Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2020 Apr 16;15(4):e0231622. doi: 10.1371/journal.pone.0231622

Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE

Xin Zhang 1, Lirong Liu 1,2, Xiaolei Ma 1, Wei Hu 3, Xue Xu 1, Saisai Huang 1, Bingzhu Hua 1, Hong Wang 1, Zhiyong Chen 1,*, Lingyun Sun 1,*
Editor: Deyu Fang4
PMCID: PMC7162454  PMID: 32298352

Abstract

Objectives

Nonthyroidal illness syndrome (NTIS), also known as low triiodothyronine (T3) syndrome, frequently affects patients with systemic lupus erythematosus (SLE) and may affect lipid metabolism. Dyslipidemia is highly prevalent and associated with the long-term prognosis of SLE. The aim of the present study was to explore the clinical significance of NTIS on disease activity and dyslipidemia in patients with SLE.

Methods

Clinical and laboratory data were collected retrospectively from 223 patients with SLE. The correlation between free triiodothyronine (FT3), SLE disease activity, and lipid profiles were estimated. The correlation coefficient (r) was calculated using a Pearson’s regression model. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for dyslipidemia in SLE.

Results

Serum FT3 levels were negatively correlated with the levels of 24 h urine protein (UP), blood urea nitrogen (BUN), creatinine (Cr) and SLE disease activity index (SLEDAI) (all p < 0.001) in NTIS patients but not in euthyroid patients. ApoB/ApoA1 was significantly correlated with SLEDAI (p < 0.01) in NTIS patients and CRP (p < 0.001) and ESR (p < 0.01) in euthyroid patients. A multivariate analysis revealed that only FT3 exhibited an independent negative association with dyslipidemia (P = 0.01; OR = 0.48; 95% CI 0.27–0.85).

Conclusion

NTIS frequently occurs in patients with SLE. Low FT3 is associated with disease activity in SLE patients complicated with NTIS. Low FT3 is an independent risk factor for dyslipidemia in patients with SLE.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production in women of childbearing age [1]. Dyslipidemia, characterized as increased total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and/or decreased high-density lipoprotein (HDL) levels in the serum, is prevalent in SLE patients with an incidence ranging between 18.1% and 75% [2]. Importantly, dyslipidemia is associated with disease activity (e.g., kidney damage and cardiovascular disease), and is closely related to the long-term prognosis of SLE patients [2–4]. Nonthyroidal illness syndrome (NTIS; also known as low triiodothyronine [T3] syndrome or euthyroid sick syndrome) is also prevalent in SLE and characterized by decreased serum T3, normal to low thyroxine (T4), and thyroid-stimulating hormone (TSH) levels [5–7]. The aim of the present study was to explore the prevalence and clinical significance of NTIS in a Chinese cohort with SLE. We hypothesized that as a critical metabolic hormone, low FT3 levels may be associated with disease activity and the lipid profile in patients with SLE.

Materials and methods

Participants and data collection

A single-center, observational and cross-sectional study was performed. A total of 271 patients hospitalized at the Affiliated Drum Tower Hospital of Nanjing University Medical School (Nanjing, China) from Dec. 2015 to Apr. 2017 were recruited consecutively (if informed consent was obtained). Clinical and laboratory data were collected retrospectively from medical records. All patients included in the analysis were informed and agreed to participate in this research. The study protocol was approved by the Ethics Review Committee of the Affiliated Drum Tower Hospital.

All SLE patients fulfilled the American College of Rheumatology (ACR) classification criteria for SLE (2009). Forty-eight patients who had a history of familial hyperlipidemia and/or thyroid disease, diabetes mellitus, and/or other rheumatic diseases, and those who took lipid-lowering agents or thyroid medications were excluded. Eventually, 223 patients were enrolled in this study. The SLE disease activity index (SLEDAI) was assessed by qualified rheumatology specialists (B.H., H.W. and Z.C.). Dyslipidemia was defined according to the Chinese guidelines for the management of dyslipidemia in adults (i.e., TC ≥ 5.2 mmol/L; TG ≥ 2.3 mmol/L; HDL < 1.0 mmol/L; LDL ≥ 4.1 mmol/L) [8].

