Rituximab and Rheumatoid arthritis by sammyc2007

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									Rituximab and RA

     Antony Lin, MD
Division of Rheumatology
Fontana Medical Center
                Rituximab
Background:
• Chimeric monoclonal antibody
• Targets the CD-20 antigen
  – Expressed on B-cell precursors and mature
    B-cells
  – NOT expressed on stem cells, plasma cells,
    dendritic cells, and other normal tissues
                                CD20:
                         An Ideal B-cell Target
      •    297 amino acid membrane-
           associated phosphoprotein
           (33–37 kD)
            – Not shed
            – No known membrane/secreted
              molecular analogues (target
              interference)
            – Calcium channel function (?)
      •    B-cell lineage antigen, not on:
            – Stem cells, early pre-B cells,
              or plasma cells
      •    Anti-CD20 binding:
            – Does not down-modulate
              expression of CD20
            – Does not cause internalization
              of CD20



Johnson P, Glennie M. Semin Oncol. 2003;30:3-8. Golay J et al. Blood. 2000;95:3900–3908.
   Postulated B-cell Role(s) in
      Rheumatoid Arthritis
• Autoantibody production

• Direct cell–cell interaction (T cells, APC)

• Indirect cell–cell interaction: cytokine
  production
         Pathogenesis of RA
• B-cell activation and proliferation
  – Germinal centers were found in RA synovium
  – Linked with the production of IgG-RF autoAbs


• Activation of T-cells by B-cells was shown
  in human synovium-SCID mouse models
       Mechanism of Actions
• Depletion of B-cells
  – In patients with NHL, circulating B-cells
    (measured as CD19+ cells as CD20 is
    blocked) are depleted within the first three
    doses of Rituxan therapy
  – B-cells remain depleted for up to 6 to 9
    months post-treatment
  – Recovery occurring at approximately 6
    months after completion of treatment.
  – Median B-cell levels return to normal by 12
    months following completion of treatment.
            Rituximab and RA
In 1998, the first prospective study of B-cell
  depletion therapy in RA was started by
  University College London
  – Rituximab was used with cyclophosphamide
  – All of five cases had major improvement



     Rheumatology 2001;40: 205-11
               Rituximab and RA
• In 2002, 17 more cases of successful treatments
  were reported
  Ann Rheum Dis 2002; 61:1-5.



• In 2004, randomized open-label study was
  published.
  – Efficacy of B-cell-targeted therapy with rituximab
    in patients with rheumatoid arthritis

  Edwards JC - N Engl J Med - 17-JUN-2004; 350(25): 2572-81
     NEJM by Edwards et al.
• 161 RA patients with active RA
  – From 26 centers in 11 countries
  – > 21 years old with seropositive RA (>20U)
  – Mean disease duration 9-12 years
  – Receiving at least 16 week of MTX
  – NSAIDs or prednisone < 12.5mg/d
  – Other DMARDs or anti-TNF agents are NOT
    used
     NEJM by Edwards et al.
• Patients were randomized to 4 groups
  – Oral MTX alone (>10mg qweek)
  – Rituximab alone
  – Rituximab with CTX (750mg IV on days 3 and
    17)
  – Rituximab with MTX
     NEJM by Edwards et al.
• Single short course of Rituximab
  – 2 doses of 1000mg IV on Days 1 and 15
  – With oral MTX or cyclophosphamide vs MTX
    alone
• Significant response at 24 and 48 weeks
     NEJM by Edwards et al.
• The primary endpoint was the proportion
  of patients achieving ACR 50 response at
  24 weeks.
• The secondary endpoints were the
  ACR20, ACR70 and patient responses
  based on the EULAR criteria.
NEJM by Edwards et al.
  80
  70
  60
  50
  40                                       ACR 20
  30                                       ACR 50
                                           ACR 70
  20
  10
   0
        MTX      Ritux   Ritux + Ritux +
       control   only     CTX     MTX
     NEJM by Edwards et al.

