Is targeting specific autoantibodies the future of rheumatoid arthritis treatment?

The outlook for patients with rheumatoid arthritis (RA) has brightened significantly in recent years. Improvements in imaging enable both disease detection at a very early stage and the assessment of even minor disease progression.

Potential biomarkers hold promise for refined diagnosis, treatment selection and monitoring. The range of available treatments for people living with RA has expanded markedly thanks to our increasing understanding of disease pathophysiology. However, despite these advances, significant unmet need remains: a substantial proportion of patients still do not achieve sustained remission, today’s recognised treatment goal.

The pathogenesis of RA is driven by a complex interaction of pro-and anti-inflammatory pathways involving many cellular and molecular mediators. The consequence is sustained inflammation in the soft inner lining of articular joints – the synovial tissue. This causes severe pain, swelling and stiffness, and can lead to permanent damage and deformity in structural joint elements like cartilage and bone. Some organ systems – such as cardiac tissue, the vascular system, kidneys, lung tissue and the nervous system – may ultimately also be damaged by systemic inflammation.

Autoantibodies – potentially harmful, pathogenic antibodies that can produce an abnormal response from the body’s immune system in which it conducts a sustained attack on a person’s own cells, tissues and organs – have been implicated in chronic conditions, including RA. In RA, autoantibodies are highly prevalent and may significantly contribute to the development and progression of this chronic inflammatory disease. Selectively blocking these autoantibodies may hold a key to alleviating disease for many patients who lack or lose response to current therapies.

For treating patients with moderate-to-high disease activity, current RA treatment guidelines target sustained disease remission, with low disease activity as a compromise target if remission is not achievable.

Initially, patients usually receive conventional monotherapy as the first line of treatment. Unfortunately, more than half of patients with early RA do not achieve remission with this step and require escalation to advanced therapies for better outcomes. Despite the advancement of treatment options, tremendous unmet need still remains, including for the 20-30% of patients living with RA who are refractory to or develop resistance to current advanced therapies. Given that RA is the most common inflammatory joint disease, affecting some 1% of our society, this translates into millions of people continuing to struggle with its debilitating impact. This typically includes not only joint pain and stiffness, but also significantly reduced physical function and health-related quality of life.

There is thus a compelling need for new therapies with novel mechanisms of action for those patients who are not experiencing remission with current treatment options.

The majority of people with RA (up to 72%) are seropositive for anti-citrullinated peptide (ACPAs) and/or rheumatoid factor (RF) autoantibodies. In fact, ACPA and RF may be present in some patients years before the onset of clinical symptoms, indicating that immune responses implicated in the development of RA are initiated very early.

These autoantibodies may be involved in pathophysiological mechanisms in the inflammatory response in RA and their presence can predict progression of joint destruction.

‘There is a compelling need for new therapies with novel mechanisms of action for those patients who are not experiencing remission with current treatment options’

Research has shown that in people who are positive for ACPAs, a type of immunoglobin G (IgG) antibodies, bone loss may start even before the onset of clinical disease – long before patients consult a rheumatologist.

Given that so many RA patients continue to have refractory disease, continued research into new treatment strategies is essential. Our aim is to pursue novel mechanisms of action, including combinations of treatments, that could shatter the efficacy ceiling still experienced by many patients with RA and other antibody-mediated immune diseases.

In RA, established treatments do not consistently reduce autoantibodies. One exciting avenue of clinical research that is currently underway targets antibody reduction. It’s building upon our ever-evolving understanding of the immune system and is enabling us to pursue actionable science to address the substantial unmet medical need of patients.

Someday, clinicians may be able to offer RA patients treatments that are tailored to their personal disease characteristics (such as having high autoantibody levels) and reduce their RA burden significantly better than current treatment options, with acceptable safety. This is a future we could all embrace.

References are available on request.