EXPERT ANALYSIS FROM RWCS 2018

MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – Arthur Kavanaugh, MD, program director for the Rheumatology Winter Clinical Symposium, likes to close out the meeting each year in high style by assembling selected conference faculty to offer their personal picks for the top developments in the field during the past year and make predictions about the year to come.

Here’s how they called it:

The top events in rheumatology during the last year

The rise of oral small molecules: The Janus kinase (JAK) inhibitors and other oral small molecules that have begun reaching the marketplace, with many more in development, will bring a paradigm shift in the treatment not only of rheumatic diseases, but in inflammatory bowel disease and skin diseases as well, predicted Alvin F. Wells, MD, PhD , a rheumatologist at Duke University in Durham, N.C., who is also director of the Rheumatology and Immunotherapy Center in Franklin, Wisc.

“The challenge is whether Medicare will cover the pills the way they cover the infusions and the other things we do,” according to Dr. Wells.

Finally, therapeutic progress in osteoarthritis: “We have more than 10 drugs for rheumatoid arthritis that can slow or stop the disease process, and yet we have more than 30 million people with osteoarthritis that we have no drugs for. But I think there are finally some things on the horizon that look promising,” observed Orrin M. Troum, MD , of the University of Southern California in Los Angeles.

A bevy of new drugs for psoriatic arthritis and psoriasis: “I think the most important advance in the past year was the approval of a profusion of drugs for psoriatic arthritis and psoriasis. It’s really opened up the landscape for us in terms of treatment options. The downside is it’s going to take us a while to sort through which drugs fit where,” noted Eric J. Ruderman, MD , professor of medicine and associate chief of clinical affairs in the division of rheumatology at Northwestern University in Chicago.

“The drug I was most impressed with was tofacitinib [Xeljanz, an oral JAK inhibitor], not just by its effectiveness but by its potential to change the game, and particularly the data in tumor necrosis factor inhibitor inadequate responders. That was pretty solid data. It really opens the way to oral small molecules for joint diseases,” he added.

Interleukin-18 binding protein for monogenic inflammasome diseases: The biggest recent breakthrough in pediatric rheumatology was the Food and Drug Administration’s April 2017 designation of Breakthrough Therapy status for the recombinant human IL-18 binding protein known as tadekinig alfa for monogenic IL-18-associated autoinflammatory conditions, as well as the biologic’s Orphan Drug Designation for treatment of hemophagocytic lymphohistiocytosis, according to Anne M. Stevens, MD, PhD , professor of pediatrics at the University of Washington, Seattle, and chief of pediatric rheumatology at Seattle Children’s Hospital.

These disorders, while uncommon, are a huge challenge for pediatric rheumatologists. They are sudden in onset, often recurrent, and have high morbidity and mortality. While many children with macrophage activation syndrome respond to anti-IL-1 therapy, a subset do not. Dr. Stevens credited a team of investigators at the National Institute of Arthritis and Musculoskeletal and Skin Diseases and several university hospitals with proving that IL-18 is a key cytokine in some of these nonresponders. The investigators got the research ball rolling with their case report of a dramatic and swift response to tadekinig alfa in a child with life-threatening macrophage activation syndrome and extraordinarily high blood levels of IL-18 ( J Allergy Clin Immunol. 2017 May;139[5]:1698-1701 ). As a result, a formal clinical trial is ongoing.

Novel treatment concept emerges in severe SLE: The study that knocked the socks off of Martin J. Bergman, MD , in 2017 was the Dutch SymBiose study, presented at both the European League Against Rheumatism and American College of Rheumatology annual meetings. It included just 14 patients with severe refractory SLE – including 10 with lupus nephritis – and tested a treatment strategy of rituximab (Rituxan) followed a few weeks later by a course of belimumab (Benlysta).

“The results were very dramatic, to say the least,” said Dr. Bergman of Drexel University in Philadelphia. Indeed, this one-two therapeutic punch resulted in sharply reduced levels of pathogenic autoantibodies and immune complex-mediated neutrophil extracellular traps while also knocking down very high baseline Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores to near zero, even while enabling patients to discontinue systemic corticosteroids and mycophenolate mofetil (CellCept). Several much larger clinical trials of this regimen and other similar ones are ongoing in an effort to duplicate the results.

Dr. Kavanaugh said the SymBiose study was one of his own top picks for study of the year as well.

“It’s an approach that makes sense: You use rituximab as a sort of induction therapy to deplete B cells, then serum levels of BAFF/BLys go sky high, so some weeks later you use belimumab to block that,” explained Dr. Kavanaugh , professor of medicine and director of the Center for Innnovative Therapy in the division of rheumatology, allergy, and immunology at University of California, San Diego.

Mainstream use of dupilumab (Dupixent) for moderate to severe atopic dermatitis: “This is a total game changer. It’s really changed a lot of people’s lives,” commented George M. Martin, MD , a dermatologist in private practice on Maui.

“Interestingly, historically drugs that started out in your realm later made their way to dermatology, but now we’re seeing the IL-23 inhibitors starting with us and then making their way into rheumatology and gastroenterology. The IL-23 inhibitors are very powerful drugs; when we’re seeing half of our psoriasis patients achieve PASI 100 responses, it’s very exciting. And these are durable responses,” he noted.

The opioid crisis: What’s the most important recent event in rheumatology?

