Topical corticosteroids are currently the cornerstone of treatment for atopic dermatitis. Aceponate methylprednisolone has recently been established as the corticosteroid of choice in the treatment of this disorder because it has been shown to be more effective and safer than other steroids of equal or greater potency.21 However, lower-potency corticosteroids are recommended for the treatment of lesions located in intertriginous areas and on the head and neck. The application of corticosteroids more than once a day is not usually necessary. It has been shown that intermittent application of potent corticosteroids (on weekends) followed by emollients and moisturizers is equivalent to the daily application of a mild- or medium-potency corticosteroid. The use of topical corticosteroids in conjunction with wet-wrap dressings is an option in recalcitrant cases.22 The most widely accepted method is to apply methylprednisolone aceponate diluted to 10% with emollients (ointment, cream, or petrolatum) directly to the skin, which is then occluded with a double layer of bandages (a moist first layer and a dry second layer). This is done once daily for an average of 7 days (2-14 days). Treatment over longer periods has not proved more effective and is more likely to result in adverse effects. This regimen is not recommended in peripubertal children because of the risk of stretch marks. Adverse effects are rare, the most common being discomfort, folliculitis, refractory lesions in untreated areas, impetigo, and herpes infection.

The routine use of a combination of topical corticosteroids and antibiotics is not recommended.23–25 While the role of antibiotic therapy when signs of superinfection are present has been clearly demonstrated, it is doubtful that the use of antistaphylococcal agents to reduce colonization with Staphylococcus aureus will modify the course and severity of atopic dermatitis. Such combinations could be used for short periods (7-10 days) on small lesions in certain areas (nostrils, flexures, perianal area, fingers and toes). They can also be used at the start of treatment followed by treatment with a corticosteroid alone. The use of topical antibiotics on large areas of skin could lead to the emergence of resistance, and in patients with widespread lesions, oral antibiotic therapy is preferable to a combination of topical corticosteroids and antibiotics. Furthermore, certain antibiotics, such as neomycin and gentamicin, are associated with a risk of sensitization after prolonged and uncontrolled use. Sensitization to fusidic acid and mupirocin is currently rare, but misuse of these drugs could make it a problem.

The calcineurin inhibitors, tacrolimus and pimecrolimus, have been shown to be safe and effective in the treatment of moderate to severe atopic dermatitis in both adults and children.26 Both these drugs have been studied extensively in clinical trials that have compared them with placebo, topical corticosteroids,27 and each other. To date, both drugs have been shown to be safe and useful in either short continuous regimens or intermittent regimens lasting up to 4 years. The safety of longer-term treatment is still unknown because tacrolimus and pimecrolimus have been on the market for less than ten years.

As well as being useful as an induction therapy, tacrolimus has also proven effective as a maintenance regimen (twice weekly), reducing the number of exacerbations in a 12-month follow-up period and prolonging disease-free intervals.28,29 Furthermore, cost-effectiveness studies of maintenance regimens in children and adults have found tacrolimus to be more effective and less expensive than the standard treatment regimen used to manage flares of atopic dermatitis.30 Tacrolimus 0.1% has been shown to be more effective and less expensive than pimecrolimus 1% for controlling atopic dermatitis in adults.31 Housman et al.32 have reviewed patterns of tacrolimus ointment use in children under 2 years of age, a population for which the only treatment approved by the US Food and Drug Administration (FDA) in atopic dermatitis is low-potency corticosteroids. They confirm the short- and long-term efficacy and safety of this treatment, comparing it with low-potency topical corticosteroids.

Furthermore, a continuous regimen of topical pimecrolimus has also proven effective in controlling disease flares, achieving results similar to tacrolimus 0.03%; a longer-term, intermittent regimen reduced the risk of relapse and the need for topical corticosteroids.33,34 This treatment improves the quality of life of both patients and their families and, over a 2-year period, has a better safety profile than topical corticosteroids. Other studies (as yet unpublished) have compared the short- and long-term safety (up to 5 years) of pimecrolimus with that of low-potency topical corticosteroids in infants with mild to moderate atopic dermatitis who started treatment between 3 and 12 months of age. They found no statistically significant differences in the development of cellular and humoral immune response to vaccination between the patients treated with pimecrolimus 1% and those treated with corticosteroids.

