Background: Antitopoisomerase I (ATA), anticentromere (ACA) and anti-RNA polymerase III (RNAP3) antibodies are included in the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis (SSc). A subset of patients with SSc satisfy criteria but may lack these specific autoantibodies, being classified as ‘triple-negative’. Methods: We conducted a retrospective evaluation of triple-negative patients with SSc prevalence and clinical features among the multicentric Systemic sclerosis Progression INvestiGation registry. Results: Out of 1480 patients with SSc, 295 (19.9%) were triple-negative, while 1185 (81.1%) had SSc-specific antibodies: ACA (54.3%), ATA (43.6%) and RNAP3 (2.1%). The triple-negative group showed a higher prevalence of myopathy (16.7% vs 10.1%, p=0.003), suggested by higher creatine phosphokinase (CPK) levels (126.2 vs 92.5 U/mL, p=0.002), more frequent CPK increase over 2–3 times (2.4% vs 0.2%, p=0.028). Triple-negative patients also exhibited fewer vascular complications, including digital ulcers (17.3% vs 22.8%, p=0.04) and calcinosis (8.2% vs 12.8%, p=0.027), and a higher prevalence of interstitial lung disease (p<0.001). Consistently, lower diffusing capacity for carbon monoxide (66.4% vs 70.98%, p=0.004) and forced vital capacity (97.01% vs 102.92%, p<0.001) were found in the triple-negative group. Triple-negative patients more frequently received corticosteroids (79.3% vs 67.9%, p=0.003), cyclophosphamide (43.4% vs 26%, p<0.001) and azathioprine (38.5% vs 22.3%, p=0.002), while less frequently received prostanoids (71.6% vs 85.9%, p<0.001), calcium channel blockers (80.1% vs 87.7%, p=0.005) and phosphodiesterase-5 inhibitors (4% vs 20%, p<0.001). Conclusions: A higher prevalence of myopathy and interstitial lung disease and a reduced vascular burden were found in the triple-negative patients, suggesting that the non-specific and non-routinely tested autoantibodies may identify an SSc endotype resembling sclero-myositis.
Batani, V., Cavazzana, I., Orlandi, M., De Angelis, R., Campochiaro, C., De Lorenzis, E., Natalello, G., Verardi, L., Bajocchi, G., Bellando-Randone, S., Zanframundo, G., Foti, R., Cacciapaglia, F., Cuomo, G., Ariani, A., Rosato, E., Lepri, G., Girelli, F., Riccieri, V., Zanatta, E., Ingegnoli, F., De Santis, M., Murdaca, G., Abignano, G., Giorgio, P., Della Rossa, A., Caminiti, M., Iuliano, A. M., Beretta, L., Bagnato, G., Lubrano, E., De Andres, I., Idolazzi, L., Bruni, C., Fornaro, M., Saracco, M., Agnes, C., Cipolletta, E., Lumetti, F., Spinella, A., De Pinto, M., Magnani, L., Codullo, V., Visalli, E., Iandoli, C., Gigante, A., Pellegrino, G., Pigatto, E., Lazzaroni, M. -., Franceschini, F., Motta, F., Tonutti, A., Mennillo, G., Di Battista, M., Mariano, G. P., Furini, F., Vultaggio, L., Parisi, S., Peroni, C. L., Bianchi, G., Fusaro, E., Sebastiani, G. D., Govoni, M., D'Angelo, S., Cozzi, F., Guiducci, S., Doria, A., Salvarani, C., Iannone, F., D'Agostino, M. A., Bosello, S. L., Dagna, L., Giuggioli, D., Ferri, C., Matucci Cerinic, M., De Luca, G., Clinical and serological features of triple autoantibody-negative patients with systemic sclerosis: insights from the multicentric SPRING registry of the Italian Society for Rheumatology, <<RMD OPEN>>, 2026; 12 (2): N/A-N/A [https://hdl.handle.net/10807/339986]
Clinical and serological features of triple autoantibody-negative patients with systemic sclerosis: insights from the multicentric SPRING registry of the Italian Society for Rheumatology
De Lorenzis, Enrico;Natalello, Gerlando;D'Agostino, Maria Antonietta;Bosello, Silvia Laura;
2026
Abstract
Background: Antitopoisomerase I (ATA), anticentromere (ACA) and anti-RNA polymerase III (RNAP3) antibodies are included in the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis (SSc). A subset of patients with SSc satisfy criteria but may lack these specific autoantibodies, being classified as ‘triple-negative’. Methods: We conducted a retrospective evaluation of triple-negative patients with SSc prevalence and clinical features among the multicentric Systemic sclerosis Progression INvestiGation registry. Results: Out of 1480 patients with SSc, 295 (19.9%) were triple-negative, while 1185 (81.1%) had SSc-specific antibodies: ACA (54.3%), ATA (43.6%) and RNAP3 (2.1%). The triple-negative group showed a higher prevalence of myopathy (16.7% vs 10.1%, p=0.003), suggested by higher creatine phosphokinase (CPK) levels (126.2 vs 92.5 U/mL, p=0.002), more frequent CPK increase over 2–3 times (2.4% vs 0.2%, p=0.028). Triple-negative patients also exhibited fewer vascular complications, including digital ulcers (17.3% vs 22.8%, p=0.04) and calcinosis (8.2% vs 12.8%, p=0.027), and a higher prevalence of interstitial lung disease (p<0.001). Consistently, lower diffusing capacity for carbon monoxide (66.4% vs 70.98%, p=0.004) and forced vital capacity (97.01% vs 102.92%, p<0.001) were found in the triple-negative group. Triple-negative patients more frequently received corticosteroids (79.3% vs 67.9%, p=0.003), cyclophosphamide (43.4% vs 26%, p<0.001) and azathioprine (38.5% vs 22.3%, p=0.002), while less frequently received prostanoids (71.6% vs 85.9%, p<0.001), calcium channel blockers (80.1% vs 87.7%, p=0.005) and phosphodiesterase-5 inhibitors (4% vs 20%, p<0.001). Conclusions: A higher prevalence of myopathy and interstitial lung disease and a reduced vascular burden were found in the triple-negative patients, suggesting that the non-specific and non-routinely tested autoantibodies may identify an SSc endotype resembling sclero-myositis.
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