Pain 101: The Latest Thinking on Rheumatoid Arthritis Pain

At the 2018 World Congress on Pain, arthritis pain researcher Camilla Svensson discussed the causes of RA pain.

Editor’s Note: At the 2018 World Congress on Pain in Boston, the biennial meeting of the International Association for the Study of Pain (IASP), researchers from around the world gathered from September 12-16 to discuss the latest pain research. Twelve young scientists attending the World Congress were selected to provide first-hand reporting from the event, as part of the PRF Correspondents program, which is a science communications training program provided by the Pain Research Forum, RELIEF’s parent site. Here, PRF Correspondent Charlie Kwok, PhD, a postdoctoral fellow at Hotchkiss Brain Institute, University of Calgary, Canada, reports on a plenary lecture delivered at the meeting by arthritis pain researcher Camilla Svensson. (RELIEF’s news coverage is editorially independent of its publisher, IASP. All editorial decisions about our reporting on IASP activities are made solely by the RELIEF editors).

Chronic pain afflicts one in five adults across the world, and a large proportion is related to arthritis. In her plenary talk at the 2018 World Congress on Pain in Boston, Camilla Svensson provided a snapshot of some of the latest thinking about the causes of pain in arthritis, in particular rheumatoid arthritis (RA).

Svensson, an arthritis pain researcher at the Karolinska Institute in Stockholm, Sweden, showed that pain is a multifaceted feature of RA involving complex interactions between bone cells, nerve cells, and immune cells. She pointed to studies in animals that are advancing the understanding of how RA pain arises, which could lead to new treatments.

What is rheumatoid arthritis?

Paleopathologists—scientists who study ancient diseases in humans and animals—have shown that even dinosaurs had arthritis, which dates this condition back to the prehistoric era. Today, researchers recognize more than 100 different types of arthritis and associated conditions. Although pain is a common symptom, the root causes of pain differ between the various forms of arthritis.

To better understand the genesis of pain in arthritis, Svensson studies RA, one of the most common forms of arthritis. RA is a condition in which the immune system malfunctions and attacks the joints. It affects up to 1% of the population and is approximately three times more common in women than men. A sizeable number of RA patients report dissatisfaction with their pain management and rate pain relief as their top priority for an improved quality of life.

At the beginning of her talk, Svensson described how RA progresses in stages. In the “pre-RA” stage, patients show an increase in autoantibodies, which are antibodies made by the immune system that attack the body’s own proteins. For example, 70% of RA patients have a type of autoantibody called anti-citrullinated protein antibody (ACPA). People with higher levels of this autoantibody, which can be detected in the blood, are more likely to develop RA.

In the pre-RA stage, although there is no obvious inflammation, pain and bone loss can already be underway. Indeed, joint pain commonly develops before the onset of joint inflammation, and can change in quality and intensity throughout the course of disease.

The next stage, known as active RA, features inflammation, pain and bone loss. The body now produces small proteins called cytokines that in this case cause inflammation and are detectable in the blood. Based on this knowledge, drug developers created new medicines that control joint inflammation and reduce destruction of bone and cartilage (the tissue that cushions the joints) by blocking the activity of the cytokines.

Finally, post-inflammatory RA is the late stage of the disease. Here, joint inflammation is no longer a problem but pain persists nonetheless.

Where does the pain come from? Looking to animals for a better understanding

Svensson said that when signals from damaged joints during RA reach the brain, this can culminate in an experience of pain. So, in order to understand what causes pain in RA, it’s necessary to study what’s happening both in the joint and in the nervous system and to assess the communication between the two.

This is something that pain researchers are doing by using animal models of arthritis pain. These models may not capture all aspects of the human disease, but they allow scientists to study biological processes in a controlled way and to measure the effects of existing and new potential therapies.

In the case of RA, a number of animal models in rodents have been developed based on the symptoms and characteristics of RA patients. This so-called “bedside to bench” strategy—taking observations first made in people as a basis for studies in animals to learn more—increases the likelihood of discovering new and effective pain relievers.

For example, in the collagen-induced arthritis (CIA) model, animals receive an injection of collagen type II (a protein found naturally in cartilage) and an inflammatory substance called complete Freund’s adjuvant (CFA). This triggers inflammation, followed by the production of antibodies against the collagen protein. This puts the cartilage under attack.

The CIA model is a good one for scientists to use because it reproduces many symptoms that human RA patients have. This includes the entry of immune cells into the joint cavity, swelling of the synovium (the soft tissue that lines the inner surfaces of joints), and the loss of bone and cartilage. The CIA model also affects multiple joints, as occurs in people with RA. The animals show pain-related behaviors that last for at least 28 days after the onset of arthritis.

