All or something: Experts debate LDA vs. remission as a target in rheumatoid arthritis
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Treating to target has, since the dawn of targeted biologic and non-biologic disease modifying anti-rheumatic drugs, permeated every aspect of rheumatology care.
Defining those treatment targets, however, is an inexact science.
The 2021 American College of Rheumatology rheumatoid arthritis recommendations suggest a goal of low disease activity, and not full remission, as the initial target for treatment. This has, among some experts, been controversial.
According to Bryant R. England, MD, PhD, of the Veterans Affairs Nebraska-Western Iowa Health Care System, and the University of Nebraska Medical Center, in Omaha, the patient voice was a key driver of the move to LDA.
“If you are a new patient and you are talking to your doctor about treatment goals, then you fail to reach remission, it can be demoralizing,” England told Healio Rheumatology. “This was an overwhelming message from our patient panel.”
Patients have used words like “failure,” “disheartening” and “defeated” to describe the experience of not reaching remission after months, or longer, of treatment, said England, who was one of the authors of the 2021 ACR recommendations for RA.
“Of course, our ultimate goal in an ideal situation is always remission,” he added. “LDA is a minimal treatment goal, an initial target. If you approach it that way, you see a lot more people being successful, and then you can build on that success.”
However, some rheumatologists, including Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center, in Dallas, see it a bit differently.
“Our initial goal should be remission, for two key reasons,” he said in an interview.
One reason is that the systemic complications of RA can put patients at risk for a number of associated and downstream comorbidities, including heart disease and malignancies. The other reason is that there is variability in the ACR-approved metrics for assessing disease activity: Disease Activity Score in 28 joints (DAS28), the Routine Assessment of Patient Index Data 3 (RAPID-3), the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI).
“The ACR guideline states that one can use any one of these measures,” Fleischmann said. “What is problematic is that if a patient is low disease activity by some of those metrics, such as the RAPID-3, they could still have very active disease determined by other metrics such as the CDAI or SDAI.”
Meanwhile, Daniel Aletaha, MD, MSc, associate professor of medicine in the department of rheumatology at the Medical University of Vienna, described the debate between LDA and remission, as an initial treatment goal, as simply “philosophical” and “semantic,” stating he understands the arguments on both sides.
“There is no debate that low disease activity is a less aspirational target than remission,” he told Healio Rheumatology. “What we need to understand is that different patients have different priorities and different psychological makeup. Some may understand the challenges in reaching for remission and accept low disease activity as the initial goal, but others may be disturbed by going for anything but the best.”
In addition to the concerns about comorbidities and disease assessment tools, other issues, ranging from the inclusion of patient voices in guideline development to improving conversations between rheumatologists and individuals with RA on a daily basis, are relevant. To fully understand the subject, it is important to understand the recommendation itself.
Source: Daniel Aletaha, MD, MSc.
‘Attention to the Patient Voice’
According to England, the ACR recommendation to use LDA as the initial treatment target for RA was born chiefly from listening to patient perspectives.
“The inclusion of the patient panel in developing these recommendations shaped this recommendation,” England said. “We really paid attention to the patient voice.”
However, England stressed that the evidence for this recommendation was based on a single observational cohort.
The study, conducted by Akdemir and colleagues and published in RMD Open, included patients with early active RA who were followed for 5 years.
The analysis included 133 patients who were treated to a target of DAS 2.4, which the researchers defined as LDA, and 175 patients treated to a target of DAS < 1.6, which they defined as remission.
Results showed that decrease in DAS score, functional ability and radiographic damage over time were similar in both arms. In addition, a similar proportion of patients in both treatment groups reached DAS 2.4. However, more patients who were targeted toward DAS < 1.6 reached that score.
“In patients with early active RA who start with comparable disease-modifying antirheumatic drug plus prednisonecombination therapy, subsequent DAS < 1.6-steered treatment is associated with similar clinical and radiological outcomes over time as DAS 2.4-steered treatment,” the researchers concluded.
England acknowledged the paucity of evidence for this recommendation, as is often the case in rheumatology.
“The evidence consisted of an observational study, so that is why the recommendation is conditional and not strong,” he said.
However, for Stanley Cohen, MD, clinical professor in the department of internal medicine at the University of Texas Southwestern Medical School, and co-medical director of the Metroplex Clinical Research Center, in Dallas, the decision to target LDA rather than remission in early treatment remains a pragmatic one.
