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Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability
Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability Eun Bin Cho MD, PhD, Ju-Hong Min MD, PhD, Hye-Jin Cho MD, Jin Myoung Seok MD, Hye Lim Lee MD, Hee Young Shin MD, Kwang-Ho Lee MD, PhD, Byoung Joon Kim MD, PhD PII: DOI: Reference:
S0022-510X(16)30604-9 doi: 10.1016/j.jns.2016.09.039 JNS 14833
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
29 April 2016 4 September 2016 20 September 2016
Please cite this article as: Eun Bin Cho, Ju-Hong Min, Hye-Jin Cho, Jin Myoung Seok, Hye Lim Lee, Hee Young Shin, Kwang-Ho Lee, Byoung Joon Kim, Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability, Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.09.039
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Low T3 syndrome in neuromyelitis optica spectrum disorder: associations with disease activity and disability
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Eun Bin Cho, MD, PhD,1 Ju-Hong Min, MD, PhD,2,3* Hye-Jin Cho, MD,4 Jin Myoung Seok,
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MD,2,3 Hye Lim Lee, MD,5 Hee Young Shin, MD,6 Kwang-Ho Lee, MD, PhD,2,3, Byoung
1
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Joon Kim, MD, PhD2,3*
Department of Neurology, Gyeongsang National University Changwon Hospital,
2
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Gyeongsang National University School of Medicine, Changwon, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Republic of Korea
Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
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Department of Neurology, The Catholic University of Korea, College of Medicine, Bucheon
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St. Mary’s Hospital, Bucheon, Republic of Korea Department of Neurology, Chungbuk National University Hospital, Cheongju, Republic of
Korea 6
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Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, Republic of Korea * Co-corresponding authors 1. Ju-Hong Min, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 1
ACCEPTED MANUSCRIPT 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea Tel: +82-2-3410-1765, Fax:+82-2-3410-0052
2. Byoung Joon Kim, MD, PhD
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E-mail: [email protected]
Department of Neurology, Samsung Medical Center,
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Sungkyunkwan University School of Medicine,
81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea
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Tel: +82-2-3410-3594, Fax:+82-2-3410-0052
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E-mail: [email protected]
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* These authors contributed equally to this work.
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Running title: Low T3 syndrome in NMOSD
Key words: neuromyelitis optica spectrum disorder, autoimmune thyroid disease, low T3
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syndrome, anti-thyroid antibodies
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Abstract
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Background: Neuromyelitis optica (NMO) sometimes coexists with serological marker-
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positive, non-organ-specific autoimmune disorders. We evaluated the prevalence of thyroid
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dysfunction and anti-thyroid antibodies in patients with NMO spectrum disorder (NMOSD) and investigated the associations between thyroid dysfunction/autoimmunity and clinical features of NMOSD.
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Methods: Forty-nine NMOSD patients with anti-aquaporin-4 antibody and 392 age- and sex-
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matched healthy controls were included. We measured the levels of thyroid hormones and anti-thyroid antibodies.
Results: The prevalence of clinical hypothyroidism, subclinical hyperthyroidism, and low T3
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syndrome were higher in patients with NMOSD (4.1%, 12.2%, and 20.4%, respectively) compared with healthy controls (0.3%, 2.8%, and 0.5%, respectively; p = 0.034, p = 0.001,
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and p <0.001, respectively). However, anti-thyroperoxidase antibody (anti-TPO)-positivity did not significantly differ between NMOSD patients (20.4%) and controls (11.5%). Low T3
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syndrome was more prevalent among patients during an attack (N = 10/19, 52.6%) than those in remission (N = 1/30, 3.3%). In addition, patients with low T 3 syndrome had significantly higher EDSS scores at the last visits as well as at sampling compared to those without low T3 syndrome. T3 levels were inversely correlated with EDSS score at the last visit after adjustment for age, sex, disease duration, clinical status (attack vs. remission), oral prednisolone use, iv methylprednisolone use, other immunosuppressive agents use, and the location of lesion (ρ = -0.416, p = 0.010).
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ACCEPTED MANUSCRIPT Conclusions: Our study suggests that thyroid dysfunction is frequent in patients with NMOSD; particularly, serum T3 levels may be a useful indicator of disease activity and
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disability in NMOSD.
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Introduction
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Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system
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(CNS) disorder that predominantly affects the optic nerves and spinal cord.(1) The discovery
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of a disease-specific autoantibody, anti-aquaporin-4-antibody (AQP4-ab), has broadened the concept of NMO to the more recent designation of NMO spectrum disorder (NMOSD).(2) In addition, several reports have described associations between NMO and non-organ specific
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autoantibodies or other autoimmune disorders, such as systemic lupus erythematosus (SLE)
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and Sjogren’s syndrome (SS),(3, 4) and the clinical coexistence of these conditions is now widely recognized in patients susceptible to autoimmune disease.(4) Autoimmune thyroid diseases (AITDs) such as Graves’ disease and Hashimoto’s
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thyroiditis are one of the most prevalent organ-specific autoimmune diseases. The association between AITD and non-organ-specific systemic disorders, such as SLE, SS, and rheumatoid
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arthritis (RA), has been reported in previous studies.(5-7) In addition, AITD has been reported in the context of several neurological disorders, such as multiple sclerosis (MS) or
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myasthenia gravis (MG).(8-10) NMO and thyroid disease were observed to coexist at a high frequency (13.6-17.0%) in previous reports,(3, 11, 12) although the definitions of thyroid disease were unclear and the numbers of NMO cases were low. So far, no studies have evaluated the clinical significance of thyroid dysfunction/autoimmunity in patients with NMO. Herein, we aimed to evaluate the prevalence of thyroid dysfunction/autoimmunity in patients
with
NMOSD
and
to
investigate
the
relationship
dysfunction/autoimmunity and the clinical features of NMOSD.
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between
thyroid
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Methods
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Patients and controls
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We reviewed medical records from the CNS demyelinating disease registry of Samsung
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Medical Center, South Korea that were collected between March 2009 and December 2014. We identified 57 patients with AQP4-ab who had been followed-up for more than 1 year in hospital.
