Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis

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Received Date : 29-Feb-2016 Revised Date : 12-Apr-2016 Accepted Date : 02-May-2016 Article type : O - Original Article

Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients:

Systematic Review and Meta-analysis

Running title: Azathioprine & skin cancer: a meta-analysis

Z. Jiyad1, 2, C. M. Olsen3, 4, M. T. Burke5, N. M. Isbel5, A. C. Green1, 6

1 Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute,

Brisbane, Queensland, Australia

2 Institute of Cardiovascular and Cell Sciences (Dermatology Unit), St George's University of

London, London, United Kingdom

3 Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland,

Australia

4 School of Public Health, University of Queensland, Brisbane, Queensland, Australia 5 Department of Nephrology, University of Queensland at Princess Alexandra Hospital,

Brisbane, Queensland, Australia

6 CRUK Manchester Institute and Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom

Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; HR, hazard ratio; KC, keratinocyte cancer; KS, Kaposi’s sarcoma; MCC, Merkel cell carcinoma; MPA,

mycophenolic acid; OR, odds ratio; OTR, organ transplant recipient; RR, relative risk; SC, skin cancer; SCC, squamous cell carcinoma; UVA, ultraviolet-A.

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Correspondence to:

Adele C. Green, Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Locked Bag 2000 Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. E-mail: Adele.Green@qimrberghofer.edu.au

ABSTRACT

Azathioprine, a purine antimetabolite immunosuppressant, photosensitises 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-centre 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 (KC) overall, and other skin cancers, in relation to azathioprine treatment. 27 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. INTRODUCTION

Solid organ transplant recipients (OTRs) are at an increased risk of developing skin cancer, particularly cutaneous squamous cell carcinoma (SCC) (1, 2). When compared with

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malignancies including basal cell carcinoma (BCC), melanoma and Merkel cell carcinoma (MCC) have also been reported with increasing frequency (4-7). As the most common malignancy post-transplantation, skin cancer represents a major cause of morbidity and mortality in this population (8, 9).

Immunosuppressive agents are contributing factors to skin carcinogenesis because they impair DNA repair mechanisms, reduce immunological clearance of malignant cells and upregulate cytokines that promote tumour progression (10-13). Azathioprine, a purine

antimetabolite immunosuppressant, is thought to additionally heighten SCC risk via

photosensitisation (14, 15) and an accumulation of 6-thioguanine in DNA, which causes the production of mutagenic reactive oxygen species when exposed to ultraviolet-A (UVA) (16).

There have been significant changes in maintenance immunosuppression over recent decades. Azathioprine was the main agent used in the early years of transplantation and continued to be an integral part of the immunosuppressant regimen until the introduction of mycophenolic acid (MPA) in the late 1990’s. However, many long-term survivors with stable graft function remain on azathioprine, with a recent USA study reporting approximately 9% of kidney transplant recipients using this agent (17). In the Australian renal transplant population, 5-7% of patients transplanted between 2006 – 2010 were on azathioprine at two years post-transplantation (18). In addition, azathioprine is used in patients who are

intolerant of MPA, particularly its gastro-intestinal side-effects. Moreover MPA is

contraindicated in women contemplating pregnancy and there has been recent upgrading of this advice by the European Medicines Agency to include avoidance of MPA by male transplant recipients whose female partner is planning a pregnancy (19). Azathioprine remains widely used after cardiothoracic transplantation, with a Spanish study reporting prevalence of azathioprine use as high as 69% in heart transplant recipients (20).

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It is speculated that azathioprine confers a greater risk of skin cancer, particularly keratinocyte cancer (KC), than other immunosuppressants, but results of studies to date have been conflicting (20, 21). A meta-analysis of patients with inflammatory bowel disease found an increased risk of KCs in patients treated with azathioprine when compared with healthy controls, or controls with inflammatory bowel disease but no azathioprine exposure (22). However, no systematic review of the risk of skin cancer in OTRs on azathioprine treatment in comparison with other immunosuppressive agents has been conducted. The question of possible carcinogenicity of azathioprine remains a very pertinent clinical question as the answer can provide new guidance on appropriate selection of immunosuppressant

medication. We therefore systematically reviewed all relevant published studies and have summarised the evidence with pooled risk estimates, aiming to resolve the question of whether skin cancer risk is increased after azathioprine treatment.

