Clinical Consultations™: Finding Opportunities to Improve the Management of Patients with Connective Tissue Disease-associated Pulmonary Arterial Hypertension (CTD-PAH)

Clinical Consulations CTD/PAH 

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

Rheumatoid Arthritis Quiz

Learn more about the latest developments in rheumatoid arthritis

Focus on Rheumatoid Arthritis

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. 

Arthur Kavanaugh, MD: Hot Topics in Rheumatoid Arthritis and Psoriatic Arthritis

Arthur Kavanaugh, MD, discusses his recent CCR East presentations “The Immunopathogenesis of Psoriatic Arthritis and Immunologically Targeted Therapy” and “Hot Topics in Rheumatoid Arthritis.”

Leonard Calabrese, DO: Immunology for the Rheumatologist

Leonard Calabrese, DO, explains the history of interferon history in rheumatology, immunology for the rheumatologist, and COVID-19 immunology regarding autoimmune and inflammatory manifestations.

Janet Pope, MD, MPH: Treating Unresponsive Rheumatoid Arthritis

Janet Pope, MD, MPH, explains her treatment strategies for unresponsive patients with rheumatoid arthritis as well as clinical pearls of 2021.

Overdrive Podcast: What's Limiting Medical Marijuana Therapy in Rheumatology?

Benjamin Nowell, PhD, and Stuart Silverman, MD, FACP, FACR, discuss the recently published review of current literature regarding cannabis for rheumatic disease pain.

Zachary S Wallace, MD: What’s New in IgG4 Disease?

Zachary S Wallace, MD, explains his approach to diagnosing and managing IgG4-related disease and some of the clinical trials that are on the horizon.

Articles

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending May 21, 2022.

Rheumatology Network's Top 5: May 21, 2022

The Committee for Medicinal Products for Human Use (CHMP) of the Europeans Medicines Agency (EMA) has issued a positive opinion to expand Novartis secukinumab (Cosentyx) indication to the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) in patients aged 6 years and older who are either intolerant or have an inadequate response to conventional therapy. The drug, if approved, will be used alone or in combination with methotrexate.

“JIA is the most common childhood rheumatic disease, affecting millions of children worldwide. Unfortunately, due to the limitations of current or available treatment options, some patients continue to experience symptoms, with an impact on their life. If approved in Europe, Cosentyx could offer a much-needed, additional effective treatment for the underserved ERA and JPsA patient populations,” stated Ivan Foeldvari, MD, of the Hamburg Centre for Pediatric Rheumatology in Germany.

The Phase 3, double-blind, placebo-controlled, randomized withdrawal study, JUNIPERA, enrolled 86 pediatric patients (aged 2 to 18) with a clinical diagnosis of JPsA or ERA, according to the International League of Associations for Rheumatology classification criteria. The primary endpoint was time to flare between week 12 and week 104 (period 2).

Results showed that patients receiving secukinumab had a significantly longer time to flare when compared with placebo (P<.001) in pediatric patients with JPsA and ERA in the EU. The risk of flare was reduced by 72% during the treatment period (Hazard ratio=0.28, 95% CI: 0.13 to 0.63, p<0.001). There were no new safety complications.

Secukinumab works by inhibiting interleukin-17A, a cytokine that is responsible for the inflammation of plaque psoriasis, psoriatic arthritis (PsA), non-radiographic axial spondyloarthritis (nr-axSpA), and ankylosing spondylitis (AS). In July 2020, the drug received EMA approval for the treatment of pediatric psoriasis in patients aged 6 to 18 years old. It has also been approved in the US, China, Japan, and Brazil to treat a variety of pediatric arthritic conditions.

“The positive CHMP opinion reinforces that children and adults living with immunologic rheumatic and dermatological diseases, and the physicians who treat them, may feel confident in the management of these diseases with Cosentyx,” stated Todd Fox, Global Head of Medical Affairs Immunology at Novartis. “We’re committed to bringing innovative treatments to young people living with rheumatic diseases across the world. With recent approvals in the US, Japan and Brazil, we are one step closer in our ambition to expand Cosentyx to 10 indications in areas of high unmet need.”

The Committee for Medicinal Products for Human Use (CHMP) issues a positive opinion to expand Novartis secukinumab indication to enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA).

Secukinumab Receives Positive CHMP Opinion for Expansion in Childhood Arthritic Conditions 

Benjamin Nowell, PhD, and Stuart Silverman, MD, FACP, FACR, discuss the recent publication of the article, “

Cannabis for rheumatic disease pain: A review of current literature

.” Investigators discovered that progress in understanding cannabis-based therapies for treating the pain associated with rheumatic disease is hindered due to a lack of standardization of clinical research and current barriers to conducting such research due to federal and state regulations. Nowell is the Director of Patient-Centered Research at 

 Research Registry. Silverman is a rheumatologist and Clinical Professor of Medicine at Cedars-Sinai Medical Center and UCLA School of Medicine, as well as a faculty member of the 

While over 90% of Americans support the legal use of medical marijuana, there are no cannabis-based medications approved by the US Food and Drug Administration (FDA) for the treatment of rheumatic diseases. In the review, investigators found that while cannabinoids effectively decrease inflammation in cells and reduce both inflammation and pain in mice and rats, there are very few studies examining these effects in humans as it relates to rheumatology. Further, the clinical trials that have been conducted were generally limited by inconsistent methods and small sample sizes.

