Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis.

ORIGINAL E n d o c r i n e

ARTICLE C a r e

Alemtuzumab-Related Thyroid Dysfunction in a Phase 2 Trial of Patients With Relapsing-Remitting Multiple Sclerosis Gilbert H. Daniels, Anton Vladic, Vesna Brinar, Igor Zavalishin, William Valente, Pedro Oyuela, Jeffrey Palmer, and David H. Margolin Department of Medicine and Thyroid Unit (G.H.D.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Neurology (A.V.), General Hospital ’Sveti Duh,’ and Department of Neurology (V.B.), Zagreb Medical School and University Hospital Center, Zagreb HR-10000, Croatia; Scientific Research Institute of Neurology of Russian Academy of Medical Sciences (I.Z.), Moscow 123367, Russia; Division of Endocrinology, Diabetes, and Nutrition (W.V.), University of Maryland School of Medicine, Baltimore, Maryland 21201; and Genzyme Corporation, a Sanofi Company (P.O., J.P., D.H.M.), Cambridge, Massachusetts 02142

Context: Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis. Objective: The objective of the study was a detailed description of thyroid dysfunction in CAMMS223. Design: Relapsing-remitting multiple sclerosis patients (n ⫽ 334) were randomized 1:1:1 to 44 ␮g sc interferon-␤-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; antithyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist. Results: During a median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (P ⬍ .0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had more than one episode of thyroid dysfunction. With alemtuzumab, Graves’ hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves’ hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII positive. The annual incidence of a first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year. Conclusions: Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves’ hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism after overt Graves’ hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism. (J Clin Endocrinol Metab 99: 80 – 89, 2014)

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by The Endocrine Society Received May 13, 2013. Accepted October 16, 2013. First Published Online October 29, 2013

80

jcem.endojournals.org

Abbreviations: CI, confidence interval; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; OR, odds ratio; RRMS, relapsing-remitting MS; TBII, thyrotropin-binding inhibitory immunoglobulin; TPO, thyroid peroxidase; TRAb, TSH receptor autoantibody; TSAb, antibody that stimulates the thyroid.

J Clin Endocrinol Metab, January 2014, 99(1):80 – 89

doi: 10.1210/jc.2013-2201

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 May 2015. at 12:41 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2013-2201

everal different medications cause thyroid dysfunction (1). Immunomodulating drugs for treating infectious, inflammatory, and neoplastic conditions are particularly known to cause painless subacute thyroiditis, hypothyroidism, and, to a lesser extent, Graves’ disease. Alemtuzumab, a humanized monoclonal anti-CD52 antibody that alters the circulating lymphocyte pool, is approved in the European Union and under regulatory review in the United States and other countries for the treatment of active relapsing-remitting multiple sclerosis (MS) (RRMS) and was previously approved for the treatment of chronic lymphocytic leukemia. In pilot RRMS studies of alemtuzumab, thyroid dysfunction occurred in approximately 30% of patients, Graves’ disease being the most common (2, 3). In a large phase 2 trial, alemtuzumab was superior to sc interferon-␤-1a (SC IFNB-1a, Rebif; EMD Serono Inc) on relapse rate and 6-month sustained accumulation of disability among RRMS patients (CAMMS223, ClinicalTrials.gov number NCT00050778). Over the initial 3-year period, thyroid dysfunction occurred more frequently with alemtuzumab (22.7%) vs SC IFNB-1a (2.8%) (4). Of alemtuzumab-treated patients, 14.8% developed hyperthyroidism, 6.9% hypothyroidism, and 4.2% thyroiditis. During continued on-study follow-up (up to 80 months), the cumulative prevalence of alemtuzumab-associated thyroid dysfunction increased to 30%, with the onset ranging from 6 to 61 months after first alemtuzumab exposure (5). Serious events including ophthalmopathy occurred in 1.4% of alemtuzumab patients. Diagnosis and management of thyroid disorders was the responsibility of local physicians. Given the high prevalence of alemtuzumab-associated thyroid dysfunction among RRMS patients, all episodes of thyroid dysfunction in this phase 2 trial population were reviewed and recategorized. This reanalysis was based on post hoc in-depth case reviews by a single endocrinologist (G.H.D.).

S

Materials and Methods CAMMS223 methods have been published (4, 5) and are briefly reviewed here.

Patients From December 2002 through July 2004, 334 RRMS patients from 49 centers in Europe and the United States were enrolled. Patients had not received prior disease-modifying MS therapy, had Expanded Disability Status Scale (EDSS) scores of 3.0 or less (indicating mild to moderate disability on a scale of 0 –10), had more than two relapses in the 2 years prior to study entry, and had more than one gadolinium-enhancing lesion on screening cranial magnetic resonance imaging. The protocol was approved


81

by the review boards of participating centers, and all patients provided written informed consent. Baseline anti-TSH receptor antibody [specifically thyrotropin-binding inhibitory immunoglobulins (TBIIs)] positivity was an exclusion criterion, but baseline antithyroid peroxidase (TPO) antibody positivity was not.

Interventions Patients were randomized 1:1:1 to SC IFNB-1a 44 ␮g three times per week or iv alemtuzumab 12 mg/d or 24 mg/d administered on 5 days at month 0, 3 days at month 12, and an optional 3 days at month 24. Hence, there were twice as many patients in the pooled alemtuzumab group as in the SC IFNB-1a group. All patients received concurrent treatment with iv methylprednisolone sodium succinate 1 g/d for the first 3 days of each treatment course. Additional methylprednisolone was permitted at the treating physician’s discretion. The initial study period lasted 36 months, but many patients remained on study thereafter and were followed for up to 80.6 months. Safety was assessed through monitoring of treatment-emergent adverse events, changes in physical examination findings, vital signs, selected clinical laboratory results, and thyroid autoantibody monitoring. This paper focuses on outcomes related to thyroid dysfunction.

