Prevalence of systemic sclerosis in a French multi-ethnic county
V. Le Guern,
A. Mahr,
L. Mouthon,
D. Jeanneret1,
M. Carzon1 and
L. Guillevin
Department of Internal Medicine, Hôpital Avicenne, Assistance PubliqueHôpitaux de Paris, Bobigny, UPRESEA 3409 Recherche Clinique et Thérapeutique, UFR-SMBH Léonard-de-Vinci, Bobigny and 1 Service Médical Assurance-Maladie Ile-de-France (CNAMTS), Bobigny, France.
Correspondence to: A. Mahr. E-mail: alfred.mahr{at}cch.ap-hop-paris.fr
 |
Abstract
|
---|
Objective. To assess the prevalence of systemic sclerosis (SSc) in a French multi-ethnic population and to examine ethnic differences.
Methods. This survey was conducted in SeineSaint-Denis County, a suburb of Paris, home to 1,094,412 adults (
15 yr), among whom 26% are of non-European background with mainly northern and sub-Saharan African, Asian and Caribbean ancestries. The study period comprised the entire calendar year 2001. Patients were ascertained through four sources: public and private hospitals, general practitioners and community specialists, the French SSc patient support group, and the National Public Health Insurance System database. Only cases meeting either the 1980 ACR and/or LeRoy and Medsger's classification criteria were included and assigned to three clinical subsets: limited (normal skin) (l), limited cutaneous (lc) or diffuse cutaneous (dc) SSc. Capturerecapture (CR) analyses using log-linear modelling were performed to correct for incomplete case finding.
Results. We retained a total of 119 patients with SSc, including 15 extrapolated from inaccessible files. CR analysis estimated that 54.2 additional cases were missed by all the sources. The overall SSc prevalence (per million adults) was 158.3 (95% confidence interval, 129187); those of lSSc, lcSSc and dcSSc were, respectively, 32.3 (1648), 83.1 (66101) and 42.9 (2560); and respective values for Europeans and non-Europeans were 140.2 (112170) and 210.8 (128293).
Conclusion. Regarding the heterogeneity of previously published estimates, this population-based survey using CR analysis might contribute to obtaining a better appraisal of SSc prevalence. Despite overlapping confidence intervals, the higher prevalence observed for non-Europeans could support potential influences of ethnic origin on the pathogenesis of SSc.
KEY WORDS: Systemic sclerosis, Epidemiology, Prevalence, Ethnicity, Capturerecapture analysis
 |
Introduction
|
---|
Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen production resulting in skin and visceral fibrosis, and is closely associated with selective autoantibodies. The natural history of this disease shows marked heterogeneity regarding the extent of cutaneous and internal organ involvement, serological features and outcome [13]. To date, the aetiology of SSc remains uncertain, with knowledge obtained from numerous casecontrol studies suggesting variable links to genetic and environmental factors [4, 5].
Over the last three decades, SSc epidemiology in many parts of the world has been described in a number of articles, which reported widely divergent SSc prevalences ranging from 7 to 1580 per million inhabitants [620]. Further support for a putative role of geographical factors came from data suggesting that the SSc phenotype might differ among subjects from different ethnic backgrounds [1, 9, 2127] and indicating a higher incidence of SSc in black versus white individuals [9, 23, 28]. However, most of those studies were based on hospital cohorts and hence subject to referral bias, and data on such ethnicity-related differences in population-based surveys remain scarce [9].
We therefore decided to undertake the present population-based survey in a French multi-ethnic county with the aims of adding another SSc prevalence estimate to the figures published hitherto and examining potential differences as a function of ethnicity.
 |
Patients and methods
|
---|
Study population
The study population consisted of residents of the SeineSaint-Denis County, a northeastern suburb of Paris, France (Fig. 1), that served as the basis for a previous epidemiological study on primary systemic vasculitides [29]. This 236 km2 area is part of the highly urbanized Parisian agglomeration (Ile-de-France Region), where 81% of the employees work in the tertiary sectors (services, commerce, transportation) and 18% in industry and construction [30]. Furthermore, two airports (Le Bourget and Roissy/Charles-de-Gaulle), the latter being the largest French airport, are partially located in SeineSaint-Denis County.

View larger version (22K):
[in this window]
[in a new window]
|
FIG. 1. Study area. SeineSaint-Denis County (cross-hatched) is part of the Ile-de-France Region and a northeastern suburb of Paris (black).
|
|
Derived from the 1999 national census estimates [31] and additional data provided by the Institut National des Statistiques et Etudes Economiques (INSEE), SeineSaint-Denis County is home to 1,382,928 residents including 1,094,412 adults aged
15 yr (male-to-female ratio 0.94). Based on data on birth nationalities and place of birth of its residents, respectively, 231,797 of those adults had non-European nationalities and 48,524 had ancestors from the French Caribbean Islands or other French overseas counties and territories. Consequently, the size of the non-European adult population can be estimated to be 280,321 individuals (26% of the general adult population) originating in the Maghreb (Morocco, Algeria, Tunisia) (11%), sub-Saharan Africa (5%), Asian countries (5%), the French Caribbean Islands and other overseas countries and territories (4%), and other areas (America, Oceania/South Pacific) (1%) (Fig. 2). Comparison of the demographic characteristics of the non-European and European subgroups reveals a different age distribution, with the non-Europeans having a higher percentage of subjects aged 2539 yr (36 vs 28%) and 4059 yr (37 vs 32%), and a lower percentage of subjects aged
60 yr (9 vs 22%) (Fig. 3). Slight differences also exist with respect to the male-to-female ratio with a female preponderance for the Europeans (male-to-female ratio 0.89) and male preponderance for the non-Europeans (1.11).

View larger version (15K):
[in this window]
[in a new window]
|
FIG. 2. Distributions of the ethnic backgrounds of the study population of SeineSaint-Denis County (A) and 104 patients with SSc (B).
|
|

View larger version (43K):
[in this window]
[in a new window]
|
FIG. 3. Age distributions of the total study population and the subpopulations of European or non-European ancestry (1999 census data).
|
|
Study period and sources of case ascertainment
The study covered the entire calendar year 2001. Patients were retrieved through four separate sources: (1) letters (with a stamped self-addressed envelope enclosed for the reply) and telephone follow-up to 30 departments of internal medicine, rheumatology, pneumatology, dermatology and nephrology including all the public hospitals, two large private clinics of the study area and one university hospital neighbouring the area under consideration, as well as five additional selected university hospital departments of the Ile-de-France region specializing in SSc (referred to as the hospitals); (2) sending follow-up questionnaires (with a stamped self-addressed envelope for the reply) to all general practitioners (n = 1100) and community specialistsrheumatologists, pneumatologists, angiologists and dermatologists (n = 123)registered in the College for Physicians of the area (referred to as community physicians); (3) members of the French SSc patient support group (Association des Sclérodermiques de France); and (4) data from the main fund (régime general) of the Public Health Insurance System of SeineSaint-Denis County. For individuals with costly or chronic diseases, e.g. SSc, the French Public Health Insurance system accords, upon application, full exoneration of payment for all treatments associated with their disease. Based on an individual's professional activity, the French Public Health Insurance System distinguishes three branches: the main fund covers salaried employees and insures 93% of the SeineSaint-Denis residents, and two other funds cover the self-employed or agricultural workers.
We asked these four sources to report any known adult (aged
15 yr) with SSc living in the study area during the calendar year 2001. Questionnaires sent to the community physicians requested that they report such cases with the first three initials of the patient's last name, the first two initials of the first name, gender, birth date, residential postal code, date of patient's last assessment and, if pertinent, the address of the hospital where they are/had been followed. Members of the patient support group were recruited after their oral consent to participate had been obtained by a telephone call from one of the group's board members. The Public Health Insurance System provided semi-anonymous data (initials, gender, birth date, residential postal code) for patients registered by 31 December 2001, with the codes 710.0 or M34 of the 9th International Classification of Diseases (ICD-9) and the revised ICD-10. For patients recruited exclusively through this source, a follow-up letter was sent, with a subsequent telephone call to non-responders, by a Public Health Insurance System physician to obtain consent to be contacted by the clinical investigators.
Inclusion criteria
Once the treating physician's accord had been obtained, we carefully reviewed the hospital charts or the information provided by the community physicians to verify the diagnoses of all the patients. For each case, standardized data forms were filled out collecting the following items: (1) demographic data including date of birth, gender, ethnic background and location of residence; (2) date of first diagnosis of SSc by any physician and (3) clinical and laboratory findings, and, when available, results of nailfold capillaroscopy, pulmonary function tests and pulmonary computed tomography (CT) scans. A patient's ethnic background was defined according to that of their first-degree relatives and required that both parents be of the same ethnic group. Raynaud's phenomenon (RP) and nailfold capillaroscopy abnormalities were considered to be present only when a hospital-based specialist corroborated the diagnosis. Serological tests were assessed with respect to the search for antinuclear antibodies (ANA), anticentromere antibodies (ACA) and/or antitopoisomerase I (anti-Scl70) antibodies. Interstitial lung disease was defined according to CT images suggestive of parenchymal involvement combined with, when available, a restrictive airway pattern on pulmonary function tests.
