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The sequence of articular inflammatory events that ultimately evolves into rheumatoid arthritis (RA) appears to begin at the synovium and tendon sheath with subsequent bone involvement, which is known as the "outside-in" hypothesis, Dutch researchers reported.

Serial MRI scans of the joints of patients enrolled in a clinically suspect arthralgia cohort showed that patients ultimately diagnosed with RA had higher scores for tenosynovitis (mean 1.7 vs 0.27, P<0.001) and synovitis (mean 2.2 vs 0.93, P<0.001) at symptom onset compared with controls, according to Robin M. ten Brinck, PhD, of Leiden University Medical Center in the Netherlands, and colleagues.

In contrast, scores for bone inflammation were not elevated at baseline compared with controls, with similar scores for both osteitis (1.9 vs 1.4, P=0.35) and erosions (1.7 vs 1.8, P=0.53), they reported online in .

Various hypotheses have been suggested to explain the process of joint inflammation that leads to RA, with the "outside-in" hypothesis representing a traditional thinking approach. An alternative "inside-out" hypothesis became popular after imaging and histologic analyses identified osteitis, also known as bone marrow edema, in RA patients, while a third hypothesis suggested that outside inflammation (in the synovium) and inside inflammation (in the bone marrow) could occur simultaneously.

To address the question of subclinical joint inflammation chronology, ten Brinck and colleagues obtained MRI scans of the wrist, metacarpophalangeal joints, and metatarsophalangeal joints of 76 patients present with arthralgias, who subsequently were also diagnosed with RA. Among that group, 31 were given a prescription for a disease modifying antirheumatic drug (supporting the diagnosis) and were included in the current analysis. A group of 62 healthy age-matched controls were also recruited from the general population.

The mean age of the 31 patients was 44, and almost three-quarters of them were women. The median tender joint count at baseline was five, 42% were tested positive for rheumatoid factor, and 29% were tested positive for anti-citrullinated protein antibody (ACPA). The median time between the presentation of arthralgias and the diagnosis of RA was 17 weeks.

Unlike at baseline, when only tenosynovitis and synovitis showed higher scores, the mean osteitis score rose from 1.9 to 2.7 (P=0.036), during the interval between the presentation of arthralgia and the diagnosis of RA. Synovitis scores continued to increase, from 2.2 to 3.4 (P=0.001), but conversely, erosion scores did not significantly increase.

Because ACPA-positive and ACPA-negative RA are considered different clinical entities today, the researchers stratified their results according to ACPA status. Compared with controls, ACPA-positive patients had higher scores at baseline for tenosynovitis, synovitis, and osteitis, whereas ACPA-negative patients showed only higher synovitis and tenosynovitis scores.

During the progression from arthralgia to RA, ACPA-negative patients had significant increases both in osteitis and synovitis (1.1 to 1.7, P=0.03 and 1.8 to 2.9, P=0.003, respectively), whereas in ACPA-positive patients, scores for osteitis and synovitis did increase, but statistical significance was not met. ACPA-positive RA typically has a more gradual symptom onset, the authors noted.

The study findings suggested that the earliest inflammatory manifestations are tenosynovitis and synovitis, that synovitis and osteitis increase in the symptomatic pre-RA phase, and that erosive damage does not appear until after RA becomes clinically apparent. "This implies that inflammation mainly starts outside of the bone (fitting the outside-in hypothesis), after which osteitis develops, which puts the joint at risk for structural damage development in the phase of clinically evident RA (if left insufficiently treated)," the authors stated.

Limitations of the study include the small sample size and the fact that MRIs were obtained only at initial presentation with arthralgia and then again when RA developed clinically.

Further exploration of the presymptomatic phase with imaging would be useful but challenging, because larger numbers of patients would need to be followed with serial imaging for there to be any lasting impact.

Nonetheless, "studies in larger patient groups are needed before the present findings can be translated to clinical practice, [but] the present data does contribute to our understanding of clinical arthritis and RA development," the researchers concluded.