Giving lupus patients a voice


Subtyping systemic lupus erythematosus symptoms into categories offers additional perspective on patient symptoms, with a focus on personalized care.

Differences between patient and physician perspective of systemic lupus erythematosus (SLE) symptoms are well known and can negatively affect the therapeutic relationship. Patients often report fatigue, widespread pain, or brain fog as the most frequent and distressing of their lupus symptoms. The etiology of symptoms is often multifactorial, and the relationship to inflammation in SLE isn’t always clear. Physicians, who traditionally assess more concrete symptoms such as inflammatory arthritis or lupus nephritis, often grapple with how best to manage and evaluate these challenging symptoms.

Rather than dismiss these symptoms as comorbidities, a new model that categorizes SLE symptoms into two categories seeks to embrace them. “Patients know their symptoms. They live with fatigue and flares. Our goal was to speak the same language and incorporate their perspective into our model,” said Jennifer L. Rogers, MD, director of the Duke Lupus Clinic in Durham, N.C., who developed the subtyping model with Duke rheumatologists Megan E.B. Clowse, MD ; Lisa Criscione-Schreiber, MD; and David Pisetsky, MD, PhD.

Addressing a wider spectrum of lupus symptoms could also help advance more personalized therapies for patients.

Dr. Jennifer L. Rogers
In this model, patient- and physician-reported measures are either type 1 symptoms, which include more classic inflammatory responses such as nephritis, serositis, malar rash, and inflammatory arthritis, or type 2 symptoms, which may be influenced by factors other than inflammation, such as fibromyalgia and mood disorders. Patients with type 2 symptoms often have fatigue, perceived cognitive dysfunction, sleep problems, widespread pain, and a general feeling of malaise.

These aren’t fixed categories. Many patients may experience a combination of type 1 and 2 symptoms, or “mixed SLE.” Or, they may have “minimal SLE” or low-activity symptoms. “Lupus is a heterogeneous disease,” Dr. Rogers said. “Some patients have more of a systemic organ involvement and others may have longstanding fatigue and distress.”

Now a staple at Duke Lupus Clinic, the model has helped guide patients’ conversations about symptoms by providing a common language and validating their experiences, said Amanda M. Eudy, PhD, an assistant professor with Duke University’s division of rheumatology and immunology. “It has also been helpful for patient education to explain symptoms, as well as treatments that are appropriate,” added Dr. Eudy, a coauthor and close collaborator of the subtyping project.

Dr. Amanda M. Eudy

An umbrella model for SLE

The subtyping project manifested 3 years ago, following a roundtable discussion among Duke’s rheumatologists. Describing their most challenging patients, “it became clear that there were several unmet needs” among those with severe, life-threatening manifestations whose medications weren’t effective, Dr. Rogers said.

Physicians were seeing large numbers of patients that, on paper, seemed to have their flaring lupus nephritis or arthritis under control. Their serology labs were improving, yet they continued to experience fatigue, poor sleep, diffused and widespread pain not evident on the physical exam, brain fog or cognitive dysfunction, and anxiety and depression.

One of the most difficult aspects of caring for lupus patients is managing fatigue, Dr. Rogers said. It significantly impacts quality of life, but not much is understood about its etiopathogenesis.

“Fatigue has been shown to be associated with numerous factors, including disease activity, but it often persists during remission and has a clear relationship with other factors such as perceived stress, depression, poor sleep, and mood disorders. We don’t have biomarkers to identify inflammatory-related fatigue or to guide specific therapy,” she added.

Questioning the underlying causes of these symptoms, how they differentiated from one another, and if they were, in fact, inflammatory symptoms, led to the idea of characterizing subtypes of lupus.

The model is unique in that it incorporates these symptoms under the larger umbrella of SLE symptoms, Dr. Rogers said. “Patients do not view or feel these symptoms in isolation. These symptoms often presented at the same time as their lupus, as such patients identify them as part of their disease. Given the interwoven nature of these symptoms, it may not be possible to dissect them and treat them discretely.”

The intent was to have a holistic approach to improve communication, patient education, and symptom management. “Furthermore, by incorporating type 2 symptoms into our disease model, we hope this will ultimately lead to a better understanding of the underlying mechanisms driving these symptoms and therapies targeting these symptoms,” Dr. Rogers noted.

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Clinical studies test subtype model

Once developed, Duke researchers tested the conceptual model in a cross-sectional study of SLE patients at the clinic. By definition, all patients met either 1997 American College of Rheumatology or Systemic Lupus Collaborating Clinics 2012 classification criteria for SLE. Patients completed the Systemic Lupus Activity Questionnaire and 2011 ACR fibromyalgia criteria.

The investigators divided up patients by classic activity based on the Systemic Lupus Erythematosus Disease Activity Index and/or active lupus nephritis versus ACR fibromyalgia criteria. “In this study, we assessed patient-reported symptoms, self-reported flares, patient disease activity, self-reported medication adherence, and all-cause hospital and ER visits,” Dr. Rogers explained.

