Philip Mease, MD
University of Washington

From November 3rd to 10th, rheumatologists gathered virtually for ACR Convergence 2021, the world’s premier rheumatology experience. Groundbreaking science including basic and clinical research, challenges and innovation in global rheumatology, immunogenomics, and improvements in patient care were discussed. This year’s conference included a compelling program focused on psoriatic arthritis (PsA).

Philip Mease, MD, is a rheumatologist who directs rheumatology research at Swedish Health Services in Renton, Washington, and Providence St. Joseph Health in Seattle, Washington. He is clinical professor of medicine at the University of Washington, scientific director of the PsA and spondyloarthritis arms of the Consortium of Rheumatology Researchers of North America, and co-chair of the PsA Task Force of the National Psoriasis Foundation. Dr Mease gave his insight into, and key takeaways from, research on PsA that was presented at the conference.

There were several poster presentations and oral sessions on PsA at ACR Convergence 2021. Which did you find most interesting or clinically impactful? 

An interesting oral presentation was made by Silje Syversen, MD, PhD, and colleagues,1 whose work involved measuring levels of infliximab in the blood in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis. One group in this study had regular testing of blood levels of infliximab. A parallel group with the same disease did not have blood levels measured. Using the results of blood testing, the researchers tweaked infliximab therapy by either increasing the dosage of infliximab if levels were low or decreasing the dosage if levels were high; more often, the first situation was the case.
 
Outcomes were better in patients who were in the therapeutic drug monitoring group; they were able to maintain effective results more consistently and persistently. This is an important finding because, in general, rheumatologists do not measure therapeutic drug levels; gastroenterologists usually do. That situation might stem from early experiences rheumatologists had with tumor necrosis factor (TNF) inhibitors for treating ulcerative colitis and Crohn disease, in which the pattern had been to treat patients to remission then back off from treatment and re-engage only when the patient had a flare.
 
With infliximab, starting and stopping dosing, rather than maintaining dosing continuously, can result in greater loss of effectiveness over time or lead to infusion reactions.
 
Early on, gastroenterologists became devotees of trying to quantitate the amount of drug in the blood and maintaining it at a certain level. So, US and European gastroenterologists tend to monitor drug levels as an important practice aid. Rheumatology has not adopted that approach. We follow clinical parameters and respond to them. So an interesting question is whether this kind of research will lead to a change in practice and encourage more therapeutic drug monitoring within rheumatology and PsA treatment.

In your phase 2b randomized controlled trial,2 brepocitinib demonstrated superior efficacy to placebo across numerous PsA disease domains in patients with active PsA at week 16, with improvements in more refractory domains continuing over 52 weeks. What are the clinical implications of these findings?

Brepocitinib is a unique Janus kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitor that is highly specific for inhibiting JAK1 and TYK2. An example of a JAK1 inhibitor that has been used in rheumatoid arthritis, axial spondyloarthritis, and PsA is upadacitinib. With upadacitinib, we found effectiveness not only in peripheral arthritis and enthesitis but also in the spine, which was demonstrated in patients with PsA who had spine disease and in patients with PsA with ankylosing spondylitis. Upadacitinib is already approved for rheumatoid arthritis; we anticipate it being approved by the US Food and Drug Administration to treat PsA in the first quarter of 2022.
 
The TYK2 inhibitory aspect of brepocitinib is specific for several cytokines, particularly interleukin (IL)-23. We know that IL-23 is implicated in the pathogenesis of psoriasis; therefore, through TYK2 inhibition, we see significant improvement in skin disease. Not only did we see very robust American College of Rheumatology (ACR) criteria responses that reflected improvement in joints, enthesitis, and dactylitis, we also saw significant improvement in skin disease. We confirmed that brepocitinib exhibits very strong benefit in musculoskeletal and skin domains.
 
Minimal disease activity (MDA) is a measure that is increasingly used in PsA trials and  comprises 7 key criteria. If 5 criteria are met, the patient is considered to be in a state of MDA; if 7 criteria are met, the patient is in a state of very low disease activity or remission. What we found unusual in the phase 2 trial with brepocitinib is first, that one-third of patients achieved MDA at the primary endpoint of 16 weeks and second, that slightly fewer than one-half of patients achieved MDA at 52 weeks. These findings contrasted with other clinical development programs, in which we have seen slightly lower response rates and achievement of MDA. The take-home message here is that the efficacy profile of brepocitinib is convincing, and we anticipated this based on its dual inhibition of JAK1 and TYK2 in treatment.
 
