Research ArticleArticles

The 15% Rule in Scleroderma: The Frequency of Severe Organ Complications in Systemic Sclerosis. A Systematic Review

Chayawee Muangchan, Canadian Scleroderma Research Group, Murray Baron and Janet Pope
The Journal of Rheumatology September 2013, 40 (9) 1545-1556; DOI: https://doi.org/10.3899/jrheum.121380

Abstract

Objective. The prevalence of organ complications in scleroderma (systemic sclerosis; SSc) varies by definition used. This study was done to determine the frequency of several features of SSc.

Methods. A search of Medline-Ovid/Embase, PubMed, and Scopus databases from 1980 to November 30, 2011, was conducted to identify relevant articles with at least 50 patients with SSc extracting prevalence of each organ complication. Study quality was assessed using the STROBE (Strengthening The Reporting of OBservational studies in Epidemiology) checklist. Pooled prevalence was calculated using the random effects method. Heterogeneity was quantified using I2.

Results. A total of 5916 articles were identified (913 from Medline-Ovid/Embase, 1009 from PubMed, and 3994 from Scopus); 5665 were excluded, leaving 251 articles for full-text review, with 69 included. Where available, frequencies were also included from the Canadian Scleroderma Research Group. Many severe complications in SSc occur about 15% of the time, including cardiac involvement (15%, 95% CI 6–24), diastolic dysfunction (16%, 95% CI 14–17), estimated pulmonary artery pressure > 40 mm Hg (18%, 95% CI 14–21), pulmonary arterial hypertension by right heart catheterization (15%, 95% CI 12–17), forced vital capacity (FVC) < 70% predicted (15%, 95% CI 12–17), FVC < 80% predicted (17%, 95% CI 12–21), myositis (13%, 95% CI 10–17), inflammatory arthritis (12%, 95% CI 9–16), Sjögren overlap (13%, 95% CI 10–16), and digital ulcers (DU; 15%, 95% CI 10–20); and 15% of DU have complications (amputations 12%, 95% CI 8–16, and hospitalizations 13%, 95% CI 6–21). Scleroderma renal crisis is uncommon but occurs in almost 15% (12%, 95% CI 5–19) of cases of disseminated cutaneous SSc. There is no 15% rule within skin and gastrointestinal tract for SSc.

Conclusion. The “15%” rule for frequency of significant organ involvement in SSc is helpful.

Key Indexing Terms:

Systemic sclerosis (SSc; scleroderma) is a systemic autoimmune connective tissue disease characterized by autoimmunity, vascular malfunction and inflammation, and fibrosis. Disease subsets can be classified into limited (lcSSc) and diffuse (dcSSc) cutaneous SSc1. Patients with dcSSc usually have more complications2,3. Steen and Medsger reported the prevalence of severe organ complication in dcSSc using the Pittsburgh Scleroderma Databank4. Many other SSc studies from different cohorts have also reported the prevalence of organ complications using different definitions. Our goal was to promote awareness of the prevalence of important organ involvement in SSc to facilitate appropriate screening and investigation. We used a metaanalysis of the published literature, where available, to define the frequency of severe organ complications of SSc and to construct a broad, easily remembered rule to help clinicians remember those frequencies.

MATERIALS AND METHODS

Identification of studies and study population

A comprehensive literature search of the Medline-Ovid/Embase, PubMed, and Scopus databases was conducted, each from 1980 [when the preliminary American College of Rheumatology (ACR) classification criteria for SSc were published] to November 30, 2011. We looked for English-language research articles for adult SSc using the following search terms: scleroderma and systemic sclerosis. We searched for organ complications using the following search terms:

  • Kidney: malignant arterial hypertension, rapidly progressive renal failure, kidney failure, acute kidney/renal failure, glomerulonephritis, scleroderma renal crisis (SRC).

  • Heart: cardiomyopathy, heart failure, ventricular dysfunction, heart block, heart muscle conduction disturbance, myocarditis, pericarditis, pericardial effusion.

  • Pulmonary hypertension: pulmonary hypertension (PH), pulmonary arterial hypertension (PAH).

  • Lung: interstitial lung disease (ILD), pulmonary fibrosis, restrictive lung disease, lung function test, lung fibrosis, spirometry.

  • Gastrointestinal (GI) system: malabsorption, hyperalimentation, intestinal pseudoobstruction, malnutrition, bacterial overgrowth.

  • Muscle: myopathy, myositis, muscle weakness, muscle disease, skeletal muscle/myopathy, polymyositis.

  • Joint: arthritis/chronic arthritis, synovitis, arthropathy, joint erosion.

  • Digital ulcer or ischemic complications: digital ulcer (DU), digital necrosis, digital gangrene, digital loss, digital amputation.

  • Skin: modified Rodnan skin score (mRSS), skin involvement, skin score. Sjögren syndrome (SS).

Studies were included if they provided numerical data (numbers and/or percentages) of the incidence and/or prevalence of the clinical manifestations of interest; and if they provided a definition of or stratified severity for each complication (described below). Studies were excluded if they were case reports/case series, had fewer than 50 patients with SSc, or were review articles. If more than 1 identified study used the same or overlap study population at the same period, the most recent or larger sample-size study was included. If publications from the same group reported different manifestations, each publication was used for nonredundant items. Two reviewers (CM and JP) separately included reports using the inclusion and exclusion criteria. If there was disagreement, the full reports were reviewed and agreement was achieved by consensus.

Severe organ complications included the following:

  • Kidney: documented SRC as defined by new-onset malignant arterial hypertension and/or rapidly progressive glomerulonephritis with serum creatinine rising by at least 20% of baseline with/without microangiopathic hemolytic anemia occurring in both the dcSSc subset and SSc in total. SRC was often defined by the authors of each report.

