Patient-perceived flares in rheumatoid arthritis: A sub-analysis of the STRASS treatment tapering strategy trial

doi:10.1016/j.jbspin.2016.10.001

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Volume 84, Issue 5, October 2017, Pages 577-581

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Abstract

Objectives

Patient's and physician's perspective can differ in rheumatoid arthritis (RA). The aim was to define the concept of patient-reported flares.

Methods

Post-hoc analysis of a randomized controlled trial of a step-down strategy in RA patients treated with anti-TNF, in DAS28-remission for ≥ 6 months, randomized to either “spacing” or “maintaining” anti-TNF. The occurrence of patient-reported flares (PRF) was evaluated every 3 months for 18 months by: “Over the last 3 months, did you experience symptoms suggestive of disease exacerbation?”. Visits with and without PRF were compared, using a linear mixed effects model, in terms of symptoms, disability based on the Health Assessment Questionnaire, quality of life based on Short Form 36 Health Survey and DAS28-based relapses (DBR), defined as an increase of DAS28 > 0.6 and an absolute value of DAS28 > 2.6. The agreement between PRF and DBR was measured by the kappa coefficient on repeated data.

Results

In all, 137 patients were analyzed: mean age 55 ± 11 years, females 78%, mean RA duration 9.5 ± 8.0 years. Over the 18 months, PRF concerned 27.2% of the 940 available visits. DBR and PRF were observed in 24% and 16% of 940 visits for 137 patients respectively. All the items were associated with PRF with standardized effect size between −0.58 (SF36 PCS) and 0.87 (DAS28). The agreement between PRF and DBR was moderate (κ = 0.44).

Conclusion

The concept of flare refers to more than just RA disease activity.

Introduction

The notion of “flare” refers to a disease exacerbation as assessed by the patient. There is currently no consensual definition of flare in rheumatoid arthritis (RA), although some authors described it as a cluster of symptoms of sufficient duration and intensity to require initiation, increase or change in therapy [1], [2], [3], [4].

The concept of patient-reported flare has been found to be important for RA patients [1], [4]. Hewlett et al. reported that flares in RA as expressed by patients usually were related not only with arthritis-related symptoms (e.g. synovitis or joint effusion), but also with more general feelings or well-being parameters [4]. This has been confirmed by Berthelot et al. [2]. However, whether the concept of flare corresponds to a well-defined entity is questionable: what is the frequency of patient-reported flare (PRF) in RA patients with stable treatment? Are PRF and DBR concordant, or in other terms, how patient opinion does fit with medical assessment, i.e., DAS28-based relapse (DBR) [5], [6]?

In the context of shared decision-making [7], a better understanding of what patients refer to as flares, would be useful. This has been recently highlighted in the context of DMARDs tapering strategies, which have been proposed to optimize DMARD treatment in RA patients in low disease activity or remission [8], [9], [10]. In these disease activity-driven down-titration strategies, RA flares or relapses should be strictly monitored in order to rapidly adjust DMARD therapy [11]. In such trials, patient-perceived flares might be used as a relevant outcome measure to assess feasibility, benefits and risks of tapering strategies. With regards to this, the concordance between the patient perspective, i.e., PRF, and the medical perspective, i.e., DBR, deserves more attention [5].

The STRASS trial is a randomized controlled trial in which a disease activity-driven tapering strategy based on progressive spacing of biologic disease-modifying antirheumatic drugs (bDMARDs) was compared to their maintenance at full dose [12]. During the study, both PRF and DBR were assessed. This enables to investigate the notion of flare from the patient perspective, and to compare it with other disease characteristics, particularly relapse as defined by physicians.

Section snippets

Methods

This is an ancillary study of the STRASS randomized controlled trial [12].

Study population

One hundred thirty-eight patients were randomized, 73 to the maintenance arm and 64 to the spacing arm, one patient withdrew consent, data of flares were available in 134 patients (Table 1). Sixty-three patients were treated with adalimumab and 74 with etanercept. At baseline, 104 (77.6%) patients were women; the mean age of patients was 55.5 ± 11.0 years, the mean disease duration 9.5 ± 8.0 years and the mean DAS28 1.8 ± 0.6. The primary analysis of this trial showed a standardized difference of 19%

Discussion

The present study demonstrates that patient-reported flares are only partly concordant with DAS28-based relapse, i.e., physician-detected flares. Our results confirm the hypothesis that the concept of flare partly differs between patients and physicians and correlates with presence of arthritis-related symptoms [2], [4].

In the patient perspective, the dominant reported symptom related to flares was pain. However, pain during flares was usually associated with another symptom (nocturnal

Disclosure of interest

The authors declare that they have no competing interest.

