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

Rheumatology, Nov 2016

Objective. LcSSc is associated with ACAs and a mild course, whereas dcSSc is associated with anti-topoisomerase 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.

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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 - 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)


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Kranenburg, Pim, van den Hombergh, Wieneke M. T., Knaapen-Hans, Hanneke K. A., van den Hoogen, Frank H. J., Fransen, Jaap, Vonk, Madelon C.. 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, Rheumatology, 2016, pp. 2001-2008, Volume 55, Issue 11, DOI: 10.1093/rheumatology/kew298