Impact of concomitant obstructive sleep apnea on pulmonary involvement and main pulmonary artery diameter in adults with scleroderma

This cross-sectional cohort study was conducted at the Marmara University Pendik Teaching and Education Hospital, Istanbul, between 01 April and 01 October 2016. Patients with a known scleroderma diagnosis attending to the Departments of Rheumatology and/or Pulmonary Medicine, without any concomitant psychiatric or neurologic disease, were invited to participate. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Ethics Committee of the Medical Faculty of the Marmara University, Istanbul (approval no.: 09.2016.208). All patients provided written informed consent. The trial was registered with the ClinicalTrials.​gov (NCT 02740569).

Anthropometrics, smoking habits, and past medical history for the whole population were obtained from the medical records. Height, weight, and waist circumference were measured, and body mass index (BMI) was calculated according to the formula body weight divided by height squared, and obesity was defined as a BMI of at least 30 kg/m² [12]. Patients were classified as having limited cutaneous systemic sclerosis or diffuse cutaneous systemic sclerosis according to the criteria of Leroy et al., based on the extension of skin involvement [13]. Anti-nuclear antibody (ANA) was detected by using immunoflourescent assay (IFA) with a screening titer of 1:160 and above. The presence of anti-topoisomerase (anti-Scl70) and anti-centromere (ACA) were measured by using immunoblotting method—extractable nuclear antigen (ENA) panel antibodies. Information about concomitant diseases at baseline, including hypertension and diabetes, was based on self-reported and/or physician-diagnosed conditions. Ongoing medications were also obtained.

Pulmonary function including forced expiratory volume in 1 s (FEV₁), and forced vital capacity (FVC), was measured with MIR Spirolab II spirometry (Medical International Research, Rome, Italy), diffusing capacity of lung for carbon-monoxide (DL_CO) in a body-plethysmograph (CareFusion Type MasterScreen PFT; Hoechberg, Germany), and a 6-min walking test (SMWT) was performed—in a 30-m flat indoor corridor—and all results were evaluated according to the ATS guidelines [14‐17].

All patients underwent a high-resolution computed tomography (HRCT) at the Department of Radiology using Siemens SOMATOM Definition Flash (Erlangen, Germany) scans. A new HRCT was performed, if the existing measurement was older than 6 months. The scans of the chest were obtained with patients in supine position and with lungs at end-inspiration. The area of the scans ranged from the lung apices to bases, with 0.6-mm collimation, 1- to 2-mm slice thickness at 0.5-mm increments. Five crucial abnormalities were distinguished and their severity was assessed with the Warrick score [18]: ground glass opacities (score 1), irregularities in the pleural margins (score 2), septal and subpleural lines (score 3), honeycomb lung (score 4), and subpleural cysts (score 5). An additional extent score was added to each severity score, i.e., abnormality involving 1–3 segments (extent score 1), 4–9 segments (extent score 2), and more than 9 segments (extent score 3), respectively. A total score range was 0–30. Pulmonary involvement was defined as a Warrick score of at least 7 on the HRCT [19]. Explicitly, the transverse axial diameter of the mPA and the ascending aorta at the level of the bifurcation of the right pulmonary artery were measured [11]. The ratio of mPAD to ascending aorta diameter (ratio PA) was also calculated. All findings were scored by the same experienced pulmonologist (S.K.) blinded to the patients’ clinical characteristics and results of the pulmonary function tests and sleep recordings.

Subjective sleepiness was evaluated using the Turkish version of the Epworth Sleepiness Scale (ESS) questionnaire, which is the most widely used index in sleep clinics [20, 21]. The ESS consists of 8 questions for assessing the chance of dozing off under 8 situations in the past month. Each item is scored from 0 to 3 (0, would never doze; 1, slight chance of dozing; 2, moderate change of dozing; 3, high chance of dozing). The ESS score ranges from 0 to 24. Excessive daytime sleepiness (EDS) was defined as the ESS score of at least 11 [22].

The portable, limited sleep study was performed with a home sleep apnea testing (HSAT) device (NOX-T3; Nox Medical Inc., Reykjavik, Iceland) and consisted of a nasal pressure detector using a nasal cannula/pressure transducer system, thoracoabdominal movement detection through two respiratory inductance plethysmography belts, and a finger pulse oximeter detecting heart rate and oxyhemoglobin saturation (SpO₂) as well as body position and movement detection. Moreover, snoring was recorded by a built-in microphone in the NOX-T3 device which provides the opportunity to play the audio along with the other recorded signals during manual scoring of the events. The patient’s sleep time was estimated on the basis of self-reporting as well as the pattern of body movement during the study. Patients with an estimated sleep time of less than 4 h were offered a new HSAT. Apnea was defined as an almost complete (≥ 90%) cessation of airflow, and hypopnea was defined as a reduction in nasal pressure amplitude of ≥ 30% and/or thoracoabdominal movement ≥ 30% for ≥ 10 s if there was a significant oxyhemoglobin desaturation (decrease by at least 3% from the immediately preceding baseline value) according to the latest recommendations of the American Academy of Sleep Medicine [23]. Moreover, total number of significant desaturations was scored, and the oxygen desaturation index (ODI) was calculated as the number of significant desaturations per hour of estimated sleep. Minimum SpO₂ and time spent below 90% SpO₂ (TS90%) values were also recorded. OSA was defined as an apnea-hypopnea index (AHI) ≥ 15 events/h of the total estimated sleep time, based on the latest International Classification of Sleep Disorders -3[24], when OSA-related symptoms are absent. All HSATs were scored by the same physician (Y.P.), blinded to patient demographics, clinical characteristics, and results of the pulmonary function tests and HRCTs.

Descriptive statistics are given as means ± SD and categorical variables as numbers (percentages). Comparison of categorical variables was done using the chi-squared test, and when appropriate, the Fisher exact test. Differences in means between groups were analyzed by Student t test, and when there was a skewed distribution, the Mann-Whitney U test was used. Pearson correlation coefficients were calculated for analyzing the associations between continuous variables of the pulmonary function tests, Warrick scores, mPAD values, and sleep recordings. A logistic regression analysis was used to test the association between OSA and pulmonary involvement as well as enlarged mPAD. All variables that were significant in the bivariate analyses were subsequently included in the multivariate model, and odds ratios (ORs) with 95% confidence intervals (CI) were calculated from the regression coefficients. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Sciences, version 25.0 for Windows® system (SPSS® Inc., Chicago, IL, USA).

First, the total number of patients in this single-center study is not sufficient for a proper prevalence study, and the results should be interpreted cautiously. However, scleroderma is a rare disease, and our clinical cohort is, indeed, to date, the largest sample in literature. Second, we did not perform a full-night PSG, and type 3–level HSAT might have resulted in an underestimation of OSA diagnosis due to overestimation of total sleep time. However, a cutoff level of AHI 15 events/h has been shown to be reliable for OSA diagnosis in the absence of OSA-related symptoms with this kind of diagnostic equipment [35]. Third, we did not perform right heart catheterization, which is the gold standard for the establishment of pulmonary hypertension diagnosis [33]. However, its risks and disadvantages have also been discussed [8]. Chest CT is routinely conducted for investigation of pulmonary involvement, and mPAD may be used in combination with echocardiography for further consideration of right heart catheterization in selected cases. Finally, a prospective follow-up study to evaluate the clinical significance of the used cutoff values for mPAD with regard to reproducibility as well as changes in response to CPAP treatment in the OSA subgroup could give better insights for the mechanisms involved in the development of pulmonary hypertension in patients with scleroderma.