, total knee arthroplasty; TNF-α, tumour necrosis factor-α; TS, temporal summation; VAS, Visual Analogue Scale; WORMS, Whole Organ MRI Score.