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Rheumatology Advance Access originally published online on June 6, 2008
Rheumatology 2008 47(8):1213-1218; doi:10.1093/rheumatology/ken176
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Assessment of the impact of flares in ankylosing spondylitis disease activity using the Flare Illustration

M. A. Stone1,2,3, E. Pomeroy1,2, A. Keat4, R. Sengupta1, S. Hickey1, P. Dieppe5, R. Gooberman-Hill5, R. Mogg1,2, J. Richardson1 and R. D. Inman3

1Royal National Hospital for Rheumatic Diseases, 2University of Bath, Bath, UK, 3University of Toronto, Toronto, Canada, 4Northwick Park Hospital, Harrow and 5MRC Health Services Collaboration Unit, Bristol, UK.

Correspondence to: M. A. Stone, Royal National Hospital for Rheumatic Diseases NHS Foundation Trust, Upper Borough Walls, Bath BA1 1RL, UK. E-mail: m.stone{at}bath.ac.uk


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Many AS patients report periods of perceived higher disease activity (flares). This pilot study aims to document disease activity patterns reported by AS patients and examine associations with disease-specific health status measures.

Methods. Consecutive AS patients (n = 114) were asked whether they experience flares, and if they experience symptoms of AS between flares. They were shown the Flare Illustration of disease patterns over time and asked to select the pattern that best described their disease (i) since symptom onset and (ii) in the past year. Associations between reported disease pattern and disease activity (Bath AS Disease Activity Index, BASDAI); functional impairment (Bath AS Functional Index, BASFI); AS Quality of Life (ASQoL); Back Pain (Nocturnal and Overall) and demographic features were assessed in a subsample (n = 83) (statistical significance defined at P ≤ 0.05).

Results. Since disease onset 108/113 patients (96%) reported flares, and 82/99 (83%) reported symptoms of AS between flares. Flares typically lasted days or weeks. When patients were asked to characterize their disease pattern using the Flare Illustration, patterns with constant symptoms predominated (>70% of patients) and patterns with constant symptoms since onset (vs intermittent symptoms) were associated with worse health status (ASQoL: P = 0.007; BASDAI: P = 0.029; BASFI: P = 0.013, overall back pain: P = 0.025).

Conclusions. Almost all AS patients report flares in disease activity: 70–80% report constant symptoms with single/repeated flares, while 20–30% report flares with no intermittent symptoms. The former is associated with a significantly poorer health status. These findings will be validated in a prospective study.

KEY WORDS: Ankylosing spondylitis, Disease activity, Flare, Outcome measures


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The arrival, at last, of a potent, effective but potentially toxic and expensive treatment (the TNF-blockers) for AS has made it imperative that individual patients be stratified according to likely outcome so that risks and benefits of biologic treatment can be balanced. The absence of good prognostic markers and the variability of symptoms both between and within individual patients make this assessment especially difficult. One such problem is the occurrence of episodes of relatively severe symptoms followed by periods of relative quiescence: how can we be sure that the clinical state at the time of assessment for biologic therapy actually reflects the real prognosis? The real course of AS in individual patients has been surprisingly little studied, as noted by the National Institute for Health and Clinical Excellence (NICE) in the context of their deliberations on the use of TNF-blockers in AS [1]. This work was undertaken, therefore, as a pilot study to help understand the significance of such symptom fluctuations or ‘flares’ in the context of AS disease-specific outcomes.

The concept of a ‘flare’ is commonly used with reference to periods of increased disease activity in various rheumatic conditions, including AS [2], SLE [3–7], RA [8–10], OA [11–13] and conditions associated with AS such as IBD [14]. For each condition, the medical definition of a flare has been problematic, often variable, and not always explicit. Definitions include increases in physician- or patient-rated disease activity/symptom scores; exacerbation of symptoms leading patients to seek increased or additional medication; levels of inflammatory markers; swollen or tender joint counts; and combinations of these. The concept of a ‘flare’ is also used in fields outside of rheumatology, including oncology [15, 16] and atopic dermatitis [17].

