Rheumatoid arthritis (RA) pain presents something of a conundrum: joint inflammation is a cardinal feature of RA and causes pain, and yet patients often report joint pain before inflammation is apparent. Pain researchers have recently discovered that various chronic pain conditions may result, in part, from an autoimmune response. New research from investigators at the Karolinska Institute in Stockholm, Sweden, now offers additional support for this concept, this time in the context of RA.
Since many RA patients make antibodies directed against their own proteins—in this case against citrulline, a non-essential amino acid made by the body—the researchers injected these so-called “autoantibodies” from RA patients into mice. They discovered that the autoantibodies caused pain-like behaviors in the animals, even though joint inflammation was not present. Rather than cause pain by directly affecting pain-sensing neurons, the antibodies acted on osteoclasts, a type of bone cell, causing those cells to release another molecule, called CXCL1, known to be important for pain signaling.
“Our observations uncover a previously unknown function of [the antibodies] and provide an attractive explanation as to why joint pain often precedes onset of arthritis in autoantibody-positive individuals, and perhaps why joint pain often persists also when inflammation has been successfully treated,” according to Camilla Svensson, who led the study. The results also suggest that drugs able to prevent the activity of CXCL1 could be a new avenue to treat RA-related pain, said Marzia Malcangio, a pain researcher at King’s College London in the United Kingdom, and who was not involved in the study.
The results were published November 27 in the journal Annals of the Rheumatic Diseases.
Autoantibodies lead to pain
Svensson and colleagues isolated autoantibodies specifically targeting citrulline from RA patients, and injected them intravenously into healthy mice. Animals that received the autoantibodies developed heightened responses to touch and temperature (both hot and cold) stimuli that lasted for at least four weeks, indicating chronic pain sensitivity, even though the mice showed no signs of joint inflammation.
To address how the autoantibodies caused pain, the authors examined neurons of the dorsal root ganglia (DRG), which communicate pain signals from the body to the spinal cord. Interestingly, they found that DRG neurons were unaffected by exposing the cells to the autoantibodies. Instead, the autoantibodies affected the activity of osteoclasts, the cells that dissolve bone. This caused those cells to release CXCL1, a type of signaling protein known as a chemokine that has been shown to induce pain. By blocking this signal, the authors were able to reduce pain-like behavior that developed after the autoantibodies were delivered to the ankle joint. This showed that CXCL1 was crucial in the ability of the autoantibodies to cause pain.
Overall, “this study shows a link between RA-associated autoantibodies and pain,” according to Malcangio. “As autoantibodies are present in serum of RA patients even when joint inflammation is controlled, it is conceivable that they maintain pain in RA patients,” she added.
While not all RA patients have these specific autoantibodies, Svensson thinks there may still be an autoimmune basis for pain in those RA patients too—perhaps different autoantibodies are involved. “We are just at the beginning of learning how antibodies can contribute to chronic pain in various painful conditions,” she said. —Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman