Blood pressure and body fat percent in women with NMOSD

Abstract Background Hypertension is a prevalent and impactful comorbid condition among patients with multiple sclerosis (MS). High level of body mass index (BMI) is associated with the risk and poor outcomes of neuromyelitis optica spectrum disorder (NMOSD) in women. However, the clinical implication of blood pressure (BP) and body fat percent (BF%) based on the Clínica Universidad de Navarra‐Body Adiposity Estimator (CUN‐BAE) in NMOSD has not been investigated thus far. Methods Case data were collected from 47 NMOSD and 28 MS patients at acute phase, 21 NMOSD and 25 MS patients at stable phase, and 68 age‐ and sex‐matched HCs. Four BP measures including systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP); BMI; and BF% between NMOSD, MS, and healthy controls were determined. Results Comparing NMOSD patients with MS patients, the former have significantly higher SBP (p < 0.001), DBP (p < 0.001), PP (p < 0.001), MAP (p < 0.001), BF% (p = 0.001), and BMI (p < 0.001) levels at acute phase after adjusting for age. Acute myelitis (OR 3.719, 95% CI 1.110–12.453) is more likely to occur in NMOSD patients with high BF% (≥30%) at acute phase. BF% was negatively correlated with 1/AQP4 titer in NMOSD at acute phase (r = −0.522, p = 0.004). Conclusions Women with NMOSD are probably more prone to have an increased BP and fat mass compared to MS.


| INTRODUC TI ON
Hypertension, which is one of the five leading causes of disability in the general population, is also a prevalent and impactful comorbid condition among patients with multiple sclerosis (MS) (Marrie et al., 2012). A meta-analysis had reported that 18.6% of the MS population had hypertension (Marrie et al., 2015), and 3.73% of an incident MS cohort was found to develop hypertension over a maximum follow-up of 30 years (Christiansen et al., 2010). Hypertension is linked to more rapid progression of ambulatory disability and an increased risk of cane use in patients with MS (Marrie et al., 2010). Pulse pressure has been associated with ambulatory functioning in patients with MS (Heffernan et al., 2011). A study also showed significantly lower systolic blood pressure (BP) readings in MS patients compared to non-MS patients (Sternberg et al., 2013). A recent study has reported that hypertension was the most prevalent comorbidity in NMO and the prevalence of hypertension among highly active NMO cases was almost three times higher versus those in matched controls (Ajmera, Boscoe, Mauskopf, Candrilli, & Levy, 2018). Another study showed no differences in the prevalence of hypertension between NMOSD compared to control participants, while it was 30%-50% higher in MS participants compared to the controls (Saroufim, Zweig, Conway, & Briggs, 2018). However, no studies to date examined the BP including systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) in patients with neuromyelitis optica spectrum disorder (NMOSD).
Recently, a study has showed that low BMI could be associated with the risk and poor outcomes of NMOSD in women (Baek et al., 2018).
However, it is still unknown about the clinical implication of BF% based on CUN-BAE in NMOSD.
There are few reports assessing BP and BF% in individuals with NMOSD, although it is important given its impact on patients' quality of life, adherence to treatment (especially steroids therapy), and prognosis. To the best of our knowledge, no specific studies have been focused on the BP and BF% based on CUN-BAE in NMOSD and MS patients without treatment. To fill this research gap, we conducted the study to compare the BP and BF% between NMOSD and MS female patients, based on SBP, DBP, PP, MAP, BMI, and BF%. Establishing the prevalence and profile of BP and BF% in NMOSD remains of key importance, not only in understanding these conditions but also for informing the development of specialist services based on the needs of individuals with these conditions.

