Read the most up-to-date information about the latest developments in psoriatic arthritis

Clinical Updates in Psoriatic Arthritis

The impact of psoriatic arthritis on patients’ quality of life and importance of an early, accurate diagnosis.

Expert Perspective on the Management of Psoriatic Arthritis

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Learn more about the latest developments in rheumatoid arthritis

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Lana Dykes is the Editor of Rheumatology Network. She is an experienced editor and technical writer with a demonstrated history of working in the banking and publishing industries. She enjoys cooking, yoga, and drawing. 

Rheumatology Network's Top 5: November 26, 2021

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Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending November 26, 2021.


Rheumatology Network interviewed Ana-Maria Orbai, MD, FACR, MHS, on her study entitled, “Guselkumab-Treated Patients with Psoriatic Arthritis Achieved Clinically Meaningful Improvements in General Health Outcomes Measured with PROMIS-29 Through 52 Weeks: Results from the Phase 3 DISCOVER-1 Trial.” Orbai is Assistant Professor of Medicine in the Division of Rheumatology at the Johns Hopkins University School of Medicine, and founding director of the Psoriatic Arthritis Program.

Can you tell me a bit about the DISCOVER-1 study design and the methods your team use to determine guselkumab efficacy in patients with psoriatic arthritis?

DISCOVER-1 was a randomized control trial, comparing guselkumab with placebo. Guselkumab is a selective interleukin 23 inhibitor, which is FDA-approved for psoriasis and psoriatic arthritis based on its efficacy. In this phase 3 trial, the primary outcome is American College of Rheumatology (ACR) 20, which is quite standard for psoriatic arthritis clinical trials. But there were also psoriatic arthritis specific outcomes like the minimal disease activity, for example, in psoriatic arthritis, and health-related quality of life outcomes. And the subject of our discussion today is the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 profile, which was also collected to gain additional information on the effect of guselkumab on health-related quality of life, instead of using the traditional measures you are accustomed to, like the 36-Item Short Form Survey (SF-36) and the health assessment questionnaire disability index (HAQ-DI) physical function measure. So, it's a step forward in trying to assess efficacy with newer measures such as the PROMIS profile.

Why did you use the PROMIS-29 instruments in your analysis as opposed to other options?

PROMIS-29 is a generic health instrument. It has several advantages over older measures. And for this reason, it's easy to interpret on the PROMIS scale. A score of 50 is the general population mean. So, if someone has a score of 50 for physical function, this means that they are at the average level in the United States. So then, if we look at scores in patients with a certain disease, or we want to see the effect of a treatment, we are able to see the scores around this 50 and how they are doing relative to the population mean. And the movement with treatment is easy to interpret as opposed to just having a dry score like we are used to with the other measures. Also, because it is a generic health instrument, we can compare the health-related quality of life and the health and function of people with psoriatic disease with other rheumatic diseases with the general population. It allows some generalizability and seeing data across diseases. Another advantage is that PROMIS-29 was generated from a database of questions that are used to assess each individual domain. And these questions were generated from interviews with patients and questions were tested to make sure they didn't perform differently for reasons other than what they are intended to measure. For example, if a question is not built with these considerations, with these scientific considerations in mind, you could easily pick an item that may perform differently in men and versus women just because of how the question is phrased or because of different concepts. So, it's a source of bias if you're not asking the question properly. These questions were tested in the general population to get rid of items or questions that would perform differently in special groups, for example, by sex or by age, and only the questions that were suitable from this perspective were selected to remain in the in the database assessing each of these domains. There is also another way of administering PROMIS instruments, for example, they can be administered as a computer adaptive test, where respondents would get the first question and then, depending on their response, they will get a subsequent question with various difficulty levels so that we can get a really precise score with a PROMIS-29 profile. It's the most simple form of these PROMIS instruments. And still, it performed very well in this clinical trial. It also takes care of concerns that, for example, with a computer adaptive test, you would get different questions every time depending on the patient's response, although that's not necessarily bad. But with the PROMIS-29, all participants got exactly the same questions for questions for each of these domains every time, so it’s identical between participants and identical when they receive the questionnaire the second and the third time.

The first finding in the study was that people with psoriatic arthritis has significantly worse scores than the general population on most PROMIS-29 domains, but particularly in physical function, social participation, fatigue, sleep quality, and a bit worse for depression and anxiety. Treatment with guselkumab versus placebo led to significant improvements in these domains. The primary outcome was at 24 weeks, so there was a statistically significant effect favoring guselkumab. So guselkumab can help patients improve their health-related quality of life scores by a third and a half of a standard deviation, which are considered to be clinically significant improvements. More so, our abstract looks at 52 weeks data. These improvements last throughout 1 year, where these outcomes were measured. So, significant improvement, clinically significant improvements, and these lasted through 52 weeks through 1 year after people started treatment.

And what is the clinical significance of these results?

We already know that from the primary outcomes of the clinical trials that guselkumab improves the manifestations of psoriatic arthritis and that it does so across the spectrum of the disease, including skin, joint disease activity, arthritis enthesitis dactylitis, as well as patient-reported outcomes like pain. It is always useful to show that not only disease outcomes are improved, but that the patient's symptoms and health-related quality of life is improved. If you're making my psoriatic arthritis better, I also expect that my fatigue, physical function, and pain will improve. And this is what has now been demonstrated with a PROMIS-29 profile. I should mention that it was also demonstrated with the SF-36 and with HAQ-DI. And we see that that we can triangulate that the effect of guselkumab can also be seen with this measure with significant improvements in fatigue, physical function participation, pain, interference, and so on.

