Patient 1

A 49-year-old male with relapsing remitting MS received Alemtuzumab in March of 2009 and 2010 as part of the CARE-MS II trial. We remain blinded to the dose (12 mg versus 24 mg) according to the study protocol. Alemtuzumab was given as an intravenous infusion for five days upon enrolment in the trial and for three days a year later. In March 2011 (one year after the second Alemtuzumab infusion), the patient started to notice symptoms of hyperthyroidism, including weight loss, increased defecation and heat intolerance. The patient does not have any family history of thyroid disease.

On examination, the thyroid was about two times the normal size, not tender and no bruit was noted. There were no findings of Graves’ eye disease.

Thyroid uptake and scan was done around four weeks after the initial presentation and showed an increased uptake of 33% (normal range 6-22%), which is compatible with GD. Anti-microsomal antibody was positive at 1:100 dilutions (it was negative upon enrolment in the trial).The patient was initiated on Propylthiouracil (PTU) 250 mg twice daily at the time of diagnosis and was decreased to 250 mg daily six weeks later upon normalization of free T4 and free T3. Seventeen weeks later the PTU was discontinued due to development of hypothyroidism and was initiated on Levothyroxine 100 mcg per day at 23 weeks after initial presentation for persistent hypothyroidism. He continues to require thyroid hormone replacement over two years later.

Patient 2

A 37 year old female with relapsing remitting MS received Alemtuzumab as part of the CARE-MS I trial. She received intravenous Alemtuzumab 12 mg per day for five days in January 2010. She subsequently received 12 mg daily for three days a year later in accordance with the study protocol. Five months after the second infusion of Alemtuzumab, she began to note tremors, palpitations, sweating, occasional shortness of breath, and weight loss of 10 kg over two months.

On examination, the thyroid gland was diffusely enlarged (25 -30 g), firm, not tender with no palpable nodules and a faint bruit was present on the right lobe. There were no findings of Graves’ eye disease.

Thyroid uptake and scan done around four weeks after the initial presentation of the patient, showed a radioactive iodine uptake of 9% (normal). Anti-microsomal antibody was positive at 1:400 dilutions (it was negative at enrolment in the trial).

The patient was prescribed propranolol for symptom management, but no anti-thyroid medication was initiated. Four weeks later, thyroid function tests were within normal. Twelve weeks after initial presentation the patient was initiated on Levothyroxine 100 mcg per day for hypothyroidism. She continues to require thyroid hormone replacement 18 months later.

Patient 3

A 34-year-old female with relapsing remitting MS received Alemtuzumab in July of 2009 and 2010 as part of the CARE-MS II trial. We remain blinded to the dose given (12 mg versus 24 mg) according to the study protocol. Sixteen months after the second Alemtuzumab infusion, she noticed shortness of breath and palpitations with minimal exertion. Her appetite was increased but despite this, she lost 10l bs. She had menorrhagia but no ophthalmic symptoms. She has a family history of both hypothyroidism and hyperthyroidism.

On examination, she had a visible left thyroid lobe enlargement. There was a large palpable left thyroid mass. Her neck was not tender and there was no bruit. There was no finding of Graves’ eye disease. Subsequent thyroid ultrasound confirmed a 3.5 cm left thyroid nodule.

Anti-TPO antibodies were elevated at 768KIU/L (normal level less than 6KIU/L), even though it was negative upon study enrolment. Thyroid uptake and scan showed an increased uptake of 58.7% consistent with GD. The dominant nodule in the left upper pole was “cold” (no uptake of tracer).

She was started on Methimazole 10 mg twice daily along with a beta-blocker (Metoprolol) for a few weeks to control her symptoms. Thyroid function tests were better nine weeks after Methimazole initiation. The patient started to feel more fatigued than usual around twenty-two weeks after starting methimazole. She briefly discontinued this agent on her own but was re-started on it at 5 mg per day two weeks later when the thyroid function tests showed a low thyroid stimulating hormome (TSH) suggestive of hyperthyroid state. Thyroid function tests 26 weeks later were normal; therefore the methimazole dose was reduced to 5 mg every other day. Methimazole was discontinued completely around 20 months after onset of GD and she remains euthyroid for the past 12 months although her TSH fluctuates between being normal and mildly suppressed.

She underwent fine needle aspiration and biopsy of the left thyroid nodule, which showed a follicular neoplasm which is likely benign. The risk of differentiated thyroid cancer in this cytology result is 15-30 %.Reference Cibas and Ali ⁶ It is therefore suggested that such patients undergo lobectomy for definitive diagnosis.Reference Cooper, Doherty and Haugen ⁷ Surveillance with thyroid ultrasound and thyroidectomy if the nodule shows progressive increase in size is an alternative option for patients who prefer a conservative approach. The patient opted to have ongoing surveillance with serial ultrasounds, which thus far showed stability in size and nodule characteristics.

