Imiquimod: Newer Perspectives to an Old Drug

Immunomodulatory action

Imiquimod acts as an agonist on toll-like receptors 7 and 8, which through a cascade of events leads to the induction of proinflammatory cytokines and chemokines along with activation of antigen presenting cells and innate immunity [Figure 1] causes activation of nuclear factor-kappa B which leads to the induction of proinflammatory cytokines and chemokines such as interferon-gamma (IFN-g), interferon-alpha and interleukin-12 (IL-12). This further leads to the activation of antigen-presenting cells and other components of innate immunity and, eventually, a profound T-helper (Th1) cellular immune response gets initiated. The mounting of T-helper Type 2 (Th-2) immune response is simultaneously inhibited.

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Figure 1:

Immunomodulatory mechanism of imiquimod.

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It also induces the migration of Langerhans cells to regional lymph nodes and enhances the antigen presentation to naive T-cells and thus perpetuating the cycle of T-cell response.

Anti-tumour action

Direct action

This is the main anti-tumour mechanism of imiquimod. Apoptosis in tumour cell lines is induced by activation of the workhorses of apoptosis (the caspase family of proteases) by intrinsic pathway.^[2] It can also independently upregulate proapoptotic proteins of the Bcl-2 family of proteins [Figure 2].

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Figure 2:

Direct anti-tumour action mechanism of imiquimod.

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Anogenital warts

The first clinical application in which imiquimod proved useful was for genital warts. The common therapeutic problems with anogenital warts are recurrence and long duration. The reason for this could be that most treatment therapies target physical destruction of the disease rather than direct antiviral activity against the human papillomavirus. Imiquimod represents a significant advancement in the treatment due to its antiviral and non-destructive properties. It has been Food and Drug Administration (FDA) approved in 5% cream formulation for overnight application (6–10 h) over warts 3 times a week for up to 16 weeks and 3.75% daily for up to 8 weeks (~50% clearance and ~30% clearance, respectively).^[5] Although there have been various modalities of treatment such as excision, electrocautery and laser vaporisation which can be used to remove warts quickly, there have been many disadvantages as they are painful, destructive and recurrences are common with these modalities (i.e., occurring in 9–72% of warts treated with ablative laser therapy).^[6] Imiquimod 5% cream showed some clearance of warts in immunosuppressed human immunodeficiency virus-infected patients with genital warts also. Major advantage of imiquimod lies in its self-application at home which decreases the hospital visits and increases compliance of the patient toward treatment. By virtue of increase in cellular immunity, it gives long-term protection against recurrences or reinfection^[1] and, hence, serves as a better alternative for genital warts [Table 2].^[7-15]

Actinic keratoses

Imiquimod 5% cream was first approved by the FDA in 2004 and all the three concentrations have been approved. Application of 3.75% cream daily for 2 weeks have shown similar efficacy with fewer cutaneous adverse effects as 5% cream twice weekly for up to 16 weeks (~50% and ~35% clearance, respectively). Another added advantage witnessed with the lower concentration of imiquimod was the wider surface area of application (i.e., 200 cm² as compared to 25 cm² for the 5% preparation of imiquimod).^[16]

Imiquimod produces its activity through augmented antigen recognition and amplified cellular immunologic response which causes development of immunologic memory and serves to reduce the development of recurrent or new AK. Field cancerization theory postulates that a large area of skin surrounding AK is also at increased risk for possible malignant transformation because it has been exposed to the same ultraviolet light for a long time. Thus, those therapies which work in a larger field have the potential to address subclinical damage, reducing AK recurrence rates and potentially reducing the risk of squamous cell carcinoma development.

