Understanding the risk of inflammatory bowel disease (IBD) and other autoimmune diseases is important for the DoD and VA. The issue is that IBD combined with immunosuppressive medication substantially increases the risk of skin cancer, such as basal cell carcinoma. One study found that ongoing thiopurine therapy increased the risk of non-melanoma skin cancer nearly 600%.
PHILADELPHIA — Inflammatory bowel disease is well known to increase the risk of cancer. Until fairly recently, the primary concern had been a six-fold increase in the risk of colon cancer among those with ulcerative colitis. As more sensitive screening technologies have reduced that risk substantially by detecting flat lesions as well as polyps, physicians and researchers have noted an association between IBD and an increased risk of skin cancers.
Understanding the risk of skin cancer in IBD is important for the DoD as well as the VA. The prevalence of IBD in the U.S. military population is estimated to be 202 cases in 100,000 individuals for ulcerative colitis and 146 in 100,000 for Crohn’s disease. Higher rates occur in females, individuals with lighter skin, and older people. Frequent sun exposure, common in certain military activities, further increases risk of skin cancer.
Inflammatory bowel disease comprises two autoimmune diseases, ulcerative colitis (UC) and Crohn’s disease (CD). In Crohn’s disease, inflammation can affect any part of the digestive tract. In ulcerative colitis, inflammation is largely restricted to the colon and rectum.
The chronic inflammation, cellular damage, and immune dysfunction characteristic of both types of IBD all also increase cancer risk. Further, the most effective drugs for management of IBD suppress the immune system, reducing the body’s ability to recognize and eliminate cancer cells. About half of patients with IBD receive an immunosuppressant within five years of diagnosis.
A number of studies over the last decade have shown that IBD combined with immunosuppressive medication substantially increases the risk of skin cancer. In 2011, a French study determined that ongoing thiopurine therapy increased the risk of non-melanoma skin cancer nearly 600% (HR: 5.9, 95% CI, 2.1-16.4; P=0.0006). With prior thiopurine use, the risk of non-melanoma skin cancer rose almost four-fold (HR, 3.9; 95% CI, 1.3-12.1; P=0.02). The researchers also found that thiopurines increased this risk even before the age of 50, with the risk rising 8% with each year of age.1
A 2018 meta-analysis of 13 studies with 149,198 participants demonstrated an increased risk of non-melanoma skin cancer in patients with IBD associated with thiopurine therapy (random effects: RR=1.88, 95% CI, 1.48-2.38; P<0.001). Notably, the analysis found no increase in the risk of melanoma, the most dangerous form of skin cancer.2
A more recent study in JAMA Dermatology also found no increased risk of melanoma with immunotherapy treatment in IBD but did not look at other types of skin cancer including basal cell carcinoma and squamous cell carcinoma.3
Extended Risk
Nabeel Khan, MD, of the Corporal Michael J. Crescenz VAMC in Philadelphia led a team of researchers who further examined the association between non-melanoma skin cancer and immunosuppressive medications. The researchers noted that while the association between increased risk of basal cell carcinoma in patients with IBD who took immunosuppressive drugs had been well documented, “there are limited data on repeated basal cell cancer occurrences among patients with inflammatory bowel disease, especially the impact of continuing immunosuppressive medications.”4
To explore the effect of medications in individuals who had already had BCC, they conducted a retrospective analysis of 54,919 veterans with IBD who received care through the VA Healthcare System. The team divided the veterans into five groups. Group 1 used only aminosalicylate (5-ASA). Group 2 actively used only thiopurine, while group 3 had discontinued use of thiopurines more than six months earlier and did not use an antitumor necrosis factor (anti-TNF). Group 5 used an anti-TNF as a monotherapy and Group 6 used an anti-TNF plus a thiopurine.
The researchers determined that 518 veterans developed basal cell carcinoma following their diagnosis with inflammatory bowel disease. On an unadjusted basis, BCC recurrences per 100 person-years were 12.8 for individuals in group 1, 34.5 for those in group 2, 19.3 for group 3, 25.4 for group 4, 17.8 for group 5, and 22.4 for group 6. Using 5-ASA monotherapy as a baseline, they found that only veterans who continued to take thiopurines had an increased risk of subsequent basal cell carcinomas.
On an adjusted basis, thiopurine was associated with a 65% increase in risk of repeated BCC (aHR: 1.65, 95% CI, 1.24-2.19; P=0.0005). None of the other groups had an increased risk of recurrent BCC. They concluded that “among IBD patients who developed an incident BCC while taking a TP and continued it, there was an increased risk of repeated BCC occurrences.”