• Responses were not observed in
  seronegative patients.
             Administration
• Premedications
  – Acetaminophen
  – Diphenhydramine
• Infusion of rituxan
  – 1000 mg given on Days 1 and 15
  – Administered over 4 hours
              Monitoring of Safety
• Adverse outcomes
   – Well-tolerated
   – Antibody production
   – Infusion-related reactions
       • Fever, chills occurs often in first infusion
       • Often seen in lymphoma patients because high B-cell load
   – Anaphylaxis/angioedema
   – More severe
       •   Lymphopenia (40%)
       •   Neutropenia (6%)
       •   Leukopenia (4%)
       •   Anemia (3%)
       •   Thrombocytopenia (2%)
       •   Rare pancytopenia
   – Mild immunosuppression
       • Sepsis (2%)
           Monitoring of Safety
• Severe autoimmune events including serum
  sickness, polyarticular arthritis, and vasculitis
  with rash have been reported in patients with
  NHL.
• To treat the hypersensitivity reaction
   –   Acetaminophen
   –   Bronchodilators
   –   Corticosteroids
   –   Diphenhydramine
   –   Epinephrine
   –   Fluid IV
        Monitoring of Safety
• One case of serious infection was reported
  from 300 patients using the med
• Nahir et al. (2004) reported that there were
  no significant differences in the incidence
  and types of adverse events and infections
  between the treatment groups at 48
  weeks.
           Rituximab and RA