The thyroid hormones, including free T3 (FT3), free thyroxine (FT4), and TSH were measured using a commercially available electrochemiluminescence (ECLIA) kit (Roche). The normal ranges were considered to be: 3.1–6.8 pmol/L for FT3; 12–22 pmol/L for FT4; and 0.27–4.2 mU/L for TSH. The following criteria for NTIS were applied in this study: FT3 less than 3.1 pmol/L; normal to low FT4; and normal TSH levels [9].

Statistical analysis

All continuous variables are presented as the mean ± standard deviation (SD). Categorical variables were compared using a chi-square test. Independent-sample t-tests were used to compare continuous normally distributed variables. Values that were not normally distributed were evaluated using a Mann-Whitney U test. The correlation coefficient (r) was calculated using a Pearson’s regression model. Variables for the risk of dyslipidemia were identified by univariate and multivariate logistic regression analyses using the following parameters: sex, age at entry into the study, the levels of FT3, FT4, TSH, creatinine (Cr), blood urea nitrogen (BUN), 24 h urine protein (24 h UP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), SLEDAI, and dose of glucocorticoids (calculated using the equivalent dose of methylprednisolone) at the time of sampling. The results were presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). A p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software (ver. 24.0, SPSS Inc, Chicago, IL) or Prism (GraphPad Software, San Diego, CA).

Results

As shown in Table 1, the incidence of NTIS in SLE patients in this study was 58.7% (131/223). There is no statistically significant difference between SLE patients in the euthyroid and NTIS groups regarding age, sex, and positive rates of anti-nuclear antibodies (ANA), anti-Sm antibodies, anti-dsDNA antibodies, and the duration of glucocorticoid treatment. The levels of FT3 (2.3 ± 0.6 pmol/L vs. 4.1 ± 0.7 pmol/L), FT4 (13.6 ± 3.3 pmol/L vs. 15.9 ± 2.3 pmol/L), and TSH (1.4 ± 0.9 mU/L vs. 1.8 ± 1.0 mU/L) were significantly decreased in patients in the NTIS group compared to those in the euthyroid group (all p < 0.001). Clinical indexes, including 24 h UP (2340.9 ± 3217.4 mg vs. 752.1 ± 863.6 mg; p < 0.001), BUN (7.8 ± 5.4 mmol/L vs. 5.0 ± 2.0 mmol/L; p < 0.001), Cr (76.1 ± 69.7 μmol/L vs. 55.0 ± 34.7 μmol/L; p < 0.01), uric acid (331.6 ± 143.5 μmol/L vs. 295.1 ± 109.0 μmol/L; p < 0.05), CRP (21.5 ± 38.9 mg/L vs. 11.9 ± 23.2 mg/L; p < 0.05), ESR (55.1 ± 33.1 mm/h vs. 32.8 ± 27.6 mm/h; p < 0.001), and SLEDAI (8.5 ± 4.6 vs. 4.0 ± 3.6; p < 0.01) displayed an obvious increase in SLE patients with NTIS compared to the euthyroid group. Regarding lipid profiles, we found that SLE patients with NTIS had a substantially higher TG (1.9 ± 1.3 mmol/L vs. 1.46 ± 0.8 mmol/L; p < 0.01), TC (4.9 ± 1.9 mmol/L vs. 4.3 ± 0.9 mmol/L; p < 0.01), LDL (2.8 ± 1.4 mmol/L vs. 2.3 ± 0.7 mmol/L; p < 0.01), apolipoprotein B (ApoB) (1.1 ± 0.5 g/L vs. 0.8 ± 0.2 g/L; p < 0.001), ApoB/apolipoprotein A1 (ApoA1) (1.1 ± 0.03 vs. 0.7 ± 0.02; p < 0.001), as well as considerably lower HDL (1.0 ± 0.4 mmol/L vs. 1.2 ± 0.6 mmol/L; p < 0.01) levels compared with patients in the euthyroid group. However, the ApoA1 levels were comparable between these two groups.

Table 1. Comparison of the characteristics of SLE patients with and without NTIS.

