INTRODUCTION — It is estimated that 2 to 5 percent of adults and older adults have atopic dermatitis (AD) [1-5]. A prevalence of approximately 9 percent has been estimated in persons older than 75 years [4]. In adults, AD may present as a chronic, persistent form of childhood AD, a relapsing form of childhood AD that had apparently resolved, or, less commonly, "adult-onset" AD [6-9]. Whether adult-onset AD is a distinct phenotypic variant of AD is unclear [10]. In patients over 50 with no history of childhood AD, new-onset, atopic-like dermatitis has been called idiopathic "chronic eczematous eruption of aging" (CEEA) [11]. Patients may report AD as first appearing in adulthood for several reasons [12]: 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. In most cases, adult AD appears before the age of 40 years and is often a recalcitrant, difficult-to-treat condition [1,12].

AD, as well as most forms of eczematous dermatitis, is characterized by three primary components: barrier failure, inflammatory immune response, and pruritus. Specific therapies should be directed at each of these components and include aggressive topical treatment with wet wraps and soaks, phototherapy, and systemic immunomodulators [13-15].

This topic will discuss the management of severe AD in adults. The treatment of AD in children is discussed separately. (See "Treatment of atopic dermatitis (eczema)" and "Management of severe atopic dermatitis (eczema) in children".)

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 confirm the diagnosis of AD are (see "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis'):

●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)) [16].

●The morphology is characteristic of AD with lichenified plaques, excoriations, and a propensity for secondary staphylococcal infection (picture 5A-D).

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

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

●AD can coexist with an exogenous dermatitis, such as allergic contact dermatitis or photodermatitis.

●Young adult AD patients can develop lesions with a nummular morphology [17]. However, adult men 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".)

●Drug eruptions, bullous pemphigoid, allergic contact dermatitis, 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 "Exanthematous (maculopapular) drug eruption" and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Clinical features and diagnosis of allergic contact dermatitis" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●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" (CEEA) [18]. 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 Th2 reaction pattern in the skin similar to AD [19].

Potential diagnostic pitfalls — Since the prevalence of atopy exceeds 20 percent in the general population of many developed nations, a positive family history for atopic disease can lead to a mistaken diagnosis of AD in an adult patient 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.

Moreover, the various skin conditions that may present in adulthood as an eczematous dermatitis (table 1) have the histopathologic features of acute or chronic dermatitis identical to AD. Thus, sequential biopsies and additional tests may be required for certain diagnoses, such as mycosis fungoides or bullous pemphigoid. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Another potential diagnostic pitfall of biopsy 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."

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 [13]:

Lack of compliance with topical treatment and undertreatment — Topical treatment of severe eczematous dermatitis may be messy, time consuming, costly, and is required daily, often for years. In addition, topical therapies are often marginally effective in chronic lichenified eczema. These downsides of topical treatment 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 AD and other forms of eczema are colonized with Staphylococcus aureus [13]. The superantigens of the bacteria enhance the immune response in the skin and reduce the response to topical therapy. When a severe eczema patient has recurrent staphylococcal infections, decolonization should be considered. Frequent bathing with or without bleach, regular use of a 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 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 — In patients with severe AD, the impaired skin barrier increases the penetration of potential allergens through the skin and the risk of sensitization [22]. The allergens found in many topical over-the-counter and prescription products (eg, lanolin, corticosteroids, propylene glycol) as well as other common allergens (eg, fragrances, preservatives, and nickel) may complicate AD. Every effort should be made to patch test patients with severe eczema before they are placed on immunosuppressive treatments that would lead to false-negative results on patch testing. (See "Common allergens in allergic contact dermatitis" and "Patch testing".)

Other factors — Factors that may contribute to 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. Phototherapy will exacerbate such patients until their skin is improved. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Selection of sunscreen and sun-protective measures".)

●Environmental and psychosocial factors – Patients living in a dry environment understandably have more xerosis. In a warm climate and when exercising, increased pruritus and frictional irritation of the skin may occur. 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].

Assessment of disease severity — Patients with severe refractory AD typically have widespread disease that limits daily activities, psychosocial functioning, and/or sleep, with a considerable negative impact on quality of life, and that has not responded to standard first-line therapies with emollients and topical corticosteroids. Several disease severity scales for AD (eg, the Scoring of Atopic Dermatitis [SCORAD] index and the Eczema Area and Severity Index [EASI]) 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].

In a practical guide to visual assessment of eczema severity that also includes the evaluation of disease impact on quality of life and psychosocial wellbeing proposed by the United Kingdom National Institute for Health and Care Excellence, severe AD is defined as "widespread areas of dry skin, incessant itching, redness (with or without excoriation, extensive skin thickening, bleeding, oozing, cracking, and alteration of pigmentation), severe limitation of everyday activities and psychosocial functioning, [and] nightly loss of sleep" [29].