I'll tell you what this means for me for my clinic. So in in the Johns Hopkins psoriatic program, as well as in many other clinics across the United States, PROMIS-29 measures are collected not only as a part of research studies, but as well as clinical care, at least in our case. So, patients come to clinic, and they complete PROMIS questionnaires before each visit. We are not only able to see the disease activity that we measure during routine care using the joint counts, the enthesitis counts, the skin assessment, and other clinical assessments, but now we also have the patient's perspective, using the PROMIS measures. And knowing that this treatment improves the patient-reported measure as well is very useful. We also have a timeline on when we should expect some of these improvements. We know that as early as week 4, pain, physical function, and all of these outcomes start to improve and then there's buildup across as people stay on treatment longer. So I think it's helpful that patients can tell us if they improve and we can use this course to track early responses to treatment, which are always encouraging and are good motivation to stay to stay on treatment because our treatments can take longer, sometimes weeks or months, to work. It's very useful to have a measure that can tell early on that this is doing something because we're going to continue to see improvement.

Ana-Maria Orbai, MD, FACR, MHS, explains how guselkumab improved PROMIS-29 scores in patients with psoriatic arthritis. 

Ana-Maria Orbai, MD, FACR, MHS: Guselkumab Improves PROMIS-29 Scores in Patients With Psoriatic Arthritis

Soumya Chakravarty, MD, PhD, discusses the unmet patient needs in immune-mediated diseases as well as Janssen’s work in scientific innovation that allows patients to live their lives more unburdened by their disease. Chakravarty is the Sr Director and Strategic Lead in the Rheumatology Therapeutics area at Janssen.

Why do you believe fewer than 10% of patients achieved sustained clinical remission?

 The ultimate goal of all of our diseases that we have in rheumatology, such as rheumatoid arthritis or psoriatic arthritis, is trying to achieve sustained clinical remission. So being able to live without symptoms, and, as you just noted, few patients are currently, with these most common kinds of diseases, achieving that. So why is that? There are a number of factors that underpin these low numbers. First of all, this is a journey for a lot of patients living with rheumatic diseases, in terms of long treatment times, living further years with their disease before actually getting an accurate diagnosis, as well as the appropriate treatment. Secondly, there's also the issue that once the patient actually receives an accurate diagnosis, that can actually take a little bit more time before an appropriate therapy is initiated. And even with the initiation of therapy, in terms of that prescription being written, there may be additional steps with respect to the fulfillment process. This can be lengthy and complicated. There's a journey here for patients as they try to navigate this system before starting on therapy. So, at the end of the day, I think it's very important for us as Janssen to be able to understand, appreciate these factors, and then be able to move forward with addressing them. And so, our ultimate goal here at Janssen, is for those patients to be able to change sustained clinical remission. And the way to really do that is to invest in research. And our R&D pipeline reflects that in terms of our next era of treatments. But it's not only the research; it's not only having a very robust pipeline and working with our R&D colleagues, but it's also innovating and collaborating with all of the different external stakeholders that are out there, be it advocacy groups, academia, private practices, or governmental organizations to be able to ensure that all of those connections that we've talked about along the journey for these patients are being made. And that there's obviously a commitment to ensuring that patients are getting the therapy that they need at the right time. And that treatment choice and shared decision making is being implemented across the board. So hopefully, that gives a little bit of an overview of where we think, at Janssen, we're going on this question of trying to attain remission for our patients.

What are some of the unmet needs and immune mediated diseases?

There’s a tremendous amount of unmet need for patients with rheumatic diseases, despite all of the advances that we've had right in terms of all of the therapies, such as biologics, targets, synthetic disease-modifying antirheumatic drugs (DMARDs), etc, partly to delay in diagnosis and treatment. So that's just what we touched upon as one of the reasons why many of our patients are still not achieving clinical remission. And I think the challenge here is that these diseases that we encounter are chronic illnesses. These are conditions that patients have to live with, have to manage, and have to navigate this journey for many, many years. So that means it can be very debilitating. There can be a lot of challenges with respect to pain and fatigue that come with moderate-to-severe disease that the patients are suffering from. Of course, there's a disruption in quality of life a potentially increased use healthcare resources, and increased cost. And I think the other issue that we have to acknowledge and address is that patients with rheumatic diseases can wax and wane in terms of their disease course. So, not only is it a very long journey that these patients have to experience, but that they can have periods of time when their symptoms flare. That can manifest itself as swollen tender joints, more stiffness, etc. And if their disease is not effectively managed, an issue we have to all be cognizant of is that there could be these recurring painful relapses. This sums up where the unmet needs and some of the challenges remain.

Podcasts

Soumya Chakravarty, MD, PhD, discusses the unmet patient needs in immune-mediated diseases and Janssen’s role in scientific innovation that allows patients to live their lives unburdened by disease. 

Overdrive Podcast: Unmet Patient Needs in Rheumatic Disease

Rheumatology Network interviewed Mithu Maheswaranathan, MD, on his ACR presentation, “Association of Limited Health Literacy with Clinical and Patient-Reported Outcomes in Systemic Lupus Erythematosus: An Analysis from the Peer Approaches to Lupus Self-Management (PALS) Program.” Maheswaranathan is a Rheumatology Fellow at Duke University.

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Can you tell me a bit about health literacy and why it's so crucial for patients with rheumatic disease?

 Health literacy is an important social determinant of health. And it's defined as the capacity for individuals to obtain, process, communicate, and understand basic health information needed to make decisions about their health. For example, adequate health literacy is needed to complete tasks like reading and comprehending prescription dosages, understanding health materials or doctor instructions, navigating the insurance and health systems, and managing medications. In rheumatology, our diseases are inherently complex, many with multi-system organ manifestations and difficult to manage medication regimens. And health literacy is crucial for patients with rheumatic disease. For instance, it can impact someone's ability to draw the correct amount of medication for subcutaneous methotrexate injection, understand the consequences of non-adherence, such as potential dialysis in uncontrolled lupus nephritis, and managing medication regimens where we're often up titrating immunosuppressants while simultaneously tapering high dose steroids at disease onset. Low health literacy is associated with worse clinical outcomes, like increased hospitalizations, higher readmission rates, greater use of emergency care, and lower medication adherence. In chronic diseases, it's an important element to address to ultimately hopefully help improve health outcomes.

