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ORIGINAL ARTICLE
Sleep pattern changes in patients with connective tissue diseases
Emad Efat
Chest, Faculty of Medicine, Menoufia University, Subk El Dahak, El Bajour, Menoufia, Egypt
Received 24 December 2015; accepted 21 January 2016
KEYWORDS
Sleep disorders; Connective tissue diseases; Obstructive sleep apnea; Apnea hypopnea index; C-reactive protein and rheumatic disorders
Abstract Objectives: To assess sleep pattern changes in patients with connective tissue diseases.
Background: There is evidence that patients with rheumatic disorders may be at an increased risk for sleep disorders, particularly obstructive sleep apnea (OSA). Sleep abnormalities have also been linked to increased pain and fatigue perception, which are common concerns in rheumatology patients. Untreated OSA with intermittent hypoxia is associated with elevated levels of systemic inflammatory markers: C-reactive protein (CRP) and pro-inflammatory cytokines.
Methods: Thirty patients diagnosed as connective tissue diseases (CTD), and 30 apparent healthy control subjects were invited to participate in the study. All the patients were subjected to full medical history, Epworth sleepiness score (ESS), thorough clinical examination with evaluation of the disease activity, laboratory assessment of CRP, and Complete overnight polysomnography.
Results: In the current work, the prevalence of Sleep apnea in CTD patients was 18/30(60%). Sleep apnea was obstructive. Mean AHI (apnea-hypopnea index) was 23.42 ± 26.27/h. Among these OSA patients, 36.7% had severe, 10% had moderate, and 36.7% had mild OSA. The study showed a significant correlation between AHI and BMI, Neck circumference, ESS, erythrocyte sedimentation rate (ESR), CRP, and hematocrit (HCT).
Conclusion: Obstructive sleep apnea is commonly associated with CTD patients. Co-existence of OSA in CTD patients may influence the disease activity and the level of circulating inflammatory markers.
© 2016 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting 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/).
Introduction
Connective tissue disorders (CTDs) are defined as a group of acquired diseases resulting from persistent immune mediated
* Tel.: +20 483848451.
E-mail address: emadefat@ymail.com
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.
inflammation. In most CTDs there is immune dysregulation resulting in generation of autoreactive T cells or autoantibodies [1].
Sleep abnormalities have been recognized in a number of different rheumatic diseases, including rheumatoid arthritis, osteoarthritis, fibromyalgia, juvenile idiopathic arthritis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, spondylarthritis, sarcoidosis and Behcet's syndrome [2].
http://dx.doi.org/10.1016/j.ejcdt.2016.01.015
0422-7638 © 2016 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting 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/).
Obstructive sleep apnea is a common disorder, characterized by recurrent narrowing and closure of the upper airway accompanied by intermittent oxyhemoglobin desaturation and sympathetic activation [3]. The presence of sleep apnea as a comorbidity may interfere with the evaluation of rheumatic disease activity and responsiveness to therapy [4].
Aim of the work
The aim of our study is to assess sleep pattern changes in patients with connective tissue diseases.
Patients and methods
Thirty patients diagnosed as CTDs attending to outpatient Immunology and Rheumatology clinic of Internal Medicine Department and outpatient clinic of Rheumatology Department of Menoufia University Hospital, and 30 apparent healthy control subjects were invited to participate in the study.
This study included 60 subjects; they were divided into two groups:
Group 1: consists of 30 patients who were diagnosed as CTD patients and on a regular medication regimen for CTD.
Group 2: consists of 30 apparent healthy subjects. Complete medical history was obtained; they were clinically free from any known CTDs.
Health Research Ethics Board of Menoufia University approved the study. Informed consent was obtained from all participants, each patient underwent:
1. Detailed clinical evaluation including history talking, general and local rheumatological examination.
2. Disease activity scores [the systemic lupus erythematosus (SLE) Disease Activity Index (SLEDAI) [5] and Disease Activity Score 28 (DAS28) [6]] for SLE & RA respectively.
3. Epworth sleepiness score (ESS).
4. Investigations:
1. Chest X-ray (posteroanterior and lateral views).
2. Electrocardiogram (ECG), echocardiography and High-resolution CT chest if needed.
3. Routine laboratory investigations and immunological profile.
4. Complete overnight polysomnography (PSG):
It was conducted in the sleep laboratory unit, Chest Department, Menoufia University Hospital over a whole night (8 h sleep). We started the study at 10 P.M. until 6 A.M. using EMBLA S 4000 system (Iceland).
