Looking Ahead in Rheumatoid Arthritis Research

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Future research in rheumatoid arthritis (RA) treatment, experts say, will involve a shift in focus, building on an increased understanding of the pathologic processes involved in the disease -- down to the cellular and molecular levels.

It's likely that methotrexate will continue to be the initial treatment for RA, but for patients with an inadequate response to that drug, the choice of a second therapy will no longer be a matter of trial and error. Currently, some 30-40% of patients with RA don't show an adequate response to the targeted biologic drugs and may undergo multiple sequential treatments with various costly agents that have different mechanisms of action and toxicities.

"The future of RA is likely to be an era that will involve predictive modeling with the goals of having less refractory disease, fewer comorbidities that worsen disease, and less drug toxicity," said Jack Cush, MD, director of Clinical Rheumatology at Baylor Research Institute in Dallas. "We'll also be seeing more ACR 50 and 70 responses," he said, referring to 50% and 70% improvements on the criteria of the American College of Rheumatology.

"I think genomics are going to play a role in this. If you look at all the genomic studies right now, they're all over the place," said Cush. "But I think with time genomic studies will start to make sense when we begin to apply machine learning and artificial intelligence, looking at patient variables among thousands and thousands of patients to help determine what should be your best therapy if methotrexate doesn't work."

One aspect of treatment that's been coming into focus in the past few years is "how bad we are at not targeting what's destructive in RA -- in particular the fibroblasts that are the source of the actual damage cascade," Cush said.

Focus on the Fibroblast

Fibroblasts are mesenchymal cells whose origins are not epithelial or hematopoietic, but are found in tissues throughout the body and express genes that encode for various types of collagen. "Fibroblasts play an important role in physiological processes including wound healing, extracellular matrix remodeling, immune response, and support for stem cell compartments," wrote Michael B. Brenner, MD, of Harvard Medical School and director of Cell and Molecular Immunology at Brigham and Women's Hospital in Boston, and colleagues, in a recent review.

"We think of RA as an inflammatory disease in the synovium, the membrane lining the joints," Brenner told MedPage Today. "For the last 20 to 30 years, everything has focused on the inflammation in the joint, the leukocytes, the inflammatory cytokines, with treatments targeting tumor necrosis factor [TNF], interleukin [IL]-6, T cells, B cells -- all the inflammatory pathways," he said. But now, much research is exploring the role played by the stromal fibroblasts.

In the primary lymph node tissues, the T and B cells in their resting state are organized around fibroblasts, he explained. When an immune response begins, such as in the context of an infection, the fibroblasts initially activate the immune cells and subsequently help terminate the immune response when it's no longer needed. They are also an important source of inflammatory cytokines and chemokines that play central roles in inflammation.

"So my group and others began to consider whether similar processes involving fibroblasts were occurring in the peripheral tissues," Brenner said. "We were asking if the fibroblasts were enabling or regulating the inflammatory response by leukocytes in the peripheral tissues, and the answer to that is yes," he said. They do this by producing the chemokines in the RA synovium, recruiting and retaining the inflammatory leukocytes, and actually become inflammatory cells themselves.

"We think of fibroblasts as producing matrix in scarring and wound healing -- they're basically protein-producing factories. But in the inflammatory state they actively produce inflammatory cytokines, particularly IL-6," he explained.

It was previously thought that fibroblasts were a homogeneous group of cells, but it's now recognized that there are a variety of fibroblasts -- probably about 10 in typical tissues -- that differ according to their origin, function, and location. Some are inflammatory, some are perivascular, and others have unique immune functions.

"Our research has been breaking down fibroblasts into individual subsets by doing single-cell RNA sequencing to help identify which are the bad fibroblasts and which are the good ones," Brenner said.

That single-cell RNA sequencing also has permitted much greater ability to evaluate gene expression at the single cell level. For instance, it has become apparent that in the RA synovium, fibroblasts are anatomically separated into lining and sublining structures, with lining fibroblasts producing metalloproteinases 1 and 3, which have been implicated in degradation of the cartilage. Sublining fibroblasts appear to be greatly expanded in the RA synovium and have been shown to express the cell-surface glycoprotein CD90, IL-6, and interferon-related genes. Lining fibroblasts predominate in osteoarthritis -- a very different disease from RA -- whereas in the RA synovium, the sublining fibroblasts are the main source of expansion.

