# Atopic Dermatitis - Pathogenesis and Management

## Epidemiology

Atopic dermatitis is one of the most common chronic inflammatory skin diseases, affecting 15 to 20 percent of children and 7 to 10 percent of adults worldwide. The onset is characteristically early in life, with 60 percent of cases presenting within the first year and 90 percent manifesting by age 5, though de novo adult-onset atopic dermatitis is increasingly recognized. Atopic dermatitis frequently occupies the initial position in the "atopic march," a temporal progression in which atopic dermatitis precedes the development of food allergy, allergic rhinitis, and asthma. The quality-of-life impact is substantial, encompassing chronic sleep disruption, psychosocial burden, and impairment comparable to other major chronic diseases. The annual healthcare cost in the United States exceeds 5 billion dollars.

## Pathogenesis

### Skin Barrier Dysfunction

The pathogenesis of atopic dermatitis involves a complex interplay between skin barrier dysfunction and immune dysregulation, with the barrier defect increasingly recognized as a primary initiating event. Filaggrin (FLG) loss-of-function mutations represent the strongest identified genetic risk factor for atopic dermatitis. Filaggrin is a critical structural protein in the stratum corneum whose breakdown products, including pyrrolidone carboxylic acid and urocanic acid, serve essential roles in maintaining skin hydration and the acidic pH of the skin surface. The most common mutations in European populations, R501X and 2282del4, have a prevalence of 8 to 10 percent in the general population. FLG mutations confer an odds ratio of 3 to 5 for developing atopic dermatitis and additionally increase the risk of peanut allergy and asthma through enhanced transcutaneous allergen sensitization. However, approximately 50 percent of atopic dermatitis patients carry FLG mutations, meaning that the other half develop barrier dysfunction through alternative mechanisms.

Additional components of barrier dysfunction include reduced levels of ceramides, which are key lipid components of the lamellar bodies in the stratum corneum; decreased production of antimicrobial peptides such as cathelicidins and beta-defensins, rendering the skin more susceptible to microbial colonization and infection; tight junction dysfunction with downregulation of claudin-1, increasing transepidermal water loss (TEWL); and elevated skin surface pH, which impairs lipid processing, activates kallikrein serine proteases that further degrade barrier components, and favors colonization by Staphylococcus aureus.

### Type 2 Immune Dysregulation

Interleukin-4 and interleukin-13 are the central cytokines driving the immunopathology of atopic dermatitis, exerting effects that create self-amplifying vicious cycles. These cytokines suppress expression of filaggrin and loricrin, further compromising the skin barrier; promote IgE class switching in B cells; suppress antimicrobial peptide production, increasing infection susceptibility; and promote pruritus through direct activation of sensory neurons. Interleukin-31, often termed the "itch cytokine," is produced predominantly by Th2 cells and activates IL-31 receptor A on sensory nerve endings, providing a key link between the immune response and the dominant symptom of pruritus. Nemolizumab, an anti-IL-31RA monoclonal antibody, has demonstrated rapid and significant reduction in pruritus scores.

Epithelial alarmins, including interleukin-33 and TSLP, are released by damaged keratinocytes and amplify the type 2 response. Interleukin-22, produced by Th22 cells, drives the epidermal hyperplasia (acanthosis) that characterizes chronic atopic dermatitis lesions. Interleukin-13 also drives periostin production, which promotes fibrosis in chronically inflamed skin. Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that contribute significantly to local type 2 cytokine production independent of adaptive immune activation.

### Microbial Dysbiosis

The skin microbiome is profoundly disrupted in atopic dermatitis. Staphylococcus aureus colonizes more than 90 percent of atopic dermatitis patients, compared with only approximately 5 percent of healthy individuals. S. aureus produces superantigens, including staphylococcal enterotoxins A and B (SEA, SEB) and toxic shock syndrome toxin-1 (TSST-1), which trigger polyclonal T cell activation and mast cell degranulation, amplifying inflammation. During disease flares, there is a dramatic loss of microbial diversity with predominance of S. aureus, and the degree of S. aureus dominance correlates with disease severity. Commensal protective species, including S. epidermidis and S. hominis, which produce antimicrobial peptides that help control S. aureus, are reduced in atopic dermatitis. In patients with head and neck-predominant atopic dermatitis, the lipophilic yeast Malassezia may drive IgE-mediated inflammatory responses.

