Vivian P. Bykerk, MD, Editor

Karen H. Costenbader, MD, MPH, Editor

Kevin Deane, MD, PhD, Editor

Despite modification of classification and diagnostic criteria to identify diseases earlier, and the emergence of very effective targeted therapies used in conjunction with early diagnosis and treatment, this has not yet resulted in cures for or prevention of these diseases, or even successful drug-free remission in most cases. In rheumatoid arthritis (RA), for example, very few persons affected can succeed in maintaining drug-free remission over an extended period of time. As such, the ability to identify and screen for these diseases very early on in the preclinical phases may yield the best chance of successful intervention to prevent full manifestations of disease. Efforts aimed at finding the earliest point in pathogenesis, when there is evidence of autoimmunity but no expression of overt disease, are underway for many rheumatic diseases. These include studies by many researchers, applying a variety of methods, including analyses of populations who are at high risk for future rheumatic disease such as first-degree relatives and people who may be in the very early phases of rheumatic disease based on the presence of specific symptoms and/or laboratory tests indicating the presence of autoimmunity.

In this issue, several scientists and clinical researchers renowned for their work to progress in understanding of the very early phases of so-called preclinical rheumatic disease have generously given their time and expertise to provide their perspective of what is known about the evolutions of rheumatic diseases and clinical arthritis. The issues are complex and have started with a common way of thinking about the stages of preclinical disease as so eloquently described by Drs Raza and Gerlag. Their overview describes consensus among researchers in this field about the perspectives of these stages. Briefly, in almost all rheumatic diseases, one can think of the preclinical phase as occurring in several stages. These include a period of genetic risk, exposure to environmental factors, followed by development of asymptomatic autoimmunity, development of nonspecific symptoms, elaboration of an immune or inflammatory response, and ultimately, definitive clinical manifestations.

Clinicians frequently see patients with evidence of autoimmunity with nonspecific manifestations and have no evidence based on clinical studies to guide them regarding management. Drs Kung and Turk have thoroughly researched and described the approaches to and challenges of interpreting symptoms and signs in the preclinical phases using preclinical RA as an example. They highlight the numerous studies ongoing to date and argue for the case that a combination of symptoms and tests that demonstrate signs of active autoimmunity is needed to implement any form of secondary prevention. They also note that symptoms at this phase may not necessarily reflect those in classification criteria. Dr Turk and coauthors, in summarizing results from an extensive systematic review of this topic, contend that given the currently available evidence for identifying those at highest risk for evolving into classifiable **RA, screening is best performed in relatives of patients with established disease or in those with symptoms and positive blood tests. Even with this approach, the odds of developing disease within a year are still low. Both Dr Willis and Dr Mandl delve into the need to consider advanced imaging to detect the earliest sign of disease because abnormal findings in high-resolution imaging often occur before an inflammatory disease is classifiable. They caution, however, that this approach is not yet ready for clinical use as the specificity of these tests can be poor.

Drs Finckh and Deane further note that to prevent overt expression and persistence of autoimmune disease it is possible to intervene at varying stages. In some situations, the best approach could ultimately be through primary prevention of initial autoimmunity or tissue injury, although at present most are approaching this through secondary prevention in which attempts to halt progression of a disease would be implemented in those already into the earliest phases of pathogenesis. Ideally, screening and prevention should occur while subjects are still in an asymptomatic or minimally symptomatic stage. However, as Dr Colange highlights, primary or secondary screening tests to identify those at risk must balance the risks and harms of intervention when considering any modification of risk factors, such as induction of tolerance, or pharmacologic interventions.

In rheumatic diseases, such as osteoarthritis (OA) or gout, not all the same stages apply. For both, there may be genetic susceptibility and environmental risk factors. However, the mechanisms of disease pathogenesis differ. In OA, this involves tissue injury as described by Dr Felson in his review of the earliest phases of OA. In gout, the earliest phases involve metabolic mechanisms. Drs MacFarlane and Kim note there are now clear associations of specific genetic polymorphisms associated with gout that are linked to altered uric acid metabolism. Thus, primary prevention by genetic manipulation could be a viable option in the future. Importantly, gout pathogenesis is often accompanied by dietary and personal factors, including obesity, before leading to the overt expression of chronic gout, making the case that risk modification is possible. This is not the case, however, for most other rheumatic diseases. For example, although much is also known about many genetic polymorphisms associated with the development of RA, the interrelation of these environmental triggers at the earliest phases of autoimmunity is only just being explored. Drs Sparks and Costenbader review data from the study of gene–environment interactions that may to lead to insights for the primary prevention of many of these diseases. They have described several of these advances in the context of a path forward to understanding the role of gene–environment interactions in inflammatory arthritis and how these might explain the biologic mechanisms underpinning the onset of autoimmunity. They provide examples that have already been worked out in the development of RA and spondyloarthropathy.

Basic scientists are looking to identify novel mechanisms of disease pathogenesis. Dr Holers describes how these may be working in the pathogenesis of RA, suggesting that the disease may originate and evolve in tissues other than joints, specifically, the oral mucosa or lungs, given recent evidence of small airways disease in individuals at risk for developing RA. In one example of pathogenesis, he describes the role of microorganisms found in the oral mucosa because they give rise to citrullinated peptide antigens. In susceptible individuals, it results in the generation of anticitrullinated peptide antibodies that expand in their repertoire with epitope spreading of new antibodies to other citrullinated protein antigens, followed by elevated cytokines and chemokines, and subsequent systemic synovial inflammation. Drs Kuhn and Demourelle expand this perspective by considering the role of altered microbiota in varying mucosal tissues because they may contribute to autoimmunity or auto-inflammatory diseases. Newer hypotheses of biologic mechanisms invoke an altered microbiome as being key to disease pathogenesis. Microbial dysbiosis is also being explored in spondyloarthropathies, which are highly associated with gut inflammation, as noted in the review by Drs Willis and Inman. Auto-antibody formation is has been considered to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Clinicians and researchers alike are aware they are present in the earliest expression of this disease. However, as Drs Robertson and James point out, the complexity of this illness, even with newer classification criteria, hampers a simple understanding of the mechanisms leading from preclinical genetic risk to autoimmunity and overt disease in SLE.

As you will appreciate by reading each of these articles, the authors tackle the issues of preclinical rheumatic disease from a different perspective. Clinical researchers are still finding ways to better understand and to identify those at risk for autoimmunity, inflammation, and tissue injury. The understanding of genetic risk and epigenetic modifications triggered by environmental factors is far from complete.

Advances toward achieving this understanding have progressed further for some diseases than others, and in particular, clinical prevention trials in type 1 diabetes have been underway for some years. Drs Simon and Michaels have aptly described how advances in this field have combined the understanding of genetic risk, use of natural history studies, and discoveries that antibodies against islet cell antigens are predictive of young children developing type 1 diabetes. When these antibodies are detected in children under the age of 2, they are highly associated with T-cell-mediated destruction islet cells and ultimate failure to produce insulin. This understanding has led to trials of secondary prevention using immunotherapy. Results of the success of this approach have not yet been realized; however, if any are effective, this will generate the first evidence that supports the rationale of secondary prevention of autoimmune disease. For most rheumatic diseases, scientists are still exploring ways to identify early expression of autoimmunity and how this may relate to genetic polymorphisms and environmental exposures.

We sincerely thank our colleagues for providing their insights and contributions to this issue. As you see, each has contributed a different perspective as to how we as clinicians, researchers, and scientists can work toward preventing the very rheumatic diseases that cause so much suffering for our patients.