EXTENDED REPORT Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies Arnd Kleyer, 1 Stephanie Finzel, 1 Jürgen Rech, 1 Bernhard Manger, 1 Manuel Krieter, 1 Francesca Faustini, 1 Elisabeth Araujo, 1 Axel J Hueber, 1 Ulrike Harre, 1 Klaus Engelke, 2 Georg Schett 1 Handling editor Tore K Kvien 1 Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany 2 Institute of Medical Physics, University of Erlangen-Nuremberg, Erlangen, Germany Correspondence to Professor G Schett, Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen D-91054, Germany; georg.schett@uk-erlangen.de AK and SF contributed equally to this paper. Accepted 24 February 2013 Published Online First 21 March 2013 To cite: Kleyer A, Finzel S, Rech J, et al. Ann Rheum Dis 2014;73:854–860. 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. INTRODUCTION Rheumatoid arthritis (RA) is characterised by chronic inflammation of the synovial membrane and its systemic consequences. 1 2 Clinical symp- toms such as swelling, pain and stiffness result from synovial inflammation, which precipitates progres- sive bone loss and cartilage damage in the affected joints. To date, bone damage is considered as the mere consequence of synovial inflammation. Current concepts of bone damage in RA suggest that synovitis promotes the synthesis of proinflam- matory cytokines, which facilitate osteoclast activa- tion and enhance bone resorption at specific anatomical sites, such as the metacarpophalangeal joints. 3–5 Bone damage accumulates during the disease course of RA, if the disease is not adequately controlled by antirheumatic therapy. Early and more recent clinical observations consist- ently revealed that local and systemic bone loss is found very early in the RA disease process. This observation is surprising, as synovitis may require some time to destroy bone to an extent which is clin- ically detectable. Van der Heijde has shown that the majority of patients show radiographic bone erosions during the first years of disease. 6 Later studies based on radiography, 7 ultrasound 8 9 and MR tomog- raphy 10–13 showed consistent evidence of bone ero- sions a few months after disease onset. In addition, other studies provided evidence for bone erosion, and periarticular and systemic bone loss in patients with recent onset RA. Thus (i) dual energy x-ray absorptiometry investigations have shown a rather high rate of osteopenia in RA patients with only a few weeks of disease duration and no exposure to glucocorticoids 14 15 ; (ii) similarly, hand bone mineral density (BMD) decreases very early in the disease process of RA and can already be visualised in recent onset RA 16 17 ; and finally (iii) bone erosions have been documented in RA patients with only a few weeks of disease duration by radiography, 18 19 ultra- sound 20 21 as well as MRI. 22 These findings raise some doubts as to whether synovitis alone is sufficient to explain bone loss in RA. Alternative concepts of bone loss in RA may consider that autoimmunity precedes the onset of clinical disease by many years. 23 Anticitrullinated protein antibodies (ACPA) emerge years before the clinical onset of the disease. Thus the syndrome of RA may start long before the onset of the clinical symptoms of disease. Terms like ‘pre-RA ’ 24 and, on a recent consensus work initiated by the European League Against Rheumatism (EULAR), ‘RA at risk’, have been created to attribute the fact that auto- immunity related to RA is present long before the onset of the clinical disease. 25 This concept raises the question of whether indi- viduals with autoantibodies (ie, ACPA) without any signs of inflammation can be considered as healthy. Recent data investigating the synovial membrane of ACPA positive individuals without arthritis have suggested that synovial inflammation is absent in these subjects and at best starts only a few weeks before clinical disease onset. 26 ACPA, however, may facilitate this transition from autoimmunity to inflammation, as animal data have shown that ACPA facilitate the development of experimental 854 Kleyer A, et al. 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