Food allergy management: Allergen-nonspecific therapies

INTRODUCTION — 

Management of immunoglobulin E (IgE) mediated food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. Allergies to certain foods, such as hen's egg and cow's milk, tend to be outgrown during childhood, whereas allergies to other foods, such as shellfish and nuts, are much more likely to persist. The ultimate goal of therapeutic approaches to food allergy is to induce permanent tolerance to the food, where allergic reactions will not recur upon reexposure after a period of abstinence (figure 1 and table 1). However, none of the available treatments or those under investigation appear to achieve permanent tolerance in a substantial number of treated patients. Rather, they only temporarily desensitize or protect patients, requiring continued treatment to maintain efficacy. (See "Management of food allergy: Avoidance" and "Food-induced anaphylaxis" and "Anaphylaxis: Emergency treatment".)

Novel therapeutic approaches to food allergy can be classified as food allergen specific (eg, immunotherapy with native or modified recombinant allergens or oral desensitization) or food allergen nonspecific (eg, anti-IgE, other monoclonal antibodies [mAbs], small-molecule inhibitors) [1]. Food allergen-nonspecific therapies are reviewed here. Oral immunotherapy (OIT) and other investigational allergen-specific therapies for food allergy are reviewed separately. (See "Food allergy management: Allergen-specific immunotherapy".)

GOALS OF TREATMENT — 

The ultimate goal of treatment for food allergy is to induce permanent tolerance to the food. Important goals for patients and their parents/caregivers are reduction of anxiety related to food allergies and improvement in quality of life. These goals may be accomplished even if the patient does not develop permanent tolerance but rather a temporary state of desensitization or protection from accidental exposures. They may also be accomplished even if dietary restrictions are not lifted by increasing the eliciting dose and thereby reducing the risk of reactions to the food. This enhanced safety often also improves quality of life. Partial reintroduction of the food may have some nutritional value as well. (See "Management of food allergy-related anxiety in children and their parents/caregivers" and "Management of food allergy: Nutritional issues".)

OVERVIEW OF NONSPECIFIC THERAPIES — 

The primary aim of nonspecific therapies for food allergy is to downregulate the allergic immune response in order to increase the reaction threshold [2]. It is unknown whether the protective effect will persist after discontinuation following an extended period of therapy.

The only nonspecific therapy approved by the US Food and Drug Administration (FDA) for food allergy is omalizumab, a monoclonal antibody (mAb) against IgE (anti-IgE) [3]. (See 'Omalizumab (anti-IgE)' below.)

Allergen-nonspecific therapies under investigation include other mAbs against IgE and blockade of vasoactive mediators (eg, leukotrienes, prostaglandins, bradykinin). Other potential biologic treatments for food allergy include mAbs against alarmins (anti-interleukin [IL] 33, anti-thymic stromal lymphopoietin [TSLP]), Bruton tyrosine kinase (BTK) inhibitor (ibrutinib), and Janus kinase (JAK) inhibitors. Additional novel approaches include use of a Toll-like receptor 9 (TLR9) agonist to decrease T helper type 2 (Th2) responses and induce T helper type 1 (Th1) responses [4], blockade of vasoactive mediators such as platelet-activating factor (PAF) from mast cells and basophils [5], and fecal transplantation. (See 'Additional therapies under investigation' below.)

OMALIZUMAB (ANTI-IgE)

Overview — Omalizumab is the most extensively studied of the anti-IgE humanized immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs) and is the only one with US Food and Drug Administration (FDA) approval for the treatment of IgE-mediated food allergies in conjunction with food allergen avoidance [3]. It is approved for use in adults and children ≥1 year of age to reduce allergic reactions including anaphylaxis due to accidental exposure to one or more foods. Omalizumab is also approved for treatment of poorly controlled asthma (from age 6 years) and chronic spontaneous urticaria (CSU; from age 12 years). As an allergen-agnostic therapy, omalizumab may improve other allergen-driven conditions such as allergic rhinitis and venom allergy. Other anti-IgE mAbs remain investigational and do not have approved indications for food allergy or other atopic diseases. (See 'Other anti-IgE mAbs' below.)

