Overview

Principal Investigator

Keith A. Sikora, M.D.

Keith Sikora, M.D., is an assistant clinical investigator in the Pediatric Translational Research Branch. He researches the pathogenesis of pediatric inflammatory disease, including juvenile arthritis and relapsing polychondritis.

Juvenile-onset spondyloarthritis (JSpA) represents early presentation of spondyloarthritic disease that often develops into ankylosing spondylitis (AS). AS is an inflammatory arthritis characterized by varying degrees of back pain and stiffness, sacroiliitis, peripheral arthritis, enthesitis (inflammation where tendons attach to bone), acute anterior uveitis, and progressive bone formation often resulting in sacroiliac joint and spinal fusion. Spondyloarthritis affects 1-1.5% of the population, with childhood-onset disease occurring in about 15-20% of SpA patients. The study of early-onset disease may offer additional clues about genetic predisposition, and becomes increasingly important as treatments that can change disease course become available.

Both JSpA and AS are believed to be complex genetic diseases, or disorders caused by specific combinations of genetic variants in multiple genes rather than a single gene. However, HLA-B27 is present in close to 90% of patients with AS compared to just 6-7% of the healthy North American population. In addition to HLA-B27, over 40 other genetic locations, such as genetic variants of the interleukin-23 (IL-23) receptor, are believed to contribute to disease susceptibility. Yet, these genes, in addition to HLA-B27, only account for around 25-30% of disease heritability.

HLA-B27 encodes a protein that has the tendency to misfold and accumulate within cells, which can lead to the production of pro-inflammatory cytokines such as IL-23 and interferon-β. Our lab has previously shown the inflammatory consequences of HLA-B27 misfolding and accumulation within a transgenic rat model of AS, which develops intestinal inflammation and arthritis. Like other forms of inflammatory arthritis, tumor necrosis factor (TNF) inhibitors are the current standard of care for axial arthritis. While this family of therapeutics undoubtedly decreases inflammation, they may not work in every patient and their effect on the long-term development of abnormal bone formation in AS is currently unknown. This has prompted intense investigation of additional therapeutic targets, such as those of the IL-23 inflammatory pathway, which has not only been implicated in genetic studies, but has also been found to be activated and expanded in AS patients.

Based on this information, our Unit of the Pediatric Translational Research lab looks to:

  • Identify genetic variants within JSpA that may contribute to early disease development.
  • Identify ways cells respond to HLA-B27 accumulation/misfolding and how to manipulate these pathways for potential disease treatment.
Depiction of cytokine production upon misfolding of HLA-B27 in ankylosing spondylitis
Depiction of cytokine production upon misfolding of HLA-B27 in ankylosing spondylitis.

Staff

Research Fellow
301-827-2892
Research Coordinator; Study Nurse
301-451-6761
Lawrence Shulman Scholar
Clinical Fellow
301-594-6196
Staff Scientist
301-451-6019
Biologist
Research Assistant
301-402-3838
Research Fellow
301-451-1207
Volunteer
301-451-7341
Special Volunteer
414-520-0811
Special Volunteer
Clinical Fellow
301-402-1376
Research Fellow
301-827-0958
Postbaccalaureate Fellow
541-760-3838

Scientific Publications

Sikora KA, Fall N, Thornton S, Grom AA. The limited role of interferon-γ in systemic juvenile idiopathic arthritis cannot be explained by cellular hyporesponsiveness. Arthritis Rheum. 2012 Nov;64(11):3799-808.

Sikora KA, Grom AA. Update on the pathogenesis and treatment of systemic idiopathic arthritis. Curr Opin Pediatr. 2011 Dec;23(6):640-6.

Kivisäkk P, Mahad DJ, Callahan MK, Sikora K, Trebst C, Tucky B, Wujek J, Ravid R, Staugaitis SM, Lassmann H, Ransohoff RM. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol. 2004 May;55(5):627-38.

Latest News

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Last Reviewed: 02/17/2017