Intersections Between Allergic Diseases and Multiple Sclerosis: Mechanisms, Clinical Implications, and Hypersensitivity Reactions to Therapy

Abstract

Multiple sclerosis (MS) and allergic diseases, traditionally considered immunologically opposing entities, may share pathogenic mechanisms rooted in immune dysregulation. While MS is predominantly mediated by Th1 and Th17 responses and allergies by Th2 responses, emerging evidence suggests overlapping immunological pathways, including the involvement of histamine, regulatory T cells, and innate lymphoid cells. This review synthesizes current knowledge on the epidemiological and immunopathological associations between MS and allergies. Epidemiological studies have yielded inconsistent results, with some suggesting a protective role for respiratory and food allergies against MS onset, while others find no significant correlation. Clinical studies indicate that food allergies in adults may be associated with increased MS inflammatory activity, whereas childhood atopy might exert a protective effect. In addition, we review hypersensitivity reactions to disease-modifying treatments for MS, detailing their immunological mechanisms, clinical presentation, and management, including desensitization protocols where applicable. Finally, we explore how treatments for allergic diseases—such as clemastine, allergen immunotherapy, montelukast, and omalizumab—may modulate MS pathophysiology, offering potential therapeutic synergies. Understanding the interplay between allergic and autoimmune processes is critical for optimizing care and developing innovative treatment approaches in MS.

1. Introduction

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS), characterized by demyelination, axonal injury, and neurodegeneration. It most commonly affects young adults and exhibits a strong female predominance [1]. Although the precise etiology of MS remains elusive, it is widely accepted to result from a complex interplay between genetic predisposition and environmental exposures. Genetic susceptibility is primarily associated with certain HLA class II alleles, especially HLA-DRB1*15:01, which has been consistently linked to increased MS risk [2]. Environmental risk factors, such as Epstein–Barr virus (EBV) infection, low vitamin D levels, smoking, and high latitude of residence, have also been implicated in MS development [3,4,5]. Dysregulation of immune tolerance plays a central role in MS pathogenesis, with autoreactive T and B cells contributing to CNS inflammation and damage [6]. Interestingly, this failure of immune regulation also underlies allergic disorders, suggesting that shared mechanisms may exist between autoimmunity and atopy. This observation opens the door to exploring how allergic responses and autoimmune mechanisms may intersect, particularly in diseases such as MS.

Allergy is defined as an inappropriate and exaggerated immune response to innocuous environmental agents, known as allergens. This response involves a form of immune dysregulation, in which the immune system fails to maintain tolerance to non-threatening antigens. Thus, allergen exposure triggers the release of several inflammatory mediators. Allergic responses are characterized by a predominant T helper 2 (Th2) immune profile, with elevated levels of key cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13).

The concept of immune dysfunction is pivotal to both allergies and autoimmune diseases, including MS, where immunological dysregulation causes the immune system to mistakenly target its own tissues or exaggerate its response to these agents [7]. The traditional view, grounded in the Th1/Th2 paradigm, has suggested a possible inverse relationship between MS (Th1-mediated) and allergy (Th2-mediated) [8]. However, recent observations, such as the parallel rise in the prevalence of both MS and allergic diseases in industrialized countries, have challenged this mutually exclusive model [9]. For instance, the global prevalence of multiple sclerosis is estimated at approximately 35.9 per 100,000 inhabitants, but this figure exceeds 150–200 per 100,000 in North America and Western Europe [10], while allergic diseases—particularly asthma, allergic rhinitis, and atopic dermatitis—affect a substantial proportion of the population, with asthma prevalence exceeding 15% and atopic dermatitis affecting up to 30% of children [9]. The coexistence of these high prevalence rates in the same geographic areas has led to growing interest in identifying shared environmental drivers and immune mechanisms.

Emerging research has suggested that the immune response in both MS and allergy is more complex than a simple Th1/Th2 dichotomy, with the possibility of overlapping or interacting immune pathways [11,12,13,14,15]. Furthermore, recent research highlights the role of other immune pathways, such as Th17 and regulatory T cells (Tregs), which contribute to the immunological complexity of both MS and allergic conditions [16]. Investigating a potential biological association between allergies and MS is imperative for a better understanding of the etiology and pathogenesis of both diseases and may have implications for the assessment of risk, disease management, and the development of new therapeutic strategies.

Despite historical assumptions of a mutually exclusive relationship between autoimmune and allergic diseases, accumulating evidence suggests a more nuanced interaction. Understanding how allergic conditions may influence MS susceptibility, disease course, or treatment response is of growing clinical and research interest. Moreover, as disease-modifying therapies (DMTs) become increasingly diverse and complex, hypersensitivity reactions to these treatments pose an emerging challenge in MS management. This review aims to synthesize current knowledge on the relationship between allergies and MS, with a dual focus: first, to explore the potential immunopathological links between the two conditions, and second, to describe hypersensitivity reactions to MS therapies, including their mechanisms, clinical presentations, and implications for patient care. Such knowledge may aid clinicians in identifying patients at higher risk of treatment-related adverse events, optimizing therapeutic decisions, and enhancing patient education regarding potential immune-mediated complications. Additionally, we examine how some therapies employed in allergic conditions may influence MS immunopathology or clinical outcomes. By consolidating evidence from both epidemiological and mechanistic studies, we seek to offer insights that may inform future research and therapeutic strategies.

2. Shared and Divergent Immunopathological Mechanisms in Multiple Sclerosis and Allergic Diseases

Multiple sclerosis is a complex immune-mediated disease in which autoreactive CD4⁺ and CD8⁺ T cells, particularly the Th1 and Th17 subtypes, play a central role. These cells infiltrate the CNS, recognize myelin-derived antigens—such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG)—and secrete proinflammatory cytokines, like IFN-γ, TNF-α, and IL-17, promoting inflammation and tissue damage [17]. Tregs, which normally suppress inflammatory responses, are dysfunctional in MS, contributing to immune dysregulation [18,19].

B cells also play a key role in MS through the production of autoantibodies targeting CNS components, antigen presentation, and secretion of proinflammatory cytokines. Additionally, ectopic lymphoid follicles have been observed in the meninges, potentially sustaining chronic inflammation [20].