AQP4-ab
statuses
were
determined
using
a
cell-based
indirect
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our
immunofluorescence assay, as previously described.(13, 14) We excluded 8 patients who did
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not have available blood samples for thyroid function tests (TFT). A total of 49 patients with AQP4-ab were ultimately included. In addition, sex- and age- matched healthy controls (N =
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392) were identified through a random number generator in SPSS from a larger sample of
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117,540 subjects who visited the Center for Health Promotion at our hospital for regular check-ups between January 2009 and June 2014. The health screening program at our center
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includes TFT such as TSH, total T3, free T4, and anti-thyroperoxidase antibody (anti-TPO). We collected data, including sex, age at onset, age at sampling, disease duration (interval
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between disease onset and blood sampling), symptomatic attack sites (optic nerve, spinal cord, and brain), and the use of prednisolone or immunosuppressive agents. In addition, we acquired the annualized relapse rate (ARR) at blood sampling, Expanded Disability Status Scale (EDSS) scores, and progression index (PI; EDSS/year) at blood sampling and at the last visit. Each attack was defined as new, worsening, or recurrent neurologic symptoms caused by a CNS demyelinating disease and lasting at least 24 hours and remission was defined as a clinically stable state for more than 3 months after an attack.
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Ethics Statement
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This study was approved by the Institutional Review Board of Samsung Medical Center,
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and written informed consent was obtained from all patients. The requirement for informed
Thyroid function tests (TFT)
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clinical purposes during the health screening exams.
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consent in healthy controls was waived, because we only used de-identified data collected for
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Serum triiodothyronine (T3; reference range, 76–190 ng/dL) and free T4 (reference range, 0.89–1.8 ng/dL) levels were measured using commercial radioimmunoassay (RIA) kits
range,
0.3–6.5 μIU/mL)
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reference
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prepared by Immunotech (Cedex, France). Serum thyroid stimulating hormone (TSH; levels
were
measured
using
a
commercial
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immunoradiometric assay kit prepared by Immunotech. Serum anti-thyroperoxidase antibody (anti-TPO; reference range, 0–60 U/mL) and anti-thyroglobulin antibody (anti-Tg; reference range, 0–60 U/mL) activity levels were measured using RIA kits (Brahms, Aktiengesellschaft,
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Germany). Thyrotropin-binding inhibitory immunoglobulin (TBII; reference range, -15–15) activity levels were measured using a second-generation TSH-receptor antibody kit (Brahms AG, Berlin, Germany). Thyroid dysfunction was classified as hypothyroidism or hyperthyroidism. Clinical hypothyroidism was defined as elevated TSH and suppressed free T4 levels with clinical symptoms commonly associated with hypothyroidism, and subclinical hypothyroidism was defined as an elevated TSH level, a free T4 level within the reference range, and the absence of symptoms. Clinical hyperthyroidism was defined as suppressed TSH and elevated free T4 7
ACCEPTED MANUSCRIPT levels with symptoms of hyperthyroidism, and subclinical hyperthyroidism was defined as a suppressed TSH level, T3 and free T4 levels within the reference ranges, and the absence of
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symptoms. Low T3 syndrome was defined as a low serum T3, normal–low free T4, and
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normal–low TSH levels. A diagnosis of AITD was based on clinical features and supportive
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laboratory findings, including anti-TPO and anti-Tg antibody positivity.(15-17)
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Statistical analysis
Mann-Whitney U test or Kruskal–Wallis test were used for continuous variables,
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Chi-square or Fisher’s exact test was used for categorical variables. P-values were corrected using Bonferroni’s method in cases involving multiple testing. For the patients, the
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associations between T3 levels and clinical parameters, such as age at sampling, sex, interval
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from disease onset to sampling, disease activity, steroid use, and other immunosuppressive
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agents use, were analyzed in multiple linear regression analysis. Spearman partial correlation coefficients were used to evaluate potential relationships between T3 levels and clinical
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parameters after controlling for potential confounders. All statistical analyses were conducted using SPSS version 20 (SPSS, Inc., Chicago, IL, USA) and were considered significant at p values of < 0.05.
Results Demographics, and clinical features of patients with NMOSD and healthy controls A total of 49 AQP4-ab-positive patients (mean age, 44.6 ± 15.6 years; female, 8
ACCEPTED MANUSCRIPT 47[88%]) met the diagnostic criteria for NMO (N = 23)(1) or met the 2015 revised diagnostic criteria for NMOSD (N = 26) (Table 1).(2) The median interval from onset to sampling
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(disease duration) was 2.0 years and the median EDSS score was 3.5. At blood sampling, 34
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patients had been treated with steroid (N=19, oral prednisolone 10mg/day; N=15, intravenous
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methylprednisolone 1000mg/day) and 26 patients with immunosuppressive agents.
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Thyroid dysfunction and autoimmunity of patients with NMOSD
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and healthy controls
Twenty-three (46.9%) patients had abnormal TFTs on at least one parameter,
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regardless of thyroid autoantibody presence. TSH and total T3 levels were significantly lower
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in patients with NMOSD than in healthy controls (both p <0.001), although free T4 and antiTPO levels did not differ between the groups (Table 1). In patients with NMOSD, the most
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prevalent thyroid dysfunction was low T3 syndrome followed by subclinical hyperthyroidism, subclinical hypothyroidism and clinical hypothyroidism. All patients with clinical
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hypothyroidism (N = 4) were diagnosed as Hashimoto’s thyroiditis during an attack, although Graves’ disease was not found in NMOSD patients. Among patients with subclinical hyperthyroidism (N = 6), 2 were taking thyroxine after thyroid cancer surgery. Compared to healthy controls, patients with NMOSD showed more frequent thyroid dysfunction (47% vs 10%; p <0.001), such as clinical hypothyroidism, subclinical hyperthyroidism and low T3 syndrome (p = 0.034, p = 0.001, and p <0.001, respectively). However, the prevalence of anti-TPO was not different between patients with NMOSD and healthy controls.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical features and thyroid dysfunction/autoimmunity in patients with NMOSD and healthy controls Controls
(N = 49)
(N = 392)
44.6 ± 15.6
Age at onset, year
40.4 ± 17.2
44.8 ± 15.1
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Age, year
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Demographic data and clinical features
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NMOSD
Sex (F:M)
43:06
0.922
344:48
1
2.2 ± 3.3
2.8 ± 2.1
<0.001
80.7 ± 26.8
116.8 ± 21.2
<0.001
1.2 ± 0.3
1.3 ± 0.2
0.422
137.0 ± 477.5
221.2 ± 1488.5
0.465
a
Definite NMO (%)
23 (47) b
2.0 (0.1-17.4)
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Disease duration, year
P value
Thyroid function test TSH (μIU/mL)
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Total T3 (ng/dL) Free T4 (ng/dL) Thyroid autoantibodies Anti-TPO antibody (U/mL)
180.3 ± 810.4
NA
†
NA†
0.1 (-7.7–13.9)
NA†
NA†
23 (46.9)
39 (9.9)
<0.001
Clinical hypothyroidism
2 (4.1)
1 (0.3)
0.034
Subclinical hypothyroidism
4 (8.2)
20 (5.1)
0.325
0 (0)
5 (1.3)
1
6 (12.2)
11 (2.8)
0.001
11 (22.4)
2 (0.5)
<0.001
10 (20.4)
45 (11.5)
0.075
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TBII (U) Prevalence of thyroid dysfunction/autoimmunity Thyroid dysfunction (%)
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Anti-Tg antibody (U/mL)
Clinical hyperthyroidism
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Subclinical hyperthyroidism Low T3 syndrome
Thyroid autoimmunity (%) Anti-TPO antibody positivity Anti-Tg antibody positivity
15/48 (31.3)
NA
†
NA†
0/48 (0)
NA†
NA†
TBII positivity
NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; F, female; M, male; TSH, thyroid-stimulating hormone; Anti-TPO positivity, anti-thyroperoxidase antibodies >60 U/mL; Anti-Tg positivity, anti-thyroglobulin antibodies >60 U/mL; Anti-TBII positivity, thyrotropin-binding inhibitory immunoglobulin >15% Values are expressed as means ± standard deviations or median (range) for continuous variables or numbers (%) for categorical variables. a
Patients meeting the revised diagnostic criteria for NMO(1)
b
Disease duration until a thyroid function test was performed.
