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Rheumatology Network's Top 5: March 5, 2021

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


This week, we spoke with Brian Skaggs, PhD, and Maureen McMahon, MD, to discuss the preliminary results of their study, “

A Panel of Biomarkers Associates With Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus

.” The doctors, who are both investigators at the UCLA David Geffen School of Medicine, wanted to more fully understand the increase in cardiovascular and cerebrovascular events for patients, specifically women, with lupus. Cardiovascular disease is linked to comorbidity and mortality in this patient population. In the longitudinal study, investigators used a PREDICTS score method to ascertain any association between adverse events in this patient population. This panel of 4 inflammatory biomarkers and 2 cardiac risk factors (age and diabetes) were better able to predict outcomes when compared with individual biomarkers and risk factors. Investigators concluded that a higher PREDICTS score, as well as hypertension, increase the risk of new cardiovascular events (CVEs) for women with lupus. In addition, women with lupus had a significantly higher risk of major cardiovascular events, with 20% of the patients with lupus experiencing these adverse effects, compared with only 5.2% of the control participants. While there is more research to be done, we briefly discuss the reasons why this may be, if the investigators were surprised by the results, and how women with SLE can minimize their risk of CVEs.

Hello, thank you for joining me today. I would like to begin by asking you to explain your initial interest in determining risk for cardiovascular events in women with lupus.

So, this is a study that we've actually started many years ago. It's been known for a while that women with lupus have an increased risk for cardiovascular disease. And certainly there's you know, a lot of treatments that we use for lupus patients such as corticosteroids that can cause complications and that are known risk factors for heart disease, such as diabetes, and hypertension. But even if you take into account all of the traditional risk factors for cardiovascular disease, we still know that women with lupus have anywhere from a 7-fold increased risk of heart attack to when you look at young women in the 35- to 44-year-old age group. We know that that risk can even be as high as 50 times higher than the general population. So, we really know that we need to be able to better identify which of our patients are at risk. But currently, there really aren't any specific lupus specific markers that we can use to help us identify that. And also to identify which patients should be targeted for earlier intervention. So that's how we became interested in this topic and trying to see if we could find any, any lupus specific panels or biomarkers that we could use to help us.

Why do you think that women, specifically younger women, have an increased risk of cardiovascular events in relation to lupus?

Well, that's really what we're trying to figure out. I think that we know that there must be something specific to lupus, but it's a little bit unclear if it's just general inflammation, or whether there are parts of the disease process. More specifically, that are really causing, you know, the increases that we see.

Were you surprised by the results of the study?

I don't really I don't know if we're necessarily that surprised. I mean, this this particular study that we're talking about, is a very longitudinal study where we're looking at patients over a 10 or more year period. And following these patients throughout that time, the initial panel of what we think are lupus specific biomarkers for cardiovascular disease was determined more in cross sectional studies. So to say that were surprised, I don't know if we would necessarily be surprised after, you know, 10 years that lupus patients, women with lupus have significant risk for cardiovascular or especially cerebrovascular events. It's not necessarily surprising. It's, of course, not good for the patients. But I think it's validating the need for lupus specific markers to be looked at, again to identify patients at risk before they have an event after.

How do you think that these results can help you treat patients with lupus, specifically women?

Well, at this point, I think that that we're still in the research phases. So you know, we, as Dr. Skaggs just mentioned, we develop these panels and based on cross sectional studies looking for patients who had thickening of their of their arteries. And over time, those markers we've shown in this most recent study not only identified the patients with thickening of the arteries, or plaques, but also with cardiovascular events. So we need to certainly take these results that we found and validate them in other populations of lupus patients to make sure that it's not just predicting events in in lupus patients at UCLA, but also events in the lupus population in general. But I hope that as we go forward, you know, these markers will not yet available to the general population of treating rheumatologists. I hope that in the short term, we'll be able to use these to identify patients who can enter into trials, so we can figure out the best strategies using the patients who are at highest risk of progression of disease. And then ultimately, we'll see if we can find a way to commercialize the panel so that physicians can check this for their patients and know if these patients are at risk and pay more attention to special risk factors.

Do you have anything to add before we wrap up in regard to your study and women with lupus?

 I think that the thing that I would add is just that for now, while we're still trying to find the best path forward for identifying patients and treating patients. I think the best we can do now is for all of us to be aware that there have this increased risk of cardiovascular disease in patients and to pay attention to the things that we know that we can control, such as smoking, controlling high cholesterol, hypertension, if it's there, and modifying those risk factors that we know about.

Thank you so much for taking the time to speak with me today. I really appreciate it.

Skaggs BJ, Grossman J, Sahakian L, et al. A Panel of Biomarkers Associates With Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus [published online ahead of print, 2021 Feb 19]. 

. 2021;10.1002/acr2.11223. doi:10.1002/acr2.11223

Videos

Brian Skaggs, PhD, and Maureen McMahon, MD, sat down with Rheumatology Network to discuss the results of their longitudinal study, “A Panel of Biomarkers Associates With Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus.”

Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus

Psychologists are masters of using their relationships with patients to promote change and the secret to psychological practice is to listen and reflect. Readers may be surprised to hear that a high percentage of health professionals, about 70%, find it difficult to do that, to develop empathy with their patients. A study of primary care physicians and surgeons reported that physicians responded to patients’ emotional clues in only 21% of primary care and 38% of surgical cases (Levinson, et al., 2000). Another study explored researchers’ intake interviews and found that most of the opportunities to address patients’ emotional cues were missed entirely (Easter & Beach, 2004). One researcher remarked, “these patients are more likely to receive suboptimal pain management, with a more disease centered orientation and less empathic behavior.” The failure to build empathy for patients is partly a consequence of a lack of adequate time, a lack of training in how to cultivate empathy, and is a consequence of the predominant culture in medical schools.