Mechanisms of action — Allergen-specific IgE antibodies play an important role in the pathophysiology of food allergy. IgE antibodies bind to high-affinity receptors (Fc-epsilon-RI) on the surface of mast cells and basophils. Cross-linking of IgE molecules on the surface of mast cells by allergen leads to the release of preformed mast cell mediators (the early phase of an allergic reaction) as well as synthesis of proinflammatory cytokines and chemokines that result in late-phase reaction [6]. Humanized IgG1 monoclonal anti-IgE antibodies (anti-IgE) bind to IgE molecules, preventing them from binding to IgE receptors. This results in downregulation of the expression of high-affinity IgE receptor on mast cells and a decrease in basophil histamine release [7]. (See "The biology of IgE" and "Anti-IgE therapy".)

Efficacy — Data from a multicenter randomized trial of omalizumab for multiple food allergies in children demonstrated an increase in reaction threshold for many patients, suggesting it may offer some degree of protection from accidental exposures [8]. These results are consistent with clinical trial results and real-world experience that support benefits for patients with food allergy who are treated with omalizumab monotherapy for asthma or chronic urticaria. A systematic review and meta-analysis of clinical trials and observational studies published prior to the above trial concluded that omalizumab monotherapy (compared with pretreatment) was associated with a significant increase in the tolerated dose of multiple foods, cow's milk, hen's egg, wheat, and milk in baked foods; improvement in quality of life; and a reduced rate of allergic reactions [9]. Omalizumab also has been shown to reduce adverse events and shortened time to maintenance therapy when used in combination with oral immunotherapy (OIT), as pretreatment, and/or as a concomitant therapy [10]. (See "Food allergy management: Allergen-specific immunotherapy", section on 'OIT plus anti-IgE' and "Anti-IgE therapy", section on 'Omalizumab therapy in asthma' and "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

In the first stage of a trial of 177 children 1 to 17 years of age with multiple food allergies who had a pretreatment reaction threshold with dose-limiting symptoms on challenge to peanut of ≤100 mg peanut protein (cumulative ingested amount 144 mg) and reaction threshold to two other foods (cashew, milk, egg, walnut, wheat, or hazelnut) of ≤300 mg protein (cumulative ingested dose 444 mg), patients were randomly assigned 2:1 to omalizumab monotherapy (dosing based upon weight and total IgE level, per asthma dosing guidelines) or placebo subcutaneously every two to four weeks for 16 to 20 weeks, with all patients instructed to continue avoidance of their food allergens [8]. Moderate-to-severe symptoms are considered dose limiting. They include systemic hives, significant facial edema, or pronounced or extensive flushing; pruritus with prolonged scratching; throat tightness that may include hoarseness; laryngeal edema or stridor; persistent cough or wheezing that may include dyspnea; persistent gastrointestinal symptoms (eg, pain, cramping, nausea, vomiting); altered mental status; and symptomatic hypotension [11]. Patients who had a history of severe anaphylaxis (defined as neurologic compromise or intubation), poorly controlled or severe asthma, or whose total IgE level and/or body weight were over the cutoffs for treatment (based upon guidelines for asthma) were excluded from the trial [8]. A planned interim analysis of the data was performed that resulted in early cessation of enrollment (total enrollment 180 patients, including three adults under 55 years of age, rather than the target of 225).