Patient 4

A 34 year old female with relapsing remitting MS received Alemtuzumab as part of the CARE-MS I trial. She received intravenous Alemtuzumab 12 mg per day for five days in January 2009. She subsequently received the same dose daily for three days a year later according to the study protocol. On routine blood work, nine months after the first dose of Alemtuzumab, she was found to have biochemical evidence of hyperthyroidism but was asymptomatic. She has no family history of thyroid disease.

On examination, the thyroid was found to be in the upper limits of normal size. There were no findings of Graves’ eye disease

Anti-microsomal antibody was positive at 1:100 dilutions (it was negative upon enrolment).

Since the patient was asymptomatic; no treatment was initiated. Twelve weeks later free T4 and free T3 were normal with a low TSH. Follow up thyroid function tests 24 weeks later showed all thyroid indices were in the normal range.

A year after the initial presentation, the patient began to be more fatigued and developed a new symptom of constipation. Thyroid function tests showed hypothyroidism (elevated TSH, low free T4 and free T3) so she was initiated on Levothyroxine therapy.

Common Causes of thyrotoxicosis

Although thyrotoxicosis and hyperthyroidism are commonly used interchangeably to designate the same disease process, there is a difference in meaning of the two terminologies. Thyrotoxicosis is a broad term denoting a state of increased thyroid hormone levels in the serum with a suppressed TSH regardless of the cause. Hyperthyroidism refers specifically to thyrotoxicosis resulting from increased thyroid hormone production as in aetiologies such as GD, toxic multinodular goitre and toxic thyroid adenoma. Grave’s Disease constitutes an autoimmune disorder that increases thyroid hormone production due to TSH receptor stimulation by thyrotropin receptor antibodies (TRAbs).Reference Mariotti, Caturegli, Piccolo, Barbesino and Pinchera ⁸ Subacute painless thyroiditis, on the other hand, is another important cause of thyrotoxicosis but results from release of preformed thyroid hormones secondary to autoimmune destruction of thyroid follicles without an increase in thyroid hormone synthesis. Both GD and SPT can present with the same symptoms but differentiating between the two causes of thyrotoxicosis is essential as the treatment differs.Reference Bahn, Burch and Cooper ⁹ Subacute painless thyroiditis is typically a self-limiting disease while GD is not and will progress causing more severe disease unless treated with appropriate therapy.

Differences between GD and SPT as a cause of thyrotoxicosis

Differentiating GD from SPT can be obvious if the pattern of the thyrotoxicosis follows a predictable clinical course.Reference Bahn, Burch and Cooper ⁹ Subacute painless thyroiditis causes an initial thyrotoxic phase secondary to the release of preformed thyroid hormones due to autoimmune thyroid destruction of thyroid follicles. Over weeks to months thyroid function recovers with the possibility of a hypothyroid phase during recovery.Reference Nikolai, Coombs and McKenzie ¹⁰ Over time, the chance of developing chronic thyroiditis and subsequent hypothyroidism is as high as 50% in all patients with SPT.Reference Samuels ¹¹ On the other hand, GD is an autoimmune process that rarely remits without treatment and in fact can become progressively worse over time. In general, the thyrotoxicosis caused by SPT is less severe than that observed with GD. However, the thyrotoxic symptoms are the same and it may be difficult to distinguish between the two diagnoses without the aid of specialized tests.

Various symptoms and signs are common to thyrotoxic states regardless of the etiology, but some are specific to GD (Table 2). The presence of Graves’ ophthalmopathy is unique to GD and results from an autoimmune-mediated accumulation of hydrophilic glycosaminoglycans (GAG) in the extraocular muscles and retro-orbital connective and adipose tissue.Reference Burch and Wartofsky ¹²

Table 2

Symptoms and Signs

* These symptoms are due to sympathetic overdrive secondary to increased thyroid hormone action in different tissues (Adapted from References Reference Trzepacz, Klein, Roberts, Greenhouse and Levey25,26,Reference Bahn27)

** Can be confused with those due to MS.

The American Thyroid Association Practice Guidelines states that in a patient with a symmetrically enlarged thyroid, recent onset of ophthalmopathy, and persistent, high levels of thyroid hormone for weeks to months, the diagnosis of GD is sufficiently likely that further evaluation of hyperthyroidism causation is unnecessary.Reference Bahn, Burch and Cooper ⁹

