Topical corticosteroids

Topical corticosteroids (TCS) are the first-line pharmacologic treatment for AD, often introduced for maintenance therapy and use in the treatment of acute flares ( ). While TCS do not have a direct antipruritic effect, multiple studies have shown that routine use reduces AD symptoms, including itch and pain due to their antiinflammatory properties and reduction in itch-related cytokines such as IL31 ( ). TCS are available in various potencies that range from very low (class VII; e.g., hydrocortisone 0.25%) to very high (class I; e.g., clobetasol 0.05%). In general, the lowest potency to achieve control of disease for that patient should be used so to minimize adverse effects. Some evidence shows that moderate-to-high potency TCS offer a greater antipruritic effect than low potency ( ). Side effects of TCS on the skin are dependent on the potency, frequency, and location of application of the agent and include atrophic changes of the skin, telangiectasias, striae, and easy bruising ( ). Skin atrophy is more likely to occur in older patients and with use of higher potency TCS in areas of the body where the skin is thin (e.g., face, neck, intertriginous areas) or with occlusive therapies. Systemic side effects such as suppression of the hypothalamic pituitary axis are possible when using high-potency dosages or with extensive body surface usage.

Topical calcineurin inhibitors

Topical calcineurin inhibitors (TCIs) are a more recently introduced class of nonsteroid antiinflammatory treatments for AD. The antipruritic effectiveness of TCIs may be due in part to their stimulatory effect of the transient receptor potential ion channel member 1 (TRPV1) in cutaneous nerves ( ). These topicals (e.g., tacrolimus 0.03% or 0.1%, pimecrolimus 1%) have been shown to reduce pruritus scores in AD and may be as effective as midpotency TCs ( ). In a randomized trial, pruritus scores with pimecrolimus 1% were significantly improved by 56% versus only 34% with vehicle alone, and benefit was noted within 48 hours of treatment ( ). Similar reduction of pruritus scores and maintenance of the antipruritic effect was also demonstrated in a 26-week study ( ). Because these agents are nonsteroidal they are preferred for areas prone to steroid-induced atrophy (i.e., face). TCIs have the notable adverse effect of burning of the skin upon application, but this effect typically diminishes after several days of use ( ). The US Food and Drug Administration (FDA) placed a black box warning on TCIs, based on animal studies and case reports showing an increased incidence of malignancy, particularly lymphoma and skin cancers, in patients with AD using this medication ( ) but recent meta-analyses have not confirmed this association ( ).

Topical phosphodiesterase-4 inhibitors

Crisaborole is a phosphodiesterase-4 (PDE4) inhibitor that reduces the release of proinflammatory cytokines ( ). This nonsteroidal topical is used for the treatment of mild to moderate AD and has shown effectiveness in phase 3 studies in reducing itch in AD ( ). In a post hoc analysis of randomized controlled trials (RCTs), crisaborole has been demonstrated to have a rapid effect on pruritus score reduction, evident within 2 to 6 days of use ( ). Reduction of pruritus while using this topical medication has been shown to lead to significant improvements in quality of life scores among patients ( ). Crisaborole is generally well tolerated with use in thin or sensitive skin areas for which TCS are not appropriate ( ). The drug has a favorable safety profile and is generally well tolerated with adverse effects such as application site burning reported infrequently.

Topical anesthetics, analgesics, and cooling agents

Topical anesthetics, analgesics, and cooling agents work by activating the nociceptors, thermoreceptors, or otherwise modulating cutaneous neural pathways. Capsaicin’s antipruritic properties are due to activation of the transient receptor potential 1 (TRPV1) receptors in keratinocytes and nociceptive C-nerve fibers. Application of topical capsaicin (0.025%–0.1% or 8% patch) has been shown to be effective in pain and itch relief of various etiologies ( ). Of note, topical capsaicin has an initial burning effect that can be avoided with pretreatment with topical anesthetics (i.e., lidocaine or EMLA). The topical anesthetic pramoxine 1% is available in formulations with ceramide moisturizers and has been shown to have antipruritic properties and provide relief in patients with AD-related itch ( ). Menthol activates thermosensitive TRPM8 ion channels present on sensory nerves to induce a cooling effect on the skin. As an antipruritic in 1% concentration, menthol is particularly useful for patients with AD who report that cooling of the skin (e.g., cold showers) improves their pruritic symptoms ( ). Menthol also has analgesic properties at low concentrations (e.g., ≤1%) but may cause irritation and cold-induced pain at higher concentrations. Polidocanol 3% concentration is another topical anesthetic with antipruritic efficacy demonstrated in a large observational study with few adverse effects noted ( ).