Empathy is defined as “a cognitive attribute involving an understanding of the patient’s experience and perspective, as a separate individual, combined with an ability to communicate that understanding to the patient” (Hojat, et al., 2002). Empathy is related to positive outcomes for patients, especially for patients with chronic disease. Empathy in the patient encounter is related to healthier patients. A researcher argued that, when a physician is empathic, patients heal faster (Trzeciak & Mazzarelli, 2019). Other studies report the physiological benefits of empathic relationships, including better immune function, shorter post-surgery hospital stays, fewer respiratory complications, stronger placebo response, shorter duration of colds, and better outcomes like medication compliance (Beach, 2018; Reiss, 2010).

In rheumatology, of course, the dynamics of the doctor-patient relationship are often more complex. Rheumatology patients have often seen many different doctors before ending up at a rheumatologist and receiving a diagnosis and treatment plan. Patients often arrive frustrated and distrustful. In one study, 41% of rheumatoid arthritis (RA) patients reported feeling uncomfortable raising concerns and fears with their physician and 22% of patients worried that if they ask too many questions, their doctor will see them as a difficult patient and it will affect the quality of their care. These patient concerns can all be easily buffered with the application of straightforward empathic listening techniques.

Empathic listening in medicine includes a commitment to hearing patients’ concerns, admitting when you don’t know an answer, and setting expectations. Leonard Calabrese, a Rheumatologist and Immunologist at the Cleveland Clinic, writes in “How to Practice Empathetic Listening” (2015) to first listen to your patient and give them the opportunity to help you understand their problem, and then validate their suffering.You don’t even have to fix all of their complaints, people want to be heard and feel seen and they’ll work harder to get your attention if they feel otherwise.

Patients turn to rheumatologists when other providers are unable to treat their ailments which means you have to work harder to establish an empathic relationship. Taking the few minutes to listen and agree, promotes patient satisfaction and well-being, in most cases, it is just that simple.

Readers may be surprised to hear that a high percentage of health professionals, about 70%, find it difficult to develop empathy with their patients.

The Secret to Quality Doctor-Patient Relationships

Patients with rheumatoid arthritis (RA) believe that prednisolone is a necessary medication, yet they are cautious about taking it due to the adverse effects, according to a study published in 

Prednisolone, an effective and fast-acting glucocorticoid agent, is the most common oral glucocorticoid prescribed in Australia. Its anti-inflammatory and disease-modifying properties have made it essential for managing RA since its introduction in the 1950s, with 50% of patients receiving it as their initial treatment and up to 30% of patients continuing to take it thereafter. Unfortunately, high-dose therapy and long-term use have been linked to adverse effects for patients. Therefore, it is generally limited to initial treatment, during disease flares, and in the interim while disease‐modifying antirheumatic drugs (DMARDs) are taking effect.

Investigators wanted to ascertain patients’ perspectives of glucocorticoid usage in order to improve clinical management, treatment adherence, and satisfaction. To accomplish this, a survey was created for patients with RA who were registered with the Australian Rheumatology Association Database (ARAD). Eligible patients had completed an ARAD questionnaire in the preceding 12 months. Demographics, medication use, patient-reported outcomes, and an Assessment of Quality of Life and Health Assessment Questionnaire (HAQ) were collected.

The survey was sent to 1010 participants, with a follow-up reminder sent out 2 weeks later for those who did not respond. Patients were asked about their personal history with prednisolone, including if they were currently taking the medicine or had denied it in the past. If they had declined the medication, they were asked a series of follow-up questions. Those who had taken prednisolone in the past also completed a Beliefs about Medicines Questionnaire (BMQ), which assessed a patient’s beliefs about overuse and harms of medicines in general as well as the necessity of prednisolone and any concerns about its usage. The responses were calculated using a 5-point Likert scale (1= strongly disagree to 5= strongly agree). The scores for patients with current prednisolone use and those who had a history of taking it were calculated separately. Responses mentioning adverse effects, stopping usage, or declining usage were analyzed in order to discover any themes or subthemes among participants.

The response rate was 79.6% (804/1010) and participants were mostly female (75.1%) with a median age of 61 years and a disease duration of 17 years. A total of 683 respondents reported prednisolone usage and 659 (96.5%) completed the additional BMQ survey. Of the responses, 251 (31.2%) had current prednisolone use, while 432 (53.7%) had previous use, and 121 (15.0%) had never taken the medication. Among those with previous prednisolone history, 103/121 (85.1%) were not offered the medication and 18/121 (14.8%) refused prednisolone when offered. Those who declined stated concerns about potential adverse effects, including weight gain and reading negative comments about prednisolone. There was no statistical difference in sex or education level between current and previous prednisolone users, but those with current usage tended to be older and had a longer disease duration with higher levels of pain, poorer disease control, and poorer health-related quality of life. Additionally, current users were more likely to be taking other DMARDs (41.4% versus 33.3%; P= 0.034). Those currently taking prednisolone had higher BMQ scores for prednisolone-specific necessity (3.6 versus 1.7; P <0.001) and concerns (2.7 versus 2.3; P <0.001). For previous prednisolone users, the most common responses for stopping the medication included adequate disease control (30.3%), adverse effects (25.2%), and predetermined short courses (21.3%). Adverse effects included weight gain (27.5%), osteoporosis (14.7%), and neuropsychiatric issues (13.8%).

“Although adequate disease control was the most commonly cited reason for stopping prednisolone, adverse effects were also a key consideration for both stopping and declining prednisolone,” investigators stated. “Prescribing practices were also an influencing factor, with prednisolone cessation commonly attributed to adequate disease control, prescribed short courses, and commencement of other agents.”