The absence of classical GD physical findings in the setting of thyrotoxicosis necessitates further investigations to distinguish between GD and SPT and to further guide treatment. A radioactive iodine uptake (RAIU) test should be performed (except during pregnancy when it is contraindicated). Radioactive iodine uptake, a measure of thyroid hormone synthesis, will be elevated and occasionally normal in cases of GD but extremely low in cases of SPT.Reference Bahn, Burch and Cooper ⁹ However, normal or even elevated RAIU has been reported in patients with SPT if RAIU is carried out during the recovery phase of SPT.Reference Nabhan, Kreher and Eugster ^{13 ,} Reference Ramtoola, Maisey, Clarke and Fogelman ¹⁴ Therefore, the earlier the RAIU is carried out at the time of diagnosis of thyrotoxicosis, the more accurate the interpretation. That is why initiating this test before a referral to endocrinology is important.

An alternative way to distinguish between GD and SPT is to measure specific thyroid antibodies.Reference Mariotti, Caturegli, Piccolo, Barbesino and Pinchera ^{8 ,} Reference Tozzoli, Bagnasco, Giavarina and Bizzaro ^{15 ,} Reference Barbesino and Tomer ¹⁶ Thyroid receptor antibodies, otherwise known as thyroid binding immunoglobulins (TBII), have a specificity of 99% and sensitivity of 97% for diagnosing GD.Reference Nabhan, Kreher and Eugster ¹³ Thyroid Peroxidase antibodies (anti-TPO) are almost always positive in SPT and up to 70% of GD; therefore they are not useful to make a distinction between the two conditions.Reference Mariotti, Caturegli, Piccolo, Barbesino and Pinchera ^{8 ,} Reference Tozzoli, Bagnasco, Giavarina and Bizzaro ¹⁵

Hypothyroidism

Symptoms and signs for hypothyroidism are less specific and overlap with those of many other medical conditions, including MS. Common symptoms of hypothyroidism include, dry skin, cold sensitivity, fatigue, muscle cramps, voice change, and constipation. Severe hypothyroidism can also present with carpal tunnel syndrome and sleep apnea. Periorbital edema, delayed relaxation of muscle stretch reflexes, and bradycardia are some physical signs associated with hypothyroidism.

A diagnosis of primary hypothyroidism in a patient with MS can be overlooked due to the non-specific symptoms that mimic those of MS. There should be a low threshold to investigate these patients by obtaining a TSH level. An elevated TSH above the reference range in a patient with new symptoms compatible with hypothyroidism is enough to confirm the diagnosis of hypothyroidism. Permanent hypothyroidism associated with Alemtuzumab treatment can occur due to progressive autoimmune destruction of thyroid tissue. However, a transient hypothyroidism can occur during the recovery phase of SPT. The diagnosis of hypothyroidism is unlikely to be missed in Alemtuzumab treated patients since screening for thyroid dysfunction in this population is recommended on a regular basis as part of their clinical and laboratory surveillance program.

The incidence of AITD

Alemtuzumab use in MS patients causes hypothyroidism and thyrotoxicosis. The latter comprises mostly SPT and GD. The incidence of AITD reported in clinical trials is briefly summarized below.

In a recent four year follow up analysis of patients in CARE MS I and II trials, the overall incidence of thyroid adverse events was ~36%. Reported thyroid adverse events in the CARE MS trials included hypothyroidism, hyperthyroidism/GD, goitre, thyroiditis, thyroid disorder, thyroid mass, thyrotoxic crisis, abnormal laboratory investigations, endocrine ophthalmopathy and thyroidectomy.Reference Twyman, Oyuela, Palmer, Margolin and Dayan ¹⁷ The definition of each adverse event is not available. Therefore, it is important to emphasize that there is probable overlap between the terminologies used to report thyroid adverse events. For instance thyroiditis could present with thyrotoxicosis (which commonly referred to as hyperthyroidism) early in its course and hypothyroidism later on. Thyroid goitre and thyroid mass are anatomic descriptions of aberrant thyroid anatomy. Patients with a thyroid goitre could be hyperthyroid (as in GD), hypothyroid (as in Hashimoto thyroiditis) or euthyroid. “Abnormal blood work” and “thyroid disorder” are very vague terms and could mean hypothyroidism or hyperthyroidism. Finally thyroidectomy is an intervention for an underlying thyroid disorder rather than a thyroid adverse event.