Innate immune cells, including microglia and infiltrating macrophages, exhibit functional polarization: during acute phases, proinflammatory (M1) phenotypes dominate, leading to demyelination, whereas in later stages, a shift toward anti-inflammatory (M2) phenotypes occurs, though this transition is often incomplete [21]. Astrocytes also become reactive, contributing to local inflammation and the formation of glial scars (gliosis) [6].

The demyelination process is marked by oligodendrocyte destruction—the cells responsible for myelin synthesis—and subsequent loss of the myelin sheath, disrupting axonal conduction and resulting in neurological deficits. This damage is mediated by various mechanisms, including proteolytic enzymes, such as calpain [22,23,24], antibody-dependent cellular cytotoxicity, and complement activation [25]. Axonal injury, which can be observed from early disease stages, is a strong predictor of irreversible disability and arises through multiple pathways: direct attack by inflammatory mediators (e.g., nitric oxide), loss of myelin-derived trophic support, dysfunction of ion channels, calcium imbalance, and energy insufficiency due to increased metabolic demands of demyelinated axons [26].

In contrast, allergic diseases are primarily driven by a Th2-dominant immune response, with cytokines, such as IL-4, IL-5, and IL-13, promoting IgE class-switching in B cells, eosinophil activation, and mast cell degranulation. IgE antibodies bind to high-affinity receptors (FcεRI) on mast cells and basophils, initiating a cascade of inflammatory mediator release—including histamine, prostaglandins, and leukotrienes—upon allergen exposure. These events underlie classic immediate hypersensitivity reactions [7]. The immunomodulatory effects of allergic inflammation have the potential to influence the balance between Th1 and Th2 responses, thereby impacting immune function. In specific circumstances, the presence of pronounced Th2-type immune responses, particularly in the context of allergies, has been demonstrated to exert a suppressive influence on Th1-mediated immunity [27].

However, the traditional Th1/Th2 dichotomy has been increasingly challenged. Recent studies have identified Th2-associated elements, such as IgE autoantibodies, in autoimmune conditions, like MS, suggesting a broader and more complex role for Th2 immunity in autoimmunity [28]. Furthermore, allergic inflammation triggers systemic cytokine and chemokine secretion, which may influence distal organ systems, potentially including the CNS [29].

One emerging immunological bridge between MS and allergy is histamine. While classically involved in allergic reactions, histamine also exerts immunomodulatory functions via its four receptors (H1–H4) on T cells and antigen-presenting cells and has been implicated in CNS inflammation relevant to MS pathogenesis [30]. Additionally, innate lymphoid cells (ILCs)—especially ILC2s and ILC3s—have been identified as potential players in both contexts. These cells act as key regulators of immune responses and tissue homeostasis and may help bridge allergic and autoimmune inflammation [31,32,33]. Likewise, allergic diseases—particularly food allergies—can alter the gut microbiota. Disruptions in the gut microbiome have been associated with MS onset and progression, suggesting a potential mechanistic link between food allergy and MS through the gut–brain axis [34,35]. The systemic effects of allergic inflammation—including histamine-driven modulation and microbiota alterations—may provide mechanistic links to CNS autoimmunity.

The observed co-occurrence of MS and allergic diseases in certain geographic regions further challenges the classical Th1/Th2 paradigm, which posits mutual exclusivity between autoimmune and allergic responses. This overlap may reflect shared genetic predispositions and common environmental exposures. Recent large-scale sequencing studies, particularly genome-wide association studies (GWAS), have begun to identify loci potentially shared between the two conditions [36]. Nonetheless, the current evidence remains limited and fragmented, with only a few genes showing replicated associations in both disease contexts. Among the strongest candidates are IL2RA and IL7RA, which encode interleukin receptors involved in T cell development and homeostasis [37,38,39]; BACH2, a transcription factor critical for the balance between regulatory and effector T cells [36,40]; CLEC16A, implicated in autophagy regulation and antigen-presenting cell function [36,37,38,39,40,41]; and IKZF3, a lymphoid transcriptional regulator [36,42]. These findings suggest the existence of partially overlapping immunogenetic mechanisms, though they do not yet support definitive conclusions regarding a shared genetic basis. Additionally, certain environmental factors—such as tobacco exposure and low vitamin D levels—have been associated with increased risk of both MS and allergic diseases and may promote immune deviation toward either autoimmune or allergic phenotypes [3,43,44].

In summary, MS and allergic diseases reflect a complex web of interactions involving both adaptive and innate immunity. The classical Th1/Th2 dichotomy is insufficient to explain their coexistence or interplay. Instead, evidence of cellular plasticity, shared immune mediators, and overlapping pathogenic mechanisms suggest a dynamic and interconnected immunological landscape.

A summary shared and divergent immunopathological mechanisms in multiple sclerosis and allergic diseases is provided in Figure 1.

3. Clinical Associations Between Allergies and Multiple Sclerosis

3.1. Epidemiological Evidence on Allergies and MS Risk

Several studies have examined the potential relationship between a history of allergic diseases and the risk of developing MS, yielding heterogeneous and, in many cases, contradictory results. Most of these investigations are retrospective and rely on data collection through self-administered questionnaires, introducing a potential recall bias. Only a few studies have employed structured face-to-face interviews or complemented clinical information with objective analytical determinations. The significant methodological and population differences among studies hinder direct comparison and the drawing of definitive conclusions.

A 2011 systematic review and meta-analysis including 10 studies published up to July 2009 found no statistically significant association between allergies (any allergic disease, asthma, allergic rhinitis, or eczema) and the risk of developing MS (pooled odds ratio [OR] 0.91, 95% confidence interval [CI] 0.68–1.23). No significant associations were observed when analyzing asthma, allergic rhinitis, or eczema separately [45]. Nevertheless, the text also states that certain individual studies, including a case-control study in northern Italy, have documented a protective effect of atopic allergies against MS, particularly allergic asthma [46].

