Azathioprine linked to increased risk of SCC in transplant recipients

Immunosuppressive treatment with azathioprine may be associated with an increased risk of squamous cell carcinoma in organ transplant recipients, but does not appear to increase the risk of basal cell carcinoma or keratinocyte cancers overall, according to a systematic review and meta-analysis of 27 studies.

While immunosuppressive agents generally are known to contribute to an increased risk of skin carcinogenesis, azathioprine – a purine antimetabolite immunosuppressant – is thought to add to this increase through its photosensitizing effects and the accumulation of mutagenic reactive oxygen species when exposed to UVA.

To address conflicting data on whether azathioprine increases the risk of skin cancer, the authors conducted the analysis of 27 studies (23 cohort studies, 1 randomized study, and 3 case control studies) published between 1996 and 2011, which evaluated skin cancer risk associated with azathioprine in people who received an organ transplant from 1963 to 2011, at a median age of 38-54 years.

In the studies that evaluated the risk of squamous cell carcinoma, risk was elevated by 56% among patients treated with azathioprine (95% CI 1.11-2.18, P less than .001), but estimates ranged from 0.64 to 8.64. The risk was sevenfold higher in two case-control studies combined, but was not significant in eight cohort studies, reported Zainab Jiyad, MD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia, and St. George’s University of London, and coauthors. They noted that there was significant heterogeneity between the studies, probably because of differences in study design, organ transplant type, and period of transplantation (Am J Transplant. 2016 Dec;16[12]:3490-503).

“Despite the substantial heterogeneity, which would tend to dilute the observed summary risk estimate, a significant effect of azathioprine was detected,” they added. “Thus, we acknowledge that our summary estimate may be a conservative estimate of the risk associated with azathioprine.”

The subgroup analysis comparing the risk among kidney and heart transplant recipients showed the increased risk of squamous cell carcinoma was significant among kidney transplant recipients but not among heart transplant recipients.

Among the six cohort studies that evaluated the risk of basal cell carcinoma, the risk was increased in four studies, while two suggested that azathioprine was actually protective against it. When the studies were pooled, the estimated risk was 0.96.

Similarly, when researchers looked at studies of keratinocyte cancers (the combined risk of squamous cell and basal cell cancers), there was no significant association with overall risk of KC.

Older age and transplantation, fair skin type, high sun exposure, childhood sunburn, a history of skin cancer, and rejection episodes in the first year of transplantation were all risk factors for developing squamous cell carcinoma. Therefore, avoiding azathioprine in organ transplant recipients “with one or more of these risk factors may help reduce the future risk” of squamous cell cancer, they wrote.

The authors added that more high quality studies were needed and that studies should evaluate the risk of squamous cell and basal cell cancer separately, because of the apparent difference in risk.

No conflicts of interest were declared.

Immunosuppressive treatment with azathioprine may be associated with an increased risk of squamous cell carcinoma in organ transplant recipients, but does not appear to increase the risk of basal cell carcinoma or keratinocyte cancers overall, according to a systematic review and meta-analysis of 27 studies.

While immunosuppressive agents generally are known to contribute to an increased risk of skin carcinogenesis, azathioprine – a purine antimetabolite immunosuppressant – is thought to add to this increase through its photosensitizing effects and the accumulation of mutagenic reactive oxygen species when exposed to UVA.

To address conflicting data on whether azathioprine increases the risk of skin cancer, the authors conducted the analysis of 27 studies (23 cohort studies, 1 randomized study, and 3 case control studies) published between 1996 and 2011, which evaluated skin cancer risk associated with azathioprine in people who received an organ transplant from 1963 to 2011, at a median age of 38-54 years.

In the studies that evaluated the risk of squamous cell carcinoma, risk was elevated by 56% among patients treated with azathioprine (95% CI 1.11-2.18, P less than .001), but estimates ranged from 0.64 to 8.64. The risk was sevenfold higher in two case-control studies combined, but was not significant in eight cohort studies, reported Zainab Jiyad, MD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia, and St. George’s University of London, and coauthors. They noted that there was significant heterogeneity between the studies, probably because of differences in study design, organ transplant type, and period of transplantation (Am J Transplant. 2016 Dec;16[12]:3490-503).

