Biologics hypersensitivity.pdf

Biologics Hypersensitivity
F2 Pongsawat Rodsaward
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Outline
• Introduction
• Classification
• Epidemiology
• Pathogenesis
• Clinical manifestation
• Management
• Specific drugs

Introduction- Biologics
• A substance that is made from a living organism or its products and is used
in the prevention, diagnosis, or treatment of cancer and other diseases.
• Biologic agents include antibodies, interleukins, and vaccines.
• Also called biological agent and biological drug.
https://www.cancer.gov/

Immunol Allergy Clin North Am. 2017 May;37(2):397-412.

Biologics Conventional Drugs
Structure Protein Synthesized chemicals
Metabolize Not metabolized - Metabolized
- Reactive intermediates
with potential immunogenicity (hapten)
Route Parental, Subcutaneous Oral, Parental
Introduction- Biologics VS Conventional Drugs
Allergy. 2006 Aug;61(8):912-20.

J Allergy Clin Immunol. 2018 Jul;142(1):159-170.e2.

Introduction- Immunogenicity of Biologics
Arch. Immunol. Ther. Exp. (2012) 60:331–344
Degree of humanization
Cofactor
• Methotrexate reduce chimaeric anti-TNF-a
antibody (Infliximab user)
Allergy. 2006 Aug;61(8):912-20.

Classification
Allergy. 2006 Aug;61(8):912-20.
acneiforme eruptions appear
very frequently in the frame
of these anti-EGFR treatments
– possibly due to cross-
reactivity with EGFR on skin
cells

Classification
Hypersensitivity reactions to biologicals: An EAACI position paper
Allergy. 2022 Jan;77(1):39-54.
within a few hours
within the 14 days

Epidemiology- Immediate reactions
Clinical Reviews in Allergy & Immunology (2022) 62:413–431

Epidemiology- Delayed reactions

Epidemiology
• Center at Brigham and Women’s Hospital
and Dana Farber Cancer Institute
• from January 1, 2014 to December 31, 2016
• HSRs to 16 mAbs for 104 patients

Epidemiology
• This study
• had higher rates of atopy than did the general population (37% vs 25%)
• significantly higher rates of adverse drug reactions (27% vs <1%)

(52/104)
(18/104)
(8/104)
(7/104)
Epidemiology

Epidemiology
- Children
Medicina (Kaunas). 2020 May 12;56(5):232.

Medicina (Kaunas). 2020 May 12;56(5):232.
Epidemiology
- Children

Epidemiology - Children
Pediatr Allergy Immunol. 2019;30:833–840.
• Longer follow-up, renal
involvement, hematologic
involvement and active
disease were more common
in reactor group.
(3.9%)

Int Arch Allergy Immunol 2021;182:844–851
Epidemiology- Children
No differences in
characteristics of the
patients who
developed reactions
and of those who
tolerated treatment.

Pathogenesis
anti-drug antibodies (ADA)
Allergy. 2022 Jan;77(1):39-54.

Pathogenesis
Allergy. 2022 Jan;77(1):39-54.

Clinical manifestation- Injection site reactions
• The most common adverse reactions to subcutaneous biologicals and
usually occur within 24–48 h but may also occur immediately after injection.
• They are characterized by erythema, edema, itching or sometimes
infiltrated plaques at the injection site and mild to moderate severity.
• Exanthematous dissemination has been reported in rare cases.
• Recall reactions
• local reactions at the site of the previous reaction
Allergy. 2022 Jan;77(1):39-54.

• Infusion-related reactions
• Clinical presentations resemble Type I or CRR but they are mild to moderate in
severity and subside gradually with the following infusion.
• Cytokine release reactions
• Fever/chills, nausea, pain, headache, and rigors
• Elevated serum TNF-α and IL-6 levels
• not responding to premedication/slower infusion rate during the first infusion
• The main difference between IRRs and CRRs is the self-limiting nature of IRRs
on repeated exposure and the response to premedication.
Clinical manifestation – Immediate reactions
Allergy. 2022 Jan;77(1):39-54.