At 16 weeks, 79 of 118 patients (67 percent) treated with omalizumab were able to consume a prespecified threshold of a single dose of ≥600 mg (cumulative dose ≥1044 mg) of peanut protein without dose-limiting symptoms compared with 4 of 59 patients (7 percent) in the placebo group [8]. For cashew, egg, and milk, 41 (28/68), 67 (34/51), and 66 (27/41) percent, respectively, were able to consume single prespecified doses of ≥1000 mg (cumulative dose ≥2044 mg) without dose-limiting symptoms compared with 3 (1/31), 0 (0/20), and 2 (2/21) percent, respectively, in the placebo group. For walnut, hazelnut and wheat, successful consumption of the threshold dose was met in 64, 65, and 75 percent, respectively, in the omalizumab-treated group compared with 13, 14, and 13 percent, respectively, in the placebo group [8]. However, 14 percent of those on active treatment reacted to a dose of 30 mg peanut protein, which was a treatment failure. It is unclear if continued dosing with omalizumab resulted in improvement. Oral food challenge (OFC) to determine reaction threshold remains the only test to assess efficacy of food allergy therapies in clinical trials, and it serves as a surrogate for protection against reactions due to accidental exposures in the real world. Injection-site reactions were more common in the omalizumab group, but adverse events were otherwise similar in the two groups.

Safety — Anti-IgE molecules are generally well tolerated. Rare adverse effects include hypersensitivity reactions, injection-site reactions, and serum sickness. Whether anti-IgE therapy increases susceptibility to parasitic infection or risk of cardiovascular disease is uncertain. The adverse effects of anti-IgE are discussed in greater detail separately. (See "Anti-IgE therapy", section on 'Adverse effects'.)

Dosing — Dosing of omalizumab is based upon pretreatment total IgE level and actual body weight using the same parameters as for treatment of asthma and ranges from 75 mg subcutaneously every four weeks to 600 mg every two weeks. Use is not recommended in patients whose IgE is over the weight-based cutoff or is <30 units/mL.

Indications and patient selection for monotherapy with omalizumab — For most patients with food allergy, we suggest avoidance alone rather than treatment with therapies that potentially raise the reaction threshold in addition to avoidance (eg, omalizumab, food-specific OIT) [12]. Omalizumab can increase the reaction threshold to food allergens for many patients. Its appeal is that it should be effective for allergy to any food. However, anti-IgE therapy is not a cure, is costly, and protection requires administration at regular intervals indefinitely as well as ongoing food allergen avoidance. Patients must also have IgE levels and weight that fall within the dosing range criteria. There are additional limitations and uncertainties, including which patients may benefit most from therapy. (See 'Efficacy' above and 'Limitations and uncertainties' below and "Management of IgE-mediated food allergy: An overview", section on 'Choice of strategy' and "Anti-IgE therapy".)

There are no formal guidelines for how to select optimal patients for omalizumab [12]. Patients that theoretically may most benefit include those who are at greatest risk of having severe allergic reactions to foods. However, some of these patient groups were excluded from the clinical trial that led to approval of this therapy (those with poorly controlled or severe asthma, history of severe, near-fatal anaphylaxis defined by prior intubation or neurologic compromise), making it difficult to know how well omalizumab would protect these types of patients. Reasonable candidates for omalizumab may include patients who have multiple food allergies, particularly to common foods that are difficult to avoid, a history of systemic reactions to trace amounts of food due to unintentional cross-contact that indicate a lower reaction threshold, or allergic comorbidities that are associated with an increased risk of a more severe reaction.

Patients for whom the costs and burdens of this therapy may outweigh the benefits include young children with food allergies that are likely to resolve over time (eg, cow's milk, hen's egg), although some children are allergic to multiple foods, and allergies to many of these foods (eg, peanut, tree nuts, seeds, seafood) are not outgrown with age in most patients. While omalizumab is approved for infants as young as one year, there is no long-term safety record for this age group, which may temper caregivers' and clinicians' willingness to use omalizumab. Thus, other options such as OIT or avoidance alone may be preferred in young children. Real-world data should shed light on the cost effectiveness of omalizumab monotherapy in food allergy, with potential cost savings derived from reduction in emergency department and office visits due to anaphylaxis/allergic reactions and asthma exacerbations in those with comorbid asthma. (See 'Limitations and uncertainties' below.)

