Abstract
Objectives:
Systemic sclerosis is a severe and rare chronic auto-immune multisystem disorder characterized by vasculopathy and skin stiffness. Ethnic and geographical origin can influence the outcomes. In this study, we compared the phenotypic characteristics of Iranian and French patients.
Methods:
This cross-sectional study was performed on 200 Iranian and 268 French systemic sclerosis patients. Iranian patients collected from the Iranian systemic sclerosis cohort of the Rheumatology Research Center, Shariati hospital, Tehran University of Medical Sciences. The French population was monocentric, and it was constituted by the patients included locally in the EUSTAR database in December 2016.
Results:
The mean age at onset was significantly lower in Iranian patients (35.58 ± 11.68 vs 47.06 ± 13.54, p-value < 0.001). The female-to-male ratio was approximately 5.2:1 and was not different in the two populations. The prevalence of diffuse cutaneous systemic sclerosis was significantly higher in Iranian patients (60.2% vs 42.85%, p-value < 0.001). Calcinosis cutis and joint synovitis were more prevalent in French patients (p-value = 0.013, <0.001). The positivity of anti-topoisomerase antibody was higher in Iranian patients, whereas the anti-centromere antibody predominated in French cases (p-value < 0.001). Restrictive pattern of pulmonary function test was more common in Iranian patients (p-value < 0.001), while estimated pulmonary arterial pressure by echocardiography was higher in French patients (p-value < 0.001).
Conclusion:
It seems that systemic sclerosis occurred in younger ages among Iranian female with the predominance of diffuse cutaneous subtype. In addition, lung interstitial disease appeared to be more prevalent and severe in Iranians than French patients.
Keywords: Scleroderma, systemic, registries, Iran, France
Introduction
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by the triad of vascular involvement, immune system dysregulation and fibrosis. 1 Its etiology is highly unclear, and it can be presented with a diverse spectrum of clinical manifestations. Similar to other auto-immune disorders; the environmental factors can trigger an auto-reactive immune response in susceptible genetic background. To date, several environmental and genetic factors are thought to play a pathogenic role in SSc, and combinations of both factors could explain the great heterogeneity among different patients and populations. 1
It was shown previously that Black population has a higher prevalence of SSc with worse prognosis and more advanced disease. 2 Some clues about various profiles of cytokines and auto-antibody positivity may contribute to more severe disease with a high probability of genetic influence, but social and economic aspects may also influence the disease process. 3 Several pieces of evidence exist regarding specificities of SSc clinical presentation in Asian populations which sound to be different from the other ethnicities. It was reported previously that Asian SSc population have an earlier age at onset with a higher prevalence of telangiectasia and pulmonary involvement. 4 There might be also a trend toward lower prevalence of anti-centromere antibody (ACA) in this group. Different Asian cohorts can further support these findings. According to the report of Singapore SSc cohort, SSc patients had higher prevalence of diffuse cutaneous systemic sclerosis (dcSSc), more severe pulmonary arterial hypertension (PAH), and lower disease onset age than non-Asian population. 5 In line with this study, the frequency of dcSSc and female disease onset age in Japanese cohort, is partially similar to mentioned cohort but the auto-antibodies profile was divergent. 6
As it was indicated, ethnicity-dependent variations in SSc clinical spectrum take us a guide to better investigate the areas which contribute more deeply in SSc development. 7 In this study, we have conducted a survey to compare the disease characteristics, demographic features and serologic markers between Iranian and French patients based on the EULAR Scleroderma Trials and Research Group (EUSTAR) database template. According to highly divergent environmental and genetic differences of mentioned nations, it appears that this comparison can help us to uncover factors with probable role in SSc pathogenesis.
Material and method
Study population
This cross-sectional study consists of 268 French and 200 Iranian patients. The Iranian patients were selected from the Iranian SSc registry that is established in the Shariati hospital, the excellence referral center of Rheumatology in Iran, which is affiliated to Tehran University of Medical Sciences. The patients in the French population were all from Caucasian origin and they were derived from the rheumatology department of Cochin Hospital, which is a center of reference for the Ile de France regional area. The recruited patients were those included locally in the EUSTAR database. 8 These are unselected patients giving their consent to participate in a cohort study based on an annual visit including a multi-organ assessment. The French patients were all from the Caucasian origin. The Iranian patients were composed of 36.5% from Fars, 33.5% from Turk, 14% from Lor, 9% from Kurd, 3% from Gilac, and 4% from other ethnicities (Bakhtiari, Arab, Armani, and Gorgi).
All the patients fulfilled the 2013 classification criteria for SSc: an American College of Rheumatology/European League against Rheumatism (ACR/EULAR) collaborative initiative. 9 The patients’ data were compared according to the EUSTAR template and definitions. 8 All the patients were randomly selected from the cohorts, and the individuals with incomplete data were excluded from the study. All the patients were anonymous upon analyses and all the results were published in a cluster.
Clinical and laboratory data
Iranian SSc patients’ data were extracted from the SSc registry of Shariati hospital. Demographic features, clinical findings, and laboratory data are collected and entered into the registry by two experienced staff who were previously trained by a rheumatologist. These variables were formatted according to EUSTAR template. 8 The clinical and laboratory data were all at the time of inclusion in the study. Disease duration was considered from the first non-Raynaud’s symptom to the time of the study. Pulmonary function tests, electrocardiography and lung high-resolution computed tomography (HRCT) were performed by the same instruments for all patients. Echocardiography was used to assess left ventricle ejection fraction and pulmonary arterial pressure (PAP), and estimated PAP higher than 40 mm Hg was considered as probable PAH. 10 Moreover, the treatment regimen of the patients at the time of the study was also included.
Statistical analysis
In this study, variables were checked for having the normal distribution by Shapiro–Wilk test. Later, analyses were performed using independent t-test, Mann–Whitney test, chi-square test, Pearson’s and Spearman’s correlation tests. P-value < 0.05 was considered to be statistically significant. Nevertheless, the Benjamini and Hochberg method was used to adjust the p-values and control for false discovery rate. 11 In this work, statistical analyses have been done by the statistical package SPSS, version 22 (SPSS Inc, Chicago IL, USA).
