Years of Thyroid Monitoring Needed After MS Drug Alemtuzumab

Nancy A. Melville

September 26, 2018

Treatment with the multiple sclerosis (MS) drug alemtuzumab (Lemtrada, Genzyme/Sanofi) is associated with thyroid dysfunction and an increased risk of Graves disease that may have onset later than previously thought and therefore could require longer-term monitoring, according to results of one of the largest case series to date, spanning 20 years.

"Alemtuzumab is a highly effective therapy for relapsing-remitting MS, [with a] number needed to treat to benefit of five [and] number needed to treat for a serious adverse event of 148," say Nadia Pariani, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom, and colleagues.

"However, the development of thyroid autoimmunity months or years after treatment is a frequent complication, requiring ongoing biochemical surveillance for at least 4 years after alemtuzumab therapy to detect and treat thyroid dysfunction promptly," they note in their article published in the Journal of Clinical Endocrinology and Metabolism.

The development of autoimmunity is established as the most notable adverse effect of alemtuzumab, a monoclonal antibody, with thyroid autoimmunity representing the most common form.

Physicians can expect to see more cases of thyroid dysfunction among these patients, the authors note. "Following recent regulatory approval of alemtuzumab for treatment of MS, endocrinologists will be required to manage this form of thyroid dysfunction more often," they write.

Alemtuzumab was approved by the US Food and Drug Administration in 2014, with a boxed warning for risk of serious, sometimes fatal autoimmune conditions, and must be prescribed and distributed in the United States through a risk evaluation and mitigation strategy (REMS). It is also licensed in the European Union.

Commenting on the new study, Barbara S. Giesser, MD, vice-chair of neurology at the Ronald Reagan UCLA Medical Center, Los Angeles, California, noted that the evidence still suggests that the benefits of alemtuzumab in MS likely outweigh the risks in terms of thyroid dysfunction.

"For patients with aggressive or unstable MS, alemtuzumab is a very effective treatment option," Giesser, who is a fellow with the American Academy of Neurology, told Medscape Medical News.

"Some other reports have suggested that alemtuzumab-associated thyroid dysfunction may be less troublesome than spontaneous thyroid disease, and in some cases remits spontaneously," she said. "The risks for neurologic deficit from MS have to be weighed against the risk of developing autoimmune disease which can usually be effectively treated."

Thyroid Dysfunction With Alemtuzumab: Fluctuating and Unpredictable

To better understand the nature of the thyroid dysfunction, Pariani and colleagues evaluated data on 248 patients with MS who were treated with alemtuzumab in clinical trials in the United Kingdom from 1993 to 2013.

They discovered 102 (41.1%) patients who went on to develop thyroid dysfunction, including 80 women and 22 men, with the cases primarily involving Graves disease (71.6%), consistent with prior research.

Although there was high variation in the time of onset of the thyroid dysfunction, the majority (89%) of cases occurred within 36 months of the last dose of alemtuzumab and 91% occurred within 4 years.

Contrary to previous studies, however, nine cases were considered "late-onset" thyroid dysfunction, including two cases at 5 years, four cases at 6 years, one case at 7 years, and two cases as late as 9 years following the last dose of alemtuzumab.

"In a previous clinical trial, risk of autoimmune dysfunction peaked at 12 to 18 months after last alemtuzumab treatment, with no recorded autoimmunity beyond 5 years after therapy," the authors note.

To take a closer look at the course of thyroid dysfunction, Pariani and colleagues analyzed data on a subgroup of 71 patients who had information available at a median of just over 5 years (67 months; range, 6 to 251 months).

Of those, 52 (73.2%) developed Graves disease, with 10 (19.2%) developing fluctuating thyroid dysfunction.

All participants who developed Graves disease were treated with antithyroid drugs, and of the 47 patients who completed a course, 16 were in remission and one developed spontaneous hypothyroidism. Meanwhile, 30 (64%) required long-term treatment, including 17 who required radioiodine therapy, five who required thyroidectomy, and eight who required long-term antithyroid drug treatment.

Comparatively, about 50% of patients with conventional Graves disease (not associated with alemtuzumab) typically require long-term treatment, the authors note.

Further outcomes suggested fluctuating levels of thyroid-stimulating hormone receptor antibody (TRAb) in the patients: among three cases of thyroiditis and 16 cases of hypothyroidism, as many as 10 were positive for TRAb, five had antithyroid peroxidase antibody positivity only, and one was of uncertain etiology.

In addition, patients who developed hypothyroidism had surprisingly high TRAb levels (mean 30.4 IU/L, range, 3.9 to > 40 IU/L), the authors point out.

"Fluctuating thyroid status in Graves disease 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," they explain.

The fluctuating courses of alemtuzumab-induced Graves disease, with swings from hyper- to hypothyroidism, or from hypothyroidism to normal thyroid function, in fact could be underestimated, they stress.

"A considerable proportion (16.4%) of our patients developed Graves disease with a fluctuating and unpredictable course, and it is conceivable that this is an underestimate, as frequent use of a block-and-replace antithyroid drug regimen may have masked additional cases."

Longer Surveillance Needed for Those Taking Alemtuzumab

Although the specific mechanisms behind autoimmunity induced by alemtuzumab are not well understood, similar autoimmunity is seen in other treatment contexts, including bone marrow transplantation or HIV antiretroviral therapy, and Graves disease is also common during recovery from lymphopenia.

As reported by Medscape Medical News, recent research has shown alemtuzumab can have important benefits in relapsing-remitting MS that are maintained as far out as 7 years, and that study showed relatively low thyroid-related adverse events, reaching just 17% at year 3.

But a prior study detailed potentially life-threatening side effects with alemtuzumab, including eight cases of acute acalculous cholecystitis, two cases of hemophagocytic lymphohistiocytosis, and one occurrence of acute coronary syndrome.

"Based on our experience, we suggest close monitoring of thyroid function in patients with alemtuzumab-treated MS, particularly if they develop Graves disease, offering early definitive treatment in drug-refractory or fluctuating cases," Pariani and colleagues reiterate.

Giesser agrees that these new results underscore the need for monitoring patients for thyroid disorders — and perhaps for longer than previously realized.

"This study should caution clinicians that autoimmune thyroid disease, while most common in the first 3 years after alemtuzumab therapy, may occur many years later, and there needs to be continued surveillance for this," she concluded.

The research was supported by funding from the National Institute for Health Research, Cambridge Biomedical Research Centre, and Wellcome Trust. Author Colin Dayan, MBBS, has given lectures and served on the advisory board for Sanofi Genzyme. Giesser has reported no relevant financial relationships.

J Clin Endocrinol Metab. 2018;103:3010-3018. Full text

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