METHODS

Search strategy

A systematic literature search of Medline (PubMed and Ovid) EMBASE, CINAHL and The Cochrane Library was conducted using the following search terms: “azathioprine”, “6 thiopurine”, “thiopurine”, “immunosuppressant*”, “immunosuppressive agent*”, “skin cancer”, “skin neoplas*”, “squamous cell cancer”, “squamous cell carcinoma”, “basal cell cancer”, “basal cell carcinoma”, “SCC”, “BCC”, “non melanoma skin cancer”,

“nonmelanoma skin cancer”, “NMSC”, “melanoma”, “malignant melanoma” and “transplant*”. A full list of search strategies for the different databases is reported in the Supplemental Methods in the Supporting Information. All relevant studies were identified by a single reviewer. Titles and abstracts were initially checked and studies which combined internal malignancies with skin cancer as an outcome were excluded, as were review articles

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and laboratory-based studies. The full-texts of identified studies were then reviewed and those which met the inclusion criteria were used to perform reference hand-searching and citation searching using the Web of Science. All excluded studies were recorded with reasons for exclusion (Table S1).

Inclusion criteria

Studies were eligible for inclusion if they examined the risk of developing skin cancer in OTRs in relation to azathioprine treatment. Studies which reported azathioprine use in any treatment combination were considered but they were excluded if there was no clear

definition of the immunosuppressive regimens or if all comparison groups contained

azathioprine. Studies that only analysed dosage of immunosuppressants were also excluded as the lack of uniformity in dosage assessment prevented comparisons between studies. Comparisons between azathioprine and cyclosporine, MPA or tacrolimus were recorded but mTOR inhibitors and corticosteroids were excluded as corticosteroid use is generally universal and mTOR inhibitors may inhibit skin cancer formation (23, 24). Whilst our primary outcome of interest was SCC risk, risk of other types of skin cancer was a secondary outcome and we therefore also included studies reporting these risks. Studies published only as abstracts were excluded. If a series of publications covered the same study population, only the most comprehensive study was included. For inclusion in the meta-analysis, it was necessary that studies reported odds ratio (OR), relative risk (RR) or hazard ratio (HR) estimates with 95% confidence intervals (CI). Studies that did not include this information were summarised narratively.

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Data extraction and quality assessment

Data from included studies were extracted according to a pre-defined protocol

(Supplemental Methods) and recorded in a data extraction table. Reporting was conducted in accordance with PRISMA guidelines (25). Data extracted included author and publication year, study location and study design, population size and sex distribution, graft type, period of transplantation, duration and type of immunosuppression, and follow-up time. The type of skin cancer assessed in relation to azathioprine exposure was also recorded and subsequently categorised into one of four groups: a) ‘SCC’ for studies which reviewed SCC risk as an outcome, b) ‘BCC’ for the outcome of BCC risk, c) ‘KC’ for studies that combined SCC and BCC risk together, with the addition of SCC in-situ in some studies, d) ‘other skin cancer’ for studies that analysed the risk of melanoma, MCC, Kaposi’s sarcoma (KS), B-cell lymphoma, lip cancer or other rare skin cancers - alone or in combination with KCs. For studies where risk estimates for azathioprine were available, additional information was extracted including numbers of cases and controls, adjusted risk estimates with 95% confidence intervals (CIs) and adjusted factors or matched variables. Disagreements and uncertainties were discussed and resolved by consensus agreement between investigators.

The quality of studies was assessed using a scoring system based on the following guidelines: MOOSE – Meta-analysis Of Observational Studies in Epidemiology (26), STROBE – Strengthening the Reporting of Observational studies in Epidemiology, (27), QATSO – Quality Assessment Tool for Systematic reviews of Observational studies (28) and Newcastle-Ottawa Scale (29). The evaluation was based on four key aspects: study design, consideration of confounding factors, exposure definition and outcome assessment. For study design, cohort studies and randomised trials were allocated two points, population-based case-control studies one point and clinic-based case-control studies 0 points. A maximum of two points were allocated for assessment of confounding: one point for age and sex

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adjustment or matching and one point for adjusting /matching for other significant factors, namely duration of immunosuppression, graft organ and donor type. A single point was awarded if studies included an adequate definition of azathioprine exposure. With regards to outcome reporting, two areas were reviewed with a maximum of three points available: firstly, two points were allocated for independent follow-up of skin cancer outcomes, one point if this was assessed via registry linkage, a local database or medical records and 0 points for self-reporting or no description. Secondly, one point was allocated for studies which had an adequate follow-up time which was deemed to be an average of five years or more. Studies with a total score of 0-2 were considered low quality, 3-5 moderate quality and 6-8 high quality.

