Evaluation and management of severe refractory atopic dermatitis (eczema) in adults

INTRODUCTION — In adults, atopic dermatitis (AD) may present as a chronic, persistent form of childhood AD; a relapsing form of childhood AD that had apparently resolved; or, less commonly, as "adult-onset" AD [1-5]. However, the diagnosis of adult-onset AD should be made with caution, as numerous skin conditions may present as an eczematous dermatitis in adulthood (table 1).

This topic will discuss the evaluation and management of severe AD in adults. The pathogenesis, clinical manifestations, diagnosis, and management of AD in adults and children are discussed separately. The treatment of severe AD in children is also discussed separately.

●(See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Treatment of atopic dermatitis (eczema)".)

●(See "Management of severe atopic dermatitis (eczema) in children".)

EPIDEMIOLOGY — It is estimated that 2 to 5 percent of adults have atopic dermatitis (AD) [6-10]. In a Finnish, population-based study, the 12-month prevalence of AD in adults ≥30 years was 10 percent [11]. In the United Kingdom, a prevalence of approximately 9 percent has been estimated in persons older than 75 years [9].

CLINICAL PHENOTYPES IN ADULTS — In adults, atopic dermatitis (AD) may present as [1-4]:

●A chronic, persistent form of childhood AD.

●A relapsing form of childhood AD that had apparently resolved.

●"Adult-onset" atopic dermatitis – Adult-onset AD is the less common form. Whether it is a distinct phenotypic variant of AD is unclear [12]. In most cases, it appears before the age of 40 years and is often a recalcitrant, difficult-to-treat condition [6,13].

●Idiopathic chronic eczematous eruption of aging – Chronic eczematous eruption of aging is defined as new-onset, atopic-like dermatitis presenting in patients over 50 years of age with no history of childhood AD [14].

Patients may incorrectly report AD as first appearing in adulthood for several reasons [13]: their childhood AD was so mild that it is not remembered; in adults from sunny, humid, tropical climates (Southeast Asia and Latin America), AD may appear when they move to drier temperate zones; and AD may appear or be exacerbated by pregnancy.

PATIENT EVALUATION

Is the diagnosis of atopic dermatitis correct? — When evaluating an adult patient with new-onset dermatitis that is persistent and relapsing, the diagnosis of atopic dermatitis (AD) should be made with caution, as a variety of skin conditions may present as an eczematous dermatitis in adulthood (table 1). The most important clinical features that suggest the diagnosis of AD are:

●Location – The skin eruption begins in or affects anatomic sites classically involved by adult AD (hand eczema (picture 1), eyelid eczema (picture 2), nipple eczema, and flexural eczema (picture 3A-B and picture 4)) [15].

●Lesion morphology – The morphology is characteristic of AD, with lichenified plaques, excoriations, and a propensity for secondary staphylococcal infection (picture 5A-D). Of note, in individuals with darkly pigmented skin, erythema may appear dark brown or violaceous instead of pink or red, as typically seen in patients with lighter complexions. Dry skin may have a whitish or ashy color, and lichenified areas typically appear hyperpigmented.

●Atopy – Other atopic conditions (asthma, allergic rhinitis, etc) are present.

However, the clinical diagnosis of AD in adults may be challenging due to multiple reasons, including:

●Atopic dermatitis coexisting with other eczematous dermatitis – AD can coexist with an exogenous dermatitis, such as allergic contact dermatitis, seborrheic dermatitis, or photodermatitis. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

●Uncommon morphology – Young adult AD patients can develop lesions with a nummular morphology [16]. However, adult males also develop classic nummular dermatitis not associated with AD that presents with weepy plaques starting on the extremities (usually one leg) (picture 6) and then generalizing. (See "Nummular eczema".)

●Atopic dermatitis mimickers – Allergic contact dermatitis, seborrheic dermatitis, psoriasis, drug eruptions, bullous pemphigoid, dermatitis herpetiformis, and cutaneous T cell lymphoma may mimic AD in adults. A high index of suspicion, repeated biopsies, and appropriate laboratory testing should be performed to rule out these conditions.

•(See "Clinical features and diagnosis of allergic contact dermatitis".)

•(See "Seborrheic dermatitis in adolescents and adults".)

•(See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

•(See "Exanthematous (maculopapular) drug eruption".)

•(See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

•(See "Dermatitis herpetiformis".)

