Potential adverse risks associated with TCSs include skin atrophy, perioral dermatitis, adrenal suppression, acne rosacea, and the development of striae. After the lesion appears to have resolved, patients should taper their use to every other day before beginning maintenance therapy. Long-term use of medium-potency TCSs with proactive twice-weekly application in conjunction with emollient use can reduce the risk of relapse for adults and children with moderate to severe forms of AD.39–41
High-potency TCSs (more than three times 1% hydrocortisone) should not be routinely used on thin skin such as the face, body folds, and groin because of the risk of cutaneous atrophy. The appropriate amount of cream or ointment that should be dispensed often for 2 weeks of use is measured in adult fingertip units, or approximately 0.5 g applied over an area the size of two adult palms. Clinicians often underestimate or overestimate the quantity of topical steroids to order. Table 8 provides a guide to appropriate quantities depending on the extent of involvement in each area.42
There are two nonsteroidal topical calcineurin inhibitors (TCIs): tacrolimus and pimecrolimus. Tacrolimus 0.1% is approved for adults only. Although tacrolimus 0.03% ointment and pimecrolimus 1% cream are officially indicated only for patients with AD older than 2 years, the recent American Academy of Dermatology guidelines recommend their off-label use in patients younger than 2 years with mild or severe disease.29 The major adverse reactions to TCI use are transient, local burning or itching sensations at the site of application (keeping the topical cream/ointment in the refrigerator may partly alleviate this). That said, long-term use of TCIs is not associated with skin atrophy, and they can preserve the epidermal barrier further weakened by topical steroid application.43 One study illustrated that tacrolimus ointment 0.1% has shown efficacy and safety for long-term treatment of up to 12 months in children with AD.44 Similarly, one open-label clinical study reported that tacrolimus 0.1% has been shown to be safe and effective in adult patients with AD.45 Moreover, a 6-month controlled clinical trial observed that 1% pimecrolimus cream was well tolerated and effective in patients (infants and adults) with AD.46
Occasionally, patients may develop an allergy to these agents, and the cost may be a deterrent for individuals who do not have coverage for these topical agents. There is a black box warning about the use of these agents and the theoretical risk of lymphoma, which was based on lymphomas noticed in mice exposed to extreme doses of the drug.47 However, there does not appear to be any increased risk of this cancer in humans using TCIs.47
Tacrolimus ointment 0.1% is indicated for moderate to severe AD, often used in combination with TCSs, while pimecrolimus cream 1% is indicated for mild to moderate AD. Topical calcineurin inhibitors are particularly recommended for the treatment of AD that manifests on the eyelid, facial regions, and intertriginous areas. Moreover, they are suitable in patients with frequent flares or persistent AD who otherwise would require the prolonged use of TCSs. Even though there are concerns of the development of malignancies with chronic use of TCIs, there is currently no short- or medium-term (<10 years) evidence of increased risk of lymphoma in patients who used TCIs for a long period relative to the general population.48,49 Recent studies have reported that patients using tacrolimus three times weekly for maintenance therapy experience greater flare prevention and longer times until first disease relapse.50
Because AD is a chronic, relapsing inflammatory disease, it is now recommended that patients follow a long-term maintenance therapy rather than following the traditional “reactive” approach to flare-ups (Table 9). The preventive approach recognizes that previously involved lesional skin is far from normal. In actuality, the skin of AD patients has subclinical signs of inflammation, epidermal barrier defects, and damage. Always recommend the daily application of emollients or moisturizers to unaffected areas. They should be applied in the following scenarios: after bathing while the skin is still damp, after handwashing, anytime the skin is dry, and in the chronic stage to prevent recurrences of flares.
Patients with bacterial infection should use topical and/or oral antibiotic therapy but should generally be restricted to short-term use in order to prevent the development of antibacterial resistance. Some evidence points to the use of first-generation cephalosporins for the treatment of S aureus that colonizes and causes superinfection in patients with AD.52 Other clinicians will order antibiotics with effects against staphylococcus that also have anti-inflammatory action (eg, doxycycline, cotrimoxazole).
Bleach (sodium hypochlorite) baths may also be recommended as an adjuvant therapy in patients with AD and frequent or extensive secondary bacterial infections. It is suggested that the antiseptic effects of bleach can reduce the colonization of the skin by S aureus.52 Patients should soak for 5 to 10 minutes in a bathtub full of lukewarm water mixed with one-quarter to one-half cup of 6% bleach solution.
