By treating pain and weight as isolated conditions, rheumatology is missing the biological pathways that connect them, according to experts at EULAR26.
For years, a 60-year-old woman cycled through various specialist departments trying to find an answer to her debilitating, multi-system symptoms.
At the infectious disease department, she was diagnosed with chronic fatigue syndrome, “a label often used as a medical dustbin when a patient’s symptoms do not fit into rigid categories,” Professor Lars Arendt-Nielsen, a pain expert at Aalborg University in Denmark, said, speaking at the European Alliance of Associations for Rheumatology congress (EULAR26) held in London.
A gastroenterologist, he continued, diagnosed her with irritable bowel syndrome (IBS).
When she felt chest pain, a cardiologist labelled it as atypical chest pain.
She finally reached the department of rheumatology, where her chronic widespread pain was recognised as fibromyalgia and nociplastic pain.
Though obtaining a correct diagnosis significantly improved her quality of life, cases like these highlighted how medical specialities routinely treat interconnected symptoms in silos, Professor Arendt-Nielsen said.
“This fragmentation is amplified for the 30% to 40% of fibromyalgia patients who are also affected by obesity, as they must additionally navigate pervasive clinical biases and the dismissive attitude that their widespread pain is merely a consequence of their weight,” he said.
“Fibromyalgia and obesity are not merely co-occurring comorbidities. They are deeply intertwined conditions driven by shared neuroendocrine pathways and systemic, subclinical inflammation.”
When these two conditions coexist, they act in synergy so that “one plus one equals three,” he said.
The neuroendocrine crosstalk
Fibromyalgia and obesity share a continuous, low-level pro-inflammatory cytokine profile.
Elevated levels of tumour necrosis factor-alpha (TNF-𝛼), interleukin-6 (IL-6), interleukin-8 (IL-8), and high-sensitivity C-reactive protein (hs-CRP) are consistently seen in both populations.
Quantitative sensory testing reveals that a higher body mass index (BMI) directly correlates with increased pain sensitisation and centralised pain gain.
This subclinical inflammatory state acts as a shared pathological driver, with an elevated pool of pro-inflammatory cytokines continuously amplifying the central nervous system’s pathways, worsening the patient’s subjective pain experience.
Professor Ernest Choy, the head of rheumatology and translational research at the Institute of Infection and Immunity and director of the Cardiff Regional Experimental Arthritis Treatment and Evaluation (CREATE) Centre at Cardiff University School of Medicine in the UK, challenged the clinical tendency to label unexplained symptoms as purely psychological.
“[It] is a throwaway word to reflect our ignorance” he said.
The brain functions as a highly connected network; sleep, depression, anxiety, and pain processing do not live in isolated compartments.
An example of this integrated biology is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress responses and demonstrates a blunted cortisol response in fibromyalgia.
This neuroendocrine network connects to adipose tissue, which secretes active signalling proteins called adipokines that signal the central nervous system to regulate appetite, energy expenditure, and immune cell behaviour.
Under standard conditions, tissue macrophages maintain a quiet, anti-inflammatory baseline state. But cellular stress from excessive fat accumulation recruits aggressive M1-type immune cells into adipose tissue.
These cellular invaders act as tiny chemical factories, driving the persistent overproduction of systemic TNF-𝛼 and IL-6. In addition, neuroendocrine mapping reveals that pro-opiomelanocortin (POMC) neurons in the hypothalamus, which regulate energy homeostasis, feeding behaviour, and stress responses, are self-inhibited by β-endorphin.
This deep metabolic entanglement became even more apparent when examining how hormone levels shift as pain and weight collide, said Professor Choy.
While fibromyalgia patients consistently exhibit high rates of insulin resistance that correlate with disease duration, their adipokine signalling displays unique abnormalities.
In contrast to the classic leptin resistance and elevated leptin levels seen in standard obesity, normal-weight fibromyalgia patients display paradoxically lower leptin levels compared to healthy controls.
This distinct neurohormonal variance underlines the fact that fibromyalgia pain involves delicate central nervous system rewiring, which directly interacts with metabolic signalling.
“Our biology connects all our systems together—the brain, our hormone system, our metabolism, our whole biology are related. To think about these individual systems in isolation is deeply problematic,” said Professor Choy.
From caloric restrictions to GLP-1 receptor agonists
Translating these biological insights into clinical practice requires an evaluation of weight-management interventions specifically in fibromyalgia cohorts.
At EULAR26, Professor Francesco Ursini, a rheumatologist at the University of Bologna, Italy, presented a comprehensive review of the clinical literature, tracing the evolution of weight-reduction strategies from behavioural modifications to targeted pharmacotherapy.
