Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific 
for rheumatoid arthritis (RA), may be found in some patients with other systemic 
autoimmune diseases. The clinical significance of ACPA in patients with 
antisynthetase syndrome (ASS), a systemic disease characterized by the 
association of myositis, interstitial lung disease, polyarthralgia, and/or 
polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, 
and response to treatment. ACPA-positive ASS patients were first identified 
among a French multicenter registry of patients with ASS. Additionally, all 
French rheumatology and internal medicine practitioners registered on the Club 
Rhumatismes et Inflammation web site were asked to report their observations of 
ASS patients with ACPA. The 17 collected patients were retrospectively studied 
using a standardized questionnaire and compared with 34 unselected ACPA-negative 
ASS patients in a case-control study. All ACPA-positive ASS patients suffered 
from arthritis versus 41% in the control group (P < 0.0001). The number of 
swollen joints was significantly higher (7.0 ± 5.0 vs 2.9 ± 3.9, P < 0.005), 
with a distribution resembling that of RA. Radiographic damages were also more 
frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a 
significantly higher transfer factor for carbon monoxide in ACPA-ASS patients, 
lung, muscle, and skin involvements had similar incidences, patterns, and 
severity in both groups. Although Nonbiologic treatments were similarly used in 
both groups, ACPA-positive patients received biologics more frequently (59% vs 
12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients 
received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) 
with good efficacy and tolerance, whereas 2 of the 5 patients treated with 
antitumor necrosis factor drugs had worsened myositis and/or interstitial lung 
disease. After a >7-year mean follow-up, extra-articular outcomes and survival 
were not different. ACPA-positive ASS patients showed an overlapping RA-ASS 
syndrome, were at high risk of refractory erosive arthritis, and might 
experience ASS flare when treated with antitumor necrosis factor drugs. In 
contrast, other biologics such as anti-CD20 mAb were effective in this context, 
without worsening systemic involvements.