CME #127
June 2006
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal as dermatologists to fight inflammatory skin disease. Prior to this development, we were often limited to topical corticosteroids, which have many side effects. Here, we’ll discuss what the studies show about the effectiveness of TCIs in treating atopic dermatitis, success with off-label uses and the recent FDA black box warnings for these drugs.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax page 60 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Christie Carroll, M.D.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 54-58 and successfully answering the questions found on pp. 59-60. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: June 2006
Expiration Date: June 2007
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation.
Off-Label Disclosures: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither the North American Center for Continuing Medical Education, nor Novartis or Astellas Pharm recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
Faculty Disclosures: Dr. Carroll has disclosed that she has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1. Identify the mechanisms of action of topical calcineurin inhibitors and approved uses with safety and efficacy.
2. Identify boxed warnings for topical calcineurin inhibitors.
3. Identify the off-label uses of topical calcineurin inhibitors.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal of treatments for combating inflammatory skin disease. Prior to the development of tacrolimus (Protopic) and pimecrolimus (Elidel), we were often limited to topical corticosteroids, which have many side effects, including skin atrophy, striae, depigmentation and telangiectasia.1 We were also limited in treating facial and genital dermatoses due to heightened side effects of topical corticosteroids.
After TCIs received FDA approval for atopic dermatitis, these medications were widely used — more than 3 million patients have used tacrolimus worldwide and more than 6 million have used pimecrolimus.2,3 Many dermatologists also began to use these medications for other inflammatory dermatoses, off-label, with success. These medications were also used off-label in the very young, as neither medication was approved in children younger than 2 years old. After a recent, extensive FDA investigation into TCIs regarding their risk to cancer, a boxed warning has been added to these medications, making many physicians wary of continued prescribing.
Overview of Tacrolimus
Tacrolimus, a macrolide lactone antibiotic was developed as a systemic immu-nosuprressant for use in transplant patients. It is formed by the microorganism Streptomyces tsukubaensis and marketed under the tradename Prograf.4 The topical formulation, tacrolimus ointment (Protopic) was developed and tested after psoriasis cleared in transplant patients receiving oral tacrolimus (FK 506).5
The mechanism of action of tacrolimus involves inhibiting calcineurin by binding with the FK-Binding protein 12 in T-lymphocytes.4,6 This complex prevents calcineurin from dephosphorylating NFAT(nuclear factor of activated T cells). When NFAT is phosphorylated it cannot travel to the nucleus to activate transcription inflammatory cytokines. By locally blocking this response, tacrolimus exerts its anti-inflammatory effect.7 As a second mechanism of action, tacrolimus also decreases the number of Langerhans cells and antigen presenting cells in the skin, also inhibiting the propagation of the inflammatory cascade.
Tacrolimus ointment, manufactured by Astellas Pharma, Inc., was FDA approved in December of 2000 for treatment of moderate-to-severe atopic dermatitis in children 2 years or older and adults. Its approval is for twice daily dosing in children aged 2 to 15 is for the 0.03% dosage form, while the 0.1% is approved for use in adults.8
Tacrolimus Studies
The efficacy of tacrolimus ointment was reported by Hanifin et al. in two 12-week, double-blind, vehicle-controlled trials with more than 600 adults with moderate-to-severe atopic dermatitis, which showed 28% reaching treatment success (>90% clearing) in the 0.03% group and 37% in the 0.1% group compared to 7% in the vehicle group (p<0.001).9 This study also showed a benefit to the 0.1% ointment — it demonstrated a statistically significant difference over the 0.03% ointment (p=0.04).
Paller et al. studied the efficacy of both 0.03% and 0.1% tacrolimus ointment in 351 children with moderate-to-severe atopic dermatitis in a similarly designed 12-week, randomized, double-blind, vehicle-controlled trial.10 Treatment success was again defined as >90% clearing and 7%, 36% and 41% treated with vehicle, 0.03% ointment, and 0.1% ointment, respectively, reached this goal (p<0.001).
Long-term efficacy in the pediatric population was studied by Kang et al. in 255 children using 0.1% tacrolimus ointment twice daily for 12 months.11 In this study, improvement was seen as early as 1 week and maintained through out the 12 months. Koo et al. studied 3,964 adult and 3,959 pediatric patients with atopic dermatitis in an open-label trial with 0.1% and 0.03% tacrolimus ointment applied twice daily to affected areas.12 There was a 52% improvement from baseline in affected body surface area at
1 month and 91% improvement at 18 months.
This suggests that improvements related to tacrolimus use are not only sustained, but continue improving long term. Also, no increases in adverse events or changes in safety profile were found.
Safety issues are at the forefront for both tacrolimus and pimecrolimus. In this section we will address only the issues presented in the trials data. (The new FDA labeling will be presented in combination later in the article.)
The most common side effects seen with tacrolimus in adult and pediatric patients during the clinical trials were local application site reactions (including skin burning, erythema and pruritus), flu-like symptoms and headache.13 The application site reactions occurred in about half the patients, and tended to decrease within the first few days of treatment.
Fleischer et al. studied 1,500 patients in the adult and pediatric trials and found no increase in cutaneous bacterial, fungal or viral infections over the vehicle groups.14 In the phase III trial of pediatric patients an examination of safety of the 0.03% vs 0.1% ointments showed no increase in adverse events.10
Two other studies supported this finding that in children 2 to 15 years old, 0.1% tacrolimus ointment is more effective than 0.03% ointment and equally safe.11,15 Patel et al. also looked at the use in children <2 years of age with low systemic blood levels and no increase in adverse events.16 These data suggest that tacrolimus is safe in both pediatric and adult patients, and even safe in children <2 years of age. Futher supporting this finding is the large open label study with nearly 8,000 patients (adults and children) showing there were no new adverse events or increase in adverse events with time.12
Overview of Pimecrolimus
Pimecrolimus (Elidel), initially developed under the name SDZ ASM 981 by Novartis, is also in the macrolactam family. It was isolated from Streptomyces hygroscopius var. ascomyceticus. It was developed as a topical anti-inflammatory agent and like tacrolimus, also works through the FK-BP-12 inhibiting the dephosphorylation of NF-AT. However, some difference between the two medications have been found.
