RBP4 Protein Levels May Predict Responses to Humira in AS

Lower blood levels of retinol-binding protein 4 (RBP4) — a protein associated with inflammation, among other processes — in people with ankylosing spondylitis (AS) are associated with better treatment responses to Humira (adalimumab), a study shows.

These findings suggest that RBP4 may be used as a biomarker to predict and monitor responses to Humira.

In addition to RBP4, researchers found that Humira treatment normalized the levels of six other proteins found at different levels in AS patients and mostly involved in inflammation or bone-related processes.

Titled “Circulating Retinol-Binding Protein 4 as a Possible Biomarker of Treatment Response for Ankylosing Spondylitis: An Array-Based Comparative Study,” the study was published in the journal Frontiers in Pharmacology.

While the cause of AS is still not fully understood, early inflammation, subsequent abnormal new bone formation, and eventual bone fusion are thought to reflect underlying disease-associated events.

The introduction of TNF-alpha inhibitors, including adalimumab (available as Humira and its biosimilars), has dramatically improved the treatment of AS, especially in patients who don’t respond to standard therapy.

By blocking the effects of TNF-alpha — a key inflammatory mediator — this type of therapy has the potential to lower inflammation and halt disease progression in rheumatic and inflammatory conditions, including AS.

While AbbVie‘s Humira has shown ability to lower inflammation and ease symptoms in AS, about 40% of patients fail to respond to TNF-alpha inhibitors — which are associated with high costs.

As such, identifying biomarkers that can predict treatment responses and help distinguish who will benefit most from these therapies is key.

A team from China set out to identify proteins produced in different levels in AS patients and those normalized with Humira, potentially providing predictors of treatment response.

They first analyzed the levels of 1,000 proteins in the blood of 39 AS patients (median age 30; 82% were men) and 20 healthy individuals (controls). Of these patients, 16 were treated with Humira for 24 weeks.

Results were then validated in two independent groups of age- and gender-matched participants comprising 43 AS patients — all treated for 24 weeks — and 39 healthy people.

Responses to Humira were assessed through changes in the Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP), with decreases of at least two points defined as a major clinical improvement, or a favorable response.

Data from the first group of participants showed that 53 proteins had significantly different levels between AS patients and controls, and that the levels of 42 proteins were significantly altered in AS patients after 24 weeks of Humira treatment.

Proteins resulting from either analysis were associated with pathways related to inflammatory response, bone metabolism, and fat metabolism — all known to be involved in AS. Notably, blood coagulation-associated pathways were significantly affected in AS patients, but not altered with Humira treatment.

These findings suggested that Humira could potentially normalize a considerable number of pathways and processes affected by AS.

In particular, compared with healthy individuals, the levels of seven proteins — most involved in inflammation or bone-related processes — were significantly different in AS patients but were normalized after Humira treatment.

RBP4, thought to be associated with inflammation and bone and fat metabolism, was among these proteins. The significantly lower levels of RBP4 in AS patients were partially restored with Humira treatment. As a result, RBP4 levels were further evaluated in the validation group of participants.

While no significant differences in RBP4 levels between AS patients and healthy people were detected, a subgroup analysis revealed that patients with favorable responses to Humira had significantly lower levels of RBP4 at the start of treatment.

Notably, lower levels of RBP4 before treatment were significantly associated with greater clinical improvements in response to Humira, and increases in RBP4 levels were accompanied by corresponding decreases in the ASDAS-CRP score over time.

“RBP4 was demonstrated to be a candidate biomarker for predicting and monitoring the response to [Humira] treatment,” the researchers wrote.

They suggested that RBP4 level differences between the first group and the validation group may be due to the higher percentage of patients responding to Humira in the first group (75%) than in the validation group (43.2%).

“Whether RBP4 works as a mediator connecting inflammation and subsequent abnormal bone formation in AS is worth further exploration,” the team wrote.