The definition of ‘flare’ has been particularly challenging in AS since objective measures such as inflammatory markers or joint counts are of limited value due to poor association with severe disease activity [18]. Brophy and Calin [2] sought to define flares in AS from the patients’ perspective and described two different types. All patients reported localized flares, characterized by acute pain above normal baseline levels and immobility in one area, such as the knee, neck, ankle or localized area of the back. Additionally, ~40% were affected by more infrequent generalized flares that were far more severe, affected the whole body and had more long-lasting effects.

However, the temporal variation in symptoms experienced by AS patients (or ‘disease pattern’), its variability between patients and the consequences of different disease patterns for clinical outcome and treatment remain inadequately understood. Therefore, we designed a pilot study to begin clarifying the nature and occurrence of flares in AS. The specific aims of this study were (i) to document the occurrence of flares in AS patients and to attempt to characterize disease patterns, (ii) to determine whether AS patients experience symptoms between flares, (iii) to investigate the implications of different disease patterns in terms of outcome measures and (iv) to consider some basic associations between different disease patterns and disease duration or gender. This study examines these issues using patient recall, and its results will provide the basis for a prospective study designed to validate our findings.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
A total of 114 AS patients from the SMART (Spondyloarthropathy Methodology and Research Therapeutics) programme were enrolled after signing written informed consent at the Royal National Hospital for Rheumatic Diseases (RNHRD), Bath, UK. The study had current ethical approval from the Gloucestershire Research Ethics Committee as part of the SMART Predictors of Outcome Study that aims to evaluate predictors of disease outcome in AS.

The attending rheumatologist (M.A.S.) asked patients (i) if they experienced flares in their disease, (ii) if they experienced symptoms of AS in between flares and (iii) how long the flares lasted (days, weeks or months). A flare was defined as an exacerbation of the disease that may have required additional treatment or necessitated a visit to a health care professional.

Patients were also shown the Flare Illustration representing possible patterns of disease activity (Fig. 1). The illustration was developed by two rheumatologists with expertise in AS following a formal consultation meeting with patient representatives and allied health professionals, who gave feedback on the design of the tool and the context in which it should be used. The illustration is easy and quick to use in the ambulatory setting, being administered by the physician to the patient and taking <5 min to complete. It consists of four possible patterns of disease activity. The patient is given a detailed explanation of each pattern as follows: Pattern A represents a scenario where patients experience a flare in disease activity and then return to an asymptomatic state in between flares. Pattern B represents flares with symptoms between flares. Pattern C represents a major period of flare that can be very intense or long lasting but with a subsequent return to a quiescent asymptomatic state until the next major flare. Pattern D represents a scenario where the patient experienced a prolonged or severe flare and thereafter returns to a baseline state in which some symptoms still persist.


Figure 1
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  		FIG. 1. The Flare Illustration shown to patients. The following patterns of disease activity are represented graphically. Pattern (A) Flares and remissions. During the remissions patients would be symptom free. Pattern (B) Flares with disease activity in between flares. Pattern (C) Severe flare lasting a long time and followed by return to a baseline for a long period of time without any symptoms. Pattern (D) This was similar to (C) except that patients did not return to a symptom-free baseline but had continued symptoms that were constant in nature over time thereafter.

 
The words ‘flare’ and ‘disease activity’ were explained to the patient to ensure that the patient understands what the doctor was asking them to do in reviewing the illustration. Each patient was given an identical explanation of the illustration in order to ensure that they understood what the patterns (A–D) represented. The schematic nature of the diagrams was emphasized, including the fact that the important features were the frequency of flares and the nature of intervening symptoms rather than precisely when a particular flare started or flares being of equal duration, as a literal interpretation of the figure could suggest. Patients were asked to select the pattern that best represented the variation in symptoms of AS they experienced.

Since the illustration is a new tool for investigating disease patterns in AS, test–retest reliability was assessed by asking 20 patients participating in the SMART Study and attending the 2-week AS rehabilitation course at the RNHRD to answer the same questions on two occasions 24 h apart.

