A pivotal phase 3 study of topical berdazimer sodium, a topical nitric oxide (NO) releasing medication has shown promising results for the treatment of MC.52 The role of NO has been well established in boosting cutaneous innate immunity and providing a wide range of antimicrobial effects.53 Berdazimer sodium suppresses DNA proliferation of human papillomavirus (HPV) 18 in vitro, and 12% topical application was suggested to be effective and safe for treatment of genital warts.54 Berdazimer sodium also reduces the activity of various T cell mediated immune pathways in atopic dermatitis patients, suggesting its immune regulatory effect.16,55
A phase 3 vehicle-controlled clinical trial with over 800 MC patients demonstrated favorable efficacy and safety of berdazimer gel, 10.3% (Novan, Inc, Durham, North Carolina, USA).52 The participants have to be at least 6 months old, healthy individuals with 3 to 70 clinically evidence MC lesions. At the end of the study, MC lesion counts were significantly reduced in the berdazimer group vs vehicle after 12 weeks of once daily application. Treatment emergent adverse events (TEAEs) were mainly mild to moderate in severity, with local pain and erythema being the most commonly reported.52 It is postulated that berdazimer sodium promotes BOTE and, ultimately, resolution of MC lesions.16
Another MC treatment option in the pipeline is a shelf-stable formulation of topical cantharidin, 0.7%.56 Cantharidin is an inhibitor of phosphodiesterase derived from blister beetles and has been used for decades as an off-label treatment option.3,57 The exact mechanism is still unclear, although it is postulated to involve desmosome destruction and skin shedding.57
VP-102 (Verrica Pharmaceuticals Inc, West Chester, PA, USA) is a drug-device designed to deliver precise concentrations of cantharidin to MC lesions. Two randomized trials evaluated VP-102 among 528 patients who were at least 2 years old with clinical diagnosis of MC. Treatment was administered once every 3 weeks until complete lesion clearance was achieved. A maximum of 4 treatment sessions were allowed. VP-102 achieved higher complete clearance rate than vehicle after one treatment as well as at the end of study.57 Concerning the safety profile, majority of the reported adverse events were mild to moderate, mostly consisting of local skin changes. The most commonly encountered TEAEs were vesicles, pain, pruritus, erythema, and scab on the application site.57
Resolution of MC is often characterized by clinical signs of inflammation and redness, or BOTE. BOTE may present with asymptomatic or pruritic scale, erythema, and hemorrhagic crusting that can be mistaken as bacterial superinfection.16 The mechanism of BOTE has yet to be elucidated.19 Recognition and diagnosis of BOTE as a herald of the natural resolution of MC could prevent unwarranted additional treatment withcorticosteroids or antibiotics.16,19 The emerging virological and immunological evidence of immune evasion mechanisms unique to MCV may serve as the basis for understanding BOTE in the resolution of infection with MC.
In summary, this review highlights the unique ability of MCV to evade the host immune system through a variety of molecular pathways. How or if these pathways impact the duration or severity of MC infections is unknown. Elucidating the precise mechanisms by which MCV and potential MC treatments affect immune-evasion pathways will remain challenging in the absence of MC cell or animal models.