Results
Demographic features
Demographic features of patients are shown in Table 1. Among Iranian population, patients were diagnosed significantly in younger age in comparison with French patients (35.58 ± 11.68 years vs 47.0 ± 13.5 years, p-value < 0.001). In addition, the majority of the Iranian patients had dcSSc (60.2%), whereas the French population predominantly had cases with limited cutaneous systemic sclerosis (lcSSc; 57.1%). The gender distribution was similar in two populations with the female to male ratio of 5.2:1. Moreover, French group included individuals with higher disease duration compared with Iranian counterparts (12.4 ± 12.3 years vs 7.2 ± 5.7 years, p-value < 0.001).
Table 1.
Demographic feature of patients.
| Variable | French (N: 268) | Iranian (N: 200) | p-value | OR (CI 95%) |
|---|---|---|---|---|
| Age at onset (years) | 47.06 ± 13.54 | 35.58 ± 11.68 | <0.001 | – |
| Disease duration (years) | 12.4 ± 12.3 | 7.28 ± 5.78 | <0.001 | – |
| Sex (female, %) | 84.01 | 84.00 | 0.997 | 0.999 (0.606–1.646) |
| SSc subtype (dcSSc, %) | 42.85 | 60.20 | <0.001 | 2.017 (1.380–2.948) |
SSc: systemic sclerosis; dcSSc: diffuse cutaneous systemic sclerosis; OR: odds ratio; CI: confidence interval.
Clinical and laboratory data
The comparison between clinical and laboratory data of the whole patients is reported in Table 2. Among clinical manifestations, joint synovitis and calcinosis were more prevalent in French population (p-value adj < 0.001 and 0.013, respectively). Moreover, the serological profile of the two populations was thoroughly different. Iranian patients were more seropositive for anti-topoisomerase I antibody (ATA), whereas the French patients had higher seropositive individuals for ACA. Nonetheless, the prevalence of anti-nuclear antibody (ANA) and anti-RNA polymerase III antibody (ARA) were comparable between the two groups. Furthermore, the estimated PAP was significantly higher in French population (32.5 ± 13.1 vs 27.8 ± 9.8, t(337) = 3.745, p-value adj < 0.001). Moreover, the prevalence of probable PAH was 6% and 9.5% in Iranian and French patients, respectively, which was not statistically different (data not shown). In addition, the pericardial effusion was detected more prevalently by echocardiography among French patients (10.4% vs 3.1%, p-value adj = 0.041). Mann–Whitney test indicated that percentage of forced vital capacity (FVC) was lower in Iranian SSc patients than in the French group (p-value adj < 0.001).
Table 2.
Clinical and laboratory data of all Iranian and French patients.
| Variables | French (total: 268) |
Iranian (total: 200) |
p-value adj | OR (CI 95%) | ||
|---|---|---|---|---|---|---|
| Number (%), mean ± SD, median (IQR25–75) | MD (%) | Number (%), mean ± SD, median (IQR25–75) | MD (%) | |||
| Sex (female, %) | 226 (84.01) | 0 (0) | 168 (84) | 0 (0) | 0.997 | 0.999 (0.606–1.646) |
| Subtype (dcSSc, %) | 108 (42.85) | 16 (5.97) | 118 (60.2) | 4 (2) | <0.001 | 2.017 (1.380–2.948) |
| RP | 256 (95.88) | 1 (0.37) | 192 (96) | 0 (0) | 0.984 | 1.031 (0.407–2.613) |
| Esophageal symptoms | 198 (74.15) | 1 (0.37) | 146 (73) | 0 (0) | 0.876 | 0.942 (0.622–1.427) |
| Gastric symptoms | 41 (15.29) | 0 (0) | 44 (22) | 0 (0) | 0.121 | 1.562 (0.974–2.503) |
| Intestinal symptoms | 81 (30.22) | 0 (0) | 51 (25.5) | 0 (0) | 0.391 | 0.790 (0.524–1.192) |
| Joint synovitis | 46 (17.16) | 0 (0) | 12 (6.09) | 3 (1.5) | <0.001 | 0.313 (0.161–0.608) |
| Muscle weakness | 7 (2.61) | 0 (0) | 11 (5.64) | 5 (2.5) | 0.172 | 2.229 (0.848–5.858) |
| Telangiectasia | 68 (49.63) | 131 (48.88) | 100 (50.50) | 2 (1) | 0.946 | 1.035 (0.670–1.601) |
| Calcinosis | 19 (17.59) | 160 (59.7) | 14 (7.07) | 2 (1) | 0.013 | 0.356 (0.171–0.743) |
| Palpitation | 44 (16.41) | 0 (0) | 42 (21.31) | 3 (1.5) | 0.049 | 1.686 (1.067–2.662) |
| Systemic HTN | 35 (13.05) | 0 (0) | 21 (10.93) | 8 (4) | 0.632 | 0.818 (0.460–1.454) |
| Renal crisis | 5 (1.86) | 0 (0) | 3 (1.5) | 0 (0) | 0.876 | 0.801 (0.189–3.392) |
| Serum creatinine (mg/dL) | 0.84 ± 0.21 | 148 (55.22) | 0.90 ± 0.67 | 9 (4.5) | 0.518 | – |
| ANA | 247 (93.2) | 3 (1.11) | 151 (86.78) | 26 (13) | 0.049 | 0.478 (0.250–0.916) |
| ATA | 84 (32.06) | 6 (2.23) | 107 (62.57) | 29 (14.5) | <0.001 | 3.543 (2.365–5.307) |
| ACA | 72 (27.27) | 4 (1.49) | 16 (10.38) | 46 (23) | <0.001 | 0.309 (0.172–0.555) |
| ARA | 8 (4.67) | 97 (36.19) | 2 (2) | 100 (50) | 0.391 | 0.416 (0.087–1.998) |
| Conduction block | 27 (11.25) | 28 (10.44) | 38 (28.78) | 68 (34) | <0.001 | 3.189 (1.840–5.526) |
| Arrhythmia | 1 (1.92) | 216 (80.59) | 5 (3.81) | 69 (34.5) | 0.633 | 2.024 (0.231–17.752) |
| LVEF (%) | 63.71 ± 4.48 | 95 (35.44) | 56.04 ± 4.66 | 19 (9.5) | <0.001 | – |
| ePAP (mm Hg) | 32.52 ± 13.15 | 103 (38.43) | 27.81 ± 9.81 | 27 (13.5) | <0.001 | – |
| Pericardial effusion | 16 (10.45) | 115 (42.91) | 4 (3.12) | 72 (36) | 0.041 | 0.276 (0.090–0.848) |
| Lung fibrosis | 86 (33.85) | 14 (5.22) | 60 (37.97) | 42 (21) | 0.521 | 1.196 (0.761–1.808) |
| Restrictive defect | 54 (25.71) | 58 (21.64) | 127 (79.37) | 40 (20) | <0.001 | 11.118 (6.795–18.191) |
| FVC (% predicted) | 98 (84–113) | 114 (42.53) | 75 (60–87.75) | 32 (16) | <0.001 | – |
RP: Raynaud’s phenomenon; HTN: arterial hypertension; ANA: anti-nuclear antibody; ATA: anti-topoisomerase antibody; ACA: anti-centromere antibody; ARA: anti-RNA polymerase III antibody; LVEF: left ventricular ejection fraction; ePAP: estimated pulmonary arterial pressure; FVC: forced vital capacity; dcSSc: diffuse cutaneous systemic sclerosis subtype; SD: standard deviation; IQR: interquartile range (25–75); MD: missing data number.
