217colorectal cancer. There was an increased risk of NMSC with thiopurine treatment
for >3 years, and secondary analysis-demonstrated exposure duration >5 years but
not 3–5 years was significantly associated with NMSC (OR 2.07; 95% CI, 1.36–
3.7). There was an additional increased risk in patients treated with both biologics
and thiopurines but not with biologics alone [ 18 ]. This points to the fact that while
the primary risk of NMSC associated with thiopurines appears to be potentiated by
anti-TNF therapy, there does not appear to be the same risk with monotherapy with
anti-TNFs.
The more extensive RA literature provides additional valuable data regarding
the risks of NMSC in patients treated with biologic therapies. A large cohort study
evaluating 15,789 patients with RA and 3639 patients with osteoarthritis (OA) by
Chakravarty et al. looked at the incidence rate of NMSC. After adjustment for
covariates in Cox proportional hazard models, RA was associated with an increased
risk of NMSC, with a HR 1.19, p = 0.042. In RA patients, NMSC development
was associated with prednisone use (HR 1.28, p = 0.014). Anti-TNFs were also
associated with an increased, though nonsignificant risk of NMSC development
(HR 1.24, p = 0.89). Anti-TNF use with concomitant methotrexate use was associ-
ated with a statistically significant increase in the development of NMSC (HR
1.97, p = 0.001) [ 19 ]. Methotrexate has been directly associated with photosensi-
tivity, likely contributing to this increased risk. These findings again indicate a
possible amplified effect of anti-TNFs when used in combination with other
immunosuppressants.
A large study in the Veteran’s Affairs (VA) population compared the risk of
NMSC among RA patients on anti-TNFs vs. non-biologic disease-modifying anti-
rheumatic drugs (DMARDs). The incidence of NMSC was found to be 18.9 per
1000 patient-years on anti-TNF agents vs. 12.7 per 1000 patient-years in patients on
non-biologic DMARDs. There was a statistically significant increased risk of
NMSC for those patients on anti-TNF agents compared to non-biologic DMARDs
(HR 1.42, 95% CI), and this was a class effect [ 20 ].
Furthermore, a study of the British Society for Rheumatology Biologics
Register included 11,881 consecutive patients with RA who were treated with
anti-TNF agents, compared to 3629 biologic-naïve patients who received non-
biologic DMARDs. There was no evidence that anti-TNF therapy further exacer-
bated the risk of basal cell carcinoma or squamous cell carcinoma when compared
to the risk associated with DMARDs, standardized incidence ratios (SIR) of 1.72
(95% CI, 1.43–2.04) in the anti-TNF group vs. 1.83 (95% CI, 1.3–2.50) in the
DMARD group [ 21 ].
Based on combined literature from both RA and IBD populations, anti-TNF
agents may be associated with a higher risk for NMSC. However, as many patients
will first cycle through immunomodulators or DMARDs, respectively, these esti-
mates are likely influenced by use of other agents such as thiopurines or methotrex-
ate, both of which have been associated with increased skin cancer risks through
mechanisms of photosensitivity [ 17 ]. This NMSC risk attributable to anti-TNF
agents appears to be potentiated by both duration of therapy, as well as the com-
bined use of other immunomodulators.
13 Tumor Necrosis Factor-Alpha Inhibitors and Risks of Malignancy