The Egyptian Rheumatologist 45 (2023) 111–114

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The Egyptian Rheumatologist

journal homepage: www.elsevier.com/locate/ejr

Thyroid dysfunction and anti-thyroid antibodies in systemic sclerosis

patients
Nermeen A. Khairy, Mohamed M. El-Wakd, Reham M. Amin, Hanaa M. Rady ⇑,1
Rheumatology Department, Faculty of Medicine, Cairo University, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Aim of the work: To assess the frequency of thyroid dysfunction and thyroid auto-antibodies in systemic
Received 28 November 2022 sclerosis (SSc) patients.
Accepted 29 November 2022 Patients and methods: This study included thirty-three SSc patients and 30 matching controls. Thyroid
Available online 13 December 2022
stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti thyroglobulin (ATG)
and anti thyroid peroxidase autoantibodies (ATPO) were measured in the sera of patients and controls.
Keywords: Results: The mean age of the patients was 45.9 ± 13.05 years; 28 females and 5 males (F: M 5.6:1) and a
Thyroid dysfunction
disease duration of 4.58 ± 3.84 years. The FT3, FT4, TSH tended to be higher in patients (T3: 2.8 ± 0.66 pg/
Systemic sclerosis (SSc)
Antithyroglobulin (anti antibodies (ATG))
ml; T4: 1.5 ± 0.65 ng/ml; TSH: 1.9 ± 2.1 ul/ml) than in controls (p = 0.07, p = 0.21 and p = 0.24 respec-
Anti thyroid peroxidase antibodies (ATPO) tively) while the ATG level in patients was 40 ± 21.3 IU/ml and ATPO 36.7 ± 88.2 IU/ml. Four patients
had hypothyroidism (12 %); 3 (9 %) subclinical hypothyroidism (SCHT) and 1 (3 %) clinical hypothy-
roidism (CHT). ATG was positive in one patient and in 2 controls while ATPO was positive in two patients
compared to one control. Both antibodies were positive in one patient. ATPO was associated with SCHT in
one (3 %) and with overt hypothyroidism in another (3 %). The thyroid profile, ATG and ATPO were com-
parable between females and males (p = 0.34, p = 0.23, p = 0.96, p = 0.77 and p = 0.35 respectively) and all
were similar between lcSSc and dcSSc except TSH (lower in dcSSc; p = 0.03). Muscle weakness was sig-
nificantly higher among ATPO positive patients (p = 0.005) while thyroid dysfunction was significantly
associated with arthralgia (p = 0.007).
Conclusion: Thyroid dysfunction mainly hypothyroidism is more frequent among SSc patients.
Ó 2022 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction in > 30 % of patients with connective tissue diseases such as

Systemic sclerosis (SSc) is a chronic disabling disorder charac-
terized by three key features: obliterative and proliferative
microvascular involvement, immune system activation and
increase of extracellular matrix deposition in skin and internal
organ [1]. Numerous rheumatic disorders, including SSc, have been
linked to thyroid dysfunction, particularly subclinical hypothy-
roidism (SCHT) [2].
Autoimmune thyroid disorders (AITD) include systemic or
organ specific autoimmune disorders characterized by the pres-
ence of anti-thyroid autoantibodies, such as antithyroglobulin
(ATG) and anti-thyroid peroxidase (ATPO) antibodies in addition
to endocrinal dysfunction (hypo- or hyperthyroidism) [3,4]. AITD
is the most common autoimmune endocrinal disease [5]. It has
been found that antithyroid autoantibodies can be detected
⇑ Corresponding author.
E-mail address: hanaarady@kasralainy.edu.eg (H.M. Rady).
1
ORCID: 0000-0003-0097-4553.
rheumatoid arthritis [6,7] systemic lupus erythematosus [8,9]
and Sjogren’s syndrome [10]. Thyroid affection as a less life-
threatening organ involvement in connective tissue diseases is
often underestimated and passes undetected for long contributing
to disease morbidity [9]. It has been linked to increased cardiovas-
cular risk [11–13] and musculoskeletal related morbidity [9].
The aim of this study was to estimate the frequency of thyroid
dysfunction and anti-thyroid antibodies in Egyptian SSc patients
and their association to clinical manifestations of the disease.
2. Patients and methods
This cross sectional case–control study included 33 SSc patients
fulfilling the 2013ACR/EULAR (American College of Rheumatology/
European League Against Rheumatism) SSc classification criteria
[14] and 30 healthy age and sex matched controls. Patients were
subdivided into two cutaneous subsets according to the criteria
reported by LeRoy et al [15]; limited cutaneous (lcSSc) and diffuse