p-value adj : adjusted by Benjamini and Hochberg method and significant values were bold.
Comparison according to SSc subtypes, ATA, and disease duration
To further investigate the impact of SSc subtypes, we have compared the disease characteristics of two populations separately for each subtype which is shown in Tables 3 and 4. It appears that inside dcSSc group, joint synovitis was more manifested in French patients. However, among serological profile, the prevalence of ATA, ACA, and ARA was similar, but the Iranian population had the higher percentage of seronegative cases for ANA (p-value adj = 0.035). Including clinical manifestations, according to Mann–Whitney test, the percentage of FVC was lower in Iranian SSc patients than in the French group (median = 70 vs. 89, p-value adj < 0.001). Moreover, the mean estimated PAP was higher in the French patients (32.67 ± 12.25 vs 27.79 ± 9.60, p-value adj = 0.018). Meanwhile different results were obtained inside lcSSc group. The prevalence of joint synovitis did not differ among two populations. On the contrary, considering serological profile, the Iranian patients were more seropositive for ATA, indeed the ACA was detected more prevalently in French patients. The mean estimated PAP did not differ significantly, but the mean percentage of FVC was lower in the Iranian patients (U = 998.50, p-value adj < 0.001). In addition, the clinicodemographic variables were compared separately in two populations based on ATA seropositivity, which is shown in Tables 5 and 6. Among Iranian population, it was a trend toward the higher prevalence of ATA among dcSSc cases which lost its significance after adjustment (p-value = 0.008 and p-value adj = 0.121). Indeed, in French patients, ATA was significantly higher among dcSSc subtype with odds ratio (OR) = 18.429 and 95% confidence interval (CI) = 9.293–36.547 (p-value adj < 0.001). Moreover, the ATA seropositivity was significantly associated with interstitial lung disease (ILD) in both populations. The rest of the clinical findings were not correlated with ATA neither in Iranian, nor in the French population. In addition, the disease characteristics were also compared between two populations according to disease duration. The set point of five years was considered, and results are shown in Supplementary data 1 and 2. In line with previous results, the mean percentage of FVC was lower in Iranian patients independent of disease duration.
Table 3.
Clinical and laboratory data of Iranian and French patients with diffuse cutaneous systemic sclerosis.
| Variable | French (total: 108) |
Iranian (total: 118) |
p-value adj | OR (CI 95%) | ||
|---|---|---|---|---|---|---|
| Number (%), mean ± SD, median (IQR25–75) | MD (%) | Number (%), mean ± SD, median (IQR25–75) | MD (%) | |||
| Sex (female, %) | 78 (72.2) | 0 (0) | 97 (82.2) | 0 (0) | 0.189 | 1.777 (0.944–3.343) |
| RP | 103 (96.3) | 1 (0.9) | 112 (94.9) | 0 (0) | 0.738 | 0.725 (0.199–2.642) |
| Esophageal symptoms | 83 (77.6) | 1 (0.9) | 90 (76.3) | 0 (0) | 0.885 | 0.929 (0.499–1.730) |
| Gastric symptoms | 12 (11.1) | 0 (0) | 34 (28.8) | 0 (0) | 0.004 | 3.238 (1.576–6.655) |
| Intestinal symptoms | 28 (25.9) | 0 (0) | 31 (26.3) | 0 (0) | 0.953 | 1.018 (0.562–1.845) |
| Joint synovitis | 21 (19.4) | 0 (0) | 6 (5.2) | 2 (1.7) | 0.004 | 0.226 (0.087–0.584) |
| Muscle weakness | 3 (2.8) | 0 (0) | 5 (4.3) | 3 (2.5) | 0.687 | 1.591 (0.371–6.824) |
| Telangiectasia | 25 (43.9) | 51 (47.2) | 64 (54.7) | 1 (0.8) | 0.358 | 1.546 (0.817–2.924) |
| Calcinosis | 8 (16.3) | 59 (24.6) | 10 (8.5) | 1 (0.8) | 0.305 | 0.479 (0.177–1.298) |
| Palpitation | 20 (18.5) | 0 (0) | 30 (25.6) | 1 (0.8) | 0.362 | 1.517 (0.801–2.874) |
| Systemic HTN | 13 (12) | 0 (0) | 8 (7.1) | 5 (4.2) | 0.362 | 0.557 (0.221–1.402) |
| Renal crisis | 2 (1.9) | 0 (0) | 3 (2.5) | 0 (0) | 0.818 | 1.383 (0.227–8.436) |
| Serum creatinine (mg/dL) | 0.84 ± 0.19 | 54 (50) | 0.91 ± 0.86 | 5 (4.23) | 0.705 | – |
| ANA | 102 (96.2) | 2 (1.9) | 89 (86.4) | 15 (12.7) | 0.035 | 0.249 (0.079–0.785) |
| ATA | 70 (66.7) | 3 (2.8) | 73 (71.6) | 16 (13.6) | 0.608 | 1.259 (0.697–2.274) |
| ACA | 2 (1.9) | 2 (1.9) | 4 (4.5) | 29 (24.6) | 0.424 | 2.447 (0.438–13.685) |