Thyroid-related laboratory assessments TPO antibodies were measured at baseline and every 6 months through month 36. Thyroid function tests (TSH, free T3, free T4) and TBII were assessed at baseline, month 1, and quarterly in all patients. When TSH was abnormal, we measured TSH [IMx ultrasensitive hTSH II (Abbott Diagnostics) and Access HYPERsensitive hTSH (Beckman Coulter)], free T3 [IMx Free T3 (Abbott Diagnostics) and Access Free T3 (Beckman Coulter)], and free T4 [IMx Free T4 (Abbott Diagnostics) and Access Free T4 (Beckman Coulter)] monthly until serum TSH concentrations normalized. Normal ranges for TSH, free T3, and free T4 were as follows: 0.47–5.01 mIU/L, 2.5–5.3 pmol/L, and 9.1–23.8 pmol/L, respectively. During the initial 3-year treatment period, thyroid function was assessed monthly for patients positive for TPO antibodies or who became TBII positive. All measurements were performed at two central laboratories: Cirion BioPharma Research Inc and Charles River Laboratories. TPO antibody titers were measured in a qualitative enzyme immunoassay (Varelisa; Sweden Diagnostics); a ratio of 1.4 or greater (vs positive control) was considered positive. TBII was measured in a quantitative RIA (DYNOtest TRAK; Alpco Diagnostics); TBII titers greater than 1.5 IU/L were considered positive. Radioiodine uptake and thyroid scans were not generally performed. For this paper, thyroid dysfunction was categorized post hoc by one clinical endocrinologist, who reviewed all thyroid function tests, thyroid autoantibody data, clinical adverse events, and treatment. Therefore, the tally and categorization of episodes of thyroid dysfunction differ from previous reports (4, 5).

Thyroid dysfunction: definitions Hyperthyroidism Overt hyperthyroidism was defined as a serum TSH less than 0.1 mIU/L with elevation of free T3 or free T4 in the absence of concomitant thyroid medication. Graves’ disease was diagnosed if hyperthyroidism persisted for more than 3 consecutive months


82

Daniels et al

Alemtuzumab-Related Thyroid Dysfunction


or if TBIIs were positive at the time of a low-serum TSH or during the 3 months before or after the low TSH was noted. Graves’ hyperthyroidism followed by spontaneous hypothyroidism was considered to be two separate episodes of thyroid dysfunction. Painless subacute thyroiditis (destructive thyroiditis) was diagnosed when thyrotoxicosis was followed by spontaneous euthyroidism or hypothyroidism and TBIIs were negative. Thyrotoxicosis due to painless subacute thyroiditis, followed by hypothyroidism, was considered a single episode of thyroid dysfunction. Subclinical hyperthyroidism was defined as a serum TSH below 0.25 mIU/L with normal free T3 and free T4 in the absence of concomitant thyroid medication. We arbitrarily selected less than 0.25 mIU/L as the upper threshold for subclinical hyperthyroidism to exclude the possibility of glucocorticoid-mediated TSH suppression (6). Subclinical hyperthyroidism that progressed directly to overt hyperthyroidism was considered a single episode of overt hyperthyroidism.

thyroid dysfunction was analyzed using Kaplan-Meier estimation, and percentages of patients with a first episode of thyroid dysfunction in each study year were based on the number of patients with evaluable safety data during that study year and who had no previous episodes of thyroid dysfunction. The relationship between prevalence of thyroid dysfunction and baseline and on-study demographics and clinical characteristics was assessed using logistic regression for the overall cohort and the pooled alemtuzumab group. The demographic and clinical characteristics considered were age, gender, weight, body mass index (kilograms per square meter), height, race, baseline EDSS score, baseline T2-weighted magnetic resonance imaging lesion volume, incidence of infection during the first 3 or 6 months of the study, lymphocyte counts at months 1 and 12, and thyroid autoantibody status. All reported P values are two sided and no adjustments were made for multiple hypothesis testing.

Hypothyroidism

Results

Overt hypothyroidism was defined as a serum TSH greater than 10 mIU/L with low free T4 in the absence of a prior history of hypothyroidism or concomitant thyroid medications. Subclinical hypothyroidism was defined as a serum TSH greater than 5 mIU/L with normal free T4 in the absence of a prior history of hypothyroidism or concomitant thyroid medications. Subclinical hypothyroidism that progressed directly to overt hypothyroidism (either on or off thyroid hormone) was considered a single episode of overt hypothyroidism.

Multiple episodes of thyroid dysfunction Some patients had more than one episode or type of thyroid dysfunction. We analyzed initial as well as total episodes of thyroid dysfunction. Therefore, the total number of episodes exceeds the total number of patients who experienced them.

Statistical methods All analyses are based on the population of patients who received at least one dose of study drug. Time to first episode of

Patients developing thyroid dysfunction Overall, 25% of patients (n ⫽ 80) developed thyroid dysfunction during a median of 57.3 months of follow-up (maximum 80.6 months, 381.3 total patient-years). Thyroid dysfunction occurred in 34% (73 of 216) of the alemtuzumab group [39%, 42 of 108 receiving 12 mg and 29%, 31 of 108 receiving 24 mg (Fisher’s exact test, P ⫽ .015)] and 6.5% (7 of 107) of the SC IFNB-1a group (P ⬍ .0001). Baseline demographic and disease characteristics of these patients have been published (4). Baseline characteristics of alemtuzumab-treated patients who developed thyroid dysfunction (Table 1) were balanced across treatment groups and similar to the full alemtuzumab-treated cohort. Baseline EDSS, disease duration, number of clinical episodes in the preceding year, T1-weighted brain

Table 1. Baseline Demographic and Disease Characteristics: Thyroid Dysfunction vs No Thyroid Dysfunction IFNB-1a

Age, mean (SD) Female, n, % Caucasian, n, % Weight, kg, mean (SD) Disease duration, y, mean (SD) Relapses in previous 1 y, n, median (minimum, maximum) Baseline EDSS, median (range) T2 lesion volume, cm3, mean (SD)

Alemtuzumab 12 mg

Alemtuzumab 24 mg

Alemtuzumab Pooled

All Patients

Thyroid Dysfunction

Thyroid Dysfunction

Thyroid Dysfunction

Thyroid Dysfunction

Thyroid Dysfunction

Yes (n ⴝ 7)

No (n ⴝ 100)

Yes (n ⴝ 42)

No (n ⴝ 66)

