Which topical immunomodulator is used to treat a client with atopic dermatitis

Topical immunomodulators are nonsteroidal agents that target the immune system for therapeutic effect in the skin. The macrolactams, pimecrolimus and tacrolimus, act as anti-inflammatory agents by binding immunophilin and inhibiting cytokine production. The imidazoquinoline amine, imiquimod, induces interferon (IFN) production and enhances immune responses, although several more potent analogs are under clinical investigation.

Topical Calcineurin Inhibitors

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Topical Calcineurin Inhibitors: Pimecrolimus and Tacrolimus at a Glance

Intracellular signaling pathways are tightly controlled to maintain immune homeostasis. The nuclear factor of activated T cells (NFAT) family of transcription factors has emerged as a central regulator in immune signaling pathways that control lymphocyte activation and cytokine production.1 In the absence of receptor-mediated, calcium-dependent signaling, NFAT is sequestered in the cytoplasmic compartment in an inactive, phosphorylated state (Fig. 221-1). Signaling pathways emanating from antigen receptors induce calcium-dependent activation of calcineurin, which removes the phosphorylation from NFAT that leads to nuclear translocation and upregulation of proinflammatory gene expression. Tacrolimus and pimecrolimus turn off inflammation by interacting with FK-506 binding protein (FKBP). This drug-protein interaction prevents calcineurin from dephosphorylating NFAT, thereby inhibiting its nuclear translocation.2 The pleiotropic effects of calcineurin inhibitors include decreased T-cell proliferation and reduced inflammatory cytokine production of interleukin-2 (IL-2), IL-3, IL-4, IL-12, tumor necrosis factor, and IFN-γ.

Figure 221-1

Mechanism of action of calcineurin inhibitors. Ca = calcium; FKBP = FK-506 binding protein; NF-AT = nuclear factor of activated T cells.

Compared to cyclosporine, tacrolimus is 10–100 times more potent, has lower molecular weight, and penetrates the skin better. These enhanced pharmacological properties of tacrolimus provided a basis for experiments demonstrating topical inhibition of contact hypersensitivity and subsequent development as an ointment for treating atopic dermatitis.3,4 With topical tacrolimus therapy, more than 70% of patients have had moderate-to-excellent improvement in 3-week controlled trials, and 30%–40% have had greater than 90% improvement.5 In general, response to topical tacrolimus has been best observed in treating thinner skin areas such as the face and neck. During remissions, dosing may be reduced in frequency, but flares occur with discontinuance. Response is slow (over days to weeks), often incomplete on extremities (especially hands and feet), and in patients with lichenified lesions. Roughly 25% of patients, especially those with the most severe disease, do not have a satisfactory therapeutic response. Additionally, patients should realize that exacerbations of atopic dermatitis may occur and require occasional intervention with topical or systemic corticosteroid therapy. The main advantage of topical tacrolimus is the provision of chronic maintenance therapy without the need for continuous topical corticosteroids. Koo et al demonstrated up to 91% reduction in affected body surface area in a study of nearly 8,000 adults and children using topical tacrolimus for up to 18 months without significant adverse events.6 Other long-term studies with tacrolimus have specifically shown no evidence of cutaneous atrophy, little or no increased infectious risk other than a slightly increased rate of herpes simplex virus in some trials, hypertension, renal toxicity, or cumulative blood levels in patients older than 2 years of age.7

Adverse effects have been primarily an intense burning and itching in 30%–40% of patients at application sites, especially in areas of flaring, excoriation, and erosion.5,7,8 These symptoms usually subside in a few days, in concert with healing of the skin. However, some patients continue to have bothersome burning, and this effect seems to be more prominent when the skin is exposed to heat such as during summer weather, or in baths or hot tubs. In general, these problems with burning sensations seem to be less in children. Up to 10% of adults experience symptoms of flushing with alcohol ingestion.9 Both acneiform and rosaceiform eruptions have been observed in conjunction with tacrolimus and pimecrolimus use and should be monitored.10–12 Other common side effects include flu-like symptoms and headache.3

Infections have not been a notable problem in tacrolimus-treated patients.3,5,7 Occasional staphylococcal skin infections occur, but they are no worse than before treatment, and studies actually demonstrate a reduction in Staphylococcus aureus colonization during prolonged therapy. In spite of the theoretical concern about immunosuppression, there have been no significant increases in frequency or severity of warts, varicella, or molluscum contagiosum infections. Some cases of eczema herpeticum have been noted in clinical trials, but the risk of this complication may also stem from underlying atopic dermatitis.