Statistical analysis

A random effects meta-analysis model was used to calculate the pooled estimate and account for the heterogeneity between studies (30). Where studies had several risk estimates for azathioprine exposure, the different groups were included in the analysis if they were believed to be mutually exclusive. Cochran’s Q test was applied to test for statistical

heterogeneity among the pooled estimates (31). We also calculated the I2 statistic to quantify the proportion of heterogeneity in individual studies (32). This value ranges from 0 to 100% with values of 25, 50 and 75% representing low, moderate and high heterogeneity,

respectively (33). To identify an excessive influence of one study, we performed sensitivity analyses by excluding individual studies one at a time and observing the influence on the pooled estimate. Publication bias was assessed by visual inspection of funnel plots and the Begg and Egger tests (34, 35). Analyses were performed for each of the main skin cancer outcomes (SCC, BCC and KC) with relative risk (RR), odds ratios (OR) and hazard ratios (HR) pooled for the meta-analysis. Where studies reported estimates of regimens including

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azathioprine or ever-use of azathioprine, the latter was preferentially chosen. If studies reported risk estimates adjusted for immunosuppression dosing, the unadjusted risk estimates were included in the meta-analysis because the focus of our study was individual drugs rather than immunosuppression dose.

Subgroup analysis

Further analysis was performed to identify significant differences between subgroups and examine the consistency of the association between azathioprine and skin cancer risk. Five pre-specified subgroups were analysed: study design (cohort vs. case-control), graft type (kidney vs. heart), immunosuppressive therapy (dual vs triple), outcome assessment

(independently assessed vs. registry linkage/local database/medical records), sun exposure (high sun exposure: study conducted at low average latitude (340-200) vs. low sun exposure: study conducted at high/middle average latitude (>340)) and quality assessment (high vs.

low-medium). All statistical analyses were performed with the software STATA version 10.0 (Stata corporation, College Station, TX, USA).

RESULTS

Study selection and study characteristics

The systematic search identified a total of 568 articles (Figure 1). After 32 duplicates were removed, 536 records were screened by title and abstract. The full-texts of 55 articles were assessed for eligibility and 28 were excluded for the following reasons (Table S1): skin cancer outcomes not reported separately (eight studies), exposure categories not clearly defined (two studies), azathioprine not specifically assessed as a risk factor (eight studies), azathioprine used in all comparison groups (three studies), conference abstract only (one

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article), relating to a larger published study (three articles) and other miscellaneous reasons (three studies; Table S1).

Twenty-seven articles were included in the final analysis, 23 cohort studies, one randomised trial and three case-control studies. Thirteen of these studies reported sufficient quantitative data to enable inclusion in the meta-analysis.

Quality assessment

The majority of included studies were deemed to be high quality (5, 6, 21, 36-47). Ten were assessed as medium quality (2, 3, 17, 20, 48-53) and two were low quality (54, 55) (Table S2).

SCC risk

Eleven studies assessed the relationship between azathioprine exposure and SCC in OTRs (3, 17, 20, 21, 36, 40, 41, 47, 48, 50, 54) (Table 1) and 10 of the 11 were eligible for inclusion in the meta-analysis (50) (Table S3). Two studies were population-based case-control studies (17, 48) whilst the remainder were cohort studies. Four studies showed a significant association between azathioprine use and SCC risk (17, 20, 47, 48) with the rest reporting no significant association.

In one study, only participants on triple therapy with cyclosporine, azathioprine and prednisolone had an increased risk of SCC (47). Similarly, another study showed that triple therapy with cyclosporine, azathioprine and prednisolone was associated with a significantly increased risk of SCC when compared with dual therapy with either azathioprine and

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The single study excluded from the quantitative analysis found no association between different immunosuppression regimens and SCC risk (risk estimates not reported) (50).

