The major goal of this proposal is to attain clinical and translational research skills to become an excellent, independent investigator in rheumatology, with a focus in scleroderma. Systemic sclerosis (scleroderma) is a complex, multisystem disease involving tissue fibrosis, immunological derangements and vascular abnormalities. Previous epidemiological studies provide compelling evidence that patients with scleroderma have an increased risk of cancer compared to the general population. Observations of a close temporal relationship between cancer diagnosis and scleroderma onset, and reports of cancer therapy halting scleroderma progression, suggest that scleroderma may be a paraneoplastic syndrome in some patients. In this proposal, the candidate will probe the temporal relationship between scleroderma and cancer, examine risk factors for cancer in scleroderma, and assess whether scleroderma autoantigen expression in tumors is associated with the immune response. This research will define patient subsets that may benefit from targeted malignancy screening, provide insight into mechanisms relevant in scleroderma pathogenesis, and offer the candidate an opportunity to build a strong clinical and translational research program in a mentored environment. The candidate has demonstrated a commitment to a career in academic rheumatology through her training in Johns Hopkins'Graduate Training Program in Clinical Investigation and her ability to initiate and complete investigations of clinically relevant questins in scleroderma. This Mentored Patient-Oriented Research Career Development Award will afford the candidate the opportunity to continue building on these skills, in part through planned coursework at the Johns Hopkins Bloomberg School of Public Health. The dedicated mentorship team, diverse clinical and research environment in the Division of Rheumatology, and resources of the School of Public Health are an ideal foundation for this mentored patient-oriented research career development award. The large team of mentors and collaborators for this proposal provide significant expertise in studying the epidemiology and basic immunologic underpinnings of scleroderma and cancer. In addition, the resources of the Johns Hopkins Scleroderma Center (JHSC);the large JHSC and Royal Free Hospital scleroderma databases of over 4800 subjects;the Bayview Biostatistics, Epidemiology and Data Management (BEAD) Core;the Johns Hopkins Division of Oncology;and the Rheumatic Diseases Research Core Center (RDRCC) are fully available to make this project a success.

Public Health Relevance

This research will probe the connection between cancer and an autoimmune disease called scleroderma. By identifying clinical and laboratory factors that are associated with an increased risk of cancer in scleroderma, this study may define a population of patients who would benefit from targeted cancer screening. This investigation will also provide insight into mechanisms of disease initiation that may be relevant for the study of autoimmune diseases in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR061439-02
Application #
8517011
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$136,755
Indirect Cost
$10,130
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mukherjee, Monica; Chung, Shang-En; Ton, Von Khue et al. (2016) Unique Abnormalities in Right Ventricular Longitudinal Strain in Systemic Sclerosis Patients. Circ Cardiovasc Imaging 9:
Paik, Julie J; Hirpara, Ram; Heller, Jennifer A et al. (2016) Thrombotic complications after radial arterial line placement in systemic sclerosis: A case series. Semin Arthritis Rheum 46:196-9
Cappelli, Laura C; Shah, Ami A; Bingham 3rd, Clifton O (2016) Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities. RMD Open 2:e000321
Xu, George J; Shah, Ami A; Li, Mamie Z et al. (2016) Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer. Proc Natl Acad Sci U S A 113:E7526-E7534
Egiziano, Giordano; Bernatsky, Sasha; Shah, Ami A (2016) Cancer and autoimmunity: Harnessing longitudinal cohorts to probe the link. Best Pract Res Clin Rheumatol 30:53-62
McMahan, Zsuzsanna H; Shah, Ami A; Vaidya, Dhananjay et al. (2016) Anti-Interferon-Inducible Protein 16 Antibodies Associate With Digital Gangrene in Patients With Scleroderma. Arthritis Rheumatol 68:1262-71
Mittoo, Shikha; Frankel, Sid; LeSage, Daphne et al. (2015) Patient Perspectives in OMERACT Provide an Anchor for Future Metric Development and Improved Approaches to Healthcare Delivery in Connective Tissue Disease Related Interstitial Lung Disease (CTD-ILD). Curr Respir Med Rev 11:175-183
Poelman, Corrie L; Hummers, Laura K; Wigley, Fredrick M et al. (2015) Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 42:236-42
Shah, Ami A; Casciola-Rosen, Livia (2015) Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening. Curr Opin Rheumatol 27:563-70
Shah, Ami A; Montagne, Janelle; Oh, Sun-Young et al. (2015) Pilot study to determine whether transient receptor potential melastatin type 8 (TRPM8) antibodies are detected in scleroderma. Clin Exp Rheumatol 33:S123-6

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