Immunosuppression with systemic calcineurin inhibitors is known to raise the relative risk of post-transplant lymphoproliferative disorder and ultraviolet light-induced cutaneous carcinomas in transplant patients, which carries theoretical concern for malignancy with long-term use of topical formulation of the same agents. A smattering of postmarketing reports of lymphoma or malignancy in patients using topical tacrolimus and a biologically plausible risk related to TCI use were the major factors in the US Food and Drug Administration (FDA) calling for a black-box warning label. Recently, a case-control study evaluated the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis and found no increased risk of lymphoma with the use of TCIs.13 Extensive review of the case reports by independent oncologists and allied task forces has not found evidence of an increased risk of lymphoma or other malignancy.14–16 However, predisposition to malignancy may require several years of constant immunosuppression. Therefore, close surveillance is indicated if TCIs are used chronically.

In addition to the concerns about hematologic malignancy, there have been reports of pigmented neoplasms in association with TCI use. In a case series of three patients, focal pigmented lesions developed where TCIs were used that were confirmed histologically to represent lentigines.17 Similarly in our experience, lentigines have arisen at the location of TCI use. The implication of these cases is whether chronic TCI use predisposes to melanoma. There has been a case report of rapid growth of melanoma develop in a child during the course of treating vitiligo with topical tacrolimus.18 Although this remains an isolated case report, it would be prudent to counsel patients to use sun protection while using TCIs. Furthermore, the utility of self-surveillance of changing moles and thorough clinical skin examination should be discussed when using TCIs.

Pimecrolimus has a similar structure to tacrolimus and interacts with the same FKBP to inhibit calcineurin activation of NFAT.19 However, clinical efficacy is less than that of tacrolimus as reflected by decreased protein-binding affinity, which necessitates a higher drug concentration in the topical medication.7 Topical pimecrolimus also appears to have little systemic immunosuppressive effect, which may reflect a wider margin of safety. Clinical trials have included infants as young as 3 months of age, although FDA approval has been limited to 2 years of age and older. A recent study of 76 infants and children revealed sustained benefit without significant adverse effect with pimecrolimus therapy for 2 years.20 Two patients in the study developed eczema herpeticum. As with tacrolimus, occasional postmarketing reports of lymphoma and malignancy moved the FDA to affix the black-box warning label to the entire class of medication, but these concerns remain at present theoretical.16 Blood levels have been detected in occasional patients, but no high or prolonged levels have been detected. Initial studies of oral pimecrolimus were promising, but, in the wake of the black-box controversy, development has been suspended.

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Imiquimod at a Glance

Imiquimod is unique in that it appears to enhance both acquired and innate immune function (Fig. 221-2). Topically applied imiquimod induces local cytokine production from keratinocytes and other cells.21,22 Imiquimod acts as an agonist of the Toll-like receptor (TLR)-7 and -8-mediated signaling cascades, resulting in the secretion of proinflammatory cytokines, such as IFN-α and IFN-γ, tumor necrosis factor-α, IL-1, IL-1 receptor antagonist, IL-6, IL-10, IL-12, granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, and the chemokines IL-8, macrophage inflammatory protein 1α, and monocyte chemotactic protein 1.23,24 Imiquimod also stimulates the innate immune response by increasing natural killer cell activity, activating macrophages and Langerhans cells, and inducing proliferation and maturation of B lymphocytes. Additionally, imiquimod has direct proapoptotic activity on tumor cells.

Figure 221-2

Mechanism of action by imiquimod. APC = antigen-presenting cell; IFN = interferon; IgG2A = immunoglobulin G2A; IL = interleukin; IP-10 = interferon-inducible protein 10; MCP-1 = macrophage chemoattractant protein 1; MIP = macrophage inflammatory protein; NF-κB = nuclear factor κB; NK = natural killer cell; PDC = peripheral dendritic cell; PMN = polymorphonuclear neutrophil; Th = T helper; TLR = Toll-like receptor; TNF-α = tumor necrosis factor-α.

