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Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037 Presse Med. 2019; //: ///
Original article
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Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study Raida Ben Salah 1, Faten Frikha 1, Hend Hachicha 2, Imen Chabchoub 1, Chifa Dammak 1, Mona Snoussi 1, Moez Jallouli 1, Sameh Marzouk 1, Hatem Masmoudi 2, Zouhir Bahloul 1
Received 2 May 2017 Accepted 30 July 2019 Available online:
1. Hedi Chaker Hospital, department of internal medicine, 3029 Sfax, Tunisia 2. Habib Bourguiba Hospital, laboratory of immunology, 3029 Sfax, Tunisia
Correspondence: Raida Ben Salah, Hedi Chaker Hospital, department of internal medicine, 3029 Sfax, Tunisia. [email protected]
Summary Objective > The Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in North Africa. Our objective was to describe a SSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies with other international SSc populations. Methods > In this retrospective observational study, Folders of patients with SSc seen in the internal medicine section of the Hedi Chaker Hospital between 2000 and 2013 were retrospectively analyzed. The diagnosis of SSc was retained according to ACR/EULAR 2013 criteria. Patients were classified into diffuse cutaneous SSc and limited cutaneous SSc subsets. Comparison with other cohorts was made based on published information. Results > A higher female: male ratio (8:1) and a higher diffuse subset prevalence (82%) was found in this Tunisian cohort comparing with others. We also found a lower prevalence of calcinosis and anticentromere antibodies. Within each subset, diffuse cutaneous and limited cutaneous scleroderma clinical findings were similar with other systemic sclerosis populations except for a very low prevalence in renal crisis and pulmonary hypertension. Our results indicate overlap syndrome defined as scleroderma associated with others connective tissue disorder's is a relatively common condition. Conclusion > With slight variations, perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other part of the world.
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tome xx > n8x > xx 2019 https://doi.org/10.1016/j.lpm.2019.07.037 © 2019 Elsevier Masson SAS. All rights reserved.
LPM-3926
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
Résumé Caractéristiques cliniques et immunologiques de la sclérodermie systémique en Tunisie : une étude observationnelle Objectifs > La prévalence de la sclérodermie systémique et ses différentes formes cliniques est variable dans le monde. Peu de séries publiées ont étudié cette pathologie en Afrique du Nord. Notre objectif a été d'étudier les caractéristiques de la sclérodermie systémique dans une cohorte tunisienne en comparant également les particularités cliniques et immunologiques de notre série par rapport aux autres séries de la littérature. Méthodes > Il s'agissait d'une étude rétrospective observationnelle qui a colligé tous les de patients ayant une sclérodermie systémique hospitalisés dans un service de médecine interne du CHU Hédi Chaker — Sfax — Tunisie sur une période allant de 2000 à 2013. Le diagnostic de la SSc était retenu en se référant aux critères ACR/EULAR 2013. Les patients sclérodermiques étaient classés selon l'étendue de la sclérose cutanée en forme cutanée diffuse et cutanée limitée. Une comparaison avec les autres séries de la littérature a été effectuée en se basant sur les données publiées. Résultats > Une prépondérance féminine a été notée (8 F/1H) ainsi qu'une fréquence plus élevée des formes diffuses (82 %) dans cette cohorte tunisienne comparativement aux autres séries de la littérature. Nous avons également observé une fréquence plus faible de la calcinose et des anticorps anti-centromère. Dans les deux formes de la sclérodermie cutanée diffuse et cutanée limitée, les manifestations cliniques étaient similaires avec d'autres séries de la littérature, à l'exception d'une très faible prévalence de la crise rénale et de l'hypertension pulmonaire. Le syndrome de chevauchement défini par l'association de la sclérodermie à une autre connectivite était relativement fréquent dans notre série. Conclusion > À part de légères différences pouvant être expliquées par des facteurs génétiques, environnementaux, la sclérodermie systémique dans cette cohorte tunisienne semble être similaire aux autres séries de la littérature.
Introduction Systemic sclerosis (SSc) also known as Scleroderma is an uncommon but serious chronic connective tissue disease with heterogeneous clinical presentation and severity. It is characterized by autoimmunity (production of auto antibodies), inflammation, small-vessel vasculopathy and fibroblast dysfunction leading to progressive skin fibrosis, and organ involvement, including the heart, the lungs, the gastrointestinal tract, and the kidneys [1]. SSc is more common in females; the female-to-male ratio is 3:1 when women are of childbearing age. Based on the extent of skin fibrosis, patients with SSc are classified into limited
Glossary
2
SSc lcSSc dcSSc ANA ILD RP
systemic sclerosis limited cutaneous SSc diffuse cutaneous SSc antinuclear antibodies interstitial lung disease Raynaud's phenomen
cutaneous SSc (lcSSc), in which the skin lesions do not extend beyond the elbows and knees in the absence of skin tautness of the arms, chest, abdomen, back, or thighs (which defines dcSSc), and diffuse cutaneous SSc (dcSSc) subsets [2–4]. Because of its rarity and heterogeneous clinical presentation, the epidemiological features of SSc are difficult to characterize. Our objective was to describe aSSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies profile with other international SSc populations.
Methods Patients All consecutive SSc patients seen at department of the internal medicine of Hedi Chaker Hospital in the period between January 2000 and December 2013 were included; we selected those who met the American College of Rheumatology/European League Against Rheumatism ACR/EULAR 2013 classification criteria for SSc [5]. For classification into subsets we followed the Leroy 2001 criteria for classification of diffuse and localized disease subset [3]. Following data were obtained: age, gender, disease duration from the onset of symptoms attributable to
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
SSc, clinical evaluation of organ involvement, routine blood tests including erythrocyte sedimentation rate, complete blood count, serum creatinine, liver function test and tests for antinuclear antibodies (ANA).