Yes (n ⴝ 31)

No (n ⴝ 77)

Yes (n ⴝ 73)

No (n ⴝ 143)

Yes (n ⴝ 80)

No (n ⴝ 243)

33.7 (8.40) 7 (100.0) 7 (100.0) 57.2 (5.73)

32.8 (9.02) 63 (63.0) 89 (89.0) 75.1 (19.43)

30.7 (8.12) 33 (78.6) 39 (92.9) 71.3 (18.28)

33.5 (7.78) 37 (56.1) 57 (87.7) 80.0 (19.46)

31.4 (7.74) 22 (71.0) 26 (83.9) 70.7 (18.13)

32.7 (9.23) 47 (61.0) 70 (90.9) 77.6 (20.19)

31.0 (7.92) 55 (75.3) 65 (89.0) 71.1 (18.10)

33.0 (8.57) 84 (58.7) 127 (88.9) 78.7 (19.83)

31.3 (7.94) 62 (77.5) 72 (90.0) 69.8 (17.79)

32.9 (8.74) 147 (60.5) 216 (88.9) 77.2 (19.70)

1.9 (1.05)

1.6 (1.01)

1.3 (0.83)

1.4 (0.82)

1.6 (0.78)

1.4 (0.84)

1.4 (0.83)

1.4 (0.83)

1.5 (0.85)

1.5 (0.91)

2.0 (1, 3)

2.0 (0, 4)

2.0 (0, 4)

2.0 (0, 3)

1.0 (0, 3)

2.0 (0, 3)

2.0 (0, 4)

2.0 (0, 3)

2.0 (0, 4)

2.0 (0, 4)

1.5 (1.0, 2.5)

2.0 (0, 3.5)

2.0 (0, 3.0)

2.0 (0, 3.0)

2.0 (0, 3.5)

2.0 (0, 3.0)

2.0 (0, 3.5)

2.0 (0, 3.0)

2.0 (0, 3.5)

2.0 (0, 3.0)

12.1 (4.45)

16.1 (15.68)

15.4 (15.00)

19.8 (29.48)

17.3 (14.34)

17.5 (17.79)

16.2 (14.64)

18.6 (23.73)

15.9 (14.15)

17.6 (20.78)

Abbreviation: IFNB-1a, interferon ␤-1a.


doi: 10.1210/jc.2013-2201


83

Table 2. Thyroid Dysfunction by Treatment Group SC IFNB-1a

Thyroid Dysfunction by Patient and Episode, n, % Hyperthyroid Overt hyperthyroid Graves’ Subacute thyroiditis Subclinical hyperthyroid Graves’ Subacute thyroiditis Uncertain etiology Hypothyroid Overt hypothyroid Subclinical hypothyroid Observed thyroid hormone levels at month 36, mean (SD) TSH, mIU/L Free T3, pmol/L Free T4, pmol/L

Patients (n ⴝ 107) 6 (5.6) 3 (2.8) 1 (0.9) 2 (1.9) 3 (2.8) 0 3 (2.8) 0 1 (0.9) 0 1 (0.9)

Episodes (n ⴝ 10)

8 (80.0) 5 (50.0) 1 (10.0) 4 (40.0) 3 (30.0) 0 3 (30.0) 0 2 (20.0) 0 2 (20.0) n ⫽ 73 1.6 (1.06) 4.3 (0.86) 13.3 (2.49)

Alemtuzumab 12 mg

Alemtuzumab 24 mg

Pooled Alemtuzumab

Patients (n ⴝ 108)



32 (29.6) 23 (21.3) 21 (19.4) 2 (1.9) 9 (8.3) 6 (5.6) 2 (1.9) 1 (0.9) 10 (9.3) 8 (7.4) 2 (1.9)

Episodes (n ⴝ 56)

39 (69.6) 28 (49.1) 26 (45.6) 2 (3.5) 11 (19.6) 6 (10.7) 3 (5.3) 2 (3.5) 17 (29.8) 12 (21.1) 5 (8.8) n ⫽ 95 4.1 (14.55) 5.7 (6.37) 15.2 (10.21)

26 (24.1) 22 (20.4) 18 (16.7) 4 (3.7) 4 (3.7) 3 (2.8) 1 (0.9) 0 5 (4.6) 4 (3.7) 1 (0.9)

Episodes (n ⴝ 46)

33 (71.7) 27 (58.7) 23 (50.0) 4 (8.7) 6 (13.0) 5 (10.9) 1 (2.2) 0 13 (28.3) 11 (23.9) 2 (4.3) n ⫽ 95 4.9 (15.08) 5.1 (5.13) 14.5 (7.81)

Episodes (n ⴝ 102)

58 (26.9) 45 (20.8) 39 (18.1) 6 (2.8) 13 (6.0) 9 (4.2) 3 (1.4) 1 (0.5) 15 (6.9) 12 (5.6) 3 (1.4)

72 (70.6) 55 (53.4) 49 (47.6) 6 (5.8) 17 (16.7) 11 (10.8) 4 (3.9) 2 (1.9) 30 (29.1) 23 (22.3) 7 (6.8) n ⫽ 190 4.5 (14.78) 5.4 (5.77) 14.9 (9.07)

Columns listed by patient represent first episode of thyroid dysfunction. Columns listed by episode represent each separate episode of thyroid dysfunction. Normal ranges for TSH, free T3, and free T4 were as follows: 0.47–5.01 mIU/L, 2.5–5.3 pmol/L, and 9.1–23.8 pmol/L, respectively. The n values in each treatment group at month 36 are lower than those at baseline due to a gradual decline over time in the number of patients available for analysis.

