Gulf War Illness (GWI) (also known as Gulf War Syndrome) is a chronic multi-symptom illness that has been implicated in as many as one-third of the 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War. Despite the time, expense, and effort, the cause of GWI remains relatively unknown and treatments have been targeted at improving symptoms. Veterans with GWI are still plagued by multiple symptoms including problems with fatigue, headaches, joint and muscle pain, gastrointestinal and sleep disturbances, neurologic and neuropsychological symptoms, respiratory issues, and cardiovascular problems. These symptoms are burdensome, impacting the patient’s ability to work and care for themselves and loved ones, and impacting activities of daily living as well as quality of life.
While treatment remains focused on symptom improvement, there have been significant advances in gaining insight into potential biologic mechanisms that cause persistence of this disabling illness. Biomarkers have been discovered that may play a role in the onset and progression of the disease, such as markers of inflammation and immune dysfunction, an immune signature that is similar to that seen in autoantibody mediated illnesses such as rheumatoid arthritis, psoriatic arthritis, and myasthenia gravis. Specifically, the immune signature would favor the production of autoantibodies, a theory Dr. Abou-Donia pursued in animal models of GWI, and most recently has demonstrated in the serum of GWI subjects. Our current research efforts using a computational biology model have identified immune function, specifically autoantibody production, as a reasonable GWI target.
Autoantibody-mediated inflammatory illnesses have been treated effectively with B-cell depleting therapies, such as rituximab. Further, there is a closely related illness with a similar immune signature, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with two Phase 2 clinical trials that have evaluated the safety and effectiveness of rituximab and have shown an improvement in 65% of those patients treated with rituximab, often with marked and sustained improvement. There have been case reports of sustained normal health for more than 4 years. This is intriguing as in ME/CFS there is no defined autoantibody, yet the immune signature that led to these studies is very similar to GWI.
Our strategy is to engage a team of highly qualified researchers to measure the clinical and biologic response to a B-cell depleting therapy (rituximab), which temporarily reduces or removes the B-cells from circulation; B-cells are responsible for antibody production, the treatment targets autoantibody production. This in turn can potentially reduce or even completely eradicate future formation of autoantibodies and reset the underlying mechanisms of disease to improve symptoms and reset homeostasis, as predicted by our computational models. The use of a B-cell depleting therapy such as rituximab not only may prove effective in treating patients but also prove that the autoantibodies seen in GWI are indeed mediators of illness persistence. If proved effective in this study, a Phase 3 study would be justified, the results of which could change the standard of care for GWI, targeting the underlying cause of disease and not just treating symptoms tied to disease persistence.
In this poorly understood disease with minimal treatment approaches, this study will provide an understanding of disease onset and progression and provide a targeted therapy for at least a subgroup of patients with GWI and drastically change the dynamic of treatment. This not only sets to determine an underlying cause of disease but change the course of treatment by moving from amelioration of symptoms to resetting immune function and memory and removing the cells producing damaging autoantibodies. |