Definition of organ involvement SSc clinical manifestations were considered to be present if predefined criteria were met during the course of the illness. Involvement of skin: the maximum extension of the skin involvement at any one time during the course of the disease was considered to define subsets (lcSSc vs. dcSSc). Organ involvement definitions were the following: upper gastrointestinal tract: manometry with esophageal dismotility, esophagram with gastroesophagic reflux or upper endoscopy with esophagitis; suspected pulmonary hypertension: echocardiogram B with estimated pulmonary systolic artery ˃ 35 mm Hg in the absence of other causes of secondary pulmonary hypertension (pulmonary involvement, valvopathies. . .); Interstitial lung disease (ILD): pulmonary interstitial disease observed in chest X-ray and/or high resolution computerized tomography; echocardiographic alterations: left or right ventricular diastolic dysfunction in the absence of arterial hypertension or pulmonary hypertension respectively, or pericardial effusion; digital ulcers: active digital ulcers or pitting scars confirmed by a physician; renal involvement: history of scleroderma renal crisis (abrupt onset of accelerated arterial hypertension and/or rapidly progressive renal failure).
Autoantibodies Laboratory detection methods were immunofluorescence on Hep2 cells for antinuclear and anticentromere antibodies; enzyme linked immunosorbent assay (Elisa) for anti-topoisomerase-I antibodies (anti-Scl-70). ANA dilutions greater or equal to 1/160 were considered positive.
Statistical analysis Categorical data were expressed in percentages, whereas continuous variables were presented using means standard
deviation when the distribution was normal, and using median and ranks when it was not. Chi2 analysis was used to determine significant differences between sets of categorical data. A Pvalue < 0.05 was considered statistically significant. The statistical package used was SPSS, v.20. Ethical approval was not necessary because the study was retrospective.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
Results Seventy-seven patients with SSc had been evaluated at the department of internal medicine (table I). The Female/male ratio was 8:1. The mean age at the time of diagnosis was 40.5 15 years (15–92 years). At the time that this study was performed, the average time of evolution (calculated using the age at onset of symptoms) was 72 months. Over half (55.1%) were still under our care. Six have died in our hospital during this period. All patients had skin involvement. This later revealed the disease in 63 patients (81.8%). The frequency of SSc late onset age over 65 years was 17.4% (6 cases). Regarding gender ratios, men were more commonly affected than women in the dcSSc subset than the lcSSc subsets. Baseline clinical and serological characteristics for the entire SSc group (n = 77), for the dcSSc group (n = 63) and for the lcSSc group (n = 14) are shown in table II.
Clinical manifestations The most common clinical sign found was Raynaud'sphenomen (RP); it was found in 90.5% of patients with diffuse SS, but only in 42.9% of patients with the limited form. Localized calcinosis was found in 6 patients. Digital ulcers and pigmentation disorders occurred in respectively in 26 and 45 cases. Digital ulcers, calcinosis and pigmentation disorders was similar in both subtypes; although conditions such as interstitial lung disease (ILD) were more common in diffuse disease: 55.6% of diffuse vs. 21.4% of limited cutaneous subset (P = 0.03). ILD was seen in 49.4% of the patients, revealing the SS in 5 cases (6.5%). In other cases, it appeared after 20.4 3 months (0–108 months). Regarding respiratory symptoms, 26 patients reported dyspnea. Cough was present in 14 patients. The postero-anterior
TABLE I General characteristics Type of systemic sclerosis
Limited cutaneous SSc
Diffuse cutaneous SSc
Number
14
(18.2%)
63
(81.8%)
Female
13
(92%)
56
(87.5%)
Mean age at diagnosis, years The interval of time between disease onset and diagnosis (months)
P
0.5
36 13
41 25
0.24
16.4
25.5
0.1
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3
SSc: Systemic sclerosis.
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
TABLE II Clinical and serological features in this Tunisian SSc cohort Limited cutaneous SSc
Diffuse cutaneous SSc
P
All over
Number
14
18.2
63
81.8
Raynaud phenomena, %
6
42.9
57
90.5
0.01
80.5
Digital ulcers, %
2
14.3
18
28.6
0.2
26
Telangiectasia's, %
1
7.1
6
9.5
0.6
9.1
Calcinosis, %
0
0
6
9.5
0.2
7.8
Antinuclear antibody, %
12
85.7
52
91.2
Anti-SCL-70, %
1
7.1
23
40.4
0.02
33.8
Anticentromeres, %
2
14
6
10.5
0.6
11.3
Interstitial lung involvement, %
3
21.4
35
55.6
0.03
49.4
Gastrointestinal manifestations, %
2
14.3
47
74.6
0.01
63.6
Articular involvement, %
4
28.6
37
58.7
0.04
53.2
Cardiac involvement, %
0
0
8
12.7
0.48
10.4
Renal involvement, %
0
0
1
1.5
0.5
1.2
77
90
SSc: Systemic sclerosis.
