Racca C, Berthelot S, Franken J, Licois M, Du Pasquier A , et al.
European journal of pain (London, England) •
Erythromelalgia is a rare disorder characterised by burning pain, erythema and increased skin temperature in the extremities. Its pathophysiological heterogeneity, together with variable treatment responses, complicates management in the absence of evidence-based guidelines. This systematic review appraised pain-management strategies across reported aetiological subtypes. Following PRISMA 2020 guidelines, the review was registered in PROSPERO (CRD420251232074). PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for studies published or registered between 1 January 2000 and 30 April 2026. Randomised controlled trials, non-randomised interventional studies, cohort studies and case series were eligible; non-randomised studies required at least five individuals. Risk of bias was assessed using Joanna Briggs Institute tools and certainty of evidence using GRADE. Of 3372 records, 25 studies reporting 591 individuals were included. Aetiological subtype was reported for 277 individuals (46.9%). Mechanistic and aetiological characterisation varied substantially across domains, with haematological data available for 72.6% and SCN9A status for 19.0% of the overall population. Moderate-certainty evidence supported aspirin in myeloproliferative neoplasm-associated erythromelalgia. Low-certainty evidence suggested benefit from mexiletine and carbamazepine in primary erythromelalgia, as well as from prostaglandin analogues, corticosteroids, selected topical therapies and sympathetic interventions in specific contexts. Evidence for selective Naᵥ1.7 inhibitors and most other interventions was of very low certainty. Treatment-response patterns in better-characterised populations suggest that aetiology and underlying mechanisms may be relevant to treatment selection. However, this mechanism-informed approach remains hypothesis-generating and requires prospective validation through systematic aetiological and mechanistic characterisation. This systematic review provides a comprehensive, graded evaluation of the full spectrum of pain-management strategies in erythromelalgia, including systemic, topical, interventional and non-pharmacological approaches, across reported aetiological subtypes. Integrating risk-of-bias appraisal and GRADE certainty ratings, it identifies moderate-certainty evidence for aspirin in myeloproliferative neoplasm-associated disease and low-certainty evidence for conventional sodium-channel blockers in selected primary forms, while evidence for other interventions remains low or very low. These patterns suggest that aetiology may inform treatment selection, but require prospective validation.
Ducrocq M, Penalba V, Castillo L, Bodemer C, Greco C , et al.
Frontiers in medicine •
Gain-of-function mutations in , which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine's efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.
Paroxysmal vascular acrosyndromes are related to a peripheral vasomotor disorder and presented as paroxysmal color changes of the fingers. They include primary Raynaud's phenomenon (RP), which is the most common, secondary RP and erythermalgia. They are to be distinguished from non-paroxysmal acrosyndromes such as acrocyanosis and chilblains, which are very frequent and often associated with RP, digital ischemia and necrosis, spontaneous digital hematoma and acrocholosis. The challenge of a consultation for a vascular acrosyndrome is to make positive diagnosis through history and clinical examination, and to specify its nature, to prescribe complementary exams. In any patient consulting for RP, assessment includes at least an antinuclear antibody test and capillaroscopy. For erythermalgia, a blood count and even a search for JAK2 mutation are required. A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed. The treatment of RP is essentially documented for secondary RP where calcium channel blockers are indicated in first line, and iloprost in severe cases. The treatment of primitive erythermalgia is based on sodium channel blockers such as mexiletine or lidocaine infusions, and on drugs effective on neuropathic pain, such as gabapentin or amitryptiline, in case of erythermalgia associated with small fiber neuropathy. The treatment of erythermalgia associated with myeloproliferative syndromes is based on etiological treatment and aspirin.
To assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). Thirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). While 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. Peripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. The association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype.
Greco C, Leclerc-Mercier S, Chaumon S, Doz F, Hadj-Rabia S , et al.
JAMA dermatology •
Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation. To examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations. In this case series, 3 patients from 2 unrelated families who had TRPV3-mutation-associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019. Clinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance. The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted. The findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.