Systemic therapy of paediatric atopic dermatitis: an update

Topical therapies are the mainstay in the treatment of atopic dermatitis, and are effective in the majority of patients with mild and localized disease. In patients with widespread or recalcitrant moderate to severe dermatitis, systemic therapies may be required. The frequently used systemic therapies are immunosuppressants, immune response modifiers, anti-inflammatories, antihistamines, and antibiotics. In this article, the indications and scientific support for the use of these medications is reviewed.     

Atopic dermatitis: systemic immunosuppressive therapy

Atopic dermatitis (AD) is a pruritic, relapsing skin disorder that negatively impacts the quality of life of those affected and that of their families. Treatment options for AD encompass a variety of emollients, topical corticosteroids, topical immunomodulators, phototherapy, and systemic agents. Such agents as systemic corticosteroids, cyclosporine, azathioprine, interferon-gamma, methotrexate, and mycophenolate mofetil have been shown to be efficacious in the treatment of moderate-to-severe AD but are not officially approved for this purpose. In this article, we review some of the data supporting efficacy of these medications and discuss some of the adverse events associated with their use.     

StabiEL: Stabilization of skin condition with Elidel – a patients’ satisfaction observational study addressing the treatment,with pimecrolimus cream,of atopic dermatitis pretreated with topical corticosteroid

Background The objective of this 4‐month multicentre observational study was to evaluate safety and efficacy of intermittent long‐term treatment of patients with atopic dermatitis (AD) with pimecrolimus cream 1% in the daily practice and to compare it with the preceding topical corticosteroid‐based therapy in retrospective. Patients and methods Overall severity of AD and individual symptoms were assessed in 3200 patients by the physician, whereas acceptance of treatment and satisfaction of patients was investigated using a patient questionnaire. Results The percentage of patients clear or almost clear of symptoms increased from 12% to 82%. Seventy‐four per cent of physician rated the treatment better than the preceding therapy, and 21% noted no difference. Seventy‐seven per cent of the patients asserted that long‐term intermittent treatment with pimecrolimus reduces the frequency of flares as opposed to less than 27% for topical corticosteroids. Patients also felt that pimecrolimus results in a higher improvement in quality of life; 84% stated that pimecrolimus stabilized the skin compared with 27% for topical steroids. Conclusion Intermittent treatment of AD patients with pimecrolimus cream 1% is effective and well tolerated, and results in higher patient satisfaction compared with topical corticosteroids in retrospective.     

Atopic dermatitis and melanocytic naevi

A study was performed to test the clinical impression that adults with severe atopic dermatitis (AD) have a low number of common naevi (CN). The number of CN > or = 2 mm was investigated in 51 Caucasian patients aged 20-63 years with severe AD since early childhood. The control group consisted of 379 randomly selected subjects, aged 30-50 years, investigated in an earlier study. Patients with AD had a significantly (P < 0.0001) lower total body count of CN (mean 9, median 5) compared with the control group (mean 67, median 53). It was also found that in the AD group there was a significant (P < 0.001) negative correlation between serum IgE and number of CN [r(s) = -0.50, 95% CI (-0.69; -0.24)]. The explanation for the low number of naevi that we have found in this highly selected subgroup of AD patients is not known. The atopic inflammation in the skin, genetics and treatment used for eczema are possible factors that may influence the formation of melanocytic naevi.     

Pimecrolimus cream 1% is effective in asteatotic eczema: results of a randomized, double-blind, vehicle-controlled study in 40 patients

BACKGROUND AND OBJECTIVE: Pimecrolimus cream 1% is an effective treatment for atopic eczema. The aim was to investigate its efficacy in asteatotic eczema, a skin disease similar to atopic eczema and its associated dry skin and itching. METHODS: Single-centre, randomized, double-blind, vehicle controlled study in 40 patients with asteatotic eczema. Efficacy was assessed by eczema area and severity index (EASI), investigators global assessment (IGA), patient's self-assessment, and pruritus severity. RESULTS: After 4 weeks of treatment, EASI, the primary efficacy variable, was reduced by 62+/-7% from baseline in patients on pimecrolimus, compared to 21+/-14% in patients on vehicle (P=0.013). With pimecrolimus there was also a better control of pruritus (P=0.042) at week 4 whereas a better control of disease according to self-assessment could only be observed at weeks 2 (P=0.01) and week 3 (P=0.08). CONCLUSION: Pimecrolimus cream 1% is effective in patients with asteatotic eczema.     