Additional factors for patients and their caregivers that drives them to seek options other than avoidance is food allergy-related anxiety and negative impact of food allergies on quality of life. Some of these issues can be addressed through mental health counseling, preferably with a mental health professional who has expertise in food allergy. (See "Management of food allergy-related anxiety in children and their parents/caregivers" and "Food allergy: Impact on health-related quality of life".)

The potential role of anti-IgE therapy in combination with food-specific OIT is still under investigation and is discussed in greater detail separately. (See "Food allergy management: Allergen-specific immunotherapy", section on 'OIT plus anti-IgE'.)

Peanut OIT and OIT for other food allergens are also discussed in greater detail separately. (See "Food allergy management: Allergen-specific immunotherapy".)

Limitations and uncertainties — There are many potential limitations and uncertainties surrounding treatment with omalizumab for food allergies:

●Are baseline reaction thresholds needed – Patients with higher reaction thresholds who are not likely to react to the typical small accidental allergen exposures that are already below their baseline thresholds may not receive substantial benefit from a therapy that can raise reaction thresholds. However, pretreatment OFCs would be necessary to determine these thresholds. The history and, in some cases, test results may allow for an estimation of threshold. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution".)

●Does it work equally well for all foods – Anti-IgE monoclonal therapies are allergen nonspecific, meaning that their effect is expected to extend to all types of foods. There are insufficient data to know whether efficacy is similar for all food allergens.

●Does the level of protection vary based upon time since last injection – Theoretically, there may be variation in threshold response based upon time since last injection, particularly if a dose was delayed or missed, but this has not been reported.

●What is the level of protection if there is an augmenting cofactor present – Raising the reaction threshold in a controlled clinical challenge is a surrogate marker for protection against an accidental ingestion. However, there are known cofactors that can lower the threshold for and/or augment an allergic reaction, including ethanol, nonsteroidal antiinflammatory drugs (NSAIDs), sleep deprivation, exercise, and infection. Thus, reactions could still occur at lower doses than anticipated if a cofactor is present. (See "Food-induced anaphylaxis", section on 'Factors affecting presentation'.)

●How to monitor for efficacy – In clinical trials, not every patient has an increased reaction threshold on OFC, and the reaction threshold may be increased for one food allergen but not for another. OFCs to each food allergen after at least 16 weeks of therapy can be performed to determine if treatment had raised the reaction threshold for the specific food, but they are time consuming, use considerable resources, and can result in significant allergic reactions. Measurement of food-specific serum IgE is not reliable following initiation of omalizumab, because of the formation of immune complexes that interfere with the measurements. Skin prick testing (SPT) was shown to significantly decrease with successful omalizumab therapy for sesame allergy in a small clinical trial [13]. In clinical trials, basophil activation shows significant reduction over the course of therapy and may prove useful for monitoring once clinically available.

●How to monitor allergy for natural resolution – There are no data as to best approaches to monitoring for natural resolution in a patient treated with omalizumab. Monitoring for resolution is most pertinent in children with food allergies that are likely to resolve over time even without intervention (eg, cow's milk, hen's egg). Monitoring for natural resolution of a food allergy typically involves following SPT and serum test results and, if favorable, possibly performing a medically supervised OFC to confirm tolerance. However, anti-IgE interferes with food-specific blood testing for allergies and causes elevation in total IgE, although IgE levels return to baseline after cessation of therapy [14]. In addition, omalizumab reduces expression of Fc-epsilon-RI in dermal mast cells and reduces the size of the skin test wheal [15].

Given that skin tests and serum tests may be uninterpretable, the clinician is left with the OFC as the only test. However, as with monitoring for efficacy, there are significant practical limitations to this approach. In addition, it is not clear which patients may most benefit from an OFC and under what circumstances such a challenge should be performed. Further data are needed to determine the best approach.