The overall summary estimate for SCC risk in relation to azathioprine treatment in any combination was 1.56 (95% CI 1.11-2.18) with significant heterogeneity (P <0.001; Figure 2) (Table 2). Estimates from all studies ranged from 0.64 to 8.64. The pooled effect estimate was significantly higher when restricting to case-control studies (n= 2) (7.04, 95% CI 3.82-12.94) whilst it was not significant in the assessment of cohort studies alone (n= 8) (1.24, 95% CI 0.99-1.54). Additionally, subgroup analysis of organ type (kidney vs. heart) showed a significant association with azathioprine exposure in the kidney transplant

recipients studies (n= 4) (1.29, 95% CI 1.00-1.68) but not in heart transplant recipients (n= 2) (1.33, 95% CI 0.70-2.53). Triple drug therapy with azathioprine was associated with a

significantly increased risk of SCC when compared with dual azathioprine

immunosuppression therapy (2.38, 95% CI 1.23-4.63). The pooled risk estimate was higher in studies which directly followed-up SCC outcomes after treatment than in those that relied on registry linkage/local database/medical records (2.01 vs. 1.60, respectively), however, there was significant heterogeneity in the analysis of the latter group (P < 0.001). Eight studies based in countries with low sun exposure had a pooled risk estimate of 1.86 (95% CI 1.04-3.33) while the risk estimate from two studies in countries with high sun exposure was not as elevated and fell short of statistical significance (1.25, 95% CI 0.95-1.64) (Table 2). The pooled estimate did not differ according to the quality of studies. There was no evidence of publication bias (P-values for Begg 0.392 and Egger 0.366).

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BCC risk

Six cohort studies evaluated the risk of BCC in relation to azathioprine exposure and all were included in the quantitative analysis (20, 21, 36, 40, 47, 54). Three studies reported a significant association with azathioprine exposure with one study showing an increased risk of BCC (21) and two showing a protective effect of azathioprine treatment (36, 47). The overall summary estimate for all studies was 0.96 (95% CI 0.66-1.40; Figure 3) and risk estimates ranged from 0.20 to 2.10 with significant heterogeneity (P = 0.001). The pooled effect estimate did not differ according to organ type, immunosuppressive therapy, method of outcome assessment, sun exposure or quality assessment. There was no evidence of

publication bias (P-values for Begg 0.087 and Egger 0.213).

KC risk

Of the eight studies that examined the risk of KC (combined risk of SCC and BCC) in relation to azathioprine exposure, seven were cohort studies (2, 21, 37-39, 44, 51) and one was a randomised trial (43). Three studies included SCC in-situ (39, 44, 51) and the remaining five evaluated BCC and SCC alone (2, 21, 37, 38, 43). A significant association between azathioprine exposure and overall KC risk was not seen in any of the studies.

Four studies which reported combined BCC and SCC risk estimates were included in the quantitative analysis (21, 37-39). The summary risk estimate was 0.84 (95% CI, 0.59-1.21; Figure 4) and across all studies the estimates ranged from 0.59 to 1.40 with borderline significant heterogeneity (P = 0.048). There were only four relevant studies from countries where sun exposure could be inferred and the smaller summary risk estimate from the low sun exposure countries had wide confidence limits (0.48, 95% CI 0.24-0.94), compared with the risk based on a single study in a high sun exposure population (1.12, 95% CI 0.85-1.48) (Table 2). The pooled estimate did not differ according to immunosuppressive therapy

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regimen or method of outcome assessment. There was evidence of significant publication bias (P-values for Begg 0.016 and Egger 0.001).

Risk of other skin cancers

Ten cohort studies and one clinic-based case-control study reported on the association between azathioprine risk and various other skin cancers. The risk of melanoma was

evaluated in six studies (5, 45, 46, 52, 54, 55), MCC in three (6, 52, 54), KS in five (20, 46, 49, 52, 53) and other rare skin cancers (e.g. atypical fibroxanthoma, B-cell lymphoma) in four studies (20, 45, 52, 54). All but three studies combined multiple types of skin cancers (5, 6, 42) and seven studies combined KCs with other skin cancers (20, 45, 46, 49, 52, 53, 55). Azathioprine exposure was associated with a significantly increased risk of melanoma (5), MCC (6), lip cancer (42), KS in combination with KCs (49), KS combined with KCs and other rare cancers (e.g. undifferentiated malignant tumours, neuroectodermal cancers) (20) and KS in combination with KCs and actinic keratosis (55). All other studies reported no significant associations with azathioprine exposure.