• Type I reactions(IgE/Non-IgE)
• Mixed reactions
• A combination of cytokine release and IgE- mediated reactions.
• Wheezing, flushing, urticaria, pruritus, with fever/chills, nausea, pain, headache,
and rigor
• Skin testing positive results and/or positive specific IgE to the implicated
biological, as well as increased levels of tryptase, IL-1, IL-6, and TNF-α
Clinical manifestation – Immediate reactions
Allergy. 2022 Jan;77(1):39-54.

• Serum sickness reactions
• It seems to be related to complement-fixing IgM and IgG antibodies targeted at
an immunogenic part of the biologicals.
• Fever, malaise, arthralgia-arthritis, jaw pain, erythematous, and sometimes
urticarial lesions, purpura, and conjunctival erythema, consistent with a serum
sickness like reaction (SSLR)
• Occasionally, these reactions can feature patchy lung infiltrates,
lymphadenopathy, splenomegaly, gastrointestinal symptoms, and limb
weakness.
Clinical manifestation – Delayed reactions
Allergy. 2022 Jan;77(1):39-54.

• Type IV reactions
• Maculopapular rash
• Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE)
• Stevens-Johnson Syndrome-Toxic epidermal necrolysis (SJS-TEN)
Clinical manifestation – Delayed reactions
Allergy. 2022 Jan;77(1):39-54.

• A 50-year-old male patient who
had been receiving infliximab
therapy for chronic plaque
psoriasis
• The eruption had begun two
days after the tenth infliximab
infusion and then spontaneously
disappeared one week later.
Clinical manifestation – SDRIFE
J Dermatol Case Rep. 2015 Mar 31;9(1):12-4.

Clinical manifestation – TEN
• A 74-year-old man who had moderately
differentiated metastatic colon
adenocarcinoma presented diffuse
erythematous plaques with dusky red centers
on trunk and extremities after treatment with
cetuximab for 8 weeks.
J Clin Oncol. 2008 Jun 1;26(16):2779-80.

SCAR
Cancer Manag Res. 2018 May 17;10:1259-1273.

Immune related adverse event in checkpoint inhibitor
Immunol Allergy Clin N Am 42 (2022) 285–305

Immune related adverse event in checkpoint inhibitor
Immunol Allergy Clin N Am 42 (2022) 285–305
• Cutaneous irAEs
• the most common irAEs
• 30% to 50% of patients
• more often with anti-CTLA-4 than anti-PD-1
• increased survival outcomes such as overall
survival and progression-free survival in
patients who develop irAEs

Clinical manifestation

Common Terminology Criteria for Adverse Events v3.0 (CTCAE)

Management – Investigation
• Skin test
• In vitro test
• Drug provocation

Investigation – Skin test
• Lack of standardized procedures, including ideal drug concentrations.
• There is insufficient evidence to date to recommend appropriate drug
dilutions for skin prick test (SPT) and IDT for most biologicals.
Allergy. 2022 Jan;77(1):39-54.

Curr Treat Options Allergy. 2020;7(1):71-83.

Grade of reaction during initial and
desensitization reactions based on
skin testing.

• ADA
• Alfa-Gal specific IgE (Cetuximab hypersensitivity)
• Tryptase
• Basophil activation test (BAT)
• Cytokines (IL-6, IL-8, IL-10, TNF-a, and IFN-g)
• Complement factors (C5a, C3a, and CH50)
• Circulating biological-specific T cells
Investigation – In vitro test
Allergy. 2022 Jan;77(1):39-54.

• ELISA
• False-negative
• circulating drug in the serum may interfere with ADA detection
• False-positive
• Cross-binding of IgG by rheumatoid factors or anti-hinge antibodies
• ImmunoCAP platform (not commercially available)
• cetuximab: sensitivity 68% to 92%, specificity 90% to 92%
• infliximab : sensitivity 26%, specificity 90%
In vitro test - ADA
Allergy. 2022 Jan;77(1):39-54.

Investigation – Drug provocation test
Allergy. 2022 Jan;77(1):39-54.