volume, and T2-weighted lesion volume did not differ significantly between patients who developed thyroid dysfunction and those who did not. Female gender was the strongest predictor overall of developing thyroid dysfunction: 29.7% (62 of 209) of females experienced thyroid dysfunction vs 15.8% (18 of 114) of males [odds ratio (OR) [95% confidence interval (CI)] 2.37 (1.30, 4.31), P ⫽ .0047]. Patients with baseline weight below the median (71.0 kg) were more likely to experience thyroid dysfunction (particularly hyperthyroidism) than their heavier counterparts [OR (95% CI) 2.33 (1.36, 3.98), P ⫽ .0021]. Because thyroid risk was higher among women, who tend to weigh less than men, the effect of weight could have been confounded by gender, which is a known thyroid risk factor (7). Age below the median (31.0 y) was also associated with a greater prevalence of thyroid dysfunction [OR (95% CI) 1.88 (1.11, 3.17), P ⫽ .0185]. Total episodes of thyroid dysfunction In total, 112 episodes of thyroid dysfunction occurred in the study: 102 episodes in 73 alemtuzumab patients and 10 episodes in seven SC IFNB-1a patients (P ⬍ .0001) (Table 2). Among alemtuzumab-treated patients who developed thyroid disorders, 70% (51 of 73) had a single episode of thyroid dysfunction, whereas 30% (22 of 73) had multiple thyroid episodes: 15 had two episodes and seven had three episodes (Table 3). Four SC IFNB-1a patients had one episode, and three patients had two episodes. Of the total episodes, 91.1% (102 of 112) were in alemtuzumab-treated patients (56 among patients receiving 12 mg and 46 among patients receiving 24 mg) and 8.9% (10 of 112) in SC IFNB-1a-treated patients (Table 2). Overall, 33.8% (73 of 216) of alemtuzumab patients developed thyroid dysfunction. Of these, 65.8% (48 of 73)

developed Graves’ hyperthyroidism (39 overt, nine subclinical), 12.3% (9 of 73) developed subacute thyroiditis, and 20.5% (15 of 73) developed hypothyroidism (12 overt, three subclinical). Of the 102 episodes of thyroid dysfunction in the alemtuzumab group, 58.8% (n ⫽ 60) were hyperthyroid due to Graves’ (49 overt, 11 subclinical), 9.8% (n ⫽ 10) were subacute thyroiditis, 29.4% (n ⫽ 30) were hypothyroid (23 overt, seven subclinical), and 2.0% (n ⫽ 2) were unknown. First episode of thyroid dysfunction Among alemtuzumab-treated patients, the nature of first episodes of thyroid dysfunction was similar to that for the total number of thyroid episodes, overt hyperthyroidism due to Graves’ disease being the most common, followed by overt hypothyroidism and overt hyperthyroidism due to subacute thyroiditis (Table 2). Overt hypothyroidism was the first episode of thyroid dysfunction in 12 alemtuzumab-treated patients. TBIIs were positive in eight of these patients (67%). Subclinical hypothyroidism was the first episode of thyroid dysfunction in three alemtuzumab patients. TBIIs were positive in one patient at the time of diagnosis and in a second 3 months later. Treatment of thyroid dysfunction Alemtuzumab patients who developed overt Graves’ hyperthyroidism were treated with antithyroid drugs alone (40.1%), antithyroid drugs and radioactive iodine (12.2%), radioactive iodine alone (6.1%), and surgery (4%). Of the two surgically treated patients, one had received antithyroid drugs alone and the other had received antithyroid drugs and radioactive iodine. Overt Graves’ hyperthyroidism spontaneously resolved in 36.7% of pa-


84

Daniels et al



Table 3. Alemtuzumab-Treated Patients With More Than One Episode of Thyroid Dysfunction Patient Number

First Thyroid Episode

Second Thyroid Episode a

1

Overt hyperthyroid due to Graves’

Subclinical hypothyroidism

2


3


Overt hyperthyroid due to Graves’ Subclinical hypothyroidisma

4


5 6 7 8 9

Overt hyperthyroid due to Graves’ Overt hyperthyroid due to Graves’ Overt hyperthyroid due to Graves’ Overt hyperthyroid due to Graves’ Overt hyperthyroid due to Graves’

10 11

Overt hyperthyroid due to Graves’ Overt hyperthyroid due to painless thyroiditis Subclinical hyperthyroidism due to Graves’ Subclinical hyperthyroidism due to painless thyroiditis

Overt hypothyroida Overt hyperthyroid due to Graves’ Overt hypothyroidisma

Subclinical hypothyroidisma

17 18

Subclinical hyperthyroidism due to Graves’ Subclinical hyperthyroidism due to Graves’ Subclinical hyperthyroidism due to Graves’ Overt hypothyroidism Overt hypothyroidisma

19

Overt hypothyroidisma

20


21 22

Subclinical hypothyroidism Subclinical hypothyroidisma

12 13

14 15 16

Subclinical hyperthyroidism due to Graves’ Overt hypothyroida Overt hypothyroida Overt hypothyroida Overt hypothyroida Overt hypothyroida

Third Thyroid Episode Overt hyperthyroidism due to Graves’ NA Subclinical hyperthyroidism of uncertain etiology NA NA NA NA NA Overt hyperthyroidism due to Graves’ NA NA


Overt hyperthyroidism due to Graves’ Subclinical hyperthyroidism due to painless thyroiditis Overt hyperthyroidism due to Graves’ NA

Subclinical hypothyroidisma

NA

Overt hypothyroidism Overt hyperthyroidism due to Graves’ Overt hyperthyroidism due to Graves’ Overt hyperthyroidism due to Graves’ Overt hypothyroidisma Subclinical hyperthyroidism due to Graves’

NA NA


NA NA NA Overt hyperthyroidism due to Graves’

Abbreviation: NA, not applicable. a

Hypothyroidism with positive TBII.

tients: 20.4% became euthyroid, whereas 16.3% became hypothyroid. Two Graves’ hyperthyroid patients (one overt, one subclinical) became spontaneously euthyroid and subsequently developed overt hypothyroidism more than 12 months after the initial event. Both were persistently TBII positive from the time of hyperthyroidism until they developed overt hypothyroidism. Of the 39 alemtuzumab-treated patients who developed overt Graves’ hyperthyroidism as their first episode of thyroid dysfunction, three developed what was considered significant ophthalmopathy; one required orbital decompression. Of these three patients, one received radioactive iodine. (A fourth patient who experienced moderate Graves’ ophthalmopathy developed Graves’ hyperthy-

roidism after an initial episode of overt hypothyroidism; that patient did not receive radioactive iodine.) Of the 11 episodes of subclinical hyperthyroidism due to Graves’ among alemtuzumab patients, 36.4% (n ⫽ 4) were treated with antithyroid drugs. The remainder resolved spontaneously: 18.2% (n ⫽ 2) became euthyroid, 18.2% (n ⫽ 2) developed subclinical hypothyroidism, and 18.2% (n ⫽ 2) developed overt hypothyroidism. The outcome was unknown for one episode (9.1%). Of the 23 episodes of overt hypothyroidism with alemtuzumab, 82.6% (n ⫽ 19) were given thyroid hormone; 17.4% (n ⫽ 4) spontaneously resolved. Of the seven episodes of subclinical hypothyroidism, 14.2% (n ⫽ 1) were given thyroid hormone.


