Immunomodulating Agent-associated Lymphoproliferative Disorders

Immunomodulating Agent-associated Lymphoproliferative Disorders
Tariq Muzzafar, MBBS
Lymph node from a patient treated with methotrexate (MTX) for rheumatoid arthritis shows diffuse large B-cell lymphoma. There are many centroblasts image and mitotic figures image.
Skin biopsy specimen from a patient treated with MTX for dermatomyositis shows a Hodgkin-like LPD. The HRS cells image were CD15(+), CD20(+), and CD30(+) (not shown).
TERMINOLOGY
Abbreviations
  • Immunomodulating agent-associated lymphoproliferative disorders (IA-LPD)
Definitions
  • LPDs in patients treated with immunosuppressive drugs, usually for autoimmune diseases
    • LPDs arising in setting of transplantation are excluded
ETIOLOGY/PATHOGENESIS
Risk Factors for IA-LPD
  • Type of immunosuppressive drug
    • Methotrexate (MTX), tumor necrosis factor (TNF)-α antagonists, etc.
  • Duration of drug therapy
  • Underlying disease type and disease activity
    • Rheumatoid arthritis (RA) appears to have highest risk
  • Patient genetic background
  • Difficult to tease out relative contributions of these factors
    • Risk factors point to potential pathogenesis
Immunosenescence and Lymphomagenesis in RA
  • RA patients with lymphoma have mean age of 70 years (range 32-91)
    • Increased age is correlated with immunosenescence
  • B-cell immune dysregulation in RA could drive B cell expansion
    • B-cell autoimmune activity increased due to
      • Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and free light chains
    • Systemic inflammation
      • Elevated erythrocyte sedimentation rate, C-reactive protein
  • Elevated B-cell survival factors: B-cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand)
  • Increased B cells infected by Epstein-Barr virus (EBV) in circulation
  • T-cell immune dysregulation in RA could lead to loss of tolerance
    • T cells have marked contraction in diversity and premature telomere shortening
  • Leads to permissive conditions for EBV(+) B-cell proliferation
Epstein-Barr Virus and Lymphomagenesis in Autoimmune Disease
  • Virus is often present in lymphomas arising in patients with immune dysregulation
  • Virus transforms primary B cells in vitro
  • EBV(+) B-cell proliferation could be due to
    • Immunosenescence in autoimmune disease
    • MTX activated lytic EBV infection in host cells
  • However, EBV can account for only fraction of increased risk
  • MTX withdrawal can lead to spontaneous regression of EBV(+) diffuse large B-cell lymphoma (DLBCL)
Lymphomas in RA Patients: General Considerations
  • RA is a multisystemic disease with increased risk of lymphoma
    • Risk correlates with cumulative inflammatory activity
    • Risk may be reduced with aggressive treatment by decreasing cumulative inflammation
    • DLBCL is most common type of lymphoma
      • Risk of DLBCL increased 100x from 1st to 3rd tertile of cumulative inflammation
  • Long duration of RA before diagnosis of lymphoma; mean: 20 years (range: 4-50 years)
RA Patients Treated with Methotrexate
  • Methotrexate is a potent immunosuppressive agent
    • Activates lytic EBV infection in host cells
    • Appears to cause IA-LPD in at least some patients in whom drug cessation leads to regression
      • Regression is more common in EBV(+) IA-LPDs
      • Complete or partial remission usually occurs within 4 weeks of cessation; remission sustained
  • However, no increase in risk of lymphoma attributable to MTX demonstrated in large, population-based studies
  • Risk associated with MTX therapy may appear falsely elevated due to selection bias
    • Patients on immunomodulating therapy are more likely to have active disease
  • Types of lymphomas described in patients treated with MTX
    • DLBCL (˜ 50% of cases)
    • Classical Hodgkin lymphoma (CHL) (20% of cases)
    • Polymorphic/lymphoplasmacytic LPD (15% of cases)
    • Follicular lymphoma (˜ 10% of cases)
    • Peripheral T-cell lymphoma (rare)
  • Risk of DLBCL correlates with prolonged duration of RA, therapy, and dose of MTX
    • Duration of RA: Median 96 months
    • Duration of MTX treatment: Median 56 months
    • Cumulative MTX dose: Median ˜ 900 mg
RA Patients Treated with Azathioprine
  • Risk of lymphoma increased
    • Lower risk than patients treated with MTX
RA Patients Treated with TNF-α Antagonists
  • Drugs include
    • Infliximab, Adalimumab, Etanercept
  • Current data indicate that treatment up to 4 years does not increase risk
  • DLBCL and CHL have been reported
  • Risk of lymphoma is difficult to estimate because
    • TNF-α antagonists are administered to RA patients with most severe disease
    • Underlying risk for lymphoma is very high in these patients
    • These drugs are often combined with MTX or used in patients who previously received MTX
  • Polymorphous LPDs that do not meet criteria for lymphoma can regress with drug cessation
RA Patients Treated with Other Drugs
  • Risk of lymphoma does not appear to be increased in patients treated with intramuscular gold or sulfasalazine
  • Risk decreased with oral steroids (odds ratio of 0.6); and intraarticular steroids
  • Risk of lymphoma not yet clear for rituximab, Abatacept, Anakinra
Crohn Disease and Lymphoma
  • Risk of LPD in inflammatory bowel disease increased
    • ˜ 2x increase independent of therapy
    • DLBCL (most common); T-cell lymphomas, CHL reported
  • Risk increased further by therapy with azathioprine and 6-mercaptopurine (6-MP)
    • DLBCL, MALT lymphoma, CHL, and plasmacytoma
    • ˜ 40% of these are EBV(+)
  • Risk with infliximab
    • Incidence of LPDs in patients receiving infliximab for Crohn disease is 0.2-1.4%
      • Small subset of cases have regressed following drug cessation
    • T-cell lymphomas have been reported
      • HSTCL (n=8), Sézary syndrome (n=2)
      • Systemic anaplastic large cell lymphoma (n=1), cutaneous CD30(+) T-cell lymphoma (n=1)
    • Infliximab may predispose to or cause lymphomagenesis due to
      • Impaired T-cell apoptosis leading to decreased activated T cells in peripheral blood
      • Impaired T-cell immune surveillance
  • Crohn disease and HSTCL
    • 100% of patients were treated with azathioprine or 6-MP in past
      • 4-year gap between thiopurine therapy and development of HSTCL
    • ˜ 80% of patients had prior treatment with infliximab
      • Interval between 1st dose and development of HSTCL: Median 33 months
    • No reported cases of HSTCL in patients treated only with TNF-α inhibitor
    • Causal role of infliximab remains unproven
CLINICAL ISSUES
Epidemiology
  • Incidence
    • Not well characterized
      • Overall risk of LPDs increased 2x in RA
      • Severe disease activity associated with higher risk
      • Concurrent treatment with ≥ 2 immunomodulator agents confounds risk assessment for specific drug
  • Age
    • DLBCL
      • Median: 62 years
    • HSTCL in Crohn disease
      • Median at diagnosis: 22 years (range: 12-40 years)
  • Gender
    • Sex ratio related to underlying disease in most instances
    • HSTCL in Crohn disease: ˜ 90% of patients are male
Site
Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Immunomodulating Agent-associated Lymphoproliferative Disorders

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