Limitations of the study included the survey-based approach and the fact that the population surveyed were older and more highly educated, which may not accurately reflect the wider RA population. Recall bias may also come into play, as the survey was geared towards evaluating lifetime use of prednisolone. Additionally, prednisolone was not specifically used in the wording of the study, although it is the most commonly prescribed glucocorticoid in Australia. Although patterns of use, dosing and duration of therapy were not collected, the response rate of participants strengthened the study. This can be used to indicate a generalizability of the findings, which were used to explore other aspects of patient-reported outcomes and experiences, as well as their personal considerations when deciding to start or stop prednisolone medications.

Roughly 85% of participants reported current or prior prednisolone usage. “The results of this study have highlighted that although cessation occurs with adequate disease control, adverse effects (namely, weight gain, osteoporosis, and neuropsychiatric effects) were a particularly important reason for stopping prednisolone in our cohort of patients with RA,” investigators concluded. “Clinicians should remain mindful of these common reasons for prednisolone cessation in shared decision‐making on treatment with patients. The small number of respondents who refused prednisolone without prior experience frequently cited concern about adverse effects, and further research to understand reasons for these beliefs should be explored.”

Venter G, Tieu J, Black R, et al. Perspectives of Glucocorticoid Use in Patients with Rheumatoid Arthritis [published online ahead of print, 2021 Feb 20]. 

. 2021;10.1002/acr2.11234. doi:10.1002/acr2.11234

Patients with rheumatoid arthritis (RA) believe that prednisolone is a necessary medication, yet they are cautious about taking it due to the adverse effects, according to a new study. 

Patients With Rheumatoid Arthritis Are Wary of Prednisolone Usage 

Investigators discovered that patients with rheumatoid arthritis (RA) not only have a higher prevalence of multimorbidity at the time of diagnosis, but they also have an increased risk of incidence thereafter, according to a recent study published in 

Multimorbidity differs from comorbidity as it is limited to chronic conditions, as opposed to all comorbidities, and it is focused on patients instead of the disease index. “This concept is useful in patients with RA because it is reflective of patient complexity and the associated challenges in providing care for patients with RA who have multiple chronic conditions (eg, the influence of other chronic conditions on RA treatment response),” investigators stated.

The population-based study included data from patients with incident RA between January 1, 1999, and December 31, 2013, in Olmsted County, Minnesota, with all patients fulfilling the 1987 American College of Rheumatology (ACR) classification criteria for RA. Overall, investigators examined 597 RA patients and 594 non-RA patients.

Information collected from participants included age, sex, race and ethnicity, smoking status, body mass index, and obesity. Within the RA cohort, 70% of participants were female, 90% were Caucasian, 40% were obese, and the mean age was 55.5 years. The non-RA patients had incredibly similar statistics, as 70% were female, 91% were Caucasian, 39% were obese, and the mean age was 55.4 years.

Each patient with RA was matched with a subject without RA of similar age, sex, and calendar year. The calendar year was used to determine if there were any trends over time. The non-RA participant was assigned an index date relating to the incidence date of the RA subject.

Investigators created a list of comorbidities for both the general population and those with rheumatic diseases using a combination of the Charlson, Elixhauser, and Rheumatic Disease Comorbidity Indexes as well as diagnostic codes from health care providers in Olmsted County. Currently there is no set list of conditions used for assessing multimorbidity. Information on patients with RA were tracked from 4 years prior to incidence/index date (the date when the patient exhibited at least 4 of the 1987 criteria for RA) until the last follow-up. The 25 most common medical conditions for patients with RA included cancer, cardiovascular disease, diabetes mellitus, valvular disease, dementia, hypertension, depression, and hypothyroidism. Rheumatic diseases were not included as comorbidities. Multimorbidity (MM2+) was defined by investigators as the presence of 2 or more chronic conditions. Substantial multimorbidity (MM5+) was defined as patients with 5 or more chronic conditions.

The groups were compared using either the Chi-Square test, Fisher’s exact test, or Mann-Whitney/Wilcoxon rank-sum test. Incidence was adjusted for the risk of death for each comorbidity, MM2+, and MM5+, which helped account for any mortality rate differences between the cohorts. Throughout the study, 121 patients with RA and 92 non-RA patients died.

Even though investigators excluded hypertension, the most common comorbidity, the differences between both cohorts persisted. MM2+ at incidence/index date was higher in patients with RA than the non-RA cohort, with 228 (38%) versus 188 (32) 

= 0.021, respectively. However, MM5+ was similar in both groups (5% and 4%, respectively). During the follow-up period, a larger percentage of patients with RA developed multimorbidity (214 versus 188, respectively). At the 10-year mark, multimorbidity for patients with RA was 56.5%, compared with only 47.9% of non-RA participants.

Further, patients with RA had an increased risk of having hypothyroidism and chronic pulmonary disease at the incidence/index date when compared with the non-RA cohort. During the study, patients with RA had increased incidence of deficiency anemias, depression, and liver disease.

Investigators believe inflammation, which is known to begin before RA symptoms appear, may be a main factor in the increased prevalence and incidence in multimorbidity for patients with RA, as it is a known contributor to cardiovascular disease as well as other comorbidities.

Strengths of the study included the duration of follow-up (11 years), which exemplified comorbidity over a long period of time. However, its retrospective design proved to be a limitation as only documented cases were eligible for assessment. Although it is unlikely that comorbidities of interest were missed, the accuracy of diagnoses may be lacking. To combat this, investigators required certain procedures, including the presence of 2 codes at least 30 days apart. Another limitation was that chronic conditions were used in defining multimorbidity burden, which tend to be unequal and underestimates the severity of certain conditions. Lastly, the limited diversity (90% Caucasian) may hinder generalizability.

“These findings underscore the complexity of caring for patients with RA, since a large proportion of these patients have multiple chronic conditions. The complexity makes healthcare decision-making more challenging than in patients without RA,” investigators concluded. “In addition, patients with rheumatic diseases are less likely to receive optimal health maintenance and preventive care services. Therefore, there is an increasing need for rheumatology care models that provide support for addressing multimorbidity and for improved coordination of healthcare between rheumatologists and primary care providers.”