<image>A multi-layer diagram showing the pathogenesis of atopic dermatitis. Top layer: external environment with allergens, irritants, microbes (S. aureus prominently shown). Second layer: epidermis showing disrupted stratum corneum with reduced filaggrin (gaps in cornified envelope), decreased ceramides in lamellar bodies, widened tight junctions, and transepidermal allergen penetration. Third layer: dermis showing the immune cascade - DCs capturing allergens and presenting to Th2 cells, which produce IL-4, IL-13, IL-31. ILC2s activated by IL-33 and TSLP from keratinocytes. Arrows showing: IL-4/IL-13 suppressing filaggrin (vicious cycle), IL-31 activating sensory nerve (itch-scratch cycle), IL-5 recruiting eosinophils, IL-4 driving B cell IgE switching. Bottom: S. aureus superantigens activating T cells. Feedback loops clearly indicated with circular arrows.</image>

## Clinical Features

### Age-Dependent Distribution

The distribution of atopic dermatitis lesions changes characteristically with age. In infants, involvement typically affects the face (cheeks and forehead), scalp, and extensor surfaces, with characteristic sparing of the diaper area. In older children, the distribution shifts to flexural surfaces, including the antecubital and popliteal fossae, wrists, ankles, and neck. In adults, flexural involvement persists, but involvement of the hands, eyelids, and head and neck region becomes more prominent, and a nummular (coin-shaped) pattern may emerge. Across all ages, pruritus is the hallmark symptom and is considered the sine qua non of the disease; its presence is required for diagnosis.

### Diagnostic Criteria (Hanifin-Rajka)

The diagnosis of atopic dermatitis is clinical, with the widely used Hanifin-Rajka criteria requiring three of four major criteria: pruritus, typical morphology and distribution for age, a chronic or relapsing course, and a personal or family history of atopy. Additionally, three or more minor criteria should be present, selected from a list that includes xerosis, ichthyosis vulgaris, immediate skin test reactivity, elevated serum IgE, early age of onset, tendency toward cutaneous infections, Dennie-Morgan infraorbital folds, keratoconus, anterior subcapsular cataracts, and periorbital darkening.

### Severity Assessment

Several validated instruments exist for severity assessment. The SCORAD (SCORing Atopic Dermatitis) index incorporates extent of involvement using the rule of nines, intensity measured across six items, and subjective symptoms, with scores below 25 classified as mild, 25 to 50 as moderate, and above 50 as severe. The EASI (Eczema Area and Severity Index) evaluates four body regions across four signs (erythema, induration/papulation, excoriation, and lichenification), with scores of 1 to 7 classified as mild, 7 to 21 as moderate, 21 to 50 as severe, and above 50 as very severe. The Investigator Global Assessment (IGA) provides a simple 0-to-4 scale used widely in clinical trials. The Patient-Oriented Eczema Measure (POEM) is a validated patient-reported outcome measure comprising seven questions.

## Management

### Foundational Therapy (All Patients)

Emollient therapy is the cornerstone of atopic dermatitis management at every severity level. Emollients should be applied liberally at least twice to three times daily, with ointments providing the greatest occlusive capacity, followed by creams and then lotions. Application within 3 minutes of bathing ("soak and seal") maximizes moisturizer efficacy by trapping water in the skin. Ceramide-containing moisturizers may offer additional benefit by directly replenishing a deficient barrier lipid. Bathing practices should include daily lukewarm baths of 5 to 10 minutes using gentle non-soap cleansers with a pH of 5 to 6. Identified irritants and relevant allergens should be avoided, along with extreme temperatures.

