To discuss the drug rituximab and the hypersensitivity reactions

1. RITUXIMAB
PRESENTOR: DR MADHAVI PAI
MODERATOR: DR. M. N PATIL

2. INTRODUCTION
• Specific mouse and human chimeric
anti-CD20 monoclonal antibody.
• IgG1 kappa monoclonal antibody
composed of a murine variable region
(Fab portion) that is fused onto a human
constant region (Fc portion)

3. • Binds CD20 antigen on:
o Pre-B cells
o Immature and mature B cells
o Memory B cells
•Does NOT target:
o Hematopoietic stem cells
o Plasma cells
(B-cell regeneration possible within 6–12
months)
MECHANISM OF
ACTION

4. • Rituximab eliminates B cells through 3
main immune mechanisms:
1. Antibody-Dependent Cellular
Cytotoxicity (ADCC):
Fc region activates NK cells kill B cells
→
2. Complement-Dependent Cytotoxicity
(CDC):
Complement system is activated B-
→
cell lysis
3. Apoptosis (Direct induction):
Binding CD20 triggers programmed
cell death

5. Beyond B-cell
Depletion:
Immunomodulat
ory Roles
• Reduces cytokine production that
modulate T-cell function
• Interferes with autoantigen
presentation to T cells
• Decreases autoreactive T-cell
activation
• Helps in non–autoantibody-driven
diseases (e.g., atopic dermatitis)

6. PHARMACOKINETICS
• IV administration (100% bioavailability)
⬇️
Distribution Small Vd (~3.1 L)
→
⬇️
Metabolism Proteolytic degradation + CYP450 system
→
⬇️
Elimination Immune complex clearance via reticuloendothelial system
→
(Fcγ-mediated endocytosis)
⬇️
Half-life 18–32 days
→

7. INDICATIONS
FDA-Approved Indications Off-Label Indications
Relapsing & refractory follicular lymphoma (Non-
Hodgkin’s)
Autoimmune Blistering Disorders
- Mucous membrane pemphigoid (MMP)
Rheumatoid arthritis
Connective Tissue Diseases
- Dermatomyositis
- Cutaneous lupus erythematosus (CLE)
- Systemic sclerosis
Pemphigus group of disorders (Approved June 2018)
Vasculitis Syndromes
- Granulomatosis with polyangiitis (Wegener’s)
- Churg–Strauss syndrome
- Microscopic polyangiitis
CLL/ SLL: In combination with cyclophosphamide and
fludarabine
Microscopic polyangiitis and granulomatosis with
polyangitis
Others
- Graft-versus-host disease
- Atopic dermatitis
- Primary cutaneous B-cell lymphoma
- Melanoma
- Kimura’s disease

8. CONTRAINDICATIONS
Absolute Contraindications Relative Contraindications
🔴 Known hypersensitivity to rituximab or murine
proteins
⚠️Active or chronic infections (e.g., TB, hepatitis
B/C)
🔴 Severe active infections ⚠️History of recurrent serious infections
🔴 Severe infusion reactions in prior rituximab
therapy
⚠️Cardiac disease (e.g., heart failure) — risk of
worsening with infusion
⚠️Pregnancy and breastfeeding — limited safety
data
⚠️Immunocompromised states (e.g., HIV/AIDS)
⚠️Prior live vaccinations within 4 weeks of
starting therapy

9. Dosage and administration
Non-Hodgkin's lymphoma: RTX
375 mg/m2
IV infusion once a
week with four infusions over a
month.
Monotherapy or combined with
other chemotherapy regimens
such as cyclophosphamide,
hydroxydaunorubicin, Oncovin,
and prednisone (CHOP regimen)
Rheumatoid arthritis: RTX 1 g
is administered as an IV infusion.
Two infusions, one on day 1 and
the other on day 15.
Rituximab + Hyaluronidase (SC
Formulation)
•FDA approved (2017)
•Subcutaneous injection faster
→
(5–7 min) vs. prolonged IV infusion
•Indications: CLL, Follicular
lymphoma, DLBCL
•Limitation: Must receive one full
IV rituximab dose first

10. INDICATIONS IN PEMPHIGUS
First-line therapy
Moderate-to-severe PV (with short course
corticosteroids)
Refractory disease Failure of steroids ± immunosuppressants
Steroid-dependent PV Relapse on tapering steroids
Relapsing disease Multiple relapses despite standard therapy
Severe/extensive PV Widespread mucocutaneous involvement
Special cases
Contraindications/intolerance to other
immunosuppressants, pediatric/elderly
patients