However, similar to the immune processes in the lymph nodes, the fibroblasts not only produce the matrix components such as collagens, but also the matrix metalloproteinases that degrade the matrix. Once fibroblasts in the RA synovium have attached to the local cartilage, they ultimately erode and degrade the cartilage and bone, leading to the permanent hard-tissue damage responsible for the joint destruction in RA.

"The leukocytes create the inflammation, but the cells that do the actual damage are the stromal fibroblasts as well as the osteoclasts that are activated by the inflammation and decalcify the bone. Once the bone has been decalcified, the fibroblasts are able to degrade the bone matrix," Brenner said.

Many of the currently used therapies that focus on blocking fibroblast-derived cytokines such as IL-6 can prevent the activation of fibroblasts but also block the activation of many other cells involved in the immune response.

Thus far no drugs have been approved that target the fibroblast itself. "Yet targeting the fibroblast to treat RA makes great sense," with less interference to the immune system itself, Brenner explained. "Although targeting immune cells in inflammatory disease inevitably compromises immune response to infections, targeting stromal cells may circumvent immunosuppression while abrogating pathology in the involved tissues," he and his colleagues wrote.

This is an active area of research among various academic groups and pharmaceutical companies. "But the unknown here is how to target fibroblasts," Brenner said. "What do you block? What receptor do you interfere with, or how do you deplete these cells, or alter the pathological, destructive behavior?"

One Failed Trial

Only one study targeting the fibroblast has been reported, and that phase II trial was unsuccessful. The agent tested was RG6125, a monoclonal antibody that targets cadherin-11, an adhesion molecule expressed on fibroblasts in the RA synovium. The antibody was developed in Brenner's laboratory and the study was conducted by Roche.

The randomized, placebo-controlled study, which was presented at the 2019 annual meeting of the European League Against Rheumatism (now the European Alliance of Associations for Rheumatology), included 109 patients with moderately to severely active RA who had shown an inadequate response to TNF inhibition. Their median age was 55, most were women, and median disease duration was 12.4 years.

At week 12, the primary endpoint of ACR50 response was not significantly different between the active treatment and placebo groups (11.1% vs 16.2%, difference of -5.1%, 95% CI -19.8% to 6.9%).

There also were few differences on other outcome measures such as ACR20 and ACR70 responses.

Brenner has been critical of the trial, however, because the patients were also being treated with TNF inhibitors, which strongly interfere with cadherin-11 expression. "TNF is a major upregulator of cadherin-11, and if you block TNF, the cadherin is downregulated and the therapeutic modulation of fibroblast behavior is compromised," he said.

Choosing the right cohort for testing is crucial in the design of clinical trials, he pointed out. For instance, the TNF inhibitors were initially developed as a treatment for sepsis, but failed. It was only years later that they were considered for the treatment of RA. "We do what we call basket trials now, testing a drug across a series of different diseases or cohorts to try to find which one it will work in, because we now realize that if you put all your effort into one big clinical trial and you haven't picked the right subset of patients, it might fail," he said.

Beyond RA

"I think the next major discoveries in drug development for RA are probably going to come from other disciplines -- infectious disease, oncology, GI, or even dermatology," Cush said in an interview.

It's not only in RA that fibroblasts appear to play an important role, but also in other inflammatory and destructive diseases and tissues, including inflammatory bowel disease and cancer. As Brenner and his colleagues wrote, "Defining the markers, mechanisms, and pathways that drive activation and differentiation of pathological fibroblast states will enable the identification of targets for fibroblast therapeutics that may impact a range of inflammatory, fibrotic, and malignant diseases."

"A drug targeting fibroblasts may work not just in RA but also across a lot of inflammatory and destructive diseases, because fibroblasts aren't just playing this role in RA. This is a big unmet need," Brenner concluded.

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms

Part 5: Second-Line Treatment of Rheumatoid Arthritis: What Are the Options?

Part 6: Managing Rheumatoid Arthritis in the Time of COVID

Part 7: Reproductive Health in Rheumatoid Arthritis

Part 8: Case Study: A Struggle to Maintain Mobility But Not for the Reason Everyone Thought

Part 9: Psychological and Emotional Health in Rheumatoid Arthritis

Part 10: Cardiovascular Disease in Rheumatoid Arthritis