Medication Summary
Topical corticosteroids are the mainstay of treatment of atopic dermatitis (AD). [59] These medications reduce inflammation and pruritus primarily by inhibiting the transcriptional activity of various proinflammatory genes. Topical steroids should be applied only to areas of acute exacerbations, whereas emollients should be used over the remainder of the skin. The regular use of emollients in children with mild-to-moderate atopic dermatitis reduces the symptom severity; they should be considered first-line treatment. [60] The absorption of topical steroids is much better through hydrated skin; thus, the ideal time for application is in the first 3 minutes after a bath or shower. The various topical steroid formulations, in ascending order of occlusiveness, include lotions, creams, gels, and ointments. The proactive wet-wrap method with diluted corticosteroids has been advocated. [61]
Crisaborole, a phosphodiesterase-4 (PDE-4) inhibitor, is approved for children. In March 2020, the FDA expanded the indication to include infants and children aged 3 months or older. Use in pediatric patients aged 3 months to less than 2 years was supported by data from a 28-day open-label, safety, and pharmacokinetics trial (n=137). [32] This boron-based PDE-4 inhibitor can be used in mild-to-moderate atopic dermatitis. [62] It reduces the dermatitis and associated pruritus without apparent undesirable side effects. Difamilast, a selective phosphodiesterase 4 inhibitor ointment for pediatric atopics, has promise too. [63]
Lotions contain water and may be drying because of the evaporative effect; thus, they are used mostly in scalp and beard areas where drying effects are not as problematic. Lotions containing alcohol may cause a burning sensation upon application, especially on skin with fissured or ulcerated areas. Lotions may contain preservatives, solubilizers, and fragrances that can irritate the skin.
Creams are generally well tolerated but are less moisturizing than ointments. Creams are popular for their nongreasy appearance on treated skin and are more convenient during hot weather because they cause less occlusion of eccrine sweat glands than ointments and gels. As with lotions, creams may contain preservatives, solubilizers, and fragrances that can irritate the skin.
Gels are highly occlusive, but the propylene glycol base is irritating to the skin and promotes dryness. Therefore, gels, similar to lotions, are used mostly in scalp and beard areas where the drying effects are not as problematic. They are very effective in the management of acute weeping or vesicular lesions of atopic dermatitis.
Ointments are the most moisturizing of the topical steroid vehicles, but their occlusiveness may not be well tolerated because of their interference with sweat gland function and resultant development of sweat retention dermatitis, especially in warm humid climates. Ointments are the preferred vehicle for thickened, lichenified plaques of atopic dermatitis.
Systemic corticosteroids have been used in severe chronic atopic dermatitis, but use has been limited in the pediatric population because of the risk of severe adverse effects associated with chronic usage, including growth retardation and immune suppression.
Oral antihistamines are effective as systemic antipruritics, sedatives, and mild anxiolytics. These are beneficial especially at nighttime because pruritus is usually worse at night. Commonly used oral antihistamines include diphenhydramine, hydroxyzine, and doxepin. Pramoxine is a topical antipruritic agent and can be found as Prax, Pramosone, or PrameGel.
Coal tar topical preparations have antipruritic and anti-inflammatory effects. [64] They work as disinfectants and astringents and help to correct abnormal keratinization by decreasing both epidermal proliferation and dermal infiltration. They are effective as second-line agents for subacute, chronic, and lichenified atopic dermatitis. Cosmetically acceptable preparations are available and include AquaTar, Estar, Fototar, PsoriGel, and Neutrogena T/Derm Tar Emollient. Tar shampoos, such as Neutrogena T-Gel, are effective for scalp involvement. Adverse effects may include folliculitis and photosensitivity.