Characteristic SLE P value
Without NTIS (n = 92) With NTIS (n = 131)
Age, years 36.9 ± 12.6 36.7 ± 13.8 NS
Male/Female, no. 10/82 6/125 NS
ANA positive, no. (%) 91 (99) 116 (89) NS
Anti-Sm positive, no. (%) 21 (22.8) 33 (25.2) NS
Anti-dsDNA positive, no. (%) 30 (32.6) 50 (38.2) NS
Duration of glucocorticoid treatment, months 12.3 ± 2.4 14.5 ± 2.9 NS
FT3, pmol/L 4.1 ± 0.7 2.3 ± 0.6 < 0.001
FT4, pmol/L 15.9 ± 2.3 13.6 ± 3.3 < 0.001
TSH, mU/L 1.8 ± 1.0 1.4 ± 0.9 < 0.001
24 h UP, mg 752.1 ± 863.6 2340.9 ± 3217.4 < 0.001
BUN, mmol/L 5.0 ± 2.0 7.8 ± 5.4 < 0.001
Cr, μmol/L 55.0 ± 34.7 76.1 ± 69.7 < 0.01
UA, μmol/L 295.1 ± 109.0 331.6 ± 143.5 < 0.05
CRP, mg/L 11.9 ± 23.2 21.5 ± 38.9 < 0.05
ESR, mm/h 32.8 ± 27.6 55.1 ± 33.1 < 0.001
SLEDAI 4.0 ± 3.6 8.5 ± 4.6 < 0.01
TG, mmol/L 1.46 ± 0.8 1.9 ± 1.3 < 0.01
TC, mmol/L 4.3 ± 0.9 4.9 ± 1.9 < 0.01
HDL, mmol/L 1.2 ± 0.6 1.0 ± 0.4 < 0.01
LDL, mmol/L 2.3 ± 0.7 2.8 ± 1.4 < 0.01
ApoA1, g/L 1.0 ± 0.3 1.0 ± 0.5 NS
ApoB, g/L 0.8 ± 0.2 1.1 ± 0.5 < 0.001
ApoB/ApoA1 0.7 ± 0.02 1.1 ± 0.03 < 0.001
Open in a new tab

Values are presented as the mean ± SD unless otherwise indicated; ANA = anti-nuclear antibody; FT3 = free triiodothyronine; FT4 = free thyroxine; TSH = thyroid stimulating hormone; 24 h UP = 24 h urine protein; BUN = blood urea nitrogen; Cr = creatinine; UA = uric acid; CRP = C reactive protein; ESR = erythrocyte sedimentation rate; SLEDAI = systemic lupus erythematosus disease activity index; TG = triglyceride, TC = total cholesterol, HDL = high-density lipoprotein, LDL = low-density lipoprotein, ApoA1 = apolipoprotein A1, ApoB = apolipoprotein B; NS = not significant.

We further explored the relationship between the associated parameters and lipid profiles for thyroid hormones and SLE disease activity in patients with or without NTIS. A regression analysis revealed that the FT3 levels were negatively correlated with 24 h UP (r = -0.301; p < 0.001; Fig 1A), BUN (r = -0.325; p < 0.001; Fig 1B), Cr (r = -0.298; p < 0.001; Fig 1C), as well as SLEDAI (r = -0.313; p < 0.001; Fig 1F). However, these correlations were not observed in patients without NTIS (Fig 2A–2C and 2F). In addition, FT3 were negatively correlated with CRP in both NTIS patients (r = -0.200; p < 0.05; Fig 1D) and euthyroid patients (r = -0.254; p < 0.05; Fig 2D), and were negatively correlated with ESR (r = -0.27; p < 0.05; Fig 2E) in NTIS patients rather than in euthyroid patients (Fig 1E). These results indicate that low levels of FT3 are closely related to a higher SLE disease activity primarily in NTIS patients rather than in euthyroid patients.

Fig 1.

Fig 1

Open in a new tab

Correlation between free triiodothyronine (FT3) and 24 h urine protein (UP) (A), blood urea nitrogen (BUN) (B), creatinine (Cr) (C), C reactive protein (CRP) (D), erythrocyte sedimentation rate (ESR) (E), and systemic lupus erythematosus disease activity index (SLEDAI) (F) in patients with NTIS.

Fig 2.

