ClinicSpeak: predicting a response to interferon-beta

Stratification: can predicting responder rates to IFNbeta save the class of drug? #ClinicSpeak #MSBlog #MSResearch

"The study below reports that some RRMSers have a specific baseline signature in their blood that can predict a poor response to IFNbeta at 2 years. This study joins an emerging number of previous studies showing similar results using these and other markers. Interestingly, the current study looks at markers that are part of the inflammasome, a structure that is typically activated by infections, but is also activated by autoimmune driven inflammation. Could these results be telling us about the cause MS, or at least the trigger of disease activity?

"Could this, and other similar, studies salvage IFNbeta as a 1st-line therapy for RRMS? If we could tell you that you had say an 80% chance of being NEDA on IFNbeta at 2-years would you select an injection therapy over an oral, or induction, treatment? Having a marker that predicts response to a drug would be a major plus as it would roll the dice in your favour. At present using IFNbeta as first line therapy puts the majority of MSers at risk of having ongoing disease activity to find the minority of responders who will do well. In my experience about 60% of MSers need to switch from IFNbeta to another therapy within 4 years of starting treatment. The question is at what cost to the MSers having to wait 2-4 years to find out that they are non-responders to IFNbeta." 

Epub: Malhotra et al. NLRP3 inflammasome is associated with the response to IFN-β in patients with multiple sclerosis. Brain. 2015 Jan 12. pii: awu388.

Background & objectives: Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in RRMSers.

Methods: 97 MSers treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of MSers , NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 MSers treated with interferon beta. 

Results: Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). 

Conclusions: These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in RRMSers.

CoI: multiple

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