Among 212 mostly female patients, 30% had type 1 SLE, 8% had type 2 SLE, and 13% had mixed SLE (both active type 1 and type 2 SLE symptoms), and 49% had minimal symptoms as defined as inactive lupus without fibromyalgia. “In evaluating patient-reported symptoms, we found patients with any degree of type 2 SLE reported greater disease activity, more frequent flares, [and] more fatigue, muscle, and joint pain irrespective of type 1 activity,” Dr. Rogers said. “Importantly, they also reported more frequent chest pain, oral ulcers, and rash – symptoms that are not related to fibromyalgia and more often related to type 1 SLE.”

This helped researchers to identify and appreciate the high level of distress in Type 2 patients, she said. “It then led to the development of a type 2 physician global assessment [PGA] score.” Similar to the type 1 PGA, which is a 3-point visual analog scale assessing overall lupus disease activity, the type 2 PGA measures polysymptomatic distress symptoms on a scale of 0-3. Unveiling their findings at the 13th International Congress on SLE in 2019, Dr. Rogers and colleagues reported that the rate of documented type 2 SLE management in 197 type 2 patients increased from 53% to 89% (P = .03) following implementation of the type 2 PGA score.
In evaluating patient-reported symptoms, we found patients with any degree of type 2 SLE reported greater disease activity, more frequent flares, [and] more fatigue, muscle, and joint pain irrespective of type 1 activity.
Duke’s clinic adopted the type 2 PGA model 2 years ago. Since then, “we have noticed a significant improvement in addressing type 2 symptoms,” which have led to a more personalized approach to symptom management, ranging from antidepressant pharmacotherapy to referrals to psychotherapy or physical therapy, Dr. Rogers said. Now more aware of type 2 symptoms, the clinic’s six rheumatologists are more likely to have discussions about fatigue, fibromyalgia, and widespread pain. These are areas of major concern for many patients, “and we want to validate their concerns. We’ve used this model to counsel our patients on what’s causing their symptoms and to make targeted decisions on their therapy,” she added.

Having a more comprehensive view of patient symptoms – not just their type 1 immunosuppression – helps personalize their treatment, Dr. Eudy said. It means that a rheumatologist may end up referring a patient for physical therapy or counseling rather than a shot of prednisone. “So far, we have not developed any new treatments for type 2 symptoms, but we are currently retrospectively analyzing our registry data to determine how we have been treating type 2 symptoms and which treatments may be the most effective,” she added.

The model has also made clinical care more rewarding for physicians, allayed that they’re on the same page at their patients. “Instead of telling patients, ‘oh no, that’s not your lupus,’ which can make the patient feel unheard or creates the potential for confrontation, we’re listening, validating their lived experience and moving forward to find solutions together,” Dr. Rogers said.

Refining the subtyping model

Since their initial study, Dr. Rogers and colleagues have undertaken new research projects to further refine the type 2 model, drawing from biomarker and validation studies. “There’s a lot of work ahead to refine patient-reported outcomes, following patients longitudinally to see how their symptoms change over time, identify biomarkers, and determine which therapies are best for these symptoms,” she said.

Patients and other rheumatologists have also weighed in on the type 2 model and how well it works. “We’ve completed interviews with patients and rheumatologists to understand their opinion on our model. Through these interviews, we’ve found our model to be reflective of both the patient experiencing living with lupus and the provider experience treating lupus. We will incorporate their valuable feedback into future iterative versions of our model,” Dr. Eudy said.

Other projects are looking at serologic and biologic differences between the two subcategories. An abstract Dr. Clowse and others presented at the 2019 annual meeting of the ACR found biological distinctions between type 1 and 2 female patients. Comparatively, another team of researchers evaluated psychological stress in 431 patients from the California Lupus Epidemiology Study, and found an independent correlation between high stress and more aggravated type 2 symptoms such as pain and fatigue, self-reported disease activity, and cognitive dysfunction.

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There’s a lot of work ahead to refine patient-reported outcomes, following patients longitudinally to see how their symptoms change over time, identify biomarkers, and determine which therapies are best for these symptoms.
At the time of this article’s publishing, Dr. Rogers was expecting preliminary results from an ongoing prospective study examining the AVISE diagnostic connective tissue blood test, and cell-bound complement activation products in the SLE subgroups. At least 100 patients have enrolled in this study, a collaboration between Exagen and Duke University.

Dr. Eudy has been awarded a grant to devise and test patient-reported outcome measures of type 2 symptoms during a clinic visit. “For next steps, I want to test the Duke Lupus Clinic’s model of managing type 1 and 2 SLE symptoms, including the use of the patient-reported outcome measure, in other rheumatology clinics to determine if the model is an effective method of managing type 2 symptoms,” she said.

Ultimately, the goal is to facilitate the development of and test treatments for type 2 SLE symptoms to increase the quality of life for patients with lupus, she added.