“Without this research, it is impossible to develop clinical guidelines for medicinal cannabis in the US, which is vital for patients a seeking the full range of treatment options to explore in partnership with their physicians. The best way to treat rheumatic conditions is through the use of FDA-approved medications, which are backed by evidence demonstrating their effectiveness and safety profile,” stated Nowell in CreakyJoint’s press release.

Podcasts

Rheumatology Network interviewed Zachary S Wallace, MD, to discuss his presentation Congress of Clinical Rheumatology (CCR) East presentation “What’s new in IgG4 disease? An Approach to the Diagnosis & Management of IgG4-RD.” Wallace is Assistant Professor of Medicine at Massachusetts General Hospital.

IgG4-related disease is an increasingly recognized condition. It first started to be recognized in the early 2000s, but obviously it's been around for many years. It has many different types of manifestations and can affect different organs. It was only in the early 2000s, that people started to kind of piece together all of these different things and put them under an umbrella of what would become known as IgG4-related disease. And like many of our other rheumatic diseases, it can affect nearly any organ, the most common ones being the salivary glands, the pancreas, the kidneys, and other sites as well. But what it does when it affects these areas is it causes these lesions that are characterized as having a lot of inflammation. What's somewhat unique is that it has a lot of inflammation that's significant for IgG4 positive plasma cells, but it also has a lot of fibrosis. They kind of look like tumors or cancers in these organs, and it can cause damage to the organ,and a lot of different types of symptoms.

What are the key points that you will be discussing in your presentation?

We’re going to review the typical manifestations of the disease and how clinicians can better recognize or think about the diagnosis and understand when they should be thinking about diagnosing someone with IgG4-related disease. We're going to talk a little bit about some of the laboratory features and pathology features that you typically see in IgG4-related disease, and we're going to spend some time going over the ACR classification criteria for IgG4-related disease. Those were published a couple of years ago, but are increasingly used in trials, different studies, and clinically to help guide clinicians as they're evaluating patients for this diagnosis. They’re a useful framework for thinking about the differential diagnosis and making sure that you're considering alternative explanations for the patient's symptoms when they present. We’re going to spend time discussing treatment approaches and how we manage IgG4-related disease these days and what’s on the horizon.

Can you tell me a bit more about the treatment approaches?

Typically, the most commonly used treatment is glucocorticoids or steroids. Most people treat for about 3 months or so. Steroids are very effective in this disease. Over 90% of patients will have a great response to steroids and if they don’t it's usually because their diseases very fibrotic. The challenge is that steroids have a lot of side effects. They lead to a lot of toxicities, especially in this population where people tend to be middle aged or older. Oftentimes men already have pancreatic disease, they're already at risk for diabetes or have diabetes. Adding steroids on top of that just leads to a lot of complications.

Also, this is a disease that tends to relapse. What we find is that even when you use steroids and you taper them down, a lot of patients within that first year of tapering down or off their steroids, a great portion of them are going to flare. Many people still use steroids, here and around the world, but we have had a lot of experience using B cell depletion, particularly with rituximab. Oftentimes, we use rituximab upfront, and we can treat without any steroids. Rituximab is pretty effective, but it has not been evaluated in a large clinical trial head-to-head with steroids and it's not FDA-approved for this indication.

There's a lot of challenges getting retirement for these patients. There are 2 kind of strategies, other things that are used are methotrexate and other common medicines that might be used to treat this. But there's a lot of enthusiasm and energy now and to identify other treatments and really investigate what might be effective for IgG4-related disease. There have been some phase 2 trials looking at other drugs, like a novel drug that targets plasma blasts. We have a trial going on right now using efalizumab, which is similar to rituximab in a number of ways. There's a lot of exciting things on the horizon that identify what the best treatment approach would be to get IgG4-related disease into remission.

What are the takeaways or clinical significance for rheumatologists?

Some takeaways would be that we're probably all seeing IgG4-related disease, but we may not be recognizing it or diagnosing it. You have to think about it and really look for it, but it is there. The other message is that there's not a diagnostic finding for IgG4-related disease. Elevated serum IgG4 concentrations and IgG4 positive plasma cell infiltrates and tissue are not specific to the to the disease and about a third of patients actually have a normal serum IgG4 concentration, so it's easy to get thrown off by those observations.

The other take home message would be that steroids are very effective but have a lot of toxicities. There are alternative therapies that may be as effective or more effective than steroids.

Videos

Zachary S Wallace, MD, explains his approach to diagnosing and managing IgG4-related disease and some of the clinical trials that are on the horizon. 

Rheumatology Network interviewed Janet Pope, MD, MPH, to delve into her recent Congress of Clinical Rheumatology (CCR) East presentations, “Treatment Strategies for the Unresponsive Patient with Rheumatoid Arthritis” and “2021 Year in Review: Clinical Pearls.” Pope is Professor of Medicine and Division Head of Rheumatology at Western University in London, Canada.

What are some of the treatment strategies that you suggest for patients with rheumatoid arthritis (RA) who are unresponsive to their current medication?