Dilute bleach baths, prepared by adding one-half cup of household bleach (6 percent sodium hypochlorite) to a full bathtub of water (approximately 40 gallons), performed 2 to 3 times weekly, reduce Staphylococcus aureus colonization on the skin. Meta-analysis by Chopra and colleagues demonstrated a number needed to treat of 4 for clinical improvement in moderate atopic dermatitis, supporting this as an evidence-based adjunctive measure.

### Topical Anti-Inflammatory Therapy

Topical corticosteroids remain the first-line anti-inflammatory therapy for atopic dermatitis. Potency selection should be matched to the body site and disease severity: low-potency agents (hydrocortisone 1 to 2.5 percent) for the face, intertriginous areas, and infants; medium-potency agents (triamcinolone 0.1 percent, mometasone 0.1 percent) for the trunk and extremities; high-potency agents (fluocinonide 0.05 percent, betamethasone dipropionate 0.05 percent) for thick or lichenified areas and palms and soles; and super-high-potency agents (clobetasol 0.05 percent) for short-term rescue only, never on the face or skin folds. Proactive therapy, in which topical corticosteroids are applied two times per week to previously affected areas during remission, has been proven to significantly reduce flare frequency and represents a key underutilized strategy. Adverse effects of topical corticosteroids include skin atrophy, striae, telangiectasia, perioral dermatitis, and hypothalamic-pituitary-adrenal axis suppression when potent agents are used over large body surface areas.

Topical calcineurin inhibitors provide a steroid-sparing alternative particularly valuable for sensitive areas. Tacrolimus is available as 0.03 percent ointment for children aged 2 years and older and 0.1 percent ointment for adults, with particular efficacy on the face and eyelids. Pimecrolimus 1 percent cream is a milder formulation approved for patients aged 2 years and older. These agents carry no risk of skin atrophy, though initial burning and stinging upon application is common. The FDA boxed warning for theoretical lymphoma risk has not been substantiated by long-term epidemiologic data. Proactive use of topical calcineurin inhibitors 2 to 3 times weekly is effective for relapse prevention.

Crisaborole 2 percent ointment is a topical phosphodiesterase-4 inhibitor approved for mild to moderate atopic dermatitis in patients aged 3 months and older, with application-site stinging in approximately 5 percent of patients. Ruxolitinib 1.5 percent cream is a topical JAK1/2 inhibitor approved for mild to moderate atopic dermatitis in patients aged 12 years and older. It provides rapid itch relief, often within 12 hours, and is applied twice daily to affected areas limited to less than 20 percent body surface area. It carries the boxed warning applied to the oral JAK inhibitor class.

<image>A stepwise treatment algorithm for atopic dermatitis organized as a pyramid or staircase. Base level (all patients): emollients, bathing practices, trigger avoidance, bleach baths. Level 2 (mild AD): low-potency TCS, TCIs for sensitive areas, crisaborole. Level 3 (moderate AD): medium-to-high potency TCS, proactive TCS/TCI therapy, topical ruxolitinib, phototherapy (nbUVB). Level 4 (moderate-severe AD): systemic therapy - dupilumab, tralokinumab, JAK inhibitors (abrocitinib, upadacitinib, baricitinib), cyclosporine, methotrexate. Level 5 (severe refractory AD): combination systemic therapies, clinical trials. Side annotations at each level showing: BSA involvement, EASI score range, IGA score, and recommended monitoring. Biologics and JAK inhibitors are highlighted with their mechanisms of action.</image>

### Phototherapy

Narrowband ultraviolet B (nbUVB) phototherapy is the most commonly used light-based therapy for moderate to severe atopic dermatitis, administered 2 to 3 times weekly. Its mechanism is immunosuppressive, inducing T cell apoptosis and reducing Langerhans cell density in the epidermis. Phototherapy serves as an effective alternative to systemic immunosuppressive therapy and can be combined with topical treatments. Practical limitations include the requirement for clinic visits, significant time commitment, and long-term skin cancer risk, though this risk is lower than with psoralen plus UVA (PUVA) therapy.

