6 days ago
Arthritis Treatment Reduces Painful Flare-Ups, Slows Disease
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A new therapeutic approach for rheumatoid arthritis (RA) could help prolong the time between flare-ups and even prevent the onset of the disease in at-risk patients.
This is the promise of a new study by researchers who have developed nanoparticles that both slow disease progression and reduce flare severity—rather than just manage symptoms.
RA is a chronic condition which cannot be cured that affects some 1.5 million people in the U.S. alone. It occurs when the immune system attacks joint tissue, causing inflammation, swelling and pain. As the disease progresses, more serious cartilage and bone damage can occur if not managed properly.
While disease-modifying anti-rheumatic drugs (DMARDs) like abatacept canreduce arthritis activity and slow progression of symptoms, most people still experience flare-ups. And for those with 'pre-RA', who may have detectable levels of RA antibodies but no symptoms, there aren't any approved treatments to prevent disease onset.
Older woman holding hand in pain.
Older woman holding hand in new treatment approach builds on previous research led by Dr. Nunzio Bottini, director of the Kao Autoimmunity Institute at Cedars-Sinai, and Nisarg Shah, chemical and nano engineering professor at University of California San Diego. They reported that calcitriol-loaded nanoparticles (CLNP)—calcitriol being the active form of vitamin D3—help regulate immune responses and decrease inflammation for autoimmune diseases in joints.
The nanoparticles were made of a polymer containing calcitriol, while the researchers also attached a small protein fragment to them. The fragment is derived from something called aggrecan (Agg), a protein in the joints that the immune system can mistakenly attack in RA. To expand on their previous work, the researchers set out to assess whether the modified nanoparticles could treat RA flares and pre-RA.
They first improved the nanoparticle formulation, focusing on size and stability, to ensure they were free from contaminants and could be safely frozen for a month.
They then confirmed the nanoparticles regulate dendritic cell activity, a type of immune cell responsible for initiating inflammation and flare-ups in RA.
"It is not well known what might prompt the onset of RA mainly because it is hard to get tissue from patients who do not have clear arthritis yet and we cannot predict the onset of flares to take blood or tissue right before they happen," Bottini told Newsweek.
"However, for disease onset it is believed the autoimmune attack grows over a long period of time without clinical symptoms, before emerging as clinical RA. And continuous T cell education by dendritic cells plays a role in the process.
"For flares it is believed that 'resident T cells' remain in the joints once the disease has been controlled and they can cause re-emergence of inflammation based on poorly understood fluctuations. But dendritic cells once again likely play a key role in generating/stimulating those T cells."
Doctor examining older patient's hand.
Doctor examining older patient's hand.
Chinnapong/Getty Images
The researchers took blood samples from people with and without RA and treated the samples with the newly formed Agg-CLNP (the nanoparticles with the protein). Agg-CLNP reduced dendritic cell activity which, in turn, reduced the cell's immune response, according to the researchers. By suppressing the immune response, Agg-CLNP could help alleviate RA symptoms like inflammation and swelling.
The team also tested Agg-CLNP in a mouse model for RA. It was found to delay inflammation and swelling when given as a preventative treatment, but had little effect when administered after the onset of RA.
In a follow-up, the researchers gave both the (currently used) arthritis drug abatacept and Agg-CLNP to the mice. They found that this combination delayed disease onset and reduced joint inflammation, swelling and bone damage.
Additional tests in mice also showed Agg-CLNP reduced future RA flare severity when administered after corticosteroid treatment, which is often used to provide symptomatic relief in conditions like RA, inflammatory bowel disease (IBD), asthma and more.
"There is currently no approved treatment to prevent flares so this would be the first. For disease prevention, some trials of immunosuppressive agents administered to patients at risk (as assessed by early symptoms or strong family history) have shown promising results but implementation will depend on risk-benefit considerations," said Bottini.
"We show that our nanoparticle combined with one of these agents enhances its preventative effectiveness, which might help eventually take the combination into the clinic."
These results highlight Agg-CLNP as a potential therapeutic to address current limitations in RA treatments, the researchers said.
"We think it will mainly help with preventing disease onset in patients at risk probably in combination with other immunosuppressants and to prolong the time to next flare in patients with good control of RA," Bottini explained.
"We don't know if one injection could be enough to prevent disease activity but if repeated injections [in the muscle] are needed we predict, they would occur at several months distance from each other. We are exploring whether this approach can be utilized in combination to reduce severity in patients who have active disease and not sufficient control with current therapies."
The promising therapy will need to go through optimization and toxicity studies, which can only be done in an industry setting after licensing of the technology.
"Currently, aggrecan is the antigen included in the particle. But our aspiration is that the nanoparticle is tailored based on information about the proteins that are attacked by the immune system in each individual patient as they can vary among patients," Bottini added.
"The final result would be an injectable therapy that could be personalized to each patient to maximize efficacy."
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References
Johnson, W. T., McBride, D., Kerr, M., Nguyen, A., Zoccheddu, M., Bollmann, M., Wei, X., Jones, R. M., Wang, W., Svensson, M. N. D., Bottini, N., & Shah, N. J. (2024). Immunomodulatory Nanoparticles for Modulating Arthritis Flares. ACS Nano, 18(3), 1892–1906.
Johnson, W. T., Wilkinson, E. L., Iyer, N., Dolmat, M., Bollmann, M., Dada, N., Wei, X., Yang, S., Zhang, T., Yoo, G., Bernardo, M., Price, M., Frame, E., Ishimori, M., Giles, J. T., Wang, W., Svensson, M. N. D., Bottini, N., & Shah, N. J. (2025). Immunomodulatory nanoparticles enable combination therapies to enhance disease prevention and flare control in rheumatoid arthritis. ACS Central Science.
