A rheumatoid arthritis patient whose blood tests look good and whose joints show little active inflammation can still be in pain and exhausted. Rheumatologists at Semmelweis University in Budapest argue that this gap is common enough to reshape how doctors respond when standard treatment appears to be working on paper but not in the patient.
The team’s conclusions were published in 2026 in Nature Reviews Rheumatology and The Lancet Rheumatology and announced by the university on May 26. Coverage resurfaced in late September through a ScienceDaily repost, so this is an explainer of months-old work rather than a new finding.
When the numbers improve and the pain does not
Modern rheumatoid arthritis care follows a treat-to-target approach: doctors set a goal such as low disease activity or remission, measure it with joint counts and inflammation markers, and adjust drugs until the goal is met. It has improved outcomes for most people. It also creates a trap, because a patient can hit the target and still hurt.
Dr. György Nagy, head of the Department of Rheumatology and Immunology at Semmelweis, put the clinical instruction in a single sentence in the university’s announcement: “When target values improve but the patient still suffers from pain and fatigue, it is worth taking a step back.” Instead of automatically prescribing more medication, he said, doctors should look for what is maintaining the symptoms, whether that is chronic pain syndrome, depression, sleep disorders or obesity. The advice is aimed at a specific moment in the clinic, the follow-up visit at which the chart looks reassuring and the patient’s account does not, and it asks the physician to treat the patient’s report as data rather than as a sign that the drugs need to be stronger.
Rheumatoid arthritis is an autoimmune disease in which the immune system attacks the lining of the joints, and the drugs that changed its outlook, including biologics and Janus kinase inhibitors, work by damping that immune activity. Those drugs address inflammation. They were never designed to treat poor sleep, low mood or the amplified pain signaling that can develop in people who have hurt for years, which is why a normal inflammation reading and a painful joint can coexist without either being an error.
Six to 28 percent of patients fall into a difficult-to-treat group
The researchers work with the concept of difficult-to-treat rheumatoid arthritis, a label for patients who fail to reach sustained remission despite standard therapy. The Semmelweis release, carried by EurekAlert, puts the share of patients in this category at roughly 6 to 28 percent. The spread is wide because studies define the group differently and count different populations.
A March 2 perspective in Nature Reviews Rheumatology, by Lilla Gunkl-Tóth and György Nagy of Semmelweis together with Iain McInnes of the University of Glasgow, argues for folding the difficult-to-treat idea into treat-to-target rather than treating them as rivals. Its authors say such cases often involve “psychosocial distress, comorbidities, chronic pain syndromes and patient or system-related barriers” beyond simple drug resistance, which calls for personalized, multidomain assessment rather than escalating treatment alone.
A vicious cycle among pain, mood, sleep and weight
The Hungarian team describes the mechanism as a loop, and its own release names the specific contributors rather than a vague notion of stress. Depression, sleep disorders, obesity and smoking can each sustain symptoms independently of joint inflammation, and they feed one another. In the release’s wording, “pain and depression may reduce physical activity, increase body weight, worsen sleep and mood – all of which can feed back into pain and everyday functioning.”
Because each link raises the next, adding another anti-inflammatory drug does not touch the parts of the cycle that inflammation is not driving, and a patient can move through several expensive drug changes while the actual sources of pain stay in place. The SciTechDaily write-up and the ScienceDaily repost present it as a warning to clinicians against reflexive escalation, and the framing follows Nagy’s own.
What treatment beyond drugs looks like
A review in the journal Rheumatology, published in May 2026 and co-authored by Nagy, Gunkl-Tóth and colleagues, sets out what the alternative might involve. It covers management of difficult-to-treat disease, including exercise, education, cognitive behavioral therapy for anxiety and depressive symptoms, mindfulness, physiotherapy and dietary changes such as a Mediterranean diet. Its authors say non-pharmacological approaches “should be considered for all patients with RA, especially in non-inflammatory D2T disease.”
The Semmelweis team says its difficult-to-treat framework has been cited more than 1,000 times and is now applied to other diseases. Its next step, according to Gunkl-Tóth as reported by the university, is to use artificial intelligence to pick out subgroups of patients and build more personalized treatment strategies.
Researchers have yet to settle which patients belong in which subgroup. Nothing in the announcement says how many of the 6 to 28 percent are held back mainly by depression, by sleep, by weight or by a pain syndrome, and that breakdown will decide whether the approach can be turned into a routine clinic checklist.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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