There are various treatment regimens available in AK

1. Conventional – Imiquimod 5% cream to be applied thrice/week (every alternate day) for about 8–16 weeks.^[4]

2. Modified regimen – Imiquimod 5% cream to be applied thrice/week every alternate day for 4 weeks which is followed by rest for 4 weeks. This whole process constitutes 1 cycle. Up to three cycles have shown better results with complete remission and lesser cutaneous side effects than the conventional regimen.^[17]

3. Combination with cryotherapy – One session of cryotherapy consists of two sprays of liquid nitrogen for 5 second each with a rest period of 5 s in between sprays. This is followed by 3.75% imiquimod cream daily for 2 weeks which is followed by 2 weeks drug-free period after which cream is again applied daily for 2 weeks.^[18]

The comparison of different modalities for AK is shown in Table 3.

Superficial BCC

BCC is a common cutaneous neoplasm that very rarely metastasises, but if neglected, it can have a locally aggressive course with destruction of underlying tissues. Although Mohs micrographic surgery remains the gold standard for the treatment of BCC, imiquimod can also be used in selected cases. For BCC, an additional mechanism of imiquimod has been suggested which occurs by blocking the activation of the Hedgehog/glioma-associated oncogene (GLI) signalling pathway (important in the pathogenesis of BCC).^[19]

Dosing – 5% imiquimod cream applied 5 times a week for 6 weeks (~75% clearance) in immunocompetent adults have been approved by FDA for superficial BCC with maximum tumour diameter <2 cm in 2004.^[20] Thicker lesions have a low response rate. Imiquimod provides a good alternative for the people who are unwilling or unfit for surgery, although the success rate is lower than Mohs micrographic surgery (99%). When compared to photodynamic therapy, imiquimod may be more effective in treating superficial BCC [Table 4]. Imiquimod has shown excellent results in patients with multiple BCC and in xeroderma pigmentosum patients with only minor side-effects.

Common warts

Imiquimod monotherapy has proved to be less efficient for treating cutaneous warts due to its decreased penetrance and absorption through wart tissue. Hence, combining it with other modalities of cytodestructive treatments such as cryotherapy, salicylic acid and occlusion can increase its penetrance thus increasing its efficiency and hence, better outcome of common warts. It may also serve as a good alternative in the management of recalcitrant warts in immunosuppressed patients.

Molluscum contagiosum

Molluscum is generally regarded as a self-limiting disease; however, its treatment is generally advised as it has a potentially protracted course and due to the risk of superinfection, scarring, autoinoculation and transmission to other members of the community. Topical imiquimod once daily under occlusion has shown remission within 3–8 weeks of treatment with only mild-to-moderate irritation in the application area.^[21]

Keloids

Imiquimod causes an indirect increase in the production of interferon alpha and, possibly, transforming growth factor beta-3 at the site of application which decreases collagen and extracellular matrix component deposits involved in scar formation. It acts as a useful adjunct to surgical resection by decreasing recurrence. It is applied once daily for around 8 weeks at the site of surgical excision of the keloid has shown minimal recurrences following excision.^[22]

Nodular and morphoeic basal cell carcinoma

Imiquimod, 5% cream can be used as an alternative in patients with small nodular and morphoeic BCCs who are poor candidates for surgery. According to a study, topical 5% imiquimod cream is well tolerated and most effective in treating nodular BCC when applied once daily for 6–12 weeks.^[23]

Cutaneous malignancies other than BCC

Imiquimod has been found to be useful in many cutaneous malignancies and can be used as a standalone or as an adjunct to on-going treatment [Table 5].^[24-26]

Mycosis fungoides

Imiquimod has proved to be an effective therapy for early-stage disease of cutaneous T-cell lymphomas, whether used alone or in combination with systemic immunomodulatory therapy. This is well tolerated and associated with a histologic and clinical response rate of 50% in patch and plaque stage.^[27]

Infantile haemangioma (IH)

It has been reported to be efficacious in the treatment of IH due to its ability to induce the production of tissue inhibitor of matrix metalloproteinase which has antiangiogenesis property. There has been significant improvement in superficial IH and little improvement in mixed IH with no or very less changes in deep hemangiomas.^[28]