Making a transfer

In another type of RA model called a transfer model, scientists take antibodies or blood serum from arthritic animals or patients and inject them into healthy animals. This allows them to study the progress of RA in a time-controlled manner—researchers can see exactly when the disease starts, how inflammation progresses over time, and the effects of therapies.

The transfer models also capture many RA symptoms that humans have. And, importantly, pain is evident before the start of inflammation and persists during and after inflammation. This allows researchers to study pain at all the different RA stages.

In one type of transfer model, researchers take ACPA autoantibodies (these are the ones found at higher levels in RA sufferers) from patients and inject them into healthy mice. This causes pain and bone loss without joint inflammation, which allows for the study of pre-RA pain.

Svensson showed that the ACPA autoantibodies can activate osteoclasts, a type of bone cell that removes old bone. These bone cells then make interleukin-8 (IL-8), a cytokine that can directly excite sensory neurons surrounding the joint, ultimately leading to pain. Interestingly, in this model, inhibiting the function of IL-8 with reparixin, a drug that blocks the protein to which IL-8 attaches, reduces pain.

Autoantibodies can also cause pain by attaching to Fc-gamma receptors, which are proteins found on immune cells as well as pain-sensing neurons. Svensson showed that by experimentally removing these proteins from pain-sensing neurons, pain could be eased in a transfer model of RA.

Together, then, the studies using these models show that autoantibodies can cause pain in at least two ways: directly, by affecting the Fc-gamma receptors found in sensory neurons, and indirectly, through their effects on osteoclasts and the cytokines those bone cells make.

A role for microglia, the immune cells of the central nervous system, in RA pain

RA pain comes about not only from increased activity of the sensory neurons surrounding the joint, but also by events in the central nervous system (spinal cord and brain). Here Svensson described another line of research showing that microglia—known as the immune cells of the central nervous system—can trigger an immune response that contributes to persistent RA pain.

For example, microglia make cathepsin S, an enzyme that breaks down proteins. This leads to the release of fractalkines (a type of small cytokine) from sensory neurons, and these molecules then enter the spinal cord from inflamed joints. Next, the fractalkines can trigger the production of other inflammatory cytokines by microglia. This increases the activity of sensory neurons that transmit electrical signals from the spinal cord to the brain, further contributing to pain.

Interestingly, stopping the release of fractalkines from sensory neurons by inhibiting the cathepsin S enzyme effectively reduces pain-related behaviors in the CIA model of RA.

All in all, this line of research shows that during joint inflammation, microglia enhance the activity of sensory neurons within the pain system. This communication between microglia and nerve cells can be a key contributor to the pain of RA.

The relationship between pain and inflammation

Studies in animal models and in people show that RA pain does not always mirror joint inflammation. This has challenged the belief that by successfully treating joint inflammation, pain will necessarily disappear.

For example, Svensson showed that in a transfer model of RA, some drugs that ease inflammation in people, including diclofenac (a so-called non-steroidal anti-inflammatory drug, or NSAID) and a different type of drug called etanercept, did not reduce pain.

Why would pain persist in the absence of inflammation? It’s likely because pain is maintained by other biological processes, Svensson told the audience.

An intriguing finding from a commonly used drug for pain

Interestingly, gabapentin, a drug that eases neuropathic pain (pain from nerve injury) in people, also reduces pain in a transfer model of RA, according to Svensson. She showed a series of studies showing signs of nerve damage in multiple animal models of RA.

For instance, molecules associated with nerve regeneration have been found in the dorsal root ganglion of the animals. This is an area at the back of a spinal nerve where signals from pain-sensing neurons in the joint are relayed into the spinal cord.

Svensson also pointed to studies in RA animal models showing an increased nerve supply in tissues in and around the joint. This can also amplify signalling in the pain pathway.

Paying the Toll

Svensson also described a role for Toll-like receptors (TLRs) in RA. These molecules sit on the surface of many different types of cells, including bone, immune and nerve cells. TLRs become activated when there is tissue damage, which spurs the production of pro-inflammatory cytokines that subsequently enhance signalling from pain-sensing neurons.

A study by Svensson’s group found that dampening the activity of TLRs during the active stage of RA prevented the development of late-stage pain in an animal model. Perhaps a similar approach could be a way to relieve RA pain in people, long after inflammation in the joints has subsided.

An intricate picture

Svensson’s talk showed that animal models are improving the understanding of what causes pain during RA—but they are telling a complex story. Indeed, scientists now know that RA pain requires many different types of cells, including bone cells, immune cells and nerve cells, all of which interact in complex ways. Further complicating the picture is that while inflammation accompanies RA, it’s not necessary for there to be pain.

By understanding how RA pain comes about, at the level of cells and molecules, researchers will be better able to design new treatments, which promises to improve the pain and functioning of millions of people who suffer from RA.

Image credit: Puwadol Jaturawutthichai/123RF Stock Photo.