Subsequent studies have produced similarly heterogeneous findings. In Iran, a case-control study that included 40 recently diagnosed MS patients and 40 matched healthy controls, found no statistically significant differences in the prevalence of allergies (50% in MS vs. 50% in controls; p = 1.00), frequency of atopy (62.5% vs. 69.2%; p = 0.637), or specific IgE positivity (50% vs. 47.5%; p = 0.821). Despite the small sample size, the strengths of this study include the careful investigation of allergy prevalence using direct interviews and analytical results [47].

Large retrospective cohort studies have explored the association between atopic conditions and autoimmune diseases more broadly. A study based on The Health Improvement Network database in the United Kingdom included 782,320 patients with allergic rhinoconjunctivitis, 1,393,570 with atopic eczema, and 1,049,868 with asthma. The results indicated higher incidences of systemic lupus erythematosus (SLE) and Sjögren’s syndrome among patients with allergic rhinoconjunctivitis; higher incidences of Sjögren’s syndrome and myasthenia gravis among asthmatics; and increased incidences of SLE, Sjögren’s syndrome, vitiligo, and psoriasis among patients with atopic eczema. However, no significant association with MS was identified [48]. Similarly, a recent study based on the Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care database, including 173,709 patients with atopic dermatitis and 694,836 matched controls, also found no differences in MS prevalence [49].

Few studies have specifically analyzed the role of different types of allergic diseases in relation to the risk of MS. A potential protective effect has been suggested, particularly for respiratory allergies. A study conducted in the United States using data from the National Ambulatory Medical Care Survey (NAMCS) reported that respiratory tract allergies were associated with a reduced risk of MS [50]. Similarly, an Iranian case-control study demonstrated an inverse association between a history of respiratory allergies and the risk of developing MS. Furthermore, regarding food and drug allergies, the same Iranian study observed a significant inverse association between a history of food or drug allergies and the risk of MS [51]. However, a recent systematic review and metanalysis of asthma in people with MS showed that asthma does not exhibit a significant relationship with MS [52].

The relationship between allergic diseases and MS has also been investigated in pediatric populations. A case-control study conducted in pediatric MS patients examined the prevalence of allergies during the first five years of life. No associations were found either with the combined outcome of all allergies or when antibiotic, environmental, and food allergies were analyzed separately [8].

Beyond classic allergic conditions, recent epidemiological research has underscored the potential role of occupational exposures to sensitizing or irritant agents in MS susceptibility. A recent systematic review and meta-analysis, including over 19,000 MS cases and 4 million controls, identified a significantly increased risk of MS among workers exposed to substances, such as pesticides or toxic fumes from oil wells, as well as in occupations, such as hairdressers, agricultural workers, and offshore workers [53]. While these exposures do not constitute allergic diseases per se, many involve contact with agents known to induce allergic sensitization or mucosal irritation. Chronic exposure to such substances may contribute to immune dysregulation by promoting low-grade systemic inflammation and epithelial barrier disruption. These findings highlight the need to consider allergen-rich occupational environments as a potentially underrecognized component of MS environmental risk.

Taken together, current evidence on the relationship between allergies and the risk of MS remains inconclusive. While certain studies suggest a potential protective effect, particularly for respiratory and food allergies, most large-scale epidemiological analyses and meta-analyses have not confirmed a statistically significant association. Methodological heterogeneity, population differences, and inconsistent definitions of allergic disease may account for the discrepancies.

Several biological hypotheses have been proposed to explain the inverse association observed in some studies between allergic conditions—particularly respiratory and food allergies—and the risk of MS. A central idea is the Th1/Th2 immune deviation: since MS is primarily mediated by Th1/Th17 pathways and allergic diseases by Th2 responses, a dominance of Th2 immunity (as seen in atopy) may downregulate autoimmune inflammation through cytokines, such as IL-4, IL-5, and IL-13 [46,47,51]. Other possible mechanisms include antigenic competition or peripheral immune diversion, in which chronic stimulation by allergens leads to immune tolerance or reallocation of immunological resources [51]. It has also been hypothesized that autoreactive T cells migrating through the lungs might be locally reprogrammed or tolerized in an allergic pulmonary environment, thus reducing their pathogenic potential in the central nervous system [51]. Additionally, an observation of lower disease activity in individuals with food allergies has raised the possibility that modulation of the gut microbiota may play a role in dampening autoimmune responses [8].

Future research should focus on longitudinal designs, standardized diagnostic criteria for allergic diseases, and validated immune markers. Only then can the potential influence of allergic history on MS susceptibility be clearly defined.

A summary of key epidemiological studies examining the association between allergic conditions and MS risk is provided in

Table 1. Summary of key epidemiological studies examining the association between allergic conditions and risk of developing MS.

Study	Design	Population	Type of Allergic Condition	Specific Manifestation	MS Risk Outcome OR/HR (95% CI)	Key Findings
Monteiro (2011) [45]	Meta-analysis	Mixed	Any allergy	Combined allergies	Pooled OR 0.91 (0.68–1.23)	No significant association between allergic diseases and MS
Pedotti (2009) [46]	Case-control	Adults, Italy	Atopic conditions	Atopic allergies; allergic asthma	OR 0.58 (0.38–0.89); OR 0.38 (0.22–0.66)	Significant inverse association, especially for allergic asthma
Karimi (2023) [47]	Case-control (questionnaire + IgE measure)	Adults, Iran	Any allergy	Rhinitis, conjunctivitis, eczema/urticaria, asthma; total/specific IgE	Not reported (NS)	No differences in allergy prevalence or IgE levels between MS and controls
Krishna (2019) [48]	Retrospective cohort	All ages, UK	Allergic diseases	Rhinitis/conjunctivitis; eczema; asthma	ORs 1.03–1.07 (all NS)	Increased risk of other autoimmune diseases but not MS
de Lusignan (2022) [49]	Retrospective cohort	All ages, UK	Atopic dermatitis	Atopic dermatitis	HR 0.95 (0.68–1.35)	No significant association with MS
Ren (2017) [50]	Case-control database	Adults, USA	Environmental allergies	Respiratory tract allergy	OR 0.29 (0.18–0.49)	Strong inverse association with MS
Sahraian (2013) [51]	Case-control	Adults, Iran	Combined allergies	Respiratory, food/drug allergies	OR 0.24 (0.13–0.43); OR 0.43 (0.28–0.66)	Significant inverse association for respiratory and food/drug allergies
Ghoshouni (2024) [52]	Meta-analysis	Adults, mixed	Asthma	Asthma	Pooled OR 1.09 (0.98–1.21)	No association between asthma and MS
Bourne (2017) [8]	Case-control	Pediatrics, USA	Multiple allergies	Food, environmental, antibiotic allergies	ORs: 0.61, 0.65, 2.05 (NS)	No higher prevalence of allergies in pediatric MS patients
Vitturi (2023) [53]	Meta-analysis	Adults, mixed	Occupational exposure	Various occupations with sensitizing agents	Hairdressers OR 8.25 (1.02–66.52); pesticides OR 3.17 (2.53–3.99)	Increased MS risk in multiple occupations

NS: Not Significant. OR: Odds Ratio. HR: Hazard Ratio. CI: Confidence Interval.

