To assess the association of gender with clinical expression, health-related quality of life (HRQoL), disability, and self-reported symptoms of depression and anxiety in patients with systemic sclerosis (SSc).
SSc patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria were assessed for clinical symptoms, disability, HRQoL, self-reported symptoms of depression and anxiety by specific measurement scales.
Overall, 381 SSc patients (62 males) were included. Mean age and disease duration at the time of evaluation were 55.9 (13.3) and 9.5 (7.8) years, respectively. One-hundred-and-forty-nine (40.4%) patients had diffuse cutaneous SSc (dcSSc). On bivariate analysis, differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, a trend was found for higher body mass index (BMI) (25.0 [4.1] vs 23.0 [4.5], p = 0.013), more frequent dcSSc, echocardiography systolic pulmonary artery pressure >35 mmHg and interstitial lung disease in males than females (54.8% vs 37.2%, p = 0.010; 24.2% vs 10.5%, p = 0.003; and 54.8% vs 41.2%, p = 0.048, respectively), whereas calcinosis and self-reported anxiety symptoms tended to be more frequent in females than males (36.0% vs 21.4%, p = 0.036, and 62.3% vs 43.5%, p = 0.006, respectively). On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender.
In SSc patients, male gender tends to be associated with diffuse disease and female gender with calcinosis and self-reported symptoms of anxiety. Disease-associated disability and HRQoL were similar in both groups.
Citation: Nguyen C, Bérezné A, Baubet T, Mestre-Stanislas C, Rannou F, Papelard A, et al. (2011) Association of Gender with Clinical Expression, Quality of Life, Disability, and Depression and Anxiety in Patients with Systemic Sclerosis. PLoS ONE 6(3): e17551. doi:10.1371/journal.pone.0017551
Editor: Ulrich Thiem, Marienhospital Herne - University of Bochum, Germany
Received: October 23, 2010; Accepted: February 8, 2011; Published: March 9, 2011
Copyright: © 2011 Nguyen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Systemic sclerosis (SSc) is a connective-tissue disease characterized by excessive collagen deposition in the dermis and internal organs, and by vascular hyper-reactivity and obliterative microvascular phenomena . SSc is responsible for diminished life expectancy, related to skin extent and visceral involvement . SSc is also responsible for tendon, joint, and vessel damage, leading to disability, handicap, and impaired health-related quality of life (HRQoL) . In addition, psychiatric symptoms, including anxiety and depression, have been reported as a consequence of disease chronicity in SSc patients, with a prevalence of depressive symptoms ranging from 18% to 65% , , , , , , , , .
Consistent with other auto-immune diseases, SSc is predominant among females, with a ratio of females to males of 1∶1 to 14∶1 , along with gender differences in disease activity and incidence. Such differences have been explained by genetic and hormonal factors and lifestyle , . Male gender is usually considered a factor of poor prognosis in SSc , . A cohort of 91 SSc patients (10% males) from Spain revealed clinical and immunological differences between the genders; arthralgias were more often encountered in females, whereas myositis and nucleolar antinuclear antibodies were more frequent in males . More recently, as compared with female SSc patients, males were found to more often exhibit renal failure, increased blood pressure, arrythmia and inflammatory myopathy and less often sicca syndrome and anti-centromere antibodies. Causes of death and mortality also differed between the sexes . In a large European cohort of 1180 patients with early SSc (19% males), features of diffuse disease were significantly more frequent in males . Recently, Hudson et al. found that the time to diagnosis was longer for women than men after the onset of Raynaud's phenomenon, and suggested that there may be possible biologic differences in the progression of disease or in the health care trajectories of men and women with early SSc .
Although gender differences in disease-related clinical manifestations are well established, few studies have compared HRQoL, disability, and psychiatric symptoms between male and female patients with SSc. In the present study, we aimed to assess the association of gender with clinical expression, HRQoL, disability, and self-reported symptoms of depression and anxiety in patients with SSc.
We performed a cross-sectional survey of 381 patients. Patients with SSc were prospectively included during 7 consecutive annual meetings of the French SSc patients' association, the “Association des Sclérodermiques de France” (ASF), between 2003 and 2009, or during their hospitalization in the internal medicine departments of Cochin (between January 2006 and June 2009) or Claude Huriez (between January and June 2009) hospitals. Since some patients were evaluated during several ASF annual meetings, only the most recent assessment of each patient was considered. Patients had to complete self-administered questionnaires first and then to undergo an interview with a physician to check for unanswered question, fully complete questionnaires, and gather clinical data.
To be eligible for the study, patients had to fulfil the American College of Rheumatology  and/or the Leroy and Medsger  criteria for SSc. Patients from the ASF were assessed within 48 hr during spring (temperature 20°C). Parameters recorded were age; sex; age at disease onset; disease duration; body mass index (BMI); disease subset (limited SSc [lSSc], limited cutaneous SSc [lcSSc] or diffuse cutaneous SSc [dcSSc]); mouth opening (inter-incisor distance measured in millimetres); skin involvement; telangiectasia; Raynaud's phenomenon; pitting scars; digital ulcers; calcinosis; gastrointestinal tract, joint and/or muscle involvement; dyspnoea (assessed by the New York Heart Association [NYHA] 4-point scale); ILD; echocardiography systolic pulmonary artery pressure [PAP]>35 mmHg); and renal crisis. History of esophagus, gastrointestinal, joint, muscle and/or heart involvement; ILD; echocardiography PAP>35 mmHg; and renal crisis was obtained from detailed clinical charts for hospitalized patients and self-reports for ASF members.
Health status was assessed by the KPS score, the scale ranging from 0 (dead) to 100 (normal no complaints; no evidence of disease) . Originally developed for cancer patients, because it strongly predicted cancer outcome , , the KPS score has been shown to provide clinical estimates of patient's physical state, performance, and prognosis and to be associated with social status in patients with SSc , .
Health-related quality of life
HRQol was assessed by the French version of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) , a self-administered questionnaire covering 8 areas: physical function, physical role, bodily pain, general health, vitality, social function, emotional role, and mental health. For each area, scores range from 0 (poorer health status) to 100 (better health status). Scores can also be summarized in 2 global scores: physical component score (PCS) and mental component score (MCS).
Global disability was assessed by use of the standard disability index of the Health Assessment Questionnaire (HAQ-DI) that contains 20 items (each scored ranging from 0 [no disability] to 3 [maximal disability]), divided into 8 domains .
Patients' perceived disability.
Patients' perceived disability was assessed by the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) . Patients were asked to select the 3 situations among activities of daily living (ADL) that caused them maximal trouble . Each item is scored on an 11-point quantitative scale (range 0–10). The global score ranges from 0 (no disability) to 30 (maximal disability). This score has been validated in SSc , .
Hand disability was assessed by the Cochin Hand Function Scale (CHFS) , a questionnaire administered by the physician that contains 18 items related to ADL. Each question is scored on a scale of 0 (performed without difficulty) to 5 (impossible to do). The total score is obtained by adding the scores of all items (range 0–90). This questionnaire has been validated in SSc .
Mouth disability was assessed by the Mouth Handicap In Systemic Sclerosis (MHISS) scale, a questionnaire administered by the physician that contains 12 items concerning difficulties in performing ADL. Each question is scored on a scale of 0 (never) to 4 (always) . The total score is obtained by adding the scores of all items (range 0–48).
Anxiety and depression
Self-reported anxiety and depression symptoms were assessed by the Hospital Anxiety and Depression scale (HADS). This scale has 7 questions for the anxiety dimension (HADa) and 7 for the depression dimension (HADd) . Each item is scored on a scale of 0 to 3, the total score ranging from 0 (no depression, no anxiety) to 21 (maximal depression, maximal anxiety). Scores of 0–7 in subscales are considered normal, 8–10 borderline and ≥11 pathologic cases . The definition of clinical anxiety and/or depression was based on the HADS score cutoff ≥8 found to be relevant in patients with autoimmune diseases .
Aesthetic impairment was assessed on an 11-point quantitative scale, the total score ranging from 0 (no aesthetic impairment) to 10 (maximal aesthetic impairment).
