A new study suggests that lingering rheumatoid arthritis symptoms are not always caused by ongoing inflammation.
For people with rheumatoid arthritis, lingering pain and fatigue are often assumed to be signs that inflammation remains active. But new research suggests the real culprit may sometimes lie elsewhere. Researchers at Semmelweis University report that sleep disorders, depression, obesity, and smoking can help sustain symptoms even when inflammation is under control, potentially trapping patients in self-reinforcing cycles that are difficult to break.
In studies published in Nature Reviews Rheumatology and The Lancet Rheumatology, the team introduced a model designed to help doctors identify and address the underlying causes of symptoms sooner.
The researchers examined the connections between depression, smoking, obesity, sleep problems, and other health conditions in people with difficult-to-treat rheumatoid arthritis.
Rheumatoid arthritis is a chronic autoimmune condition in which the immune system mistakenly attacks the joints, leading to pain, swelling, and stiffness. The disease affects tens of thousands of people in Hungary. While most patients respond to treatment, an estimated 6 to 28 percent fall into the “difficult-to-treat” category because they do not achieve sustained remission despite therapy.
The findings suggest that conditions such as depression, obesity, smoking, and sleep disorders do more than simply occur alongside rheumatoid arthritis. They may also contribute to the persistence of the disease and its symptoms.
The Vicious Cycle of Pain, Depression, and Poor Sleep
For example, pain and depression can reduce physical activity, contribute to weight gain, and worsen both sleep quality and mood. These effects can then intensify pain and interfere with daily functioning, creating a self-reinforcing cycle that is difficult to break.
In addition to identifying these patterns, the researchers developed a model aimed at improving care for patients with difficult-to-treat rheumatoid arthritis. Under the widely used “treat-to-target” strategy, doctors regularly track measurable indicators of disease activity and adjust treatment if inflammation remains uncontrolled. This may involve increasing medication doses or switching to a different therapy.
The researchers argue that this approach can serve another purpose as well. It may act as an “early warning system” that helps identify cases in which symptoms are not primarily caused by inflammation.
“When target values improve, but the patient still suffers from pain and fatigue, it is worth taking a step back. In such cases, instead of automatically prescribing more medication, doctors should look for what is maintaining the symptoms – whether it is chronic pain syndrome, depression, sleep disorders, or obesity,” said Dr. György Nagy, head of the Department of Rheumatology and Immunology at Semmelweis University.
A New Early Warning System for Persistent Symptoms
The team has observed that this approach can improve outcomes for patients with difficult-to-treat disease. In many cases, it may also strengthen the relationship between doctors and patients.
Their model has gained significant international attention. The publications that introduced the concept of difficult-to-treat disease and the associated treatment strategy have been cited more than 1,000 times by other researchers. The definition is now used worldwide not only for rheumatoid arthritis but also for other medical conditions.
The researchers are now focused on the next phase of their work. Alongside their ongoing studies, they plan to participate in projects that use artificial intelligence to develop more effective treatments for people with rheumatoid arthritis.
“With AI-based pattern recognition, we could identify subgroups among patients, and with the help of these data, we could create more effective, almost personalized treatment strategies for them,” explained Dr. Lilla Gunkl-Tóth, PhD student at Semmelweis University and first author of the publications.
References:
“Bridging the gap: combining treat-to-target and difficult-to-treat strategies in the management of rheumatoid arthritis” by Lilla Gunkl-Tóth, Iain B. McInnes and György Nagy, 2 March 2026, Nature Reviews Rheumatology.
DOI: 10.1038/s41584-026-01354-w
“Associated lifestyle factors and comorbidities of difficult-to-treat rheumatoid arthritis: a systematic review and meta-analysis” by Wenhui Xie, Tong Chen, Yuan Chen, Zhuoli Zhang and Shiyu Xiao, 15 April 2026, The Lancet Rheumatology.
DOI: 10.1016/S2665-9913(26)00041-X
“Lifestyle factors in difficult-to-treat rheumatoid arthritis” by Lilla Gunkl-Tóth and György Nagy, 15 April 2026, The Lancet Rheumatology.
DOI: 10.1016/S2665-9913(26)00108-6
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