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axSpA and axPsA Highlights
My Take on New Data in axPsA and axSpA Management From ACR 2021

Released: December 23, 2021

Expiration: December 22, 2022

Philip Mease
Philip Mease, MD, MACR
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At the 2021 meeting of the American College of Rheumatology (ACR 2021), many studies were presented that provide new insights on the treatment and management of our patients with psoriatic arthritis (PsA) and axial spondyloarthritis (SpA). In this commentary, I will describe findings from several studies on which I was coinvestigator.

Guselkumab for Axial PsA
In a previous post hoc pooled analysis of the phase III DISCOVER-1 and -2 trials, the selective interleukin (IL)-23p19 inhibitor guselkumab led to improved symptoms by Week 24 among biologic-naive patients with active PsA with investigator-identified axial involvement and imaging changes consistent with sacroiliitis. At ACR 2021, my coinvestigators and I presented a longer follow-up in this same patient population from the DISCOVER-2 trial. The analysis was performed using nonresponder imputation, which is the most conservative way of analyzing data.

This substudy is important because, before the phase III DISCOVER studies, it was thought that IL-23 inhibition did not work in ankylosing spondylitis. This was based on 2 previous trials showing no difference from placebo among patients with ankylosing spondylitis who received IL-23‒blocking therapies, including risankizumab and ustekinumab. Hence, there was some question about whether IL-23 inhibition with guselkumab would lead to a response in patients with axial PsA.

Axial PsA has many similarities to axial SpA or ankylosing spondylitis. For example, there can be inflammation and eventual ankylosis of sacroiliac joints, as well as damage in the spine with syndesmophyte formation bridging vertebral bodies. But there also are some important differences between axial PsA and axial SpA. For example, only 30% of axial PsA patients are typically HLA-B27 positive. Also, on imaging, axial PsA may lack evidence of sacroiliitis, or there may be only unilateral sacroiliitis, and the bridging syndesmophytes between vertebral bodies typically look different in axial PsA vs ankylosis spondylitis. The clinical presentation of spine pain also is different between the 2 diseases.

There was a great deal of focus and interest on this subset of patients in the DISCOVER program. The data presented at ACR 2021 included 246 patients with confirmed sacroiliitis from the DISCOVER-2 trial. In total, 60% of patients were male, which is a slightly lower frequency than you might see in a pure ankylosing spondylitis patient population.

Clinical responses were measured by several methods, including Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), spinal pain, modified BASDAI, and Ankylosing Spondylitis Disease Activity Score (ASDAS). At Week 24, all of these scores were improved among patients receiving guselkumab vs placebo, and these findings were sustained through Week 100. So, guselkumab treatment consistently improved symptoms and signs of disease. Moreover, these improvements were seen regardless of HLA-B27 status.

These data tell us that there might be an exception to the idea that IL-23 inhibition does not work well in the spondylitis aspect of the diseases we treat. Perhaps axial PsA is distinct enough from ankylosing spondylitis from a clinical imaging, genetic, and immunobiologic perspective that IL-23 inhibition has a role in treatment.

Based on these outcomes, we have the interest and confidence to proceed with a phase IV study of guselkumab dedicated only to patients with axial PsA. Known as the STAR study, this trial will provide a more definitive answer about the utility of IL-23 inhibition in patients with axial PsA.

Patient and Healthcare Professional Perspectives in PsA Care
The next study examined the perspectives of both patients and physicians in PsA care. The basic structure was to hold focus group discussions with groups of patients in 3 cities in the United States: Seattle, Washington; Cleveland, Ohio; and Washington, DC. The meetings were led by a medical anthropologist who asked patients to discuss their experience of having PsA, including their key symptoms, the impact of their disease on daily life, and their concerns about living with PsA. These focus groups were recorded, transcribed, and used to create a set of word clouds that emphasized the key issues patients were facing. These data informed a list of 51 items that was then used in a Delphi exercise in which both patients and physicians ranked each item according to their perception of its importance.

So, what did we learn from this exercise? The top items for patients were arthritis and fatigue. This is an important finding because we know that inflammation can lead to subtle or not-so-subtle alterations in central nervous system neurochemistry. One of the consequences is fatigue, and this may add to fatigue the patient already has from sleep disturbance or some element of depression, but it is above and beyond what those particular comorbidities may contribute to fatigue. It also is one of the items that some patients will say is the first thing to improve when they begin an appropriate therapy.

The third-highest item among patients was disease activity, meaning how significantly inflammation is occurring. Of interest, the fourth item was access to care. This represented a concern that patients had about receiving adequate care from their physician, including effective treatment now and in the future. After that came pain, then physical function and stiffness, the latter of which is an intriguing issue related to inflammation, which leads to what I call the “Tin Man” experience. Like the Tin Man in The Wizard of Oz, patients are stiff first thing in the morning.

Future health uncertainty was another concern in the top 10 list from patients. This is related to access to care, in that patients worry about whether their care will be as good in the future as it is now and whether their disease status will change and further affect their physical functioning or quality of life. Will they become more physically disabled? Will they become a burden to others? Finally, patients considered sleep quality and spine pain symptoms among their top 10 concerns.

Physicians were largely in sync with patients among their top 3 items, which were primarily disease activity, arthritis, and fatigue. However, they did not rank concerns about access to care, future health uncertainty, stiffness, or sleep quality. Physicians were primarily focused on adequately assessing and controlling the manifestations of disease activity, pain, and physical function.

