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Non-melanoma Skin Cancer
In the USA, NMSC is the most commonly diagnosed malignancy. NMSC includes
both squamous cell carcinoma and basal cell carcinoma. Risk factors for the devel-
opment of NMSC include environment risk factors such as ultraviolet (UV) light
exposure or chemical exposures, as well as host risk factors such as human papil-
loma virus (HPV), genetic susceptibilities, and immunosuppression [ 8 ]. In a
descriptive analysis of population-based claims, the US Census Bureau, and a
population- based cross-sectional survey using multiple US government data sets,
NMSC has an estimated overall incidence of 3.5 million [ 9 ]. A further increased
incidence has been found in solid organ transplant populations [ 10 – 12 ].
Various cohort studies have provided evidence that immunosuppressive thera-
pies used in the treatment of IBD and other autoimmune conditions are associated
with an increased risk of NMSC. It is also possible that the underlying immune
dysfunction of these autoimmune conditions also plays a role. A retrospective
cohort study of NMSC in 26,403 Crohn’s patients and 26,934 patients with ulcer-
ative colitis published by Long et al. in 2010 demonstrated a significantly increased
risk of NMSC (incidence rate ratio (IRR) 1.64; 95% CI, 1.51–1.78) with an overall
annual incidence rate of 733 per 100,000 in the IBD population compared to con-
trols, who had an incidence rate of 447 per 100,000 [ 13 ]. A nested case-control
study then evaluated the use of immunosuppressive medications in IBD patients.
This demonstrated an increased odds of NMSC with recent thiopurine use (within
90 days) (adjusted OR 4.56; 95% CI, 2.81–4.50) or recent biologic use (anti-TNF)
(adjusted OR 2.07; 95% CI, 1.28–3.33), as well as persistent/long-term use of thio-
purine or biologic therapy. There was some suggestion that longer duration of ther-
apy may further increase risk. Additionally, the overall odds of developing NMSC
were found to be highest with combined immunomodulator and biologic therapy
(adjusted OR 5.85; 95% CI, 2.62–4.10) [ 13 ].
Two other European studies have also evaluated the incidence of NMSC in
patients with IBD [ 14 , 15 ], and both of these studies also showed an increased risk
of NMSC in IBD patients. However, these studies were performed prior to the wide-
spread use of biologic therapies. This suggests an innate increased risk in IBD
patients independent of biologic use or risks associated with other classes of medi-
cations. Factors influencing the development of NMSC may include fair skin, UV
light exposure, and impaired DNA repair, likely exacerbated by thiopurine use [ 16 ].
Thiopurines have been associated with selective photosensitivity to ultraviolet-A
(UV-A) light and oxidative DNA damage [ 17 ]. Thus, some of the prebiologic risk
of NMSC is likely associated with thiopurine use. As many patients receive thiopu-
rines prior to or in combination with anti-TNFs, it is difficult to determine the inde-
pendent effects of anti-TNFs on NMSC risk.
The risk of NMSC from anti-TNF therapy with concomitant immunomodula-
tors has been further investigated in a large Quebec claims database study. This
study evaluated 19,582 eligible patients regarding the use of thiopurines and bio-
logics and risk of various malignancies: NMSC, melanoma, lymphoma, and
J.T. Hughes and M.D. Long