Rheumatoid arthritis (RA) — an autoimmune condition in which the body mistakenly attacks healthy joints — causes pain, swelling, and joint damage. A chronic, progressive disease, RA will get worse over time if left untreated. But how, exactly, does this destructive process get kicked off? That’s something scientists are still trying to find out.

For years experts debated two main theories: The “outside-in” hypothesis suggests that RA inflammation starts in the synovial membrane (which lines the capsule of certain joints) and eventually spreads to the marrow inside the bone. An opposing theory, “inside-out,” suggests that inflammation starts within the marrow and later moves out into the synovial membrane.

A new study, published in the journal Arthritis Research & Therapy, comes down on the side of the outside-in hypothesis.

To conduct the study, researchers from Leiden University Medical Center in the Netherlands reviewed MRI scans of the wrist, the metacarpophalangeal joints in the fingers, and the metatarsophalangeal joints in the feet in 76 patients with joint pain who were believed to be developing rheumatoid arthritis. They also measured tender points as well as antibodies and inflammation markers. The participants with joint pain were compared to 62 healthy control subjects.

The researchers found that scores of synovitis and tenosynovitis — inflammation of the synovial membranes and tendons, respectively — were higher in the joint pain patients compared to in the controls. As the disease progressed — 31 patients were officially diagnosed with RA during the study and started on disease-modifying anti-rheumatic drugs (DMARDs) — there was a further increase in synovitis as well as osteitis (bone inflammation).

The pattern that occurred as patients went from joint pain to full-blown RA suggests that the “outside-in” hypothesis is correct, the authors concluded.

“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),” they wrote.

This was a small study and more research is needed, but hopefully these findings will move experts one step closer to getting to the root of RA and perhaps eventually being able to diagnose and treat patients much earlier in the disease process.

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