With regard to adverse events during this trial, we concluded that the safety profile of brepocitinib was very similar to other JAK inhibitors, with only a few cases of herpes zoster occurring and some abnormalities in liver function tests being recorded. Since this was a small trial, we did not observe venous thromboembolisms or deaths in the treatment group. Overall, the safety profile of brepocitinib will be comparable to what we have seen with other JAK inhibitors.
 
This research is planned to proceed into phase 3, with the ultimate goal that brepocitinib will be approved for treating PsA. The important outcome of approval is that it would add a drug to the therapeutic armamentarium for PsA. This is important because our experience treating this disease is that the human body tends to become accustomed to medications that we prescribe for chronic inflammatory diseases. New medications, such as brepocitinib, will allow us to switch up treatments, so to speak, in an effort to maintain low disease activity or remission.

You were part of an expert Q&A session on emerging therapies for spondyloarthritis, including PsA. What were some key discussion points? What can patients and clinicians look forward to?

Spondyloarthritis is an umbrella term for multiple disease conditions, including axial spondyloarthritis and PsA. I’ve found that, in presentations on PsA research and progress, and on emerging therapies, interest has mushroomed into better understanding this spondyloarthritic condition and how best to define it.
 
For example, many patients with back pain are sequestered in orthopedic or chiropractic practices, highlighting the importance of educating non-rheumatologists on how to identify patients whose disease is along the spectrum of spondyloarthritis.
 
Interesting studies on the use of machine learning as an emerging therapy for spondyloarthritis were also discussed,3 in which algorithms have been developed to assess radiographs and magnetic resonance imaging scans. Using these algorithms not only provides a more accurate reading of images but improves the efficiency of diagnostic approaches to spondyloarthritis.
 
On an unrelated theme, but with a similar goal of early detection and diagnosis, various abstracts addressed screening questions that can be employed within the electronic medical record to improve identification of spondyloarthritis by non-rheumatologists, thus allowing for earlier diagnosis.4
 
Another interesting point of discussion was anticipating the approval of 2 JAK inhibitors — upadacitinib and tofacitinib — for treating axial spondyloarthritis. In addition, we saw longer-term data regarding bimekizumab, which has shown a high degree of effectiveness because of its ability to inhibit both IL-17A and IL-17F.5 Bimekizumab has shown convincing results in PsA and axial spondyloarthritis.
 
An interesting substudy of guselkumab, an IL-23p19 inhibitor, is a phase 3 program that looks at the drug’s effectiveness in patients with PsA who present with axial or spinal disease.6 Results show that guselkumab is effective in alleviating symptoms in those patients. A larger interventional trial — STAR (ClinicalTrials.gov Identifier: NCT04929210) — is being conducted to assess the effectiveness of guselkumab in the axial PsA domain. This study will likely give us more insight into how the drug works, especially because IL-23 inhibition in the axial domain of PsA has become quite an intriguing subject. Questions remain whether axial PsA is the same as axial spondyloarthritis and whether there are important differences between the 2 conditions genetically, clinically, and immunophenotypically. Several research efforts are underway to better define patients with psoriatic PsA who also have axial disease.

Based on what you learned from 4 focus groups in your own research,7 are current patient-reported outcome (PRO) instruments optimized to capture the entire patient experience in active PsA?

Together with a medical anthropologist, we gave patients various PRO measures used in PsA clinical trials, including patient global outcomes, the pain visual analogue scale, and the quality-of-life 36-Item Short Form Survey. The patients were then asked for their thoughts about these measures, including whether they effectively captured the patients’ experience. There was strong endorsement of a new instrument that we’ve developed, the Psoriatic Arthritis Impact of Disease, which is a measure of function and quality of life that is being incorporated into clinical trials. Another version of the instrument has also been developed for clinical practice.8
 
The other measure ranked highly by patients was the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score, which underscores how important fatigue is for patients.  Interestingly, fatigue as a PRO is often left out or reported toward the end of efficacy data, just before safety data are presented. It is clear that this measure, along with others such as patient global outcomes, needs to be more prominently displayed.
 
An interesting point about a phenomenon we call “accommodation to symptoms” was discussed. Essentially, this is when patients accept certain symptoms as part of their disease by accommodating them, which results in patients recording these symptoms as being less severe than they really are — a finding that I thought was interesting and insightful.
 
During these focus groups, we also noted that patients found themselves frustrated that the questions being used to determine PROs were the same at each visit, which they felt did not quite capture their experience. My response to that was, clinically, we need to have standardized measures that cannot be customized to a patient-specific experience — to which the patients responded that they were concerned that the depth of their experience wasn’t being captured. Another important finding was that the experience of having the disease — including the cost and the time-consuming process of receiving care — was not captured in any of the presented PROs.

Treatment with upadacitinib and guselkumab for active PsA was featured prominently at ACR Convergence 2021. Mechanistically, the target molecules of these 2 drugs are different, but their effects in reducing disease activity appear to be similar. What are your thoughts on these treatments?

My observation is that all effective drugs appear to have a fairly similar degree of benefit in the clinical domains measured. For example, ACR domain responses tend to be seen in more than 60% of patients, with resolution of enthesitis and dactylitis occurring in similar percentages. Basically, what we are observing is that effective treatments work in different clinical domains of skin, musculoskeletal, fatigue, and physical function. That being said, there seems to be a threshold phenomenon at which we don’t achieve 100% improvement but have 25% to 35% of patients with MDA. Upadacitinib and guselkumab are effective treatments that work across all PsA domains, regardless of the biomolecular target, and that’s what we want.


Upadacitinib and guselkumab are effective treatments that work across all PsA domains, regardless of the biomolecular target, and that’s what we want.

An abstract presented by Schwartzman and colleagues9 found that in a cross-sectional survey of patients with PsA, more than one-quarter were not taking any immunomodulatory therapy. Guidelines published in 2018 by the ACR and the National Psoriasis Foundation encourage the use of biologic agents, including as initial therapy.10 Why haven’t these guidelines been fully implemented yet in clinical practice? What can be done to change that situation?

The first thing to settle is the fact that not all patients need “big-gun” therapy. Some have mild disease. For these patients, nonsteroidal anti-inflammatory drugs work adequately. Then there are patients who need more aggressive therapy but don’t have good medical care or adequate insurance, or who are in a place where they simply don’t have access to advanced therapies. The ACR guidelines are unique in that they recommend patients to be initiated on a TNF inhibitor prior to methotrexate once systemic medication is indicated.
 
Guidelines also say that depending on the patient’s clinical situation, insurance, and decision-making, consideration needs to be given to the choice of treatment when selecting among TNF inhibitors, IL-17 inhibitors, and methotrexate to name a few. The low percentage of patients reported to be on immunomodulatory therapy exists because these patients either do not need immunomodulatory therapy, don’t have access to care, or simply prefer not to go on one of these systemic medications.

The importance of shared decision-making, which requires that the clinician understands “what matters” to each patient regarding their disease, was also presented at the conference.7 This study highlights the need for physicians to work more closely with patients to address areas of concern and optimize shared treatment decision-making. What challenges need to be overcome in patient–clinician communication to optimize treatment approaches to active PsA?

I enlisted the aid of a medical anthropologist to conduct patient focus groups in Seattle, Cleveland, and Washington, DC. The patients were asked basic questions: “What matters to you about your experience of PsA?” “What are the most important domains of your experience of the disease?” And “What impacts you the most?”
 
We then interviewed 13 expert PsA clinicians and had them take part in a similar exercise, in which they were asked, “What do you think are the most important issues for your patients?”
 
We compared patients’ and clinicians’ answers and had both groups engage in a Delphi exercise and rank different items from most important to least important. Physicians and patients agreed that arthritis was ranked most important; patients ranked fatigue second in importance. Fatigue was ranked farther down by clinicians. I think clinicians are aware of it, but it’s not quite as important to them.
 
With autoimmune rheumatic disease and the effects of proinflammatory cytokines in the nervous system, there is a unique fatigue that occurs as part of having an inflammatory disease, and that can be relieved by treating the disease. One of the first things some patients say to me when they come for their first or second visit after treatment is, “The pain is better and I appreciate that, but what really makes a difference in my life is that this fog and shrouding fatigue I’ve been experiencing has lifted. I can think more clearly. I feel a little bit more energy. I have more agency around my daily tasks.”
 
Another finding from the focus groups was that 2 items that ranked highly with patients weren’t even on our radar as clinicians: future health uncertainty and access to care. To me, this means that, today, the patient is in a reasonable place; they are getting treated and seeing a rheumatologist with whom they are comfortable. But they now have this lifelong illness. What does the future hold for them? Will they lose independence? Will they eventually be crippled? Will they have joint destruction? Will their financial prospects change significantly, and will they lose their health insurance? I liken it to walking on a frozen pond, wondering, “Am I going to fall through or not?” This is something we clinicians need to seriously consider when communicating with our patients and supporting them with their treatment decisions.

Any final thoughts to add about ACR Convergence 2021 or advances in the understanding and treatment of active PsA?

I’m really appreciating how prominent the PsA and spondyloarthritis aspect of the ACR Convergence conferences has become. It isn’t as much in the shadow of rheumatoid arthritis as it was at past ACR meetings. There is new basic science research, disease-state research, as well as big population studies. I think PsA is coming into its own.
 
