The Future of Rheumatology: Targeting Treatments, Promoting Multidisciplinary Care

In opening the session on the future of rheumatology at the virtual Interdisciplinary Autoimmune Summit, Dr Leonard Calabrese, professor of medicine and the RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic Lerner College of Medicine, first looked to the past. He noted that that rheumatology was the first discipline to introduce treatment via immunosuppression some 70 to 80 years ago, and to use biologics as a mainstay of therapy more than 2 decades ago with the introduction of tumor necrosis factor inhibitors (TNFis).

There are more than 30 targeted and biologic therapies, including biosimilars, available now for the treatment of IMIDs, he observed. Still, in drug development for autoimmune conditions, “It’s a whole new world out there, there is just so much happening!”

While the field is accustomed to targeting individual cytokines, “but now we’re looking at immunomodulation as opposed to immunosuppression.” He noted that Chimeric Antigen Receptor (CAR) T cell therapy was pioneered just over 10 years ago at the Children’s Hospital of Philadelphia. “CAR T cells are coming out of the domain of oncologists and being harnessed to work in IMIDs,” Dr Calabrese explained. “B cells are bad actors in a lot of IMIDs.”

Recently, CAR T cell therapy showed impressive results in inducing and maintaining remission of highly refractory systemic lupus erythematosus in 6 patients. These patients did not experience potential adverse effects such as cytokine storm, and most remarkably, Dr Calabrese reported, mounted robust response to vaccines administered after their treatment.

“So, the conclusion of just this one therapy is that this is feasible,” Dr Calabrese said. “It’s a proof of concept and the numbers are way too small to get overly exuberant, but there is certainly enough to make us think that this may be a therapy for more than just lupus.” 

Dr Joseph Merola, associate professor in the department of dermatology and the division of rheumatology at Harvard Medical School and Brigham & Women’s Hospital in Boston, commented, “We can wax poetic about our B cell-driven disorders, but we’re starting to hear about this potentially in areas that are not B cell-driven,” such as hidradenitis suppurativa and other conditions that are typically T cell-mediated. “I think that’s particularly exciting in our world, in dermatology.”

Dr Joel Gelfand, professor of dermatology and epidemiology, vice chair of Clinical Research and medical director of the Dermatology Clinical Studies Unit at the University of Pennsylvania Perelman School of Medicine, suggested the possibility of developing CAR T therapy to target a particular subset of B cells, rather than all, as with rituximab. “The big challenge will be of course to see whether it works, but also there’s the cost and the scale of manufacturing CAR T cells that would be required.”

Dr Stephen Hanauer, the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine and medical director of the Digestive Health Center at Northwestern University in Chicago, asked, “Why do you think there is the selectivity? The therapy is just hitting the cells that are pathogenic, yet allowing immune responses, as with the vaccines.”  

“I think that what is happening is very similar to auto-stem cell transplants. You go in and wipe out the compendium of existing B cells and then regenerate from a naïve population of B cells. It’s essentially resetting the immune system,” Dr Calabrese replied.

Dr Hanauer observed that the latest highly promised therapy for IBD is the Janus kinase (JAK) inhibitors. However, “we have one arm tied behind our backs due to the FDA restrictions. The ORAL Surveillance study has put us back probably 5 to 10 years,” he said, referencing a study of rheumatoid arthritis patients that led the US Food and Drug Administration to require that patients with IBD fail to respond or lose response to a TNFi before being treated with JAKs.

Still, “there is a lot of excitement in about JAK inhibitors,” Dr Hanauer said. “We’re starting to use them in hospitalized patients. They seem to work very quickly.” Dr Adam Cheifetz, director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center in Boston and associate professor at Harvard Medical School, agreed. “The JAKs, especially upadacitinib, are very effective and rapid acting in ulcerative colitis,” he said.

Dr Calabrese noted that the introduction of glucocortcoids in the 1940s was greeted as a major advance for inflammatory diseases. Now, however, the panel agreed, there is a price to pay for the use of glucocorticoids. The 2021 American College of Rheumatology guidelines for treatment of rheumatoid arthritis for the first time downgraded glucocorticoids, recommending conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) be used without glucocorticoids for both short-term and longer-term treatment.