Pimecrolimus seems to be specific for T-cells and mast cells and has no actions on the dendritic cells or Langerhans cells.17 It also has effects on the inflammatory cytokines, suppressing IL-2, Il-3, IL-4, IL-5, INF-g and TNF-a. Pimecrolimus has also been shown to have less penetration through the skin than tacrolimus, allowing for less systemic absorption.18 However, both medications have been studied extensively and the systemic blood levels for both medications are minimal and not clinically significant.16,19-22
Pimecrolimus is marketed in a 1% cream formulation that is indicated as a second-line therapy for treatment of mild-to-moderate atopic dermatitis in adults and children over the age of 2.23
Pimecrolimus Studies
Eichenfield et al. presented the efficacy data from a 6-week, double-blind, vehicle-controlled trial in 403 children (aged 1-17) which showed 35% of patients clear or almost clear when treated with pimecrolimus 1% cream vs 18% in the vehicle group (p<0.05).24
The change in Eczema Area and Severity Index (EASI) was also significant with a 45% improvement vs. 1% improvement when comparing pimecrolimus to vehicle (p<0.001). Another 6-week, double-blind, vehicle-controlled study with 186 infants (aged 3 to 23 months) showed 55% of pimecrolimus treated patients 24% of the vehicle treated patients were clear or almost clear at the end of study (p<0.001).25
Long-term efficacy was also examined by Kapp et al. in a 1-year study of infants aged 3 to 23 months using pimecrolimus versus vehicle in treatment of early signs of disease, and allowing treatment with topical corticosteroids for more severe flares.26 In this study pimecrolimus was more effective than vehicle in reducing the number of flares. Fifty-seven percent of the pimecrolimus treated group had no flares requiring topical corticosteroids in 12 months versus only 28% in the vehicle treated group. An open-label extension of this study presented 76 patients who continued for another year of pimecrolimus use with a reported decrease of EASI score of 69% at 3 months and 71% at 24 months, showing continued efficacy long term. 27
Pimecrolimus has proven to be a very safe topical medication in the clinical trials. In the initial trials presented by Eichenfield et al., the application site reactions were higher in the vehicle group at 35% than in the pimecrolimus group at 28%.24 The most common adverse events in treatment and vehicle groups were upper respiratory tract infections, headache, cough and nasopharyngitis.
Paul et al. presented data on 1,133 infants (aged 3 to 23 months) with mild-to-severe atopic dermatitis treated for up to 2 years with no significant change in the risk profile.28 They did note that in the pimecrolimus group they had more episodes of noticeable teething than in the vehicle group. Also in this study, 35 infants had blood concentrations of pimecrolimus drawn and more than 80% were below 1ng/ml for up to 1 year.
Comparing TCIs to Topical Corticosteroids
As previously mentioned, both primary care physicians and dermatologists traditionally have treated atopic dermatitis with corticosteroids. For more mild disease, lower potency topical steroids, for more severe disease, higher potency topical steroids and even oral steroids are sometimes given. After the arrival of TCIs to the market, there was an immediate rush to avoid topical corticosteroids and their side effects, such as atrophy and striae. Several studies have examined the efficacy of the TCIs versus commonly used topical corticosteroids.
Reitamo et al. presented a randomized, double blinded trial of topical tacrolimus (both 0.1 and 0.03% against hydrocortisone butyrate (Class V). 29 In the 570 adults with moderate-to-severe atopic dermatitis the efficacies of tacrolimus 0.1% and the topical corticosteroid were comparable. Two other studies with tacrolimus, both the 0.1% and the 0.03%, showed efficacy over hydrocortisone acetate 1%, which is a lower potency topical corticosteroid (Class VII).15, 30
Luger et al. presented data on pimecrolimus 1% cream vs. triamcinalone acetonide cream (Class III) in 658 adult patients with moderate to severe atopic dermatitis.31 Although both medications showed improvement, the efficacy was significantly better in the triamcinalone group as compared to the pimecrolimus group at 1 week (68% vs. 37%) and 3 weeks (76% vs. 57%), and at 7 months (86% vs.77%), but at 13 months (89% vs. 82%) there was not a significant difference. This study suggests a benefit in safety from the pimecrolimus group because one subgroup (>30% BSA) showed a lower incidence of skin infections with pimecrolimus than with the triamcinalone, and there were three reports of striae in the triamcinalone group.
This suggests that tacrolimus performs better against standard topical corticosteroid therapies, however, since the corticosteroid potencies varied with the trials, these results should not be compared directly.
Head-to-Head Comparison of TCIs
Not surprisingly, with two medications with similar risk profiles and the same target market in atopic dermatitis, the efficacy of tacrolimus versus pimecrolimus has been an issue. Although both medications act via the FK-binding protein-12 (FKBP-12), tacrolimus ointment has three times greater binding affinity for the FKBP than pimecrolimus.32
Three 6-week, double-blind, head-to-head trials with tacrolimus ointment (both 0.1% and 0.03%) and pimecrolimus 0.1% cream with a total of 1,065 patients (both children and adults) were completed.33 The combined analysis showed significantly higher rates of treatment success for tacrolimus at weeks 3 and 6 (p<0.001 and p<0.0001, respectively). The adverse event profiles in these studies were markedly similar, with only the adult patients using tacrolimus ointment 0.1% reporting a significantly higher rate of burning at the application site (p=0.02).