Six studies reported risk estimates, however the results were not pooled as the skin cancer outcomes varied considerably in these studies (5, 6, 20, 42, 49, 54).

DISCUSSION

We found the risk of SCC in OTRs treated with azathioprine was significantly

increased by 56% compared to SCC risk in those not treated with azathioprine but with other immunosuppressant drugs. However, there was pronounced heterogeneity between studies, likely due to differences in study design, organ type and period of transplantation. Despite the substantial heterogeneity which would tend to dilute the observed summary risk estimate, a significant effect of azathioprine was detected. Thus we consider our summary estimate

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may be a conservative estimate of the risk associated with azathioprine. When grouped by study design, population-based case-control studies showed a much greater pooled risk estimate than cohort studies. This is possibly due to the variation in exposure definition (both case-control studies in the meta-analysis defined azathioprine exposure as never-ever,

compared with cohort studies that mainly assessed specific regimen combinations containing azathioprine, or reported on recent immunosuppressant use without regard to prior exposure). The pooled estimate for SCC risk was higher in countries with low sun exposure compared to those with high sun exposure. This may be because both case-control studies were based in low sun exposure countries and it may also be that the association with azathioprine is masked in the presence of the dominant effect of high sun exposure.

This result is supported by studies which have highlighted the potential carcinogenic mechanism of azathioprine. Firstly, it has been shown that azathioprine sensitises the skin to UVA radiation and causes the accumulation of 6-thioguanine in DNA (14, 16). A further study examining the effect of biologically relevant doses of UVA in cells cultured with 6-thioguanine show that 6-6-thioguanine and UVA are synergistically mutagenic, generating high levels of reactive oxygen species which may increase the risk of SCC (16).

No significant association was found between azathioprine treatment and BCC or KC risk. It is likely that KC combines heterogeneous skin cancers outcomes if azathioprine affects SCC vs BCC risk differentially. It is also possible that because the incidence of BCC increases linearly following transplantation whereas SCC rises exponentially, a greater number of studies with a lengthy follow-up period are required to accurately assess the influence of azathioprine on BCC risk (56).

Tailoring immunosuppressive regimens post-transplantation is important for controlling undesirable effects in patients at increased risk of specific conditions or under circumstances such as family planning. Risk factors for developing SCC after organ

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transplant include older age at transplantation, fair skin type, high sun exposure, frequent sunburns in childhood, a history of skin cancer pre-transplantation and rejection episodes in the first year of transplantation (47, 57, 58). Therefore, the avoidance of azathioprine in OTRs with one or more of these risk factors may help reduce the future risk of SCC.

Strength and limitations

This study is novel in systematically summarising all available data on azathioprine use and skin cancer risk in OTRs and providing a pooled risk estimate separately for SCC and BCC, with detailed assessment of the methodological quality of included studies. However, the definition of azathioprine exposure varied considerably between studies ranging from ever exposure, to use at baseline, use at one year post-transplant whilst in many studies it was undefined. Additionally, some studies examined azathioprine use with any combination of immunosuppressants, others outlined specific regimens and several studies did not provide any treatment detail despite the demonstrated importance of treatment combinations (3, 59, 60). In fact, only nine of the 13 studies included in the meta-analysis provided an adequate definition by which to assess azathioprine exposure. We did not limit the study to a single organ type to ensure a more comprehensive review. However, doses of immunosuppressant medication vary widely between graft organs and some studies have suggested it is dosage, rather than individual drugs, that is a significant risk factor for skin cancer (3, 58, 61, 62). Dosage of immunosuppression could not be collectively and fully assessed as most studies did not analyse this or did not do so in a reproducible, straightforward manner (e.g. they used their own weighted formulae). It is not uncommon for OTRs to undergo changes in their maintenance immunosuppression and this poses a further challenge when attempting to analyse the effects of a single agent. Additionally, referent immunosuppression groups were not consistent amongst studies with variations ranging from no exposure to azathioprine,

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cyclosporine alone, cyclosporine and prednisolone, cyclosporine with MPA and prednisolone and in some studies this was undefined.