In rheumatoid arthritis, roughly 1/6 to 1/3 of patients are considered difficult to treat. This could mean that the drugs stopped working, never worked, the patient does not tolerate them, or there's contraindications to them. So, in this pool of patients, which isn't too uncommon, we go through an algorithm based on guidelines. The American College of Rheumatology (ACR), for instance, has guidelines. And basically, we try to continue to treat the patient to get them into remission or low disease activity, because that gives better quality of life and less joint damage down the road. The algorithms we tend to use are our conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) like methotrexate, and in Canada, we use other csDMARDs and combine them. In the US, it would often be adding a different drug, such as a biologic disease-modifying antirheumatic drug (bDMARD) like a tumor necrosis factor (TNF) inhibitor, or possibly an oral JAK inhibitor.

After that, we really don't know what to do next. We usually go out of class to something else, but we don't know, in any one patient, what will be their home run drug. And even if we find a home run drug, it might not last forever. So that's sort of the dilemma in these difficult-to-treat patients. It is evidence based, but we also fly by the seat of our pants.

I asked rheumatologists at the CCR what they would do next. The options were split and there was no consensus, and they were all right answers potentially. We need research that will help us to define what will be the next best treatment. In rheumatology, for RA treatment, we have lots of options. But as I say, we don't know what one will be the best for benefit and tolerability and for the longest amount of time. By the data, it’s probably better to go out of the TNF class to something else to get a deeper and longer response on the average patient.

The other thing is to not give up trying work with your patient and trying to see what's driving the difficulty. Are they not taking it because they don't tolerate it? Can they afford it? Are they afraid because their friend told them there might be issues with the drug? We also must look at the reasons why someone might be difficult-to-treat that isn't necessarily related to the drug but related to taking the drug and the fear or the access tissues.

Your second presentation focuses on the clinical pearls from the last year. What are some of your favorite developments that you discussed?

One thing that's really interesting is there are a lot of trials that have gone on with gout involving treating to a target and what we know about gout. For example, common risk factors of crystal arthritis are age, poor kidneys, alcohol, and diuretics. It's very common that people living with gout, if we target the uric acids to try to lower it, you don't have to target it too low. You get no added benefit coupled with more potential drug changes and side effects. So, targeting to a normal level is good enough.

We also know that uric acid itself is a risk factor for heart attack. It’s independent risk factor for coronary artery disease. They've looked at studies on treating asymptomatic uric acid, which have yielded mixed results; some indicate it decreases cardiovascular risk, but some don’t.

There were also a lot of trials last year in osteoarthritis where drugs or injections weren't successful. Some drugs that might be disease-modifying have, in the long run, not proven to be of any greater benefit than our standard of care and have potential neuropathy or nerve toxicity side effects. So, they're not going to be developed further, as far as I can tell, unfortunately.

There's also a lot of news about injecting platelet-rich plasma, stem cells, and other expensive products into joints. And, in general, the benefit is not there when you compare it to a standard of care in randomized controlled trials. I'm not saying that in all cases it's non-beneficial, but in general, platelet-rich plasma is not going to help your knee osteoarthritis. It might help elbow tendonitis, but that's not as common as knee osteoarthritis.

Some of it has to do with trial design, but when new results come out, we're enthusiastic and then over time, we have to ask ourselves if these products are actually going to be effective for our patients or not.

Janet Pope, MD, MPH, explains her treatment strategies for unresponsive patients with rheumatoid arthritis as well as clinical pearls of 2021. 

Rheumatology Network interviewed Julie J Paik, MD, MHS, to discuss her Congress of Clinical Rheumatology (CCR) East presentations “Clinicoserological Spectrum of Inflammatory Myopathy in the Context of Systemic Rheumatic Diseases” and “Can Autoantibody Profiles Predict Myositis Phenotype and Disease Course?” Paik is Assistant Professor of Medicine and Director of Clinical Trials at Johns Hopkins Myositis Center, Division of Rheumatology.

Can you give me some of the key takeaways of your spectrum of inflammatory myopathy in rheumatology presentation?

I highlighted key pearls about how to classify different subgroups of myositis, which then enables clinical providers to better subset these diseases. Sometimes, when someone comes in with weakness, you're thinking about a lot of differential diagnoses. But when you divide up the different types of myositis into distinct subgroups, it's better to have a plan of attack in terms of treatment and diagnosis So, I went over the key subgroups: dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis.

Then within each subgroup, I embedded in cases and went through how to approach the diagnosis. What are some of the key clinical features we should be aware of? What is the treatment algorithm for each subgroup? How do I treat this patient? And then I added in a layer of the emerging treatments and promising clinical trials in each subgroup. I also mentioned a clinical trial in immune-mediated necrotizing myopathy. There are, unfortunately, no clinical trials in inclusion body myositis where there's any data that can be read as positive results. Inclusion body myositis is difficult because there's no like treatment for it. I talk largely about dermatomyositis because there are a lot of a lot of pipelined clinical trials and drugs that are in development right now.

Can you speak a little bit more about some of those pipeline trials that you discussed?

It’s an exciting time for dermatomyositis because we have the first FDA-approved drug for dermatomyositis ever that is efficacious, which is intravenous immunoglobulin, as of July 2021. It should be easier for rheumatologists to prescribe it now because there's an FDA indication.