A smaller study (n=141), using tacrolimus ointment 0.03% versus pimecrolimus cream 1% in pediatric patients with moderate atopic dermatitis34 showed no statistical difference between the two groups, though one explanation of these findings is that the study may have been underpowered because of low sample size. They did find that application site reactions (erythema/irritation) were higher in tacrolimus at 19% versus 8% with pimecrolimus. These reactions were also shorter in duration for pimecrolimus.
Overall these studies suggest improved efficacy of tacrolimus ointment over pimecrolimus cream with very similar safety profiles, with, perhaps, a slight increase in tolerability to the pimecrolimus cream.
The Boxed Warning
As previously mentioned, the FDA has recently added a boxed warning to both topical tacrolimus and pimecrolimus. The warning discusses the theoretical risk of malignancy, specifically skin malignancies and lymphoma. It also recommends avoiding continuous use and off-label use, especially in children under the age of 2 years. This has been a matter of significant concern for those prescribing these medications, especially in our increasingly litigious society.
The data reported to the FDA showed a total of 28 malignancies related to topical calcineurin use, with 10 related to pimecrolimus and 19 related to tacrolimus (one common case).35 These malignancies were in both adults (21 cases) and children (7).
A majority of the malignancies were not reported at the application site, and of those that were, four were squamous cell carcinomas, two were t-cell lymphomas, one was Kaposi's sarcoma and the last was a lymphoma not otherwise specified. Berger et al., in reporting on the American Academy of Dermatology Association Conference in July 2005, also suggests that it is plausible that the cases of T-cell lymphomas were misdiagnosed and inappropriately treated as atopic dermatitis, but may have been a cutaneous lymphoma at the onset.36
Other malignancies reported were hepatoblastoma, lymphomas (non-Hodgkins, follicular, general and one EBV assoc B-cell), esophageal cancer, new onset metastatic melanoma, granulomatous lymphadenitis, intraductal papilloma of the nipple and basal cell carcinoma. The average onset of these malignancies was 90 days after starting topical treatment in the pimecrolimus cases and 150 days in the tacrolimus cases. These short onset times, with our basic knowledge of tumor oncogenesis, make the association unlikely.
In general, the data for the topical calcineurin inhibitors may actually show a protective effect against malignancy and lymphoma specifically. The rates of lymphomas in the tacrolimus patients is 0.65/100,000 versus 22/100,000 in the U.S. population (using the SEER data).35,37 Also using the SEER data, the expected number of malignancies in adults would be 42 and would be four in children, but the reported numbers are two and one, respectively.
Another concern has been whether the use of topical calcineurin inhibitors puts patients at increased risk for skin malignancies. This issue is even more heated than the systemic cancer issue, as many of the patients using these medications are children. At this time it is still too early to tell if years of exposure as a child will increase the risk of malignancy as adult. This will require long-term studies, most likely at least 20 to 40 years. Examining the data that we have does not show a likelihood of skin cancer as a long-term side effect. A review of 9,813 adult and pediatric patients with atopic dermatitis, using tacrolimus for a mean of 208 days reported 13 adults with development of nonmelanoma skin cancer (NMSC) during the study.38 This was compared to age adjusted cohorts and showed no increased risk of NMSC. Of note, some of the off-label conditions that are treated with TCIs, such as lichen sclerosus et atrophicus and mucosal lichen planus, have an increased risk of squamous cell carcinoma unrelated to treatments.39-41
An Important Tool in Treating Atopic Dermatitis
The topical calcineurin inhibitors are important tools in the treatment of atopic dermatitis and many other inflammatory skin conditions. TCIs act through the immune system and inhibit NFAT from activating the transcription factors necessary to start the inflammatory cascade on both a cellular and cytokine level. They have been proven to be effective treatments for atopic dermatitis and many other inflammatory disorders and in some cases equivalent to standard topical therapy with corticosteroids. Although there have been concerns regarding the risk of malignancies with their use, the current data does not support a direct risk. Long-term studies are being undertaken to further investigate this issue. Until this is resolved, prudent use of these effective medications, with education of our patients is critical.
CME #127
June 2006
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal as dermatologists to fight inflammatory skin disease. Prior to this development, we were often limited to topical corticosteroids, which have many side effects. Here, we’ll discuss what the studies show about the effectiveness of TCIs in treating atopic dermatitis, success with off-label uses and the recent FDA black box warnings for these drugs.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax page 60 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Christie Carroll, M.D.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 54-58 and successfully answering the questions found on pp. 59-60. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: June 2006
Expiration Date: June 2007
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation.
Off-Label Disclosures: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither the North American Center for Continuing Medical Education, nor Novartis or Astellas Pharm recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
Faculty Disclosures: Dr. Carroll has disclosed that she has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1. Identify the mechanisms of action of topical calcineurin inhibitors and approved uses with safety and efficacy.
2. Identify boxed warnings for topical calcineurin inhibitors.
3. Identify the off-label uses of topical calcineurin inhibitors.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal of treatments for combating inflammatory skin disease. Prior to the development of tacrolimus (Protopic) and pimecrolimus (Elidel), we were often limited to topical corticosteroids, which have many side effects, including skin atrophy, striae, depigmentation and telangiectasia.1 We were also limited in treating facial and genital dermatoses due to heightened side effects of topical corticosteroids.
After TCIs received FDA approval for atopic dermatitis, these medications were widely used — more than 3 million patients have used tacrolimus worldwide and more than 6 million have used pimecrolimus.2,3 Many dermatologists also began to use these medications for other inflammatory dermatoses, off-label, with success. These medications were also used off-label in the very young, as neither medication was approved in children younger than 2 years old. After a recent, extensive FDA investigation into TCIs regarding their risk to cancer, a boxed warning has been added to these medications, making many physicians wary of continued prescribing.
