Lymphoma-genesis in autoimmunity

Joydeep SR, medical oncology

Arch Intern Med. 2005;165:2337-2344

• 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).

Mechanisms of lymphoma development

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

How FAS FASL works??..

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)

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

• 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

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

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

• 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])

• 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)

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

• 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

Final conclusion …

• 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

• 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

• 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

Thank you….