To ensure homogeneous classification, all the data were recorded by the same physician (VLG). A case was definitively included in the study when he/she was a resident of SeineSaint-Denis County for at least part of 2001, was aged
15 yr and fulfilled the 1980 American College of Rheumatology (ACR) diagnostic criteria [32] and/or those established by LeRoy and Medsger [33] for classification purposes of early SSc. ACR criteria require one major criterion, taut skin involvement proximal to the metacarpophalangeal joints, or two or more minor criteria among the following three items: sclerodactyly, digital pitting scars or loss of substance of the distal finger pad, bibasilar pulmonary fibrosis. LeRoy and Medsger's criteria require objective RP as a major criterion combined with nailfold capillary abnormalities (dilatation and/or avascular areas) and/or presence of SSc-associated autoantibodies [33]. Patients with overlap features of systemic lupus erythematosus (e.g. facial rash, photosensitivity, serositis, glomerulonephritis) or polymyositis (e.g. elevated creatinine kinase levels combined with a myopathic pattern on electromyography or histologically proven myositis) and antiribonucleic protein (RNP) antibodies alone were considered to have undifferentiated mixed connective tissue disease and were not accepted for this study.
The disease duration was calculated from the date at which a given patient first fulfilled one of the abovementioned classification criteria to the time of the last update of the patient's status after 1 January 2001. According to the presence and the extent of skin involvement at the last time of disease assessment, the patients were categorized into three distinct SSc subtypes: limited (l) (normal skin), limited cutaneous (lc) (sclerodactyly or skin thickening distal to the elbows) or diffuse cutaneous (dc) (skin thickening proximal to the elbows and/or of the trunk) [33]. The presence of taut facial skin did not differentiate between lcSSc and dcSSc.
Statistical analyses
Capturerecapture analysis was used to overcome potential incomplete case finding so as to correct the calculation of prevalence rates. As described elsewhere [29, 34], this technique takes advantage of duplicate information derived from multiple, disaggregated sources of case ascertainment and provides estimates of the number of cases missed by any one source, and thus of the total number of cases in a given area. For the present study, cases were considered duplicates upon concordance of the first three initials of the last name, the first two initials of the first name, date of birth, gender and the residential postal code. To obtain a conventional three-source capturerecapture design, the two numerically least important sources of case retrieval (community physicians and the patient support group) were pooled into a single source.
Log-linear modelling was used to assessand eventually to adjust forpotential violations of the assumptions of intersource independency and equal catchability [35, 36]. Source dependency was investigated by constructing the eight models accounting for all possible two-source dependency interactions. Based on the results of maximum of likelihood statistics [deviance G2, Akaike information criterion (AIC), Bayesian information criterion (BIC)] and the weighted BIC [37], we selected the model that best fitted the data and, when ambiguous, the one that contained the fewest interaction terms (principle of parsimony). Subsequently, we verified the assumption of equal catchability by assessing the representativeness of the sources. For each of the three sources used for capturerecapture analysis, we analysed the patient distribution with respect to SSc subtype (l, lc or dc), ethnic background (European or non-European origins) and disease duration (stratified into two groups according to the median value). These variables were chosen because it could be hypothesized that differences theoretically exist across sources with respect to disease severity, and to ultimately provide unbiased stratified estimates for the SSc subtypes and ethnic backgrounds. As previously suggested [38], for each source, we compared the case distribution of these variables to that expected by the best-fitting log-linear model retained in the previous step. Potential unequal catchability was corrected by the addition of an interaction term to that log-linear model. The variances of capturerecapture estimates were calculated according to the method described by Hook and Regal [39]. Prevalence rates were calculated with the number of cases estimated by capturerecapture analysis as the numerator and the adult (aged
15 yr) population as the denominator.
All statistical analyses were computed using the SAS Statistical Package, version 8.12 (SAS Institute Inc., Cary, NC, USA). Quantitative variables are expressed as means ± standard deviation (S.D.) and were compared with non-parametric KruskalWallis tests. Qualitative variables were compared using
2 and, when appropriate, Fisher's exact tests. Log-linear modelling was performed using the PROC GENMOD procedure. All statistical analyses were two-tailed and P values <0.05 were considered to be significant. Confidence intervals were calculated at the 95% level (95% CI).