What was the study design and the methods your team used to determine the association of health literacy with clinical and patient-reported outcomes?

This study used observational and cross-sectional data obtained as part of the Peer Approaches to Lupus Self-Management, or PALS, study, which was an NIH-funded randomized control trial evaluating a peer mentorship program for African American women with lupus. And the trial examined whether this peer mentoring intervention could improve disease, self-management of disease activity, and health-related quality of life in Black women with lupus. As part of enrollment into this study and ongoing follow up, participants completed various health assessments, including health literacy. We were interested to evaluate the associations with limited health literacy in this population. We used some descriptive statistics and other statistical analyses to basically compare the association of limited health literacy with these various clinical factors, including some patient-reported outcomes, and then specifically disease activity as well as damage for some of the other clinical outcomes.

We found patients with limited health literacy had worse patient-reported outcomes as well as clinical outcomes across multiple domains, including lower self-efficacy and worse patient activation, increased rates of depression and anxiety, as well as higher disease activity and lupus damage compared with those that had adequate health literacy.

We knew from some previous work that lupus patients with limited health literacy have worse patient-reported outcomes. However, this study allowed greater insight into what some of the specific factors are that are impacted by limited health literacy. We were surprised at which areas seem to be impacting our patients with limited health literacy related to disease understanding. For example, there were not statistically significant differences between the limited health literacy versus adequate health literacy group for questions on the patient activation measure (PAM) that were related to knowing what prescribed medications do and have confidence to tell their doctor their concerns. However, what was striking was on the problems related to physician patient communication reported in the patient centered care survey. In that survey, those with limited health literacy were more likely to report difficulty in getting answers to their questions that were understandable, having their physician take enough time to answer their questions, and getting as much medical information as they wanted from their physician compared to those without adequate health literacy. These results highlighted a need for rheumatologists to be better informed about ways that we communicate with our patients. Using language that they can understand and spending time to address their questions may be an important element in in terms of things that we can do to improve health literacy.

Were there any strengths or limitations of the study that you would like to highlight?

Our study did include a large cohort of Black women living with lupus and offered insight into this unique patient population with respect to health literacy, a topic that's been under-studied in lupus compared to other chronic diseases. Because various measures were obtained at baseline enrollment and followed up into the PAL study, we were able to analyze the association of many clinical factors with limited health literacy that have not yet been explored in that kind of causal pathway between health literacy and adverse health outcomes. one limitation was that the patient's all self-identified as Black race. So, we don't know whether these results would be generalizable to other groups and patient populations.

Is there anything else that you would like our audience to know before we wrap up?

I do want to thank Dr Edith Williams, who was the PI on the PAL study for the collaboration. And if anyone has any questions, feel free to reach out to me on Twitter @MithuRheum.

Mithu Maheswaranathan, MD, discusses the association of health literacy in terms of both clinical and self-reported outcomes for patients with systemic lupus erythematosus.

Mithu Maheswaranathan, MD: Impact of Health Literacy in Clinical and Patient-Reported Outcomes in SLE

Rheumatology Network interviewed Robert Terkeltaub, MD, to discuss his ACR presentation, “Phase 2 Study Results from a Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate Efficacy and Safety of Tigulixostat, a Novel Non-purine Selective Xanthine Oxidase Inhibitor, in Gout Patients with Hyperuricemia.” Terkeltaub is Professor of Medicine at the University of California, San Diego and Chief of Rheumatology at the VA Medical Center in San Diego.

What initially sparked your interest in addressing the efficacy and safety of tigulixostat in gout patients?

Well, this is a pharma-done study. I'm an advisor, as is Dr Kenneth Saag, to the program. In terms of my interest in advising, I think it's pretty clear when we treat gout patients that we could benefit from having more urate-lowering options in our toolkit. Allopurinol has a fair number of safety issues and dosing limitation issues, especially related to genetics, ethnic, and racial factors in terms of hypersensitivity, as well as issues in terms of some allopurinol resistance described in certain patient populations including Mexican Americans, and South and East Asians, who have a particularly high frequency of a gene variant that is involved in handling allopurinol oxipurinol. We also have issues in dosing allopurinol in patients with more advanced forms of chronic kidney disease. The dosing in the United States is limited compared to the worldwide dosing and so we're often stuck, as clinicians, in terms of having options for primary uric acid lowering that work in specific subsets of patients. We would benefit from other uric acid lowering options. Xanthine oxidase inhibition is the primary targeted route for lowering serum urate. I'm really enthusiastic about new xanthine oxidase inhibitor strategies where we have potent, effective, and safe agents.

Can you tell me a bit about the study design your team developed?

This was a randomized, multicenter, double-blinded, placebo-controlled phase 2 study. It took place in the United States because United States gout patients are different than gout patients outside of the country. There was also a very small active comparator group. But the primary purpose here was to explore the doses that are safe and effective and then to pursue more advanced drug development strategies.

 And what were the results of this study?

There were 3 doses of tigulixostat: 50, 100, and 200 milligrams received once daily and comparisons were relative to placebo. There really wasn't much difference between the 50 and 100 milligram dose, but the 200 milligram dose was substantially more potent. But basically, you're looking at the proportion of subjects who achieved serum urate target. The proportion of subjects who achieved a serum urate of less than 5 milligrams per deciliter was the primary endpoint. This is a more potent and effective target for limiting uric crystal deposits and promoting the resolution of uric crystal deposits. So, the fact that we were looking at a target level of less than 5 milligrams per deciliter was a significant feature of the study.