chest X-ray images were suggestive of fibrotic changes in the lungs in 24.7% of the population with diffuse SS. For economic reasons, high resolution computerized tomography was performed only in 21 patients. It showed lung fibrosis (figure 1) in 4 cases and ILD in 20 cases. Gastrointestinal manifestations were frequent. They had appeared in 49 patients (63.6%). Dysphagia and gastrointestinal
Figure 1
4
Interstitial lung disease in scleroderma patient
reflux were presented respectively in 36 (46%) and 15 patients (18%). Clinical signs of malabsorption were found in 2 patients. Renal involvement was rare. Only, one patient had scleroderma renal crisis. Two patients had only essential hypertension. Pulmonary arterial hypertension was suspected in 6 cases. The other manifestations were pericarditis (4 cases), heart failure (3 cases), myocarditis (1 patient) and heart rhythm disorder (2 cases). Forty-one patients (53.2%) had osteo-articular involvement. This was arthralgia in all cases, arthritis in 9 cases (11.7%), and resorption of phalangeal tufts in 18 cases (23.4%). ANA were positives in 61 cases (69.2%). table III gives details about the presence of each of these auto-antibodies. Anti-Scl-70 was the most frequent observed in 21 patients (27%). In the other cases, there was anti RNP (6 patients), anticentromeres (5 cases), anti-PM-Scl (2 cas), anti SSA and anti Ro52 in one case. Others immunological abnormalities were observed: rheumatoid factor (14 cases), cryoglobulinémia in ten cases and anticardiolipin antibodies in one patient only. Anticentromere antibodies were not associated with suspected pulmonary hypertension. On the other hand, ILD was more frequent in patients with anti-Scl-70 and diffuse clinical subset. Overlap syndrome, an entity that satisfies the criteria of at least two connective tissue diseases, was observed in 23%. Among 18 patients with overlap, 10 had dermatomyositis, 3 had Systemic lupus erythematosus and 5 had Sjogren syndrome. Others associations with autoimmune disease were observed: Hashimoto thyroiditis (2 cases), primary biliary cirrhosis (1 case). A
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
TABLE III Frequency of disease subsets and autoantibody profiles in different SS cohorts France [10]
United state [10]
Germany [12]
Italy [11]
Eustar [8]
Brazil [7]
Argentina [6]
Tunisia
Number
127
247
1438
1012
3656
947
234
77
Limited cutaneous, %
54
42
45.5
64
56.8
56.4
76.1
18
Diffuse cutaneous, %
19
47
32.7
14
43.1
31
23.9
82
Anti-Scl-70, %
35
22
27.6
36
28.1
16.1
16.2
27
Anticentromere, %
18
21
36.4
39
29.5
22.1
52.9
6.5
Discussion The current study is a large cross-sectional analysis of SSc disease subsets. When evaluating a rare disease such as SSc, the importance of disease registries lies in their ability to assist in the longitudinal observation of trends in disease presentation, management, and outcome. To our knowledge, this is the first study in SSc African patients in whom clinical and immunological characteristics have been defined for each cutaneous subset and differences between lcSSc and dcSSc were emphasized. We conducted a Pubmed review in order to find SSc cohorts with clear data published regarding visceral involvement, autoantibodies and disease subsets classification. For comparisons, we chose the limited data from Argentina [6] and that published from Brazil [7], the EULAR Scleroderma Trials and Research cohort [8] and cohorts from Mexico [9], US and France [10], Italy [11], Germany (Registry of the German Network for Systemic Sclerosis) [12] and Spain [13]. Frequencies of visceral involvement in diffuse and limited forms are shown in table III, the proportion of disease subsets and autoantibody profile in table IV. In the current large Tunisian cohort, we found a greater female preponderance: women outnumbered men by 8 to 1. This gender ratio is within the range reported in smaller cohorts from the UK and Japan (female: male ratio 3:1 and 14:1, respectively) [14,15] and is similar to that observed in the EUSTAR cohort [8]. In different cohorts, the frequency of dcSSis between 14 and 47% [6,8,10]. Contrastingly, in small series of African SSc patients, the dcSSc is the most frequent subset: 82% in Kenya [16], 65% in black South Africa [17] and 57.1% in Nigeria [18]. Sine scleroderma is rarely reported. We haven't any cases of this subset in our cohort. It was however not reported in the black African series of Tager and Tikly [17]. Epidemiological studies suggest that SSc is more common, occurs at a younger age and is more severe in African-Americans
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than Caucasians. In Pittsburgh Scleroderma Databank, the proportion of patients with diffuse skin changes was greater in African-American than in Caucasian patients (56% vs. 43%, P < 0.03) [19]. The higher frequency of diffuse scleroderma in African patients is again confirmed in our study, being present in 82% of cases in our cohort. LcSSc patients were younger at diagnosis than dcSSc subsets. The interval of time between disease onset and diagnosis was shorter for lcSSc than for dcSSc subsets (16.4 months vs. 25.5 months, P = 0.1) but not significant. This finding is different from other series. It was reported that the mean age of diagnosis of dcSSc subset is shorter than lcSSc. This is related to the progression of the skin thickening that occurs early in dcSSc [8,20]. We found some differences in visceral involvement. ILD was significantly more frequent in dcSSc than in lcSSc subtype. (21.4 vs. 55.6) and over the half of the all series suggesting that ILD is one of the most frequent visceral impairments in dcSSc patients. Within each disease subset, clinical manifestations were quite similar to other cohorts except for a very low prevalence for renal crisis (table IV). We believe that different referral patterns in different institutions may be in part responsible for these differences, aside from different genetic and or environmental backgrounds. Serum autoantibodies directed against a variety of intracellular antigens are present in more than 95% of patients and are considered a hallmark of SSc. They are usually present at disease onset and persist throughout the course of the disease [21]. Anti-topoisomerase I (Scl-70) and anti-RNA polymerase III are associated with dcSSc. In contrast, anticentromere antibodies occur in lcSSc. Other antibodies such as anti-U1 RNP, Pm/Scl, and Ku occur in overlap syndromes: anti-U1 RNP are associated with mixed connective tissue disease, anti-Pm-Scl with overlap myositis. Many of these autoantibodies are specific to nuclear antigens and represent important diagnostic and prognostic agents with strong association with demographic, clinical, organ system, and survival features [20–22]. For instance, ILD is associated with anti-topoisomerase I (Scl-70); digital necrosis and
5
neoplastic disorder was associated with SSc in two cases: pancreatic neoplasia and skin lymphoma.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
TABLE IV Clinical findings in different cohorts according to disease subset France [10]
United states [10]
Germany [12]
Italy [11]
Eustar [8]
Spain [13]
Argentina [6]
Tunisia
30
119
484
177
1349
243
56
63
Gastrointestinal manifestation %
79
67
69.3
69
68.2
71.2
64.3
63.6
ILD, %
57
30
56.1
71
53.4
70
65.3
55.6
Diffuse systemic sclerosis (n)
Isolated PH
12
2
18.5
NR
5.9
13.7
2.6
Renal crisis
7
17
15.8
12
4.2
7.8
0.02
1.5
Digital Ulcer
NR
NR
34.4
51
42.7
63.8
32.1
28.6
Calcinosis
16
23
NR
20
NR
NR
23.5
9.5
Cardiac involvement
10
11
12.7
10.3
NR
12.7
97
128
674
177
2101
568
178
14
Gastrointestinal manifestation %
63
67
59.2
55
66.8
57.3
64.5
14.3
ILD, %
39
37
20.8
53
34.7
39.3
26.7
21.4
Isolated PH
9
31
14.9
NR
9.2
8.8
7.3
0
Renal crisis
0
2
9.1
6
1.1
0.7
0
0
Digital Ulcer
NR
NR
23.8
43
32.9
39
28.1
14.3
Calcinosis
36
42
NR
22
NR
19.8
NR
0
Cardiac involvement
14
19
23
20.4
31.1
10
0
Limited systemic sclerosis (n)
ILD: interstitial lung disease; PH: pulmonary hypertension; NR: not reported.