Topical ketamine blocks N -methyl- d -aspartate receptors (NMDA) and sodium channels to reduce the sensitivity of peripheral nerves. A combination cream of ketamine 5% to 10%, amitriptyline 5%, and lidocaine 5% (KAL) has been used in the treatment of chronic pruritus, and in one study, including patients with AD, pruritus scores were significantly improved with relief achieved within a few minutes on average ( ). KAL has been reported to be well tolerated in limited clinical studies, with burning sensation and redness reported in a minority of patients ( ). Ketamine is a controlled substance with potential for psychoactive effects if ingested, and therefore patients should be advised to not ingest the product and to limit use to prescribed areas only (<20% body surface area).

Topical cannabinoids

Endocannabinoids such as N-palmitoylethanolamine (PEA), an agonist of the cannabinoid 2 receptor, have been demonstrated to have antiinflammatory and antipruritic properties ( ). An open-label, noncontrolled, prospective cohort study in a group of nearly 2500 subjects with AD demonstrated that a cream containing PEA decreased pruritic symptoms by 47% within 6 days and by 60% after 4 to 6 weeks, improved sleep quality reported by patients, and was well tolerated ( ).

Wet wrap treatment

Wet wrap treatment (WWT) consists of a topical agent (i.e., TCS) applied to the skin and then covering the area with a wetted layer of bandages or nonirritant fabric (i.e., cotton) followed by an overlying layer of dry fabric. WWT may be left on for several hours and is typically continued for several days up to 2 weeks. WWT is often recommended for severe flares or recalcitrant disease to attain a relatively rapid reduction in symptoms, including itch. This method reduces itch through various mechanisms, including cooling of the skin, improving penetration of topical medications, and providing a physical barrier to prevent excoriation. The presence of a physical barrier may also prevent stimulation of cutaneous nerve fibers that are in close proximity to the damaged skin barrier ( ). WWT has been shown to be efficacious in reducing objective and subjective AD symptoms, including pruritus, as well as improvement in quality of life measures ( ). Because of the enhanced effect of the topical agents being applied it is recommended that low to medium potency corticosteroids be used or they be diluted to 5% to 10% of their original strength ( ).

Cyclosporine A

Cyclosporine A, an immunosuppressant targeting T cells and IL2, has the strongest body of evidence among the systemic immunosuppressants as a first-line systemic agent for short-term use in moderate to severe AD ( ). In RCTs, cyclosporine has demonstrated significant reduction in pruritus and improvement of quality of life measures among those with AD ( ). The use of cyclosporine in AD is limited by its numerous potential adverse effects, including opportunistic infection secondary to immunosuppression, nephrotoxicity, hypertension, and increased risk of certain malignancies ( ). In addition to these effects, rapid discontinuation of cyclosporine may cause a rebound flare of AD symptoms. This effect can be mitigated by tapering and coadministration of other systemic agents ( ).

Azathioprine

Azathioprine is a purine analog that interferes with DNA production and therefore B- and T-cell proliferation that has been shown to be efficacious in AD and is used off-label for treatment of refractory disease ( ). In RCTs, azathioprine has demonstrated significant antipruritic effects and quality of life improvements in AD patients in comparison to placebo ( ). In a comparison trial with methotrexate, comparable reductions in pruritus measures and quality of life improvement were achieved with each treatment ( ). Azathioprine has apparent antipruritic effects aside from its use in AD, as it has been shown to be effective in patients with itch of unknown etiology ( ). Its adverse effect profile includes the potential for lymphocytopenia, for which laboratory monitoring may be considered, as well as a hypersensitivity reaction that occurs in a subset of patients within the first few weeks of treatment ( ). Of particular concern is the apparent increased risk of nonmelanoma skin cancer, associated with increased dosage, duration of use, and sun exposure ( ). Reduced activity of the thiopurine methyltransferase (TPMT) due to genetic polymorphisms is common in the general population and affects the toxicity of azathioprine. Thus baseline TPMT levels should be obtained prior to initiating therapy, with dosage adjustments accordingly.