Outcome definitions were also variable. Studies that defined the outcome as ‘skin cancer’ included KCs as well as actinic keratosis, KS, melanoma, MCC, B-cell lymphoma, vulval intraepithelial neoplasia and atypical fibroxanthoma. One study that defined the outcome as ‘nonmelanoma skin cancer’ also included KS, undifferentiated tumours and adenocarcinomas and therefore this was analysed under the outcome category ‘other skin cancer’. We analysed the outcome of KC because many studies did not separate BCC and SCC, but grouped these together as nonmelanoma skin cancer. However, we believe that azathioprine may not have a similar effect on both cancers and we recommend that future studies avoid combining risks. Moreover, it was for this reason that we only examined KC risk if studies had combined SCC and BCC, rather than amalgamating all studies under this heading.

Several studies based the outcome assessment on registry data which has significant limitations with regards to skin cancer reporting (1, 63). This may partly explain the result of the subgroup analysis of studies that directly assessed SCC which showed a significantly higher pooled estimate than those that used other less rigorous methods of assessing the outcome.

The year of transplantation ranged from 1963-2011 in the included studies and most reported sole use of azathioprine prior to 1983, after which cyclosporine came into general use. These period differences can affect skin cancer rates due to changes in induction protocols over time, increased awareness and improved detection of skin cancer and increasing survival of OTRs, which some attribute to the introduction of cyclosporine (64-68). Subgroup analysis was not conducted for transplant period as there was significant overlap between time periods within studies and meaningful analysis was not possible.

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In summary, based on current published data, we found an increased risk of SCC in OTRs treated with azathioprine, although considerable variations in measurement of azathioprine exposure and skin cancer outcomes existed between studies. Further high-quality studies are required using standard categorisation to quantify azathioprine exposure and facilitate study comparisons. We also strongly recommend that future studies examine SCC and BCC risk separately, as there appears to be a differential risk post-transplantation in response to azathioprine treatment.

ACKNOWLEDGMENTS

Dr. Michael Burke is supported by a Jacquot Research Fellowship.

DISCLOSURE

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Figure Legends

Figure 1: Flow diagram of study selection and search strategy

Figure 2: Forest plot of the association between azathioprine exposure and squamous cell carcinoma

Figure 3: Forest plot of the association between azathioprine exposure and basal cell carcinoma

Figure 4: Forest plot of the association between azathioprine exposure and keratinocyte cancer

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Supporting Information

Additional Supporting Information may be found in the online version of this article. Supplemental Material

Table S1. Summary of excluded studies with reasons for exclusion Table S2. Quality assessment of 27 included sites

Table S3. Summary of 13 studies included in the meta-analysis, with reported risk estimates in relation to azathioprine exposure

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44. Geusau A, Dunkler D, Messeritsch E, Sandor N, Heidler G, Rodler S et al. Non-melanoma skin cancer and its risk factors in an Austrian population of heart transplant recipients receiving induction therapy. International journal of dermatology 2008;47(9):918-925.

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47. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Nicol DL, Harden PN. Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland, Australia. Journal of the American Academy of Dermatology 2003;49(3):397-406. 48. Ingvar A, Smedby KE, Lindelof B, Fernberg P, Bellocco R, Tufveson G et al. Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2010;25(8):2764-2771.

49. Einollahi B, Nemati E, Lessan-Pezeshki M, Simforoosh N, Nourbala MH, Rostami Z et al. Skin cancer after renal transplantation: Results of a multicenter study in Iran. Annals of transplantation : quarterly of the Polish Transplantation Society 2010;15(3):44-50.

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51. Hayashida MZ, Fernandes VM, de Melo Fernandes DR, Ogawa MM, Tomimori J. Epidemiology and clinical evolution of non-melanoma skin cancer in renal transplant recipients: a single-center experience in Sao Paulo, Brazil. International journal of dermatology 2015;54(10):e383-388.

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53. Serdar ZA, Eren PA, Canbakan M, Turan K, Tellioglu G, Gulle S et al. Dermatologic findings in renal transplant recipients: Possible effects of immunosuppression regimen and p53 mutations. Transplantation proceedings 2010;42(7):2538-2541.

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posttransplantation: a retrospective analysis of 28 years' experience at a single centre. Transplantation proceedings 1997;29(1-2):828-830.

