Biologicals and Hypersensitivity Reactions

• Biologicals are critical therapeutic agents in oncology, immunology, and inflammatory diseases due to their selectivity
• The use of biologicals in clinical practice is expanding
• Hypersensitivity reactions (HSRs) can be caused by biologicals, especially with increasing treatment options through personalized medicine
• Patients may develop HSRs after the initial exposure or with repeated exposure
• The underlying mechanisms and optimal management of HSRs to biologicals remain incompletely understood

HSRs

• Hypersensitivity reactions

mAbs

• Monoclonal Ab

-omab

• Murine (0% human) mAbs

-ximab

• Chimeric mAb

-zumab

• Humanized mAb

-mumab

• Fully human mAb

...cept

• The names of the fusion proteins end in

IRR

• Infusion related reaction

IFNs

• Interferons

IL

• Interleukins

CRR

• Cytokine release reaction

Introduction

• Biologicals are large molecular weight therapeutics synthesized by living organisms that bind to specific determinants like cytokines or receptors
• Any biological with a reported HSR rate higher than 1% and/or anaphylaxis on individual indication is presented on Table-1
• Hypersensitivity reactions (HSRs) to biologicals have increased rapidly in the 21st century, occurring on first or subsequent exposure

Methods – Search Strategy

• A task force group did an intensive electronic literature search in scientific databases using keywords like "biologicals", "hypersensitivity reactions", "allergy", and more
• Searches also included in vivo and in vitro trials in English
• The task force group consulted in meetings from June 2017 to October 2019
• Statements, recommendations, and unmet needs were reviewed, and evidence quality was graded

Classification

• Adverse reactions to biologicals are classified differently from chemical drugs
• First classification proposed five types of adverse side-effects based on pathomechanisms
• Recent classification considers phenotypes, endotypes, and biomarkers indicating underlying endotypes
• Immediate HSRs to biologicals are classified as infusion-related (IRR), cytokine release, type 1 (IgE/non-IgE), and mixed reaction

Infusion-Related Reactions (IRR)

• Patients often experience common IRR during the first infusion
• Pathogenesis is unclear but is affected by infusion rate, which may be a non-immunologic mechanism involving inflammatory cytokines

Cytokine Release Reactions

• Clinical signs result from cytokine release, with elevated TNF-alpha and IL-6 levels compared to baseline
• IRR is self-limiting upon repeated exposure and responds to premedication
• Cetuximab infusion reaction is an exceptional IgE-mediated reaction at first exposure due to preformed IgE antibodies

Type I Reactions (IgE/non-IgE)

• Reactions involve IgE or non-IgE mediated mast cell/basophil degranulation
• Reactions lead to histamine, leukotrienes, and prostaglandins release
• Reactions typically occur after at least one administration without reaction, similar to IgE-mediated reactions
• Skin prick test distinguishes IgE from non-IgE mediated reactions because it is negative for non-IgE mediated reactions

Mixed Reactions

• This reaction combines cytokine release and IgE-mediated reactions with skin test positivity and/or specific IgE
• Increased levels of tryptase, IL-1, IL-6, and TNF-alpha can be observed

Epidemiology and Risk Factors

• All biologicals can cause HSRs, which are increasingly reported due to increased usage
• HSR rates to mAbs vary per agent
• Rates of immediate-type HSRs are 5–10% for rituximab, 2–3% for infliximab, 3–22% for cetuximab, and 0.6–5% for trastuzumab
• Risk factors include underlying disease, immune status, concomitant drugs, degree of humanization, glycosylation pattern, cell type, dosing interval, and allergenic excipients
• Anti-drug antibodies (IgG or IgE) increase the risk of immediate HSRs
• Positive skin tests correlate with greater initial reaction severity
• Women are more prone to drug allergy, especially to chemotherapy medications, new biologicals, and monoclonal antibodies
• Breakthrough reactions during desensitization occur in 13.5% to 23% of patients with 2.3-2.6% multiple reactors
• Correlation between breakthrough reactions and skin test positivity is controversial

