|Year : 2013 | Volume
| Issue : 3 | Page : 54-61
Atopic dermatitis and tacrolimus: Current perspectives
Department of Dermatology, Venereology and Leprosy, Muzaffarnagar Medical College and Hospital, Muzaffarnagar, Uttar Pradesh, India
|Date of Web Publication||26-Nov-2013|
Department of Dermatology, Venereology and Leprosy, Muzaffarnagar Medical College and Hospital, Muzaffarnagar - 251 203, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
The purpose of the following study is to convey the range of current understanding in relation to atopic dermatitis (AD) and tacrolimus. A brief structured description is given starting with introducing the subject and continuing with the discussion of the etiology of AD, a comparative evaluation of the diagnostic criteria, presents management algorithm, structure, pharmacodynamics and pharmacokinetics of topical calcineurin inhibitors (TCI) and the comparative efficacy and safety of available TCIs. Etiological hypothesis is still evolving. Until date, no single universally applicable diagnostic Criteria or scoring system exists. Diagnostic Criteria and scoring system are to adopt according the design and population of any study. TCIs provide a safe alternate to the present topical steroid dependent system of management of AD. This is not a systemic review or meta-analysis. The studies cited were not compared statistically. Beneficial to practitioners of pediatric dermatology to get an idea about the range of current understandings.
Keywords: Atopic dermatitis, FK506, immunosuppressant drug, topical tacrolimus
|How to cite this article:|
Goyal T. Atopic dermatitis and tacrolimus: Current perspectives. Indian J Paediatr Dermatol 2013;14:54-61
| Introduction|| |
The spectra of the prevalence of skin diseases vary world-wide and from country to country. Therefore, the information about the local prevalence of diseases is very important in helping the development of appropriate health improvement policies for promotion of better management. 
Atopic dermatitis (AD) is the most common chronic inflammatory skin disorder in children with a world-wide 8-20% cumulative prevalence. The number of AD patients is beyond the level that can be dealt with at clinics and it is time to make an effort to reduce the number of AD patients in the community. Thus, caretakers and all persons involved with AD management, including health care providers, educators, technologists and medical policy makers, should understand the development and the management of AD.  AD has a chronic or chronically relapsing course with remissions and exacerbations of variable length. Typical clinical features include multiple lesions with erythema, excoriation, erosions accompanied by a serous exudate, accentuated skin markings (lichenification), fibrotic papules, severely dry skin and a susceptibility to cutaneous infections.  The main symptom is intense itching and excessive scratching can cause further damage such as excoriation, erosions and infections.  The lesions have a typical age-dependent distribution pattern. In infants, nummular or seborrheic type eczema occurs on the cheeks, chin and trunk. Among 1-4-year-old children, affected areas include extensor and sometimes flexural sides of the extremities, the hands, face and neck and perioral area. Among 4-16-year-old children, flexural eczema predominates, with face, hands, feet and gluteal area affected. 
Topical calcineurin inhibitors (TCI) are a relatively new class of drugs used in dermatology. There are two drug forms available - tacrolimus 0.03% or 0.1% ointment and 1.0% pimecrolimus cream. The drugs act by inhibiting the synthesis of proinflammatory cytokines [Figure 1] and [Figure 2]. The only approved indication for using TCI is the treatment of AD. The TCI may be used as an alternative therapy to corticosteroids (CS). Tacrolimus is used to treat moderate-to-severe AD. TCI do not cause skin atrophy and the drug absorption through the skin is minimal. The TCI have been well-studied, their efficacy was evaluated in a number of vast, long-term studies. 
| Multifactorial pathogenesis of AD|| |
It is well-known that genetic factors are involved in all diseases and many genetic factors with allergic disease have been reported [Figure 3]. A cohort study by Kim et al. has found out that when both parents had a family history and showed sensitization to allergens in a skin prick test, the cumulative prevalence of AD up to 1-year of age was 41.7%; when only the mother showed sensitization the rate was 30.7%. However, the rates of AD in children with only a sensitized father were 22.2% only.