Allergy. 2022 Jan;77(1):39-54.

Reactions Management
Cutaneous
reactions
Urticaria/pruritus • Slowing infusion rate (as low as 10 mL/h)
• pretreatment with antihistamines
• Recurrent symptoms with premedication or slower infusion rate may
require desensitization
Systemic
Reactions
Infusion reactions • Stop infusion, then restart at a slower rate.
• Control or prevent symptoms with H1 antihistamines and
corticosteroids during or prior to infusions
CRS • Stop infusion, treat with rescue medications epinephrine, IV fluids, H1
antihistamine, oxygen, high dose IV steroids
HSR/Anaphylaxis • Stop infusion, treat with rescue medications epinephrine, IV fluids, H1
antihistamine, oxygen.
• Corticosteroids for delayed symptoms may be used.
Management of Immediate reactions

Premedication for CRS
• Acetaminophen 650 mg
• Corticosteroids
• Options include the following
• Prednisone 50 mg, 3 doses in 12 h prior to infusion
• Hydrocortisone 100 mg IV 20 min prior to infusion
• Methylprednisolone 20–40 mg IV 20 min prior to infusion

Premedication for CRS
• Fluid
• Prophylactic fluids (normal saline) had less severe reactions (1 vs 1.4), and
patients who received fluids after breakthrough reactions had a decrease in
reaction severity.
• Cytokine-release reactions
• 100 cc/hour (Step 1-11)
• 250 cc/hour (Step 12)
• 500 cc/hour (During a reaction - symptoms resolve)

Management
Allergy. 2022 Jan;77(1):39-54.

Management

Desensitization
Allergy. 2022 Jan;77(1):39-54.

A and B, Phenotypes and severity of initial reactions
Desensitization
• During desensitization, a change from type I
to cytokine-release reactions was observed.
• The mechanism of this conversion is unclear.
During desensitization, the predominant
symptoms were rigors 24%, chills 23%, and
back pain 18% with cytokine-release
reactions as the major HSR phenotype (52%)

C and D, Phenotypes and severity of desensitization reactions.
• Reactions occurring during desensitization were
significantly less severe than were the initial HSRs.
• Notably on the first desensitization there were no
severe grade III symptoms such as hypotension,
syncope, and/or oxygen desaturation.
(Brown’s severity grading
of anaphylaxis)
J Allergy Clin Immunol. 2004 Aug;114(2):371-6.

E, Severity of initial reaction versus reaction during first desensitization. G, Severity of reaction based on number of desensitizations.
Desensitization

Desensitization

Premedication before desensitization
• H1 blockers and H2 can be administered
• H1 blockers (such as cetirizine −10 mg orally)
• H2 blockers (such as famotidine −20 to 40 mg orally or intravenously)
• ASA and montelukast
• ASA 325 mg orally, 2 days before and on the day of desensitization
• Montelukast 10 mg orally, 2 days before and on the day of desensitization
Allergy. 2022 Jan;77(1):39-54.

Use of RDD in Delayed Hypersensitivity Reactions to
Chemotherapy and Monoclonal Antibodies

Use of RDD in Delayed Hypersensitivity Reactions to
Chemotherapy and Monoclonal Antibodies
RDD is a potentially safe
and effective procedure in
patients suffering from
delayed reactions to ChD
and mAb
Front Allergy. 2022 Jan 14;2:786863.

Specific drug - Rituximab

The incidence of IRRs in patients premedicated with
corticosteroid for their first infusion was significantly
lower when compared to patients not pretreated
with corticosteroid prior to rituximab infusion
Oncology. 2014;86(3):127-34.
The infusion rate during first 30 min was
faster in IRR-related infusion

• First Infusion
• Initiate infusion at a rate of 50 mg/hr.
• In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30
minutes, to a maximum of 400 mg/hr
• Subsequent Infusions
• Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity,
increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
• Interrupt the infusion or slow the infusion rate for infusion reactions
• Continue the infusion at one-half the previous rate upon improvement of symptoms.
• Premedicate patients with an antihistamine and acetaminophen prior to dosing.
• For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30
minutes prior to each infusion.
fda.gov