| ARA | 5 (7.9) | 45 (41.7) | 2 (3.2) | 55 (46.6) | 0.371 | 0.380 (0.071–2.038) |
| Conduction block | 9 (9.1) | 9 (8.3) | 23 (31.5) | 45 (38.1) | <0.001 | 4.600 (1.977–10.704) |
| Arrhythmia | 1 (4.5) | 86 (79.6) | 4 (5.5) | 45 (38.1) | 0.897 | 1.217 (0.129–11.494) |
| LVEF (%) | 63.35 ± 5.36 | 40 (37.03) | 55.96 ± 4.64 | 11 (9.32) | <0.001 | – |
| ePAP (mm Hg) | 32.67 ± 12.25 | 45 (41.66) | 27.79 ± 9.60 | 14 (11.86) | 0.018 | – |
| Pericardial effusion | 5 (8.6) | 50 (46.3) | 3 (3.8) | 39 (33.1) | 0.371 | 0.418 (0.096–1.827) |
| Lung fibrosis | 63 (59.4) | 2 (1.9) | 41 (43.2) | 23 (19.5) | 0.060 | 0.518 (0.296–0.908) |
| Restrictive defect | 39 (45.3) | 22 (20.4) | 72 (76.6) | 24 (20.3) | <0.001 | 3.944 (2.082–7.472) |
| FVC (% predicted) | 89 (70.50–99.50) | 47 (43.51) | 70 (57–86) | 19 (16.10) | <0.001 | – |
RP: Raynaud’s phenomenon; HTN: arterial hypertension; ANA: anti-nuclear antibody; ATA: anti-topoisomerase antibody; ACA: anti-centromere antibody; ARA: anti-RNA polymerase III antibody; LVEF: left ventricular ejection fraction; ePAP: estimated pulmonary arterial pressure; FVC: forced vital capacity; SD: standard deviation; IQR: interquartile range (25–75); MD: missing data number.
p-value adj : adjusted by Benjamini and Hochberg method and significant values were bold.
Table 4.
Clinical and laboratory data of Iranian and French patients with limited cutaneous systemic sclerosis.
| Variable | French (total: 144) |
Iranian (total: 78) |
p-value adj | OR (CI 95%) | ||
|---|---|---|---|---|---|---|
| Number (%), mean ± SD, median (IQR25–75) | MD (%) | Number (%), mean ± SD, median (IQR25–75) | MD (%) | |||
| Sex (female, %) | 133 (92.4) | 0 (0) | 68 (87.2) | 0 (0) | 0.284 | 0.562 (0.228–1.390) |
| RP | 137 (95.1) | 0 (0) | 77 (98.7) | 0 (0) | 0.279 | 3.934 (0.475–2.348) |
| Esophageal symptoms | 109 (75.7) | 0 (0) | 54 (69.2) | 0 (0) | 0.368 | 0.722 (0.391–1.334) |
| Gastric symptoms | 26 (18.1) | 0 (0) | 9 (11.5) | 0 (0) | 0.286 | 0.592 (0.262–1.336) |
| Intestinal symptoms | 48 (33.3) | 0 (0) | 19 (24.4) | 0 (0) | 0.279 | 0.644 (0.346–1.200) |
| Joint synovitis | 22 (15.3) | 0 (0) | 6 (7.8) | 1 (1.3) | 0.206 | 0.469 (0.181–1.210) |
| Muscle weakness | 3 (2.1) | 0 (0) | 6 (7.9) | 2 (2.6) | 0.094 | 4.029 (0.978–16.587) |
| Telangiectasia | 39 (59.1) | 78 (54.2) | 34 (44.2) | 1 (1.3) | 0.150 | 0.547 (0.281–1.065) |
| Calcinosis | 10 (20) | 94 (65.3) | 3 (3.9) | 1 (1.3) | 0.013 | 0.162 (0.042–0.623) |
| Palpitation | 20 (13.9) | 0 (0) | 19 (25) | 2 (2.6) | 0.094 | 2.067 (1.024–4.170) |
| Systemic HTN | 22 (15.3) | 0 (0) | 11 (14.5) | 2 (2.6) | 0.905 | 0.938 (0.429–2.055) |
| Renal crisis | 3 (2.1) | 0 (0) | 0 (0) | 0 (0) | 0.284 | – |
| Serum creatinine (mg/dL) | 0.86 ± 0.23 | 88 (61.1) | 0.88 ± 0.18 | 3 (3.8) | 0.566 | – |
| ANA | 132 (91.7) | 0 (0) | 62 (91.2) | 10 (12.8) | 0.905 | 0.939 (0.337–2.619) |
| ATA | 14 (9.8) | 1 (0.7) | 34 (51.5) | 12 (15.4) | <0.001 | 9.790 (4.704–20.375) |
| ACA | 63 (44.1) | 1 (0.7) | 12 (15.4) | 16 (20.5) | 0.005 | 0.305 (0.150–0.621) |
| ARA | 3 (3.1) | 47 (32.6) | 0 (0) | 42 (53.8) | 0.368 | – |
| Conduction block | 18 (14.1) | 16 (11.1) | 15 (26.3) | 21 (26.9) | 0.095 | 2.183 (1.009–4.723) |
| Arrhythmia | 0 (0) | 119 (82.6) | 1 (1.3) | 22 (28.2) | 0.566 | – |
| LVEF (%) | 63.71 ± 3.89 | 50 (34.7) | 56.36 ± 4.73 | 8 (10.3) | <0.001 | – |
| ePAP (mm Hg) | 32.92 ± 14.43 | 52 (36.1) | 28.07 ± 10.26 | 11 (14.1) | 0.070 | – |
| Pericardial effusion | 11 (12.9) | 59 (41) | 1 (2.1) | 30 (38.5) | 0.094 | 0.143 (0.018–1.145) |
| Lung fibrosis | 22 (16.5) | 11 (7.6) | 19 (30.6) | 16 (20.5) | 0.078 | 2.229 (1.099–4.524) |
| Restrictive defect | 15 (13.3) | 31 (21.5) | 53 (82.8) | 14 (17.9) | < 0.001 | 31.479 (13.498–73.411) |
| FVC (% predicted) | 103 (93–118) | 61 (42.4) | 76 (67–90) | 11 (14.1) | < 0.001 | – |
RP: Raynaud’s phenomenon; HTN: arterial hypertension; ANA: anti-nuclear antibody; ATA: anti-topoisomerase antibody, ACA: anti-centromere antibody; ARA: anti-RNA polymerase III antibody; LVEF: left ventricular ejection fraction; ePAP: estimated pulmonary arterial pressure; FVC: forced vital capacity; SD: standard deviation; IQR: interquartile range (25–75); MD: missing data number.
p-value adj : adjusted by Benjamini and Hochberg method and significant values were bold.
