Sunrise, Sunset: A Look Back on the Year in Rheumatology

WASHINGTON, D.C.—Although 365 days is a long time to account for when it comes to advances in a field such as rheumatology, the two speakers at the ACR Convergence 2024 Year in Review lecture did a wonderful job summarizing key highlights.

Can RA Be Prevented?

The first speaker was Michael Pillinger, MD, professor of medicine and of biochemistry and molecular pharmacology at New York University Grossman School of Medicine, who provided the clinical year in review talk. Dr. Pillinger began by asking the question: Can rheumatoid arthritis (RA) be prevented by preclinical intervention? Because abatacept blocks co-stimulation during antigen presentation and acts at an early stage in the immune process of RA, two studies this past year evaluated this medication’s ability to prevent RA.

In the APIPPRA study, 213 individuals with inflammatory joint pain and antibodies to citrullinated protein antigens (ACPAs) and rheumatoid factor were randomized to receive either abatacept or placebo for 12 months. Participants were followed for an additional 12 months. After 12 months, about 30% of participants in the placebo group had RA or inflammation in ≥3 joints vs. only 6% in the abatacept group. At 24 months of follow up, 37% of participants in the placebo group had developed RA vs. 25% in the abatacept group.¹

In the ARIAA study, individuals with ACPA positivity who showed signs of inflammation on magnetic resonance imaging (MRI) were randomized to receive abatacept or placebo for six months and were, then, observed for 12 months without treatment. Improvement in inflammation on MRI was seen in 61% of patients in the abatacept group compared with 31% in the placebo group, and 34.7% of participants in the placebo group had progressed to RA by six months vs. 8.2% in the abatacept group.²

Based on these studies, Dr. Pillinger concluded that abatacept provides proof that treating pre-RA by blocking T cell co-stimulation can reduce progression to frank RA and that a minority of patients may be able to avoid long-term therapy. However, further studies are needed to explore this topic.

Cardiovascular Risk in Gout

Dr. Pillinger next discussed gout, a condition that clinicians have long recognized to be associated with an increased risk of cardiovascular disease. What is new, however, is an emerging understanding of how fast that risk can increase. In a study from Cipolletta et al., researchers looked at patients with newly diagnosed gout—which they considered to be a surrogate for the patient’s first flare—and created three time periods: pre-exposure baseline (i.e., before gout diagnosis), exposed period (i.e., 120 days after gout diagnosis) and post-exposure baseline (i.e., more than 120 days after gout diagnosis).

The study found that, in the period of 30 days after a new diagnosis of gout, patients are at about a 1.7-fold increased risk of cardiovascular events, which included fatal and nonfatal myocardial infarction, ischemic or hemorrhagic stroke and transient ischemic attack, compared with their baseline risk before gout diagnosis.³

Dr. Pillinger agreed with the study authors that these findings support the need for cardiovascular risk management as early as the time of first gout consultation, particularly in the first 30 days after diagnosis.

Osteoarthritis

Dr. Pillinger went on to discuss osteoarthritis (OA), the most common form of arthritis and the one that is still lacking in disease-modifying treatments. Although a study by Laslett et al. found that krill oil did not show any benefit for patients with knee OA, a study evaluating methotrexate was more promising.⁴

In this study by Kingsbury et al., mor than 200 patients with symptomatic, radiographic knee OA were randomized to receive either oral weekly methotrexate—with a six-week escalation of 10 to 25 mg—or matched placebo over 12 months along with continued usual analgesia. At six months, a statistically significant reduction in pain, stiffness and function was seen, though Dr. Pillinger noted that the total reduction was modest for each measure.⁵

In a separate study looking at once-weekly semaglutide, a GLP-1 receptor agonist, in patients with obesity (BMI ≥30) and knee OA with moderate to severe pain, Bliddal et al. found the mean change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score was statistically significant at 68 weeks (-41.7 points with semaglutide compared with -27.5 points with placebo).⁶ No biomarkers were collected during the study, so Dr. Pillinger explained that we do not know if pain reduction was related to weight loss or if other mechanisms contributed to improvement. However, in either case, semaglutide may be an option to help knee OA in patients also suffering from obesity.

Dr. Pillinger proceeded to discuss additional work on lupus, myositis, systemic sclerosis, vasculitis and Sjogren’s disease.

Semaglutide may be an option to help knee OA in patients also suffering from obesity.