  • Heart: documented cardiomyopathy with a decrease in left ventricular ejection fraction (LVEF) by echocardiography; symptoms of congestive heart failure; left diastolic dysfunction by echocardiography; arrhythmia attributable to scleroderma heart disease requiring treatment; and symptomatic pericarditis or moderate to large pericardial effusion.

  • PH and PAH: PH was defined by Doppler echocardiography providing estimated systolic (sPAP) or mean pulmonary artery pressure (mPAP). We stratified PH according to the cutoff level of sPAP or mPAP used by each study. PAH was defined by right heart catheterization (RHC).

  • Lung: documented restrictive lung disease using percentage of predicted FVC (FVC % predicted) or total lung capacity (TLC % predicted) by standard pulmonary function testing (PFT). The severity of restriction was classified by FVC % predicted or TLC % predicted used by each study. We did not include ILD defined solely by chest radiograph because it is common in SSc, including asymptomatic patients.

  • GI system: clinically documented malabsorption syndrome, repeated episodes of intestinal pseudoobstruction, or severe GI problems requiring hyperalimentation. Gastroesophageal reflux and dysphagia were not included because they were thought to be very common. We also did not include bacterial overgrowth syndrome because most studies defined this by a variety of tests but it is often a clinical diagnosis in patients with SSc.

  • Muscle: clinically documented (proximal, symmetrical) muscle weakness; proximal muscle weakness with elevated creatine kinase, electromyographic testing (EMG), and muscle biopsy evidence of inflammatory myositis, fulfilling or not fulfilling the Bohan and Peter criteria for myositis5,6, i.e., dermatomyositis (DM)/polymyositis (PM).

  • Arthritis: clinically documented arthritis or synovitis using the swollen joint count (SJC) with/without the tender joint count (TJC) and those with inflammatory arthritis who had erosions on radiographs, which is a subset population. We did not include inflammatory arthritis defined solely by radiographs or ultrasound.

  • Digital ulcer or ischemic complications: clinically documented digital ischemic vasculopathy as prevalent digital ulcer (a loss of continuity of epithelial coverage that can be denuded or covered by a scab or necrotic tissue); current gangrene, necrosis anywhere on the digit, and complications including amputation (autoamputation or surgical) or hospitalization due to digital ulcers. Digital pits/scars and Raynaud’s phenomenon (RP) were not included because they are extremely frequent in SSc.

  • Skin: documented mRSS above various levels and classified to the cutoff levels according to each study definition.

  • SS: documented by fulfilling any standard criteria for diagnosis of SS. The frequency of overlap of SSc with SS was studied. We did not include sicca symptoms with SSc because they have a variety of classification definitions and tests that are not readily pooled.

Study population from the Canadian Scleroderma Research Group (CSRG)

We also studied the prevalence of each organ complication in the database of the CSRG if the data were not currently in the published literature. The CSRG is a multicenter, prospective national registry of adult SSc across Canada. Clinical and laboratory data are collected annually in a comprehensive database of subjects enrolled between August 2004 and April 2010 who fulfilled preliminary ACR (formerly the American Rheumatism Association) criteria for the classification of SSc (scleroderma); or who were diagnosed by their rheumatologist as having SSc. They were included if the prevalence of organ complications was provided. The following CSRG definitions of organ complication were used, because they were predefined and were the same as in other databases where possible. Renal: SRC was recorded from a physician-completed form. Heart: cardiomyopathy was defined as LVEF ≤ 45% by standard echocardiography; conduction system abnormalities were defined as any conduction abnormalities or arrhythmias on electrocardiography; we had no specific information on symptoms of congestive heart failure, and there was no routine reporting of left ventricular diastolic dysfunction by echocardiography; pericarditis was defined as at least moderate pericardial effusion by standard echocardiography; PH was defined with a surrogate: sPAP ≥ 45 mm Hg by standard echocardiography or diagnosis of PAH. Lung: pulmonary restriction was defined by FVC < 70% predicted on PFT. GI system: hyperalimentation and intestinal pseudoobstruction were recorded from the physician-completed standardized forms. Muscle: proximal limb girdle muscle weakness was recorded from physical examination using a score ≤ 4 based on 5-point Likert scale; EMG and muscle biopsies are not provided in the registry. Arthritis was defined clinically as SJC ≥ 1 and TJC ≥ 1. The CSRG database does not include joint radiographs. Digital ulcers and ischemic complications: current digital ulcer(s)/gangrene/amputation were recorded from physical examination (anywhere on the digit), which was recorded at each visit. Skin: The mRSS was recorded. SS was defined by patient questionnaires about sicca symptoms; SS information, such as labial biopsy results, was not recorded.

Data extraction

Data extraction was performed by 1 investigator (CM). The following data were extracted from each study: first author, year of publication, location of study; study design; sample size; and prevalence in number and/or percentage of each organ complication. The prevalence of various organ involvements was extracted from studies, and forest plots were constructed. The CSRG data did not necessarily contain identical definitions, or in some cases, any data for certain outcomes. In addition, if publications from the CSRG database were available, then they were used and the prevalence was not recalculated from the updated database (because the former were papers published in peer-reviewed journals). If publications used distinctively different definitions of a certain organ, the rates were not pooled, resulting in some plots of different definitions of organ involvement. For instance, estimates were not pooled for various FVC cutoff values, and echocardiographic estimates of PH were not pooled with RHC-proven PAH.

Quality assessment

Study quality was assessed by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort, case-control, and cross-sectional studies7,8. The STROBE checklist consists of 22 items: 18 items are common to all 3 study designs and 4 items (6a/6b, 12d, 14c, 15) are specific to cohort, case-control, or cross-sectional studies. The maximum score varies based on the number of applicable items on the checklist. Two items on the checklist (12e and 16c) pertain to statistical methods (12e describes any sensitivity analysis of the main results; 16c is scored where the relative risk is translated into absolute risk for a meaningful time period) so these items were not relevant to all the articles. One item applied only to matched studies (6b), and another only to cohort studies (14c). The maximum attainable score was 32. The purpose of STROBE is not to give a quality score but to ensure clear presentation of reporting.