Gunderson TM, Myasoedova E, Davis JM 3rd, Crowson CS. Multimorbidity Burden in Rheumatoid Arthritis: A Population-Based Cohort Study [published online ahead of print, 2021 Feb 15]. J Rheumatol. 2021;jrheum.200971. doi:10.3899/jrheum.200971

Investigators believe inflammation, which is known to begin before rheumatoid arthritis (RA) symptoms appear, may be a main factor in the increased prevalence and incidence in multimorbidity for patients with RA. 

Patients With Rheumatoid Arthritis Have an Increased Risk of Multimorbidity Burden

Part II: Systemic Lupus Erythematosus (SLE)  

First, the good news: tremendous progress has been made toward revolutionizing the evaluation and treatment of lupus nephritis (LN). By applying analysis of urine proteomics, a commercialized urine liquid biopsy may soon be developed to replace renal biopsy for the identification of lupus nephritis (LN). Similarly, substantial optimism has been generated by a veritable avalanche of 4 new medications that have demonstrated favorable results in the treatment of LN. Of the 4, 2 have been approved, 1 is undergoing the dreaded Phase III trial (which until recently had been where so many promising new therapies had gone to die), and 1 has completed Phase II with report due out very soon.

However, not all of the recent developments in SLE have painted as rosy a picture of the future. A great deal of attention has been brought to recent efforts to borrow the treat-to-target (T2T) approach from other chronic diseases, notably rheumatoid arthritis (RA), for application to the real-world management of SLE. Yet several barriers remain that may call into question whether T2T in SLE is ready for prime time. Finally, patient nonadherence, the dirty little secret of the practice of Rheumatology, and the resulting negative impact on outcome, has returned to the spotlight in light of recent studies. In particular, the tremendous magnitude of the increased mortality seen among hydroxychloroquine (HCQ) nonadherent patients in SLE is a stark reminder of the critical importance of rheumatologists learning to better assess and optimize adherence with treatment, an obligation that is often woefully unmet.

 in SLE, the era of meta-omics analysis has arrived in SLE. This revolution in cutting-edge, clinically relevant, basic science research is largely due to the substantial investment of time, effort, and dollars in the Accelerating Medicines Partnership (AMP).

For those Rheumatologists, particularly clinicians, who have not kept up with the progress of the AMP researchers in SLE and RA, the time is now to do so. The initial fruits of this labor provide clear hints as to the future of clinical care in these diseases and, through derivative follow, other rheumatic diseases. The latest AMP in SLE study

 demonstrates the potential value of urine proteomics paired with single-cell genomics that may portend replacement of renal biopsy for LN with the development of urine-based, liquid biopsies. An elegant series of urine proteomics studies tracking 1000 urine protein biomarkers identified an immune activation gradient in active LN. By comparing with subsequent renal single-cell RNA-Seq results, it was recognized that this signature is driven predominantly by interferon (IFN)-γ from infiltrating immune cells. As the authors correctly describe in introducing the topic, the promise of these findings may go far beyond the obvious reduction in the invasiveness of the diagnostic testing required to evaluate LN.

Numerous, recognized limitations of the current, histopathologically-based treatment paradigm may be avoided by the proposed switch to liquid biopsy. Specifically, transitions in histopathologic class have been noted in prior repeat biopsy studies. Histopathological transitions within individual patients speak to a dynamic process that is neither reflected in the current single-biopsy-based paradigm nor easily addressed, given the invasiveness of the procedure, by sequential biopsy in the real-world. The development of a non-invasive test would be expected to result in more aggressive testing of milder, less clear-cut cases where biopsy may be delayed because of its invasiveness. Similarly, the lack of invasiveness would encourage more frequent repeat testing. In both cases, a urine-based, liquid biopsy would allow recognition of active nephritis at an earlier stage and, therefore, improve outcomes.

Additional factors favor urine-based liquid biopsy over the conventional approach. Interstitial renal disease is recognized to have pathophysiologic relevance but is not adequately accounted for by current histopathologic scoring. Renal biopsy results may be confounded by sampling error, a factor not seen in liquid biopsy. These and other factors likely contribute to variable outcomes that have been demonstrated among patients within a given histologic class; variability that may be minimized by an effective urine-based, liquid biopsy. Even more importantly, histopathologic scoring in LN appears to have limited ability to serve as a companion diagnostic test to predict individual-level medication response, in much the same manner as synovial biopsy recently was in RA.

 Histopathology simply cannot distinguish individual-level differences in the underlying molecular pathways that give rise to the shared phenotypes demonstrated at biopsy. By contrast, recent studies

 have identified urine biomarkers, including IL-16 and TGFb1, that correlate with initial histopathology but that also decrease among responders to therapy (e.g., IL-16, TGFb1, and CD163). Though significant work remains to validate the findings of these studies and generate from them a commercially available, urine-derived liquid biopsy, the path forward in the diagnosis of LN will almost certainly leverage this approach in the future.