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The values at the time of blood sampling.
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Tests for Anti-Tg antibody and Anti-TBII were not performed in healthy controls.
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Low T3 syndrome in patients with NMOSD After excluding patients with clinical hypothyroidism (N = 2) and those with
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previous thyroid cancer surgery (N = 2), 45 patients were divided into two subgroups based
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on T3 levels: low T3 (N = 11) and normal T3 (N = 34) (Table 2). The patients with low T3 syndrome included a higher proportion of patients during an attack and those on oral prednisolone and intravenous methylprednisolone, compared to those with normal T3 (p
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<0.001, p = 0.031, and p = 0.001, respectively). In addition, patients with low T3 syndrome showed a higher proportion of symptomatic spinal cord lesions and higher EDSS scores at the
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time of TFT and at the last visit than those with normal T3 levels (p = 0.023, p = 0.005, and p = 0.013, respectively). Other clinical features and serological findings did not differ
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significantly between the two groups.
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ACCEPTED MANUSCRIPT Table 2. Clinical and serologic features of patients with low T3 syndrome Patients with NMOSD (N = 45)a Without low T3 syndrome (N = 34)
P value
Age, years
44 (20–86)
44 (16–70)
0.926
Age at onset, years
42 (15–85)
37 (12–69)
0.663
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With low T3 syndrome (N = 11)
Female (%)
10 (90.9)
29 (85.3)
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During attack, yes (%)
10 (90.9)
7 (20.6)
<0.001
1.9 (0.1–12.1)
2.0 (0.1–17.5)
0.958
2.21 (0.01-11.13)
1.53 (0.08-11.99)
0.989
Interval from onset to sampling, years
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Interval from sampling to the last visit, years
0.7 (0.3–2.0)
0.7 (0.2–6.4)
0.499
EDSS score at sampling at the last visit Treatment at sampling
4.5 (3.0–9.0) 4.5 (2.5–9.5)
3.25 (0–9.5) 3.0 (0–8.0)
0.005 0.013
1 (9.1)
17 (50.0)
0.031
6 (54.5)
19 (55.9)
0.938
8 (72.7)
5 (14.7)
0.001
7 (63.6)
17 (50.0)
0.431
11 (100.0)
22 (64.7)
0.023
9/11 (81.8)
14/22 (63.6)
0.430
7 (63.6)
14 (41.2)
0.194
1/7 (14.3)
1/14 (7.1)
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Anti-TPO antibody positivity
3 (27.3)
5 (14.7)
0.343
Anti-Tg antibody positivity
4 (36.4)
8 (23.5)
0.403
FANA
9 (81.8)
25 (73.5)
0.578
Elevated RF
3 (27.3)
6 (17.6)
0.488
ds-DNA
2 (27.3)
9 (26.5)
0.578
SSA or SSB
6 (54.5)
10 (29.4)
0.130
ANCA
0/10 (0)
5/24 (20.8)
0.291
Anti-cardiolipin Ab
0/5 (0)
3/20 (15.0)
1
Sjogren’s syndrome
3 (27.3)
6 (22.2)
0.488
SLE
1 (9.1)
4 (11.1)
1
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ARR
Oral prednisolone use (%)
Lesion at attack (%) Optic nerve Spinal cord Brain
≥6 segments
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LETM
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IV Methylprednisolone use (%)
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Immunosuppressive agents use (%)
Hypothalamic lesion
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Thyroid autoimmunity (%)
Associated autoantibodies (%)
Rheumatologic diseases (%)
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ACCEPTED MANUSCRIPT NMOSD, neuromyelitis optica spectrum disorder; ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; ; PI, progression index (EDSS/year); IV, intravenous; LETM, longitudinally extensive transverse myelitis; FANA, fluorescent antinuclear antibody; RF, rheumatoid factor; ds-DNA, double stranded DNA; SSA or SSB, anti-Ro/SSA or anti-La/SSB antibody; ANCA, anti-neutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus
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Values are expressed as median (ranges) for continuous variables or numbers (%) for categorical variables. a
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Excludes patients with clinical hypothyroidism (N = 2) and those with no available T3 levels (N = 2)
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Associations between T3 levels and disease disability and clinical
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disease activity
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Total T3 levels were significantly lower during an attack (median, 67.1 ng/dL; range,
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21.0 – 143.0) than in remission (median, 89.9 ng/dL; range, 63.3–142.4) (p = 0.003). In a multiple linear regression analysis, T3 levels were associated with age at sampling and clinical status (attack vs remission) (β = -0.55; p = 0.031 and β = -37.48; p = 0.008,
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respectively) (Table 3). In addition, T3 levels were inversely correlated with EDSS score at
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the last visit (ρ[rho] = -0.381, p = 0.013) and this persisted after adjustment for age, sex, clinical status (attack vs. remission), disease duration, steroid use, other immunosuppressive
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agents use, and the location of lesion (ρ = -0.416, p = 0.010) (Figure 1).
