Biologicals and Hypersensitivity Reactions

• Biologicals are critical therapeutic agents in oncological, immunological, and inflammatory diseases due to their selectivity
• Biologicals usage in clinical practice is expanding
• Hypersensitivity reactions (HSRs) are commonly caused by biologicals
• Development of personalized and precision medicine increased HSRs

HSR Development

• Patients can develop HSRs to biologicals upon first exposure or after repeated exposures

Prevalence and Mechanisms

• Underlying mechanisms and optimal management of HSRs to biologicals are not completely known despite a high prevalence of HSRs

Position Paper Recommendations

• This paper provides evidence-based recommendations for diagnosing and managing HSRs to biologicals
• The paper also identifies unmet needs for future research
• Key words include biologicals, hypersensitivity reactions, allergy, monoclonal Abs, interferon, interleukins, drug hypersensitivity, and desensitization

Definitions and Abbreviations

• HSR is hypersensitivity reaction
• mAbs are monoclonal Ab
• omab signifies murine (0% human) mAbs
• ximab means chimeric mAb
• zumab refers to humanized mAb
• mumab indicates fully human mAb
• ...cept names fusion proteins
• IRR is infusion related reaction
• IFNs are interferons
• IL labels interleukins
• CRR signifies cytokine release reaction

Introduction to Biologicals

• Biologicals are large molecular weight therapeutics synthesized by living organisms
• Biologicals bind to a specific determinant, such as a cytokine or receptor
• Biologicals with a reported HSR rate higher than 1% and/or anaphylaxis on individual conditions are presented on Table-1

Significance of Biologicals

• Biologicals are critical therapeutic agents in oncological, immunological and their use in clinical practice is broadening

Hypersensitivity Reactions

• Biologicals are among the most common drugs that can cause HSRs
• HSRs have increased rapidly in the twenty-first century
• New treatment options through personalized and precision medicine has contributed to HSRs
• Patients can develop HSRs during first exposure or after repeated exposure to biologicals

Paper Focus

• Mechanism and management of HSRs to biologicals remains incompletely explained
• Evidence-based recommendations for diagnosing and managing HSRs to biologicals are provided
• A panel of experts was called by the EAACI Drug Allergy Section and Biological WG

Search Strategy

• An intensive electronic literature search was performed by the task force group (TF) in databases like MEDLINE, PubMed, Web of Science, and Google Scholar
• Primary key words used were biologicals, hypersensitivity reactions, allergy, monoclonal Abs, interferon, interleukins, drug hypersensitivity, desensitization
• Each TF member used extra key words for each section
• The search included in vivo and in vitro trials in English language

Meetings and Evidence Grading

• The TF group consulted and discussed the process in meetings in June 2017in Helsinki, in November 2017 in Verona, in May 2018 in Munich, in November 2018 in Porto, in June 2019 Lisbon, and in October 2019 in Rimini/Italy
• Statement, recommendation and unmet needs were carefully reviewed
• The TF members graded evidence quality using the SIGN criteria (Grade A, B, C, D)

Classifying Adverse Reactions

• Adverse reactions to biologicals cannot be classified according to traditional classification because of their different properties from chemical drugs
• Pichler proposed a classification with five types of adverse side-effects of biologicals based on pathomechanisms
• Recently, a new classification was proposed considering phenotypes, endotypes and biomarkers indicating underlying endotype
• Immediate HSRs to biologicals are further classified into infusion-related (IRR), cytokine release, type 1 (IgE/non IgE) and mixed reaction

Infusion-Related Reactions

• Patients mostly suffer from common IRR at first infusion
• Pathogenesis is unclear, but usually affected by infusion rate, pointing out the possibility of a non-immunologic mechanism and the role of inflammatory cytokines like IL-6 and tumor necrosis factor-α