11. Treatment protocols followed in
pemphigus
Lymphoma protocol: 375/m2
of RTX iv infusion is administered once a week for 4
weeks
Rheumatoid arthritis protocol: M/C Two doses, 1 g each of RTX is administered at an
interval of 15 days apart. Economical to the patient due to less number of infusions
involved
Combination therapy: RTX is combined with IVIG, dexamethasone pulse, or
immunoadsorption.Rheumatoid arthritis protocol is followed here
Long-term therapy with regular infusions of RTX every 4 or 12 weeks following the
induction phase of RTX infusion.
Low-dose RTX: Two doses of 500 mg each of RTX are administered at an interval of 15
days. This can be followed up with one injection of 500 mg once in 6 months or if there
is a relapse.
Ultra low dose RTX: 2 doses of 100mg RTX iv at 3 months interval

12. Special
Patient
Populations
• Hepatic impairment Dosing undefined
→
• Renal impairment No dose adjustment needed
→
• Pregnancy & Breastfeeding
o No proven teratogenicity, but risk of transient B-cell depletion
o Pregnancy test before initiation
o Contraception during treatment & 12 months post-treatment
o Breastfeeding: Avoid during & for 6 months after therapy
• Pediatric Use
o Approved: CD20+ B-cell NHL, GPA, MPA
o Off-label: Relapsed/refractory ALL, pemphigus vulgaris, autoimmune
hemolytic anemia, chronic ITP, PTLD ( 11 mo), refractory SLE ( 8 yrs)
≥ ≥
o Dosing as per package insert/institutional protocol
• Older Patients
o Safe & effective with close monitoring

13. ADVERSE EFFECTS
Infusion Reactions (most common &
serious)
• Seen in 80–90% (RCTs), usually within
30–120 min of 1st infusion
• Range: mild life-threatening
→
• Symptoms: fever, chills, rash, urticaria,
angioedema, hypotension, ARDS,
arrhythmia, shock, anaphylaxis, death
Infections
• Bacterial, viral, fungal
(serious/opportunistic)
• Viral reactivation: JC virus (PML), HBV, HCV,
HSV, CMV, VZV, WNV
• HBV screening & monitoring mandatory
(HBsAg, anti-HBc, HBV DNA)
• Live vaccines contraindicated (give 4
≥
weeks before therapy)
Hematologic
• Lymphopenia (most common)
• Leukopenia, neutropenia,
thrombocytopenia, anemia
Dermatologic / Mucocutaneous
• Pruritus, rash, alopecia
• Severe: TEN, Stevens-Johnson,
paraneoplastic pemphigus
Cardiovascular
• Tachycardia, arrhythmias, non-ischemic
cardiomyopathy, HTN, edema, chest
pain
Constitutional
• Asthenia, fever, chills, myalgia, arthralgia,
back pain, night sweats, fatigue

14. Renal
• Tumor lysis syndrome (hypoCa, hyperK,
hyperPO₄, hyperuricemia, ARF) occurs
→
within 24 hrs of 1st infusion
• ↑ risk with high tumor burden hydration +
→
uric acid–lowering therapy
Respiratory
• URI, cough, rhinitis, bronchospasm, dyspnea
• Rare: ILD, hypersensitivity pneumonitis,
bronchiolitis obliterans
Gastrointestinal
• Nausea, vomiting, diarrhea
• Rare: bowel obstruction & perforation
Neuropsychiatric: Dizziness, headache,
anxiety, depression,insomnia
Pregnancy
• Crosses placenta (esp. 2nd/3rd trimester) →
neonatal immunosuppression
• Neonates: avoid live vaccines for 6 mo
• Effective contraception during therapy & 1 yr
after last dose
Drug–Drug Interactions
• Absolute contraindication: live vaccines,
cidofovir, talimogene laherparepvec

15. MONITORING
Baseline (Before initiation) During & After Treatment
CBC (Hb, WBC with differential, platelets)
CBC, electrolytes, renal function before each infusion & every 3–6
months thereafter
Routine chemistries: renal (BUN, creatinine), electrolytes (Na, K, Ca,
phosphate), liver function (AST, ALT, ALP, bilirubin)
Serum immunoglobulin levels every 3–6 months during and every
6–12 months after; consider IVIG if recurrent infections
Serum immunoglobulin levels
Liver function tests & HBV DNA every 3–6 months during and 12
≥
months after (if at risk)
Chest X-ray
Continuous monitoring for infusion reactions (premedication:
acetaminophen + antihistamine ± steroid)
Viral serology: HBV, HCV, HIV →
If HBsAg/anti-HBc (+): HBV DNA PCR Entecavir if (+), Lamivudine if
→
(–)
Cardiac monitoring during infusion if cardiac history
ECG (all patients 40 yrs or with CV risk factors)
≥ Monitor for late-onset neutropenia, infections
Echocardiogram (if history of cardiac disease, arrhythmia, CHF, or
risk factors)
Neurological assessment for new deficits (risk of PML)
Screening for latent TB (TST or IGRA ± CXR in endemic/at-risk
patients)
Long-term monitoring for opportunistic infections
Pregnancy test (in women of child-bearing potential)