“Of course we should still be shooting for remission, but the idea is that we should not be looking to switch or move to combination therapy in a patient who is doing well with low disease activity,” Cohen said.
Both England and Cohen suggested that the recommendation may not drastically alter clinical practice, or even how patients fare with current treatment paradigms.
That said, England raised a broader issue that may have consequences in RA care moving forward.
“The more important piece is the strong recommendation made for a treat-to-target approach,” he said.
In short, rheumatologists may use LDA as the target and a treat-to-target approach to reach therapeutic goals. However, these recommendations serve yet another purpose: “We can use them to shape and frame the conversation about that target with patients,” England said.
This is particularly important because patients in 2022 enter the clinic with the expectation that they will be part of the decision-making process for their care — and they come armed with a flood of information available online and from other resources. Rheumatologists can use the language in documents like ACR guidelines as a tool or starting point for discussing treatment goals with their patients.
Not a Matter of Either/Or?
England is adamant that in counseling patients about RA, the ideal goal continues to be zero disease activity.
“I tell my patients, ‘I want you to not even remember that you have RA, except for the fact that you have to take your medications,’” he said.
The issue is that setting the benchmark at perfection can be problematic.
“Every RA patient is different,” England said. “There is a spectrum of how active the disease is, from highly active — which can be terribly disruptive to a patient’s life and make her miserable — to a minor inconvenience, to not even knowing they have it.”
The goal, then, is to move patients from the “miserable and disruptive” column over to the other side.
“Like every rheumatologist I know, I would love to have every patient in remission,” England said. “The issue is that it is not remission at all costs.”
It is also important to understand that balancing risks and benefits is an important driver of the conversation with patients, according to England.
“We have to factor in the comorbidities, the risks associated with treatments and the number of previous therapies the patient has received,” he said.
Another essential aspect of the doctor-patient conversation, according to England, is being realistic.
“In some patients, achieving LDA, and not remission, may provide the best balance of benefits to risks,” he said. “To tell them otherwise could be problematic.”
Liana Fraenkel, MD, MPH, director of Patient Centered Population Health Research at Berkshire Medical Center, in Pittsfield, Massachusetts, and adjunct professor of medicine at Yale University, finds it helpful to communicate to patients that the question of LDA or remission is not, in fact, an either/or proposition.
“It should be clarified that both low disease activity and remission are important treatment goals in rheumatoid arthritis,” Fraenkel, another author of the ACR recommendations, told Healio Rheumatology. “However, the ACR felt that low disease activity was the preferred initial goal. A shared decision making approach could then inform whether or not patients would prefer to subsequently escalate care to achieve remission.”
Like England, Fraenkel noted that patients could be discouraged by the failure to reach remission.
“Conversations really need to be individualized,” Fraenkel said. “There is no reason not to first set a goal of low disease activity and then to continue the conversation over time to determine whether the patient would prefer to advance the goal towards remission.”
It is also critical to acknowledge that beneath the umbrella of LDA is a wide range of symptomatology, intensity of disease and quality of life (QOL) parameters, according to Fraenkel.
“Therefore, it is not surprising that some patients are content to remain at a target of low disease activity, whereas for others this level of disease activity is not acceptable,” she said.
Fleischmann agreed that the conversation should be individualized and noted that, as long as the discussion is frank and honest, even if the goal of remission is not reached, the patient is less likely to be disappointed.
“I tell my patients, ‘I am going to get you as close to remission as I possibly can,’” Fleischmann said. “If we don’t get there no matter what we do, but you see 75% improvement, it is going to make a world of difference.”
Although shared decision-making has become something of a buzzword in the field recently, Fleischmann said that it has “always” been part of his practice.
“Whatever the goal is, you have to have patients buy in,” he said. “Changing the goal will not change that. If you cannot agree on the treatment goal, it will be difficult for the patient to adhere to the medications you prescribe.”
Another concern Fleischmann has regarding the recommendation for LDA is that only 10 patients were on the panel, and that the patient interviews were led by one person. The resulting communication to the voting panel came from just two of the patients who spoke for the entire patient group. It is not clear that their recommendation was based on a unanimous decision of the patients or whether it reflected the bias of only two patients.
