Table 2. Targeted and disease-modifying... | Rockefeller University Press

Table 2.

Targeted and disease-modifying therapies reported in PADs

Therapy	Mechanism	PAD mechanism targeted	Typical clinical indication	Utilized in PADs	Select references
Dupilumab	Anti-IL-4Rα mAb blocking IL-4/IL-13 signaling	Type 2 cytokine amplification	Atopic dermatitis; asthma; chronic rhinosinusitis with nasal polyps; eosinophilic esophagitis	STAT3 DN; STAT6 GOF; DOCK8 deficiency (HIES); CARD11 (CADINS); IPEX; ZNF341 deficiency; Omenn syndrome; Netherton syndrome	(13, 58, 59, 106, 107, 108, 109, 110, 111, 112, 113, 114)
JAKinibs (e.g., baricitinib, tofacitinib, ruxolitinib, upadacitinib)	JAK-STAT pathway inhibition	Cytokine signaling amplification or loss of counter-regulation	Inflammatory diseases (agent-specific); atopic dermatitis for upadacitinib (systemic) and ruxolitinib cream (topical)	STAT6 GOF; JAK1 GOF; selected PADs with JAK-STAT dysregulation	(9, 13, 50, 51, 53, 57, 115)
Omalizumab	Anti-IgE mAb	Effector cell (IgE-FcεRI) pathway	Allergic asthma; chronic spontaneous urticaria; chronic rhinosinusitis with nasal polyps; IgE-mediated food allergy (reduction of reactions with accidental exposure)	Selected IgE- or urticaria-predominant PAD phenotypes	(116, 117, 118, 119)
Mepolizumab, benralizumab, reslizumab	Anti-IL-5 (mepolizumab, reslizumab) or anti-IL-5Rα (benralizumab) mAbs; eosinophil depletion	Eosinophil-dominant type 2 inflammation	Severe eosinophilic asthma (all); eosinophilic granulomatosis with polyangiitis (mepolizumab)	PADs with prominent eosinophilia or eosinophilic asthma (limited to several case reports)	(59, 120)
HSCT	Replacement of defective hematopoietic and blood-derived immune compartments	Global immune dysregulation/tolerance failure	Curative therapy for selected IEIs	WAS; DOCK8 deficiency; STAT3 DN (selected); CARMIL2 deficiency; Omenn syndrome; IL2RA/IL2RB deficiency	(7, 121, 122, 123, 124, 125, 126)

Therapy	Mechanism	PAD mechanism targeted	Typical clinical indication	Utilized in PADs	Select references
Dupilumab	Anti-IL-4Rα mAb blocking IL-4/IL-13 signaling	Type 2 cytokine amplification	Atopic dermatitis; asthma; chronic rhinosinusitis with nasal polyps; eosinophilic esophagitis	STAT3 DN; STAT6 GOF; DOCK8 deficiency (HIES); CARD11 (CADINS); IPEX; ZNF341 deficiency; Omenn syndrome; Netherton syndrome	(13, 58, 59, 106, 107, 108, 109, 110, 111, 112, 113, 114)
JAKinibs (e.g., baricitinib, tofacitinib, ruxolitinib, upadacitinib)	JAK-STAT pathway inhibition	Cytokine signaling amplification or loss of counter-regulation	Inflammatory diseases (agent-specific); atopic dermatitis for upadacitinib (systemic) and ruxolitinib cream (topical)	STAT6 GOF; JAK1 GOF; selected PADs with JAK-STAT dysregulation	(9, 13, 50, 51, 53, 57, 115)
Omalizumab	Anti-IgE mAb	Effector cell (IgE-FcεRI) pathway	Allergic asthma; chronic spontaneous urticaria; chronic rhinosinusitis with nasal polyps; IgE-mediated food allergy (reduction of reactions with accidental exposure)	Selected IgE- or urticaria-predominant PAD phenotypes	(116, 117, 118, 119)
Mepolizumab, benralizumab, reslizumab	Anti-IL-5 (mepolizumab, reslizumab) or anti-IL-5Rα (benralizumab) mAbs; eosinophil depletion	Eosinophil-dominant type 2 inflammation	Severe eosinophilic asthma (all); eosinophilic granulomatosis with polyangiitis (mepolizumab)	PADs with prominent eosinophilia or eosinophilic asthma (limited to several case reports)	(59, 120)
HSCT	Replacement of defective hematopoietic and blood-derived immune compartments	Global immune dysregulation/tolerance failure	Curative therapy for selected IEIs	WAS; DOCK8 deficiency; STAT3 DN (selected); CARMIL2 deficiency; Omenn syndrome; IL2RA/IL2RB deficiency	(7, 121, 122, 123, 124, 125, 126)

Summary of immunomodulatory biologics, small-molecule inhibitors, and HSCT that have been used to treat PADs, organized by therapeutic mechanism, the pathogenic pathway targeted, and reported clinical indications. Reported PAD use is derived predominantly from case reports and small case series rather than randomized controlled trials. Therapeutic efficacy appears greatest when the drug’s mechanism of action aligns closely with the underlying molecular and immunological pathogenesis of the specific PAD.

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