This study identified important areas of overlap between patients and physicians, but also some major discrepancies. It is important for physicians to know about these discrepancies in priorities so they can ask patients about their concerns and be attuned to symptoms such as stiffness and sleep quality. This kind of awareness promotes a greater degree of trust in physicians, so that patients understand we care about their concerns. When I present this material to physicians, I emphasize the need to take a moment and ask patients, “What are your concerns?” I know we need to get a lot of information from our patients about the tender and swollen joint count, the quantity of pain they’re experiencing, and any adverse events they are having. But if we just take a moment to sit back, disengage from the computer, and ask an open-ended question—and then be willing to listen to the answer—this goes a long way toward improving the overall trust in the patient/physician relationship.

Treat to Target in Ankylosing Spondylitis
The treat-to-target paradigm in rheumatology has emerged as an important strategy. Originally practiced in the management of rheumatoid arthritis, it was shown that if we treated to the target of remission or low disease activity (LDA) as measured by various measures, patients had better outcomes across the board, including lessening of progressive structural damage, improvements in pain and patient-reported outcome measures of quality of life or function, and improved work productivity. So, treat to target became an increasingly popular and important paradigm of treatment in rheumatoid arthritis and, eventually, PsA.

With ankylosing spondylitis, it has been challenging to determine the ideal target for a treat-to-target strategy. The TICOSPA trial evaluated a treat-to-target strategy vs usual care with the primary endpoint of >30% improvement in the Assessment of SpondyloArthritis international Society (ASAS) health index, which is a combination of a patient-reported outcome measure of function and quality of life. The trial did not achieve its primary endpoint, but some other important measures were achieved, including ASDAS LDA.

The current study assessed whether ASDAS LDA could serve as an appropriate target of treatment in the large, real-world CorEvitas PsA/SpA Registry. Eligible participants had a diagnosis of radiographic axial SpA, also known as ankylosing spondylitis; were initiating treatment with biologics between March 2013 and March 2021; were not in a state of ASDAS LDA at initiation; and had a 6-month follow-up visit.

Among 130 participants, 25% achieved ASDAS LDA within 6 months of initiating biologic disease-modifying antirheumatic drugs (DMARDs), and 75% did not. There were interesting baseline differences between patients who went on to achieve ASDAS LDA vs not. Only 34% of achievers were female vs 62% of nonachievers. The duration of disease was similar between achievers and nonachievers, as was the frequency of HLA-B27 positivity. Nonachievers had higher rates of comorbidities—including depression, uveitis, or inflammatory bowel disease—suggesting that there might be some impact of having comorbidities. Patients who were achievers were much more likely to be previously biologic naive compared with nonachievers. Several patient-reported outcome measures—including pain, fatigue, morning stiffness, and work impairment—were significantly more prevalent at baseline among nonachievers. Likewise, baseline clinical disease measures such as the ASAS health index, BASDAI, tender and swollen joint count, and enthesitis count were significantly worse in nonachievers.

Looking at outcomes at 6 months, all of the patient-reported outcome measures—including overall pain, spine pain, nocturnal spine pain, fatigue, morning stiffness, and overall work impairment—were significantly improved in the achiever population vs the nonachiever population. The same was true for the outcome measures of ASAS health index, BASDAI, enthesitis count, and tender or swollen joint count, as well as ASAS 20/40 and ASAS partial remission. What this tells me is that the ASDAS LDA measure is a good and appropriate target for treatment in patients with ankylosing spondylitis. We should be increasingly employing this type of quantitative measurement so that we can consider when it is appropriate to tweak or intensify therapy. Moreover, we should share these goals with the patient so that we are in league with one another in trying to achieve these optimal outcomes.

Ixekizumab and Pain Improvement in Ankylosing Spondylitis
For patients with ankylosing spondylitis, pain is one of the first improvements they experience with effective treatment. This is often accompanied by improvements in inflammation, as measured by markers such as c-reactive protein (CRP), MRI scan, or BASDAI questions 5 and 6 (which ask about stiffness and are used as a patient-reported surrogate for inflammation). In some studies, it appears that pain improves extremely rapidly, sometimes within the first week or 2, even before signs of inflammation have diminished. When this was observed in studies of JAK inhibitors, subsequent analyses suggested that some of the improvement in pain could be a direct effect of the JAK inhibitor on the central nervous system neurophysiology of pain and that there is a mechanism of direct analgesic effect, as opposed to simply reducing pain caused by inflammation.

This analgesic effect had not been investigated with IL-17 inhibitors before the next study, but we hypothesized that they might have a similar mechanism. So, the objective of the phase III COAST-V study was to evaluate the longitudinal improvement in pain with ixekizumab based on objective measures of inflammation by MRI, CRP, and BASDAI questions 5 and 6 from baseline through Week 16. Patients in this study had active ankylosing spondylitis, were biologic DMARD naive, and were randomized to receive either ixekizumab every 2 weeks, ixekizumab every 4 weeks, placebo, or adalimumab. At Week 16, patients in the placebo and adalimumab arms were rerandomized to ixekizumab. 

The primary outcome from this study previously demonstrated that pain improved significantly with ixekizumab and adalimumab compared with placebo. For the current analysis, we looked at pain measures among patients with and without controlled inflammation and demonstrated that pain reduction occurred in both groups with ixekizumab therapy and that the change was rapid.

In particular, ixekizumab significantly reduced spinal pain at night, which is one of the key measures of ankylosing spondylitis pain, and further gains were achieved when patients moved from adalimumab to ixekizumab. This supports the hypothesis that IL-17 inhibition can have a direct and central analgesic effect and suggests that ixekizumab reduces pain by mechanisms that cannot be attributed only to the reduction of inflammation.

Your Thoughts?
Which new data from ACR 2021 will most affect your management of patients with PsA or axial SpA? Answer the polling question and join the conversation by posting a comment.

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