Topical immunotherapy for skin disease

In the last 10 years, great advances have been made in our understanding of the molecular basis for skin diseases. This is particularly true for immunologically mediated skin diseases owing to the advent of novel immunotherapies. These new therapies have not only resulted in major advances in our therapeutic interventions but have also greatly expanded our understanding of the molecular bases of these diseases. A dramatic and practical example of this understanding is the role of systemic anti-tumor necrosis factor (TNF) agents and, more recently, inhibitors of IL-12/23 in the treatment of psoriasis and psoriatic arthritis [1]. The TNF-inhibitory agents (infliximab, etanercept and adalumimab) can induce dramatic remission in skin disease and halt bone joint destruction in psoriasis patients with psoriatic arthritis. These agents have shown dramatic benefits in the quality of life of these patients. Advances in topical immunomodulatory therapy have also been profound. This review will focus on three key skin diseases and also highlight new topical immunomodulating medications [2].

Atopic dermatitis

Acute-phase atopic dermatitis (AD) is considered to be an allergic disease, with Th2 CD4⁺ cells playing the key role. CD4⁺ cells are divide d into two classes (Th1 or Th2) based on the cytokines that they secrete. Th1 cells stimulate cell-mediated or innate immunity. Psoriasis is an example of a Th1-mediated disease and acute AD is classically considered as a Th2 disorder. The CD4⁺ cells in AD produce a cytokine profile that favors antibody production. Relatively high levels of IL-4, -5, -6, -9, -10 and -13 are observed. This information suggests that topical immunosuppressants should control AD.

Since topical hydrocortisone was developed in the early 1950s, topical steroids have been the first line of therapy for AD [3]. Coupled with a good skin-care regime, steroid therapy can temporarily stop many of the characteristic signs of atopy. Unfortunately, even in topical form, the side effects of steroids significantly limit their use. Permanent local skin atrophy, telangiectasia, glaucoma and acneiform eruptions are just a few of the observed complications. Topical calcineurin inhibitors have emerged as selective immunosuppressants that show none of the side effects of topical steroids [4].

The transplantation community has used the calcineurin inhibitor ciclosporin since the early 1980s to decrease T-cell function. Calcineurin acts in T cells to dephosphorylate a nuclear transcription factor that, when complexed in the nucleus, assists in cytokine transcription. The cytokines produced include IL-2, -3 and -4, and TNF-α [5]. Although systemic ciclosporin is effective in AD, when applied topically it does not adequately penetrate the skin [6].

Tacrolimus (Protopic^®) and pimecrolimus (Elidel^®) are two effective topical calcineurin inhibitors that have been US FDA approved for AD. Their mechanism of action differs only slightly from ciclosporin. Tacrolimus is typically used in both short- and intermediate-term courses on moderate and severe AD. The lower strength, 0.03%, is approved in patients aged 2 years and older, whereas the 0.1% concentration is used in those aged 15 years and older. Clinically, it is as effective as a mid-potency topical steroid. Its common side effect is to create mild and transient pruritis and erythema during the first few days of treatment. Pimecrolimus acts similarly to tacrolimus in that it prevents the activity of calcineurin. Compared with tacrolimus, it has a threefold-lower binding affinity to macrophilin 12, the first key step in the process of inhibition [7]. Clinically, pimecrolimus is effective in mild-to-moderate AD. It has fewer local side effects than tacrolimus.

Recently, the FDA became alarmed by the off-label use of both tacrolimus and pimecrolimus in children under the age of 2 years. They were further worried by animal studies that showed evidence of carcinogenicity (lymphoma) of the calcineurin inhibitors. The studies were conducted using massive doses of the compounds such that the animals were systemically immunosuppressed. There is no evidence of systemic immunosuppression in humans when the agents are used topically [8]. Nevertheless, the FDA felt forced to place a ‘black box warning’ on the package insert for the products. This is the strongest possible warning the FDA can issue, short of withdrawing a medication. Many have said that the main objective of the FDA was to halt its use in very young patients. No clinical evidence for problems has emerged from the tens of thousands of clinical trial participants or from post-marketing surveillance involving several million prescriptions [8]. A recent nested case–control study used a database of almost 300,000 AD patients [9]. It assessed the association of topical immunosuppressants with lymphoma. No independent increased risk of lymphoma was found in patients who used calcineurin inhibitors. Interestingly, lymphoma appeared more frequently in those patients with the more severe AD.

While both tacrolimus and pimecrolimus are frequently prescribed, they are usually not used as first-line therapy for AD. Although some clinicians would argue that they are safer alternatives to corticosteroids, particularly for AD of the face, in which atrophy and telangiectasia from steroid use could be problematic. This is especially true in young children where systemic absorption of corticosteroid can lead to significant adverse effects. These agents are also useful in a variety of other diseases, including lichen sclerosis and erosive lichen planus [10].

Several new avenues for directed immunosuppressants are being explored. One therapy targets the overactive Th2 pathway seen in AD. Overexpression of Th2 pathway leads to a hyper-IgE state that virtually defines AD [11]. IL-4 and -13 are known to enhance production of IgE; however, the exact role of these cytokines is unclear, although some evidence suggests that IL-4 inhibition can improve AD. Targeting of IgE looks more promising. Omalizumab is a chimeric monoclonal antibody that binds to IgE, preventing mast cell and basophil activation. It is used systemically to control other hyper-IgE states, such as asthma and allergic rhinitis. Researchers are now finding that the medication also shows benefit in AD patients [12].

