Anti-thyroid autoantibodies as biomarkers for alemtuzumab associated thyroid autoimmunity.

In this article of EBioMedicine, Tobias Ruck and colleagues demonstrate that anti-thyroid autoantibodies are possible biomarkers for thyroid secondary autoimmune disorders in alemtuzumab treated people with relapsing-remitting multiple sclerosis [1]. Alemtuzumab, a humanized monoclonal antibody against CD52, is a highly effective treatment for multiple sclerosis [[2], [3], [4]]. The most important immunological effect of alemtuzumab is the very effective and long-lasting depletion of T cells [5]. However, this high therapeutic efficacy is associated with potential serious side effects, such as infections and secondary autoimmunity probably driven by dysregulated B cell repletion [[5], [6], [7]]. Secondary autoimmune diseases were reported in up to 40% of all people treated with alemtuzumab, with thyroid autoimmunity as the most frequent condition. Since alemtuzumab-related secondary autoimmune disorders occur frequently they strongly affect its risk-benefit ratio. Therefore, predictive markers are urgently needed to identify patients which might benefit from this treatment. Currently, alemtuzumab, like natalizumab or fingolimod, is considered as a second-line treatment for relapsing-remitting multiple sclerosis in patients with ongoing disease activity despite treatment with approved disease-modifying drugs [4,8]. All three treatments are associated with potential severe side effects such as natalizumab-associated progressive multifocal leukoencephalopathy. Recently it was demonstrated that a positive anti-John Cunningham virus antibody serostatus, a prior use of immunosuppressants and an increased duration of natalizumab treatment, alone or in combination, were predictive markers for the development of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis [9]. This important finding raises the question whether similar risk biomarkers can also be identified for alemtuzumab-associated secondary autoimmune diseases.

Therefore, the aim of the study by Ruck et al is well justified and of high clinical relevance. The authors have determined serum levels of the anti-thyroid autoantibodies anti-thyroglobulin and anti-thyroid-peroxidase at baseline by standard testing in 106 alemtuzumab-treated patients [1]. They present an interim-analysis with a median follow-up of 36 months. Their results suggest that positive anti-thyroid autoantibody testing of both, anti-thyroglobulin and/or anti-thyroid-peroxidase, is associated with an increased risk for (hazard ratio 12.15, 95% CI 4.73–31.2) and a shorter time to (median 10 versus 23 months) thyroid secondary autoimmune diseases. The authors suggest that the assessment of thyroid autoantibody testing at baseline should therefore be used in clinical decisions.

However, this study also has some limitations. First, whereas the specificity of thyroid autoantibodies for the future development of secondary thyroid autoimmunity is high (94.7%), the sensitivity is low (48.3%). The positive and negative predictive values were 77.8% and 82.6%, respectively. Thus, not all of the patients might benefit from this marker and it's use as a predictive marker should be seen with caution. But it may certainly help to inform patients for choice of treatment because the presence of these antibodies is associated with an increased risk for secondary autoimmunity. According to the results, a combination of both antibodies, anti-thyroglobulin and anti-thyroid-peroxidase, had the highest predictive value, but anti-thyroid-peroxidase had a similar performance. These differential effects and the predictive role of other autoantibodies should now be explored in further studies. As outlined by the authors in their discussion thyroid antibodies have been associated with hypothyroidism and autoimmune thyroid disease in individuals with a positive family history for these disorders and healthy individuals. There is evidence from epidemiological studies that the prevalence of thyroid autoimmunity is comparable between people with multiple sclerosis and matched controls [10] and therefore the highly increased risk for thyroid autoimmunity in alemtuzumab treated patients is caused by this therapy. Finally, this study is an interim analysis of a relatively small cohort with only 29 seropositive people with thyroid autoimmune diseases and larger studies are now needed to confirm these results.

To conclude, the results reported by Ruck and colleagues are important and relevant, and if confirmed, might pave the way for a clinically highly relevant biomarker.

Author contribution

Conception, Writing, Literature Search: Markus Reindl.

Declaration of Competing Interest

Dr. Reindl reports grants from Euroimmun AG (Germany), outside the submitted work; and The Neurological Research Laboratory (Medical University of Innsbruck and Tirol Kliniken, head Dr. Reindl) receives payments for antibody assays (AQP4, MOG and anti-neuronal antibodies) and for AQP4- and MOG-antibody validation experiments organized by Euroimmun AG (Germany).