The continued risk for skin cancer in IBD patients makes annual screening particularly important, along with patient education on prevention of and self-monitoring for skin cancer. As other researchers noted, “in addition to knowledge of risk, patients also require guidance in tools to minimize this risk. Given the young age at IBD diagnosis, there is ample opportunity to intervene, educate, and reduce the cumulative risk of skin cancer development in this population.”
The latest practice guidelines from the American Gastroenterology Association, authored by William J. Sandborn, of the VA San Diego Healthcare System and the University of California-San Diego and colleagues, also directly addressed the need for discussing skin care with IBD patients. They recommend that, in light of the increased risk for basal cell and squamous cell carcinoma, “patients using thiopurines for the treatment of IBD, particularly white patients, should avoid excessive sun exposure and use high-strength sun block. Health care deliverers should ensure that patients undergo appropriate dermatological evaluations and investigate suspicious skin lesions in these patients.”5
The issue isn’t limited to IBD or specific agents, however, but appear to affect a range of patients on therapies affecting the immune system. An current article published earlier this year in the International Journal of Surgery Case Reports put a spotlight on the problem of skin cancer related to solid organ transplantation.
Researchers led by The Ohio State University and including participation from the Puget Sound VA Health Care System in Seattle and the Hunter Holmes McGuire VAMC in Richmond, VA, noted, “Solid organ transplantation has evolved along with dramatic advancements in definitive treatment for irreversible and uncompensated organ failure. Transplanted organ survival has improved as a result of reduced allograft rejection. However, negative long-term outcomes which were largely due to the adverse effects of rapidly evolving immunosuppressive regimens are still evident. The emergence of malignancies following prolonged exposure to immunosuppression treatment has affected the quality of life in transplant recipients.”
The report noted that those patients are about 100-times more likely to develop squamous cell carcinoma (SCC) compared to the general population, while the incidence of malignant melanomas, basal cell carcinomas, and Kaposi’s sarcomas are also increasing. “The incidence of de novo malignancies ranges from 9 to 21% and is commonly seen in the skin and the lymphoreticular system in these patients,” the authors pointed out.
Because of advances in immunology, the study recommended peripheral blood mononuclear cell sequencing and immune profiling to identify immune phenotypes associated with keratinocyte cancers to recognize patients who are more susceptible for SCC following organ transplantation and immunosuppression.6
- Peyrin-Biroulet L, Khosrotehrani K, Carrat F, Bouvier AM, Chevaux JB, Simon T, Carbonnel F, Colombel JF, Dupas JL, Godeberge P, Hugot JP, Lémann M, Nahon S, Sabaté JM, Tucat G, Beaugerie L; Cesame Study Group. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011 Nov;141(5):1621-28.e1-5. doi: 10.1053/j.gastro.2011.06.050. Epub 2011 Jun 25. PMID: 21708105.
- Huang SZ, Liu ZC, Liao WX, Wei JX, Huang XW, Yang C, Xia YH, Li L, Ye C, Dai SX. Risk of skin cancers in thiopurines-treated and thiopurines-untreated patients with inflammatory bowel disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2019 Mar;34(3):507-516. doi: 10.1111/jgh.14533. Epub 2018 Nov 22. PMID: 30393891.
- Esse S, Mason KJ, Green AC, Warren RB. Melanoma Risk in Patients Treated With Biologic Therapy for Common Inflammatory Diseases: A Systematic Review and Meta-analysis. JAMA Dermatol. 2020;156(7):787–794. doi:10.1001/jamadermatol.2020.1300
- Khan N, Patel D, Trivedi C, et al. Repeated Occurrences of Basal Cell Cancer in Patients With Inflammatory Bowel Disease Treated With Immunosuppressive Medications. Am J Gastroenterol. 2020;115(8):1246-1252. doi:10.14309/ajg.0000000000000679
- Hanauer SB, Sandborn WJ, Lichtenstein GR. Evolving Considerations for Thiopurine Therapy for Inflammatory Bowel Diseases-A Clinical Practice Update: Commentary. Gastroenterology. 2019 Jan;156(1):36-42. doi: 10.1053/j.gastro.2018.08.043. Epub 2018 Sep 7. PMID: 30195449.
- Ruwanpathirana AS, Fernando SJ, Vinati Molligoda M, Fernando JG, Zhang WW, Premaratne S. Recurrent squamous cell carcinoma in a post cardiac transplant patient. Int J Surg Case Rep. 2021 Feb;79:275-280. doi: 10.1016/j.ijscr.2021.01.031. Epub 2021 Jan 15. PMID: 33757259; PMCID: PMC7889445.