Statistical analysis

Proportions were pooled with a random effects model9. A random effects model was used because it assumes that true frequencies from the individual studies have a probability distribution, and it assigns a more balanced weight to each study. Forest plots were created to estimate prevalence with 95% CI. The I-square (I2) statistic was used to quantify the magnitude of heterogeneity (i.e., mild 0–30%, moderate 31%–50%, high > 50%), tau-square was the square-root of the between-study variance, and p value was for Cochran’s Q statistic, the classic measure of heterogeneity. Publication bias was determined using funnel plots.

RESULTS

Search results

The literature search identified 5916 potentially relevant articles that were screened for eligibility. A total of 5665 articles were excluded. There were 173 repeated citations among the search terms and/or different databases. Two articles were identified by hand-searching key references. Eleven further articles were excluded: 9 used the same study population at the same period or at least contained the same patients as part of single-center, national, or multinational databases, 1 article selectively collected data on SSc patients with digital ulcers, and 1 had a different definition for organ involvement, yielding 69 articles included in the metaanalysis (Figure 1).

Figure 1.
Figure 1.

The search strategy. SSc: systemic sclerosis.

Description of studies included

Characteristics of the 69 articles included in the metaanalysis are shown in Table 1. The studies incorporated data for SSc patients from different locations: North America4,12,17,26,27,34,43,58,60,70,76,77, South America16,53, Europe10,11,14,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,47,48,49,50,51,52,57,59,61,62,63,66,68,69,71, Africa55, Asia13,24,25,38,46,54,56,64,65,67,74, and Australia15,44,45,75. Eighty-five percent of the pooled study population from 69 articles were women. The mean age of patients with SSc (at cohort entry or first diagnosis) from 69 articles was 51.7 years (range 29.4–60.5 yrs) and mean disease duration from onset of first non-Raynaud’s symptoms to study period was 8.8 years (range 0.8–15 yrs). The attainable maximum score was 32 for the STROBE checklist and mean score of the 69 articles was 24.9 (range 17–31).

View this table:
Table 1.

Characteristics of 69 articles included in the metaanalysis.

Frequency of complications in CSRG cohort

There were 1145 SSc patients included from August 18, 2004, to April 27, 2010 (duration of total followup 5 years, 8 months); data were available for analysis from 1043 of these patients according to their disease subset, either lcSSc or dcSSc. Eighty-six percent were women, with mean age 55.4 years and disease duration from onset of first non-Raynaud’s symptoms to baseline visit of 11.0 years. Thirty-eight percent had dcSSc, of whom 117 (10.6% of total) had early dcSSc (< 3 yrs since onset). Frequency of each organ complication in the CSRG cohort is shown in Table 2.

View this table:
Table 2.

Frequency of organ complications in systemic sclerosis (SSc) from the Canadian Scleroderma Research Group (CSRG).

Analysis

Forest plots were calculated to provide pooled OR estimates (Figure 2) for frequencies of several organs. Frequencies of organ complications in SSc and the dcSSc subset are shown in Table 3: it can be seen that many clinically relevant organ complications occurred in 15% of patients with SSc. For cardiac involvement we had 2 additional categories other than predefined organ system involvement, which were a combination of various cardiac complications in SSc (congestive heart failure, symptomatic pericarditis, symptomatic arrhythmia, and cardiomyopathy, as described above) and within the dcSSc subset, because that is how they were reported in the literature. We did not have pooled prevalence of skin involvement, because there were not at least 2 studies that used the same cutoff level for skin sclerosis by the mRSS.

Figure 2.

Forest plots of some organ complications in scleroderma.

View this table:
Table 3.

Summary of frequency of organ complications in systemic sclerosis (SSc).

DISCUSSION

This systematic review reports the prevalence of severe organ complications in patients with SSc, except those very common in SSc such as RP, gastroesophageal reflux disease (GERD), dysphagia, and skin involvement. Data from the CSRG were used because it is a large national database with well-defined complications. Although some definitions of organ involvement were not standardized, we compared studies with similar definitions.

The frequency of organ involvement might change over time by both disease duration and year of publication. This may be true for SRC, which could be decreasing over time. The studies in our metaanalysis included patients with SRC in the period before use of angiotensin-converting enzyme inhibitors and afterward. Small cohorts were not included because their estimates of prevalence of organ involvement would potentially have a large degree of variability. We tried to exclude studies that contained the same patients.

Most organ involvement occurred in about 15% of cases, within the 95% CI. These included pooled data for severe cardiac involvement (congestive heart failure or symptomatic pericarditis, symptomatic arrhythmia, and cardiomyopathy) in both dcSSc and SSc, diastolic dysfunction, symptomatic arrhythmias or conduction abnormalities, and PH, as well as PAH, pulmonary restriction by various definitions of FVC (as a surrogate for ILD), myositis, arthritis, prevalent DU, complicated ulcers ever, and SS. The estimated prevalence of PAH in SSc defined by RHC was 15% (95% CI 12%–17%). When different studies were combined, the prevalence of PH by echocardiography in SSc was 14% (95% CI 8%–20%), prevalence by sPAP > 35 mm Hg was 14% (95% CI 9%–19%), and prevalence by sPAP > 40 or 45 mm Hg was 18% (95% CI 14%–21%). Considering FVC % predicted, the prevalence of FVC % predicted < 80% or 70% was 15% (i.e., for mild restrictive changes), but for very severe pulmonary restriction (FVC % predicted < 50%) the 15% rule did not apply.

