Topical Calcineurin Inhibitors—Efficacy and Safety in Atopic Dermatitis

L. Guenther, MD, FRCPC

Division of Dermatology, University of Western Ontario, London, ON, Canada

Atopic Dermatitis

Atopic Dermatitis (AD) is a chronic or chronic-relapsing inflammatory skin disease associated with hyperreactivity to environmental triggers; it can affect up to 20% of children [Williams H, et al. J Allergy Clin Immunol 103(1 Pt 1):125-38 (1999 Jan).]. Symptoms include flexural (facial and extensor in children) erythema, excoriations, lichenification, and xerosis.

• Part of the atopic triad (AD, hay fever, asthma).
• Itch is often so intense that patients cannot sleep or concentrate.
• Patients commonly scratch to the point of bleeding and may have secondary infection.
• Significantly impacts the sufferer as well as his or her family. It is a ‘life-altering’ disease.

Treatments include:

• Avoidance of triggers
• Emollients
• Topical corticosteroids
• Topical calcineurin inhibitors (TCIs)
• Antimicrobials for infection
• Oral antihistamines for pruritus
• Systemic corticosteroids, systemic immunosuppressants and phototherapy for severe disease

Mechanism of Action of TCIs

• Blocks T-cell activation and suppress release of pro-inflammatory cytokines.
• Binds to FK-506 binding protein-12, forming a complex that inhibits calcineurin, thereby preventing activation of the nuclear factor of activated T cells (NFAT), which in turn blocks gene transcription for interleukin-2.
• Tacrolimus reduces Langerhans cell activation of T cells, and cytokine production in eosinophils, mast cells, and basophils.

[Alomar A, et al. Br J Dermatol 151(Suppl 70):3-27 (2004 Dec).]

Approved Indication of TCIs

• The US FDA approved tacrolimus ointment for moderate-to-severe AD (0.03% for 2+ years, 0.1% for 16+ years) in December 2000, and pimecrolimus 1% cream for mild-to-moderate AD for 2+ years in December 2001.
• Both medications are indicated for short-term and intermittent long-term treatment in patients for whom conventional therapies are contraindicated, not tolerated, or not sufficiently effective.

Black Box Warning for TCIs

• A Black Box warning, issued in January 2006, resulted from the FDA’s concern that the TCIs were aggressively and inappropriately marketed as first-line agents for AD and that physicians were using them off-label in children
• Rare cases of malignancy, including skin cancer and lymphoma, have been reported, although a causal relationship has not been established.
• Long-term safety is not established.
• Avoid long-term continuous use in any age group.
• Limit application to areas affected with AD.
• Only the 0.03% tacrolimus concentration is indicated for 2- to15-year-old children. [FDA Public Health Advisory issued January 19, 2006.
• Following the FDA’s action, Health Canada issued a “dear doctor” letter to outline these concerns to Canadian healthcare professionals.

Efficacy

• Three studies (n=589) showed that 41% of subjects were clear/almost clear after 6 weeks of pimecrolimus (vs. 20% on vehicle).[Eichenfield LF, et al. J Am Acad Dermatol 46(4):495-504 (2002 Apr); Ho VC, et al. J Pediatr 142(2):155-62 (2003 Feb).]
• Three weeks of betamethasone valerate 0.1% cream was superior to pimecrolimus (50% vs. 11%, respectively, clear/almost clear).[Luger T, et al. Br J Dermatol 144(4):788-94 (2001 Apr).]
• Three studies (n=655) showed 90+% improvement after 12 weeks of tacrolimus 0.1% in 37% and tacrolimus 0.03% in 28% of adults, and 41% and 36% of children (0.1% and 0.03%, respectively) vs. 7% on vehicle.[Hanifin JM, et al. J Am Acad Dermatol 44(1 Suppl):S28-38 (2001 Jan); Paller A, et al. J Am Acad Dermatol 44(1 Suppl): S47-57 (2001 Jan).]
• Tacrolimus 0.1% has similar efficacy to hydrocortisone butyrate (midpotent steroid).[Reitamo S, et al. J Allergy Clin Immunol 109(3):547-55 (2002 Mar).]
• Tacrolimus 0.03% and 0.1% are more effective than 1% hydrocortisone ointment.[Reitamo S, et al. J Allergy Clin Immunol 109(3):539-46 (2002 Mar).]
• Tacrolimus 0.1% is more efficacious than pimecrolimus 1% in adults (54.1% vs. 34.9% respective reduction in EASI score, p<0.0001) and children (67.2% vs. 56.4% respective reduction, p=0.04) with moderate-tovery severe AD.[Paller AS, et al. J Am Acad Dermatol 52(5):810-22 (2005 May).]
• Tacrolimus 0.03% ointment and pimecrolimus 1% have similar efficacy in children with mild AD (52.1% vs. 42.7% respective reduction in EASI score, p=0.07).[Paller A, et al. J Am Acad Dermatol 44(1 Suppl):S47-57 (2001 Jan).]
• Treatment with 0.1% tacrolimus ointment over 6 months was shown to be significantly more efficacious than a corticosteroid ointment regimen in adults with moderate-to-severe AD.[Reitamo S, et al. Br J Dermatol 152(6):1282-9 (2005 Jun).