Clinical Presentation

• Hypersensitivity reactions can occur on first or repeated exposure, limiting biologicals' use and affecting quality of life
• HSRs include local site reactions and systemic infusion reactions; systemic HSRs range from mild cutaneous to life-threatening
• Injection site reactions are common with subcutaneous biologicals

Injection Site Reactions

• Occurs within 24-48 hours after injection or immediately after injection
• Characterized by erythema, edema, itching, or infiltrated plaques at the injection site
• Generally lasts 1-5 days and doesn't lead to therapy cessation
• Exanthematous dissemination is rare
• Some develop recall reactions at previous reaction sites

Infusion Reactions

• Onset is during or within hours following first or subsequent infusion
• Typically more systemic, delayed reactions are more localized for subcutaneous use

Overall

• Immediate HSRs vary from mild to life-threatening; mucocutaneous symptoms are most common, then respiratory and cardiac symptoms
• Novel classification aids clinicians in describing clinical presentation by onset and severity

Delayed/Nonimmediate IRRs

• They usually occur after 14 days after the infusion
• Symptoms consist of fever, malaise, joint pain, skin lesions, conjunctival erythema, lymphadenopathy, and splenomegaly
• More serious type IV reactions sometimes occur such as SJS and TEN can be misdiagnosed as PNP
• Immunofluorescence can confirm/differentiate type IV reactions from PNP
• Rituximab use is discouraged in type IV HSR cases such as SDRIFE, SJS, TEN, and SSLR

Pathogenesis of Immediate and Delayed Reactions

• Pathogenesis complex picture that isn't fully clarified
• Biologicals can induce immune response against a drug, resulting in anti-drug antibodies = immunogenicity
• Immediate and delayed reactions split into ADA-mediated and non-ADA-mediated reactions

ADA-Mediated Reactions

• ADA produced from biological uptake
• ADAs include immunoglobin subtypes, affinity, and specificity
• IgE isotype and type I hypersensitivity may not be as rare as previously thought
• IgE development results from a Th2-skewed cellular immune response
• Preexisting IgE can sustain cetuximab-induced reactions
• Polysorbate in drug formulations as culprit factor of IgE-mediated reactions in biologicals-exposed patients
• Sensitization comes from previous exposure from formulation ingredients from vaccines and/or cosmetics
• Delayed reactions often correlated with SSLR and thrombosis along with skin reactions

Non-ADA-Mediated Reactions

• Cytokine Release Reaction characterized
• Large number of cells are activated and release proinflammatory cytokines
• CRS are clinically heterogeneous
• Complement activation leads to anaphylatoxins that causes mast cell activation
• C′ activation may result activation-related pseudoallergy

Statements and Recommendations

• ADA and non-ADA-mediated reactions may be clinically indistinguishable (Grade D)
• IgE-mediated reactions are responsible for some immediate type HRS, even if the majority of immediate type reactions are mediated by IgG ADA (Grade D)
• CRS and C'activation are responsible for some immediate type HRS (Grade C)
• T cells play a role in the development of ADA involved in immediate HRS (grade B)
• The definition of neutrophils and macrophages involvement in non-IgE-mediated reactions is needed
• More info on the association between ADA development and delayed systemic hypersensitivity reactions is needed
• Clearer distinction between the role of T cells in both delayed disseminated skin reactions and ISR is necessary

Diagnostic Approach

• Positive skin testing has been reported for patients with previous HSR towards rituximab, anti-TNF agents and trastuzumab
• Positive skin test with biological agents has confirmed the in vitro detection of serum drug-specific IgE
• Skin testing as reliable and readily available diagnostic tests
• Limitations include standardized concentrations lacking
• There is a high concordance between serum IgE detection
• Performing IDT is essential due to negative prick tests
• Experience of groups using infliximab & adalimumab could be referenced for anti-TNF alpha agents

Other relevant factors

• The time between the reaction and the evaluation is important, as well as the skin mast cell responsiveness
• Limited or no information exists on safety or negativization rate of skin testing
• In vivo tests have mainly been done on pt w/ Interferon generalized skin reactions.
• IDT has seemingly been effective in Pt after 72 hours