Another promising pipeline drug and promising treatment that I discussed was a phase 2/3 clinical trial of ravulizumab. It's a C5 inhibitor, a complement inhibitor, and the trial is about to start very soon. It's a multicenter, international trial of a complement inhibitor in adult dermatomyositis patients.

I was the principal investigator on a proof-of-concept study of a JAK inhibitor in refractory dermatomyositis or tofacitinib. There are ongoing phase 2 studies internationally looking at a JAK inhibitor in dermatomyositis based on some of the work that we've done that showed a very good response of JAK inhibitors in dermatomyositis.

How can autoantibody profiles predict myositis phenotype and its disease course?

It’s easier to look at these autoantibody associations by looking at those subgroups that I highlighted in my first talk. I went into the classic autoantibody associations we see in dermatomyositis and some of those updates regarding those phenotypic associations. First and foremost, one of the key pearls is that autoantibodies are helpful in diagnosis and prognosis. There are studies to show that these autoantibodies may even better predict someone's phenotype than a muscle biopsy. And so that's the reason why we order them. But specifically, in looking at dermatomyositis, I talked about some of the phenotypes. For example, anti-melanoma differentiation-associated gene 5 (MDA5) is associated with these “kissing papules” on the hands. The beauty of dermatomyositis is that I can tell the patient exactly what they have just by looking for these kissing papules or ulcers on the hands. And they also tend to have more rapidly progressive interstitial lung disease.

There’s also so much data and literature showing that link of cancer and transcription intermediary factor 1-gamma (TIF1-γ), which is a specific autoantibody associated with the dermatomyositis in the US cohorts, as well as in Asia and Europe. I made it a point that TIF1-γ is one of the most common autoantibodies. Not everyone who has TIF1-γ is going to have a cancer. But as a provider, you’re thinking about it in the context of someone not responding, like in refractory dermatomyositis. You really want to take a step back and analyze if they are not responding because they don’t have enough treatment or if there is a proven cancer, a cell malignancy, that's driving the disease process.

Is there anything else that you'd like our audience know before we wrap up?

One thing I did a highlight a lot throughout is that it's important that rheumatologists, or any providers treating myositis, aggressively treat patients early on so that they do not accumulate damage in their muscles because it's irreversible.

Julie J Paik, MD, MHS, discusses the clinicoserological spectrum of inflammatory myopathy in the context of rheumatic diseases and how autoantibody profiles can help predict myositis phenotype and disease course. 

Julie J Paik, MD, MHS: Inflammatory Myopathy in Systemic Rheumatic Diseases

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.

Usual interstitial pneumonia (UIP) pattern

Low rheumatoid factor immunoglobulin A (RF-IgA)

High-resolution computed tomography (HRCT) scores showing pulmonary impairment at baseline

Many rheumatoid arthritis (RA) patients experience lung manifestations such as interstitial lung disease, but what are the implications and who is most at risk?  Test your knowledge with this quiz.

Rheumatoid Arthritis Quiz: Interstitial Lung Disease

Rheumatology Network interviewed Leonard Calabrese, DO, to discuss his Congress of Clinical Rheumatology (CCR) East Conference presentations “Interferon History Immunology and Beyond,” “Immunology for the Rheumatology Provider Adjourns,” and “COVID Immunology and the Rheumatologist COVID-19: Autoimmune & Inflammatory Manifestations.” Calabrese is Professor of Medicine at the Cleveland Clinic.

Why is it important for rheumatologists to take immunology into account when treating their patients?

Rheumatologists, by definition, are clinical immunologists, which means that that is anyone who applies the principles of basic, translational, and clinical immunology to patient care. We do that every day in virtually almost all our patients. So, it's very important. And given how dynamic this field is, it's challenging to keep up, particularly if you're not doing work in research in this area or are associated with an academic center where it's constantly being discussed. So, we take this as an opportunity.

What is the history of utilizing interferons in rheumatology?

The history of interferon in rheumatology goes back a long way from their discovery in the mid 60s and the struggle to purify these compounds. It took almost 20 years to make these initial observations that interferon, particularly type 1 interferon, were present in excessive amounts in certain immune-mediated diseases, such as lupus, juvenile rheumatoid, and Sjogren’s. And over the ensuing 40 years, the field now has developed robustly to recognizing it's not only a biomarker but probably driving immunopathogenesis, in particular in lupus, and possibly in other diseases. It's been a long road.

What do you believe the future holds for interferons in this field?

I think that the centrality of interferon and driving a number of these diseases, in particular certain end organ manifestations, is very promising. We're also finding that this interferon signature is present in diseases outside of the centrality of rheumatology, and particularly the devastating syndrome of long COVID-19, where 8 months after recovery people who are persistently symptomatic develop regulations of multiple types of interferon, could be a treatable target.

Speaking of COVID, how does COVID-19 affect immunology in patients with rheumatic disease?