Atopic dermatitis and cancer risk

BACKGROUND: Epidemiological studies have provided growing evidence of a link between atopy and cancer risk. OBJECTIVES: To review the evidence from case-control studies and cohort studies on a possible association between atopic dermatitis (AD) and cancer risk, with particular attention to the case definition of AD. METHODS: Studies with quantitative data on the association between AD (eczematous disease) and cancer risk were obtained from MEDLINE in combination with a review of cited references. RESULTS: In 23 publications, AD was implicated in the risk of haematological [childhood leukaemia (n = 3), adult leukaemia (n = 3), non-Hodgkin lymphoma (NHL; n = 4) and different haematological cancers (n = 1)], pancreatic (n = 5), skin (n = 2) and brain malignancies (n = 5). The overall picture of the results of these studies shows that a history of AD may be associated with a decreased risk of pancreatic cancer, brain tumour and childhood leukaemia, although in most instances the findings were not statistically significant. No consistent associations were observed for skin cancer or NHL. The definition of AD had varying quality, and was imprecise in the majority of publications. CONCLUSIONS: The findings of the epidemiological studies tend to support a lower risk of cancer among persons with a history of AD. Although a more careful definition of AD is needed, these epidemiological studies could provide an estimate of the background cancer risk in patients with AD when the long-term effects of treatments for AD are assessed.     

The caseload, assessment and treatment of atopic dermatitis: a survey of Australian dermatologists

In early 1995 we surveyed all 250 practicing Australian members of the Australasian College of Dermatologists by a mail-out questionnaire to determine information, such as the caseload imposed by atopic dermatitis, the severity of cases seen by dermatologists, current treatment and dermatologists' satisfaction with treatment. One hundred and forty-nine responses were received. Fifty per cent of patients with atopic dermatitis seen by dermatologists were younger than 10 years, 18% were 10-16 years, and 52% were older than 16 years. Disease was considered to be severe in 18% of patients, moderate in 41% and mild in 41%. Emollients and topical corticosteroids were the most commonly used treatments but there was wide variation in other treatments used by individual dermatologists. Only 10% of respondents were very satisfied with existing treatments for severe atopic dermatitis; 20% of patients with severe disease were considered as refractory or non-responsive. New therapies such as cyclosporin have the potential to improve existing standards of care.     

Topical calcineurin inhibitors in the treatment of atopic dermatitis - an update on safety issues

Atopic dermatitis is a common chronic skin disorder whose management is complex. Topical corticosteroids have been the mainstay of atopic dermatitis treatment for more than 50 years but have multiple side effects. Topical calcineurin inhibitors including tacrolimus and pimecrolimus are safe and efficacious in atopic dermatitis. In 2005 the FDA issued "black box" warnings for pimecrolimus cream and tacrolimus ointment because of potential safety risks, including skin cancers and lymphomas. However, these concerns are not supported by current data. Topical calcineurin inhibitors are particularly indicated for treating patients with atopic dermatitis in whom topical corticosteroid therapy cannot be employed or may cause irreversible side effects. They can be used advantageously in problem zones. A novel regimen of proactive treatment has been shown to prevent, delay and reduce exacerbations of atopic dermatitis. Therapy with topical calcineurin inhibitors should be managed by an experienced specialist and each patient should receive proper education on how to use them and what possible unwanted effects may be expected.     

Recent developments in the treatment of adult atopic dermatitis

Atopic dermatitis is a common inflammatory skin condition with increasing incidence in recent decades. The mainstay of treatment has been the combination of emollients and topical corticosteroids, with the addition of systemic therapies in severe cases. New drugs such as the topical calcineurin inhibitors have shown promise in treating mild-to-severe atopic dermatitis. Other novel therapies that have been reported in the literature include leukotriene antagonists, monoclonal antibodies such as infliximab, leflunomide, recombinant interferon gamma and intravenous immunoglobulin. This review will focus on the treatment of adult atopic dermatitis.     

Atopic dermatitis in older patients: particular points

We review the particular characteristics of atopic dermatitis (AD) in adult life, and compare findings with those of AD in childhood. AD affects 1–3% of adults world‐wide, and can present as adult‐onset AD, or as infantile/childhood AD that persists, or recurs after many years. Eczema in adults usually exists for years, compromising quality of life, sex life and occupational choices. The flexural areas, shoulders, head‐and‐neck, and hands are typically affected. In elderly adults, eczematous erythroderma is common. The intrinsic (non‐IgE‐allergic) eczema subtype affects 5–15% of cases. Classical food allergy has a low importance, although non‐IgE‐mediated and pseudoallergic reactions can cause eczema. Sensitivity to aeroallergens, especially dust mite, is demonstrated in the majority of adult AD patients, including elderly adults, by immunoglobulin E‐mediated tests and/or atopy patch tests. Occupational allergic and irritant contact dermatitis is increased. In adults, as in children, Staphylococcus aureus colonization is very high, whereas adult skin is more heavily colonized with Malassezia yeasts. Immediate and delayed sensitization to Malassezia sympodialis is specific for intrinsic and extrinsic AD, occurring especially in head‐and‐neck eczema. Concerning therapy, older patients are prone to certain adverse drug effects. In conclusion, differences exist between childhood and adult disease. As we should be seeing more adults with AD in the future, there is a need for more clinical and immunological studies in older patients.     