Topical calcineurin inhibitors (eg, tacrolimus, pimecrolimus) are the newest class of topical medications for atopic dermatitis. These nonsteroidal immunomodulators act by down-regulating the mediator release or cytokine expression of various cells, including Th1 helper cells, Th2 helper cells, mast cells, eosinophils, keratinocytes, and Langerhans cells. Calcineurin inhibitors may be especially useful for treating face, groin, or axillary areas, where steroid-sparing treatments are preferred. The safety of pimecrolimus has been stressed for infants and other children, with the conclusion made that labeling restrictions be lifted. [65] Calcineurin inhibitors and corticosteroids have similar benefit, but the former is more expensive and may produce skin burning and pruritus. [59]
Several studies have documented the rapid and prolonged improvement in clinical severity scores in children and adults with a range of severity of atopic dermatitis treat with topical calcineurin inhibitors. Research has shown the beneficial effect of topical calcineurin inhibitors in patients refractory to topical corticosteroid therapy. [66, 67] The most common adverse effect is a local burning sensation upon application, but this symptom tends to diminish after the first few days of use.
In January 2006, the Food and Drug Administration (FDA) approved a black box warning for tacrolimus and pimecrolimus topical medications. The warning emphasized the lack of long-term safety data and a possible link to malignancies. No causal link between these agents and the development of malignancies has been established. Long-term studies on the safety of these agents in humans are not yet available, and the black box warning was based on case reports in humans and on animal studies. An analysis of tacrolimus ointment use in patients with atopic dermatitis over 4 years did not show any increased risk of infections or cancer. [68] However, longer term studies (10 y of follow-up or longer) are needed before firm conclusions about these concerns can be reached. The safety of pimecrolimus has been stressed; labeling restrictions may be unnecessary. [65]
Establishing the long-term safety profile of topical calcineurin inhibitors is of paramount importance because they appear to provide an effective alternative to topical corticosteroid treatment in certain patients. Furthermore, pimecrolimus has been shown to improve the epidermal skin barrier without the concurrent risk of local skin atrophy commonly seen with topical corticosteroid treatment. [69] Thus, pimecrolimus appears to be an attractive candidate for long-term use in either a therapeutic or preventative capacity.
At the present time, physicians are advised to use the following guidelines when prescribing topical immunomodulators such as tacrolimus and pimecrolimus [70, 71] :
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Use in patients older than 2 years
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Use intermittently as needed, not on a daily basis for prolonged periods (ie, >6 wk)
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Avoid use in immunocompromised patients or in those with neoplasms
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Atypical atopic dermatitis, including new onset disease in an adult, should warrant a skin biopsy prior to topical immunomodulator use, to rule out other diagnoses (eg, cutaneous T-cell lymphoma, Netherton syndrome)
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Encourage sun protection to reduce the risk of photocarcinogenesis
Dupilumab, a monoclonal antibody targeting the α-subunit of the interleukin (IL)–4 receptor to produce inhibition of both the IL-4 and IL-13 pathways, is of value in moderate-to-severe atopic dermatitis. [33, 34, 35, 36, 72, 73]
The Janus kinase (JAK) inhibitors upadacitinib (oral) and ruxolitinib (topical) have been approved by the FDA for treatment of atopic dermatitis in adults and adolescents. [41, 42, 40]
Oral cyclosporine has proven beneficial in patients with severe atopic dermatitis refractory to treatment with topical steroids. Discontinuation of cyclosporine frequently results in rapid relapse of skin disease. Significant adverse effects (eg, nausea, abdominal discomfort, hypertrichosis, paresthesias, hypertension, hyperbilirubinemia, renal impairment) have diminished enthusiasm for this drug, especially with the advent of the topical immunomodulators mentioned above.
Experimental treatments for atopic dermatitis have included trials of gamma-interferon and IL-2; both are inhibitors of Th2 cell functions and have been promising. Oral mycophenolate mofetil, an inhibitor of purine synthesis, has also been shown to be an effective alternative form of treatment for severe disease. A small study of 6 patients with severe atopic dermatitis showed promising results for treatment with anti-CD20 monoclonal antibody (Rituximab). [74]
Some evidence suggests that the use of traditional Chinese medicine herb combinations may result in short-term improvements in SCORing of Atopic Dermatitis (SCORAD) index scores, quality of life scores, and topical steroid use. [75] However, larger trials to evaluate safety and long-term efficacy are needed.