| Samples and study design
This is a prospective study approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University.
All study participants have provided written consent for research and publication. All study participants were Chinese Han women.  (Wingerchuk et al., 2015) and the McDonald criteria 2010 (Polman et al., 2011), respectively. All data of these NMOSD and MS patients at acute phase were collected before treatment (methylprednisolone pulse therapy or IV immunoglobulin or immunosuppressive therapy). Patients were tested for antiaquaporin-4 (AQP4) antibody using cell-based assay from a commercial BIOCHIP kit (EUROIMMUN, Lübeck, Germany) (Long et al., 2012).
Data of 21 NMOSD patients with low-dose glucocorticoid therapy (<10 mg prednisone or 8 mg methylprednisolone daily) and 25 MS patients without steroids or other disease-modifying immunosuppressive therapy were collected at stable phase of disease. Patients who had experienced a relapse within the past month were considered to be in the acute phase, whereas those who were in a stable condition and had not experienced a clinical relapse for more than 1 month were considered to be in the stable phase. A relapse was defined as new or worsening CNS symptoms or signs that persisted for more than 24 hr. These patients included the patients who visited our hospital for the first time at the onset of the disease and the patients who visited the hospital at the relapse or stable stage. Our hospital, which is located on Guangzhou City, Guangdong Province, is a tertiary medical center and the major research unit focused on  Table 4). All patients were scored using the Expanded Disability Status Scale (EDSS). In addition, the patient's serum antinuclear antibody (ANA), anti-Sjogren syndrome A (anti-SSA) antibody, and anti-Sjogren syndrome B (anti-SSB) antibody were detected.
The remaining clinical data collected were as follows: age at the time of disease onset, disease duration, and annualized relapsing rate (ARR). And no patients and HCs had obviously abnormal thyroid function and habit of smoking. Subjects presenting serious concomitant illnesses (i.e., cancer or hepatitis) or treatments (i.e., chemotherapy) possibly interfering with cardiovascular risk were excluded.

| Height and weight
Height and weight were measured to the nearest 0.1 cm and 0.1 kg, respectively. Participants wore clothing (uniform hospital clothing) and no shoes while assessing weight and height.

| Body mass index (BMI)
BMI was calculated as weight in kilograms divided by height in meters squared. BMI was classified as follows: underweight, BMI<18.5 kg/m 2 ; normal weight, BMI = 18.5 to 24.9 kg/m 2 ; overweight, BMI = 25.0 to 29.9 kg/m 2 ; and obese, BMI ≥30.0 kg/m 2 . The BMI of NMOSD and MS at acute phase is measured before the use of steroid treatment.

| Blood pressure
Resting SBP and DBP were measured with an automatic blood pressure cuff (Omron HEM-7130, Omron Healthcare, Dalian, China) in a supine position (10 min rest) after 10 min of quiet rest by the average of two times. When the BP readings in these patients were recorded, these patients were not in situation with acute discomfort, anxiety, or sharp pain. And PP and MAP were calculated.

| Statistical analyses
Age at the time of recruitment was compared across study cohorts (NMOSD, MS, and HCs) by using chi-square test and Kruskal-Wallis test, respectively. Height was compared across study cohorts (NMOSD, MS, and HCs) by using ANOVA test. Characteristics were compared between NMOSD and MS patients using chi-square (or Fisher's exact) tests for categorical variables and 2-sample t (or Mann-Whitney U) tests for continuous variables. SBP, DBP, PP, MAP, BMI, and BF% were compared at both acute and stable phases using Kruskal-Wallis tests and multivariate linear regression analyses between the two study cohorts (NMOSD and MS), and at acute phase among the three study cohorts (NMOSD, MS, and HCs) while using Mann-Whitney U tests between every two cohorts. We also investigate the differences between high BF% (≥30%) and low BF% (<30%) and the clinical characteristics in acute NMOSD patients, adjusting for the demographic characteristics.
All statistical analyses were performed using SPSS 22. A twosided p<0.05 was considered statistically significant. In both the unadjusted and adjusted models, the mean SBP, PP, and MAP level of NMOSD patients at acute phase were significantly higher than HCs (adjusted p < 0.001 for SBP; adjusted p < 0.001 for PP; adjusted p < 0.001 for MAP, respectively). The adjusted mean and standard deviation were 115.5 ± 1.7 vs. 107.9 ± 7.0 mmHg for SBP, 41.4 ± 0.01 vs. 36.7 ± 4.5 mmHg for PP, and 87.9 ± 1.7 vs.

| Baseline characteristics
83.5 ± 4.0 mmHg for MAP, respectively. In the adjusted models, the BMI (p < 0.001), BF% (p = 0.033), and DBP (p < 0.001) levels of NMOSD patients were higher than HCs. In addition, lower BMI (p = 0.011) and BF% (p = 0.011), and higher SBP (p = 0.018) and PP (p = 0.001) levels were observed in MS patients at acute phase compared to HCs. We did not observe any statistically significant difference in DBP and MAP level between MS patients at acute phase and HCs using both the unadjusted and adjusted models (Table 3).