Laure Gossec has received fees for speaking and/or consulting from AbbVie, BMS, Celgene, Janssen, MSD, Novartis, Pfizer/Wyeth, Roche and UCB.

Bruno Fautrel has received fees for speaking and/or consulting from AbbVie, BMS, Celgene, Janssen, MSD, Pfizer/Wyeth, Roche and UCB.

Acknowledgements

The authors wish to thank all the patients who participated in the trial, as well as the investigators of the inclusion centers: Dr S. Pavy (Bicêtre Hospital, Paris); Pr P. Dieudé (Bichat Hospital, Paris); Dr M. N’Guyen and Pr M. Dougados (Cochin Hospital, Paris); Pr F. Lioté (Lariboisière Hospital, Paris); Drs A. Economou, C. Fevre and Pr X. Chevalier (Créteil); Dr V. Foltz and Dr B. Banneville (Pitié Hospital, Paris); Dr J. Sellam and Pr F. Berenbaum (St-Antoine Hospital, Paris); Dr M. De

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Validation of flare-RA, a self-reported tool to detect recent or current rheumatoid arthritis flare

Arthritis Rheumatol

(2016)

Cited by (9)

Differences and Determinants of Physician's and Patient's Perception in Global Assessment of Rheumatoid Arthritis
2022, Reumatologia Clinica
The impact of a disease flare during tapering of DMARDs on the lives of rheumatoid arthritis patients
2020, Seminars in Arthritis and Rheumatism
Citation Excerpt :
However, the POET trial did show that stopping the TNF-inhibitor had a significant short-term impact on physical and mental health status compared to patients who continued their TNF-inhibitor [31]. Furthermore, the STRASS trial investigated whether the patient's perspective of a flare was the same as the physician's perspective of a flare, which was measured with the DAS28 [32]. The investigators concluded that the patient reported flare overlapped with the DAS28-based flare.
To determine the impact of a disease flare on patient reported outcome measures (PROMs) in rheumatoid arthritis (RA) patients, who are tapering treatment.
Data were used from the TARA trial; a multicenter, randomized controlled trial in which RA patients, with a well-controlled disease (DAS≤2.4 and SJC≤1) for at least 6 months, gradually tapered their DMARDs. PROMs of patients with a flare (DAS>2.4 and/or SJC>1) were compared every three months before and after a flare with their own norm values. Linear Mixed Models were used to investigate whether a disease flare influenced functional ability (HAQ-DI), fatigue (BRAF-MDQ), quality of life (EQ-5D and SF36), anxiety and depression (HADS), morning stiffness, general health (GH) and worker productivity, and if so, the duration was determined. For unemployment and sick leave we used descriptive statistics.
A flare negatively influenced GH, morning stiffness, HAQ-DI, EQ-5D, BRAF-MDQ, and the SF36 physical component scale and this effect lasted >3 months. Except for the HAQ-DI, effect sizes exceeded the minimum clinically important differences (MCIDs). For the physical outcomes effects lasted >6 months. Worker productivity was not significantly affected by a flare.
A disease flare influenced patients’ lives, the largest effect was seen in the physical outcomes, and lasted 6 months. Although on a group level effect sizes for the separate PROMs were not always significant or larger than specific MCIDs, a disease flare can still be of great importance for individual patients.
Definition and construct validation of clinically relevant cutoffs on the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire
2020, Seminars in Arthritis and Rheumatism
Citation Excerpt :
The work on defining flare cut-offs with the RA flare questionnaire (RA-FQ) developed by the OMERACT group is ongoing [15]. Other studies have also reported moderate agreement between patient-reported flares and DAS28-based flares [16]. The discrimination for the cut-offs on the general subscale in our study was somewhat lower, particularly for “change of anti-rheumatic treatment” in patients with RA duration > 5 years, suggesting the general subscale may be driven by cumulative joint damage or other issues that may not require immediate treatment adjustment.
The Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire was devised for the detection of flares in patients with RA. We aimed to define construct validity and cut-off(s) for the FLARE-RA questionnaire.
This cross-sectional study included adult patients with prevalent RA (2010 ACR/EULAR criteria) attending outpatient rheumatology clinics in France (n = 138), Denmark (n = 253), USA (n = 75), and Argentina (n = 105). Flare occurrence over the past 3 months was assessed with the FLARE-RA questionnaire scoring from 0 (no flare) to 10 (maximum flare). The cut-offs for the FLARE-RA score were defined using the following anchor items obtained at the same encounter: (1) Patient report of flare; (2) DAS28-CRP > 3.2; (3) Change of anti-rheumatic treatment, based on the area under the receiver operating characteristic curve (AUC) and distance to (0,1).
Four hundred seventy four patients with RA duration ≥2 years (mean age 58.6 years, 74.9% female) were included in the main analysis. The discrimination for the FLARE-RA cut-offs was acceptable-to-excellent: AUC for the global FLARE-RA score ranged from 0.71 to 0.92. The cut-offs for the FLARE-RA score were lower using “patient report of flare” than DAS28-CRP and “change of anti-rheumatic treatment”. Proposed FLARE-RA cut-offs for clinical detection and change of anti-rheumatic treatment are 2 and 5, respectively, for patients with RA duration 2–5 years, and 2 and 3.5, respectively, for patients with RA duration >5 years.
Proposed FLARE-RA cut-offs have acceptable discriminative capacity across the tested anchor items and are expected to aid in early recognition and timely management of RA flares.
How is symptom flare defined in musculoskeletal conditions: A systematic review
2018, Seminars in Arthritis and Rheumatism
Citation Excerpt :
DAS 28 was sensitive (88–100%) but not specific (57–65%) to the identification of a flare [53]. Portier et al. [54] showed difference in conceptualisation of flare between patients and DAS28 (which was considered to reflect the physician’s opinion; Kappa 0.44). Patient-reported flares emphasised physical and mental domains, but joint pain was rarely indicated as the only flare symptom (16.8% of the total flares).
To systematically review the definitions for “flare” in musculoskeletal conditions, the derivation processes, and validation of definitions for the 12 most burdensome musculoskeletal conditions.
A literature search was conducted in MEDLINE, EMBASE, CINAHL, AMED, PsycInfo and Lilacs to identify studies that investigated derivation or validation of a flare definition, which we considered as a phrase or group of domains.
Reports of derivation of flare definitions were identified for 9/12 musculoskeletal conditions. Validation of flare definitions was initiated for 4/12. For each condition, different derivation and validation methods have been used, with variable levels of consumer involvement, and in some cases different groups have worked on the process in parallel. Although some flare definitions began simply as “symptom worsening” or “change in treatment”, most evolved into multidimensional definitions that include: pain, impact on function, joint symptoms, and emotional elements. Frequently initial attempts to create phrase to define the term flare evolved into consensus on the breadth of domains involved. Validation has compared flare definitions/domains against measures of disease activity, clinicians’ diagnosis, response to drug therapy, or a combination.
This review suggests that greater characterisation and definition of flares in musculoskeletal conditions are linked to the inclusion of multiple perspectives, multifaceted domains and compound comparators for their validation. Further work is required to optimise and test the derived definitions for most musculoskeletal conditions. As some elements are disease-specific, flare definitions cannot be extrapolated to other conditions. Research regarding flare in back pain (most burdensome disease) is limited.
Insights Into the Concept of Rheumatoid Arthritis Flare
2022, Frontiers in Medicine
A workshop to improve the physician/patient relationship in the management of a chronic disease. An innovative learning approach based on involvement of a clinical psychologist and a communication teacher
2020, Pedagogie Medicale