Overview of Tacrolimus
Tacrolimus, a macrolide lactone antibiotic was developed as a systemic immu-nosuprressant for use in transplant patients. It is formed by the microorganism Streptomyces tsukubaensis and marketed under the tradename Prograf.4 The topical formulation, tacrolimus ointment (Protopic) was developed and tested after psoriasis cleared in transplant patients receiving oral tacrolimus (FK 506).5
The mechanism of action of tacrolimus involves inhibiting calcineurin by binding with the FK-Binding protein 12 in T-lymphocytes.4,6 This complex prevents calcineurin from dephosphorylating NFAT(nuclear factor of activated T cells). When NFAT is phosphorylated it cannot travel to the nucleus to activate transcription inflammatory cytokines. By locally blocking this response, tacrolimus exerts its anti-inflammatory effect.7 As a second mechanism of action, tacrolimus also decreases the number of Langerhans cells and antigen presenting cells in the skin, also inhibiting the propagation of the inflammatory cascade.
Tacrolimus ointment, manufactured by Astellas Pharma, Inc., was FDA approved in December of 2000 for treatment of moderate-to-severe atopic dermatitis in children 2 years or older and adults. Its approval is for twice daily dosing in children aged 2 to 15 is for the 0.03% dosage form, while the 0.1% is approved for use in adults.8
Tacrolimus Studies
The efficacy of tacrolimus ointment was reported by Hanifin et al. in two 12-week, double-blind, vehicle-controlled trials with more than 600 adults with moderate-to-severe atopic dermatitis, which showed 28% reaching treatment success (>90% clearing) in the 0.03% group and 37% in the 0.1% group compared to 7% in the vehicle group (p<0.001).9 This study also showed a benefit to the 0.1% ointment — it demonstrated a statistically significant difference over the 0.03% ointment (p=0.04).
Paller et al. studied the efficacy of both 0.03% and 0.1% tacrolimus ointment in 351 children with moderate-to-severe atopic dermatitis in a similarly designed 12-week, randomized, double-blind, vehicle-controlled trial.10 Treatment success was again defined as >90% clearing and 7%, 36% and 41% treated with vehicle, 0.03% ointment, and 0.1% ointment, respectively, reached this goal (p<0.001).
Long-term efficacy in the pediatric population was studied by Kang et al. in 255 children using 0.1% tacrolimus ointment twice daily for 12 months.11 In this study, improvement was seen as early as 1 week and maintained through out the 12 months. Koo et al. studied 3,964 adult and 3,959 pediatric patients with atopic dermatitis in an open-label trial with 0.1% and 0.03% tacrolimus ointment applied twice daily to affected areas.12 There was a 52% improvement from baseline in affected body surface area at
1 month and 91% improvement at 18 months.
This suggests that improvements related to tacrolimus use are not only sustained, but continue improving long term. Also, no increases in adverse events or changes in safety profile were found.
Safety issues are at the forefront for both tacrolimus and pimecrolimus. In this section we will address only the issues presented in the trials data. (The new FDA labeling will be presented in combination later in the article.)
The most common side effects seen with tacrolimus in adult and pediatric patients during the clinical trials were local application site reactions (including skin burning, erythema and pruritus), flu-like symptoms and headache.13 The application site reactions occurred in about half the patients, and tended to decrease within the first few days of treatment.
Fleischer et al. studied 1,500 patients in the adult and pediatric trials and found no increase in cutaneous bacterial, fungal or viral infections over the vehicle groups.14 In the phase III trial of pediatric patients an examination of safety of the 0.03% vs 0.1% ointments showed no increase in adverse events.10
Two other studies supported this finding that in children 2 to 15 years old, 0.1% tacrolimus ointment is more effective than 0.03% ointment and equally safe.11,15 Patel et al. also looked at the use in children <2 years of age with low systemic blood levels and no increase in adverse events.16 These data suggest that tacrolimus is safe in both pediatric and adult patients, and even safe in children <2 years of age. Futher supporting this finding is the large open label study with nearly 8,000 patients (adults and children) showing there were no new adverse events or increase in adverse events with time.12
Overview of Pimecrolimus
Pimecrolimus (Elidel), initially developed under the name SDZ ASM 981 by Novartis, is also in the macrolactam family. It was isolated from Streptomyces hygroscopius var. ascomyceticus. It was developed as a topical anti-inflammatory agent and like tacrolimus, also works through the FK-BP-12 inhibiting the dephosphorylation of NF-AT. However, some difference between the two medications have been found.
Pimecrolimus seems to be specific for T-cells and mast cells and has no actions on the dendritic cells or Langerhans cells.17 It also has effects on the inflammatory cytokines, suppressing IL-2, Il-3, IL-4, IL-5, INF-g and TNF-a. Pimecrolimus has also been shown to have less penetration through the skin than tacrolimus, allowing for less systemic absorption.18 However, both medications have been studied extensively and the systemic blood levels for both medications are minimal and not clinically significant.16,19-22
Pimecrolimus is marketed in a 1% cream formulation that is indicated as a second-line therapy for treatment of mild-to-moderate atopic dermatitis in adults and children over the age of 2.23
Pimecrolimus Studies
Eichenfield et al. presented the efficacy data from a 6-week, double-blind, vehicle-controlled trial in 403 children (aged 1-17) which showed 35% of patients clear or almost clear when treated with pimecrolimus 1% cream vs 18% in the vehicle group (p<0.05).24
The change in Eczema Area and Severity Index (EASI) was also significant with a 45% improvement vs. 1% improvement when comparing pimecrolimus to vehicle (p<0.001). Another 6-week, double-blind, vehicle-controlled study with 186 infants (aged 3 to 23 months) showed 55% of pimecrolimus treated patients 24% of the vehicle treated patients were clear or almost clear at the end of study (p<0.001).25
Long-term efficacy was also examined by Kapp et al. in a 1-year study of infants aged 3 to 23 months using pimecrolimus versus vehicle in treatment of early signs of disease, and allowing treatment with topical corticosteroids for more severe flares.26 In this study pimecrolimus was more effective than vehicle in reducing the number of flares. Fifty-seven percent of the pimecrolimus treated group had no flares requiring topical corticosteroids in 12 months versus only 28% in the vehicle treated group. An open-label extension of this study presented 76 patients who continued for another year of pimecrolimus use with a reported decrease of EASI score of 69% at 3 months and 71% at 24 months, showing continued efficacy long term. 27
Pimecrolimus has proven to be a very safe topical medication in the clinical trials. In the initial trials presented by Eichenfield et al., the application site reactions were higher in the vehicle group at 35% than in the pimecrolimus group at 28%.24 The most common adverse events in treatment and vehicle groups were upper respiratory tract infections, headache, cough and nasopharyngitis.