57. Gogia R, Binstock M, Hirose R, Boscardin WJ, Chren MM, Arron ST. Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation. Journal of the American Academy of Dermatology 2013;68(4):585-591. 58. Caforio AL, Fortina AB, Piaserico S, Alaibac M, Tona F, Feltrin G et al. Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000;102(19 Suppl 3):Iii222-227.

59. Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet (London, England) 1997;349(9049):398.

60. Hiesse C, Rieu P, Kriaa F, Larue JR, Goupy C, Neyrat N et al. Malignancy after renal transplantation: analysis of incidence and risk factors in 1700 patients followed during a 25-year period. Transplantation proceedings 1997;29(1-2):831-833.

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recipients with a first nonmelanoma skin cancer: a multicenter cohort study. Archives of dermatology 2010;146(3):294-299.

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Article

Table 1. Characteristics of 27 included studies

Author , publish ed year Study locatio n Study design Popula tion size Sex (% mal e) Age at first transpl ant Org an type 1 Transp lant period Exposure2 Follo w-up time Outco me Categ ory3 Sanders

2015 USA Case-control 388 61% NS

4 K H 1970-2011 A Never/ever exposure NS SCC Ingvar

2010 Sweden Case-control 396 68% Median 51

years K Li K-Li K-P H-Lu 1970-1997 A Never/ever exposure Medi an 6.6 years SCC Keller

2010 Switzerland Cohort 243 63% NS K 2002-2005 A NS SCC

Euvrard

2006 France Cohort 188 84% K: Mean

43 years H: Mean 54 years K H 1967-2003 CA CAP AP TAP NS SCC Jensen

1999 Norway Cohort 2561 65% K: median

47 years H: median 52 years K H 1963-1992 AP CAP K: Medi an 4.8 years H: Medi an 3.5 years SCC Wisger hof 2010 The Netherl ands Cohort 1906 65 % Median 42 years K 1966-2006 A In any combination Medi an 20.6 years SCC BCC Brewer

2009 USA Cohort 312 73% Mean 47

years H 1988-2006 A Time-dependent variable according to most recent use at four different intervals 2097 perso n-years (mea n 6.7 years ) SCC BCC Ramsay

2003 Australia Cohort 361 60% Median 40

years K NS AP CA CAP At one year post-Medi an 7.56 years SCC BCC

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years Lu H- Lu-Li Time-dependent variable according to most recent use at four different intervals years Other SC Molina

2010 Spain Cohort 3393 85% Mean 51

years H 1984-2003 A Use in first three months only; any combination Medi an 5.2 years SCC BCC Other SC Bouwes Bavinc k 1996 Australi

a Cohort 1098 57% With cancer:

mean 46 years. Withou t cancer: mean 41 years. K 1969-1994 A: before 1980 A: after 1980 C then A CA With cance r: medi an 8.9 years With out cance r: medi an 3.9 years SCC BCC KC Hayashi da 2015 Brazil Cohort 68 74 % NS K NS A CA TA NS KC Gallagh

er 2010 Australia Randomised trial 481 57% NS K 1983-1986 AP C then AP

after three months Since transplant Medi an 20.6 years KC Macken zie 2010 New

Zealand Cohort 384 58% Mean age 42

years K 1972-2007 AP CAP Median 5.3 years KC Geusau

2008 Austria Cohort 322 81% Median 54

years H 1984-2003 CAP 6.2 years KC Navarro 2008 Spain Cohort 1017 71%5 NS K K-P K-P-Li 1979-2007 A Median 10 years KC Wimme r 2007 German y Cohort 2419 65% Mean 45 years K 1978-2005 A CA At time of transplant Mean 9.5 years KC Fuente

2003 Spain Cohort 174 68% Median 45

years K 1989-1999 CAP At time of Medi an 6 years KC

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2015 8 % 49 years H Li Lu Oth er6 2009 Baseline immunosuppr ession 789 perso n-years (mea n 4.5 years ) SC Robbin s 2015 USA Cohort 139’99 1 63% NS K H Li Lu Oth er6 1987-2010 A At time of transplant Medi an 4.0 years Other SC Mackin tosh 2013 UK Cohort 610 61 % NS K NS CAP TAP At one year post transplant Medi an 10 years Other SC Belloni-Fortina 2012 Italy Cohort 161 72 % Mean 47 years Li 1987-2006 A Mean 6 years Other SC Savoia

