Thyroid problems post alemtuzumab in MS, the endocrinologists take on this

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Thyroid dysfunction is the commonest treatment related side effect after alemtuzumab.

Alemtuzumab targets CD52 on the surface of T and B cells taking them out of circulation. The precursor cells to the adult T and B cells are left intact because of their lack of the CD52 surface marker. After cell depletion, which occurs very quickly there is then a period of immune reconstitution resulting in repopulation – this can take 6 months to 1/2 years.

This effect of re-setting the immune system is its greatest advantage of this drug, both for MS and in some blood cancers, but also its biggest Achilles heel as there doesn’t seem to be a limit to development of the type of autoimmunity.

Fortunately for alemtuzumab, the commonest autoimmunity is autoimmune thyroid disease, namely Grave’s disease that is easily treatable. How and why it occurs is not well understood, but it is interesting to see what endocrinologists that manage hormonal derangements think about this.

In a review of 121 cases, 41 of whom developed Grave’s disease the group from Saville noted some patterns:

  1. If you have a 1st degree relative with autoimmune thyroid disease then the likelihood of developing autoimmune Grave’s disease post alemtuzumab was high (14.6% vs 1.5% in their study).
  2. Clinical symptoms of thyroid dysfunction were not common, with only 39% having symptoms (e.g. tremor, heat intolerance, changes in bowel habit). Therefore, majority of the abnormality is sub clinical and picked up only in the blood tests.
  3. Also, there is a high proportion with a fluctuating course in thyroid function that occurs abruptly and unexpectedly, which is different to the classical form of the disease that occurs in the population. Those with fluctuating thyroid function also tended to have a more aggressive disease course.
  4. Roughly three quarters of cases responded to carbimazole, the remaining quarter required surgery for removal of the thyroid gland for resolution. Those who underwent surgery were younger (likely something to do with immune senescence/aging). This was also noted in their modelling, including those who actively smoked also seem to require a thyroidectomy.
  5. Being female increased the likelihood of autoimmune Grave’s disease, but had a more favourable outcome, as did those not actively smoking.

Following these findings they have recommended a monitoring scheme for doctors to use in those starting alemtuzumab:

Figure: Proposed screening for Graves’s disease and follow-up in patients on Alemtuzumab treatment. *Determination TPOAb and TRAb before Alemtuzumab: assess the determination when available. Currently, their routine determination is not recommended due to factors such as their low prevalence in the general population, although recent research has proposed that baseline positivity to these antibodies is a risk factor for the development of Alemtuzumab-induced thyroid disorders.
GD-IA: Graves’s disease induced by Alemtuzumab; TPOab: anti-thyroid peroxidase antibodies; TRab: anti-TSH receptor antibodies; T4l: free T4 (thyrotropin); T3l: free T3 (triiodothyronine); BMI: Body Mass Index; HR: heart rate; BP: blood pressure; CV: coefficient of variation

Abstract

J Endocrinol Invest. 2022 Jun 20.

Graves’ disease induced by Alemtuzumab in relapsing-remitting multiple sclerosis patients: an observational study in a reference center

P Rodríguez de Vera Gómez J J García-González R Ravé-García R López Ruiz A Torres-Cuadro S Eichau-Madueño C García-García T Martín-Hernández 

Objectives: Graves’ disease induced by Alemtuzumab (GD-IA) is one of the most frequently observed adverse events in patients with multiple sclerosis (MS) treated with this drug. The aim of this study is the sequencing and description of these events, along with the identification of the risk factors leading to their development.

Materials and methods: We conducted a retrospective observational study identifying patients with relapsing-remitting multiple sclerosis (RRMS) and GD-IA, studying their baseline clinical features and variables related to the natural history of the disease.

Results: A total of 121 participants treated with Alemtuzumab were included, of whom 41 developed GD-IA (33.9%). A higher percentage of first-degree relatives with autoimmune thyroid disease was documented in the subgroup who developed the abovementioned event (14.6% vs 1.5%; p < 0.01). A total of 70.7% of patients diagnosed with GD-IA (n = 29/41) had fluctuations in thyroid function during follow-up, and 24.4% (n = 10/41) required total thyroidectomy for resolution of the condition. In 54.8% of participants diagnosed with GD-IA, a pattern of significant TSH decline was identified in the month prior to diagnosis of the event, with high predictive ability and associated with a more favorable clinical course (fewer weeks to normalization of thyroid function, HR = 8.99; 95% CI [2.11-38.44]; p = 0.0003).

Conclusion: GD-IA has an atypical course compared to classical forms of the disease. The identification of risk factors for the development of the disease before starting treatment with Alemtuzumab and early monitoring of thyroid function once this treatment is initiated prove to be useful strategies in the diagnosis and clinical management of this condition.

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Neuro Doc Gnanapavan

4 comments

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  • I remember reading somewhere that patients with secondary autoimmunity have a better MS outcome. Could it be the change in regulatory cells equilibrium on top of cell depletion? a. what comes back is different; b. when the bad cells come back they can’t do as much as before.

    • I believe this hasn’t been substantiated, definitely the reconstituted population will be expected to be different not in their surface markers but functionally – the latter is what is difficult to confirm.

  • Thanks for this.

    My Graves’ disease was picked up by my annual blood tests at my MS clinic. Further investigations showed that my heart rate was high, there was a tremor (subtle) in some of my fingers, plus I’d lost weight (all the changes were subtle and had developed slowly, but I hadn’t really noticed them – I thought the weight loss was due to my exercise regime). The endocrinologist put me on tablets to address the issue but different doses didn’t calm things down. After 18 months of trying I had radio-active iodine treatment. This was straightforward and I began thyroxine. It took about a year to get the dose right. Alemtuzumab stopped my aggressive relapses so the thyroid issue was a small price to pay. It certainly shouldn’t put anyone off having Alemtuzumab., but shows the importance of regular monitoring.

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