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3.2. Impact of Allergies on the Clinical Course of Multiple Sclerosis

While much of the literature has examined whether allergic conditions influence the risk of MS onset, relatively few studies have addressed their impact on the clinical course and disease activity in patients with established MS.

A limited number of clinical studies have explored how different types of allergies impact relapse frequency and magnetic resonance imaging (MRI) activity in MS. One of the most comprehensive studies, involving over 1300 adult patients, found that individuals with food allergies experienced a 27% higher relapse rate and more than twice the odds of having gadolinium-enhancing lesions (GELs) compared to patients without allergies. However, environmental allergies (e.g., pollen, dust mites) and drug allergies did not show any significant association with inflammatory activity or disability [54].

In pediatric populations, the findings suggest the opposite trend. A case-control study in children with MS showed that those with early life food allergies had a significantly lower annualized relapse rate than their non-allergic peers [8]. Some authors propose that this discrepancy could be attributed to immunopathological differences between pediatric and adult-onset MS [55].

When evaluating long-term disability progression, the current body of evidence suggests that allergic comorbidities do not significantly affect neurologic decline as measured by the Expanded Disability Status Scale (EDSS) or composite severity scores, like the Multiple Sclerosis Severity Score (MSSS). Even in patients with heightened inflammatory activity due to food allergies, no measurable impact on long-term disability has been observed [54]. Similarly, a study in over 600 patients found no difference in the time to reach EDSS milestones between patients with and without asthma [56]. Another study from Kuwait found no association between food allergies and MSSS but identified factors such as higher education and regular physical activity as protective against disease severity [57].

Despite these clinical data, no studies to date have stratified levels of neurodegenerative biomarkers—such as neurofilament light chain (NfL) or glial fibrillary acidic protein (GFAP)—based on allergic status. This represents an important gap in the literature. Given the increasing use of these biomarkers to detect subclinical neuronal damage in MS, their assessment in allergic vs. non-allergic patients could help clarify whether increased relapse activity translates into more sustained neuroaxonal loss.

Although allergies do not appear to impact disability progression, they may nonetheless exacerbate symptom burden and negatively affect quality of life. In one study, patients with comorbid asthma reported significantly worse mental health outcomes compared to non-asthmatic counterparts [56]. In another population-based analysis, allergies were among the most frequent comorbidities reported by patients with MS and were associated with increased productivity loss and a greater number of workdays lost annually [58]. These findings underscore the broader impact that allergic comorbidities may exert on daily functioning and patient well-being, even when they do not affect objective neurological impairment.

Taken together, the available evidence suggests a nuanced relationship between allergic diseases and the clinical course of MS. While long-term neurological disability does not appear to be influenced by allergies, certain allergy types—particularly food allergies in adults—are associated with greater inflammatory activity, including more frequent relapses and MRI lesions. In contrast, early life atopic manifestations in children may confer a protective effect, though this requires further investigation. Biomarker data remain sparse and warrant exploration, especially regarding NfL and GFAP levels in allergic subgroups. Clinically, the presence of allergies may contribute to higher symptom load and reduced quality of life, reinforcing the need for comprehensive care approaches that address both MS and its comorbidities.

Future longitudinal studies are needed to clarify the immunological interplay between allergic mechanisms and central nervous system autoimmunity and to determine whether targeting allergic pathways—such as mast cells, histamine receptors, or IgE—might hold therapeutic value in selected subsets of patients with MS.

A summary of key clinical studies examining the impact of allergic conditions on the course of MS is provided in

Table 2. Summary of key clinical studies examining the impact of allergic conditions on the disease course of multiple sclerosis (MS).

Study	Design	Population	Type of Allergic Condition	Specific Manifestation	Outcome	Key Findings
Fakih (2019) [54]	Cross-sectional	Adults, USA	Food, environmental, drug allergies	Any food, environmental, or drug allergy	Relapse Ratio 1.27 (95% CI 1.02–1.59); GELs OR 2.53 (95% CI 1.25–4.59) for food allergy	Higher MS activity in adults with food allergies; no differences in disability outcomes
Bourne (2017) [8]	Case-control	Pediatrics, USA	Multiple allergies	Food, environmental, antibiotic allergies	ARR: 0.14 vs. 0.48 (p = 0.01) for food allergy	Lower MS activity in pediatric food allergies
Manouchehrinia (2015) [56]	Retrospective cohort	Adults, UK	Asthma	Asthma	HR EDSS 4.0: 1.29 (0.93–1.77); HR EDSS 6.0: 1.33 (0.93–1.89)	Asthma not associated with greater disability; worse mental health scores in asthmatics
Albatineh (2020) [57]	Cross-sectional	Adults, Kuwait	Food allergy	Food allergy	Not reported (NS)	No association between food allergy and MS severity (MSSS)
Chen (2020) [58]	Cross-sectional	Adults, Australia	Any allergy	Any allergic condition	Productivity loss: ~35.7 days/year; ~18% with allergies	Allergies linked to higher productivity loss and poorer self-reported health

GELs: Gadolinium-Enhancing Lesions. EDSS: Expanded Disability Status Scale. MSSS: Multiple Sclerosis Severity Score. HR: Hazard Ratio. OR: Odds Ratio. NS: Not Significant. ARR: Annualized Relapse Rate.