Data analysis involved use of Systat 9 (SPSS Inc., Chicago, IL, USA). Quantitative variables were described with means ± standard deviations (SD) and qualitative variables with frequencies and percentages. For bivariate analysis, parametric tests were used since all parameters met criteria for normal distribution. Comparisons between male and female groups involved the Pearson chi-square test for qualitative variables and two-sample t test for quantitative data. Bonferroni adjustment was used for multiple comparisons (43 comparisons); therefore a p value less than 0.001 was considered statistically significant. Multivariate analysis was used to determine the association of gender and SSc-related variables. Backward stepwise regression all-inclusive analysis was run, including all dependent variables, with values of 0.20 to enter and 0.10 to stay in the model. Adjustment for age and type of recruitment from either patient association or hospitalization was performed. Odds ratios (OR) and 95% confidence intervals were calculated.
This survey was conducted in compliance with the protocol of Good Clinical Practices and Declaration of Helsinki principles. Patients gave their consent to participate after being orally informed about the study protocol. In accordance with European regulation (Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data), French observational studies from data obtained without any additional therapy or monitoring procedure, do not need formal approval of an Institutional Review Board or an Independent Ethics Committee, and a formal written consent from the patients is not required for this kind of project.
Demographic and clinical data
Overall, 381 patients were included. One-hundred-and-forty-three of them were recruited during their hospitalization in the internal medicine departments of Cochin (n = 127) or Claude Huriez (n = 16) hospitals, and the remaining 238 patients were recruited during ASF annual meetings from 2003 to 2009. The proportion of patients from the ASF who agreed among those who were asked to participate were 51 among 80 (63.8%) (44 females) in 2003, 50 among 80 (62.5%) (44 females) in 2004, 71 among 98 (72.4%) (59 females) in 2005, 70 among 95 (73.7%) (55 females) in 2006, 70 among 101 (69.3%) (55 females) in 2007, 86 among 130 (66.1%) (74 females) in 2008 and 2009 alltogether. Of the 381 patients, 62 were males (16.4%), with a female to male ratio of 5∶1. The mean age at the time of evaluation was 55.9 (13.3) years, and mean disease duration was 9.5 (7.8) years. A total of 149 (40.4%) patients had dcSSc, 187 (50.7%) had lcSSc, and 34 (9.2%) had lSSc. The mean KPS was 77.6 [11.7] (range 50–100) (Table 1).
Association of gender with SSc clinical expression
Males and females were comparable in age at the time of evaluation and at disease onset, disease duration and health status as assessed by the KPS score. For other clinical variables, some differences were observed between males and females, without reaching statistical significance. Indeed, BMI was higher in males than females (25.0 [4.1] vs 23.0 [4.5], p = 0.013) (Table 2). DcSSc was more frequent in males (54.8 vs 37.2%, p = 0.010), whereas lSSc was more frequent in females (10.7% vs 1.6%, p = 0.024). Regarding visceral involvement, males more often exhibited ILD and echocardiography PAP>35 mmHg than did females (54.8% vs 41.2%, p = 0.048; and 24.2% vs 10.5%, p = 0.003, respectively), and females more often calcinosis than males (36.0% vs 21.4%, p = 0.036). On multivariate logistic regression, gender was significantly associated with BMI (OR 1.12, 95% confidence interval [CI] 1.01–1.24) and echocardiography PAP>35 mmHg (OR 0.23, 95% CI 0.07–0.76).
Association of gender with SSc HRQoL and disability
HRQol assessed by the SF-36 was comparable in both groups. PCS and MCS were similar, and lower than 40 out of 100, for both males and females (34.2 [10.0] and 35.9 [9.6], p = 0.240, and 35.1 [12.3] and 34.3 [13.0], p = 0.667, respectively). Consistently, regarding global, patient-perceived, and location-specific disability as assessed by the HAQ, MACTAR, and CHFS and MHISS, respectively, we found no gender differences within each of these variables. Both groups exhibited similar aesthetic impairment (Table 3).
Association of gender with SSc self-reported symptoms of depression and anxiety
On bivariate analysis, some differences were observed between males and females for self-reported symptoms of depression and anxiety, but without reaching statistical significance. Indeed, self-reported symptoms of anxiety, as defined by HADa subscale score ≥8 were more frequent in females than males (62.3% vs 43.5%, p = 0.006), whereas absence of self-reported symptoms of both depression and anxiety, as defined by HADa and HADd subscale scores <8 was more often encountered in males than females (46.8 vs 31.6%, p = 0.021) (Table 4). Males and females did not differ in depression symptoms. On multivariate analysis, gender was associated with anxiety only (OR 5.50, 95% CI 1.12–27.04).
In the present study of 381 patients with SSc, we found a ratio of females to males of 5 to 1, which is in agreement with previous studies . Some differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, dcSSc, echocardiography PAP>35 mmHg and ILD were more often encountered in males, whereas lSSc and calcinosis were more often encountered in females. Females were more frequently found with self-reported symptoms of anxiety. Conversely, we found no association with gender regarding perceived health status, HRQoL and reported global and location-specific disability. On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender.
The prevalence of dcSSc in male patients was high and reached 54.8%. DcSSc was more frequent than lcSSc in males. The exact opposite was observed in females and was more consistent with previous reports of epidemiology studies of both male and female SSc patients. In two large US and German studies, the prevalence of lcSSc and dcSSc among SSc patients was 66.2% and 33.8%, and 45.5% and 32.7%, respectively , . In 3 cohorts of 1,012 Italian, 249 Swedish and 185 Canadian patients, dcSSc was more frequent in males than females (range from 37% to 67%) , , . Conversely, 2 studies from Spain comparing male and female SSc patients found no gender differences by disease type , . Finally, from a recent retrospective French survey of 121 SSc patients, dcSSc was more frequent in males than in females (22% vs 5%) . In these last 3 studies, the male sample sizes were rather small (n = 9, n = 26 and n = 36, respectively).
We found BMI significantly lower in females than in males. This finding might be of clinical relevance despite lack of clear explanatory reports. Indeed, in a prospective multiethnic cohort of 250 SSc patients, low BMI was among the 7 independent variables predictive of mortality. The authors even hypothesized that strong association of low BMI with mortality could be an objective and/or complete surrogate for generalized deconditioning or gastro-intestinal involvement .
Females were also more likely to have calcinosis, which is a frequent manifestation of SSc and found in about 25% of patients . Calcinosis mainly affects the extremities, at sites of recurrent microtrauma such as the forearms, elbows or fingers . It occurs predominantly at a late stage of disease and is not restricted to patients with the lSSc . However, clinical features associated with calcinosis remain poorly described. Recently, we provided evidence that calcinosis is an independent factor associated with digital ulcers (OR 2.33, 95% CI 1.04–5.19) .
In agreement with previous studies, we found that men were more likely than women to have echocardiography PAP>35 mmHg and ILD, for prevalences of 24.2% and 54.8%, respectively. Lung involvement is common in the course of SSc, and together, ILD and pulmonary hypertension are considered the 2 main causes of death in this disease . ILD is more frequent in male SSc patients at the time of diagnosis and during follow-up . In addition, male gender is associated with pulmonary hypertension during follow-up . In 1180 SSc patients (19% men) studied at early stages of the disease, men more often than women were found to have lung fibrosis and lower diffusing lung capacity for carbon monoxide than women . Thus, lung involvement in male SSc patients requires special attention and specific care because of its frequency and association with poor prognosis.
Interestingly, we found gender differences for both self-reported symptoms of depression and anxiety in SSc. Females more often exhibited self-reported symptoms of anxiety, whereas men were more often free of self-reported symptoms of both anxiety and depression. In a recent cross-sectional survey of 108 patients visiting a rheumatology outpatient department, the only factor significantly associated with psychiatric symptoms was gender . Conversely, in another cross-sectional study of 111 patients visiting a rheumatology clinic, 9% with SSc, gender had no effect on the frequency of anxiety and depression . Finally, in a study designed to assess psychological adjustment of 112 patients with early polyarthritis, female gender was found to be associated with high levels of depression and anxiety . Substantial evidence indicates that females report greater fear and are more likely to have anxiety disorders than are males. Complex processes underlie gender differences in anxiety. Individual differences in etiological factors of anxiety and fear are moderated by socialization processes that prescribe gender-specific expectations for expression of anxiety and the acceptable means of coping with anxiety . Finally, we found no differences in depression symptoms by gender (40.3 vs 40.8%, p = 0.96), which is consistent with recent findings by Thombs et al .
Remarkably, despite our finding of gender differences in clinical expression in SSc, males and females experienced comparable loss of function, global and location-specific disability, and HRQoL impairment, as evidenced by similar HAQ, CHFS, MHISS, MACTAR and SF-36 scores. Gender may not be a major determinant of perceived disability and impaired HRQoL in patients with SSc, and functional and social issues should be considered as severe in males as in females. Consistently, we recently found in a cohort of 87 SSc that employment status was strongly associated with perceived disability and health status but not with gender . In addition, using the World Health Association Disability Assessment Schedule II to assess HRQoL, Hudson et al found that clinical correlates of HRQoL did not include gender . HRQoL and functional disability may be associated with the meaning that SSc patients ascribe to their condition, which may be comparable for both males and females, rather than with its severity or its organ manifestation.
Our work has some limitations. Our sample of males was small, and our inability to demonstrate statistically significant differences between the two groups might be due to the lack of statistical power. Another limitation was the procedure used to recruit patients. Since all patients belonged to the French association of patients or were hospitalized in tertiary care units, they may not be representative of the whole French SSc population. Patients had longstanding disease, which could imply more symptoms. HAQ scores were high but remained comparable to those reported from previous studies conducted in tertiary care settings . Moreover, patients recruited from the patient association may have had more severe SSc than hospitalized patients . Further studies conducted in other cohorts are required to confirm the gender differences we observed. Finally, our study was not designed to explore the reasons for the observed gender differences. One can only hypothesize about the associated etiological factors, which may involve hormonal influences; genetics such as X-chromosome inactivation and monosomy, or microchimerism; as well as lifestyle (e.g., the debated connection with silicone implants) .
In conclusion, we confirm the association of gender and clinical manifestations in patients with SSc. Diffuse disease and lung involvement are more frequent in males, whereas females more often exhibit calcinosis and self-reported symptoms of anxiety. Despite SSc patients displaying gender-related clinical differences, the disease impact on perceived health status, HRQol and disability, is comparable in both groups. Studies comparing male and female patients living in different countries, with different occupational, lifestyle and medical exposure, would also be of interest to further clarify the role of environmental factors in such gender differences.
We thank the patients from the ASF for their participation in the study. We also thank members of the ASF for their logistical help. Luc Mouthon, Alice Bérezné, and Loïc Guillevin are members of the Groupe Français de Recherche sur la Sclérodermie.
Conceived and designed the experiments: CN TB AB AP CM-S LM LG SP MR FR SM-D. Performed the experiments: CN TB AB AP CM-S LM LG SP MR FR SM-D. Analyzed the data: CN TB AB AP CM-S LM LG SP MR FR SM-D. Contributed reagents/materials/analysis tools: CN TB AB AP CM-S LM LG SP MR FR SM-D. Wrote the paper: CN TB AB AP CM-S LM LG SP MR FR SM-D.
- 1. Tamby MC, Chanseaud Y, Guillevin L, Mouthon L (2003) New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev 2: 152–157.
- 2. Steen VD, Medsger TA Jr (2000) Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 43: 2437–2444.
- 3. Poole JL, Steen VD (1991) The use of the Health Assessment Questionnaire (HAQ) to determine physical disability in systemic sclerosis. Arthritis Care Res 4: 27–31.
- 4. Angelopoulos NV, Drosos AA, Moutsopoulos HM (2001) Psychiatric symptoms associated with scleroderma. Psychother Psychosom 70: 145–150.
- 5. Benrud-Larson LM, Haythornthwaite JA, Heinberg LJ, Boling C, Reed J, et al. (2002) The impact of pain and symptoms of depression in scleroderma. Pain 95: 267–275.
- 6. Haythornthwaite JA, Heinberg LJ, McGuire L (2003) Psychologic factors in scleroderma. Rheum Dis Clin North Am 29: 427–439.
- 7. Hyphantis TN, Tsifetaki N, Pappa C, Voulgari PV, Siafaka V, et al. (2007) Clinical features and personality traits associated with psychological distress in systemic sclerosis patients. J Psychosom Res 62: 47–56.
- 8. Legendre C, Allanore Y, Ferrand I, Kahan A (2005) Evaluation of depression and anxiety in patients with systemic sclerosis. Joint Bone Spine 72: 408–411.
- 9. Matsuura E, Ohta A, Kanegae F, Haruda Y, Ushiyama O, et al. (2003) Frequency and analysis of factors closely associated with the development of depressive symptoms in patients with scleroderma. J Rheumatol 30: 1782–1787.
- 10. Roca RP, Wigley FM, White B (1996) Depressive symptoms associated with scleroderma. Arthritis Rheum 39: 1035–1040.
- 11. Straszecka J, Kucharz EJ, Jonderko G, Kotulska A, Bednarczyk-Kaluzny M, et al. (1996) Depression and anxiety in patients with systemic sclerosis. Clin Rheumatol 15: 621.
- 12. Thombs BD, Hudson M, Taillefer SS, Baron M (2008) Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum 59: 504–509.
- 13. Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J (2008) Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 37: 223–235.
- 14. Oliver JE, Silman AJ (2009) Why are women predisposed to autoimmune rheumatic diseases? Arthritis Res Ther 11: 252.
- 15. Simeon CP, Castro-Guardiola A, Fonollosa V, Armadans L, Clemente C, et al. (1996) Systemic sclerosis in men: clinical and immunological differences. Br J Rheumatol 35: 910–911.
- 16. Peters-Golden M, Wise RA, Schneider P, Hochberg M, Stevens MB, et al. (1984) Clinical and demographic predictors of loss of pulmonary function in systemic sclerosis. Medicine (Baltimore) 63: 221–231.
- 17. Wynn J, Fineberg N, Matzer L, Cortada X, Armstrong W, et al. (1985) Prediction of survival in progressive systemic sclerosis by multivariate analysis of clinical features. Am Heart J 110: 123–127.
- 18. Joven B, Almodovar R, Carreira PE (2006) Gender differences in systemic sclerosis clinical expression and survival [abstract]. Ann Rheum Dis 65: 395.
- 19. Carreira PE, Carmona L, Joven BE, Allanore Y, Walker U, et al. (2009) Gender differences in early systemic sclerosis patients: a report from the EULAR scleroderma trials and research group (EUSTAR) database [abstract]. Ann Rheum Dis 68: 96.
- 20. Hudson M, Thombs B, Baron M (2009) Time to diagnosis in systemic sclerosis: is sex a factor? Arthritis Rheum 61: 274–278.
- 21. (1980) 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 23: 581–590.
- 22. LeRoy EC, Medsger TA Jr (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28: 1573–1576.
- 23. Mouthon L, Rannou F, Bérezné A, Pagnoux C, Guilpain P, et al. (2008) Patient preference disability questionnaire in systemic sclerosis: a cross-sectional survey. Arthritis Rheum 59: 968–973.
- 24. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, et al. (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363: 1665–1672.
- 25. Evans C, McCarthy M (1985) Prognostic uncertainty in terminal care: can the Karnofsky index help? Lancet 1: 1204–1206.
- 26. Nguyen C, Poiraudeau S, Mestre-Stanislas C, Rannou F, Bérezné A, et al. (2010) Employment status and socio-economic burden in systemic sclerosis: a cross-sectional survey. Rheumatology (Oxford) 49: 982–9.
- 27. Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30: 473–483.
- 28. Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, et al. (2002) Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. Arthritis Rheum 46: 2410–2420.
- 29. Tugwell P, Bombardier C, Buchanan WW, Goldsmith CH, Grace E, et al. (1987) The MACTAR Patient Preference Disability Questionnaire–an individualized functional priority approach for assessing improvement in physical disability in clinical trials in rheumatoid arthritis. J Rheumatol 14: 446–451.
- 30. Nguyen C, Mouthon L, Mestre-Stanislas C, Rannou F, Bérezné A, et al. (2010) Sensitivity to Change in Systemic Sclerosis of the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR): Shift in Patient Priorities Over Time. J Rheumatol 37: 359–364.