•(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●Nonspecific (idiopathic) eczematous dermatitis – Older adult patients with chronic idiopathic pruritus may develop a nonspecific eczematous dermatitis, the so-called "eruption of senescence" or idiopathic "chronic eczematous eruption of aging" [17]. They usually have associated xerosis and pruritus that is disproportionately severe compared with the skin eruption. This nonspecific dermatitis may result from age-related barrier failure and immune imbalance, which lead to a predominately T helper type 2 (Th2) reaction pattern in the skin, similar to AD [18].

When to biopsy — A skin biopsy should be performed in adult patients presenting with recalcitrant, eczematous dermatitis. Various skin conditions that present in adulthood as an eczematous dermatitis (table 1) have histopathologic features of acute or chronic eczema similar to those of AD. If, after appropriate treatment, the eruption is not significantly improved, repeat biopsies and additional tests may be required to rule out or confirm certain diagnoses, such as scabies, mycosis fungoides, bullous pemphigoid, or cutaneous T cell lymphoma. A biopsy will not be helpful in differentiating AD from allergic contact dermatitis. (See "Scabies: Epidemiology, clinical features, and diagnosis" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Potential diagnostic pitfalls

●Family history of atopy may be misleading – Since the prevalence of atopy exceeds 20 percent in the general population of many resource-abundant nations, a positive family history for atopic disease can lead to a mistaken diagnosis of AD in an adult presenting with an eczematous eruption. Once the diagnosis of AD is placed in the patient's medical record, further diagnostic considerations may be ignored. As an example, a patient with cutaneous T cell lymphoma may not be biopsied, or appropriate patch testing may not be performed in a patient with allergic contact dermatitis.

●Biopsy of previously treated skin – A potential biopsy diagnostic pitfall is the misdiagnosis of dermatitis treated with potent topical steroids, which may show residual dermal inflammation in the absence of the typical epidermal changes of spongiosis and hyperkeratosis that characterize AD and other eczemas. In these cases, the biopsy report may be signed out as "urticaria" or "urticarial hypersensitivity." (See "Urticarial dermatitis".)

Features suggestive of alternative diagnosis

●Allergic contact dermatitis is the most common condition that may be confused with AD and may occur along with AD. For example, a history of recurrent exacerbations occurring in similar settings (eg, when using a certain topical product or medication or during a particular exposure in a job or recreational situation) suggests concomitant allergic contact dermatitis. (See "Clinical features and diagnosis of allergic contact dermatitis".)

●Scabies should be considered if there is a known household exposure. Scabies also often affects the genital area, which is less commonly affected by AD. In older adults, scabies is often associated with recently being in a long-term care facility. (See "Scabies: Epidemiology, clinical features, and diagnosis".)

●Bullous pemphigoid usually presents with tense bullae and is often localized to areas such as the lower legs. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

●Mycosis fungoides is rarely as widespread as adult AD and tends to present with lesions that are well demarcated from normal skin. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

IDENTIFYING THE CAUSES OF RECALCITRANT DISEASE — Many patients with severe adult eczema have had their condition for a long time, often years. The factors underlying an exacerbation of chronic, severe eczema that should be considered and addressed include lack of adherence to treatment, secondary infection, coexisting allergic contact dermatitis, or photosensitive dermatitis [19].

Lack of adherence to topical treatment/undertreatment — The downsides of topical treatment (messy, time consuming, costly, long term) predictably lead to decreased adherence to treatment over time and persistent or worsening disease. In addition, concerns about adverse effects may lead to inadequate application of the topical medication. Topical corticosteroid phobia, defined as a concern or fear about using topical corticosteroids, is common, with a prevalence among patients and caregivers ranging from 20 to over 80 percent worldwide [20].

Secondary staphylococcal infection — The skin of patients with atopic dermatitis (AD) and other forms of eczema are colonized with Staphylococcus aureus [19]. When a patient with severe eczema has recurrent staphylococcal infections, decolonization should be considered. Frequent bathing with or without bleach, regular use of a chlorinated swimming pool, chlorhexidine showers, and nasal mupirocin can all be helpful to reduce carriage [21]. Pets can be carriers of S. aureus, and tubs of creams can be contaminated with bacteria. Often, family members or cohabitating individuals are S. aureus carriers, and treatment of the whole housing unit can stop frequent infections. (See "Treatment of atopic dermatitis (eczema)", section on 'Management of infection'.)

Allergic contact dermatitis — Concurrent allergic contact dermatitis should be considered in all patients with severe AD, as the impaired skin barrier increases the penetration of potential allergens through the skin and the risk of sensitization [22]. Thus, all patients with severe eczema should be patch tested before they are placed on immunosuppressive treatments, which may lead to false-negative results on patch testing. The allergens found in many topical over-the-counter and prescription products (eg, lanolin, corticosteroids, neomycin, propylene glycol) as well as other common allergens (eg, fragrances, preservatives, and nickel) may complicate AD. (See "Common allergens in allergic contact dermatitis" and "Patch testing".)

