Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study

Abstract

Objectives: Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression.Methods: One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2–L4) by dual-energy X-ray absorptiometry (DXA).Results: Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity (p = 0.02) and IL-6 plasma levels (p = 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones (p = 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones (p = 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones (p = 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11–5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27–39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up.Conclusions: Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.

The Role of Autoimmunity on the Relation Between Erosions and Bone Mineral Density in Rheumatoid Arthritis: A Clinical Research

“…In our RA patients, 17.5% had osteoporosis at the hip and/or spine based on DXA assessment. This result is consistent with the literature; indeed, the described prevalence of densitometric osteoporosis ranges from 10 to 50% (14) (15) . A large proportion of our patients presented at least one osteoporotic risk factor (84%), and 31.5% were treated or had been treated with at least one anti-osteoporotic treatment.…”

“…The major factors for erosion (SHSe total score) were disease duration, hip T-score and BMD. This last association was also described by Bruno et al in a cohort of early RA patients (n = 128) (14) . The exclusion of disease duration did not change the results, and hip T-score or BMD included separately were still signi cant independent factors for erosion severity.…”

“…As previously reported, we showed that hip BMD or hip T-score were signi cantly associated with BMI and sex in multivariate analysis. Obviously, women had lower BMD and T-scores at the hip, and BMI is known to be protective against bone loss (14) .…”

“…Currently, the gold standard for the diagnosis and monitoring of osteoporosis is dualenergy X-ray absorptiometry (DXA) performed on the spine and hip. The prevalence of densitometric osteoporosis in RA varies from 10 to 50% according to the literature (14) (15)(16)(17)(18) (19) . Additionally, it has already been demonstrated that ACPA titer or status are "signi cant predictors of bone mineral density (BMD) changes in the proximal femur" (20) .…”

“…by ACPAs due to the presence of citrullinated peptides on their surface. As a consequence, TNF-alpha and receptor activator of nuclear factor kappa B ligand (RANK-L) synthesis are increased, leading to osteoclast differentiation and activation a second time (24) (10) (14)(26) (27)(28))(29) (30) . Serum RANK-L is reported to be increased in ACPA-positive patients independent of acute phase reactants and pro-in ammatory cytokines, thus a rming the role of autoimmunity passing through ACPA itself on local osteoclastogenesis (22) .…”