SRC in the dcSSc subset was 12% (95% CI 5%–19%), with a wide CI including 15%. Organ involvement that did not meet the 15% criterion included SRC in SSc (3%, 95% CI 3%–4%), cardiomyopathy in SSc (3%, 95% CI 1%–6%), symptomatic congestive heart failure in SSc (5%, 95% CI 1%–9%), symptomatic pericarditis or moderate to large pericardial effusion in SSc (3%, 95% CI 1%–5%), FVC % predicted < 50% in SSc (8%, 95% CI 4%–13%), TLC % predicted < 80% in SSc (23%, 95% CI 22%–25%), malabsorption, intestinal pseudoobstruction and/or severe GI problems requiring hyperalimentation in SSc (5%, 95% CI 3%–6%), proximal muscle weakness (24%, 95% CI 17%–30%), radiographic erosions in those with clinical arthritis in SSc (9%, 95% CI 4%–14%), and digital gangrene in SSc (2%, 95% CI 1%–3%). The estimated prevalence of 15% does not apply to RP, GERD, and skin involvement by various mRSS cutoff scores (which we did not include in the analyses). The estimated prevalence of 15% for significant organ involvement in SSc is not a universal rule, but can help clinicians to be aware of the frequency of several complications of SSc.

A random effects model was used to pool the studies. However, differences in features of the study population in each cohort, such as ethnicity78,79,80, geography78, socioeconomic status79,80, disease subtype, disease duration, environmental factors, variable definitions of organ involvement, and other unknown factors/potential confounders, resulted in clinical heterogeneity of most of the pooled studies. Cohorts from Japan, India, and Thailand had lower age at disease onset compared to those from Europe and North America. Asian cohorts also had more pulmonary complications78 and fewer digital ulcers26. Chinese patients experienced less SRC but more myositis compared to Europeans27. Pulmonary fibrosis occurred more often and was more severe in African Americans compared to whites79,80, and they had pulmonary hypertension at a younger age81. Hispanics and African Americans had more diffuse skin involvement, digital ulcers, lower FVC % predicted, and poorer socioeconomic status than whites82,83. Patients with less high school completion were reported to have more arthritis84. Sex and disease subset ratios varied between some cohorts, which could affect the frequency and severity of organ involvement85,86. Therefore, heterogeneity can affect the rate of complications, which is important when pooling data from several cohorts.

We tried to include large studies and as many studies as were available concerning each predefined organ system to diminish the variance, but some organ definitions yielded only a couple of studies where data could be pooled. Pooled studies of at least 4 cohorts for various organ prevalences were analyzed (Table 3), whereas the rates may be less certain and less generalizable in the analyses that included fewer studies. Some definitions of organ involvement had very few studies. There was also statistical heterogeneity (I2 > 50%) in some analyses and results could not be pooled. There may have been publication bias, because some of the funnel plots appeared to have asymmetry, and did not resemble inverted funnels, especially those with fewer or smaller studies (data not shown). Even some larger studies had asymmetrical funnel plots. This may be due to clinical and methodological heterogeneity. Smaller studies or studies from tertiary centers might have been performed in a selected SSc population.

The estimated prevalence of PAH defined by RHC in SSc of 15% (95% CI 12%–17%) was slightly higher than that from a metaanalysis from 5 studies (9%, 95% CI 6%–12%)21. The prevalence of PH in SSc by echocardiography (14%, 95% CI 8%–20%), or by sPAP > 35 mm Hg (14%, 95% CI 9%–19%), or by sPAP > 40 or 45 mm Hg (18%, 95% CI 14%–21%) in our study was roughly consistent with the prevalence of suspected PH by echocardiography leading to RHC (13%, 95% CI 7%–23%) reported by Avouac, et al21.

Some studies had higher than expected prevalence, such as the pooled prevalence of severe cardiac involvement. Also, some frequencies were higher in more severe organ involvement, such as for PH in SSc with sPAP > 35 mm Hg, which should be more frequent than that of sPAP > 40 mm Hg or 50 mm Hg. This can be due to selection bias of patients included in the studies and we could not adjust for this in the analyses.

Another limitation is that a pooled prevalence could not be calculated for every manifestation because some analyses included only 1 publication and different definitions of significant organ involvement were used in the publications (e.g., “severe skin sclerosis” used different cutpoints of the mRSS). The strength of our study is the large number of articles that could be pooled for various complications, and only cohorts that were relatively large were included. Not every organ system fits neatly into the 15% rule, such as GI involvement, RP, SRC (only in the early dcSSc subset), clinical congestive heart failure, etc. However, we observed that the 15% rule is often generalizable. SRC in dcSSc had a wide CI, so the point estimate may actually be different from 15%, but it overlaps 15%.

Many complications in SSc, including ILD as measured by a low percentage-predicted FVC, PAH, diastolic dysfunction, arrhythmias, inflammatory arthritis, myositis, SS, and digital ulcers and their complications, occur in about 15% of patients. SRC is uncommon overall but occurs in almost 15% of the dcSSc subset. The 15% rule of SSc organ involvement may help clinicians be aware of the frequency of many features of SSc.

Acknowledgment

The authors thank Dr. Heather Thiessen Philbrook for creation of forest plots.

APPENDIX 1 List of study collaborators

Investigators of the Canadian Scleroderma Research Group (CSRG): J. Markland, Saskatoon, Saskatchewan; D. Robinson, Winnipeg, Manitoba; N. Jones, Edmonton, Alberta; N. Khalidi, Hamilton, Ontario; P. Docherty, Moncton, New Brunswick; E. Kaminska, Hamilton, Ontario; A. Masetto, Sherbrooke, Quebec; E. Sutton, Halifax, Nova Scotia; J-P. Mathieu, Montreal, Quebec; M. Hudson, Montreal, Quebec; S. Ligier, Montreal, Quebec; T. Grodzicky, Montreal, Quebec; S. LeClercq, Calgary, Alberta; C. Thorne, Newmarket, Ontario; M. Fritzler, Advanced Diagnostics Laboratory, Calgary, Alberta.

