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We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment...
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment.
In many studies SCC is registered along with basal cell carcinoma in non-melanoma skin cancer. However, the biological behaviour of these tumours is distinct and SCC can become extremely difficult to treat in certain patient subgroups, notably immunosuppressed patients.2 We suggest that the increased SCC rate among CD patients probably reflects the preferential use of azathioprine (AZA) for immune modulation in this group of patients compared to patients with all other diagnoses. Long term AZA is relatively well-tolerated in CD achieving sustained disease remission with an additional steroid-sparing effect.3 Thus recent treatment guidelines instigate AZA as an early treatment choice for CD patients.4 Moreover, among all other immunomodulatory strategies AZA is preferentially tested against biologicals in ongoing trials for patients with CD.5
However, AZA is a well established photocarcinogen too, as it increases the photosensitivity of the skin to ultraviolet A (UVA)6 through substitution of guanine for 6-thio-guanin in the DNA of patients under treatment. The accumulation of 6-thio-guanin moieties in the DNA of epidermal keratinocytes intensifies energy absorption at the DNA level with subsequent increased mutation and carcinogenesis rates.7,8 In transplanted patients the use of AZA has been associated with significant increase in the risk of skin malignancies,9,10 however the corresponding data concerning AZA-associated skin carcinogenesis in patients with inflammatory bowel diseases are not conclusive.11-13 Thus, in the light of the evidence of the recent adalimumab metaanalysis,1 the increased incidence of skin SCC among patients with CD becomes an important finding that merits further analysis.
The safety of biological therapies and their use is expanded as we learn to screen and be vigilant for acute infections. However, the next step will be to prevent long-term side-effects and from current experience with immunomodulation / immunosuppression regimes, non-melanoma skin cancer will be among the most perturbing ones.2,9,10 In this context the data of Burmester et al1 are also an important reminder that future studies should address explicitly the effect of the combination of biologicals and specific immunomodulatory drugs, like AZA, on skin carcinogenesis in order to ensure proper selection of combination regimens.
1. Burmester GR, Mease P, Dijkmans BAC, Gordon K, Lovell D, Panaccione R, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009. DOI:10.1136/ard.2008.102103.
2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17.
3. Prefontain E, Sutherland LR, MacDonald JK, Cepoiu M. Azathioprine or 6-mercapopurine for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000067. DOI: 10.1002/14651858.CD000067.pub2.
4. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomoulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130: 940-87.
5. Etchevers MJ, Aceituno M, Sans M. Are we giving azathioprine too late? The case of early immunomodulation in inflammatory bowel disease. World J Gastroenterol 2008;14:5512-8.
6. Perrett CM, Walker SL, O'Donovan P, Warwick J, Harwood CA, Karran P, et al. Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. Br J Dermatol 2008;159: 198-204.
7. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-4.
8. Zhang X, Jeffs G, Ren X, O’Donovan P, Montaner B, Perrett CM, et al. Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light. DNA Repair 2007;6:344-54.
9. Ulrich C, Stockfleth E. Azathioprine, UV light, and skin cancer in organ transplant patients – do we have an answer? Nephrol Dial Transplant 2007;22:1027-9.
10. Harwood CA, Attard NR, O'Donovan P, Chambers P, Perrett CM, Proby CM, et al. PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. Br J Cancer 2008;21:1276-84.
11. Austin AS, Spiller RC. Inflammatory bowel disease, azathioprine and skin cancer: case report and literature review. Eur J Gastroenterol Hepatol 2001;13:193-4.
12. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002;16:1225-32.
13. Maddox JS, Soltani K. Risk of nonmelanoma skin cancer with azathioprine use. Inflamm Bowel Dis 2008;14:1425-31.