Other factors — Factors that may contribute to the increased severity of AD include:

●Photosensitivity – When eczematous dermatitis is severe, minimal amounts of ultraviolet (UV) radiation can trigger a flare in some patients. This may be a clue to the diagnosis of photosensitive eczema or may simply be a manifestation of severe dermatitis. In such patients, aggressive photoprotection with good ultraviolet A (UVA) coverage may improve the eczema, while phototherapy will exacerbate it. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Selection of sunscreen and sun-protective measures".)

●Environmental and psychosocial factors – Exposure to dry climate or sweating can worsen AD. Patients living in a dry environment understandably have more xerosis, resulting in worsening of eczema. In a warm climate and when exercising, some patients may experience increased pruritus and frictional irritation of the skin. Fortunately, most patients with long-standing AD recognize and try to minimize these exposures. Patients often attribute worsening of AD with psychologic stress [23].

●Vitamin D deficiency – Low vitamin D can be associated with increased severity of AD and more frequent skin infections in the patient with AD [24-27].

APPROACH TO MANAGEMENT

Assessment of disease severity and impact on quality of life — Patients with severe refractory atopic dermatitis (AD) that has not responded to standard first-line therapies with emollients and topical corticosteroids typically have widespread disease that limits daily activities, psychosocial functioning, and/or sleep, with a considerable, negative impact on quality of life.

In clinical practice, in addition to visually evaluating the extent and severity of eczema, clinicians may assess the impact of AD on the patient's quality of life by asking open-ended questions on the intensity of symptoms; frequency of flares; and impact of disease on daily activities, psychosocial functioning, and sleep [19]. The burden of treatment, including time spent on treatment, cost of medications, and frequency of health provider visits, should also be assessed.

Several disease severity scales for AD (eg, the Scoring Atopic Dermatitis [SCORAD] index, the Eczema Area and Severity Index [EASI], the Patient-Oriented Eczema Measure [POEM]) and patient quality-of-life measurement scales have been tested and validated for use in clinical trials, but they are not commonly used in clinical practice and may not accurately identify patients who need more aggressive topical therapies or systemic therapies [28].

Patient education — Patients should be educated about their condition and receive detailed instructions on both the regular treatment of their skin and what to do when flares occur [19]:

●Enhancing adherence – Educating patients about their condition and how the prescribed treatment is targeted to the causes of their skin inflammation will enhance compliance. To increase adherence to topical regimens, patients should be provided with medications in a vehicle (ie, ointment, cream, or lotion) they like and will actually use. In addition, patients may be instructed to apply the medication only once daily, since there is limited evidence that more frequent treatment is better [29-32].

●Addressing cost concerns – Cost may be reduced by once-daily application and also by diluting the topical corticosteroid with a moisturizer when used under occlusion (eg, wet wraps). These diluted preparations are not stable long term, but for managing an acute flare that requires large volumes of a topical agent used with occlusion, this can lead to substantial savings without reducing efficacy [33,34].

When is systemic therapy warranted? — The decision to start systemic therapies in adults with severe AD that is not controlled by topical therapy is based upon consideration of disease severity, patient's adherence to topical therapies, frequency of flares, and impact on the patient's quality of life [19,35]. Systemic therapy is warranted in the following situations (algorithm 1):

●Patients who have persistent, severe disease, despite a trial of intensive topical therapy (see 'Intensive topical therapy and phototherapy' below)

●Patients in whom the initial response to intensive topical therapy cannot be maintained with standard topical therapy

●Patients for whom phototherapy is not feasible or acceptable (see 'Phototherapy' below)

Goals of therapy — In adult patients with severe eczema, an improvement (rather than complete clearance) in the signs and symptoms of AD and, especially, a reduction of associated pruritus may be acceptable goals of therapy if the amount of residual disease no longer interferes with daily activities and does not impact the patient's quality of life. As an example, a reduction of approximately 50 percent in pruritus intensity assessed over a period of 24 hours by using the Peak Pruritus Numerical Rating Scale (a scale of 0 to 10, with 0 being "no itch" and 10 being "worst itch imaginable") can be a reasonable goal in adults with recalcitrant AD [36].

INTENSIVE TOPICAL THERAPY AND PHOTOTHERAPY — Soak and smear/wet wrap topical therapy and phototherapy are appropriate initial therapies in adults with severe dermatitis. They can be used in a stepwise manner or in combination.

