Thyroid disease with Alemtuzumab – risk mitigation

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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!

Figure 1: Survival plot displaying the cumulative hazard and patients at risk for time to thyroid autoimmune disease for each set of antibody.

Abstract

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.

Ruck T, Schulte-Mecklenbeck A, Pfeuffer S, Heming M, Klotz L, Windhagen S, Kleinschnitz C, Gross CC, Wiendl H, Meuth SG.

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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.

INTERPRETATION:

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.

About the author

Neuro Doc Gnanapavan

10 comments

  • Very interesting article! I have MS and thyroid antibodies as well.
    Had been monitoring my thyroid levels for twenty years before the MS diagnosis. My mom developed Graves’ disease in her 50’s.

  • I guess no one talks about how bad this thyroid disease is.

    Does it compensate the possible benefits of Alemtuzumab? Because if having MS is hard enough, specially SPMS, it will be even harder to have MS and a thyroid problem . A bit tricky if Alemtuzumab does not stop MS, am I wrong ?

    If you can predict if a patient will or will not suffer from thyroid problems by having Alemtuzumab will you go ahead with the medication, knowing that Patient will have a thyroid problem?

    • Maria,

      I developed Graves’ disease after receiving Alemtuzumab (c.3 years after my second infusion). It was picked up by my MS clinic and after a year of so I had radioactive iodine treatment. I now take 1 small levothyroxine tablet a day. The Graves’ disease was a mild inconvenience compared to my highly active MS (my relapses were very disabling). I’ve had 12 years with no relapses and stable EDSS. Thank you Alemtuzumab. Graves is a small price to pay for the benefits I have had from Alemtuzumab. It may be different for others, but I’d do it all again (I’d be in a wheelchair now if it wasn’t for Alemtuzumab).

    • My take on the thyroid dysfunction post-alemtuzumab is that it’s entirely manageable with treatment. But the section on severity is new to me and will not be considering it on those who are TSH-R and TPO positive. Just to highlight positive TSH-R on baseline blood test is exclusion for alemtuzumab treatment.

      • Graves was one of 3 new autoimmunities I developed after alemtuzumab (so far), and I can attest that it was the easiest to treat by far. It was complicated by concurrent ITP and radioiodine was too slow, but once the thyroidectomy was done it was sorted.

        Interestingly the thyroid antibodies continue to hang around 18 months after the glands removal, although their levels are slowly decreasing. There seems to be a question of whether the presence of these is indicative of ongoing autoimmune risk? In my case I went on to develop autoimmune haemolytic anaemia – perhaps there’s some cross-reactivity involved?

  • I had thyrotoxicosis a few months before my first Lemtrada infusion. I had been on Tecfidera. It resolved on its own and the endocrinologist suspected it was due to an infection. I didn’t have any medication for it.

    I wonder if some cases of Graves post Lemtrada are thyrotoxicosis and will resolve on its own.
    If thyrotoxicosis can last up to 12 weeks, then it would be interesting to know how long pwMS wait before starting medication for Graves? if they have had Lemtrada and their blood test results are abnormal.

  • 9 months after R1, my thyroid went wonky (Hashitoxicosis) and I was diagnosed with Hashimoto’s (TPO and TG positive) shortly thereafter. I will never know if I was on the cusp of unmasking this without alemtuzumab or not, and at this point maybe it doesn’t matter. If alemtuzumab works as hoped it will have been 100% worth it. If not…maybe it’s worth it for some hope? I’m not sure yet. Hypo is a lot more fun than hyper, though, by far.

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