The PSG consisted of Somnologica studio software, elec-troencephalography sensor with its cables, electrooculography electrodes, electromyography electrodes for the chin and anterior tibialis muscle, Nasal canula and nasal thermistor, Thoracic and abdominal belt, Pulse oximetry sensor, electro-cardiography electrodes with their cables, Snoring microphone, and Body position sensor (see Graph 5). Data obtained from this study were:
- Apnea index (AI): Complete cessation of airflow breathing at the nostrils and mouth for at least 10 s or longer.
- Hypopnea index (HI): A decrease in rate and depth of breathing by 50% for 10 s or longer.
- Apnea-hypopnea index (AHI): Average number of apnea and hypopnea per hour of sleep. Persons with an AHI < 5 are not considered to have OSA. In contrast, an AHI P 5 and < 15, AHI P 15 and < 30, and an AHI P 30 are classified as mild, moderate, and severe respectively [7].
Results
Table 1 shows that:
Group 1 (cases): included 11 males (36.7%) and 19 females (63.3%), the age ranged from 23 to 74 years with a mean ± SD value of 41.87 ± 15.01 years, the Body mass index (BMI) of the patients ranged from 19.1 to 58.6 kg/m2 with a mean ± SD value of 35.74 ± 11.20 kg/m2.
Group 2 (control): included 12 males (40.0%) and 18 females (60.0%), the age ranged from 33 to 83 years with a mean ± SD value of 52.50 ± 12.39 years, the BMI of the subjects ranged from 20 to 60 kg/m2 with a mean ± SD value of 31.0 ± 9.39 kg/m2.
Table 2 shows a statistical significant difference between all patients & control group as regard Epworth sleepiness scale (ESS) and significant difference between them as regard Neck circumference and smoking.
Table 3 displays Polysomnography parameters across the studied groups that shows:
Total sleep time (TST), Sleep efficiency, REM Latency from Sleep Onset, Spontaneous Arousals Index, PLMS sequences, AHI, Oxygen Desaturation Events (OD), percentage of Snoring Time in TST, and Total AHI in NREM were significantly different in the cases compared with control group. There were no significant differences in Sleep Onset, flow limitation index,% of sleep in supine position, A + H/h in supine position, Average Oxygen Saturation, (%) of Lowest Oxygen Saturation, % of REM in TST, and Total AHI in REM across two groups.
Table 4 shows Sleep disorders by AHI, cases were subdivided according to results of polysomnography into:
Mild OSA (AHI P 5 and <15): consisted of 4/30(13.3%) patients, moderate OSA (AHI P 15 and <30): consisted of 3/30(10%) patients, severe OSA (AHI P 30): consisted of 11/30(36.7%) patients, negative (AHI < 5): consisted of 12/30(40%) patients without OSA.
Table 5 shows a significant positive correlation between AHI in patients and age, uric acid, and creatinine. In addition, there were highly significant positive correlations between AHI in patients and BMI, Neck circumference, ESS, ESR, CRP, and HCT.
Table 6 shows a significant positive correlation between OD in patients and age and Neck circumference. In addition, there were highly significant positive correlations between OD in patients and BMI, ESS, ESR, CRP, and HCT.
Table 7 shows the binary logistic regression model for risk factors of sleep related breathing disorders (SRBD), which demonstrates that ESR is independent risk factors for, SRBD with odds ratio 1.90 and CI (1.01-4.55).
Discussion
Sleep disorders have been described in more than 75% of subjects suffering from various forms of rheumatic diseases [8].
r = 0.73 P vaue <0.001
Graph 5 Correlation between C-reactive protein (CRP) and apnea hypopnea index (AHI).
Table 1 Age, sex and BMI distribution among cases and control.
The studied cases Test of sig. P value
Cases Control
N =30 N =30
Age (year)
X ± SD 41.87 ± 15.01 46.10 ± 8.01 U
Range 23-74 33-66 1.75 0.08
BMI (kg/m2)
X ± SD 35.74 ± 11.20 31.0 ± 9.39 t-Test
Range 19.1-58.6 20-60 1.78 0.08
No % No %
Male 11 36.7 12 40.0 X2
Female 19 63.3 18 60.0 0.07 0.79
Table 2 Clinical data among cases and control.