In Vitro Tests

• Used to verify immune response characterized by ADA
• Number of formats exist to test immune response
• ELISA is commonly used to evaluate ADA in treated patients
• False positives can appear in the ELISA format because of cross-binding of IgG caused by rheumatoid factors
• ADA positive samples have to be screened for the IgE isotype
• ImmunoCAP sensitivity relies on BA
• Weak association exists between ADA development and onset of delayed reactions ADA
• ADA tests could be used to evaluate skin complications
• Tests exist for non-isotype-specific ADA; more tests are needed for more biologicals
• Detecting the lack of IgE ADA tests is a crucial unmet need

ADA Factors

• ADA+ pts are at risk of developing HSR, as well as pts re-exposed after interruption
• High levels or early onset of ADA can infer HSR development
• Infliximab, anti-drug IgE, drug levels and ADA should be monitored
• Cytokine (IL-6, IL-10, TNF-a, IFN-g) and complement factor lvls should be watched

Tryptase Factors

• Serum lvls should be checked (30min-2hrs) in anaphylaxis pts; tryptase is the most studied anaphylaxis marker, altho there still needs to be new biomarkers for the marker
• BAT has been tested for its ability to test for HSR (mainly Rituximab)
• T cell assays still have an unknown diagnostic tool for detection
• Drug concentration standardization is an unmet need

Statements and Recommendation

• Skin testing is the most readily accessible testing method and can replace with in vitro
• BAT is useful and intradermal tests should be performed due to negative prick tests
• Biological skin testing is safe and useful
• Cross reactivity can be assessed via testing specific IgE and BAT testing
• Commercial availability of in vitro assay for the evaluation of IgE ADA is a must
• Drug concentrations during the test must be standardized and the negativization rate needs evaluation

Drug Provocation Testing

• Although used since 2009, this wasn't described until 2015 for biologicals, by Ramon Y Cajal University Hospital in Spain
• Drug Provocation Testing is the drug administration for DHR study

Indications and Constraints

• Might be done prior to Rapid Drug Desensitization to prevent unneeded procedures
• Studies show it can prevent referrals
• Should be performed with trained personnel and proper resources, as well as not for pts changing drugs
• Expert centers with institutional ethical boards should be the only one practicing usage

ProVac Pratice

• 67-69% of performed DPT w/ biologicals are negative
• Most negative results come from pts moderate to severe according to the Brown scale; symptoms tend to be cutaneous and repiratory

Overall

• Important drug decisions and implementation should be local with flexibility

Statements and Recommendations:

• Drug provacation testing is the Gold standard and DPT prevets drug desensitization
• A good safety profile can be achieved if done in specialized centers
• It's a high risk technique so benefits form dedicated spaces and expert personnel
• More must be done to standardize and multicentered studies need to identify differences in populations and valid local variations

Therapeutical Aproach

• Ensure safe and supervised administrations should be primary directive of allegist
• Specifics protocol and multidisciplinary team setting
• Pts can be empowered after information from team members + physicans
• Risk assement must be in effect with appropriate resources and personnel

Desensitization

• Theraputic plan and approach to needed medication
• Can substitute first line options in therapy in specific instances
• Skin test + BAT testing in those instances is optimal
• Institutional protocol for desensitization has shown to be optimal

Upon Occurence

• Skin test + BAT should be done weeks after
• Prior to this, premedication + H1 + H2 blockers must be performed alongisde and ASA
• Must be performed on pts test positive for the test already
• If those are grade 1 then a challenge can be applied
• RDD can be applied if those don't work and is grade 2 and 3

Statements and Recommendations

• Type 1 and Cytokine Syndome pts can still canndidate
• Rapid desensitization is still affective w/ breakthrough reacions
• Type 4 HSR (exclduing) can still candidiate with good effects
• If you do get drug efficiacy it will have long term effects, and different protocols are effective overall

Biologicals are important in treating diseases like cancer due to their selectivity. However, they can also cause hypersensitivity reactions (HSRs) after initial or repeated exposure. The mechanisms and management of these reactions are still not fully understood.