Rituximab for Autoimmune Diseases

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Rituximab for Autoimmune Diseases

• Case descriptions
• Published experience
• Mechanism of action
• Questions
• No financial disclosures
• Off label use of rituximab

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Evans Syndrome
HPI 56 bf, admitted 9/2003 w 1 wk of fatigue,
nausea, anorexia, lightheadedness PH SLE
5/2002, not active PE afebrile, 63, 179,
petechiae/purpura BLE Lab hgb 4.5, plt 6K, LDH
1270, Cr 1.5, retic 18.9, many sphero, rare
schisto ANA 15120 speckled, anti-DNA 123.4, DAT
pos IgG, Indirect neg U/A 5 rbc, 1
pro Hospital course Pred, plt rbc transfusions.
On day 4 IVIG AMS. MRI punctate brain
hemorrhages diffusely. Found unresponsive later,
expired.
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Refractory TTP
HPI 25 bf, admit 8/2005 w 2 d n/v, bloody
emesis, petechiae, headache, nosebleed. PH TTP
3/2001, ADAMTS13 lt5, inhibitor 5 U/ml at CR,
ADAMTS13 lt5, inhibitor 16 U/ml PE afebrile,
62, 180, petechiae arms, chest, neck Lab hgb
12.2, plt 9K, LDH 1898, Cr 1.8, many schisto,
some sphero, u/a gt50 rbc, 3 protein, DAT neg,
ADAMTS13 lt4, Inh gt 8 U/ml Hospital course Pred,
PE. Day 3 comatose. CT neg. Rituximab. V tach,
seizures, bleeding, oliguric RF, DIC. Day 25
ADAMTS13 lt4, inh 1.1 U/ml. Expired.
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Responsive TTP
HPI 62 bf, admitted w AMS, aphasia, ataxia,
falling PH None significant PE afebrile, 68,
249, petechiae arms, chest, neck Lab hgb 7.3,
plt 19K, LDH 1719, Cr 1.2, many schistocytes,
u/a 0 rbc, 3 protein, casts DAT neg, ADAMTS13
lt4, Inh 0.9 U/ml Hospital course Prednisone,
PE, plus 4 wks of VCR, rituximab. Day 31
discharged w LDH 303, plts 208K, ADAMTS13 lt4,
inhibitor 1.1 U/ml. Follow up Day 120, ADAMTS13
gt67
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Autoimmune Cytopenias

• Patient 1 Evans Syndrome or TTP AIHA
• Patient 2 CR w persistent ADAMTS13 deficiency
  and high-titer inhibitor fatal relapse at 4
  years refractory to rituximab
• Patient 3 CR w persistent ADAMTS13 deficiency
  normal ADAMTS13 at 3 months after rituximab

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Rituximab for ITP
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Demographics and Responses
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Time Course of Responses
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Responders Non-Responders
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Adverse Events

• 9 SAEs in 6 of 36 patients (17)
• 2 NR serum sickness
• 1 NR CTC grade 2 hypotension w dose 3
• 1 CR primary varicella w dose 1
• 1 NR hosp w grade 4 bleeding Rx IVIG
• 1 NR hosp x4 w bleeding
• CTC grade 1-2 chills, fever, resp sx w dose 1 in
  17 of 36 patients (47)

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Persistent ADAMTS13 Deficiency in TTP
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Primary TTP
3
7
6
8
14
Primary TTP
10
11
12
15
Relapsing TTP
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21
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Idiopathic TTP Clinical Course
20 dead within with 5 weeks 80 complete
response in average of 16 days (range, 3-36) 40
of responders have exacerbations within first
week after initial CR 30 of responders relapse
within 2 years
Rock et al, New Eng J Med 1991 325 393-397
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Clinical Characteristics
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Inhibitors Predict Delayed Response
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ADAMTS13 Clinical Correlations
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ADAMTS13 Clinical Correlations

• ADAMTS13 deficiency (lt5) predicts
• Idiopathic TTP
• CR to plasma exchange
• Survival
• ADAMTS13 inhibitor predicts
• Prolonged time to CR
• Relapse
• Death

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Rituximab in TTP
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Patient Characteristics
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Short-Term Outcomes
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ADAMTS13 after Rituximab
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Rituximab for Refractory TTP

• At least 18 reports, 43 patients failed PE, many
  failed steroids, vincristine, splenectomy
• Rituximab 375 mg/m2 weekly, up to 8 doses
• Responses in 2-5 weeks
• 38 durable complete responses
• 2 late relapses, 1 achieved CR upon retreatment
• 1 partial response
• 2 no response (one with lung cancer)

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Rituximab Mechanisms
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Rituximab Mechanisms

• Killing of CD20-positive cells
• Phagocytosis
• Complement-mediated lysis
• Antibody-dependent cytotoxicity
• Apoptosis induction (signaling)
• But plasma cells lack CD20
• Killing depends on natural apoptotic death

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Rituximab Mechanisms

• Most plasma cells live lt 2 weeks
• Primary Ab responses cease in days to weeks
• Can be replenished from memory B cells
• Reside in spleen, nodes gt marrow
• Some plasma cells live for years
• Repeated immunization, T-dependent Ag
• Require survival signals (cytokines, etc)
• Reside in marrow, gut gt spleen, nodes

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Questions

• Why IVIG often helps ITP but not TTP?
• Why (CRPR) 40 in ITP, CR 90 in TTP
• Platelet clearance harder to block than ADAMTS13
  inhibition?
• Why ITP and TTP responses in 2-5 weeks
• Bad antibody is limiting, rapidly decreases?
• Rituximab-lymphocytes clog the RE system?

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Questions

• Best use of ADAMTS13 assays
• Confirm mechanism (Evans S. versus TTP)?
• How to treat persistent ADAMTS13 deficiency
• Preemptive immunosuppression?
• How to kill long-lived plasma cells?
• TRAIL agonists, bortezomib, anti-BLIMP1, et al?