Introduction
rheumatoid arthritis, inflammation, RA, Rheumatoid Arthritis
DISORDER, RHEUMATOID ARTHRITIS, RHEUMATOID ARTHRITIS, INFLAMMATION, PATHOPHYSIOLOGY, INFLAMMATION, CHRONIC INFLAMMATION
At least 25% of the 697,000 U.S. military personnel who served in the 1990–91 Gulf War, Operations Desert Shield and Desert Storm, meet a case definition for Gulf War illness (GWI) [The mission of GWI research is to improve the health-related quality of life (HRQOL) of Veterans with GWI. To this end we have employed a translational research strategy. Our goal was to discover an evidence-based treatment for this deployment-related illness that would alleviate symptoms and mitigate the long-term detrimental health effects of the disorder.The process began with the hypothesis that there are biomarkers in blood that will reveal something about the underlying pathophysiology of GWI. To test the hypothesis, we conducted an observational study of blood from Gulf War Veterans who met the Fukuda CDC-10 GWI case definition (GWI+) and those who did not (GWI-) [The biological functions of the 12 GWI-associated biomarkers revealed a proinflammatory biomarker fingerprint. This observation led to the hypothesis that chronic inflammation is an underlying component of GWI pathophysiology. The GWI inflammation hypothesis was tested in a randomized controlled trial (RCT) measuring the effects of an anti-inflammatory drug and placebo on clinically relevant endpoints. The Gulf War Illness Inflammation Reduction Trial (GWIIRT) is a proof-of-concept study. Additional support for the GWI inflammation hypothesis comes from discoveries by other investigators of additional GWI-associated biomarkers of inflammation [The selection of an evidence-based intervention for this study was guided by the identification of a specific therapeutic target. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor that functions as a key regulator of inflammation. Activated NF-κB induces the expression of numerous proinflammatory genes including some coding for GWI biomarkers [Glucocorticoids (cortisol, cortisone, etc.), have pleiotropic effects on the immune system. Synthetic glucocorticoid derivatives (dexamethasone, prednisone, etc.) are anti-inflammatory drugs that block pro-inflammatory gene expression [Chronotherapy is the delivery of a medication in coordination with circadian rhythms. The optimal time for delivery of a glucocorticoid is in the early morning hours when the expression of genes coding for proinflammatory cytokines such as IL-6 are at their circadian peaks [The efficacy of low-dose prednisone chronotherapy as a treatment for rheumatoid arthritis (RA) has been demonstrated in two Phase 3 RCTs. Circadian Release of Prednisone in Rheumatoid Arthritis (CAPRA)-1 compared MR-prednisone taken at bedtime to the standard immediate-release formulation of prednisone taken in the morning [