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EULAR 2021
My Take on Key Studies on axSpA and axPsA Presented at EULAR 2021

Released: August 10, 2021

Expiration: August 09, 2022

Philip Mease
Philip Mease, MD, MACR
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Some of the most exciting news from EULAR 2021 involved real-world data that will affect the management of patients with axial psoriatic arthritis (axPsA) and axial spondyloarthritis (axSpA). The new data clarified differences between the 2 diseases; illustrated the high symptom burden experienced by these patients; demonstrated differences in disease severity and outcomes between men and women; and showed how fibromyalgia (FM) affects patient-reported outcomes.

CorEvitas PsA/SpA Registry: Baseline Disease Activity and Patient-Reported Measures Among Patients With axPsA vs axSpA
In this study, my colleagues and I used the CorEvitas PsA/SpA Registry to compare disease activity and patient-reported measures among adult patients with axPsA or axSpA.

We found that patients with axSpA are younger than patients with axPsA, more likely to be male, and have higher rates of uveitis and inflammatory bowel disease. They also report greater overall pain and spine pain, as assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Patients with axPsA have lots of peripheral arthritis and enthesitis whereas patients with axSpA may not. AxSpA often presents as back pain and can be easily dismissed by healthcare professionals as mechanical back pain or something else. However, I think it is noteworthy that spine pain is also high in axPsA.

Imaging studies have shown that patients with axPsA often do not have sacroiliitis, or if present, it may be bad on one side and completely normal on the other—in other words, an asymmetric sacroiliitis. When patients have syndesmophyte formation, it tends to be irregular and asymmetric, and the calcium bridges themselves are chunky and stand out further from the vertebra than what is typically seen in axSpA.                                                                                                               

Currently, we lack knowledge about the immunobiology of the bone and the ligament attachments to the spine in patients with axSpA and axSpA, as we cannot biopsy in those areas. However, based on differences in the ways that various drugs appear to work in axPsA vs axSpA, there might be differences in the immunobiology of each disease.

Historically, we used data from axSpA trials to make conclusions about the efficacy of drugs in axPsA. For example, in treatment guidelines, we have said that tumor necrosis factor inhibitors work in axPsA because we used the axSpA trials as a surrogate. As another example, interleukin (IL)-17 inhibitors work in axSpA, so we assumed that they would work in axPsA. Indeed, the phase III MAXIMISE study showed that secukinumab works in axPsA. On the other hand, we were surprised when large studies evaluating IL-23 inhibitors, such as risankizumab (which targets the IL-23 p19 subunit) and ustekinumab (which targets the p40 subunit of IL-12 and IL-23), failed in ankylosing spondylitis.

To explain why these trials failed, we speculated that one immunobiologic difference could be a population of inflammatory cells in the spine in ankylosing spondylitis that produce IL-17 without the need for IL-23 stimulation, and so blocking IL-23 does not provide any benefit.

A substudy of the phase III DISCOVER-1 and DISCOVER-2 trials with the IL-23p19 subunit inhibitor guselkumab was done to identify patients with axPsA. In this substudy, patients were required to have abnormal x-rays or MRI scans of the sacroiliac joints or the spine. Analysis of BASDAI, spine pain, and Ankylosing Spondylitis Disease Activity Score (ASDAS) scores showed statistically significant improvement with guselkumab vs placebo.

Even more important will be a phase IV axPsA study with guselkumab (NCT04929210). In this study, only patients with axPsA and abnormal MRI scans of the sacroiliac joints or spine will be enrolled. The primary outcome will be change from baseline in BASDAI score at Week 24, so this study should provide definitive proof of whether an IL-23 inhibitor can work in axPsA. We should see results in a couple of years.

In terms of seeing patients in the office tomorrow, remember that the axial component of PsA tends to occur later in the disease process than in SpA. For example, back pain in a 45-year-old patient who has PsA should not be automatically ascribed to degenerative arthritis using a lumbar x-ray provided by the primary care professional. Be vigilant and consider the possibility of immunologic inflammation.

COAST: Comparison of Baseline Characteristics and Ixekizumab Response Through Week 52 by Sex Among Patients With axSpA
EULAR 2021 also featured a study by van der Horst-Bruinsma and colleagues, which stratified baseline characteristics and ixekizumab response through Week 52 by sex across the phase III COAST trials: COAST-V and COAST-W in radiographic axSpA and COAST-X in nonradiographic axSpA.

At baseline, women were found to have a slightly higher disease burden, as measured by various disease outcome measures (Assessment of SpondyloArthritis international Society 40, ASDAS <2.1, BASDAI, and BASDAI Item Score changes). Women also presented with higher scores for fatigue/tiredness and spinal pain at night vs men. Although disease activity improved with ixekizumab treatment regardless of sex, time to improvement and peak response were longer for women than men.