doi: 10.1210/jc.2013-2201


TPO antibodies TPO antibodies were positive at baseline in 8.0% (16 of 206) of alemtuzumab patients and 5.9% (6 of 101) of SC IFNB-1a patients. Almost 69% (11 of 16) of alemtuzumab patients who were TPO antibody positive at baseline developed thyroid dysfunction compared with 31.0% (62 of 200) of patients who were TPO antibody negative at baseline (P ⫽ .0043) (Table 4). However, 85% of patients who developed thyroid dysfunction in the alemtuzumab group were TPO antibody negative at baseline. All SC IFNB-1a patients who developed thyroid dysfunction (n ⫽ 7) were TPO antibody negative at baseline. Among the alemtuzumab patients who were TPO antibody positive at baseline, 43.8% (7 of 16) developed hyperthyroidism (five Graves’, two subacute thyroiditis) and 25% (4 of 16) developed hypothyroidism as their

85

initial episode of thyroid dysfunction. The remainder (5 of 16) were euthyroid throughout the study. Of the 73 alemtuzumab patients who developed thyroid dysfunction, 15.1% (11 of 73) were TPO antibody positive at baseline and 54.8% (40 of 73) became TPO antibody positive. Of these, 30.1% (22 of 73) remained TPO antibody negative throughout the study. Among SC IFNB-1a patients, the corresponding figures were 0, 28.6% (two of seven), and 71.4% (five of seven). At the time of first thyroid dysfunction, TPO antibodies were positive in 38.4% of alemtuzumab patients with thyroid dysfunction and 14.3% among SC IFNB-1a patients. De novo TPO antibody positivity without thyroid dysfunction was found in 10.5% (15 of 143) of alemtuzumab patients and 11.0% (11 of 100) of SC IFNB-1a patients.

Table 4. Antibody Characteristics of Thyroid Dysfunction by Diagnosis

Overt hyperthyroid due to Graves’ Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, % Overt hyperthyroid due to subacute thyroiditis Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, % Subclinical hyperthyroid due to Graves’ Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, % Subclinical hyperthyroid due to subacute thyroiditis Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, % Overt hypothyroid Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, % Subclinical hypothyroid Patients, n Episodes, n TPO⫹ at baseline, patients, n, % TPO⫹ upon diagnosis, episodes, n, % TBII⫹ upon diagnosis, episodes, n, %

IFNB-1a

Alemtuzumab 12 mg

Alemtuzumab 24 mg

Alemtuzumab Pooled

1 1 0 0 0

21 26 2 (9.5) 10 (38.5) 21 (80.8)

18 23 2 (11.1) 7 (30.4) 19 (82.6)

39 49 4 (10.3) 17 (34.7) 40 (81.6)

2 4 0 1 (25.0) 0

2 2 0 0 0

4 4 1 (25.0) 0 0

6 6 1 (16.7) 0 0

0 0 0 0 0

6 6 1 (16.7) 3 (50.0) 6 (100)

3 5 0 3 (60.0) 5 (100)

9 11 1 (11.1) 6 (54.5) 11 (100)

3 3 0 1 (33.3) 0

2 3 0 2 (66.7) 0

1 1 1 (100) 0 0

3 4 1 (33.3) 2 (50.0) 0

0 0 0 0 0

8 12 1 (12.5) 7 (58.3) 10 (83.3)

4 11 2 (50.0) 4 (36.4) 7 (63.6)

12 23 3 (25.0) 11 (47.8) 17 (73.9)

1 2 0 0 0

2 5 1 (50.0) 2 (40.0) 2 (40.0)

1 2 0 1 (50.0) 1 (50.0)

3 7 1 (33.3) 3 (42.9) 3 (42.9)

TPO positive (TPO⫹) numbers at baseline are reported by patient, whereas TBII positive (TBII⫹) and TPO⫹ upon diagnosis are reported by episode of thyroid dysfunction. Percentages reflect the number of patients TPO⫹ at baseline relative to the number of patients with the specified thyroid disorder (ie, denominator is not all study patients).


86

Daniels et al



Anti-TSH receptor antibodies (TBII) Per exclusion criteria, all patients were TBII negative at baseline; 2 of 509 screened patients were TBII positive and hence excluded. TBII antibodies developed in 38% of alemtuzumab patients and 1.9% of SC IFNB-1a patients. Thyroid dysfunction developed in 75.6% of alemtuzumab patients who became TBII positive vs 12.7% of those who remained TBII negative (P ⬍ .0001). At the time of thyroid dysfunction, TBIIs were present in 70.0% of episodes in the alemtuzumab group and no episodes in the SC IFNB-1a group; additional antibody data are available in Table 4. TBIIs were found in 84.7% (61 of 72) of episodes of overt or subclinical hyperthyroidism in the alemtuzumab group, and 100% of patients with Grave’s disease. TBIIs were found in 76.7% (23 of 30) of episodes of overt or subclinical hypothyroid in the alemtuzumab group.

cluding B cells (CD19⫹) and T cells (CD4⫹ and CD8⫹)] are depleted and then reconstitute at varying rates. We found no association of thyroid dysfunction with month 1 total and subset lymphocyte counts, subsequent lymphocyte reconstitution rates, infection within 3– 6 months of alemtuzumab administration, or number of alemtuzumab courses received (data not shown).