Footnotes

  • The Canadian Scleroderma Research Group is supported by the Canadian Institutes of Health Research (CIHR) and the Fonds de Recherché en Santé du Québec; and the Scleroderma Society of Canada, Scleroderma Society of Ontario, Sclérodermie Québec, and Cure Scleroderma Foundation.

  • Accepted for publication May 13, 2013.

REFERENCES

  1. 1.↵
    1. LeRoy EC,
    2. Black C,
    3. Fleischmajer R,
    4. Jablonska S,
    5. Krieg T,
    6. Medsger TA Jr.,
    7. et al.
    Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol 1988;15:202–5.
    OpenUrlPubMed
  2. 2.↵
    1. Steen VD,
    2. Medsger TA Jr.
    . Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin North Am 1990;16:1–10.
    OpenUrlPubMed
  3. 3.↵
    1. Steen VD
    . Clinical manifestations of systemic sclerosis. Semin Cutan Med Surg 1998;17:48–54.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Steen VD,
    2. Medsger TA Jr.
    . Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000;43:2437–44.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Bohan A,
    2. Peter JB
    . Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292:403–7.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Bohan A,
    2. Peter JB
    . Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Von Elm E,
    2. Altman DG,
    3. Egger M,
    4. Pocock SJ,
    5. Gøtzsche PC,
    6. Vandenbroucke JP; and
    7. STROBE Initiative
    . Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007;335:806–8.
    OpenUrlFREE Full Text
  8. 8.↵
    1. Vandenbroucke JP,
    2. von Elm E,
    3. Altman DG,
    4. Gøtzsche PC,
    5. Mulrow CD,
    6. Pocock SJ,
    7. et al.
    Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology 2007;18:805–35.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. DerSimonian R,
    2. Laird N
    . Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Walker UA,
    2. Tyndall A,
    3. Czirják L,
    4. Denton C,
    5. Farge-Bancel D,
    6. Kowal-Bielecka O,
    7. et al.
    Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis 2007;66:754–63.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Pérez-Bocanegra C,
    2. Simeón-Aznar CP,
    3. Campillo M,
    4. Fonollosa-Pla V,
    5. Vilardell-Tarrés M
    . Age-related survival and clinical features in systemic sclerosis patients older or younger than 65 at diagnosis. Rheumatology 2010;49:1112–7.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. De Marco PJ,
    2. Weisman MH,
    3. Seibold JR,
    4. Furst DE,
    5. Wong WK,
    6. Hurwitz EL,
    7. et al.
    Predictors and outcomes of scleroderma renal crisis: The high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002;46:2983–9.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Hashimoto A,
    2. Tejima S,
    3. Tono T,
    4. Suzuki M,
    5. Tanaka S,
    6. Matsui T,
    7. et al.
    Predictors of survival and causes of death in Japanese patients with systemic sclerosis. J Rheumatol 2011;38:1931–9.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Montagna GL,
    2. Baruffo A,
    3. Maja L,
    4. Tirri E,
    5. Matrone C,
    6. Vatti M,
    7. et al.
    Scleroderma renal crisis analysis of prevalence and outcome in a large Italian series. J Clin Rheumatol 1997;3:186–93pmid:19078185.
    OpenUrlPubMed
  15. 15.↵
    1. Walker JG,
    2. Ahern MJ,
    3. Smith MD,
    4. Coleman M,
    5. Pile K,
    6. Rischmueller M,
    7. et al.
    Scleroderma renal crisis: Poor outcome despite aggressive antihypertensive treatment. Intern Med J 2003;33:216–20.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Coral-Alvarado P,
    2. Rojas-Villarraga A,
    3. Latorre MC,
    4. Mantilla RD,
    5. Restrepo JF,
    6. Pardo AL,
    7. et al.
    Risk factors associated with pulmonary arterial hypertension in Colombian patients with systemic sclerosis: review of the literature. J Rheumatol 2008;35:244–50.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Khimdas S,
    2. Harding S,
    3. Bonner A,
    4. Zummer B,
    5. Baron M,
    6. Pope J; and
    7. Canadian Scleroderma Research Group
    . Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry. Arthritis Care Res 2011;63:142–9.
    OpenUrlCrossRef
  18. 18.↵
    1. Nagy Z,
    2. Czirják L
    . Predictors of survival in 171 patients with systemic sclerosis (scleroderma). Clin Rheumatol 1997;16:454–60.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Allanore Y,
    2. Meune C,
    3. Vonk MC,
    4. Airo P,
    5. Hachulla E,
    6. Caramaschi P,
    7. et al.
    Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Ann Rheum Dis 2010;69:218–21.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Hunzelmann N,
    2. Genth E,
    3. Krieg T,
    4. Lehmacher W,
    5. Melchers I,
    6. Meurer M,
    7. et al.
    The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology 2008;47:1185–92.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Avouac J,
    2. Airò P,
    3. Meune C,
    4. Beretta L,
    5. Dieude P,
    6. Caramaschi P,
    7. et al.
    Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and metaanalysis of 5 studies. J Rheumatol 2010;37:2290–8.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Avouac J,
    2. Airò P,
    3. Dieude P,
    4. Caramaschi P,
    5. Tiev K,
    6. Diot E,
    7. et al.
    Associated autoimmune diseases in systemic sclerosis define a subset of patients with milder disease: results from 2 large cohorts of European Caucasian patients. J Rheumatol 2010;37:608–14.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Czirják L,
    2. Kumánovics G,
    3. Varjú C,
    4. Nagy Z,
    5. Pákozdi A,
    6. Szekanecz Z,