Paul et al. presented data on 1,133 infants (aged 3 to 23 months) with mild-to-severe atopic dermatitis treated for up to 2 years with no significant change in the risk profile.28 They did note that in the pimecrolimus group they had more episodes of noticeable teething than in the vehicle group. Also in this study, 35 infants had blood concentrations of pimecrolimus drawn and more than 80% were below 1ng/ml for up to 1 year.
Comparing TCIs to Topical Corticosteroids
As previously mentioned, both primary care physicians and dermatologists traditionally have treated atopic dermatitis with corticosteroids. For more mild disease, lower potency topical steroids, for more severe disease, higher potency topical steroids and even oral steroids are sometimes given. After the arrival of TCIs to the market, there was an immediate rush to avoid topical corticosteroids and their side effects, such as atrophy and striae. Several studies have examined the efficacy of the TCIs versus commonly used topical corticosteroids.
Reitamo et al. presented a randomized, double blinded trial of topical tacrolimus (both 0.1 and 0.03% against hydrocortisone butyrate (Class V). 29 In the 570 adults with moderate-to-severe atopic dermatitis the efficacies of tacrolimus 0.1% and the topical corticosteroid were comparable. Two other studies with tacrolimus, both the 0.1% and the 0.03%, showed efficacy over hydrocortisone acetate 1%, which is a lower potency topical corticosteroid (Class VII).15, 30
Luger et al. presented data on pimecrolimus 1% cream vs. triamcinalone acetonide cream (Class III) in 658 adult patients with moderate to severe atopic dermatitis.31 Although both medications showed improvement, the efficacy was significantly better in the triamcinalone group as compared to the pimecrolimus group at 1 week (68% vs. 37%) and 3 weeks (76% vs. 57%), and at 7 months (86% vs.77%), but at 13 months (89% vs. 82%) there was not a significant difference. This study suggests a benefit in safety from the pimecrolimus group because one subgroup (>30% BSA) showed a lower incidence of skin infections with pimecrolimus than with the triamcinalone, and there were three reports of striae in the triamcinalone group.
This suggests that tacrolimus performs better against standard topical corticosteroid therapies, however, since the corticosteroid potencies varied with the trials, these results should not be compared directly.
Head-to-Head Comparison of TCIs
Not surprisingly, with two medications with similar risk profiles and the same target market in atopic dermatitis, the efficacy of tacrolimus versus pimecrolimus has been an issue. Although both medications act via the FK-binding protein-12 (FKBP-12), tacrolimus ointment has three times greater binding affinity for the FKBP than pimecrolimus.32
Three 6-week, double-blind, head-to-head trials with tacrolimus ointment (both 0.1% and 0.03%) and pimecrolimus 0.1% cream with a total of 1,065 patients (both children and adults) were completed.33 The combined analysis showed significantly higher rates of treatment success for tacrolimus at weeks 3 and 6 (p<0.001 and p<0.0001, respectively). The adverse event profiles in these studies were markedly similar, with only the adult patients using tacrolimus ointment 0.1% reporting a significantly higher rate of burning at the application site (p=0.02).
A smaller study (n=141), using tacrolimus ointment 0.03% versus pimecrolimus cream 1% in pediatric patients with moderate atopic dermatitis34 showed no statistical difference between the two groups, though one explanation of these findings is that the study may have been underpowered because of low sample size. They did find that application site reactions (erythema/irritation) were higher in tacrolimus at 19% versus 8% with pimecrolimus. These reactions were also shorter in duration for pimecrolimus.
Overall these studies suggest improved efficacy of tacrolimus ointment over pimecrolimus cream with very similar safety profiles, with, perhaps, a slight increase in tolerability to the pimecrolimus cream.
The Boxed Warning
As previously mentioned, the FDA has recently added a boxed warning to both topical tacrolimus and pimecrolimus. The warning discusses the theoretical risk of malignancy, specifically skin malignancies and lymphoma. It also recommends avoiding continuous use and off-label use, especially in children under the age of 2 years. This has been a matter of significant concern for those prescribing these medications, especially in our increasingly litigious society.
The data reported to the FDA showed a total of 28 malignancies related to topical calcineurin use, with 10 related to pimecrolimus and 19 related to tacrolimus (one common case).35 These malignancies were in both adults (21 cases) and children (7).
A majority of the malignancies were not reported at the application site, and of those that were, four were squamous cell carcinomas, two were t-cell lymphomas, one was Kaposi's sarcoma and the last was a lymphoma not otherwise specified. Berger et al., in reporting on the American Academy of Dermatology Association Conference in July 2005, also suggests that it is plausible that the cases of T-cell lymphomas were misdiagnosed and inappropriately treated as atopic dermatitis, but may have been a cutaneous lymphoma at the onset.36
Other malignancies reported were hepatoblastoma, lymphomas (non-Hodgkins, follicular, general and one EBV assoc B-cell), esophageal cancer, new onset metastatic melanoma, granulomatous lymphadenitis, intraductal papilloma of the nipple and basal cell carcinoma. The average onset of these malignancies was 90 days after starting topical treatment in the pimecrolimus cases and 150 days in the tacrolimus cases. These short onset times, with our basic knowledge of tumor oncogenesis, make the association unlikely.