The prevalence of allergic diseases increases in a community with a high socio-economic level and was inversely proportional to the prevalence of bacterial infections such as tuberculosis and its incidence rate was relatively low in a larger families or rural areas. This hypothesis has been questioned with regard to AD. ,
Immaturity or Abnormality of Defense Mechanisms
Although the prevalence of AD has increased greatly compared with the past, its tendency to occur most frequently among infants aged 1-year or less and to reduce with increasing age has been maintained. Therefore, while the incidence of AD is greatly affected by changes in the environment, overall physical immaturity is expected to be an important factor influencing this incidence. In summary, immaturity of skin barrier function, mucosal immunity, systemic immunity and digestive enzymes are considered to be factors that influence the development of AD symptoms in infancy.
Environmental factors resulting from industrialization have been studied as possible reasons why the incidence of bronchial asthma, allergic rhinitis and AD has skyrocketed since the 1980s. Air pollution generated by cars, energy production and factories, air-conditioning and heating, indoor environmental changes and dietary changes have been suggested as factors in the development and aggravation of AD. ,,
The skin environment of the lesions plays a key role in the incidence of AD. The skin of patients with AD is mostly colonized by Staphylococcus aureus, a toxin-producing organism.  The skin of AD patients has been found to be deficient in antimicrobial peptides, one of the components of the innate response essential for host defense against bacteria, fungi and viruses. ,
| AD: Diagnostic Criteria|| |
The above major and minor criteria by Hanifin and Rajka  exist as a guideline for arriving at a diagnosis of AD [Table 1]. Minor features vary with ethnicity and genetic background and can be used to aid diagnosis.
| Evaluation of minor criteria: AD in children|| |
Wahab et al. [Figure 4] evaluated 20 minor criteria during their study in 201 patients of 1-12 years age and found out that most common minor criteria were cutaneous infection (80%), influence by an environmental factor (66.7%), high IgE level (60%), intolerance of wool (50%), xerosis (43.8%), infraorbital fold (39.5%), ichthyosis (34.3%), early age onset (31%), itch on sweating (26.7%), palmer hyperlinearity (24.8%), food hypersensitivity (19%), keratosis pilaris (14.8%), pityriasis alba (14.3%), cheilitis (10.5%), hand eczema (9%), foot eczema (7.6%), intolerance to lipid solvent (6.7%), scalp scaling (5.2%) infra-auricular fissure (4.8%) and facial erythema (1.9%). These features were present singly or in combination. The result evidenced that minor criteria are many a times important for the diagnosis where major criteria are uncertain.
|Figure 4: Evaluation of minor criteria: Atopic dermatitis in children age group 1-12 years (n=201)|
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Kanwar et al., suggested diffuse scalp scaling and infra auricular fissuring as more significant minor indicators for diagnosis, which may be explained by high colony counts of Pityrosporum producing subacute dermatitis. This study also noted an early age of onset and put forward the logic of atopic facies.
| AD: Associations|| |
The term "atopic diathesis" refers to the presence of allergic rhinitis, bronchial asthma or AD.  AD (AD, atopic eczema and eczema) occurs in families with atopic diseases (AD, bronchial asthma and/or allergic rhino-conjunctivitis) [Figure 5].  Surveys from Western countries have shown that these features, in particular the minor features, vary with ethnicity and genetic background and can be used to aid diagnosis.
| Relationship of AD and Age|| |
Hadiuzzaman et al. evaluated 1753 children in the age group up to 14 years and found that 355 children (20%) in various age groups were suffering from AD [Figure 6]. About 60% of children presented with AD in age groups of 1-5 years and 11-14 years.
|Figure 6: Relation of age group with number of atopic dermatitis cases Age Group 1-14 years (n=355)|
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| Scoring system in AD|| |
Presently, four tools are used to assess AD severity. They are the scoring atopic dermatitis (SCORAD) index, the objective SCORAD, the eczema area and severity index and the three-item severity (TIS) score. Each of these assessment tools has its own advantages and disadvantages. The SCORAD and objective SCORAD indices were developed by the European task force on AD [Table 2]. The SCORAD index is based on three parameters: The disease extent, intensity and some subjective items. To measure the extent of AD, the rule of nines is applied in a front-to-back drawing of the patient's inflammatory lesions. The extent can be graded 0-100. The intensity scoring consists of six items: Erythema, edema, excoriations, lichenification, oozing or crusting and dryness. Each item is graded on a scale of 0-3. The subjective items include daily pruritus and sleeplessness and both items can be graded on a 10-cm visual analog scale.
