Survival and organ involvement in patients with limited cutaneous systemic sclerosis and anti-topoisomerase-I antibodies: determined by skin subtype or auto-antibody subtype? A long-term follow-up study
Survival and organ involvement in patients with limited cutaneous systemic sclerosis and anti- topoisomerase-I antibodies: determined by skin subtype or auto-antibody subtype? A long-term follow-up study
Pim Kranenburg 0
Wieneke M. T. van den Hombergh 0
Hanneke K. A. Knaapen-Hans 0
Frank H. J. van den Hoogen 0
Jaap Fransen 0
Madelon C. Vonk 0
0 Department of Rheumatology, Radboud University Medical Center , Nijmegen , The Netherlands Submitted 9
Objective. LcSSc is associated with ACAs and a mild course, whereas dcSSc is associated with antitopoisomerase antibodies (ATAs) and a more severe course. However, ATAs are also present in lcSSc. Little is known about survival and organ involvement in this subgroup. The aim of this study is to determine whether survival and organ involvement of lcSSc ATA-positive patients differs from lcSSc ATA-negative or dcSSc ATA-positive patients. Furthermore, transition from lcSSc to dcSSc was evaluated. Methods. Data from The Nijmegen Systemic Sclerosis cohort were used, with up to 15 years of follow-up. Kaplan Meier analysis was performed for survival and organ involvement, including interstitial lung disease, pulmonary arterial hypertension, cardiac involvement and Scleroderma Renal Crises. Cox proportional hazard modelling was performed to adjust for confounders. Results. A total of 460 patients were included: 58 (13%) lcSSc ATA-positive patients, 237 (52%) lcSSc ATA-negative patients and 78 (17%) dcSSc ATA-positive patients. Cumulative survival in lcSSc ATA-positive patients was 75%, in lcSSc ATA-negative patients 58% and in dcSSc ATA-positive patients 53%. Interstitial lung disease was more prevalent in lcSSc ATA-positive patients (49%) than in lcSSc ATAnegative patients (25%), but less than in dcSSc ATA-positive patients (60%). Forty-eight patients developed dcSSc: 24 ATA-negative and 24 ATA-positive (P < 0.001). Conclusion. LcSSc ATA-positive patients differ from lcSSc ATA-negative patients and dcSSc ATA-positive patients concerning survival and organ involvement. LcSSc patients who are ATA-positive are more likely to develop dcSSc than lcSSc patients who are ATA negative.
systemic sclerosis; skin involvement; auto-antibodies; survival; organ involvement
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Rheumatology key messages
. SSc patients with limited skin involvement and presence of ATA differ from other SSc subsets.
. SSc patients who are anti-topoisomerase-I positive are more likely to develop diffuse skin involvement.
Introduction
SSc is a generalized autoimmune disease characterized
by microvascular changes, immunological abnormalities
and accumulation of connective tissue. The hallmark
of SSc is fibrosis of the skin; however, the fibrosis of
internal organs, including the heart, kidneys, lungs and
gastrointestinal tract, may cause severe morbidity and
premature death.
The pathogenesis of SSc is complex and involves
inflammatory cells, cytokines and fibroblasts [
1
]. The role of
auto-antibodies in the pathogenesis of SSc remains
unclear. However, previous studies have shown that
anti-topoisomerase antibodies (ATAs) bind directly to
fibroblast surfaces, which indicates a pathogenetic role
for these auto-antibodies in SSc [
2, 3
]. The possibility
arises that ATAs transform fibroblasts into myofibroblasts
and therewith induce the production of collagen I, leading
to fibrosis [4]. Still, the pathogenesis of SSc is not well
understood [
1
].
To date, no cure for SSc is available; however, evidence
is accumulating that early and aggressive
immunomodulation may result in less severe organ involvement [
5
]. For
prognostication it is of importance to recognize patients
prone to severe organ involvement and premature death.
In current clinical practice, patients with SSc are
subclassified in two main clinical subsets: lcSSc and dcSSc,
based on the extent of skin involvement by the
classification criteria of Leroy et al. [
6
].
Clinical differences in the natural disease course of
lcSSc and dcSSc are apparent. Patients classified as
having lcSSc are known to generally have a less severe
disease course and slow progression of symptoms,
whereas patients classified as having dcSSc tend to
have a more severe disease course, with rapid
progression and a higher mortality [
7
].
The difference in mortality between lcSSc and dcSSc
has grown smaller over recent decades [
8, 9
]. Mortality is
tightly linked to organ involvement, with interstitial lung
disease (ILD), pulmonary arterial hypertension (PAH) and
cardiac involvement being the main causes of death [10].
Until the 1980s, scleroderma renal crisis (SRC) was the
most frequent fatal complication of SSc, but its
occurrence has decreased since then [
11
].
Different patterns of organ involvements occur in the
two subtypes of SSc. PAH occurs in both dcSSc and
lcSSc; however, it tends to develop earlier in the disease
course in dcSSc [
12
]. ILD, cardiac involvement and SRC
occur more often and earlier in dcSSc [13 17], but also
occur in lcSSc. (...truncated)