One study evaluated 33 patients with fibromyalgia placed on a strict, uncooked vegan regimen. After 12 weeks, participants saw a 45% reduction in resting pain and a 17% reduction in BMI, though it was unclear if the benefit came from the weight loss or the diet’s specific composition.
A later study added Cognitive Behavioural Therapy (CBT) and physical activity to caloric restriction. While the average weight loss was modest at 4.4%, it led to statistically significant improvements in Fibromyalgia Impact Questionnaire (FIQ) scores, although pain severity decreased by only 13%.
Related
Other studies investigated the impact of bariatric surgery on patients with fibromyalgia. In one, a substantial 40% reduction in total body weight led to a 61% reduction in pain at rest, along with a significant decrease in the number of painful, localised tender points.
Another one observed the prevalence of musculoskeletal manifestations drop from 25% to 2% following substantial weight loss.
“The interesting part of these studies is that for the first time [we see that] with a significant, substantial weight loss, the benefit can extend well beyond the mechanically loaded joints, so as to achieve non-mechanically loaded joints,” Professor Ursini said.
This finding was further validated by the TSD (Therapeutic Small Diet) randomised controlled trial.
Patients were prescribed either a strict 1200 kcal/day diet for six months or given general healthy eating guidelines.
Patients in the intervention group who lost 10% of their body weight showed significant improvements in FIQ scores and reduced tender point counts, even in upper body sites like the trapezius, suggesting weight loss has benefits beyond just unloading mechanical joints.
An important observation across these studies is that profound symptom improvement often occurs rapidly, well before substantial tissue mass is lost, Professor Ursini explained.
For instance, a very low-calorie, liquid meal replacement (800 kcal/day) diet study demonstrated that 72% of patients experienced a 30% or greater reduction in symptoms within just two weeks, while weight loss remained marginal.
This suggests that severe caloric restriction may have an immediate analgesic effect independent of actual weight loss.
Professor Ursini’s team evaluated a low-carbohydrate ketogenic diet (LCKD) in patients with fibromyalgia.
Over a six-month period, participants achieved a 14% weight reduction alongside a 40% drop in FIQ scores. In addition, 89% of participants reached the minimal clinically important difference (MCID) by week 4, even though their total weight loss was still under 6%.
Generalised estimating equation modelling confirmed that changes in BMI over time were not statistically associated with improvements in patient-reported outcomes, indicating that the benefits of ketogenesis are driven by biochemical changes, such as increased gamma-aminobutyric acid (GABA), decreased neuroinflammation, and enhanced mitochondrial function, rather than by mechanical unloading alone.
“Symptom improvement was observed also at non-weight bearing sites, supporting the potential role for biochemical mechanisms beyond mechanical factors,” Professor Ursini said.
Emerging research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists (such as semaglutide) may help treat both obesity and fibromyalgia pain.
Preclinical studies demonstrated that GLP-1 receptors are selectively expressed on the spinal dorsal horn – the primary relay station for pain signals in the spinal cord – of both normal and neuropathic rats.
Intrathecal injections of exenatide, the first GLP-1 receptor agonist, reduced the hypersensitivity phase of pain while completely sparing acute, protective pain perception.
This effect was driven by the release of pain-blocking 𝛽-endorphins. The researchers subsequently showed that exenatide prompts a protective cellular transformation in the spinal cord’s immune cells (microglia).
Essentially, the drug flips these cells from an aggressive, M1 pro-inflammatory state that amplifies pain into a soothing, M2 anti-inflammatory state. This shift increases the production of interleukin-10 (IL-10), a potent natural anti-inflammatory cytokine that calms local nerve irritation.
Clinically, a large-scale retrospective cohort study utilising US electronic health records confirmed that patients prescribed GLP-1 receptor agonists had significantly lower odds of requiring opioid prescriptions, alongside fewer diagnostic codes for severe pain and fatigue.
A call for an interdisciplinary approach
The clinical lessons of the past 25 years show that while achieving a weight loss threshold exceeding 10% is important for long-term fibromyalgia management, lifestyle modifications alone frequently fall short, Professor Ursini said.
Clinicians must remain vigilant regarding standard prescribing habits; common gabapentinoids, such as pregabalin, act as potent weight-inducing agents that can inadvertently worsen a patient’s metabolic profile.
“We forget that some of the drugs that we use commonly, like normal painkillers, sometimes are actually our weight gaining drugs,” he warned.
Historically, the rapid expansion of biologic therapies has focused rheumatology heavily on joint destruction and overt peripheral inflammation.
However, with a growing cohort of patients rotating unsuccessfully through multiple biologics due to persistent nociplastic pain, Professor Arendt-Nielsen called for a stronger collaboration between rheumatologists and pain specialists.
“Rheumatology and pain [management] should go hand in hand,” he said.
The EULAR 2026 Congress was held in London from 3-6 June.