In the objective SCORAD, the two subjective items are omitted and only the extent and intensity items are considered. The formula for the objective SCORAD is A/5+7B/2, where A is the extent (0-100) and B is the intensity (0-18).
The maximum objective SCORAD score is 83 (plus an additional 10 points for severe disfiguring eczema on the face and hands). The TIS score is a simple scoring system that uses three of the intensity items of the SCORAD index, i.e., intensity of erythema, edema and excoriations (scratches). Each of the three items is graded on a 0-3 scale. Therefore TIS scores range from 0 to 9. The objective SCORAD should be used in clinical trials, whereas the TIS score is preferred in epidemiological studies and in daily practice. The TIS has a great advantage because it is simple, quick and easy to perform in routine settings and is shorter to complete. 
| Stepwise management of AD Guideline in children|| |
The above atopic dermatitis organizer guideline [Table 3] is written with the concept of AD as:
- A multifactorial disease,
- One of the most common chronic childhood diseases predominantly found in infants and young children,
- A disease that tends to wax and wane over time, and
- A disease that disappears with increasing age and/or progresses to bronchial asthma or allergic rhinitis.
| Tacrolimus, Its Mechanism of Action and Pharmacokinetics in Pediatric Patients|| |
Tacrolimus ointment contains tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is for topical dermatologic use only. Chemically, tacrolimus is designated as [3S[3R*[E (1S*, 3S*, 4S*)], 4S*, 5R*, 8S*, 9E, 12R*, 14R*, 15S*, 16R*, 18S*, 19S*, 26aR*]]5, 6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a-hexadecahydro-5, 19-dihydroxy3- [2-(4-hydroxy-3-methoxycyclohexyl)-1- methylethenyl]- 14, 16-dimethoxy-4, 10, 12, 18-tetramethyl- 8-(2-propenyl)-15, 19-epoxy-3H- pyrido [2, 1-c] [1, 4] oxaazacyclotricosine- 1, 7, 20, 21 (4H, 23H)-tetrone, monohydrate.
Tacrolimus ointment, 0.03% for children aged 2-15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe AD in non-immunocompromised children who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable.
| Mechanism of Action|| |
Pharmacokinetics in Pediatrics Patients
In a pharmacokinetic study of 14 pediatric AD patients, between the ages of 2 and 5 years, peak blood concentrations of tacrolimus ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03% tacrolimus ointment, with 86% of patients having peak blood concentrations below 2 ng/mL throughout the study.
In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages 6-12 years) with AD, peak tacrolimus blood concentrations ranged from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% tacrolimus ointment, with 91% of evaluable patients having peak blood concentrations below 2 ng/mL throughout the study period. In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed, with 98% of pediatric patients having a blood concentration below 2 ng/mL.
The effect of renal insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated. The mean clearance of intravenous administered tacrolimus in patients with renal disease was similar to that of normal volunteers. On the basis of this information dose-adjustment is not expected to be needed.
The effect of hepatic insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated but dose-adjustment is not expected to be needed. ,
| Efficacy and Safety of Tacrolimus Ointment in AD|| |
Difficult to control AD presents a therapeutic challenge and often requires combinations of topical and systemic treatment. Anti-inflammatory treatment of severe AD most commonly includes topical CS and topical calcineurin antagonists used for exacerbation management and more recently for proactive therapy in selected cases. Topical CS remains the mainstay of therapy, the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti-inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection contribute to disease exacerbation and thus justify additional antimicrobial/antiseptic treatment. Pruritis caused by AD is not always controlled by topical CS therapy, but use of tacrolimus often helps to soothe such intractable pruritis in clinical settings.