6
pulmonary hypertension (unrelated to ILD) with anticentromere antibodies, anti-U3 RNP/fibrillarin, and renal crisis with antiRNA polymerase III [21]. In an Italian multicenter study of 1012 patients, 10-year survival rate was 72.2% in patients with anti-topoisomerase I, 85.9% in patients with anticentromere antibody, and 72.6% in patients with antinucleolar antibody (U3 RNP, NOR 90, or Pm-Scl). Tenyear survival was 75.1% in patients with lcSSc and 53.4% in those with dcSSc (P < 0.0001) [11]. A study of 275 patients in Japan showed that 10-year survival rate was 93% in patients with anticentromere antibodies, 72% with anti-U1 RNP, 66% with anti-topoisomerase I, and 30% with anti-RNA polymerase I [22]. In a recent Tunisian retrospective study analyzing ILD in SSc patients, among 65 cases of SSc over a period of 13 years, antibodies anti-Scl-70 were noted more frequently in patients with ILD (79% of the cases, P = 0.001) [23]. In our study, anticentromere antibodies were not associated with pulmonary isolated hypertension and with limited disease. Similar to other cohort, anti-Scl-70 antibodies were associated with ILD and diffuse cutaneous involvement [8,13]. Of the 77 patients, 23% were categorized as scleroderma overlap syndrome in our cohort. This frequency is in agreement with
other reported data, ranging between 10% and 38% [12,24–28]. The overlap syndrome is defined as an entity that satisfies the diagnostic criteria of at least two connective tissue diseases [25]. The most common combinations are systemic sclerosis with Sjogren's syndrome, overlap myositis, rheumatoid arthritis, and systemic lupus erythematosus. A combined pathology has impact on the clinical features, diagnosis and treatment. High steroid doses continue to be a major treatment in lifethreatening SLE, myositis and vasculitis. In overlap syndrome patients with diffuse skin involvement the steroid dosage should be modified because of possible provocation of renal crisis. Reduction in steroid dose may be achieved with aggressive immunosuppression including novel biological therapies [24]. Our results indicate that overlap syndrome is a relatively common condition. In our cohort SSc associated with overlap myositis was the most common combination: 11% of all SSc patients and 43% of overlap syndrome. In a Canadian cohort of 100 patients with inflammatory myopathy, 29% had features of SSc and constituted 42% of 24 overlap syndrome patients in this cohort [25]. Some authors showed that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement [28]. The absence of separation of overlap syndrome to the others subsets of SSc can be considered as a limitation in our study. There were some others limitations when comparing subsets and clinical data with other SSc populations. First of all, although our series is considered as a large cohort of SSc patients seen in a single center in south of Tunisia, the number is relatively small comparing to international series. In other hand, patients were not homogeneously classified in different cohorts: there wasn't similar cohort with the same genetic and environmental characteristics in Africa, in the German cohort [12] patients were classified into limited cutaneous, diffuse cutaneous, overlap syndromes, sclerosis sine scleroderma; Italian patients [11] were classified into limited cutaneous, intermediate cutaneous and diffuse cutaneous systemic sclerosis. We were not able to determine other SSc-related autoantibodies (i.e. RNAp III, U3RNP, etc) besides ANA, Scl-70 and anticentromere. Organ involvement was not defined similarly in all the cohorts. Another major limitation of this study is the lack of more accurate confirmation of pulmonary hypertension by right heart catheterization due to scarce resources. These limitations may also account for some of the differences we found. In spite of these possible differences, our data support the clinical and serologic characteristics found in SSc patients in Tunisia. The strength of this study is that it is the largest from North Africa to describe SSc patients. In our cohort of patients, the dcSSc subtype is the most frequent subtypes in the difference of the largest cohorts of SSc patients. Respiratory and gastrointestinal involvement were frequents affecting over the half of patients in our series while renal crisis and cardiac involvement were rare.
This distribution is similar to the studies conducted in black Africans patients. Contributions from genetic factors remains probable, which is an important aspect to be incorporated into anticipated prospective studies.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
Key message
To our knowledge, this is the first study in SSc north-African patients in whom clinical and immunological characteristics have been defined for each cutaneous subset and differences between lcSSc and dcSSc were emphasized.
Diffuse SSc is most frequently found in this cohort than the limited form.
Within each disease subset, clinical manifestations were quite similar to other cohorts except for a very low prevalence for renal crisis.
Interstitial lung disease and gastrointestinal involvement were frequents affecting over the half of patients in our series while renal crisis and cardiac involvement were rare.
Similar to other cohort, anti-Scl-70 antibodies were associated with ILD and diffuse cutaneous involvement.
Funding: None. Acknowledgement: we, authors of this manuscript would like to offer our special thanks to Professor Rania Khelil for her great help and constructive suggestions for revising the English language of this work. Disclosure of interest: the authors declare that they have no competing interest.
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7
[1]
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
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involvement. Rheumatology (Oxford) 2008;47:1185–92. Simoen CP, Fonolllosa V, Losa-Vilela. et al. Registry of the Spanish network for systemic sclerosis: clinical pattern according to cutaneous subsets and immunological status. Semin Arthritis Rheum 2012;41:789–800. Silman A, Jannini S, Symmons D, Bacon P. An epidemiological study of scleroderma in the West Midlands. Br J Rheumatol 1988;27:286–90. Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res 1991;283:366–71. Illovi CS, Oyoo GO. Characteristics of systemic sclerosis patients in Nairobi, Kenya: a retrospective study. Afr J Rheumatol 2013;1(1):8–12. Tager RE, Tikly M. Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in black South Africans. Rheumatology 1999;38(5):397–400. Adelowo OO, Oguntona S. Scleroderma (systemic sclerosis) among Nigerians. Clin Rheumatol 2009;28:1121–5.
