Background/Purpose: Although anti-centromere antibodies (ACA) typically associate with limited cutaneous subset of systemic sclerosis (lcSSc) this reactivity is also seen in some cases with diffuse skin disease (dcSSc). Since both antibody specificity and disease subset may influence clinical features and organ manifestation, we explored the impact of ACA on outcome in dcSSc, as it has previously been reported protective for renal crisis (RC) and interstitial lung disease (ILD). Objectives: We describe clinical characteristics of dcSSc patients with ACA positivity (ACA+diffuse), and compare with ACA positive lcSSc (ACA+limited) and ACA negative dcSSc (non-ACA diffuse).

Methods: First, we identified all ACA positive systemic sclerosis cases in our cohort (n=1313). Those with dcSSc (n=36, 2.7%) were compared with representative groups of consecutive patients ACA+limited (n=160) and consecutive patients non-ACA diffuse (n=260). Long-term survival and frequency of major organ based complications were compared.

Results: The peak modified Rodnan skin score (mRSS) was not significantly different between the dcSSc subgroups with or without ACA (respectively 24.0±9.9 vs 27.4±10.4, p=0.07), but peak mRSS occurred later in disease in ACA+diffuse (88.8±77.2 vs 30.7±33.1 months, p<0.001). Survival in ACA+ was similar for both subsets with survival rates at 5, 10 and 15 years of 96%, 84% and 73% in ACA+limited and 94%, 80% and 72% in ACA+diffuse. Comparing with ACA+diffuse, non-ACA diffuse had significantly lower survival of 85%, 72% and 55% at 5, 10 and 15 years respectively (p=0.002). ACA+diffuse had higher incidence of ILD than ACA+limited (p=0.018), but significantly lower than non-ACA diffuse (p=0.003). Non-ACA diffuse developed ILD mostly in the first 5 years from disease onset, while in ACA+diffuse it occurred later in disease course. During follow-up at 5 years, 15% of ACA+diffuse developed ILD (3% – ACA+limited; 36% – non-ACA diffuse), and at 15 years, 26% had ILD (5% – ACA+limited; 49% – non-ACA diffuse). More patients had pulmonary hypertension (PH) in ACA+diffuse (27.8%), than in the other groups (12.5% – ACA+limited; 11.9% – non-ACA diffuse), though this was mainly due to their longer follow-up. Cumulative incidence of PH in ACA+diffuse was not different from the other groups (at 5 years: 8% – ACA+diffuse, 6% – ACA+limited, 6% – non-ACA diffuse; at 15 years: 24%, 20% and 18% respectively). Similarly, cardiac involvement was more frequent in ACA+diffuse (8.3%) vs 1.9% in ACA+limited and 6.5% in non-ACA diffuse, but differences were not significant adjusting for time of follow-up. In contrast, incidence of RC was higher in non-ACA diffuse (13.9%), affecting only 2 patients in ACA+diffuse (5.6%) and none in ACA+limited.

Conclusion: Although uncommon, ACA+diffuse has a distinct clinical phenotype. These patients have more insidious onset of skin and major organ involvement, which may allow early therapeutic intervention. We confirm that even in dcSSC, ACA appears protective for organ-based complications, namely ILD and RC, and associates with a better survival than expected in dcSSc. Therefore, ACA or factors determining its development, may act as a phenotype modifier in dcSSc.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinctive-clinical-phenotype-of-anti-centromere-antibody-positive-diffuse-systemic-sclerosis/