●When to stop – There are no clear guidelines regarding stopping omalizumab. Data from use of omalizumab for other conditions indicates that allergic reactivity gradually returns to pretreatment levels following discontinuation. Thus, the treatment would need to be continued indefinitely to maintain the level of protection. (See "Anti-IgE therapy", section on 'Observations post-treatment'.)

●Potential to increase risk of reactions – Patient populations that are typically at higher risk of having reactions, particularly life-threatening reactions, are an appealing target population. However, such patients, for example adolescents and young adults, might be more likely to ingest foods that may be risky and/or not carry autoinjectable epinephrine if they thought they were protected against accidental exposures, whether from treatment with omalizumab or other therapy that increases the reaction threshold. As is routine for food allergy management, patients and their caregivers should be educated about the importance of continued avoidance and having autoinjectable epinephrine available at all times to treat allergic reactions, and this should be reinforced at each follow-up visit.

●What if the patient has food allergen sensitization only – Patients under consideration for omalizumab treatment may be avoiding foods to which they are not actually allergic. This situation happens when patients test "positive" to a food that was never introduced into the diet or was subsequently avoided after the "positive" test, but they have no history of a known exposure that triggered a reaction (eg, sensitization without clinical reactivity). In patients with "positive" tests to foods that are, by diagnostic methods, likely to be tolerated, OFCs prior to starting omalizumab to confirm that they are not true allergens is a reasonable approach. There may be foods where diagnostic tests, absent actual exposure, are essentially confirmatory of allergy, and it would not be appropriate to trial such foods in clinical practice. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Food allergy in children: Prevalence, natural history, and monitoring for resolution" and "Oral food challenges for diagnosis and management of food allergies".)

ADDITIONAL THERAPIES UNDER INVESTIGATION

Monoclonal antibodies (mAbs)

Other anti-IgE mAbs — The mechanisms of action and safety of anti-IgE are discussed in brief above and in greater detail separately. (See 'Omalizumab (anti-IgE)' above and "The biology of IgE" and "Anti-IgE therapy".)

●Talizumab – One clinical trial using talizumab as monotherapy for peanut allergy demonstrated an increase in mean baseline threshold of sensitivity in all groups with an apparent dose response that was only significant in the 450 mg group (increased from 178 to 2805 mg, or half a peanut to nearly nine peanuts, an effect that should provide protection against most accidental ingestion) [16]. However, even at the highest dose of talizumab, approximately 25 percent were not protected. This molecule is no longer in development.

●Ligelizumab – Ligelizumab has significantly higher potency (88-fold) of binding to the high-affinity IgE type I receptor (Fc-epsilon-RI) on the surface of basophils and mast cells, but not to low-affinity IgE receptor type II (Fc-epsilon-RII, CD23), compared with omalizumab. Despite promising initial results, ligelizumab was less efficacious for asthma and not different than omalizumab in chronic spontaneous urticaria (CSU) [17,18]. A phase III trial of ligelizumab in 6- to 55-year-old patients with peanut allergy was terminated prematurely by the sponsor in January 2024 (NCT04984876).

●Quilizumab – Quilizumab is an anti-IgE monoclonal humanized IgG1 molecule specifically targeting the M1 prime epitope of cell membrane-bound IgE. In randomized trials for allergic asthma and CSU, it was found to decrease IgE levels but did not improve clinical parameters [19,20]. It has not been studied for the treatment of food allergy.

●UB-221– UB-221 is an anti-IgE mAb that is distinct from omalizumab and ligelizumab. UB-221 is superior to both omalizumab and ligelizumab in CD23-mediated downregulation of IgE production. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level. UB-22 will undergo further evaluation in a phase I clinical trial (NCT04175704) in adults with CSU [21]. It is uncertain if UB-221 will be evaluated in food allergy.