Poor efficacy of oral tacrolimus in the treatment of severe generalized atopic eczema in adults: A small retrospective case series

We report a small, but novel case series of four adults with severe generalized atopic eczema (AE) not responsive to several other immunomodulatory therapies, who were treated with oral tacrolimus (5 mg twice‐daily). Three of the four patients failed therapy with systemic tacrolimus, despite two of these showing an initial clinical response; the fourth patient remains on tacrolimus monotherapy with good control of skin disease. Although oral tacrolimus was well‐tolerated in this small group of adults, the clinical efficacy in this series for severe AE was poor. Tacrolimus may yet have a role in less severe disease, but larger prospective studies are required to qualify its place as a treatment option in AE.     

Atopic dermatitis made easy: The Schachner Ladder

The vast majority of atopic dermatitis follows a mild, chronic relapsing course. In this article, we highlight the art and practice of treating atopic dermatitis based upon a foundation of maintenance care and a ladder of therapy that can teach patients and their families how to best tailor their pharmaceutical options to optimize the management of their disease.     

Paediatric atopic dermatitis in Perth general practice

Ninety-seven Perth general practitioners completed a self-administered postal questionnaire that aimed to examine their caseload and management practices for childhood atopic dermatitis (AD). General practitioners saw a median of two new cases and three follow-up consultations per month for childhood AD, and referred a median of 10% of cases to a specialist, usually a dermatologist. Most (77%) recommended emollients for all patients, but only 21% specifically reported advising their use immediately after bathing. Sixty-one percent would use topical corticosteroids in all or most patients, but cream preparations were more commonly used (58%) than ointments (40%). Atrophy was rated as a common or very common side-effect of topical corticosteroid therapy by 23% of general practitioners. Twenty-six percent reported using oral corticosteroids in children with AD. Dietary changes would be recommended in at least a few AD patients by 79% of general practitioners, and 31% would recommend a change from cow's milk to soy in the absence of a history of dietary triggers. We conclude that general practitioners appeared generally well informed about AD management. However, dermatologists, through targeted education, may be in a position to help general practitioners further improve outcomes for these patients.     

Macrolactam immunomodulators (tacrolimus and pimecrolimus): new horizons in the topical treatment of inflammatory skin diseases

Tacrolimus and pimecrolimus are new macrolactam immunomodulators which were developed for the treatment of inflammatory skin diseases, mainly atopic dermatitis. In this article, we review the pharmacologic properties of the drugs, their side effects, and their clinical uses.     

Managing atopic dermatitis with systemic therapies in adults and adolescents: An Australian/New Zealand narrative

With the rapid development of new, targeted therapies for the treatment of moderate/severe atopic dermatitis, it is opportune to review the available conventional systemic agents. We assess the published evidence for systemic therapies for atopic dermatitis and amalgamate this with real-world experience. Discussions are centred on when systemic therapy should be considered, which drug(s), what dose, how to sequence or combine these therapies, how long they should be continued for and what is considered success.     

Meta-analysis on the comparison between two topical calcineurin inhibitors in atopic dermatitis

Topical calcineurin inhibitors have proved to be suitable for the treatment of AD. We conducted a meta-analysis comparing efficacy and tolerance of tacrolimus with pimecrolimus in treatment of AD. According to our meta-analysis, tacrolimus 0.1% was more effective than pimecrolimus 1% in adult patients (week 3: risk ratio [RR] 0.55, 95% confidence interval [CI] 0.42-0.73), and tacrolimus (a combination of 0.03% and 0.1%) was also more effective than pimecrolimus 1% in pediatric patients (week 6/end of study: RR 0.76, 95% CI 0.63-0.92). Regardless of age or illness severity, tacrolimus 0.1% had higher efficacy than pimecrolimus 1% in the treatment of AD (week 3: RR 0.55, 95% CI 0.42-0.72). In adult patients, tacrolimus 0.1% had more adverse events than pimecrolimus 1% (RR 1.30, 95% CI 1.02-1.66), but the incidence of adverse events between tacrolimus 0.1% (or 0.03%) and pimecrolimus 1% was not significantly different in pediatric patients. No matter whether the patients were adult or pediatric, more pimecrolimus-treated patients withdrew from the trials because of a lack of efficacy. Regardless of age and illness severity, more pimecrolimus 1%-treated patients withdrew from the trials because of a lack of efficacy, compared with tacrolimus 0.1% (or 0.03%)-treated patients. More pimecrolimus-treated pediatric patients withdrew from the trials because of adverse events (RR 0.26, 95% CI 0.1-0.68). More pimecrolimus 1%-treated patients withdrew from the trials because of adverse events, compared with tacrolimus 0.03%-treated patients, regardless of age (RR 0.1, 95% CI 0.02-0.53). In conclusion, tacrolimus ointment has higher efficacy and better tolerance than pimecrolimus cream in treatment of AD.     