Soak and smear/wet wraps — A trial of intensive topical therapy (ie, soak and smear or wet wraps) for the initial treatment of patients with severe atopic dermatitis (AD) not controlled by standard topical therapy may be considered in patients who agree to attempt it. These approaches are mainly based on evidence from a limited number of observational studies and low-quality clinical trials in children and adults that have not consistently suggested benefit [37-40]:

●Soak and smear – The patient soaks for 15 minutes in a comfortable tub of water. A high-potency to super high-potency corticosteroid is applied to the whole body, except the groin, axillae, and face, in patients with widespread eczema. In patients with more localized disease, topical corticosteroids may be applied only to affected regions, but the normal skin surrounding the eczematous dermatitis should also be treated. For example, if the eczema is on the lower leg in spots, treat the whole lower leg. Once patients have learned the "soak and smear" approach, they can apply it to break flares of their eczema.

●Wet wrap therapy – For wet wrap therapy, mid-potency to super-potency steroid preparations (groups 1 to 3 (table 2)), usually in an ointment base, are applied to the involved areas. Super-potent corticosteroids may be diluted with a tolerated moisturizer or petrolatum. The treated areas are then occluded with wet wraps (or moist pajamas covered by dry pajamas). The occlusion should be maintained for a minimum of four hours and should initially occur twice daily. The wet layer should not be allowed to dry up. Such therapy applied by skilled nurses in a daycare setting is particularly effective. Crude coal tar ointment can be added to the topical corticosteroids for additional benefit, although staining and odor are not acceptable to many patients [41,42].

Once improvement is achieved, less aggressive topical therapy may control the eczema in some patients. Some experts suggest applying medium- to high-potency topical corticosteroids two to three times per week to normal-appearing skin at sites of frequent flares (proactive therapy) [19]. Those in whom remission cannot be maintained with intermittent use of topical corticosteroids and liberal use of emollients ultimately require a more aggressive approach with phototherapy or systemic therapies.

Phototherapy — If available, feasible, and acceptable to the patient, phototherapy is an option for the treatment of severe adult eczema that is not controlled by intensive topical therapy (algorithm 1). Although narrowband ultraviolet B (NBUVB), ultraviolet A1 (UVA1), or psoralen plus ultraviolet A (PUVA; bath or systemic) have been shown to be effective, we prefer NBUVB and UVA1 over PUVA due to their better safety profile [19,43,44].

Systemic or bath PUVA are treatment options in patients at low risk of skin cancer (skin types 3 to 6 (table 3)) and if treatments are infrequent (see "UVB phototherapy (broadband and narrowband)" and "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy"):

●Administration – Phototherapy is administered two to three times per week initially. The starting doses are generally low and may be administered in combination with aggressive topical treatment as outlined above. (See "UVB phototherapy (broadband and narrowband)", section on 'Treatment initiation, frequency, and dose increments' and 'Soak and smear/wet wraps' above.)

Once weekly or less frequent bath PUVA treatments can control some cases of severe adult eczema. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Bath PUVA'.)

●Supporting evidence – The use of phototherapy for the treatment of severe AD is supported by several randomized trials and systematic reviews [44-46]. Although the included studies were generally of low quality and heterogeneous regarding the severity assessment criteria, irradiation techniques, and outcome measures, all provided some evidence that NBUVB and UVA1 phototherapy are effective for the treatment of severe AD. Whether UVA1 is preferable to NBUVB for the treatment of acute AD remains uncertain, since most of the studies included in systematic reviews did not specify if patients had chronic, severe AD or acute AD exacerbation. The evidence supporting oral or bath PUVA for the treatment of AD is also limited:

•In one randomized, eight-week, crossover trial, 47 participants with moderate to severe AD were randomized to receive medium-dose UVA1 or NBUVB three times per week for six weeks [47]. Intention-to-treat analysis showed that the two treatments were equally effective in reducing pruritus and disease severity. Eczema severity (assessed with the Six Area Six Sign Atopic Dermatitis [SASSAD] score) was reduced from the baseline in both study periods by 44 percent in the UVA1 group and by 39 percent in the NBUVB group.

•In a low-quality, randomized, crossover trial that compared oral PUVA with medium-dose UVA1 for severe, generalized AD, PUVA decreased the severity of disease to a greater extent, led to more rapid improvement, and induced a longer remission period post-treatment [48].

•In another small, randomized, half-side comparison study including 12 patients with severe, chronic AD, bath PUVA was as effective as NBUVB in reducing the signs and symptoms of AD (baseline Scoring Atopic Dermatitis [SCORAD] reduction at six weeks was 66 and 64 percent, respectively) [49].