### Systemic Therapy

#### Dupilumab (Dupixent)

Dupilumab, an anti-IL-4Ralpha monoclonal antibody that blocks both IL-4 and IL-13 signaling, is approved for moderate to severe atopic dermatitis in patients aged 6 months and older, making it the systemic therapy with the broadest age indication. Adult dosing is 300 mg subcutaneously every 2 weeks following a 600 mg loading dose, with weight-based dosing in children. The SOLO 1 and 2 trials demonstrated achievement of IGA scores of 0 or 1 in 36 to 38 percent of patients versus 8 to 10 percent with placebo, and EASI-75 responses in 44 to 52 percent. The CHRONOS trial confirmed sustained efficacy with concomitant topical corticosteroid use over 1 year. Adverse effects include injection site reactions in 15 percent and conjunctivitis in 8 to 10 percent of atopic dermatitis patients (notably rare in patients treated for asthma). No laboratory monitoring is required, and dupilumab does not cause clinically significant immunosuppression. Its ability to simultaneously address comorbid asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis makes it particularly valuable in patients with multiple atopic comorbidities.

#### Tralokinumab (Adbry)

Tralokinumab is a monoclonal antibody that specifically targets IL-13 without blocking IL-4, distinguishing it mechanistically from dupilumab. It is approved for moderate to severe atopic dermatitis in patients aged 12 years and older. Dosing is 300 mg subcutaneously every 2 weeks following a 600 mg loading dose, with the option to extend to every 4 weeks in established responders. The ECZTRA 1 and 2 trials demonstrated IGA 0 or 1 responses in 15.8 to 22.2 percent versus 7.1 to 10.9 percent with placebo. Conjunctivitis occurs in approximately 7 percent of patients.

#### JAK Inhibitors (Oral)

Abrocitinib is a selective JAK1 inhibitor available at 100 mg or 200 mg daily for atopic dermatitis. The JADE trial program demonstrated that the 200 mg dose showed superiority over dupilumab at week 2 for itch reduction in the JADE COMPARE trial, though not at week 16 for IGA response. A distinguishing feature of oral JAK inhibitors is remarkably rapid itch relief, often within 1 to 2 days. Upadacitinib, another selective JAK1 inhibitor available at 15 mg or 30 mg daily, has the strongest efficacy data among atopic dermatitis systemic therapies, with the Heads Up trial demonstrating superiority of upadacitinib 30 mg over dupilumab for EASI-75 at week 16 (71 percent versus 61 percent). Baricitinib, a JAK1/2 inhibitor at 2 mg or 4 mg daily, is approved for atopic dermatitis in the European Union and Japan but not in the United States.

All oral JAK inhibitors carry class-wide boxed warnings based on the ORAL Surveillance study of tofacitinib in rheumatoid arthritis patients aged 50 years and older with cardiovascular risk factors, which demonstrated increased risks of major adverse cardiovascular events, venous thromboembolism, and malignancy. Herpes zoster reactivation is dose-dependent, and vaccination should be considered before initiation. Laboratory monitoring includes complete blood count, lipid panel, and liver function tests at baseline, 4 weeks, and every 12 weeks thereafter, with screening for tuberculosis and hepatitis. Contraindications include concomitant use of strong CYP3A4 inhibitors (for abrocitinib), live vaccines, and lymphocyte counts below 500 cells/mcL.

| Systemic Agent | Mechanism | Dose | Onset | Key Monitoring | Notable Features |
|---------------|-----------|------|-------|---------------|-----------------|
| Dupilumab | Anti-IL-4Ralpha (blocks IL-4 + IL-13) | 300 mg SC q2 wks | 4-8 wks | None required | Conjunctivitis ~10%; broadest age range (>=6 mo) |
| Tralokinumab | Anti-IL-13 | 300 mg SC q2 wks | 4-8 wks | None required | Can extend to q4 wks in responders |
| Abrocitinib | JAK1 inhibitor | 100-200 mg PO daily | 1-2 days (itch) | CBC, lipids, LFTs, TB/hepatitis screen | Rapid itch relief; boxed warning |
| Upadacitinib | JAK1 inhibitor | 15-30 mg PO daily | 1-2 days (itch) | CBC, lipids, LFTs, TB/hepatitis screen | Strongest efficacy data (Heads Up); boxed warning |
| Cyclosporine | Calcineurin inhibitor | 3-5 mg/kg/day PO | 2-4 wks | BP, creatinine, electrolytes, lipids | Max 1-2 yrs (nephrotoxicity); first-line traditional |
| Methotrexate | Antimetabolite | 10-25 mg/wk PO | 8-12 wks | CBC, LFTs, creatinine | Add folate; limited RCT data in AD |
| Mycophenolate | Inosine monophosphate dehydrogenase inhibitor | 1-3 g/day PO | 4-8 wks | CBC, LFTs | GI side effects most common |

