360info
Originally published under Creative Commons by 360info™.
Lupus is thought to affect at least five million people worldwide, but treatments for the severe autoimmune disease have changed little in 60 years.
While the commonly used medications glucocorticoids, also called corticosteroids or “steroids”, are effective at treating the symptoms of the disease, they also cause toxic side effects.
But a leap forward has been made in the decades-long search for a new anti-inflammatory drug to reduce the use of these steroids.
A difficult and unpredictable disease
Lupus, sometimes referred to as systemic lupus erythematosus, develops when a patient’s overactive immune system attacks healthy tissues.
It is more common in women and people of colour, in whom it is a leading cause of illness, disability and death.
Inflammation in lupus commonly affects the kidneys, skin and joints, but the disease can occur in virtually any organ of the body.
This variability has made lupus the scapegoat diagnosis for all baffling and unusual presentations on the popular medical TV show, House.
More importantly, this means that it is a difficult and unpredictable disease to treat, with outcomes in lupus remaining poor even after decades of research has advanced understanding of the disease.
On average, a person diagnosed with lupus has a 10 percent chance of dying within a decade, a sobering thought for patients who are typically diagnosed in their 20s, 30s or 40s.
Although many factors contribute to this high mortality rate, the stagnation in lupus treatment bears much of the blame for keeping outcomes poor.
Steroids a double-edged sword
Progress in developing new treatments in lupus has lagged behind that of other autoimmune diseases.
For example, the discovery of “biological” treatments — made from large naturally occurring molecules in the body — has transformed rheumatoid arthritis from a disease in which people inevitably ended up in a wheelchair, to one which is now highly treatable.
In contrast, lupus treatment has scarcely changed in the past 60 years, with many patients still relying on long-term steroid treatment to control their disease.
Steroids (not to be confused with anabolic steroids) are naturally-produced hormones that regulate essential immune and metabolic processes in the body.
When synthetically-produced versions of these steroids are given as a drug, they cause powerful anti-inflammatory effects.
Since their discovery earned researchers the Nobel Prize in Medicine in 1950, steroids have become one of the most widely used medications in the world.
Aside from lupus, they are used to treat many common conditions such as asthma, psoriasis and cancer.
However, the side effects of steroid use, particularly long-term use, are as innumerable as their clinical applications.
Steroids cause bone-thinning, increase the risk of heart attacks, accelerate cataract development, and can even interfere with mood and the menstrual cycle.
Aside from this, steroids are particularly harmful in lupus where they increase the accumulation of organ damage over time, which can eventually lead to organ failure.
To combat this, there has been a slow increase in the number of therapies developed for lupus in recent decades.
One of these is the drug anifrolumab, which recently became the first targeted treatment for lupus to be reimbursed on the Pharmaceutical Benefit Scheme in Australia.
Anifrolumab works by dampening type I interferon, an inflammatory pathway that is active in lupus. Although, anifrolumab is associated with reduced side effects compared to steroids, its efficacy remains to be seen as a clinical trial reported a response rate of just 16.3 percent above placebo.
Therefore, progress is slow, and cost, availability and effectiveness limit the wide use of these emerging treatments.
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Meanwhile, lupus patients continue to swallow the consequences of toxic steroid treatment.
New hope for patients
To understand what makes steroids so effective at treating inflammation, researchers looked at the underlying molecules which are switched on by steroid treatment.
One of these is the glucocorticoid-induced leucine zipper, more snappily known by its acronym GILZ.
GILZ was discovered in 1997 and has since been found to cause most, if not all, of the same anti-inflammatory effects as steroids.
GILZ can rival steroids in the treatment of inflammation, while the available evidence suggests that it is also relatively safer.
Aside from its link with steroids, GILZ plays an important part in maintaining balance within the immune system.
In a healthy person, GILZ is high and acts as a barrier to prevent the immune system becoming activated in inappropriate situations.
In contrast, patients with lupus have low GILZ, meaning that this protective barrier is reduced. Indeed, the lower GILZ is, the worse the disease is.
The same is true in multiple other autoimmune diseases aside from lupus, such as rheumatoid arthritis and psoriasis, in which GILZ has been shown to relieve inflammation.
Restoring GILZ to healthy levels may protect against disease in lupus and a range of other inflammatory diseases.
How to boost GILZ
But boosting GILZ is not as simple as making a synthetic version of it, popping it into a pill and giving it to people with lupus.
That’s because GILZ works inside our cells and so is incredibly hard to produce on a large scale.
Australian researchers had to find a different way of boosting GILZ.
Molecules are kept in check by inhibitory or activating signals, so they first examined what blocks GILZ under normal conditions.
This led to the discovery of a new regulator of GILZ, which, when inhibited, increases it and suppresses inflammation.
Think of it as if GILZ is a runner sitting at the back of a race due to a handicap incurred in a previous heat. Removal of this restriction may allow GILZ to win gold.
In the same way, an inhibitor of GILZ is being blocked to produce a net increase in GILZ.
This strategy has demonstrated great promise in preclinical studies and has resulted in the formation of a biotech spin-out company from Monash University, GILZ Rx, which aims to commercialise this research in order to bring it to the clinic.
Screening is underway to develop a small molecule drug, which can be taken as a daily tablet, keeping the costs of the medication low.
This venture has received funding from government and philanthropic bodies, with the end goal of bringing a new drug into the arsenal of safe treatments for lupus.
Hope is afoot that decades of stagnation in treating this debilitating disease may be about to end.
Iolanda Miceli is a MD-PhD student in the Rheumatology Research Laboratory of Associate Professor Sarah Jones at Monash University. Her PhD project is focused on the development of safer therapies for patients with autoimmune diseases, in particular lupus.
Iolanda is involved in pre-clinical development at GILZ Rx, which will be taking these findings to clinical trials.
Originally published under Creative Commons by 360info™.