Methotrexate

Methotrexate is an oral medication that inhibits dihydrofolate reductase, inhibiting the synthesis of purines and limiting T-cell proliferation. The off-label use of methotrexate in AD is typically limited to refractory AD, and it has been shown to be effective in improving AD symptoms, including itch ( ). In a comparison trial with azathioprine, similar efficacy in reducing pruritus was noted between the two agents ( ). Low-dose methotrexate (up to 15 mg weekly) can be effective for itch caused by inflammatory skin diseases ( ). Adverse effects of methotrexate are well described as nausea and gastrointestinal upset. Although they are uncommonly seen at low doses, hepatoxicity and bone marrow suppression are concerns with use of this medication, and laboratory monitoring may be considered. Because of its antifolate mechanism of action, concurrent folate supplementation (skipping folate on the day of methotrexate intake) is recommended to reduce the potential for hematologic effects.

Mycophenolate

Mycophenolate mofetil is an immunosuppressant that inhibits B- and T-cell proliferation by blocking de novo purine synthesis. Multiple studies have demonstrated its efficacy in reducing AD symptoms, including pruritus, and it is considered an alternative systemic therapy for refractory AD ( ). A single-blinded RCT showed mycophenolate mofetil may be as effective as cyclosporine for AD maintenance therapy and showed comparable antipruritic effect, but it requires a longer treatment time to show benefit ( ). Gastrointestinal complaints are common with use of this medication, which can be mitigated by use of the enteric-coated formulation. Also hematologic adverse effects are a concern, warranting laboratory monitoring for cytopenia ( ).

Biologic therapies

Dupilumab is a monoclonal antibody targeting the receptor for IL4 that blocks Th2-mediated inflammatory signaling, and has demonstrated in large RCTs to be an effective treatment for moderate to severe AD ( ). Significant improvement in pruritus scores was seen within 2 weeks of initiating therapy in these trials along with improvements in quality of life and sleep ( ). A longer term study showed significant improvements in pruritus scores maintained through 52 weeks with a significant reduction in peak pruritus rating of up to 56.2% versus 28.6% for placebo ( ). Adverse effects known to be associated with dupilumab include conjunctivitis and injection site reactions. Considering its dramatic effects on AD symptoms and favorable safety profile, dupilumab may be considered for first-line treatment of severe AD or AD-related pruritus.

Additional biologic therapies that target the AD inflammatory signaling pathways show promise with respect to their antipruritic effects in early phase RCTs. Nemolizumab is an IL31 inhibitor that has demonstrated antiitch efficacy in phase 2 trials for patients with moderate to severe AD ( ). IL13 is a cytokine produced by Th2 lymphocytes, which can induce IgE production. Similar to IL4, IL13 is an important player in AD pathogenesis, and IL13 mRNA expression is elevated in patients with AD and increases with disease severity ( ). Lebrikizumab is a monoclonal antibody against IL13 that was tested in a phase 2 trial in AD patients and was used in combination with topical corticosteroid therapy. It showed significant improvement in EASI scores, along with a reduction in pruritus scores, and improvements in sleep loss ( ). IL17, an inflammatory cytokine produced by Th17 cells, is elevated in AD patients (particularly in Asian patients) ( ). Secukinumab, a monoclonal antibody directed against IL17A, is currently approved for plaque psoriasis, and a place 2 trial for adults with moderate to severe AD is currently in its recruitment phase ( ).

The Janus kinase (JAK) inhibitors are small-molecule agents that target the JAK-STAT pathway activated by cytokine signaling. Tofacitinib has FDA approval for use in rheumatologic conditions and has demonstrated antipruritic effects in case series of patients with AD ( ). Other agents—baricitinib, abroctinib, and upadacitinib—show promise for rapid antipruritic effects in AD in phase 2 and 3 trials ( ). Emerging immunomodulators and targeted treatments are further discussed in Chapter 23 .

Phototherapy

Phototherapy (ultraviolet A [UVA] and UVB) has long been used for treating inflammatory skin conditions such as AD and psoriasis. It has a local immunosuppressive effect by targeting activated T cells ( ). Low reactive level laser therapy was also shown to reduce itch sensation in AD patients ( ). However, compliance and feasibility of obtaining regular phototherapy is a challenge for patients and physicians.

Complementary therapies

Interventions to reduce stress and anxiety can be beneficial in patients with chronic itch, who suffer from significant emotional and psychological distress. Habit reversal training, relaxation training, and cognitive behavioral therapy can be offered to patients in addition to medical therapy if they are open-minded to alternative therapies ( ). In patients with AD, psychological interventions can reduce disease severity, itch intensity, and scratching behavior ( ). Acupuncture, as well as progressive muscle relaxation techniques, can significantly reduce pruritus in patients with AD ( ). Complementary and alternative modalities are further discussed in Chapter 26, Chapter 27 .

