A 46-year-old female patient presented with a 4-year history of erythromelalgia marked by nightly episodes of burning pain, erythema, and heat intolerance affecting the hands and feet, with symptoms relief achieved only by prolonged immersion in cold water, according to a recent case report.
Erythromelalgia is a rare neurovascular pain disorder characterized by episodic erythema, increased skin temperature, and burning pain, often triggered by heat or exertion. The patient’s neurologic examination was normal outside of symptomatic flares, and she reported no sweating abnormalities. Her medical history included class 1 obesity (body mass index [BMI] = 33.9 kg/m²), antiphospholipid syndrome, homozygous MTHFR C677T and heterozygous prothrombin G20210A mutations, prior transient ischemic attack and episode of pulmonary embolism, and chronic migraine with aura. The patient had no history of diabetes or insulin resistance.
Laboratory testing, including inflammatory markers, thyroid function, and hemoglobin A1c was unremarkable. Genetic testing across 24 genes identified no pathogenic variants. Skin biopsy demonstrated normal intra-epidermal nerve fiber density (12.5/mm), and nerve conduction studies were normal. Quantitative sensory testing showed mildly elevated thermal detection thresholds in a non–length-dependent and asymmetric pattern that was inconsistent with small-fiber neuropathy.
Prior treatments provided limited or no relief. Increasing aspirin to 150 mg daily produced modest benefit, and misoprostol was discontinued as a result of abdominal cramping. The patient hadn't used gabapentin, pregabalin, or antidepressants because of concerns about the adverse effects.
The glucagon-like peptide (GLP)-1 receptor agonist semaglutide was initiated for weight management at 0.25 mg weekly and titrated to 1 mg. By week 4, the patient's erythromelalgia symptoms had resolved completely. At the time of remission, BMI had decreased from 33.9 kg/m² to 33.2 kg/m², corresponding to a 2-kg weight reduction. After 15 months of treatment, total weight loss reached approximately 30 kg, with the patient's BMI declining to 23.2 kg/m². She remained on semaglutide 1.0 mg weekly with no recurrence of erythromelalgia symptoms during follow-up.
Repeat quantitative sensory testing demonstrated normalization of thermal thresholds. Clinical photographs documented resolution of distal erythema, swelling, and mottling, with normal appearance of the hands under warm conditions.
The researchers noted that erythromelalgia pathophysiology involves microvascular dysfunction and, in some cases, small-fiber abnormalities. In this patient, normal nerve fiber density and absence of thermal allodynia argued against small-fiber neuropathy, while sensory testing suggested functional dysregulation. The researchers outlined potential mechanisms for GLP-1 receptor agonists, including anti-inflammatory effects, modulation of nociceptive signaling, and improved endothelial function with reduced arteriovenous shunting.
The rapid resolution of symptoms prior to substantial weight loss supported a pharmacologic rather than metabolic effect. However, the researchers highlighted that causality cannot be established from a single case. Additional limitations included the study's retrospective assessment, absence of validated pain scoring, and lack of continuous perfusion or temperature monitoring. The researchers also noted that responses may differ across GLP-1 receptor agonists.
The report represented, to the researchers’ knowledge, the first documented case of complete erythromelalgia remission following GLP-1 receptor agonist therapy and may help generate hypotheses for future controlled studies in neurovascular pain syndromes.
"Given the growing use of GLP-1 [receptor agonists] and the unmet need for effective [erythromelalgia] therapies, further investigation of their role in neurovascular pain syndromes is warranted," concluded lead study author Susanna Sofie Laugsand, RN, BScN, of the Department of Gastrointestinal Surgery at St. Olavs Hospital at Trondheim University Hospital in Norway.
Co–study author Tore Wergeland, MD, PhD, reported receiving honoraria from TEVA, Roche, Lilly, and Lundbeck and holding stock in Vilje Bionics AS and Keimon Medical AS. The study authors reported no other conflicts of interest.
Source: JAAD Case Reports