[19] Steen VD. A clinical and serologic comparison of africanamerican and caucasian patients with systemic sclerosis. Arthritis Rheum 2012;64(9):2986–94. [20] Steen VD. The many faces of scleroderma. Rheum Dis Clin North Am 2008;34(1):1–15. [21] Meyer O. Prognostic markers for systemic sclerosis. Joint Bone Spine 2006;73(5):490– 4. [22] Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 1994;37:75–83. [23] Aydi Z, Rachdi I, Ben Dhaou B, Dridi M, Daoud F, Baili L, et al. Epidemiological, clinical and evolutionary peculiarities of interstitial lung disease in systemicsclerosis. Rev Pneumol Clin 2016;72(2):122–8. [24] Galluccio F, Ulrich A, Svetlana N, Moinzadeh, Hunzelmann, Krieg T, et al. Registries in systemic sclerosis: a worldwide experience. Rheumatology 2011;50:60–8.
[25] Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. IMAJ 2011;13 (1):14–20. [26] Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore) 2005;84:231–49. [27] Caramaschi P, Biasi D, Volpe A, et al. Coexistence of systemic sclerosis with other autoimmune diseases. Rheumatol Int 2007;27:407–10. [28] Moinzadeh P, Aberer E, Ahmadi-Simab K, Blank N. Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2015;74 (4):730–7.
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Original article
en ligne sur / on line on www.em-consulte.com/revue/lpm www.sciencedirect.com
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study Raida Ben Salah 1, Faten Frikha 1, Hend Hachicha 2, Imen Chabchoub 1, Chifa Dammak 1, Mona Snoussi 1, Moez Jallouli 1, Sameh Marzouk 1, Hatem Masmoudi 2, Zouhir Bahloul 1
Received 2 May 2017 Accepted 30 July 2019 Available online:
1. Hedi Chaker Hospital, department of internal medicine, 3029 Sfax, Tunisia 2. Habib Bourguiba Hospital, laboratory of immunology, 3029 Sfax, Tunisia
Correspondence: Raida Ben Salah, Hedi Chaker Hospital, department of internal medicine, 3029 Sfax, Tunisia. [email protected]
Summary Objective > The Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in North Africa. Our objective was to describe a SSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies with other international SSc populations. Methods > In this retrospective observational study, Folders of patients with SSc seen in the internal medicine section of the Hedi Chaker Hospital between 2000 and 2013 were retrospectively analyzed. The diagnosis of SSc was retained according to ACR/EULAR 2013 criteria. Patients were classified into diffuse cutaneous SSc and limited cutaneous SSc subsets. Comparison with other cohorts was made based on published information. Results > A higher female: male ratio (8:1) and a higher diffuse subset prevalence (82%) was found in this Tunisian cohort comparing with others. We also found a lower prevalence of calcinosis and anticentromere antibodies. Within each subset, diffuse cutaneous and limited cutaneous scleroderma clinical findings were similar with other systemic sclerosis populations except for a very low prevalence in renal crisis and pulmonary hypertension. Our results indicate overlap syndrome defined as scleroderma associated with others connective tissue disorder's is a relatively common condition. Conclusion > With slight variations, perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other part of the world.
1
tome xx > n8x > xx 2019 https://doi.org/10.1016/j.lpm.2019.07.037 © 2019 Elsevier Masson SAS. All rights reserved.
LPM-3926
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
Résumé Caractéristiques cliniques et immunologiques de la sclérodermie systémique en Tunisie : une étude observationnelle Objectifs > La prévalence de la sclérodermie systémique et ses différentes formes cliniques est variable dans le monde. Peu de séries publiées ont étudié cette pathologie en Afrique du Nord. Notre objectif a été d'étudier les caractéristiques de la sclérodermie systémique dans une cohorte tunisienne en comparant également les particularités cliniques et immunologiques de notre série par rapport aux autres séries de la littérature. Méthodes > Il s'agissait d'une étude rétrospective observationnelle qui a colligé tous les de patients ayant une sclérodermie systémique hospitalisés dans un service de médecine interne du CHU Hédi Chaker — Sfax — Tunisie sur une période allant de 2000 à 2013. Le diagnostic de la SSc était retenu en se référant aux critères ACR/EULAR 2013. Les patients sclérodermiques étaient classés selon l'étendue de la sclérose cutanée en forme cutanée diffuse et cutanée limitée. Une comparaison avec les autres séries de la littérature a été effectuée en se basant sur les données publiées. Résultats > Une prépondérance féminine a été notée (8 F/1H) ainsi qu'une fréquence plus élevée des formes diffuses (82 %) dans cette cohorte tunisienne comparativement aux autres séries de la littérature. Nous avons également observé une fréquence plus faible de la calcinose et des anticorps anti-centromère. Dans les deux formes de la sclérodermie cutanée diffuse et cutanée limitée, les manifestations cliniques étaient similaires avec d'autres séries de la littérature, à l'exception d'une très faible prévalence de la crise rénale et de l'hypertension pulmonaire. Le syndrome de chevauchement défini par l'association de la sclérodermie à une autre connectivite était relativement fréquent dans notre série. Conclusion > À part de légères différences pouvant être expliquées par des facteurs génétiques, environnementaux, la sclérodermie systémique dans cette cohorte tunisienne semble être similaire aux autres séries de la littérature.
Introduction Systemic sclerosis (SSc) also known as Scleroderma is an uncommon but serious chronic connective tissue disease with heterogeneous clinical presentation and severity. It is characterized by autoimmunity (production of auto antibodies), inflammation, small-vessel vasculopathy and fibroblast dysfunction leading to progressive skin fibrosis, and organ involvement, including the heart, the lungs, the gastrointestinal tract, and the kidneys [1]. SSc is more common in females; the female-to-male ratio is 3:1 when women are of childbearing age. Based on the extent of skin fibrosis, patients with SSc are classified into limited
Glossary
2
SSc lcSSc dcSSc ANA ILD RP
systemic sclerosis limited cutaneous SSc diffuse cutaneous SSc antinuclear antibodies interstitial lung disease Raynaud's phenomen
cutaneous SSc (lcSSc), in which the skin lesions do not extend beyond the elbows and knees in the absence of skin tautness of the arms, chest, abdomen, back, or thighs (which defines dcSSc), and diffuse cutaneous SSc (dcSSc) subsets [2–4]. Because of its rarity and heterogeneous clinical presentation, the epidemiological features of SSc are difficult to characterize. Our objective was to describe aSSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies profile with other international SSc populations.