Ethical aspects
This study was approved by the Commission Nationale de lInformatique et des Libertés (National Commission of Informatics and Freedom) (no. 792764).
 |
Results
|
---|
Response rates and number of patients ascertained
All the contacted hospital departments participated in the study and 91 patients were recorded by this source. Concerning the questionnaires sent to the community physicians, responses from 57% of the general practitioners and 57% of the specialists yielded 74 cases. All 13 patients identified through their membership of the patient support group consented to participate in the study and 102 patients were registered by the Public Health Insurance System as having SSc. After excluding intersource matches (according to the abovementioned matching criteria), a total of 218 cases had been identified by at least one source. Among those, case records were inaccessible for 34 patients, all exclusively retrieved from the Public Health Insurance System, due to refusal or non-response to our request for study participation.
Review of the 184 medical charts studied in detail led to the exclusion of 80 additional cases given other diagnoses (n = 33), not fulfilling the diagnostic criteria (n = 27), living outside the area studied (n = 12), having been diagnosed after the year 2001 (n = 4) or because of death before 2001 (n = 4). The remaining 104 cases satisfying our inclusion criteria comprised 17, 64 and 23 cases with lSSc, lcSSc and dcSSc respectively, and 32 patients of non-European background. To estimate the number of definite SSc cases among the 34 patients whose medical files could not be screened, we calculated the proportion of patients who met our diagnostic criteria among the other individuals ascertained exclusively through the Public Health Insurance System and to whose medical charts we had access. The obtained value of 0.44 was then multiplied by 34, yielding 15 additional hypothetically definite SSc cases including, according to similar algorithms, two, nine and four cases with lSSc, lcSSc and dcSSc, respectively, and five individuals of non-European background.
Ultimately, we retained a total of 119 patients, including 19 lSSc, 73 lcSSc and 27 dcSSc, and 37 individuals of non-European origin.
Patient data
Table 1 summarizes the main demographic, clinical and laboratory data, disease duration, and the frequencies of patients fulfilling the ACR and LeRoy and Medsger's classification criteria for the 104 patients whose medical files could be examined. SSc was diagnosed in a university hospital for 101 of those patients and in private clinics for the remaining three. Results are shown for the entire cohort and with respect to the SSc subtype. Notably, eight of the 17 lSSc patients had both abnormal nailfold capillaroscopy and positive ACA and/or anti-Scl70 serologies (one patient was positive for both ACA and Scl70 antibodies); moreover, 13 cases were found to have additional characteristic manifestations of SSc with telangiectasia (n = 7), calcinosis (n = 3), digital infarctions (n = 2), clinical symptoms consistent with oesophageal hypomotility (n = 6) and/or pulmonary hypertension as assessed by Doppler echocardiography (n = 1). The 32 individuals of non-European ancestry came from Maghreb (n = 17), sub-Saharan Africa (n = 7), Asia (n = 7) and the French Caribbean islands (n = 1), i.e. presenting a distribution similar to that of the background population (Fig. 2); none of them had been diagnosed with SSc before living in continental France. Comparison of disease expression according to the ethnic background showed that non-Europeans were significantly younger at disease onset (45.3 ± 14.3 vs 52.4 ± 14.5 yr; P = 0.02), more frequently diagnosed with dcSSc (34 vs 17%; P = 0.04) and tended more frequently to have anti-Scl70 antibodies (38 vs 20%; P = 0.05) and interstitial lung disease (53 vs 33%; P = 0.06). Conversely, the sex ratio (P = 0.25), mean disease duration (P = 0.89) and ACA positivity (41 vs 46%; P = 0.58) did not differ between individuals of non-European and European ancestry.
Capturerecapture analysis
Fig. 4 shows the relative contributions of the three individual sources used for capturerecapture analysis to identifying the 119 retained cases.

View larger version (22K):
[in this window]
[in a new window]
|
FIG. 4. Contributions of the three sources used for capturerecapture analysis to the 119 retained SSc cases (values in parentheses correspond, respectively, to the numbers of l, lc and dcSSc, and non-Europeans).
|
|
The results of the log-linear regression model including the different 2-source-dependency interactions are reported in Table 2. The model with a single interaction term between the hospitals and the community physicians/patient support group had a non-significant P-value for G2, the lowest AIC and BIC values, and an estimated number of cases missed close to that estimated by the weighted BIC, and was thus selected as the best-fitting model. This model estimated the number of cases missed by any source to be 54.2 and, thus, a 69% completeness of case ascertainment.