Conclusion
  – B-cell depletion with rituximab is increasingly
    being used for refractory cases worldwide
Rituximab and Autoimmune
        Diseases
         Antony Lin, MD
    Division of rheumatology
    Fontana Medical Center
     Potential Treatments for other
         Rheumatic Diseases
• Systemic lupus erythematosus (SLE)
• ANCA-associated vasculitis
    – Wegener’s Granulomatosis
•   Autoimmune thrombocytopenia
•   Dermatomyositis
•   Cryoglobulinemia
•   Amyloidosis
          Rituximab and SLE
Leandro MJ - Arthritis Rheum - 01-OCT-2002;
  46(10): 2673-7
  – Evaluate the safety and efficacy of B lymphocyte
    depletion therapy in refractory systemic lupus
    erythematosus (SLE)
  – METHODS: Six female patients with active SLE,
    resistant to standard immunosuppressive therapy,
    were treated on an open-label basis
  – During a 2-week period, each patient received two
    500-mg infusions of rituximab, two 750-mg infusions
    of cyclophosphamide, and high-dose oral
    corticosteroids
           Rituximab and SLE
Leandro MJ - Arthritis Rheum - 01-OCT-2002;
  46(10): 2673-7
  – RESULTS- Clinical:
  – Patient 1 had not improved at 3 months but was then
    lost to follow up. At 6 months, all 5 remaining patients
    had improved, as evidenced by improvement in
  – British Isles Lupus Assessment Group global scores
    Decrease from a median of 14 (range 9-27) at
    baseline to a median of 6 (range 3-8) at 6 months.
  – Manifestations of SLE such as fatigue,
    arthralgia/arthritis, and serositis responded
    particularly well to this protocol.
          Rituximab and SLE
Leandro MJ - Arthritis Rheum - 01-OCT-2002;
  46(10): 2673-7
  – RESULTS- LAB:
  – Hemoglobin levels increased in patients 2, 3, 5, and
    6.
  – ESR decreased in patients 2, 3, 4, and 5 and was
    stable in patient 1.
  – C3 serum levels increased in all 5 patients who had
    low levels at baseline; in two of these patients,
    patients 2 and 5, C3 values were normal at 6 months.
  – The variation in the level of anti-double-stranded DNA
    antibody was different in individual patients.
         Rituximab and SLE
Leandro MJ - Arthritis Rheum - 01-OCT-
  2002; 46(10): 2673-7
  – No significant adverse events were observed
    during follow up.
  – CONCLUSION:
    • Combination of B cell depletion and steroid/CTX
      was associated with improvement in global lupus
      activity
    • This study provides sufficient evidence for the
      safety and possible efficacy of B lymphocyte
      depletion therapy in SLE to justify a formal
      controlled trial.
           Rituximab and SLE
Anolik JH - Arthritis Rheum - 01-NOV-2004;
  50(11): 3580-90
   – This study showed that specific B cell
     depletion therapy with rituximab dramatically
     improves abnormalities in B cell homeostasis
     and tolerance that are characteristic of this
     disease.
            Rituximab and SLE
Anolik JH - Arthritis Rheum - 01-NOV-2004;
  50(11): 3580-90
  – Compared with normal controls, SLE patients
    displayed several abnormalities in peripheral B cell
    homeostasis at baseline, including naive
    lymphopenia, expansion of a CD27-,IgD- (double
    negative) population, and expansion of circulating
    plasma blasts.
          Rituximab and SLE
Anolik JH - Arthritis Rheum - 01-NOV-2004;
  50(11): 3580-90
• RESULTS:
  – lab abnormalities resolved after effective B cell
    depletion with rituximab and immune reconstitution.
    The frequency of autoreactive VH4.34 memory B
    cells also decreased 1 year post-treatment, despite
    the presence of low levels of residual memory B cells
    at the point of maximal B cell depletion and
    persistently elevated serum autoantibody titers in
    most patients
   Wegener’s Granulomatosis
• Characterized by granulomatous
  inflammation.
• Cyclophosphamide remains the most
  effective treatments for severe diseases.
  – Some patients may be refractory to the
    treatments.
  – CTX may be contraindicated in some patients.
        Rituximab and WG
• Pathogenesis of WG
• B lymphocytes may play a central
  pathogenic role
• ANCA are produced mostly by Short-lived
  plasma cells.
         Rituximab and WG
• Mechanism of Actions
• ANCA play a major role in the
  pathogenesis of WG
• Treatment can effectively reduce
  precursors of ANCA-producing plasma
  cells
• Depletion of their CD20+ will stop ANCA
  production
         Rituximab and WG
ANCA-associated vasculitis (AAV)
Keogh KA, et. Arthritis Rheum. 2005
 Jan;52(1):1-5
  – 11 patients with active refractory AAV,
    reactive to anti-proteinase 3
  – Mean disease duration was 57.8 months
  – received maximal tolerated doses of CTX or
    CTX-contraindicated
  – Rituximab infusion and glucocorticoids
    Keogh KA, et. Arthritis Rheum.
            2005;52:1-5
•   Treatment protocol
•   4 weekly doses of Rituximab of 375mg/m2
•   prednisone up to 1mg/kg/day
•   3 patients with renal disease also received
    plasma exchange.
  Keogh KA, et. Arthritis Rheum.
          2005;52:1-5
• Results
• Remissions was maintained in every
  patients as long as B lymphocytes were
  undetectable.
  – Remissions is defined as a BVAS/WG score
    of 0.
   Keogh KA, et. Arthritis Rheum.
           2005;52:1-5
ANCA-associated vasculitis (AAV)
RESULTS: Rituximab therapy was well tolerated
 by all patients, and adverse events were rare.
 Following the rituximab infusions, circulating B
 lymphocytes became undetectable, and ANCA
 titers decreased significantly. Remission was
 achieved in all patients and was maintained
 while B lymphocytes were absent.
   Keogh KA, et. Arthritis Rheum.
           2005;52:1-5
ANCA-associated vasculitis (AAV)
RESULTS: Rituximab therapy was well tolerated
 by all patients, and adverse events were rare.
 Following the rituximab infusions, circulating B
 lymphocytes became undetectable, and ANCA
 titers decreased significantly. Remission was
 achieved in all patients and was maintained
 while B lymphocytes were absent.

								
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