A secondary endpoint was the more conventional study endpoint of a serum urate target of less than 6 milligrams per deciliter. Typically, with allopurinol use in clinical trial settings, in terms of getting people below 6 milligrams per deciliter, you're talking about 30% to 40%. Here at Week 12 we had between 44% and 47% of people on the lower doses reaching that endpoint of less than 5 milligrams per deciliter. At 200 milligrams a day, 62.2% achieved this goal. And then when you looked at the secondary endpoint, the more conventional endpoint, and one where allopurinol will typically get somewhere between 30% and 40% of people to serum urate target, 50 and 100 milligrams per day got about 60% of people to that particular conventional serum urate target and a whopping 78.4% with 200 milligrams per day. Placebo was negligible at about 3%.

This is very potent, urate-lowering agent. The advantage of a serum urate target of less than 5 is that that's the bare minimum target that we use for people with palpable tophi, which is about 15% to 20% of patients.

Were you surprised by the results of this study?

I was pleased by the results of the study. But I mean, there was background experience that argued for this particular study design and that we would see results that look like this. Importantly, this is the first study in the United so, you really don't know until you try it in that particular population. And gout patient populations are different in Japan and Korea and China from the way they are in the United States, for example. I'm pleased to see that this drug was so effective and then that there were no particular safety signals.

Is there anything else you would like our audience to know about the study or gout before we wrap up?

This is one of a multitude of agents that are now being developed. And I think that the approaches to treating gout are going to benefit from not only monotherapies like this, but also potentially combining approaches to tackle how uric acid is handled in the kidneys and how uric acid is handled in the gut. We're improving the ways that we have of cleaning out urate in the vasculature for the most severely ill patients with gout by tuning immune suppression to recombinant urate therapy. So, it's a pretty exciting era to be working on advancing the effectiveness of care in this disease. This is an example of some of the drug development that's going on that looks very promising.

Robert Terkeltaub, MD, explains the results from a phase 2, dose-finding study to determine the safety and efficacy of tigulixostat in patients with gout. 

Robert Terkeltaub, MD: Safety and Efficacy of Tigulixostat in Gout Treatment 

Ingrid Torjesen is a UK-based freelance health journalist with more than 30 years of experience in health and medical communications. She works for numerous publications including Rheumatology Network, the BMJ and the Economist’s Intelligence Unit. Before her freelance career, her staff jobs included news editor of both Pulse and GP (the two leading UK weekly titles for primary care doctors), and opinion and features editor of the Health Service Journal (the UK’s leading health policy title). She also spent a few years working in Australia, including on Australian Doctor.

Janus kinase (JAK) inhibitors are the newest class of drugs used to treat rheumatoid arthritis. How much do you know about these drugs? Test your knowledge with this quiz.

Rheumatoid Arthritis Quiz: JAK Inhibitors

Rheumatology Network interviewed Courtney Wells, PhD, MPH, MSW, to discuss her ACR study entitled: “Impact of the COVID-19 Pandemic on the Quality of Life of Patients with Rheumatic Conditions: A Qualitative Analysis of Perceived Risk and Decision Making.” Wells is a medical advisor to CreakyJoints, an Assistant Professor at the University of Wisconsin – River Falls, sits on the Minnesota Arthritis Foundation Leadership Board, and serves as the Mental Health Director for the largest arthritis camp in the US. We discuss her initial interest in patient-reported outcomes for a generally underrepresented patient population, the study’s key findings, and strengths of her research.

What first sparked your interest in quality of life during the pandemic for generally underrepresented patients with rheumatic disease?

When we started designing this study, Kristine Carandang, PhD, and several other authors who are also working on the project, were always interested in patient perspectives. That's the work that we do; patient engagement in particular. We have several authors on this project who are patients themselves. And Kristine and I are also both patients who have rheumatic diseases. So, for us, that's square one. We start with the patient perspective and then as we watched the data that was coming out and people's experiences. We realized that there were some pretty significant disparities that were happening. We knew that those disparities exist anyway, but they were becoming clearer and clearer as the data was coming out. We decided that we were going to try to make that a focus of the paper. Certainly, that's not the whole project and we asked about a lot of other things. But that became an integral part of how we recruited for our participants, as well as the questions that we asked.

What were the key findings of your study?

The overall finding by far was that people are struggling not just emotionally during the pandemic but socially [as well]. Their rheumatic diseases were potentially being affected by the stress level that they were experiencing. For some people it was that they had a preexisting mental health condition and that was exacerbated by the stress of the pandemic and then that may be exacerbating their physical health. For other people, they had never had a mental health condition before, and they were either newly diagnosed or they were just really overwhelmed. Maybe they didn't have a mental illness, but they just felt like they were having a hard time coping and they had new symptoms that they didn't really know what they were or how to handle them. But everybody we talked to said that they were pretty overwhelmed. They were struggling to manage their mental health and that that was impacting their physical health, in most cases. Not everybody saw that, but a lot of people said that. And also, one of the things that we found really interesting was that it seemed to be that people's perception of their risk, how at risk they were for developing symptoms of COVID-19, or getting sick, or even dying from COVID impacted their ability to function, their emotions, the decisions that they made around how to cope, and what they were going to do in their day-to-day life.

Is there anything else that you would like our audience to know, before we wrap up?

