Targeted Biologics Show Promise for Severe Allergy in Rare Genetic Immune Disorders

People born with inborn errors of immunity, a large family of more than 550 inherited disorders of the immune system, have long been known for their vulnerability to recurrent and severe infections. Yet clinicians increasingly recognize that many of these patients suffer from something quite different: relentless eczema, asthma, food allergy, and other atopic disease that can dominate their lives and sometimes appear as the very first sign that something is wrong. A new systematic review published in Frontiers in Allergy brings together, for the first time, the scattered published experience of treating these patients with modern targeted drugs, offering the most complete picture to date of how biologics and Janus kinase inhibitors perform in this genetically defined population.

The research team, led by Mahnaz Jamee of the Garvan Institute of Medical Research in Sydney together with collaborators in Egypt, Iran, and Saudi Arabia, searched PubMed, Web of Science, and Scopus from their beginnings through April 2026. After screening more than 5,200 records and assessing 129 full-text articles, they identified 81 studies describing 172 patients with sequencing-confirmed genetic diagnoses who had received a biologic or a JAK inhibitor specifically for atopic manifestations. The review followed the PRISMA 2020 reporting standard, appraised study quality with Joanna Briggs Institute checklists, and rated the certainty of evidence using GRADE principles, which placed every outcome at very low certainty because nearly all the underlying reports were single-patient case reports or small series.

The genetic landscape of the treated patients was strikingly concentrated. STAT3 loss-of-function disease, the classic form of hyper-IgE syndrome, accounted for 52 patients, or 30.2 percent of the cohort. Netherton syndrome, a devastating epithelial-barrier disorder caused by SPINK5 mutations, contributed 32 patients, and DOCK8 deficiency, a combined immunodeficiency notorious for severe eczema and recurrent viral infections, accounted for 19. JAK1 gain-of-function disease and CARD11-associated atopy with dominant interference of NF-kappa-B signaling rounded out the leading diagnoses. Nearly half of the patients carried multiple atopic manifestations at once, most often atopic dermatitis overlapping with asthma or with food allergy, and almost two-thirds were children at the time treatment began.

Dupilumab dominated the published experience. The antibody, which blocks the shared alpha subunit of the receptors for the type 2 cytokines interleukin-4 and interleukin-13, had been given to 120 patients, roughly 70 percent of the entire cohort. It was used most often in STAT3 loss-of-function disease, DOCK8 deficiency, Netherton syndrome, and CADINS, with atopic dermatitis as the leading indication, followed by asthma and food allergy. Among the 118 patients with reported outcomes, a complete or major clinical response was described in 82.2 percent, with partial responses, relapses, and non-response making up the remainder. Beyond the skin, clinicians documented broader benefits in more than two-thirds of patients, including fewer cutaneous infections, weight and height gain, hair and nail regrowth, and improved sleep and quality of life.

The biology behind these responses is instructive. Type 2 inflammation, driven by helper T cells, mast cells, and innate lymphoid cells producing interleukins 4, 5, 13, and 31, sits at the center of allergic disease, recruiting eosinophils and driving B cells toward IgE production. By binding a single target, IL-4Rα, dupilumab silences signaling through both type I and type II interleukin-4 and interleukin-13 receptors, and the breadth of reported benefit reflects the pleiotropic downstream consequences of blocking that shared subunit rather than action on multiple molecular targets. Adverse effects were subtle, chiefly conjunctivitis and transient hypereosinophilia, consistent with large real-world studies in ordinary atopic dermatitis. Notably, dupilumab also served as a bridge to hematopoietic stem cell transplantation in seven patients, most of them with DOCK8 deficiency, holding severe disease at bay until a potentially curative transplant could be performed.

Omalizumab, the anti-IgE antibody that binds circulating free IgE and strips it from FcεRI receptors on mast cells and basophils, appeared in 16 patients, most frequently those with STAT3 loss-of-function disease. Outcomes were reported for 14 of them, and a complete or major response was described in 78.6 percent, with particular benefit in atopic dermatitis and asthma. Thirty-seven and a half percent of these patients were able to stop corticosteroids entirely, and several experienced a reduction in infection rate, an observation the authors suggest may make omalizumab especially valuable for immunodeficient patients who cannot tolerate steroids. The reviewers caution, however, that measured total IgE often rises after omalizumab initiation because drug-IgE complexes clear slowly, so the laboratory changes reported in the literature must be read descriptively rather than as proof of mechanism.