Table 5.
Clinical and laboratory data of Iranian patients regarding anti-topoisomerase antibody seropositivity.
| Variable | ATA positive (total: 107) |
ATA negative (total: 64) |
p-value adj | OR (CI 95%) | ||
|---|---|---|---|---|---|---|
| Number (%), mean ± SD, median (IQR25–75) | MD (%) | Number (%), mean ± SD, median (IQR25–75) | MD (%) | |||
| Sex (female, %) | 90 (84.1) | 0 (0) | 53 (82.8) | 0 (0) | 0.918 | 1.099 (0.479–2.522) |
| Subtype (dcSSc, %) | 73 (68.2) | 0 (0) | 29 (47.5) | 0 (0) | 0.121 | 2.369 (1.241–4.523) |
| RP | 105 (98.1) | 0 (0) | 60 (93.8) | 0 (0) | 0.322 | 3.500 (0.623–19.678) |
| Esophageal symptoms | 76 (71.0) | 0 (0) | 53 (82.8) | 0 (0) | 0.304 | 0.509 (0.235–1.101) |
| Gastric symptoms | 26 (24.3) | 0 (0) | 8 (12.5) | 0 (0) | 0.268 | 2.247 (0.948–5.323) |
| Intestinal symptoms | 26 (24.3) | 0 (0) | 16 (25.0) | 0 (0) | 0.918 | 0.963 (0.470–1.974) |
| Joint synovitis | 4 (3.8) | 2 (1.8) | 5 (7.9) | 1 (1.5) | 0.50 | 0.459 (0.119–1.779) |
| Muscle weakness | 2 (1.9) | 3 (2.8) | 7 (11.7) | 1 (1.5) | 0.121 | 0.157 (0.032–0.781) |
| Telangiectasia | 55 (52.4) | 2 (1.8) | 32 (50.0) | 0 (0) | 0.918 | 1.100 (0.591–2.049) |
| Calcinosis | 5 (4.7) | 1 (0.9) | 6 (9.4) | 0 (0) | 0.50 | 0.479 (0.140–1.637) |
| Palpitation | 22 (21.0) | 2 (1.8) | 14 (21.9) | 0 (0) | 0.918 | 0.947 (0.444–2.017) |
| Systemic HTN | 7 (6.8) | 4 (3.7) | 10 (16.1) | 2 (3.1) | 0.268 | 0.379 (0.136–1.055) |
| Renal crisis | 2 (1.9) | 0 (0) | 1 (1.6) | 0 (0) | 0.918 | 1.200 (0.107–13.504) |
| Serum creatinine (mg/dL) | 0.85 (0.7–0.98) | 1 (0.9) | 0.8 (0.7–0.9) | 4 (6.2) | 0.890 | – |
| Conduction block | 21 (30.9) | 39 (36.4) | 10 (23.8) | 22 (34.3) | 0.775 | 1.430 (0.595–3.436) |
| Arrhythmia | 3 (4.4) | 39 (36.4) | 1 (2.4) | 22 (34.3) | 0.825 | 1.892 (0.190–18.812) |
| LVEF (%) | 55.0 (55.0–60.0) | 10 (9.3) | 55.0 (55.0–60.0) | 4 (6.2) | 0.825 | – |
| ePAP (mm Hg) | 25.0 (20.0–31.75) | 21 (19.6) | 26.0 (20.0–34.0) | 9 (14.0) | 0.825 | – |
| Pericardial effusion | 4 (5.8) | 38 (35.5) | 0 (0) | 23 (32.8) | 0.322 | – |
| Lung fibrosis | 34 (39.5) | 21 (19.6) | 14 (26.9) | 12 (18.7) | 0.322 | 1.775 (0.836–3.757) |
| Restrictive defect | 69 (79.3) | 20 (18.7) | 39 (75.0) | 12 (18.7) | 0.825 | 1.278 (0.566–2.885) |
| FVC (% predicted) | 72.29 ± 20.81 | 25 (23.3) | 78.66 ± 17.48 | 9 (14.0) | 0.268 | – |
RP: Raynaud’s phenomenon; HTN: arterial hypertension; ANA: anti-nuclear antibody; ATA: anti-topoisomerase antibody; ACA: anti-centromere antibody; ARA: anti-RNA polymerase III antibody; LVEF: left ventricular ejection fraction; ePAP: estimated pulmonary arterial pressure; FVC: forced vital capacity; dcSSc: diffuse cutaneous systemic sclerosis subtype; SD: standard deviation; IQR: interquartile range (25–75); MD: missing data number.
p-value adj : adjusted by Benjamini and Hochberg method and significant values were bold.
Table 6.
