Torok Lab

Dr. Kathryn S. Torok's laboratory conducts multiple juvenile scleroderma clinical and translational research studies, including hosting the National RegiChildhood-Onsetood Onset Scleroderma (NRCOS) at the University of Pittsburgh, Children’s Hospital of Pittsburgh. The lab's primary areas of focus include discovery of juvenile scleroderma immunophenotypes and biomarker development, genomic analyses to determine genetic links to disease activity and progression, and development and validation of outcome measures in pediatric scleroderma. These themes are both interwoven and complementary to achieve our research team’s overall goal of providing better care for patients with pediatric-onset scleroderma.  

Overview

Pediatric localized scleroderma (LS) and systemic sclerosis (SSc) are disfiguring autoimmune diseases of the skin and underlying tissues. Smoldering disease activity leads to fibrosis and atrophy, causing physical and psychological disability that continues throughout childhood into adulthood.  Available therapies for LS and SSc are variably effective and are associated with morbidity themselves.  A better understanding of the pathophysiology of LS and SSc, especially during the active inflammatory phase, would lead toward more targeted and effective therapies.  Our lab uses multiple approaches to increase understanding of LS and SSc, including disease immunophenotyping, genomic analyses, and quality of life measures.

Current Research Projects

Determining the immunophenotypes of juvenile localized scleroderma and systemic sclerosis.

Preliminary work in our lab studying the peripheral blood chemokine/cytokine milieu and associated circulating cellular phenotype has identified CXCL9, CXCL10 (IP-10), and TNF-α chemokines/cytokines, and TH1 cell subpopulations as potential LS biomarkers, especially contributing during the active disease phase. The lab was awarded a Scleroderma Foundation Collaborative Research (SCORE) grant by the Scleroderma Foundation to further expand these findings through 18 pediatric rheumatology centers in the USA and Canada, leveraged through collaboration with the Childhood Arthritis and Rheumatology Research Alliance (CARRA) organization.  We hope that this information, along with a quality of life questionnaires, laboratory and clinical data will serve as composite biomarkers to predict subsets of LS and SSc, as well as disease flares or relapses.

Discovery of differential gene expressions (DEGs) relating to localized scleroderma immunophenotypes. 

RNA sequencing (RNAseq) technology provides a new approach for investigating LS disease operation and cellular influence by probing the genetic expression seen in blood specimens. This technique also provides utility for existing paraffin-embedded skin tissue from patients that can be used to extract RNA for the investigation of differential gene expressions (DEGs) relating to the immunophenotype of the disease. We have discovered significantly up- or down-regulated DEGs relating to TH populations and associated cytokines/chemokines in the skin and blood (CXCL10, CXCL11, CXCL9, IFN-gamma) of pediatric LS patients, which indicates that disease activity present in the lesioned skin is mirrored to some degree in the blood.

Understanding pediatric quality of life in localized scleroderma and systemic sclerosis.

Existing Quality of Life measures (QoL), or Patient Reported Outcome (PRO) measures, have limited utility in pediatric scleroderma, given the unique features of skin fibrosis and atrophy compared to other dermatological conditions, as well as the extra-cutaneous manifestations not typically captured in other skin PROs.  With the large emphasis on patient impact and their opinion on disease improvement/worsening in more recent clinical studies and trials, it is important that this is captured correctly for pediatric scleroderma patients. Dr. Torok’s mentees, Dr Kaveh Ardalan (MD) and Dr. Christina Kelsey Zigler (PhD) conducted pediatric scleroderma focus groups to obtained impact domains and variables directly from patients’ opinions and developed the Localized Scleroderma Quality of Life Instrument (LoQI): A Disease-Specific Measurement Tool using Anchoring Vignettes.  This is being further tested through multiple pediatric rheumatology and dermatology sites with ongoing collaborations.

