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Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study

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The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk.


We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model.


We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1–45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98–1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32–45, SIR 1.21 (95% CI 1.21–1.42), and 46–51, SIR 1.11 (95% CI 1.11–1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007–1.093). The exposure to other DMTs did not modify the risk.


The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.

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The authors would like to thank Dr. Clara Milanese, retired neurologist of Neurological Institute C. Besta, who first approved this study, and Dr. Giulia Turri for her contribution to data update in the Center of Verona.

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All data relevant to the study are included in the article or uploaded as supplementary information.

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Authors and Affiliations



Loredana La Mantia: Conceptualization; Methodology; Original Draft Preparation; Writing, Reviewing and Editing Data; Data Collection and Data Interpretation; Supervision. Maria Donata Benedetti: Methodology and Statistical Analysis; Writing, Reviewing and Editing; Data Collection and Data Interpretation, Visualization, Supervision. Milena Sant: Methodology and Statistical Analysis, Data Interpretation, Critical Revision. Roberto Lillini: Statistical analysis; Writing, Reviewing and Editing; Visualization. Alessia d’Arma: Statistical Analysis, Data Management, Visualization. Sonia Di Tella: Statistical Analysis, Visualization. Laura Mendozzi, Antonio Marangi, Marco Turatti, and Domenico Caputo: Data Collection and Revision. Marco Rovaris: Data Collection and Critical Revision.

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Correspondence to Loredana La Mantia.

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The project has been approved by the Institutional Board (Number 1404201691626).

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The authors declare no competing interests.

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La Mantia, L., Benedetti, M.D., Sant, M. et al. Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study. Neurol Sci 42, 5157–5163 (2021).

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