Fig 2

Open in a new tab

Correlation between free triiodothyronine (FT3) and 24 h urine protein (UP) (A), blood urea nitrogen (BUN) (B), creatinine (Cr) (C), C reactive protein (CRP) (D), erythrocyte sedimentation rate (ESR) (E), and systemic lupus erythematosus disease activity index (SLEDAI) (F) in euthyroid patients.

There is increasing evidence to show that the atherogenic ApoB/ApoA1 ratio is an independent prospective predictor of cardiovascular events both in the general population and in patients with rheumatic diseases [10–13]. We also found that the ApoB/ApoA1 ratio was significantly associated with SLEDAI (r = 0.251; p < 0.01; Fig 3E) but not with CRP, ESR, Cr, or 24 h UP (Fig 3A–3D) in NTIS patients. In euthyroid patients, the ApoB/ApoA1 ratio was significantly associated with CRP (r = 0.428; p < 0.001; Fig 4A) and ESR (r = 0.315; p < 0.01; Fig 4B), but not with Cr, 24 h UP and SLEDAI (Fig 4C, 4D and 4F). These results indicate that the atherogenic ApoB/ApoA1 ratio are somewhat related to the SLE disease activity in NTIS patients, as well as immunologic inflammation in euthyroid patients.

Fig 3.

Fig 3

Open in a new tab

Correlation between the atherogenic ApoB/ApoA1 ratio and C reactive protein (CRP) (A), erythrocyte sedimentation rate (ESR) (B), creatinine (Cr) (C), 24 h urine protein (UP) (D), and systemic lupus erythematosus disease activity index (SLEDAI) (E) in patients with NTIS.

Fig 4.

Fig 4

Open in a new tab

Correlation between the atherogenic ApoB/ApoA1 ratio and C reactive protein (CRP) (A), erythrocyte sedimentation rate (ESR) (B), creatinine (Cr) (C), 24 h urine protein (UP) (D), and systemic lupus erythematosus disease activity index (SLEDAI) (E) in euthyroid patients.

Since dyslipidemia was found to be more prevalent in SLE patients with NTIS and correlated with SLE disease-related parameters and poor long-term survival [4], we performed a multivariate logistic analysis to determine whether the level of FT3 was independently associated with the presence of dyslipidemia in patients with SLE. As shown in Table 2, the following factors with a p value less than 0.1 in the univariate analysis underwent a multivariate analysis: FT3, FT4, BUN, CRP, ESR, SLEDAI, and the glucocorticoid dose. Among these factors, only FT3 showed an independent negative association with dyslipidemia (p = 0.01; OR = 0.48; 95% CI 0.27 ‒ 0.85).

Table 2. Results of the univariate and multivariate logistic analyses for factors associated with dyslipidemia in patients with SLE.

Variables Univariate analysis Multivariate analysis
P OR 95% CI P OR 95% CI
Gender 0.82 0.88 0.29–2.63
Age 0.78 1 0.98–1.03
FT3 <0.001 0.52 0.39–0.70 0.01 0.48 0.27–0.85
FT4 0.05 0.91 0.82–1.00 0.71 1.03 0.88–1.21
TSH 0.71 1.06 0.78–1.44
Cr 0.31 1 0.99–1.01
BUN 0.04 1.09 1.00–1.19 0.82 1.02 0.90–1.15
24 h UP 0.33 1 1.00–1.00
CRP 0.04 1.02 1.00–1.04 0.97 1.00 0.98–1.02
ESR 0.001 1.02 1.01–1.03 0.06 1.02 0.99–1.03
SLEDAI 0.08 1.07 0.99–1.16 0.54 0.97 0.88–1.07
Dose of glucocorticoid 0.05 1.02 1.00–1.03 0.97 1.00 0.98–1.02
Open in a new tab

FT3 = free triiodothyronine; FT4 = free thyroxine; TSH = thyroid stimulating hormone; Cr = creatinine; BUN = blood urea nitrogen; 24 h UP = 24 h urine protein; FGB = fasting blood glucose; CRP = C reactive protein; ESR = erythrocyte sedimentation rate; SLEDAI = systemic lupus erythematosus disease activity index.