The other message that we want to send out is that people were generally pretty frustrated with their healthcare. Yes, there were some providers who were great. And they transitioned fine onto telehealth and they were able to do that. But a lot of people didn't have that. They had providers who were saying [they were not] going to see patients for months at a time or people who said that they had to come into the clinic [at a time when] people didn't feel comfortable coming into the clinic. Or there were people who just felt really frustrated with our public health system and how vaccines were being allocated and that people with autoimmune and rheumatic diseases were not being prioritized. We heard a lot of information about all levels of healthcare and that people had a lot of frustrations.

Videos

Courtney Wells, PhD, MPH, MSW, discusses the impact of the pandemic on the quality of life of patients with rheumatic conditions, with an emphasis on perceived risk and decision making. 

Courtney Wells, PhD, MPH, MSW: Impact of COVID-19 on the Quality of Life of Patients with Rheumatic Disease

Rheumatology Network interviewed Robert F Spiera, MD, To discuss his ACR presentation entitled, ”Background Mycophenolate (MMF) Treatment Is Associated with Improved Outcomes in a Phase 3 Trial of Lenabasum in Diffuse Cutaneous Systemic Sclerosis (dcSSc).” Spiera is the Director of the Vasculitis and Scleroderma/Vasculitis Program at the Hospital for Special Surgery and Professor of Clinical Medicine at Weill Cornell Medical College. He explains more about mycophenolate, the study design, and the clinical significance of these results.

Can you give me a little bit of background on mycophenolate?

So mycophenolate is an immunosuppressive drug that we've been using in rheumatology for a long time and actually often using it off label. It was originally a drug that was of interest to the transplant world. But now, probably going back about 20 years, it emerged as a really important drug in the treatment of lupus nephritis. And it’s widely used in that context. In the past decade, it's been used more and more in systemic sclerosis scleroderma. Much of that experience has been based on descriptive series of retrospective experiences looking at how patients fared on mycophenolate. There's very little in the way of prospective trial experience with mycophenolate and really no double-blinded, randomized, placebo-controlled trials specifically looking at the efficacy of mycophenolate in scleroderma. Some of the organized experience we have with it, though, does come from clinical trials. So 1 trial was an interstitial lung disease trial, called scleroderma lung study, to where cyclophosphamide was compared to mycophenolate in the treatment of scleroderma-associated interstitial lung disease, with the thought being that mycophenolate is a safer alternative of cyclophosphamide. And in that double-blinded, randomized, controlled trial, patients treated with mycophenolate did as well as patients treated with cyclophosphamide. So it wasn't showing superiority, but it showed non-inferiority with what we thought was the safer medicine. The second robust clinical trial experienced with mycophenolate was in a trial that wasn't specifically designed to look at mycophenolate, but it was in the census trial that showed to be an effective therapy and preventing progression of scleroderma-associated interstitial lung disease. But in that trial, at the discretion of the investigators, patients were allowed to be on background mycophenolate or be on no background therapy, and then would get either [the medication] or placebo. And when they analyzed how patients did in the context of that trial, who were not on mycophenolate, some people were on mycophenolate and some on placebo, it was recognized that patients that had mycophenolate had less decline in their lung function than patients who were not on mycophenolate. So those were some of the background studies that led this to being a drug that's been interested in the treatment of systemic sclerosis, and actually really widely used by clinicians in many parts of the world.

 Does your team plan on doing any further research on this topic?

We have a lot of analyses to do, both of this data and other data embedded in this very robust 365-patient trial. Whether there's any further development of, lenabasum, specifically, is really unclear treatment and did not reach its primary endpoint in this trial. On the other hand, there were some benefits seen, if you did certain post hoc analyses in which for example, patients were on their background immunosuppressive therapies for more than 2 years of the point that when lenabasum was added to their therapy, there seemed to be an advantage. Patients who were on no background immunosuppressive therapy, and then received lenabasum, seemed to do better than patients on no background immunosuppressive therapy that received placebo. But I really don't know whether further development of that will happen. I think that a lot will be learned from this database about the treatment of systemic sclerosis and its various manifestations in general.

Robert F Spiera, MD, explains background mycophenolate treatment and its associated improved outcomes in patients with systemic sclerosis receiving lenabasum. 

Robert F. Spiera, MD: Mycophenolate Treatment Is Associated with Improved Outcomes in Trial of Lenabasum in Patients With Systemic Sclerosis 

Rheumatology Network's Top 5: November 19, 2021

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending November 19, 2021.


Rheumatology Network spoke with Kelly Gavigan, MPH, to discuss her upcoming ACR presentation entitled, “Changes in Patient-Reported Outcome (PRO) Scores During the COVID-19 Pandemic: Data from the ArthritisPower Research Registry.” Kelly is the manager of research and data science at Global Healthy Living Foundation and works on patient-centered research through Global Healthy Living Foundation’s online patient research registry called ArthritisPower. She discusses the importance of patient wellness and wellbeing throughout the pandemic, the key findings of the study, and the clinical significance of these results.

What first sparked your team's interest in determining patient-reported outcomes during the pandemic?

We knew pretty early on in the COVID-19 pandemic that patients with autoimmune and rheumatic disease are at an increased risk of infection for COVID-19. And since many patients as a result followed strict social distancing protocols, this created a heightened sense of isolation. And so, we wanted to better understand whether the patient-reported outcomes scores for mental, social, and physical health fluctuated throughout the COVID 19 pandemic as the result of this.

What study design did your team utilize to determine changes in this patient population?

We tested the null hypothesis that there was no change in the monthly average Patient-Reported Outcomes Measurement Information System (PROMIS) scores across the 15-month observation period, which was January 2020 to April 2021. We did an assessment of the analysis of the mean. We had the mean score for each assessment throughout the 15-month period. And then we looked at each month during the 15-month period to see if during that month, the mean score was significantly different, either better or worse, compared to the overall mean score for that assessment.

