Abstract
ContextAlemtuzumab, a highly effective treatment for multiple sclerosis (MS), predisposes to Graves disease (GD), with a reportedly indolent course.ObjectiveTo determine the type, frequency, and course of thyroid dysfunction (TD) in a cohort of alemtuzumab-treated patients with MS in the United Kingdom.DesignCase records of alemtuzumab-treated patients who developed TD were reviewed.ResultsA total of 41.1% (102 out of 248; 80 female and 22 male) of patients developed TD, principally GD (71.6%). Median onset was 17 months (range 2 to 107) following the last dose, with the majority (89%) within 3 years. Follow-up data (range 6 to 251 months) were available in 71 case subjects, of whom 52 (73.2%) developed GD: 10 of these (19.2%) had fluctuating TD. All 52 patients with GD commenced antithyroid drugs (ATDs): 3 required radioiodine (RAI) due to ATD side effects, and drug therapy is ongoing in 2; of those who completed a course, 16 are in remission, 1 developed spontaneous hypothyroidism, and 30 (64%) required definitive or long-term treatment (RAI, n = 17; thyroidectomy, n = 5; and long-term ATDs, n = 8). Three cases of thyroiditis and 16 cases of hypothyroidism were documented: 5 with antithyroid peroxidase antibody positivity only, 10 with positive TSH receptor antibody (TRAb), and 1 of uncertain etiology. Bioassay confirmed both stimulating and blocking TRAb in a subset of fluctuating GD cases.ConclusionsContrary to published literature, we recorded frequent occurrence of GD that required definitive or prolonged ATD treatment. Furthermore, fluctuating thyroid status in GD and unexpectedly high frequency of TRAb-positive hypothyroidism suggested changing activity of TRAb in this clinical context; we have documented the existence of both blocking and stimulating TRAb in these patients.
Highlights
Contrary to published literature, we recorded frequent occurrence of Graves disease (GD) that required definitive or prolonged antithyroid drug (ATD) treatment
thyroid dysfunction (TD) was more commonly seen in women, we acknowledge that the known excess female preponderance of multiple sclerosis (MS) could have influenced this sex distribution
The onset of TD was highly variable, but 89% occurred within 36 months of last administration of alemtuzumab and 91% within 4 years, the period recommended for regular thyroid surveillance
Summary
We undertook detailed analysis of all patients with MS who developed TD after treatment with alemtuzumab in clinical trials prior to its licensing at Addenbrooke’s Hospital in Cambridge and University Hospital Wales in Cardiff over a 20-year period (1993 to 2013).Alemtuzumab was administered intravenously on consecutive days for one or more cycles (5 consecutive days for the first cycle and 3 consecutive days for subsequent cycles). We undertook detailed analysis of all patients with MS who developed TD after treatment with alemtuzumab in clinical trials prior to its licensing at Addenbrooke’s Hospital in Cambridge and University Hospital Wales in Cardiff over a 20-year period (1993 to 2013). The initial dose (20 mg/d) was increased to 24 mg/d in 2003 following a change in supplier. From 2006, the dose was reduced to 12 mg/d to conform with the phase 3 study protocol. All patients receiving alemtuzumab at either center had baseline thyroid function tests [TSH and free T4 (FT4)] prior to commencement of the drug, with TSH, FT4, and antithyroid peroxidase (TPO) antibody measurement every 3 months for 2 years, every 6 months for 2 years, and annually, or sooner if symptoms of TD developed. One patient with preexisting thyroid disease, noted from her past medical history, was excluded from this analysis
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