Issue: March 2021
Source: Ferreira RJO, et al. Ann Rheum Dis. 2018;doi:10.1136/annrheumdis-2018-214199.

Kvrgic Z, et al. Arth Care & Res. 2017;doi:10.1002/acr.23501.

Nowell WB, et al. Arth Res & Ther. 2021;doi:10.1186/s13075-021-02430-0.
Disclosures: Calabrese, da Silva and Ferreira report no relevant financial disclosures. Davis reports receiving research funding from Pfizer. Strand reports consulting fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi and UCB, as well as advisory board involvement with AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi and UCB.
March 17, 2021
12 min read
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Pursuing the ‘obvious ethical imperative’ of a dual-target strategy in RA

Issue: March 2021
Source: Ferreira RJO, et al. Ann Rheum Dis. 2018;doi:10.1136/annrheumdis-2018-214199.

Kvrgic Z, et al. Arth Care & Res. 2017;doi:10.1002/acr.23501.

Nowell WB, et al. Arth Res & Ther. 2021;doi:10.1186/s13075-021-02430-0.
Disclosures: Calabrese, da Silva and Ferreira report no relevant financial disclosures. Davis reports receiving research funding from Pfizer. Strand reports consulting fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi and UCB, as well as advisory board involvement with AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi and UCB.
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The last 2 decades of rheumatology management, including the treatment of rheumatoid arthritis, have been marked by improved drugs aiming at increasingly more refined therapeutic targets.

However, the question of whether those improvements have boosted patient satisfaction remains up for debate. It is for this reason that a movement toward a dual-target strategy for managing RA has arisen.

Source: Adobe Stock.
Source: Adobe Stock.

“The dual-target paradigm posits that we should have a disease activity target — including tender joints, swollen joints and acute phase reactant — and disease impact target, such as patient global assessment (PGA) or other patient-reported outcomes (PROs),” John M. Davis, III, MD, practice chair and vice chair of the division of rheumatology at Mayo Clinic and professor of medicine at the Mayo Clinic College of Medicine and Science, told Healio Rheumatology.

A growing body of evidence is showing that patients in near-remission with a persistently elevated patient global assessment typically do not experience improvement in domains such as pain, fatigue or physical function, even when inflammation is well controlled with disease-modifying anti-rheumatic drugs, according to Davis.

Of the body of evidence Davis referenced, the most direct call for a dual-target strategy was put forward in a paper by Jose A. P. da Silva, MD, full professor of rheumatology in the Faculty of Medicine and head of department, and Ricardo J. O. Ferreira, RN, PhD, a registered nurse in the rheumatology department, both from Centro Hospitalar e Universitário de Coimbra, in Portugal.

“We believe that the patient impact target should not be seen, necessarily, as a fixed and well-defined numerical objective, but rather as a flexible target depending on the patient’s abilities, comorbidities, resources and goals,” da Silva said in an interview. “The target could be defined as providing each patient with the best possible experience of the disease without forcing everyone to a common strictly-defined concept of remission.”

While many rheumatologists may get on board with this idea in the abstract, updating the very definition of disease remission in this way could prove challenging. In fact, with so many tools to assess disease activity available to rheumatologists, simply gaining consensus on how the dual-target strategy might be carried out seems like a long shot.

“In terms of the current target of remission, or at least LDA, the patient voice can get lost now when a patient rates their global assessment higher than the provider, yet management is not changed in some way,” noted John M. Davis, III, MD. “Patients in so-called near remission miss the target due to their elevated PGA while objective signs of inflammation are not present. How clinicians should address this situation is a gap in current treatment recommendations.”

Source: Mayo Clinic.

But it is a shot worth taking, according to Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic. “I am a very strong advocate for the dual-target strategy,” he said. “That is not to say that I am against the disease activity measures we have used for decades. The issue is that they provide an incomplete picture of the patient. The approach to diseases like RA and other conditions needs to be holistic.”

Advocacy from experts like Calabrese is one thing. Putting a novel approach like this into clinical practice is another.

