A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation – JOELLE study)

Abstract

BackgroundThere is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.ObjectiveThe aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.MethodsThis is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis.ResultsWe included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.ConclusionUse of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results.

Socioeconomic deprivation and regional variation in Hodgkin’s lymphoma incidence in the UK: a population-based cohort study of 10 million individuals

“…Previous concordance studies have demonstrated that HL diagnoses have high validity in CPRD when compared with the NCR (positive predictive value for lymphoma 89.6%, sensitivity 97.3%) and any such effect is therefore unlikely to have materially affected the findings 24. In addition, CPRD has established use in cancer epidemiology in the literature24–27 and previous population-based cohort studies have demonstrated the feasibility of HL research using CPRD 28–30. Outcome misclassification in this study was further reduced through use of HES-linked data, which improved validity of HL diagnoses by supplementing GP records with hospital data to capture cases that might have been missed in CPRD.…”

Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta‐analysis

“…Thirdly, when evaluating subjective symptoms, as a minimum the blinding of participants should be required to reduce possible bias. Finally, the long‐term safety of TCI should be confirmed by well‐designed studies, as some studies reported that TCI may be carcinogenic (including oropharyngeal cancer, squamous cell carcinoma, malignant melanoma and lymphoma) . The carcinogenicity of tacrolimus may be not only due to immune suppression, and tacrolimus also showed an impact on cancer signalling pathways such as the mitogen‐activated protein kinase and p53 pathways …”

The potential for malignancy from atopic disorders and allergic inflammation: A systematic review and meta‐analysis

“…While it is possible that control of atopic dermatitis inflammation could reduce subsequent cancer risk, as is the case for inflammatory conditions such as ulcerative colitis, careful consideration must be given with regard to the agents used to alleviate allergic responses as links between several therapies and increased malignancy rates have been identified. For example, calcineurin inhibitors which are used topically to treat eczema have been associated with increased cancer risk in various organs, including the skin . Additionally, the FDA has raised concerns regarding increased cancer rates in patients treated with the anti‐IgE antibody omalizumab.…”