Takeuchi et al. evaluated relief from pruritis with tacrolimus monotherapy group versus emollient group and found out the efficacy rate in controlling pruritis with tacrolimus monotherapy was 76.2% compared with 0% with emollient group. This difference was statistically significant [Figure 7].
Cumulative itch recurrence in the tacrolimus monotherapy maintenance group and emollient maintenance group at day 28 was 23.8% and 100% respectively in maintenance treatment.
|Figure 7: Changes in visual analogue scale (VAS)-itch score and disease severity after add-on tacrolimus therapy. (a) There was a significant decrease in VAS-itch score in responders after the add-on therapy. (b) Scoring atopic dermatitis score reduced after the add-on topical tacrolimus therapy|
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Hon et al. evaluated the clinical efficacy of topical tacrolimus for reducing the sensation of pruritis in children with AD. Nocturnal scratching activity measured using a DigiTrac movement recorder was reduced from 115 g/min to 71.5 g/min after 2 weeks of treatment.
Healy et al. evaluated children with moderate and severe AD, twice-weekly maintenance treatment with tacrolimus ointment and tacrolimus was found to be more effective and less costly treatment than the standard treatment regimen.
Kirsner et al. evaluated patients with AD previously treated with CS and then given tacrolimus or pimecrolimus [Figure 8], [Figure 9], [Figure 10], [Figure 11]. Majority of the patients in mild, moderate or severe AD were evaluated for the efficacy of tacrolimus ointment v/s pimecrolimus cream [Table 4].
|Figure 8: Efficacy of Tacrolimus ointment v/s Pimecrolimus cream in all patient of atopic dermatitis (at baseline) at the end of day 43/end of study (n=171, n=176)|
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|Figure 9: Efficacy of Tacrolimus ointment v/s Pimecrolimus cream in severe/very severe patients of atopic dermatitis (at baseline) at the end of day 43/end of study (n=19, n=32)|
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Dhar and Banerjee  evaluated 15 children with moderate to severe AD after treatment with topical tacrolimus (0.1%) ointment. There was a significant reduction in severity when compared to sunflower oil application in all 15 children. Topical tacrolimus (0.1%) was found to be safe and effective in moderate to severe AD in children.
The improvements in Investigator Global Atopic Dermatitis Assessment status are depicted in [Figure 8], [Figure 9], [Figure 10], [Figure 11] showing that tacrolimus ointment is better than pimecrolimus cream in the management of mild, moderate and severe AD.
|Figure 10: Efficacy of Tacrolimus ointment v/s Pimecrolimus cream in moderate disease (at baseline) of AD at the end of day 43/end of study (n=65, n=51)|
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|Figure 11: Efficacy of Tacrolimus ointment v/s Pimecrolimus cream in mild disease (at baseline) of AD at the end of day 43/end of study (n=87, n=93)|
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| Conclusions|| |
The first line therapy of topical CS for treatment of AD patients has continued for a long time. The chronic use of topical CS, particularly to sensitive and widely extensive areas, is an important concern for patients and health care providers. Non-compliance or under treatment issues may arise from patient's fears about the safety of topical CS ("steroid phobia") and can result in reduction of disease control.
Results from the International Study of Life with Atopic Eczema reported that while the majority of patients with AD received topical CS, 49% of respondents were concerned about their use, 39% of respondents applied them less frequently or for shorter time periods than prescribed and 74% of respondents would prefer to apply a non-steroid treatment.
The management of AD with tacrolimus and pimecrolimus may overcome some of the limitations associated with topical CS use and may be used as part of an integrative or multiple-therapy approach for improving the overall management of AD.
Comparison of tacrolimus and pimecrolimus in various studies has shown that tacrolimus is better than pimecrolimus with a safer adverse event profile compared with pimecrolimus.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2], [Table 3], [Table 4]