Imiquimod has been shown to be an effective treatment for anogenital warts. A 16-week study of 311 immunocompetent adults with external anogenital warts compared three times weekly 5% imiquimod cream, 1% imiquimod cream, and placebo.25 Clearance was achieved in more than 70% of women and 30% of men with the 5% cream and with both strengths significantly better than placebo. Response rates greater than 30% have been seen in uncircumcised males treated under the foreskin, suggesting that increased moisture may account for this gender discrepancy. Similarly, local factors may account for lower response rates in nongenital warts. The primary benefit of imiquimod cream relative to other available wart therapies is ease of administration. In adults, home therapy for genital warts is preferred, given the sensitive nature of this problem. Likewise in children, genital warts may be a result of sexual abuse (although in the minority of younger children), and an atraumatic topical therapy that can be rapidly applied in a nonthreatening environment is ideal. Recurrence rates following use of imiquimod cream have ranged from 13%–19%.25

In vitro evidence of antitumor effects formed the basis for evaluation of imiquimod in the treatment of cutaneous neoplasms. A multicenter, randomized, open-label dose-response trial showed an almost 90% histologic clearance rate of superficial basal cell carcinoma (BCC) when 5% imiquimod cream was applied daily for 6 weeks. Twice daily application led to an improved response rate but a higher incidence of local skin reactions.26 Geisse et al subsequently reported that two phase III double-blind, randomized, vehicle-controlled trials showed histologic clearance of 82% with five times weekly treatment.27 Daily therapy was no more effective, and response was positively correlated with signs of inflammation, including erythema, erosion, and crusting. These studies formed the foundation for using imiquimod to treat small, superficial BCC in low-risk locations such as the trunk and extremities. These are anatomical sites that may tolerate the lower cure rates better than more cosmetically sensitive areas.23 The use of imiquimod as monotherapy in this context was endorsed by a recent systematic review.28

Imiquimod has also been approved as a treatment for actinic keratosis of the head and neck. Hadley et al recently reviewed the use of imiquimod for actinic keratoses. In five randomized controlled trials lasting 12–16 weeks involving 1,293 patients, complete clinical clearance was seen in 50% of imiquimod patients versus 5% using vehicle. Adverse events were significantly higher in imiquimod-treated groups, including erythema (27%), crusting/scabbing (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%).29 Lower potency imiquimod preparations (2.5, 3.75%) are currently under development for the treatment of head and neck AKs. These compounds theoretically permit increased frequency of use without prohibitive application site reaction, while also allowing a greater surface area to be treated. Early safety and efficacy trials are promising.30

Although not yet clinically indicated as an antiangiogenic agent, imiquimod has demonstrated antiangiogenic properties in vitro and in a series of case reports. The antiangiogenic properties of imiquimod stem from the production of antiangiogenic cytokines, including IFN-γ, IL-10, and IL-12; the upregulation of endogenous antiangiogenic mediators, including tissue inhibitor of matrix metalloproteinase; and downregulation of the proangiogenic factors, basic fibroblast growth factor, and matrix metalloproteinase 9.31 In a mouse model of hemangioendothelioma, imiquimod application resulted in fewer and smaller tumors.32 Numerous clinical reports have noted clinical response treating vascular neoplasms, including hemangiomas of infancy and pyogenic granulomas.33–36 Ongoing clinical trials are further defining the role of imiquimod in the treatment of various vascular lesions.37

Derived from its antiviral effects, imiquimod has been used successfully to treat molluscum contagiosum. In an observer-blinded, randomized trial of 74 children, imiquimod resulted in slower clearance with higher expense, but was tolerated with less pain and improved cosmesis when compared to liquid nitrogen.38 There have been few cases in which imiquimod was effective in treating granuloma annulare when used for 6–12 weeks.39,40 Whether the efficacy is the result of proapoptotic effects of imiquimod remains to be determined. While not intended to be exhaustive, other published off-label uses of imiquimod include treating extramammary Paget disease, scar cosmesis, low-grade vulvar intraepithelial neoplasms, dysplastic nevi, lentigo maligna, ecthyma contagiosum, porokeratoses, and lymphomatoid papulosis.41–47 These off-label uses of imiquimod await confirmation and precise dosing recommendation from randomized clinical trials.

Adverse effects relate primarily to cutaneous irritation at the application site, leading to moderate erythema and erosion in roughly one-third and one-tenth of patients, respectively. Studies suggest that both the response rate, particularly in males, and the likelihood of side effects will increase with daily therapy. Imiquimod is a category C drug, and it is not known to what extent topically applied imiquimod is excreted in the breast milk of nursing mothers. Imiquimod has not been thoroughly studied in children younger than 18 years of age. Imiquimod has been investigated for a variety of other infectious conditions with varying degrees of success.