Timing of thyroid dysfunction The annual incidence of the first episode of thyroid dysfunction increased each year through year 3 and then decreased each subsequent study year: year 1, 4.6%; year 2, 13.3%; year 3, 16.1%; year 4, 11.3%; year 5, 7.2%; year 6, 0%; and year 7, 5.9%. Annual event rates for individual thyroid diagnoses followed a similar trend (data not shown). Kaplan-Meier estimated percentage of patients with an episode of thyroid dysfunction by treatment group is shown in Figure 1. Relative to the start of therapy, time to diagnosis of a first episode of thyroid dysfunction was not associated with any baseline or onstudy demographics or clinical characteristics.

Several different immunomodulatory drugs are associated with an increased risk of thyroid dysfunction (1). Thyroid dysfunction after IFNB-1a therapy in hepatitis C patients is due to both an autoimmune attack and a direct toxic effect on the thyroid (9), leading most often to painless subacute thyroiditis or primary hypothyroidism, with a minority developing Graves’ disease (10). By contrast, Graves’ hyperthyroidism is the most common form of thyroid dysfunction observed in so-called reconstitution autoimmunity (11). HIV-1-infected patients may develop Graves’ disease several months after the initiation of therapy during the reconstitution of CD4 lymphocytes (12). Graves’ disease also occurred in 31% (4 of 13) of type 1 diabetes patients after islet cell transplantation after discontinuing immunomodulatory therapy; all four patients had been TPO antibody positive at baseline (13). It is likely that differences in the timing of B and T cell reconstitution

Percentage of Patients with Thyroid Adverse Events

Additional predictors of thyroid dysfunction During the first month after alemtuzumab administration, total blood lymphocyte and lymphocyte subsets [in-

Efficacy among patients with thyroid dysfunction Alemtuzumab’s clinical efficacy for RRMS was not statistically significantly different between patients who developed thyroid dysfunction and the full alemtuzumab cohort (data not shown) (4, 5, 8).

Discussion

SC IFNB−1a 44 µg Alemtuzumab 12 mg Alemtuzumab 24 mg Alemtuzumab Pooled

55 50 45 40 35 30 25 20 15 10 5 0 0

6

12

18

24

30

36

42

48

54

60

66

72

78

44 48 58

40 45 58

34 37 53

21 27 38

4 7 11

1 0 2

Months

No. at Risk SC IFNB–1a 44 µg 107 Alemtuzumab 12 mg 108 Alemtuzumab 24 mg 108

99 106 107

91 102 104

85 94 102

78 86 95

73 77 90

63 63 79

44 53 64

Figure 1. Time to first episode of thyroid dysfunction among CAMMS223 patients.


doi: 10.1210/jc.2013-2201

also play an important role in the pathogenesis of thyroid dysfunction after alemtuzumab treatment of MS, although the pathogenesis of postalemtuzumab autoimmune disorders has not been fully established. Despite widespread use of alemtuzumab therapy for chronic B cell leukemia at a much higher total dose than used for RRMS, thyroid dysfunction is not commonly observed here (14). However, thyroid dysfunction has been reported in patients receiving alemtuzumab after renal transplantation and in MS (2, 4, 5, 15). In a previous analysis of the 3-year CAMMS223 data, 22.7% of patients developed thyroid dysfunction, of whom 51% had Graves’ disease (4). After long-term follow-up, the cumulative prevalence of thyroid dysfunction rose to 34.2% (66% Graves’ disease) (5). The significantly higher prevalence of thyroid dysfunction associated with alemtuzumab therapy for MS compared with leukemia suggests something unique about the MS population. Whether there is an increased prevalence of thyroid disease in patients with MS is controversial; a recent analysis suggests not (16). Regardless, the prevalence of thyroid dysfunction after alemtuzumab therapy for MS is substantially above the background rate. In contrast to other publications concerning alemtuzumab-induced thyroid dysfunction, all thyroid data in our study were reviewed by a single endocrinologist, allowing uniformity of diagnosis. In addition, thyroid dysfunction was further analyzed to include overt and subclinical thyroid dysfunction and multiple episodes of thyroid dysfunction in the same patient. Overall, 34.2% of alemtuzumab patients developed thyroid dysfunction: 23% Graves’ hyperthyroidism, 7.4% hypothyroidism, and 4.2% subacute thyroiditis. Multiple episodes of thyroid dysfunction were found in 30% of the alemtuzumab group with thyroid dysfunction. In the SC IFNB-1a group, 6.5% developed thyroid dysfunction (0.9% Graves’, 4.7% subacute thyroiditis, and 0.9% hypothyroidism) and more than half had two episodes of thyroid dysfunction. Although patients who were TPO antibody positive at baseline were more likely to develop thyroid dysfunction after alemtuzumab treatment, 85% of alemtuzumab patients who developed thyroid dysfunction were TPO antibody-negative at baseline, suggesting that the latter were not protected against thyroid dysfunction. Anti-TPO titers were not quantitated in our study. It is possible that knowledge of titer level could further strengthen the positive association of anti-TPO and thyroid risk but would not alter the low predictive utility of a negative test. Thyrotropin receptor antibodies tend to be a mixture of antibodies that stimulate the thyroid (TSAb) and those that block thyrotropin action. At any time, either antibody


