Predicting the Future: Prognostication in Rheumatoid Arthritis

EULAR 2022 (VIRTUAL)—When a patient is diagnosed with rheumatoid arthritis (RA), several questions often come to mind: How does this affect life activities? Will I develop joint deformities? What can I expect my future to look like? At the 2022 Congress of the European Alliance of Associations for Rheumatology (EULAR), an abstract session on the subject of prognosis and prediction in RA highlighted several fascinating research projects that help clinicians better understand how to respond to patients when they ask these questions.

Active Discordance

Rudresh Shukla, MD, clinical research fellow in rheumatology, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, England, delivered the first talk, which was on the subject of discordance between certain disease activity scores and ultrasound findings in patients with RA. Dr. Shukla introduced the concept of active discordance, in which the Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28ESR) score for a patient indicates active disease but synovitis is not found on power Doppler ultrasound, and remission discordance, in which the DAS28ESR score indicates disease remission but synovitis is seen on power Doppler.

Dr. Shukla et al. used data from the VERDERA trial (i.e., very early etanercept and methotrexate vs. methotrexate with delayed etanercept in RA) to analyze features related to active and remission discordance and concordance—the latter meaning that DAS28ESR and ultrasound findings are consistent and both show either disease activity or remission.¹

In an evaluation of the 120 patients in this study, several trends were noted. First, about one-third of patients transitioned from active concordance at baseline to active discordance early on with treatment. Second, a sizable number of patients continued to show active discordance despite disease-modifying treatment. Third, early treatment with etanercept, together with methotrexate, increased the probability of imaging and clinical remission, even as early as week 12. Finally, the presence of power Doppler tenosynovitis at baseline was a predictor of DAS28 remission with or without synovitis seen on power Doppler ultrasound.

Early treatment with etanercept, together with methotrexate, increases the probability of imaging & clinical remission even as early as week 12.

Tenosynovitis on MRI

In the second talk, Nikolet K. den Hollander, MD, PhD, research physician, Leiden University Medical Center, the Netherlands, discussed the value of magnetic resonance imaging (MRI) in detecting rheumatoid arthritis early on in patients with contemporary undifferentiated arthritis. For this study, contemporary undifferentiated arthritis was defined as a patient with features of rheumatoid arthritis who did not meet either the 1987 or 2010 ACR/EULAR classification criteria for RA.² Den Hollander et al. looked at undifferentiated arthritis patients in the Leiden early arthritis cohort from 2010 to 2020.

At baseline, these patients underwent MRI of the hands and feet and were evaluated for swollen joint count, positivity for rheumatoid factor and anti-citrullinated protein antibodies (ACPA), and elevation of C-reactive protein. The primary outcome measure was development of RA at one year of follow-up.

The researchers found that tenosynovitis, as seen on MRI in these patients, was independently associated with RA development, especially among patients with the absence of rheumatoid factor and ACPA. In patients without tenosynovitis in oligoarthritis or polyarthritis, essentially no progression to RA was seen.

These data are helpful in both preventing overtreatment and identifying patients at higher risk of progression to RA, although Dr. den Hollander noted that implementation of such routine use of MRI in real-world clinical practice may be challenging.

Synovial Tissue Macrophages

In the third lecture, Stefano Alivernini, MD, PhD, consultant in rheumatology, Catholic University of the Sacred Heart, Milan, Italy, talked about the transcriptomic signature of sustained remission in RA as seen in synovial tissue macrophages. Essentially, Alivernini et al. sought to evaluate the histological composition of synovial tissue in RA patients who were in sustained clinical and ultrasound remission.³ The researchers hoped to identify synovial biomarkers that are predictive of disease flares or, conversely, of disease remission using histology, macrophage phenotyping and spatial transcriptomics.

The researchers found that synovial tissue enhancement of macrophages positive for MerTK (a member of the Tyro-AxlMerTK family of receptor tyrosine kinases) was associated with remission maintenance in RA patients in sustained remission after treatment modification.

In addition, digital spatial profiling analysis revealed unique transcriptomic signatures of lining and sublining macrophages in patients in remission that are then associated with subsequent disease flare after treatment modification.

By understanding RA on this molecular level, researchers and clinicians may one day be able to identify features that predict maintenance of remission or high likelihood of relapse of disease.

2 New Antibodies

Later in the session, Diane van der Woude, MD, PhD, rheumatologist and head of the Outpatient Clinic, Leiden University Medical Center, the Netherlands, spoke about two new antibodies that may be relevant in patients with seronegative RA. Dr. van der Woude noted that antimalondialdehyde-acetaldehyde (antiMAA) antibodies have, in the past, been described in patients with seropositive and seronegative RA, osteoarthritis, systemic lupus erythematosus and a number of cardiovascular diseases.

Anti-advanced glycated end-products (anti-AGE) antibodies have been seen in patients with diabetes and cardiovascular disease, but some data indicates that, in RA, these antibodies may correlate with disease activity.

In evaluating nearly 1,200 patients enrolled in the Leiden early arthritis cohort, van der Woude et al. were able to measure anti-MAA and anti-AGE antibodies and perform statistical analyses looking at the prevalence and co-occurrence of antibodies, associations with genetic risk factors and associations with different phenotypes of disease.⁴

These researchers were able to show that anti-MAA and anti-AGE antibodies exist in patients with seropositive and seronegative RA and, at a lower prevalence, in patients with such conditions as psoriatic arthritis and crystalline arthritis. More specifically, these antibodies help identify a subgroup among patients with seronegative RA who are also positive for HLA-DRB1*03:01, have increased markers of inflammation and have shown some degree of radiographic progression. Although these antibodies are not a panacea, they may help sub-classify patients within disease categories.

In Sum

A great deal remains to be learned about disease pathogenesis, identifying patients at risk for progression of disease and knowing when to intervene in preclinical disease.

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Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Emery P, Horton S, Dumitru RB, et al. Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: The VEDERA trial. Ann Rheum Dis. 2020 Apr;79(4):464–471. [Published correction appears in Ann Rheum Dis. 2021 Mar;80(3):e45.]
2. den Hollander N, Verstappen M, Sidhu N, et al. Hand and foot MRI in contemporary undifferentiated arthritis: In which patients is MRI valuable to detect rheumatoid arthritis early? A large prospective study [OP0083]. Ann Rheum Dis. 2022;81(suppl 1):55–56.
3. Perniola S, Tolusso B, Elmesmari A, et al. Digital spatial profiling reveals distinct synovial tissue macrophage transcriptomic signature of sustained remission in rheumatoid arthritis patients at risk of disease flare after treatment cessation [OP0084]. Ann Rheum Dis. 2022;81(suppl 1):56.
4. van Wesemael TJ, van den Beukel MD, Hoogslag ATW, et al. Antibodies against advanced glycation end-products (anti-age) distinguish patients with a more inflammatory profile and worse outcome in seronegative rheumatoid arthritis [OP0086]. Ann Rheum Dis. 2022;81(suppl 1):57.