So, we ended up looking at outcomes or assessment results from over 2200 participants, and each participant contributed an average of 4.5 observations. And we found that the scores for anger and anxiety were 1 standard deviation higher than the overall study period mean and the depression scores were 1/2 standard deviation worse than the overall study period mean for the months of May and June in 2020. And similarly, social isolation scores were highest in June and the emotional support scores worsened in December of 2020. We also looked at the physical health scores throughout this time period and found that the physical health assessment scores did not meaningfully vary from the overall mean throughout the observation period. So, it was really the mental health in the anger, anxiety, and depression scores, and social health in the social isolation and emotional support scores that did significantly vary during this period.

Were you surprised by the results of the study?

It was clear that mental health and social health fluctuated during the 15 months that we observed and I wouldn't say that was entirely surprising, especially when looking at how significantly anger, anxiety, depression, and social isolation increased in the month of May and June. Just considering what was going on in the country during that time that kind of corresponds with the first wave of the pandemic. And also, a point when, especially in June, when there was this realization that the pandemic was not going away very easily or very quickly. So, it's very understandable to see anger, anxiety, depression, social isolation all increased during that time and throughout the 15-month observation period. We were certainly surprised that the scores for physical health, the physical health assessments, didn't meaningfully vary during the time. However, it was definitely reassuring to us that the participants disease wasn't worsening during this period on top of everything else going on.

What is the clinical significance of these results?

I think that it's very important that the mental health concerns and the social support of rheumatic disease patients gets attention by their providers and by their caregivers during this time. And I think that that's not something that can be set aside or overlooked, especially considering that participants physical health, during at least the observation period that we studied, didn't seem to fluctuate very much. It's easy to think that patients are doing just fine. But it's very clear from the results of this study that their mental health and their social wellbeing took a toll.

Kelly Gavigan, MPH, discusses the changes in patient-reported outcome scores during the COVID-19 pandemic. 

Kelly Gavigan, MPH: Patient-Reported Outcome Scores During the COVID-19 Pandemic

Rheumatology Network interviewed Eric Morand, MD, about his ACR presentation entitled, “Attainment of the Lupus Low Disease Activity State in Response to Anifrolumab in 2 Phase 3 Trials.” Morand is Professor of Medicine at Monash University and Head of Rheumatology at Monash Health.

Why is the lupus low disease activity state (LDAS) a treat-to-target endpoint for patients with lupus?

So, prior to 5 years ago, there were no validated treat-to-target endpoints for lupus, unlike in rheumatoid arthritis, psoriatic arthritis, etc, where treat-to-target has become standard of care. There was no way to make that standard of care in lupus until you first devised endpoints to treat towards. So, low disease activity is a good target. Although of course, remission is the ideal target. Remission attainment in lupus is extremely rare. So, the group of us who devised lupus low disease activity state set out to devise an endpoint which would be associated with protection from long-term outcomes. And that's been shown to be the case in multiple retrospective cohort studies, but also in a prospective validation study. Attainment of low disease activity states is protected from flare, protected from damage accrual, protective of health-related quality of life. And in a separate abstract at this ACR meeting, we'll also show it's protected from mortality. So, it's a highly validated treat to target endpoint state for lupus.

Can you tell me a bit about the TULIP-1 and TULIP-2 study designs?

 So both studies were 52-week studies done globally, in multiple countries with multiple ancestral backgrounds of patients with moderate-to-severe active lupus that were randomized to receive either placebo or anifrolumab in addition to standard care. Patients who entered the study had to have active disease. The 2 studies were identical apart from 2 differences: firstly, in TULIP-1, there were 2 doses of anifrolumab 300 milligram per month and 150 milligram per month, whereas in TULIP-2, there was only 300 milligrams a month. And also, they had different primary outcome measures. And both trials had multiple hits on goal with significant differences between anifrolumab and placebo, though into TULIP-1, the primary outcomes were not significantly different between anifrolumab and placebo. But the totality of evidence illustrates that anifrolumab is effective in the treatment of active lupus.

What were the the clinical significance of these results?

In the TUPLIP-2 abstract, we took the endpoint and applied it to the pooled TULIP-1 and TULIP-2 datasets to evaluate LDAS as a clinical trial endpoint per se, and, secondly, to evaluate whether any follow up treatment resulted in higher attainment of low disease activity state. The findings were firstly that LDAS payment was observed. And that fits with our hypothesis of low disease activity being a stringent endpoint and that analysis was done regardless of therapy. Then we split the patients into anifrolumab-treated and placebo-treated and found highly significant difference in LDAS attainment for anifrolumab-treated patients compared to placebo. So, basically we found that anifrolumab was more likely to put patients into LDAS than placebo. The significance of this is that LDAS has been shown to be protected from damage of, health-related quality of life reduction, and death. And these data show that anifrolumab puts more patients into that favorable treat-to-target state.

Does your team plan on doing any further research on this topic?

Yes, we would like to analyze these data for proportion of patients attaining remission. We'd also like to see the LDAS endpoint tested in other clinical trial cohorts that's already been done retrospectively in a few examples. But we'd like to see it adopted as a standard outcome measure for lupus clinical trials.

Eric Morand, MD, discusses “Attainment of the Lupus Low Disease Activity State in Response to Anifrolumab in 2 Phase 3 Trials.”

Eric Morand, MD: Lupus Low Disease Activity State in Response to Anifrolumab

Kim A. Gorgens, PhD, ABPP, is a full-time Professor in the Graduate School of Professional Psychology at the University of Denver. She teaches Psychophysiology, Clinical Neuropsychology, and Psychology of Criminal Behavior. She completed a postdoctoral fellowship in Clinical Neuropsychology and is board certified in Rehabilitation Psychology. She is a fellow of the American Psychological Association's Division 22, Rehabilitation Psychology.