View this table:
[in this window]
[in a new window]
|
TABLE 2. Capturerecapture estimates (using log-linear modelling) of the number of SSc cases missed (x) by any source of case ascertainment and total number of cases (N) in the study area
|
|
Examination of the characteristics of the three sources with respect to the variables chosen to potentially generate unequal catchability showed that case capture was heterogeneous regarding the ethnic background (results not shown). In fact, for the community physician/patient support group source, the percentage of non-Europeans observed was significantly lower than expected by the log-linear model (14 vs 31%; P = 0.02). However, the log-linear model including the corresponding interaction term (community physician/patient support group x ethnic background) yielded an only slightly better fit to the data but did not affect the estimated number of cases missed (Table 2). Applying the principle of parsimony, inclusion of this interaction term was consequently restricted to the capturerecapture estimates stratified for the ethnic backgrounds (Table 2).
Eventually, capturerecapture analysis estimated the total number of cases to be 173.2 and, after stratification, 35.3 lSSc, 91.0 lcSSc and 46.9 dcSSc. The stratified capturerecapture analysis estimated that a total of 114.1 patients were of European ancestry with 59.1 cases of non-European origin (Table 2).
Prevalence estimates
Table 3 summarizes the derived prevalence estimates for all SSc, and according to the SSc subtype and ethnic origin for the adult population of the study area. Thus, the overall prevalence estimates for the non-European population (210.8; 95% CI 128293) was found to be 1.5-fold higher than that for the Europeans (140.2, 95% CI 112170), even though the 95% CI intervals overlapped.
 |
Discussion
|
---|
This population-based survey has enabled us to estimate the prevalence of SSc in the SeineSaint-Denis County, France, to be 158.3 per million adults. To the best of our knowledge, this study is also the first prevalence estimate based on a European multi-ethnic population, with our results demonstrating a slightly higher prevalence among the subjects of non-European ancestry.
Using multiple sources of case retrieval is a major prerequisite for achieving complete case identification in population-based surveys. For the present study, patients were recruited through four distinct sources, including inquiries addressed to hospital departments, general practitioners and community specialists, and data provided by a patient support group and the Public Health Insurance System. The latter source, in particular, referred a number of patients who would have been overlooked by case retrieval based exclusively on direct medical care dispensers, an observation that emphasizes the importance of the selected sources implying diverse routes of patient identification. Because of issues of confidentiality, however, the diagnoses of 34 subjects recorded as having SSc in the Public Health Insurance database could not be verified. We therefore assumed that these patients comprised the same proportion of definite SSc cases as the other subjects retrieved uniquely through the same source.
Moreover, we performed capturerecapture analysis to appraise the degree of completeness of case finding and to correct our estimates for potential under-ascertainment. In a setting with at least three separate case-retrieval sources being available, log-linear modelling can be applied to accurately handle violations of this method's major assumptions of independence and homogeneous case-capture among sources. Because of the exponential relationship between the number of sources included and the number of source interactions to assess, we pooled the two numerically least important sources (community physicians and patient support group) to obtain the logistically most effective three-source design. Finally, capturerecapture analysis estimated the crude rate of completeness of patient identification to be 69%, a value that might be a reflection of the difficulty of achieving exhaustive case ascertainment in cross-sectional studies.
Disease definitions used in this study were based on the 1980 preliminary ACR classification criteria for SSc [32] and those recently proposed by LeRoy and Medsger [33]. Although it is widely accepted that ACR criteria enable dcSSc to be classified with a high sensitivity, major criticism has been expressed concerning their inadequate incorporation of lcSSc [3, 40, 41]. Authors of earlier epidemiological surveys resolved this problem by usingin addition to the ACR criteriaother specifically designed criteria with the purpose of classifying patients with lcSSc [6, 9, 12, 15, 28]. For the present study, we addressed this issue by applying the LeRoyMedsger criteria [33], which may represent the currently most valuable approach for consensual classification of lcSSc. Although they have not yet been validated, our findings based on the 104 patients whose medical charts could be reviewed indirectly indicated that these criteria assure classification of lcSSc with high sensitivity. Indeed, 69% of the patients considered to have lcSSc satisfied the ACR criteria (Table 1), a result that is in agreement with previously reported sensitivities of 75% [3] and 79% [41] for the ACR criteria for patients that had been diagnosed with lcSSc by an expert clinician.
