Efficacy and Safety of Platelet-rich Plasma, Metformin and Cryotherapy in Treatment of Non-genital Warts

1. Evaluation of the efficacy and safety of intralesional injection of autologous platelet-rich plasma in treatment of various types of cutaneous non genital warts
2. Evaluation of the efficacy and safety of intralesional injection of metformin in treatment of various types of cutaneous non genital warts
3. Comparing the efficacy and safety of intralesional injection of autologous platelet-rich plasma and intralesional injection of metformin with that of cryocautery in treatment of various types of cutaneous non genital warts.

Cutaneous warts caused by human papillomavirus (HPV) are benign proliferative lesions that occur at any age in human life.

More than 100 different types of HPVs have been fully characterized . Warts may exist in different forms according to the epithelial surface affected and HPV type responsible for the infection. Common warts (Verruca vulgaris), plantar warts (Verruca plantaris), flat or plane warts (Verruca plana) and genital warts (Condyloma acuminata) are some of the clinical manifestations of HPV infection .

Although lesions can resolve spontaneously within 2 years without treatment, treatment is sought by many who are unwilling to wait for spontaneous clearance, by those who do not experience such resolution and for reasons of preventing infections of other individuals and reducing the risk of malignancy . Additionally, pain, discomfort, recurrent bleeding, functional limitation, and esthetic disfigurements due to cutaneous warts are common indications for seeking treatment.

Several therapeutic modalities have been used to treat HPV infections. The choice of treatment should take into account factors such as age, location, number and size of the lesions, clinical subtype and the patient's immunological status.

Available treatments are aimed at either breakdown or removal of visible warts or induction of cytotoxicity against infected cells .

They include destructive agents (keratolytic, cryotherapy, curettage and cautery, laser, photodynamic therapy), antimitotic agents (podophyllin, bleomycin, retinoids), immune stimulants (topical sensitizers, cimetidine), and topical virucidal agents \[formaldehyde (formalin), glutaraldehyde (Glutaral) .

Unfortunately, no single treatment is satisfactory for all patients. Many treatments are time consuming, painful and can leave scars or hypopigmentation; moreover, recurrence rates after any treatment range from 6% to 100% . So, the development of new effective and safe treatments seems to be an urgent need.

Cryocautery represents a first line of therapy for cutaneous warts. It uses liquid nitrogen to freeze tissues and destroy warts.

Liquid nitrogen cryotherapy involves freezing a wart with liquid nitrogen for 10 to 20 seconds every two to three weeks. Precisely how cryotherapy destroys warts is not well understood, but the prevailing theory is that freezing causes local irritation, leading the host to mount an immune reaction against the virus.

However, side effects for cryocautery are common, they include pain, depigmentation, delayed healing, ulceration, scar formation and recurrence

Platelet- rich plasma (PRP) is a small volume of plasma rich in platelets. It has become a hopeful therapy in the last decade to treat several cutaneous diseases due to its increased concentrations of growth factors. As it is of autologous origin, it reduces the possibility of adverse effects and transfusion transmitted infections.

PRP has been utilized in the treatment of numerous cutaneous diseases such as alopecia, skin ulcers, and acne vulgaris. Its utility has been extended to other cutaneous diseases as melasma, hyperpigmentation, and burns, in addition to its usefulness in tissue repair and regeneration.

To the best of our knowledge the efficacy of PRP in the treatment of plane warts was assessed in a single uncontrolled clinical trial which revealed that intralesional injection of PRP was effective and well-tolerated immunotherapy for treating of multiple recalcitrant plane warts.

Moreover, complete remission of multiple resistant plantar warts after treatment by combined intralesional autologous PRP injections and local application of salicylic acid 30% was observed in only one case report.

Mechanisms suggested for such promising response of warts to intralesional injection of PRP included induction of expression of numerous pro-inflammatory cytokines as interleukin-6, interleukin-8, tumor necrosis factor-alpha, and C-C motif chemokine ligand 5 which then activate several immune cells leading to increased inflammation.

Also, platelets expressed CD40L, on its activation; it modulates its interaction with CD40 presenting on macrophages, B-cells, monocytes, endothelial cells, dendritic cells, and mediates their activities.

Platelets may modulate the innate immunity and provide antimicrobial activities either by synthesis of antimicrobial peptides or by modulating the immune activities of other immune cells as neutrophils and monocytes.

These interesting findings open the way for future studies to evaluate the usefulness of PRP in treating different clinical types of warts.

Metformin, a widely used drug to treat type 2 diabetes mellitus and metabolic syndrome, has been used systemically in different dermatological diseases such as hormonal acne, hidradenitis suppurativa (HS) and acanthosis nigricans in which it may act through improving hyperinsulinemia . Additionally, it was found effective when used topically in treatment of melasma with an equivalent effect to triple combination cream , and acne vulgaris .

Metformin has immunomodulatory activity that reduces the production of proinflammatory cytokines, it also inhibits the cytokine production of pathogenic Th1 and Th17 cells .

Furthermore, many studies, both in vitro and in vivo with small animal models, have highlighted the antiviral properties of metformin.

Additionally, Metformin has shown antitumorigenic potential in HPV-positive cancer cells. Such properties suggests that metformin might be effective therapeutic option for viral warts. However, to the best of our knowledge, no studies have been conducted to explore that hypothesis.

Eligibility Criteria:
Inclusion Criteria:

* Patients with cutaneous (extragenital) viral warts (single , new or recurrent, common, plane and/or planter warts.
* Age ranged from 8 to 60 years old.
* No concurrent systemic or topical treatment of warts.

Exclusion Criteria:

* Patients with fever or signs of any inflammation or infection
* Pregnancy and lactation.
* Immunosuppression or being under any kind of treatment causing absolute or relative immunosuppression.
* History of any bleeding, clotting disorder or using anticoagulants
* Chronic systemic diseases such as diabetes, chronic renal failure, hepatic insufficiency, and cardiovascular disorders.
* atients using concurrent treatments for warts or one month before .
* Any generalized dermatitis, allergic skin disorders