In general, the data for the topical calcineurin inhibitors may actually show a protective effect against malignancy and lymphoma specifically. The rates of lymphomas in the tacrolimus patients is 0.65/100,000 versus 22/100,000 in the U.S. population (using the SEER data).35,37 Also using the SEER data, the expected number of malignancies in adults would be 42 and would be four in children, but the reported numbers are two and one, respectively.
Another concern has been whether the use of topical calcineurin inhibitors puts patients at increased risk for skin malignancies. This issue is even more heated than the systemic cancer issue, as many of the patients using these medications are children. At this time it is still too early to tell if years of exposure as a child will increase the risk of malignancy as adult. This will require long-term studies, most likely at least 20 to 40 years. Examining the data that we have does not show a likelihood of skin cancer as a long-term side effect. A review of 9,813 adult and pediatric patients with atopic dermatitis, using tacrolimus for a mean of 208 days reported 13 adults with development of nonmelanoma skin cancer (NMSC) during the study.38 This was compared to age adjusted cohorts and showed no increased risk of NMSC. Of note, some of the off-label conditions that are treated with TCIs, such as lichen sclerosus et atrophicus and mucosal lichen planus, have an increased risk of squamous cell carcinoma unrelated to treatments.39-41
An Important Tool in Treating Atopic Dermatitis
The topical calcineurin inhibitors are important tools in the treatment of atopic dermatitis and many other inflammatory skin conditions. TCIs act through the immune system and inhibit NFAT from activating the transcription factors necessary to start the inflammatory cascade on both a cellular and cytokine level. They have been proven to be effective treatments for atopic dermatitis and many other inflammatory disorders and in some cases equivalent to standard topical therapy with corticosteroids. Although there have been concerns regarding the risk of malignancies with their use, the current data does not support a direct risk. Long-term studies are being undertaken to further investigate this issue. Until this is resolved, prudent use of these effective medications, with education of our patients is critical.
CME #127
June 2006
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal as dermatologists to fight inflammatory skin disease. Prior to this development, we were often limited to topical corticosteroids, which have many side effects. Here, we’ll discuss what the studies show about the effectiveness of TCIs in treating atopic dermatitis, success with off-label uses and the recent FDA black box warnings for these drugs.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax page 60 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Christie Carroll, M.D.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 54-58 and successfully answering the questions found on pp. 59-60. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: June 2006
Expiration Date: June 2007
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation.
Off-Label Disclosures: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither the North American Center for Continuing Medical Education, nor Novartis or Astellas Pharm recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
Faculty Disclosures: Dr. Carroll has disclosed that she has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1. Identify the mechanisms of action of topical calcineurin inhibitors and approved uses with safety and efficacy.
2. Identify boxed warnings for topical calcineurin inhibitors.
3. Identify the off-label uses of topical calcineurin inhibitors.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs) are newer medications that have added to our arsenal of treatments for combating inflammatory skin disease. Prior to the development of tacrolimus (Protopic) and pimecrolimus (Elidel), we were often limited to topical corticosteroids, which have many side effects, including skin atrophy, striae, depigmentation and telangiectasia.1 We were also limited in treating facial and genital dermatoses due to heightened side effects of topical corticosteroids.
After TCIs received FDA approval for atopic dermatitis, these medications were widely used — more than 3 million patients have used tacrolimus worldwide and more than 6 million have used pimecrolimus.2,3 Many dermatologists also began to use these medications for other inflammatory dermatoses, off-label, with success. These medications were also used off-label in the very young, as neither medication was approved in children younger than 2 years old. After a recent, extensive FDA investigation into TCIs regarding their risk to cancer, a boxed warning has been added to these medications, making many physicians wary of continued prescribing.
Overview of Tacrolimus
Tacrolimus, a macrolide lactone antibiotic was developed as a systemic immu-nosuprressant for use in transplant patients. It is formed by the microorganism Streptomyces tsukubaensis and marketed under the tradename Prograf.4 The topical formulation, tacrolimus ointment (Protopic) was developed and tested after psoriasis cleared in transplant patients receiving oral tacrolimus (FK 506).5
The mechanism of action of tacrolimus involves inhibiting calcineurin by binding with the FK-Binding protein 12 in T-lymphocytes.4,6 This complex prevents calcineurin from dephosphorylating NFAT(nuclear factor of activated T cells). When NFAT is phosphorylated it cannot travel to the nucleus to activate transcription inflammatory cytokines. By locally blocking this response, tacrolimus exerts its anti-inflammatory effect.7 As a second mechanism of action, tacrolimus also decreases the number of Langerhans cells and antigen presenting cells in the skin, also inhibiting the propagation of the inflammatory cascade.
Tacrolimus ointment, manufactured by Astellas Pharma, Inc., was FDA approved in December of 2000 for treatment of moderate-to-severe atopic dermatitis in children 2 years or older and adults. Its approval is for twice daily dosing in children aged 2 to 15 is for the 0.03% dosage form, while the 0.1% is approved for use in adults.8
Tacrolimus Studies
The efficacy of tacrolimus ointment was reported by Hanifin et al. in two 12-week, double-blind, vehicle-controlled trials with more than 600 adults with moderate-to-severe atopic dermatitis, which showed 28% reaching treatment success (>90% clearing) in the 0.03% group and 37% in the 0.1% group compared to 7% in the vehicle group (p<0.001).9 This study also showed a benefit to the 0.1% ointment — it demonstrated a statistically significant difference over the 0.03% ointment (p=0.04).
Paller et al. studied the efficacy of both 0.03% and 0.1% tacrolimus ointment in 351 children with moderate-to-severe atopic dermatitis in a similarly designed 12-week, randomized, double-blind, vehicle-controlled trial.10 Treatment success was again defined as >90% clearing and 7%, 36% and 41% treated with vehicle, 0.03% ointment, and 0.1% ointment, respectively, reached this goal (p<0.001).