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4. Hypersensitivity and Immune-Mediated Reactions to Disease-Modifying Treatments in Multiple Sclerosis

4.1. Glatiramer Acetate

Glatiramer acetate (GA) is a subcutaneous injectable immunomodulator composed of a mixture of synthetic peptides, widely used in the treatment of relapsing–remitting multiple sclerosis (RRMS). Although its safety profile is considered favorable, various hypersensitivity reactions have been documented.

Local injection site reactions, characterized by erythema, pruritus, and oedema, are highly prevalent, affecting up to 80–90% of patients [59]. Additionally, 10% to 15% of patients experience immediate post-injection systemic reactions (IPIRs), which typically present as facial flushing, dyspnea, palpitations, chest tightness, and anxiety. These reactions usually resolve spontaneously within minutes and are not accompanied by cardiovascular instability [60]. While IPIRs are not considered classical hypersensitivity reactions, several mechanisms have been proposed, including both IgE-mediated and non-IgE-mediated pathways. Notably, the latter may involve direct mast cell activation through MRGPRX2 receptors, independent of IgE [61]. Importantly, the occurrence of IPIRs is not associated with an increased risk of future anaphylaxis and should be carefully distinguished from true anaphylactic reactions to avoid unnecessary discontinuation of therapy [59].

True systemic allergic reactions to GA, including anaphylaxis, are rare but potentially life-threatening. These may occur after prolonged exposure or even after the first administration [62,63]. IgE-mediated mechanisms have been confirmed in several cases through positive skin tests (prick and intradermal) and the detection of specific IgE antibodies against the drug or its excipients, particularly mannitol [63,64]. The diagnosis of GA-induced anaphylaxis requires a compatible clinical history, skin testing with non-irritating dilutions, and, when available, specific IgE determination or basophil activation testing [64,65]. In suspected cases, GA should be immediately discontinued, and emergency treatment initiated, including intramuscular epinephrine, antihistamines, corticosteroids, and referral to an allergist for diagnostic confirmation and management [62].

In patients with confirmed GA-induced anaphylaxis and no suitable therapeutic alternatives, desensitization protocols represent a viable option. These protocols involve the supervised administration of incrementally increasing doses of GA at regular intervals until the full therapeutic dose is achieved. A standard desensitization protocol begins with a subcutaneous dose of 0.00002 mg, doubling approximately every 20 min until the target dose of 20 mg is reached. The inclusion of premedication—such as anti-inflammatory agents and leukotriene receptor antagonists, like montelukast—may improve tolerability [66,67]. While generally safe and effective, this procedure must be conducted in a hospital setting under close medical supervision, with immediate access to emergency care in case of breakthrough hypersensitivity reactions.

4.2. Beta Interferons

Beta interferons (IFN-β) represent one of the most established disease-modifying therapies for RRMS. Different formulations are used: intramuscular and subcutaneous interferon beta-1a, interferon beta-1b, and a pegylated version of beta-1a, which differ in dosing frequency, immunogenicity, and adverse effect profiles. Although generally well tolerated, IFN-β can induce local and systemic immunological reactions. Among the most common are inflammatory reactions at the injection site, affecting up to 90% of treated patients [68].

A common adverse effect, although not immunoallergic, is the so-called flu-like syndrome, observed in a significant proportion of patients treated with IFN-β. It presents with fever, myalgia, chills, headache, and general malaise, typically after the first doses and tends to subside over time. Its pathophysiology is related to the induction of proinflammatory cytokines (IL-6, IFN-γ, and TNF-α) in response to exogenous IFN-β [68,69]. This phenomenon reflects a nonspecific immune activation, not mediated by hypersensitivity. Management is symptomatic and includes prophylactic use of paracetamol or NSAIDs, as well as nighttime administration of the drug to reduce clinical impact [70]. Although bothersome, it rarely warrants discontinuation of treatment.

Less frequent but clinically significant are systemic allergic reactions. Episodes of anaphylaxis, generalized urticaria, and angioedema have been documented in patients treated with IFN-β, consistent with type I IgE-mediated hypersensitivity [71,72]. Very rarely, type II reactions mediated by IgG or IgM antibodies directed against cellular antigens, such as autoimmune cytopenia, autoimmune hepatitis, or drug-induced lupus, type III reactions mediated by immune complexes, such as vasculitis or nephrotic syndrome, and type IV reactions mediated by sensitized T lymphocytes, such as generalized eczema or lichenoid dermatitis [70,73], have been described.

In the presence of severe allergic reactions, discontinuation of interferon is the general recommendation. In highly selected cases, where alternatives are contraindicated or ineffective, successful use of IFN-β desensitization protocols has been documented, particularly in patients with confirmed IgE-mediated reactions [74]. These protocols must be conducted in specialized hospital settings, under close supervision and long-term follow-up, as the induced tolerance is temporary and is lost if administration is interrupted.

4.3. Fumarates

Dimethyl fumarate (DMF) and diroximel fumarate (DRF) are esters of fumaric acid with immunomodulatory effects. Both are metabolized into monomethyl fumarate, which exerts anti-inflammatory and antioxidant actions primarily through activation of the nuclear transcription pathway Nrf2/Keap1. One of the most common adverse effects of this pharmacological group is flushing, a frequent and benign reaction caused by prostaglandin release following activation of the GPR109A receptor by monomethyl fumarate [75]. Unlike true allergic reactions, flushing does not require prior sensitization, is not mediated by IgE or T cells, and responds well to premedication with NSAIDs or antihistamines.

On the other hand, infrequent but potentially serious allergic reactions have been described, including urticaria, angioedema, delayed skin rashes, and systemic conditions such as eosinophilic gastroenteritis or myocarditis [76,77,78,79,80]. Most reported cases involve DMF, given its longer clinical use, although DRF is presumed to be capable of inducing similar reactions due to the shared active metabolite. Immediate reactions, such as urticaria following the first dose, may correspond to type I hypersensitivity. However, in some cases, sensitization could not be confirmed by skin testing, suggesting alternative mechanisms, such as direct mast cell activation [77,79].