It's a complicated question. I think at first, patients with rheumatic diseases, by and large, respond somewhat similar to healthy patients when you control for comorbidities. So, if you're not on any therapy, and your diseases is inactive even though you have baseline rheumatoid arthritis, or mild lupus, or other conditions, and you don't have diabetes, obesity, or other traditional risk factors, patients do fairly comparably. But since our patients often have end organ damage, kidney damage, lung damage, etc, they are more frequently vulnerable to the sequelae of COVID-19. And finally, the biggest issue for our patients is therapy. The therapies that we use are immunosuppressive or immunomodulatory. We're now learning that not all these therapies are equal. As a matter of fact, they're not even close to being equal. Certain patients are highly immunocompromised, and others are not.

What are some of the inflammatory and autoimmune manifestations that you discussed in your presentation?

On one level, COVID-19 itself is an immunologically driven viral illness. So, the mere natural history of COVID-19 is immune-mediated. Most patients get over COVID with what we call phase 1 and phase 2. They acquire the virus and trigger an innate immune response. In the second week, you make some antibodies and cell-mediated immunity and you're better. However, a small population progressed to this hyper-inflammatory phase 3, which is characterized by elevated cytokines, acute phase reactants, clotting, and activation. That is a devastating sequela. For patients with rheumatic disease, there are also other questions. Can COVID activate their underlying rheumatic disease? We’re just starting to learn that it can occur. Most of the time, it does not, and usually it's modest. But can it manifest new autoimmune manifestations? Again, it’s a work in progress because there's compelling evidence that COVID-19 drives autoimmunity, even in healthy people. What that's doing to them right now is not totally clear.

In your opinion, what are some of the biggest challenges that are facing rheumatologists and immunologists today?

Rheumatologists, in particular, are challenged to keep pace with both their declarative knowledge about immunology. The field is like tsunami in terms of developments. What you learned in medical school and training is out of date if you've been out of school for more than a couple of years. And if you are keeping pace with declarative knowledge, you need to know the procedural knowledge of how to use it. What is the state-of-the-art in terms of diagnostics and biomarkers? How should we be using our targeted therapies? The landscape changes constantly and diseases, like COVID 19, have challenged all of us. This is a disease that 2 years ago didn't exist and now affects our patients. We need to master yet another disorder that is immunologically driven.

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

The last thing I'd like to remind rheumatologists is that we are part of the next phase of the epidemic, which will be the continued exposure and vulnerability of our patients to endemic SARS-CoV-2 infection, and we need to be forthrightly involved in managing COVID-19 in the immunocompromised. That means educating our patients, educating ourselves, knowing where the care pathways are, and how to access antivirals and monoclonal antibodies in keeping our patients from severe sequelae of COVID-19. That's going to be an ongoing challenge and I hope everyone is buying into that.

Leonard Calabrese, DO, explains the history of interferon history in rheumatology, immunology for the rheumatologist, and COVID-19 immunology regarding autoimmune and inflammatory manifestations. 

Leonard Calabrese, DO: Immunology for the Rheumatologist 

Rheumatology Network interviewed Arthur Kavanaugh, MD, to discuss his recent Congress of Clinical Rheumatology (CCR) East presentations “The Immunopathogenesis of Psoriatic Arthritis and Immunologically Targeted Therapy” and “Hot Topics in Rheumatoid Arthritis.” Kavanaugh is Professor of Medicine and Director of the Center for Innovative Therapy at UC San Diego.

What are some of the hot topics in rheumatoid arthritis that you discussed at the CCR conference?

There are so many hot topics, but I really focused on the early disease and treatment of early diseases, even including pre-diagnosis of rheumatoid arthritis, and reviewed some of the data for that. I talked a little bit about the newer therapies and newer information on some of the older therapies, including discussing corticosteroids and touching on the optimization for non-steroidal anti-inflammatory drugs. I talked a little bit about the treatment paradigms and need for personalized medicine, which we don't have because we didn't really know which medicine to use and in which order for any individual patient, which is a little bit disappointing, but something that there's been a lot of research looking at. And finally, a lot of discussion about the safety and recent data with the ORAL surveillance study and putting the information from that in clinical context for the practicing rheumatologist.

What are some of the newer therapies in rheumatoid arthritis treatment that you discussed?

 The newer ones are the JAK inhibitors. They're the latest to enter the file of therapies that we have available to us for rheumatoid arthritis. We now have tofacitinib, which we've had for a while, and baricitinib, which we’ve have for some years, and upadacitinib is the most recent edition.

What are some of the key takeaways for rheumatologists?

It’s still interesting treating early rheumatoid arthritis or even pre-rheumatoid arthritis, but it's challenging because not all the patients meet the suspicion. They have clinically suspected arthralgia, but not all will develop rheumatoid arthritis. That raises issues about the how best to approach a treatment, including from an ethical standpoint, because we're trying not to over-treat patients.

Another take home point is that there is still an unmet need to figure out which therapy is going to be best for which patient both in terms of effectiveness and also in safety and tolerability. And finally, safety issues. Initially, they’re kind of scary and certainly safeties are important. But it's also important to be able to put it into context so that we can have discussions with our patients about the relative magnitude of the risk and the characteristics that may make people more or less likely to suffer some of the adverse events that we're talking about.

What are some of the challenges facing rheumatologists today?

There are not enough rheumatologists. We have a manpower issue. The prevalence of rheumatic diseases is increasing and we don't have enough fellows, which means we don't have enough young rheumatologists to even replace those who are going to leave the profession by retiring. While it's great to be busy, it's perhaps not so great to not have enough rheumatologists available.

