Pulmonary hypertension screening in patients with systemic sclerosis, in a tertiary center, in Turkey; a cross-sectional original study

Amac: Sistemik Sklerozda (SS) Pulmoner Hipertansiyon (PH) gelisimi hastaligin survisini onemli olcude azaltmaktadir ve erken tani ve tedavi cok onemlidir. Calismamizda SS tanisiyla romatoloji klinigi tarafindan takip ve tedavi altinda olan ve ve bilinen PH tanisi olmayan hastalarin PH varligi acisindan taranmasi amaclanmistir. Gerec ve Yontemler: Bu kesitsel calisma SS tanisi olan 51 hasta ve cinsiyet ve komorbidite acisindan benzer ozellikte 51 gonulluden olusan kontrol grubuyla tamamlandi. Demografik, laboratuvar ve ekokardiyografik verileri kayit edildi. Bulgular: Sistemik skleroz hasta grubunun ortanca yasi 53 (46-60), kontrol grubunun 50 (45-55) idi. SS hastalarinin 42 (%82,4)’si kadin, kontrol grubunun 39 (%76,5)’si kadin cinsiyetten olusmaktaydi. Transtorasik ekokardiyografide pulmoner arter basinci yuksek saptanan (>40 mmHg) 3 hastaya sag kalp kateterizasyonu yapildi. Ikisinde grup 1 PH (%3,9); birinde grup 2 PH (%1,9) saptandi Sonuc: Calismamizda, tersiyer bir merkezde sistemik skleroz tanisiyla takipli ve tedavi altinda olan 51 hastada %5,8 oraninda pulmoner hipertansiyon saptamis bulunmaktayiz. Bu hastalarin belirli sikliklarla PH taramasindan gecirilmis olmasina ragmen bu bulguya ulasmamiz dikkat cekicidir. Muhtemelen sinirda pulmoner arter basinc yuksekligi olan hizli progresyon gosteren hastalari saptadigimizi dusunmekteyiz. Calismamiz, sinirda pulmoner arter basinc yuksekligi olan SS hastalarinin daha sik taranmasi gerektigini desteklemektedir.


Introduction
Systemic sclerosis (SS) is a systemic disease of unknown with multiple organ and tissue system involvement, skin being the most common target, and results inflammation, vasculopathy and fibrosis. The most differentiating characteristic of the disease is skin fibrosis called scleroderma, however it may also involve internal organs such as the gastrointestinal tract, kidney, lung and heart, therefore it is termed as systemic sclerosis.
Lung involvement is one of the most severe and lethal organ involvement. Pulmonary hypertension (PS) is another lethal complication that is frequent in SS(1). In SS, the incidence of pulmonary arterial hypertension (PAH) is reported to be 10-15% (2-4) and 3 years of survival has been reported in patients with PAH developed (5). Although SS patients with PAH have been known to have poorer treatment response than idiopathic PAH patients, recent studies showed that similar responses can be achieved with aggressive treatment (6,7). Early diagnosis and treatment is critical in SS related PAH and it is recommended to screen the patients for PH in their follow-ups (8).
In our study, we aimed to investigate the presence of PH in patients who were followed and treated in our hospital with the diagnosis of SS and who did not have a known diagnosis of PH.

Material and Methods
This is a cross-sectional study that aims to investigate the presence of pulmonary hypertension in patients who are being treated with systemic sclerosis diagnosis. Fifty-one patients aged 18 years and over who had admitted to Dışkapı Training and Research Hospital and been treated and followed up for at least 3 years by the Rheumatology outpatient clinic with the diagnosis of Systemic Sclerosis were included in the study. SS diagnosis was based on the diagnostic criteria of American College of Rheumatology (9). The control group of the study consisted 51 subjects with similar age and gender. Autoimmune disease, cardiac valve disease, structural, coronary and congenital heart diseases, arrhythmias, active infection, lung disease, thyroid disease, malignancy, kidney failure, liver disease, electrolyte disorders and pregnancy have been determined as exclusion criteria for the formation of SS patient and control groups. SS and control groups were similar in terms of the presence of hypertension, diabetes mellitus, hyperlipidemia. Moreover, patients who had known severe pulmonary involvement and those with prior diagnosis of pulmonary hypertension were excluded from the SS patient group.
Venous blood samples were obtained from peripheral antecubital vein after 10 hours of fasting.
Whole blood count, fasting blood glucose, renal function tests and erythrocyte sedimentation rate and CRP values were tested. In addition, antinuclear antibody (ANA), anticentromere antibody (ACA) and anti SCL70 antibody tests results were also included as retrospective autoimmune antibody tests.
Height and weight measurements of all participants were made and body mass indexes were calculated. Diagnosis year, medications used and comorbidities were recorded, and patients were classified in terms of diffuse and limited scleroderma involvement (9).
Informed consent forms were obtained from all patients.
Helsinki Declaration was adhered in the study. Approval of the hospital ethical committee was obtained.