• A systematic review
• Review from inception to September 2014
• 33 patients with SSLR
• Mean age of presentation was 39 yr
• Female preponderance (77%)
• Majority of cases were associated with an underlying rheumatologic condition (52%).
• The classic triad of serum sickness (fever, rash, and arthralgia) was reported in 16
(48.5%) cases.
• Corticosteroids were the most commonly used treatment (n = 21), with all cases
reporting a complete resolution of symptoms in 2.15 +- 1.34 d.
Semin Arthritis Rheum. 2015 Dec;45(3):334-40.

Hematology unit,
Department of Medicine, KCMH

Specific drug - Cetuximab
• Cetuximab is an IgG1 chimeric monoclonal antibody that binds specifically to the extracellular
domain of the human EGFR.
• Severe reactions (grades 3 and 4) associated with its use vary between 1.1% and 5% and tend
to occur during the first administration.
• Alpha gal hypersensitivity
• The carbohydrate galactose-a-1,3- galactose is expressed on nonprimate mammalian proteins and
present on the cetuximab heavy chain.
• In a 2008 study, Chung et al found that among 25 patients who had presented with a hypersensitivity
reaction to cetuximab, 17 had a positive test for galactose-a-1,3-galactose IgE in pretreatment serum.
• anticetuximab IgE may help predict high-risk patients who would present hypersensitivity and
offer increased vigilance during the infusion.
J Allergy Clin Immunol Pract. 2015 Mar-Apr;3(2):175-85

Specific drug - Omalizumab
• Omalizumab is a recombinant humanized monoclonal anti-body, which
targets the high-affinity receptor binding site on human IgE.
• Post-marketing reports showing an incidence of 0.2% of anaphylaxis in
57,300 patients in a period of 3.5 years.
• The majority of anaphylaxis cases (68%) occurred in the first 3
administrations of the drug, but one case was reported after a 3-month gap
in the treatment of a patient who had been receiving omalizumab
continuously for 19 months.

• The majority of reactions occurred within 2 hours.
• The recommendation of an observation period of 2 hours for the first 3 injections
and 30 minutes for subsequent injections.
• It is advisable that patients who receive omalizumab are instructed to recognize
signs and symptoms of anaphylaxis and to use the epinephrine autoinjector.
• Injection site reactions (ISR)
• Occur in approximately 45% of patients
• Occur within 1 hour of the injection and tend to subside in the following 8 days

Allergy Asthma Proc. 2007 May-Jun;28(3):313-9.
Case reports of
anaphylaxis to
polysorbate in
formulation

Omalizumab desensitization
J Allergy Clin Immunol Pract. 2021 Jun;9(6):2505-2508.e1.

Case
J Allergy Clin Immunol Pract. 2022 Oct 22;S2213-2198(22)01060-1.
• A 50-year-old man with refractory Hodgkin lymphoma stage IVB who had
anaphylactic shock after the second dose of Brentuximab (83 mg of
medication) needed two doses of 0.5 ml adrenaline (1:1000)
intramuscularly for treatment.

Case
Intradermal test with brentuximab 0.05 mg/mL

• The 1st time desensitization
• The 16 step desensitization
• Breakthrough reaction onset
• At the beginning of step 16
• Symptoms
• Generalized pruritus
• Hypotension
• Treatment
• 3 doses of intramuscular epinephrine
• Norpinephrine IV
Case
• The 2nd time desensitization (Ibrutinib pretreatment)
• The 16 step desensitization
• Breakthrough reaction onset
• During step 16
• Symptoms
• Generalized urticaria
• Treatment
• CPM 10 mg IV

Case

Case
1st RDD
2nd RDD
(Pretreatment
with Ibrutinib)
3rd RDD

Biologic Hypersensitivity
• Introduction
• Classification
• Epidemiology
• Pathogenesis
• Clinical manifestation
• Management
• Specific drugs

Biologics hypersensitivity.pdf

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