The introduction of biological disease modifying anti-rheumatic drugs (DMARD) has led to substantial improvements in the management of patients with rheumatoid arthritis (RA) during the past 2 decades. However, there remain significant gaps in RA treatment, largely stemming from the heterogeneous and complex nature of the disease. Specifically, recognizing an RA flare represents an ongoing challenge for clinicians due to the range of potential factors that may characterize a flare and the various instruments available to assess for flare, among other aspects.1

In a review1 published in March 2022 in Frontiers in Medicine, Bozzalla-Cassione et al assert that the concept of flare in RA is “blurred,” stating that the “difficulty lies in the complexity of the multifaceted manifestations of rheumatoid arthritis, where subjective and objective domains converge in determining disease activity.” While the current criteria for the definition of RA flare represent an important starting point in elucidating the concept in research, they “still appear to lack those desirable omni-comprehensive capabilities for the routing application in real-life clinical practice.”1

To gauge clinician perspectives on the topic, we spoke to several rheumatologists: Arthur M. Mandelin, MD, PhD, associate professor of medicine in the division of rheumatology at the Feinberg School of Medicine at Northwestern Medicine in Chicago; Maria I. Danila MD, MSc, MSPH, associate professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham; and Vivian P. Bykerk, MD, FRCPC, director of the Inflammatory Arthritis Center at Hospital for Special Surgery in New York and member of the OMERACT Flare Group.


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What are your thoughts about the suggestion by Bozzalla-Cassione et al1 that the concept of RA flare is “blurred”?

Dr Mandelin: I could not agree more with the study authors regarding the concept of RA flare being “blurred.” As they correctly point out, we have no solid understanding of how a flare happens at the pathophysiologic level, and we have no biomarker for the flare state. While disease activity measurement is now, in my opinion, quite good in terms of practical day-to-day clinical use, even this is not adequate to define a flare because the experience of a flare is a broad state of being that goes beyond disease activity alone.

As the article points out, more experienced patients may be more practiced at adapting to flares and thus less likely to consider their disease to be flaring than patients who are adjusting to having a new diagnosis of RA. Different patients will have different levels of need for disease control. A person with an office job might not be as strongly affected by a transient increment in their pain from 4 out of 10 to 6 out of 10 and might not report this as a flare, whereas someone who works outside exposed to the elements and on their feet all day might view the same increase in disease activity as very troublesome.  

Dr Danila: I agree that the concept of a flare or disease exacerbation in RA is “blurred.” This is because, in practice there are different definitions that are used, and patients and their rheumatologists do not always agree about whether a flare is present. There are many facets of disease that are included in the concept of a flare, including the presence of joint pain and stiffness, limitation in function, and systemic issues such as fatigue. There are also many instruments that can be used to define an RA flare, all contributing to a flare’s heterogeneity.

Dr Bykerk: Flare is a difficult concept for a few reasons, but I would not say it is blurred. We have addressed many of the flare constructs: domains, escalation of worsening, state of worsening, patients’ and clinicians’ perspectives, and management. Some key questions and points to consider include:

  • Is flare the process of worsening inflammation in the synovial tissue (ie, “flaring”)? Is flare the state of increased synovial inflammation once the flaring has stopped escalating (“in a flare”)? This has been a contentious point of discussion for all flare researchers, as the latter arguably is a new disease activity state.
  • Defining flare, whether it is the actual phase of escalation or the new state of worsened disease activity, is also contentious from the perspective of who defines it. Patients have repeatedly stated that they know what a flare is and they will tell the doctor when they are ready to consider a change in treatment, aside from a temporary use of glucocorticoids. There are 5 patient domains that can be used to measure flare: pain, function, fatigue, stiffness, and social participation.2 In research, clinicians have defined flare using a change in a composite clinical disease activity measure. For example, a worsening of the Disease Activity Score-28 (DAS28) by 1.2, which is 2 standard deviations around the DAS28 disease activity estimate.1
  • There has been much research around what amount of worsening, as measured by a clinical composite index, constitutes meaningful worsening. This is not the inverse of a meaningful improvement. For instance, a clinical disease activity index (CDAI) improvement of 10 to 12 reliably identifies improvement, but a CDAI of 2 to 7 identifies a flare when compared to other measures of transition. We have published3,4 this and explored thresholds using multiple definitions of flare, including DAS28 flare, patient and physician global assessments of flare, and use of single transition questions such as, “Are you much worse, somewhat worse, or the same?”
  • One other issue is “from where you start.” If RA inflammation is already high (ie, disease activity measures are in the moderate to high range), neither patient nor clinician can reliably identify worsening as the process of disease escalation. The most reliable way to quantify flare is from a state of disease being in good control, meaning in remission or low disease activity (LDA). To extend this concept, most will define flare as loss of disease control, such as going from remission to LDA or from LDA to moderate or high disease activity.
  • An additional concept is defining flare in the context of treatment change; this is where duration comes into play. For instance, a 2- to 7-day flare, even if very intense on many domains, is unlikely to warrant a change in DMARDs and can be temporarily managed. Conversely, a duration of over a week, which we usually see flares 2 to 3 weeks in with no sign of improvement, might warrant a change or switch of long-term modulating therapy.

