What about gout?
Gout is a form of arthritis often depicted in popular culture as a rich man’s disease – a tycoon with his leg propped up on a footstool and with an enormous bandage swaddling his big toe.
One of the curiosities of multiple sclerosis is that MS and gout are almost mutually exclusive: people with MS rarely get gout, and people with gout rarely get MS. This observation sparked researchers’ curiosity: what’s the connection between the two conditions?
Gout is caused by a build-up of uric acid (UA) in the bloodstream brought on by genetic factors, or by what was once characterized as a “rich man’s diet” (high amounts of meat, seafood, alcohol and sweetened drinks), although gout is most commonly found among the Maori of New Zealand. UA is produced by your body’s metabolism and is the main constituent of urine in humans and primates. Other animals generally don’t produce UA because they have an enzyme that breaks down UA (and which means that other animals don’t develop gout). Humans lost that enzyme at some point during evolution, which makes us more susceptible to changes in our diet.
As UA builds up in the bloodstream (called hyperuricemia), it forms crystals that collect in the joints, causing a very painful form of arthritis. But those high UA levels also appear to protect against the development of MS. The reason is that UA acts as “free radical” scavenger in the body. As part of metabolism, the body produces highly reactive molecules (such as nitric oxide and peroxynitrite), which promote inflammation and are toxic to nerve fibres. UA acts as an antioxidant and mops up peroxynitrite, and has been shown in animal models of MS to reduce inflammatory flare-ups in the brain and slow the passage of inflammatory cells into the central nervous system (Mattle and colleagues. Ther Umsch 2004;61:553-555).
The relationship between UA levels and brain inflammation had obvious implications for MS and raised three important questions.
The first question that researchers investigated was: if UA reduces inflammation, does this mean that UA levels are different in people with MS? In fact, several studies did find that UA levels were lower in people with MS (or other inflammatory neurological conditions) compared to other people. More recently, a large two-year study found that UA levels declined during the course of MS, which suggested that the periodic flare-ups of inflammation that occur in MS may ultimately exhaust the body’s antioxidant reserves (Moccia and colleagues. J Neurol 2015;262:961-967).
Secondly, does UA affect MS? A meta-analysis of research studies found that UA levels fluctuated during periods of relapse and remission (Liu and colleagues. Neurol Res 2012;34:163-171). UA levels were lower during an MS relapse (so less anti-inflammatory effect), and slightly higher during relapse-free periods. However, one study found the link between UA and relapses appeared to be important in women but not in men (Zoccolella and colleagues. PLoS One 2012;7:e40608). To date, one study found that lower UA was associated with higher disability scores (Guerrero and colleagues. Neurol Sci 2011;32:347-350). The two-year study mentioned above also reported that lower UA was associated with disability progression, as well as with impairments in cognition (Moccia 2015).
The third question is the most practical: If UA plays a role in inflammatory flare-ups, would boosting the body’s supply of UA improve MS? In other words, could UA (or inosine, its chemical precursor) work as an MS treatment?
As a first step, researchers examined what happens to UA in the bloodstream during treatment with Copaxone or an interferon (Constantinescu and colleagues. Mult Scler 2000;6:378-381). They found that UA increased in 9 of 10 people taking Copaxone, but were unchanged in people taking an interferon (Avonex or Rebif).
Three studies have since looked at whether inosine is useful as an MS therapy. A small study found that inosine supplements did appear to reduce inflammatory activity in the brain seen on MRI (Markowitz and colleagues. J Altern Complement Med 2009;15:619-625). A larger trial, called ASIIMS (for Association of Inosine and Interferon-beta in RRMS), which added inosine to Rebif, found that inosine taken for two years had no added impact on disability progression compared to Rebif alone (Gonsette and colleagues. Mult Scler 2010;16:455-462). The most recent study combined inosine and Rebif (Munoz Garcia and colleagues. Acta Neurol Scand 2015;131:405-410). As in the previous study, the addition of inosine appeared to provide little benefit. And like other therapies, inosine did cause side effects, such as kidney disease.
The MS-gout connection was an interesting observation and has shed some light on the MS disease process. It may also have inspired new research, with newer treatments such as Tecfidera purporting to have antioxidant effects. But unfortunately, inosine did not pan out as an MS add-on therapy. Inosine is available as a supplement. But its use is not recommended since it has failed to show that it’s effective for MS, and it can cause potentially serious side effects.
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