Discussion
RA, inflammatory illness
INFLAMMATORY BOWEL DISEASE, DISEASE, PATHOPHYSIOLOGY, STD, MULTIPLE SCLEROSIS, REMISSION, SYNDROME, CHRONIC INFLAMMATION, DISEASES, INFLAMMATORY DISEASE
Employing the change in physical HRQOL from baseline as the primary outcome measure for this study assumes that a prednisone-induced decrease in GWI symptoms, i.e., reduced KSS, will translate into improved physical HRQOL, i.e., increased PCS. The statistically significant negative linear correlation between KSS and PCS, The potential relevance of the observed prednisone-related increase in the PCS to the long-term health and well-being of GWI+ Veterans was evaluated by comparing the results of CAPRA-2 and the GWIIRT. Both studies were placebo-controlled RCTs employing low-dose prednisone chronotherapy as the intervention. For CAPRA-2, the mean PCS changes from baseline at 12 weeks were 3.6Many RA clinical trials have reported robust placebo effects [Power analysis was used to estimate the minimum sample size of a prospective Phase 3 RCT. Using the low PCS subgroup mean PCS values at 8 weeks and the weighted mean std dev (σ = 7.67), the calculation determined that at least 231 subjects per group would be needed to detect a 2-point difference in the PCS between prednisone and placebo with 80% power at the p = 0.05 significance level. Thus, with the addition of baseline PCS <40 to the inclusion criteria, a Phase 3 RCT of low-dose prednisone chronotherapy is feasible.All statistically significant PCS changes occurred in the low PCS subgroups. All statistically significant MCS changes occurred in the high PCS subgroups. These divergent subgroup responses indicate there are substantial pathophysiologic differences between the two ends of the PCS spectrum in GWI.Inflammatory diseases, e.g., RA, multiple sclerosis, and inflammatory bowel disease, can fluctuate between periods of active disease which respond to prednisone treatment and periods of remission which are unresponsive. The evidence in this study that the low PCS subgroup responded to prednisone with improved physical HRQOL, and the high PCS subgroup did not, is consistent with the hypothesis that GWI is a relapsing-remitting inflammatory illness.The treat-to-target strategy is a widely accepted management paradigm for relapsing-remitting inflammatory diseases. First, an anti-inflammatory drug is used to treat active disease. Management goals are evaluated by regular assessments of disease activity using objective outcome measures. If remission is achieved, then sustaining the remission becomes the new objective [The prednisone-induced PCS increase returned to the baseline level following cessation of treatment. In this Phase 2 study there was only one treatment time point at 8 weeks. The effects of longer treatment are unknown. It is possible that continuation of low-dose prednisone chronotherapy will result in higher PCS levels and maintaining the maximum prednisone effect may produce a stable steady state that is no longer drug dependent, i.e., remission [The inflammaging hypothesis proposes that chronic inflammation accelerates the normal aging process [Unexplained illnesses have been reported by many U.S Military Veterans of more recent deployments to Iraq and Afghanistan. Burn pits are one source of toxic exposures that may be responsible for this emerging pathophysiology. The burn pit syndrome manifests GWI-like symptoms [