Scratching will induce histamine and other mediator release, thereby exacerbating the pruritus. This can become frustrating because patients may have difficulty sleeping. Both sedating and nonsedating oral antihistamines are often prescribed, with the nonsedating antihistamines less useful in managing AD for control of the pruritus. Sedating oral antihistamines (eg, hydroxyzine, diphenhydramine, doxepin) have been shown to improve patient sleep quality.56 However, there is currently no evidence to suggest that antihistamines mitigate the AD progress.
There are myriad environmental and psychological factors that can aggravate and/or trigger AD. Patients should avoid common skin irritants including harsh antibacterial soaps, detergents, fabric softeners, chemicals, wool or nylon clothing, abnormal temperature/humidity, or sudden changes in temperature.57 Cotton or corduroy clothes are often most comfortable next to the skin surface. Encourage patients to double rinse their clothing with white vinegar to remove detergent residue in the clothes. Launder new clothing before use and maintain a pleasant temperature and humidity level in the patient’s environment.
Positivity to aeroallergens tends to increase with age. Dust mites in particular are the most common allergen in patients with AD, and avoiding them has been helpful to patients.60,61 Dust mites live in pillows, mattresses, and carpets. It is recommended that patients wash their bedding weekly in hot water; encase pillows and mattresses; vacuum frequently;57,63 and minimize use of carpeting, curtains, and drapes to control or mitigate AD.
When patients fail to see any improvement from first- and second-line therapies, systemic anti-inflammatory treatments may be required.64 The oral anti-inflammatory agents listed in Table 10 are all immunosuppressive and are generally restricted for those with severe, frequent flares and/or those patients who are using hazardous levels of topical therapies. Patients should be carefully assessed before prescribing anti-inflammatory agents and closely monitored for potential adverse reactions, and treatment should be limited to a short duration.
Phototherapy is a therapeutic option for those patients whose AD cannot be controlled with topical medications alone and/or who have extensive body spread.74 Phototherapy can work in tandem with TCSs to treat AD. Incorporating the use of both oral and topical psoralen with UV light therapy has been shown to reduce symptoms of pruritus within the first 2 weeks of treatment.76
One novel technique used to treat AD is the boron-based benzoxaborole compound crisaborole, available as a 2% topical ointment. Crisaborole is a nonsteroidal, anti-inflammatory medication that is capable of selectively targeting PDE4.78,79 By inhibiting PDE4, crisaborole effectively up-regulates concentrations of intracellular cyclic adenosine monophosphate, which is also a regulator of nuclear factor κ light-chain enhancer of activated B cells and nuclear factor of activated T-cell signaling pathways.80 This results in the suppression of various proinflammatory cytokines, thereby controlling inflammation.81,82 Data from two large randomized controlled phase 3 clinical trials demonstrated that crisaborole topical ointment 2% could be used safely and efficaciously in children, adolescents, and adults with mild to moderate AD.83,84
The most promising biologic for AD is dupilumab. It is a human monoclonal antibody directed at the α subunit of IL-4 receptors. Inhibiting the α subunit blocks IL-4 and IL-13 signaling and effectively reduces the TH2 response. Dupilumab has caused significant improvement in inflammation and pruritus with no dose-limiting toxicity.72 Advantages include lack of immunosuppressive effects or need for bloodwork monitoring. The most common adverse reactions include injection site reactions and conjunctivitis (10% each). It is used for the treatment of adults with moderate to severe AD who have failed current topical and systemic treatment options.73 The treatment is expensive and not covered by all insurance providers.
The future of AD management begins with identifying the at-risk baby at birth. Conceptual models of hydrating the skin from the first few days of life and topically seeding protective skin bacteria are all intriguing hypotheses that may prevent or modify the atopic march. The recognition of the genes responsible for defective barrier function is key to immune modulation and the development of newer classes of therapies, including Janus kinase signaling pathway inhibitors, additional PDE4 inhibitors, and agonists of the aryl hydrocarbon receptor. Above all, new drugs are useful only in concert with patient-centered care, a patient support network, and interprofessional healthcare teams. Innovative solutions can lead to improved AD prevention and management.
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