It has been frustrating that we have to meet virtually and cannot reunite in front of posters. That’s a limitation of a virtual conference. On the other hand, we get to move between sessions quite efficiently, attend more presentations, and get to see them in an archived manner as well.
 
Overall, we are seeing tremendous advances in our understanding of PsA through basic science research on disease mechanisms, research on clinical aspects of disease in clinical trials and disease registries, and many clinical trials of approved and emerging therapies. This is an exciting time for clinicians and patients as we work to improve the lives of patients.

Key Takeaways

  • Compelling research was presented at ACR Convergence 2021 about the benefit of monitoring blood levels of rheumatologic drugs and adjusting their dosage accordingly to drive better outcomes. These findings raise interesting questions about a potential need for a shift in rheumatology and PsA practice from following clinical parameters and responding to them toward more therapeutic drug monitoring.
  • In a phase 2b, randomized controlled trial, brepocitinib, a unique JAK and TYK2 inhibitor, was found to have superior efficacy compared with placebo in improvements to joints, enthesitis, dactylitis, and skin disease. This research is planned to proceed into phase 3 trials with the ultimate goal of having brepocitinib approved as a treatment for PsA.
  • Guselkumab, an IL-23p19 inhibitor, featured prominently at ACR Convergence 2021. A phase 3 trial looking at its effectiveness in patients with PsA who present with axial or spine disease shows that the drug is effective in relieving their symptoms. The larger STAR trial to assess the effectiveness of guselkumab in the axial PsA domain is set to provide more insight into how the drug works in patients with PsA.
  • Great efforts are being made to capture the patient experience in PsA, which has revealed a phenomenon known as “accommodation to symptoms.” This occurs when a patient accepts certain symptoms as part of their disease, and then records those symptoms as less severe than they really are. This phenomenon requires further research to ensure that PROs and treatment outcomes are being measured effectively.

This Q&A was edited for clarity and length.

References

  1. Syversen SW, Goll GL, Jørgensen KK, et al. Therapeutic drug monitoring compared to standard infliximab therapy in patients with immune-mediated inflammatory diseases: a randomized controlled trial (abstract 1946). Arthritis Rheumatol. 2021;73(suppl 10).
  2. Mease P, Helliwell P, Silwinska-Stanczyk P, et al. Efficacy and safety of brepocitinib (tyrosine kinase 2/Janus kinase 1 Inhibitor) for the treatment of active psoriatic arthritis: results from a phase 2b randomized controlled trial (abstract 0488). Arthritis Rheumatol. 2021;73(suppl 10).
  3. Sun D, Allaway R, Wang J, et al. A crowdsourcing approach to develop machine learning models to quantify radiographic joint damage in rheumatoid arthritis (abstract 0168). Arthritis Rheumatol. 2021;73(suppl 10).
  4. Jackson L, Annapureddy N, Saag K, et al. Development, refinement, and validation of an emergency department gout flare electronic medical record alert (abstract 0676). Arthritis Rheumatol. 2021;73(suppl 10).
  5. Mease P, Deodhar A, McInnes I, et al. Bimekizumab in patients with psoriatic arthritis: 3-year results for overall and tumor necrosis factor inhibitor (TNFi)-naïve populations from a phase 2b open-label extension study (abstract 1338). Arthritis Rheumatol. 2021;73(suppl 10).
  6. Behrens F, Mease P, Helliwell PS, et al. Efficacy of guselkumab across BASDAI components in treating axial-related symptoms of psoriatic arthritis: results from two phase 3, randomized, placebo-controlled studies (abstract 1811). Arthritis Rheumatol. 2021;73(suppl 10).
  7. Mease P, Furst D, Siegel E, et al. “What matters”: patient and clinician perspectives in psoriatic arthritis care (abstract 1165). Arthritis Rheumatol. 2021;73(suppl 10).
  8. Gossec L, de Wit M, Kiltz U, et al. A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the PsAID questionnaire, a 13-country EULAR initiative. 2014;73(6):1012-1019. doi:10.1136/annrheumdis-2014-205207
  9. Schwartzman M, Abutalib Z, Mandl L. Current medication practices and preferences among patients with psoriatic arthritis (PsA) (abstract 1810). Arthritis Rheumatol. 2021;73(suppl 10).
  10. Singh JA, Guyatt G, Ogdie A, et al. 2018 ACR/National Psoriasis Foundation guidelines for the treatment of psoriatic arthritis. Arthritis Rheumatol. 2019;71(1):5-32. doi:10.1002/art.40726

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Reviewed December 2021