Methods Patients All consecutive SSc patients seen at department of the internal medicine of Hedi Chaker Hospital in the period between January 2000 and December 2013 were included; we selected those who met the American College of Rheumatology/European League Against Rheumatism ACR/EULAR 2013 classification criteria for SSc [5]. For classification into subsets we followed the Leroy 2001 criteria for classification of diffuse and localized disease subset [3]. Following data were obtained: age, gender, disease duration from the onset of symptoms attributable to
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
SSc, clinical evaluation of organ involvement, routine blood tests including erythrocyte sedimentation rate, complete blood count, serum creatinine, liver function test and tests for antinuclear antibodies (ANA).
Definition of organ involvement SSc clinical manifestations were considered to be present if predefined criteria were met during the course of the illness. Involvement of skin: the maximum extension of the skin involvement at any one time during the course of the disease was considered to define subsets (lcSSc vs. dcSSc). Organ involvement definitions were the following: upper gastrointestinal tract: manometry with esophageal dismotility, esophagram with gastroesophagic reflux or upper endoscopy with esophagitis; suspected pulmonary hypertension: echocardiogram B with estimated pulmonary systolic artery ˃ 35 mm Hg in the absence of other causes of secondary pulmonary hypertension (pulmonary involvement, valvopathies. . .); Interstitial lung disease (ILD): pulmonary interstitial disease observed in chest X-ray and/or high resolution computerized tomography; echocardiographic alterations: left or right ventricular diastolic dysfunction in the absence of arterial hypertension or pulmonary hypertension respectively, or pericardial effusion; digital ulcers: active digital ulcers or pitting scars confirmed by a physician; renal involvement: history of scleroderma renal crisis (abrupt onset of accelerated arterial hypertension and/or rapidly progressive renal failure).
Autoantibodies Laboratory detection methods were immunofluorescence on Hep2 cells for antinuclear and anticentromere antibodies; enzyme linked immunosorbent assay (Elisa) for anti-topoisomerase-I antibodies (anti-Scl-70). ANA dilutions greater or equal to 1/160 were considered positive.
Statistical analysis Categorical data were expressed in percentages, whereas continuous variables were presented using means standard
deviation when the distribution was normal, and using median and ranks when it was not. Chi2 analysis was used to determine significant differences between sets of categorical data. A Pvalue < 0.05 was considered statistically significant. The statistical package used was SPSS, v.20. Ethical approval was not necessary because the study was retrospective.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
Results Seventy-seven patients with SSc had been evaluated at the department of internal medicine (table I). The Female/male ratio was 8:1. The mean age at the time of diagnosis was 40.5 15 years (15–92 years). At the time that this study was performed, the average time of evolution (calculated using the age at onset of symptoms) was 72 months. Over half (55.1%) were still under our care. Six have died in our hospital during this period. All patients had skin involvement. This later revealed the disease in 63 patients (81.8%). The frequency of SSc late onset age over 65 years was 17.4% (6 cases). Regarding gender ratios, men were more commonly affected than women in the dcSSc subset than the lcSSc subsets. Baseline clinical and serological characteristics for the entire SSc group (n = 77), for the dcSSc group (n = 63) and for the lcSSc group (n = 14) are shown in table II.
Clinical manifestations The most common clinical sign found was Raynaud'sphenomen (RP); it was found in 90.5% of patients with diffuse SS, but only in 42.9% of patients with the limited form. Localized calcinosis was found in 6 patients. Digital ulcers and pigmentation disorders occurred in respectively in 26 and 45 cases. Digital ulcers, calcinosis and pigmentation disorders was similar in both subtypes; although conditions such as interstitial lung disease (ILD) were more common in diffuse disease: 55.6% of diffuse vs. 21.4% of limited cutaneous subset (P = 0.03). ILD was seen in 49.4% of the patients, revealing the SS in 5 cases (6.5%). In other cases, it appeared after 20.4 3 months (0–108 months). Regarding respiratory symptoms, 26 patients reported dyspnea. Cough was present in 14 patients. The postero-anterior
TABLE I General characteristics Type of systemic sclerosis
Limited cutaneous SSc
Diffuse cutaneous SSc
Number
14
(18.2%)
63
(81.8%)
Female
13
(92%)
56
(87.5%)
Mean age at diagnosis, years The interval of time between disease onset and diagnosis (months)
P
0.5
36 13
41 25
0.24
16.4
25.5
0.1
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3
SSc: Systemic sclerosis.
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
TABLE II Clinical and serological features in this Tunisian SSc cohort Limited cutaneous SSc
Diffuse cutaneous SSc
P
All over
Number
14
18.2
63
81.8
Raynaud phenomena, %
6
42.9
57
90.5
0.01
80.5
Digital ulcers, %
2
14.3
18
28.6
0.2
26
Telangiectasia's, %
1
7.1
6
9.5
0.6
9.1
Calcinosis, %
0
0
6
9.5
0.2
7.8
Antinuclear antibody, %
12
85.7
52
91.2
Anti-SCL-70, %
1
7.1
23
40.4
0.02
33.8
Anticentromeres, %
2
14
6
10.5
0.6
11.3
Interstitial lung involvement, %
3
21.4
35
55.6
0.03
49.4
Gastrointestinal manifestations, %
2
14.3
47
74.6
0.01
63.6
Articular involvement, %
4
28.6
37
58.7
0.04
53.2
Cardiac involvement, %
0
0
8
12.7
0.48
10.4
Renal involvement, %
0
0
1
1.5
0.5
1.2
77
90
SSc: Systemic sclerosis.