The studied cases Test of sig. P value
Cases Control
N =30 N =30
Neck circumference (cm)
X ± SD 39.64 ± 3.19 37.67 ± 2.80 t-Test
Range 34.5-44 33-44 2.55 0.01
X ± SD 17.73 ± 3.30 7.97 ± 2.70 U
Range 12-23 3-12 6.63 <0.001
No % No %
Smoking
Non smokers 22 73.3 30 100 FE
Smokers 8 26.7 00 9.23 0.005
Table 3 Polysomnography parameters across the studied groups.
The studied cases U test P value
Cases N =30 Control N =30
Total sleep time (TST) (minute) X ± SD 281.95 ± 99.64 Range 47.5-477.5 374.75 ± 141.19 158-8.13 2.54 0.01
Sleep onset (minute) X ± SD Range 26.71 ± 21.99 0.5-79 30.55 ± 25.68 2-88 0.38 0.71
Sleep efficiency X ± SD Range 56.63 ± 29.26 0.5-96.5 74.0 ± 14.50 38-99 2.26 0.02
REM Latency from Sleep Onset (minute) X ± SD 55.78 ± 95.13 Range -79-338 126.95 ± 108.28 0-328 2.34 0.02
Spontaneous Arousals Index X ± SD Range 54.84 ± 29.81 0-102.7 32.25 ± 28.75 4-91 2.32 0.02
Flow limitation index% total X ± SD Range 17.28 ± 18.69 0-59 13.67 ± 12.32 0.4-48 0.30 0.77
% of sleep in supine position X ± SD Range 49.15 ± 33.96 0-100 57.15 ± 31.73 11-100 1.09 0.27
A + Hfh in ssupine position X ± SD Range 10.94 ± 17.06 0-61.4 6.59 ± 11.99 0-43 0.03 0.98
PLMS sequences X ± SD Range 1.63 ± 2.24 0-8 0 ± 0 0-0 4.0 <0.001
Average Oxygen Saturation (%) X ± SD 93.29 ± 5.26 Range 77.8-99 94.05 ± 2.68 86-99 0.40 0.69
Lowest Oxygen Saturation (%) X ± SD 82.80 ± 12.58 Range 54-98 87.75 ± 5.49 69-94 0.61 0.55
AHI X ± SD Range 23.42 ± 26.27 0-91 4.75 ± 8.76 0-38 2.42 0.02
Oxygen Desaturation Events (OD) X ± SD 23.97 ± 25.15 Range 0-88 3.77 ± 3.17 0-11 3.63 <0.001
% of Snoring Time in TST X ± SD Range 9.19 ± 17.08 0-72.2 1.33 ± 2.63 0-8 2.41 0.02
% of REM in TST X ± SD Range 15.16 ± 18.08 0-87.5 10.75 ± 7.85 0-28 0.36 0.72
Total AHI in NREM X ± SD Range 98.63 ± 123.83 0-485 4.52 ± 8.83 0-37 3.41 <0.001
Total AHI in REM X ± SD Range 27.90 ± 55.50 0-233 9.10 ± 12.75 0-45 0.12 0.90
Table 4 Sleep disorders by AHI among cases.
AHI Cases
Negative 12 40.0
Mild 4 13.3
Moderate 3 10.0
Sever 11 36.7
Table 5 Correlation between apnea hypopnea index and patient investigations.
AHI among cases
r P value
Age 0.43 0.02
BMI 0.68 <0.001
Neck circumference 0.65 <0.001
ESS 0.79 <0.001
ESR 0.74 <0.001
CRP 0.73 <0.001
HCT (%) 0.72 <0.001
RF (mg/dl) 0.50 0.08
Uric acid (mg/dl) 0.44 0.02
Creatinine (mg/dl) 0.41 0.03
Table 7 Binary logistic regression analysis for independent risk factors of SRBD.
Standard Wald P Odds 95%
error (SE) X2 value ratio confidence
interval (CI)
Lower Upper
ESR 0.05 3.43 0.02 1.90 1.01 4.55
CRP 0.14 0.86 0.35 1.10 0.56 1.88
RF 0.53 0.97 0.33 0.99 0.34 3.65
ANA 0.79 2.52 0.11 0.86 0.21 2.68
Table 6 Correlation between oxygen desaturation and patient investigations.
Oxygen desaturation
r P value
Age 0.38 0.04
BMI 0.57 0.001
Neck circumference 0.43 0.02
ESS 0.60 0.001
ESR 0.57 0.001
CRP 0.68 <0.001
HCT (%) 0.78 <0.001
ANA -0.29 0.12
RF (mg/dl) 0.17 0.57
Uric acid (mg/dl) 0.21 0.28
Creatinine (mg/dl) 0.27 0.15
Co-existence of sleep apnea in rheumatic disease patients may influence the severity of reported symptoms of pain and fatigue, accelerate the risk of cardiovascular events and possibly influence levels of circulating inflammatory markers and mediators [4].