JAK inhibitors occupied a conceptually distinct niche. These small molecules interrupt the Janus kinase–STAT pathway, the main conduit by which cytokines transmit inflammatory signals from the cell membrane to the nucleus. Twenty-one patients received them, most commonly baricitinib and ruxolitinib, and the pattern of use was strikingly genotype-specific: ruxolitinib was given to patients with JAK1, STAT5B, and STAT6 gain-of-function disease, baricitinib exclusively to JAK1 gain-of-function patients, and abrocitinib only to those with Netherton syndrome. A complete or major response was described in 76.2 percent of published patients, and additional benefits included resolution of food intolerance and normalization of hepatic inflammation. Adverse events such as anemia, lightheadedness with nausea, and body odor appeared in a minority, but the authors emphasize that with so few patients and a median follow-up of only two years, the data cannot exclude serious infections, cytopenias, thrombosis, or malignancy, particularly in patients whose antiviral or antifungal immunity is already compromised.

Perhaps the most intellectually valuable contribution of the review is its framework for thinking about when these drugs make sense. The authors distinguish four therapeutic models: pathway-corrective treatment, in which the drug directly counters the causal signaling abnormality, as with ruxolitinib in JAK1 gain-of-function disease; phenotype-directed treatment, in which a downstream atopic manifestation is targeted without fixing the underlying defect, as with dupilumab in STAT3 loss-of-function or Netherton syndrome; bridge therapy before stem cell transplantation; and symptomatic adjunctive therapy after conventional treatment has failed. These models carry different expectations and should not be pooled into a single conclusion about effectiveness. Organized by mechanism, the published experience spans dominant type 2 signaling disorders, JAK-STAT hyperactivation, combined immunodeficiencies with severe atopy, hyper-IgE syndromes, epithelial-barrier defects, and regulatory T-cell disorders such as IPEX.

The authors are careful about the limits of their evidence. Favorable outcomes are far more likely to be published than treatment failures, so the response proportions are descriptive summaries of published experience, not estimates of how well these drugs work in the underlying population. Many patients received concurrent corticosteroids, immunoglobulin replacement, antimicrobial prophylaxis, or other targeted agents, making it impossible to attribute improvement to a single drug. Adverse events were systematically under-ascertained in reports whose primary purpose was to showcase success, and a median follow-up of twelve months is far too short to detect late complications such as malignancy or opportunistic infection. No biologic or JAK inhibitor holds regulatory approval for atopic manifestations in these disorders, meaning every use described is off-label with respect to the underlying genetic condition.

Even with those caveats, the synthesis marks a turning point for a field long dependent on anecdote. It suggests that dupilumab offers the largest and most encouraging published experience across multiple genetic backgrounds, that omalizumab may be a steroid-sparing option for immunodeficient patients with asthma and eczema, and that JAK inhibitors are uniquely suited to disorders driven by gain-of-function mutations in their own target pathway. The authors call for long-term longitudinal studies with standardized allergy testing, objective outcome measures, and systematic safety surveillance. Until such data exist, they conclude, treatment should remain individualized and genotype-informed, accompanied by careful infection monitoring, a prescription that captures both the promise and the prudence demanded by precision medicine in some of the rarest and most difficult allergic diseases known.

Subject of Research: Use of biologics and JAK inhibitors to treat atopic manifestations in inborn errors of immunity

Article Title: Biologics and JAK inhibitors for atopic manifestations in inborn errors of immunity: a systematic review

Article References: Jamee, M., Al-Gaweesh, R. M., Hajialigol, A., Mohammed, S. G., Tirandazi, P., Alangari, A. A., & El-Owaidy, R. (2026). Biologics and JAK inhibitors for atopic manifestations in inborn errors of immunity: a systematic review. Frontiers in Allergy, 7, Article 1867183. https://doi.org/10.3389/falgy.2026.1867183

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1867183

Keywords: inborn errors of immunity, dupilumab, omalizumab, JAK inhibitors, atopic dermatitis, hyper-IgE syndrome, Netherton syndrome, DOCK8 deficiency, STAT3, systematic review, type 2 inflammation, precision medicine