Approaches to Difficult-to-Manage Spondyloarthritis

WASHINGTON, D.C.—In my extremely biased opinion, rheumatology is the best specialty on the planet. I could cite hundreds of reasons to back this up, but my personal favorite is our unique ability to give people their lives back. The patient who hasn’t been able to work for months is back on the job. The patient wheelchair bound due to joint pain just walked into clinic for the first time. The patient crying in pain every single day can’t remember the last time they reached for the tissue box.

The list goes on, but every now and then is a patient we just can’t seem to help. What then? At the ACR Convergence 2024 session Approach to Difficult-to-Manage Spondyloarthritis, two experts spoke about identifying difficult-to-manage (D2M) patients with spondyloarthritis (SpA), differentiating active disease from fibromyalgia (FM) and therapy selection in these patients.

Difficult to Manage vs. Difficult to Treat

Liron Caplan, MD, PhD

Liron Caplan, MD, PhD, founder and co-director of the University of Colorado Program to Advance SpA Treatment and associate professor, medicine-rheumatology, University of Colorado Anschutz Medical Campus, Aurora, spoke on Chronic Pain in Spondyloarthritis: Differentiating Active Disease From Fibromyalgia. He kicked off his talk explaining the difference between D2M and difficult-to-treat (D2T) patients. “I think of D2T as synonymous with treatment refractory. The broader concept of D2M can also include extrinsic factors. So, D2T is a subcategory of D2M,” he explained.

To be more specific, D2T SpA speaks to intrinsic factors like nonresponse to medications. D2M SpA also includes extrinsic factors that prevent SpA patients from getting better, like:

• other causes of symptoms, like fibromyalgia
• access to care and medications
• medication adherence
• adequate medication dosage relative to patient body mass index
• fear of adverse effects of medication (without actual adverse effects)

Last but not least, Dr. Caplan noted that the diagnosis itself needs to be evaluated as an extrinsic factor that might explain why a patient has D2M disease. Perhaps a patient isn’t getting better because the diagnosis isn’t correct.

The Assessment of SpondyloArthritis International Society (ASAS) proposed a definition for D2M spondyloarthritis in an abstract at this year’s ACR Convergence.¹ Dr. Caplan explained, “We are trying to better define these categories to give providers guidance as to minimum standards of care and best practices. We’re also trying to limit inappropriate switching of medications and to provide practitioners a framework for how to understand disease.”

Dr. Caplan added that once extrinsic factors contributing to D2M disease are identified, the relative size of each of these factors needs to be considered as well as how they combine and/or interact to affect the individual patient.

Distinguishing FM from Active SpA

How do we know when D2M disease is driven by active inflammation, and how do we know when it’s actually due to noninflammatory causes like FM?

Dr. Caplan walked us through a framework for how to approach this million-dollar question. He joked, “I subtitled this section of my talk ‘A Case Study in How to Practice Medicine.’ Perhaps this a little obnoxious, but that’s what I did.”

To distinguish FM from active SpA, think through:

1. Do symptoms vary with dosing intervals of current therapy (“off phenomenon”)? Do pain symptoms correlate with other manifestations of disease (e.g., irritable bowel syndrome vs. inflammatory bowel disease, uveitis vs. headache).
2. Physical Exam. Dr. Caplan noted that combination physical exam maneuvers are more helpful than single physical exam maneuvers because they can help increase the positive likelihood ratio that a finding correlates with a diagnosis.²
3. “Erythrocyte sedimentation rate and C-reactive protein are helpful measures of disease activity in SpA,” he said.
4. He noted, “MRI [magnetic resonance imaging] of the sacrum has a critical role in distinguishing the presence of active disease, and I believe that this is highly underutilized.” Point-of-care ultrasound is also useful in assessing for peripheral synovitis and enthesitis.³
5. Integration of these. In other words, none of the clues above can be evaluated in a vacuum. Clinicians must look at the whole picture.

Ultimately, Dr. Caplan offered, “Maybe differentiating [FM from active disease] might not be the ideal approach because you’re starting with a patient who has pain, and you’re trying to ascribe it to a single cause. It may make more sense to independently look at each of these entities, and treat them all in kind. The presence of one doesn’t exclude the treatment of the other.” This point was specifically articulated in the 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria.⁴

As for final thoughts to differentiate FM from active SpA, Dr. Caplan said, “In many cases we have a lot of these techniques at our disposal. The real problem is implementation.”

