What are the next steps for a patient with oral pemphigoid refractory to Dupixent (dupilumab) and oral steroid therapy, currently on mycophenolate?

Management of Refractory Oral Pemphigoid

For oral pemphigoid refractory to dupilumab, oral steroids, and mycophenolate, you should add rituximab (1g IV infusions 2 weeks apart, rheumatoid arthritis protocol) as the next-line therapy, potentially combined with immunoadsorption or IVIG for severe refractory disease. 1

Rationale for Rituximab as Next Step

The British Association of Dermatologists guidelines for pemphigus vulgaris (which shares pathophysiology with mucous membrane pemphigoid) specifically recommend rituximab for refractory disease, noting it can take up to 26 weeks to work 1. For ocular mucous membrane pemphigoid (OMMP), the ophthalmology guidelines state that refractory cases may benefit from combination IVIG and rituximab 1.

• Rituximab targets B-cell mediated autoantibody production, addressing the underlying pathogenic mechanism in pemphigoid 1
• The standard dosing is 2 infusions of 1g each, separated by 2 weeks (RA protocol) 1
• Clinical improvement typically occurs within weeks to months, though full effect may take 6 months 1

Additional Therapeutic Options for Severe Refractory Disease

Immunoadsorption Combined with Rituximab

Immunoadsorption should be strongly considered in combination with rituximab for recalcitrant cases 1:

• Removes circulating pathogenic antibodies rapidly (up to 95% reduction in desmoglein antibodies over 3 consecutive days) 1
• Provides immediate antibody reduction while rituximab prevents new antibody formation 1
• Uses matrices like staphylococcal protein A or tryptophan 1
• Reserved for patients resistant to conventional approaches 1

Intravenous Immunoglobulin (IVIG)

IVIG represents another option for resistant disease 1:

• Particularly useful when skin/mucosal features are prominent 1
• Can be combined with rituximab for refractory cases 1
• Generally well-tolerated with good safety profile 1

Cyclophosphamide

For severe inflammation unresponsive to other agents, cyclophosphamide should be considered 1:

• Indicated for severe inflammation or disease unresponsive to mycophenolate, dapsone, azathioprine, or methotrexate 1
• Can be given as monthly IV pulses (1g monthly for 6 months, then every 2 months) 1
• More toxic than other options but effective for sight-threatening or life-threatening disease 1

Important Caveats and Monitoring

Disease-Specific Considerations

• Mucous membrane pemphigoid is chronic and progressive with frequent remissions and exacerbations, making response assessment difficult 1
• Use grading systems and photographic documentation to accurately assess disease progression 1
• Systemic immunosuppressive therapy is required to inhibit inflammation, prevent keratopathy, and prevent conjunctival scarring progression 1

Treatment Monitoring

• A physician with expertise in immunosuppressive therapy should administer and monitor treatment to minimize side effects 1
• Aggressive lubrication for associated dry eye should be maintained 1
• Any ocular procedures (like cataract surgery) may worsen disease and require perioperative immunosuppression 1

Why Dupilumab May Have Failed

Note that dupilumab is primarily studied in bullous pemphigoid (BP), not mucous membrane pemphigoid 2. The evidence for dupilumab in pemphigoid is limited to case series showing variable efficacy 2, and it may not adequately address the B-cell mediated pathology of mucous membrane pemphigoid.

Treatment Algorithm Summary

1. Continue mycophenolate while adding rituximab (2 x 1g IV, 2 weeks apart) 1
2. If inadequate response after 3-6 months: Add immunoadsorption (3 consecutive days) with continued rituximab 1
3. If still refractory: Consider combination IVIG + rituximab 1
4. For severe, sight-threatening disease: Switch to cyclophosphamide 1

The key is recognizing that mucous membrane pemphigoid requires aggressive systemic immunosuppression to prevent irreversible scarring and functional impairment 1.