| Comparisons between NMOSD and MS patients at stable phase
In both the unadjusted and adjusted models, the mean BMI and

| Comparisons between acute and stable phases in NMOSD and MS patients
After adjusting for age, lower BMI (p < 0.001), and BF% (p = 0.016), higher SBP (p < 0.001), DBP (p < 0.001), and MAP (p < 0.001) levels were observed in acute phase compared to stable phase in NMOSD patients. We did not observe any statistically significant difference in PP level between acute phase and stable phase in NMOSD patients using both the unadjusted and adjusted models (Table 2).
In addition, statistically significant differences were not observed in BMI, BF%, SBP, PP, and MAP levels between acute phase and stable phase in MS patients using both the unadjusted and adjusted models. Only higher DBP (p < 0.024) level was observed in acute phase compared to stable phase in MS patients in the adjusted model (Table 2).
Our analyses identified that no significant correlations were observed between BMI or BF% and the four BP measures (SBP, DBP, PP, and MAP) in patients with NMOSD at acute phase. BP measures between NMOSD patients at acute phase with high BF% (≥30%) and with low BF% (<30%) were also calculated, while statistically significant differences were not found between two groups for SBP, DBP, PP, and MAP. This result suggested that BF% is not the likely explanation for higher BP readings in NMOSD. We also did not observe any significant correlations between EDSS and the four BP measures (SBP, DBP, PP, and MAP) in patients with NMOSD at acute phase. Similarly, the presence of hypertension was not associated with the EDSS scores in MS (Zhang et al., 2018). Interestingly, the present analyses indicated that acute myelitis more often occurred in NMOSD patients with high BF% (≥30%) at acute phase. The association between acute myelitis and high BF% should be researched further.
Glucocorticoid treatment is the recommended standard therapy for NMOSD, while high-dose corticosteroids (typically intravenous methylprednisolone 1g/day for 3 to 5 days) are the mainstay of acute treatment and low-dose corticosteroids are considered as part of F I G U R E 2 Scatter plot of the association between BF% and 1/ AQP4 titer in women with NMOSD at acute phase. N = 28 TA B L E 4 Comparison between NMOSD with high BF% (≥30%) and NMOSD with low BF% (<30%) at acute phase the maintenance treatment of patients at stable phase (Bruscolini et al., 2018). However, the adverse effect on BP is dependent on the administered dose. Elevated BP had not been observed in those patients who accepted low-dose corticosteroid therapy (Jackson, Beevers, & Myers, 1981;Panoulas et al., 2008). In our study, low- However, the relatively higher prevalence of overweight and obesity in patients with NMOSD at stable phase compared to acute phase may be due to vitamin D deficiency, chronic corticosteroid therapy, and chronic inflammation.
In women with MS, there was no significant relation between BF% and EDSS (Lambert, Lee Archer, & Evans, 2002). The current study also did not find an association between BMI or BF% and ARR and EDSS in NMOSD. A recent study has showed that low BMI could be associated with the risk and poor outcomes of NMOSD in women (Baek et al., 2018). The prospective and longitudinal data are needed to further assess this association.
Interestingly, the present result indicated that BF% was significantly related to 1/AQP4 titer in NMOSD patients at acute phase.
The role of adipose tissue in the pathogenesis of MS has become subject of great interest (Guerrero-García et al., 2016). It is believed that increased fat mass, as well as the elevated levels of adipokines, may be involved in the altered immune response and inflammatory processes in NMOSD. Therefore, increased fat mass may not only affect cardiovascular risk in NMOSD but also influence NMOSD progress.

| Limitations
Our study has several limitations. Only a single ethnic population from a single center was evaluated, which can result in unintentional bias.
The numbers of patients were relatively small. Besides, this study was performed only among female patients. The limited number of male patients with NMOSD could be responsible for it. Finally, the current study relied on CUN-BAE for assessment of BF%. While DXA is a valid and reliable method for assessment of lean vs. fat mass, it is not able to assess more detailed aspects of body composition. Additional analysis of these fat stores using more advanced methods such as magnetic resonance imaging (MRI) may provide additional understanding of the impact of body composition on comorbidities in NMOSD.

| CON CLUS IONS
Women with NMOSD are probably more prone to have an increased BP and fat mass compared to MS. Furthermore, for the individuals with NMOSD, there were no statistically significant relations between the body composition measures and EDSS score.

ACK N OWLED G M ENTS
This work was supported by grant to Y Jiang from the National Natural Science Foundation of China (81671182) and the Natural Science Foundation of Guangdong Province (2016A030313228).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

CO N FLI C T O F I NTE R E S T
All authors declare that there are no conflicts of interest.

AUTH O R S' CO NTR I B UTI O N S
Y. J. contributed to the conception and design of this study. Y. J., X.
C., X. C., R. F., J. H., and F. P. analyzed the data. Y. J., Y.C., Z. C., X. C., and R. F. drafted the manuscript. All the authors read and approved the final manuscript.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The study was conducted according to the principles expressed in the Declaration of Helsinki and approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University.
All study participants gave written informed consent for research and publication.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.