Clinical and laboratory data of French patients regarding anti-topoisomerase antibody seropositivity.
| Variable | ATA positive (total: 84) |
ATA negative (total: 178) |
p-value adj | OR (CI 95%) | ||
|---|---|---|---|---|---|---|
| Number (%), mean ± SD, median (IQR25–75) | MD (%) | Number (%), mean ± SD, median (IQR25–75) | MD (%) | |||
| Sex (female, %) | 60 (71.4) | 0 (0) | 160 (89.9) | 0 (0) | <0.001 | 0.281 (0.143–0.555) |
| Subtype (dcSSc, %) | 70 (83.3) | 0 (0) | 35 (21.3) | 14 (7.8) | <0.001 | 18.429 (9.293–36.547) |
| RP | 81 (97.6) | 1 (1.1) | 170 (95.5) | 0 (0) | 0.607 | 1.906 (0.396–9.179) |
| Esophageal symptoms | 60 (72.3) | 1 (1.1) | 134 (75.3) | 0 (0) | 0.751 | 0.857 (0.475–1.544) |
| Gastric symptoms | 6 (7.1) | 0 (0) | 34 (19.1) | 0 (0) | 0.052 | 0.326 (0.131–0.810) |
| Intestinal symptoms | 18 (21.4) | 0 (0) | 61 (34.3) | 0 (0) | 0.122 | 0.523 (0.285–0.959) |
| Joint synovitis | 20 (23.8) | 0 (0) | 24 (13.6) | 1 (0.5) | 0.122 | 1.992 (1.028–3.859) |
| Muscle weakness | 1 (1.2) | 0 (0) | 5 (2.8) | 1 (0.5) | 0.607 | 0.414 (0.048–3.604) |
| Telangiectasia | 20 (46.5) | 41 (48.8) | 46 (51.7) | 89 (50.0) | 0.751 | 0.813 (0.392–1.685) |
| Calcinosis | 4 (13.3) | 54 (64.2) | 13 (17.3) | 103 (57.8) | 0.751 | 0.734 (0.219–2.462) |
| Palpitation | 14 (16.7) | 0 (0) | 29 (16.3) | 0 (0) | 0.939 | 1.028 (0.511–2.066) |
| Systemic HTN | 12 (14.3) | 0 (0) | 23 (12.9) | 0 (0) | 0.798 | 1.123 (0.530–2.382) |
| Renal crisis | 2 (2.4) | 0 (0) | 3 (1.7) | 0 (0) | 0.771 | 1.423 (0.233–8.679) |
| Serum creatinine (mg/dL) | 0.9 (0.7–1.0) | 47 (55.9) | 0.8 (0.7–0.9) | 97 (54.4) | 0.532 | – |
| Conduction block | 7 (8.9) | 5 (5.9) | 20 (12.9) | 23 (12.9) | 0.607 | 0.656 (0.265–1.625) |
| Arrhythmia | 1 (5.3) | 65 (77.3) | 0 (0) | 158 (88.7) | 0.448 | – |
| LVEF (%) | 65.0 (60.0–65.0) | 26 (30.9) | 65.0 (60.0–65.0) | 66 (37.0) | 0.595 | – |
| ePAP (mm Hg) | 30.0 (26.0–37.0) | 29 (34.5) | 30.0 (25.0–33.0) | 70 (39.3) | 0.754 | – |
| Pericardial effusion | 3 (6.0) | 34 (40.47) | 13 (13) | 78 (43.8) | 0.448 | 0.427 (0.116–1.575) |
| Lung fibrosis | 48 (59.3) | 3 (3.5) | 35 (21.2) | 12 (6.7) | <0.001 | 5.444 (3.050–9.716) |
| Restrictive defect | 28 (42.4) | 18 (21.4) | 26 (18.6) | 38 (21.3) | <0.001 | 3.231 (1.690–6.175) |
| FVC (% predicted) | 95.0 (70.25–113.75) | 36 (42.8) | 99.0 (89.0–114.0) | 75 (42.1) | 0.132 | – |
RP: Raynaud’s phenomenon; HTN: arterial hypertension; ANA: anti-nuclear antibody; ATA: anti-topoisomerase antibody; ACA: anti-centromere antibody; ARA: anti-RNA polymerase III antibody; LVEF: left ventricular ejection fraction; ePAP: estimated pulmonary arterial pressure; FVC: forced vital capacity; dcSSc: diffuse cutaneous systemic sclerosis subtype; SD: standard deviation; IQR: interquartile range (25–75); MD: missing data number.
p-value adj : adjusted by Benjamini and Hochberg method and significant values were bold.
Comparison according to lung involvement
To better compare the severity of pulmonary involvement, the median percentage of FVC level was compared between the two populations in whom the HRCT or chest x-ray (CXR) confirmed the SSc-related ILD (data not shown). According to the Mann–Whitney U test, the median percentage of FVC level was significantly lower in Iranian patients with ILD than in French patients (median = 43.43 vs 56.94, p-value = 0.02). In addition, the frequency of different New York Heart Association (NYHA) functional classifications was compared between Iranian and French patients (Supplementary data 3). Among the entire patients and dcSSc subtype group, frequency of NYHA functional classes were not significantly different between the two populations with the p-value of 0.165 and 0.760, respectively. Nonetheless, distribution of patients in NYHA functional classes was significantly dissimilar in lcSSc subtype group (p-value = 0.022). Furthermore, the FVC, estimate PAP and lung fibrosis of patients were also compared between two populations based on NYHA functional classes (Supplementary data 4). In both populations, the FVC-predicted percentage and estimated PAP were associated with NYHA functional classes. Moreover, the ILD prevalence was correlated with NYHA functional classes in French population (p-value = <0.001), but no association was identified among Iranian patients (p-value = 0.199).
Treatment regimen
At the time of the study, 100% of the Iranians were receiving an immunosuppressive and steroid. Among the Iranian population, 21% were on cyclophosphamide (CYC), 38% on mycophenolate mofetil (MMF), 22% on azathioprine (AZA), 17% on methotrexate (MTX), and 3% on rituximab (RTX). Meanwhile, 30.6% of the French patients were receiving an immunosuppressive agent: 0% CYC, 2.5% MMF, 4.2% AZA, 16% MTX, and 7.9% RTX (Supplementary data 5). The percentage of patients receiving vasoactive agents including calcium channel blockers (CCBs), phosphodiesterase (PDE)-5 inhibitors, endothelin receptor antagonists (ERAs), prostacyclin analog, angiotensin-converting enzyme inhibitor (ACEI), and angiotensin II receptor blocker (ARB) is also shown in Supplementary data 5. Among the Iranian patients, 82% were prescribed with CCB, 20% with PDE-5 inhibitors, 5.5% with ERA, and 22.5% with ACEI/ARB. In comparison, 84.5% of French patients were on CCB, 6.7% on PDE-5 inhibitor, 5.5% on ERA, and 12.9% on ACEI/ARB.