Discussion

In the present study, NTIS was found to occur with a high frequency in SLE patients (58.7%). We also observed that the level of FT3 was closely associated with the level of 24 h UP, Cr, BUN, and SLEDAI. These correlations were primarily found in NTIS patients compared to euthyroid patients, which suggests a common pathogenesis between SLE and NTIS. Our results differed somewhat with the study of Colombian patients, in which it was found that autoimmune thyroid disease did not affect SLE severity [14]. An important finding in the present study was that low FT3 was identified as an independent risk factor for dyslipidemia in SLE.

SLE patients have higher blood lipid levels, with an atherogenic lipid profile, termed a ‘lupus pattern’, which is characterized by elevated concentrations of TC, TG, LDL, and ApoA, as well as decreased HDL [15]. Dyslipidemia is one of the major risk factors for ischemic heart diseases, and several studies have shown a high prevalence of premature atherosclerosis and coronary artery disease in women with SLE [16, 17]. Moreover, lupus nephritis (LN), a common and potentially life-threatening manifestation of SLE, occurs in almost half of all SLE patients [18]. It has been well-established that impaired renal function is associated with dyslipidemia [19, 20]. A study by Kashef et al. reported decreased HDL and elevated TG levels in SLE patients with proteinuria of over 0.5 g/day [21]. Moreover, Chong et al. determined that there was a negative correlation between TG and the glomerular filtration rate (GFR) in patients with lupus nephritis [22]. In the present study, we found that the ApoB/ApoA1 ratio was significantly correlated with the SLEDAI in NTIS patients and with CRP and ESR in euthyroid patients. There is also increasing evidence to show that treating dyslipidemia is effective for preventing major cardiovascular complications in patients with chronic kidney disease and decreasing the progressive severity of renal failure [23]. Together, these data indicate that dyslipidemia is an important factor associated with renal function, disease activity, and poor prognosis in SLE patients. Thus, the early detection of risk factors and treatment for dyslipidemia is of substantial importance in managing SLE patients; however, the risk factors for dyslipidemia have not been fully elucidated in patients with SLE.

The most important finding of the present study was that FT3, but not SLE disease activity-related parameters (i.e., Cr, BUN, 24 h UP, or SLEDAI), were independently associated with dyslipidemia in SLE. Thyroid hormone plays a critical role in the growth, differentiation, development, and maintenance of metabolic homeostasis [9]. However, the pathogenesis of NTIS remains unknown. Cytokines that are released during illness are known to affect a variety of genes involved in thyroid metabolism and are therefore considered to be a major determinant of NTIS. NTIS is also associated with other illnesses, including severe infections, trauma, major surgery, myocardial infarction, inflammatory conditions, and kidney diseases. Several studies have investigated the effectiveness of thyroid hormone replacement therapy in patients with an underlying disease and NTIS, with controversial results. It was found that synthetic L-T3 replacement therapy significantly improved the neuroendocrine profile and ventricular performance in patients with chronic heart failure [24]. Moreover, short duration postoperative T3 therapy was shown to increase the cardiac index but did not alter mortality following coronary artery bypass surgery [25]. Although the administration of thyroid hormone in various clinical settings associated with NTIS did not improve the clinical outcome or organ function [26], the duration of replacement therapy was relatively short in most studies. Since the impact of dyslipidemia on the prognosis of SLE continues over a long duration, our results present evidence for the effect of long-term thyroid hormone replacement therapy in patients with SLE and NTIS.

Our study has several limitations. First, this cohort study is from one single center, and a multi-center study would provide more persuasive data. Second, since this is a cross-sectional study, a future long-term prospective study with a larger sample size is required. However, our study is strengthened by the selection of patients who did not have a history of familial hyperlipidemia and/or thyroid disease, and/or diabetes mellitus, and/or other rheumatic diseases, and those who did not take lipid-lowering agents or thyroid medication.

In conclusion, our findings indicate that NTIS frequently occurs in SLE and a low FT3 is associated with SLE disease activity in NTIS patients. Thus, we show for the first time, that a low FT3 is an independent risk factor for dyslipidemia in patients with SLE. Our results suggest that T3 replacement therapy may be useful for improving dyslipidemia and the long-term prognosis of SLE.

Data Availability

All relevant data are within the paper.

