Clinical Trials

Fatigue is the most common symptom of multiple sclerosis (MS), affecting up to 90% of people with the disease. MS-related fatigue can be disabling even when other features of MS are mild. It can interfere with physical activity, memory and thinking, social and family activities, and ability to work. Initial treatment consists of energy conservation techniques such as rest periods or naps but when these approaches fail doctors usually recommend a trial of medications. Amantadine, modafinil, and other stimulants are commonly used but help only about half of those who try them. It is unlikely that these drugs directly affect the cause of MS-related fatigue. It has been difficult to develop new drug therapies for MS-related fatigue because we do not fully understand its causes and do not have precise ways to measure it. We rely on a person?s self-report about their fatigue but individuals experience and report fatigue differently. Recent research has shown that some fatigue aspects, such as difficulty maintaining mental concentration (?cognitive fatigue?) and physical activity (?motor fatigue?), can be measured more precisely and require further study. We recently reported results from a study showing that people taking the equivalent of four regular aspirin tablets (1300 mg) daily had reduced MS-related fatigue compared with placebo (sugar pill). The current proposal will attempt to confirm the benefit of aspirin in a larger group of people and to determine if the benefit is related to inflammation. One hundred and thirty-five people with MS-related fatigue will participate at MS clinics at three Mayo Clinic sites. Participants will complete questionnaires that ask about the severity and impact of their fatigue, memory testing to assess cognitive fatigue, and have blood testing to measure markers of inflammation. At the Arizona site, participants will also do strength testing in a motor laboratory to assess motor fatigue. After obtaining two separate baseline evaluations, the participants will be randomly assigned treatment such that one-third will receive 1300 mg per day of aspirin, one-third will receive 162 mg per day of aspirin and one-third will receive a matching placebo. All participants will then return to the clinic on two more occasions over the next eight weeks to repeat the questionnaires, memory and strength testing, blood tests, and report any side-effects. At the end of the study, the results of one of the fatigue questionnaires will be analyzed to determine if aspirin significantly improved fatigue compared with the placebo. The results of other questionnaires and the memory and strength testing will be analyzed as supportive evidence. If this study is successful, it will provide strong scientific evidence that aspirin helps MS-related fatigue. It will add an important new option for treatment of all MS patients that is also familiar, inexpensive, and has a good long-term safety record. At the same time, it will allow us to better understand the causes of MS-related fatigue and how to measure it more precisely. This information will be extremely useful for development of other therapies in the future.

The overall goal of this project is to determine whether well-established environmental and genetic risk factors for adult onset MS play an important role in susceptibility to pediatric-onset MS. Our study design is based on the hypothesis that genetic influences, specifically variation at HLA-DRB1 and other confirmed non-MHC MS loci, as well as environmental exposures including EBV infection and tobacco smoke, contribute to disease risk. In addition, we will also examine the relationship between serum levels of 25(OH) vitamin D3 and prior vitamin D status, and risk for pediatric onset MS. Finally, we will investigate whether specific G x E, and other multivariable relationships influencing risk exist for pediatric-onset MS. There are 12 collaborating sites other than UCSF that will enroll cases and controls for this study.

Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease has both a genetic and an environmental predisposition. MHC class II region on chromosome 6 accounts for majority of familial clustering in MS. Among the potential environmental factors, microbes and particularly gastrointestinal (GI) bacteria have been suggested to play an essential role in the etiopathogenesis of MS. The human GI track contains enormous (1014) population of microorganism. Despite the vast microbial burden and the close contact between the microbes and host, commensal intestinal microbiota are considered to be beneficial. The interaction of the intestinal microbes with the innate immune system might be a critical epigenetic factor modifying inflammatory and autoimmune diseases such as MS. This hypothesis is further supported by recent findings that levels of certain commensal bacteria such as Prevotella species and bifidobacterium are decreased in stool of patients of rheumatoid arthritis and Crohn's disease.
While much is known about the genetic and environmental triggers for MS, our understanding of the disease is incomplete, in particular, there are important questions which need to be addressed.

1. What is the composition of fecal microbiota of MS patients and if it differ from fecal microbiota of healthy control?  The differences in the composition of intestinal microbiota and in the function of immune system might determine which patients get MS. In addition, detail fecal microbiota analysis might lead to identification of bacteria that negatively correlate with the autoimmune state and prove to be useful as a potential therapeutic target.

2. If the fecal microbiota in MS patients is influenced by MHC genotype of individual? Of note the host genotype appears to affect the composition of the microbiota. MHC genes responsible for modulation of the immune system and affecting the risk of MS might also guide the composition of intestinal microbiota.