In contrast, delayed hypersensitivity reactions mediated by T cells (type IV) have been documented. These include positive findings in patch testing and lymphocyte transformation tests, supporting a specific immunological basis [77,81]. Furthermore, in some patients, an immunological shift toward a Th2 phenotype has been observed under DMF treatment, which could favor the development of atopic phenomena and eosinophilia [82].

The management of these reactions depends on their severity. In cases of isolated urticaria or mild reactions, treatment continuation has been achieved through progressive desensitization protocols carried out under strict medical supervision [79]. However, in the presence of severe reactions, such as anaphylaxis or visceral involvement with eosinophilia, re-exposure to the drug is contraindicated. Switching between DMF and DRF is generally not a viable option in confirmed allergy cases due to cross-reactivity with the shared active metabolite [78].

4.4. Teriflunomide

Teriflunomide is an oral immunomodulator approved for the treatment of relapsing forms of MS. It is the active metabolite of leflunomide and acts by inhibiting the enzyme dihydroorotate dehydrogenase, essential for de novo pyrimidine synthesis, thereby reducing the proliferation of activated lymphocytes. Since its introduction into clinical practice, rare but occasionally severe allergic reactions have been reported. Described manifestations include type I reactions, such as angioedema, anaphylaxis, and severe type IV cutaneous reactions, including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) [83,84,85]. Immunological pulmonary reactions, such as hypersensitivity pneumonitis, have also been described, albeit exceptionally [85].

The structural similarity between teriflunomide and leflunomide implies cross-reactivity and therefore contraindicates the use of teriflunomide in patients allergic to either compound [85].

The pharmacokinetics of teriflunomide are particularly relevant in this context, given its extremely long half-life—estimated between 15 and 18 days—with complete elimination from the body potentially taking up to 2 years due to high lipophilicity and enterohepatic recirculation [85]. This implies that hypersensitivity reactions may persist or reactivate even after drug discontinuation, unless active measures are taken to accelerate its elimination. The most employed accelerated elimination protocol involves the administration of cholestyramine. Alternatively, activated charcoal may be used [85]. This intervention is critical in severe reactions, where the persistence of the pharmacologic antigen could worsen or delay clinical resolution. Management of such reactions must be immediate, including permanent drug withdrawal, pharmacological washout, and initiation of symptomatic or immunosuppressive treatment depending on severity. There are no published desensitization protocols for teriflunomide, as reintroduction is not recommended after a severe reaction.

4.5. Cladribine

Cladribine is an oral purine analogue with selective cytotoxicity for B and T lymphocytes. In MS, it is typically administered in two annual cycles, each consisting of two weeks of treatment separated by approximately one month. Although its safety profile is generally favorable, allergic reactions—though uncommon—have been documented, including cutaneous rash, urticaria, and in isolated cases, severe hypersensitivity reactions, such as glottic edema or severe immunologic rashes [86]. In pivotal trials, like CLARITY, the incidence of allergic reactions was slightly higher in the cladribine group than in the placebo (11% vs. 7%), mostly mild and transient [87]. Although no confirmed cases of anaphylaxis were reported in these trials, post-marketing surveillance—particularly in oncology settings where higher cumulative doses were used—has included reports of serious hypersensitivity events [88]. Real-world clinical practice reflects similar hypersensitivity rates, generally occurring in the first months after administration [89]. Interestingly, in the context of hairy cell leukemia—where cladribine is administered using different dosages and routes—its use has been associated with an increased incidence of antibiotic allergies, possibly due to treatment-induced immune dysregulation [90]. However, to our knowledge this association has not been reported in MS patients under cladribine treatment.

Some documented cases presented with severe late-onset rashes (up to six months post-dose), and a small number developed late-onset autoimmune phenomena, such as leukocytoclastic vasculitis or alopecia areata (type III and IV) [89]. Severe allergic skin reactions have been described not only in people receiving cladribine for hematological malignancies but also in people with MS [91].

Though severe cases are rare, timely recognition and management are essential. In selected cases where the initial reaction was moderate (e.g., rash without anaphylaxis), treatment has been continued under corticosteroid and antihistamine premedication, allowing safe re-exposure in most patients [91]. There are currently no standardized desensitization protocols for cladribine, and the general recommendation after anaphylaxis is permanent discontinuation. In contrast, if the reaction was purely cutaneous and limited in severity, reintroduction may be considered with prophylactic measures, always under strict medical supervision. Patient education on warning signs (e.g., urticaria, facial swelling, respiratory difficulty) is crucial, as many reactions may appear days or weeks after drug administration [89], which contrasts with other intravenous treatments that typically cause immediate reactions.

4.6. Anti-CD20 Monoclonal Antibodies

Anti-CD20 agents (rituximab, ocrelizumab, ofatumumab, and ublituximab) are monoclonal antibodies targeting the CD20 antigen on B cells [92]. Their administration may be associated with immunologically adverse events, mainly infusion-related reactions (IRRs) [93]. These are more frequent with intravenous antibodies (rituximab, ocrelizumab, ublituximab), typically occurring during or shortly after the first infusion and presenting as mild-to-moderate symptoms, such as fever, rash, pruritus, urticaria, nasal congestion, irritative cough, or bronchospasm [94]. IRRs appear to result from the release of proinflammatory cytokines following Fc fragment binding to FcγRIIIa (CD16) receptors on NK and B cells [95]. Rituximab, a chimeric antibody, has high IRR rates (~67–78% at first infusion) [94]; ocrelizumab, a humanized antibody, shows somewhat lower incidence (~34–40%) [93]; and ublituximab, also chimeric, reaches ~47% [96]. These reactions can be mitigated by premedication (corticosteroids, antihistamines, antipyretics) and slowing the infusion rate. Ofatumumab, a fully human subcutaneously administered antibody, causes mild transient systemic reactions in ~14% of patients—mostly flu-like symptoms—without requiring systematic premedication [93].

