The Role of Matrix Molecules in the Early Diagnosis of Rheumatoid Arthritis

Early treatment for rheumatoid arthritis (RA) is recommended, which typically involves disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX). However, for many patients, DMARD therapy alone is inadequate to halt progression, and subsequent treatment with more targeted therapies, such as those that target tumor necrosis factor, is common.¹ A significant proportion of patients with RA — approximately 40% — do not respond to this approach.¹

Ideally, early diagnosis — and early treatment — is most effective in reducing inflammation. One major obstacle to this is that the existing biomarkers of disease can’t predict prognosis or patients’ response to treatment.¹ In the United Kingdom, researchers evaluated whether targeting proinflammatory signals from the extracellular matrix that develops during inflammation can provide a new treatment option for RA.

Does Tenascin Hold the Key to New Treatment Options?

Tenascin-C (TNC) is a large, multimodular extracellular matrix molecule that is limited in healthy tissues, but increasingly found in areas with cellular stress and tissue injury, where it triggers inflammation by activating toll-like receptor 4 (TLR4).² Lasting expression of TNC is believed to be the catalyst for chronic inflammation in autoimmune, neurological, metabolic, and fibrotic diseases.² Elevated serum TNC is not specifically associated with RA.¹ In fact, raised serum levels of TNC have been reported in diseases without a known arthritic manifestation, including cryptogenic pneumonia, chronic hepatitis C, inflammatory bowel disease, sepsis, and cardiovascular diseases (eg myocardial infarction and dilated cardiomyopathy).¹

Regarding its role in detecting RA, earlier research concluded that tenascin was found in normal synovium just beneath the whole lining cell layer.³ A higher density and wider distribution of the protein was observed in patients with RA and osteoarthritis, but the correlation was unclear at that time.³ Further investigation has determined that TNC levels were elevated in both RA cartilage and synovium, and the TNC soluble form was detectable in synovial fluids of patients with RA.³ It was then that researchers began connecting high serum TNC levels with joint erosion in patients with RA.³ High TNC also is a predictor of poor response to biological treatment.²

Promising Research

During experimental joint disease, mice lacking TNC are protected from prolonged synovial inflammation and tissue destruction.² Although inflammation is induced in these animals, it’s also quickly resolved. During the mapping of the active domain within TNC, researchers discovered a unique structural epitope in the fibrinogen like globe (FBG) that is essential for TNC to bind to and activate TLR4.² More specifically, distinct modes of receptor activation and diverse downstream effects induced by FBG compared with pathogenic TLR4 agonists presented a potential therapy for reducing inflammation while preserving a patient’s defense against infection.²

To assess antibody efficacy in synovial cells from patients with RA, researchers examined samples from 4 cohorts of patients with RA. Staining biopsies of inflamed synovia with these antibodies revealed evidence of protein very early in the onset of RA and at higher levels than in people with established disease.² Prophylactic administration of anti-FBG antibodies in rats with collagen-induced arthritis didn’t affect the induction of joint inflammation, but did inhibit the disease’s progression and prevented joint damage.² In short, early changes in the synovial microenvironment contribute to the development of RA. However, blocking inflammatory signals from the extracellular matrix could offer a new therapeutic strategy for treating this disease.

A Closer Look at Anti-FBG Antibodies

Current approaches to targeting TLR4 in RA have focused on antibodies that prevent receptor reaction.² Spurring the production of anti-FBG antibodies during this most recent study, however, provides evidence of a nonredundant role for TNC activation of TLR4.² These antibodies are a useful tool for learning more about how endogenous inflammatory stimuli shape immune responses, researchers say, and could enable a shift from blocking TLR4-mediated inflammation at the receptor level to targeting only disease-specific stimuli.² Because TNC is necessary for joint inflammation to continue, researchers believe that blocking it will reduce inflammation without affecting global immune response.²

Pioneering New RA Treatments

Earlier research found that whereas TNC levels increase over the course of RA progression, treatment with infliximab produces a rapid reduction in serum TNC levels, more so than in patients receiving just MTX.¹

During the recent UK study, in rats with joint inflammation induced by type II collagen, increasing doses of the antibody C3 significantly reduced clinical score and paw swelling.² In addition, C3 therapy reduced the number of affected paws per animal and reduced the incidence of histopathological changes in the joint.²

Some questions remain²:

1. Does activation of TLR4 by the FBG domain occur in isolation or concurrently with signaling by other TNC domains?

2. How are signals from TNC integrated within complex tissue networks?

3. How are tissue-specific responses to TNC mediated?

4. How are different forms of TNC distributed across different tissues?

Future Implications

Recent research reveals that antibodies can target proinflammatory signals from the extracellular matrix. Testing for the presence of anti-FBG cTNC in the serum of patients with early signs of inflammation may help diagnose RA earlier.³ Further, these patients may benefit from therapeutically targeting the same FBG TNC domain with specific monoclonal antibodies at the start of treatment.³ This approach has the potential to block proinflammatory and immune signals from tenascin inside the synovial tissue.³

The topic should be further explored for use in clinical practice for treating RA, including that window within which anti-FBG treatment is most efficacious.

References

1. Page TH, Charles PJ, Piccinini AM, Nicolaidou V, Taylor PC, Midwood KS. Raised circulating tenascin-C in rheumatoid arthritis. Arthritis Res Ther. 2012;14(6):R260.

2. Aungier SR, Cartwright AJ, Schwenzer A, et al. Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy? Ann Rheum Dis. 2019;78(2):186-191.

3. Cutolo M, Soldano S, Paolino S. Potential roles for tenascin in (very) early diagnosis and treatment of rheumatoid arthritis [published online February 1, 2019]. Ann Rheum Dis doi: 10.1136/annrheumdis-2019-215063