Combination therapy — The combination of aggressive soak and smear treatment and phototherapy with ultraviolet B (UVB) and crude coal tar (modified Goeckerman regimen) may be helpful in patients for whom phototherapy alone is ineffective. In a small study, five patients with chronic, severe AD unresponsive to NBUVB, broadband UVB, or systemic immunosuppressants were treated in an outpatient setting with daily broadband UVB followed by a topical regimen of crude coal tar and potent or super-potent topical corticosteroids for an average of 27 days [50]. All patients experienced a marked improvement, with an average reduction of the baseline SCORAD score of 75 percent, and remained in remission for 5 to 12 months.

SYSTEMIC THERAPIES — Adults with severe, recalcitrant atopic dermatitis (AD) who are not candidates for or do not respond to intensive topical therapy or phototherapy require systemic therapies (algorithm 1) [19,51-53].

The choice of a systemic treatment depends upon consideration of AD severity, impact on the patient's quality of life, the patient's age and sex, family planning issues, presence of comorbidities, the patient's preferences, and costs. Because some systemic immunosuppressive agents, such as oral cyclosporine, methotrexate, azathioprine, and corticosteroids, are all associated with potentially serious adverse effects and require close clinical and laboratory monitoring, candidates for systemic therapy with these agents must be carefully selected. Newer biologic agents, including dupilumab and tralokinumab, have fewer systemic adverse effects and do not require laboratory monitoring.

First-line therapies — First-line therapies include biologic drugs that block interleukin (IL) 4 and IL-13 or IL-13 alone. Available options in the United States include dupilumab and tralokinumab. If treatment with a biologic agent is not successful, then treatment with an oral conventional (nontargeted) immunosuppressive agent may be considered.

Dupilumab — We suggest dupilumab as first-line systemic treatment for adults with severe AD. Dupilumab is an IL-4/13 receptor-alpha antagonist approved by the US Food and Drug Administration (FDA) and European Medicines Agency for the treatment of adults and children older than six months with moderate to severe AD not adequately controlled with topical prescription therapies:

●Administration – In adults, dupilumab is initially administered subcutaneously as a loading dose of 600 mg, followed by a maintenance dose of 300 mg every two weeks. Laboratory monitoring is not required. In the author's clinical practice, improvement may be noted in the first month of treatment, but three months or more may be required to achieve maximum benefit. Combining dupilumab with an appropriate topical corticosteroid or other topical agent improves response. Dupilumab has been shown to be associated with a reduced risk of skin infections, including eczema herpeticum [54].

●Efficacy – The efficacy of dupilumab for moderate to severe AD in adults and children is supported by several randomized trials [55,56] (see "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'). In one trial, at least a 75 percent improvement from baseline in the Eczema Area and Severity Index (EASI-75) was achieved by approximately 50 percent of patients taking dupilumab compared with approximately 15 percent of patients taking placebo [55]. In a study evaluating the efficacy of dupilumab in 138 consecutive adult patients with difficult-to-treat AD in a real-life setting, treatment with dupilumab for 16 weeks induced a mean reduction in the Eczema Area and Severity Index (EASI) score of 73 percent [57].

●Adverse effects – Dupilumab generally has a favorable safety profile. Frequent adverse effects of dupilumab include injection site reactions, conjunctivitis (up to 37 percent), and facial redness [58-61]. There have been several reports of inflammatory arthritis and enthesitis associated with dupilumab treatment, in most cases occurring during the first few months of treatment [62-64]. Patients should be counseled about the risk of new-onset joint pain, and that if it occurs, it is generally mild and can be conservatively managed without a need to discontinue dupilumab. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

Tralokinumab — Tralokinumab may be an alternative to dupilumab for severe AD in adults. Tralokinumab is a fully human monoclonal anti-IL-13 antibody approved in Europe and the United States for the treatment of adults with moderate to severe AD that is not adequately controlled with topical prescription therapies [65,66].

Tralokinumab is administered subcutaneously as a loading dose of 600 mg once, followed by 300 mg once every other week. Tralokinumab can be used in combination with topical corticosteroids. The efficacy of tralokinumab as monotherapy or in combination with topical corticosteroids has been evaluated in randomized trials [65,66] (see "Treatment of atopic dermatitis (eczema)", section on 'Tralokinumab'). Adverse effects of tralokinumab include viral upper respiratory infection, headache, conjunctivitis, and exacerbation of AD.

