Topical Non-Steroidal Immunomodulators in Dermatology

Abstract

Immunological abnormality is the pathological basis of many dermatological disorders. Although steroids are the backbone of topical therapy in dermatology, the side effects are encountered quite frequently. Thorough knowledge of non-steroidal immunomodulators will broaden our treatment options. A summary of important non-steroidal immunomodulators has been given to help the residents understand the mechanism of action, indications, application, and adverse effects of these drugs.

Introduction

Immunomodulators are the agents that modify the response of the immune system by stimulating or suppressing the immune system.^[1] They act by two mechanisms: 1) immunosuppression—reduction in the immune response in autoimmune diseases and allergies and 2) immunostimulation—enhancement of the immune surveillance against various infections or malignancies.

The topical agents have been classified into steroidal and non-steroidal immunomodulatory agents.^[2] Topical steroids are widely used immunomodulators in dermatology. However, the pharmacological resistance and side effect profile of potent steroids preclude their long-term usage. This review outlines the major non-steroidal drugs which are useful alternatives in chronic dermatological disorders.

The topical non-steroidal immunomodulators of dermatological importance are:

1. Macrolactams:
These compounds bind to calcineurin blocking its ability to dephosphorylate the transcription factor NFAT-1 (nuclear factor of activated T cells 1). This prevents its translocation into the nucleus, and transcription of gene-encoding IL-2 (interleukin 2) is blocked, causing reduced proliferation of T cells.^[3] Pimecrolimus acts by reducing NFAT-2 activity in follicular keratinocytes when applied topically.^[3] It suppresses thymic stromal lymphopoietin (TSLP) which is an IL-7-like cytokine having a role in allergic inflammation.
Sirolimus acts by binding to its target protein serine-kinase, the mTOR (mammalian target of rapamycin) that regulates cell growth. It also inhibits vascular endothelial growth factor (VEGF).^[4] Various calcineurin inhibitors are summarized in Table 1.

2. Contact allergens:
These compounds act by inducing an allergic reaction in a naïve host. According to the theory of “antigenic competition,” an immunological response to one antigen inhibits the development of the immune response to other unrelated antigens.^[6] Used widely as contact allergens in the past, these are now accepted as immunomodulators due to the following actions:

1. Immunoregulatory activity: They cause increased expression of VEGF in follicular keratinocytes and endothelial cells in the skin of the affected alopecia areata cases which stimulates angiogenesis. They also increase the expression of skin-associated chemokine CCL27 on keratinocytes, which stimulates the accumulation of cutaneous lymphocyte-associated antigen (CLA +) T-cell subsets to replace autoreactive (allergen-specific) CD4+ T-cell subsets. They inhibit the T cells which release interferon- γ (IFN-γ) and transforming growth factor-β (TGF-β) and stimulate the T cells which release cytokines responsible for the release of IL-2, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) which plays a role in proliferation of epithelium.
2. Anti-tumor activity: Dinitrochlorobenzene (DNCB) acts by haptenization, i.e., combines with weak tumor antigens and develops an immune response against the tumor cells. However, none of the dermatological indications is FDA-approved. Various contact allergens are summarized in Table 2.
3. Immunostimulators: Imiquimod is a non-nucleoside heterocyclic amine.^[7] It activates toll-like receptor 7 (TLR-7) and induces secretion of TNF-α, IFN-γ, IFN-α, IL-6, IL-1α, IL-1β, IL-8, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF).^[7] FDA-approved indications include genital warts, actinic keratosis (AK), and basal cell carcinoma (BCC). Other off-label indications are cutaneous warts, molluscum contagiosum, melanoma in situ, herpes simplex,^[7] keloids,^[2] and extramammary Paget’s disease.^[2] Resiquimod is an imidazoquinoline amine^[8] and a potent, soluble analog of imiquimod. Above agents with their formulations, indications, applications, and side effects are given in Table 3.
4. Miscellaneous:
1. Zinc:
Zinc is an essential micronutrient which plays an important role in immune regulation, reproduction, and wound healing. Important properties are as follows:

• i) Anti-inflammatory: It inhibits IFN-γ-induced activation of keratinocytes as well as the production of TNF-α^[10] and IL-6.^[10]
• ii) Antiviral properties: Its TLR-mediated action is responsible for dendritic cell regulation. It is required for normal T-cell production^[10] and Langerhans cell (LC) survival. It has been found that lower zinc levels induce apoptosis of LC. Hence, immune function is impaired in zinc-deficient states.
• iii) Activity on melanocytes: Zinc upregulates the proliferation of melanocytes.
• iv) Anti-pruritic activity: It inhibits mast cell degranulation and reduces the secretion of histamine.^[10]
• The various formulations of zinc with their details are given in Table 4:
2. Vitamin D analogs:
They act by binding to the vitamin D receptors on the keratinocytes, reducing the proliferation of keratinocytes and inducing differentiation. They act on activated mononuclear cells to inhibit the release of IL-6 and IFN-γ. The only FDA-approved indication is psoriasis.^[18] Off-label it has shown efficacy in morphea, vitiligo, epidermolytic hyperkeratosis, ichthyosis, porokeratosis, pityriasis rubra pilaris, prurigo nodularis, and cutaneous T-cell lymphoma.
Table 5 shows a summary of various vitamin D analogs:

3. Anthralin:
It causes the formation of reactive oxygen species. It causes inhibition of deoxyribonucleic acid (DNA) synthesis, repair, and replication within keratinocytes, lymphocytes, and fibroblasts and inhibits mitochondrial metabolism.^[2] Anthralin has an inhibitory effect on LC.^[19]
The only FDA-approved indication is chronic plaque psoriasis. Off-label it has shown efficacy in alopecia areata. It is available as an ointment, cream, or gel (0.1–5%). A novel lecithinized microemulsion system composed of isopropyl myristate acetate and polyoxyethylene sorbitan oleate which contains dithranol has shown enhanced skin penetration, which enhances topical delivery of dithranol.^[19]
Application is initiated with a lower concentration such as 0.1% for 10–20 mins. The duration of treatment is increased gradually weekly until the total contact is up to 1 hour and then washed off to prevent cutaneous irritation. Side effects include irritant contact dermatitis and staining of clothes, hair, and nails.

4. Interferon:
Immunoregulatory action is by induction of class I & II MHC (major histocompatibility complex) antigens, increase in the number of natural killer (NK) cells, and inhibition of production of T-helper-2 (TH2) cytokines such as IL-4, IL-5, and IL-6.^[2] Topical IFN-α has been used for the treatment of herpes simplex in various studies which have shown efficacy in reducing the viral shedding and recurrences.^[20] IFN-α-2b eyedrops have been proposed for the management of BCC as an adjuvant at a dose of 1 drop of IFN-α-2b at 1 million IU/mL 4 times per day for 3 to 4 months and 1 drop every 12 hours as maintenance therapy.^[21] No side effects have been reported with topical therapy.

Table 1: Macrolactams with their formulations, indications, applications, and safety profiles

Table 2: Contact allergens with their formulations, indications, applications, and safety profiles

Table 3: Immunostimulators with their formulations, indications, applications, and safety profiles

Table 4: Various zinc formulations with their formulations, indications, applications, and safety profiles

Table 5: Vitamin D analogs with their formulations, indications, applications, and safety profiles

Conclusion

When used judiciously and cautiously, non-steroidal immunomodulators are safe and effective alternatives in the management of dermatological diseases with a wide range of applications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.