Calcinosis Working Group

Summary of current project(s) of working group:

• Safety and efficacy of topical sodium metabisulfite for the treatment of calcinosis in patients with systemic sclerosis. This is an ongoing proof-of-concept pilot trial aimed to assess the safety and efficacy of topical 25% sodium metabisulfite versus placebo applied twice daily for four months for the treatment of calcinosis of the hands in patients with SSc.
• Evaluating the role of genetic variants in calcinosis associated with systemic sclerosis and dermatomyositis. Genetic variants in the ABCC6 and ENPP1genes were found to be more prevalent in a Stanford cohort of SSc and dermatomyositis patients with severe calcinosis compared to the general population. We are currently validating our findings in the Johns Hopkins SSc cohort. We are also analyzing the HLA subtypes in the original cohort to identify if there are certain subtypes associated with the identified genetic variants. Since ABCC6 and ENPP1 genes play an important role in the inorganic pyrophosphate (PPi) pathway which inhibits mineralization, we are analyzing the PPi levels in patients with these variants.
• Association of Paraoxonase 1 activity with Calcinosis in Patients with Scleroderma and Dermatomyositis: An Exploratory Analysis. Bae et al. identified that lower levels of HDL-Apo-A-1 associate with the presence of calcinosis in UCLA’s cohort of idiopathic inflammatory myopathies (IIMs). We are validating this association in the Stanford cohort of adult dermatomyositis patients and exploring if the association applies to SSc patients as well.
• Risk of calcinosis with proton pump inhibitor use in adult dermatomyositis and systemic sclerosis. Recent findings suggest a link between proton pump inhibitor (PPI) use and calcinosis in SSc. This study aims to evaluate the relationship between PPI use and the presence of calcinosis in patients with DM and to confirm this association in SSc in two centers.
• Definition of severity in SSc and DM-related calcinosis. Currently, there is no accepted definition of what constitutes severe SSc-related calcinosis. In collaboration with MIHRA (Myositis International Health and Research Alliance), we are developing such a definition for both adult and pediatric patients. Through a survey of patients, families, and providers, we aim to identify the factors that signify “severe disease.” Establishing a clear definition of severity will not only enhance patient–clinician communication but also strengthen research efforts in SSc-related calcinosis.
• Development and validation of AI-driven quantitative outcome measures of calcinosis burden on radiographs in systemic sclerosis. By combining multicenter data, advanced AI methods, and rigorous validation, this work aims to deliver a research-ready imaging biomarker to improve trial efficiency and accelerate therapeutic discovery in SSc.

Progress to date for working group:

• Topical Sodium Metabisulfite Study: Renewed funding from SCTC (WG RFA 2025) to support an open-label extension, allowing follow-up of participants through 12 months.
• Genetic Study: Preliminary results have been presented at ACR Convergence 2023 and 2024. The manuscript is currently being finalized.
• PON-1 Activity: Preliminary results will be presented at ACR Convergence in October 2025.
• PPI and Calcinosis Study: Preliminary results from the first center will be presented as a poster at ACR Convergence 2025.
• Definition of Severity in SSc and DM-related Calcinosis: The survey has been finalized, reviewed and approved.
• AI-driven Quantitative Outcome Measures: A preliminary set of radiographs has been rigorously de-identified, preprocessed, and annotated by an expert musculoskeletal radiologist.

Next steps:

• Submit a Betty Z. Benedict Grant application for the AI project.
• Complete enrollment of patients for the topical sodium metabisulfite study.
• Complete data extraction for the second cohort in the PPI project.
• Distribute the survey to respondents for the definition of severity project.
• Submit manuscript for genetic study and PON-1 study.

What are expected deliverables and timelines for grant/working group?

• Submit application to the Scleroderma Clinical Trials Consortium Betty Z. Benedict Award and the 2025 Request for Proposals to Advance Clinical Trials and Translational Medicine in Systemic Sclerosis – October 2025.
• Complete recruitment of SSc patients with calcinosis by May 2026.
• Submit manuscripts for genetic study and PON-1 study by December 2025

Publications:

Osteoclastogenesis in Patients With Systemic Sclerosis With and Without Calcinosis Cutis

Valenzuela A, Pérez G, Chung L, Sánchez F, Iturriaga C, Montalva R, Borzutzky A. ACR Open Rheumatol. 2025 Apr;7(4):e70029. doi: 10.1002/acr2.70029. PMID: 40176384; PMCID: PMC11965697.

