In the USA, NMSC is the most commonly diagnosed malignancy. NMSC includes both squamous cell carcinoma and basal cell carcinoma. Risk factors for the development of NMSC include environment risk factors such as ultraviolet (UV) light exposure or chemical exposures, as well as host risk factors such as human papilloma 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 f urther increased incidence has been found in solid organ transplant populations [10–12].

Various cohort studies have provided evidence that immunosuppressive therapies 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 ulcerative 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 controls, 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 thiopurine or biologic therapy. There was some suggestion that longer duration of therapy 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 widespread use of biologic therapies. This suggests an innate increased risk in IBD patients independent of biologic use or risks associated with other classes of medications. 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 thiopurines prior to or in combination with anti-TNFs, it is difficult to determine the independent effects of anti-TNFs on NMSC risk.

The risk of NMSC from anti-TNF therapy with concomitant immunomodulators has been further investigated in a large Quebec claims database study. This study evaluated 19,582 eligible patients regarding the use of thiopurines and biologics and risk of various malignancies: NMSC, melanoma, lymphoma, and colorectal 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 thiopuri nes 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 associated with a statistically significant increase in the development of NMSC (HR 1.97, p = 0.001) [19]. Methotrexate has been directly associated with photosensitivity, 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 exacerbated 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 estimates are likely influenced by use of other agents such as thiopurines or methotrexate, 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 combined use of other immunomodulators.

In the USA, melanoma is the fifth most common cancer for men and the seventh most common cancer for women. It is responsible for more than 9000 deaths annually. Overall, the absolute risk of melanoma is much less than that of NMSC, and thus larger populations are needed in order to evaluate specific medication associations. As with other skin cancers, there are significant physical, psychological, financial, and societal costs of melanoma.

The prior literature is limited by the individual sample sizes of many studies.

In a systematic review and meta-analysis, the incidence rate of melanoma in patients with IBD was 27.5 cases/100,000 person-years (95% CI, 19.9–37.0). IBD was associated with a 37% increase in risk of melanoma (12 studies; RR, 1.37; 95% CI, 1.10–1.70). The risk was increased among patients with both CD and UC [22]. This increased risk predated the biologic era, showing that IBD itself may be associated with an increased risk of melanoma.

The Quebec claims database study previously referenced for NMSC also assessed the risk of melanoma. Out of the 19,582 patients who met study inclusion criteria, a total of 102 cases of melanoma were identified. Neither biologics nor thiopurines were found to be associated with an increased risk of melanoma [18]. In contrast, a larger retrospective cohort using LifeLink Health Plan Claims Database in the USA evaluated 108,579 patients with IBD from 1997 to 2009. In a nested case-control study of melanoma in patients with IBD, there were 209 cases of melanoma and 823 matched controls. A total of 26 out of 209 cases of melanoma had documented biologic use (12.4%) vs. 56 out of 823 controls (6.8%). The use of any biologic anti-TNF was associated with melanoma in crude (OR, 2.08; 95% CI 1.24–3.51) and adjusted analyses (OR, 1.88; 95% CI 1.08–3.29), while there was no significant association with any thiopurine or any 5-ASA use. The use, less than 120 days’ duration, showed no associated risk of melanoma (crude OR, 0.97; 95% CI, 0.19–4.98). Long-term use, as designated by a surrogate marker of current use of anti-TNF at the time of entry into cohort follow-up, was associated with an adjusted OR of 3.93 (95% CI, 1.82–8.50) compared to patients not using these drugs at enrollment [23].

The link between anti-TNFs and melanoma has been studied more comprehensively in the RA population. A systematic review and meta-analysis by Olsen et al. evaluated six studies. Four of the studies looked at the risk of melanoma in RA patients receiving anti-TNF therapy compared to patients treated with non-biologic DMARDS and found a 1.60 (95% confidence interval, 1.16–2.19) pooled effect estimate. Five of the studies examined the risk of melanoma in RA patients receiving ant-TNFs compared to the general population, and the pooled effect estimate was 1.87 (95% confidence interval, 1.53–2.30). A systematic literature review and meta-analysis of biologic registers demonstrated the relative risk of melanoma to be 1.17 (95% CI, 0.86–1.59) [24]. These findings overall suggest the use of anti-TNFs is an independent risk factor for the development of melanoma in the RA population [25].