87

can predominate (17). In general, spontaneous remissions of Graves’ hyperthyroidism occur when TSH receptor autoantibodies (TRAbs) disappear, when TSAbs are balanced by antibodies that block thyrotropin action, or when persistent TSAbs are thwarted by associated autoimmune thyroiditis. Assessing the rate of spontaneous remission for Graves’ hyperthyroidism in the general population is difficult because most patients require treatment. In one study, 31% of patients with Graves’ hyperthyroidism treated with propranolol alone developed a sustained, spontaneous remission (18). In our study, 36% of overt Graves’ hyperthyroidism episodes with alemtuzumab spontaneously resolved. However, our patients also had an unusually high prevalence of spontaneous hypothyroidism after overt (16%) or subclinical Graves’ hyperthyroidism (33%). Three patients developed overt primary hypothyroidism, followed by overt Graves’ hyperthyroidism (example in Figure 2) and one patient developed overt subclinical hypothyroidism followed by subclinical Graves’ hyperthyroidism. Others developed multiple discrete episodes of thyroid dysfunction. In general endocrine practice, spontaneous transition from Graves’ hyperthyroidism to hypothyroidism is uncommon, and most reported episodes occur long after antithyroid drug treatment has ceased (19). By contrast, hypothyroidism occurred relatively quickly in CAMMS223, without antithyroid drug therapy. In several reports, hypothyroidism arising after treatment for hyperthyroidism was shown to be due specifically to blocking TRAb (20 – 22). The TBII assay used in our study measures the inhibition of TSH binding its receptor but does not distinguish between stimulating and blocking antibodies. It seems likely that spontaneous conversion from Graves’ hyperthyroidism to hypothyroidism, and vice versa, is mediated by an alteration in the ratio of stimulating to blocking TRAbs. An unusual feature in our study population is the high prevalence of TBII in the hypothyroid population: 67% of patients who developed overt hypothyroidism as their initial episode of thyroid dysfunction were TBII positive. All patients who developed spontaneous hypothyroidism after Graves’ hyperthyroidism were TBII positive. An additional two patients developed overt hypothyroidism more than 1 year after spontaneous resolution of Graves’ hyperthyroidism. TBIIs have previously been associated with hypothyroidism, most notably and convincingly in patients with transient neonatal hypothyroidism due to transplacental passage of blocking TRAbs (23). By contrast, TBIIs are uncommonly present in adults with primary hypothyroidism due to autoimmune thyroiditis, and their role in the pathogenesis of hypothyroidism is uncertain (24). Tamaki et al (25) found TBIIs in only 7% of hypothyroid patients with goitrous Hashimoto’s thyroid-


88

Daniels et al



Our study has a number of intrinsic weaknesses. Patients were evalu35 ated clinically only at the study site 30 and not at a central location. Addi25 tional parameters of interest such as 20 thyroid size and TBII titers were not 15 always available for analysis. Fi10 nally, we were unable to distinguish 5 between blocking and stimulating 0 TRAbs, which might have helped us TBII Anti-TPO to understand both the transition −18 −12 −6 6 0 12 18 24 30 36 42 48 54 60 66 72 78 84 from Graves’ hyperthyroidism to Months hypothyroidism and the etiology of Test TSH (mlU/L) Free T (pmol/L) Free T (pmol/L) spontaneous primary hypothyroidFigure 2. Sample thyroid dysfunction values from CAMMS223 study patient. This sample ism. Nonetheless, to our knowlpatient from the CAMMS223 study initially developed overt hypothyroidism with positive TBII at edge, this is the largest prospective month 12. Thyroid hormone was not given and the hypothyroidism spontaneously resolved. The analysis of TRAb development and patient subsequently developed overt hyperthyroidism due to Graves’ disease at month 18. The patient was treated with radioactive iodine, became hypothyroid, and was treated with thyroid its consequences in a euthyroid hormone. Serum TSH concentrations from baseline through month 66, as well as free T3 and population. free T4, are shown. Horizontal red dotted lines represent upper and lower level of normal for The study’s safety monitoring TSH. Antithyrotropin receptor (TBII) and anti-TPO antibody positivity are shown as ⫹ signs at various time points. program effectively detected episodes of thyroid dysfunction, often before the emergence of symptoms, itis and 14% of those with atrophic thyroiditis. Given the and allowed for early and effective treatment. Although rapid appearance of hypothyroidism after hyperthyroidwe were unable to reevaluate this population to determine ism and the very high prevalence of TBIIs in our overtly the clinical severity of the episodes of thyroid dysfunction, hypothyroid patients, it is tempting to attribute hypothyprevious analyses found that most episodes were mild to roidism in those patients to TSH receptor blockade. Unmoderate in severity (4, 5). fortunately, we have no information about thyroid size in Thyroid dysfunction occurring after alemtuzumab our patients with hypothyroidism. therapy for RRMS is an example of reconstitution autoOverall, 76.5% (62 of 81) of alemtuzumab patients immunity. Thyroid dysfunction may manifest as TBII-mewith TBII developed thyroid dysfunction, whereas 23.5% diated hyperthyroidism (Graves’ disease), hypothyroid(19 of 81) did not. It is uncertain why these TBII-positive ism with or without TBII, or subacute thyroiditis. It is individuals remained euthyroid. Possibilities include balimportant for clinicians caring for alemtuzumab-treated anced production of blocking and stimulating TRAbs, RRMS patients to be aware of the multiple types of thyroid TRAb titer insufficient to cause hyperthyroidism or hydysfunction that can occur and to keep in mind that the pothyroidism, or a destructive autoimmune process that same patient can experience multiple episodes. counteracted stimulating TRAbs. In a Japanese study of adults having a general health check-up, 1.2% were TBII positive and 32% of these were euthyroid (25). In previous publications, alemtuzumab demonstrated Acknowledgments superiority over SC IFNB-1a in reducing relapse rate and We thank Azita Razzaghi and Catherine Pennella for their conrisk for sustained accumulation of disability and fostering tributions to this manuscript. Jenna Hollenstein, a medical writer recovery from RRMS-related disability (4, 5, 8). In this employed by Genzyme, Inc, contributed to the writing of this analysis, we note that the efficacy of alemtuzumab was not report. G.H.D. analyzed the data and wrote the manuscript. significantly different in patients who did and did not de- A.V., V.B., I.Z., W.V., P.O., J.P., and D.H.M. reviewed and provided critical input into the manuscript. velop thyroid dysfunction. This study is listed under the Clinical Trial registration numOther antibody-mediated autoimmune disorders have ber of NCT00050778. been reported after alemtuzumab therapy in MS patients at much lower rates, including immune thrombocytopenia Address all correspondence and requests for reprints to: and glomerular nephropathy (26, 27). In our study, 94.1% Gilbert H. Daniels, MD, Thyroid Unit, Massachusetts General of thyroid dysfunction events in alemtuzumab patients were Hospital, ACC 730S, Boston, Massachusetts 02114-3117. either antibody mediated or associated with TBII. E-mail: [email protected]. Result 40

3

4


doi: 10.1210/jc.2013-2201

This work was supported by Genzyme and Bayer Schering Pharma, which provided financial support for the clinical trial and approved its design; only Genzyme participated in the data analysis, interpretation, and preparation of this report. G.H.D. reviewed all the data, wrote the manuscript, and had final responsibility, in consultation with Genzyme, for the decision to submit for publication. Disclosure summary: G.H.D. consults for Genzyme. A.V., V.B., I.Z., and W.V. have nothing to declare. P.O., J.P., and D.H.M. are employed by Genzyme.