https://doi.org/10.1016/j.ejr.2022.11.008
1110-1164/Ó 2022 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
N.A. Khairy, M.M. El-Wakd, R.M. Amin et al. The Egyptian Rheumatologist 45 (2023) 111–114

cutaneous (dcSSc). The patients were recruited from Rheumatol- Table 1

ogy and Rehabilitation Department outpatient clinic, Faculty of Clinical manifestations of the systemic sclerosis patients.

Medicine, Cairo University hospitals. Patients with thyroid malig- Manifestation n (%) SSc patients (n = 33)
nancy, thyroidectomy and those who were pregnant were Raynaud’s phenomena 33 (100)
excluded from the study. This study was approved by the local Fatigue 19 (57.6
ethics committee. Informed consent was obtained from all patients Weight loss 24 (72.7
Cutaneous 33 (100)
and controls. Sclerodactyly 29 (87.9)
Full history taking, clinical examination and relevant laboratory Digital ulcer 23 (69.7)
investigations were done to all patients. The modified Rodnan skin Digital pitting scar 16 (48.5)
thickness score (mRss) was evaluated [16]. High resolution com- Digital gangrene 9 (27.3)
Skin pigmentation 11 (33)
puterized tomography (HRCT) and echocardiography were per-
Telangiectasia 6 (18.2)
formed to the patients. Calcinosis 6 (18.2)
Free triiodothyronine (FT3), free thyroxine (FT4) and thyroid Cardio-Pulmonary 26 (78.8)
stimulating hormone (TSH) were measured by microplate enzyme Dyspnea 25 (75.8)
linked immunosorbant assay (ELISA). Values from 1.3 to 5 pg/ml, Interstitial lung disease 21 (63.6)
Pulmonary hypertension 6 (18)
0.8–2 ng/dl and 0.4–4 ul/ml were considered normal respectively.
Pericardial effusion 2 (6)
Clinical and subclinical hypothyroid were defined as having ele- Gastrointestinal 24 (72.7)
vated TSH with low and normal thyroid hormone levels respec- Distal dysphagia 19 (57.5)
tively. Clinical and subclinical hyperthyroid were used to Proximal dysphagia 14 (42.4)
Constipation/Diarrhea 0 (0)
describe low TSH with elevated and normal thyroid hormones,
Musculoskeletal 21 (63.6)
respectively [17]. Arthralgia 21 (63.6)
The ATG and ATPO were measured in the sera of patients and Arthritis 6 (18.2)
controls by indirect solid phase ELISA for the quantitative measure- Muscle weakness 3 (9.1)
ment of IgG class autoantibodies. Ranges below 100 IU/ml were Fibromyalgia 5 (15.2)
Secondary Sjögrens 5 (15.2)
considered normal those above 150 IU/ml were elevated levels
mRss 15.4 ±7.9
for ATG while those for ATPO were 50 and 75 IU/ml respectively.
Statistical analysis: Statistical Package for Social Science (SPSS) SSc: systemic sclerosis. mRss: modified Rodnan skin thickness score.
program version 15 was used. Data were presented as mean and
standard deviation or numbers and percentages. Student’s–t test
Table 2
or Chi-square (v2)–test was used to compare between two groups. Laboratory investigations of the systemic sclerosis patients.
Spearmans correlation was done. Significance was considered at
Parameter n (%) SSc patients (n = 33)
p < 0.05.
ESR (mm/1st hr) 42.4 ± 24.2 (10–117)
Hb (g/dl) 11.8 ± 1.9 (6.8–11.5)
WBC (x103/mm3) 8 ± 2.4 (4–14)
Platelets (x103/mm3) 302.6 ± 95.9 (145–553)
3. Results Proteinuria 2 (6.1)
AST (U/L) 20.1 ± 6.2 (10–39)
The study included 33 SSc patients with a mean age of ALT (U/L) 18.2 ± 9.3 (7–42)
45.9 ± 13.05 (21–69) years; 28 females and 5 males (F:M 5.6:1) CPK (mg/dl) 53.1 ± 41.3 (0–135)
Creatinine (mg/dl) 0.79 ± 0.55 (0.4–3)
and a disease duration of 4.58 ± 3.84 (1–20) years and an age at
ANA 17 (51.5)
disease onset of 41.36 ± 12.2 (19–64) years. The 30 controls were FT3 (pg/ml) 2.8 ± 0.66 (1–4.3)
of matched age (43.7 ± 13.79; 20–66, years) and gender F:M FT4 (ng/ml) 1.5 ± 0.65 (0.5–3.8)