Cytokine Release Reactions

• Clinical symptoms and signs are usually due to the cytokine release, characterized by elevated serum TNF-alpha and IL-6 levels compared with normal baseline
• IRR self-limits on repeated exposure and responds to premedication which distinguishes it from cytokine release reactions
• Infusion related reaction with Cetuximab is an IgE-mediated reaction occurring at the first exposure due to preformed IgE antibodies

Type I Reactions (IgE/non-IgE)

• Reactions are associated with IgE or non-IgE mediated mast cell/basophil degranulation that leads to massive histamine, leukotrienes, and prostaglandins release
• The reactions occur after at least one administration without any reaction and its symptomology is similar to IgE-mediated reactions
• The distinctive point between IgE and non-IgE mediated reactions is a negative skin prick test for non-IgE mediated reactions.

Mixed Reactions

• Mixed reactions are a combination of cytokine release and IgE-mediated reactions
• Skin test positivity/specific IgE to implicated biologicals and increased tryptase, IL-1, IL-6 and TNF-alpha can occur

Epidemiology of HSRs

• All biologicals have the potential to cause HSRs, and due to increased use, HSRs have become more frequently reported
• Reactions to mAbs vary by agent
• Immediate-type HSRs to specific biologicals rates are 5–10% for rituximab, 2–3% for infliximab, 3–22% for cetuximab, and 0.6–5% for trastuzumab (12-14)

Risk Factors

• Risk factors for HSR include:
  • Patient's characteristics
  • Underlying disease
  • Immune status
  • Other drugs taken concomitantly
  • Drug-related factors
    • Degree of humanization
    • Glycosylation pattern
    • Type of cells it was obtained from
    • Dosing interval
    • Excipients with allergenic potential
• Patients with anti-drug antibodies (IgG or IgE) developed during treatment or preexisting are more likely to have increased HSR risk
• An association between positive skin test and greater severity of initial reaction was reported
• Women are more prone to drug allergy, in particular to chemotherapy medications and new biologicals and monoclonal antibodies

Breakthrough reactions

• Breakthrough reactions during desensitization appear in approximately 13.5% to 23% of patients with 2.3-2.6% multiple reactors
• A correlation between breakthrough reactions and skin test positivity has been controversial, a recent paper reported a positive skin test result is the main predictor; however, recent papers have not supported this finding

Clinical Presentation of Hypersensitivity Reactions

• HSRs can occur on the first exposure or repeated exposures, which may limit biological use, leading to therapy interruption and impaired quality of life
• HSRs include local injection site reactions and systemic infusion reactions
• Systemic immediate presentation varies from mild cutaneous manifestations to life-threatening reactions

Injection Site Reactions

• Common adverse reactions to subcutaneous biologicals usually occurring within 24-48 hours or immediately after injection
• Reactions include erythema, edema, itching, or infiltrated plaques at the injection site, mild to moderate in severity
• Reaction generally lasts 1-5 days and doesn't lead to therapy cessation
• Exanthematous dissemination has been reported in rare cases
• Recall reactions may develop in some patients, local reactions at previous reaction site

Infusion Reactions

• Immediate HSRs occur during or within a few hours of first or subsequent infusion, particularly with subcutaneous administration
• Immediate reactions are more frequently systemic, while delayed reactions are more frequently local after subcutaneous administration of biologicals

Clinical Manifestations

• Immediate HSRs vary considerably from mild to severe, even life-threatening
• Mucocutaneous symptoms are most common, followed by respiratory and cardiac symptoms

Phenotype Classification

• A novel classification helps clinicians describe clinical presentation
• Phenotypes classify HSRs according to symptom onset, such as immediate vs. delayed HSRs, and according to symptom severity, defined as Grade I, II, and III for type I reactions