“Despite the substantial heterogeneity, which would tend to dilute the observed summary risk estimate, a significant effect of azathioprine was detected,” they added. “Thus, we acknowledge that our summary estimate may be a conservative estimate of the risk associated with azathioprine.”

The subgroup analysis comparing the risk among kidney and heart transplant recipients showed the increased risk of squamous cell carcinoma was significant among kidney transplant recipients but not among heart transplant recipients.

Among the six cohort studies that evaluated the risk of basal cell carcinoma, the risk was increased in four studies, while two suggested that azathioprine was actually protective against it. When the studies were pooled, the estimated risk was 0.96.

Similarly, when researchers looked at studies of keratinocyte cancers (the combined risk of squamous cell and basal cell cancers), there was no significant association with overall risk of KC.

Older age and transplantation, fair skin type, high sun exposure, childhood sunburn, a history of skin cancer, and rejection episodes in the first year of transplantation were all risk factors for developing squamous cell carcinoma. Therefore, avoiding azathioprine in organ transplant recipients “with one or more of these risk factors may help reduce the future risk” of squamous cell cancer, they wrote.

The authors added that more high quality studies were needed and that studies should evaluate the risk of squamous cell and basal cell cancer separately, because of the apparent difference in risk.

No conflicts of interest were declared.

Immunosuppressive treatment with azathioprine may be associated with an increased risk of squamous cell carcinoma in organ transplant recipients, but does not appear to increase the risk of basal cell carcinoma or keratinocyte cancers overall, according to a systematic review and meta-analysis of 27 studies.

While immunosuppressive agents generally are known to contribute to an increased risk of skin carcinogenesis, azathioprine – a purine antimetabolite immunosuppressant – is thought to add to this increase through its photosensitizing effects and the accumulation of mutagenic reactive oxygen species when exposed to UVA.

To address conflicting data on whether azathioprine increases the risk of skin cancer, the authors conducted the analysis of 27 studies (23 cohort studies, 1 randomized study, and 3 case control studies) published between 1996 and 2011, which evaluated skin cancer risk associated with azathioprine in people who received an organ transplant from 1963 to 2011, at a median age of 38-54 years.

In the studies that evaluated the risk of squamous cell carcinoma, risk was elevated by 56% among patients treated with azathioprine (95% CI 1.11-2.18, P less than .001), but estimates ranged from 0.64 to 8.64. The risk was sevenfold higher in two case-control studies combined, but was not significant in eight cohort studies, reported Zainab Jiyad, MD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia, and St. George’s University of London, and coauthors. They noted that there was significant heterogeneity between the studies, probably because of differences in study design, organ transplant type, and period of transplantation (Am J Transplant. 2016 Dec;16[12]:3490-503).

“Despite the substantial heterogeneity, which would tend to dilute the observed summary risk estimate, a significant effect of azathioprine was detected,” they added. “Thus, we acknowledge that our summary estimate may be a conservative estimate of the risk associated with azathioprine.”

The subgroup analysis comparing the risk among kidney and heart transplant recipients showed the increased risk of squamous cell carcinoma was significant among kidney transplant recipients but not among heart transplant recipients.

Among the six cohort studies that evaluated the risk of basal cell carcinoma, the risk was increased in four studies, while two suggested that azathioprine was actually protective against it. When the studies were pooled, the estimated risk was 0.96.

Similarly, when researchers looked at studies of keratinocyte cancers (the combined risk of squamous cell and basal cell cancers), there was no significant association with overall risk of KC.

Older age and transplantation, fair skin type, high sun exposure, childhood sunburn, a history of skin cancer, and rejection episodes in the first year of transplantation were all risk factors for developing squamous cell carcinoma. Therefore, avoiding azathioprine in organ transplant recipients “with one or more of these risk factors may help reduce the future risk” of squamous cell cancer, they wrote.

The authors added that more high quality studies were needed and that studies should evaluate the risk of squamous cell and basal cell cancer separately, because of the apparent difference in risk.

No conflicts of interest were declared.