Advances in the diagnosis of LN seem to be arriving just in time, as numerous new therapeutic options are now, or soon will be, available to treat it. In 2011, when belimumab was approved, it marked the only approved biologic Disease-modifying antirheumatic drug (DMARD) for SLE, and the only newly approved SLE drug in nearly 50 years. In December 2020, with data from a 2-year, randomized controlled trial (RCT) demonstrating efficacy of belimumab plus standard of care besting placebo plus standard of care,

 belimumab also became the first approved treatment for adult LN. However, after voclosporin plus standard of care was demonstrated in a Phase III trial to be nearly twice as effective as the standard of care alone in delivering a renal response at 52 weeks,

 voclosporin became the second drug approved for adult LN just 1 month later. Next, obinutuzumab which had been approved to treat CLL in 2013 and was more recently approved for lymphoma, has been repurposed for the treatment of LN. After promising Phase II results at up to 2 years,

 a Phase III study of obinutuzumab in LN is currently enrolling

 with preliminary results expected in 2023. Finally, despite the disappointment of the prior TULIP-1 trial

 which failed to meet its primary endpoint in treating extrarenal SLE, the reconfigured, BILAG-based Composite Lupus Assessment (BICLA)-based analysis of the TULIP-2 trial

 demonstrated the superiority of anifrolumab over placebo. Filing for FDA approval of anifrolumab for extrarenal disease followed in 2020 and remains pending to date.But is anifrolumab effective in LN? The answers will soon be revealed as the Phase II, TULIP-LN1 trial has been completed

 but the results have not yet been released.

With numerous therapeutic options, the question becomes how is a rheumatologist to decide which of these new medications to choose to treat individuals with LN? Although, on the one hand, this is certainly a nice problem to have as prescribers will likely soon have to attempt to choose from amongst these medications. Furthermore, payers will have to determine which of these drugs to add to their formularies and in what relative position. It is extremely unlikely that head-to-head trials will be conducted. Thus, there is considerable risk that prescribing patterns could be driven by factors other than those conforming to the principles of precision medicine, determining the right drug, for the right patient, in the right dose, at the right time. Rather, devolution to the scenario seen in RA, where formulary financial arrangements rather than precision phenotyping and personal pathophysiology have driven medication choice, is possible if not likely. How might we be rescued from another disease riddled by the opaque and Byzantine system of monetary handoffs among a cavalcade of middlemen that have conspired to generate runaway costs of RA treatment? In the best case, companion diagnostic tests will be developed to allow prediction of response to these new drugs for LN at the individual level.As currently applied in oncology, only those with a high likelihood of response according to a medication-specific biomarker test would receive that treatment. Certain molecular pathways in SLE that are relevant for the current crop of new medications may be developed to serve this purpose. For instance, advances in the evaluation of differences in the interferon signature of individuals with SLE

 may identify those more likely to respond to IFN-directed therapies such as anifrolumab.

 The challenge is that no such biomarkers that pertain to these new medications for LN have yet been identified and the medications are likely to come to market in the absence of them. The search for companion biomarkers of response is planned in the next phase of the AMP SLE investigations.

A short-term solution in the absence of such biomarkers is the development of value-based drug pricing arrangements for the new SLE drugs. Under this model, a pharmaceutical manufacturer “bets” on the effectiveness of its medication by receiving full payment for the drug only when individual patients demonstrate a predetermined level of response by a specific timepoint. For those individual patients who do not meet response criteria, an outcome adjustment is made in the form of a payment from the manufacturer back to the payer, effectively lowering the overall cost of the drug. Which payer(s) might collaborate in such programs to assert control over cost of drug by linking formulary position to a manufacturer’s willingness to tie the drug cost directly to the value they deliver to individual patients? Which pharmaceutical manufacturer believes in its product enough to bet on the outcomes it will generate? Can such deals be brokered for these new medications? Only time will tell the answers to these questions. An addition to these arrangements that greatly enhances the likelihood of their success is the inclusion of a neutral, third-party to function as a fulcrum between the competing interests of payers and manufacturers in the 0-sum game of a value-based pricing arrangement. Taking a step back, however, opinions are mixed as to whether lupus researchers have identified and validated 1 further element that is required for both T2T approaches and value-based pricing arrangements: an adequately-validated, clinically applicable, and effective measure of disease activity.

A variety of attributes of SLE as a disease state make it a uniquely complicated challenge for the application of T2T principles or value-based contracts. The challenges are elucidated by comparing the attributes of SLE to RA, a disease in which both of these outcome-focused approaches have been applied to significant success. First, although RA can affect multiple organ systems, outcome measures that assess a single target organ system

 through joint counts along with physician and patient global assessments have been demonstrated to capture the risk of disease progression

 though not perhaps the entirety of the experience of disease from a patient perspective.

 In SLE, however, Protean manifestations across multiple organ systems challenge either the completeness with which an outcome measure captures the different domains on the one hand, or the applicability to the time constraints of real-world practice settings on the other. For example, according to one recent disease activity measure, the Lupus Low Disease Activity State (LLDAS),

 a patient may be considered to be in low disease activity despite having either significant arthritis or 2 of 3 other common flare manifestations (rash, oral/nasal ulcers, or alopecia). From a patient perspective is this really low disease activity?

Secondly, although both diseases are associated with fluctuations in disease activity, the cycling rate of flares in SLE is much faster than RA. For instance, among patients with active disease, 1 recent study in lupus found the mean flare rate is 3 flares per year,

 while another in RA found that just over one-third (38%) of patients flared each year.

 This rapid rate of flare in SLE makes “landmark-based” outcome measures, those that assess disease activity at discrete moments in time, less accurate. For instance, if the outcome measure is applied at follow-up, in-person visits only, it is possible if not likely that, given this rapid cyclic of flares in SLE, that a flare may be missed entirely. Yet all of the current SLE disease activity indices are landmark-based. Efforts have been made to address this issue by adapting the instruments used such as establishing as a primary outcome measure a threshold percentage of visits during which a patient is in LLDAS.

 The ideal approach would be to apply determine disease activity levels continuously and to calculate the area-under the curve (AUC).A more realistic possibility may be to extend the assessment of disease activity beyond in-person visits by determining the patient acceptable symptom state (PASS) across SLE domains and generating remote, application-based assessments that capture the patient experience of disease activity. Thus, the SLE outcome measure of the future might combine frequent remotely captured assessment of the disease activity from the patient perspective including comparison to predetermined threshold levels of the PASS for each SLE domain with demonstration of the absence of organ threat, including to those organ systems like renal disease that do not bear attendant symptoms, via home urine proteomics testing, to address these challenges.

