Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies

Abstract

Objective Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. Methods We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. Results ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm 3 ) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant ( p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly ( p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). Discussion Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.

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“…The plasma levels of ACPA are an index of disease activity and joint damage (45). A recent study has shown that ACPA can stimulate osteoclast differentiation, and that in ACPA-positive patients with RA there is more frequent evidence of bone loss and thinning of cortical thickness than in APCA-negative patients with RA (46)(47)(48). Recently, a significant correlation has been observed between RA related osteoporosis and risk of erosions (49,50).…”

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“…Bone loss starts very early in the disease course of RA [71]. It is driven by the induction of bone-resorbing osteoclasts by autoantibodies, leading to the first structural changes in the pre-disease phase and aggravated by the action of proinflammatory cytokines [72,73].…”

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“…The erosion tends to occur at sites subjected to mechanical stress or loading, thus the periarticular, cortical sites are more vulnerable. Also, as stated above, recent evidence suggests that ACPA can directly stimulate this process via enhanced osteoclast differentiation [15].…”

“…Higher levels of these antibodies are associated with an increased risk of joint damage and cardiovascular diseases [14]. Whilst the effect of these antibodies in the disease process is not fully understood, recent work has shown that ACPA can stimulate osteoclast differentiation and that in pre-RA individuals, those who are ACPA-positive, there is more frequent evidence of bone loss and reductions in cortical thickness as compared with ACPA-negative individuals [15]. The production of these antibodies is associated with more generalised inflammation, as indicated by higher levels of C-reactive protein (CRP) and higher erythrocyte sedimentation rates [16].…”