16. Rituximab
Hypersensitivity:
From Clinical
Presentation to
Management
Ghada E. Fouda1
Sevim Bavbek2*
•1
Allergy and Immunology Center, Al-Azhar University, Cairo, Egypt
•2
Division of Immunology and Allergy, Department of Chest Diseases, Ankara
University School of Medicine, Ankara, Turkey

17. Trend:
• Increased use of rituximab → rise in
hypersensitivity reactions
Clinical Concerns:
• Severe infusion reactions in ~10% of
patients
• Detection of anti-rituximab IgG or IgE
antibodies in some cases
• Rare but life-threatening delayed
reactions:
• Stevens–Johnson Syndrome (SJS)
• Toxic Epidermal Necrolysis (TEN)
🧪 Types of Hypersensitivity Reactions
(HSRs):
• Infusion-related reactions
• Cytokine-release reactions
• Type I (IgE-mediated or non-IgE-
mediated)
• Mixed reactions (Type I + cytokine release
overlap)
• Type III (serum sickness)
• Type IV (delayed-type; e.g.,
maculopapular rash, SJS/TEN

18. 🔍 Type B includes both immune-mediated (allergic) and non-
immune mechanisms.
Type Description Example (Rituximab)
Type A
Augmented reactions
— common,
predictable, dose-
dependent
Cytopenia, infections
due to B-cell
depletion
Type B
Bizarre reactions —
uncommon,
unpredictable, occur in
susceptible individuals
Hypersensitivity
reactions (HSRs),
anaphylaxis
1.TRADITIONAL CLASSIFICATION
CLASSIFICATIO
N OF HSR’s

19. 2.Gell & Coombs Classification
(Immune-Mediated HSRs)
Type Mechanism Example in Rituximab HSRs
Type I IgE-mediated (immediate)
Anaphylaxis, urticaria,
bronchospasm
Type II Antibody-mediated cytotoxicity
Not commonly reported with
rituximab
Type III Immune complex-mediated Serum sickness
Type IV T cell-mediated (delayed) Maculopapular rash, SJS/TEN

20. 3.Pichler’s Classification for Biological
Agents
Type Mechanism Description
Type α Cytokine release
High cytokine levels (TNF-α, IL-
6); non-specific
Type β
Hypersensitivity reactions
(IgE, IgG, T cell)
Immediate/delayed HSRs;
IgE/non-IgE/Complement
involvement
Type γ
Cross-reactivity with native
proteins
Autoimmune-like side effects
Type δ Immune imbalance syndrome
Exacerbation of underlying
autoimmune disease
Type ε
Non-immunologic adverse
effects
Off-target effects, e.g., organ
toxicity

21. 4. Phenotype-Based Classification of
Rituximab Reactions (Isabwe et al., 2018)
Phenotype Mechanism Clinical Features Prevalence (%)
Type I (IgE/Non-IgE)
Mast cell/basophil
degranulation
Flushing, urticaria,
wheezing,
hypotension,
anaphylaxis
63%
Cytokine Release
Cytokine surge (IL-6,
TNF-α)
Fever, chills, rigors,
nausea, headache
13%
Mixed Reaction
Both Type I + Cytokine
release
Combined features of
Type I and cytokine-
release
21%
Type IV (Delayed)
T cell-mediated
delayed
hypersensitivity
Rash, SJS/TEN (rare) 3%

22. 5.Brown’s Classification of Reaction
Severity
Grade Severity Clinical Features
Grade 1 Mild
Skin-only symptoms: rash,
urticaria, itching
Grade 2 Moderate
GI symptoms, respiratory
distress, mild hypotension
Grade 3 Severe
Life-threatening: airway
compromise, shock,
arrhythmia, organ failure

