Preclinical RA: an ACR roundup

5 minute read

The race is on for both definition and therapy as researchers currently pull vigorously in multiple directions.

There is always a buzz of activity at any rheumatology conference around the definition and significance of early or subclinical rheumatoid arthritis.

ACPA positivity in the general population is common and of uncertain significance. MRI inflammation in the dominant hand may be a better marker of risk but needs to be combined with a clear clinical archetype which is yet to be defined.

As a result, researchers currently pull vigorously in multiple directions, resulting in an unclear and possibly zero net vector to overall progress. Nonetheless, there is much to talk about.

The Great Debate on the Sunday encapsulated a lot of these issues neatly, with a sensible summary being that there might be benefit in trying to prevent development of clinical RA, but we don’t yet have enough evidence to determine how that is best achieved, nor in whom it should be attempted. 

The ‘whom it should be attempted’ part of this discussion has been raging for decades. We know that people with a positive family history, personal or passive smoking history, evidence of imaging inflammation (MRI or US) and ACPA positivity are all at higher risk of progressing to RA.

In time we might add DNA methylation of white blood cells, based on data presented in abstract 0531, where machine learning techniques predicted development of seronegative RA with a sensitivity of 90%, specificity of 88% and accuracy of 89%.

Perhaps ACPA detection in sputum will play a role. Dr Timothy Wilson MD has demonstrated a hazard ratio of 4.2 for the development of RA within 5 years of this finding in abstract 0533.

Interestingly, this links in with the scientific session by Dr Paul Noble on interstitial pneumonia with autoimmune features (12S116). Dr Noble offered the opinion in this session that most ACPA-positive patients with ILD develop RA eventually. Audience members seemed agreeable to the idea of being a bit more open to diagnosing RA in this subpopulation.

This last point, however, is contentious and circles back to why there is argument regarding the definition of RA.

CCP-associated ILD may be a disease in its own right, but treatment along RA algorithms would be impossible since they are largely based on tender and swollen joint counts.

During the Great Debate an audience member asked if we should be treating ACPA-positive patients with IHD along similar lines to preclinical RA patients. Her question was largely dismissed but bears investigation.

Abstracts 1646, 1649 and 1650 present a clear case for worsened cardiovascular and all-cause mortality outcomes in patients with poorly controlled RA. The joints don’t kill these patients. Other things (mostly heart attacks) do. Is there a subtype of ACPA-positive disease that might first affect the lung or heart? Would such a disease even fall within the remit of a rheumatologist to treat?

Into this theme of disease activity emerging before joint pathology was an abstract session in which Dr Duncan Porter MD identifies increased rates of bacterial infection in patients with preclinical RA (12S140). Using a combination of clinical cohorts and database analysis, he has captured increased rates of infection occurring 12 months before onset of RA symptoms.

He offered several interesting hypotheses.  Maybe infections or the antibiotics used to treat them trigger autoimmunity. Maybe disease itself causes increased susceptibility due to tissue damage. Maybe the relationship is coincidental. Or perhaps most alluring is the concept of a bidirectional disease – infection promoting autoimmunity which in turn promotes infection.

Starting to answer the question of ‘Is there benefit to early treatment?’ was an abstract presented by Dr Juergen Rech MD which demonstrates the ability to decrease progression to clinical RA with six months of abatacept given to preclinical patients.

These findings are largely emergent, unproven in large trials and important mostly for their capacity to inspire further lines of enquiry. It remains unclear how to define emerging RA.

As stated convincingly in the Great Debate we do not want to treat biomarkers for an uncertain net benefit. There would be enormous and unpredictable impacts on the health system, and patients’ psychological, physical and financial wellbeing if we tried.

But equally, it is difficult to return disease to health once it becomes well established. Prevention is better than disease modulation. And this debate needs to continue.

Sessions and abstracts

13S127. The Great Debate: To Treat or Not? The Role of DMARDS in Subclinical Rheumatoid Arthritis 

12S140. Abstracts: RA – Diagnosis, Manifestations, and Outcomes I: Pre- and Early Disease (abstracts 0530–0535)

0531. Development and Performance of a Diagnostic Precision Biomarker for Seronegative Rheumatoid Arthritis Based on DNA Methylation in Blood

0533. Sputum RA-Associated Autoantibodies Independently Associate with Future Development of Classified RA in an At-Risk Cohort of Individuals with Systemic Anti-CCP Positivity

M14M114. Abstracts: RA – Diagnosis, Manifestations, and Outcomes II: Cardiovascular and Other Comorbidities (abstracts 1646–1650)

1646. Major Adverse Cardiovascular Events and Mortality with Opioids versus NSAIDs Initiation in Patients with Rheumatoid Arthritis

1649. Five-Year Cardiovascular Event Risk in Early Rheumatoid Arthritis Patients Who Received Treat-to-Target Management

1650. Systemic Immune Inflammation Index Predict All-Cause and Cardiovascular Mortality in Rheumatoid Arthritis

12S116. Interstitial Pneumonia with Autoimmune Features: What the Rheumatologist Needs to Know

Dr Maxine Isbel is a Perth-based final year rheumatology trainee and is currently doing a master’s in clinical research.

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