Inflammatory lesions in the bone marrow of rheumatoid arthritis patients: a morphological perspective

The synovial tissue stands at the epicenter of joint pathology in rheumatoid arthritis (RA). As a primary target of the disease, studies on the synovium have provided invaluable insights into the mechanisms involved in disease pathogenesis. Recent work has, however, revealed the importance of a previously unseen anatomic compartment in direct contact with the joint space, namely the subchondral bone marrow. Bone marrow edema (BME) visible on magnetic resonance imaging (MRI) is clinically meaningful in both early and late RA as it associates with future development of bone erosions and poor functional outcomes. Although the histopathologic correlates of MRI-based BME in early RA remain obscure, studies in advanced disease are consistent in describing lymphocytic inflammatory infiltrates within the subchondral marrow cavity of affected joints. In this review, we discuss the nature of bone marrow lesions in patients with RA, analyze their relationship with synovitis, and explore their potential contribution to the pathological processes of the disease.Rheumatoid arthritis (RA) is traditionally regarded as an archetypal disease of the synovial tissue. The synovial membrane indeed undergoes early inflammatory changes, which include increased vascularity as well as intimal lining layer hyperplasia and accumulation of macrophages, plasma cells, T cells, B cells, dendritic cells, natural killer cells and mast cells in the sublining, among other changes [1]. Collectively, localization of inflammation to the synovium is primarily responsible for the dysregulated cellular and molecular mechanisms that ultimately lead to the typical signs and symptoms of RA, including joint pain, stiffness, swelling and structural changes. Although the pathogenic and clinical importance of synovitis is beyond question, it is becoming increasingly apparent that a ''synovio-centric'' model of RA could be limiting. Indeed, other anatomic compartments appear to be involved at all stages of the disease. The most important example comes from the recognition that clinical arthritis and subclinical synovitis are anticipated by a pre-articular immunologic phase possibly developing in lymphoid tissues as well as in the lungs [2,3]. Full-blown joint disease itself spreads well beyond synovial tissue inflammation. Established arthritis can be characterized by the involvement of at least two other compartments that are in direct contact with the joint space. These include the draining lymph nodes (LNs) [4,5] and, of special relevance, the subchondral bone marrow (BM) [6].As dysregulated B cell responses are central pathogenic events in RA and B-cell autoreactivity originates, at least in part, from defective checkpoints within the BM (a primary lymphoid organ) [7], the role of this compartment in the immunopathogenesis of RA has attracted great attention over the years. Data supporting the existence of BM abnormalities were mainly derived from studies on marrow aspirates/biopsies from the sternum and the iliac crest, which are primary hematopoietic and immunologic sites in adult life. The role that the ''red marrow'' might play in the immunologic disturbances of RA thus appears interesting but not completely unexpected. Less predictably, evidence has accumulated supporting the additional involvement of the BM adjacent to inflamed joints at peripheral sites. This is normally a fat-rich tissue (''yellow marrow'') where hematopoiesis is not prominent. In RA, the fat can be replaced by a vascularized, cell-rich inflammatory tissue. Combined with imaging data coming from magnetic resonance imaging (MRI) studies, histopathologic changes described within the subchondral BM have been postulated to be intimately involved in the pathological processes producing local inflammation and tissue remodeling in RA joints [6,8-10]. Here we will discuss the most relevant findings related to BM alterations in RA, focusing on their morphological characteristics and pathologic significance. In view of the clinical relevance of MRI findings, special emphasis is given to the subchondral BM.