Dupilimab (anti-IL-4) — Dupilumab is a fully human mAb that binds to the alpha subunit of the interleukin (IL) 4 receptor and inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T lymphocytes (Th2) that are believed to play a key role in atopic diseases. It is indicated for the treatment of moderate-to-severe atopic dermatitis, moderate-to-severe asthma with eosinophilic phenotype, eosinophilic esophagitis (EoE), and chronic rhinosinusitis with nasal polyposis. Ongoing clinical trials are evaluating efficacy and safety of dupilumab as monotherapy (NCT03793608) or with oral immunotherapy (OIT) (NCT03682770) [22]. The monotherapy trial was an open-label study that enrolled 24 participants. Following 24 weeks of dupilumab dosing every two weeks (dose of 200 or 300 mg subcutaneously based on body weight), 8.3 percent (95% CI, 1.03-27.00) of the participants met the primary endpoint of passing a double-blind placebo-controlled food challenge (DBPCFC) with at least 444 mg (cumulative) peanut protein. This disappointing result led to discontinuation of investigation into dupilumab monotherapy for peanut allergy. Use of dupilumab in combination with OIT is discussed in greater detail separately. (See "Food allergy management: Allergen-specific immunotherapy", section on 'OIT plus dupilumab'.)

mAbs targeting alarmins — Etokimab, an mAb against the alarmin IL-33 (anti-IL-33), was evaluated in a six-week placebo-controlled phase IIa study in 20 adults with peanut allergy assigned 3:1 to treatment or placebo, with inconclusive results [23].

IgG4 mAbs to Ara h 2 — A highly conserved, immunodominant Ara h 2 epitope was identified in patients with peanut allergy using a single-cell ribonucleic acid (RNA) sequencing platform, and recombinant IgE mAbs against this epitope were created [24]. These mAbs elicited mast cell degranulation and anaphylaxis on peanut challenge in a humanized mouse model. IgG4 mAbs to this epitope were then created and shown to partially inhibit mast cell degranulation in vitro. These results are consistent with findings that persons with sustained unresponsiveness to peanut with OIT produce IgG that primarily targets this Ara h 2 epitope [25]. With identification of additional immunodominant epitopes, a combination of recombinant IgG neutralizing mAbs may offer an additional treatment for food allergy.

Small-molecule inhibitors — Alternative therapeutic strategies are drugs targeting either activation of T cells or the signaling cascade in effector cells leading to inhibition of activation and degranulation of preformed mediators. Some of these drugs are small-molecule drugs administered orally, including Bruton tyrosine kinase (BTK) and Janus kinase (JAK) inhibitors.

BTK inhibitors — Bruton tyrosine kinase (BTK), located downstream of the IgE receptor, is a cytoplasmic kinase expressed in selected immune cells such as mast cells, basophils, B cells, macrophages, and platelets. Cross-linking of Fc-epsilon-RI promptly activates BTK in mast cells and basophils. The release of histamine and inflammatory cytokines by mast cells and basophils is reduced in BTK-null mice and patients with BTK deficiency. BTK inhibitors include ibrutinib, acalabrutinib, and remibrutinib. Small, short-duration studies of these drugs have been performed or are underway, but further studies are needed to delineate the safety and utility of prolonged administration of BTK inhibitors in patients with food allergy to prevent anaphylaxis from an accidental food exposure.

●Ibrutinib – Ibrutinib inhibits B cell proliferation and survival by irreversibly binding the BTK. Off-target, ibrutinib binds to C-terminal Src kinases and inhibits cell differentiation and growth, which can lead to side effects such as left atrial enlargement and atrial fibrillation. It is US Food and Drug Administration (FDA) approved for chronic lymphocytic leukemia (CLL) and other indications.