2011 Italy Cohort 282 61% Median 50

years

K

1974-2009 Antimetabolite category Median 7.9 years Other SC Einolla hi 2010 Iran Cohort 11’255 63 % With cancer: mean 47 years. Withou t cancer: mean 38 years. K NS A NS Other SC Serdar

2010 Turkey Cohort 163 60% NS K 1989-2009 CAP TAP Mean 5.6

years Other SC Terhors t 2009 German

y Case-control 139 69% Cases: mean

50 years Control s: mean 53 years K H Li Lu K-P NS A NS Other SC van Leeuwe n 2009 Australi a Cohort 8162 59% Median 43 years K 1982-2003 A Time-dependent variable to represent current receipt at different intervals NS Other SC

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1K: kidney; H: heart; Li: liver; Lu: lung; P: pancreas.

2A: azathioprine; C: cyclosporine; P: prednisolone; T: tacrolimus.

3Outcome categories: SCC, BCC, KC (SCC + BCC +/- SCC in-situ), other skin cancer, SC

(any of the following alone or combined with KCs: actinic keratosis, MM, MCC, KS, B cell lymphoma, vulval intraepithelial neoplasia, cancer of lower vermillion lip, other rare

cancers).

4NS: not stated. 5Of those with cancer. 6Organ types not stated.

BCC, basal cell carcinoma; KC, keratinocyte cancer; KS, Kaposi’s sarcoma; MCC, Merkel cell carcinoma; SCC, squamous cell carcinoma.

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This article is protected by copyright. All rights reserved.

Table 2. Meta-analysis results using a random effects model: association of squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and keratinocyte cancer (KC) with azathioprine treatment

SCC BCC KC

Studies Risk estimate (95% CI)

I2

(%)

P het Studies Risk estimate

(95% CI)

I2

(%)

P het Studies Risk estimate

(95% CI) I2 (%) P het All studies 10 1.56 (1.11-2.18) 67.1 <0.001 6 0.96 (0.66-1.40) 65.7 0.001 4 0.84 (0.59-1.21) 52.8 0.048 Study Design Case-control Cohort 2 8 7.04 (3.82-12.94) 1.24 (0.99-1.54) 0.0 21.7 0.423 0.218 0 6 NA - - 0 4 NA - - Organ type Kidney Heart 4 2 1.29 (1.00-1.68) 1.33 (0.70-2.53) 0.0 72.8 0.642 0.055 3 2 0.94 (0.57-1.55) 0.92 (0.34-2.45) 68.5 85.4 0.002 0.009 3 0 NA - - Immunosuppressive therapy Dual Triple 4 2 1.14 (0.75-1.73) 2.38 (1.23-4.63) 0.0 0.0 0.700 0.836 3 1 0.52 (0.14-1.94) 1.00 (0.50-2.00) 86.2 - 0.001 - 1 1 1.10 (0.68-1.80) 0.67 (0.32-1.40) - - - - Outcome assessment Independently assessed Registry linkage/local database/medical records 3 6 2.01 (1.22-3.33) 1.60 (1.04-2.46) 0.0 75.0 0.913 <0.001 2 3 0.58 (0.26-1.31) 1.23 (0.82-1.85) 71.9 75.5 0.014 0.038 2 2 0.37 (0.10-1.40) 1.04 (0.80-1.34) 71.1 0.6 0.063 0.403 Sun exposure

High sun exposure

Low sun exposure

2 8 1.25 (0.95-1.64) 1.86 (1.04-3.33) 0.0 79.2 0.526 <0.001 2 4 0.90 (0.51-1.58) 1.03 (0.60-1.74) 72.8 58.0 0.001 0.067 1 3 1.12 (0.85-1.48) 0.48 (0.24-0.94) 0.0 45.6 0.690 0.159 Quality assessment High Low-Medium 5 5 1.21 (0.96-1.54) 2.08 (0.94-4.61) 0.0 85.0 0.616 <0.001 4 2 0.88 (0.56-1.39) 1.42 (0.92-2.19) 69.5 0.0 0.001 0.625 4 0 NA - -

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