Limitations
Until the FDA approves a MC treatment, the standard of care will likely continue to be "watch and wait." It is anticipated that if MC treatments are FDA-approved, data regarding immunocompromised or skin of color MC will remain scarce but recent therapeutic advances toward treating MC hold promise.56
A phase 3 vehicle-controlled clinical trial with over 800 MC patients demonstrated favorable efficacy and safety of berdazimer gel, 10.3% (Novan, Inc, Durham, North Carolina, USA).52 The participants have to be at least 6 months old, healthy individuals with 3 to 70 clinically evidence MC lesions. At the end of the study, MC lesion counts were significantly reduced in the berdazimer group vs vehicle after 12 weeks of once daily application. Treatment emergent adverse events (TEAEs) were mainly mild to moderate in severity, with local pain and erythema being the most commonly reported.52 It is postulated that berdazimer sodium promotes BOTE and, ultimately, resolution of MC lesions.16
Another MC treatment option in the pipeline is a shelf-stable formulation of topical cantharidin, 0.7%.56 Cantharidin is an inhibitor of phosphodiesterase derived from blister beetles and has been used for decades as an off-label treatment option.3,57 The exact mechanism is still unclear, although it is postulated to involve desmosome destruction and skin shedding.57
VP-102 (Verrica Pharmaceuticals Inc, West Chester, PA, USA) is a drug-device designed to deliver precise concentrations of cantharidin to MC lesions. Two randomized trials evaluated VP-102 among 528 patients who were at least 2 years old with clinical diagnosis of MC. Treatment was administered once every 3 weeks until complete lesion clearance was achieved. A maximum of 4 treatment sessions were allowed. VP-102 achieved higher complete clearance rate than vehicle after one treatment as well as at the end of study.57 Concerning the safety profile, majority of the reported adverse events were mild to moderate, mostly consisting of local skin changes. The most commonly encountered TEAEs were vesicles, pain, pruritus, erythema, and scab on the application site.57
Resolution of MC is often characterized by clinical signs of inflammation and redness, or BOTE. BOTE may present with asymptomatic or pruritic scale, erythema, and hemorrhagic crusting that can be mistaken as bacterial superinfection.16 The mechanism of BOTE has yet to be elucidated.19 Recognition and diagnosis of BOTE as a herald of the natural resolution of MC could prevent unwarranted additional treatment withcorticosteroids or antibiotics.16,19 The emerging virological and immunological evidence of immune evasion mechanisms unique to MCV may serve as the basis for understanding BOTE in the resolution of infection with MC.
In summary, this review highlights the unique ability of MCV to evade the host immune system through a variety of molecular pathways. How or if these pathways impact the duration or severity of MC infections is unknown. Elucidating the precise mechanisms by which MCV and potential MC treatments affect immune-evasion pathways will remain challenging in the absence of MC cell or animal models.
Limitations
Until the FDA approves a MC treatment, the standard of care will likely continue to be "watch and wait." It is anticipated that if MC treatments are FDA-approved, data regarding immunocompromised or skin of color MC will remain scarce but recent therapeutic advances toward treating MC hold promise.56
CONCLUSION
MCV is a unique poxvirus, replicating only in the human epidermis. It results in acute cutaneous infection and resolves when immune system pathways engage and recognize the virus. The infected patient has no risk of systemic viral infection. The unique immune evasion proteins produced by MCV may lend to persistent infections lasting months to years. BOTE, an indicator of host immune activation, is the natural resolution signal; potential therapeutic strategies may influence the initiation of BOTE. However, the impact of current and/or potential therapeutic MC treatments and their ability to promote BOTE via modulation of MC immune evasion proteins and pathways remains elusive and challenging due to research model limitations. Nevertheless, recent studies show 2 topically applied agents in phase 3 development clear MC lesions better than vehicles. Topical berdazimer gel 10.3% may promote BOTE via release of NO, whereas cantharidin is thought to enhance shedding of infected keratinocytes. Recent advances in the understanding and characterization of MC evasion proteins may lead to targeted therapeutics to treat this common and bothersome infectious disease.
DISCLOSURES
HH, CS, and FY have no conflicts of interest to disclose. BB serves as a Novan-consultant.
REFERENCES
1. Badri T, Gandhi GR. Molluscum contagiosum. In: StatPearls. Treasure Island: StatPearls Publishing; 2022.
2. James WD, Elston DMD, McMahon PJ. Andrews' Diseases of the Skin Clinical Atlas E-Book: Expert Consult. 12th ed. New York: Elsevier Health Sciences; 2016.
3. Meza-Romero R, Navarrete-Dechent C, Downey C. Molluscum contagiosum: an update and review of new perspectives in etiology, diagnosis, and treatment. Clin Cosmet Investig Dermatol. 2019;12:373-381.
2. James WD, Elston DMD, McMahon PJ. Andrews' Diseases of the Skin Clinical Atlas E-Book: Expert Consult. 12th ed. New York: Elsevier Health Sciences; 2016.
3. Meza-Romero R, Navarrete-Dechent C, Downey C. Molluscum contagiosum: an update and review of new perspectives in etiology, diagnosis, and treatment. Clin Cosmet Investig Dermatol. 2019;12:373-381.