Another issue raised at the time this study was designed was whether or not we should include patients presenting with features of SSc but no sclerodermatous skin changes. Referred to as sine scleroderma SSc [2, 42], normal skin SSc [43] or limited SSc (lSSc) [33], there has been an increasing tendency to include this form in the spectrum of SSc disease and we eventually adopted such a three-subtype system categorizing patients as having lSSc, lcSSc or dcSSc [33]. In response to the criticism of the LeRoyMedsger criteria as lacking specificity to allow classification of lSSc as definite SSc [44], most of the lSSc cases that we identified also had other signs typical of SSc, e.g. telangiectasia, calcinosis, digital infarctions and/or internal organ involvement. According to stratification analysis, lSSc accounted for 20% of our overall prevalence estimate, a finding that would suggest the true frequency of this subtle variant of SSc to be higher than previously described based on hospital cohorts [42, 43].
It is likely that the heterogeneity of published SSc prevalence estimates might partly have resulted from differing methodologies. Studies retrieving patients through single sources of ascertainment [10, 11, 16, 19, 20] and/or using the ACR criteria alone to define cases [10, 11, 16, 19] might have underestimated the real frequency of SSc, whereas the inverse effect could be suspected by inclusion of overlap diseases [6, 14] and/or estimates based on longer study periods [8, 9, 13]. The highest reported prevalence figures of 750 [19] and 1580 per million [12] were derived from sample surveys based on the screening of SSc patients among individuals with self-reported, and then clinically confirmed, RP, and subsequent multiplication of the observed percentage by that of RP in the general population. Notably, those studies identified only a small number of SSc cases and it could also be hypothesized that their results might have been positively biased by an increased tendency of individuals suffering from SSc to participate in those investigations. Regarding the currently available data, it has been postulated that SSc might be more frequent in the US than in Europe or Japan [5] and, although among the highest reported for a European area, our estimate would roughly fit this gradient (Table 4).
View this table:
[in this window]
[in a new window]
|
TABLE 4. Summary of selected studies reported as a function of increasing SSc prevalence in each geographical area
|
|
This study moreover aimed to look for ethnic disparities in the prevalence of SSc. So as to obtain sufficiently large denominators allowing meaningful statistical analysis, we approached this objective by pooling the inhabitants with a non-European background in a single population. Although these results must be interpreted with caution because of overlapping confidence intervals, the SSc prevalence for the non-Europeans was 1.5-fold higher than that for those of European origin. Further prudence is warranted because our non-European population comprised a higher percentage of middle-aged individuals at risk for SSc, although this potential confounding effect might have been counterbalanced by the higher male-to-female ratio. Notably, our results would be consistent with previously reported 1.2-fold higher prevalence in black versus white individuals [9] and 1.8-fold higher incidence in black versus white women [23]. Additionally, in accordance with previous findings in AfricanAmerican [1, 9, 23, 2527], HispanicAmerican [27] or Asian [21, 24] SSc patients, as compared with white Americans [1, 9, 21, 23, 2527] or Australians [24], the non-Europeans were significantly more likely to have dcSSc [9, 23, 24, 27], anti-Scl70 antibodies [2426] and interstitial lung disease [21, 25] and were younger at diagnosis [1, 9, 23, 25], with this latter finding potentially also being accounted for by the younger age structure of the non-European population.
Thus, these results would support the idea of ethnicity influencing the susceptibility to develop SSc and its clinical profile. Admitting this assumption, a fundamentaland as yet unresolvedissue is whether this effect of ethnicity on SSc might reflect a genetic or, alternatively, an environmental input [45]. The disparate geographical origins of the non-European patients identified in our survey might render improbable the role of a universal ethnic-specific environmental or lifestyle trigger, but it cannot be ruled out that these individuals share socio-economic or reproduction-related risk factors. On the other hand, higher frequencies of SSc in specific ethnic groups could also have a genetic basis. To date, the most stringent evidence for genetics determining the ethnic susceptibility for SSc came from an isolated Amerindian Choctaw tribe with high SSc prevalence and in which the disease was primarily observed in full-blooded descendants [46]. Thus, although SSc has been associated with diverse human leucocyte antigen (HLA) alleles, analysis of the current data does not clearly confer a central role to HLA genes in the differing risks across ethnic backgrounds [45].