Funding Statement

This study was supported by Nanjing Medical Science and Technique Development Foundation (Z.C., ZKX16039). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Lim SS, Bayakly AR, Helmick CG, Gordon C, Easley KA, Drenkard C. The incidence and prevalence of systemic lupus erythematosus, 2002–2004: The Georgia Lupus Registry. Arthritis Rheumatol. 2014; 66:357–368. 10.1002/art.38239 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Amaya-Amaya J, Sarmiento-Monroy JC, Caro-Moreno J, Molano-Gonzalez N, Mantilla RD, Rojas-Villarraga A, et al. Cardiovascular disease in latin american patients with systemic lupus erythematosus: a cross-sectional study and a systematic review. Autoimmune Dis. 2013; 2013: 794383 10.1155/2013/794383 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Borba EF, Bonfá E. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus. 1997; 6:533–539. 10.1177/096120339700600610 [DOI] [PubMed] [Google Scholar]
  • 4.Tisseverasinghe A, Lim S, Greenwood C, Urowitz M, Gladman D, Fortin PR. Association between serum total cholesterol level and renal outcome in systemic lupus erythematosus. Arthritis Rheum. 2006; 54:2211–2219. 10.1002/art.21929 [DOI] [PubMed] [Google Scholar]
  • 5.Neto AM, Zantut-Wittmann DE. Abnormalities of Thyroid Hormone Metabolism during Systemic Illness: The Low T3 Syndrome in Different Clinical Settings. International Journal Of Endocrinology. 2016; 2016: 2157583 10.1155/2016/2157583 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Watad A, Mahroum N, Whitby A, Gertel S, Comaneshter D, Cohen AD, et al. Hypothyroidism among SLE patients: Case-control study. Autoimmun Rev. 2016; 15: 484–486. 10.1016/j.autrev.2016.01.019 [DOI] [PubMed] [Google Scholar]
  • 7.Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. Journal of Clinical Endocrinology & Metabolism. 2008; 93: 1351–1358. 10.1210/jc.2007-2210 [DOI] [PubMed] [Google Scholar]
  • 8.Joint committee issued Chinese guideline for the management of dyslipidemia in adults. 2016 Chinese guideline for the management of dyslipidemia in adults. Zhonghua Xin Xue Guan Bing Za Zhi. 2016; 44: 833–853. 10.3760/cma.j.issn.0253-3758.2016.10.005 [DOI] [PubMed] [Google Scholar]
  • 9.Lee S, Farwell AP. Euthyroid Sick Syndrome. Compr Physiol. 2016; 6:1071–1080. 10.1002/cphy.c150017 [DOI] [PubMed] [Google Scholar]
  • 10.Lind L, Vessby B, Sundstrom J. The apolipoprotein B/AI ratio and the metabolic syndrome independently predict risk for myocardial infarction in middle-aged men. Arterioscler Thromb Vasc Biol. 2006; 26: 406–410. 10.1161/01.ATV.0000197827.12431.d0 [DOI] [PubMed] [Google Scholar]
  • 11.McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008; 372: 224–233 10.1016/S0140-6736(08)61076-4 [DOI] [PubMed] [Google Scholar]
  • 12.Ohman M, Ohman ML, Wallberg-Jonsson S. The apoB/apoA1 ratio predicts future cardiovascular events in patients with rheumatoid arthritis. Scand J Rheumatol. 2014; 43: 259–264. 10.3109/03009742.2013.877158 [DOI] [PubMed] [Google Scholar]
  • 13.Walldius G, Jungner I. The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy—a review of the evidence. J Intern Med. 2006; 259: 493–519. 10.1111/j.1365-2796.2006.01643.x [DOI] [PubMed] [Google Scholar]
  • 14.Franco JS, Amaya-Amaya J, Molano-Gonzalez N, Caro-Moreno J, Rodriguez-Jimenez M, Acosta-Ampudia Y, et al. Autoimmune thyroid disease in Colombian patients with systemic lupus erythematosus. Clin Endocrinol (Oxf). 2015; 83:943–950. 10.1111/cen.12662 [DOI] [PubMed] [Google Scholar]
  • 15.Bultink IE, Turkstra F, Diamant M, Dijkmans BA, Voskuyl AE. Prevalence of and risk factors for the metabolic syndrome in women with systemic lupus erythematosus. Clinical & Experimental Rheumatology. 2008; 26: 32–38 [PubMed] [Google Scholar]
  • 16.Bruce IN. ‘Not only…but also’: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology. 2005; 44:1492–1502. 10.1093/rheumatology/kei142 [DOI] [PubMed] [Google Scholar]
  • 17.Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jansenmcwilliams L, et al. Age-specific Incidence Rates of Myocardial Infarction and Angina in Women with Systemic Lupus Erythematosus: Comparison with the Framingham Study. American Journal of Epidemiology. 1997; 145: 408–415. 10.1093/oxfordjournals.aje.a009122 [DOI] [PubMed] [Google Scholar]
  • 18.Maroz N, Segal MS. Lupus nephritis and end-stage kidney disease. American Journal of the Medical Sciences 2013; 346: 319–323 10.1097/MAJ.0b013e31827f4ee3 [DOI] [PubMed] [Google Scholar]
  • 19.Vaziri ND, Moradi H. Mechanisms of dyslipidemia of chronic renal failure. Hemodialysis International. 2006;10:1–7. 10.1111/j.1542-4758.2006.01168.x [DOI] [PubMed] [Google Scholar]
  • 20.Attman PO, Alaupovic P. Lipid and apolipoprotein profiles of uremic dyslipoproteinemia—relation to renal function and dialysis. Nephron. 1991; 57:401–410. 10.1159/000186303 [DOI] [PubMed] [Google Scholar]
  • 21.Kashef S, Ghaedian MM, Rajaee A, Ghaderi A. Dyslipoproteinemia during the active course of systemic lupus erythematosus in association with anti-double-stranded DNA (anti-dsDNA) antibodies. Rheumatology International. 2007; 27: 235–241. 10.1007/s00296-006-0195-3 [DOI] [PubMed] [Google Scholar]
  • 22.Chong YB, Yap DY, Tang CS, Chan TM. Dyslipidaemia in patients with lupus nephritis. Nephrology. 2011; 16: 511–517. 10.1111/j.1440-1797.2011.01456.x [DOI] [PubMed] [Google Scholar]
  • 23.Group SC. Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. American Heart Journal. 2010; 160: 785–794.e10. 10.1016/j.ahj.2010.08.012 [DOI] [PubMed] [Google Scholar]
  • 24.Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2008; 93:1351–1358. 10.1210/jc.2007-2210 [DOI] [PubMed] [Google Scholar]
  • 25.Kaptein EM, Sanchez A, Beale E, Chan LS. Clinical review: Thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab. 2010; 95: 4526–4534. 10.1210/jc.2010-1052 [DOI] [PubMed] [Google Scholar]
  • 26.Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab. 2009; 94:3663–3675. 10.1210/jc.2009-0899 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Deyu Fang