What are the key takeaways from your immunopathogenesis of psoriatic arthritis presentation?

There is more understanding of the different components of the dysregulated immune system and the inflammatory response that seems very relevant in psoriatic arthritis. We've learned more from basic outcomes research in terms of imaging and biomarkers. We've also learned a lot from the results of studies of highly targeted therapies that have given us answers about which domains of psoriatic arthritis may respond as to what specific mechanisms of action. Domains such as skin psoriasis, nail psoriasis, enthesitis, dactylitis, as well as the affiliated conditions like anterior uveitis and also inflammatory bowel disease.

How can this targeted therapy treatment method help both patients and rheumatologists?

Patients want to feel better and they want to feel better across all aspects of their condition. The rheumatologist wants to help them get there and they want to find the therapy that works best for them and is the best for them.

Arthur Kavanaugh, MD, discusses his recent CCR East presentations “The Immunopathogenesis of Psoriatic Arthritis and Immunologically Targeted Therapy” and “Hot Topics in Rheumatoid Arthritis.” 

Arthur Kavanaugh, MD: Hot Topics in Rheumatoid Arthritis and Psoriatic Arthritis 

Healthy Lifestyle Modifications May Lower Risk of Genetically Induced Gout

While genetics are linked to gout diagnosis and lifestyle factors are related to risk, the association between healthy choices and risk mitigation remained unclear.

Rheumatoid Arthritis Quiz: RA and Cardiovascular Risk

Rheumatoid arthritis is known risk factor for cardiovascular disease, but how much do you know about the association? Test your knowledge with this quiz.

From Living BLISSfully to BEATing Lupus: Future Considerations for Biologic Therapy in SLE

After years of frustration and failure, trials of targeted biologic therapy in systemic lupus erythematosus are beginning to show success. New drugs, including anifrolumab (Saphnelo) and belimumab (Benlysta), are paving the way for an exciting new era. However, this raises new questions as to how these novel therapeutics will be incorporated into future clinical practice.

Long-term Data Suggests Deucravacitinib Safe, Effective for Treating Plaque Psoriasis

Data from the POETYK PSO long-term extension (LTE) trial showed deucravacitinib was clinically effective and safe for treating adult patients with moderate-to-severe plaque psoriasis.

Ustekinumab, TNFi Show Similar Persistence at 1 Year in Real-World PsA Study

One-year results from the PsABio study provide evidence on factors that may impact treatment selection and decisions in clinical practice.

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending May 14, 2022.

Rheumatology Network's Top 5: May 14, 2022

New safety data from the POETYK PSO long-term extension (LTE) trial showed deucravacitinib, an oral, selective allosteric tyrosine kinase 2 (TYK2) inhibitor, was clinically effective and safe for treating adult patients with moderate-to-severe plaque psoriasis, according to 

. Efficacy was maintained for up to 2 years, with 77.7% of patients achieving Psoriasis Area and Severity Index (PASI) 75 by week 60 and 58.7% achieving the static Physicians Global Assessment (sPGA) response rate of 0/1 (clear/almost clear skin).

Spanning 2482 patient years, results are consistent with previous phase 3, multicenter, randomized, double-blind POETYK PSO-1 (

) trials, which evaluated the safety and efficacy of deucravacitinib compared with apremilast and placebo for the treatment of moderate-to-severe plaque psoriasis. Common adverse events (AEs) reported, of which most were mild to moderate in severity, were headache, upper respiratory tract infection, and nasopharyngitis. Rates of serious AEs remained low during the 2-year LTE trial. The drug did not increase a patient’s risk of developing COVID-19 nor did it impact the severity of COVID-19 infection. No clinically meaningful changes from baseline were observed in laboratory values.

The drug represents a new class of small molecules and is the first and only TYK2 inhibitor being studied across multiple immune-mediated diseases, including psoriasis, psoriatic arthritis, lupus, and inflammatory bowel diseases. Deucravacitinib selectively inhibits TYK2, but does not interfere with JAK1, JAK2, or JAK3. It is currently under review with the US Food and Drug Administration (FDA), European Medical Association (EMA), and Japan’s Ministry of Health, Labor, and Welfare for the treatment of moderate-to-severe plaque psoriasis.

“Plaque psoriasis is a chronic, systemic immune-mediated disease associated with multiple serious comorbidities, and there remains a strong unmet need for new treatments, particularly oral medicines, as many patients are undertreated or are dissatisfied with current options,” stated Richard B Warren, Professor at The University of Manchester. “Long-term research showing durable efficacy, in addition to a well understood safety profile, is critical for clinicians and patients making treatment decisions, and these new two-year data underscore the potential of deucravacitinib to be an important new oral treatment option for people living with moderate to severe plaque psoriasis who require systemic therapy.”

Data from the POETYK PSO long-term extension (LTE) trial showed deucravacitinib was clinically effective and safe for treating adult patients with moderate-to-severe plaque psoriasis. 

