What is the comparative efficacy and safety of Dupixent (dupilumab) vs Tralokinumab, Lebrikizumab, oral Janus Kinase (JAK) inhibitors (Abrocitinib, Upadacitinib, Baricitinib), and Methotrexate for severe or refractory atopic dermatitis or asthma?

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

Primary Recommendation

Dupilumab is the first-line systemic therapy for severe/refractory atopic dermatitis, with all guideline workgroup members favoring it over other systemic agents due to its excellent safety profile and proven efficacy over more than 5 years of clinical use. 1, 2, 3

Comparative Efficacy Rankings

Highest Efficacy (Network Meta-Analysis Data)

• 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 and were superior to dupilumab in head-to-head clinical trials 1, 4
• High-dose upadacitinib is among the most effective for 5 of 6 patient-important outcomes with high-certainty evidence 4
• High-dose abrocitinib and low-dose upadacitinib (15 mg daily) are among the most effective for 2 patient-important outcomes 4

Intermediate Efficacy

• Dupilumab (300 mg every 2 weeks) achieves EASI 75 in 63-64% of patients at 16 weeks when combined with topical corticosteroids 2, 3
• Tralokinumab (300 mg every 2 weeks) is somewhat less effective than dupilumab at 16 weeks based on network meta-analysis 1, 4
• Lebrikizumab demonstrates intermediate effectiveness with high-certainty evidence 4

Lower Efficacy

• Low-dose baricitinib (2 mg daily) is among the least effective options 4
• Methotrexate (10-25 mg weekly) has only conditional recommendation based on low certainty evidence 1

Comparative Safety Profile

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, 3
• 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, 3
• Tralokinumab and lebrikizumab are among the safest options, modestly increasing conjunctivitis risk 4
• No laboratory monitoring is required before initiation or during treatment with biologics 1

Higher Safety Concerns (JAK Inhibitors)

• Upadacitinib and abrocitinib are among the most harmful in increasing adverse events despite their superior efficacy 4
• FDA applied class warnings for JAK inhibitors including increased risk of serious heart-related events, cancer, blood clots, and death based on data from tofacitinib in rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors 1
• Increased risk of serious and opportunistic infections, including herpes zoster 1
• Required monitoring: complete blood count with differential, liver enzymes at baseline and 4 weeks after initiation for abrocitinib; lipids at 4 weeks for abrocitinib and 12 weeks for upadacitinib; testing for viral hepatitis, tuberculosis, and pregnancy at baseline 1
• Shingles vaccination recommended before initiating JAK inhibitors, particularly for older patients 1

Methotrexate Safety

• Methotrexate receives only a conditional recommendation based on low certainty evidence 1
• Requires regular laboratory monitoring (specific frequency not detailed in guidelines but standard practice includes baseline and periodic CBC, liver function, renal function) 1

Treatment Algorithm

Step 1: First-Line Systemic Therapy

Initiate dupilumab 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 2, 3

• Dosing: 600 mg subcutaneous loading dose, then 300 mg every 2 weeks 1, 2
• No laboratory monitoring required 1
• Counsel patients about conjunctivitis risk and provide preservative-free ocular lubricants 2, 3

Step 2: Alternative Biologics

Consider tralokinumab as an alternative first-line biologic if dupilumab is contraindicated or patient preference 1

• Dosing: 600 mg at initiation followed by 300 mg every 2 weeks 1
• Similar safety profile to dupilumab with slightly lower efficacy 1, 4

Step 3: JAK Inhibitors (Second-Line)

Reserve JAK inhibitors for patients who have failed other systemic therapies or when biologics are inadvisable 1

• Upadacitinib 15 mg or 30 mg daily for maximum efficacy with rapid onset 1
• Abrocitinib 100 mg or 200 mg daily as alternative 1
• Baricitinib 2 mg or 4 mg daily is less efficacious than upadacitinib and abrocitinib 1
• Avoid in patients aged ≥50 years with cardiovascular risk factors, history of malignancy, or thromboembolic disease 1
• Administer shingles vaccine before initiation if age-appropriate 1

Step 4: Older Immunosuppressants

Consider methotrexate, cyclosporine, azathioprine, or mycophenolate only when biologics and JAK inhibitors are unavailable, contraindicated, or unaffordable 1

• These receive conditional recommendations based on low or very low certainty evidence 1
• Methotrexate: 10-25 mg PO or SC weekly 1
• Cyclosporine: Up to 3000 mg PO daily divided BID, limited to 1 year of use 1

Critical Clinical Pearls

When to Choose JAK Inhibitors Over Dupilumab

• Patients requiring faster onset of action (JAK inhibitors work more rapidly) 2
• Patients with pre-existing severe ocular surface disease who cannot tolerate conjunctivitis risk 2, 3
• Patients with dupilumab-related ocular surface disease refractory to ophthalmologic management 2, 3

When to Avoid JAK Inhibitors

• Age ≥50 years with cardiovascular risk factors (myocardial infarction, stroke, thromboembolism risk) 1
• Current or history of malignancy 1
• Active serious infections 1
• Pregnancy or breastfeeding 1

Methotrexate Positioning

Methotrexate should be reserved for severe/refractory cases only when FDA-approved biologics and JAK inhibitors are not accessible 1

• The evidence base is weak (low certainty) compared to newer agents 1
• Requires more intensive monitoring than biologics 1
• Less effective than biologics and JAK inhibitors based on available data 4

Common Pitfalls to Avoid

• Do not use systemic corticosteroids for atopic dermatitis due to substantial risk of serious adverse events and rebound flares upon discontinuation (conditional recommendation against) 1, 2
• Do not discontinue dupilumab prematurely for mild conjunctivitis; manage with preservative-free ocular lubricants and topical antihistamine eyedrops 2, 3
• Do not use JAK inhibitors as first-line therapy unless biologics are contraindicated or unavailable, as they are FDA-approved only after failure of other systemic therapies 1
• Do not fail to establish ophthalmology referral pathway before initiating dupilumab for management of severe ocular complications 3
• Do not forget to vaccinate for shingles before initiating JAK inhibitors in eligible patients 1