View all citing articles on Scopus

¹: CRI-IMIDIATE, Clinical Research Network, France.

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Original articlePatient-perceived flares in rheumatoid arthritis: A sub-analysis of the STRASS treatment tapering strategy trial

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Study population

Discussion

Disclosure of interest

Acknowledgements

Developing a standardized definition for disease “flare” in rheumatoid arthritis (OMERACT 9 Special Interest Group)

J Rheumatol

A tool to identify recent or present rheumatoid arthritis flare from both patient and physician perspectives: the “FLARE” instrument

Ann Rheum Dis

Construct and criterion validity of several proposed DAS28-based rheumatoid arthritis flare criteria: an OMERACT cohort validation study

Ann Rheum Dis

“I’m hurting, I want to kill myself”: rheumatoid arthritis flare is more than a high joint count--an international patient perspective on flare where medical help is sought

Rheumatology (Oxford)

Patient self-assessment of flare in rheumatoid arthritis: criterion and concurrent validity of the Flare instrument

Clin Rheumatol

Validation of OMERACT preliminary rheumatoid arthritis flare domains in the NOR-DMARD study

Ann Rheum Dis

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

Ann Rheum Dis

Dose REduction strategy of subcutaneous TNF inhibitors in rheumatoid arthritis: design of a pragmatic randomised non inferiority trial, the DRESS study

BMC Musculoskelet Disord

Flare rate in patients with rheumatoid arthritis in low disease activity or remission when tapering or stopping synthetic or biologic DMARD: a systematic review

J Rheumatol

Evaluation of DAS28-based flare definitions in rheumatoid arthritis: data from a three year clinical trial

Arthritis Care Res (Hoboken)

Validation of flare-RA, a self-reported tool to detect recent or current rheumatoid arthritis flare

Arthritis Rheumatol

Original article
Patient-perceived flares in rheumatoid arthritis: A sub-analysis of the STRASS treatment tapering strategy trial