Second-line therapies

Methotrexate — Methotrexate is the author's preferred agent for long-term control of severe AD in adult and older adult patients unable or unwilling to use biologic agents and in whom the risk of adverse effects with methotrexate is small:

●Dosing and monitoring – Methotrexate is usually administered in a single weekly dose of 7.5 to 25 mg in combination with daily supplementation with folic acid 1 mg to reduce the risk of several common methotrexate toxicities. (See "Major side effects of low-dose methotrexate".)

Laboratory monitoring, including complete blood count and renal and liver function, is required (see "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease"). New methods for monitoring for liver fibrosis, such as serum amino terminal peptide of type III procollagen and ultrasound-based transient elastography, have reduced the need for liver biopsies [67,68]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

●Duration of treatment – The effect of methotrexate usually starts after a few weeks but may be delayed. The maximum benefit is often not seen for several months. Methotrexate is thus not a first-line treatment but is typically started while tapering other therapies (eg, cyclosporine or systemic corticosteroids) with rapid onset of action.

●Supporting evidence – In a small, randomized trial including 42 adults with AD who were unresponsive or intolerant to cyclosporine, methotrexate and azathioprine were similarly effective in reducing eczema severity [69]. Patients were treated for 12 weeks and permitted to use topical corticosteroids and oral antihistamines. At the end of 12 weeks, the severity of eczema as assessed by the Scoring Atopic Dermatitis (SCORAD) score decreased by approximately 40 percent in both groups. Treatment was continued by 95 percent of patients in the methotrexate group and 84 percent of patients in the azathioprine group, with reduction in the SCORAD score at 24 weeks of 48 and 43 percent, respectively. Adverse events, none of which were serious, included infections, gastrointestinal upset, and increased liver enzyme levels and occurred in equal proportion in both treatment groups, although lymphocytopenia occurred more frequently in the azathioprine group than in the methotrexate group. Among the 35 patients who continued, interrupted, or switched treatment (reflecting real-life clinical practice) and were followed up at three-month intervals for an additional two years, the clinical response was maintained at two years in both groups (SCORAD index reduced by 63 and 53 percent in the methotrexate and azathioprine groups, respectively) [70].

Oral JAK inhibitors — Abrocitinib and upadacitinib are oral selective Janus kinase (JAK) inhibitors approved in Europe, the United States, and other countries for the treatment of AD in adults whose disease is not controlled with other systemic therapies, including biologics, or when the use of those therapies is not indicated [71-73]:

●Dosing – Abrocitinib is given at the dose of 100 mg once daily. For insufficient response after 12 weeks, the dose can be increased to 200 mg once daily.

Upadacitinib is given at the dose of 15 mg once daily. The dose can be increased to 30 mg once daily if the response is inadequate.

●Efficacy – The efficacy of abrocitinib and upadacitinib for the treatment of AD is supported by several randomized trials [71,74]. (See "Treatment of atopic dermatitis (eczema)", section on 'JAK inhibitors'.)

●Adverse effects – Frequent adverse effects of abrocitinib and upadacitinib reported in AD trials include nausea, acne, headache, nasopharyngitis, and AD flares. Long-term studies of the safety of these agents in patients with AD are lacking. However, based on data from a large, randomized safety trial of patients with rheumatoid arthritis, the US FDA issued a boxed warning for oral JAK inhibitors regarding the increased risk of serious infections, major cardiovascular events (eg, heart attack, stroke), cancer (eg, lymphoma, lung cancer), thrombosis, and death [75].

Third-line therapies — Third-line therapies include a short course of systemic corticosteroids, cyclosporine, mycophenolate mofetil (MMF), and azathioprine. Due to their adverse effects, these agents should be used for a limited period of time as rescue therapy for immediate relief of acute flares or bridge therapy to other agents relatively safer to use over a prolonged period, if needed [19]. (See "Major adverse effects of systemic glucocorticoids".)

Short-term systemic corticosteroids — There is a general consensus among experts that systemic corticosteroids should be generally avoided for the management of AD due to adverse effects of prolonged use and risk of rebound flares when interrupted [76]. However, they can occasionally be used for a short period of time in the following circumstances [76]:

●When other options are not available or contraindicated

●As a bridge therapy to other systemic therapies or phototherapy

●For the immediate relief of acute flares

●In the most severe cases

These principles are in agreement with most clinical practice guidelines [77-81]. The dose and duration of a "short course" of systemic corticosteroids have not been determined. The European Task Force on Atopic Dermatitis/European Academy of Dermatology and Venereology Task Force position statement on the treatment of AD suggests that a typical regimen of systemic corticosteroids might be methylprednisolone 0.5 mg/kg per day for one to two weeks tapered over one month [79].