Although the evidence supporting the use of oral corticosteroids in atopic dermatitis is now classified as only level IV due to the paucity of evidence from clinical trials, it is clear that these drugs are still the mainstay of rescue treatment for flares of atopic dermatitis in both adults and children. Clinical trials have shown that corticosteroid concentrations in the skin following the administration of a potent topical corticosteroid (clobetasol propionate 0.05%, hydrocortisone 2.3%, or triamcinolone 0.1%) are similar to those achieved with medium doses of oral prednisone.42 When the skin is very damaged, however, the distribution of topical treatments is extremely irregular and oral administration is safer and more controllable. In all other situations, topical corticosteroids are the preferred option. Moreover, several authors have reported an increase in the production of IgE by B cells in patients with atopic dermatitis after treatment with oral prednisolone.43 This finding reflects the immunomodulatory effect of corticosteroids and explains the dreaded rebound phenomenon that occurs after abrupt cessation of corticosteroid therapy. Consequently, once clinical improvement has been obtained, it is very important to taper the dosage gradually over time to minimize the likelihood of a rebound effect.

Ciclosporin has typically been used as a rescue treatment in recalcitrant atopic dermatitis, playing a role similar to that of corticosteroids; It suppresses T-cell activation by inhibiting the transcription of IL-2 and other cytokines. An article published in 2007 reviewed a total of 15 studies including 602 patients—the largest meta-analysis on the use of ciclosporin in this setting in the literature.44 Ciclosporin achieves a very rapid, dose-dependent response in under 2 weeks; the initial dose ranges from 4 or 5mg/kg/d to 7 mg/kg/d. It has been shown to reduce severity by 22% when used at doses lower than 3 mg/kg/d and by 40% with doses higher than 4 mg/kg/d. Efficacy increases with the length of treatment, and the reduction in severity after 6 to 8 weeks treatment ranges from 55% to 70%. Efficacy is similar in children and adults, but tolerance is better in children. Corticosteroids or topical calcineurin inhibitors can be added to the regimen as adjuvant therapy. Adverse effects are dose dependent and much more common in adults than in children. The following are some of the most commonly reported adverse effects: gastrointestinal symptoms (40%), infections (13%), > 30% elevation in creatinine (11%), hypertension (6%), headache, distal paresthesia, and hypertrichosis. These effects usually resolve after cessation of treatment, and no life-threatening adverse events have been reported. The immunomodulatory effect of low doses of ciclosporin administered over a longer period is perhaps a more novel concept. In late 2010, a study was published that assessed the efficacy and safety of long-term oral ciclosporin treatment in patients with moderate to severe atopic dermatitis.45 It included 147 patients, both children and adults, 61 of whom received ciclosporin treatment for over 6 months. The mean dose of ciclosporin was 3 mg/kg/d and the mean duration of treatment was 18 months. Atopic dermatitis was classified as extrinsic or intrinsic depending on whether or not it was associated with other atopic diseases, elevated IgE levels, and positive specific IgE. A statistically significant reduction in SCORAD was observed in both children and adults from the first month of treatment and in both moderate and severe atopic dermatitis. IgE levels were significantly lower after treatment. A much greater improvement was observed in extrinsic atopic dermatitis (associated with other signs of atopy, elevated IgE levels, and positive specific IgE). The following were the most commonly reported adverse effects: hypertension (7.6%), nausea and abdominal pain (4.9%), hypertrichosis (1.6%), and abnormal creatinine clearance (1.6%). The explanation of this immunomodulatory effect is that low doses of ciclosporin in patients with atopic dermatitis increase the population of regulatory T cells, which are immune modulators.46 Thus, the clinical improvement achieved in atopic dermatitis with ciclosporin treatment is due not only to the inhibition of T-cell activation by higher doses but also, indirectly, to enhanced numbers of regulatory T cells. Concerns about reductions in bone mineral density during long-term treatment in children were addressed by a study in which this parameter was measured in 60 children aged between 5 and 16 years who had moderate to severe atopic dermatitis and a history of treatment with corticosteroids and/or ciclosporin in the previous 5 years.47 The authors concluded that low bone mineral density did not occur with greater frequency in the treated group than in the general population.

Mycophenolate mofetil is an immunosuppressant drug currently approved by the FDA for the prevention of renal transplant rejection. It is considered an effective treatment for moderate to severe atopic dermatitis because it achieves clinical improvement within 4 to 8 weeks and has an excellent long-term safety profile, even better than those of corticosteroids and ciclosporin.52 Many experts recommend it as the first choice for maintenance treatment in atopic dermatitis; however, this recommendation is based solely on expert opinion since there is no evidence to support its validity. While gastrointestinal symptoms were at one time among the most frequently reported adverse effects of mycophenolate mofetil,53 the introduction of an enteric-coated molecule (mycophenolic acid) has completely eliminated this side effect without reducing safety and efficacy. The problem of this new formulation is its high cost, so it should only be prescribed to patients who experience adverse effects. Serious adverse effects are rare; there has been only 1 case of progressive multifocal leukoencephalopathy and 1 case of septicemia and endocarditis caused by S aureus. The longest follow-up period reported is that of Murray and Cohen,54 who studied 20 patients for 200 weeks using an average dose of 1 g/12h and obtained improvement in 17 patients at 4 weeks. Of these, 10 achieved complete remission and 7 continued on maintenance therapy. The findings of Ballester et al.55 in Spain were not as positive. They reported improvement in 5 out of the 8 patients studied, with only one in complete remission and 4 on maintenance therapy during a follow-up period that ranged from 16 to 72 weeks. The results published by Heller et al.56 from a group of 14 pediatric patients in the United States are more promising. They obtained complete remission in 4 patients, almost complete improvement (> 90%) in 4, and partial improvement (60%-90%) in 5 patients; only 1 patient did not respond to treatment.