Tacrolimus ointment, 0.03% and 0.1% applied twice daily, was studied extensively in clinical trials that included adults and children as young as 2 years of age.2 Pharmacokinetic studies showed low percutaneous absorption initially in 10%–20% of patients with atopic dermatitis, but generally blood levels were undetectable by 1 week as healing and re-establishment of the skin barrier occurred. Rarely were blood levels greater than 2 ng/mL, in contrast with trough levels of 5–15 ng/mL in transplant patients treated systemically with tacrolimus.5 The notable exception is the use of topical tacrolimus in patients with Netherton syndrome, where blood levels within or above the established therapeutic trough range for oral tacrolimus in organ transplant recipients may be observed.48

In an open label study of twice-daily pimecrolimus use in infants ranging in age from 5.7–11.9 months at baseline with moderate-to-severe atopic dermatitis, Lakhanpaul et al found no accumulation of the drug and systemic levels ranging from below the limit of detection to 1.94 ng/mL.49 There were no significant adverse events over the course of this 1-year-long trial.

The half-life of systemically administered imiquimod, either oral or subcutaneous, is 2–4 hours in healthy volunteers. The half-life of intravenously administered imiquimod is 14 hours, and less than 1% of the drug is recovered in the urine after a single topical application. The major systemic metabolite of imiquimod, S26704, is a hydroxylation product that achieves plasma concentrations of less than 20% of the parent compound.50 Higher levels have been noted with both intravaginal administration in healthy volunteers or systemic administration in chronically ill patients. With topical administration in healthy volunteers, there is very little measurable imiquimod and no detectable S26704.

Box 221-1 Indications for Use

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Box 221-1 Indications for Use

Box 221-2 Contraindications

In light of concerns with long-term safety and questions raised by the widely publicized black-box warning label, initiation of TCI therapy should begin by addressing parental and patient concerns. These agents should be considered second line and are indicated when standard therapy, including topical steroids and emollients, are either ineffective or harmful. Comparisons of these agents with standard therapy have not as yet consistently shown a relative clinical or pharmacoeconomic benefit compared with topical steroids.51 Once the decision to initiate TCI therapy has been made, consideration must be given to the choice of either pimecrolimus or tacrolimus. Pimecrolimus is available as a 1% cream formulation and is indicated for mild-to-moderate atopic dermatitis. Tacrolimus is available as an ointment in two strengths, 0.03% for children 2–15 years old as an on-label indication, and 0.1% in patients 16 years and older. Topical tacrolimus is indicated for moderate to severe atopic dermatitis. In Europe, the application twice weekly to prevent recurrence at sites of repeated flares is an approved indication; this 2–3 times weekly application to sites of involvement during quiescence has been shown to decrease the requirement for topical steroid use.52

Both products have been extensively studied and have excellent safety and efficacy records compared with placebo in the short term. Therefore, patient vehicle preferences and disease severity help determine the appropriateness of either agent for an individual patient. Paller et al found tacrolimus to be more effective than pimecrolimus with a similar side effect profile in three comparison trials.53

Pimecrolimus or tacrolimus should be applied sparingly only to affected areas of skin twice daily. The smallest amount of medicine should be used, and therapy should be discontinued where signs and symptoms of redness and itch have resolved for 1 week. Adjunctive therapies, such as emollients, should be continued. If applied after bathing, as often recommended, pimecrolimus or tacrolimus should be applied first to affected areas, and emollients subsequently to unaffected skin. Application site stinging from TCIs may be more severe in areas of excoriation. Efforts to limit these open areas of skin by pretreating for 2–7 days with a topical steroid may improve adherence to therapy.

Imiquimod should be applied sparingly to affected areas when treating warts or superficial BCC. A broader but circumscribed treatment area is recommended either on the face or scalp, but not both, when treating actinic keratosis. For anogenital warts, initial frequency should be three times weekly. If little or no effect is seen after 2–4 weeks, advancing to daily use may enhance efficacy, although risk of an irritant dermatitis commensurately will increase. Application before sleeping is generally recommended and imiquimod should be left on the skin for 6–10 hours. It should be made clear to patients treating warts that imiquimod therapy does not eliminate the risk of transmission of human papilloma virus to physical contacts. The frequency of application for the treatment of superficial BCC (five times weekly) and actinic keratosis (two times weekly) differs as noted in the Table 221.1.

