Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model
Authors: Garaiman Alexandru , Steigmiller Klaus , Gebhard Catherine , Mihai Carina , Dobrota Rucsandra , Bruni Cosimo , Matucci-Cerinic Marco , Henes Joerg , de Vries-Bouwstra Jeska , Smith Vanessa , Doria Andrea , Allanore Yannick , Dagna Lorenzo , Anić Branimir , Montecucco Carlomaurizio , Kowal-Bielecka Otylia , Martin Mickael , Tanaka Yoshiya , Hoffmann-Vold Anna-Maria , Held Ulrike , Distler Oliver , Becker Mike Oliver ,   EUSTAR Collaborators, Randone Silvia Bellando , Lepri Gemma , Walker Ulrich , Iannone Florenzo , Jordan Suzana , Becvar Radim , Gindzienska-Sieskiewicz Ewa , Karaszewska Katarzyna , Cutolo Maurizio , Cuomo Giovanna , Siegert Elise , Rednic Simona , Avouac Jérome , Desbas Carole , Caporali Roberto , Cavagna Lorenzo , Carreira Patricia E , Novak Srdan , Czirják László , Iudici Michele , Kucharz Eugene J , Zanatta Elisabetta , Coleiro Bernard , Moroncini Gianluca , Bancel Dominique Farge , Airò Paolo , Hesselstrand Roger , Radic Mislav , Balbir-Gurman Alexandra , Hunzelmann Nicolas , Pellerito Raffaele , Giollo Alessandro , Morovic-Vergles Jadranka , Denton Christopher , Damjanov Nemanja , Pecher Ann-Christian , Santamaria Vera Ortiz , Heitmann Stefan , Krasowska Dorota , Hasler Paul , Foeldvari Ivan , Salvador Maria João , Stamenkovic Bojana , Selmi Carlo Francesco , Ananieva Lidia P , Herrick Ariane , Müller-Ladner Ulf , De Palma Raffaele , Engelhart Merete , Szücs Gabriela , de la Puente Carlos , Midtvedt Øyvind , Garen Torhild , Fretheim Håvard , Hachulla Eric , Riccieri Valeria , Ionescu Ruxandra Maria , Gheorghiu Ana Maria , Sunderkötter Cord , Distler Jörg , Ingegnoli Francesca , Mouthon Luc , Cantatore Francesco Paolo , Ullman Susanne , Pozzi Maria Rosa , Eyerich Kilian , Wiland Piotr , Vanthuyne Marie , Alegre-Sancho Juan Jose , Herrmann Kristine , De Langhe Ellen , Baresic Marko , Mayer Miroslav , Yavuz Sule , Granel Brigitte , de Souza Müller Carolina , Agachi Svetlana , Stebbings Simon , Mathieu D'Alessandro , Vacca Alessandra , Solanki Kamal , Veale Douglas , Loyo Esthela , Tineo Carmen , Li Mengtao , Rosato Edoardo , Oksel Fahrettin , Yargucu Figen , Tanaseanu Cristina-Mihaela , Foti Rosario , Ancuta Codrina , Maurer Britta , van Laar Jacob , Olesinska Marzena , Kayser Cristiane , Fathi Nihal , de la Peña Lefebvre Paloma García , Martin Jorge Juan Gonzalez , Sibilia Jean , Litinsky Ira , Del Galdo Francesco , Saketkoo Lesley Ann , Kerzberg Eduardo , Bianch Washington , Bianchi Breno Valdetaro , Castellví Ivan , Limonta Massimiliano , Rimar Doron , Couto Maura , Spertini François , Marcoccia Antonella , Kahl Sarah , Hsu Ivien M , Martin Thierry , Moiseevand Sergey , Novikov Pavel , Chung Lorinda S , Schmeiser Tim , Majewski Dominik , Zdrojewski Zbigniew , Martínez-Barrio Julia , Bernardino Vera , Riemekasten Gabriela , Levy Yair , Rezus Elena , Pamuk Omer Nuri , Puttini Piercarlo Sarzi , Poormoghim Hadi , Kötter Ina , Cuomo Giovanna , Gaches Francis , Belloli Laura , Sfikakis Petros , Furst Daniel , Ramazan Ana-Maria , Scherer H U , Huizinga Tom W J , Truchetet Marie-Elise , Lescoat Alain , De Luca Giacomo , Campochiaro Corrado , van Laar J M , Rudnicka Lidia , Oliveira Susana , Atzeni Fabiola , Kuwana Masataka , Mekinian Arsene , Landron Cédric , Puyade Mathieu , Roblot Pascal , Kubo Satoshi , Todoroki Yasuyuki 
Published: July 2022

Abstract

Objective
To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor.

Methods
We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors.

Results
Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs.

Conclusion
The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.