In a small, open-label study, six patients with peanut and/or tree nut allergy were treated with a standard dose of ibrutinib, 420 mg daily, for up to seven days [26]. Skin prick testing (SPT) and basophil activation tests (BATs) were performed before, during, and after ibrutinib treatment. Ibrutinib was well tolerated and significantly reduced mast cell and basophil reactivity to peanut and tree nut allergens. After two doses of ibrutinib, all SPT reactions were smaller, 44 percent had become negative, and IgE-mediated BAT responses were absent. Additional doses of ibrutinib for up to seven days did not increase SPT suppression compared with two doses. The effects of ibrutinib waned within seven days following the last dose.

●Acalabrutinib – Acalabrutinib is a selective and irreversible BTK inhibitor that binds to the active BTK site, inhibiting BTK enzyme activity. It is US FDA approved for several indications including CLL.

In a phase II clinical study, 10 adults with challenge-confirmed peanut allergy received four standard doses of acalabrutinib, 100 mg twice daily, and underwent repeat food challenge [27]. The threshold dose of ingested peanut protein to elicit an objective clinical reaction during oral food challenge (OFC) increased from a median of 29 mg of peanut protein at baseline to a median 4044 mg (range 444 to 4044 mg). Seven participants tolerated the maximum dose of peanut protein without symptoms, and, in the remaining three participants, peanut tolerance increased between 32- and 217-fold. A total of four nonserious, transient adverse events that were possibly related to acalabrutinib were reported in three patients.

●Remibrutinib – Remibrutinib is another highly selective, oral BTK inhibitor. It has no US FDA-approved indications but is under investigation for moderate-to-severe CSU in addition to food allergy.

A one-month, phase II, multicenter, randomized trial is planned to assess the safety, efficacy, and tolerability of remibrutinib in adults with a confirmed diagnosis of IgE-mediated peanut allergy (NCT05432388). OFCs will be performed at baseline and at the end of the treatment period to assess symptoms to increasing doses of peanut allergen.

JAK inhibitor (abrocitinib) — Janus kinase (JAK) inhibitors, also known as jakinibs, are immune-modulating drugs that inhibit the activity of one or more of the JAK family of enzymes (JAK1, JAK2, JAK3, tyrosine kinase [TYK] 2), thereby interfering with the JAK-signal transducer and activator of transcription (STAT) signaling pathway in lymphocytes. Abrocitinib is a selective oral jakinib indicated for the treatment refractory, moderate-to-severe atopic dermatitis (AD) in persons ≥12 years of age whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

Abrocitinib is under investigation for food allergy in a single-center, randomized pilot study. Forty adults 18 to 50 years old with AD and symptomatic IgE-mediated allergy to peanut, cashew, walnut, hazelnut, sesame, cod, and/or shrimp will be randomly assigned 1:1 to abrocitinib 100 mg or 200 mg daily for four months (NCT05069831). The primary outcomes are changes in basophil activation and SPT reactivity at four months compared with baseline.

Targeting gut microbiome — Recognition of the critical role of the gut microbiome in oral tolerance and evidence of dysbiosis associated with food allergy has spurred several therapies aimed at restoring normal gut microbiota in persons with food allergy.

Fecal microbiota transplantation — Study of oral encapsulated fecal microbiota transplantation (FMT) in adults with peanut allergy is ongoing (NCT02960074). This is a phase II, randomized trial evaluating the safety and tolerability of oral encapsulated fecal microbial transplantation therapy (MTT) in patients with peanut. The primary objective is to evaluate whether MTT with antibiotic pretreatment can increase the threshold of peanut reactivity during a DBPCFC from ≤100 mg peanut protein to 300 mg after 28 days of MTT/placebo therapy and four months post-therapy initiation.

VE416 — VE416 is a consortium of commensal bacteria administered orally in a capsule (NCT03936998). It is under investigation in a single-center, randomized phase I/II trial with four arms evaluating VE416 in combination with vancomycin as pretreatment or concurrent treatment in comparison to low-dose peanut OIT alone.