We typically prescribe prednisone 40 to 60 mg per day for one week and taper the dose over the following two to three weeks. While systemic corticosteroids are tapered off, patients are transitioned to another systemic agent with a better safety profile (eg, biologics or methotrexate) for long-term treatment.

Cyclosporine — Cyclosporine is an option for severe AD in adults who do not have obvious contraindications to its use and who will benefit from a rapid resolution of symptoms [82]. Contraindications to the use of cyclosporine include abnormal renal function, uncontrolled hypertension, uncontrolled infection, and concurrent malignancy (see "Pharmacology of cyclosporine and tacrolimus"):

●Dosing – The cyclosporine dose ranges from 2.5 to 5 mg/kg per day. Besides systemic corticosteroids, cyclosporine is the most rapidly acting and effective agent for the management of severe AD. The dermatitis often begins to improve as quickly as within the first week, and the degree of improvement can be dramatic (approaching 100 percent) in eight weeks. Itching improves within days.

●Treatment duration – Long-term use of cyclosporine (ie, beyond one year) is limited by its side effects, mainly hypertension and kidney toxicity, especially in older adults. Moreover, as relapse can be very rapid after discontinuation of treatment, many patients will need to be transitioned to an immunosuppressive agent with a better safety profile while discontinuing cyclosporine.

As an example, patients who are stable on cyclosporine may also be given a low dose of methotrexate (eg, 5 to 10 mg per week) for three weeks. The cyclosporine dose is then halved, and the methotrexate dose is increased to 15 to 20 mg per week. After two weeks, cyclosporine is discontinued. During this period of dual immunosuppression, prophylaxis to prevent Pneumocystis pneumonia should be considered. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

●Supporting evidence – The efficacy of cyclosporine for the treatment of AD is supported by several randomized trials and systematic reviews [52,82-84]:

•In a 2013 systematic review, 14 trials evaluated the efficacy of cyclosporine versus placebo or other systemic immunomodulating agents (eg, intravenous immunoglobulins [IVIGs], prednisolone, MMF) [84]. After short-term treatment ranging from 10 days to 8 weeks, cyclosporine was found to be more effective than placebo in all trials, with a mean improvement from baseline of 50 to 95 percent in different clinical severity scores. In head-to-head trials, cyclosporine was found to be more effective than prednisolone and IVIG and as effective as MMF. Higher doses (5 mg/kg per day) induced a more rapid response than lower doses (2.5 to 3 mg/kg per day).

•One well-performed, randomized trial compared prednisolone with cyclosporine in 38 adults with severe AD [85]. Treatment consisted of a two-week tapering dose of oral prednisolone with a constant daily dose of cyclosporine for six weeks; patients were allowed to use a mid-potency topical corticosteroid, emollients, and oral antihistamines. The authors noted that this regimen reflects a common treatment approach in clinical practice. The primary outcome measure was the proportion of patients with stable remission, defined as improvement in the SCORAD index of at least 50 percent relative to baseline at week 2 in the prednisolone group and week 6 in the cyclosporine group and no flare within a 12-week follow-up. Although the response rate was not significantly different in the two groups at the end of the active treatment period, the relapse rate during the 12-week follow-up was much higher in the prednisolone group than in the cyclosporine group (89 versus 45 percent, respectively).

Mycophenolic acid/mycophenolate mofetil — Mycophenolate mofetil (MMF) and mycophenolic acid (MPA) can be considered as treatment options in patients in whom other immunosuppressive agents are not tolerated or are contraindicated. MMF and MPA are usually very well tolerated, and laboratory abnormalities are infrequent. Common adverse effects include fatigue, flu-like symptoms, and gastrointestinal upset. MMF and MPA are typically given at a dose of 1 to 2 g/day and 720 to 1440 mg/day, respectively. The response to treatment is usually delayed, often not seen before six to eight weeks.

The response to MMF and MPA seems to be dependent on a uridine diphosphate glucuronosyltransferase 1-9 (UGT1A9) polymorphism affecting the metabolism of the medication [86]. Approximately 85 percent of individuals who carry this polymorphism are nonresponders [86]. Patients who respond to treatment usually tolerate long-term therapy, given the relatively good toxicity profile of these agents. Nausea (reduced with enteric-coated mycophenolate sodium [EC-MPS]) is the most common adverse effect. At high doses, usually above 2 g per day, rest tremor can occur.