Delayed/Nonimmediate IRRs

• Delayed/nonimmediate IRRs occur within 14 days after infusion
• Symptoms are fever, malaise, arthralgia-arthritis, jaw pain, erythematous/urticarial lesions, purpura and conjunctival erythema, consistent with serum sickness-like reaction (SSLR)
• Patchy lung infiltrates, lymphadenopathy, splenomegaly, gastrointestinal symptoms and extremity weakness may be accompanied
• Delayed type IV reactions are mosly presented with maculopapular rash
• More severe reactions, such as symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported
• The vast majority of cases experience at least one administration without reaction
• There might be a false diagnosis of SJS due to clinical findings, pathology and prognosis resembling paraneoplastic pemphigus (PNP)
• Direct and indirect immunofluorescence can confirm SJS/TEN and differentiate from PNP
• There is general agreement about avoiding rituximab, that has caused type IV HSR such as SDRIFE, SJS, TEN, as well as SSLR

Pathogenesis of Immediate and Delayed Reactions to Biologicals

• HR pathogenesis to biologics is complex and not fully clarified
• Immunogenicity is a key biological feature, the ability of agents to induce an immune response, and leads to anti-drug antibodies (ADA) development
• Immediate and delayed reactions can be split between ADA-mediated and non-ADA-mediated reactions
• The classification is an oversimplification, but it is a useful "starting point" when performing a diagnostic work-up

ADA-Mediated Reactions

• The development of ADA is due to complete adaptive immune response that begins with biological uptake by dendritic cells and its presentation to T cells that help B cells in antibody production
• ADAs are heterogeneous in composition (isotype, affinity, specificity), which can explain why the clinical impact of immunogenicity may differ
• ADAs may belong to the IgE isotype, and IgE-mediated [type I] hypersensitivity reactions to biologicals may not be as rare as previously thought
• IgE development results from a Th2-skewed cellular immune response against biologicals:
• Rituximab is clearly demonstrated
• Infliximab is clearly demonstrated
• IgE mediated reactions may occur as a first dose event:
• Cetuximab induced reactions
• Sustained by pre-existing cross-reacting IgE against “foreign” glycan structures in the therapeutic antibody
• Additive present in the drug formulation is the culprit factor of IgE-mediated reactions in biologicals-exposed patients:
• Polysorbate Omalizumab
• Erythropoietin
• Darbepoetin
• Sensitization might derive from previous contact with excipients used in vaccines and/or cosmetics

Association of ADAs

• ADA development is associated with SSRL and thrombosis among delayed reactions
• Disseminated skin reactions seem to be less associated with ADA

Non ADA-Mediated Reactions - The Cytokine Release Reaction

• It appears when a large number of cells are activated through different mechanisms
• Cytokine Release Reaction leads to the release of very high levels of pro-inflammatory cytokines
• Clinically heterogeneous and symptoms can occur within minutes (immediate reactions) to hours or days after treatment commences (delayed reactions)

Complement Activation

• Represented the second non ADA-mediated mechanism for infusion reactions to BAs
• Can involve immediate and delayed reactions
• The C' cascade may be directly activated by the drug, aggregates or additives such as lipid excipients, or circulating or tissue immune-complexes (ICs) formed between drug and ADA
• C'activation leads to the release of anaphylatoxins (C3a and C5a) with subsequent mast cell activation during immediate events, while delayed reactions may be mediated by deposition of ICs that activate C', resulting in tissue damage and recruitment/activation of inflammatory cells such as skin vasculitis and glomerular disease
• C'activation may occur regardless of ADA development, and causes a unique adverse immune phenomenon
• A C’ activation-related pseudoallergy (CARPA) can lead to an immediate HSR

Role of T Cells

• Specific cellular immune response against the biological agent may be involved in mechanism of reaction
• Hypothesis on data confirming has not been reported until now and only a few cases have been analysed
• Some delayed reactions to skin result from inherent effects on the immune system as a direct molecular target-dependent event
• Cutaneous adverse events induced by EGFR antagonists
• Exacerbation of psoriasis during TNF alpha antagonist
• Role for T-lymphocytes-mediated delayed-type skin reactions present in some local site reactions

