Synovial Biopsy Findings Drive Precision Medicine for RA Closer to the Clinic

Sharon Worcester

February 26, 2020

Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.

"I have no doubt about that — I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy," Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.

Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network's efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can't come soon enough.

"Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated," they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).

Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.

In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial — the first randomized, controlled, biopsy-driven trial in RA — were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have "massive implications" for RA management and outcomes.

Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.

Why STB?

Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn't reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.

Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.

A recent study in Portugal by Romao et al., for example, showed "remarkably high" patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).

A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).

Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.

Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.

"It has been very, very well tolerated," she said of the biopsy procedure used in the course of the studies — and that's despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.

"We've had no problems, no complications," she said, also noting the importance of careful patient selection.

Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.

In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.

Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.

"We posit that transcriptional signatures in macrophages...will predict responsiveness to specific nonbiologic and/or biologic therapies," they wrote, adding that future studies will "entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy."

The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.

A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.

"We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets," they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).

Next Steps

These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for "unlocking the hidden secrets to personalized medicine."

The question, however, is whether they have moved the field closer to "translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis," she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).

"Three sides of our square are in place: clinical expertise, technology, and patient willingness," she said, arguing that the fourth side is "standardization in the handling, evaluation, and interpretation of STB."

In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).

The groups, based on member survey responses, proposed a "consensual set of analysis items" to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.

One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a "robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses."

In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).

"Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification," they concluded.

In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).

Together, these emerging findings are "advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA," they wrote, concluding that incorporation of synovial assessments into clinical management of patients is "the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions."

Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.

Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.

"It requires a lot of training, there is a credentialing exam, and it's not necessary for practicing rheumatology, but there is a lot of growth," she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. "It's been a nice collaboration, and I think it's just going to push the field really is exciting — I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven't even thought of."

However, Dr. Pitzalis stressed that there remains much work to do.

"It's important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials," he said of the R4-RA findings.

Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.

He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that "we can tell, by 4 weeks, which patients will respond or not."

Dr. Pitzalis and his colleagues are also working on their "next set of trials," which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.

"If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice," he said.

The authors interviewed for this article reported having no relevant financial disclosures.

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