Scleroderma patients with ANCA autoantibodies have a higher prevalence of interstitial lung disease (ILD) and pulmonary embolism, as well as a greater mortality risk than those without these antibodies, according to new research.
The study, “Significance of anti-neutrophil cytoplasmic antibodies in systemic sclerosis,” was published in the journal Arthritis Research & Therapy.
Anti-neutrophil cytoplasmic antibodies (ANCA) target immune cells called neutrophils and monocytes, and underlie ANCA-associated vasculitis (AAV). Different subtypes of these antibodies — targeting enzyme PR3 or MPO — are found in different subsets of this disease.
Patients with scleroderma may have ANCA antibodies in their serum, although only a minority develops an overlap syndrome with AAV. The development of ANCA antibodies or AAV itself may also be induced by D-penicillamine, a medication no longer used to treat scleroderma.
The scleroderma type with a higher prevalence of AAV has been unclear. Therefore, a research team from Australia collected data from five centers in the Australian Scleroderma Cohort Study to evaluate the prevalence of ANCA antibodies in a large group of patients with scleroderma, as well as the association between these antibodies and the patients’ clinical symptoms, other autoantibodies, treatments, and mortality.
A total of 1,303 patients were included — 1,125 (86.3%) women, 974 (74.8%) with limited scleroderma, and 329 (25.2%) with diffuse disease. The majority was Caucasian (90.4%), and 49% had never smoked. The mean age of scleroderma onset was 46.4 years, and it was 57.7 years at recruitment. Median duration of follow-up was approximately 3.5 years.
ILD was present in 311 patients (23.9%), and pulmonary arterial hypertension in 163 (12.5%). Nearly half (49.6%) had digital ulcers, 39.7% had synovitis (inflammation of the joint lining), 8.6% had gastric antral vascular ectasia (also known as watermelon stomach), and 2.7% had a renal crisis.
Overlap features with other connective tissue diseases — such as rheumatoid arthritis and systemic lupus erythematosus — were present in 5.8% of patients, with rheumatoid arthritis being the most frequent overlap syndrome (27 patients or 2.1%).
Results showed that out of the 1,303 patients analyzed, 116 (8.9%) were positive for ANCA antibodies. Antibodies targeting PR3 (13.8%) were more common than ones targeting MPO (11.2%). Only three ANCA antibody-positive patients had AAV.
No significant differences in gender, disease subtype, age at scleroderma onset, disease duration, or duration of follow-up were found between patients who were positive for ANCA antibodies and those who were negative. However, the group with ANCA antibodies had a higher proportion of Asian patients (12.9% vs. 3.7% for the ANCA-negative group), and was less likely to have smoked (36.2% vs 50.3%).
In terms of scleroderma autoantibodies, ANCA-positive patients were more likely to have anti-Scl-70 (25% vs 12.8% for the ANCA-negative patients), and anti-Ro antibodies (11.2% vs 6.2%), but less likely to have anti-centromere antibodies (29.3% vs 48.8%).
As for other diseases, ILD was more frequent in ANCA antibody-positive patients (44.8% vs 21.8%) — regardless of having anti-Scl-70 antibodies — and in those with anti-PR3 (50.0% vs 23.4%), compared with patients without either antibody type. Pulmonary embolism — blockage of a pulmonary artery — was also more common in ANCA-positive (8.6% vs 3.0%) and anti-PR3-positive patients (16.7% vs 3.3%).
In addition, ANCA-positive patients, compared with the ANCA-negative group, were more likely to have synovitis (54.3% vs 38.2%), overlap features with another connective tissue disease (12.1% vs 5.2%) and with Sjogren’s syndrome (4.3% vs 1.6%), and malignancy (26.7% vs 18.6%).
They were also hospitalized more often (49.1%) than ANCA-negative patients (36.5%).
Importantly, having ANCA antibodies was associated with a 1.6-fold increased risk of mortality, even after adjusting for age and sex.
“This study reveals a significant association between ANCA in (scleroderma) and ILD, pulmonary embolism, synovitis, and overlap syndrome with other connective tissue diseases,” the scientists wrote, adding that “patients who are ANCA-positive have increased mortality, independent of sex or age at diagnosis.”
According to the team, the findings suggest that “ANCA should be tested at baseline in (scleroderma) patients as it is associated with a worse prognosis, and necessitates vigilant monitoring and follow-up.”