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ACCEPTED MANUSCRIPT Table 3. Multivariable linear regression analysis for the relationship between T3 levels and clinical features with neuromyelitis optica spectrum disorder
-8.98 (8.05) -10.00 (8.46)
0.272 0.245
-10.58 (7.71)
0.178
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Brain
0.052 1 0.364
-7.03 (7.64)
Lesion locations Optic nerve Spinal cord
0.008
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-23.28 (10.03) -0.63 (13.01) reference
Other immunosuppressive agents*
0.031 0.938 0.272
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-0.55 (0.25) 0.83 (10.60) 1.05 (0.94) -37.48 (13.40)
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Age at sampling Female Interval from onset to sampling During an attack Treatment at sampling Oral prednisolone use IV methylprednisolone use No steroid use
P value
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B (SE)
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Linear regression analysis adjusting for age at sampling, sex, interval from disease onset to sampling, clinical status of an attack or remission, lesion locations, the prednisolone use and other immunosuppressant use
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B, beta coefficient; SE, standard error; IV, intravenous
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*No use of other immunosuppressive agents was a reference category.
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Thyroid autoantibodies in patients with NMOSD We further compared patients with and without thyroid autoantibody (anti-TPO
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and/or anti-Tg) (Table e-1). No significant differences were observed between the two groups
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in demographics, clinical features, and laboratory findings. In addition, the proportion of LETM did not differ between patients with and without anti-TPO (N = 7/7, 100% vs N =
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21/33, 63.6%; p = 0.081).
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Discussion
We demonstrated that thyroid dysfunction, particularly low T3 syndrome, was frequently
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observed in patients with NMOSD, although the prevalence of anti-TPO antibody was not
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different between patients and healthy controls. In our healthy controls, the overall prevalence of thyroid dysfunction was 9.9%, which was similar to 11.8% in a previous study
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of healthy Korean subjects.(18) Low T3 syndrome has been reported in various acute and chronic systemic conditions(19); particularly, the prevalence of low T3 syndrome was
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reported as 3% to 16.7% in patients with SLE and 2.8% in patients with MS.(20-22) We found that low T3 syndrome was much frequently observed in NMOSD patients (20.4%), even compared to the previous reports of SLE and MS.(20-22) Previous studies showed that glucocorticoids can lower serum TSH levels and decrease TSH secretion,(23) and high-dose dexamethasone caused a decrease in serum T3 levels within several days.(24) Although 70% of our patients had been treated with oral prednisolone or methylprednisolone, T3 levels were not affected by the steroid use in a multiple regression analysis. Serum T3 levels of NMOSD patients were lower during attack than in remission and were associated with clinical attack even after controlling for potential confounding factors. This is 17
ACCEPTED MANUSCRIPT consistent with findings from a previous study of SLE, where there was a significant association between SLE disease activity and low T3 syndrome (25) Several underlying
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mechanisms of low T3 syndrome have been suggested, including hypothalamic-pituitary-
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thyroid (HPT) axis modification as a cause of central hypothyroidism.(26) Although lesions
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involving the hypothalamus are characteristic of NMOSD,(27) a hypothalamic lesion was observed in only one patient with low T3 syndrome in our study. As another mechanism, IL-6
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has been reported to play an additional role in low T3 syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.(28) Previously, a
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negative correlation between serum T3 levels and IL-6 levels have been observed in hospitalized patients with various medical conditions.(29) In NMOSD, it was reported that
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cerebrospinal fluid IL-6 levels were elevated during relapse (30) and that IL-6-dependent B-
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cell subpopulation is involved in the pathogenesis of the disease.(31-33) We also observed an
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inverse correlation between T3 levels and EDSS scores in NMOSD patients, which is congruous with a recent report showing that the release of IL-6 and IL-21 by activated CD4+ T cells was correlated directly with EDSS scores in patients with NMO.(34) Still, it remains
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to be elucidated that low T3 level predispose to NMOSD and modify disease disability or is an epiphenomenon of disease process. However, the association between low T3 levels and EDSS scores at the last visit may imply that patients with low T3 syndrome need early and aggressive treatment, such as plasmapheresis or adjunctive treatments with thyroxin or T3.(35) Otherwise, the therapy targeting anti-inflammatory cytokine, IL-6, such as tocilizumab, may result in the suppression of T3 levels and improve the disease disability in NMOSD. In our patients, the rates of anti-TPO (20.4%) and anti-Tg antibody (31.3%) positivity 18
ACCEPTED MANUSCRIPT were similar with previous studies; anti-TPO and anti-Tg antibody positivity rates were 20.9– 49.0% and 27.9–38.8% in patients with AQP4-ab, which were significantly higher than those
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observed in patients with MS or healthy controls.(36-38) Recently, the associations between
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anti-thyroid antibodies and myelitis occurrence, EDSS scores or cord lesion severity have
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been suggested in patients with NMOSD, (36, 38) which were not observed in our study. Our study has several limitations; first, this was a retrospective analysis of registry-based
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data at a single hospital, which might have led to unintentional bias. In addition, we included a single ethnic population and did not consider genetic heterogeneity.
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In conclusion, thyroid dysfunction, particularly low T3 syndrome, occurs frequently in patients with NMOSD. We suggest that serum T3 levels may be a useful indicator of disease
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activity and disability in NMOSD, although the causal relationship is unclear. To elucidate
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the pathophysiologic and therapeutic role of T3 in NMOSD, large-scale prospective studies
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with serial analysis of thyroid hormones during relapse and remission will be needed.
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Acknowledgements
This working was supported by Korea Centers for Disease Control and Prevention (No. 2014-E63004-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
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Figure Legend Figure 1. Relationships of T3 levels with the Expanded Disability Status Scale (EDSS)
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scores in patients with neuromyelitis optica spectrum disorder (NMOSD) An inverse correlation was observed between T3 levels and the EDSS scores at the last visit
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in patients with NMOSD. Although the correlation coefficient (ρ) and p value were calculated using the Spearman rank correlation, the linear regression line is presented in this graph. The
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dashed lines represent the 95% confidence limits.
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ρ, Spearman correlation coefficient
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criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-9. consensus
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ACCEPTED MANUSCRIPT Highlights (3~5 개) The levels of thyroid hormones and anti-thyroid antibodies were measured from 49 patients with seropositive NMOSD and 392 healthy subjects.