    7. et al.
    Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Ann Rheum Dis 2008;67:59–63.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Nishimagi E,
    2. Tochimoto A,
    3. Kawaguchi Y,
    4. Satoh T,
    5. Kuwana M,
    6. Takagi K,
    7. et al.
    Characteristics of patients with early systemic sclerosis and severe gastrointestinal tract involvement. J Rheumatol 2007;34:2050–5.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Foocharoen C,
    2. Mahakkanukrauh A,
    3. Suwannaroj S,
    4. Nanagara R
    . Spontaneous skin regression and predictors of skin regression in Thai scleroderma patients. Clin Rheumatol 2011;30:1235–40.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Schmajuk G,
    2. Bush TM,
    3. Burkham J,
    4. Krishnan E,
    5. Chung L
    . Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients. Clin Exp Rheumatol 2009;27:22–5.
    OpenUrlPubMed
  27. 27.↵
    1. Low AH,
    2. Johnson SR,
    3. Lee P
    . Ethnic influence on disease manifestations and autoantibodies in Chinese-descent patients with systemic sclerosis. J Rheumatol 2009;36:787–93.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Picha L,
    2. Pakas I,
    3. Guialis A,
    4. Moutsopoulos HM,
    5. Vlachoyiannopoulos PG
    . Comparative qualitative and quantitative analysis of scleroderma (systemic sclerosis) serologic immunoassays. J Autoimmun 2008;31:166–74.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Shand L,
    2. Lunt M,
    3. Nihtyanova S,
    4. Hoseini M,
    5. Silman A,
    6. Black CM,
    7. et al.
    Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum 2007;56:2422–31.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Nguyen C,
    2. Bérezné A,
    3. Baubet T,
    4. Mestre-Stanislas C,
    5. Rannou F,
    6. Papelard A,
    7. et al.
    Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis. PLoS One 2011;6:e17551.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Hügle T,
    2. Schuetz P,
    3. Daikeler T,
    4. Tyndall A,
    5. Matucci-Cerinic M,
    6. Walker UA,
    7. et al.
    Late-onset systemic sclerosis — A systematic survey of the EULAR scleroderma trials and research group database. Rheumatology 2011;50:161–5.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Minier T,
    2. Nagy Z,
    3. Bálint Z,
    4. Farkas H,
    5. Radics J,
    6. Kumánovics G,
    7. et al.
    Construct validity evaluation of the European Scleroderma Study Group activity index, and investigation of possible new disease activity markers in systemic sclerosis. Rheumatology 2010;49:1133–45.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Joven BE,
    2. Almodovar R,
    3. Carmona L,
    4. Carreira PE
    . Survival, causes of death, and risk factors associated with mortality in Spanish systemic sclerosis patients: results from a single university hospital. Semin Arthritis Rheum 2010;39:285–93.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Chang B,
    2. Wigley FM,
    3. White B,
    4. Wise RA
    . Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003;30:2398–405.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Follansbee WP,
    2. Zerbe TR,
    3. Medsger TA Jr.
    . Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): a high risk association. Am Heart J 1993;125:194–203.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. de Groote P,
    2. Gressin V,
    3. Hachulla E,
    4. Carpentier P,
    5. Guillevin L,
    6. Kahan A,
    7. et al.
    Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis 2008;67:31–6.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Hanitsch LG,
    2. Burmester GR,
    3. Witt C,
    4. Hunzelmann N,
    5. Genth E,
    6. Krieg T,
    7. et al.
    Skin sclerosis is only of limited value to identify SSc patients with severe manifestations — an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register. Rheumatology 2009;48:70–3.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Poormoghim H,
    2. Poorkarim MA,
    3. Lakeh MM,
    4. Heshmati BN,
    5. Almasi S,
    6. Hakim M
    . Preliminary study of cardiovascular manifestations and cardiac severity scale in 58 patients with systemic sclerosis in Iran using the Medsger scale. J Tehran Heart Cent 2010;5:14–8.
    OpenUrlPubMed
  39. 39.↵
    1. Morelli S,
    2. Sgreccia A,
    3. Ferrante L,
    4. Barbieri C,
    5. Bernardo ML,
    6. Perrone C,
    7. et al.
    Relationships between electrocardiographic and echocardiographic findings in systemic sclerosis (scleroderma). Int J Cardiol 1996;57:151–60.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Alivernini S,
    2. De Santis M,
    3. Tolusso B,
    4. Mannocci A,
    5. Bosello SL,
    6. Peluso G,
    7. et al.
    Skin ulcers in systemic sclerosis: determinants of presence and predictive factors of healing. J Am Acad Dermatol 2009;60:426–35.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Aguglia G,
    2. Sgreccia A,
    3. Bernardo ML,
    4. Carmenini E,
    5. Giusti De Marle M,
    6. Reali A,
    7. et al.
    Left ventricular diastolic function in systemic sclerosis. J Rheumatol 2001;28:1563–7.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    1. Launay D,
    2. Mouthon L,
    3. Hachulla E,
    4. Pagnoux C,
    5. de Groote P,
    6. Remy-Jardin M,
    7. et al.
    Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol 2007;34:1005–11.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Pope JE,
    2. Lee P,
    3. Baron M,
    4. Dunne J,
    5. Smith D,
    6. Docherty PS,
    7. et al.