chest X-ray images were suggestive of fibrotic changes in the lungs in 24.7% of the population with diffuse SS. For economic reasons, high resolution computerized tomography was performed only in 21 patients. It showed lung fibrosis (figure 1) in 4 cases and ILD in 20 cases. Gastrointestinal manifestations were frequent. They had appeared in 49 patients (63.6%). Dysphagia and gastrointestinal
Figure 1
4
Interstitial lung disease in scleroderma patient
reflux were presented respectively in 36 (46%) and 15 patients (18%). Clinical signs of malabsorption were found in 2 patients. Renal involvement was rare. Only, one patient had scleroderma renal crisis. Two patients had only essential hypertension. Pulmonary arterial hypertension was suspected in 6 cases. The other manifestations were pericarditis (4 cases), heart failure (3 cases), myocarditis (1 patient) and heart rhythm disorder (2 cases). Forty-one patients (53.2%) had osteo-articular involvement. This was arthralgia in all cases, arthritis in 9 cases (11.7%), and resorption of phalangeal tufts in 18 cases (23.4%). ANA were positives in 61 cases (69.2%). table III gives details about the presence of each of these auto-antibodies. Anti-Scl-70 was the most frequent observed in 21 patients (27%). In the other cases, there was anti RNP (6 patients), anticentromeres (5 cases), anti-PM-Scl (2 cas), anti SSA and anti Ro52 in one case. Others immunological abnormalities were observed: rheumatoid factor (14 cases), cryoglobulinémia in ten cases and anticardiolipin antibodies in one patient only. Anticentromere antibodies were not associated with suspected pulmonary hypertension. On the other hand, ILD was more frequent in patients with anti-Scl-70 and diffuse clinical subset. Overlap syndrome, an entity that satisfies the criteria of at least two connective tissue diseases, was observed in 23%. Among 18 patients with overlap, 10 had dermatomyositis, 3 had Systemic lupus erythematosus and 5 had Sjogren syndrome. Others associations with autoimmune disease were observed: Hashimoto thyroiditis (2 cases), primary biliary cirrhosis (1 case). A
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
TABLE III Frequency of disease subsets and autoantibody profiles in different SS cohorts France [10]
United state [10]
Germany [12]
Italy [11]
Eustar [8]
Brazil [7]
Argentina [6]
Tunisia
Number
127
247
1438
1012
3656
947
234
77
Limited cutaneous, %
54
42
45.5
64
56.8
56.4
76.1
18
Diffuse cutaneous, %
19
47
32.7
14
43.1
31
23.9
82
Anti-Scl-70, %
35
22
27.6
36
28.1
16.1
16.2
27
Anticentromere, %
18
21
36.4
39
29.5
22.1
52.9
6.5
Discussion The current study is a large cross-sectional analysis of SSc disease subsets. When evaluating a rare disease such as SSc, the importance of disease registries lies in their ability to assist in the longitudinal observation of trends in disease presentation, management, and outcome. To our knowledge, this is the first study in SSc African patients in whom clinical and immunological characteristics have been defined for each cutaneous subset and differences between lcSSc and dcSSc were emphasized. We conducted a Pubmed review in order to find SSc cohorts with clear data published regarding visceral involvement, autoantibodies and disease subsets classification. For comparisons, we chose the limited data from Argentina [6] and that published from Brazil [7], the EULAR Scleroderma Trials and Research cohort [8] and cohorts from Mexico [9], US and France [10], Italy [11], Germany (Registry of the German Network for Systemic Sclerosis) [12] and Spain [13]. Frequencies of visceral involvement in diffuse and limited forms are shown in table III, the proportion of disease subsets and autoantibody profile in table IV. In the current large Tunisian cohort, we found a greater female preponderance: women outnumbered men by 8 to 1. This gender ratio is within the range reported in smaller cohorts from the UK and Japan (female: male ratio 3:1 and 14:1, respectively) [14,15] and is similar to that observed in the EUSTAR cohort [8]. In different cohorts, the frequency of dcSSis between 14 and 47% [6,8,10]. Contrastingly, in small series of African SSc patients, the dcSSc is the most frequent subset: 82% in Kenya [16], 65% in black South Africa [17] and 57.1% in Nigeria [18]. Sine scleroderma is rarely reported. We haven't any cases of this subset in our cohort. It was however not reported in the black African series of Tager and Tikly [17]. Epidemiological studies suggest that SSc is more common, occurs at a younger age and is more severe in African-Americans
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than Caucasians. In Pittsburgh Scleroderma Databank, the proportion of patients with diffuse skin changes was greater in African-American than in Caucasian patients (56% vs. 43%, P < 0.03) [19]. The higher frequency of diffuse scleroderma in African patients is again confirmed in our study, being present in 82% of cases in our cohort. LcSSc patients were younger at diagnosis than dcSSc subsets. The interval of time between disease onset and diagnosis was shorter for lcSSc than for dcSSc subsets (16.4 months vs. 25.5 months, P = 0.1) but not significant. This finding is different from other series. It was reported that the mean age of diagnosis of dcSSc subset is shorter than lcSSc. This is related to the progression of the skin thickening that occurs early in dcSSc [8,20]. We found some differences in visceral involvement. ILD was significantly more frequent in dcSSc than in lcSSc subtype. (21.4 vs. 55.6) and over the half of the all series suggesting that ILD is one of the most frequent visceral impairments in dcSSc patients. Within each disease subset, clinical manifestations were quite similar to other cohorts except for a very low prevalence for renal crisis (table IV). We believe that different referral patterns in different institutions may be in part responsible for these differences, aside from different genetic and or environmental backgrounds. Serum autoantibodies directed against a variety of intracellular antigens are present in more than 95% of patients and are considered a hallmark of SSc. They are usually present at disease onset and persist throughout the course of the disease [21]. Anti-topoisomerase I (Scl-70) and anti-RNA polymerase III are associated with dcSSc. In contrast, anticentromere antibodies occur in lcSSc. Other antibodies such as anti-U1 RNP, Pm/Scl, and Ku occur in overlap syndromes: anti-U1 RNP are associated with mixed connective tissue disease, anti-Pm-Scl with overlap myositis. Many of these autoantibodies are specific to nuclear antigens and represent important diagnostic and prognostic agents with strong association with demographic, clinical, organ system, and survival features [20–22]. For instance, ILD is associated with anti-topoisomerase I (Scl-70); digital necrosis and
5
neoplastic disorder was associated with SSc in two cases: pancreatic neoplasia and skin lymphoma.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