Low T3 syndrome was the most frequent thyroid dysfunction and T3 levels were inversely correlated with EDSS scores in NMOSD patients.
Serum T3 levels may be a useful indicator of disease activity and disability in NMOSD.
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S0022-510X(16)30604-9 doi: 10.1016/j.jns.2016.09.039 JNS 14833
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
29 April 2016 4 September 2016 20 September 2016
Please cite this article as: Eun Bin Cho, Ju-Hong Min, Hye-Jin Cho, Jin Myoung Seok, Hye Lim Lee, Hee Young Shin, Kwang-Ho Lee, Byoung Joon Kim, Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability, Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.09.039
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Low T3 syndrome in neuromyelitis optica spectrum disorder: associations with disease activity and disability
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Eun Bin Cho, MD, PhD,1 Ju-Hong Min, MD, PhD,2,3* Hye-Jin Cho, MD,4 Jin Myoung Seok,
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MD,2,3 Hye Lim Lee, MD,5 Hee Young Shin, MD,6 Kwang-Ho Lee, MD, PhD,2,3, Byoung
1
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Joon Kim, MD, PhD2,3*
Department of Neurology, Gyeongsang National University Changwon Hospital,
2
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Gyeongsang National University School of Medicine, Changwon, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Republic of Korea
Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
4
Department of Neurology, The Catholic University of Korea, College of Medicine, Bucheon
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3
St. Mary’s Hospital, Bucheon, Republic of Korea Department of Neurology, Chungbuk National University Hospital, Cheongju, Republic of
Korea 6
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Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, Republic of Korea * Co-corresponding authors 1. Ju-Hong Min, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 1
ACCEPTED MANUSCRIPT 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea Tel: +82-2-3410-1765, Fax:+82-2-3410-0052
2. Byoung Joon Kim, MD, PhD
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E-mail: [email protected]
Department of Neurology, Samsung Medical Center,
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Sungkyunkwan University School of Medicine,
81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea
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Tel: +82-2-3410-3594, Fax:+82-2-3410-0052
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E-mail: [email protected]
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* These authors contributed equally to this work.
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Running title: Low T3 syndrome in NMOSD
Key words: neuromyelitis optica spectrum disorder, autoimmune thyroid disease, low T3
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syndrome, anti-thyroid antibodies
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Abstract
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Background: Neuromyelitis optica (NMO) sometimes coexists with serological marker-
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positive, non-organ-specific autoimmune disorders. We evaluated the prevalence of thyroid
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dysfunction and anti-thyroid antibodies in patients with NMO spectrum disorder (NMOSD) and investigated the associations between thyroid dysfunction/autoimmunity and clinical features of NMOSD.
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Methods: Forty-nine NMOSD patients with anti-aquaporin-4 antibody and 392 age- and sex-
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matched healthy controls were included. We measured the levels of thyroid hormones and anti-thyroid antibodies.
Results: The prevalence of clinical hypothyroidism, subclinical hyperthyroidism, and low T3
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syndrome were higher in patients with NMOSD (4.1%, 12.2%, and 20.4%, respectively) compared with healthy controls (0.3%, 2.8%, and 0.5%, respectively; p = 0.034, p = 0.001,
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and p <0.001, respectively). However, anti-thyroperoxidase antibody (anti-TPO)-positivity did not significantly differ between NMOSD patients (20.4%) and controls (11.5%). Low T3
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syndrome was more prevalent among patients during an attack (N = 10/19, 52.6%) than those in remission (N = 1/30, 3.3%). In addition, patients with low T 3 syndrome had significantly higher EDSS scores at the last visits as well as at sampling compared to those without low T3 syndrome. T3 levels were inversely correlated with EDSS score at the last visit after adjustment for age, sex, disease duration, clinical status (attack vs. remission), oral prednisolone use, iv methylprednisolone use, other immunosuppressive agents use, and the location of lesion (ρ = -0.416, p = 0.010).
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ACCEPTED MANUSCRIPT Conclusions: Our study suggests that thyroid dysfunction is frequent in patients with NMOSD; particularly, serum T3 levels may be a useful indicator of disease activity and
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disability in NMOSD.
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Introduction
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Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system
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(CNS) disorder that predominantly affects the optic nerves and spinal cord.(1) The discovery
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of a disease-specific autoantibody, anti-aquaporin-4-antibody (AQP4-ab), has broadened the concept of NMO to the more recent designation of NMO spectrum disorder (NMOSD).(2) In addition, several reports have described associations between NMO and non-organ specific
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autoantibodies or other autoimmune disorders, such as systemic lupus erythematosus (SLE)
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and Sjogren’s syndrome (SS),(3, 4) and the clinical coexistence of these conditions is now widely recognized in patients susceptible to autoimmune disease.(4) Autoimmune thyroid diseases (AITDs) such as Graves’ disease and Hashimoto’s
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thyroiditis are one of the most prevalent organ-specific autoimmune diseases. The association between AITD and non-organ-specific systemic disorders, such as SLE, SS, and rheumatoid
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arthritis (RA), has been reported in previous studies.(5-7) In addition, AITD has been reported in the context of several neurological disorders, such as multiple sclerosis (MS) or
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myasthenia gravis (MG).(8-10) NMO and thyroid disease were observed to coexist at a high frequency (13.6-17.0%) in previous reports,(3, 11, 12) although the definitions of thyroid disease were unclear and the numbers of NMO cases were low. So far, no studies have evaluated the clinical significance of thyroid dysfunction/autoimmunity in patients with NMO. Herein, we aimed to evaluate the prevalence of thyroid dysfunction/autoimmunity in patients
with
NMOSD
and
to
investigate
the
relationship
dysfunction/autoimmunity and the clinical features of NMOSD.
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between
thyroid
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Methods
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Patients and controls
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We reviewed medical records from the CNS demyelinating disease registry of Samsung
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Medical Center, South Korea that were collected between March 2009 and December 2014. We identified 57 patients with AQP4-ab who had been followed-up for more than 1 year in hospital.
