Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of adult patients with active multiple sclerosis (MS) in more than 65 countries [1, 2]. In clinical trials, alemtuzumab demonstrated superior efficacy compared to an active comparator (subcutaneous interferon beta-1a) in both treatment-naive patients and in those with inadequate response to prior therapy [3‐5]. The mechanism by which alemtuzumab exerts its therapeutic effects in MS is not fully elucidated. However, research suggests immunomodulatory effects through the depletion of mature and circulating B- and T lymphocytes, followed by a repopulation and long-lasting shift in immunological balance, including alterations in the number, proportions, and properties of some lymphocyte subsets, increased representation of regulatory T-lymphocyte subsets, and increased representation of memory T- and B lymphocytes. This mechanism may be relevant to the durable efficacy of this drug [6‐8]. Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediated adverse events. Autoimmune thyroid disease (AITD) has been the most common autoimmune disorder, followed by immune thrombocytopenia (ITP), and nephropathies. According to a hypothesis, differential kinetics of lymphocyte subset reconstitution causing early hyperrepopulation of immature B lymphocytes may explain the occurrence of autoimmune events [9]. A risk management plan (RMP) has been implemented to mitigate the risk of autoimmune conditions in MS patients treated with alemtuzumab. Thyroid function tests, such as serum thyroid stimulating hormone (TSH) levels, should be obtained prior to initiation of treatment and every 3 months thereafter until 48 months following the last infusion. After this period, testing should be performed based on the clinical findings suggestive of thyroid dysfunction. Systematic thyroid function monitoring was integrated as of the phase 2 clinical trial [3]. In the phase 3 clinical trials and the extension study, 40.7% (CARE-MS I) and 37.7% (CARE-MS II) of alemtuzumab-treated subjects developed thyroid adverse events (TAEs) within 5 years, more precisely thyroid dysfunction, with a peak incidence in the third year following the first administration [10‐13]. In the event of abnormal findings, the treating physician will have to decide how to manage the sequence of additional tests, possible treatments, and the need to refer the patient to an endocrinologist for further treatment and follow-up. Post-marketing surveillance figures have not been published so far. Due to the current lack of practical clinical guidance with regard to managing thyroid-related autoimmunity after alemtuzumab treatment, a Belgian taskforce was created in 2016 consisting of experts in MS and in thyroid disease, with the objective of issuing practical recommendations to guide the treating physician.

A Belgian taskforce, consisting of 6 experts in MS (E.B., V.D., M.D., S.E., P.S., B.V.) and 2 experts in thyroid disease (B.D., C.D.) first met on May 23, 2016, with the objective of discussing thyroid autoimmunity related to treatment with alemtuzumab based on scientific evidence and personal experience, and designing a clinical management algorithm. During this meeting, the results from the phase 3 CARE-MS I and II and the extension study were discussed along with the major practice points. Next, a draft clinical algorithm was created, which was further developed and discussed through electronic correspondence among the experts, eventually resulting in a consensus clinical algorithm falling into 2 parts: thyroid-related management prior to and post administration of alemtuzumab.

AITD represents the most common autoimmune disease with an estimated prevalence of 5%, and is more frequent in females [14]. The risk of AITD is further increased in the presence of other autoimmune disease(s), such as MS [15]. Usually, AITD presents as 1 of 3 classical phenotypes: autoimmune hypothyroidism or Hashimoto’s disease (HD), autoimmune hyperthyroidism or Graves’ disease (GD), or silent thyroiditis (ST). AITD, however, has to be considered as a dynamic spectrum of diseases, including non-classical phenotypes.

HD is the most common phenotype of AITD. It is a form of painless chronic lymphocytic thyroiditis, and usually slowly develops over years to decades, eventually and most frequently irreversibly leading to hypothyroidism due to thyroid tissue destruction. In most cases, serum thyroperoxidase (TPO) antibodies (Abs) are increased. The treatment consists of lifelong synthetic thyroxine (levothyroxine; LT4) supplementation [16, 17].

GD represents the second most common AITD phenotype, usually developing over weeks to months. GD results in hyperthyroidism, caused by uncontrolled stimulation of the TSH or thyrotropin receptor (TR) by thyrotropin receptor antibodies (TRAbs). TRAbs are thus pathogenic by causing thyroid gland stimulation and thyroid hormone overproduction. Increased TRAb titers represent the hallmark of GD. Rarely, neutral or even blocking TRAbs develop instead of stimulating TRAbs [18]. TPOAbs can also be increased and define the signature of AITD. GD treatment is more complex and consists of reversible medical treatment for 12–18 months with thionamides, anti-thyroid drugs (ATDs) interfering with the TPO enzyme and thus thyroid hormone synthesis, or irreversible non-surgical (radioactive iodine) or surgical (thyroidectomy) treatment [19, 20]. The treatment choice is the result of shared clinical decision between the endocrinologist and the patient. Usually, ATD treatment is well tolerated. However, there are rare cases of severe side-effects, such as agranulocytosis, vasculitis, and liver dysfunction [21]. GD can also target the retro-orbital fat and muscle tissue, resulting in Graves’ orbitopathy (GO), characterized by unilateral or bilateral asymmetrical redness, swelling, diplopia, and very rarely dysthyroid optical neuropathy. The risk of GO is increased with severe hyperthyroidism, high TRAbs, smoking, and in males [22].

