220
The risk of lymphoma in patients on anti-TNFs has also been evaluated in the
RA population, where thiopurine use is less common. A meta-analysis demon-
strated the relative risk of lymphoma on anti-TNF agents to be 0.90 (CI 0.62–1.31),
thus leading to the conclusion that anti-TNFs did not contribute to the risk of lym-
phoma in RA patients [ 24 ].
Hepatosplenic T-Cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is characterized by the infiltration by
malignant T cells of the spleen and liver, and it comprises 5% of peripheral T-cell
lymphomas. HSTCL is more common in young people, and it is more common in
men than women—34 out of 41 cases available in one study were found to be men.
Among these patients, 36 out of 45 patients were deceased at the time of data col-
lection, with a median survival of 8 months. Though rare, HSTCL carries a signifi-
cant risk of mortality [ 27 ].
The majority of the data on HSTCL and an association with anti-TNF therapies
have been compiled from case reports. The FDA AERS received eight cases of
HSTCL in young patients (ages 12–31) using infliximab to treat IBD as of October
5, 2006. A total of seven of these cases were in CD, and one case was in UC. Of
these, seven of the patients reported hepatosplenomegaly, and six out of eight cases
were fatal. All eight of these patients were using concomitant immunosuppressant
therapy with azathioprine, and some were additionally using mesalamine or predni-
sone. There were 15 additional cases of lymphoma with infliximab use (all indica-
tions and ages) which were also reviewed, but it is not clear whether these cases
represented HSTCL. There has been only one fatal case of gamma/delta subtype of
HSTCL associated with azathioprine and one fatal case associated with mercapto-
purine alone. There is no established primary role for infliximab in the pathogenesis
of HSTCL, but it does appear evident that there is an association [ 28 ].
The above FDA report was later updated to include 15 total cases of biologic-
associated HSTCL between 1998 and June 30, 2008. Thirteen of these cases
involved the use of infliximab only, while two of these cases represented treatment
with infliximab, followed by adalimumab. All patients ranged in age between 12
and 29 years old and were receiving concomitant immunosuppressants, including
azathioprine or mercaptopurine in all cases. The authors of this study again con-
cluded that young patients using biologics may be at greater risk for developing
HSTCL [ 29 ]. Nearly all of these cases were male (14 out of 15 patients), suggest-
ing that there may be a gender-specific risk associated with the development of
HSTCL. Additionally, the concomitant use of immunomodulator therapies such as
azathioprine or mercaptopurine in all of the cases of HSTCL raises concern about
their potential risks when used together with biologics in young, male patients.
The review from the FDA AERS system described above also demonstrated a
larger number of cases of HSTCL were identified with TNF-alpha inhibitors used
in combination with an immunomodulator (29 cases) compared with those with
J.T. Hughes and M.D. Long