Maddy Pontius is a Master’s Student in Forensic Psychology at the University of Denver with interests in rehabilitation psychology, health psychology, and neuropsychology. She is hoping to work within the overlap of offender rehabilitation and healthcare in the future.

As common as stress and burnout are in healthcare, the reluctance to access mental health treatment is equally ubiquitous. A recent study surveyed more than 12,000 physicians across over 29 specialties found that 47% of physicians report that burnout and depression have had a significant impact on their lives.

 Of the physicians who endorsed symptoms of burnout and depression, 36% of them reported that they get easily frustrated with patients and 15% reported making mistakes they would not normally make. The relationship between depression and medical errors is bidirectional, meaning depressive symptoms may lead to more medical errors in practice and medical errors may lead to the development of or worsened depressive symptoms. In other words, physician well-being is critical to patient care.

Polling data suggest that half of female physicians believe they meet the criteria for a diagnosis of a mental illness and 38% of male physicians report feelings of burnout and depression.

 Sixty six percent of professionals never received mental health treatment, largely due to concerns relating to stigma and repercussions from licensing boards.

 An analysis of 52 medical licensing boards reported that 90% of state medical boards have licensing forms that include questions about mental health.

 Though these questions are intended to keep patients and physicians safe, they result in physicians subverting their mental health concerns. Physicians hold themselves to high standards, meaning mental health issues are often perceived as weaknesses. On licensing board applications, mental health issues may receive greater scrutiny than physical health issues or other conditions. That creates legitimate concern that disclosure may impact the ability to practice medicine or damage professional reputation.

With the ongoing impact of the COVID-19 pandemic, it is more important than ever for physicians to have access to quality, non-stigmatized mental health care. There are programs that specialize in addressing stress and burnout in the medical field and they are skilled at addressing this stigma in the context of professional identity and licensure concerns. The 

 have searchable databases of confidential mental health service providers. If you need immediate help, you can call the 

While psychotherapy is an effective way to address burnout, there are important institutional changes that can be implemented to reduce workplace stress. For example, healthcare organizations can set realistic expectations for physicians regarding patient load, working hours, boundaries, and managerial support. Healthcare organizations can also provide a safe, non-punitive space for physicians to recognize and discuss mental health needs in medicine to normalize stress and burnout in physicians. Individually, there are tools you can use to prioritize self-care and fight fatigue by taking breaks when necessary, finding healthier ways to cope with stress, and leaning on your colleagues for support. Mental wellness for physicians is a complex issue comprised of individual and systemic components that reflects your commitment to your own health and the highest standard of care for your patients.

Medscape. (2021). Death by 1,000 Cuts: Medscape National Physician Burnout and Suicide Report 2021. Retrieved from 

https://www.medscape.com/slideshow/2021-lifestyle-burnout-6013456

Medscape. (2018). Medscape National Physician Burnout and Depression Report 2018. Retrieved from 

https://www.medscape.com/slideshow/2018-lifestyle-burnout-depression-6009235#11

Gold, K., Andrew, L., Goldman, E., & Schwenk, T. (2016). “I would never want to have a mental health diagnosis on my record”: A survey of female physicians on mental health diagnosis, treatment, and reporting. 

51-57. doi: 10.1016/j.genhosppsych.2016.09.004.

Polfliet, S. (2008). A National Analysis of Medical Licensure Applications. 

Journal of the American Academy of Psychiatry and the Law, 

http://jaapl.org/content/jaapl/36/3/369.full.pdf

The relationship between depression and medical errors is bidirectional, meaning depressive symptoms may lead to more medical errors in practice and medical errors may lead to the development of or worsened depressive symptoms. In other words, physician well-being is critical to patient care.

Suffering in Practice: Getting the Help You Need (Part 2)

Burnout is technically defined as energy depletion or exhaustion, feeling mental distance from or negative feelings about your job, and reduced professional efficacy. That experience is a result of chronic stress in your workplace and with life. Feeling burned out is very common in medicine, rheumatology in particular. In a recent workforce survey of more than 12,000 physicians across 29+ specialties, 50% of rheumatologists reported significant burnout or depression, making rheumatology the second-highest ranking field for burnout (after critical care).

 The increasing pressures of the pandemic have only made matters worse. One study indicated that 22% of physicians know another physician who has committed suicide, 8% have considered self-harm, and 18% have increased their use of medications, alcohol, or illicit drugs.

 This latter poses significant health risks where 10-15% physicians will misuse drugs or alcohol at some point in their career.

Intense professional pressure, demanding hours, heavy workloads, expectations for self-sufficiency, and the high-stress culture of your profession all contribute to the risk for burnout and self-destructive behavior/impairment and these same factors also make you less likely to seek mental healthcare when you need it. The stigma associated with complaints of depressed mood and burnout is intractable as early as medical school. There, medical students report fears of embarrassment if their peers knew about their mental health needs and believe that disclosing their mental health struggles could adversely impact their professional development.

 That stigma continues into practice. One survey of 5,800 physicians applying for or renewing licensure reported that 40% of them were hesitant to seek necessary mental healthcare because they were concerned it would negatively impact their medical licensure.

Burnout and professional impairment are often thought of as 2 sides of the same coin. Burnout is an occupational syndrome related to the external work environment that can often be resolved by taking breaks, setting limits, and practicing self-care. For some, the exhaustion, cynicism, and stress of burnout can indirectly lead to more serious issues like depression, anxiety, and suicidal thoughts. If the symptoms of burnout become more acute and start to interfere your practice and personal life, there is greater concern for impairment. Ongoing symptoms may be an indicator that it is time to seek professional help.