Safety of Calcineurin Inhibitors

• Skin burning and pruritus may occur at the start of treatment; typically resolve within the first 2 weeks.
• Low blood levels seen in a small minority of patients (not invthe range typically associated with immunosuppression).
• High blood levels rarely seen in patients with compromised epidermal barriers, e.g., Netherton syndrome. [Allen A, et al. Arch Dermatol 137(6):747-50 (2001 Jun).Arch Jun).]
• Do not cause atrophy, striae, or pigmentation changes (in contrast to topical steroids).
• No increase in systemic infections, and no increased risk of malignancy in clinical studies.[FDA Pediatric Advisory Committee. February 15, 2005, Briefing Information.]
• The American Academy of Dermatology (AAD) task force found that “there is no causal proof that TCIs cause lymphoma or nonmelanoma skin cancer.”[Berger TG, et al. J Am Acad Dermatol 54(5):818-23 (2006 May).]
• Animal studies showed an increase in lymphoma at doses far exceeding those achieved with topical use. The applicability of animal studies to humans is poor due to differences in biology, concomitant exposures, and innate protective mechanisms.[Berger TG, et al. J Am Acad Dermatol 54(5):818-23 (2006 May).]
• The blood concentrations detected in a few patients with AD, including young children with extensive disease, have been insufficient to cause sustained immunosuppression leading to the development of lymphomas.[Bieber T, et al. Dermatology 211(2):77-8 (2005).]
• There have been rare spontaneous reports of lymphomas in the >7.5 million patients treated with TCIs, but their histology and clinical presentation are not in keeping with lymphomas occurring in the setting of immunosuppressive therapy.[Ormerod AD. Br J Dermatol 153(4):701-5 (2005 Oct).]
• An odds ratio analysis (with a 95% Confidence Interval [CI]) of 293,253 patients with A.D. showed no increased risk of lymphoma in patients treated with TCIs. [Arellano FM, et al. J Invest Dermatol 127(4):808-16 (2007 Apr).]
• DNA repair in keratinocytes is inhibited in vitro by TCIs, suggesting a theoretical risk that they might affect local skin carcinogenesis. Clinical evidence is however lacking.[Berger TG, et al. J Am Acad Dermatol 54(5):818-23 (2006 May).]
• The AAD task force recommends use in patients at high risk for developing skin cancer (e.g., patients on immunosuppressants, or with xeroderma pigmentosum or nevoid basal cell carcinoma syndrome) only after failure
  of reasonable alternatives. Broad-spectrum sunscreen should be applied to exposed skin.
• The TCI task force of the American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma, and Immunology concluded that the risk/benefit ratio of TCIs was similar to those of most
  conventional therapies for chronic relapsing AD. Use in children

Conclusions

TCIs have an important place in the therapeutic armamentarium for AD. They are approved as second line agents for individuals >2 years of age, and have a good safety profile when used short-term or intermittently long-term. Studies so far have not shown an increase in malignancy in humans, but long-term vigilance is required to ensure that this remains the case.

Dermatologic Diagnostic Challenge

Question: An 83 year-old Caucasian male presents with a slowly enlarging plaque on his leg. He has a history of actinic keratoses on his face for which he receives periodic liquid nitrogen cryotherapy. What is your diagnosis?

a. Squamous cell carcinoma
b. Wart
c. Amelanotic melanoma
d. Seborrheic keratosis
e. Keratoacanthoma
f. Basal cell carcinoma

Case study submitted by Benjamin Barankin, MD FRCPC