In summary, accurate description of SSc epidemiology in different geographical regions represents an important approach to unravelling the aetiological mechanisms underlying this disease. Our observations should encourage further investigation of ethnically heterogeneous populations to discern the role that ethnicity might play in the risk of developing SSc. In light of the rather moderate relative risk of developing SSc associated with ethnic background, our results support that this factor represents only one among a variety of, and possibly interacting, keys to the pathogenesis of SSc.
 |
Acknowledgments
|
---|
The authors would like to thank the following physicians for their help in case identification and/or diagnostic confirmation: R. Ghozlan (Aubervilliers), D. Malbec (Aulnay-sous-Bois), M. H. André, M. C. Boissier, P. Cohen, A. Krivitzky, J. Ramanoelina, D. Sterin, A. Tazi, D. Valeyre (Bobigny), O. Fain (Bondy), J. C. Roujeau (Créteil), L. Marie (Montfermeil-Le Raincy), Y. Allanore, G. Belangé, J. Cabane, K. Champion, B. Crickx, C. Francès, M. Gayraud, A. Kahan, P. MBappe, O. Meyer, T. Papo, M. Rybojad (Paris), G. Dennewald, F. Lhote (Saint-Denis), J. E. Kahn (Suresnes), and all the general practitioners and community specialists of SeineSaint-Denis County. We are also grateful to Ms W. Degorre and Ms M. Lienhard from the Association des Sclérodermiques de France, and Ms J. Jacobson for editorial assistance. The authors of this study received a research grant from Actelion Pharmaceuticals, Paris, France.
Loïc Guillevin is a member of the International Advisory board of Actelion Ltd and a member of the scientific committee of Actelion France. The other authors have declared no conflicts of interest.
 |
References
|
---|
- Medsger TA Jr, Masi AT, Rodnan GP, Benedek TG, Robinson H. Survival with systemic sclerosis (scleroderma). A life-table analysis of clinical and demographic factors in 309 patients. Ann Intern Med 1971;75:36976.[ISI][Medline]
- Giordano M, Valentini G, Migliaresi S, Picillo U, Vatti M. Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis. J Rheumatol 1986;13:91116.[ISI][Medline]
- Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (19531983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol 1988;15:27683.[ISI][Medline]
- Silman AJ. Epidemiology of scleroderma. Curr Opin Rheumatol 1991;3:96772.[Medline]
- Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am 1996;22:75164.[ISI][Medline]
- Roberts-Thomson PJ, Jones M, Hakendorf P et al. Scleroderma in South Australia: epidemiological observations of possible pathogenic significance. Int Med J 2001;31:2209.[CrossRef][ISI]
- Silman A, Jannini S, Symmons D, Bacon P. An epidemiological study of scleroderma in the West Midlands. Br J Rheumatol 1988;27:28690.[ISI][Medline]
- Shinkai H. Epidemiology of progressive systemic sclerosis in Japan. In: Black CM, Myers AR (eds). Progressive Systemic Sclerosis (Current Topics in Rheumatology). New York: Gower, 1985:7981.
- Mayes MD, Lacey JV Jr, Beebe-Dimmer J et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48:224655.[CrossRef][ISI][Medline]
- Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res 1991;283:36671.[ISI][Medline]
- Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis. J Rheumatol 2002;29:186773.[ISI][Medline]
- Valter I, Saretok S, Maricq HR. Prevalence of scleroderma spectrum disorders in the general population of Estonia. Scand J Rheumatol 1997;26:41925.[ISI][Medline]
- Asboe-Hansen G. Epidemiology of progressive systemic sclerosis in Denmark. In: Black CM, Myers AR (eds). Progressive Systemic Sclerosis (Current Topics in Rheumatology). New York: Gower, 1985:78.
- Chandran G, Smith M, Ahern MJ, Roberts-Thomson PJ. A study of scleroderma in South Australia: prevalence, subset characteristics and nailfold capillaroscopy. Aust NZ J Med 1995;25:68894.[ISI][Medline]
- Englert H, Small-McMahon J, Davis K, OConnor H, Chambers P, Brooks P. Systemic sclerosis prevalence and mortality in Sydney 197488. Aust NZ J Med 1999;29:4250.[ISI][Medline]
- Geirsson AJ, Steinsson K, Guthmundsson S, Sigurthsson V. Systemic sclerosis in Iceland. A nationwide epidemiological study. Ann Rheum Dis 1994;53:5025.[Abstract]
- Giordano M. Epidemiology of progressive systemic sclerosis in Italy. In: Black CM, Myers AR (eds). Progressive Systemic Sclerosis (Current Topics in Rheumatology). New York: Gower, 1985:727.
- Haustein UF, Ziegler V, Zchunke E, Munzberger H, Kopping H. Progressive systemic sclerosis with silicosis in the German Democratic Republic. In: Black CM, Myers AR (eds). Progressive Systemic Sclerosis (Current Topics in Rheumatology). New York: Gower, 1985:13841.