References 1. Barbesino G. Drugs affecting thyroid function. Thyroid. 2010;20: 763–770. 2. Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999;354:1691–1695. 3. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253:98 –108. 4. CAMMS223 Trial Investigators, Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon ␤-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786 –1801. 5. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon ␤-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78:1069 –1078. 6. Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab. 2009;23:793– 800. 7. Moore KL, Boscardin WJ, Steinman MA, Schwartz JB. Age and sex variation in prevalence of chronic medical conditions in older residents of US nursing homes. J Am Geriatr Soc. 2012;60:756 –764. 8. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon ␤-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011;10: 338 –348. 9. Akeno N, Smith EP, Stefan M, et al. IFN-␣ mediates the development of autoimmunity both by direct tissue toxicity and through immune cell recruitment mechanisms. J Immunol. 2011;186:4693– 4706. 10. Ward DL, Bing-You RG. Autoimmune thyroid dysfunction induced by interferon-␣ treatment for chronic hepatitis C: screening and monitoring recommendations. Endocr Pract. 2001;7:52–58. 11. Weetman A. Immune reconstitution syndrome and the thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23:693–702. 12. Jubault V, Penfornis A, Schillo F, et al. Sequential occurrence of thyroid autoantibodies and Graves’ disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients. J Clin Endocrinol Metab. 2000;85:4254 – 4257. 13. Gillard P, Huurman V, Van der Auwera B, et al. Graves hyperthy-


14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24. 25.

26.

27.

89

roidism after stopping immunosuppressive therapy in type 1 diabetic islet cell recipients with pretransplant TPO autoantibodies. Diabetes Care. 2009;32:1817–1819. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist. 2008;13:167–174. Kirk AD, Hale DA, Swanson SJ, Mannon RB. Autoimmune thyroid disease after renal transplantation using depletional induction with alemtuzumab. Am J Transplant. 2006;6:1084 –1085. Marrie RA, Yu BN, Leung S, et al. The incidence and prevalence of thyroid disease do not differ in the multiple sclerosis and general populations: a validation study using administrative data. Neuroepidemiology. 2012;39:135–142. McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 2013;23:14 –24. Codaccioni JL, Orgiazzi J, Blanc P, Pugeat M, Roulier R, Carayon P. Lasting remissions in patients treated for Graves’ hyperthyroidism with propranolol alone: a pattern of spontaneous evolution of the disease. J Clin Endocrinol Metab. 1988;67:656 – 662. Wood LC, Ingbar SH. Hypothyroidism as a late sequela in patient with Graves’ disease treated with antithyroid agents. J Clin Invest. 1979;64:1429 –1436. Chung HK, Kim WB, Park DJ, Kohn LD, Tahara K, Cho BY. Two Graves’ disease patients who spontaneously developed hypothyroidism after antithyroid drug treatment: characteristics of epitopes for thyrotropin receptor antibodies. Thyroid. 1999;9:393–399. Tamai H, Hirota Y, Kasagi K, et al. The mechanism of spontaneous hypothyroidism in patients with Graves’ disease after antithyroid drug treatment. J Clin Endocrinol Metab. 1987;64:718 –722. Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous hypothyroidism in patients with Graves’ disease treated with antithyroidal drugs: clinical, immunological, and histological findings in 26 patients. J Clin Endocrinol Metab. 1989;69:49 –53. Arikawa K, Ichikawa Y, Yoshida T, et al. Blocking type antithyrotropin receptor antibody in patients with nongoitrous hypothyroidism: its incidence and characteristics of action. J Clin Endocrinol Metab. 1985;60:953–959. Rees Smith B, McLachlan SM, Furmaniak J. Autoantibodies to the thyrotropin receptor. Endocr Rev. 1988;9:106 –121. Tamaki H, Amino N, Kimura M, Hidaka Y, Takeoka K, Miyai K. Low prevalence of thyrotropin receptor antibody in primary hypothyroidism in Japan. J Clin Endocrinol Metab. 1990;71:1382–1386. Cuker A, Coles AJ, Sullivan H, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011;118: 6299 – 6305. Meyer D, Coles, AJ, Oyuela, P, Purvis, A, Margolin, DH. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2013;2:60 – 63.


Sexual dysfunction in patients with multiple sclerosis.

Urogenital dysfunction in patients with multiple sclerosis.

Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.

Re: Renal deterioration in multiple sclerosis patients with neurovesical dysfunction.

Lower motor neuron dysfunction in patients with multiple sclerosis.

Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: a randomized clinical trial.

Preliminary trial of 3,4-diaminopyridine in patients with multiple sclerosis.

Thyroid dysfunction in a prospectively followed series of patients with progressive systemic sclerosis.

Cerebellar Dysfunction in Multiple Sclerosis.

Autonomic dysfunction in multiple sclerosis.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.

Cardiovascular Dysfunction in Multiple Sclerosis.

Vesicourethral dysfunction in multiple sclerosis.

Corrigendum to "Sexual dysfunction in patients with multiple sclerosis" [Mult. Scler. Relat. Disord. 2 (2) (2013) 117-123].

Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial.

Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.

Multidisciplinary Management of Sexual Dysfunction, Perineal Pain, and Elimination Dysfunction in a Woman with Multiple Sclerosis.

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.

Deep breathing exercises with positive expiratory pressure in patients with multiple sclerosis - a randomized controlled trial.

A randomized controlled phase II trial of riluzole in early multiple sclerosis.

Orienting network dysfunction in progressive multiple sclerosis.

Cognitive dysfunction in pediatric multiple sclerosis.

Baclofen, a new antispastic drug. A controlled, multicenter trial in patients with multiple sclerosis.

Paroxysmal brain stem dysfunction in multiple sclerosis.