We know that approximately 15% of people with PsA, axSpA, rheumatoid arthritis, or lupus have overt FM. We also know that 36% to 50% of patients with these diseases have some degree of central sensitization (or “fibromyalgia-ness”). I think that the difference between the 15% with overt FM and the 36% to 50% with some degree of central sensitization may have influenced some of the outcomes in the van der Horst-Bruinsma study.

The COAST findings that ixekizumab response is slower in women was consistent with findings from the EXCEED trial, which compared secukinumab with adalimumab in PsA. In that trial, women had greater baseline severity than men, and overall, women had a lower treatment response than men.

This study highlights the need for the practicing rheumatologist to be aware of potential sex-related differences in axSpA in terms of the disease severity and treatment outcomes.

Comparison of Patient-Reported Outcomes Among Patients With Primary FM vs Spondyloarthritis With or Without Secondary FM
Another intriguing study at EULAR 2021 was reported by Baraliakos and colleagues. We know that the pathogenesis of SpA is distinct from FM, but SpA and FM can have overlapping symptoms such as pain and stiffness. Patients with axSpA and PsA sometimes develop secondary FM with higher disease activity scores, except for the ASDAS-CRP, which I consider the more objective measure.

Baraliakos and colleagues compared the performance of patient-reported outcomes originally developed for spondyloarthritis in patients with FM alone vs patients with axSpA or PsA, with or without secondary FM.

Patients with axSpA plus FM had worse disease-specific indices, for example, a mean BASDAI score of 6.9 vs 5.2 in patients with axSpA alone; a mean fatigue score of 7.8 vs 5.7 in axSpA alone; and a Bath Ankylosing Spondylitis Functional Index (BASFI) of 7.1 vs 5.4 in axSpA alone.

In patients with PsA, the Disease Activity Index for Psoriatic Arthritis was worse at 46.5 in patients with PsA plus FM vs 32.0 in patients with PsA only. The SpA Research Consortium of Canada score and the Leeds Enthesitis Index score were both worse in the PsA patients with FM. So any of the measures with a subjective component—for example, the BASFI, the BASDAI, or the enthesitis assessment—were worse in the patients with concomitant FM.

Another key point is that patients with “pure” FM had elevated scores of these measures even without having axSpA or PsA. This suggests that these instruments are somewhat nonspecific despite being designed to measure disease activity in axSpA or PsA. The implication for the rheumatologist is that it is important to determine whether FM, or a certain degree of fibromyalgia-ness, is present in the patient in front of you. The presence of FM will influence how you assess the severity of their axSpA or PsA and even their response to treatment.

Central Sensitization Significantly Associated With Quality of Life in Patients With axSpA
What I liked about this study by Kieskamp and colleagues is the use of the central sensitization index (CSI), an instrument that I have not used before. The CSI comprises 2 parts (A and B) with many questions, so there is a certain amount of patient burden associated with its use.

The authors evaluated the role of central sensitization in quality-of-life measurements for patients with axSpA. The CSI has a quantitative threshold of ≥40, which defines patients with central sensitization—or chronic widespread pain or “fibromyalgia-ness”—vs those with a CSI score <40 and no central sensitization. They found that CSI ≥40 was significantly associated with higher AS quality-of-life score, higher ASDAS score, and female sex.

The patients who fall into the fibromyalgia-ness group have worse quality of life despite an ASDAS score in the inactive or low disease activity range. When fibromyalgia-ness is present with a good ASDAS score, the patient can have a bad quality of life. This means that even though you think that your patient is responding beautifully to treatment, he or she will be unhappy if there is concomitant FM as measured by CSI. However, you should not be lured into addressing their unhappiness by changing biologics. Instead, acknowledge that their unhappiness is due to their fibromyalgia-ness and offer them antidepressant medicine or biofeedback therapy.

The clinical implication of this study is that we should assess and take into account central sensitization or fibromyalgia-ness. In our practice, we use the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale developed by Frederick Wolfe. We have patients in the CorEvitas PsA/SpA Registry fill out the WPI or the SS, and we evaluate their degree of fibromyalgia-ness by looking for high scores. If you choose not to use the WPI or the CSI instruments, then you must use your own “radar” for FM. In other words, when considering how well your patients are responding to treatment, be aware that if they are not responding well and have poor quality of life, then the FM issue should be addressed.

Your Thoughts?
Which of the studies described in this commentary will most likely affect your management of patients with axPsA/axSpA? Answer the polling question and leave a comment in box below. 

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