Advancements in Basic Science

The second half of the session, led by S. Louis Bridges Jr., MD, PhD, Franchellie M. Caldwell Professor of Medicine, physician-in-chief and chair, Department of Medicine, Hospital for Special Surgery, New York, focused on basic science advancements.

Picking up on the topic of OA, Dr. Bridges noted that Nav1.7 voltage gated sodium ion channels are encoded by the gene SCN9A. In a study from Fu et al., human OA chondrocytes were found to express functional Nav1.7 channels, which appear to regulate secretion of molecules, such as HSP70 and midkine, that help to maintain cartilage integrity. In mouse models of OA, blocking Nav1.7 in chondrocyctes lessened progression of structural joint damage, indicating that Nav1.7 may be a potential target for future disease-modifying OA therapies and non-opioid pain relief medications for OA.⁷

Pain with Low Inflammatory Synovitis

Next, Dr. Bridges discussed a paper that hints at why patients with RA who do not have active synovitis may still experience joint pain and tenderness.

Bai et al. identified a group of more than 2,200 genes that are preferentially expressed in the synovial tissues of patients with RA and low inflammatory synovitis but significant joint pain. The researchers then used a machine learning approach to identify a set of 815 pain-related genes. They found that these genes are most highly expressed in the lining layer of synovial fibroblasts. Moreover, pain scores were positively associated with expression of these pain-related genes among patients with established RA and low inflammatory synovitis. In contrast, this association was not seen among patients with RA and high inflammatory synovitis.⁸

Dr. Bridges explained that these findings may help explain the mechanism underlying pain and tenderness in patients with RA without synovitis and that these pathways may provide targets for novel treatments to alleviate joint pain in patients with RA and other chronic forms of arthritis.

Why Autoimmune Diseases Are More Common in Women

Dr. Bridges also summarized a study by Dou et al. that looked at why autoimmune diseases are more common among women than men.⁹ Among the possible reasons for this difference is X chromosome inactivation (XCI) in which one of the two X chromosomes in females is randomly silenced in each cell in early embryonic development to balance gene expression between XX females and XY males. XCI is regulated by Xist, a long non-coding RNA. Because several binding proteins, such as La/SS-B, are known autoantigens in autoimmune disease, the researchers used an inducible transgenic expression of Xist in male mice to introduce Xist RNP complexes and produce autoantigens.

In male mice models of lupus, those expressing transgenic Xist developed more severe multi-organ pathology than wild types. Additionally, reactivity of serum from human lupus patients to multiple components of Xist RNP complex was found to be higher than that of individuals from the general population. These findings would, therefore, support a model of autoimmunity in which expression of Xist and formation of the Xist RNP complex in females leads to changes in T and B cells and epigenetic changes that could lead to the production of autoantibodies.

In Sum

From start to finish, the session was enlightening and high yield. 2024 was clearly a big year for rheumatology, and 2025 promises to be the same.

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. Cope AP, Jasenecova M, Vasconcelos JC, et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): A randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. 2024 Mar 2;403(10429):838–849.
2. Rech J, Tascilar K, Hagen M, et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): A randomised, international, multicentre, double-blind, placebo-controlled trial. 2024 Mar 2;403(10429):850–859.
3. Cipolletta E, Nakafero G, Richette P, et al. Short-term risk of cardiovascular events in people newly diagnosed with gout. Arthritis Rheumatol. 2024 Sep 15. Epub ahead of print.
4. Laslett LL, Scheepers LEJM, Antony B, et al. Krill oil for knee osteoarthritis: A randomized clinical trial. 2024 Jun 18;331(23):1997–2006. Erratum in JAMA. 2024 Sep 26. Online ahead of print.
5. Kingsbury SR, Tharmanathan P, Keding A, et al. Pain reduction with oral methotrexate in knee osteoarthritis: A randomized, placebo-controlled clinical trial. Ann Intern Med. 2024 Sep;177(9):1145–1156.
6. Bliddal H, Bays H, Czernichow S, et al. Once weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024 Oct 31;391(17):1573–1583.
7. Fu W, Vasylyev D, Bi Y, et al. Na_v7 as a chondrocyte regulator and therapeutic target for osteoarthritis. Nature. 2024 Jan;625(7995):557–565.
8. Bai Z, Bartelo N, Aslam M, et al. Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis. Sci Transl Med. 2024 Apr 10;16(742):eadk3506.
9. Dou DR, Zhao Y, Belk JA, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. 2024 Feb 1;187(3):733–749.e16.