Abstract
BackgroundUp to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). However, the majority of these patients do not manifest ANCA-associated vasculitis (AAV) and the significance of ANCA in these patients is unclear. The aim of this study is to determine the prevalence of ANCA in a well-characterised SSc cohort and to examine the association between ANCA and SSc clinical characteristics, other autoantibodies, treatments and mortality.MethodsClinical data were obtained from 5 centres in the Australian Scleroderma Cohort Study (ASCS). ANCA positive was defined as the presence of any one or combination of cytoplasmic ANCA (c-ANCA), perinuclear ANCA (p-ANCA), atypical ANCA, anti-myeloperoxidase (anti-MPO) or anti-proteinase-3 (anti-PR3). Associations of demographic and clinical features with ANCA were investigated by logistic or linear regression. Survival analysis was performed using Kaplan-Meyer curves and Cox regression models.ResultsOf 1303 patients, 116 (8.9%) were ANCA positive. Anti-PR3 was more common than anti-MPO (13.8% and 11.2% of ANCA-positive patients, respectively). Only 3 ANCA-positive patients had AAV. Anti-Scl-70 was more common in ANCA positive vs ANCA negative (25% vs 12.8%, p < 0.001), anti-MPO positive vs anti-MPO negative (38.5% vs 13.6%, p = 0.006) and anti-PR3 positive vs anti-PR3 negative patients (44.4% vs 13.4%, p < 0.001). A higher prevalence of interstitial lung disease (ILD) was found in the ANCA positive (44.8% vs 21.8%, p < 0.001) and the anti-PR3 positive groups (50.0% vs 23.4%, p = 0.009). In multivariable analysis, ANCA-positive status remained associated with ILD after adjusting for anti-Scl-70 antibodies. Pulmonary embolism (PE) was more common in ANCA-positive patients (8.6% vs 3.0%, p = 0.002) and anti-PR3-positive patients (16.7% vs 3.3%, p = 0.022). ANCA-positive status remained associated with PE in a multivariable analysis adjusting for anti-phospholipid antibodies. Kaplan-Meier analysis revealed increased mortality in ANCA-positive patients (p = 0.006). In Cox regression analysis, ANCA was associated with increased mortality, after adjusting for age and sex.ConclusionsANCA is associated with increased prevalence of ILD and PE in SSc. ANCA should be tested in SSc, as it identifies individuals with worse prognosis who require close monitoring for adverse outcomes.
Highlights
Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA)
There are three different types of Anti-neutrophil cytoplasmic antibodies (ANCA), which display distinct patterns under indirect immunofluorescence (IIF). These are the cytoplasmic pattern (c-ANCA), perinuclear pattern (p-ANCA) and “atypical” ANCA [5]. cytoplasmic ANCA (c-ANCA) directed against proteinase-3 (PR3) is associated with granulomatosis with polyangiitis (GPA), while perinuclear ANCA (p-ANCA) is typically directed against myeloperoxidase (MPO) and is commonly detected in microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) and pauci-immune idiopathic crescentic glomerulonephritis [7]
Almost half (49.6%) of patients had digital ulcers, 39.7% had synovitis, 8.6% had Gastric antral vascular ectasia (GAVE) and 2.7% had a renal crisis. Overlap features with another connective tissue disease were present in 5.8%, and comorbid rheumatoid arthritis was the most common overlap syndrome, present in 27 patients (2.1%)
Summary
Up to 12% of patients with systemic sclerosis (SSc) have anti-neutrophil cytoplasmic antibodies (ANCA). Systemic sclerosis (SSc) is a multisystem autoimmune disease characterised by a triad of progressive skin and internal organ fibrosis, autoantibody production and small vessel vasculopathy [1, 2]. Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against enzymes found within primary granules of neutrophils and lysosomes in monocytes and are implicated directly in the pathogenesis of the small vessel vasculitis [5, 6]. There are three different types of ANCA, which display distinct patterns under indirect immunofluorescence (IIF) These are the cytoplasmic pattern (c-ANCA), perinuclear pattern (p-ANCA) and “atypical” ANCA [5]. Alternative target antigens for p-ANCA include elastase, lactoferrin, bactericidal/ permeability-increasing protein (BPI) and cathepsin G, and the pathophysiological significance, and specific disease associations of these minor target antigens are unclear [8, 9]
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