‘A ton of hurdles’ stand in the way of precision medicine for rheumatoid arthritis


The slow march toward precision medicine in rheumatoid arthritis features increased use of serum biomarkers and novel approaches to biopsy, but “a ton of hurdles” remain, according to a presenter at the Biologic Therapies Summit.

“We have been struggling for years to advance RA therapeutics toward more precision medicine,” Stanley Cohen, MD, clinical professor in the department of internal medicine at the University of Texas Southwestern Medical School, and medical co-director of the Metroplex Clinical Research Center, told attendees.

He suggested that a decade ago, the conventional thinking was that much of RA pathogenesis moved through TNF and interleukin-6 pathways, and that medication targeting those pathways was most likely to be successful.

However, what Cohen called the “age of omics” — genomics, proteomics, transcriptomics and metabolomics — has pushed the field closer to more specific treatment paradigms.

According to Cohen, four areas may push RA treatment toward precision medicine: rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA) or shared epitope positivity; the role of synovium in treatment selection; prime cells; and liquid biopsies.

Regarding seropositivity, Cohen noted that analyses of rituximab (Rituxan, Genentech) showed that positivity for both RF and ACPA correlated with a greater therapeutic response.

“But Rituxan in RA is generally used as a salvage therapy,” he said.

Seropositive patients demonstrate a greater response to the drug than those who were seronegative.

Similarly, in a post-hoc analysis of a trial comparing abatacept (Orencia, Bristol Myers Squibb) and adalimumab (Humira, Abbvie), results indicated that higher ACPA titers yielded an improved response to abatacept. However, Cohen was loathe to draw firm conclusions.

“Possibly abatacept might have a somewhat better response in ACPA-positive patients,” he said.

Findings from the AMPLE study offered similar conclusions.

“It looked like there was a signal here that high titer ACPA or shared epitope positivity may have better response to abatacept,” Cohen said.

Further research is needed to describe the biomarker-therapy relationships more clearly, he added.

Turning to the synovium, Cohen discussed how the histologic pathotypes in RA, including lymphoid/myeloid, diffuse myeloid and fibroid pauci-immune, may have clinical use.

“Patients with lymphoid/myeloid are more likely to have RA than non-specific arthritis,” he said. “For the first time, information from the synovium may provide information on what might happen to patients in terms of prognosis.”

Although the data on this are not yet ready for “prime time,” Cohen expressed hope that the synovium may also help guide RA treatment toward precision medicine.

“Synovial gene expression may help us understand which patients may need to be more aggressively treated,” he said.

To that point, in the R4RA study, which compared rituximab with tocilizumab (Actemra, Genentech), RNA sequencing and gene expression of the synovium showed that patients with a diffuse myeloid signature demonstrated a better response to tocilizumab.

If there is an approach that remains in the distant future in RA precision medicine, it is prime cells, according to Cohen. He noted data from Dana Orange, MD, MSc, which showed that PRIME cells were activated in the blood by B cells shortly before RA flares.

“I don’t know where we’re going to be going with this data, but it is fascinating,” Cohen said.

Meanwhile, liquid biopsy is a precision medicine approach that may have use because of the challenges in performing synovial biopsies, he added.

“We are not good at synovial biopsy,” Cohen said. “It is hard to get tissue.”

Liquid biopsies are blood-based and therefore less invasive.

Cohen highlighted the PRISM RA tool as a predictor of non-response to a TNF inhibitor as a potential minimally invasive way to guide clinical decision making. However, although data have shown high positive predictive values, there have been different levels of sensitivity and specificity associated with this product.

“There are a ton hurdles for precision medicine in RA, but we are making headway,” Cohen said, before paraphrasing Winston Churchill: “We are at the end of the beginning.”

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