Long-term efficacy in the pediatric population was studied by Kang et al. in 255 children using 0.1% tacrolimus ointment twice daily for 12 months.11 In this study, improvement was seen as early as 1 week and maintained through out the 12 months. Koo et al. studied 3,964 adult and 3,959 pediatric patients with atopic dermatitis in an open-label trial with 0.1% and 0.03% tacrolimus ointment applied twice daily to affected areas.12 There was a 52% improvement from baseline in affected body surface area at
1 month and 91% improvement at 18 months.
This suggests that improvements related to tacrolimus use are not only sustained, but continue improving long term. Also, no increases in adverse events or changes in safety profile were found.
Safety issues are at the forefront for both tacrolimus and pimecrolimus. In this section we will address only the issues presented in the trials data. (The new FDA labeling will be presented in combination later in the article.)
The most common side effects seen with tacrolimus in adult and pediatric patients during the clinical trials were local application site reactions (including skin burning, erythema and pruritus), flu-like symptoms and headache.13 The application site reactions occurred in about half the patients, and tended to decrease within the first few days of treatment.
Fleischer et al. studied 1,500 patients in the adult and pediatric trials and found no increase in cutaneous bacterial, fungal or viral infections over the vehicle groups.14 In the phase III trial of pediatric patients an examination of safety of the 0.03% vs 0.1% ointments showed no increase in adverse events.10
Two other studies supported this finding that in children 2 to 15 years old, 0.1% tacrolimus ointment is more effective than 0.03% ointment and equally safe.11,15 Patel et al. also looked at the use in children <2 years of age with low systemic blood levels and no increase in adverse events.16 These data suggest that tacrolimus is safe in both pediatric and adult patients, and even safe in children <2 years of age. Futher supporting this finding is the large open label study with nearly 8,000 patients (adults and children) showing there were no new adverse events or increase in adverse events with time.12
Overview of Pimecrolimus
Pimecrolimus (Elidel), initially developed under the name SDZ ASM 981 by Novartis, is also in the macrolactam family. It was isolated from Streptomyces hygroscopius var. ascomyceticus. It was developed as a topical anti-inflammatory agent and like tacrolimus, also works through the FK-BP-12 inhibiting the dephosphorylation of NF-AT. However, some difference between the two medications have been found.
Pimecrolimus seems to be specific for T-cells and mast cells and has no actions on the dendritic cells or Langerhans cells.17 It also has effects on the inflammatory cytokines, suppressing IL-2, Il-3, IL-4, IL-5, INF-g and TNF-a. Pimecrolimus has also been shown to have less penetration through the skin than tacrolimus, allowing for less systemic absorption.18 However, both medications have been studied extensively and the systemic blood levels for both medications are minimal and not clinically significant.16,19-22
Pimecrolimus is marketed in a 1% cream formulation that is indicated as a second-line therapy for treatment of mild-to-moderate atopic dermatitis in adults and children over the age of 2.23
Pimecrolimus Studies
Eichenfield et al. presented the efficacy data from a 6-week, double-blind, vehicle-controlled trial in 403 children (aged 1-17) which showed 35% of patients clear or almost clear when treated with pimecrolimus 1% cream vs 18% in the vehicle group (p<0.05).24
The change in Eczema Area and Severity Index (EASI) was also significant with a 45% improvement vs. 1% improvement when comparing pimecrolimus to vehicle (p<0.001). Another 6-week, double-blind, vehicle-controlled study with 186 infants (aged 3 to 23 months) showed 55% of pimecrolimus treated patients 24% of the vehicle treated patients were clear or almost clear at the end of study (p<0.001).25
Long-term efficacy was also examined by Kapp et al. in a 1-year study of infants aged 3 to 23 months using pimecrolimus versus vehicle in treatment of early signs of disease, and allowing treatment with topical corticosteroids for more severe flares.26 In this study pimecrolimus was more effective than vehicle in reducing the number of flares. Fifty-seven percent of the pimecrolimus treated group had no flares requiring topical corticosteroids in 12 months versus only 28% in the vehicle treated group. An open-label extension of this study presented 76 patients who continued for another year of pimecrolimus use with a reported decrease of EASI score of 69% at 3 months and 71% at 24 months, showing continued efficacy long term. 27
Pimecrolimus has proven to be a very safe topical medication in the clinical trials. In the initial trials presented by Eichenfield et al., the application site reactions were higher in the vehicle group at 35% than in the pimecrolimus group at 28%.24 The most common adverse events in treatment and vehicle groups were upper respiratory tract infections, headache, cough and nasopharyngitis.
Paul et al. presented data on 1,133 infants (aged 3 to 23 months) with mild-to-severe atopic dermatitis treated for up to 2 years with no significant change in the risk profile.28 They did note that in the pimecrolimus group they had more episodes of noticeable teething than in the vehicle group. Also in this study, 35 infants had blood concentrations of pimecrolimus drawn and more than 80% were below 1ng/ml for up to 1 year.
Comparing TCIs to Topical Corticosteroids
As previously mentioned, both primary care physicians and dermatologists traditionally have treated atopic dermatitis with corticosteroids. For more mild disease, lower potency topical steroids, for more severe disease, higher potency topical steroids and even oral steroids are sometimes given. After the arrival of TCIs to the market, there was an immediate rush to avoid topical corticosteroids and their side effects, such as atrophy and striae. Several studies have examined the efficacy of the TCIs versus commonly used topical corticosteroids.