Echocardiographic examination
Transthoracic echocardiographic examinations were performed by using a 2.5-5 MHz transducer with Philips iE33 system (Andover, MA, USA) echocardiographic imaging device. With the widest area at the end of systole, the right atrium area in apical 4-chamber view was measured by tracing the right atrium endocardium from the lateral of tricuspid annulus to septal annulus, excluding the area between the leaflets and the annulus, inferior and superior caval veins and apendix (11).
Color Doppler was used to evaluate valvular insufficiency.
Left ventricular diastolic filling patterns were evaluated, E and A peak flow rates were recorded and deceleration time was calculated by using pulse-flow Doppler examination.  Kolmogorov-Smirnov test was used to determine the normal distribution of the data. Student t-test or Mann-Whitney U test was used for numerical variables and chi-square test was used for categorical data.

Results
Total of 102 patients, 51 systemic sclerosis patients and 51 healthy subjects, were included in the study. Demographic characteristics and laboratory results of both groups and the overall population are shown in Table 1. The median age of the systemic sclerosis group was 53 (46-60) years and control group was (45-55) years and there was no significant difference between the groups (p=0.182). There were 42 (82.4%) female patients. In the SS group, number and ratio of hypertensive patients was 16 (31.4%) and 18 (35.3%) in the control group (p=0.834). Median erythrocyte sedimentation rate of the SS group was 20 (15-29.7) mm/h and median ESR of the control group was 8 (7-10) and this difference was statistically significant (p<0.001). Median CRP of the SS group was 4.5 (2.6-10.5) mg/dl and median CRP of the control group was 4.5 (2.6-10.5) and the difference was statistically significant (p=0.001).
Clinical and serological features of the systemic sclerosis patients are shown in Table 2. There was diffuse cutaneous involvement in 22 (43.1%) patients and limited cutaneous involvement in 29 (56.9%) patients. The median diagnosis year of the patients was 5 (3-9) years. In SS group ANA positivity ratio was 78.4%, anticentromere antibody positivity was 25.5%, anti=SCL 70 antibody positivity was 17 Table 3. There was no difference between the groups in terms of left ventricular end diastolic diameter and left ventricular end systolic diameter. The comparison of left atrium diameter revealed median left atrium diameter of 3.4 (3.1-3.7) in the SS group and 2.9 (2.9-3.1) in the control group, and the difference was statistically significant (p<0.001).
The evaluation of mitral diastolic filling patterns showed that E/A ratio was 0.931±0.357 in the SS group and 1.377±0.245 in the control group and the difference was statistically significantly lower (p<0.001). In tissue Doppler examination, mitral lateral annulus Em velocity was 9.7±2.9 cm/s and statistically significantly lower than the control group, which was 12.7±2.3 cm/s (p<0.001). E/Em ratio was 7±2.8 in the SS group and 6.3±1.6 in the control group, and the difference was not statistically significant (p=0.179). Right heart catheterization was performed for 3 patients who had been detected to have high pulmonary artery pressure.
One patient had mean pulmonary artery pressure=32 mmHg; PCEP=8 mmHg, PVR=4 WU, minimal interstitial lung disease finding in the thorax tomography and FVC was >70% in SFT. Therefore, the patient was considered as group 1 PH and endothelium antagonist treatment was started.

Discussion
Based on the results of this cross-sectional study, pulmonary hypertension was detected in 5.8% of the study population by randomized cross-sectional screening of patients with systemic sclerosis who were receiving treatment and being follow-up and had no known diagnosis of pulmonary hypertension.
These patients had been closely monitored in a tertiary center and pulmonary hypertension was thought to be excluded in them, therefore detecting pulmonary hypertension in three patients is worthy of attention.
Therefore, the prevalence of PH may be higher in these previous studies. In another study, it was reported that patients with DLCO≥80% may still have PH (28). In our patients detected with PH, we believe that PH may be excluded in rheumatologic follow-up in a similar way.

Limitation of the study
We believe that the cross-sectional design of our study was a limitation. A prospective study where SS patients are followed up and incidence of PH is determined in addition to its prevalence could have been more valuable. Due to our study design, we were unable to access the previous echocardiography and other examinations in rheumatology follow-up and therefore could not evaluate the rate and duration of PH development. The PASP 40 mmHg threshold value for the right heart catheterization indication may be a high threshold and therefore the prevalence of PH could be lower than its actual value.

Conclusion
In our study, we detected pulmonary hypertension in 5.8% of 51 patients who have been treated and monitored with systemic sclerosis diagnosis in a tertiary center. Two of these three patients were in 1 PH class and one was in 2 PH class.
It is noteworthy that we have detected PH in patients who had been closely monitored, screened for pulmonary HT in their follow-up visits and thought to be excluded in terms of PH. We believe that our study supports the notion that the presence of pulmonary hypertension, a serious condition that significantly increases morbidity and mortality in systemic sclerosis, should be evaluated with more detailed algorithms and that especially the patients with borderline pulmonary artery systolic pressure should be more closely monitored.