In my talk at the American College of Rheumatology (ACR) Convergence 2022 titled “Cytokine regulation of inflammation in rheumatic diseases,” I discussed the role of immune molecules called cytokines in the pathogenesis of rheumatoid arthritis (RA) and other disease processes.

Cytokines are key actors in the body’s response to infection. They help white blood cells attack bacteria and other invaders by giving them chemical signals to eliminate their targets. For people with autoimmune disorders such as RA and lupus however, cytokines activate white cells in the joints, where they can destroy healthy tissues like cartilage.

In the 1980s and 1990s, researchers showed that patients with rheumatologic conditions could benefit from medications that suppress cytokines. Those discoveries led to the development of several effective drugs designed to block a range of cytokines, including tumor-necrosis factor, interleukin-6 and interleukin-1. My laboratory helped link RA with a cytokine communication system called the JAK-STAT pathway. Subsequently, drugs that inhibit the JAK pathway were developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with RA and other inflammatory diseases.

We also learned that individual patients appeared to have different cytokine reactions, and that finding the most important cytokine for each patient was essential in maximizing the chances of successful treatment—in other words, personalized medicine.

But the last 30 years have not seen the story play out as many of us had hoped. Cytokine therapy, even when highly tailored to the individual, hasn’t worked as well as expected. For starters, clinicians have a hard time identifying which cytokine to target with medication. You can’t block them all because doing so would deprive the body of its ability to fight infections and cancer. And when they do find the right one, up to half of patients experience only a partial response and another third are resistant to treatment.

This unmet medical need has led us in new, very promising directions. Along with my colleagues Franck Barrat, PhD, and Mary “Peggy” Crow, MD, we are starting to make exciting advances in our understanding of how cytokines interact with the genes of cells. In particular, we have been looking at how certain cytokines affect proteins that instruct genes to become more or less active.

Our understanding of this process, called epigenetics, and how it relates to rheumatologic diseases is incomplete. But we believe that the interplay of cytokines and epigenetics may be a key step in autoimmunity. By interrupting these signals, we think we can short-circuit the immune system’s assault on joints and other parts of the body.

A focus of our work recently has been on a cytokine called interferon (IFN). This molecule has been approved by the FDA for treating a variety of diseases, including infection with the hepatitis C virus and blood cancer. In contrast, blocking the effects of IFN is effective in treating lupus.

COVID-19 has given us several new ideas about IFNs that might be helpful in achieving this goal. Early in the pandemic, researchers observed that patients with severe illness often generated massive amounts of inflammatory cytokines in response to the infection. This response, which is called a “cytokine storm,” seems to be an all-hands-on-deck call to the immune system to rally the defenses against the virus. This cytokine storm happened later in the course of the illness, and in collaboration with Dr. Barrat we implicated IFNs in the cytokine storm occurring via epigenetic mechanisms. In other words, some of the same immune issues we see with COVID-19 are also happening with autoimmune diseases like lupus and RA.

Intriguingly, this observation meshes with our studies of Janus kinases (JAKs). These molecules are known to be involved in a variety of autoimmune diseases, including ulcerative colitis (UC) and Crohn’s disease, as well as RA. Drugs that inhibit JAKs have been approved by the FDA for several indications, and researchers have found that the medications also appear to help patients with COVID-19.

Much of the scientific community believes that JAK inhibitors work by suppressing genes that are induced by interferon. Although this view is correct, our lab has shown that the JAK system also connects to many other cytokines linked to RA, including interleukin-6. We’ve also shown that we can use JAK inhibitors to regulate these pathogenic genes, likely through epigenetic mechanisms.

Scientists at HSS are excited about the future of cytokine research and the benefits this can bring to patients with rheumatic diseases. We believe that effective targeting of cytokine-related signaling pathways and epigenetic mechanisms can lead the way towards remissions and even cures.

-  Lionel B. Ivashkiv, MD, chief scientific officer at HSS