Severe anaphylactic reactions have been reported at low rates with all agents. Their likelihood appears to correlate with the degree of antibody humanization: chimeric antibodies (rituximab, ublituximab) are more immunogenic, while humanized (ocrelizumab) and fully human (ofatumumab) forms have lower risk [93,94,96,97]. Rituximab and, to a lesser extent, ocrelizumab have been associated with serum sickness (a type III hypersensitivity reaction), presenting with fever, arthralgia, and elevated acute-phase reactants 1–2 weeks post-infusion [98,99]. DRESS syndrome has also been linked to ocrelizumab [97], and recent reports describe delayed skin reactions associated with ofatumumab [100].

Management depends on severity. Mild IRRs can be controlled with infusion rate reduction, symptomatic treatment, and cautious resumption. In severe reactions, such as anaphylaxis, infusion must be stopped immediately and treated per emergency protocols. When anti-CD20 therapy is indispensable, successful desensitization protocols have been described, particularly with rituximab and ocrelizumab, allowing continuation under strict monitoring [101,102]. Alternatively, switching to a more humanized anti-CD20 agent or a different therapeutic class may be considered based on individualized risk–benefit assessment [103].

4.7. Natalizumab

Natalizumab is a humanized monoclonal antibody targeting the α4-integrin, which prevents immune cell migration into the CNS. Like anti-CD20 therapies, it has been associated with non-allergic infusion-related reactions (IRRs), which are common but typically benign. Differentiating these from true allergic reactions is essential.

Most allergic reactions to natalizumab are immediate hypersensitivity reactions occurring during or shortly after infusion [104]. These are classified as type I IgE-mediated reactions or anaphylactoid reactions via non-IgE mechanisms [105,106]. Their incidence ranges from ~1% to 6%, typically presenting during early doses—often on the second infusion following sensitization. Symptoms include pruritus, generalized urticarial rash, facial flushing, dyspnea, chest tightness, hypotension, wheezing, nausea, and/or angioedema [104]. Severe cases may lead to anaphylaxis [106].

Delayed immune complex–mediated reactions (type III), resembling serum sickness, have also been reported days after infusion, presenting with fever, rash, and arthralgia [107,108].

A higher frequency and severity of hypersensitivity reactions have been observed in patients with anti-natalizumab IgG antibodies, which are also associated with reduced clinical efficacy [108,109], justifying immunological monitoring in suspected cases.

Recent studies have identified a genetic predisposition: certain class II HLA alleles (e.g., HLA-DRB113 and DRB114) are associated with an increased risk of allergic reactions to natalizumab, while HLA-DRB1*15 appears to confer protection [106]. These findings suggest that HLA-mediated antigen presentation plays a key role in immunological sensitization to the drug.

Close monitoring during infusions and early symptom recognition are essential to optimize treatment safety. Permanent discontinuation of the drug is the usual strategy following a severe allergic reaction, although successful desensitization protocols have been described in selected patients [110,111].

4.8. Sphingosine-1-Phosphate Receptor Modulators

Sphingosine-1-phosphate receptor modulators (fingolimod, siponimod, ozanimod, and ponesimod) act primarily by sequestering lymphocytes in lymph nodes. All have been associated with rare but clinically relevant allergic reactions, predominantly mediated by type I hypersensitivity mechanisms, with occasional reports of type IV reactions.

Fingolimod, with the longest post-marketing experience, has been linked to maculopapular rash, urticaria, angioedema, and, exceptionally, a case of Stevens–Johnson syndrome, prompting specific warnings in its summary of product characteristics [112]. Isolated reports of Wells syndrome (eosinophilic cellulitis) have also been published [113].

In contrast, siponimod, ozanimod, and ponesimod appear to have even lower incidences of allergic reactions, though sporadic cases of rash and urticaria have been reported [114,115,116]. It is worth noting a specific contraindication for siponimod in patients allergic to peanuts or soy due to its excipients [116].

There are no specific desensitization protocols developed for these drugs. In the event of confirmed hypersensitivity, permanent treatment discontinuation is recommended, with consideration of alternative therapies involving different mechanisms of action.

4.9. Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody targeting CD52. Its mechanism of action involves profound T and B lymphocyte depletion, followed by immune reconstitution that modifies disease course. It is administered intermittently in two main annual cycles. However, intravenous administration is frequently associated with infusion-related reactions (IRRs), affecting more than 90% of patients, with higher intensity during the first treatment cycle [117,118].

These reactions are typically mild to moderate—fever, headache, rash, urticaria, nausea—but approximately 2–3% can be severe, including anaphylaxis, bronchospasm, or angioedema [117,119]. Most IRRs are effectively managed with premedication (corticosteroids, antihistamines, and antipyretics) and supportive care, although close monitoring is essential during and after infusion in hospital settings.

From an immunological perspective, most IRRs are caused by cytokine release syndrome, triggered by innate immune cell activation—such as neutrophils and NK cells—rather than classical hypersensitivity mechanisms [120]. Although rare, immediate IgE-mediated hypersensitivity has been reported, with positive skin tests and elevated tryptase levels, consistent with true anaphylaxis after prior sensitization [121].

In confirmed anaphylaxis, the drug must be discontinued, and emergency measures applied. However, if the patient’s clinical profile justifies continued use of alemtuzumab and no equivalent therapeutic alternatives are available, desensitization may be considered. Reports of successful rapid desensitization protocols with dose escalation in a controlled setting have enabled re-administration without recurrence of the reaction [121,122].

Notably, serious adverse events have recently been reported following alemtuzumab infusion—including myocardial infarction, cerebral hemorrhage, cervicocephalic arterial dissection, alveolar hemorrhage, and thrombocytopenia. These events typically occur within the first three days after drug administration, with highest incidence in the first 24 h. The European Medicines Agency (EMA) has issued a safety alert recommending strict monitoring during and after infusion [119,123]. The exact mechanism behind these events is not fully understood, but the rapid release of proinflammatory cytokines during infusion may induce acute endothelial dysfunction, promoting thrombotic or hemorrhagic phenomena [124].

5. Effects of Allergic Treatments on Multiple Sclerosis

Several therapies used in allergic diseases act on immune pathways also involved in MS, such as mast cell activation, Th2/Th17 signaling, and cytokine production. Consequently, some of these agents may influence MS risk or alter its clinical course, with variable effects depending on the type of intervention.

