Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis

Abstract

Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single-center studies to date has been inconsistent. We aimed to resolve the issue of azathioprine's carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty-seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11-2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66-1.40) or KC (0.84, 95% CI 0.59-1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study

“…Observational studies have shown a significant association between azathioprine and skin cancer in the kidney transplant population 33 and in the inflammatory bowel disease population, 34 found a higher risk of all-cause mortality among sirolimus patients, but the proportion of cancer-related death was similar between the groups. 29 Based on the available evidence, cancer-related death is a significant issue amongst long-term kidney transplant recipients, and the use of mTORI has not been shown to modify this risk.…”

Spectrum of Immune-Related Conditions Associated with Risk of Keratinocyte Cancers among Elderly Adults in the United States

“…Transplant recipients use immunosuppressant medications to prevent organ rejection (3, 5). Some immunosuppressants have documented photosensitizing properties, and so elevations in KC risk may not be solely due to immunosuppression (9, 10, 20, 21). …”

“…Among transplant recipients, elevated KC risk may be driven by specific immunosuppressant medications, with particularly high risk observed among people taking azathioprine or cyclosporine (9–11). Immunomodulatory therapy has also been linked to KC incidence among people with rheumatoid arthritis or inflammatory bowel disease, two common autoimmune conditions (12).…”

Clinical Findings, Treatments and Outcomes of Transplant Recipients with Metastatic Skin Cancer

“…In the past, immunosuppression in SOTRs was predominantly maintained using cyclosporine and azathioprine 24 . A systematic review involving twenty-seven studies found a 56% increased risk of SCC development in SOTRs on azathioprine versus other immunosuppressants 29 . This is thought to be mediated by azathioprine induced skin hypersensitivity to UVA radiation and increased 6-thioguanine levels in DNA; both of which are thought to increase reactive oxygen species and subsequent SCC risk 30,31 .…”