Original article
R. Ben Salah, F. Frikha, H. Hachicha, I. Chabchoub, C. Dammak, M. Snoussi, et al.
TABLE IV Clinical findings in different cohorts according to disease subset France [10]
United states [10]
Germany [12]
Italy [11]
Eustar [8]
Spain [13]
Argentina [6]
Tunisia
30
119
484
177
1349
243
56
63
Gastrointestinal manifestation %
79
67
69.3
69
68.2
71.2
64.3
63.6
ILD, %
57
30
56.1
71
53.4
70
65.3
55.6
Diffuse systemic sclerosis (n)
Isolated PH
12
2
18.5
NR
5.9
13.7
2.6
Renal crisis
7
17
15.8
12
4.2
7.8
0.02
1.5
Digital Ulcer
NR
NR
34.4
51
42.7
63.8
32.1
28.6
Calcinosis
16
23
NR
20
NR
NR
23.5
9.5
Cardiac involvement
10
11
12.7
10.3
NR
12.7
97
128
674
177
2101
568
178
14
Gastrointestinal manifestation %
63
67
59.2
55
66.8
57.3
64.5
14.3
ILD, %
39
37
20.8
53
34.7
39.3
26.7
21.4
Isolated PH
9
31
14.9
NR
9.2
8.8
7.3
0
Renal crisis
0
2
9.1
6
1.1
0.7
0
0
Digital Ulcer
NR
NR
23.8
43
32.9
39
28.1
14.3
Calcinosis
36
42
NR
22
NR
19.8
NR
0
Cardiac involvement
14
19
23
20.4
31.1
10
0
Limited systemic sclerosis (n)
ILD: interstitial lung disease; PH: pulmonary hypertension; NR: not reported.
6
pulmonary hypertension (unrelated to ILD) with anticentromere antibodies, anti-U3 RNP/fibrillarin, and renal crisis with antiRNA polymerase III [21]. In an Italian multicenter study of 1012 patients, 10-year survival rate was 72.2% in patients with anti-topoisomerase I, 85.9% in patients with anticentromere antibody, and 72.6% in patients with antinucleolar antibody (U3 RNP, NOR 90, or Pm-Scl). Tenyear survival was 75.1% in patients with lcSSc and 53.4% in those with dcSSc (P < 0.0001) [11]. A study of 275 patients in Japan showed that 10-year survival rate was 93% in patients with anticentromere antibodies, 72% with anti-U1 RNP, 66% with anti-topoisomerase I, and 30% with anti-RNA polymerase I [22]. In a recent Tunisian retrospective study analyzing ILD in SSc patients, among 65 cases of SSc over a period of 13 years, antibodies anti-Scl-70 were noted more frequently in patients with ILD (79% of the cases, P = 0.001) [23]. In our study, anticentromere antibodies were not associated with pulmonary isolated hypertension and with limited disease. Similar to other cohort, anti-Scl-70 antibodies were associated with ILD and diffuse cutaneous involvement [8,13]. Of the 77 patients, 23% were categorized as scleroderma overlap syndrome in our cohort. This frequency is in agreement with
other reported data, ranging between 10% and 38% [12,24–28]. The overlap syndrome is defined as an entity that satisfies the diagnostic criteria of at least two connective tissue diseases [25]. The most common combinations are systemic sclerosis with Sjogren's syndrome, overlap myositis, rheumatoid arthritis, and systemic lupus erythematosus. A combined pathology has impact on the clinical features, diagnosis and treatment. High steroid doses continue to be a major treatment in lifethreatening SLE, myositis and vasculitis. In overlap syndrome patients with diffuse skin involvement the steroid dosage should be modified because of possible provocation of renal crisis. Reduction in steroid dose may be achieved with aggressive immunosuppression including novel biological therapies [24]. Our results indicate that overlap syndrome is a relatively common condition. In our cohort SSc associated with overlap myositis was the most common combination: 11% of all SSc patients and 43% of overlap syndrome. In a Canadian cohort of 100 patients with inflammatory myopathy, 29% had features of SSc and constituted 42% of 24 overlap syndrome patients in this cohort [25]. Some authors showed that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct
tome xx > n8x > xx 2019
To cite this article: Ben Salah R, et al. Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study. Presse Med. (2019), https://doi.org/10.1016/j.lpm.2019.07.037
from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement [28]. The absence of separation of overlap syndrome to the others subsets of SSc can be considered as a limitation in our study. There were some others limitations when comparing subsets and clinical data with other SSc populations. First of all, although our series is considered as a large cohort of SSc patients seen in a single center in south of Tunisia, the number is relatively small comparing to international series. In other hand, patients were not homogeneously classified in different cohorts: there wasn't similar cohort with the same genetic and environmental characteristics in Africa, in the German cohort [12] patients were classified into limited cutaneous, diffuse cutaneous, overlap syndromes, sclerosis sine scleroderma; Italian patients [11] were classified into limited cutaneous, intermediate cutaneous and diffuse cutaneous systemic sclerosis. We were not able to determine other SSc-related autoantibodies (i.e. RNAp III, U3RNP, etc) besides ANA, Scl-70 and anticentromere. Organ involvement was not defined similarly in all the cohorts. Another major limitation of this study is the lack of more accurate confirmation of pulmonary hypertension by right heart catheterization due to scarce resources. These limitations may also account for some of the differences we found. In spite of these possible differences, our data support the clinical and serologic characteristics found in SSc patients in Tunisia. The strength of this study is that it is the largest from North Africa to describe SSc patients. In our cohort of patients, the dcSSc subtype is the most frequent subtypes in the difference of the largest cohorts of SSc patients. Respiratory and gastrointestinal involvement were frequents affecting over the half of patients in our series while renal crisis and cardiac involvement were rare.
This distribution is similar to the studies conducted in black Africans patients. Contributions from genetic factors remains probable, which is an important aspect to be incorporated into anticipated prospective studies.
Original article
Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study
Key message
To our knowledge, this is the first study in SSc north-African patients in whom clinical and immunological characteristics have been defined for each cutaneous subset and differences between lcSSc and dcSSc were emphasized.
Diffuse SSc is most frequently found in this cohort than the limited form.
Within each disease subset, clinical manifestations were quite similar to other cohorts except for a very low prevalence for renal crisis.
Interstitial lung disease and gastrointestinal involvement were frequents affecting over the half of patients in our series while renal crisis and cardiac involvement were rare.
Similar to other cohort, anti-Scl-70 antibodies were associated with ILD and diffuse cutaneous involvement.
Funding: None. Acknowledgement: we, authors of this manuscript would like to offer our special thanks to Professor Rania Khelil for her great help and constructive suggestions for revising the English language of this work. Disclosure of interest: the authors declare that they have no competing interest.
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