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, impact of disease on daily activities, psychosocial functioning, and sleep [13]. The burden of treatment, including time spent on treatment, cost of medications, and frequency of health provider visits, should also be assessed.

APPROACH TO MANAGEMENT

Patient education — Educating patients about their condition and how the prescribed treatment is targeted to the causes of their skin inflammation will enhance compliance. Patients should be educated on both the regular treatment of their skin and what to do when flares occur [13]. To enhance 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 [30-33]. 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 [34,35].

When is systemic therapy warranted? — The decision to start systemic therapies in adults with severe atopic dermatitis (AD) that is not controlled by topical therapy is based upon consideration of disease severity, frequency of flares, and impact on the patient's quality of life. Because 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 must be carefully selected. A reasonable approach to identify patients in whom systemic therapy is warranted involves a trial of intensive topical therapy and, if available and acceptable to the patients, phototherapy [13,14]. (See 'Intensive topical therapy' below.)

Systemic therapy is warranted in the following situations (algorithm 1):

●Patients who have persistent severe disease, despite a trial of intensive topical therapy

●Patients for whom phototherapy is not feasible or acceptable

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

Goals of therapy — In adult patients with severe eczema, a reduction (rather than complete clearance) in the signs and symptoms of AD, and in particular of the associated pruritus, may be an acceptable goal of therapy if the amount of residual disease no longer interferes with daily activities. 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 — The two forms of topical therapy that can be effective in severe eczema cases are soak and smear/wet wrap therapy and phototherapy. They can be used in a stepwise manner or in combination.

Soak and smear/wet wraps — We suggest 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, rather than phototherapy or systemic therapies. These approaches are mainly based on evidence from a limited number of studies in children and adults [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 initially should occur twice daily. 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 [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) [13]. 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, we suggest phototherapy 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 [13,43,44]. (See "UVB therapy (broadband and narrowband)" and "UVA1 phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

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

Initial benefit is usually seen after a minimum of 10 treatments, and up to 24 treatments are required to judge whether phototherapy will be adequate to control severe eczema. A home light unit may be considered for patients with severe adult eczema who respond well to phototherapy. Since long-term light treatment to control eczema is limited by the time commitment (a minimum of once-a-week treatment is usually required), a home light unit may address this problem. A home light unit is a cost-effective approach compared with immunosuppressive therapies.

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. Bath PUVA avoids the need for eye protection. 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'.)

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. 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. 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 limited. 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 failing phototherapy alone. 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) that is not controlled by intensive topical treatment or phototherapy and those for whom phototherapy is not a viable option require systemic therapies (algorithm 1) [13,51-53].

Choice of treatment — 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.

A rational approach involves the initial use of an agent with rapid onset of action (eg, oral cyclosporine, oral corticosteroids) to achieve rapid control of symptoms. Due to their adverse effects, these agents should be used for a limited period of time as a rescue therapy for immediate relief of acute flares or bridge therapy to other agents relatively safer to use over a prolonged period, if needed [13]. (See "Major side effects of systemic glucocorticoids".)

Cyclosporine — We suggest cyclosporine rather than systemic corticosteroids as first-choice systemic therapy for AD and other severe eczemas in adults who do not have obvious contraindications to its use and who will benefit from a rapid resolution of symptoms [54]. Contraindications to the use of cyclosporine include abnormal renal function, uncontrolled hypertension, uncontrolled infection, and concurrent malignancy. (See "Pharmacology of cyclosporine and tacrolimus".)

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.

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 (see 'Methotrexate' below). 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'.)

The efficacy of cyclosporine for the treatment of AD is supported by several randomized trials and systematic reviews [52,54-56].

In a 2013 systematic review, 14 trials evaluated the efficacy of cyclosporine versus placebo or other systemic immunomodulating agents (eg, intravenous immunoglobulins [IVIGs], prednisolone, mycophenolate mofetil) [56]. 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 mycophenolate mofetil. 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 [57]. 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 Scoring Atopic Dermatitis (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).

Systemic corticosteroids — In patients with severe AD in whom the use of oral cyclosporine is contraindicated, we suggest a short course of a moderate dose of a systemic corticosteroid for the rapid control of symptoms. 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 immunosuppressive agent with a better safety profile (eg, methotrexate) for long-term treatment.

Systemic corticosteroids are frequently used in clinical practice for the treatment of severe AD in children and adults, despite a paucity of studies evaluating their role in the management of AD [57-59]. Although there is a general consensus among experts that systemic corticosteroids should be generally avoided, particularly in children and adolescents, they can be occasionally used for a short period of time in the following circumstances [60]:

●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 [61-65]. However, 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 [63].