    Prevalence of elevated pulmonary arterial pressures measured by echocardiography in a multicenter study of patients with systemic sclerosis. J Rheumatol 2005;32:1273–8.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Cox SR,
    2. Walker JG,
    3. Coleman M,
    4. Rischmueller M,
    5. Proudman S,
    6. Smith MD,
    7. et al.
    Isolated pulmonary hypertension in scleroderma. Intern Med J 2005;35:28–33.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Phung S,
    2. Strange G,
    3. Chung LP,
    4. Leong J,
    5. Dalton B,
    6. Roddy J,
    7. et al.
    Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis. Intern Med J 2009;39:682–91.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Yamane K,
    2. Ihn H,
    3. Asano Y,
    4. Yazawa N,
    5. Kubo M,
    6. Kikuchi K,
    7. et al.
    Clinical and laboratory features of scleroderma patients with pulmonary hypertension. Rheumatology 2000;39:1269–71.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Hachulla E,
    2. Gressin V,
    3. Guillevin L,
    4. Carpentier P,
    5. Diot E,
    6. Sibilia J,
    7. et al.
    Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792–800.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Mukerjee D,
    2. St. George D,
    3. Coleiro B,
    4. Knight C,
    5. Denton CP,
    6. Davar J,
    7. et al.
    Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088–93.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. Vonk MC,
    2. Broers B,
    3. Heijdra YF,
    4. Ton E,
    5. Snijder R,
    6. van Dijk AP,
    7. et al.
    Systemic sclerosis and its pulmonary complications in The Netherlands: an epidemiological study. Ann Rheum Dis 2009;68:961–5.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Avouac J,
    2. Guerini H,
    3. Wipff J,
    4. Assous N,
    5. Chevrot A,
    6. Kahan A,
    7. et al.
    Radiological hand involvement in systemic sclerosis. Ann Rheum Dis 2006;65:1088–92.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Beretta L,
    2. Santaniello A,
    3. Cappiello F,
    4. Chawla NV,
    5. Vonk MC,
    6. Carreira PE,
    7. et al.
    Development of a five-year mortality model in systemic sclerosis patients by different analytical approaches. Clin Exp Rheumatol 2010;28:S18–27.
    OpenUrlPubMed
  52. 52.↵
    1. Plastiras SC,
    2. Karadimitrakis SP,
    3. Kampolis C,
    4. Moutsopoulos HM,
    5. Tzelepis GE
    . Determinants of pulmonary arterial hypertension in scleroderma. Semin Arthritis Rheum 2007;36:392–6.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Cordeiro de Azevedo AB,
    2. Sampaio-Barros PD,
    3. Torres RM,
    4. Moreira C
    . Prevalence of pulmonary hypertension in systemic sclerosis. Clin Exp Rheumatol 2005;23:447–54.
    OpenUrlPubMed
  54. 54.↵
    1. Murata I,
    2. Takenaka K,
    3. Yoshinoya S,
    4. Kikuchi K,
    5. Kiuchi T,
    6. Tanigawa T,
    7. et al.
    Clinical evaluation of pulmonary hypertension in systemic sclerosis and related disorders. A Doppler echocardiographic study of 135 Japanese patients. Chest 1997;111:36–43.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Tager RE,
    2. Tikly M
    . Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in Black South Africans. Rheumatology 1999;38:397–400.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Kumar U,
    2. Ramteke R,
    3. Yadav R,
    4. Ramam M,
    5. Handa R,
    6. Kumar A
    . Prevalence and predictors of pulmonary artery hypertension in systemic sclerosis. J Assoc Physicians India 2008;56:413–7.
    OpenUrlPubMed
  57. 57.↵
    1. Hachulla E,
    2. Carpentier P,
    3. Gressin V,
    4. Diot E,
    5. Allanore Y,
    6. Sibilia J,
    7. et al.
    Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology 2009;48:304–8.
    OpenUrlAbstract/FREE Full Text
  58. 58.↵
    1. Steen VD,
    2. Conte C,
    3. Owens GR,
    4. Medsger TA Jr.
    . Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;37:1283–9.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Ostojic P,
    2. Damjanov N
    . Different clinical features in patients with limited and diffuse cutaneous systemic sclerosis. Clin Rheumatol 2006;25:453–7.
    OpenUrlCrossRefPubMed
  60. 60.↵
    1. Duchini A,
    2. Sessoms SL
    . Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome. Am J Gastroenterol 1998;93:1453–6.
    OpenUrlCrossRefPubMed
  61. 61.↵
    1. Parodi A,
    2. Sessarego M,
    3. Greco A,
    4. Bazzica M,
    5. Filaci G,
    6. Setti M,
    7. et al.
    Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol 2008;103:1257–62.
    OpenUrlCrossRefPubMed
  62. 62.↵
    1. Szamosi S,
    2. Szekanecz Z,
    3. Szucs G
    . Gastrointestinal manifestations in Hungarian scleroderma patients. Rheumatol Int 2006;26:1120–4.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Marie I,
    2. Ducrotté P,
    3. Denis P,
    4. Menard JF,
    5. Levesque H
    . Small intestinal bacterial overgrowth in systemic sclerosis. Rheumatology 2009;48:1314–9.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    1. Mimura Y,
    2. Ihn H,
    3. Jinnin M,
    4. Asano Y,
    5. Yamane K,
    6. Tamaki K
    . Clinical and laboratory features of scleroderma patients developing skeletal myopathy. Clin Rheumatol 2005;24:99–102.
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Balbir-Gurman A,
    2. Braun-Moscovici Y
    . Scleroderma overlap syndrome. Isr Med Assoc J 2011;13:14–20.
    OpenUrlPubMed
  66. 66.↵
    1. Avouac J,
    2. Walker U,
    3. Tyndall A,
    4. Kahan A,
    5. Matucci-Cerinic M,
    6. Allanore Y,
    7. et al.
    Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol 2010;37:1488–501.
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Jinnin M,