23. Rituximab Hypersensitivity Reactions
1.Infusion-Related Reactions
• Most common reaction; up to 77% of patients
during the first infusion
• Symptoms: fever, chills, flushing, rigors,
nausea, headache
• Mechanism: Likely non-immunologic, related
to rapid infusion causing release of
inflammatory cytokines (IL-6, TNF-α)
• Usually mild to moderate and diminish with
subsequent infusions
• Management: slow infusion rate,
premedication with antihistamines and
corticosteroids

24. 2.Cytokine Release Reactions
•
Systemic symptoms: high fever, chills,
muscle pain, nausea, and hypotension
•
Excessive release of cytokines from
activated immune cells upon first exposure
•
Laboratory findings: Elevated IL-6, TNF-α,
and other pro-inflammatory cytokines
•
Can mimic sepsis but without infection
•
Management involves symptomatic
treatment and infusion adjustments

25. 3.Type I Hypersensitivity Reactions (IgE/Non-
IgE mediated)
•Mediated by mast cells and basophils
•Urticaria, flushing, bronchospasm, angioedema, hypotension,
and anaphylaxis
•Confirmed by positive skin tests and BAT(Basophil activation
test), elevated tryptase levels and specific anti-rituximab IgE
antibodies in some patients
•Risk factors:Previous exposure to rituximab or related
biologics
•Requires prompt treatment with epinephrine, antihistamines,
corticosteroids, and may necessitate stopping therapy

26. 4.Mixed Reactions
•Exhibit features of both Type I hypersensitivity and cytokine release
•Combination of respiratory symptoms (wheezing), skin reactions (rash, urticaria), and
systemic symptoms (fever, chills)
•Biomarkers may include elevated tryptase (mast cell activation) and inflammatory cytokines
•Challenge in diagnosis and management; desensitization protocols may be required for
continued therapy

27. 5.Type III Hypersensitivity (Serum Sickness)
•Delayed immune complex-mediated reaction occurring 7–14
days post-infusion
•Symptoms: fever, rash, arthralgia, lymphadenopathy, and
sometimes proteinuria
•Positive RF, immunoglobulins, and human anti-chimeric
antibody (HACA) levels
•Formation of anti-drug antibodies (IgG, IgM) that form
immune complexes activating complement
•Mostly reported in patients with autoimmune diseases
•Usually self-limited but may require corticosteroids for
symptom control

28. 6.Type IV Delayed Hypersensitivity
•T-cell mediated delayed reactions occurring days
to weeks after exposure
•mild maculopapular rash to life-threatening SJS
and TEN
•Rare but severe; requires immediate
discontinuation of rituximab and intensive
supportive care
•Skin biopsy and immunofluorescence to
differentiate from mimickers such as
paraneoplastic pemphigus

30. 1. Detailed clinical history
Identifies Type & Severity
Differentiates Similar Symptoms
Timing
Guides Diagnostic Testing
Personalizes Treatment
Ensures Patient Safety
Diagnosis

31. 2. In Vivo Diagnostic
Tests
Skin Prick Test (SPT) and Intradermal Test
(IDT) are primary diagnostic tools.
•SPT uses concentrated rituximab (10 mg/ml).
•IDT performed with serial dilutions (1:1000 to
1:1). (more sensitive)
•Optimal timing: Tests ideally performed 2–4
weeks after reaction to avoid false negatives.
•Skin test positivity indicates IgE-mediated
hypersensitivity.
•Positive skin tests linked to increased respiratory
symptoms.
•Skin test positivity may predict higher risk of
severe breakthrough reactions during
desensitization.

32. 3. Drug Provocation Test (DPT)
•Controlled re-administration of a suspected drug under medical supervision to confirm or
rule out a hypersensitivity reaction.
•When to Use:
o Negative or equivocal skin test results.
o Mild/moderate initial reaction.
o Drug is essential with no good alternatives.
•When NOT to Use:
o History of severe reactions (e.g., anaphylaxis, SJS/TEN).
o Unstable or high-risk patients.
The Ramon y Cajal University Hospital (RCUH) group is the pioneer of DPT with the largest reported
series with antineoplastics and biologicals.

33. •Procedure:
o Performed in specialized centers with emergency
setup.
o Drug given in small, increasing doses at intervals.
o Close monitoring throughout and after dosing.
o Test stopped if any reaction occurs.
•Precautions:
o Risk of inducing allergic reactions.
o Requires trained staff and resuscitation equipment.
•Role in Rituximab Hypersensitivity:
o Used in select cases when skin test is negative but
suspicion remains.
o Helps guide Rapid Drug Desensitization (RDD).
o Data limited; used mainly in expert centers.

