Rheumatoid Arthritis and Lymphoproliferative Disease

1
Rheumatoid Arthritis and Lymphoproliferative
Disease

• Dr. Kevin Kuo
• PGY 3, Internal Medicine
• University of Toronto
• Rheumatology Rounds
• Tuesday, December 18, 2007

2
Case

• 47 year-old female
• 15 year history of Rheumatoid arthritis
• On MTX and Plaquenil
• Noticed left axillary lymphadenopathy on
  self-breast examination
• Also had fever and sweats, decreased appetite for
  the past 6 months, initially attributed to
  perimenopause
• Subsequent CT thorax done by family physician
  revealed bilateral axillary and mediastinal
  lymphadenopathy
• Biopsy of the left axillary lymph node revealed
  Diffuse Large B-cell Lymphoma

3
Question

• Is rheumatoid arthritis associated with increased
  risk of lymphoproliferative disorder?
• Is it disease-related or treatment related?
• What is the postulated mechanism behind such
  association?

4
Objectives

• Review the evidence behind the association
  between Rheumatoid Arthritis and
  Lymphoproliferative diseases
• Discuss the rationale of B-cell targeting in the
  treatment of Rheumatoid Arthritis
• Discuss the efficacy and safety profile of
  Rituximab, an anti-CD20 antibody, in the
  treatment of Rheumatoid Arthritis

5
Risk Of Lymphoma Associated With RA

• Zintzaras E. et al. The risk of lymphoma
  development in autoimmune diseases a
  meta-analysisArch Intern Med. 2005 Nov
  14165(20)2337-44
• SIR 3.9 (95 CI 2.5 5.9)
• Conventional treatment 2.5 (95 CI, 0.7 9.0)
• Cytotoxics 5.1 (95 CI, 0.9 28.6)
• Biologics 11.5 (95 CI, 3.7 26.9)

RE random effect, SIR standarized incidence
rate
6
Disease - or Treatment-related?

• Ekstrom Smedby et al. Danmark and Sweden Registry
  Data, Matched case-control study, JNCI 2006
  Jan98(1)51-60
• n 3055 NHL patients, n 89 RA (3)
• Significant increase in risk of NHL observed in
  patients with RA who were treated vs. those
  un-treated, particularly with immunosuppressants
  (azathioprine, CyA, MTX, CTX, CLB)
• Multivariate analysis showed marginal increase
  in risk
• Authors concluded these were due to covariation
  with disease activity

7
Ekstrom Smedby et al.JNCI 2006 Jan98(1)51-60
8
Ask The Question The Other Way

• Baecklund et al. Sweden, Case-control
  studyArthritis Rheum. 2006 May54(3)692-701
• n 378 with malignant lymphoma out of 75,651RA
  patients between 1964 and 1995
• Disease activity classified by 9-point scoring
  system Low 3-4, Medium 5-8, High 9

Steinbrocker functional class
9
Baecklund et al. Arthritis Rheum. 2006
May54(3)692-701
Adjusted for disease activity, and number of
other DMARDS taken (CLB, CyA, CTX, auranofin,
podophyllotoxin, D-penicillamine)
10
How about anti-TNFa therapy?

• Wolfe et al. Arthritis Rheum. 2007
  May56(5)1433-1439
• USA National Data Bank for Rheumatic Diseases,
  1998-2005, n 19,591
• Incidence of Lymphoma
• Had anti-TNFa 43 / 10,815 patients
• No anti-TNFa 50 / 8,747 patients
• OR 1.0 (95 CI 0.6 1.8)
• anti-TNFa MTX OR 1.1 (95 CI 0.6 2.0)

11
Wolfe et al. Arthritis Rheum. 2007
May56(5)1433-1439
12
Baecklund et al. Arthritis Rheum. 2006
May54(3)692-701

• Mean time from RA to NHL 20 years (1-59)
• Specimens re-examined and tested for EBV
• B-cell lymphoma 78
• DLBCL 48, others 0.3 - 9.0
• EBV-associated 12
• What role does B-cell play in the pathogenesis of
  RA?

13
Multiple Roles Played By B-cell
FDC follicular dendritic cells From Dörner T.
Crossroads of B cell activation in autoimmunity
rationale of targeting B cells. J Rheumatol
Suppl. 2006 May773-11
14
Role Of B-cells In Pathogenesis Of RA

• Lack of proper selection of B-cells after
  differentiation in extra-nodal environment
• From Dörner T. Crossroads of B cell activation in
  autoimmunity rationale of targeting B cells. J
  Rheumatol Suppl. 2006 May773-11

15
T-cell Independent B-cell Activation
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Effect of Rituximab on RA

• Takemura et al., murine model, B-cell dependent
  T-cell activation -gt inflammation -gt Formation
  of lymphoid follicles with germinal centers with
  FDC networks
• Anti-CD20 Ab -gt B-cell depletion -gt destruction
  of GC and loss of FDC networks

Takemura S, et al. T-cell activation in
rheumatoid synovium is B cell dependent.J Immunol
20011674710-8.
17
Rituximab in RA and Lymphoma

• First case reports noting treatment of lymphoma
  with Rituximab induced remission of RA
• Stewart M et al. Lymphoma in a patient with
  rheumatoid arthritis receiving Methotrexate
  treatment successful treatment with Rituximab.
  Ann Rheum Dis 200160892-3
• Protheroe A et al. Remission of inflammatory
  arthropathy in association with anti-CD20 therapy
  for non-Hodgkins lymphoma. Rheumatology Oxford
  1999381150-2

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DANCER REFLEX

• 2 studies on the use of Rituximab in patients
  with active RA and patients with RA that are
  refractory to anti-TNFa therapy
• DANCER Phase IIb RCT, double-blind,
  placebo-controlled, dose-ranging study
• REFLEX Phase III RCT, double-blind,
  placebo-controlled

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DANCERArthritis Rheum. 2006 May54(5)1390-400

• Eligibility Criteria
• Moderate to severe RA
• MTX 10-25mg gt12 weeks
• Failed gt1 DMARD (other than MTX)
• d/c from DMARD x4 weeks
• d/c from TNFa inhibitor or Leflunomide x8 weeks

• N
• 149
• 124
• 192

20
REFLEXArthritis Rheum. 2006 Sep54(9)2793-806

• Eligibility Criteria
• Active RA
• Inadequate response to gt1 anti-TNFa agents
• RTX 2 x 1000 mg MTX or placebo MTX
• Rate of serious infections 5.2/100 vs. 3.7/100
  patient years

21
Summary

• Rheumatoid arthritis is associated with increased
  risk of developing lymphoma, primarily B-cell
  lymphoma
• It is not associated with treatment of RA,
  including the use of biologics
• B-cell dysregulation within the extra-nodal
  germinal centers is thought to be the cause
  underlying both disease processes
• B-cell depletion therapy with anti-CD20 Ab shows
  promise in treatment of RA, along with other
  agents that target different parts of the B-cell
  maturation pathway