There is a popular old saying in English – “forewarned is forearmed”. Prior knowledge that something is going to happen offers tactical advantage, whether you’re at war or simply everyday life. The difficulty, however, is that more often than not we are transfixed by the detail of the matter, resulting in numerous avenues of investigation in the process, some of which are dead ends.
Take for instance the co-occurrence of autoimmune thyroid disease (particularly Grave’s disease) and multiple sclerosis; I call this the footprint of poly-autoimmunity. It is a jack in the box waiting to be opened, sometimes associating with more than a single autoimmune disorder. Alemtuzumab replicates this concept in certain individuals true to form, and like in real-life the thyroid autoimmunity is also the commonest described adverse event. Alemtuzumab-treated MS individuals have 38-41% chance of developing thyroid auto-immunity up to 4y after the last treatment.
Previously, the Cambridge group reported on elevated IL-21 levels as a potential biomarker of the risk of developing autoimmune disease after alemtuzumab treatment. But, unfortunately owing to technical difficulties with the kit, this finding was dropped.
Now, Ruck et al. from Germany (see abstract below), state that prior occurrence of anti-thyroid antibodies can predict the risk of developing autoimmune thyroid disease after alemtuzumab treatment.
Roughly 48% of individuals with positive thyroid antibodies developed thyroid autoimmune disease, as opposed to 5% that didn’t develop thyroid autoimmune disease, but were antibody positive. This is therefore about relative risks, but one that forms a convincing argument. I would go so far as to say that those who are thyroid antibody positive beforehand probably already have autoimmune thyroid disease, and alemtuzumab simply hastens along the pathobiology.
The latter is supported by their finding that the presence of baseline antibodies were associated with a shorter time to development of autoimmune thyroid disease (by as much as 10 months). Equally, a higher proportion of those who were antibody positive also needed radioiodine therapy +/- thryroidectomy (surgical removal of thyroid gland), suggesting potentially a more severe disease course.
Antibodies to TPO (thyroid peroxidase), an enzyme that is important for the formation of thyroid hormones, not surprisingly also was the most sensitive in predicting this risk (see Figure 1 below).
In the original alemtuzumab clinical trials the presence of baseline anti-TSH receptor antibody positivity and not anti-TPO antibody formed the exclusion criteria. If both had been excluded then it’s likely that the reports of cases would have been less!
EBioMedicine. 2019 Jul 29. pii: S2352-3964(19)30504-3. doi: 10.1016/j.ebiom.2019.07.062. [Epub ahead of print]
Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: A prospective cohort study.
Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions.
We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti-thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months.
Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73-31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity.
Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation.