There is now a potential mechanism by which alternative treatments can be provided much earlier in the course of the disease Researchers in the UK have discovered a genetic marker that can predict, with 90% accuracy, which rheumatoid arthritis patients will not respond to methotrexate. With previous studies showing between 35 to 59% of patients […]
There is now a potential mechanism by which alternative treatments can be provided much earlier in the course of the disease
Researchers in the UK have discovered a genetic marker that can predict, with 90% accuracy, which rheumatoid arthritis patients will not respond to methotrexate.
With previous studies showing between 35 to 59% of patients failing to achieve a clinically meaningful response to methotrexate, this discovery could be “a first step toward personalised medicine in rheumatoid arthritis”, the study authors say.
Using blood samples from methotrexate responders, non-responders and health controls, the researchers used an established ISO-certified industrial platform (namely EpiSwitch) to identify a “chromosome conformation signature”. This signature consisting of alterations in the chromosome conformations across five genomic regions (IFNAR1, IL-21R, IL-23, IL-17A and CXCL13) that could discriminate between responders and non-responders to methotrexate.
Researchers then validated the predictive power of this signature among a blinded, independent cohort of 19 early rheumatoid arthritis patients (nine responders and 10 non-responders). The signature demonstrated a negative predictive value of 90% for methotrexate response.
While the study, published recently in the Journal of Translational Medicine, is only small, the researchers say it provides a proof of principle that a priori stratification of response to methotrexate is possible.
“Historically, identifying predictive biomarkers for methotrexate response has been difficult,” the researchers said. We have well-established clinical predictors of rheumatoid arthritis disease itself, but these have not correlated with how well, or even if, these patients respond to treatment.
The blood samples used in this study came from the SERA (Scottish Early Rheumatoid Arthritis) study, a large, multi-institutional investigational program that was specifically designed to identify predictive markers of rheumatoid arthritis. The strict selection criteria for inclusion in the SERA study as well as its high standards in terms of processes and follow-up of outcomes, added to the strength of this study, the researchers said.
“This combination of clinical rigour and quality assurance of the inputs to the [chromosome conformation signature] are particular strengths of this study,” they said.
What the researchers could not determine was whether the observed epigenetic markers were cause or effect (secondary to the inflammatory response). They suggested future research might look at greater numbers of patients and include individuals treated with other anti-rheumatic agents, other than just methotrexate.
Nonetheless, the discovery of this stratifying signature, the study authors suggest, is a major advance as it offers a biomarker that can be used clinically.
“The validated classifier described here, which is based on five conditional binary biomarkers detected in the blood, offers cost-effective detection by an established ISO-certified platform … The practicality [of] this method to stratify patients has the potential to be routinely available within clinical practice,” they said.
The chromosome conformation signature offers a mechanism by which alternative treatments can be provided to non-responders much earlier in the course of the disease.
“This could facilitate earlier access to more effective therapies, thus avoiding disease progression, unnecessary exposure to potentially toxic drugs and diminished quality of life,” the study authors said.
References:
1. Carini et al. J Transl Med (2018) 16:18 doi: 10.1186/s12967-018-1387-9