Conflicting results have been reported regarding the use of probiotics (eg, Lactobacillus, Bifidobacterium) in preventing atopic dermatitis or in controlling symptoms in children. [75] A 2008 meta-analysis indicated that prenatal and postnatal probiotic supplementation may be helpful in preventing the development of atopic dermatitis in young children but does not appear to be effective in treating existing atopic dermatitis. [54] Further studies on the subject are needed prior to developing firm conclusions on the usefulness of this complementary medicinal treatment. Deo et al have suggested low-dose methotrexate as a treatment option in the pediatric population. [76]
In addition to the anti-IL-13 inhibitor, tralokinumab, many new medications are in various stages of development. [77] Lebrikizumab, an investigational anti–IL-13 monoclonal antibody, may prove of value in children as an add-on to topical corticosteroid therapy. [78]
Topical corticosteroids
Class Summary
In older children and adolescents, treat mild cases of atopic dermatitis with a low-potency (class VI or VII) topical steroid twice a day to decrease inflammation. Examples include hydrocortisone cream or ointment, 1% and 2.5%. For moderate cases of atopic dermatitis, intermediate-potency steroids (class III, IV, V) may be used for brief periods (< 2 wk) to control an eczematous flare. Subsequently, low-potency steroids can be used to maintain remission. For severe cases of atopic dermatitis, pulse therapy with high-potency topical steroids (class II) or oral steroids may be beneficial in adolescents. Use only low-potency steroids on the face, axillae, groin, and intertriginous areas because of increased absorption and increased local steroid adverse effects.
For mild atopic dermatitis in infants, class VI or VII topical steroids should be effective. If the infant has more severe atopic dermatitis, a moderate-potency steroid can be prescribed for as long as 1 week and then tapered down to a lower-potency medication for maintenance therapy. In general, do not treat infants with topical steroids in the high-potency classes (class II or above) without a referral to a dermatologist.
Cordran tape is a corticosteroid-impregnated polyethylene film that enhances topical steroid penetration up to 100-fold. Occlusion of a topical steroid under plastic wrap seems to work equally well. These methods are especially useful for chronic lichenified plaques of atopic dermatitis.
In order to achieve a quick, complete remission of atopic dermatitis symptoms, adequate amounts of topical steroid must be used. Many patients initially use suboptimal amounts of topical steroid products, leading to poor control of their atopic dermatitis symptoms and ultimate discontinuation of their therapy. Approximately 30 grams of medication is needed to cover the entire surface area of an adult body. For children, the fingertip unit (FTU) has been shown to accurately measure an appropriate amount of medication. The FTU is defined as the amount of topical medication that will cover the child's index finger from the tip to the metacarpophalangeal joint. For topical steroids, 1 FTU covers the hand or groin, 2 FTUs cover the face or foot, 3 FTUs cover an arm, 6 FTUs cover a leg, and 14 FTUs cover the trunk.
Atopic dermatitis increases the risk of developing lymphoma (both Hodgkin disease and non-Hodgkin lymphoma). This risk correlates with increasing severity of disease. An even higher risk of lymphoma occurs in patients with atopic dermatitis treated with topical corticosteroids. The risk reportedly rose with increasing potency of the topical corticosteroid and with longer duration of use.
Hydrocortisone topical (Cortizone, Dermolate, Westcort)
Hydrocortisone topical is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects, resulting in anti-inflammatory activity.
Triamcinolone topical (Kenalog)
It treats inflammatory dermatosis that is responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Flurandrenolide (Cordran Tape)
Flurandrenolide is an intermediate-potency topical corticosteroid. Each square cm provides 4 mcg.