#### Traditional Immunosuppressants

Cyclosporine at 3 to 5 mg/kg/day offers rapid onset of action (2 to 4 weeks) and is recommended as first-line traditional systemic therapy in many international guidelines. Monitoring includes blood pressure, renal function (creatinine), electrolytes, and lipids, with maximum continuous use of 1 to 2 years due to cumulative nephrotoxicity risk. Methotrexate at 10 to 25 mg weekly with supplemental folate has a slower onset (8 to 12 weeks) and limited randomized controlled trial data in atopic dermatitis. Mycophenolate mofetil at 1 to 3 g daily is used off-label with gastrointestinal side effects as the most common limitation. Azathioprine at 1 to 3 mg/kg daily requires thiopurine methyltransferase (TPMT) testing before initiation and has a relatively slow onset. Systemic corticosteroids should be avoided for chronic atopic dermatitis management due to the near-universal rebound flares upon discontinuation and significant long-term toxicity.

## Complications

Eczema herpeticum, the disseminated cutaneous herpes simplex virus infection occurring in atopic dermatitis, is a medical emergency. It presents with clusters of vesicles and punched-out erosions accompanied by fever and malaise. Treatment requires intravenous acyclovir, and immunosuppressive therapies must not be started or continued during the infection. Eczema vaccinatum, representing dissemination of smallpox vaccine in patients with atopic dermatitis, is primarily of historical significance but remains relevant for military personnel. Staphylococcal skin infections, including impetigo, folliculitis, and abscess formation, are common and require appropriate antibiotic therapy. Ocular complications include keratoconus, anterior subcapsular cataracts, allergic conjunctivitis, and atopic keratoconjunctivitis. Psychosocial comorbidities are significant, including depression, anxiety, associations with attention deficit hyperactivity disorder, and chronic sleep disruption.

## Key Clinical Pearls
- Filaggrin mutations are the strongest genetic risk factor for AD but are present in only ~50% of patients; barrier dysfunction occurs through multiple mechanisms
- Proactive therapy (TCS or TCI applied 2x/week to previously affected sites) reduces flare frequency and is a key strategy often underutilized
- Dupilumab has no required laboratory monitoring and no clinically significant immunosuppression; conjunctivitis occurs in ~10% of AD patients (rarely in asthma patients)
- Oral JAK inhibitors (upadacitinib, abrocitinib) provide more rapid itch relief than dupilumab but carry class-wide boxed warnings (MACE, VTE, malignancy, infections)
- Avoid chronic systemic corticosteroids in AD; rebound flares are nearly universal upon discontinuation
- Dilute bleach baths (0.005% NaOCl) reduce S. aureus burden and improve AD; NNT ~4
- Eczema herpeticum is a medical emergency requiring IV acyclovir; hold immunosuppressants

## References
1. Langan SM, et al. Atopic dermatitis. *Lancet*. 2020;396(10247):345-360.
2. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis (SOLO 1 and SOLO 2). *N Engl J Med*. 2016;375(24):2335-2348.
3. Blauvelt A, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (CHRONOS). *Lancet*. 2017;389(10086):2287-2303.
4. Guttman-Yassky E, et al. Upadacitinib plus topical corticosteroids in atopic dermatitis (Heads Up). *Lancet*. 2021;397(10290):2151-2168.
5. Wollenberg A, et al. European guideline (EuroGuiDerm) on atopic eczema - part II. *J Eur Acad Dermatol Venereol*. 2022;36(11):1904-1926.