The most commonly reported thyroid adverse events in the CARE MS trials are hypothyroidism, hyperthyroidism/GD and SPT. Overall the majority of thyroid adverse events occurred within the first three years following the first Alemtuzumab infusion with the incidence peaking at year three. This similar pattern of appearance of thyroid disease was seen previously in the CAMMS223 phase II trial.Reference Twyman, Oyuela, Palmer, Margolin and Dayan ^{17 ,} Reference Daniels, Vladic and Brinar ¹⁸ The yearly incidence of hypothyroidism ranged from 5.7-20.9%, whereas that of all causes of thyrotoxicosis, including GD, ranged from 1.2 -11.9%; the yearly incidence of SPT ranged between 0.7 - 1.9%. A summary of incidence of thyroid adverse events in CARE MS trials is presented in Table 3.Reference Twyman, Oyuela, Palmer, Margolin and Dayan ¹⁷

Table 3

Reported thyroid adverse events in CARE MS Trials

* Serious adverse events represent grade 4 or above based on national cancer institute common terminology criteria of adverse events version 3.0.

** No details available

AE=adverse events

Two patients in CARE MS I and one patient in CARE MS II are reported to have papillary thyroid cancer diagnosed during the trial. In CARE MS I, one patient had a thyroid nodule on study entry and the second patient was found to have a suspicious thyroid nodule by thyroid ultrasound while on treatment for thyrotoxicosis. The patient subsequently underwent hemithyroidectomy followed by radioactive iodine treatment. Thyroid nodules are common in the general population with a prevalence of around 60% based on thyroid ultrasound studies.Reference Cooper, Doherty and Haugen ⁷ Only five percent of all thyroid nodules turn out to be biopsy-proven thyroid cancer. Rotie et al reported that 4.1% of patients who underwent thyroidectomies for GD or multinodular goitre were incidentally found to have micropapillary thyroid cancerReference Roti, Rossi and Trasforini ¹⁹ In a large autopsy study from multiple countries, the incidence of occult papillary thyroid cancer was 5.6-28 %.Reference Fukunaga and Yatani ²⁰ Further studies are required to assess the causal relationship between thyroid cancer and Alemtuzumab treatment.

Daniels et alReference Daniels, Vladic and Brinar ¹⁸ did an extensive review of all thyroid dysfunction that occurred in the phase II study of Alemtuzumab in MS (CAMMS223). Thyroid adverse events were defined clearly and included overt and subclinical hyperthyroidism and overt and subclinical hypothyroidism. Hypothyroidism occurred in 6.9% of patients. Overall 23% of patients who received Alemtuzumab developed GD, which was diagnosed if thyrotoxicosis persisted for more than three consecutive months or if TBIIs were positive during the three months before or after the low TSH was noted. Subacute painless thyroiditis was reported in 4.2% of patients, diagnosed when thyrotoxicosis was followed by spontaneous euthyroidism or hypothyroidism and TBIIs were negative. In addition, 30% of patients with AITD experienced more than one episode of GD, hypothyroidism or SPT over time (same or different). Interestingly, spontaneous resolution of overt GD occurred in 36% of patients and some went on to develop spontaneous hypothyroidism.Reference Daniels, Vladic and Brinar ¹⁸ A summary of incidence of thyroid adverse events in CAMMS223 trial is presented in Table 4.

Table 4

Reported thyroid adverse events in CAMMS223*

Median of 57.3 months of follow-up

GD=Grave’s disease

Cossburn et al.Reference Cossburn, Pace and Jones ²¹ reported higher thyroid autoimmune adverse event rate of 77.36% of 248 patients who received Alemtuzumab (a median cumulative dose of 96 mg over one to four courses). GD accounted for 70.73% and transient thyroiditis for 12.2% of all thyroid adverse events, with the remainder developing hypothyroidism.

Management of SPT versus GD in general

Beta-adrenergic blockers can be used to treat thyrotoxic symptoms regardless of the cause. In SPT, anti-thyroid drugs that block thyroid hormone production in the thyroid follicular cells are not needed since new hormone synthesis is already low in these patients. Rarely, corticosteroids have been used to ameliorate the severity and to shorten the course of thyrotoxicosis due to SPT, but they should be reserved only for severe cases.Reference Bahn, Burch and Cooper ⁹ It is possible that some patients will have recurrent episodes of SPT, separated by years,Reference Nikolai, Coombs and McKenzie ¹⁰ requiring a similar treatment strategy.

Grave’s disease should be managed by any of the following modalities: anti-thyroid medication, ¹³¹I therapy or thyroidectomy. The treatment choice is based on patient preference and recommendation from a qualified internist or endocrinologist. Medical treatment is generally suggested in patients with mild disease, with small goitres and low TRAb titres, since these patients tend to have good rates of disease remission. Hence there is often no need to expose patients to the surgical risks involved with thyroidectomy or the need for long term thyroid hormone replacement therapy expected with ¹³¹I therapy.Reference Mariotti, Caturegli, Piccolo, Barbesino and Pinchera ⁸

Management approach to Alemtuzumab induced thyroid dysfunction