1. Lymphoma-genesis in
autoimmunity
Joydeep
SR, medical oncology

2. Arch Intern Med. 2005;165:2337-2344

3. • Pubmed database
• 1974 to 2005 april
• Key words : SLE, RA, Sjogrens, pSS, NHL
• 20 studies were taken into analysis
• Results:
– high risk for pSS (random effects SIR, 18.8; 95% confidence
interval [CI], 9.5-37.3);
– moderate risk for SLE (random effects SIR, 7.4; 95% CI, 3.3-
17.0); and
– lower risk for RA(random effects SIR, 3.9; 95% CI, 2.5-5.9).

6. Mechanisms of lymphoma
development

7. Apoptosis dysregulation
• Dramatically illustrated by the autoimmune
lymphoproliferative syndrome (ALPS) of
childhood
• ALPS is the result of dominant heterozygous
inheritance of a mutated (inactive) gene,
TNFRSF6, which encodes the transmembrane
protein Fas (also known as CD95), a major
mediator of lymphocyte apoptosis

8. How FAS FASL works??..

9. Clinically..
• Gen LNE, AIHA, neutropenia,
thrombocytopenia and
hypergammaglobulinemia
• NIH study: lymphoma occurred in 13% cases
• Included HD, TCRBCL, BL, follicular lymp.
• FAS mutations occurs in about 16% cases of
lymphomas
(Klaus Rajewsky,Cologne, Germany)

10. Sustained antigenic stimulation..
• Exemplified by MALT lymphomas
• Host produces a sustaines but non-eradicating
antigenic drive that leads to prolonged
stimulations of lymphocytes
• Acquisition of signature mutations( like
t(11;18) in MALToma) also contribute to
lymphomagenesis

11. • Chronic HCV infection leads to similar chronic antigenic
stimulations and may contribute to
– Immune conditions like vasculitis
– Lymphoma
• BLyS:
– Group of proteins called B lymphocyte stimulators
– Mice having transgene with BAFF(B cell activating factor), a
member of BLyS family have very high incidence of LPD
– In SLE, sjogrens, RA, very high levels of such BLyS has been
found
» Mackay F, Tangye SG. The role of the BAFF/APRIL system in B cell
homeostasis and lymphoid cancers. Curr Opin Pharmacol
2004;4:347-54

12. Mutagenecity of B cells..
• Many autoiimune disease are characterized by
constant changes in the variable regions of
immunoglobulins, which are brought about by
DNA breaks and rearrangements
• Some mutagenic translocations can be the
result of such a mechanism leading to
lymphoma-genesis
• Examples: burkitts lymphoma

13. Genetic factors..
• It has been suggested that there could be
some inherited mutations causing
susceptibility to both autoimmune diseases
and lymphomas
• Some small studies have shown association,
but larger studies failed to show any increased
risk in relatives of patients with proved
autoimmune diseases

15. • 24,728 NHL patients in Denmark (years 1977–
1997) and Sweden (years 1964–1998) and 55,632
controls
• Results:
– A personal history of systemic auto-immune diseases
(RA, SLE, Sjogren’s syndrome, systemic sclerosis) was
clearly linked with NHL risk
– In contrast, a family history of systemic autoimmune
diseases was modestly and non-significantly
associated with NHL (ORh 1.31 [95% CI 0.85–2.03])

17. • Statistically significantly increased risks of Hodgkin lymphoma
associated with personal histories of several autoimmune
conditions, including rheumatoid arthritis (OR = 2.7, 95% CI =
1.9 to 4.0), systemic lupus erythematosus (OR = 5.8, 95% CI =
2.2 to 15.1), sarcoidosis (OR = 14.1, 95% CI = 5.4 to 36.8), and
immune thrombocytopenic purpura (OR = ∞, P = .002)
• A statistically significant increase in risk of Hodgkin lymphoma
was associated with family histories of sarcoidosis (OR = 1.8,
95% CI = 1.01 to 3.1) and ulcerative colitis (OR = 1.6, 95% CI =
1.02 to 2.6)

19. Therapy of autoimmune diseases..
• It has been suggested in some, but not all,
studies that the treatment of autoimmune
diseases (with methotrexate and TNF-α
blocking agents) might play a role in the
development of subsequent lymphoma

21. • 25 new cases of lymphoma were recorded
• Median age 53yrs
• Median duration of RA: 16yrs
• Median duration of MTX : 15.2 yrs
• RF was positive in 24/25 cases
• Extranodal location : 52% cases

24. Final conclusion …

26. • 757 patients treated with etanercept or
infliximab included between 1 February 1999 and
31 December 2002 were identified.
• Compared to pts with conventional treatment
• The lymphoma relative risk (RR) was 11.5 (95% CI
3.7 to 26.9) and 1.3 (95% CI 0.2 to 4.5), in antiTNF
and standard groups respectively
• Conclusion:
– A possible increased risk for lymphoma associated
with TNF blockers was based on few cases and needs
confirmation

28. • 26 cases of lymphoproliferative disorders
following treatment with
– etanercept (18 cases)
– infliximab (8 cases)
• NHL: 81%
• Median duration from start of therapy to
lymphoma : 8 weeks
• Limitations: small size, not epidemiological

30. • Demirkaya et al
• Assessed the sensitivity of cells of children of
JRA who received anti TNF therapy
• Showed that lymphocytes from these patients
were more sensitive to ROS induced damage,
and their repair mechanism were also
deranged

32. Thank you….