The treatment of facial atopic dermatitis in children who are intolerant of, or dependent on, topical corticosteroids: a randomized, controlled clinical trial

Background  Atopic dermatitis (AD) is most prevalent in areas of reduced skin barrier reserve, like face and neck, especially in children. Treatment with topical corticosteroids (TCS) is limited due to heightened risk of treatment-associated side-effects, thus necessitating alternative AD therapies.
Objectives  The primary study objective was to determine the efficacy of pimecrolimus cream 1% in children with mild–moderate facial AD dependent on/intolerant of TCS. Secondary objectives included effects on overall Eczema Area and Severity Index (EASI), head/neck EASI, pruritus severity and time to clearance of facial AD.
Methods  A multicentre, double-blind (DB) study of ≤ 6 weeks, followed by a 6-week, open-label (OL) phase was conducted. Two hundred patients (aged 2–11 years) were randomized 1 : 1 to pimecrolimus cream 1% ( n  =   99) or vehicle ( n  =   101) twice daily until clearance of facial AD or for a maximum of 6 weeks (DB phase). Sixteen patients receiving vehicle were allowed to switch to the OL phase at day 22.
Results  Significantly more pimecrolimus-treated vs. vehicle-treated patients were cleared/almost cleared of facial AD (Investigators' Global Assessment 0/1): 74·5% vs. 51·0%, P  <   0·001 (day 43) [57·1% vs. 36·0%, P  =   0·004 (day 22)]. Median time to clearance was 22·0 vs. 43·0 days (pimecrolimus vs. vehicle, respectively). Statistically significant differences for pimecrolimus vs. vehicle were also seen on head/neck EASI, overall EASI, and head/neck pruritus scores. Adverse events were mainly mild–moderate, occurring with similar frequency in both treatment groups.
Conclusions  In children with facial dermatitis intolerant of/dependent on TCS, pimecrolimus cream 1% effectively controls eczema and pruritus and is well tolerated.     

Azathioprine in severe adult atopic dermatitis: a double-blind,placebo-controlled,crossover trial

BACKGROUND: There is a limited range of treatments for severe atopic dermatitis (AD). Azathioprine has often been used but there has been no randomized controlled trial of this drug to confirm its efficacy in AD. OBJECTIVES: To establish or refute the efficacy of azathioprine in severe AD. To investigate the safety and tolerability of azathioprine in this patient population. METHODS: We performed a double-blind, randomized, placebo-controlled, crossover trial of azathioprine in adult patients with severe AD. Each treatment period was of 3 months' duration. Treatments were azathioprine 2.5 mg kg(-1) day(-1) and matched placebo. Disease activity was monitored using the SASSAD sign score. In addition, severity of pruritus, sleep disturbance and disruption of work/daytime activity were monitored using visual analogue scales. Adverse events were recorded and haematological and biochemical monitoring was performed. RESULTS: Thirty-seven subjects were enrolled, mean age 38 years (range 17-73). Sixteen were withdrawn, 12 during azathioprine treatment and four during placebo treatment. The SASSAD score fell by 26% during treatment with azathioprine vs. 3% on placebo (P < 0.01). Pruritus, sleep disturbance and disruption of work/daytime activity all improved significantly on active treatment but not on placebo. The difference in mean improvement between azathioprine and placebo was significant for disruption of work/daytime activity (P < 0.02) but not for pruritus or sleep disturbance. Gastrointestinal disturbances were reported by 14 patients during azathioprine treatment and four were withdrawn as a result of severe nausea and vomiting. Leukopenia was observed in two patients and deranged liver enzymes in eight during treatment with azathioprine. CONCLUSIONS: Azathioprine is an effective and useful drug in severe AD although it is not always well-tolerated. Monitoring of the full blood count and liver enzymes is advisable during treatment.