Emerging therapies, novel approaches in RA change the ‘default’
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The emergence of novel therapies over the last decade has turned the treatment of rheumatoid arthritis upside down.
Patients were long forced to manage their disease simply by mitigating pain with over-the-counter drugs and reducing inflammation with steroid injections. First disease-modifying anti-rheumatic drugs, then biologic therapies, have allowed rheumatologists to treat toward more specified targets, ushering the treatment of RA in the direction of personalized medicine.
The American College of Rheumatology recognized this shift and accordingly, recently updated their guidelines for the treatment of RA. Liana Fraenkel, MD, MPH, of Berkshire Medical Center and one of the authors of the document, presented the recommendations at ACR Convergence 2020 last month. If there was one over-arching idea that drove the development team, it was that glucocorticoids are no longer the “default” option, according to Fraenkel.
“The objective of the panel was to change the default for clinicians, that the norm should not be to always prescribe prednisone, even as a bridge,” Fraenkel said. “The underlying theme was a strong push to use methotrexate before going on to other DMARDs.”
The move away from steroids was largely due to the harms incurred not only at high doses over the long term, but at low doses and in short durations, as well. But the move also reflected an expanding array of approved therapies.
Zeroing in on biologics
While methotrexate and conventional synthetic DMARDs form the backbone of RA therapy, biologic and biosimilar therapies often garner the most attention. David Liew, FRACP, a rheumatologist in clinical practice and a research fellow in the department of clinical pharmacology and therapeutics at Austin Health in Melbourne, Australia, offered Healio a soup-to-nuts tour of the biologic armamentarium.
“There might be little in general to choose between our biologic and targeted synthetic therapies,” he said. “But there are definitely situations where a possible incremental advantage might exist from specific agents, and our patients deserve all the advantages we can reasonably give them.”
TNF inhibitors are still the first line for inadequate responders to combination conventional synthetic DMARDs, according to Liew. “We have unparalleled safety data in this space with over 20 years of widespread experience, which reassure me about long-term use,” he said.
The first FDA-approved TNF inhibitor was etanercept (Enbrel, Amgen). Today, rheumatologists have four other choices, including infliximab (Remicade, Janssen), adalimumab (Taltz, Eli Lilly & Co.), certolizumab pegol (Cimzia, UCB) and golimumab (Simponi, Janssen).
Arguably the most attractive characteristic of janus kinase inhibitors is their oral formulation, according to Liew. He favors these drugs in patients with a “strong fibromyalgic component” but who are not at risk for venous thromboembolism.
While tofacitinib (Xeljanz, Pfizer) is currently the only FDA-approved JAK inhibitor, a number of compounds are either approved in Europe or in clinical trials on their way to FDA approval.
Liew described the utility of interleukin-6 inhibitors in RA. “Patients with refractory seronegative rheumatoid arthritis, especially those with a polymyalgic-onset phenotype, may be candidates for IL-6 inhibition,” he said.
Tocilizumab (Actemra, Genentech) and sarilumab (Kevzara, Sanofi Genzyme) are the key drugs in the IL-6 class.
For patients with refractory seropositive arthritis, particularly those with RA-associated interstitial lung disease, a B-cell inhibitor such as rituximab (Rituxan, Roche) may be an option, according to Liew.
Regarding T-cell inhibition with drugs such as abatacept (Orencia, Bristol Myers Squibb), Liew offered keen clinical insight. “In patients where safety is a concern, in older patients with seropositive rheumatoid arthritis, or there is some possibility that their inflammatory arthritis may in fact eventually represent lupus arthritis, a T-cell inhibitor may be an option,” he said.
While experts like Fraenkel are excited about what the future holds for biologic therapies, the authors of the guideline stressed that many of the recommendations for their use are conditional rather than strong, largely because of a “relative lack of long-term experience” with them. Rheumatologists should approach their use with as much information as possible.
Shared decision-making
Beyond biologics, if there is another critical component to RA care that has evolved in recent years, it is the move toward a shared decision-making paradigm rather than a paternalistic model of care. In short, patients have a voice in the treatments that will ultimately be used to manage their disease.
“I don’t think you can have a standard approach to [shared decision-making], because fundamentally different patients want different things of me, and I try to tailor this reactively,” Liew said. “I have some patients who are incredibly engaged and medically literate and are happy to read quite sophisticated material.”
Liew said it is possible to have “an almost peer-to-peer discussion” with such patients.
“At the other end of the spectrum, I have patients who seem bewildered that I might consider their choices and take the attitude ‘whatever you think is best, doctor’,” he said.
There are a number of components to successful shared decision-making, according to Liew. Clinicians should understand patient needs and goals, first and foremost. They should consider not only the information that they will present to the patient, but how that information is presented. It may be necessary to differentiate fact from fiction for some patients, and it is always necessary to answer their questions honestly and directly.
“I use everything they tell me to gauge what is important to them, whether it be safety, or route of administration, or chance of success, and try and tailor the conversation appropriately,” Liew said.
That said, a good clinician will also have a mental list of the advantages and disadvantages of all potential agents and, perhaps, a preferred choice. “I try to only offer options to my patients that I think are reasonable for their specific circumstance, and then focus the discussion on the key pivot points, because otherwise it is overwhelming for the vast majority of patients,” Liew said.
Patience is critical, according to Liew. “I never rush my patient into a decision,” he said. “I give them time to ask questions, and if we run out of time on the day, I ask them to go away and then come back with a list of questions they might have. Ultimately, given that all of our therapies have similar, and good, response rates, the most important thing for me is that the patient has confidence in their choice.”
Taper and switch
If the right therapeutic choice has been made, a patient may enter remission, at which point it may be possible to consider tapering or even discontinuing treatment. But this decision should not be taken lightly.
“I rarely initiate conversations about tapering of biologic or targeted synthetic agents in rheumatoid arthritis, unlike in ankylosing spondylitis,” Liew said. “For me, risk of flare is always there, and there is little yield in terms of safety.”
When a patient raises the question of tapering, Liew has a direct conversation about risks and benefits, often suggesting concomitant methotrexate to reduce the risk of immunogenicity. “Having said that, I would always ask my patients to taper steroids first, and I rarely have any divergent views from my patients,” he said.
If there is another clinical decision that must be made, it is to switch therapies if one is not working. “I still take the simplistic approach, that for a patient who has had a primary failure to a class of drugs I will choose the next most suitable drug for them, based on previous thinking,” Liew said. “It is only really if a patient's thinking has changed, or an adverse event or comorbidity has emerged to change my thinking, that I diverge from that.”
Fraenkel offered a final word on the subject. “Tapering should only be considered in patients who have been at target for over 6 months,” she said.
For more information:
David Liew, FRACP, can be reached at Department of Rheumatology, Level 1, North Wing, Heidelberg Repatriation Hospital, 300 Waterdale Road, PO Box 5444, Heidelberg West VIC 3081, Australia; email: david.liew@austin.org.au.
Liana Fraenkel, MD, can be reached at 725 North Street, Pittsfield, MA 01202; email: liana.fraenkel@yale.edu.
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