Effect of Sublingual Isolated Transfer Factors in a Case of Therapy Resistant Periungual Warts

Background: Periungual warts (PW), also known as verruca vulgaris, are caused by the human papilloma virus and appear as skin lesions located around the nailfold but can also affect the nail plate. Unfortunately, some of the therapies mentioned are destructive by nature and can also damage the nail matrix, hyponychium or underlying bone. Case description: Here we describe a patient resistant to a range of standard treatments. His clinical condition dramatically improved after use of isolated transfer factors (TF). Conclusion: As shown in this case, TF could be a possible effective alternative to treat therapy resistant PW and we hope this report will lead to further investigation, including controlled trials with TF in this patient group.

keratolytics, immunotherapy etc) [4,5]. Unfortunately, some of the therapies mentioned are destructive by nature and can also damage the nail matrix, hyponychium or underlying bone, in addition to the possibility to not solve the clinical condition [2].
Here we describe a patient resistant to a range of standard treatments. His clinical condition dramatically improved after use of isolated transfer factors (TF, which consist of oligo-or polypeptides isolated from porcine spleen). TF are formed by short chains of amino acids with small pieces of ribonucleic acid (RNA) attached [6]. They are produced by T helper cells [7] and contain two subunits within its molecule: tufstin (peptide fraction, believed to be the subunit that stimulates the production of macrophages) and splentopentin, providing immune system-enhancing activity [8]. The release of TF is an indication that T helper cells (Th1 immunity) are active in the mechanistic elimination of pathogens (reason why there were chosen for the treatment of the patient here described), stimulating the production of new T helper cells, natural killer (NK) cells, macrophages and cytotoxic T cells. The general strengthening of the Th1 response is also the result of the suppression in the production of Th2 cells and their related cytokines such as IL-4, IL-5, IL-6 and IL-13, while there is an increase in Th1 cytokine levels (essentially IFN-γ) [9,10].
Although transfer factors are known since 1950s, recent technological improvements including ultrafiltration and peptides characterization, have made the technology a safe therapeutic option [11], available as oral nutritional supplement (under the commercial

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Introduction
Periungual warts (PW), also known as verruca vulgaris, are caused by the human papilloma virus and appear generally as skin lesions located around the nailfold, but can also affect the nail plate [1,2]. The challenge in treating the latter is the difficulty to target the virus effectively. To date, no single therapy has been 'the gold standard' for PW, and it usually shows recurrence after treatment [2,3]. Common treatment options include both physical approaches (chemical-and eletro-cautery, radiotherapy, hyperthermia, cryotherapy, radiotherapy, laser ablation and others) and local or systemic pharmacological options (inhibitors of mitosis, ted in February 2019: 2 sublingual drops of a 100 mg/mL solution, 3-times daily after the meal. No other concomitant treatment was prescribed. The patient returned after 2 months (April 2019), reporting (almost) complete disappearance of the PW ( Figure 1B). In the follow-up visit, in May 2019, the patient remained in remission ( Figure 1C) and the dose was reduced to twice-daily for one more month. The dermoscopy performed after the treatment also showed the improvement in the patient's condition. In his last visit (February 2020), he was still in remission. During all the period using TF, no adverse reaction was observed or reported by the patient.

Discussion
The importance of immunotherapy in the treatment of warts had already been shown in the 70s and 80s, with the use of dinitrochlorobenzene, which induces cell-mediated immunity [13]. However, to our knowledge, this is the first report on the use of isolated TF for PW -although there have been reports on the efficacy of TF in other warts: In combination with levamisole for flat wart patients [14], and in 2 pediatric patients (aged 2 and 12) with the Wiskott-Aldrich syndrome [15,16].
TFs are part of the immune system, and they are believed to act as a unique type of messenger used in cell-to-cell communication. They behave as hybrids between interleukins and antibodies, carrying messages from one cell to another (like interleukins), and binding to antigens in a similar manner to what antibodies do. They consist of small natural peptides which are non-species-specific: They are composed of oligoribonucleotides attached to a peptide molecule inherent and have shown efficacy in a wide range of different viruses [10,11]. Their possible role in this case is due tocoul be related to their immunoregulatory effects, strengthening the Th1 response. The remission observed after 9 months is a good indicative of the potential of this therapy for PW. name of Imuno TF®) in countries such as Brazil, Spain and South Africa, to cite a few.
The product has already been used in treatment of different infection diseases, as can be seen in detail in a review article from Viza, et al. [11]. One of the most important clinical studies showing the ability of TF to prevent viral infection has been publised in the New England Journal of Medicine. In this controlled study, TF was used in children with acute leukaemia. Patients were randomized, receiving either TF or placebo. Sixteen patients in the TF group and 15 in the placebo were exposed to varicella zoster virus. Only one patient in the TF group became infected versus 13 in the placebo group [12]. This encouraged to test the product for the patient with the case of periungual warts described in this paper.

Case Description
A 52-year-old man businessman sought dermatological care at our center in June 2017. He complained of injuries in the back of the right and left hand fingers. On clinical examination, he had hyperkeratotic verrucose plaques on the back of the 1 st , 4 th and 5 th left hand fingers and on the back of the 1 st and 2 nd right hand fingers (no photo was taken at this time). In dermoscopy, he presented thrombosed vessels, a suggestive picture of PW. He was being followed up with rheumatology due to the diagnosis of ankylosing spondylitis and had been using adalimumab regularly for the last 7 years. The patient underwent several different treatments for PW (Table 1).
After all treatments, the patient returned with either no clinical response ( Figure 1A), or with an exacerbation of the disease (emergence of new keratotic papules in the palmar region). Because of the therapy resistant nature of the disease and the reported success of transfer factors in the treatment of viruses [11], treatment with isolated TF (Imuno TF®, InfinityPharma, Brasil) was star-

Conclusion
As shown in this case, TF could be a possible effective alternative to treat therapy resistant PW and maintain the patient in remission. We hope this report will lead to further investigation, including controlled trials with TF for this clinical condition.