How do you define RA flare in your own practice?

Dr Mandelin: I define a flare as an increase in disease activity compared with the patient’s baseline, which has a negative impact on the patient’s level of function or causes the patient to put forth more effort or summon more stoicism in order to maintain their baseline level of function. Most of the time, determining whether a patient is flaring is a matter of patient-reported outcomes. I take a “snapshot” of each patient at each visit by asking about pain levels, duration of morning stiffness, patient global assessment score, and the patient’s response to an open-ended request for a list of common activities that are currently more challenging than they should be or more challenging than they were before the patient developed RA. 

Dr Danila:In my own practice I use the Clinical Disease Activity Index (CDAI) to monitor disease activity and the context of disease because the presence of other diseases such as osteoarthritis can influence CDAI. I find that CDAI is easy to calculate, has both subjective and objective components and helps me guide treatment. Unfortunately, I cannot use the CDAI for telemedicine visits, so for those visits, flare definition is more subjective. 

Dr Bykerk: The contentious issue with flare is when regional soft tissue non-articular pain or centralized widespread nociplastic pain comes into play, such as myofascial pain, referred pain, or generalized pain due to central sensitization. This is why the Flare Group3,4 defined flare as the worsening of inflammation in synovial tissues and the use of disease worsening, which in our case refers to RA manifestations, became the common way to phrase “flare.”

What are other considerations for clinicians regarding this topic? 

Dr Mandelin: I think it is important to always be willing to recognize that “flare” means different things to different people, and that since we lack fully objective measures of disease flare, the determination of who is flaring and how badly will continue to depend entirely on asking a few carefully-worded, open-ended questions and then taking the time to listen to the patient’s complete response while resisting the temptation to cut the patient off short and continue with the rest of the visit. 

Dr Danila:I recommend that clinicians continue to listen to their patients. As patients get more “experience” with disease, their impression of what a significant disease flare is may change. We need to be careful not to underestimate the presence of flares, the so called “bad days.” 

Dr Bykerk: There can be a discordance between patient- and clinician-identified flare, but I would say if more specific information is gleaned from patients, then this discordance is easily resolved. That is, you need to know – a flare of what?

In my experience, it is clinicians who can most often discriminate, and most patients know the difference. More often than not, when a patient says they need to come in because they are flaring, they really are flaring. In the OMERACT Flare Group, following much work with a large group of international clinicians, metrologists, psychologists, and patients over a period of almost 10 years, we reached consensus that a flare can be identified when there is an increase in pain and function, a dramatic increase in fatigue, possibly an increase in stiffness, though patients often and understandably conflate stiffness and pain as they co-occur, and the flare impacts their lives. That is, their ability to do their work, usual day-to-day tasks, and planned social activities.

What should be the focus of future research in this area?

Dr Mandelin: I think we have to go all the way back to basic science and develop a better understanding of how RA works at the pathophysiologic level. Before we can truly have an objective measure of RA flare, we need a truly objective and accurate measure of RA disease activity. While our current metrics are useful for guiding medical decision-making on a practical level, they continue to rely on significant amounts of subjective data. 

Dr Danila:I think we need to better understand the biochemical processes that underline disease exacerbations or flares. Having a sensitive and specific biomarker of RA flare that is widely available would be exceptionally helpful in clinical practice. While several instruments have defined thresholds for flare, the OMERACT-RA flare instrument does not, and I would like to see work being done in this area. While our understanding of how to monitor disease activity in RA has improved, how many flares should be allowed before changing baseline treatment is also known. In addition, more work is needed to examine how a rheumatologist can assess flare remotely during telemedicine visits. Some groups, including our group at UAB, are doing some work in using thermographic camera images to assess joint inflammation and hope to help the field. 5

References

  1. Bozzalla-Cassione E, Grignaschi S, Xoxi B, et al. Insights into the concept of rheumatoid arthritis flare. Front Med (Lausanne). 2022;9:852220. doi:10.3389/fmed.2022.852220
  2. Alten R, Pohl C, Choy EH, et al; OMERACT RA Flare Definition Working Group. Developing a construct to evaluate flares in rheumatoid arthritis: a conceptual report of the OMERACT RA Flare Definition Working Group. J Rheumatol. 2011;38(8):1745-1750. doi:10.3899/jrheum.110400
  3. Bykerk VP, Bingham CO, Choy EH, et al. Identifying flares in rheumatoid arthritis: reliability and construct validation of the OMERACT RA Flare Core Domain Set. RMD Open. (2016) 2:e000225. doi:10.1136/rmdopen-2015-000225
  4. Bartlett SJ, Barbic SP, Bykerk VP, et al. Content and construct validity, reliability, and responsiveness of the rheumatoid arthritis flare questionnaire: OMERACT 2016 Workshop Report. J Rheumatol. 2017;44(10):1536–1543. doi:10.3899/jrheum.161145
  5. Echols H. Infrared cameras added to telemedicine visits for arthritis patients. UAB News. Accessed online July 6, 2022.