Systemic corticosteroids
Class Summary
Symptoms typically dramatically improve in the first few days of treatment with systemic steroids, only to be followed by an equally dramatic rebound flare after cessation of treatment. Tapering oral steroids over 10-14 days may mitigate this effect. In addition, an intensified focus on hydration with bathing and appropriate use of topical steroids should be emphasized to prevent rebound phenomena after discontinuation of systemic steroids.
Prednisone (Deltasone, Orasone)
Prednisone decreases inflammation by reversing increased capillary permeability and suppressing PMN activity.
Antimicrobials
Class Summary
Antistaphylococcal antibiotics (eg, topical mupirocin or bacitracin, first-generation cephalosporins, macrolides, penicillinase-resistant extended-spectrum penicillins such as oxacillin or dicloxacillin if resistant strains of S aureus are encountered, amoxicillin-clavulanate) are helpful in secondary bacterial infections. Herpes simplex superinfections (eczema herpeticum) should be suspected if vesicles are present or if no improvement is observed with oral antibiotics. Tzanck smear of the base of vesicles is positive in 70% of cases. Treat with oral or intravenous acyclovir for 10 days. Varicella infections may become severe in the setting of atopic dermatitis, and early treatment with acyclovir is recommended. Counsel all children with atopic dermatitis as to the benefits of vaccination against varicella. Treat dermatophyte infections with topical or oral antifungals, such as topical ketoconazole cream or shampoo.
Mupirocin topical cream or ointment (Bactroban)
Mupirocin topical cream or ointment inhibits bacterial growth by inhibiting RNA and protein synthesis.
Cephalexin (Keflex, Keftab)
Cephalexin is a first-generation cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms. Its primary activity is against skin flora.
Erythromycin (E.E.S., Erythrocin) or azithromycin (Zithromax)
Erythromycin is a macrolide antibiotic that inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.
Oxacillin (Bactocill)
Oxacillin is a bactericidal antibiotic that inhibits cell wall synthesis. It is used in the treatment of infections caused by penicillinase-producing staphylococci and may be used to initiate therapy when a staphylococcal infection is suspected.
Amoxicillin and clavulanate (Augmentin)
This drug combination treats bacteria resistant to beta-lactam antibiotics. Base dosage regimen on amoxicillin content. Because of different amoxicillin-clavulanic acid ratios in the 250-mg tablet (250/125) versus the 250-mg chewable tablet (250/62.5), do not use the 250-mg tablete until the child weighs more than 40 kg.
Acyclovir (Zovirax)
Patients experience less pain and faster resolution of cutaneous lesions when used within 48 hours of rash onset. Acyclovir may prevent recurrent outbreaks.
Ketoconazole (Nizoral)
Ketoconazole is an imidazole broad-spectrum antifungal agent. It inhibits the synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
Dicloxacillin
Dicloxacillin is a bactericidal antibiotic that inhibits cell wall synthesis. It is used in the treatment of infections caused by penicillinase-producing staphylococci and may be used to initiate therapy when a staphylococcal infection is suspected.
Antipruritics
Class Summary
Topical local anesthetics or antihistamines (topical or systemic) may be used to decrease pruritus.
Pramoxine topical (Azo Itch Relief Maximum Strength Analgesic Cream, Eczemin, Itch-X Gel)
Pramoxine elicits anesthetic effect by blocking nerve conduction and impulses by inhibiting depolarization of neurons.
Doxepin cream (Prudoxin, Xepin, Zonalon)
Doxepin topical cream is a potent antihistamine and is indicated for pruritus.
Diphenhydramine (Alka-Seltzer Plus Allergy, Benadryl, Benadryl Allergy Dye-Free LiquiGels)
Diphenhydramine can be used for symptomatic relief of symptoms caused by the release of histamine in allergic reactions.
Hydroxyzine (Vistaril)
Hydroxyzine can be used for symptomatic relief of symptoms caused by the release of histamine in allergic reactions.