And finally, for those that view this discussion of future state outcome measures as too esoteric and far-fetched, we turn to a goal has been recognized as important, long held as a theoretical priority, but remains in the bucket of “failing to do what we know.” We must sadly concede that the routine assessment of medication nonadherence among lupus patients remains an element of future, not present, standard of care. Recent examples highlight how critically important this single pivot in the focus of our care is to the 2 of the direst and dreaded outcomes in SLE, rapidly progressive end-stage renal disease and death. In the first case, the only risk factors that identified patient with SLE who progressed to end-stage renal disease (ESRD) in less than 3 years in a large retrospective study of those patients with SLE were patient nonadherence and details of their specific histopathology.

In an even more dramatic example of the hazards on nonadherence, antimalarial medication nonadherence among patients with newly diagnosed SLE led to a 71% greater risk of death.

 have indicated that HCQ is taken as prescribed by less than 50% of SLE patients. Furthermore, a recent systematic review

 demonstrated that monitoring HCQ adherence with a simple blood test was clinically useful. Specifically, when HCQ levels were low there was a 3-fold increased likelihood of nonadherence. Evidence of a dose response curve between HCQ blood level and disease activity score was noted with a 58% lower risk of active disease among those with HCQ levels 

750ng/ml. Yet the routine monitoring of HCQ levels remains a rarity in clinical practice and specific approaches that have been demonstrated to improve adherence to treatment including motivational interviewing

 are rarely employed. In the end, it is perhaps not surprising that effective medications are more effective when taken effectively. As we progress deeper into the future era of value-based medicine, it is somewhat surprising that we have not attended to the fact that 1 of the ways that a provider can “cheat” the value game is to become expert in encouraging adherence to treatment plans across the rheumatic diseases and by this approach alone, achieve the greater compensation by delivering better patient outcomes.

In the end, delivering on the promise of innovations in lupus care is contingent upon all of us. The practice of real-world Rheumatology must be provided the tools with which to optimize the delivery of meta-omic diagnostic and therapeutic revelations and targeted immunomodulatory pharmacologic advances by seeking to optimize the delivery of care. To do so, translational researchers need to provide adequate outcome measures that capture the complexity of the phenotypic heterogeneity in patient relevant terms at far more frequent intervals. Clinicians must learn to better address non-disease specific limitations to outcome including socioeconomic and racial disparities, behavioral health and other comorbidities and, notably, nonadherence. Health plans and manufacturers have an opportunity to play a role in crafting better care for SLE. By partnering in innovative outcome-based pricing arrangements that link the cost of new medications to the value that they deliver at the individual patient level, cost may be controlled even as new medications with greater effectiveness are introduced. The same overarching approach might be applied to RA. In that disease however, the institution of an effective value driven system must also contemplate how to unwind the established labyrinth of perverse incentives that has resulted in spiraling costs that have grown beyond the control of any single stakeholder, resulted in rising insurance premiums, and to threaten to bankrupt the entire healthcare system.

On that ominous note, time for a reminder: the topic of the next installment will be “A Vision of the Future of RA Care.”

1.Fava A, Buyon J, Mohan C, et al.Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis.

https://doi.org/10.1172/jci.insight.138345

2.Hoover P, Der E, Berthier CC, et al.Accelerating medicines partnership: organizational structure and preliminary data from Phase 1 studies of lupus nephritis.

3.Humby F, Durez P, Buch MH, et al.Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA):16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised clinical trial.

4. Fava A, Buyon J, Mohan C, et al.Urine proteomics and single cell transcriptomics identify IL-16 as a biomarker for lupus nephritis.Abstract 0936, Paper presented at: American College of Rheumatology Convergence 2020.

5. Mejia-Vilet J, Zhang XL, et al.Urinary soluble CD163: a novel noninvasive biomarker of activity for lupus nephritis.

, 2020; 31(6); DOI: https://doi.org/10.1681/ASN.2019.2019121285.

6. Aragon CC, Tafur R-A, Suarez-Avellaneda A, et al. Urinary biomarkers in lupus nephritis

, 2020.https://doi.org/10.1016./j.auto.2020.100042.

7. Furie R, Rovin BH, Houssiau F, et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.

8. Arriens C, Polyakova S, Adzerikho I, et al.AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis.[abstract taken from 

http://dx.doi.org/10.1136/annrheumdis-2020-eular.5010

9. Furie R, Aroca G, Alvarez A, et al.Two-year results from a randomized, controlled study of obinutuzumab for proliferative lupus nephritis.Abstract 0988, Paper presented at: American College of Rheumatology Convergence 2020.

10.A Study to Evaluate the efficacy and safety of obinutuzumab in patients with ISN/RPS 2003 class III or IV lupus nephritis (REGENCY).ClinicalTrials.gov identifier: NCT04221477. https://www.clinicaltrials.gov/ct2/show/NCT04221477.Updated February 18, 2021. Accessed February 26, 2021.

11. Furie RA, Morand EF, Bruce IN, et al.Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial.

https://doi.org/10.1016/S2665-9913(19)30076-1

12. Morand EF, Furie R, Tanaka Y, et al.Trial of anifrolumab in active systemic lupus erythematosus. 

13.Safety and efficacy of two doses of anifrolumab compared to placebo in adult subjects with active proliferative lupus nephritis (TULIP-LN1)

ClinicalTrials.gov identifier: NCT02547922. https://www.clinicaltrials.gov/ct2/show/NCT02547922.Updated January 27, 2021. Accessed February 26, 2021.

14.Chaichian Y & Strand V.Interferon-directed therapies for the treatment of systemic lupus erythematosus: a critical update.

, 2020; https://doi.org/10.1007/s10067-020-05526-1.

