Background
Rheumatoid arthritis (RA) is a chronic immune-inflammatory disease associated with several forms of skeletal remodeling including peri-articular osteopenia, marginal joint erosions and generalised bone loss. Pro-inflammatory cytokines are traditionally regarded as key drivers of articular and extra-articular bone tissue destruction [
1‐
3]. However, recent experimental evidence indicates that RA-associated autoantibodies, in particular anti-citrullinated protein antibodies (ACPA), can independently stimulate bone remodeling by inducing the differentiation of bone-resorbing osteoclasts [
4,
5].
Clinically, the association between ACPA and further progression in joint damage has been reported in several independent studies, [
6‐
8]. This association appears at least partially independent of inflammation. Despite having a similar response to steered treatment strategies, ACPA-positive patients with RA indeed have higher rates of joint damage progression over time [
9], and serum receptor activator of nuclear factor kappa B ligand (RANKL) is reported to be increased in ACPA-positive patients independent of acute phase reactants and pro-inflammatory cytokines [
10]. More intriguingly, elegant imaging studies have recently demonstrated impairment in the bone microstructure in the metacarpophalangeal joints of ACPA-positive healthy individuals despite no signs of arthritis [
11].
As ACPA precede the clinical onset of RA by years and are at least initially produced at extra-articular sites [
12], it could be expected that ACPA-positive patients with early RA may already show signs of generalised bone loss in addition to destruction in the joints. However, the pathophysiology of secondary osteoporosis in RA is complex and mostly attributed to long-standing, disabling disease [
13,
14]. Accordingly, the few studies available in early RA have reported overall bone mineral density (BMD) almost comparable to that of non-RA controls [
15‐
20], and the potential effect of autoantibodies has not been systematically evaluated.
The Pavia Early Arthritis Clinic is a single-centre inception cohort of patients with recent-onset inflammatory arthritis, who are treatment-naïve at inclusion, and who undergo standardised clinical, laboratory and imaging assessments upon referral [
21,
22]. Baseline BMD measurement has been systematically introduced since 2012. Here, we took advantage of this cohort to tackle the question of whether RA-associated autoantibodies affect systemic BMD independent of classical demographic and disease-related risk factors in the initial stages of arthritis.
Discussion
We show here that, overall, systemic BMD is preserved in patients with early RA, and classic disease-related risk factors, including disease duration, inflammatory activity and functional ability, have negligible impact on measurable bone remodeling at this stage of the disease. However, ACPA appear associated with significantly reduced BMD, and the concomitant presence of high levels of RF further enhances the risk of bone loss. Whilst the effect of ACPA on the trabecular bone of the spine is readily appreciable, changes in the cortical bone of the hip require higher levels of autoantibodies.
The small proportion of patients with reduced BMD in our study is consistent with earlier reports [
15‐
20] and confirms that overt secondary osteoporosis in RA mostly develops in association with chronic, disabling disease. The short symptom duration and the low levels of functional impairment and radiographic damage in our contemporary cohort diagnosed according to the 2010 criteria may explain the lack of association between disease-related factors and BMD, as compared with historical groups of patients with early RA with longer disease duration and variable treatment [
15,
19,
20].
Whilst synovial inflammation may thus take longer to produce systemic effects at joint-remote sites [
30], we show here that RA-associated autoimmunity appears coupled with reduced BMD from the early stages of clinical disease. Although functional verification of the pathogenic effects of autoantibodies on extra-articular bone in our study is lacking, our data fit with recent evidence linking ACPA to bone changes in vitro and in vivo [
4‐
6]. Relevantly, the association between ACPA and BMD loss was enhanced by high levels of RF. Sensitive imaging techniques have shown that RF dose-dependently influences the size of bone erosions on an ACPA background [
24], and the combined presence of ACPA and RF mediates increased pro-inflammatory cytokine production in vitro [
31,
32]. The immune-complex activity of RF may have thus elicited a subclinical inflammatory milieu able to enhance ACPA-mediated osteoclast activation also at joint-remote sites. The different associations between autoantibody levels and spine and hip BMD loss might be explained by the higher rate of turnover in trabecular compared to cortical bone [
33].
Our study has some limitations. Although we cannot exclude RA over-diagnosis according to the 2010 criteria [
34], differential diagnoses were carefully evaluated and applying the 1987 criteria did not affect the results. The frequency of autoantibodies was lower than expected [
35‐
37], but still comparable with other early arthritis cohorts from similar geographical areas [
38], including the
Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort, in which 46–49 % of the patients fulfilling the RA classification criteria at inclusion are reported as ACPA-positive [
39‐
41]. Irrespective of the prevalence of autoantibodies, however, we believe that the observed differences in BMD according to autoantibody levels clearly confirm the specific association between RA autoimmunity and systemic bone loss. Although the small number of single-positive patients hampers definitive conclusions on the independent associations with ACPA and RF, spine BMD was significantly reduced in ACPA-positive patients with low RF (Fig.
1e) in the absence of the definitive effects of low RF (Fig.
1c). This finding indirectly supports the notion that ACPA are key drivers of bone damage, and RF becomes important when ACPA are also present [
24]. Also, the cross-sectional character of this study hampers definition of the potential effect of autoantibodies on the progression of BMD loss. DXA follow up is ongoing to define whether treatment can halt autoantibody-dependent systemic bone remodeling. It is also equally important to emphasise that additional measures of bone quality, including micro-architecture, mineralisation and turnover [
42‐
44], might help better define the net impact of autoantibodies and autoantibody levels on bone. Finally, it is important to recall that vitamin-D is a key determinant of bone health [
45], and patients with RA have significantly lower vitamin D serum levels compared to healthy controls [
46]. As vitamin D deficiency might be more prevalent in ACPA-positive patients [
47], we cannot exclude that possibility that the observed association between autoantibodies and reduced BMD might be at least partly mediated by lower vitamin D levels.