Long-term Data Suggests Deucravacitinib Safe, Effective for Treating Plaque Psoriasis 

Rheumatology Network interviewed Anne Winkler, MD, to discuss her upcoming CCR East presentation, “Targeting Lupus Nephritis.” Winkler is an independent rheumatologist who does outreach work to help provide specialty rheumatology care to more underserved areas, including an affiliation with Mercy Hospital in Carthage, Missouri.

What sparked your interest in focusing on patients with lupus nephritis?

We finally have some agents that have been FDA-approved. Even though we have used agents which were not FDA approved, we're finally starting to get some that are effective, not just in lupus specifically, but in lupus nephritis. It’s essentially the number one killer of our lupus patients and certainly the thing we worry most about with our patients. Lupus nephritis is particularly prevalent in young women of color, a very underserved population, and access to health care for them can be difficult for a variety of reasons.

The other thing, not just in lupus nephritis, although what's nice about lupus nephritis is that we have very objective measures we can use to show efficacy, but I think we're also getting a better handle on how to treat lupus and using better measures in clinical trials.

The old measure was the systemic lupus erythematosus (SLE) responder index 4 (SRI-4), which was a very insensitive measure. Now they're using the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), which puts more focus on the British Isles Lupus Assessment Group (BILAG), allowing us to finally see more agents that are going to be affected. We’re flying by the seat of our pants.

In terms of treatment, we seem to keep throwing options at people. For those of us who have had young patients die, particularly in lupus nephritis but in lupus as well, what's exciting about right now in the world of rheumatology is that we actually have things that show that our standard of care can be improved by some of these additional medicines that are now coming in. We’re on the forefront and we're going to see significantly more agents available for lupus in the next 5 years.

What are some of the unmet needs within this patient population?

Access to healthcare is the issue. A lot of these patients have trouble initially seeing a rheumatologist. They have trouble having their disease recognized. Not every rheumatologist is as attuned to doing the screens and learning guidelines. We’re supposed to screen every 3 months for the first 5 years for high-risk patients. I'm not sure every rheumatologist is as cognizant as they should be. Additionally, I also have patients who have trouble physically getting to the clinic. They're young, they may be trying to work, they may have little kids, it's hard for them to take off to even come to the clinic, etc. Plus, I’m sure you’re aware of the rheumatologist shortage.

One of the good things is that we're moving more and more toward more women in the field of rheumatology. Not that men haven’t done a great job, but I think sometimes women are a little more attuned to those socioeconomic factors that are so important to our young patients, and particularly for those with lupus or lupus nephritis.

There’s also a disconnect between patients showing up in the emergency room, probably having listened to providers, and actually getting them in the office to get started on treatment. The ER is not the place to start treatment. It’s not their area of expertise. However, if you look at some of the data, there's still many patients who aren't on immunosuppressive within 3 and 6 months of biopsy. They should be on treatment 2 days after their biopsy.

I recently spoke with a doctor who specialized in lupus, and he said that even if a patient is symptomatic, even if they have a rash and aches and pains, it can sometimes take his patients to up to 5 years to reach his clinic because it's like a puzzle to diagnosis. A puzzle that can be sometimes fatal.

Lupus is very hard to diagnose. It's one of those things that, if you're experienced, you can see it. When a patient shows up in clinic, we can kind of just walk in the room and have a sense that this person has lupus. Whereas primary caregivers, and it’s not their fault, have very little training in rheumatology. They don't really know the questions to ask. And that makes it difficult.

The other thing is that they will often do an antinuclear antibody (ANA) test, which is 1 very small part of making a lupus diagnosis. They don’t know how to interpret the results. I don't know how many times we see a patient with back pain where somebody did an ANA test on them. An ANA has nothing to do with back pain. These doctors are grappling with something they've had no experience with, no education, and that's not their fault. But it really would be nice if they had some because they might have a better clue about what questions to ask.

Anne Winkler, MD, discusses her upcoming CCR East presentation, “Targeting Lupus Nephritis.” 

Anne Winkler, MD: Targeting Lupus Nephritis

Patients with ankylosing spondylitis (AS) had a poor adherence to exercise therapy, with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) noted as a significantly associated factor, according to a study published in 

“Although the treatment of AS has been revolutionized with the advent of biological therapies, rehabilitation is still a promising nonpharmacological therapy in AS, which usually include aerobic exercise, respiratory kinesiotherapy, strengthening, stretching, and balance and gait training,” investigators stated. “In AS, the main goals of exercise focus on pain control, prevention and delay of stiffness, improvement of function and gait, and correction of deformity in combination with pharmacological therapy. However, reports on adherence to physical exercises in patients with AS are relatively rare, and the criteria for adherence to exercises have been inconsistent.”

In this cross-sectional study, data collected included the subject’s sociodemographic (age, sex, body mass index [BMI], education level, smoking habits, outpatient information, and family history), radiographic, disease-related, and laboratory information. Eligible patients were between 18 and 50 years of age, did not have a history of psychiatric disorders or cognitive disfunction, and completed the Exercise Attitude Questionnaire (EAQ) questionnaire.

Adherence to exercise therapy was analyzed using the 18-item EAQ with a 4-point Likert scale. Cases were grouped as either poor adherence or good adherence using the cutoff score of 60. A multivariate logistic regression model was used to identify possible factors related to poor adherence to exercise therapy.

