A bygone era: AZA, MTX, CYC increase cancer risk in MS


BMC Neurol. 2017 Aug 8;17(1):155. doi: 10.1186/s12883-017-0932-0.

Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study.

Ragonese P, Aridon P, Vazzoler G, Mazzola MA, Lo Re V, Lo Re M, Realmuto S, Alessi S, D’Amelio M, Savettieri G, Salemi G.



The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs.


We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups.


On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67-73.3; p = 0.013).


The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.

The association between MS therapies and cancer risk is neither simple nor clear cut. However, context is all, and cancer is undoubtedly the single most important thing in a person’s life – not too banal to be buried under some statistic or to exercise tolerance over…And yet our understanding of it has not improved. A work in progress.

Here, Ragonese et al., report that simply having MS does not increase your cancer risk. Although, other epidemiological research have alluded to a link based on the type of cancer. The authors, however did note an increase cancer risk in those who took the older immunosuppressant drugs – azathioprine (AZA), mitoxantrone (MTX) and cyclophosphamide (CYC); compared to age-adjusted controls (hazard ratio 11.05; 95% CI 1.67-73.3). This risk appears to be largely driven by AZA and MTX, rather than CYC where no cancers were observed (although the group receiving CYC was small and the follow up was not as long as for the other drugs). The average treatment period was 5y for AZA and 1y for MTX, but this alone led to a 4-fold increase in cancer. With MTX, the association was with leukaemia, which is a known risk of the drug. We no longer use AZA/MTX in MS, but continue to do so in neuromyelitis optica, sarcoidosis, for example, and as such should be more cautious over their long-term use. Improved surveillance programmes may be the answer.

Unfortunatly, this work does not look at the newer agents (Copaxone, Interferons, and monoclonal antibody therapies). Again, the data on this from other studies are conflicting, and it’s not certain whether these drugs are exposing an intrinsic cancer susceptibility in MS.

In summary, cancer risk from immunosuppressant use is a realistic one. It is a debate worth having. Make it your agenda for this year and the next.

About the author

Neuro Doc Gnanapavan


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  • pffft i said the exact thing on this blog 2 years ago, on the advice of my partner's oncologist lol.

    but say now, you must be kidding. i have the word of melbourne's renowned neuro that ongoing immunomodulation or suppression associated with indefinite use of tysabri, gilenya etc (or MABS), unlike hsct, are not at all associated with cancer 😀

    that was pre aus rituximab and ocrelizumab

    my partner's oncologist sorta gave a blank look about that but let's not dwell.

    ah i should stop being a snarky boo and thank you for the entry instead 😀

  • Given the immune system's role in abnormal cell surveillance, could we de facto assume that there's probably a cancer risk with all DMTs?

    • perhaps. my partner's oncologist, breast surgeon and haemo are all undecided about that – possibly. long term immunosuppression has more theoretical chance than others. but not all b cells are involved in all cancers… so really it all depends 😀

      the oncologist and the haemo do both agree that life long suppression of b cells is a bit problematic in terms of ongoing health 😀

      but again, not to dwell lol



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