Dr Hanauer noted that rather than steroid-sparing therapy, the trend is toward steroid replacement. “Once patients are treated with steroids, the disease changes,” he stated. Dr Merola added, “I see JAKs as a steroid-sparing agents; with some patients, where once I would have reached for steroids, now I use JAKs.”

Dr Gelfand called for “stratified therapy” with atopic dermatitis. “It’s incredibly common, maybe 10% to 20% of the population. You can’t put all of those patients on a JAK inhibitor. Some patients will do fine if you put them on prednisone and then taper off. Others will have a harder time staying in remission when tapered.”

The most recent drug breakthrough in rheumatology is the interleukin (IL)-6 inhibitor, which has shown efficacy among patients across a variety of disease states. “We see patients achieve sustained remission,” Dr Calabrese noted. “This is a real game-changer for us, and I am so grateful that we have found another piece of the puzzle.”

Dr Alexis Ogdie, associate professor of medicine and epidemiology in the Perelman School of Medicine and director of the Penn Psoriatic Arthritis and Spondyloarthritis Program, raised the subject of whether IMIDs are cytokine- or phenotype-driven disease. “If you know the cytokine profile of an IMID, you treat for that and the disease features should improve.”

Noting that TYK 2 inhibitors are effective in conditions as varied as psoriatic diseases and SLE, Dr Ogdie asked, “Does that say something about these diseases?” Cross-disease medication efficacy could offer insight into the mechanisms of varying IMIDs.

Dr Merola suggested, “I would argue that some of our diseases need laser-targeted therapies but others may need broader targets.” Dr Gelfand added, “In dermatology, you may see patients with more psoriatic conditions, that in others appear more eczematous. Some have both and some may shift back and forth.” Dr Hanauer likened this to patients with ulcerative colitis who may develop conditions that are more like Crohn disease.

Dr Ogdie explored recent studies of combining biologics to treat IMIDs, such as the VEGA trial, which studied the combination of IL-23 inhibitor guselkumab plus the TNFi golimumab versus guselkumab or golimumab monotherapy in patients with ulcerative colitis. “What are the therapies that we don’t want to put together—and which ones do we want to combine?” she asked.

Dr Merola said, “I have had patients at the end of their rope. An IL-17 inhibitor cleared their skin but patients still had joint pain. We layered on a JAK for joint pain, and it worked.” However, he explained, “I make it clear that we don’t know about long-term risks of combining these drugs.”

“Are we dosing our medications properly?” Dr Ogdie asked, to a resounding NO from the panelists. “We have a lot to learn about dosing,” she said. Comparing doses of the same drugs in IBD vs rheumatology, she said, the rheumatology doses are consistently lower. Dr Merola observed that in a study of secukinumab, when patients who were not meeting the endpoints received twice the previous dose, they did much better.

The move toward multidisciplinary care is widely applauded, but Dr Ogdie asked, “How do you prove it’s better? We inherently know this is better but it’s another thing to prove it.” Dr Cheifetz observed, “It’s great for big academic center, but most IBD pts are cared for out in the community. There aren’t that many IBD centers of excellence.”

Across the board, Dr Ogdie observed, women tend to have worse outcomes than men with IMIDs. Noting that many of the outcomes were from patient reports, the panelists queried whether pain thresholds are lower among men, if antibody differences exist, the possible role of genetics and sex hormones, and other factors. “Maybe men and women have different ‘targets’,” Dr Ogdie suggested. Dr Merola wondered, “Are we doing a good job of designing and validating our outcome measures?”

Dr Hanauer noted that patient-reported outcomes are now considered insufficient evidence of efficacy in trials for IBD treatment; there must be evidence from endoscopy or biomarkers, as well. Dr Calabrese added that throughout the range of IMIDs, “pain, fatigue, sleep disturbance, are all present. This is biologic.”

—Rebecca Mashaw

Calabrese L, Ogdie, A. The Future of Rheumatology. Presented at: Interdisciplinary Autoimmune Summit. April 26, 2023. Virtual.