Doxepin (Silenor)
Doxepin can be used for symptomatic relief of symptoms caused by the release of histamine in allergic reactions.
Immunomodulators
Class Summary
Topical tacrolimus ointment and pimecrolimus cream have both been shown to diminish pruritus and inflammation markedly within 3 days of initiating therapy and to have persistent effects for as long as 12 months.
Tacrolimus, topical (Protopic)
The mechanism of action of tacrolimus in atopic dermatitis is not known. This agent reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-α, all of which are involved in the early stages of T-cell activation. Additionally, this agent may inhibit the release of preformed mediators from skin mast cells and basophils, and it may down-regulate the expression of FCeRI on Langerhans cells. It is used for the short-term or intermittent long-term treatment of moderate-to-severe atopic dermatitis that is unresponsive to first-line therapies (eg, topical corticosteroids) or in cases in which first-line therapies are not applicable. The manufacturer and FDA recommend that the smallest amount and lowest potency that is efficacious be used to achieve control of symptoms. It is available as an ointment in concentrations of 0.03% and 0.1%.
Pimecrolimus (Elidel cream)
Pimecrolimus is the first nonsteroid cream approved in the US for mild-to-moderate atopic dermatitis. It is derived from ascomycin, a natural substance produced by the fungus Streptomyces hygroscopicus var. ascomyceticus. This agent selectively inhibits production and release of inflammatory cytokines from activated T cells by binding to cytosolic immunophilin receptor macrophilin-12. The resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release. Cutaneous atrophy was not observed in clinical trials, a potential advantage over topical corticosteroids. This agent is indicated only after other treatment options have failed. Pimecrolimus is available as a 1% cream.
Cyclosporine (Sandimmune, Neoral)
Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions.
Topical Phosphodiesterase-4 (PDE-4) Inhibitors
Class Summary
A topical PDE-4 inhibitor is a nonsteroidal option for atopic dermatitis treatment.
Crisaborole topical (Eucrisa)
PDE-4 inhibitors allow for cyclic adenosine monophosphate (cAMP) to remain intact in order to decrease the proinflammatory response (eg, cytokine release) associated with atopic dermatitis. Crisaborole is indicated for mild-to-moderate atopic dermatitis in adults and children aged 3 months or older.
Targeted Biologic Therapies (Interleukin Inhibitors)
Class Summary
Interleukin (IL)–4, IL-5, and IL-13 appear to play critical roles in the etiology of atopic dermatitis in response to activation by epidermal cell–derived cytokines.
Dupilumab (Dupixent)
Dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signaling by blocking the shared IL-4Ra. It is indicated for patients aged 6 years or older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. It is administered as a subcutaneous injection every 2 weeks. It may be used with or without topical corticosteroids. It also may be coadministered with topical calcineurin inhibitors, but these should be reserved for problem areas only (eg, face, neck, intertriginous and genital areas).
Dermatologics, JAK Inhibitors
Class Summary
The JAK inhibitors block off the overactive pathway of JAK1, JAK2, JAK3 enzymes, which limits cytokine production and reduces eczema symptoms, such as itch and inflammation.
Upadacitinib (Rinvoq)
An oral JAK-1 selective inhibitor indicated for refractory, moderate to severe atopic dermatitis in patients aged ≥12 years whose disease is not adequately controlled with other systemic drug products, including biologics, or who are unable to use such therapies.
Ruxolitinib topical (Opzelura)
Indicated for topical short-term and noncontinuous long-term treatment of mild-to-moderate atopic dermatitis (AD) in nonimmunocompromised patients aged 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advised.
Abrocitinib (Cibinqo)
An oral JAK1 inhibitor indicated for treatment for patients aged 12 years and olderadults with moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic therapies or for whom those therapies are inadvisable.
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Typical atopic dermatitis on the face of an infant.
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Flexural involvement in childhood atopic dermatitis.