Discussion
The aim of this study was to compare the disease characteristics of two different populations of Iran and France. Upon the analyses, regarding demographic features, the mean age at onset in the Iranian population was approximately 12 years earlier than French patients. According to a worldwide global analysis published in 2009, it was reported that the mean age at onset is 34 and 48 years in Asian and European patients, respectively. 4 However, reports from the Asian cohorts indicate the age at onset of 39 years in Malaysia, 46 years in Singapore, 47 years in Japan, 49 years in Thailand and Turkey, and 51 years in Taiwan.5,6,12–15 Moreover, the mean age at onset of Raynaud’s phenomenon (RP) and first non-RP were 42 and 46 years, respectively, in EUSTAR cohort. 16 According to these results, although it seems that the age at onset is lower in Asian countries, the Iranians affect at younger ages which appears to be significantly different from its Asian counterparts. 17 In addition, the proportion of cases with dcSSc subtype was also significantly higher in the Iranian population. The Iranian patients were collected in Shariati hospital, which is the national center of excellence in Rheumatology that patients recruited from all over the country. Rheumatology’s center at Cochin hospital is also an expert hospital with broad recruitment, but Paris hosts some other expert centers for SSc and related disorders. Therefore, some differences might be explained by referral bias. Most of the previous cohort-based studies reported that the lcSSc constitute more than half of the patients and the dcSSc percentage was in a range of 18% (Sweden) to 38% (Singapore).6,7,13,15,16,18,19 Nonetheless, data from data from Chinese and Thai cohorts reported the prevalence of 59.7% and 68.6% for dcSSc, respectively.20,21 The higher rate of dcSSc in Iranian patients compared to most of the Asian studies can be either due to referral bias or due to genetic variations that need to be further investigated. Moreover, the gender distribution was similar between Iranian and French population. The female-to-male ratio was reported ranging from 1:1 to 14:1 in different studies. 22 In this work, this ratio was approximately 5:1, which is similar to the data in EUSTAR database (6:1) 16 and certain Asian countries,5,14,20,23 indeed the more female predominance was reported in Turkey and Japan with the female-to-male ratio of 13:1 and 10:1, respectively.6,15
Regarding the comparison of auto-antibody profiles, the Iranian patients were more seropositive for ATA, whereas the French cases had higher level of ACA. After stratification of the patients based on their SSc cutaneous subtype mentioned differences were only replicated for lcSSc group, and dcSSc cases did not show any difference regarding their auto-antibody profile. The prevalence of ATA was reported between 15%–42% in different studies which is mainly associated with dcSSc, lung fibrosis, and poor prognosis. 24 In this work, the ATA prevalence was 32% in French patients which is similar to the prevalence reported in the EUSTAR cohort (36.8%). 16 Nevertheless, 62.5% of Iranian patients were seropositive for ATA that is greatly different from the major Asian countries reported approximately a mean of 29%. 4 However, studies published on Chinese and Thai patients showed a prevalence of 59.9% and 85.7% for ATA, respectively.20,21 In addition, the ACA prevalence was 10.3% and 27.2% in Iranian and French patients, respectively. Its prevalence in the French population was compatible with previously reported works on Europeans, but its distribution is variable among Asian countries ranging from 12% in Singapore to 40% in Japan.5,6,15,16,20 In our study, the ATA and ACA prevalence was not different in dcSSc patients, but the differences among lcSSc group seem to be related to genetic factors which need further investigations. The prevalence of ARA was 4.6% in French patients and 2% in Iranians. Its prevalence is highly variable ranging from 0% to 41%, which seems to take effect from geographic distribution. 25 ARA was detected in 7% (95% CI = 5–9) in Asia and 9% (95% CI = 6–13) in Europe, 25 and consequently, the lower seropositive cases in this study appears to be related to a low number of cases with an available full panel of laboratory data.
In this study, pulmonary involvement, including lung fibrosis and alveolitis were detected by HRCT, and the percentage of FVC was considered as a severity index measured by the spirometer. The prevalence of pulmonary involvement on HRCT was similar in both populations even after regrouping based on SSc subtype and disease duration. However, the median percentage of FVC was lower in Iranians than in French patients in all of the analyzing groups. Lung fibrosis was detected in approximately 38% and 33% of Iranian and French patients, respectively. Certain studies reported that lung involvement is more prevalent in Asian patients, but they did not compare the severity of the involvement. 4 Among Asian cohorts, reports indicate a heterogeneous result ranging from 34% in Turkish patients, which is similar to Iranians followed by a prevalence of nearly 50% in patients from Japan and Singapore.5,6,15 Nonetheless, none of these studies measured the severity of pulmonary involvement. The lung fibrosis diagnosed by HRCT was reported in 52% of EUSTAR cohort, which is not compatible with the results of this study. 16 Although, it is reported previously that White patients have a lower prevalence of pulmonary involvement with less severe disease than African-American and Hispanic patients. 26 Hence, according to our study, it appears that the prevalence of pulmonary involvement is similar in Iranian and French populations, but it is more severe in Iranian patients, which is independent of SSc subtype and disease duration. We have considered several hypotheses which can probably explain this difference. First, it can be due to the referral bias of the Iranian cohort that the patients of this study collected from the Rheumatology center of excellence of Iran containing referral complicated patients. Second, the technical reasons can be contributed. For the spirometer instrument, there are no data from healthy Iranian cohort to calibrate calculate FVC volume and percentage (%) predicted, which is therefore calculated according to the international data. Based on limited previous studies, it seems that normal Iranian population also has lower pulmonary function volumes compared to reference values of American Thoracic Society. 27 In addition, environmental factors, including air pollution and dusts, may also influence lung capacities, which are thought to be affected in Iran, but this would require further investigations. Finally, the sedentary lifestyle of Iranians possibly contributes to reducing the cardiopulmonary capacity. 28
In this study, the prevalence of articular involvement in the form of arthritis was diagnosed clinically in 6% and 17% of Iranian and French patients (p-value adj < 0.001), respectively. According to a meta-analysis, the prevalence of clinical arthritis was 23%, and it was diagnosed more frequently in Asian patients than in European patients.4,29 The prevalence of synovitis among our French patients was similar to previously reported in European descendent. 16 On the contrary, limited studies from Asian countries reported variable results ranging from 9% in Thailand, 29% in Turkey, and 71% in China.15,30,31 The statistically different prevalence of arthritis between the two nations of this study may come from the routine prescription of low-dose steroid for the SSc patients in Iran. This can probably justify the lower prevalence of pericardial effusion among Iranian patients than in French cases (3% vs 10.4%, p-valueadj = 0.041).
