Erythromelalgia and the Association With Paraproteinemias: A Retrospective Case Series

Erythromelalgia (EM) is a rare and underrecognized condition characterized by pain, erythema, and warmth of the extremities. EM has been associated with genetic mutations and underlying systemic diseases, including myeloproliferative disorders and autoimmune conditions. Despite these connections, most cases of EM are regarded as idiopathic. This study reports a case series of 38 patients with EM, three of whom had concomitant paraproteinemia, and hypothesizes a possible association between EM and monoclonal gammopathy of undetermined significance (MGUS). We conducted a retrospective review of adults ≥ 18 years with a diagnosis of EM (ICD-10 [I73.81]) who were seen by a dermatologist between January 1, 2012, and January 1, 2024, at a single academic affiliated practice. Patients were identified using the electronic medical record, and the study was approved by the review board at the University of Kentucky on December 4, 2023. Abstracted information included patient demographics, medical history, and disease characterization. Study data were managed using REDCap (Research Electronic Data Capture). Descriptive statistics were used to summarize patient characteristics, medical history, and clinical information. Data analysis was performed using GraphPad Prism Version 10.0.0. We identified 38 patients with EM (28 women [74%], 10 men [26%]; mean [SD] age at diagnosis, 55.0 [20.7] years) (Table 1). Eighteen patients (47%) and 30 (79%) demonstrated upper and lower extremity involvement, respectively. Most patients (34 [90%]) demonstrated bilateral involvement. Five (13.2%) patients showed involvement of additional body regions, including the mouth and face. Serum protein electrophoreses (SPEP) and immunofixation electrophoreses (IFE) were obtained in 13 (34%) and 15 (40%) patients, respectively. 13 (34%) patients had these tests performed following their EM diagnosis. Of the 15 patients with an IFE, three (20%) were diagnosed with MGUS (Table 2). Of the three patients with concomitant MGUS and EM, none of them had a prior diagnosis of a myeloproliferative disorder or autoimmune condition. Total Protein: 6.9 Albumin: 4.3 Alpha-1: 0.4 Alpha-2: 0.8 Beta-1: 0.5 Beta-2: 0.3 Gamma: 0.6 (L) IgG: 627 (L) IgA: 37 (L) IgM: 151 Total Protein: 6.2 Albumin: 4.0 Alpha-1: 0.3 Alpha-2: 0.5 Beta-1: 0.4 Beta-2: 0.2 Gamma: 0.8 IgG: 831 IgA: 162 IgM: 22 (L) Total Protein: 6.2 Albumin: 3.9 Alpha-1: 0.2 Alpha-2: 0.7 Beta: 0.9 Gamma: 0.5 IgG: 494 (L) IgA:105 IgM: 59 (L) Whether by coincidental association or pathological relation, the current literature suggests a significant overlap between conditions associated with MGUS and those associated with EM [1, 2]. Given the poorly understood pathogenesis of EM, current research should analyze associated conditions to understand the possible pathogenic mechanisms at play better. Although EM is a rare condition with an incidence of around 1 per 100,000 patients [1], MGUS is relatively common, with the highest incidence being in nonagenarian males at 530 per 100,000 patients [3]. Although our study is limited by the sample size and its inability to discuss causality, the observed incidence of MGUS in our cohort of EM patients was greater than the predicted rate of MGUS in EM patients if the two pathologies occurred independently. Regarding the management of patients with concomitant MGUS and EM, our cohort demonstrated subjective improvement with multimodal approaches (Table 2). Given that current guidelines recommend risk-stratifying and monitoring patients with MGUS, it is unclear whether the presence of MGUS with EM would impact management. Previous literature has demonstrated an association between IgM monoclonal gammopathies and symmetric distal polyneuropathy, primarily affecting large sensory fibers [4]. This neuropathy has been attributed to the demyelination of peripheral nerves by M-proteins. Likewise, there appears to be a profound association between EM and small and large fiber neuropathies [1], although patients with EM may not exhibit reduced nerve density [5]. EM is a relatively rare and underrecognized condition, both within the dermatologic community and the medical community at large. Our findings indicate that patients with EM may have a higher incidence of paraproteinemia compared to the general population, a finding that could help explain the neuropathic component of EM. Larger cohorts are required to elucidate whether paraproteins play a role in the clinical course of EM. The authors declare no conflicts of interest.