Part of that determination involves an assessment of the complications that may be seen in any given individual patient.
A Complicated Equation
The crux of the issue for Fleischmann is that patients with even very low disease activity can be at risk for several complications due to active and systemic inflammation, including MACE, malignancy, systemic inflammatory event, venous thromboembolism and mortality.
“This is part of the conversation I have with patients,” he said. “I let them know the risks if we do not reach remission.”
An emerging body of data describes these risks.
In a paper published in Rheumatology (Oxford), Nikiphorou and colleagues investigated function, QOL and structural outcomes in a cohort of 2,701 patients with early RA who were treated either to remission or LDA. Outcomes were assessed as a mean score between years 1 and 5. Remission was defined as DAS <2.6, while LDA was defined as DAS 2.6 to 3.2.
Results showed that 21% of the cohort reached mean remission, 12% reached mean LDA, 10% reached sustained DAS remission, 7.5% reached sustained low DAS activity and 3% reached sustained Boolean remission.
Patients in the mean DAS remission group demonstrated improvement across multiple parameters, compared with those with low DAS activity, including HAQ, Short Form 36 Health Survey Questionnaire (SF-36) in both the physical (PCS) and mental (MCS) component scores. In addition, remission bested low disease activity in Sharp van der Heijde (SvdH) score.
“I agree with Dr. Fleischmann that reaching remission is important not only to preserve joint integrity, but to preserve all organ systems at risk with systemic inflammation,” Aletaha said.
This is of particular concern because RA patients, almost across the board, are at an increased risk for these outcomes compared with the general population. In a paper published in PLoS One, Jeong and colleagues made just such a comparison.
“Patients with RA had more comorbidities including hypertension, dyslipidemia, myocardial infarction (MI) or angina, stoke, osteoarthritis, lung cancer, colon cancer, pulmonary tuberculosis, asthma, diabetes, depression, thyroid disease and chronic kidney disease,” compared with the general population, they wrote.
Fleischmann was clear about what to make of such findings.
“The lower you go in terms of disease activity, the better patients do,” he said.
According to England, rheumatologists now realize that RA is not just a joint disease, but a systemic disorder.
“Which is why we ultimately want to optimize disease control and, yes, get them into remission whenever possible,” England said.
He, like Fleischmann, noted that disease activity and the risk for cardiovascular outcomes, infections and other comorbidities are “dose dependent.”
“Another factor is that comorbidities are not unidirectional,” he said. “They are often present in patients and impact the way we treat them at the outset.”
The implication here is that patients with severe, or myriad of, complications beyond RA may not be excellent candidates for remission, which is why LDA may be the more universally applicable alternative.
“For example, a patient with a history of cardiovascular disease who has failed multiple biologic DMARDs is in low disease activity,” England said. “If you want to push them into remission, the next therapy you might typically choose is a JAK inhibitor. But new data on JAKs is showing a signal of higher CV events.”
For his own part, Cohen offered another key factor regarding the potential impact of treatment on certain patient populations: “You are unlikely to achieve remission in patients who already have significant joint damage,” he said.
It is the rheumatologist’s responsibility to sort out these often complicated equations pertaining to the risks and benefits of treatment strategies in their patients. Disease assessment tools are often a helpful, if imperfect, way to solve these equations.
‘No Gold Standard’ for Outcome Measures
The conversation surrounding the effectiveness, or lack thereof, of outcome measures is endemic throughout the rheumatology field. And the debate over LDA vs. remission is no exception.
According to Fleischmann, part of the issue is that patients who achieve low disease activity by some metrics may still have active disease.
“For example, if you assess the patient’s disease state with a RAPID-3, and they are in ‘remission,’ they may well have significant inflammation and have moderate or high disease activity by CDAI, DAS28 ESR or SDAI,” he said. “And remember, DAS28 CRP overestimates how well a patient is doing when using cutoffs validated for DAS28 ESR.
“The ACR recommendation suggests that DAS28 ESR is similar to DAS28 CRP when assessing disease activity,” he added. “This is a major fault of the ACR recommendations with dire consequences for patients.”
England acknowledged that there is “no gold standard” disease activity measure for RA.
“DAS28 is an effective clinical trial measure, but even with patients in DAS28 remission, if you do an MRI, you can find synovitis,” he said.
