This study demonstrates that inflammatory bowel disease patients have an increased risk of NMSC (IRR 1.64 95% CI 1.51–1.78). This risk may be attributed, in part, to the underlying immune dysfunction of IBD, although the use of immunosuppressive medications appears to be a key driver as well. In particular, we observed that IBD patients with long term use of thiopurines, other immunosuppressive agents, and patients with CD on anti-TNF medications or a combination of anti-TNF and immunosuppressive medications appear to be at the highest risk of developing NMSC. The findings presented in this study strongly suggest that NMSC can be considered a potential adverse effect of many IBD treatments, and should be considered when weighing the risks and benefits of different therapeutic approaches.
A similar association between immunosuppressive use and NMSC in patients post solid-organ transplant has also been demonstrated.16
Squamous cell and basal cell skin cancers account for more than 90% of all skin cancers in post-transplant patients.6, 17
The risk of SCC is 65 to 250 times more common in transplant recipients than in the general population.6
Both duration and level of immunosuppression have been positively associated with NMSC. Over 80% of transplant recipients have developed SCC 20 years post transplant, demonstrating the cumulative effects of long-term immunosupression.18
The magnitude of the association between immunosuppressant use and NMSC observed in this study was less than that observed in transplant recipients, perhaps related to lesser degrees of immunosuppression in IBD patients and/or the exclusion of patients ≥ 64 years of age in our study.
Few previous studies have evaluated the risk of NMSC in patients with IBD. In a Danish study, patients with UC were found to have an increased risk of NMSC (RR 1.4, 95% CI 1.0–1.9).7
A second Swedish study of patients with IBD demonstrated an increased risk of squamous cell skin cancer (SIR 2.2 95% CI 1.1–3.9)8
. Both of these studies did not have access to data on medication exposures and were performed in Northern European populations, where skin type and susceptibility to sun exposure may be different than that in the United States. Our study also permitted further identification of risk factors for NMSC, including geographical region (a proxy for sun exposure) and use of immunosuppressive medications.
Although immunosuppressive use in general has been previously associated with NMSC, to our knowledge this is the first epidemiological study to describe an association between NMSC and use of biologic therapies, specifically anti-TNF agents in patients with IBD. However, this association has been suggested in case-reports of patients with rheumatoid arthritis (RA) treated with biologic therapies.19
Additionally, a meta-analysis of the side-effects of anti-TNF agents in the rheumatology population did find an overall increased risk of malignancy (pooled OR 3.3 (95% CI, 1.2–9.1)).20
Chakravarty et al demonstrated that patients with RA treated with anti-TNF agents alone or in combination with methotrexate have an increased risk of NMSC.21
In contrast to rheumatologic disease, anti-TNF medications have not previously been associated with an increased risk of malignancy in patients with IBD.22,23
Until now, little was known about the risk of NMSC in patients with IBD treated with anti-TNF agents or the combination of anti-TNF agents and other immunosuppressive medications.
An interesting observation in our study was that the risk of NMSC seems to be greatest among thiopurine (6MP/azathioprine) users. This finding is consistent with previous work demonstrating that azathioprine can increase photosensitization of human skin.24
Patients treated with azathioprine have a reduced minimal erythema dose (lowest amount of radiation required to produce erythema 24 hours after irradiation) for UVA light, but not UVB light. 24
The selective sensitivity to UVA in azathioprine treated patients is consistent with the production of 6-thioguanine DNA photoproducts. UVA light makes up a majority of incident midday solar radiation, is able to penetrate through glass and is present throughout the year.25
Therefore, many patients would be exposed to this harmful radiation inadvertently. However, the carcinogenic effects of ultraviolet radiation are thought to be mostly caused by UVB rather than UVA exposure.25
This underscores the need for further studies which elucidate the biological mechanism responsible for this association.
The most significant strengths of this study include the large sample size and geographic diversity of the study population, as well as the ability to assess both exposures and outcomes in both the inpatient and outpatient settings. By drawing from a large number of health plans of varying size, type, and location throughout the United States, we believe these results to be broadly generalizable. Another strength of this study was the ability to use pharmacy claims to assess medication exposure, rather than relying on patient recall and/or medical records which indicate medications prescribed (although not necessarily filled).
This study also has some limitations that merit consideration. First, as with all epidemiologic studies using administrative data, there is always the possibility of misclassification of exposure and outcome related to the lack of clinical detail. To minimize this risk, we used stringent definitions of both exposures and outcomes. Similar previous administrative definitions of IBD have been used by our group, 10, 11
The administrative definition of NMSC consisting of an ICD-9 diagnosis code in association with a pathology CPT code has also been used previously.14
Due to overlapping ICD-9 codes, we were unable to distinguish between basal cell and squamous cell skin cancers. Thus, the outcome was classified as NMSC.
Another limitation to this study is that although our data source is generalizable to the commercially insured population of the United States, the elderly and uninsured were not represented in our population. To the extent that NMSC incidence increases with age, we may have underestimated the overall incidence of this condition. However, this would not affect the estimates of risk observed in our study, as measured by incidence rate ratios. Additionally, our database did not contain data on race or ethnicity. Race could be an unmeasured confounder if it is associated with both the outcome and the exposure. Race is associated with the outcome of NMSC. Race may or may not be associated with our exposures of IBD (in the cohort study) and immunosuppressive medication use (in the nested case-control study). Several studies suggest that the incidence of IBD among African Americans is approaching that of Caucasians. Among studies that have shown differences in immunosuppressive medication use by race,27
many quote access to care and socioeconomic factors as a potential cause. In our study, all patients are insured and have access to care, thereby alleviating many of the socioeconomic factors.
A potential source of bias in the cohort portion of this study could be detection bias, either due to increased health care contact by patients with IBD and/or lower thresholds for referral for biopsy of suspicious skin lesions. The incidence rate of NMSC in our control group was 447 per 100,000. The incidence rate of NMSC in the US is in the range of 333–433 per 100,000. Therefore, detection bias in the control group is likely relatively small. Additionally, we included only insured patients, so access to care should be similar. Detection bias is less likely to have occurred in the case-control study, as our IBD definition required both access to and utilization of health care resources. A final limitation is that information regarding potential confounders, such as smoking and sun exposure, are not available in administrative data. However, our analysis was matched on region, as a proxy for sun exposure. Smoking alone is unlikely to have caused the robust effect estimates observed in this study.
In summary, we have demonstrated an increased incidence of NMSC in patients with IBD, and especially among those on immunosuppressive medications such as thiopurines and to a lesser extent, patients with CD on anti-TNF medications. Given the increased use of these steroid-sparing regimens by IBD patients and the potential for decades of exposure time, we anticipate that the risks presented here will be magnified in years ahead. The findings in this study have important implications for skin cancer screening and prevention. Although definitive recommendations should be based not only on disease risk, but also on the benefits, harms, and costs of screening and ultimate treatment, this study represents an important first step in the development of prevention programs for patients with IBD. Such programs might include behavior alterations such as sun avoidance and/or increased use of sun protective clothing and broad spectrum sunscreen. Education for patients with IBD in regards to the increased risk of NMSC associated with immunosuppressive medication use is also needed in order to change behaviors. Finally, there may also be a role for skin cancer screening programs, including full skin examinations performed at regular intervals by trained dermatologists.