In this work, the prevalence of probable PAH (estimate PAP > 40) was 6% and 9.5% in Iranian and French patients, respectively, which was not statistically different. Nevertheless, the mean estimated PAP was higher in French population. Based on the method used to evaluate PAH, its prevalence can broadly vary. 32 According to a meta-analysis including 3818 patients, the prevalence of PAH was estimated to be 9%, which is compatible with our findings. 33 In line with this finding, PAH was recorded in 5% of European Caucasian patients. 33 On the contrary, PAH was reported more frequently in Asian countries, ranging from 16% in Japan, 20% in Iraq, 24% in Singapore, 32% in India, 43% in Turkey, and 59% in Thailand.5,6,15,34–36 It must be pointed out that these variable results can be related to different detection method and dissimilar definitions for PAH, although it is established that only right heart catheterization can provide a meaningful diagnosis. 37 In general, it seems that probable PAH was detected less frequently in Iranian patients than in other Asian countries. This finding could be related to the high prescription rate of PDE-5 inhibitors in Iranian patients for reasons other than PAH including RP and digital ulcers. At the time of data collection, 20% of the Iranian and 6.7% of French patients were receiving PDE-5 inhibitor.
In addition, the association of clinicodemographic features with ATA was also investigated in this study. In the French population, ATA was significantly more detected among patients with ILD, whereas it was not correlated with FVC-predicted percentage. Among Iranian population, ILD was identified in 39.5% of ATA-positive patients in comparison to 26.9% of ATA negative cases, but it did not reach statistical significance (p-value = 0.132, p-value adj = 0.322 and OR (95% CI) = 1.775 (0.836–3.757)). It appears that this non-significant association comes from the low number of cases with available data for either ATA status and ILD diagnosis. The association of ATA and ILD was reported globally among Asian, European, Australian, and North American population.19,38–40 Nonetheless, this association was not detected in certain other countries including Brazil which is also probably linked to a low number of cases. 41 Moreover, ATA was not correlated in either population with lung involvement severity measured by FVC in our study. In line with this finding, prospective Norwegian SSc cohort did not show any association between ATA and annual FVC decline. 42 This result was also replicated in other studies as well.41,43 Nevertheless, several papers have reported the significant prognostic and predictive role of ATA for ILD progression.40,44,45 Furthermore, the result obtained in our study did not reveal any association between ATA and estimate PAP. Similarly, this correlation was not previously reported in African-American, Swedish, and Australian SSc patients.40,46,47 Moreover, evidence did not support the association between ATA and survival of patients with SSc-related PAH. 48
In a treatment point of view in Iran, all of the patients prescribed with an immunosuppressive agent plus low-dose steroid. At the time of the study, 100% of the Iranians were receiving an immunosuppressive and steroid. The principle immunosuppressive agent is selected according to the extent of cutaneous and pulmonary involvements. Patients with MRSS below 14 scores and spared lung will be put on MTX or AZA. Patients with pulmonary involvement (diagnosed by HRCT and/or PFT) will be prescribed with CYC, MMF, or RTX which will be chosen according to the severity of the lung involvement and the fertility saving desire of the patients. It is noticeable to mention that all of the medications mentioned in EULAR recommendations for the treatment of SSc are prescribed and available in Iran. 49 Meanwhile, 30.6% of the French patients were receiving an immunosuppressive agent. Guidance is based on skin and lung extent, the trend of changes with time, and disease duration. Overall, the higher disease duration may be a key explanation of lower rate of immunosuppressant in the French patients because their use is temporarily restricted to the earliest years of the disease.
This study was conducted primarily to compare the clinical and laboratory manifestations of Iranian and French patients. This work is the first investigation showing the characteristics of Iranian patients by using the EUSTAR template as a structured and validated method. In addition, the number of participants was sufficient enough to reach a preliminary result to conduct further studies. Although the research has reached its aim, it also had certain limitation which is necessary to mention. First, as it was discussed previously, discrepancies between the referral systems may concentrate more severe patients in Iranian center than in French center. One might add that availability of the most specialized Iranian physician in Shariati hospital may also promote the inclusion of more complicated cases in the Iranian center. Furthermore, according to the Iranian referral system, the Rheumatology Research Center of Shariati hospital hosts patients from all over the country in addition to Tehran province. Whereas, patients solely for Ile de France regional area were admitted to Cochin hospital which significantly covers lower population in comparison to Shariati hospital. Second, the lack of reference values for pulmonary function parameters of normal Iranian population can profoundly influence interpretation of the results of this study. Finally, in this work, the PAP was estimated by echocardiography. Although it is the key screening tool for pulmonary hypertension diagnosis, the right heart catheterization remains the gold standard in diagnosis algorithm. 50
In conclusion, this study showed that Iranian patients are affected at a younger age with a higher proportion of dcSSc and more severe lung involvement. In this study, the referral bias can have influenced the findings, but geographical or genetic explanations cannot be ruled out and will need further investigations. To the best of our knowledge, this is the first report showing the clinical and laboratory characteristics of Asian Iranian patients using a structured and validated method of assessment that might help in the future to stratify risk SSc patients.
Supplemental Material
Supplemental material, Supplementary_data for Comparison of the clinical phenotype of systemic sclerosis patients in Iran and France in two university centers by Yannick Allanore, Farhad Gharibdoost, Ahmad Reza Jamshidi, Ali Javinani, Jérôme Avouac, Elnaz Rastkar, Sadid Hooshmandi and Hoda Kavosi in Journal of Scleroderma and Related Disorders
Footnotes
Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. In addition, informed consent was obtained from all individual participants included in the study.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Hoda Kavosi 
https://orcid.org/0000-0003-4762-6943
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Supplementary Materials
Supplemental material, Supplementary_data for Comparison of the clinical phenotype of systemic sclerosis patients in Iran and France in two university centers by Yannick Allanore, Farhad Gharibdoost, Ahmad Reza Jamshidi, Ali Javinani, Jérôme Avouac, Elnaz Rastkar, Sadid Hooshmandi and Hoda Kavosi in Journal of Scleroderma and Related Disorders