Despite the attitudinal barriers to mental healthcare for medical professionals, you obviously have a commitment to competence and self-regulation that requires you to recognize and address impairment. Recognizing and addressing your own burnout will be addressed in part 2 of this column since it is sometimes easier to act on behalf of your colleagues than it it for yourself. Hubris being what it is, we are lousy at self-reflection but are actually quite skilled at recognizing these needs in our colleagues. You may notice changes in their mood, hygiene, their practice or organization. You may hear complaints about poor sleep, fractious relationship dynamics, and self-destructive behaviors.

Invite your colleague to a non-judgmental conversation to express your concerns clearly. The first step can often be a simple “How can I help?” Encourage your colleague to get a consultation with a mental health colleague who understands the unique pressures of working in healthcare. Certainly you can access your internal EAP programming but, for anonymous treatment options, the 

 have searchable directories to connect physicians to free, confidential mental health services targeted towards healthcare professionals.

When more immediate care is warranted or if your worry is about impairment and not burnout, consider referring your colleague to your state’s 

. Physician Health Programs (PHPs) work with state medical boards to advocate for the physician, arrange treatment, and monitor physician impairment. PHPs deliver treatment to practicing physicians – they make no disciplinary or punitive actions and can operate confidentially as long as no patient harm has occurred. Like any other health complaint, early identification and intervention are key for successful outcomes. Perhaps the most important message that you can give an impaired colleague is that you see their distress and that help is ready. 

The Physicians Foundation. (2020). 2020 Survey of America’s Physicians: COVID-19 Impact Edition. Retrieved from 

https://physiciansfoundation.org/wp-content/uploads/2020/09/2020-Physicians-Foundation-Survey-Part2.pdf

Baldiserri, M. (2007). Impaired healthcare professional. 

(2), 106-116. doi: 10.1097/01.CCM.0000252918.87746.96.

Wimsatt, L., Schwenk, T., & Sen, A. (2015). Predictors of Depression Stigma in Medical Students: Potential Targets for Prevention and Education. 

American Journal of Preventative Medicine, 49

(5), 703-714. doi: 10.1016/j.amepre.2015.03.021.

Dyrbye, L., West, C., Sinksy, C., Goeders, L., Satele, D., & Shanafelt, T. (2017). Medical Licensure Questions and Physician Reluctance to Seek Care for Mental Health Conditions. 

(10), 1486-1493. doi: 10.1016/j.mayocp.2017.06.020.

In a recent workforce survey of more than 12,000 physicians across 29+ specialties, 50% of rheumatologists reported significant burnout or depression, making rheumatology the second-highest ranking field for burnout (after critical care).

Suffering in Practice: Reaching Out to Colleagues in Need (Part 1)

 is the ability to understand the disease and deal with the practical, physical and psychological impacts that come along with it

 is a multicomponent complex intervention

 Combination of methotrexate plus a non–TNF inhibitor

 Combination of methotrexate plus tsDMARDs

 Patients who have not been previously treated with either biologic disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs

 Patients who have had an inadequate response to biologic DMARDs or targeted synthetic DMARDs

 All patients with early or established rheumatoid arthritis

Rheumatoid arthritis is a complex condition. How much do you know about RA treatment? 

Rheumatoid Arthritis Quiz: RA Treatment 

Rheumatology Network interviewed Jeffrey Curtis, MD, MS, MPH, to discuss his ACR Convergence presentation entitled, “Malignancies in Patients Aged ≥ 50 Years with RA and ≥ 1 Additional Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors.” Curtis is Professor of Medicine in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham. He explains the ORAL Surveillance study design, the most common malignancies observed in patients with rheumatoid arthritis, and the clinical significance of these results.

What initially sparked your interest in analyzing malignancies in patients with rheumatoid arthritis who received tofacitinib?

There's a tremendous interest in understanding the safety profile of Janus kinase inhibitors, or JAK inhibitors, in relation to other therapies like tumor necrosis factor (TNF) inhibitors or other biologic drugs in patients with rheumatoid arthritis. This topic has been rather controversial and a source of a lot of intense regulatory agency interests, given the safety profile of JAK inhibitors versus TNF inhibitors, resulting from the large industry-sponsored safety study that recently read out earlier this year.

What were the most common malignancies you observed in patients with rheumatoid arthritis?

The most common malignancies that we observed were both lung cancer and breast cancer. And those, frankly, are common malignancies that we see in patients with rheumatoid arthritis (RA) in general. So, there wasn't anything terribly unexpected or untoward with respect to the kinds of malignancies that are common. Lymphomas, of course, are always high on people's radar. And in patients with RA, with the immune system effects on that kind of hematologic malignancy, it was lung and breast cancer that accounted for the majority of them.

Why do you believe malignancies were higher in patients receiving tofacitinib?

There's a lot of speculation about whether the mechanism of action or other factors about what tofacitinib does or how JAK inhibitors work and affect the immune system. The immune system, of course, was responsible for immune surveillance, including protecting us against malignancies and our own cancer cell transformation. The short answer is that you can posit a whole number of biologic mechanisms for causality but results from this large safety study nevertheless yielded the results that they did. That said, there were some interesting subgroup analyses. In lower risk people, people who weren't over age 65 and those who had never smoked, there was no increase in risk. It appeared that the risk was confined to older people over age 65 and those with a history of smoking. There be some Interplay there with a history of tobacco use. So, as that's post hoc, you have to take that with something of a grain of salt. But it looked like in sort of the average risk patient or even lower risk patients, there really wasn't a difference. It was only older people and those who were smokers that had the vast majority of this excess risk.

Jeffrey Curtis, MD, MS, MPH, discusses malignancies in older patients with rheumatoid arthritis and cardiovascular risks being treated with either tofacitinib or tumor necrosis factor (TNF) inhibitors. 