Key points

Background

Inflammatory rheumatic diseases are common and are associated with significant morbidity, as a consequence of articular and extra-articular manifestations, as well as reduced life expectancy.

In patients with rheumatoid arthritis (RA), a considerable body of research has shown that early treatment leads to significantly improved outcomes. For example, the initiation of disease-modifying antirheumatic drug therapy within the first 12 weeks of the onset of symptoms significantly reduces the rate of radiological progression compared with treatments started later, with patients with more aggressive disease benefiting most from early therapy. Although data are most robust for RA, there are data for other inflammatory rheumatic diseases suggesting that early treatment may also improve long-term outcomes. However, treatments in the established phases of disease, even if given early, are rarely curative.

A desire to cure and even prevent disease has led to increased interest in the earliest phases of the inflammatory rheumatic diseases, including both the earliest phases of clinically apparent disease (before patients have developed the full set of characteristics that allow them to be classified as having the disease in question), and the phases of disease before the onset of symptoms.

This article focuses on RA, although many of the concepts discussed are equally relevant to other inflammatory rheumatic (eg, systemic sclerosis and systemic lupus erythematosus) and nonrheumatic (eg, type 1 diabetes) diseases.

The initial identification of a preclinical phase of rheumatoid arthritis

Although understanding of the preclinical phase of RA has increased considerably in the last few years, the existence of such a phase was first appreciated in the 1980s. Pioneering work from Finland made use of serum samples from individuals participating in a series of community-based cardiovascular studies, because it was possible to identify those who had developed RA after sample collection. Of 30 subjects who developed seropositive RA (between a few months and 9 years after the collection of serum samples), 16 were positive for rheumatoid factor with the frequency of positivity being greater in those nearer the onset of clinically manifest arthritis. The presence of antiperinuclear and antikeratin antibodies in individuals before the onset of RA was subsequently reported. Research in this area grew rapidly through the 1990s and 2000s and was the subject of a recent review by van Steenbergen and colleagues.

As research interest increased, so did the number of terms used by researchers to describe the earliest phases of RA, including pre-RA, preclinical RA, autoantibody-positive arthralgia, early RA, very early RA, and extremely early RA. A lack of consistency regarding terminology made it difficult to compare results between studies and a paucity of information regarding the terminologies used in original articles made it difficult to understand what phase of disease individual researchers were reporting on. In order to develop an agreed set of terminologies regarding the phases of disease leading up to the development of RA, the EULAR (European League Against Rheumatism) Standing Committee for Investigative Rheumatology established the Study Group for Risk Factors for RA. Many of the principles underlying the nomenclature developed by this Study Group are applicable to the earliest phases of other chronic autoimmune/chronic inflammatory diseases.

Background

Inflammatory rheumatic diseases are common and are associated with significant morbidity, as a consequence of articular and extra-articular manifestations, as well as reduced life expectancy.

In patients with rheumatoid arthritis (RA), a considerable body of research has shown that early treatment leads to significantly improved outcomes. For example, the initiation of disease-modifying antirheumatic drug therapy within the first 12 weeks of the onset of symptoms significantly reduces the rate of radiological progression compared with treatments started later, with patients with more aggressive disease benefiting most from early therapy. Although data are most robust for RA, there are data for other inflammatory rheumatic diseases suggesting that early treatment may also improve long-term outcomes. However, treatments in the established phases of disease, even if given early, are rarely curative.

A desire to cure and even prevent disease has led to increased interest in the earliest phases of the inflammatory rheumatic diseases, including both the earliest phases of clinically apparent disease (before patients have developed the full set of characteristics that allow them to be classified as having the disease in question), and the phases of disease before the onset of symptoms.

This article focuses on RA, although many of the concepts discussed are equally relevant to other inflammatory rheumatic (eg, systemic sclerosis and systemic lupus erythematosus) and nonrheumatic (eg, type 1 diabetes) diseases.

The initial identification of a preclinical phase of rheumatoid arthritis

Although understanding of the preclinical phase of RA has increased considerably in the last few years, the existence of such a phase was first appreciated in the 1980s. Pioneering work from Finland made use of serum samples from individuals participating in a series of community-based cardiovascular studies, because it was possible to identify those who had developed RA after sample collection. Of 30 subjects who developed seropositive RA (between a few months and 9 years after the collection of serum samples), 16 were positive for rheumatoid factor with the frequency of positivity being greater in those nearer the onset of clinically manifest arthritis. The presence of antiperinuclear and antikeratin antibodies in individuals before the onset of RA was subsequently reported. Research in this area grew rapidly through the 1990s and 2000s and was the subject of a recent review by van Steenbergen and colleagues.