A new topical nuclear factor (NF)-κB inhibitor (IMD-0354) showed improvement in AD symptoms in mice. NF-κB is a transcription factor that translocates to the nucleus when cells are exposed to inflammatory signals; this results in further cytokine production and cell proliferation. The NF-κB pathway is probably critical for much of the immune dysregulation observed in AD [13]. When the molecule is applied to the skin of model AD mice, manifestations of the disease were lessened significantly [12].

New data suggest exciting approaches using certain oligodeoxynucleotides (ODNs) as selective immunosuppressants [14,15]. Classically, ODNs were felt to stimulate Toll-like receptor (TLR)9 as part of the innate immune system. Studies in cell culture suggest that ODNs can be recognized by keratinocytes independent of TLR9. They appear to express anti-inflammatory properties by suppressing IL-8.

Warts: common & genital

Human papillomavirus (HPV) infects keratinocytes of the skin and mucosa. Any of the 100 genotypes of HPV typically infect different parts of the body. Although a plantar wart is typically harmless, it can spread and become a source of embarrassment and pain. Some genotypes of genital warts (e.g., HPV 16 and 18) are known to induce cervical cancer [16]. Treatment for warts is classically destructive, typically either mechanically or chemically.

Clinically, a wart appears when the immune system fails to recognize that the keratinocytes are infected. Antigen-presenting cells fail to present viral antigens. Apparently, patients manifesting the disease lack memory T cells specific to HPV or lack the ability to activate the immune system [17]. The essential role of the cell-mediated immune system in preventing warts is highlighted in organ-transplant recipients [18,19]. After 1 year following transplantation, approximately half of all patients have warts. The vast majority are infected after 5 years. Their warts also resist classical therapy. Imiquimod should be an ideal medication, owing to its ability to enhance Th1 response and increase the activity of antigen-presenting cells.

Imiquimod 5% cream (Aldara^®) is in the imidazoquinolinamine class of medications. These drugs are TLR agonists. Imiquimod is known to act primarily on TLR7, one of ten described TLRs. TLRs are pattern-recognition receptors that play a key role in the innate immune system. Unlike the adaptive or acquired immune system, the innate system does not require presentation of antigens by major histocompatibility complexes. Thus, an advantage of the innate system is that it can respond rapidly. It uses pattern-recognition receptors on macrophages and dendritic cells to initiate pathways to induce proinflammatory cytokines and chemokines [20]. When TLRs are stimulated, IFN-α, TNF-α, and IL-1, -6 and -12 are produced. The net result is that the Th1 response is stimulated, whereas the Th2 response is suppressed. Imiquimod also stimulates antigen-presenting cells in the skin (Langerhan’s cells). It both enhances their maturation and encourages migration to lymph nodes where they also induce the adaptive immune system [21]. Thus, there are several possible mechanisms of action for imiquimod treatment.

Imiquimod was FDA approved in 1997 for genital warts (condyloma acuminta). It is typically used three-times weekly for up to 16 weeks. Complete cure rates range from 37 to 50% [22]; partial cure rates approach 80%. Women have better success with the therapy than men, probably because their mucosa allows better absorption of the cream. Almost as important as the cure rate is the very low rate of recurrence seen after a complete cure with imiquimod. We individualize all treatments but encourage most patients to supplement the topical immunotherapy with a gently destructive modality, such as cryotherapy. Patients benefit from the synergy of the therapies: the destructive modality interrupts the skin barrier allowing the topical agent to penetrate completely.

Unfortunately, there will still be a need for treatment of genital warts even with the FDA’s approval in 2006 of a new highly effective quadrivalent HPV vaccine (Gardasil^®). If widely administered, it would greatly reduce, but not completely eliminate, the incidence of genital warts [23]. The vaccine is not effective in the large number of patients already exposed to the virus.

Basal cell carcinoma

Approximately 700,000 basal cell carcinomas (BCCs) are diagnosed each year in the USA [24]. The tumors are typically pearly or scaly red papules that gradually erode the skin and surrounding tissues. The tumors are typically removed surgically. The molecular basis of BCC is well established [25,26]. Besides damaging DNA directly, UV radiation also induces relative immunosuppression in the skin [27]. The Th1 response is decreased, thereby inhibiting the ability of antigen-presenting cells to induce immunity to BCCs. The dramatic increased incidence of BCCs in chronically immunosuppressed transplant patients lends further evidence for a strong role of the immune system in preventing and treating BCCs. Clinically, topical immunotherapy with imiquimod is successful [16].

Imiquimod 5% cream is FDA approved for the treatment of superficial BCCs on the neck, trunk, arms and legs. Large randomized studies have shown that when the cream is applied five-times weekly for as few as 6 weeks, 80% of BCCs are cured [28]. After treatment, the skin frequently has minimal-to-no scarring. Side effects are mild to moderate. Local skin irritation and mild-to-moderate tenderness of the treatment site are common.

While monotherapy with imiquimod in the treatment of BCC does not achieve the same efficacy as surgery (surgical cure rates range from 92 to 99% [29] vs 80% for imiquimod), this remains a useful treatment modality for patients in whom surgery is not an option. Furthermore, imiquimod has a significant role as adjuvant therapy in the treatment of high-risk BCC. Imiquimod is showing promise in a variety of other dermatological diseases, including Bowen’s disease (in situ squamous cell carcinoma) [30]. This is particularly true in the genital area where imiquimod can save the patient from disfiguring surgical intervention.

Summary

Understanding of the molecular basis of skin disease has greatly advanced over the past several years, particularly in the area of immune-mediated disease. Novel immune interventions have not only aided our ability to care for patients but have further advanced our understanding of the pathophysiology of these diseases.