Page 60 - THE EVOLUTION OF EARLY ARTHRITIS AND CARDIOVASCULAR RISK Samina A. Turk

CHAPTER 3
WHEN DOES EARLY RA BECOME ESTABLISHED RA?
This question gives rise to the suggestion that there is a difference between the pathology at the beginning of the disease and what is found later on, and that this distinction has clinical significance. In fact, this is closely related to the concept of a therapeutic “window of opportunity,” which states that treatment initiated at an early stage of the disease is more successful than when it is started later on. “Early” would mean that there is joint inflammation of recent onset, which may at this stage still resolve without further consequences or at least decrease to a barely detectable minimum, if treated adequately. “Established” on the other hand would mean the inflammation is there to stay, more or less pronounced, whatever intervention is applied. Moreover, the concept of “established” RA will generally include damage to the joints, and diverse comorbidities with their complications such as osteoporosis or cardiovascular disease, which may arise as a consequence of the ongoing inflammation.
To begin with, the pathology of RA does not suddenly start around the onset of clinical arthritis. RA-specific systemic autoimmunity as well as nonspecific subclinical inflammation occurs in concert on average 5 years before the onset of symptoms(71, 72). During the period of presymptomatic autoimmunity, there is a maturation of the immune response to citrullinated and carbamylated antigens, which is consistent with an increasing break of tolerance(73). Thus, the number and levels of different ACPA specificities increase toward the onset of arthritis; however, there is no further increase once clinical arthritis has begun(74). Accordingly, the number and type of ACPA specificities do not differ largely between early and late disease(75). Anti- immunoglobulin G (IgG) antibodies or RF arise later and less frequently than ACPA, and they may continue to increase in prevalence after the onset of arthritis(74, 76).
The synovial infiltrate of knee joints of RA patients that had not been clinically swollen before, nevertheless, showed chronic inflammation(77). In animal models of RA, inflammation in joint pathological specimens precedes clinically detectable inflammation. Persons at an increased risk of RA have increased numbers of T-cells in their knee synovium even if they did not yet have knee symptoms(78), again suggesting that the transition to chronic inflammation takes place before the onset of clinically apparent arthritis. Once the symptoms begin, a higher number of recognized ACPA specificities are associated with a higher rate of transition to clinical arthritis(73). This means that once a person notices the first symptoms of RA, the pathological immune response has matured to a large extent, but not completely.
Although the immunological driving processes of RA do not seem to differ between early and late RA, it is well known that better clinical results can be obtained by treating RA patients early and aggressively(79). A recent analysis concluded that this window of opportunity starts to close 4 months after the onset of symptoms(80). This implies it is still possible during that period to interrupt certain processes perpetuating the
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