There are questions pertaining to how the dual-target strategy fits in with other developments in rheumatology patient care, such as treat-to-target and shared decision-making. A fundamental reassessment of how rheumatologists and patients communicate may be required. And the effort to reach an effective dual-target paradigm will require education, time and a bedrock of clinical trials. Healio Rheumatology takes a closer look.

Redefining Remission

At the heart of the discussion is the fact that patients may be receiving enough medication to reach remission in terms of disease activity targets, but not in terms of the impact on functioning and well-being.

In the study by da Silva and Ferreira in Annals of the Rheumatic Diseases, it was suggested that between 12% and 38% of patients with RA fail to reach remission as defined by disease activity indices, solely due to a PGA score >1.

This result has one important consequence, according to the researchers: overtreatment. This, obviously, comes with its own perils, but there are other concerns as well.

“Many studies have shown that in this situation, the persistently elevated PGA typically correlates with remaining pain, fatigue or depressed mood,” Davis said. “Health domains such as pain and fatigue are partially independent from inflammatory disease activity, such as peripheral or central sensitization, secondary fibromyalgia, and even more so when inflammation is not evident by physical examination or laboratory testing.”

For da Silva, the concept of remission should be integrated with the movement toward personalized medicine seen across health care specialties. While they acknowledged that their own concept of remission “is not established,” he and Ferreira offered a guiding light for the way forward.

Jose A. P. da Silva, MD
Jose A. P. da Silva

“In our proposal, a three-variable definition of remission — including tender and swollen joint counts and CRP — might be appropriate to this purpose,” da Silva said. “We and others have provided substantial evidence that PGA of disease activity has a very poor relationship with the inflammatory process, especially in low levels of disease activity. We have also demonstrated that the three-variable definition of remission is more reliable than the current four-variable definition in predicting good radiographical outcome.”

“The percentage of three-variable remission will probably increase by 40% to 60% over that of four-variable remission,” da Silva added. “However, the dual-target strategy emphasizes that remission of the inflammatory process is not the highest-ranking objective: it is simply a very important means to achieve what really matters, which is the patient’s enjoyment of life, in the short and long term.”

Ricardo J. O. Ferreira, RN, PhD
Ricardo J. O. Ferreira

Davis brought the issue back to the root of the discussion in the first place. “In terms of the current target of remission, or at least LDA, the patient voice can get lost now when a patient rates their global assessment higher than the provider, yet management is not changed in some way,” he said. “This is the problem specifically that is addressed by Ferreira and colleagues in the dual-target paradigm. Patients in so-called near remission miss the target due to their elevated PGA while objective signs of inflammation are not present. How clinicians should address this situation is a gap in current treatment recommendations.”

If there is a final piece of the puzzle regarding the definition of remission, it is that patients may not completely understand it, either because it is a difficult concept to comprehend, or because remission can mean different things to different clinicians, or because it has not been properly explained. “It would be easier for most patients to define their own meaningful goals,” Ferreira said.

Right Tool for the Job

Despite their confidence in the dual-target approach, da Silva and Ferreira acknowledge that there is still work to be done to properly define the relevant targets, particularly given that there are already a number of ways to measure both disease activity and patient satisfaction available to clinicians and researchers. One key question in the discussion is whether to create new tools for assessing both clinical and patient-centered outcomes or to refine existing measures.

“We have plenty of tools,” Vibeke Strand, MD, adjunct clinical professor in the division of immunology/rheumatology at Stanford University School of Medicine, said in an interview. “The issue is that we have lots of measures for clinical trials, but not as many for clinical practice.”

Vibeke Strand, MD
Vibeke Strand

Given time constraints in the clinic, Strand said that the ideal measures should be easy to interpret, efficient and easily transferable into an EMR format. “We mostly use CDAI, or if you have a CRP or sedimentation rate, you do an SDAI,” she said.

In terms of assessing patient outcomes, Strand believes that the routine assessment of patient index data 3 (RAPID-3) tool could be effective with one important modification: “It does not take into account fatigue, which is so important to so many of our patients,” she said.