Current Lab Members

Kathryn S. Torok, M.D. - Principal Investigator 
Kaila Schollaert-Fitch, M.A. - Clinical Research Coordinator
Emily Mirizio, B.S.- Technician
Aly Boucher  - Undergraduate Student
Shalini Jose - Undergraduate Student
Christopher Liu - Undergraduate Student

Selected Publications

  1. Kurzinski K, Zigler CK and Torok KS (2018). Prediction of Disease Relapse in a Cohort of Juvenile Localized Scleroderma Patients.  Br J of Dermatol.  2018 Oct 13.  doi: 10.1111/bjd.17312. [Epub ahead of print] PMID: 30315656
  2. Mirizio E, Marathi A, Hershey N, Ross C, Schollaert K, Salgadgo CM, Reyes-Mugica M and Torok KS.  Identifying the signature immune phenotype present in pediatric Localized Scleroderma.  Journal of Investigative Dermatology.  Accepted September 24, 2018. 
  3. Li SC, Li X, Pope E, Stewart K, Higgins GC, Rabinovich CE, O'Neil KM, Haines KA, Laxer RM, Punaro M, Jacobe H, Andrews T, Wittkowski K, Nyirenda T, Foeldvari I, Torok KSNew Features for Measuring Disease Activity in Pediatric Localized Scleroderma. J Rheumatol. 2018 Sep 15. pii: jrheum.171381. dsoi: 10.3899/jrheum.171381. [Epub ahead of print] PubMed PMID: 30219769.
  4. Constantin T, Foeldvari I, Pain CE, Palinkas A, Höger P, Moll, M, Nemkova D, Weibel L, Laczkovski M, Clements P and Torok KS. Development of Minimum Standards of Care for Juvenile Localized Scleroderma. Eur J Pediatr (2018) 177: 961.  https://doi.org/10.1007/s00431-018-3144-8.  PMID: 29728839
  5. Foeldvari I, Klotsche J, Torok KS, Kasapcopur O, et. al. Are diffuse and limited juvenile systemic sclerosis different in clinical presentation?  Clinical characteristics of a juvenile systemic sclerosis cohort. J Scleroderma relat disorder; First Published August 7, 2018.  DOI: 10.1177/2397198318790494
  6. Stevens BS, Torok KS, Li SC, Hershey N, Curran M, Higgins GC, Moore KF, Rabinovich CE, Dodson S, Stevens A, and The CARRA Registry Investigators.  Clinical Characteristics and factors associated with disability and impaired quality of life in children with juvenile systemic sclerosis. Arthritis Care Res (Hoboken). 2018 Dec;70(12):1806-1813. doi: 10.1002/acr.23547. Epub 2018 Nov 8. PMID: 29457372
  7. Stevens AM, Kanaan SB, Torok KS, Medsger TA, et.al. HLA in Juvenile Systemic Sclerosis:  HLA DRB1. DQA1 and DQB1 in Juvenile Onset Systemic Sclerosis. Arthritis & Rheumatol; 2016 Nov; 68 (11): 2772-2777. DOI: 10.1002/art.39765 PMID: 27214100
  8. Ardalan K, Zigler CK, and Torok KS. Predictors of Longitudinal Quality of Life in Juvenile Localized Scleroderma. Arthritis Care Res (Hoboken) 2017; 69: 1082-1087.
  9. Kelsey CE and Torok KS. The Localized Scleroderma Cutaneous Assessment Tool: responsiveness to change in a pediatric clinical population. J Am Acad Dermatol 2013; 69: 214-220
  10. Kurzinski K and Torok KS. Cytokine profiles in localized scleroderma and relationship to clinical features. Cytokine 2011; 55: 157-164.
  11. Magee KE, Kelsey CE, Kurzinski KL, et al. Interferon-gamma inducible protein-10 as a potential biomarker in localized scleroderma. Arthritis research & therapy 2013; 15: R188.
  12. Poff S, Li SC, Kelsey CE, et al. Durometry as an outcome measure in juvenile localized scleroderma. Br J Dermatol 2016; 174: 228-230.
  13. Torok KS. Pediatric scleroderma: systemic or localized forms. Pediatric clinics of North America 2012; 59: 381-405.
  14. Torok KS and Arkachaisri T. Methotrexate and corticosteroids in the treatment of localized scleroderma: a standardized prospective longitudinal single-center study. J Rheumatol 2012; 39: 286-294
  15. Torok KS, Kurzinski K, Kelsey C, et al. Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma: T-helper cell-associated cytokine profiles. Semin Arthritis Rheum 2015; 45: 284-293

A full list of Dr. Torok's publication can be found on NCBI