ST, the third classical AITD phenotype, is characterized by a self-limiting painless subacute lymphocytic thyroiditis, lasting for weeks to months. TPOAbs are often increased. In the first phase, increased thyroid hormone levels can be observed due to leakage caused by thyroid inflammation, whereas transient hypothyroidism can develop in the second phase. Eventually thyroid function is restored [23].

Thyroid dysfunction and AITD are associated with increased risk for infertility, obstetrical complications, and neuropsychological problems in the offspring [24]. Women with known AITD who are attempting to become pregnant need to be informed of the risks by the endocrinologist and gynecologist. Euthyroidism is mandatory pre-conception. In pregnant women treated with ATDs and/or having persistently high TRAbs, fetal or neonatal hypo- and hyperthyroidism may develop [25].

The diagnosis of AITD is made by measurement of serum thyrotropin or TSH (primary screening parameter for any thyroid dysfunction), thyroid hormones, and antibodies (TPOAbs in case of hypothyroidism, TRAbs in case of hyperthyroidism). If a hyperthyroid patient is symptomatic, nonspecific beta-blockade (propranolol) is indicated independent of the underlying cause. In case of GD and ST, and in case of clinical thyroid gland abnormalities (e.g., goiter), anatomical and functional imaging is indicated by means of ultrasonography and scintigraphy (with radioactive technetium or iodine as tracer), respectively. In a hyperthyroid patient, decreased tracer uptake is suggestive of ST, whereas normal or increased uptake is suggestive of GD [16, 17, 19, 20].

AITD is the most frequently observed autoimmune adverse event in MS patients treated with alemtuzumab [3‐5, 26]. TAEs can develop from 6 months post-alemtuzumab onward and have a peak incidence in year 3 after the first course and a gradual decline afterwards [10, 11]. In clinical trials, half the patients who tested positive for TPO Ab at baseline and a quarter of patients who tested negative developed a thyroid event. The vast majority (approximately 80%) of patients who presented with a thyroid event after treatment were TPO Ab negative at baseline [27]. In contrast to the general population, AITD after alemtuzumab presents 4 times more often as hyperthyroidism than as hypothyroidism. The thyroid dysfunction is usually mild to moderate, and easily controlled with conventional therapy. Mild cases can resolve spontaneously. Serious TAEs such as GO, neonatal GD, and psychiatric events were rare (1–2%) [28‐31]. Furthermore, GD tends to spontaneously resolve in around 1 of 3 cases, which could be due to a higher occurrence of neutral or blocking instead of the classical stimulating TRAbs. Therefore, AITD post-alemtuzumab seems to clinically present as rather ‘non-classical’ phenotypes, also reported in other immune reconstitution circumstances such as HIV treatment, and might, therefore, require a different treatment approach compared to AITD in the general population [32, 33]. Furthermore, the occurrence of thyroid dysfunction did not affect quality of life of alemtuzumab-treated MS patients [34‐36].

Before deciding to treat an eligible patient with alemtuzumab, 2 practical steps should be undertaken with regard to risk assessment for thyroid dysfunction. First, attention should be paid to past or current risk factors known to interfere with thyroid function, including medication and smoking behavior [37]. Second, careful interpretation of the mandatory baseline thyroid tests is needed along with adequate action in case of abnormal findings. The schematical overview of the proposed pre-alemtuzumab clinical management algorithm is shown in Fig. 1.

Thyroid disease represents particular risks in women who are pregnant. Thyroid dysfunction during pregnancy increases the risk of miscarriage as well as obstetrical and fetal problems. In mothers with GD, maternal TRAbs can be transferred to the fetus, which can potentially result in transient fetal and neonatal hyperthyroidism. Placental transfer and potential pharmacologic activity of alemtuzumab were observed in mice during gestation and following delivery. Women of childbearing potential should use effective contraceptive measures during treatment and for 4 months following a course of alemtuzumab [2].

Additionally, the Belgian taskforce proposes that female patients who want to become pregnant at any time after having been treated with alemtuzumab for MS irrespective of past thyroid function problems, serum TSH should be checked along with TPOAb and TRAb status and a clinical thyroid examination. In case of normal findings there is no contraindication for pregnancy from a thyroid point of view. However, in case one or more abnormal parameters are detected, or if the patient is currently receiving treatment for a thyroid problem, referral is indicated to an endocrinologist for advice with regard to thyroid-related pregnancy risk.

Available evidence suggests that in case of active MS, potential thyroid-related adverse events usually do not represent a contra-indication for treatment with alemtuzumab, as AITD most often has a mild clinical course. However, autoimmune TAEs occur frequently and necessitate patient education, careful clinical and biochemical monitoring, and adequate diagnostic and therapeutic action if thyroid dysfunction occurs. The proposed clinical management algorithm can serve as a tool in the daily clinical care for the alemtuzumab-treated MS patient. Beyond 4 years after the last alemtuzumab infusion we propose a lifelong yearly measurement of serum TSH as a minimal follow-up. Close interaction and collaboration is needed between the neurologist and endocrinologist, especially in case of (current or past) hyperthyroidism, GO, intolerance to ATDs, and in case of women seeking pregnancy. Finally, there is a need for more insight in the pathophysiology of alemtuzumab-induced thyroid dysfunction. Data on long-term outcomes in the clinical trials will certainly be of great help in the understanding of non-classical post-alemtuzumab AITD.