Reitamo et al. presented a randomized, double blinded trial of topical tacrolimus (both 0.1 and 0.03% against hydrocortisone butyrate (Class V). 29 In the 570 adults with moderate-to-severe atopic dermatitis the efficacies of tacrolimus 0.1% and the topical corticosteroid were comparable. Two other studies with tacrolimus, both the 0.1% and the 0.03%, showed efficacy over hydrocortisone acetate 1%, which is a lower potency topical corticosteroid (Class VII).15, 30
Luger et al. presented data on pimecrolimus 1% cream vs. triamcinalone acetonide cream (Class III) in 658 adult patients with moderate to severe atopic dermatitis.31 Although both medications showed improvement, the efficacy was significantly better in the triamcinalone group as compared to the pimecrolimus group at 1 week (68% vs. 37%) and 3 weeks (76% vs. 57%), and at 7 months (86% vs.77%), but at 13 months (89% vs. 82%) there was not a significant difference. This study suggests a benefit in safety from the pimecrolimus group because one subgroup (>30% BSA) showed a lower incidence of skin infections with pimecrolimus than with the triamcinalone, and there were three reports of striae in the triamcinalone group.
This suggests that tacrolimus performs better against standard topical corticosteroid therapies, however, since the corticosteroid potencies varied with the trials, these results should not be compared directly.
Head-to-Head Comparison of TCIs
Not surprisingly, with two medications with similar risk profiles and the same target market in atopic dermatitis, the efficacy of tacrolimus versus pimecrolimus has been an issue. Although both medications act via the FK-binding protein-12 (FKBP-12), tacrolimus ointment has three times greater binding affinity for the FKBP than pimecrolimus.32
Three 6-week, double-blind, head-to-head trials with tacrolimus ointment (both 0.1% and 0.03%) and pimecrolimus 0.1% cream with a total of 1,065 patients (both children and adults) were completed.33 The combined analysis showed significantly higher rates of treatment success for tacrolimus at weeks 3 and 6 (p<0.001 and p<0.0001, respectively). The adverse event profiles in these studies were markedly similar, with only the adult patients using tacrolimus ointment 0.1% reporting a significantly higher rate of burning at the application site (p=0.02).
A smaller study (n=141), using tacrolimus ointment 0.03% versus pimecrolimus cream 1% in pediatric patients with moderate atopic dermatitis34 showed no statistical difference between the two groups, though one explanation of these findings is that the study may have been underpowered because of low sample size. They did find that application site reactions (erythema/irritation) were higher in tacrolimus at 19% versus 8% with pimecrolimus. These reactions were also shorter in duration for pimecrolimus.
Overall these studies suggest improved efficacy of tacrolimus ointment over pimecrolimus cream with very similar safety profiles, with, perhaps, a slight increase in tolerability to the pimecrolimus cream.
The Boxed Warning
As previously mentioned, the FDA has recently added a boxed warning to both topical tacrolimus and pimecrolimus. The warning discusses the theoretical risk of malignancy, specifically skin malignancies and lymphoma. It also recommends avoiding continuous use and off-label use, especially in children under the age of 2 years. This has been a matter of significant concern for those prescribing these medications, especially in our increasingly litigious society.
The data reported to the FDA showed a total of 28 malignancies related to topical calcineurin use, with 10 related to pimecrolimus and 19 related to tacrolimus (one common case).35 These malignancies were in both adults (21 cases) and children (7).
A majority of the malignancies were not reported at the application site, and of those that were, four were squamous cell carcinomas, two were t-cell lymphomas, one was Kaposi's sarcoma and the last was a lymphoma not otherwise specified. Berger et al., in reporting on the American Academy of Dermatology Association Conference in July 2005, also suggests that it is plausible that the cases of T-cell lymphomas were misdiagnosed and inappropriately treated as atopic dermatitis, but may have been a cutaneous lymphoma at the onset.36
Other malignancies reported were hepatoblastoma, lymphomas (non-Hodgkins, follicular, general and one EBV assoc B-cell), esophageal cancer, new onset metastatic melanoma, granulomatous lymphadenitis, intraductal papilloma of the nipple and basal cell carcinoma. The average onset of these malignancies was 90 days after starting topical treatment in the pimecrolimus cases and 150 days in the tacrolimus cases. These short onset times, with our basic knowledge of tumor oncogenesis, make the association unlikely.
In general, the data for the topical calcineurin inhibitors may actually show a protective effect against malignancy and lymphoma specifically. The rates of lymphomas in the tacrolimus patients is 0.65/100,000 versus 22/100,000 in the U.S. population (using the SEER data).35,37 Also using the SEER data, the expected number of malignancies in adults would be 42 and would be four in children, but the reported numbers are two and one, respectively.
Another concern has been whether the use of topical calcineurin inhibitors puts patients at increased risk for skin malignancies. This issue is even more heated than the systemic cancer issue, as many of the patients using these medications are children. At this time it is still too early to tell if years of exposure as a child will increase the risk of malignancy as adult. This will require long-term studies, most likely at least 20 to 40 years. Examining the data that we have does not show a likelihood of skin cancer as a long-term side effect. A review of 9,813 adult and pediatric patients with atopic dermatitis, using tacrolimus for a mean of 208 days reported 13 adults with development of nonmelanoma skin cancer (NMSC) during the study.38 This was compared to age adjusted cohorts and showed no increased risk of NMSC. Of note, some of the off-label conditions that are treated with TCIs, such as lichen sclerosus et atrophicus and mucosal lichen planus, have an increased risk of squamous cell carcinoma unrelated to treatments.39-41
An Important Tool in Treating Atopic Dermatitis
The topical calcineurin inhibitors are important tools in the treatment of atopic dermatitis and many other inflammatory skin conditions. TCIs act through the immune system and inhibit NFAT from activating the transcription factors necessary to start the inflammatory cascade on both a cellular and cytokine level. They have been proven to be effective treatments for atopic dermatitis and many other inflammatory disorders and in some cases equivalent to standard topical therapy with corticosteroids. Although there have been concerns regarding the risk of malignancies with their use, the current data does not support a direct risk. Long-term studies are being undertaken to further investigate this issue. Until this is resolved, prudent use of these effective medications, with education of our patients is critical.