CLB-004 — CLB-004 is a butyrate postbiotic in copolymer (micelles) delivered orally and precisely targeting the lower gut. Butyrate contributes to regulating gut immunity and maintaining epithelial barrier function, but its clinical application is limited by strong odor and quick absorption in the upper gut. When administered intragastrically to mice, these novel polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM), release butyrate from their polymeric core in different regions of the gastrointestinal tract and protect peanut-allergic dysbiotic mice from an anaphylactic reaction to peanut challenge and rescue their antibiotic-induced dysbiosis by increasing the abundance of Clostridium cluster XIVa. Butyrate micelle treatment also reduces the severity of colitis in a murine model. CLB-004 remains in the preclinical phase.

Two other studies were registered (one using probiotics for treatment of cow's milk or hen's egg allergy [NCT03639337] and one using Trichuris suis ova as an immunomodulator to treat peanut or tree nut allergy [NCT01070498]) and listed as completed, but results were not posted.

Traditional Chinese medicine — Herbs have been used in Asia for centuries for treatment of various ailments, including asthma and environmental allergies. Traditional Chinese medicine (TCM) attracted interest because of its reported effectiveness, favorable safety profile, and low cost [28,29]. The mechanism of action of TCM is largely unknown despite extensive clinical experience with TCM in Asia. One double-blind, placebo-controlled multicenter clinical trial evaluated the safety and efficacy of enhanced, butanol-purified food allergy herbal formula 2 (E-B-FAHF-2) for inducing remission in patients undergoing omalizumab-facilitated multiallergen OIT [30]. Omalizumab-facilitated multifood OIT was safe and effective, and remission was achieved in approximately one-quarter of subjects. However, outcomes were not improved by addition of E-B-FAHF-2. At this time, TCM has no proven role in treatment of food allergy. (See "Chinese herbal medicine for the treatment of allergic diseases".)

SUMMARY AND RECOMMENDATIONS

●Overview – Management of food allergy consists of strict avoidance of the food allergen and treatment of accidental exposures with medications. The ultimate goal of therapy for food allergy is to induce tolerance, which means the patient can consume the food ad libitum without symptoms or fear of a reaction. However, a reduction in the risk of allergic reactions through desensitization, even if the food cannot be fully reintroduced into the diet, may be a sufficient outcome for many patients (figure 1 and table 1). Novel therapeutic approaches to food allergy can be classified as food allergen specific or food allergen nonspecific. The primary aim of nonspecific therapies for food allergy is to downregulate the allergic immune response. (See 'Introduction' above and 'Goals of treatment' above and 'Overview of nonspecific therapies' above.)

The general approach to management of food allergy is discussed in detail separately, as is oral immunotherapy (OIT) for food allergy. (See "Management of IgE-mediated food allergy: An overview" and "Food allergy management: Allergen-specific immunotherapy".)

●Omalizumab (anti-IgE) – For most patients with food allergy, we suggest avoidance alone rather than avoidance plus omalizumab, an anti-immunoglobulin E (anti-IgE) monoclonal antibody (mAb) that potentially raises the reaction threshold (Grade 2B). Omalizumab can be used for any food allergen, but the treatment is costly and is not curative, protection is not uniform, and duration of treatment is indefinite. It is also unclear which patients will most benefit from this therapy. In theory, reasonable candidates for omalizumab may include patients who have multiple food allergies, particularly to common foods that are difficult to avoid; a history of systemic reactions to trace amounts of food due to unintentional cross-contact that indicate a lower reaction threshold; or allergic comorbidities that are associated with an increased risk of a more severe reaction. (See 'Omalizumab (anti-IgE)' above and "Food allergy management: Allergen-specific immunotherapy".)

●Other unproven nonspecific therapies with limited data – Additional therapies under investigation for the management of food allergy include other mAbs, small-molecule inhibitors, and fecal microbiota transplantation (FMT). (See 'Additional therapies under investigation' above.)