2 Mar 2020

PONE-D-19-35454

Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE

PLOS ONE

Dear Dr. Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

As what recognized by the reviewer, the observation that a correlation of the low FT3 with SLE disease activity in a Chinese population provide some useful insights for a better understudying the disease pathogenesis. However,  important analysis of these correlations in patients with NTIS and in patients without NTIS separately is missing, which is critical to understand whether the association of low FT3 with SLE is associated to NTIS pathogenesis . Please carefully address all reviewer's concerns and the editor will be happy to consider its possible publication. 

We would appreciate receiving your revised manuscript by March 30th. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Deyu Fang, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors performed Pearson's regression model as well as univariate and multivariate logistic regression analyses, and provided correlations between FT3 and UP, GBG, EST, BUN, SLEDAI, Cr, as well as CRP. Thus, they concluded that low FT3 is assosiated with disease activity and an independent risk factor for dyslipidemia in patients with SLE. This article was presented in an intelligible fashion and written in standard English.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: comments.docx

Click here for additional data file. (13KB, docx)
PLoS One. 2020 Apr 16;15(4):e0231622. doi: 10.1371/journal.pone.0231622.r002

Author response to Decision Letter 0

13 Mar 2020

Comments from the editor:

1.This study “Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE” validated the association between FT3 and SLE disease. They discovered that a low FT3 is associated with SLE disease activity, and a low FT3 is an independent risk factor for dyslipidemia in patients with SLE. This study, while confirmative, provided useful information for FT3 in Chinese population. Despite the authors identified FT3 is a risk factor for dyslipidemia in SLE patients, they didn’t provide the direct correlation analysis between TF3 and biomarkers of lipid profiles.