AQP4-ab
statuses
were
determined
using
a
cell-based
indirect
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our
immunofluorescence assay, as previously described.(13, 14) We excluded 8 patients who did
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not have available blood samples for thyroid function tests (TFT). A total of 49 patients with AQP4-ab were ultimately included. In addition, sex- and age- matched healthy controls (N =
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392) were identified through a random number generator in SPSS from a larger sample of
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117,540 subjects who visited the Center for Health Promotion at our hospital for regular check-ups between January 2009 and June 2014. The health screening program at our center
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includes TFT such as TSH, total T3, free T4, and anti-thyroperoxidase antibody (anti-TPO). We collected data, including sex, age at onset, age at sampling, disease duration (interval
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between disease onset and blood sampling), symptomatic attack sites (optic nerve, spinal cord, and brain), and the use of prednisolone or immunosuppressive agents. In addition, we acquired the annualized relapse rate (ARR) at blood sampling, Expanded Disability Status Scale (EDSS) scores, and progression index (PI; EDSS/year) at blood sampling and at the last visit. Each attack was defined as new, worsening, or recurrent neurologic symptoms caused by a CNS demyelinating disease and lasting at least 24 hours and remission was defined as a clinically stable state for more than 3 months after an attack.
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Ethics Statement
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This study was approved by the Institutional Review Board of Samsung Medical Center,
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and written informed consent was obtained from all patients. The requirement for informed
Thyroid function tests (TFT)
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clinical purposes during the health screening exams.
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consent in healthy controls was waived, because we only used de-identified data collected for
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Serum triiodothyronine (T3; reference range, 76–190 ng/dL) and free T4 (reference range, 0.89–1.8 ng/dL) levels were measured using commercial radioimmunoassay (RIA) kits
range,
0.3–6.5 μIU/mL)
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reference
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prepared by Immunotech (Cedex, France). Serum thyroid stimulating hormone (TSH; levels
were
measured
using
a
commercial
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immunoradiometric assay kit prepared by Immunotech. Serum anti-thyroperoxidase antibody (anti-TPO; reference range, 0–60 U/mL) and anti-thyroglobulin antibody (anti-Tg; reference range, 0–60 U/mL) activity levels were measured using RIA kits (Brahms, Aktiengesellschaft,
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Germany). Thyrotropin-binding inhibitory immunoglobulin (TBII; reference range, -15–15) activity levels were measured using a second-generation TSH-receptor antibody kit (Brahms AG, Berlin, Germany). Thyroid dysfunction was classified as hypothyroidism or hyperthyroidism. Clinical hypothyroidism was defined as elevated TSH and suppressed free T4 levels with clinical symptoms commonly associated with hypothyroidism, and subclinical hypothyroidism was defined as an elevated TSH level, a free T4 level within the reference range, and the absence of symptoms. Clinical hyperthyroidism was defined as suppressed TSH and elevated free T4 7
ACCEPTED MANUSCRIPT levels with symptoms of hyperthyroidism, and subclinical hyperthyroidism was defined as a suppressed TSH level, T3 and free T4 levels within the reference ranges, and the absence of
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symptoms. Low T3 syndrome was defined as a low serum T3, normal–low free T4, and
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normal–low TSH levels. A diagnosis of AITD was based on clinical features and supportive
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laboratory findings, including anti-TPO and anti-Tg antibody positivity.(15-17)
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Statistical analysis
Mann-Whitney U test or Kruskal–Wallis test were used for continuous variables,
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Chi-square or Fisher’s exact test was used for categorical variables. P-values were corrected using Bonferroni’s method in cases involving multiple testing. For the patients, the
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associations between T3 levels and clinical parameters, such as age at sampling, sex, interval
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from disease onset to sampling, disease activity, steroid use, and other immunosuppressive
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agents use, were analyzed in multiple linear regression analysis. Spearman partial correlation coefficients were used to evaluate potential relationships between T3 levels and clinical
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parameters after controlling for potential confounders. All statistical analyses were conducted using SPSS version 20 (SPSS, Inc., Chicago, IL, USA) and were considered significant at p values of < 0.05.
Results Demographics, and clinical features of patients with NMOSD and healthy controls A total of 49 AQP4-ab-positive patients (mean age, 44.6 ± 15.6 years; female, 8
ACCEPTED MANUSCRIPT 47[88%]) met the diagnostic criteria for NMO (N = 23)(1) or met the 2015 revised diagnostic criteria for NMOSD (N = 26) (Table 1).(2) The median interval from onset to sampling
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(disease duration) was 2.0 years and the median EDSS score was 3.5. At blood sampling, 34
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patients had been treated with steroid (N=19, oral prednisolone 10mg/day; N=15, intravenous
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methylprednisolone 1000mg/day) and 26 patients with immunosuppressive agents.
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Thyroid dysfunction and autoimmunity of patients with NMOSD
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and healthy controls
Twenty-three (46.9%) patients had abnormal TFTs on at least one parameter,
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regardless of thyroid autoantibody presence. TSH and total T3 levels were significantly lower
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in patients with NMOSD than in healthy controls (both p <0.001), although free T4 and antiTPO levels did not differ between the groups (Table 1). In patients with NMOSD, the most
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prevalent thyroid dysfunction was low T3 syndrome followed by subclinical hyperthyroidism, subclinical hypothyroidism and clinical hypothyroidism. All patients with clinical
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hypothyroidism (N = 4) were diagnosed as Hashimoto’s thyroiditis during an attack, although Graves’ disease was not found in NMOSD patients. Among patients with subclinical hyperthyroidism (N = 6), 2 were taking thyroxine after thyroid cancer surgery. Compared to healthy controls, patients with NMOSD showed more frequent thyroid dysfunction (47% vs 10%; p <0.001), such as clinical hypothyroidism, subclinical hyperthyroidism and low T3 syndrome (p = 0.034, p = 0.001, and p <0.001, respectively). However, the prevalence of anti-TPO was not different between patients with NMOSD and healthy controls.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical features and thyroid dysfunction/autoimmunity in patients with NMOSD and healthy controls Controls
(N = 49)
(N = 392)
44.6 ± 15.6
Age at onset, year
40.4 ± 17.2
44.8 ± 15.1
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Age, year
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Demographic data and clinical features
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NMOSD
Sex (F:M)
43:06
0.922
344:48
1
2.2 ± 3.3
2.8 ± 2.1
<0.001
80.7 ± 26.8
116.8 ± 21.2
<0.001
1.2 ± 0.3
1.3 ± 0.2
0.422
137.0 ± 477.5
221.2 ± 1488.5
0.465
a
Definite NMO (%)
23 (47) b
2.0 (0.1-17.4)
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Disease duration, year
P value
Thyroid function test TSH (μIU/mL)
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Total T3 (ng/dL) Free T4 (ng/dL) Thyroid autoantibodies Anti-TPO antibody (U/mL)
180.3 ± 810.4
NA
†
NA†
0.1 (-7.7–13.9)
NA†
NA†
23 (46.9)
39 (9.9)
<0.001
Clinical hypothyroidism
2 (4.1)
1 (0.3)
0.034
Subclinical hypothyroidism
4 (8.2)
20 (5.1)
0.325
0 (0)
5 (1.3)
1
6 (12.2)
11 (2.8)
0.001
11 (22.4)
2 (0.5)
<0.001
10 (20.4)
45 (11.5)
0.075
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TBII (U) Prevalence of thyroid dysfunction/autoimmunity Thyroid dysfunction (%)
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Anti-Tg antibody (U/mL)
Clinical hyperthyroidism
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Subclinical hyperthyroidism Low T3 syndrome
Thyroid autoimmunity (%) Anti-TPO antibody positivity Anti-Tg antibody positivity
15/48 (31.3)
NA
†
NA†
0/48 (0)
NA†
NA†
TBII positivity
NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; F, female; M, male; TSH, thyroid-stimulating hormone; Anti-TPO positivity, anti-thyroperoxidase antibodies >60 U/mL; Anti-Tg positivity, anti-thyroglobulin antibodies >60 U/mL; Anti-TBII positivity, thyrotropin-binding inhibitory immunoglobulin >15% Values are expressed as means ± standard deviations or median (range) for continuous variables or numbers (%) for categorical variables. a
Patients meeting the revised diagnostic criteria for NMO(1)
b
Disease duration until a thyroid function test was performed.
