Mortality in systemic sclerosis: An international meta-analysis of individual patient data

doi:10.1016/j.amjmed.2004.04.031

The American Journal of Medicine

Volume 118, Issue 1, January 2005, Pages 2-10

https://doi.org/10.1016/j.amjmed.2004.04.031 Get rights and content

Purpose

Studies on mortality associated with systemic sclerosis have been limited by small sample sizes. We aimed to obtain large-scale evidence on survival outcomes and predictors for this disease.

Methods

We performed a meta-analysis of individual patient data from cohorts recruited from seven medical centers in the United States, Europe, and Japan, using standardized definitions for disease subtype and organ system involvement. The primary outcome was all-cause mortality. Standardized mortality ratios and predictors of mortality were estimated. The main analysis was based only on patients enrolled at each center within 6 months of diagnosis (incident cases).

Results

Among 1645 incident cases, 578 deaths occurred over 11,521 person-years of follow-up. Standardized mortality ratios varied by cohort (1.5 to 7.2). In multivariate analyses that adjusted for age and sex, renal (hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.4 to 2.5), cardiac (HR = 2.8; 95% CI: 2.1 to 3.8), and pulmonary (HR = 1.6; 95% CI: 1.3 to 2.2) involvement, and anti-topoisomerase I antibodies (HR = 1.3; 95% CI: 1.0 to 1.6), increased mortality risk. Renal, cardiac, and pulmonary involvement tended to occur together (P <0.001). For patients without adverse predictors for 3 years after enrollment, the subsequent risk of death was not significantly different from that for the general population in three cohorts, but was significantly increased in three cohorts that comprised mostly referred patients. Analyses that included all cases in each center (n = 3311; total follow-up: 19,990 person-years) yielded largely similar results.

Conclusion

Systemic sclerosis confers a high mortality risk, but there is considerable heterogeneity across settings. Internal organ involvement and anti-topoisomerase I antibodies are important determinants of mortality.

Section snippets

Overall design

The IMMISS is an international collaborative meta-analysis of individual-level data.¹⁶ In late 1999, a protocol was distributed to 30 investigators worldwide who were involved in systemic sclerosis care and research. They were invited to contribute data on survival outcomes of their patients using a common set of definitions for each considered parameter. Seven teams contributed patient data adhering to the requested structure and definitions of the meta-analysis. Submitted databases were

Results

Seven medical centers (two from the United States, four from Europe, and one from Japan) contributed data on 1645 incident cases of systemic sclerosis followed for 11,521 person-years (578 deaths) (Table 1). With inclusion of prevalent cases, the entire database comprised 3311 subjects, 1135 deaths, and 19,990 person-years of follow-up. In four cohorts (Athens, Keio, Mayo, and Florence), investigators stated that local cases were far more common than referred patients. Referred patients were

Discussion

This international collaborative meta-analysis provides large-scale evidence for the determinants of prognosis in systemic sclerosis. This disease clearly increased the risk of death as compared with the general population, with standardized mortality ratios ranging between 1.5 and 7.2 across the different cohorts. Six other cohorts from Barcelona,⁴ Copenhagen,⁵ Italy,³ London,⁷ Lund,² and Montreal¹ have also published data on systemic sclerosis patients enrolled primarily in the last 20 years

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Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact?
Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival.
Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk.
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ReviewsMortality in systemic sclerosis: An international meta-analysis of individual patient data

Purpose

Methods

Results

Conclusion

Section snippets

Overall design

Results

Discussion

Blood

Semin Arthritis Rheum

Chest

Lancet

J Clin Epidemiol

Predicting mortality in systemic sclerosisanalysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival

Medicine (Baltimore)

Mortality and causes of death in a Swedish series of systemic sclerosis patients

Ann Rheum Dis

Systemic sclerosisdemographic, clinical, and serologic features and survival in 1,012 Italian patients

Medicine (Baltimore)

Mortality and prognostic factors in Spanish patients with systemic sclerosis

Rheumatology (Oxf)

Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma)

Br J Rheumatol

Influence of clinical features, serum antinuclear antibodies, and lung function on survival of patients with systemic sclerosis

J Rheumatol

Survival following the onset of sclerodermaresults from a retrospective inception cohort study of the UK patient population

Br J Rheumatol

Disease severity of 100 patients with systemic sclerosis over a period of 14 yearsusing a modified Medsger scale

Ann Rheum Dis

Skin thickness score as a predictor and correlate of outcome in systemic sclerosishigh-dose versus low-dose penicillamine trial

Arthritis Rheum

Severe organ involvement in systemic sclerosis with diffuse scleroderma

Arthritis Rheum

A disease severity scale for systemic sclerosisdevelopment and testing

J Rheumatol

Predictors of survival in systemic sclerosis (scleroderma)

Arthritis Rheum

Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis

Arthritis Rheum

Choosing appropriate patients with systemic sclerosis for treatment by autologous stem cell transplantation

J Rheumatol Suppl

Practical methodology of meta-analyses (overviews) using updated individual patient data

Stat Med

Reviews
Mortality in systemic sclerosis: An international meta-analysis of individual patient data