If three patients present with rheumatoid arthritis symptoms to their doctor each may be prescribed methotrexate, an antifolate. Statistically, this medication will work for only one of the three. The other two will return to the doctor to be switched to a more expensive biologic therapy. In the meantime the hope is that irreversible damage to their joints hasn’t occurred. Researchers in the field of arthritis are beginning to believe that arthritis patients respond differently to different drugs because they are suffering with different diseases.
Rheumatoid arthritis treatment is often ineffective
“At the moment, rheumatoid arthritis is thought of as one disease but it is probably hundreds of diseases,” says John Isaacs, a clinical rheumatologist at Newcastle University. Scientists in this field are hoping to increase our understanding of this type of disease to allow more targeted treatment for patients. As our knowledge increases patients may be diagnosed with different endotypes of rheumatoid arthritis, and be treated with specific sets of drugs accordingly.
Drugs for arthritis are currently ineffective for 50% of patients. This statistic is worse for drugs in other classes with 57% and 60% of drugs for diabetes and asthma respectively being ineffective. Researchers are now using a variety of ‘omics’ tools to search for underlying biomarkers of pathology that could help to predict which patients will respond to which drugs.
One of the earliest examples of defining disease according to the underlying pathology was the separation of diabetes as type I (insulin deficient) and type II (insulin resistant) in the 1930s; though characterisation of the molecular pathways underlying these differences took until the turn of the millennium. Indeed, personalised treatment for cancer care is now almost commonplace. “Personalised healthcare has revolutionised treatment for cancer. It’s hard to imagine treating breast cancer without first identifying whether a patient is HER2 positive to decide whether they should receive Herceptin,” says Clodagh Beckham, country medical lead at Swiss pharmaceutical company Roche.
A quarter of Roche’s phase 2 and phase 3 drugs pipeline consists of immunology, inflammatory or ophthalmology drugs, and the vast majority of these are being evaluated with a companion diagnostic, or a biomarker is being sought. “After cancer, the next wave of stratified medicines will be in immunology and inflammation. Current treatments are just not doing enough — patients still have severe disease or flare ups,” says Beckham.
Asthma, like rheumatoid arthritis, is likely an umbrella term for patients with different types of inflammation leading to similar symptoms. Approximately 10% of patients have severe disease that doesn’t respond to standard therapy and salbutamol, the most commonly used asthma treatment, is associated with different levels of effectiveness in different patient populations.
Esteban Buchard, principal investigator at the asthma origins laboratory at University of California, San Francisco, says that subtypes of asthma have been recognised for a number of years now, but treatments have only been tested in a narrow group of patients. In 1999, his team identified a particular genetic variation, which increases asthma severity in white patients, was 40% more prevalent in black patients. Eight years later, his team discovered that salbutamol is less effective at expanding the airways of black and Puerto Rican patients with moderate and severe asthma.
Newer therapies aimed at targeting possible asthmatic endotypes include a monoclonal antibody therapy from GSK that targets IL-5- a protein expressed by eosinophils, immune cells that play an important role in inflammation in some types of asthma. However, during its first set of trials it appeared largely ineffective. When a patient has inflammation caused by eosinophils, lots of these cells are present in the sputum. It used to be assumed that all asthma patients would have eosinophilic inflammation, but after sputum testing was brought in, it became clear that some do and some don’t. When the IL-5 targeted treatment was later administered to patients with ongoing eosinophilic inflammation it worked very well.
So a better understanding of the inflammatory nature of asthma has led to new treatments and the recognition that patient selection is important. Tim Harrison, clinical associate professor at the Faculty of Medicine and Health Sciences, Nottingham University, believes there are probably three or four types of inflammation that lead to asthma. “Eosinophilic is the classic allergic asthma. But for patients with non-eosinophilic inflammation it is usually neutrophilic, which may be a consequence of chronic infection of the innate immune system.”
Irritable bowel disease (IBD) is yet another catch-all term containing within it numerous different illnesses, such as ulcerative colitis and Crohn’s disease. Yet, even within these IBD subtypes a wealth of clinical heterogeneity exists. Though the course of inflammatory diseases can vary greatly between individuals, there has been real progress in understanding them. More than 160 different regions of the genome have been identified that contribute to a patient’s susceptibility to IBD and researchers are now fine mapping these regions in order to define the actual causal variants.
IBD is historically associated with Europeans, but more recently increases have been noted in East Asia, where Crohn’s disease is strongly linked to the TNF-? superfamily 15 (TNFSF15). Similarly early onset IBD, which develops in children a few years after birth, may be yet another different disease that falls under the IBD umbrella. In cases of early onset IBD defects in the anti-inflammatory cytokine IL-10 have been implicated. Affected children have genetic variants in the IL-10 signalling pathway and are seemingly resistant to almost all existing therapies- the only effective treatment is a bone marrow transplant.
The hope is that in the future we will be able to test for the genetic variants of disease-associated genes and treat patients with therapies targeted to the specific different aberrant signalling pathways.
Yet as we pursue a more molecular tack in tracking down the causes of disease the overlap between different inflammatory conditions has been highlighted. IBD shares susceptibility genes with ankylosing spondylitis, a chronic inflammatory condition affecting the spine and other areas of the body, as well as psoriasis and type I diabetes. With genes influencing numerous conditions locating the correct drug becomes more complicated, as certain gene variants may increase the risk of IBD but decrease the risk of other conditions, whilst other variants may increase the risk of both.
Another layer of complexity in diseases like IBD is an individual’s microbiome. The interactions of a patient’s microbiome with their genetic profile may work as a trigger for an inflammatory response.
To understand the contributions of each of these factors to complex inflammatory diseases researchers in these fields are now undertaking genomic, transcriptomic, metabolomic and proteomic studies to understand the abnormalities in the immune system that lead to these inflammatory conditions.
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