Statements

• ADA and non-ADA-mediated reactions may be clinically indistinguishable (Grade D)
• IgE-mediated reactions are responsible for immediate type HRSs; most immediate reactions are mediated by IgG ADA (Grade D)
• CRS and C'activation are responsible for immediate type HRS (Grade C)
• T cells play a role in the development of ADA involved in immediate HRS (grade B)

Unmet Needs

• The definition of neutrophils and macrophages involvement in non-IgE-mediated reactions
• The association between ADA development and delayed systemic hypersensitivity reactions
• Definition of the role of T cells in both delayed disseminated skin reactions and ISR

Diagnostic Approach-Skin Tests

• Positive skin testing reported for patients with previous HSR towards RTX, anti-TNF agents, and trastuzumab
• Small series, positive skin testing confirmed vitro detection of serum drug-specific IgE, and biological activity of BA-specific IgE in mast cells activation
• Perform IDT, prick tests are usually negative, data from literature displays a very high concordance between serum IgE (ImmunoCAP) and skin testing positivity, skin testing may be useful in replacing in vitro test for the diagnosis of immediate IgE-mediated HSR to biologicals
• Limitations of skin testing due to lack standardized procedures for drug concentrations
• There is insufficient evidence to date to recommend appropriate drug dilutions for skin prick test and intradermal test.
• Anti TNF data exists for 1:10 and 1:1 dilution and evaluated concentrations for omalizumab
• Multicenter studies are designed to drug skin tests

Limiting Factors in Testing

• Use of standard protocls are lacking
• Test solution availbility is low, and also reduces diffusion diagnostic approach especially in small centers

Time and Results

• Reaction/ evaluation timing is a crucial point due to unresponsiveness of skin mast cells
• Decrease in IgE specific in biologicals
• There is an insufficient evidence to recommend the timing for biological testing now, for when you have a patient

In Vivo Allergy Tests

• Regarding delayed, not many available
• Mainly carried out for generalized skin reactions of patient development with Interferon (IFN)
• IDT average of 72 h seems to be useful for generalized reactions to IFNs
• Role of delayed reading cutaneous reactions is never fully investigated

In Vitro Test for HSR

• Aims at immune response verifying development of an immune response characterized by ADA
• Radioimmunoassay (RIA)
• Radioimmuno precipitation (RIP) assay
• Surface plasmon resonance
• Electrochemiluminescence

Tests

• Bridging ELISA is most commonly used to evaluate
• ELISA is a drug
• Sensitive detection with detection leading to false negative results
• False positives may occur in ELISA
• All ADA tests evaluated
• Further characterization requires IgE defining which Isotype

ImmunoCap Platform

• (not commercially available) and homemade immunoassays
• Immuno CAP Sensitivity depends on BA involved
• ImmunoCAP to toxi ranging is 68% to 92%
• Specificity is 90% to 92% depending on severity

ADA Association With Reactions

• ADA weak association to relation and suggested evaluation of skin and vaculitis to thromboembloic and SSLR
• Commercial test available for Isotope detection for laboratory products; also if the company creates one with diagnostics for it

IgE AND IgA Detection

• Represents cruical needs

ADA Positive

• Positive patients are at risk

Recommendations

• ADA levels should be monitored in treatment and detections for advice
• For non- ADA parameters check
• Serial time frames to assess as anaphylaxis must cells is anaphylaxis needs Biomarker
• Some Papers to basophil tests
• Largers group of of T with Delayed HSR

Skin Testing Recommendations

• Readily and easily available, grade D
• Substitute from invtro to vivo
• Intadermal with tested biologicals
• Skin testing is a safe alternative
• testing like BAT and IGE testing can be a cross reactivity or between medications

Standards and Evaluations Needed

• Testing standards
• negativity
• Testing
• Delyed idt and patch test and T Cell