Modifying RAPID-3 to include a fatigue domain would be a good step toward reaching the patient-centric target, according to Strand. But whether consensus would gather around this suggestion remains to be seen.

“We believe that the rheumatoid arthritis impact of disease score (RAID) in seven separate items represents a very promising tool to this end,” da Silva said. “According to the available data it might not be used as a defined numerical target but rather as a guide to seek continuous improvement of the disease impact, open to the individual patient’s preferences and goals. The therapeutic means to seek this objective are not well established at the moment but may justify rather simple adaptation in practice in the future.”

While experts sort through measures for disease assessment parameters and how they may or may not apply to the dual-target approach, rheumatologists in both the clinic and the community are grappling with ways to include patients in the discussion of their RA.

Shared Decision-making

It is impossible to overstate the importance of shared decision-making in this discussion, according to da Silva. “The movement toward shared decision-making is strong in all fields of medical care, and it emerges as an obvious ethical imperative in modern medicine,” he said.

Using shared decision-making in a dual-target approach requires tailoring the interaction to the individual patient and their needs, according to Strand. This can help build trust that will ultimately lead to therapeutic success in terms of both disease activity parameters and patient satisfaction. “When you simply show the patient that you can help them in a way they would like to be helped, then you have started to build that trust,” she said.

Ferreira offered an example of this point. Disease activity parameters aside, patients may just want to sleep better, or for longer. “This may include a tailored plan for increased physical activity, changing food or drinking habits before going to bed, not using digital screens after dinner or adjusting medication scheme,” he said. “We believe that the dual-target, by clearly separating targets and by promoting access to multidisciplinary team, will prompt patient participation, decisions and satisfaction.”

Strand acknowledged, however, that shared decision-making requires investment on behalf of the clinician. “Have you offered patients enough information and education?” she said. “Have you recommended the right resources, or provided opportunities for communication with other patients about medications?”

To solve these problems, Strand recommends patients check out CreakyJoints.com or find a patient support group. After they have done so, she then conveys one important message: “Come back with questions, and I will answer them,” she said.

If there is another issue that can inhibit shared decision-making in the clinic, it is time constraints, according to Ferreira. “This forces the clinicians to select the most important issues and tasks,” he said. “Although shared decision-making would ultimately facilitate the achievement of the medical targets, this is not implemented by many and we completely understand.”

There is no doubt that shared decision-making is growing in acceptance in the rheumatology community. But to fully employ the dual-target strategy, it may be necessary to improve overall communication between rheumatologists and their patients.

Empathetic Communication

Davis was an author on another key paper in 2017 that pushed RA treatment toward a dual-target strategy. The title of this paper from Kvrgic and colleagues in Arthritis Care & Research includes a quote from a patient: “Like no one is listening to me.”

Leonard H. Calabrese, DO
Leonard H. Calabrese

“That title says it all,” Calabrese said.

The researchers recruited 20 patients with RA who had reported patient-provider discordance as defined by an absolute difference of 25 or more between global assessments on a visual analog scale (VAS) of disease activity.

Metrics used included the Health Assessment Questionnaire (HAQ) II, pain VAS, and Patient Health Questionnaire 9 depression scale. In addition, patient interviews were conducted.

Results showed six major themes of discordance and disease assessment: “being misunderstood by others, limitations of provider assessments, discrepancy with provider findings, inadequate active listening on the part of health care providers, unmet psychosocial needs, and lack of patient empowerment,” the researchers concluded.

Strand believes that simply listening to a patient can have a “huge impact” on both their satisfaction levels and their treatment outcomes. She offered practical advice for how to make patients feel heard in the clinic. “I never did charts while talking to a patient,” she said. “I never typed information into their EMR while talking to them.”

Focusing on the patient, rather than the disease, is also critical, according to Strand. “I would never ask, ‘How is your arthritis?’” she said. “I ask patients: ‘How are you doing?’”

In discussing the Kvrgic paper, Calabrese recalled the words of the physician Eric Cassell. “He reminds us that the diagnosis of RA is what we give to the patient, but the patient experiences an illness that affects every part of their being, mind, body and soul,” he said.