As research interest increased, so did the number of terms used by researchers to describe the earliest phases of RA, including pre-RA, preclinical RA, autoantibody-positive arthralgia, early RA, very early RA, and extremely early RA. A lack of consistency regarding terminology made it difficult to compare results between studies and a paucity of information regarding the terminologies used in original articles made it difficult to understand what phase of disease individual researchers were reporting on. In order to develop an agreed set of terminologies regarding the phases of disease leading up to the development of RA, the EULAR (European League Against Rheumatism) Standing Committee for Investigative Rheumatology established the Study Group for Risk Factors for RA. Many of the principles underlying the nomenclature developed by this Study Group are applicable to the earliest phases of other chronic autoimmune/chronic inflammatory diseases.

Terminologies to describe individuals in phases leading up to the development of rheumatoid arthritis

In order to develop a set of terminologies to describe individuals in phases leading up to the development of RA, a multidisciplinary group including rheumatologists, laboratory scientists, and a patient representative reviewed and provided descriptive terms for the phases that individuals may pass through before the development of RA and commented on terms and phrases widely used in the literature to describe these phases. Proposals for new terminologies were discussed during a 2-day workshop, at the end of which consensus was reached. It was recommended that, in prospective studies, individuals at risk of developing RA would be described as having:

• 1.
  

  Genetic risk factors for RA

  
  
• 2.
  

  Environmental risk factors for RA

  
  
• 3.
  

  Systemic autoimmunity associated with RA

  
  
• 4.
  

  Symptoms without clinical arthritis (the term arthritis being used to denote clinically apparent soft tissue swelling or fluid and not bony overgrowth alone)

  
  
• 5.
  

  Unclassified arthritis

  
  
• 6.
  

  RA

This nomenclature is illustrated in Fig. 1 . Recognizing that individuals typically progress through these phases, an important aspect of these terminologies was that A to E could be used in a combinatorial manner if appropriate. Thus, for example, a study of asymptomatic individuals who were anti-citrullinated protein/peptide antibody (ACPA) positive would be capturing individuals at phase C, whereas a study of patients who were ACPA positive but who also had inflammatory-sounding musculoskeletal symptoms (but without a clinically swollen joint) would be capturing individuals in phase C and D. The combinatorial nature of this system of terminology is also an acknowledgment that:

• 1.
  

  An individual does not necessarily move through all phases in turn before developing RA (see dashed lines in Fig. 1 ). For example, an individual in phase D may never have had detectable systemic autoimmunity associated with RA, particularly for example in the case of autoantibody-negative individuals.

  
  
• 2.
  

  The phases do not necessarily occur in the same order in all patients. For example, some patients may develop autoantibodies before the development of inflammatory joint symptoms and other patients may develop these after the onset of such symptoms.

The 5 phases (A–E) an individual may pass through in the transition from health to the development of RA (phase F). The open circle in phase D represents a painful but nonswollen joint. The filled shapes in phases E and F represent joints with clinically apparent soft tissue swelling.

The terms used to describe the different phases before the development of RA are intentionally broad. Thus “Genetic risk factors for RA” and “Environmental risk factors for RA” deliberately did not define any particular genetic or environmental risk factors. “Systemic autoimmunity associated with RA” did not define any specific immune abnormalities, such as any specific autoantibody, and “Symptoms without clinical evidence of arthritis” did not define any specific symptoms. This was a very conscious decision, because restricting these categories by specifying risk factors and features known at the time of the development of the terminologies would have rendered the nomenclature rapidly redundant in this advancing field. It was recognized that future research would define additional risk factors and features relevant to each of these phases, beyond current knowledge, and would assess the predictive utility of each of these. In addition, there are currently recognized biomarkers that are known to be present before the development of RA and that are not specifically reflected in the nomenclature. The presence of synovitis on imaging, but not clinically, is an example of this. This is not to suggest that the study group viewed this as an unimportant biomarker. Rather, the nomenclature should provide a framework for future research to assess at which phases, and for transit to which phases, this, like other biomarkers, is useful.

