Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis.

OBJECTIVES: Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (TFH) and is important in the formation of plasma cells. PD-1 exists in a bioactive soluble form (sPD-1) and is thought to be implicated in disease activity in chronic rheumatoid arthritis (RA). METHOD: We measured sPD-1 at baseline and 9 months after treatment initiation in plasma from early RA patients (n = 34). We tested for correlations with the Disease Activity Score using 28 joint counts (DAS28), the Health Assessment Questionnaire (HAQ) score, immunoglobulin M rheumatoid factor (IgM-RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), interleukin-21 (IL-21), and total Sharp score (TSS). We also measured sPD-1 in plasma from healthy volunteers (HV) (n = 20) and in plasma and synovial fluid (SF) from patients with chronic RA (> 8 years of disease, n = 30). We further investigated the cellular expression of PD-1 and its ligand PD-L1. RESULTS: sPD-1 concentrations in early [median 0.421 ng/mL, interquartile range (IQR) 0.04-2.560 ng/mL] and chronic (median 0.239 ng/mL, IQR 0.184-0.584 ng/mL) RA were increased compared with HV (median 0.04 ng/mL, IQR 0.04-0.04 ng/mL) (all p < 0.005). In early RA the change in sPD-1 was associated with DAS28 (r = 0.363, p < 0.05) and HAQ score (r = 0.554, p < 0.05) and inversely with TSS at 3-5 years (r = -0.468, p < 0.05). sPD-1 concentration correlated with IgM-RF, anti-CCP antibodies, and IL-21 (all p < 0.05). PD-1 was primarily expressed by synovial memory T cells whereas PD-L1 was mainly expressed by synovial monocytes. CONCLUSIONS: The significantly elevated plasma levels of sPD-1 in early RA, the association with core disease parameters, and the inverse correlation with TSS suggest that sPD-1 is an important mediator in inflammatory and radiographic disease progression.

Soluble macrophage-derived CD163 is a marker of disease activity and progression in early rheumatoid arthritis.

OBJECTIVES: To investigate the expression of the soluble form of the resident macrophage marker CD163 (sCD163) and its association with core parameters for disease activity, including radiographic progression in early rheumatoid arthritis (RA). METHODS: In a longitudinal sample set from early RA patients (n=34) we measured plasma levels of sCD163 at initiation of treatment and after 9 months of treatment and correlated levels with disease activity in 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and total Sharp score (TSS). We also measured plasma levels of sCD163 in 55 healthy volunteers (HV) and in a transverse sample set of chronic (>8 years of disease) RA patients (n=24) and OA patients (n=24) with paired plasma and joint fluid. RESULTS: Early RA patients had significantly higher plasma levels of sCD163 (1.69mg/l (1.42-2.10)) (median (IQR)) at baseline than after 9 months of treatment (1.28mg/l (0.963-1.66), p=0.001), but not significantly changed compared with HV (1.66mg/l (1.22-2.02)). In early RA patients, baseline levels of sCD163, correlated with DAS28, CRP and ESR. Interestingly, sCD163 at 9 months was associated with radiographic progression (TSS) between year 0 and 5 (r=0.468, p=0.02). Levels of sCD163 were higher in RA patients, than in OA patients and higher in SF than in plasma. CONCLUSIONS: Plasma levels of macrophage derived sCD163 are associated with disease activity and predict radiographic progression in early RA patients, supporting that sCD163 may have a role as a biomarker of disease activity and that resident macrophages are important for joint destruction.