The evidence supporting the use of MMF for AD is limited and mainly based upon small, observational studies [87]. No randomized trials have evaluated its efficacy as first-line treatment for severe AD. One small trial compared EC-MPS with cyclosporine as a maintenance treatment in 55 adult patients with AD unresponsive to potent topical corticosteroids [88]. All patients were treated for a six-week run-in period with cyclosporine 5 mg/kg per day to achieve rapid remission and then randomized to cyclosporine 3 mg/kg per day or EC-MPS 1440 mg per day for 30 weeks. The severity of eczema, measured using the SCORAD index, was comparable in both study arms until the end of the maintenance phase. After treatment discontinuation, relapse was more rapid in the cyclosporine group than in the EC-MPS group. There were no serious adverse events.

Azathioprine — Azathioprine is an additional option for the treatment of severe AD in adults:

●Dosing – The starting dose is 2 to 3 mg/kg. A baseline thiopurine methyltransferase (TPMT) should be performed before initiating the treatment to determine if dose adjustment is required. Clinical response is seen on average in four weeks but may not be seen for six to eight weeks. Long-term use of azathioprine can be associated with lymphopenia, progressive anemia, and transient elevation of liver enzymes.

●Efficacy – The efficacy of azathioprine for the treatment of AD has been evaluated in a few randomized trials [69,89,90]:

•One small trial including 37 patients with severe AD reported a reduction of 26 percent in the Six Area Six Sign Atopic Dermatitis (SASSAD) score in patients treated with azathioprine compared with 3 percent in patients treated with placebo [89]. However, 16 of 37 patients (43 percent) withdrew from the study. Adverse effects of azathioprine included nausea, vomiting, and gastrointestinal disturbances.

•In a small, randomized trial including 42 adults with AD, methotrexate and azathioprine were similarly effective in reducing eczema severity [69]. At 12 weeks, both treatments induced a 40 percent reduction of the SCORAD score. (See 'Methotrexate' above.)

•In another trial, 63 patients with active AD not controlled by optimal topical therapy were treated with azathioprine (1 mg/kg daily or 2.5 mg/kg daily in patients with reduced or normal TPMT activity, respectively) or placebo [90]. After 12 weeks, the SASSAD score was reduced by 37 percent in the azathioprine group compared with 20 percent in the placebo group. Azathioprine was generally well tolerated. However, two patients developed a drug hypersensitivity reaction.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atopic dermatitis".)

SUMMARY AND RECOMMENDATIONS

●Clinical phenotypes of atopic dermatitis in adults – In adults, atopic dermatitis (AD; eczema) may present as a chronic, persistent form of childhood AD; a relapsing form of childhood AD that had apparently resolved; or, less commonly, as "adult-onset" AD. (See 'Clinical phenotypes in adults' above.)

●Patient evaluation – When evaluating an adult patient with new-onset dermatitis that is persistent and relapsing, the diagnosis of AD should be made with caution, as a variety of skin conditions may present as an eczematous dermatitis in adulthood (table 1). Once the diagnosis of AD is confirmed, the causes of recalcitrant disease should be considered and addressed. (See 'Patient evaluation' above.)

●Approach to management – Our approach to the management of adult patients with severe, recalcitrant AD is as follows (algorithm 1):

•We suggest an initial trial of intensive topical therapy with corticosteroids (ie, soak and smear or wet wraps) rather than systemic therapy for patients who agree to attempt it (Grade 2C). Narrowband ultraviolet B (NBUVB) therapy can be an alternative or an adjunct to intensive topical therapy. (See 'Intensive topical therapy and phototherapy' above and 'Phototherapy' above.)

•For patients who are unwilling or unable to attempt a trial of intensive topical therapy and/or phototherapy and for those who do not improve with such treatments, we suggest dupilumab as first-line systemic therapy rather than other systemic agents (Grade 2C). Dupilumab, an interleukin (IL) 4/13 inhibitor, is the treatment of choice for such patients because it has a favorable safety profile, has been shown to be effective in this setting, and can be used for long-term control of symptoms. Tralokinumab, an IL-13 inhibitor, may be an alternative to dupilumab. (See 'Dupilumab' above and 'Tralokinumab' above.)

•For patients unable or unwilling to use biologic agents and in whom the risk of adverse effects is small, methotrexate is the author's preferred agent. Oral abrocitinib and upadacitinib (small molecule Janus kinase [JAK] inhibitors) can be an alternative option. However, due to the increased risk of serious infections, major cardiovascular adverse events, and cancer associated with JAK inhibitors, benefits and risks of treatment should be carefully evaluated in the individual patient. (See 'Oral JAK inhibitors' above.)