Low doses of methotrexate have demonstrated efficacy in the treatment of moderate to severe atopic dermatitis, especially in adult patients.57 In a retrospective study of 20 adults with moderate to severe atopic dermatitis who had been treated with methotrexate at doses of 10 to 25 mg/wk for 8 to 12 weeks, the authors reported that the therapeutic response began between week 2 and 12.58 They found the treatment to be more effective in cases of adult-onset atopic dermatitis than in childhood-onset disease. The SCORAD decreased significantly in 60% of the patients, with response classified as moderate (26%-50%) in 15%, marked (51%-75%) in 20%, and excellent (76%-100%) in 25% of cases. Similarly, DLQI improved in 70% of cases; improvement was moderate (26%-50%) in 20%, marked (51%-75%) in 15%, and excellent (76%-100%) in 35% of cases. The main adverse effects recorded were digestive symptoms (resolved by switching to subcutaneous administration) and an increase in liver enzymes; there was 1 case of peripheral neuropathy that resolved when treatment was discontinued. Experience with methotrexate in childhood atopic dermatitis is scarce in the literature. However, some authors have made reference to its effectiveness and better tolerance in children.13

PPARs are nuclear hormone receptors expressed in keratinocytes and immune cells that can regulate epidermal barrier homeostasis and immune responses. Experimental studies have shown that PPAR ligands are decreased in both acute and chronic atopic dermatitis.59 Rosiglitazone at a dose of 4 to 8 mg/d in combination therapy has been shown to be useful as a steroid-sparing treatment, with onset of response between 4 and 12 weeks.60 However, owing to its adverse effects, especially cardiac risk, the FDA has decided to withdraw this drug from the market.

There are no large case series providing evidence of the efficacy and safety of biologic agents in atopic dermatitis.61 In most cases, the only available evidence comes from isolated case reports or the extrapolation of experience in other immune-mediated diseases. These drugs can be divided into 3 groups according to the target of their action.

High doses of intravenous immunoglobulin have been shown to be effective in the treatment of moderate to severe atopic dermatitis.68 The problem with this treatment is its high cost, approximately €45 000 per year (estimated cost for an adult weighing 70 kg on a regimen of 2 g/kg/mo). One solution that has been proposed to reduce the cost of this treatment is to increase the interval between doses in patients in remission or to reduce the per-session dose to 0.5 or 1 g/kg from 2 g/kg) and encourage patients to lose weight. In adults, the response is poorer with monotherapy (59%) than with combination regimens (80%), but a 90% response has been demonstrated in children treated with intravenous immunoglobulins alone. This treatment would therefore appear to be more appropriate in children than in adults (the estimated cost of treatment for a 25-kg child on a regimen of 2 g/kg/mo is €16 000 per year). In 2011, the authors of a randomized, double-blind, placebo-controlled clinical trial in children concluded that treatment with intravenous immunoglobulin achieves clinical improvement in atopic dermatitis after 3 months of treatment, although improvement may decrease 6 months after discontinuation of treatment.69 No changes have been observed in IgE levels or eosinophil count in peripheral blood. While the adverse effects are usually mild (headache, abdominal pain, nausea, vomiting, diarrhea), we must not underestimate the serious adverse effects that can endanger the lives of patients, such as the procoagulant and hypertensive effects of this treatment. A concomitant prophylactic dose of low-molecular-weight heparin should be added at the time of infusion, and the speed of infusion should be adjusted taking into account the patient's blood pressure values during treatment. Concurrent immunodeficiency must always be ruled out because of the danger of cross-reactions.