15.Lever E, Alves MR, & Isenberg D.Towards precision medicine in systemic lupus erythematosus.

, 2020; http://doi.org/10.2147/PGPM.S205079.

16.Rios-Garces R, Espinosa G, van Vollenhoven R & Cervera R.Treat-to-target in systemic lupus erythematosus: where are we?

, 2020; https://doi.org/10.1016/j.ejim.2020.01.018.

17.Navarro-Compan V, Gherghe AM, Smolen J, et al.Relationship between disease activity indices and their individual components and radiographic progression in RA: a systematic literature review.

18.Scott IC, Machin A, Mallen CD & Hider SL.The extra-articular impacts of rheumatoid arthritis: moving towards holistic care.

, 2018; https://doi.org/10.1186/s41927-018-0039-2.

19.Franklyn K, Lau CS, Navarra SV, et al.Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).

http://dx.doi.org/10.1136/annrheumdis-2015-207726

20.McElhone K, Abbott J, Hurley M, et al.Flares in patients with systemic lupus erythematosus.

, 2020; doi:10.1093/rheumatology/keaa777.

21.Rutherford AI, Scott DL, Subesinghe S et al.The Incidence and Predictors of Flare in a Cohort of Rheumatoid Arthritis Patients. [Abstract taken from 

https://doi.org/10.1093/rheumatology/kew132

22. Sharma C, Raymond W, Eilertsen G & Nossent J.Achieving lupus low disease activity state (LLDAS-50) is associated with both reduced damage accrual and mortality in patients with systemic lupus erythematosus. 

23. Tselios K, Gladman DD, Taheri C, et al.Factors associated with rapid progression to end stage kidney disease in lupus nephritis.

24.Hoque MR, Avina-Zubieta A, De Vera MA, et al.Impact of antimalarial adherence on mortality among patients with newly diagnosed systemic lupus erythematosus: a population‐based cohort study.

25.Mehat P, Atiquzzman, Esdaile JM, et al.Medication nonadherence in systemic lupus erythematosus: a systematic review.Arthritis Care Res, 2017;

26.Garg S, Unnithan R, Hansen KE, et al.The clinical significance of monitoring hydroxychloroquine levels in patients with systemic lupus erythematosus: a systematic review and meta‐analysis.Arthritis Care Res, 2020; 

27. Gossec L, Molto A, Romand X, et al.Recommendations for the assessment and optimization of adherence to disease-modifying drugs in chronic inflammatory rheumatic diseases: a process based on literature reviews and expert consensus.Joint Bone Spine, 2019; 

https://doi.org/10.1016/j.jbspin.2018.08.006

In the second portion of this series, Dr. Concoff discusses the path forward in the evaluation and treatment of systemic lupus erythematosus (SLE).  

Rheumatology 2021: Quo Vadis? Part II 

Rheumatology Network's Top 5: February 26, 2021

Slideshows

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


Febuxostat started at the onset of an acute gout flare does not prolong the duration of the current flare, according to the results of a study published in 

1 Further, the “treat-to-target” rate was higher at the 7-day mark for the febuxostat group and the rate of recurrent flares did not increase.

While urate-lowering treatment (ULT) is important for patients with gout, there have been conflicting recommendations on starting ULT treatment during an acute flare. Typically, it is held off until the flare has resolved in order to avoid prolongation of symptoms. However, investigators theorized that starting ULT at the beginning of a flare may reduce outpatient treatment visits while increasing patient compliance.

The placebo-controlled, single-blinded, multicenter trial focused on 140 patients who were experiencing an acute gout flare that had begun within the last 72 hours. The research team sought to measure “days to resolution” of the flare, and randomized participants 1:1 to either febuxostat (40 mg/day) or placebo. Exclusion criteria included taking anti-inflammatory drugs and having taken ULT drugs in the last 6 months. The mean age of participants in the placebo group was 41.41 years and 42.13 in the febuxostat group, with a mean disease duration of 3.46 and 3.77 years, respectively.

Trial participants received diclofenac (150 mg/day) for the first 7 days and then open-labelled day 8 through 28. Patients in remission received 40 mg of febuxostat and 75 mg of diclofenac daily from day 8 through 28.

Participants assessed joint pain, swelling, tenderness, and erythema using 5- and 3-point Likert scales throughout the trial either in person at or via a video call. At baseline, pain scores for the placebo and febuxostat groups were 2.87 and 2.89, respectively, with no significant differences in the first 5 days. On day 7, a self-assessment of pain was reduced to 0.13 and 0.26. Joint swelling scores for the placebo group were 1.99 and 1.93 in the febuxostat group, which decreased to 0.13 and 0.20 on day 7. Joint tenderness scores went from 1.61 for the placebo group and 1.60 in the febuxostat group down to 0.14 and 0.19. Lastly, joint erythema scores were 1.46 and 1.40 at baseline, which decreased to 0.10 and 0.15.

Investigators also tested c-reactive proteins (CRP) via a blood analysis at baseline and at 7 days. Average CRP levels were 17.16 mg/l for the placebo group and 22.30 mg/l for the febuxostat group (

 = 0.225). On day 7, CRP levels were reduced to 7.59 and 9.40 mg/L (

 = 0.513). Serum uric acid (sUA) levels were tested and were significantly lower at day 7 for patients in the febuxostat group, which was to be expected.

Using an intent-to-treat (ITT) analysis, the mean days to resolution was 5.98 days in the placebo group and 6.50 days for patients taking febuxostat. In the per-protocol analysis, patients receiving the placebo had an average of 6.16 days to resolution, while the febuxostat group’s flare resolved in 6.58 days. Within 7 days, 84.38% of the placebo group had recovered from their flare, as opposed to 76.92% of patients in the febuxostat group. Recurrent gout flares were 10% for the placebo group and 6.56% for the febuxostat group during the remission period.

