These results align with those obtained in patients with early rheumatoid arthritis [8, 9] and gas the hypothesis that ACPAs alone are not the main and/or single pathogenic factor contributing to joint erosions. also independent of the presence of rheumatoid factor (RF). Methods Patients with Clinically Suspect Arthralgia (n = 507) underwent determination Rabbit Polyclonal to CDH19 of ACPA and RF and 1.5?T contrast-enhanced MRI of the metacarpophalangeal, wrist and metatarsophalangeal joints at baseline. MRIs were scored for presence of local inflammation and erosions. Comparisons of erosion scores were performed using the Kruskal-Wallis test. To evaluate if inflammation is usually, in statistical terms, intermediary in the causal path of ACPA and erosions, three-step mediation analysis was performed using linear regression. Results ACPA-positive patients experienced higher erosion scores than ACPA-negative patients ((%)390(77)?Family history of RA, (%)147(29)?Symptom duration in weeks, median (IQR)17(9C32)?Presence of morning stiffness 60?min, (%)182(36)?Current smoker, (%)137(27)?68-TJC, median (IQR)6(3C10)?Increased CRP (5?mg/L), (%)106(21)?Presence of local subclinical joint inflammation, (%)255(50)?Positive for EULAR definition for arthralgia suspicious for progression to RA [17], (%)325(64)Autoantibody status?Unfavorable for IgM-RF and ACPA, (%)385(76)?IgM-RF-positive (3.5?IU/mL), ACPA-negative, (%)52(10)?ACPA-positive (7?U/mL), IgM-RF-negative, (%)15(3)?IgM-RF-positive and ACPA-positive, (%)55(11)ACPA-level (U/ml) in ACPA-positive patients, median (IQR)162(35C340)?ACPA-level (U/ml) in ACPA-positive patients without local joint inflammation, median (IQR)129(23C340)?ACPA-level (U/ml) in ACPA-positive patients with local joint inflammation, median (IQR)191(38C340) Open in a separate window Local subclinical joint inflammation?was identified if the?prevalence of magnetic resonance imaging (MRI)-detected bone marrow edema, synovitis or tenosynovitis was higher than that of Mdivi-1 age-matched symptom-free controls anti-citrullinated peptide antibody, C-reactive protein, Western League Against Rheumatism, immunoglobulin M rheumatoid factor, interquartile range, rheumatoid arthritis, rheumatoid factor, standard deviation, tender joint count ACPA with concomitant inflammation, but not ACPA alone, associated with higher erosion scores First a comparison was made between all ACPA-positive patients and ACPA-negative patients: ACPA-positive patients had higher erosion scores than ACPA-negative patients ( em p /em ?=?0.006; Fig.?1a). Also Mdivi-1 the presence of MRI-detected subclinical inflammation was associated with higher erosion scores ( em p /em ? ?0.001; Fig.?1b). Open in a separate windows Fig. 1 Histograms showing median erosion scores in patients with Clinically Suspect Arthralgia comparing anti-citrullinated protein antibodies (ACPA)-positive and ACPA-negative patients (a), patients positive or unfavorable for local subclinical joint inflammation (b), ACPA positivity and negativity in relation to the concomitant presence of magnetic resonance imaging (MRI)-detected subclinical inflammation (c), or rheumatoid factor (d). Median erosion scores with the upper limit of the interquartile range (75th percentile): ** em p /em ? ?0.01; * em p /em ? ?0.05; NS, non-significant. The following comparisons have been made: ACPA+ vs. ACPA? (a) ( em p /em ?=?0.006) and MRI+ vs. MRI? (b) ( em p /em ? ?0.001). Next, ACPA+MRI? vs. ACPACMRIC patients (c) ( em p /em ?=?0.68), ACPA+MRI+ vs. ACPA?MRIC patients (c) ( em p /em ? ?0.001) and finally ACPA+MRI? vs. ACPA+MRI+ (c) ( em p /em ?=?0.016). ACPA+ rheumatoid factor (RF)? patients vs. ACPA?RF? patients (d) ( em p /em ?=?0.30) and ACPA+RF+ patients vs. ACPA?RF? patients (d) ( em p /em ?=?0.006) Next, stratification was applied for both ACPA and local subclinical joint inflammation. After this stratification, it was observed that in the absence of local subclinical inflammation ACPA-positive (ACPA+/MRI?) patients did not have higher erosion scores than ACPA-negative (ACPA?MRI?) patients ( em p /em ?=?0.68). In Mdivi-1 contrast, ACPA-positive patients with local inflammation (ACPA+/MRI+) did have higher erosion scores than ACPA-negative patients without local inflammation (ACPA?/MRI?; em p /em ? ?0.001; Fig.?1c). Furthermore, comparing ACPA-positive patients without local inflammation (ACPA+/MRI?) to ACPA-positive patients with local inflammation (ACPA+/MRI+) revealed that this latter group experienced significantly higher erosions scores ( em p /em ?=?0.016, Fig.?1c). This suggests that ACPA with concomitant inflammation, but not ACPA alone, was associated with higher erosion scores. When any inflammation (considering inflammation positive if either local subclinical joint inflammation was present or CRP was elevated) was analyzed, stratified analyses revealed similar results (Additional?file?1: Determine S1). Also here, patients that experienced ACPA and inflammation experienced higher Mdivi-1 erosion scores, in contrast to patients that experienced ACPA without concomitant inflammation ( em p /em ?=?0.056). ACPA levels Mdivi-1 within ACPA-positive patients (comparing tertiles) were not associated with erosion scores (Additional?file?1: Determine S2). Mediation analyses; local inflammation is in the causal path of ACPA and erosions We analyzed whether local inflammation is usually intermediary in the causal path of ACPA and erosions in three actions using mediation analyses. In linear regression analysis (Fig.?2), the presence of.