- Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018; 131(13):1442-1455.
- Strikingly high levels of IL-18 distinguish patients with systemic juvenile idiopathic arthritis and macrophage activation syndrome (MAS) from many other rheumatic diseases. The exact role of IL18 in systemic juvenile idiopathic arthritis (SJIA) and MAS remains unclear, but IL18 transgenic mice exhibited more severe experimental MAS induced by chronic TLR9 stimulation. We also observed strong correlation between extraordinary high levels of free IL-18 and MAS susceptibility in the Cincinnati Children's Hospital Medical Center cohort of SJIA patients with and without MAS. Further experiments in mice suggested that high IL18 levels might decrease the threshold for MAS triggers to lead to MAS episodes. Based on these observations, we obtained an Expanded Access IND for the use of tadekinig alfa (rhIL-18BP) for treatment of a 5-year old male with SJIA complicated by recurrent MAS, failure of all prior biologic treatments, chronic high dose steroids with flare of SJIA and MAS upon attempts to wean steroids. Treatment with rhIL-18BP improved patient disease course with less frequent and easily controlled MAS episodes raising optimism about the use of rhIL-18 BP in patients with IL-18 driven disease preventing life threatening MAS.
- Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial. Annals of the rheumatic diseases. 2018; 77(1):annrheumdis-2016-210456-annrheumdis-2016-210456.
- Golimumab is a fully human monoclonal antibody approved for use in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Researchers consider that this antibody may be a step forward from the humanized antibody adalimumab or the chimeric antibody infliximab. Administration of the medication in children is subcutaneously once per month or every two months via intravenous route. Coordinated by the Pediatric Rheumatology Collaborative Study Group (PRCSG), this international clinical trial of subcutaneous golimumab in juvenile idiopathic arthritis (n=173) confirmed in open –label study a profound and quick reduction of arthritis signs and symptoms. As such 89% of patients had a 30% improvement by week 12 of the trial. Injections site reactions occurred with <1% of all injections. Although the primary endpoint of the trial was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyarticular forms of juvenile idiopathic arthritis. Golimumab was well tolerated and no unexpected safety events occurred.
- Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Annals of the rheumatic diseases. 2018; 77(6):819-828.
- Treat to target is an approach shown as a treatment in several randomized controlled trials to improve outcomes for patients with rheumatoid arthritis. Using a data driven approach, an international Steering Committee of pediatric rheumatologists, including Dr. Daniel J. Lovell, MD, MPH, used nominal group techniques to develop guiding principles and recommendations for treat to target approaches for children with juvenile idiopathic arthritis. A larger 30 person international task force, including Dr. Esi Morgan, MD, MSCE, amended and voted on their recommendations. The task force agreed on six overarching principles and eight recommendations. These principles include that the treatment target (remission or, alternatively, low disease activity), and the treatment strategy should focus on a shared decision with parents/patients, and declare that abrogation of inflammation is key to achieving treatment goals. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasize the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target.
- Transancestral mapping and genetic load in systemic lupus erythematosus. Nature Communications. 2017; 8:16021-16021.
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals with various racial backgrounds. We identified race specific genetic risk loci in addition to 24 novel SLE regions. Comparing results across the ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
- Thrombin promotes diet-induced obesity through fibrin-driven inflammation. Journal of Clinical Investigation. 2017; 127(8):3152-3166.
- Obesity is a worldwide epidemic that can promote chronic inflammation associated with several disease states. Research documents coagulation system dysregulation in animal models of obesity and in patients with fatty liver disease. The contributions of the thrombin/fibrinogen axis to obesity associated pathology are not well defined. The studies utilized mice deficient in fibrinogen, factor XIII, thrombomodulin or protease activated receptor-1 and analyzed for changes in body weight gain and altered inflammatory and metabolic parameters in adipose tissue and liver of high fat diet fed mice. Findings provide a mechanistic link between elevated procoagulant function and fibrinogen-driven inflammation that exacerbates obesity and obesity associated pathologies. Treatment with a thrombin inhibitor limited high fat diet induced obesity, suggesting that targeting thrombin or fibrinogen may limit pathologies associated with obesity.
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