Inorganic pyrophosphate is reduced in patients with systemic sclerosis.

Hsu VM, Kozák E, Li Q, Bocskai M, Schlesinger N, Rosenthal A, McClure ST, Kovács L, Bálint L, Szamosi S, Szücs G, Carns M, Aren K, Goldberg I, Váradi A, Varga J. Rheumatology (Oxford). 2022 Mar 2;61(3):1158-1165. doi: 10.1093/rheumatology/keab508. PMID: 34152415; PMCID: PMC9052889.

Validation of a novel radiographic scoring system for calcinosis affecting the hands of patients with systemic sclerosis.

Chung L, Valenzuela A, Fiorentino D, Stevens K, Li S, Harris J, Hutchinson C, Assassi S, Beretta L, Lakshminarayanan S, Rodriguez-Reyna TS, Denton CP, Taillefer RG, Herrick AL, Baron M; Scleroderma Clinical Trials Consortium Calcinosis Working Group. Arthritis Care Res (Hoboken). 2015 Mar;67(3):425-30. doi: 10.1002/acr.22434. PMID: 25155948

Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study.

Valenzuela A, Baron M; Canadian Scleroderma Research Group; Herrick AL, Proudman S, Stevens W; Australian Scleroderma Interest Group; Rodriguez-Reyna TS, Vacca A, Medsger TA Jr, Hinchcliff M, Hsu V, Wu JY, Fiorentino D, Chung L. Semin Arthritis Rheum. 2016 Dec;46(3):344-349. doi: 10.1016/j.semarthrit.2016.05.008. Epub 2016 Jun 2. PMID: 27371996

An Interim Report of the Scleroderma Clinical Trials Consortium Working Groups.

Baron M, Kahaleh B, Bernstein EJ, Chung L, Clements PJ, Denton C, Domsic RT, Ferdowsi N, Foeldvari I, Frech T, Gordon JK, Hudson M, Johnson SR, Khanna D, McMahan Z, Merkel PA, Narain S, Nikpour M, Pauling JD, Ross L, Valenzuela Vergara AM, Vacca A. J Scleroderma Relat Disord. 2019 Feb;4(1):17-27. doi: 10.1177/2397198318783926. Epub 2018 Jul 18. PMID: 30906878

Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis.

Valenzuela A, Baron M, Rodriguez-Reyna TS, Proudman S, Khanna D, Young A, Hinchcliff M, Steen V, Gordon J, Hsu V, Castelino FV, Schoenfeld S, Li S, Wu JY, Fiorentino D, Chung L. Semin Arthritis Rheum. 2020 Oct;50(5):891-896. doi: 10.1016/j.semarthrit.2020.06.007. Epub 2020 Jun 17. PMID: 32898758

Change in calcinosis over 1 year using the scleroderma clinical trials consortium radiologic scoring system for calcinosis of the hands in patients with systemic sclerosis.

Valenzuela A, Stevens K, Chung MP, Rodriguez-Reyna TS, Proudman S, Baron M, Castelino FV, Hsu V, Green L, Galdo FD, Li S, Fiorentino D, Chung L. Semin Arthritis Rheum. 2022 Apr;53:151980. doi: 10.1016/j.semarthrit.2022.151980. Epub 2022 Feb 10. PMID: 35183935

Subcutaneous calcinosis: Is it different between systemic sclerosis and dermatomyositis?

Valenzuela A, Chung L. J Scleroderma Relat Disord. 2022 Feb;7(1):7-23. doi: 10.1177/23971983211053245. Epub 2021 Oct 28. PMID: 35386947

Patient Experience of Systemic Sclerosis-Related Calcinosis: An International Study Informing Clinical Trials, Practice, and the Development of the Mawdsley Calcinosis Questionnaire.

Saketkoo LA, Gordon JK, Fligelstone K, Mawdsley A, Chaudhry HA, Valenzuela A, Christensen A, Khalique SM, Jensen K, Weinmann SC, Busman E, Chung L, Hsu VM, Russell AM, Steen VD. Rheum Dis Clin North Am. 2023 May;49(2):463-481. doi: 10.1016/j.rdc.2023.01.017. PMID: 37028847 Review.

Contact information for how can members get involved:

• Dr. Lorinda Chung (shauwei@stanford.edu)
• Dr. Antonia Valenzuela (antonia.valenzuela@uc.cl)