26:4; 6.5:1). Twenty-six patients (78.8 %) had lcSSc while seven TSH (ul/ml) 1.9 ± 2.1 (0.4–11)
(21.2 %) had dcSSc. Clinical manifestations and laboratory investi- Anti-TG (IU/ml) 40 ± 21.3 (21.4–120)
Anti-TPO (IU/ml) 36.7 ± 88.2 (7.8–400.9)
gations of the patients are shown in Tables 1 and 2. The muscle
power of the patients was normal in 5 patients and grade 4 in 28 ESR: erytherocyte sedimetnation rate, Hb: hemoglobin, WBC; white blood cell, AST:
(84.8 %). HRCT was abnormal in 20 (60.6 %) and the echocardiogra- aspartate transaminase, ALT: alanine transaminase, CPK: creatine phosphokinase,
ANA: antinuclear antibody, FT3: free triiodothyronine, FT4: free thyroxine, TSH:
phy abnormal in 10 (30.3 %). The FT3, FT4, TSH tended to be higher thyroid stimulating hormone, ATG: antithyroglobulin (ATG), ATPO: anti-thyroid
in patients than in controls (T3: 2.47 ± 0.71 pg/ml; T4: 1.39 ± 0.4 peroxidase.
7 ng/ml; TSH: 1.45 ± 0.7 ul/ml; p = 0.07, p = 0.21 and p = 0.24
respectively). Twenty-nine (87.9 %) of patients were euthyroid, 3
(9 %) had SCHT and 1 (3 %) had overt hypothyroidism while all was significantly lower in the dcSSc (1 ± 0.57 ul/ml) compared to
the controls were euthyroid. All patients with hypothyroidism lcSSc (2.2 ± 2.4 ul/ml; p = 0.03).
were of lcSSc type. Regarding musculoskeletal manifestations, patients who were
Serum ATPO and ATG antibodies were observed in 4 (12 %) ATPO positive had significantly higher frequency of muscle weak-
patients; 2 (6 %) with ATPO, 1 (3 %) with ATG and another (3 %) ness (33.3 % vs 6.7 %, p = 0.005). Patients with hypothyroidism
with both. They were positive in 3 (9.9 %) controls with ATPO in had significant higher frequency of arthralgia (100 % vs 58.8 %,
1 (3.3 %) and 2 with ATG (6.6 %). ATG was associated with euthy- p = 0.007). The 4 patients with thyroid dysfunction all had muscu-
roid in one (3 %) patient, ATPO antibody was associated with SCHT loskeletal manifestations. The T4, TSH, ATG and ATPO were compa-
in another (3 %) and with overt hypothyroidism in one patient rable between those with and without cardiopulmonary
(3 %). Both antibodies were associated with euthyroid in one manifestations (p = 0.67, p = 0.69, p = 0.56 and p = 0.25) while
patient. The thyroid profile (T3, T4, TSH), ATG and ATPO were com- the T3 was significantly lower in those with cardiopulmonary
parable between females and males (p = 0.34, p = 0.23, p = 0.96, manifestations (2.7 ± 0.62 pg/ml) compared to those without (3.3
p = 0.77 and p = 0.35 respectively). The thyroid profile (T3, T4), ± 0.61 pg/ml; p = 0.036).
ATG and ATPO were comparable between lcSSc and dcSSc
(p = 0.24, p = 0.17, p = 0.32, p = 0.13 respectively) while the TSH
112
N.A. Khairy, M.M. El-Wakd, R.M. Amin et al.
There was no significant correlation between the measured
parameters (T3, T4, TSH, ATG and ATPO) with the age, disease
duration or mRss.
4. Discussion
Systemic sclerosis (SSc) is a systemic autoimmune disease in
which gastrointestinal disorders represent a complication in up
to 90 % of patients. SSc may associate with thyroid autoimmune
disorders [18]. In this study, there were 78.8 % with lcSSc and
21.2 % dcSSc which is in line with another Egyptian study on SSc
with 61.8 % lcSSc and 38.2 % dcSSc [19] while the mRss was much
lower. Thyroid involvement in SSc is an overlooked issue,thyroid
autoantibodies are a cause of its dysfunction [20]. A previous study
found hyperthyroidism to be highly prevalent among SSc patients
and can inversely impact their survival. Accordingly, a preventative
screening may be necessary for all SSc patients and more research
is needed to determine if optimal treatment and good control of
hyperthyroidism may result in a reduction of all-cause mortality