34. 4. In Vitro Tests
• Support diagnosis when skin tests are inconclusive or can't be performed.
Aid in identifying IgE, non-IgE, or cytokine-mediated reactions.
• Supportive, not diagnostic.
• Always consider clinical history and skin test results.
• Used in specialized allergy/immunology centers or for research.

35. Test Name Use in HSR Type
Specific IgE (sIgE) Type I (IgE-mediated) reactions
Basophil Activation Test (BAT) Type I (IgE & non-IgE mediated)
Serum Tryptase Immediate reactions (esp. anaphylaxis)
Cytokines (IL-1, IL-6, TNF-α) Cytokine-release reactions
Lymphocyte Transformation Test (LTT) Delayed Type IV hypersensitivity

36. MANAGEMENT OF RITUXIMAB HSR’S
Manage Mild–Moderate Infusion Reactions With:
• Slowing infusion rate
• Premedication: antihistamines, acetaminophen, corticosteroids
• Allergy referral if required
Avoid Rituximab In:
• Type IV HSRs: SJS, TEN, EM, DRESS
• Serum Sickness
• For other HSRs, Rapid Drug Desensitization (RDD) is a safe and effective alternative:

37. Candidate Selection for Rapid Drug
Desensitization (RDD)
• Rituximab is clinically necessary with no better alternatives
• Patient has had a prior HSR (except Type IV/RISS)
• Positive skin/in vitro tests, or moderate–severe past reaction
Brigham and Women’s Hospital (BWH) The Ramon y Cajal University Hospital (RCUH)
Skin Test Result
Initial Reaction
Severity
Recommended
Action
Positive Any grade
Proceed with
RDD
Negative Grade I (mild)
Consider drug
challenge
Negative
Grade II/III
(moderate–
severe)
Proceed with
RDD
BWH Protocol RCUH Approach:
•Always risk-assess (ST, cytokines,
comorbidities, patient preference)
•DPT before RDD if feasible

38. Premedication Strategies in RDD –
Controversies & Consensus
• ⚠️Beta-blockers and ACE inhibitors should be stopped 24 hrs prior if possible.
🔹 BWH Recommendations
(Comprehensive Premedication):
• Cetirizine, montelukast/zileuton
• H2 blockers (famotidine)
• Aspirin, NSAIDs, acetaminophen
• Steroids (methylprednisolone)
• Benzodiazepines (for anxiety)
🔸 RCUH Strategy
(Minimalist Approach):
• Standard manufacturer/institutional
premeds only
• Additional premeds only based on
patient’s prior/breakthrough reaction

39. Rapid Drug Desensitization (RDD)
Protocols
Common Protocols:
• 12-step BWH protocol (3 bags, dose
escalation every 15 min)
• 16-step protocol for high-risk cases
• Modified protocols (e.g., 3–8 step) used in
some centers
Success Rates:
• Most studies show >95% success
• Breakthrough reactions often mild, occur
during final steps
Bag Concentration Steps Purpose
Bag 1 1:100 dilution Steps 1–4
Introduce
trace
amounts
Bag 2 1:10 dilution Steps 5–8
Moderate
doses
Bag 3 Full strength
Steps 9–
12
Deliver
majority of
the dose

40. Managing Breakthrough Reactions
(BTRs) During RDD
• Stop infusion immediately
• Treat symptoms (e.g., antihistamines, epinephrine,
steroids)
• Restart RDD after resolution
Customize Future RDD Protocols Based On:
• Severity/type of BTR
• Add or adjust premeds
• Modify dilution steps or infusion rates
• Most BTRs are mild (e.g., cutaneous), and do not
require stopping the full RDD.
Hypersensitivity symptoms that
occur during a rapid drug
desensitization (RDD) protocol,
even though the patient is being
carefully reintroduced to the drug in
incremental doses.

41. Conclusion
Rituximab is generally well tolerated, but increased use has led to a rise in hypersensitivity
reactions (HSRs).
Multiple HSR classifications exist (traditional, Pichler’s, phenotype-based), with overlapping
features, emphasizing the need for individualized evaluation.
Each HSR type has unique mechanisms and management strategies—understanding these is
key to effective care.
Skin testing (2–4 weeks post-reaction) is the first diagnostic step. If negative, and in a safe
setting, Drug Provocation Test (DPT) can be used.
Rapid Drug Desensitization (RDD) is the cornerstone for managing immediate-type HSRs,
but is underused and requires greater awareness.
A multidisciplinary team approach, especially involving allergists, is critical for safe and
effective management of rituximab HSRs.