Unlike 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 therapy, with longer duration putting patients at higher risk of development of melanoma. The mechanism of this risk is unclear and may not be linked to photosensitivity, as is seen with thiopurines.

Hepatosplenic T-cell lympho ma (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 collection, with a median survival of 8 months. Though rare, HSTCL carries a significant 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 prednisone. There were 15 additional cases of lymphoma with infliximab use (all indications 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 mercaptopurine 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 concluded 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), suggesting 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 TNF-alpha inhibitor alone (1 case) [30]. This again echoes the concern for potentiated risk of HTCL with joint anti-TNF and immunomodulator use. Finally, the occurrence of HSTCL has been noted in patients receiving ant-TNF therapy in the RA and psoriasis populations, with four and one cases cited by the FDA AERS study, respectively [30].

Prior literature has also investigated the association between anti-TNF use and solid organ tumors. A nationwide cohort of 56,146 patients with IBD in Denmark from 1999 to 2012 focused on the 4553 patients who were exposed to anti-TNFs. The authors found no significant associations between anti-TNF exposure and the development of solid tumors, including those of the lip, oral cavity, pharynx, digestive organs, lungs, breast, and genitourinary system. Additionally, the multivariable relative risks for most cancers were actually decreased after adjusting for azathioprine exposure [31].

The association between anti-TNFs and solid tumors has been studied in the rheumatology literature. The British Society for Rheumatology Biologics Register, a national prospective cohort study, evaluated the rates of solid cancer occurrence in patients with RA receiving anti-TNFs vs. DMARDs. There were 427 solid cancers reported in 52,549 patient-years in the anti-TNF group and 136 per 11,672 patient-years in the DMARD cohort. After adjustment for baseline characteristics, there was no difference in risk of solid cancer for TNF inhibitors vs. DMARDs [32]. A review of the RA literature by Lebrec et al. also did not reveal any association between anti-TNF use and solid tumor development [33]. In fact, an analysis of the Corona RA Registry found a decreased risk of solid cancer associated with anti-TNFs compared to methotrexate [34].

Various factors have been associated with cervical cancer risk in the general population. The most important risk factor is human papilloma virus (HPV) infection. Other associated risks include immunosuppression (such as human immunodeficiency virus), smoking, age, oral contraceptive use, and exposure to diethylstilbestrol (DES). Cervical cancer is relatively rare; the low absolute risk may be associated with detection and treatment of cervical cancer precursors through screening programs [35].

In the IBD population, a population-based Danish cohort demonstrated an increased risk of cervical dysplasia in both CD and UC patients. The risk of cervical cancer was increased only in the CD population. It has been theorized that immunosuppressive medications can lead to increased cervical dysplasia due to impaired ability clear human papilloma virus (HPV) infections [36]. Kane et al. conducted a case-control study evaluating 40 patients with IBD and their incidence of abnormal pap smears as compared to the control population. Patients with IBD did have a higher risk of an abnormal pap smear as compared to healthy controls. In addition, patients with a history of immunomodulator use were more likely to have an abnormal pap smear associated with high risk strains of HPV (serotype 16 or 18) [37]. However, the outcome of this study was abnormal pap rather than cervical dysplasia or cancer.

Singh et al. evaluated data from the University of Manitoba IBD Epidemiology Database, matching 19,692 women with cervical cytologic or histologic abnormalities on pap smear with 57,898 controls with normal pap smears [38]. While there was no associated risk for abnormal pap smears in patients with UC and CD who had not been prescribed ten or more prescriptions of oral contraceptives, there was an increased risk associated with concomitant corticosteroid and immunosuppressant use. The immunosuppressant medications used among patients in this study were azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, or infliximab. Interestingly, the increased risk was not present with either corticosteroid or immunosuppressant use alone [38]. While there have been conflicting reports about the baseline risk of abnormal cervical dysplasia and cancer in IBD patients, there does appear to be an association with increased immunosuppression use in this population. The limited available data cannot distinguish risks by specific classes of medications.