What is the comparative efficacy and safety of dupilumab (Dupixent) vs tralokinumab, lebrikizumab, oral Janus kinase (JAK) inhibitors (abrocitinib, upadacitinib, baricitinib), and methotrexate for treating severe or refractory atopic dermatitis?

Comparative Efficacy and Safety of Systemic Therapies for Severe/Refractory Atopic Dermatitis

Dupilumab should be your first-line systemic therapy for severe/refractory atopic dermatitis, as all American Academy of Dermatology guideline workgroup members favored it over other agents due to its excellent safety track record with over 5 years of clinical use and proven efficacy. 1, 2

Efficacy Hierarchy

Highest Efficacy (But Not First-Line)

• High-dose upadacitinib 30 mg daily and high-dose abrocitinib 200 mg daily demonstrate the highest efficacy at reducing EASI scores up to 16 weeks among all currently available treatments in network meta-analyses 1, 2, 3
• These JAK inhibitors were superior to dupilumab in head-to-head clinical trials 1, 2
• High-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes with high-certainty evidence 3

Intermediate Efficacy (First-Line Options)

• Dupilumab 300 mg every 2 weeks achieves EASI-75 in 63-64% of patients at 16 weeks when combined with topical corticosteroids 2, 4
• Dupilumab is somewhat less efficacious than higher doses of JAK inhibitors but comparable to upadacitinib 15 mg daily 1
• Among biologics, dupilumab is likely more effective than tralokinumab and lebrikizumab based on network meta-analyses 5
• Tralokinumab and lebrikizumab have intermediate effectiveness with high-certainty evidence 3

Lower Efficacy

• Low-dose baricitinib was among the least effective treatments in network meta-analyses 3
• Baricitinib is less efficacious than upadacitinib and abrocitinib based on indirect comparisons 1

Uncertain Efficacy

• Methotrexate has insufficient high-quality evidence for efficacy in atopic dermatitis, with low certainty of evidence 3

Safety Profile Comparison

Safest Options (Biologics)

• Dupilumab has an excellent safety track record with few major emergent safety concerns after more than 5 years in clinical practice 1, 2, 4

• Conjunctivitis is the most common adverse event (6-15% in trials, up to 26.1% in real-world data), but only 4.2% discontinue due to ocular complications 2, 4

• Most conjunctivitis is self-limited and managed with artificial tears; ophthalmology referral needed only for severe, persistent, or refractory cases 1

• No laboratory monitoring is required before initiation or during dupilumab treatment 1, 2

• Tralokinumab and lebrikizumab are among the safest treatments, modestly increasing conjunctivitis similar to dupilumab 3

Higher Risk Options (JAK Inhibitors)

• The FDA applied class warnings for all JAK inhibitors including increased risk of serious heart-related events, cancer, blood clots, and death based on safety data from other JAK inhibitors in higher-risk populations 1, 2
• JAK inhibitors were among the most harmful in increasing adverse events with high-certainty evidence 3
• Required monitoring for JAK inhibitors includes:
  • Baseline: Complete blood count with differential, liver enzymes, lipids, viral hepatitis, tuberculosis, pregnancy testing 1
  • After initiation: Labs at 4 weeks for abrocitinib; lipids at 4 weeks for abrocitinib and 12 weeks for upadacitinib 1
  • Patients should receive needed live vaccines before initiating JAK inhibitors 1

Treatment Algorithm

Step 1: First-Line Systemic Therapy

Initiate dupilumab 600 mg subcutaneous loading dose, then 300 mg every 2 weeks for patients with moderate-to-severe atopic dermatitis affecting multiple body areas with inadequate response to optimized topical therapies and significant quality of life impairment 1, 2, 4

Step 2: When to Consider JAK Inhibitors Instead

Reserve JAK inhibitors for second-line use after failure of other systemic therapies (immunosuppressants, corticosteroids, antimetabolites, injectable biologics) or when they are inadvisable, as FDA approval specifies they are not first-line therapy 1

Consider JAK inhibitors as first-line only in these specific scenarios:

• Patients requiring faster onset of action than dupilumab provides 2
• Patients with pre-existing severe ocular surface disease who cannot tolerate conjunctivitis risk 2, 4
• Patients with dupilumab-related ocular surface disease refractory to ophthalmologic management 4

Step 3: Dosing for JAK Inhibitors

• Upadacitinib: 15 or 30 mg orally daily 1
• Abrocitinib: 100 or 200 mg orally daily 1
• Baricitinib: 2 or 4 mg orally daily (not FDA-approved for AD in US, but approved in Europe) 1

Step 4: When to Use Methotrexate

Reserve methotrexate (10-25 mg orally or subcutaneously weekly) for severe/refractory cases only when FDA-approved biologics and JAK inhibitors are not accessible 1, 2

Critical Clinical Pearls

• Continue topical agents concurrently with systemic therapy for maintenance of response, rescue, or treatment of flares 1, 2
• Counsel patients about ocular adverse events before initiating dupilumab or tralokinumab, emphasizing that most cases are self-limited 2, 4
• Establish an ophthalmology referral pathway before starting biologics for management of severe ocular complications 4
• Do not discontinue dupilumab prematurely for mild ocular symptoms; use preservative-free ocular lubricants and topical antihistamine eyedrops first 4

Common Pitfalls to Avoid

• Never use systemic corticosteroids for atopic dermatitis due to substantial risk of serious adverse events and rebound flares upon discontinuation (conditional recommendation against) 2
• Do not use JAK inhibitors as first-line therapy unless biologics are contraindicated or unavailable 1, 2
• Do not fail to check cardiovascular risk factors before prescribing JAK inhibitors, as warnings are based on patients aged ≥50 years with cardiovascular risk factors 2
• Do not use PUVA phototherapy as there is insufficient data to make recommendations 1

Indications for Dupilumab Withdrawal

Discontinue dupilumab if any of the following occur:

• Progressive loss of visual acuity 4
• Progressive conjunctival cicatrization 4
• Significant quality of life loss from ocular symptoms 4
• Requirement for prolonged ocular topical corticosteroid therapy 4