The issue, however, is not necessarily the synovitis, according to England.
“The question is whether the findings we observe on imaging will be clinically relevant down the road,” he said.
Despite their flaws, Aletaha said there are “great” outcome measures in RA.
“But in any individual patient, we may have to consider factors that are not measured by any metrics,” he said. “Our disease activity measures do not cover everything, including side effects, worries and other issues that impact patient lives.”
Meanwhile, Cohen suggested a practical consideration.
“It may be useful to consider an overall treatment paradigm that includes not just the biologic or DMARD, but medications to control pain, sleep or even cardiovascular outcomes,” he said.
Taking a hard look at these outcome measures, and their limitations, could ultimately benefit patients with RA, according to Aletaha. However, perhaps the final piece of the puzzle comes back to the original idea of patient satisfaction. For all the ability to assess joint damage or synovitis, treatment success may ultimately best be determined by whether the patient feels good or not.
Hurt, Tired and Sleep Deprived
“Someone can be doing well in terms of the disease assessment tools, but they might not meet the criteria for remission because of ongoing pain syndrome impacting their patient global,” Cohen said. “Or they may just not be feeling well in general. So, what happens is the outcome measures sometimes fail us because the patient is having symptoms related to other factors, such as fibromyalgia or degenerative disc disease, not pertinent to their RA disease activity.”
Data have shown evidence of this phenomenon. In a review paper published in Modern Rheumatology, Ishida and colleagues assessed findings from 68 published papers that described residual symptoms and disease burden among patients treated to the target of remission vs. LDA. According to the findings, patients in remission and LDA experienced ongoing pain, fatigue and morning stiffness, along with mental health comorbidities, sleep disturbance, reduced work productivity, functional disability and impaired QOL.
“Patients do not come into my clinic and say, ‘I have a CDAI of 12 and want to get it below 4,’” Cohen said. “They come in and say, ‘I hurt. I’m tired all the time. I can’t sleep.’”
According to Cohen, the job of the rheumatologist is to determine the amount of disease activity that is causing these QOL disruptions and act on them.
“Whatever the target, that still needs to be an essential treatment goal for our patients,” he said. “We need to understand their quality of life.”
For Fraenkel, the discussion of disease activity measures and QOL highlights the importance of communicating with patients.
“The most important thing is to engage in shared decision making with our patients to make sure that we are adjusting treatment plans in order to meet each patient’s goals and respect their preferences,” she said.
Looking to the future, Aletaha challenged the rheumatology research community to continue to search for biomarkers that can allow clinicians to hit targets with even greater precision.
“Whatever the goal is, whether it is LDA or remission, we as rheumatologists can see when our patients are not doing well and need a new drug,” he said. “We know that another drug or class may have an incremental benefit to get them to the next level, but we do not yet have biomarkers that can tell us exactly how to get there. This is where I hope we will make progress in the next couple of years.”
- References:
- Akdemir G, et al. RMD Open. 2018;doi:10.1136/rmdopen-2018-000649.
- Fraenkel L, et al. Arth Care & Res. 2021;doi: 10.1002/acr.24596.
- Ishida M, et al. Mod Rheumatol. 2018;doi: 10.1080/14397595.2017.1416940.
- Jeong H, et al. PLoS One. 2017;doi:10.1371/journal.pone.0176260.
- Nikiphorou E, et al. Rheumatology (Oxford). 2020;doi: 10.1093/rheumatology/kez461.
- For more information:
- Daniel Aletaha, MD, MSc, can be reached at Spitalgasse 23, 1090 Wien, Austria; email: daniel.aletaha@meduniwien.ac.at.
- Stanley Cohen, MD, can be reached at 8144 Walnut Hill Ln., Suite 800, Dallas, TX 75231; email: arthdoc@aol.com.
- Bryant R. England, MD, PhD, can be reached at 986270 Nebraska Medical Center, Omaha, NE 68198; email: bryant.england@unmc.edu.
- Roy Fleischmann, MD, can be reached at 8144 Walnut Hill Ln., Suite 810, Dallas, TX 75231; email: rfleischmann@arthdocs.com.
- Liana Fraenkel, MD, MPH, can be reached at 725 North St., Pittsfield, MA 01202; email: liana.fraenkel@yale.edu.
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