The use of interferon-γ in atopic dermatitis was a proposal considered highly interesting when it was thought that the disorder was due to a pure type 2 immune response in which interferon-γ was greatly reduced. Several clinical trials70 demonstrated its efficacy and safety (short and long term > 2 years) with few adverse effects, mainly the onset of flu-like syndrome, local reaction at the injection site, and hypersensitivity. Compared to placebo, interferon-γ has been observed to achieve significant reductions in erythema, pruritus, and excoriations. Other symptoms improve, but the differences are not statistically significant. It was initially thought that treatment with interferon-γ reduced circulating IgE levels by blocking the synthesis of IL-4-induced IgE. However, despite clinical improvement, experimental studies have failed to demonstrate any reduction in IgE levels, and the exact mechanism of action of this therapy remains unclear. With regard to the dosage and treatment regimen, it has been shown that both high-dose (75μg or 1.5 MIU/m2) and low-dose (25μg or 0.5 MIU/m2) regimens administered 3 times a week for 12 weeks are safe and effective treatments for severe atopic dermatitis. However, in the early phases of treatment, the high-dose regimen has shown greater efficacy.71

Nocturnal pruritus in patients with atopic dermatitis has been the subject of many studies, with results showing that it is independent of cytokine, eosinophil, and IgE levels and does not correlate with disease severity. Conversely, brain-derived neurotrophic factor (produced by circulating eosinophils) and substance P have been implicated in its pathophysiology.72 Experimental studies have shown that substance P induces an arachidonic acid cascade, resulting in an increase in leukotriene levels. This would explain the poor performance of antihistamines in controlling pruritus in these patients and the possible beneficial role of leukotriene inhibitors, such as montelukast. The findings in the literature regarding the role of montelukast are inconsistent. Friedmann et al.73 designed a randomized double-blind, placebo-controlled trial with montelukast 10 mg/d in adults who had moderate to severe atopic dermatitis and found no statistically significant differences between the treatment groups. On the same date, Ehlayel et al.74 published a randomized, double blind, placebo-controlled trial with montelukast 10 mg/d in children with moderate to severe atopic dermatitis. They reported an improvement in the extent and severity of disease, eosinophil and IgE levels, pruritus, and sleep disturbance in the group treated with montelukast. Based on the results of these studies, several authors have suggested that the patients most likely to benefit from treatment with montelukast are children and also adults with extrinsic atopic dermatitis.

Serotonin secretion has also been implicated in the pathogenesis of pruritus: elevated serotonin levels are found in inflamed skin and serotonin is involved in mast cell release. Stress and anxiety exacerbate the symptoms of atopic dermatitis, especially pruritus. Therefore, psychological interventions, in particular the control of serotonin levels, can be useful in the management of atopic dermatitis. Two drugs have proven effective in this respect: ondansetron and tandospirone citrate. Ondansetron, a serotonin receptor antagonist, administered at doses of 8 to 12 mg/d improved intractable pruritus associated with various skin diseases, including atopic dermatitis.75 Tandospirone citrate, a partial agonist that reduces the synthesis and release of serotonin, at a dose of 30 mg/d for 4 weeks led to improvements in SCORAD and reductions in the anxiety, depression, stress, and insomnia associated with atopic dermatitis.76

Perhaps the most novel approach to the control of pruritus in atopic dermatitis is the use of the opioid receptor antagonist naltrexone.77 In a randomized, double-blind, placebo-controlled trial, naltrexone 50 mg/d for 2 weeks achieved statistically significant reductions in pruritus measured on a visual analog scale.77 The most important of the adverse effects commonly reported for this drug are gastrointestinal symptoms, which in some cases limit its use. Other adverse events, relating to the cardiovascular and nervous systems or involving musculoskeletal and allergic effects, have also been reported, but these are much less frequent. The nerve terminals that transmit painful stimuli and the itching sensation to the central nervous system run parallel to the dorsal spinal cord and are interconnected by interneurons.78 Opiate agonists make the interneurons block the nerve endings that transmit pain, thereby producing analgesia; however, they also stimulate the nerves that conduct the itching sensation, producing reactive pruritus. In the same way, but in reverse, opiate antagonists make the interneurons block the fibers that transmit the itching sensation, and sometimes produce reactive pain.

Cromoglicic acid is a chromone that was developed as an inhaled powder treatment for asthma and has subsequently been used in the management of allergic rhinoconjunctivitis, food allergies, and disseminated mastocytosis. It was initially thought that its mechanism of action was mast cell stabilization, but in the skin it acts primarily by inhibiting the activation of the nerve fibers that receive and transmit the itching sensation. Several studies have investigated the effect of its topical application in atopic dermatitis.79–81 Although results have been varied, some studies found a significant reduction in pruritus. Cromoglicic acid is usually marketed in an emulsion formulation at concentrations of between 1% and 10%; the best results have been obtained with the highest concentrations. Tolerance is satisfactory and no adverse effects have been reported. Results obtained with oral formulations are confusing and contradictory.82