The study was limited by being conducted at 3 separate centers, as the consistency of diagnosis could not be guaranteed. Additionally, since the placebo was not identical in appearance to the febuxostat, investigators theorized that there may have been some observational bias from participants who noticed the difference.

“We found that initiation of febuxostat administration during an acute gout flare did not prolong acute flares, and the rate of ‘treat to target’ was higher in the febuxostat group,” investigators concluded. “This may increase patient compliance.”

Jia E, Zhang Y, Ma W, et al. Initiation of febuxostat for acute gout flare does not prolong the current episode: a randomized clinical trial [published online ahead of print, 2021 Jan 6]. Rheumatology (Oxford). 2021;keaa908. doi:10.1093/rheumatology/keaa908

Initiation of Febuxostat Does Not Prolong Acute Gout Flares

Some treatments for rheumatic diseases have shown promise for treating COVID-19, but many should be avoided in patients with confirmed or suspected COVID-19. How much do you know about the use of treatments for rheumatic diseases in patients with COVID-19? Take our quiz to find out.

Rheumatoid Arthritis Quiz: COVID-19 and RA Treatment

investigators explored the connection between patients with systemic lupus erythematosus (SLE) and an increased risk of asthma and chronic obstructive pulmonary disease (COPD), which concurrently correlated with worse patient-reported outcomes (PROs) cross-sectionally.

Over the course of 3 years, investigators used 2 US-based SLE cohorts, FORWARD (The National Databank for Rheumatic Diseases in Wichita, Kansas) and the University of California San Francisco’s Lupus Outcomes Study (LOS), to examine prevalence, incidence, and impact of asthma and COPD for patients with SLE. They defined prevalence as the presence of the conditions at the onset of the study and incidence as any new reports over the 3 years. In the FORWARD group, participants received questionnaires every 6 months, while the LOS group collected data from annual telephone interviews. Both groups provided sociodemographic and health status details, which included smoking history. The PRO section asked about pain, sleep, health ratings, any depressive symptoms, lupus activity, and flare.

The mean age for the FORWARD group was 50.5 years and participants were 87.2% white non-Hispanic with a mean SLE duration of 15.8 years and 36.1% obesity. The LOS participants had a mean age of 46.7 years, 68.5% were white non-Hispanic, they had an SLE duration of 12.6 years, and 25.7% obesity. More than 90% of both cohorts were female and 40% had a history of smoking.

In the FORWARD cohort, both patients with asthma at baseline and those who developed it within the 3-year period were more frequently female, had obesity, and higher SLE activity ratings. Both patients with COPD at baseline or those who developed COPD tended to be older, obese, had lower incomes, a history of smoking, and had active lupus with a longer duration. In the LOS cohort, participants with asthma or COPD at baseline or those who developed it within the study period were generally older, had a history of smoking and obesity, had lower incomes and education, and rated their lupus as more active.

The Rheumatic Disease Comorbidity Index (RDCI) reported comorbid conditions including cardiovascular conditions, stroke, hypertension, depression, diabetes, cancer, ulcer, and fracture in the FORWARD cohort. LOS summarized conditions such as hypertension, heart disease, myocardial infarction, stroke, cancer, ulcer, and back problems.

A longitudinal analysis was created to compare preexisting asthma and COPD with the individual’s last observation at the end of the 3-year study. Two models were created, adjusting for baseline age, sex, race, disease duration, education, income, obesity, history of smoking, comorbidities, and lupus manifestations. The second model added the baseline value of the dependent variable (PRO) to account for any changes.

At the start, the LOS cohort reported 36% of patients with either asthma or COPD and the FORWARD group had 19.8% (487/2457) with asthma and 8.3% (179/2149) with COPD. During the course of 3 years, 87 reported asthma (4.4%) and 101 reported COPD (4.2%). The national average of adult females with asthma is 9.7% and COPD is 6.1%.

Analysis showed that asthma and COPD were associated with greater self-reported SLE activity and worse lupus-specific and generic PROs, even after adjusting for sociodemographic and health factors, including smoking. “A clear pattern of worse status on PROs was noted when comparing individuals with asthma or COPD and those without in both cohorts…Self‐reported SLE disease activity was also greater in those with these comorbidities,” stated investigators. “Symptoms from asthma and COPD may lead patients to perceive worsening in their SLE that would not be recognized in clinical assessments of SLE activity, potentially leading to discordance in patient and provider assessments.”

This study was limited by the possibility that self-reporting may lead to inaccuracies, including under-responding. Additionally, current smokers and those with low education are less likely to follow up, which can lead to underestimation. However, strengths of the study include the large size of the cohort and a variety of PROs.

“We found evidence of increased prevalence of asthma and COPD in these cohorts of individuals with SLE. We also found that the presence of these conditions was associated with worse status on physical function, fatigue, perceived cognitive function, and pain, all of which are important PROs in SLE, in both cohorts,” explain investigators. “These findings suggest that health care providers should routinely screen individuals with SLE for asthma and COPD and ensure that they are receiving adequate treatment for those conditions. In addition, counseling for smoking cessation and screening for occupational exposures that are linked to the development of pulmonary conditions is also advisable. Future analyses of PROs in SLE should also include asthma and COPD as important comorbid conditions.”

Katz P, Pedro S, Trupin L, Yelin E, Michaud K. The Impact of Asthma and Chronic Obstructive Pulmonary Disease (COPD) on Patient-Reported Outcomes in Systemic Lupus Erythematosus (SLE) [published online ahead of print, 2021 Feb 20]. 

. 2021;10.1002/acr2.11212. doi:10.1002/acr2.11212

Investigators explored the connection between patients with systemic lupus erythematosus (SLE) and an increased risk of asthma and chronic obstructive pulmonary disease (COPD), which concurrently correlated with worse patient-reported outcomes (PROs) cross-sectionally.