Among antihistamines, clemastine fumarate has been one of the most studied in relation to MS. Originally indicated for allergic symptoms, this first-generation antihistamine crosses the blood–brain barrier and has antimuscarinic properties. In preclinical studies, clemastine promoted the differentiation of oligodendrocyte precursor cells and facilitated remyelination after demyelinating lesions in animal models. This effect has been attributed to M1 muscarinic receptor antagonism, which promotes intracellular signaling pathways leading to oligodendrocyte maturation and myelin synthesis [125]. Based on these findings, the ReBUILD trial was designed to evaluate clemastine in patients with relapsing–remitting MS and chronic optic nerve damage. The study showed a modest but significant reduction in visual evoked potential latency, interpreted as indirect evidence of functional remyelination [126]. However, a subsequent trial (TRAP-MS) assessing clemastine in progressive MS was terminated early due to accelerated disability accumulation observed in some participants.

Another area of interest is allergen immunotherapy (AIT), used to induce immune tolerance to specific allergens. Although historically associated with concerns about safety in autoimmune diseases, the available evidence suggests that these concerns are largely anecdotal. A paradigmatic case reported the onset of MS following subcutaneous immunotherapy and simultaneous influenza vaccination, raising the possibility of a trigger in predisposed individuals [127]. Nevertheless, broader observational studies have not shown a significant increase in autoimmune diseases, including MS, after AIT administration [128]. Current guidelines do not consider stable MS a strict contraindication to allergen immunotherapy [129]. Individual risk–benefit assessment is advised, and initiation during periods of high inflammatory activity should be avoided. Clinical reports describe cases of AIT in patients receiving disease-modifying therapies without evidence of MS reactivation or relevant adverse effects [130].

Leukotriene receptor antagonists, such as montelukast, commonly used in asthma and allergic rhinitis, have shown beneficial effects in MS models. In animals, montelukast suppresses Th17 responses and reduces central nervous system inflammation [131]. Retrospective human studies have associated its use with lower relapse rates in people with MS [132]. Although these findings require prospective confirmation, they suggest therapeutic repurposing potential.

Among monoclonal antibodies used in allergy, omalizumab—an anti-IgE agent approved for severe allergic asthma and chronic spontaneous urticaria—is the most studied in the context of MS. It has been safely administered to MS patients with allergic comorbidities. Although mast cells and IgE may play a secondary role in MS pathophysiology [28], no neurologic adverse events or negative interactions with immunomodulatory therapies have been reported [133].

Overall, most allergological treatments appear to be safe for patients with MS. Some, such as clemastine or montelukast, might offer additional benefits if future studies confirm their efficacy. Comprehensive care for individuals with MS should include appropriate management of allergic comorbidities, which may contribute to improved clinical outcomes and quality of life.

6. Discussion

The relationship between allergic diseases and MS represents an emerging field of interest in clinical immunology. Traditionally considered opposing entities within the immunological spectrum—Th2-mediated in the case of allergies, and Th1/Th17-mediated in MS—both conditions share elements of immune dysfunction that challenge this simplistic dichotomy. The evidence presented in this review suggests that shared immunopathological mechanisms exist, including the involvement of non-conventional helper T cells (Th17), innate lymphoid cells (ILCs), and soluble mediators, such as histamine, which may bridge allergic processes and central nervous system autoimmunity.

From an epidemiological perspective, data on the association between allergies and MS risk are inconsistent. While some observational studies point to a protective effect of certain allergies—particularly respiratory and food allergies—most large-scale population analyses have not confirmed a statistically significant relationship. This disparity may be explained by methodological heterogeneity, population differences, and the lack of standardized diagnostic criteria for allergic diseases.

Regarding MS disease course, some data suggest that adult food allergies may be associated with increased inflammatory activity, whereas atopic manifestations during childhood may confer a protective effect. However, no consistent impact has been demonstrated on the progression of neurological disability or on neurodegeneration biomarkers. This highlights the need to assess symptom burden and quality of life independently from conventional disability metrics, especially considering that allergic comorbidities may exacerbate physical and psychological distress in patients with MS.

Hypersensitivity reactions to disease-modifying therapies represent a clinically relevant and often underestimated issue. Although most reactions are mild or manageable with premedication, severe cases, such as anaphylaxis, DRESS, and Stevens–Johnson syndrome, have been reported with various drugs. Early recognition, individualized management, and, in selected cases, controlled desensitization can allow continuation of effective treatments without compromising patient safety.

Given this context, fostering close collaboration between neurologists and allergists is becoming increasingly important. Joint care facilitates the differential diagnosis of adverse reactions, optimizes therapeutic selection, and improves the clinical experience for patients—especially in complex cases involving overlapping autoimmune and atopic phenomena. This multidisciplinary approach may be key to preventing unnecessary treatment interruptions and ensuring comprehensive care.

Finally, certain treatments used in allergic diseases may have therapeutic applications in MS. Notable examples include clemastine, which has demonstrated remyelinating potential, and montelukast, which exerts immunomodulatory effects on Th17 cells. These findings open the door to drug repurposing strategies targeting shared immunological pathways.

7. Conclusions and Future Directions

Allergic diseases and MS, far from being immunologically exclusive conditions, may share pathogenic and immunomodulatory pathways. Despite the lack of epidemiological consensus, mechanistic evidence supports a complex interaction between atopy and central nervous system autoimmunity. This interplay may influence not only susceptibility to MS but also its inflammatory activity and treatment response.

Current studies underscore the need for a more integrative approach in the management of patients with MS and allergic comorbidities, acknowledging the potential impact on quality of life and treatment adherence. In this context, interdisciplinary collaboration between neurologists and allergists emerges as a key pillar for providing personalized, safe, and effective care.

Furthermore, future research directions should include prospective epidemiological studies using standardized methodologies and longitudinal follow-up, to accurately characterize the influence of allergies on MS risk and clinical course; assessment of the impact of allergies on biomarkers, such as NfL and GFAP; and exploration of therapies targeting shared immune pathways—such as mast cells, histamine, IgE, or Th2/Th17 cells—as adjunct strategies in MS. A deeper understanding of these interactions could yield clinically meaningful advances in both fields, offering new tools for risk stratification, therapeutic decision-making, and improving quality of life in people with MS.