- Maricq HR, Weinrich MC, Keil JE et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum 1989;32:9981006.[ISI][Medline]
- Michet CJ Jr, McKenna CH, Elveback LR, Kaslow RA, Kurland LT. Epidemiology of systemic lupus erythematosus and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1985;60:10513.[ISI][Medline]
- Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger TA Jr, Wright TM. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody. Arthritis Rheum 1999;42:46574.[CrossRef][ISI][Medline]
- Kuwana M, Okano Y, Kaburaki J, Tojo T, Medsger TA Jr. Racial differences in the distribution of systemic sclerosis-related serum antinuclear antibodies. Arthritis Rheum 1994;37:9026.[ISI][Medline]
- Laing TJ, Gillespie BW, Toth MB et al. Racial differences in scleroderma among women in Michigan. Arthritis Rheum 1997;40:73442.[Medline]
- McNeilage LJ, Youngchaiyud U, Whittingham S. Racial differences in antinuclear antibody patterns and clinical manifestations of scleroderma. Arthritis Rheum 1989;32:5460.[ISI][Medline]
- Greidinger EL, Flaherty KT, White B, Rosen A, Wigley FM, Wise RA. AfricanAmerican race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998;114:8017.[Abstract/Free Full Text]
- Reveille JD, Durban E, Goldstein R, Moreda R, Arnett FC. Racial differences in the frequencies of scleroderma-related autoantibodies. Arthritis Rheum 1992;35:21618.[ISI][Medline]
- Reveille JD, Fischbach M, McNearney T et al. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 2001;30:33246.[CrossRef][ISI][Medline]
- Steen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA Jr. Incidence of systemic sclerosis in Allegheny County, Pennsylvania. A twenty-year study of hospital-diagnosed cases, 19631982. Arthritis Rheum 1997;40:4415.[Medline]
- Mahr A, Guillevin L, Poissonnet M, Aymé S. Prevalence of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis and ChurgStrauss syndrome in a French urban population in 2000: a capturerecapture estimate. Arthritis Rheum 2004;51:929.[CrossRef][Medline]
- Blin F, Denais MC. Institut National des Statistiques et des Etudes Economiques: Gros Plan sur lEmploi Francilien en 1999; 2001.
- Recensement de la Population de 1999. Tableaux, références et analysesexploitation principale: SeineSaint-Denis. Institut National des Statistiques et des Etudes Economiques; 2000.
- Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:58190.[ISI][Medline]
- LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:15736.[ISI][Medline]
- McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 1995;38:126070.[Medline]
- Bishop YMM, Fienberg SE, Holland PW. Discrete Multivariate Analysis: Theory and Practice. Cambridge, MA, 1975.
- Cormack R. The statistics of capture-recapture methods. Oceanogr Mar Biol Ann Rev 1968;6:455506.
- Draper D. Assessment and propagation of model uncertainty. J R Statist Soc 1995;57:4570.[ISI]
- Gallay A, Vaillant V, Bouvet P, Grimont P, Desenclos JC. How many foodborne outbreaks of Salmonella infection occurred in France in 1995? Application of the capturerecapture method to three surveillance systems. Am J Epidemiol 2000;152:1717.[Abstract/Free Full Text]
- Hook EB, Regal RR. Capturerecapture methods in epidemiology: methods and limitations. Epidemiol Rev 1995;17:24364.[ISI][Medline]
- Lonzetti LS, Joyal F, Raynauld JP et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001;44:7356.[CrossRef][ISI][Medline]
- Medsger TA Jr. Comment on Scleroderma Criteria Cooperative Study. In: Black CM, Myers AR (eds). Progressive Systemic Sclerosis (Current Topics in Rheumatology). New York: Gower, 1985:1617.
- Poormoghim H, Lucas M, Fertig N, Medsger TA, Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features, and survival in forty-eight patients. Arthritis Rheum 2000;43:44451.[CrossRef][ISI][Medline]
- Scussel-Lonzetti L, Joyal F, Raynauld JP et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore) 2002;81:15467.[CrossRef][ISI][Medline]
- Wigley FM. When is scleroderma really scleroderma? J Rheumatol 2001;28:14713.[ISI][Medline]
- Reveille JD. Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep 2003;5:1607.[Medline]
- Arnett FC, Howard RF, Tan F et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum 1996;39:136270.[Medline]
Submitted 1 October 2003;
revised version accepted 10 May 2004.