    2. Ihn H,
    3. Yamane K,
    4. Asano Y,
    5. Yazawa N,
    6. Tamaki K
    . Clinical features of patients with systemic sclerosis accompanied by rheumatoid arthritis. Clin Exp Rheumatol 2003;21:91–4.
    OpenUrlPubMed
  68. 68.↵
    1. La Montagna G,
    2. Sodano A,
    3. Capurro V,
    4. Malesci D,
    5. Valentini G
    . The arthropathy of systemic sclerosis: a 12 month prospective clinical and imaging study. Skeletal Radiol 2005;34:35–41.
    OpenUrlCrossRefPubMed
  69. 69.↵
    1. Tiev KP,
    2. Diot E,
    3. Clerson P,
    4. Dupuis-Siméon F,
    5. Hachulla E,
    6. Hatron PY,
    7. et al.
    Clinical features of scleroderma patients with or without prior or current ischemic digital ulcers: Post-hoc analysis of a nationwide multicenter cohort (ItinérAIR-Sclérodermie). J Rheumatol 2009;36:1470–6.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Wigley FM,
    2. Wise RA,
    3. Miller R,
    4. Needleman BW,
    5. Spence RJ
    . Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis. Arthritis Rheum 1992;35:688–93.
    OpenUrlPubMed
  71. 71.↵
    1. Nihtyanova SI,
    2. Brough GM,
    3. Black CM,
    4. Denton CP
    . Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2008;67:120–3.
    OpenUrlAbstract/FREE Full Text
  72. 72.
    1. Sunderkötter C,
    2. Herrgott I,
    3. Brückner C,
    4. Moinzadeh P,
    5. Pfeiffer C,
    6. Gerss J,
    7. et al.
    Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors. Br J Dermatol 2009;160:835–43.
    OpenUrlCrossRefPubMed
  73. 73.
    1. Harrison BJ,
    2. Silman AJ,
    3. Hider SL,
    4. Herrick AL
    . Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum 2002;46:3312–6.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Wangkaew S,
    2. Kasitanon N,
    3. Sivasomboon C,
    4. Wichainun R,
    5. Sukitawut W,
    6. Louthrenoo W
    . Sicca symptoms in Thai patients with rheumatoid arthritis, systemic lupus erythematosus and scleroderma: a comparison with age-matched controls and correlation with disease variables. Asian Pac J Allergy Immunol 2006;24:213–21.
    OpenUrlPubMed
  75. 75.↵
    1. Swaminathan S,
    2. Goldblatt F,
    3. Dugar M,
    4. Gordon TP,
    5. Roberts-Thomson PJ; and
    6. South Australian Cohort
    . Prevalence of sicca symptoms in a South Australian cohort with systemic sclerosis. Intern Med J 2008;38:897–903.
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Wigley FM,
    2. Lima JA,
    3. Mayes M,
    4. McLain D,
    5. Chapin JL,
    6. Ward-Able C
    . The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 2005;52:2125–32.
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Ingraham KM,
    2. Steen VD
    . Morbidity of digital tip ulcerations in scleroderma [abstract]. Arthritis Rheum 2006;54 Suppl:P57.
    OpenUrl
  78. 78.↵
    1. Coral-Alvarado P,
    2. Pardo AL,
    3. Castano-Rodriguez N,
    4. Rojas-Villarraga A,
    5. Anaya JM
    . Systemic sclerosis: a worldwide global analysis. Clin Rheumatol 2009;28:757–65.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Steen V,
    2. Domsic RT,
    3. Lucas M,
    4. Fertig N,
    5. Medsger TA Jr.
    . A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum 2012;64:2986–94.
    OpenUrlCrossRefPubMed
  80. 80.↵
    1. McNearney TA,
    2. Reveille JD,
    3. Fischbach M,
    4. Friedman AW,
    5. Lisse JR,
    6. Goel N,
    7. et al.
    Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum 2007;57:318–26.
    OpenUrlCrossRefPubMed
  81. 81.↵
    1. Beall AD,
    2. Nietert PJ,
    3. Taylor MH,
    4. Mitchell HC,
    5. Shaftman SR,
    6. Silver RM,
    7. et al.
    Ethnic disparities among patients with pulmonary hypertension associated with systemic sclerosis. J Rheumatol 2007;34:1277–82.
    OpenUrlAbstract/FREE Full Text
  82. 82.↵
    1. Reveille JD,
    2. Fischbach M,
    3. McNearney T,
    4. Friedman AW,
    5. Aguilar MB,
    6. Lisse J,
    7. et al; and
    8. GENISOS Study Group
    . Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, socioeconomic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 2001;30:332–46.
    OpenUrlCrossRefPubMed
  83. 83.↵
    1. Nietert PJ,
    2. Mitchell HC,
    3. Bolster MB,
    4. Shaftman SR,
    5. Tilley BC,
    6. Silver RM
    . Racial variation in clinical and immunological manifestations of systemic sclerosis. J Rheumatol 2006;33:263–8.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Mansour S,
    2. Bonner A,
    3. Muangchan C,
    4. Hudson M,
    5. Baron M,
    6. Pope JE,
    7. et al.
    Low socioeconomic status (measured by education) and outcomes in systemic sclerosis: data from the Canadian Scleroderma Research Group. J Rheumatol 2013;40:447–54.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    1. Denton CP,
    2. Krieg T,
    3. Guillevin L,
    4. Schwierin B,
    5. Rosenberg D,
    6. Silkey M,
    7. et al.
    Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry. Ann Rheum Dis 2012;71:718–21.
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    1. Simeón-Aznar CP,
    2. Fonollosa-Plá V,
    3. Tolosa-Vilella C,
    4. Espinosa-Garriga G,
    5. Ramos-Casals M,
    6. Campillo-Grau M,
    7. et al.
    Registry of the Spanish network for systemic sclerosis: clinical pattern according to cutaneous subsets and immunological status. Semin Arthritis Rheum 2012;41:789–800.
    OpenUrlCrossRefPubMed
View Abstract
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

 Request Permissions

Save to my folders

Jump to section

Keywords

SCLERODERMA
RENAL CRISIS
PULMONARY ARTERY HYPERTENSION
PULMONARY FIBROSIS
MYOPATHY
DIGITAL ULCER

Keywords