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The values at the time of blood sampling.
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Tests for Anti-Tg antibody and Anti-TBII were not performed in healthy controls.
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Low T3 syndrome in patients with NMOSD After excluding patients with clinical hypothyroidism (N = 2) and those with
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previous thyroid cancer surgery (N = 2), 45 patients were divided into two subgroups based
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on T3 levels: low T3 (N = 11) and normal T3 (N = 34) (Table 2). The patients with low T3 syndrome included a higher proportion of patients during an attack and those on oral prednisolone and intravenous methylprednisolone, compared to those with normal T3 (p
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<0.001, p = 0.031, and p = 0.001, respectively). In addition, patients with low T3 syndrome showed a higher proportion of symptomatic spinal cord lesions and higher EDSS scores at the
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time of TFT and at the last visit than those with normal T3 levels (p = 0.023, p = 0.005, and p = 0.013, respectively). Other clinical features and serological findings did not differ
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significantly between the two groups.
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ACCEPTED MANUSCRIPT Table 2. Clinical and serologic features of patients with low T3 syndrome Patients with NMOSD (N = 45)a Without low T3 syndrome (N = 34)
P value
Age, years
44 (20–86)
44 (16–70)
0.926
Age at onset, years
42 (15–85)
37 (12–69)
0.663
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With low T3 syndrome (N = 11)
Female (%)
10 (90.9)
29 (85.3)
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During attack, yes (%)
10 (90.9)
7 (20.6)
<0.001
1.9 (0.1–12.1)
2.0 (0.1–17.5)
0.958
2.21 (0.01-11.13)
1.53 (0.08-11.99)
0.989
Interval from onset to sampling, years
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Interval from sampling to the last visit, years
0.7 (0.3–2.0)
0.7 (0.2–6.4)
0.499
EDSS score at sampling at the last visit Treatment at sampling
4.5 (3.0–9.0) 4.5 (2.5–9.5)
3.25 (0–9.5) 3.0 (0–8.0)
0.005 0.013
1 (9.1)
17 (50.0)
0.031
6 (54.5)
19 (55.9)
0.938
8 (72.7)
5 (14.7)
0.001
7 (63.6)
17 (50.0)
0.431
11 (100.0)
22 (64.7)
0.023
9/11 (81.8)
14/22 (63.6)
0.430
7 (63.6)
14 (41.2)
0.194
1/7 (14.3)
1/14 (7.1)
1
Anti-TPO antibody positivity
3 (27.3)
5 (14.7)
0.343
Anti-Tg antibody positivity
4 (36.4)
8 (23.5)
0.403
FANA
9 (81.8)
25 (73.5)
0.578
Elevated RF
3 (27.3)
6 (17.6)
0.488
ds-DNA
2 (27.3)
9 (26.5)
0.578
SSA or SSB
6 (54.5)
10 (29.4)
0.130
ANCA
0/10 (0)
5/24 (20.8)
0.291
Anti-cardiolipin Ab
0/5 (0)
3/20 (15.0)
1
Sjogren’s syndrome
3 (27.3)
6 (22.2)
0.488
SLE
1 (9.1)
4 (11.1)
1
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ARR
Oral prednisolone use (%)
Lesion at attack (%) Optic nerve Spinal cord Brain
≥6 segments
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LETM
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IV Methylprednisolone use (%)
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Immunosuppressive agents use (%)
Hypothalamic lesion
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Thyroid autoimmunity (%)
Associated autoantibodies (%)
Rheumatologic diseases (%)
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ACCEPTED MANUSCRIPT NMOSD, neuromyelitis optica spectrum disorder; ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; ; PI, progression index (EDSS/year); IV, intravenous; LETM, longitudinally extensive transverse myelitis; FANA, fluorescent antinuclear antibody; RF, rheumatoid factor; ds-DNA, double stranded DNA; SSA or SSB, anti-Ro/SSA or anti-La/SSB antibody; ANCA, anti-neutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus
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Values are expressed as median (ranges) for continuous variables or numbers (%) for categorical variables. a
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Excludes patients with clinical hypothyroidism (N = 2) and those with no available T3 levels (N = 2)
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Associations between T3 levels and disease disability and clinical
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disease activity
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Total T3 levels were significantly lower during an attack (median, 67.1 ng/dL; range,
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21.0 – 143.0) than in remission (median, 89.9 ng/dL; range, 63.3–142.4) (p = 0.003). In a multiple linear regression analysis, T3 levels were associated with age at sampling and clinical status (attack vs remission) (β = -0.55; p = 0.031 and β = -37.48; p = 0.008,
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respectively) (Table 3). In addition, T3 levels were inversely correlated with EDSS score at
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the last visit (ρ[rho] = -0.381, p = 0.013) and this persisted after adjustment for age, sex, clinical status (attack vs. remission), disease duration, steroid use, other immunosuppressive
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agents use, and the location of lesion (ρ = -0.416, p = 0.010) (Figure 1).
