Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE

Abstract

Established and emerging data demonstrate that a 'preclinical' period of disease precedes the onset of clinical rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as other autoimmune rheumatic diseases (ARDs).This preclinical stage of development of disease is characterized by abnormalities in disease-related biomarkers before the onset of the clinically apparent signs and symptoms. Numerous genetic and environmental risk factors for ARDs have also been identified, and many of these factors are likely to act before the clinical appearance of tissue injury to initiate and/or propagate autoimmunity and autoimmune disease. Thus, biomarkers representative of these autoimmune processes could potentially be used in conjunction with other clinical parameters during the preclinical period of ARDs to predict the future development of clinically apparent disease. This Review focuses on the preclinical stages of RA and SLE, as our current understanding of these diseases can be used to present an overall model of the development of ARDs that might ultimately be used to develop screening programmes and preventive strategies. Important considerations for the future development of such approaches, in particular, the issues that require additional research and how they might be addressed, are also discussed.

Figure 1

Overall model of the development of autoimmune rheumatic disease. Autoimmunity is probably initiated owing to a combination of a | genetic, environmental and stochastic factors, and b | at an anatomic site, which might not be the main target of the subsequent autoimmune response. c | Initially, autoimmunity can be present in absence of clinically apparent tissue injury, but might be detectable through analysis of disease biomarkers. d | Over time, further pathogenic changes in autoimmune responses occur, mediated by ongoing genetic, environmental and stochastic factors. e | Eventually, clinically apparent tissue injury occurs and the affected individual subsequently presents to a health-care provider. Processes a–d are considered to represent the ‘preclinical’ phases of disease development. Abbreviations: ACPA, anti-citrullinated peptide antibody; ANA, antinuclear antibody; RF, rheumatoid factor; SLE, systemic lupus erythematosus.

Figure 2

Points in the natural history of autoimmune rheumatic disease development that might represent therapeutic windows to prevention of initiation or progression of disease. In this model, intervention at point 1, probably involving modification of risk factors, might prevent the initial development of autoimmunity (primary prevention). Intervention at point 2, potentially by modification of potentiating risk factors or by targeting immune processes underlying the development of autoimmunity, might halt the progression of ‘benign’ (preclinical) autoimmunity to a more pathogenic state, and perhaps ‘reset’ the immune system and restore immune tolerance (secondary prevention). Therapeutic intervention at point 3 could, potentially, block or abrogate the progression of early symptomatic disease to fully differentiated disease, or prevent substantial organ injury and other complications (tertiary prevention), but might be unlikely to reverse clinically relevant autoimmune responses and thus prevent the development of persistent clinical disease. Of note, defining intervention at point 2 as ‘secondary prevention’ could be controversial, as autoimmunity in absence of obvious tissue injury might indicate to some that true disease has not yet occurred; however, intervention at this point in individuals at risk of developing clinical disease could conceivably hold more promise for preventing chronic disease than initiation of treatment at a point when tissue damage is already evident. Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.