If effective, TCIs may be incorporated into the long-term therapeutic regimen for atopic dermatitis. Prescribing physicians must ensure that patients are using these products intermittently and only to treat active dermatitis. Adverse events, including application site reactions, should be monitored. Patients should be evaluated for cutaneous infections with particular vigilance against eczema herpeticum, which was noted with slightly increased frequency in some premarketing trials. Any evidence of lymphadenopathy should be documented and followed closely. Skin examinations for signs of cutaneous malignancy are prudent. No routine serologic monitoring is indicated; however, if clinical evidence suggests the possibility of systemic immunosuppression, serum levels of tacrolimus or pimecrolimus may be obtained. If blood levels are sought, care must be taken to first remove any residual medication, particularly at the antecubital location, a common site for both venipuncture and atopic dermatitis. Failure to do so may lead to spuriously elevated drug levels. Despite reassuring safety data, the lesson of the black-box controversy is that definitive long-term safety has not been established; and therefore, ongoing vigilance for potential TCI adverse effects, including immunosuppression and malignancy, must continue.

Imiquimod therapy for warts, if tolerated, should be continued until complete clearance of warts or a maximum of 4 months before declaring a treatment failure. If no response or clinical deterioration is seen at 8 weeks, other therapeutic options should be entertained. If an incomplete response is obtained, continuing therapy may be warranted. Increasing from three times weekly to daily treatment may be indicated if imiquimod is well tolerated. No serologic monitoring is necessary. Irritant reactions may be treated initially by temporary cessation of therapy in addition to or followed by appropriate topical anti-inflammatory intervention. Imiquimod therapy can then be resumed as necessary at a decreased frequency as indicated. Similar principles govern the use of imiquimod for superficial BCC and actinic keratosis, but closer clinical follow-up is indicated.

Box 221-3 Risks and Precautions

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Box 221-3 Risks and Precautions

Box 221-4 Complications

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Box 221-4 Complications

1. Baine I, Abe BT, Macian F: Regulation of T-cell tolerance by calcium/NFAT signaling. Immunol Rev 231:225, 2009

2. Ruzicka T, Assmann T, Homey B: Tacrolimus: The drug for the turn of the millennium? Arch Dermatol 135:574, 1999

3. Hanifin JM et al: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol 53:S186, 2005

4. Saripalli YV, Gadzia JE, Belsito DV: Tacrolimus ointment 0.1% in the treatment of nickel-induced allergic contact dermatitis. J Am Acad Dermatol 49:477, 2003

5. Pascual JC, Fleisher AB: Tacrolimus ointment (protopic) for atopic dermatitis. Skin Therapy Lett b:1, 2004

6. Koo JY et al: Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: Results in 8000 patients. J Am Acad Dermatol 53:S195, 2005

7. Shainhouse T, Eichenfield LF: Long-term safety of tacrolimus ointment in children treated for atopic dermatitis. Expert Opin Drug Saf 2:457, 2003

8. Paller AS: Use of nonsteroidal topical immunomodulators for the treatment of atopic dermatitis in the pediatric population. J Pediatr 138:163, 2001

9. Milingou M et al: Alcohol intolerance and facial flushing in patients treated with topical tacrolimus. Arch Dermatol 140:1542, 2004

10. Antille C, Saurat JH, Lubbe J: Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 140:457, 2004

11. Bakos L, Bakos RM: Focal acne during topical tacrolimus therapy for vitiligo. Arch Dermatol 143:1223, 2007

12. El Sayed F, et al: Rosaceiform eruption to pimecrolimus. J Am Acad Dermatol 54:548, 2006

13. Arellano FM et al: Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 127:808, 2007

14. Berger TG et al: The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J Am Acad Dermatol 54:818, 2006

15. Fonacier L et al: Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 115:1249, 2005

16. Qureshi AA, Fischer MA: Topical calcineurin inhibitors for atopic dermatitis: Balancing clinical benefit and possible risks. Arch Dermatol 142:633, 2006

17. Hickey JR et al: Does topical tacrolimus induce lentigines in children with atopic dermatitis? A report of three cases. Br J Dermatol 152:152, 2005

18. Mikhail M et al: Rapid enlargement of a malignant melanoma in a child with vitiligo vulgaris after application of topical tacrolimus. Arch Dermatol 144:560, 2008

19. Wolff K: Pimecrolimus 1% cream for the treatment of atopic dermatitis. Skin Therapy Lett 10:1, 2005

20. Wahn U et al: Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 110:e2, 2002

21. Chang YC et al: Current and potential uses of imiquimod. South Med J 98:914, 2005

22. Sapijaszko MJ: Imiquimod 5% cream (Aldara) in the treatment of basal cell carcinoma. Skin Therapy Lett 10:2, 2005

23. Schiller M et al: Immune response modifiers—Mode of action. Exp Dermatol 15:331, 2006

24. Schon MP, Schon M, Klotz KN: The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. J Invest Dermatol 126:1338, 2006