Methotrexate — Methotrexate is the author's preferred agent for long-term control of severe AD in adult and older adult patients. 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".)

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 and azathioprine were similarly effective in reducing eczema severity in a small randomized trial including 42 adults with AD who were unresponsive or intolerant to cyclosporine [66]. 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 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 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 in the azathioprine groups, respectively) [67].

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 [68,69]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic tests".)

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

The efficacy of azathioprine for the treatment of AD has been evaluated in a few randomized trials [66,70,71]. 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 those treated with placebo [70]. However, 16 of 37 patients (43 percent) withdrew from the study. Adverse effects of azathioprine included nausea, vomiting, and gastrointestinal disturbances. 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 [71]. 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.

Long-term use of azathioprine can be associated with lymphopenia, progressive anemia, and transient elevation of liver enzymes.

Other therapies

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 (UDP)-glucuronosyltransferase 1-9 (UGT1A9) polymorphism affecting the metabolism of the medication [72]. Approximately 85 percent of individuals who carry this polymorphism are nonresponders [72]. Patients who respond to treatment usually tolerate a 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 [73]. 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 [74]. 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.

Dupilumab — Dupilumab is an interleukin (IL) 4 receptor alpha antagonist approved by the US Food and Drug Administration and by the European Medicine Agency for the treatment of adults and children older than six years with moderate to severe AD not adequately controlled with topical prescription therapies. In adults, dupilumab is initially administered as a loading dose of 600 mg given by subcutaneous injection, followed by a maintenance dose of 300 mg every two weeks. Laboratory monitoring is not required.

The efficacy of dupilumab is supported by several manufacturer-sponsored trials involving now more than 1300 patients [75,76] (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 those taking placebo [75]. Weekly dosing of 300 mg does not improve overall response, rate of response, or degree of pruritus reduction [75,77].

However, the efficacy of dupilumab for the treatment of severe, recalcitrant eczema remains unclear. In fact, the trials included a large proportion (over 50 percent) of patients with moderate AD, and no preplanned or post-hoc subgroup analysis was performed to assess the efficacy of dupilumab in patients with severe disease [78]. Adverse effects of dupilumab include injection-site reactions, conjunctivitis, and headache [79]. Dupilumab has been shown to be associated with a reduced risk of skin infections, including eczema herpeticum [80].

The early experience with dupilumab in the author's clinical practice has mirrored the results of published trials. However, the high cost of this agent limits its use as first-line therapy. 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.

INEFFECTIVE THERAPIES

Rituximab, ustekinumab, omalizumab — Despite initial anecdotal reports of efficacy in atopic dermatitis (AD), rituximab, ustekinumab, and omalizumab have failed to produce benefit reproducibly and are not recommended for the treatment of adult eczemas [81-86].

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

●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, "adult-onset" AD. (See 'Introduction' above.)

●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.)

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

•For most patients with severe, recalcitrant AD, we suggest an initial trial of intensive topical therapy with corticosteroids (ie, soak and smear or wet wraps) rather than systemic immunosuppressive therapy. (Grade 2C). (See 'Intensive topical therapy' above.)

•For patients with severe eczema that is not controlled by intensive topical therapy, we suggest phototherapy if it is available, feasible, and acceptable to the patient (Grade 2B). We prefer phototherapy with narrowband ultraviolet B (NBUVB) due to its superior safety profile. NBUVB can be used alone or in combination with intensive topical corticosteroid therapy. (See 'Phototherapy' above and 'Combination therapy' above.)

•For patients who do not improve with intensive topical therapy and/or phototherapy, we suggest starting systemic treatment with oral cyclosporine rather than other systemic therapies (Grade 2B). Once improvement is achieved and stable, patients can be transitioned to an immunosuppressive agent with a better long-term safety profile while discontinuing cyclosporine. (See 'Cyclosporine' above.)

•In patients with severe AD in whom the use of oral cyclosporine is contraindicated, we suggest a short course of a moderate dose of a systemic corticosteroid for the rapid control of symptoms (Grade 2C). (See 'Systemic corticosteroids' above.)

•For long-term control of symptoms, we suggest low-dose methotrexate rather than azathioprine (Grade 2C). The two agents appear to be equally effective, but methotrexate is generally better tolerated. (See 'Systemic corticosteroids' above and 'Methotrexate' above.)

•Dupilumab, an interleukin (IL)-4 receptor alpha antagonist approved for the treatment of adult patients with moderate to severe AD, is an additional treatment option, but cost may be a limitation to its use. (See 'Dupilumab' above.)