Treatment of Refractory, D2T Disease

Dennis McGonagle, FRCPI, PhD, professor, Leeds Institute of Rheumatic & Musculoskeletal Medicine, St James Hospital, University of Leeds, U.K., spoke on Therapy Selection in Difficult to Manage Spondyloarthritis, focusing on the subset of D2M patients who fall under the D2T category. These are the patients who have failed multiple therapies with different mechanisms of action. “The big issue we face when treating these patients is immune heterogeneity,” Dr. McGonagle said.

He kicked off his talk with some humble common sense. He said, “When you’re running down the refractory pathway, the first thing you need to ask yourself is, ‘Was my original diagnosis correct?’”

Next, he spoke to diagnostic measures. As we all know, rheumatology remains a highly clinical specialty, particularly when it comes to the diagnosis and management of SpA. “The reality is that we don’t often use MRI. We go flying in the dark. And this is an area we need to get out of,” Dr. McGonagle said.

As for treatment, the 2022 ASAS EULAR guidelines recommended sequential monotherapy.⁵ That’s to say, start one biologic, and if that doesn’t work, pick a new one. He noted, “We do this and end up running out of road, so what should we do? I’d say most of you out there have empirically gotten some of these D2T cases under control using combination therapy that isn’t licensed.”

Combination Biologic Therapy

Dr. McGonagle first mentioned bimekizumab, an interleukin-17A and 17F (IL-17A/Fi) inhibitor that was recently approved by the U.S. Food and Drug Administration to treat moderate to severe plaque psoriasis, psoriatic arthritis (PsA), non-radiographic axial SpA and ankylosing spondylitis. From an insurance approval headache perspective, bimekizumab alone isn’t technically combination therapy. But the dual blockade of both IL-17A and IL-17F has shown promise over single IL-17 blockade alone. He highlighted an abstract at this year’s meeting that illustrated his point. He noted, “In psoriasis patients who failed a single IL-17 blocker, the additional blockade [with bimekizumab] seemed to buy back efficacy.”⁶

As for true combination biologic therapy, we’re starting to see more papers to this effect. “We’re learning a lot even through small studies. They’re starting to give us insights into disease,” he said. Some approaches, like the combination use of a tumor necrosis factor inhibitor (TNFi) and IL-12/23i were effective but accompanied by frequent infections. “So, we ran out of enthusiasm for blocking three cytokines,” he explained.⁷ “Combination strategies using a novel drug that targeted both TNFi and IL-17i at the same time also failed,” he continued.⁸

So where is there promise? Dr. McGonagle noted, “The state of the art is actually in the gastroenterology space. Unlike rheumatology, the gastro guys are able to do tissue biopsies pre- and post-intervention. The combination of guselkumab (IL-23i) and golimumab (TNFi) was superior to single biologic therapy with no added toxicity.”⁹ We can look forward to future data examining this combination in PsA soon.

As an interesting side note, Dr. McGonagle discussed studies examining fecal microbiota transplant (FMT) as a potential treatment for PsA. Unfortunately, he said, “These patients had worse outcomes. FMT effectively triggered a reactive arthritis, so the place of FMT in these patients isn’t clear.”¹⁰

Ultimately, when it comes to truly refractory patients, Dr. McGonagle shared, “I focus not on sequential monotherapy but move toward combination therapy. This is currently an active game. The game is in play, and we are all part of it.”

In Sum

D2T SpA refers specifically to treatment refractory disease. It’s a subset of D2M SpA, which also involves extrinsic reasons a patient doesn’t feel better, like FM. History, physical exam, labs and imaging (particularly MRI of the sacrum) are vital to differentiating inflammatory, noninflammatory and other extrinsic contributions to disease activity. When a patient isn’t getting better, Dr. McGonagle reminded us that “You’ve got to ask yourself, ‘Did I get it wrong?’” For patients with inflammatory disease truly refractory to biologic monotherapy, combination therapy may be the way to go and continues to be an area of active research.

Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.

References

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