219Unlike the data on NMSC where the risk may be mediated through alternate
concomitant medications (such as thiopurines), anti-TNFs seem to be more directly
and independently linked to the risk of melanoma. These findings are echoed in the
RA literature. Additionally, this effect does appear to be related to duration of ther-
apy, with longer duration putting patients at higher risk of development of mela-
noma. The mechanism of this risk is unclear and may not be linked to photosensitivity,
as is seen with thiopurines.
Lymphoproliferative and Myeloproliferative Disorders
Lymphomas
There are two broad types of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s
lymphoma. Within each of these broad categories, there are numerous subtypes.
Based on data from the National Cancer Institute’s Surveillance, Epidemiology, and
End Results (SEER) Program, Cancer Statistics Review (1975–2012), an estimated
788,939 people are living with or are in remission from lymphoma in the USA. Of
these, an estimated 181,967 people have Hodgkin’s lymphoma, and 609,972 have
non-Hodgkin’s lymphoma. Approximately 21,270 people are expected to die from
lymphoma annually.
A study of 16,023 IBD patients without HIV in the Kaiser Permanente IBD
Registry from 1996 to 2009 examined the standardized incidence rate ratio (SIRR)
of lymphoma. The most common lymphomas overall were diffuse large B-cell lym-
phoma (44%), follicular lymphoma (14%), and Hodgkin’s disease (12%). For
patients with IBD, not receiving anti-TNF or thiopurine therapy, the standardized
incidence rate ratio (SIRR) of lymphoma was 1.0. For patients who had received
thiopurines alone, the SIRR was 0.3 for past use and 1.4 for current use. For patients
receiving anti-TNFs, with or without a concomitant thiopurine, the SIRR was 5.5
for past use and 4.4 for current use. Notably, nearly all of the patients were treated
with thiopurines prior to anti-TNF therapy [ 26 ].
A review of 3,130,267 reports from the Food and Drug Administration (FDA)
Adverse Event Reporting System (AERS) of patients on anti-TNF therapy identi-
fied 91 cases (and nine additional cases in a MEDLINE literature search) of T-cell
NHL. A total of 28 of these cases were in RA, 36 were in CD, 11 were in psoriasis,
9 were in UC, and 6 were in ankylosing spondylitis (AS). A total of 68% of cases
had exposure to both anti-TNF and an immunomodulator, including azathioprine,
6-mercaptupurine, methotrexate, leflunomide, or cyclosporine. The risk for devel-
opment of T-cell NHL when TNF-alpha inhibitors were used alone was not elevated
vs. a fivefold increase in reported risk with anti-TNFs combined with thiopurines
and eightfold risk with thiopurines alone. Again, these data highlight the multiple
factors contributing to the development of lymphoma in patients with autoimmune
diseases, particularly the compounded effect of anti-TNFs when used with
immunomodulators.
13 Tumor Necrosis Factor-Alpha Inhibitors and Risks of Malignancy