Pemphigus foliaceus (PF) is an autoimmune skin disorder characterized by the loss of intercellular adhesion of keratinocytes in the upper parts of the epidermis (acantholysis), resulting in the formation of superficial blisters [1,2]. It has an endemic forms, and previously, we described a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia (El Bagre-EPF), (AKA pemphigus Abreu-Manu). It is an autoimmune disease presenting in a circumscribed geographic area with genetic and environmental factors influencing its pathogenesis [1]. This new variant, El Bagre-EPF, occurs in a gold-mining region; it predominantly affects males between 30 and 60 years of age, as well as a few post-menopausal females [1-8]. El Bagre-EPF patients demonstrate complex clinical, epidemiological and immunopathologic features, differing from Fogo selvagem and the Tunisian EPF [1-8]. El Bagre-EPF patients have polyclonal autoantibodies directed not only to epidermal cell junctions, but also to the cell junctions in the skin appendices, their neurovascular bundles and to mesenchymal-endothelial cell junctions [1-8]. The main laboratory findings found in El Bagre-EPF patients include autoantibodies to multiple cell junctions in the skin, and in one third of the patients against cells junctions in multiple organs [1-8]. A subclinical oral involvement [9], and in about one third of the patients, we discovered autoantibodies that appeared to be directed against the optic nerve envelope and its cell junctions [10], to cutaneous nerves and receptors [11], to the cell junctions of the cardiovascular system including its conductive system [12-14], and to cell junctions within the kidney [15]. In this study, we investigated nail abnormalities in patients affected by El Bagre-EPF as reported in the old Portuguese literature in patients affected by FS.

The study was approved by a human quality assurance review board at the hospital in El Bagre, and all participants provided signed informed consent. We performed a case–controlled study of 40 patients with El Bagre-EPF and 40 healthy controls from the endemic area, matched by age, gender, race, demographics, comorbidities, and living and work activities. All subjects were evaluated clinically for the presence of nail alterations. The clinical examination was done independently by two board-certified dermatologists. Bacteriological and mycological studies were performed.

The majority of these patients were not included in our initial description of EPF [1-9]. Only four of the patients originally studied were still alive at the time of this study. Each year, there is a prevalence of around 4–6 new patients, but also 3–4 deaths/year, creating a steady prevalence of the disease endemicity [1-9].

We included only patients who fulfilled the complete diagnostic criteria for El Bagre-EPF: including: clinical and epidemiological features as previously described [1-9], residence in the endemic area[1-9], serum displaying intercellular staining between keratinocytes by direct immunofluorescence (DIF) and to the basement membrane zone (BMZ) of the skin by either DIF or by indirect immunofluorescence (IIF), using fluorescein isothiocyanate (FITC) conjugated monoclonal antibodies to IgG and/or to IgG4, as described previously [1-9]. The patients also must have serum reactivity against desmoglein 1 (Dsg1) and plakin molecules using immunoblotting (IB) [7,8]. The patient’s serum should also immunoprecipitated a Concanavalin A affinity-purified 45 kDa fragment of Dsg1 [1-9]. The final diagnostic criteria are that the patients must show positive for autoantibodies to pemphigus foliaceus antigens by ELISA [9]. All the patients and controls from the endemic area were tested by the same techniques.

For ethical reasons, we did not take biopsies because the patients have to walk in the jungles, and work inside dirty rivers and creeks and biopsies with open shoes and a biopsy would increase their risk for overt infection especially, in the toenails of the lower limbs.

The toenails were involved in 25/40 El Bagre-EPF and the changes in the nails were seen in patients with the chronic form of the disease (p < 0.05). Acute patients suffering El Bagre-EPF for less than six months showed no alterations. No patients hand finger nails were affected (p < 0.05). The more common nail alterations included change of color yellowish (Viera’s sign) (25/40) (p < 0.05). This yellowish stain resembles the one seen as if dipped in iodine, Vieira’s sign). None of the controls presented with the Viera’s sign. Subungual hyperkeratosis was also very common 20/40) (Fig. 1), and was often associated with distal onycholysis (18/40) (p < 0.05). In 2/40 controls that had psoriasis, distal onycholysis was also observed (Fig. 1). The Viera’s sign was not seen in any control. Other toenails alterations included paronychia, onychorrhexis, onychatrophia in some areas of the area near the nail cuticle, and onychomadesis (most were often seen together) (18/40) El Bagre-EPF patients, and no such changes were seen in controls. Onychogryphosis (nail thickening and scaling under the nail), common in the elderly, was seen equally in cases and controls (10/40) (Fig 1).

Involvement of the nail unit in pemphigus is believed to be uncommon, especially in pemphigus foliaceus (PF) [16-18]. In this study, we found that in patients with a chronic El Bagre-EPF variant, the toenails are altered as described by the old Portuguese literature in patients affected by FS. We speculate that the cell junctions are targets within the nails in El Bagre-EPF patients, and are likely damaged by the autoantibodies; however, this is just speculation because for ethical reasons we did not perform biopsies. The can speculate that the toenails were affected because the continue trauma that these nails embrace due to the outside working activities of these patients often using open shoes. The autoantibodies, the continue inflammation and the trauma can make the toenails more prom for the clinical findings we observed. We were not able to determine the cause of the Viera’s sign in this study.

With regards to the putative cause of the chronic paronychia we can speculate it to be a result of acantholysis of the lateral nail fold and the chronic inflammation in the adjacent dermis. With regards to the onychomadesis, we hypothesize that this may be the result of inhibition of normal nail plate growth and development; alternatively, the formation of blisters underneath the nail may result in detachment of the nail plate.

Unknown etiologies, predisposing factors and discrepancies evident in the current literature suggest that further investigation of endemic pemphigus foliaceus of the nail may result in additional clinical findings and may contribute to our understanding of the extent of the disease.

Our findings indicate that patients affected by El Bagre-EPF demonstrate significant toenail findings, especially in chronic cases. We suggest that the nails in the patients affected by other variants of EPF including FS and the Tunisian EPF need to be study.