Reply: Thank you for you critical comments, we revised our manuscript according your advice (see below).

Comments from the reviewers:

1.The authors found that FT3 levels in serum are negatively correlated with the levels of UP, FBG, ESR, BUN, SLEDAI, Cr, as well as CPR. However, the correlations are weak, as shown by the values of correlation coefficients (r) in figure 1. Moreover, it’s unknown how NTIS pathogenesis contributes to these correlations. Therefore, analyzing these correlations in patients with NTIS and in patients without NTIS separately may better address this question.

Reply: Thank you for you critical comments. We analyzed the associations in patients with NTIS and in patients without NTIS separately. The results showed that the FT3 levels were negatively correlated with 24 h UP (r = -0.301; p < 0.001; Fig. 1A), BUN (r = -0.325; p < 0.001; Fig. 1B), Cr (r = -0.298; p < 0.001; Fig. 1C), as well as SLEDAI (r = -0.313; p < 0.001; Fig. 1F). However, these correlations were not observed in patients without NTIS (Fig. 2A, 2B, 2C and 2F). In addition, FT3 were negatively correlated with CRP in both NTIS patient (r = -0.200; p < 0.05; Fig. 1D) and euthyroid patients (r = -0.254; p < 0.05; Fig. 2D), ESR (r = -0.27; p < 0.05; Fig. 2E) in NTIS patients rather than in euthyroid patients (Fig. 1E). These results indicate that low levels of FT3 are closely related to a higher SLE disease activity mainly in NTIS patients rather than in euthyroid patients.

SLE is a heterogeneous disease and the aetiology is very complicated. The weak but statistically significant correlations found in this study suggests that NTIS maybe one of the factors impacting the disease activity and long-term prognosis of SLE.

2.The above concern applies also to relationships between the ApoB/ApoA1 and CRP, ESR, Cr, UP, as well as SLEDAI in figure2.

Reply: We analyzed the associations in patients with NTIS and in patients without NTIS separately. We found that the ApoB/ApoA1 ratio was significantly associated with SLEDAI (r = 0.251; p < 0.01; Fig.3E) but not with CRP, ESR, Cr, or 24 h UP (Fig. 3A, 3B, 3C and 3D) in NTIS patients. In euthyroid patients, the ApoB/ApoA1 ratio was significantly associated with CRP (r = 0.428; p < 0.001; Fig 4A) and ESR (r = 0.315; p < 0.01; Fig. 4B), but not with Cr, 24 h UP and SLEDAI (Fig. 4C, 4D and 4F). These results indicate that the atherogenic ApoB/ApoA1 ratio are somewhat related to the SLE disease activity in NTIS patients, as well as immunologic inflammation in euthyroid patients.

3.The resolution for Figure1 and Figure2 could be improved.

Reply: We increased the figure resolution to 300 × 300 dpi.

4.The actual number of recruited patients is 223. However, it’s inconsistent in the article.

Reply：Thank you for your careful review, we corrected this error.

In addition, we deleted the data about fasting blood glucose, because it is neither a criteria of dyslipidemia nor a criteria for SLEDAI.

Attachment

Submitted filename: comments-Pone.docx

Click here for additional data file. (15.1KB, docx)

Decision Letter 1

Deyu Fang

30 Mar 2020

Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE

PONE-D-19-35454R1

Dear Dr. Chen,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Deyu Fang, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors fully addressed my concerns, and the added new data support their conclusions. The statistical analysis has been performed appropriately.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Deyu Fang

2 Apr 2020

PONE-D-19-35454R1

Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE

Dear Dr. Chen:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Deyu Fang

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: comments.docx

    Click here for additional data file. (13KB, docx)
    Attachment

    Submitted filename: comments-Pone.docx

    Click here for additional data file. (15.1KB, docx)

    Data Availability Statement

    All relevant data are within the paper.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES