To determine whether sex plays a role in the time to diagnosis of systemic sclerosis (SSc).
To determine whether sex plays a role in the time to diagnosis of systemic sclerosis (SSc).
In the Canadian Scleroderma Research Group registry, dates of onset of Raynaud's phenomenon, the first non–Raynaud's disease symptom, and diagnosis were recorded based on patient reports. Association between sex and time to diagnosis was assessed for the group as a whole and stratified based on extent of skin involvement, either limited or diffuse.
Of the 408 patients studied (347 women, 61 men, 44% with diffuse cutaneous SSc), the time to diagnosis after the onset of Raynaud's phenomenon was significantly longer for women than men (log rank P = 0.001), but not significantly different after the onset of the first non–Raynaud's disease manifestation. In an analysis stratified by limited or diffuse status, the time to diagnosis from onset of Raynaud's phenomenon was also significantly longer for women than men with diffuse cutaneous SSc (log rank P = 0.008). A trend toward a longer period between onset of Raynaud's phenomenon and SSc diagnosis was observed in women compared with men with limited cutaneous SSc (median 4.6 years in women versus 2.1 years in men; P = 0.085), and there was no sex difference in time to diagnosis after the onset of the first non–Raynaud's disease manifestation.
In SSc, the time to diagnosis is longer for women than men after the onset of Raynaud's phenomenon, suggesting 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.
Systemic sclerosis (SSc) is a chronic, multisystem disorder characterized by thickening and fibrosis of the skin and internal organs. It mainly affects women in the prime of their lives and is associated with significant morbidity, including pain, disability, depression, reduced quality of life, increased mortality, and high costs. SSc is thought to affect more than 16,000 Canadians and up to 100,000 Americans. There is currently no known cure.
SSc can be difficult to identify in the general clinic due to its rarity and heterogeneity, and this may give rise to delays in diagnosis. The onset of SSc is often heralded by Raynaud's phenomenon, but Raynaud's phenomenon is not specific for SSc. In addition, primary Raynaud's phenomenon is more common among women than men (1), and thus may be less likely to raise suspicion of SSc in women. Finally, in the general patient population, medically unexplained symptoms are more prevalent among women than men and are sometimes mistakenly understood as psychosocial in nature, which can result in less vigorous efforts to seek a medical reason for symptoms (2). Skin tightening is often the telltale sign of SSc and gives rise to its 2 common clinical subsets recognized in terms of skin involvement: either limited cutaneous SSc (lcSSc; skin involvement distal to the elbows and knees) or diffuse cutaneous SSc (dcSSc; skin involvement proximal to the elbows and knees in addition to the trunk) (3). However, although women are more commonly affected by SSc than men, little is known on sex differences in SSc, including differences in the onset of disease and the progression of early disease.
Given these considerations, we hypothesized that sex differences in the length of time to diagnosis could provide evidence of either differential health care trajectories or differential biologic processes in women and men with SSc. Therefore, we undertook this study to determine whether there were sex differences in the length of time to diagnosis of SSc.
The study design was a cross-sectional study of a convenience sample of patients with SSc. The study subjects consisted of those enrolled in the Canadian Scleroderma Research Group (CSRG) registry. Patients in the CSRG registry are recruited from 15 centers across Canada. They must have a diagnosis of SSc made by the referring rheumatologist, be age ≥18 years, and be fluent in English or French. The patients included in this study were those whose baseline visit was between August 2004 and August 2007. The CSRG registry patients are mostly women (85%), with a median age of 55 years, and median disease duration since diagnosis of 6 years. Except for race (>90% white), the demographic profile of these patients is comparable to those of other large SSc cohorts described in the US and Europe (4, 5).
Patients recruited into the CSRG registry underwent an extensive standardized evaluation including a medical history, physical evaluation, and laboratory investigations. Additionally, physicians documented the dates of onset of Raynaud's phenomenon, onset of the first non–Raynaud's disease symptom, and diagnosis of SSc based on patient report. They also performed a complete skin examination and classified patients into lcSSc and dcSSc subsets, based on the definition by LeRoy et al (3). Ethics committee approval for this study was obtained at each site and each patient provided written informed consent to participate in this study.
Descriptive statistics were used to summarize the baseline characteristics of the patients. The unadjusted association between sex and time to diagnosis was assessed using Kaplan-Meier curves and the log rank test. A multivariate Cox proportional hazards model was used to test the association between time to diagnosis and sex, after adjusting for limited versus diffuse skin involvement, age, education, and marital status. Given that patients with lcSSc may have a prolonged time between the onset of Raynaud's phenomenon and other manifestations of SSc, we also performed a stratified analysis. We repeated the above mentioned analyses, stratifying by extent of skin involvement, whether limited or diffuse, and adjusted for the demographic variables, namely age, education, and marital status. All statistical analyses were performed with SPSS statistical software, version 15 (SPSS, Chicago, IL).
Of 408 patients studied, the median age was 55 years, 85% were women, 71% were married, 45% had education beyond high school, 44% had dcSSc, and median time to diagnosis was 2.0 years (interquartile range [IQR] 0.5–7.9) from the onset of Raynaud's phenomenon and 0.8 years (IQR 0.2–3.0) from the onset of the first non–Raynaud's disease manifestation (Table 1). The mean ± SD disease duration since the onset of Raynaud's phenomenon was 13.2 ± 10.0 years, since the onset of non-Raynaud's symptoms was 10.8 ± 8.9 years, and since diagnosis of SSc was 8.2 ± 7.6 years. Mean ± SD time to diagnosis from onset of Raynaud's phenomenon was 5.0 ± 6.3 years, and from non-Raynaud's symptoms was 2.6 ± 4.5 years.
|No. (%)||408 (100)||347 (85)||61 (15)|
|Age, median (IQR) years||55 (47–63)||55 (47–63)||53 (47–63)|
|More than high school education, no. (%)||185 (45)||160 (46)||25 (41)|
|Married, no. (%)||288 (71)||242 (70)||46 (75)|
|Diffuse skin involvement, no. (%)||180 (44)||148 (43)||32 (53)|
|Disease duration, median (IQR) years|
|Since onset of Raynaud's phenomenon||11.5 (4.9–19.5)||11.8 (4.9–19.6)||7.8 (4.5–17.0)|
|Since onset of the first non–Raynaud's disease manifestation||8.9 (3.7–15.1)||9.4 (3.7–15.2)||6.3 (3.4–13.6)|
|Since diagnosis||6.1 (2.2–12.5)||6.3 (2.2–12.4)||5.3 (2.0–12.7)|
|Time to diagnosis, median (IQR) years|
|After onset of Raynaud's phenomenon||2.0 (0.5–7.9)||2.3 (0.5–8.9)||1.0 (0.3–3.2)|
|After onset of the first non–Raynaud's disease manifestation||0.8 (0.2–3.0)||0.7 (0.2–3.0)||0.8 (0–1.3)|
In Kaplan-Meier analyses, the time to diagnosis was significantly longer for women than men when disease onset was measured from the onset of Raynaud's phenomenon (log rank P = 0.001) (Figure 1A), but not significantly different from the onset of the first non–Raynaud's disease manifestation (log rank P = 0.093) (Figure 1B). Similarly, in Cox proportional analyses adjusted for demographic variables and extent of skin involvement, time to diagnosis was also significantly different when measured from onset of Raynaud's phenomenon, but not from the onset of the first non–Raynaud's disease manifestation. Female sex was significantly related to longer time to diagnosis (hazard ratio [HR] 1.6, 95% confidence interval [95% CI] 1.2–2.1; P = 0.001) after the onset of Raynaud's phenomenon. However, there was no significant difference in time to diagnosis between men and women after the onset of the first non–Raynaud's disease manifestation (HR 1.2, 95% CI 0.9–1.6; P = 0.139). Post hoc testing of models with income as a covariate (n = 358) did not alter results substantively, and income was not significantly related to time to diagnosis from onset of Raynaud's or non-Raynaud's symptoms.
Given differences in the natural course of lcSSc and dcSSc, we repeated the above mentioned analyses, stratifying the patients into limited and diffuse groups (Table 2). In those with lcSSc, the median time to diagnosis after the onset of Raynaud's phenomenon was 4.6 years (95% CI 3.2–5.9) in women and 2.1 years (95% CI 0.3–3.8) in men. In those with dcSSc, median time to diagnosis after the onset of Raynaud's phenomenon was 1.0 years (95% CI 0.8–1.2) in women and 0.7 years (95% CI 0.4–0.9) in men, suggesting a difference that could be as long as 0.8 years (9.5 months). In Kaplan-Meier analyses, although the time was more than twice as long for women than men with lcSSc, this was not statistically significant (log rank P = 0.085). However, the difference between women and men with dcSSc was statistically significant (log rank P = 0.008). There were no significant differences in the time to diagnosis between women and men, whether with lcSSc or dcSSc, after the onset of the first non–Raynaud's disease manifestation. Similar results were obtained in analyses adjusting for demographic differences (data not shown).
|No.||Time to diagnosis from onset of Raynaud's phenomenon, years||Time to diagnosis from onset of first non–Raynaud's disease manifestation, years|
|Median (95% CI)||Log rank P||Median (95% CI)||Log rank P|
|Women||199||4.6 (3.2–5.9)||0.085||1.0 (0.6–1.4)||0.271|
|Men||29||2.1 (0.3–3.8)||0.9 (0.2–1.7)|
|Women||148||1.0 (0.8–1.2)||0.008||0.6 (0.5–0.7)||0.344|
|Men||32||0.7 (0.4–0.9)||0.6 (0.3–0.8)|
To address potential biologic differences in progression of disease, we repeated the analyses comparing the time between onset of Raynaud's phenomenon and onset of the first non-Raynaud's symptoms between women and men. Again, we found significant sex differences in patients with dcSSc, with female sex significantly related to longer time between onset of Raynaud's phenomenon and first non–Raynaud's disease symptom in both unadjusted (log rank P = 0.046) and adjusted (HR 1.8, 95% CI 1.1–2.8) analyses.
In SSc, the time to diagnosis is long, and it is longer for women than men. In stratified analyses, this remains significantly true for women with dcSSc after the onset of Raynaud's disease, where the difference in time to diagnosis could be as long as 0.8 years (9.5 months). Although not statistically significant, the time to diagnosis after the onset of Raynaud's phenomenon was still more than twice as long in women (4.6 years) compared with men (2.1 years) with lcSSc. Although this study remains hypothesis generating, the findings are both concerning and thought provoking. They provide impetus for further research to identify possible biologic differences between and differences in the delivery of health care to women and men with this devastating disease.
This study was designed to determine whether or not there were sex differences in time to diagnosis, not to explain why those differences exist. This is well beyond the scope of our current data. However, possible reasons for the differences found could include the following: perceptual bias of physicians toward understanding symptoms of women more than men as psychosomatic, sex differences in the communication of symptoms, sex differences in health care trajectories, and potential biologic differences in the onset and progression of early disease, including the impact of sex-based lifestyle differences (nutrition, stress, exposure to infection, etc.). Our finding that the time between onset of Raynaud's phenomenon and the first non–Raynaud's disease symptom is longer in women compared with men with dcSSc certainly supports the possibility that progression of early disease may, in fact, be different between men and women. Understanding the mechanisms underlying such possible biologic differences will require further investigation of genetic, hormonal, vascular, immunologic, and other environmental differences between women and men with this disease.
The time of onset of SSc remains a matter of uncertainty. Many have specifically used the time of onset of the first non–Raynaud's disease manifestation (6, 7). However, others have not clearly specified whether Raynaud's phenomenon is included as a symptom signaling the onset of SSc. This may explain why a wide range of times to diagnosis have been reported. For example, in one study of 813 Canadian patients, mean time between the “onset of symptoms” (not otherwise defined) and diagnosis was 2.4 years (8). This is in contrast to another study of 127 French and 247 American patients, in which mean time between onset of symptoms “attributable to disease” and diagnosis was reported to be 5.1 years (9). To our knowledge, our study is the first detailed description of the time to diagnosis both from the onset of Raynaud's phenomenon and from the onset of the first non–Raynaud's disease manifestation. In either case, the time to diagnosis was considerable (median 2.0 years from the onset of Raynaud's phenomenon and 0.8 years from the onset of the first non–Raynaud's disease manifestation). In addition, our data is unique in that, to date, no study has examined differences in time to diagnosis between men and women with SSc.
One limitation of our study was that due to the relatively small number of men in the cohort, it was not possible to reasonably evaluate whether the type of first non-Raynaud's symptoms differed across sex. Another limitation is that this is a retrospective study and the main outcome variables are based on recall. There are 2 main possible origins of recall bias in this study. One may originate from the clinician inquiring about the onset of symptoms, and the other may originate from the patient recalling their history. Both may result in biased reporting of symptoms and these may differ by sex. However, the extent and direction of such bias is difficult to ascertain in our study. Finally, Raynaud's phenomenon is not a necessary precondition to the diagnosis of SSc. However, it is well established that the vast majority of patients with SSc have Raynaud's phenomenon and it usually presents before or at the time of disease onset (10). Therefore, for the purpose of this analysis, we selected only patients who had Raynaud's phenomenon and our data is generalizable only to SSc patients who have Raynaud's phenomenon.
The significance of our findings lies in the fact that based on current prevalence estimates, SSc likely affects ∼100,000 North Americans, the majority of which are women (4), and in dcSSc, skin thickening and severe internal organ involvement generally occur in the first 3 years of disease (11). Therefore, earlier diagnoses for women could potentially reduce the hardship associated with the uncertainty present before SSc is diagnosed (12) and allow them to access potentially beneficial treatments in a timely manner. However, to reduce any delays in diagnosis and to understand why there is a greater delay in diagnosis of women compared with men with dcSSc, further research will be required to investigate possible biologic differences in the natural progression of the disease and/or behavioral differences in the health care trajectories of men and women with SSc.
Actelion Pharmaceuticals and Pfizer, Inc., had no role in the design of the study, analysis of the data, preparation of the manuscript, and decision to submit the manuscript for publication.
Dr. Hudson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Hudson, Thombs, Baron.
Acquisition of data. Hudson, Baron.
Analysis and interpretation of data. Hudson, Thombs, Baron.
Manuscript preparation. Hudson, Thombs, Baron.
Statistical analysis. Hudson, Thombs.
Additional members of the Canadian Scleroderma Research Group not listed as coauthors include J. Markland: Saskatoon, Saskatchewan; J. Pope: London, Ontario; D. Robinson: Winnipeg, Manitoba; N. Jones: Edmonton, Alberta; P. Docherty: Moncton, New Brunswick; M. Abu-Hakima, S. Le Clercq: Calgary, Alberta; N. A. Khalidi, E. Kaminska: Hamilton, Ontario; E. Sutton: Halifax, Nova Scotia; C. D. Smith: Ottawa, Ontario; J.-P. Mathieu, S. Ligier: Montreal, Quebec; P. Rahman: St. John's, Newfoundland, Canada.