“That’s easy: The biggest thing in all of medicine is the opioid crisis. Whether you recognize it or not, it’s gigantic. It’s $500 billion of the U.S. economy, every year. Forty percent of rheumatoid arthritis patients and 30% with ankylosing spondylitis are on opioids, and what goes along with that is a lot of ugly stuff,” said John J. Cush, MD , professor of medicine and rheumatology at Baylor University in Dallas.

“We’re all worried because our patients do need pain management, and if someone has a significant pain problem, they’re now a pariah. No one wants to take care of you, no one will treat you. We do not in my clinic prescribe opioids anymore. We’ll prescribe tramadol and occasionally Tylenol No. 3, but that’s it. Pain doctors want nothing to do with these patients, primary care doesn’t want them. It’s a gigantic public health problem,” he continued.

Moreover, the FDA is now so leery of opioids that the agency has set the bar unrealistically high for approval of newer agents offering reduced abuse potential.

“I’ve been involved with or watched at least six FDA advisory panels looking at new, lower abuse-potential opioids in the last couple years. Only one agent got through,” according to Dr. Cush.

Dr. Troum commented, “I really think this whole opioid epidemic started with the campaign to make pain the fifth vital sign back in the 1990s. Some of the pharmaceutical companies took that concept and really ran with it.”

Rapamycin for inclusion body myositis: Dr. Kavanaugh’s pick for study of the year was what he described as “a brilliant presentation” of a French multicenter, placebo-controlled clinical trial of rapamycin for patients with inclusion body myositis at the 2017 ACR annual meeting.

“The French group considers IBM [inclusion body myositis] to be essentially Alzheimer’s disease of the muscle, marked by amyloid deposition. They chose to study rapamycin, which not only has immunosuppressive properties because it binds to mTOR [the mammalian target of rapamycin], but it also has the ability to inhibit amyloid protein deposition,” he explained.

The investigators reported improved 6-minute-walk distance and pulmonary function in the rapamycin group, whereas placebo-treated controls rapidly deteriorated.

“This is an approved drug for other indications, and we scratch our heads with IBM. It’s super nice to have something like that,” Dr. Kavanaugh observed.

A look at what’s in store

More tele-rheumatology: “I think the biggest thing is going to be more tele-rheumatology, more tele-ultrasound. Kaiser Permanente said 49% of their visits last year were virtual visits; that number is just going to grow,” predicted Dr. Wells.

Especially in medically underserved areas of the country, including large rural expanses, demand for remote tele-rheumatologic consults with high-quality imaging is going to increase, he added.

Here come cannabinoids for pain control: Dr. Troum predicted that in the depths of the national opioid epidemic, in a climate that discourages legitimate prescribing of traditional pain medications, rheumatologists can anticipate growing patient demand for cannabidiol and other cannabinoids for pain relief.

“I have patients coming in their 60s, 70s, and 80s – these are not young people – who are whispering to me, ‘Can I use this for my chronic pain?’ I think there’s going to be a big push for ways other than opioids to treat our patients’ pain,” according to Dr. Troum.

Tipping point nears for JAK inhibitors: In 2018, it will become clear just how seriously the Food and Drug Administration views the signal of possible increased venous thromboembolic risk associated with the oral JAK inhibitors for rheumatoid arthritis. The agency is expected to rule on Eli Lilly and Incyte’s resubmitted application for marketing approval for the JAK inhibitor baricitinib, which was tripped up earlier based in part upon VTE concerns.

“I think the big story in 2018 will be how the JAK story shakes out – whether this VTE thing has legs,” Dr. Ruderman predicted. “A sea change could be coming in our field, and it’s not coming next year or the year after, but 10 years from now: Are we going to move past the era of methotrexate and use generic small molecules instead? We’re going to find out within the next year whether that’s going to happen.”

Phase 3 results coming on tocilizumab for systemic sclerosis: “I think we’re going to see some really exciting systemic sclerosis data coming out this year,” Dr. Stevens said. Based upon the positive phase 2 results presented for tocilizumab (Actemra) last year, she’s optimistic that the ongoing phase 3 randomized trial will demonstrate a significant advantage over placebo in lung function. Also, ongoing separate clinical trials are evaluating an antifibrotic drug and rapamycin for systemic sclerosis.

Dr. Bergman, too, has high hopes for these studies: “I think we may finally be getting to a place where we can see effective drugs in systemic sclerosis.”

Amazon, Berkshire Hathaway, and JPMorgan Chase form a nonprofit to improve employee health care: In a recent press conference, the three CEOs weren’t specific about their plans, but Dr. Martin predicted the companies are likely to self-insure, bypassing Cigna and the other major health insurance companies and then contracting with physicians. He forecast that “probably within the next 5 years, what they do is going to affect everybody in this room.”

Rheumatologists will need to master a new mindset: Many rheumatologists have gotten comfortable with an all-tumor necrosis factor inhibitor treatment menu for their patients with moderate or severe rheumatoid arthritis. That’s got to change, according to Dr. Cush.

“We now have two IL-6 inhibitors, two IL-17 inhibitors, and we’ll soon have two JAK inhibitors. That’s going to be a direct threat to the not right- or left-brain, but the TNF-brain rheumatologist who now writes prescriptions for three TNF inhibitors in a row before questioning the efficacy. The idea is you will now be using drugs with other mechanisms of action first-line, or at the very least, second-line, and that’s going to be a paradigm shift for a lot of people,” he explained.

None of the speakers reported having financial conflicts regarding their comments.

bjancin@frontlinemedcom.com

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