Anti-thyroid autoantibodies as biomarkers for alemtuzumab associated thyroid autoimmunity

Abstract

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-thyroidperoxidase at baseline by standard testing in 106 alemtuzumabtreated patients [1]. They present an interim-analysis with a median follow-up of 36 months. Their results suggest that positive antithyroid autoantibody testing of both, anti-thyroglobulin and/or antithyroid-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...

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

“…However ulterior analyses limited its use as a biomarker since there is some overlapping between patients who develop AAIEs and those who not, and detection tests currently available could not distinguish accurately between both groups of patients (20). Likewise, pretreatment presence of serum anti-thyroid autoantibodies associated with increased risk for clinical onset of thyroid autoimmunity after alemtuzumab treatment (21), but this biomarker would only benefit a small group of patients. MS is a heterogeneous disease with different immunological mechanisms playing a main role in the inflammatory response (22).…”