The prevalence of allergic diseases continues to rise. Within this broad group are a set of rare disorders that pose significant diagnostic and therapeutic challenges. Fortunately, although progress has been slow, scientific research in this field has begun to accelerate — driven by new immunologic tools, advances in molecular biology, and increasingly targeted therapeutic strategies that are moving the field toward personalized medicine.

The development of monoclonal antibodies that modulate the immunoglobulin E (IgE) response and specific cytokines, combined with new immunotherapy and desensitization approaches, is expanding treatment options once reserved mainly for common allergies. At the same time, the adoption of immunologic biomarkers and advanced diagnostic tools is changing how patients are identified and classified — a key step toward personalized allergy care.

What Counts as a Rare Allergy?

Although there is no single, universal definition, the term “rare allergies” is generally used to describe low‑prevalence hypersensitivity reactions that have a high clinical impact because of their severity and the difficulty of diagnosis and treatment. In many cases, these are complex entities whose pathophysiology does not always fit classic IgE‑mediated allergy mechanisms, which makes diagnosis harder.

This group includes, for example, hypersensitivity to complex drugs, especially in hospital settings, such as reactions to chemotherapeutics or certain biologics. Hereditary angioedema is also part of this sphere, although it is now considered a bradykinin‑mediated disorder. Some specific food allergies — such as those associated with nonspecific lipid transfer proteins (nsLTPs) found in fruits and vegetables — and other conditions such as eosinophilic esophagitis (EoE), a chronic inflammatory disease of the esophagus related to immune responses to certain foods, are included as well.

Also included are reactions to less conventional allergens, such as those derived from parasites. A well‑known example is Anisakis allergy, related to consumption of parasitized fish and capable of causing reactions ranging from urticaria to anaphylaxis.

Targeted Biologics

With the scope defined, the most important therapeutic advances in recent years have come from targeted biologic therapies — specifically monoclonal antibodies that act on immune pathways involved in allergic inflammation. Unlike traditional treatments such as antihistamines or corticosteroids, these drugs not only relieve symptoms but also block the mechanisms that trigger the allergic reaction, whether by acting on IgE‑mediated signaling or on certain cytokines.

In the case of EoE — whose treatment options were previously limited to exclusion diets and topical corticosteroids — the Spanish Agency of Medicines and Medical Devices approved dupilumab in 2024 as the first biologic authorized in Spain for this disease. Dupilumab is a monoclonal antibody that blocks signaling of the cytokines interleukin‑4 (IL-4) and interleukin‑13 (IL-13), two central mediators of type‑2 inflammation implicated in EoE pathogenesis.

Its inclusion in the therapeutic armamentarium represents a major change in EoE management and has prompted the development of a clinical consensus for the use of this biologic with participation from the Spanish Society of Allergology and Clinical Immunology (SEAIC). That document defines the patient profiles considered candidates for treatment and emphasizes the need for collaboration between allergists and gastroenterologists.

Many specialists consider this approval one of the clearest recent milestones in therapeutic innovation for rare allergies, offering for the first time a specific biologic option for a disease that until now had limited alternatives.

New Molecules and Personalized Medicine

Building on that advance, biologic research has expanded into other complex allergies — notably severe food allergies and chronic urticaria. Among the most studied molecules are ligelizumab, a next‑generation anti‑IgE antibody, and other agents targeting different inflammatory pathways, such as UB‑221, dupilumab, etokimab, and tezepelumab. The aim is to act more precisely on the immunologic mechanisms that trigger the allergic reaction.

According to SEAIC, these studies represent a promising route toward more specific and potentially safer treatments that, in addition to reducing the risk for severe reactions, may improve patients’ quality of life.

In chronic spontaneous urticaria, biologics have already transformed clinical management. Nevertheless, new agents such as lifelizumab are still being evaluated for patients who do not respond adequately to current therapies. In Spain, for example, trials such as the CUPID studies are underway to evaluate dupilumab in chronic urticaria that is resistant to antihistamines.

In hereditary angioedema, innovation has focused on the development of kallikrein inhibitors and specific monoclonal antibodies, enabling a shift from treating acute episodes only to long‑term prevention strategies. Although the primary mechanism of this disorder is no longer considered allergic, its clinical management sits at the intersection of allergology and clinical immunology.

More Accurate Diagnostics for Drug Allergies 

Although drug allergic reactions are uncommon, they can have a major impact — especially when they involve chemotherapeutic agents or essential biologic therapies.

A team at the Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain (a biomedical research institute affiliated with the Ramón y Cajal University Hospital), has studied hypersensitivity to platinum compounds and taxanes— two families of drugs widely used in oncology — to identify the immunologic phenotypes involved and find biomarkers to improve diagnosis and clinical decision‑making. The main challenge is distinguishing patients with IgE‑mediated reactions from those with other mechanisms or mixed profiles because this information is critical for deciding whether treatment can continue, whether it should be changed, or whether alternative strategies are required.

In this context, rapid or ultrarapid desensitization protocols have gained prominence; they allow administration of the drug that previously caused a reaction in very small, gradually increasing doses under strict medical supervision. This approach can induce temporary tolerance, enabling completion of treatment when no equivalent alternative exists.

These protocols increasingly rely on advanced diagnostic tools such as specific IgE testing, skin tests, and tryptase measurement, along with new biomarkers and genetic studies that help identify patients at the highest risk.

Innovation in Immunotherapy

Another active line of research is specific immunotherapy, which aims to modify the immune response to the allergen. Unlike treatments that merely control symptoms, the goal here is to induce tolerance so the body no longer overreacts to a substance.

In complex food allergies — where traditional treatment has been strict avoidance — strategies are being developed to allow patients to tolerate small amounts. The IRYCIS, funded by the Spanish National Institute of Health Carlos III, has an ongoing project studying immunologic and epigenetic mechanisms associated with sublingual immunotherapy directed at nsLTPs, such as Pru p 3, the principal peach allergen.

Research examines how immunotherapy modifies T and B cells and certain epigenetic mechanisms that might explain why some patients respond better than others. Investigators also seek biomarkers to predict treatment response and to better select candidate patients and tailor dosing.

Additionally, combinations of immunotherapy with biologic treatments — for example, anti‑IgE antibodies or inhibitors of IL‑4 and IL‑13 pathways — are being explored to facilitate desensitization processes and increase safety. Although most evidence to date comes from more common allergies such as peanut, milk, and egg, these approaches are progressively extending to less prevalent allergies.

Genetics and AI

Diagnosis of rare allergies is also being transformed by the incorporation of immunologic biomarkers, molecular diagnostic tools, and new data‑analysis technologies.

In genetic research, a Spanish study published in Human Vaccines & Immunotherapeutics in 2025 analyzed gene variants that may influence response to drugs such as omalizumab, one of the biologics most used in allergology. In parallel, component‑resolved diagnostics is consolidating as a key tool for complex allergies. Where traditional tests used whole extracts, this approach identifies specific allergenic proteins to help differentiate primary sensitizations from cross‑reactivities with other allergens — especially useful in rare or complex food allergies.

Added to these tools is the use of AI applied to allergy diagnostics, with computer‑vision‑based systems that can automatically analyze skin‑test results and detect wheals precisely, facilitating analysis of large volumes of clinical data. Finally, deep‑learning algorithms are also being used to analyze sequences of allergenic proteins in search of potential new allergens. These technologies could accelerate the discovery of rare allergies and improve diagnostic and treatment capabilities. 

This story was translated from Univadis Spain, part of the Medscape Professional Network.