Paying attention to emerging data can help clinicians understand how, exactly, the disease impacts their being. For example, recent findings from Nowell and colleagues in Arthritis Research & Therapy demonstrated that the PROs ranked as most meaningful for tracking were PROMIS fatigue, physical function, pain intensity, pain interference, duration of morning joint stiffness and sleep disturbance.

That said, the data may only bring a rheumatologist so far in understanding the patient experience. “Doctors are very good at sorting out chief complaints,” Calabrese said, and acknowledged that the average rheumatologist can find the source and duration of a patient’s pain, and what makes it better or worse. “We are not so good at sorting out chief concerns, life concerns.”

Calabrese recounted some of the anxieties he has heard from patients. “I am afraid of losing my job. My sex life with my partner is nonexistent because of this disease. I am unable to play with my children or grandchildren,” he said. “It is harder to find information about this in clinical trials, and it is not captured in a CDAI.”

An interesting twist in this discussion pertains to the increasingly more robust therapeutic armamentarium on which rheumatologists can rely, according to Calabrese. “An ironic consequence of this wealth of drugs we have been handed over the past 20 years is that while we can do incredible things to slow radiographic progression and reduce inflammation, it can also allow us to minimize the patient’s perspective of their own illness,” he said.

There may be a practical reason to listen to patients about their response to any given medication, noted Strand. “You can’t just go running through therapies without seeing why someone is not doing well,” she said. “If you do that, you may never find the drug that is most effective.”

In addition, it may be necessary to reconsider the exact role all of these drugs should play in the clinic and in the patient’s life, according to da Silva. “Even the core immunosuppressive agents would now be seen in a different and more positive light, as instruments to serve the patients’ elected goals,” he said.

Putting it into Practice

If the dual-target approach is going to become part of standard rheumatology practice, Ferreira suggested that a reorganization of certain parts of the specialty is necessary. “It consists of a progressive investment in establishing a multidisciplinary rheumatology team or network that will allow for the proper assessment and ongoing management of additional targets,” he said. “These complementary targets may be identified with the support of the patient-reported outcome measures, or more widely.”

These are big changes, and it is for this reason that the dual-target strategy “may not be ready for prime time,” according to Davis. “Ultimately, further development and testing of this new paradigm will be required before implementation in routine clinical practice,” he said.

In particular, knowledge and skills pertaining to the measurement and interpretation of PROs will be necessary for all clinicians to develop. “Patients and clinicians will need high-quality evidence about the benefits versus potential harms they can realistically expect for various management options to improve patient-important health domains,” Davis said, noting that deeper understanding of non-pharmacologic management of diseases and conditions is essential. “There are concerns about further complicating targets in routine clinical practice, so feasibility would need to be tested.”

Once the paradigm is established, Davis suggested that support systems to facilitate the accomplishment of these goals are required. “The development of the dual-target paradigm could actually foster greater communication around the issues that are impeding improvement in health status and quality of life for many patients,” he said.

Hope for Widespread Acceptance

Strand offered a practical opinion as to whether a dual-target approach featuring shared decision-making and more empathetic communication is likely to take hold across the rheumatology community. “Of course, there are many places in the country where there is only one rheumatologist,” she said. “But anywhere there is more than one, the more popular rheumatologist is going to be the one who actually talks to her patients and listens to her patients.”

Organizations like ACR and EULAR will be critical to evolution of the specialty, as well, according to Davis. “It is important for these organizations to continue to include patient partners in the development of treatment guidelines,” he said. “Moreover, the patient voice should be included at an early stage during the conception of the approach for target development.”

Da Silva and Ferreira state that they “honestly believe” that the dual-target strategy is the best current proposal to ensure that the patient voice is clearly and regularly heard. Ferreira anticipates that “this approach will also promote a stronger interprofessional collaboration, including specialist nurses, physiotherapists, occupational therapists and psychologists, among many others.”

“The patients will now have a target of their own, that they can comprehend and use to communicate with their caring physicians,” da Silva said. “We hope that many rheumatologists will adhere to future recommendations on how to define and use this target to the best possible interest of the patient.”