SAGES Magazine

THE SOUTH AFRICAN GASTROENTEROLOGY REVIEW 2023 | VOLUME 21 | ISSUE 1 | 24 would intuitively place these patients at higher risk of developing malignancy, especially NMSC. 6 Azathioprine is an inactive prodrug which is sequentially metabolized through multiple enzymatic pathways yielding its active metabolite 6-thiodeoxyguanosine (6-TG). This highly active metabolite acts as a purine nucleotide analogue allowing it to be incorporated into DNA. The resultant defective 6-TG nucleic acid sequence is identified by DNA mismatch repair systems resulting in programmed cell death which forms the basis of its therapeutic effects. 4,7 The defective 6-TG nucleic acid sequence is a highly photosensitive and when it absorbs ultraviolet A energy it produces a reactive oxygen species capable of disrupting DNA facilitating mutagenesis. The therapeutic immunosuppressive effects of thiopurines may further promote carcinogenesis by impairing DNA repair mechanisms, limiting immunological clearance of neoplastic cells and upregulating tumour promoting cytokines. These combined effects are the likely cause for the increased risk of both BCC and SCC in patients taking azathioprine. 9 Loss of function pharmacogenetic variants in genes encoding for thiopurine metabolizing enzymes namely thiopurine methyltransferase (TPMT) and NUDT15 have been implicated in thiopurine-induced hematopoietic toxicity by increasing 6-TG accumulation within DNA potentially leading to an eventual excess of mutagenic reactive oxygen species promoting carcinogenesis. 10,11 A 2019 paediatric based study found that patients receiving 6-MP who possessed NUDT15 loss of function mutations where potentially at increased risk of developing secondary malignancies such as basal cell carcinoma, bladder cancer and osteosarcoma. 13 Potential pharmacological strategies such as TPMT and NUDT15 genotype guided thiopurine dosing aimed at pre-emptively mitigating thiopurine toxicity have been proposed might additionally limit thiopurine exposure thereby reducing its associated carcinogenic risk. 13 A retrospective analysis comparing the long term safety of low dose azathioprine in combination with allopurinol (LDAA) with first line azathioprine monotherapy in patients with normal TPMT activity. 2 They demonstrated that the LDAA group receiving 25% of the thiopurine dose were able to achieve comparable clinical effects with fewer adverse events, this intuitively may be a viable strategy for limiting thiopurine exposure particularly in high risk patient populations. This case demonstrates a potential therapeutic dilemma in that our patient was initiated on standard induction and maintenance doses of methotrexate and successfully maintained clinical remission of her Crohns Disease. Despite this therapeutic substitution she still developed multiple recurrences including new NMSC lesions. This poses an important clinical question as to whether the inherent NMSC risk associated with methotrexate justifies its use versus its cessation and whether the initiation of biologic therapy aimed at reducing the risk of further skin cancer recurrences is a compelling indication. A retrospective cohort study comparing any methotrexate vs no methotrexate in patients treated for rheumatoid arthritis (RA) found in 4.6-fold increased incidence of BCC or SCC in the methotrexate group. The associated NMSC risk was found to be significantly higher with cumulative doses greater than 8000mg compared to cumulative doses below 5000mg, similar to the doses used in IBD. 14 Another retrospective cohort study comparing the NMSC risk associated with methotrexate, thiopurines and biologics in patients with RA and IBD found that methotrexate use the RA group for more than one year and a prior history of NMSC had a significantly higher risk for developing a second NMSC with longer duration of therapy having a 60% higher risk if used in excess of 3 years but this was not demonstrated in the IBD group. 15 With regards to the use of biologics a meta-analysis revealed a greater risk of NMSC compared with no biologics use in RA and psoriasis but did not demonstrate an increased risk for those with IBD 16 A recent meta- analysis of adalimumab revealed an increased risk in NMSC in patients receiving combination therapy with an immunomodulator but not with adalimumab monotherapy. 17 Interestingly with regards to the risk of NMSC recurrence a retrospective cohort study in IBD patients found that thiopurine use in combination with an anti-TNF was not associated with an increased risk of a second NMSC vs anti-TNF monotherapy. However, thiopurine monotherapy compared to anti-TNF monotherapy appeared to have a higher incidence of a second NMSC. 15 In the South African context our index patient who has oculocutaneous albinism with a light skin complexion while living in an area with high ambient UV exposure on high doses of immunosuppression for a prolonged duration without having implemented UV light protective measures, with multiple recurrences would be considered very high risk for recurrence. 10 Oculocutaneous albinism has been associated with an increased risk for NMSC especially SCC but considering the fact that she had only developed these lesions three years after the initiation of azathioprine highlights the growing concern for its long term use in high risk patient populations. In retrospect the use of azathioprine and methotrexate despite achieving its intended therapeutic objective of inducing and mainting CD remission potentially contributed to the development of her NMSC. There is a paucity of conscensus guidance with regards to the utilization of biologics in the abscence of compelling intestinal indications in high risk groups. The use of anti-TNF monotherapy may be a viable safer alternative to methotrexate and should be considered in patients with prior history of SCC and multiple BCCs who are at risk for future recurrences. In addition to this patient related environmental risk factors should not be overlooked or underestimated. Thus, clinician driven primary and secondary preventive strategies aimed at environmental and behavioural modification is of paramount importance. These would include the avoidance of outdoor activities between 10am and 4pm if possible, the use of sun protective skin products with a sun-protection factor of 30 or higher, wearing protective long-sleeved garments, broad- brimmed hats including sunglasses. Education regarding monthly skin-self-examination and patient documentation using a skin-health diary. Clinician conducted total body skin examination particularly in high-risk patients should be performed every 6 months as part of each routine CASE REPORT