Defining these phases should facilitate the study of mechanisms underlying the transitions between each of these phases and the biomarkers that predict these transitions; critical issues if interventions are to be implemented to prevent progression to RA in at-risk individuals.

Pre-rheumatoid arthritis

At the time these terminologies were developed, the phrase pre-RA was widely used, with many investigators describing individuals in phase C, for example, as having pre-RA. The recommendations suggested that the prefix “pre-RA with” could be used before any one or any combination combinations of A to E but only to retrospectively describe a phase an individual was in once it is known that they had developed RA. For example, given that healthy individuals who are ACPA positive do not necessarily develop RA, it was thought inappropriate to label them as being, or refer to them having, pre-RA. The personal implications (including emotional and financial) of a diagnosis of RA were recognized to be such that the inevitability of developing RA suggested by the phrase pre-RA was thought to be inappropriate. In contrast, in a prospective study of individuals RA-at risk phase C in which some patients did develop RA it was thought appropriate to use the phrase “pre-RA with” to describe phases in which the patient (now known to have RA) had previously been.

Avoiding the phrase pre-RA unless it is known that the individual is going to develop RA is also an acknowledgment that individuals may follow a backward disease course. For example, some individuals present with an unclassified arthritis (phase E) that entirely resolves without specific therapy. The study of patients with resolving outcomes will potentially provide new data on proresolution mechanisms and may provide novel proresolution biomarkers and treatment approaches that can be used to prevent progression in patients at risk.

Preclinical disease

The phrase “preclinical” RA is also widely used, often to describe all phases before the development of a disease classifiable as RA. The terminologies recommended by the EULAR study group effectively divide at-risk phases into those that are asymptomatic (A, B, and C) and those that are symptomatic (D and E). The term preclinical disease is recommended to be used for patients in phases A to C, with patients in phases D and E being in clinically apparent at-risk phases.

The measurement of disease duration

Disease duration is a frequently reported variable in studies of disease mechanisms, observation studies addressing predictors of outcome, and in intervention studies in patients with early disease. However, the definition of disease duration is usually ignored and depends on the point of onset from which disease duration is being reported.

The identification of a point of onset is difficult because it is currently not know where, let alone when, disease begins. Furthermore, in patients who progress through phase C toward the development of RA, it is impossible to define the time of onset of phase C outside the context of a prospective study of at-risk individuals in phases A and B who are subjected to frequent follow-up. However, as individuals move through the preclinical phases of disease to the clinical disease phases, points can be identified more easily from which duration could be timed. Historically, in those studies that have reported the point from which disease duration is being timed, there has been a diversity of approaches to the dating of onset, including from (1) onset of any joint symptoms related to the current episode, including arthralgia/morning stiffness; (2) onset of self-reported joint swelling; (3) onset of clinically observed swelling; (4) time of fulfillment of classification criteria for RA. However, because an evolution of pathologic processes during the clinically apparent at-risk phases would suggest that treatments need to be tailored depending on symptom duration, it is important to understand whether pathologic processes change following the onset of symptomatic disease (phase C onward). It is therefore important that the duration of symptoms, and a description of the symptoms from which duration is timed, be made more explicit in studies of at-risk individuals.

The EULAR study group has recommended that, as best practice, the following dates are recorded in prospective cohort studies and that disease duration is timed for each of them:

• 1.
  

  First musculoskeletal symptoms relevant (in the opinion of the assessing rheumatologist) to the current complaint

  
  
• 2.
  

  First persistent (ie, chronic until presentation) patient-reported joint swelling

  
  
• 3.
  

  Initial fulfillment of criteria for RA (1987 American College of Rheumatology [ACR] and 2010 ACR EULAR ) based on data obtained retrospectively from the patient’s history

  
  
• 4.
  

  Initial fulfillment of criteria for RA (1987 ACR and 2010 ACR EULAR) based on the rheumatologist’s assessment

Of these 4, the first is perhaps the most contentious because it can sometimes be difficult to identify which of a patient’s symptoms were related to, and marked the onset of, inflammatory joint disease. Recent data suggest that the spectrum of symptoms that mark the onset of phase C is varied. Ongoing research is designed to identify those symptoms with the highest predictive value of the future development of RA; these data will help define the subset of symptoms that should most appropriately mark the onset of time point 1 (as listed earlier).