Calcinosis Working Group Update SCTC Business Meeting ACR October 26, 2013 Lorinda Chung

Calcinosis

Multi-disciplinary International Effort Rheumatology Radiology Dermatology US UK Europe Canada Australia Turkey Mexico

Research Agenda Evaluation of frequency, incidence, and associated clinical features Development of radiographic scoring system Development of patient reported outcome measure for clinically apparent calcinosis Development of classification system Development of physical exam measurements of calcinosis burden Studies to understand pathophysiologic mechanisms underlying development of calcinosis

Progress Evaluation of frequency, incidence, and associated clinical features – Antonia Valenzuela Development of radiographic scoring system – Lorinda Chung Development of patient reported outcome measure for clinically apparent calcinosis – Lesley Saketkoo Development of classification system – Vivien Hsu

Frequency of calcinosis “Frequency of calcinosis in a multi-center international cohort of patients with Systemic Sclerosis: A Scleroderma Clinical Trials Consortium Study” – Presented at the 13 th Scleroderma Research Workshop August 2013 in Boston, MA – Data from electronic survey answered by 16 centers

Frequency of calcinosis Overall frequency of calcinosis of 22% in a multi- center international cohort of 7056 SSc patients. – 17% in patients with diffuse cutaneous SSc – 25% in patients with limited cutaneous SSc – 28% in patients with systemic sclerosis sine scleroderma Patients with calcinosis had longer mean disease duration from the first non-Raynaud’s symptom than those without Valenzuela A, Cuomo G, Sutton E, Gordon J, Spiera R, Rodriguez-Reyna T, Proudman S, et al. Frequency of calcinosis in a multicenter international cohort of patients with Systemic Sclerosis: A Scleroderma Clinical Trials Consortium Study. 13 th Scleroderma Research Workshop. Boston, US, August 3-7, 2013.

Next steps “Incidence of calcinosis and identification of associated risk factors in a multi-center international collaborative study of patients with Systemic Sclerosis: A Scleroderma Clinical Trials Consortium Study”

Incidence of calcinosis Specific Aims: 1.To determine the cumulative incidence of calcinosis in patients with SSc. 2.To assess for an association between clinical features and specific autoantibodies and the subsequent development of calcinosis in patients with SSc. – Disease duration and maximum mRSS – Digital ulcers, pulmonary arterial hypertension, or scleroderma renal crisis – Anti-centromere, RNA polymerase III, and anti-beta (2)- glycoprotein I antibodies

Incidence of calcinosis Methods: – Retrospective cohort study including patients with SSc enrolled in each study location database. – We will collect demographics, dates of diagnosis, clinical features and autoantibody information.

Incidence of calcinosis Study Locations: – Stanford University School of Medicine, Palo Alto, CA, US – Hospital for Special Surgery, New York, NY, US – Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico – Royal Adelaide Hospital, Adelaide, Australia – St Vincent's Hospital, Melbourne, Australia – Rutgers-RWJMS Scleroderma Program, New Brunswick, NJ, US – A.O.U. of Cagliari, Cagliari, Italy – Istanbul University, Istanbul, Turkey – Jewish General Hospital, Montreal, QC, Canada – University of Pittsburgh Medical Center, Pittsburgh, PA, US – University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK – University of Texas Health Science Center at Houston, Houston, Texas, US – Northwestern University Feinberg School of Medicine, Chicago, IL, US

Validation of a Novel Radiographic Scoring System for Calcinosis Affecting the Hands of Patients with Systemic Sclerosis Lorinda Chung 1, Antonia Maria Valenzuela Vergara 1, David Fiorentino 1, Kate Stevens 1, Shufeng Li 1, Jonathan Harris 2, Charles Hutchinson 3, Shervin Assassi 4, Lorenzo Beretta 5, Santhanam Lakshminarayanan 6, Tatiana Rodriguez Reyna 7, Christopher P. Denton 8, Rebecca G. Taillefer 9, Solene Tatibouet 10, Ariane Herrick 11, Murray Baron 10 on behalf of the Scleroderma Clinical Trials Consortium Calcinosis Working Group 1 Stanford University School of Medicine, 2 Salford Royal Hospital, 3 University of Warwick, 4 University of Texas in Houston, 5 Policlinico di Milano, 6 University of Connecticut School of Medicine, 7 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 8 Royal Free Hospital, 9 University of Montreal, 10 McGill University, 11 University of Manchester ACR, Oct 27, 2013: Poster 679

Radiographic Scoring System OBJECTIVE To develop and validate a novel radiographic scoring system for calcinosis affecting the hands of patients with SSc for potential use in future clinical trials

Radiographic Scoring System Methods – 12 investigators 8 rheumatologists 1 dermatologist 3 radiologists – Rating of 12 hand radiographs using a simple and complex scoring system Re-scoring of 2 XR at least 24 hours later – Assessment of inter- and intra-rater reliability

Simple Scoring System Mild—single site of low density Moderate—medium density at one or more sites OR a single site of high density Severe—more than one site of high or mixed density Johnstone et al. Rheumatology. 2012; 51(12):

Complex Scoring System Sum of scores for 22 weighted areas affecting each hand: % area coverage (0-100) X density (1-3) X weight for each area

Reliability SIMPLE SCORING SYSTEMKAPPA (95% CI) OVERALL INTER-RATER0.39 ( ) DICHOTOMIZED INTER-RATER*0.51 ( ) INTRA-RATER#0.67 ( ) COMPLEX SCORING SYSTEMICC (95% CI) INTER-RATER0.89 ( ) INTRA-RATER0.93 ( ) *Dichotomized mild/moderate vs. severe #One rater only re-scored one XR

Calcinosis: PROM Content Collection: 5 Focus Groups – Atlanta, New Orleans, New York, San Diego – 18 Participants Initial Strategies: – Item Collection to Saturation (or 30 ) – Proceed with content validation, Q development, factor anal Preliminary Data Review: – Anticipate confounding elements in content – Strongly disparate as well as unifying concepts – Suggestive of >1 process / general experience of calcinosis – Calcinosis not well understood at basic level Relinquish timeline on goal-oriented PROM development Continue focus on exploration of patient perspective – Carefully characterize important differences – Perhaps accommodating distinct groups

Next Steps Calcinosis Working Group Meeting – Aqua 308 8:30-9:30 PM Agenda Present and finalize protocol on incidence and associated clinical features of calcinosis: – Antonia Valenzuela Vergara Discuss further development of patient focus groups for patient reported outcome measure: – Lesley Saketkoo Present and discuss classification of calcinosis: – Vivien Hsu