Bret S. Stetka, MD; Lionel Ivashkiv, MD

Disclosures

December 13, 2016

Editorial Collaboration

Medscape &

Editor's Note: As chief scientific officer at Hospital for Special Surgery and professor of medicine and immunology at Weill Cornell Medicine, Lionel Ivashkiv, MD, has for years studied the molecular pathways behind rheumatologic conditions, work that has advanced the pathophysiologic understanding of conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), while also uncovering new therapeutic targets. While onsite at the American College of Rheumatology 2016 Annual Meeting in Washington, DC, Medscape spoke with Dr Ivashkiv about both his work and the future of managing inflammatory arthritis.

Medscape: Can you briefly summarize your research exploring the molecular pathways that contribute to RA?

Dr Ivashkiv: Today I presented[1] on metabolic pathways that regulate macrophages. We're interested in this in large part because macrophages are a key pathogenic cell that makes cytokines—like tumor necrosis factor (TNF) and interleukin-6—that are therapeutic targets in RA. The idea is to determine whether or not metabolic changes increase their pathogenicity and contribute to disease. Ideally, we will be able to turn off inflammatory cytokine production in macrophages in a disease-specific way that preserves host defense.

Our work has also led us to pathways that control the differentiation of macrophages into osteoclasts. We think that if we could target some of these pathways, we could also help control the pathologic bone resorption that occurs in RA.

Medscape: Osteoclasts are cells that break down bone or help resorb it, correct?

Dr Ivashkiv: Yes. They're really the only cell that's capable of breaking down bone. And this process is responsible for a lot of the morbidity in RA due to bone and cartilage damage. It's part of what drives a lot of the pain, the stiffness, the lack of mobility.

Osteoclasts are activated during inflammation but also sometimes in noninflammatory settings like postmenopausal osteoporosis; in these noninflammatory states, our treatments that target osteoclasts work very well—treatments like bisphosphonates. However, what's been found in RA, because of the inflammatory drive, is that it's much harder to treat and prevent erosions unless you completely suppress inflammation, which is very hard to do because of side effects.

Medscape: Are these pathways involved in disorders beyond just RA?

Dr Ivashkiv: Yes. We think of these in the context of RA, but I think any condition that would be driven by TNF might be involved, including psoriatic arthritis. From some of the other talks here, we're also learning about the inflammation that occurs with aging and how that causes the degeneration of various tissues—including musculoskeletal and fat tissue.

So one of our goals is not just to treat and reverse inflammatory arthritis but to think of ways to prevent or delay the tissue degeneration that occurs with aging. This could be a major benefit for all of us!

Medscape: Tell us about your previous work leading to therapeutic targets in rheumatology?

Dr Ivashkiv: We were the first people to link the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway to RA. This was work done in 1993-1994 that we published in 1995.[2,3] I think that we and John O'Shea, who was really a main contributor, were at the forefront of understanding this pathway as it relates to rheumatic diseases. A lot of the thinking back then was that the JAKs and JAK-3 might be important in lymphocytes, and our work looked at the idea that the JAK-STAT pathway in RA in macrophages could be important as well. And we think that one of the reasons the JAK inhibitors work so well is that they really turn off cytokine production in macrophages.

I was a small part of this work, and it took 20 years. But it paid off!

Another thing we've been interested in are the bromodomain and extraterminal (BET) inhibitors—inhibitors of so-called bromodomain proteins, which are regulators of chromatin. We've shown that inhibitors of these BET proteins—the one we work with is called I-BET, and there's another called JQ1—are very effective at inhibiting bone loss that occurs in arthritis. We worked on this with GlaxoSmithKline, who is looking at these for cancer. But the big question, when you try to repurpose a cancer drug for RA, is: Is it going to be safe enough? That said, I think this approach will be effective.

Medscape: What are the clinical implications of your work?

Dr Ivashkiv: The clinical relevance is that as we're discovering new basic and fundamental mechanisms that control the inflammatory response, I think we're going to be able to very selectively target parts of inflammation to match it to disease pathogenesis, an approach that will most likely use gene-specific therapy using epigenetic approaches. I think that the benefit and clinical breakthroughs here will be in precision medicine: You target the pathway that's gone wrong in the patient. But it's also a safety approach in which you target just the pathway that's gone wrong in a particular patient. You can suppress it selectively so that people don't get the side effects—including infections—that limit the usefulness of current therapies.

My take on the current evidence is that in rheumatic diseases, it's more functional genomics than gene sequencing. There is a strong genetic component in diseases like RA, but there's also a strong functional genomic component—what controls the genes, or the way the environment controls gene expression. We'd like to target epigenetic mechanisms in a very gene-specific way.

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