25. Edwards L, Ferenczy A, Eron L, et al: Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol 134:25, 1998

26. Marks R et al: Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: Results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 44:807, 2001

27. Geisse J et al: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50:722, 2004

28. Love WE, Bernhard JD, Bordeaux JS: Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: A systematic review. Arch Dermatol 145:1431, 2009

29. Hadley G, Derry S, Moore RA: Imiquimod for actinic keratosis: Systematic review and meta-analysis. J Invest Dermatol 126:1251, 2006

30. Swanson N et al: Optimizing imiquimod for treating actinic keratoses of the full face or balding scalp: Imiquimod 2.5% and 3.75% applied daily for two 2-week cycles. Montana Academy of Dermatology Annual Meeting Big Sky, MT, 2010

31. Li VW et al: Imiquimod as an antiangiogenic agent. J Drugs Dermatol 4:708, 2005

32. Sidbury R et al: Topically applied imiquimod inhibits vascular tumor growth in vivo. J Invest Dermatol 121:1205, 2003

33. Gencoglan G, Inanir I, Gunduz K: Pyogenic granuloma in two children successfully treated with imiquimod 5% cream. Pediatr Dermatol 26:366, 2009

34. Martinez MI et al: Infantile hemangioma: Clinical resolution with 5% imiquimod cream. Arch Dermatol 138:881, 2002

35. Tritton SM et al: Pyogenic granuloma in ten children treated with topical imiquimod. Pediatr Dermatol 26:269, 2009

36. Welsh O et al: Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol 51:639, 2004

37. McCuaig CC et al: A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma. Pediatr Dermatol 26:203, 2009

38. Al-Mutairi N et al: Comparative study on the efficacy, safety, and acceptability of imiquimod 5% cream versus cryotherapy for molluscum contagiosum in children. Pediatr Dermatol, 27(4):388-394, 2009

39. Badavanis G et al: Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases. Acta Derm Venereol 85:547, 2005

40. Stephenson S, Nedorost S: Granuloma annulare: dramatically altered appearance after application of 5% imiquimod cream. Pediatr Dermatol 25:138, 2008

41. Agarwal S, Berth-Jones J: Porokeratosis of Mibelli: Successful treatment with 5% imiquimod cream. Br J Dermatol 146:338, 2002

42. Berman B et al: Double-blind, randomized, placebo-controlled, prospective study evaluating the tolerability and effectiveness of imiquimod applied to postsurgical excisions on scar cosmesis. Dermatol Surg 31:1399, 2005

43. Dusza SW et al: Treatment of dysplastic nevi with 5% imiquimod cream, a pilot study. J Drugs Dermatol 5:56, 2006

44. Erbağci Z, Erbağci I, Almila Tuncel A: Rapid improvement of human orf (ecthyma contagiosum) with topical imiquimod cream: report of four complicated cases. J Dermatolog Treat 16:353, 2005

45. Hughes PS: Treatment of lymphomatoid papulosis with imiquimod 5% cream. J Am Acad Dermatol 54:546, 2006

46. Le T et al: Preliminary results of 5% imiquimod cream in the primary treatment of vulva intraepithelial neoplasia grade 2/3. Am J Obstet Gynecol 194:377, 2006

47. Zampogna JC et al: Treatment of primary limited cutaneous extramammary Paget's disease with topical imiquimod monotherapy: Two case reports. J Am Acad Dermatol 47:S229, 2002

48. Allen A et al: Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol 137:747, 2001

49. Lakhanpaul M et al: Low systemic exposure in infants with atopic dermatitis in a 1-year pharmacokinetic study with pimecrolimus cream 1%*. Exp Dermatol 15:138, 2006

50. Sauder DN: Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol 43:S6, 2000

51. Ashcroft DM et al: Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: Meta-analysis of randomised controlled trials. BMJ 330:516, 2005

52. Breneman D et al: Intermittent therapy for flare prevention and long-term disease control in stabilized atopic dermatitis: A randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle. J Am Acad Dermatol 58:990-999, 2008

53. Paller AS et al: Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: Results from 3 randomized, comparative studies. J Am Acad Dermatol 52:810, 2005