In the current work, the prevalence of Sleep apnea in CTDs was 18/30(60%). Sleep apnea was obstructive. Mean AHI was 23.42 ± 26.27/h. Among these OSA patients, (36.7%) had severe OSA (AHI > 30/h), (10%) had moderate OSA (AHI 15-30/h), (36.7%) had mild OSA (AHI 5-15/h).
In this study, OSA was diagnosed in 9/12(75%) of RA patients, 5/12(42%) of SLE patients, 4/5(80%) of Behcet's disease and 0/1(0%) of ankylosing spondylitis. The current study results agree with those of study done by Iaboni et al. [9],
which studied PSG recordings in SLE patients with disabling fatigue. Of the 35 patients studied, 26% met criteria for sleep apnea. This finding was in harmony with our result. Palagini et al. [10] showed that the prevalence of OSA in the SLE patients has ranged from 26-50%, which is considerably higher than the general healthy persons. These findings were in harmony with our results.
In the present work there were highly significant positive correlations between AHI in patients and BMI (r = 0.68, P < 0.001), Neck circumference (r = 0.65, P < 0.001), ESS (r = 0.79, P < 0.001), ESR (r = 0.74, P < 0.001), CRP (r = 0.73, P < 0.001), and HCT (r = 0.72, P < 0.001) (Table 5).
It is of interest that we recorded higher levels of CRP in CTD patients with OSA. In consistent with our study, Fouda and Abdel Dayem [11] have demonstrated increased CRP values among OSA patients.
In accordance with our results, Yousef and Alkhiary [12] reported that OSAS patients had a significantly higher oxygen desaturation index, Epworth sleepiness scale and significantly lower minimal, basal oxygen saturation, sleep efficiency and rapid eye movement sleep when compared to control subjects. In addition, hematocrit was significantly higher in OSAS.
Our study also confirmed previous findings of Valencia et al. [13] that sleep apnea, periodic limb movements (PLMS), a poor sleep pattern (higher percentage of wake stage, increased number of awakenings, and decreased sleep efficiency) are common sleep disorders in patients with CTDs, also Hypersomnolence was common in our CTD patients, and can be objectively associated with total sleep time of oxygen desaturation and sleep fragmentation.
Lessened sleep efficiency was a recorded polysomnographic finding among patients, as the mean value of sleep efficiency was (56.63 ± 29.26). In consistent with our study, several works have demonstrated decreased sleep efficiency among patients with ankylosing spondylitis and SLE [14,15,9].
In the present work there were significant positive correlations between OD in patients and age (r = 0.38, P = 0.04) and Neck circumference (r = 0.43, P = 0.02). In addition, there were highly significant positive correlations between OD in patients and BMI (r = 0.57, P = 0.001), ESS (r = 0.60, P = 0.001), ESR (r = 0.57, P = 0.001), CRP (r = 0.68, P < 0.001), and HCT (r = 0.78, P < 0.001).
Our results agree well with an earlier study by Peppard et al. [16] that found BMI is an important predictor of the severity of OD during apneic and hypopneic events of sleep-disordered breathing, independent of age, gender, sleeping position, smoking history, baseline SaO2 , and event duration.
Serum creatinine in OSA patients was significantly higher than controls (1.42 ± 0.50). Serum creatinine correlated significantly with AHI (P = 0.03). This is in agreement with the study of Buchner et al. [17] who recorded that Serum creatinine correlated significantly with AHI.
Similar to our findings, Ruiz et al. [18] found a significant correlation between uric acid levels and some sleep parameters (number of respiratory events, number of desaturations, or the cumulative percentage of time with oxygen saturation less than 90%). Additionally, they showed that those patients with severe OSAS (AHI P 30) had higher uric acid levels than those with mild or no OSAS.
Conclusion
In conclusion, OSA is commonly associated with patients with CTDs. These findings possibly suggest common underlying pathological mechanisms, which may be linked to chronic inflammation. Co-existence of OSA in CTD patients may influence the disease activity and the level of circulating inflammatory markers in these patients. Considering diagnosis and treatment of this sleep disorder in CTD patients may help improve clinical care, better prognosis and avoid rheumatoid-associated morbidities.
Conflict of interest
The authors declare that they have no conflict of interest. References
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