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ACCEPTED MANUSCRIPT Table 3. Multivariable linear regression analysis for the relationship between T3 levels and clinical features with neuromyelitis optica spectrum disorder
-8.98 (8.05) -10.00 (8.46)
0.272 0.245
-10.58 (7.71)
0.178
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Brain
0.052 1 0.364
-7.03 (7.64)
Lesion locations Optic nerve Spinal cord
0.008
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-23.28 (10.03) -0.63 (13.01) reference
Other immunosuppressive agents*
0.031 0.938 0.272
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-0.55 (0.25) 0.83 (10.60) 1.05 (0.94) -37.48 (13.40)
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Age at sampling Female Interval from onset to sampling During an attack Treatment at sampling Oral prednisolone use IV methylprednisolone use No steroid use
P value
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B (SE)
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Linear regression analysis adjusting for age at sampling, sex, interval from disease onset to sampling, clinical status of an attack or remission, lesion locations, the prednisolone use and other immunosuppressant use
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B, beta coefficient; SE, standard error; IV, intravenous
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*No use of other immunosuppressive agents was a reference category.
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Thyroid autoantibodies in patients with NMOSD We further compared patients with and without thyroid autoantibody (anti-TPO
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and/or anti-Tg) (Table e-1). No significant differences were observed between the two groups
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in demographics, clinical features, and laboratory findings. In addition, the proportion of LETM did not differ between patients with and without anti-TPO (N = 7/7, 100% vs N =
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21/33, 63.6%; p = 0.081).
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Discussion
We demonstrated that thyroid dysfunction, particularly low T3 syndrome, was frequently
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observed in patients with NMOSD, although the prevalence of anti-TPO antibody was not
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different between patients and healthy controls. In our healthy controls, the overall prevalence of thyroid dysfunction was 9.9%, which was similar to 11.8% in a previous study
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of healthy Korean subjects.(18) Low T3 syndrome has been reported in various acute and chronic systemic conditions(19); particularly, the prevalence of low T3 syndrome was
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reported as 3% to 16.7% in patients with SLE and 2.8% in patients with MS.(20-22) We found that low T3 syndrome was much frequently observed in NMOSD patients (20.4%), even compared to the previous reports of SLE and MS.(20-22) Previous studies showed that glucocorticoids can lower serum TSH levels and decrease TSH secretion,(23) and high-dose dexamethasone caused a decrease in serum T3 levels within several days.(24) Although 70% of our patients had been treated with oral prednisolone or methylprednisolone, T3 levels were not affected by the steroid use in a multiple regression analysis. Serum T3 levels of NMOSD patients were lower during attack than in remission and were associated with clinical attack even after controlling for potential confounding factors. This is 17
ACCEPTED MANUSCRIPT consistent with findings from a previous study of SLE, where there was a significant association between SLE disease activity and low T3 syndrome (25) Several underlying
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mechanisms of low T3 syndrome have been suggested, including hypothalamic-pituitary-
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thyroid (HPT) axis modification as a cause of central hypothyroidism.(26) Although lesions
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involving the hypothalamus are characteristic of NMOSD,(27) a hypothalamic lesion was observed in only one patient with low T3 syndrome in our study. As another mechanism, IL-6
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has been reported to play an additional role in low T3 syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.(28) Previously, a
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negative correlation between serum T3 levels and IL-6 levels have been observed in hospitalized patients with various medical conditions.(29) In NMOSD, it was reported that
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cerebrospinal fluid IL-6 levels were elevated during relapse (30) and that IL-6-dependent B-
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cell subpopulation is involved in the pathogenesis of the disease.(31-33) We also observed an
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inverse correlation between T3 levels and EDSS scores in NMOSD patients, which is congruous with a recent report showing that the release of IL-6 and IL-21 by activated CD4+ T cells was correlated directly with EDSS scores in patients with NMO.(34) Still, it remains
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to be elucidated that low T3 level predispose to NMOSD and modify disease disability or is an epiphenomenon of disease process. However, the association between low T3 levels and EDSS scores at the last visit may imply that patients with low T3 syndrome need early and aggressive treatment, such as plasmapheresis or adjunctive treatments with thyroxin or T3.(35) Otherwise, the therapy targeting anti-inflammatory cytokine, IL-6, such as tocilizumab, may result in the suppression of T3 levels and improve the disease disability in NMOSD. In our patients, the rates of anti-TPO (20.4%) and anti-Tg antibody (31.3%) positivity 18
ACCEPTED MANUSCRIPT were similar with previous studies; anti-TPO and anti-Tg antibody positivity rates were 20.9– 49.0% and 27.9–38.8% in patients with AQP4-ab, which were significantly higher than those
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observed in patients with MS or healthy controls.(36-38) Recently, the associations between
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anti-thyroid antibodies and myelitis occurrence, EDSS scores or cord lesion severity have
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been suggested in patients with NMOSD, (36, 38) which were not observed in our study. Our study has several limitations; first, this was a retrospective analysis of registry-based
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data at a single hospital, which might have led to unintentional bias. In addition, we included a single ethnic population and did not consider genetic heterogeneity.
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In conclusion, thyroid dysfunction, particularly low T3 syndrome, occurs frequently in patients with NMOSD. We suggest that serum T3 levels may be a useful indicator of disease
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activity and disability in NMOSD, although the causal relationship is unclear. To elucidate
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the pathophysiologic and therapeutic role of T3 in NMOSD, large-scale prospective studies
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with serial analysis of thyroid hormones during relapse and remission will be needed.
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Acknowledgements
This working was supported by Korea Centers for Disease Control and Prevention (No. 2014-E63004-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
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Figure Legend Figure 1. Relationships of T3 levels with the Expanded Disability Status Scale (EDSS)
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scores in patients with neuromyelitis optica spectrum disorder (NMOSD) An inverse correlation was observed between T3 levels and the EDSS scores at the last visit
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in patients with NMOSD. Although the correlation coefficient (ρ) and p value were calculated using the Spearman rank correlation, the linear regression line is presented in this graph. The
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dashed lines represent the 95% confidence limits.
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ρ, Spearman correlation coefficient
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ACCEPTED MANUSCRIPT Highlights (3~5 개) The levels of thyroid hormones and anti-thyroid antibodies were measured from 49 patients with seropositive NMOSD and 392 healthy subjects.
Low T3 syndrome was the most frequent thyroid dysfunction and T3 levels were inversely correlated with EDSS scores in NMOSD patients.
Serum T3 levels may be a useful indicator of disease activity and disability in NMOSD.
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