Anticonvulsants

Neural hypersensitization plays an important role in chronic pruritus and in AD-related itch, and it may be reduced by certain treatments ( ). Gabapentinoid anticonvulsant medications such as gabapentin and pregabalin can be used to manage pruritus as well as chronic pain. Although not yet tested in studies for AD, this class of medications has been shown to be effective in treating different types of itch and to reduce neural sensitization ( ). Weight gain, drowsiness, and lower extremity edema are side effects ( ).

Kappa agonists and mu antagonists

Butorphanol is a mixed κ-opioid receptor agonist and μ-opioid receptor antagonist that reduces itch sensation transmission in the central nervous system ( ). It is administered intranasally and has been shown to be effective in patients with intractable pruritus of different types, including inflammatory skin conditions such as atopic eczema ( ). μ-Antagonists such as naltrexone have also been reported to reduce the itch of AD ( ).

Mirtazapine

Mirtazapine, a serotonergic antidepressant, can be used in low dosages to decrease nocturnal pruritus, which is a common problem in patients suffering from AD ( ). It also has been shown to increase the nociceptive threshold in healthy subjects ( ). Furthermore, it may indirectly reduce itch through its anxiolytic properties. The most common side effects of mirtazapine are somnolence, appetite stimulation, and weight gain ( ). Therefore mirtazapine is a good option in AD patients who are anxious, thin, itchy, and need to sleep better.

TRP inhibitors

Chronic pruritus is mediated mainly through the nonhistaminergic pathway ( ). Transient receptor potential ankyrin (TRPA) and transient receptor potential vanilloid (TRPV) channels are cation channels involved in generating action potentials in response to certain pruritogens via unmyelinated C fibers ( ). Therefore TRP channel inhibitors are potential targets for itch management. The long-term antipruritic effect of botulinum neurotoxin A in mice is thought to be associated with the downregulation of TRPA1 and TRPV1 ( ). Furthermore, RNA sequencing has shown that overexpression of TRPV1 in itchy skin correlates with itch intensity in AD patients, and TRPA1 gene expression was increased in itchy atopic skin ( ).

Nav 1.7 inhibitors

Voltage-gated sodium (Nav) channels are activated by TRPV1 and TRPA, and control action potentials involved in itch propagation ( ). In animal models, a Nav 1.7 monoclonal antibody provided pain relief and neuropathic and inflammatory itch reduction ( ). Furthermore, a Nav 1.7 antagonist reduced pain and itch in rodent models, suggesting Nav 1.7 to be a promising therapeutic target for both itch and pain in AD ( ). Neu-P12, an investigational drug that is a combination of a TRPV1 antagonist with a Nav 1.7 inhibitor, has been recently developed for the treatment of itch ( ).

Topical nonsteroidal antiinflammatory agents

Tapinarof is a new topical nonsteroidal agent that has shown efficacy in patients with AD and psoriasis. Its antiinflammatory properties are mediated through the activation of the aryl hydrocarbon receptor (AhR), which is expressed in various cell types, including human skin. Tapinarof induces barrier gene expression in keratinocytes and reduces Th17 cytokine responses, which are beneficial in treating AD symptoms ( ). A phase 2 trial was conducted for tapinarof in AD patients, which showed treatment efficacy with minimal adverse events ( ).

NK-1 inhibitors

Substance P activates the neurokinin-1 (NK-1) receptor, which is involved in nonhistaminergic itch signaling; gene transcripts of substance P and NK-1 are elevated in atopic patients ( ). An oral NK-1 receptor antagonist, serlopitant, improved pruritus scores in patients suffering from chronic pruritus in a phase 2 clinical trial with no significant safety concerns ( ). Serlopitant also reduced pruritus scores in AD patients in a phase 2 clinical trial; however, the differences were not statistically significant. Overall, with serlopitant meeting the primary endpoint in three of four studies assessing its efficacy in chronic pruritus, NK-1 antagonism is a promising mechanism for itch reduction across a range of patient populations ( ). Tradipitant is another NK-1 inhibitor undergoing a phase 2 trial, which has shown preliminary improvements in itch of AD patients ( ).