- 31. Duruoz MT, Poiraudeau S, Fermanian J, Menkes CJ, Amor B, et al. (1996) Development and validation of a rheumatoid hand functional disability scale that assesses functional handicap. J Rheumatol 23: 1167–1172.
- 32. Rannou F, Poiraudeau S, Berezne A, Baubet T, Le-Guern V, et al. (2007) Assessing disability and quality of life in systemic sclerosis: construct validities of the Cochin Hand Function Scale, Health Assessment Questionnaire (HAQ), Systemic Sclerosis HAQ, and Medical Outcomes Study 36-Item Short Form Health Survey. Arthritis Rheum 57: 94–102.
- 33. Mouthon L, Rannou F, Berezne A, Pagnoux C, Arene JP, et al. (2007) Development and validation of a scale for mouth handicap in systemic sclerosis: the Mouth Handicap in Systemic Sclerosis scale. Ann Rheum Dis 66: 1651–1655.
- 34. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67: 361–370.
- 35. Bjelland I, Dahl AA, Haug TT, Neckelmann D (2002) The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 52: 69–77.
- 36. Honarmand K, Feinstein A (2009) Validation of the Hospital Anxiety and Depression Scale for use with multiple sclerosis patients. Mult Scler 15: 1518–1524.
- 37. Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, et al. (2008) The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology (Oxford) 47: 1185–1192.
- 38. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, et al. (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48: 2246–2255.
- 39. Al-Dhaher FF, Pope JE, Ouimet JM (2010) Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum 39: 269–277.
- 40. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, et al. (2002) Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 81: 139–153.
- 41. Hesselstrand R, Scheja A, Akesson A (1998) Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis 57: 682–686.
- 42. Gaultier JB, Hot A, Cathebras P, Grange C, Ninet J, et al. (2008) [Systemic sclerosis in men]. Rev Med Interne 29: 181–186.
- 43. Assassi S, Del Junco D, Sutter K, McNearney TA, Reveille JD, et al. (2009) Clinical and genetic factors predictive of mortality in early systemic sclerosis. Arthritis Rheum 61: 1403–1411.
- 44. Robertson LP, Marshall RW, Hickling P (2003) Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis 62: 267–269.
- 45. Boulman N, Slobodin G, Rozenbaum M, Rosner I (2005) Calcinosis in rheumatic diseases. Semin Arthritis Rheum 34: 805–812.
- 46. Black CM (1993) The aetiopathogenesis of systemic sclerosis. J Intern Med 234: 3–8.
- 47. Mouthon L, Mestre-Stanislas C, Bérezné A, Rannou F, Guilpain P, et al. (2010) Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis. Ann Rheum Dis 69: 214–217.
- 48. Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 66: 940–944.
- 49. Azad N, Gondal M, Abbas N (2008) Frequency of depression and anxiety in patients attending a rheumatology clinic. J Coll Physicians Surg Pak 18: 569–573.
- 50. Waheed A, Hameed K, Khan AM, Syed JA, Mirza AI (2006) The burden of anxiety and depression among patients with chronic rheumatologic disorders at a tertiary care hospital clinic in Karachi, Pakistan. J Pak Med Assoc 56: 243–247.
- 51. Ramjeet J, Koutantji M, Barrett EM, Scott DG (2005) Coping and psychological adjustment in recent-onset inflammatory polyarthritis: the role of gender and age. Rheumatology (Oxford) 44: 1166–1168.
- 52. McLean CP, Anderson ER (2009) Brave men and timid women? A review of the gender differences in fear and anxiety. Clin Psychol Rev 29: 496–505.
- 53. Hudson M, Thombs BD, Steele R, Watterson R, Taillefer S, et al. (2008) Clinical correlates of quality of life in systemic sclerosis measured with the World Health Organization Disability Assessment Schedule II. Arthritis Rheum 59: 279–284.
- 54. Georges C, Chassany O, Mouthon L, Tiev K, Toledano C, et al. (2005) Validation of French version of the Scleroderma Health Assessment Questionnaire (SSc HAQ). Clin Rheumatol 24: 3–10.
- 55. Mestre-Stanislas C, Poiraudeau S, Bérezné A, Rannou F, Pagnoux C, et al. (2010) Differences in patients with systemic sclerosis recruited from associations and tertiary care settings. Presse Med.