in patients with SSc. [21].
Thyroid dysfunction, in particular SCHT, has been frequently
reported in association with several rheumatic diseases, including
SSc [22]. In the present study, thyroid dysfunction was found in
12 % of the SSc patients and none of the 30 controls. All of the
patients had hypothyroidism: three subclinical and one overt.
ATG was positive in one of them while ATPO was positive in two.
All patients with hypothyroidism were of lcSSc subtype. Kahl and
colleagues [23] evaluated thyroid dysfunction in SSc patients and
found that 10 % were hypothyroid and antithyroid antibodies were
present in 50 % of the hypothyroid patients. Paolee et al., [24]
reported SCHT in 11 % of Thai SSc patients and CHT in 4.5 %. Inno-
cencio and colleauges found hypothyroidism comparable between
SSc patients and control [25]. In another study clinical hypothy-
roidism was (4 % vs 0.3 %), SCHT (17 % vs 6 %) and were more com-
mon in female scleroderma subjects than controls [26]. These are
higher than reported in the present study which could be due to
the larger number of studied patients but ATPO antibodies were
not significantly different between hypothyroid and euthyroid
patients which are in harmony with the current findings. Previous
studies reported prevalence of primary hypothyroidism between
10 and 14 % in SSc (13.8 % in Japan, 10–14 % in the United States,
and 9.4 % in New Zeeland) [27–30]. In a study of 138 patients with
scleroderma, ATPO antibodies were increased in patients with
lcSSc, whereas the levels of these antibodies in patients with dcSSc
were similar to those in healthy controls [31]. In previous studies,
the proportion of antithyroid antibodies varied from 12 to 52 %
[26,27,31]. The use of immunosuppressive drugs and corticos-
teroids in SSc, as well as the diversity of the examined groups in
terms of gender and age, may at least in part account for this wide
range.
In the present study, arthralgia was present in 63.6 % and arthri-
tis in 18.2 % of the patients while fibromyalgia syndrome was
shown in 15.2 %. In a previous study on Egyptian SSc patients,
arthritis was present in 37.5 % [32] and FMS was reported in only
6.7 % [33]. Patients with thyroid dysfunction had higher prevalence
of arthralgia compared to euthyroid patients. ATPO was associated
with higher prevalence of muscle weakness. A previous study on a
cohort of Egyptian SLE patients found significantly higher fre-
quency of arthritis and fibromyalgia among patients with SCHT [9].
Cardiopulmonary manifestations were present in 78.8 %; inter-
stitial lung disease (ILD) in 63.6 % and pulmonary hypertension in
18 %. In line, in a previous study on Egyptian SSc, ILD was present
in 54.8 % and pulmonary hypertension in 35.7 % [34]. The T4, TSH,
ATG and ATPO were comparable between patients with and with-
113
The Egyptian Rheumatologist 45 (2023) 111–114
out cardiopulmonary manifestations however T3 was significantly
decreased.
Interestingly, there is a notable high prevalence of thyroid dis-
orders in patients with SSc and SSc is associated with increased
risks of thyroid dysfunction. Considering that thyroid autoimmune
diseases and SSc might share same autoimmune elements, it is
likely that these diseases could coexist in the same patient [35].
The present study has some limitations as the small size of the
sample and lack of follow up or detailed analysis in relation to the
medications received.
In conclusion, thyroid dysfunction mainly hypothyroidism is
more frequent among SSc patients and can be related to increased
musculoskeletal manifestations.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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