Of 185 outpatients that completed the questionnaire, 146 patients (78.9%) were considered to have poor adherence (EAQ score ≤ 60) to exercise therapy (with only 39 patients [21.1%] exhibiting good adherence). The mean EAQ score among participants was 49.4 (IQR, 40.7–59.3).

Patients in the poor adherence group were more likely to use NSAIDs, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and tumor necrosis factor-α inhibitors (TNFi) (p=0.001, p=0.027, p=0.018, respectively). However, the multivariate logistic model only reported significant associations between current NSAID usage (OR=3.517; p=0.016; 95% CI, 1.259–9.827). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were also significantly higher in patients with poor adherence (p=0.025 and p=0.014, respectively).

The single-center, cross-sectional nature of the study limited it and, as such, results were not generalizable. Further, exercise adherence tends to decline over time. The small sample size did not allow for investigators to draw correlations between other risk factors. Lastly, certain sociodemographic influences, such as marital status, dietary choices, disease-related factors, and income were not included in the assessment.

“Lack of adherence to exercise therapy is a major concern in the treatment of patients with AS,” investigators concluded. “Clinically, there is an urgent need to develop comprehensive strategies to improve adherence to exercise therapy in patients with AS, and future studies can aim to determine the reasons behind the lack of adherence to exercise therapy.”

Ma S, Zhang L, Man S, et al. Patient-reported adherence to physical exercises of patients with ankylosing spondylitis [published online ahead of print, 2022 May 3]. 

. 2022;10.1007/s10067-022-06189-w. doi:10.1007/s10067-022-06189-w

Of 185 outpatients that completed the questionnaire, 146 patients (78.9%) were considered to have poor adherence to exercise therapy.

Poor Exercise Adherence Reported in Patients with Ankylosing Spondylitis 

A healthy lifestyle was associated with a lower risk of gout, mitigating risk related to genetic factors by almost a third, according to a study published in 

“Risk genes linked to the development of gout have been identified, and lifestyle factors are related to gout risk. It remains unclear whether healthy lifestyle factors can mitigate the genetic risk of gout,” investigators stated. “We aimed to explore whether and to what extent a healthy lifestyle can mitigate the risk of gout related to genetic factors.”

A total of 416,481 healthy controls (ages 37-74) were identified at baseline within the UK Biobank database, which recruited more than 500,000 participants. Information including sex, education, body mass index (BMI), disease history, socioeconomic status, employment status, and age was collected. Polygenic risk for developing gout was analyzed and categorized as low, middle, and high. Healthy lifestyle factors were listed as no or moderate alcohol consumption, regular physical activity, no smoking, and a healthy diet. Participants were placed into 3 categories: unfavorable (0 or 1), intermediate (2), and favorable (3 or 4).

Over the following 12.1 years, 6206 participants developed gout. Those who ultimately received a gout diagnosis were more likely to older, male, physically inactive, smokers, excessive alcohol drinkers, had lower educational attainment and socioeconomic status, and had an unhealthy diet. The hazard ratios (HRs) and 95% confidence intervals (CIs) of gout was 1.44 (1.35-1.54) for the middle cohort and 1.77 (1.66-1.89) for the high genetic risk when compared with participants with low genetic risk.

HRs of gout were 0.63 (0.59-0.67) for participants with a favorable lifestyle and 0.79 (0.75-0.85) for those with an intermediate lifestyle, compared with unfavorable habits. Gout related to a favorable lifestyle was 0.64 for low those with low genetic risk, 0.65 for those with middle genetic risk, and 0.62 for those with high genetic risk. A significant additive interaction was reported between participants with an unfavorable lifestyle and a high genetic risk for developing gout.

In terms of joint analysis, when compared with participants with a low genetic predisposition and a favorable lifestyle, the HRs of gout were 2.39 (2.12-2.70)/3.12 (2.79-3.52) for those with middle or high genetic predispositions coupled with unfavorable lifestyle choices, and 1.53 (1.35-1.74)/1.98 (1.74-2.24) for patients with middle and high genetic predisposition and favorable lifestyle profiles, respectively.

The large sample study coupled with the long follow-up period strengthened the study, in addition to the standardized measures of data collection and comprehensive diagnoses. However, any changes in lifestyle factors after baseline were not evaluated. Further, gout diagnosis was determined using medical records, which opens up the possibility that well-controlled gout or patients with minor flares may not have been recorded in hospitalization records, resulting in underestimation. Generalizability may be hindered because most patients were of White British descent and those who volunteered for the UK Biobank tended to be more health-conscious than those who did not participate, adding to underestimation of gout. While sources of bias were accounted for, confounding factors and reverse causation may remain.

“We found that genetic predisposition and unhealthy lifestyle factors were associated with increased risk of gout. However, a healthy lifestyle may attenuate the risk of gout related to genetic factors,” investigators concluded. “Our findings highlight the importance of maintaining a healthy lifestyle for the prevention of gout in people with a genetic predisposition.”

Zhang Y, Yang R, Dove A, et al. Healthy lifestyle counteracts the risk effect of genetic factors on incident gout: a large population-based longitudinal study. BMC Med. 2022;20(1):138. Published 2022 Apr 29. doi:10.1186/s12916-022-02341-0