All questions were asked with reference to two time periods: for the overall disease course (since first experiencing symptoms until present) and within the last year, as we were aware that recall bias would be an issue when asking patients to rate disease activity patterns overall the entire disease course, but may be less so in the last year.

To examine any potential relationship between the disease patterns depicted in the Flare Illustration and standard disease-specific health status measures, reported disease patterns (A–D) for 83 of the 108 patients reporting flares were compared with the following health status measures recorded at the same visit: the Bath AS Disease Activity Index (BASDAI) [19], Bath AS Functional Index (BASFI) [20], AS Quality of Life (ASQoL, scored on a scale of 0–18, higher scores indicate poorer quality of life) [21] and Nocturnal and Overall Back Pain in the last week (rated by the patient on a visual analogue scale (VAS) of 0, no pain, to 10, most severe pain). Data on outcome measures were missing for 15 patients as questionnaires were either not completed due to time constraints or completed incorrectly. The data were also analysed for any associations between disease pattern and gender, age at symptom onset or disease duration since symptom onset.

Statistical analysis
Associations between the presence or absence of flares and gender were tested using chi-square tests, and with age using Mann–Whitney U-tests (due to non-normal data distribution).

Kruskall–Wallis tests were used to examine associations between reported disease patterns as depicted in the Flare Illustration and health status measures. Disease patterns were also grouped (Fig. 1) as those with constant symptoms (B or D) and those with intermittent symptoms (A or C) and associations with health status measures were retested using Mann–Whitney U-tests.

Associations between reported disease patterns and gender were tested using Fisher's exact test (due to low expected values in a number of cells) or chi-square test when patterns were grouped as those with constant symptoms vs those with intermittent symptoms. Statistical significance was defined as a P-value ≤0.05 throughout.

The {kappa}-statistic was used to assess test–retest reliability, since this is appropriate for nominal data with a small number of categories. A {kappa}-value <0.4 is considered to reflect poor reliability, 0.4–0.6 reflecting fair reliability, 0.6–0.8 reflecting good reliability and 0.8–1.0 reflecting excellent reliability [22].


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
A total of 114 patients participated in this study, and summary statistics describing the characteristics of the group are presented in Table 1. Sample sizes for responses to individual questions vary due to questionnaires being incomplete or completed incorrectly.


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  		TABLE 1. Characteristics of the study cohort

 
Occurrence of flares
Out of 113 patients, 108 (96%) reported that they experience flares in their disease and 84/109 (77%) reported that they had a flare in the year preceding their clinic visit (sample sizes for each question vary due to missing data points). Forty out of 101 patients (40%) stated that the flares lasted days, 32/101 (32%) stated that they lasted for weeks, and 29/101 patients (29%) reported flares lasting for months (Table 2). Overall, 82/99 patients (83%) reported that they experienced symptoms of AS (pain and stiffness) in between past flares, and 80/96 (83%) reported symptoms of AS in between flares that they experienced in the past year.


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  		TABLE 2. Duration of flares and reported patterns of disease over the entire disease course and the previous year

 
There was no association between the occurrence of flares and gender (since disease onset: P = 0.330; past year: P = 0.301) or age (since disease onset: P = 0.738; past year: P = 0.160).

Pattern of flares
When asked to characterize their disease pattern over the preceding year using the Flare Illustration, 45/82 patients (55%) reported Pattern B that was flare on a background of disease activity, as compared with 9/82 patients (11%) who reported Pattern A that was a relapsing and remitting pattern of disease activity. The results for the overall disease course were similar, (Table 2), although the frequency of Pattern A was higher and that of Pattern B lower for the overall disease course than for the previous year. Patterns with constant symptoms (B and D) clearly predominate over those with intermittent symptoms (Patterns A and C).

Relationship with AS disease-specific outcome measures
Disease pattern for the overall disease course was associated with quality of life (P = 0.016). Patients reporting patterns B or D typically had poorer quality of life reflected in higher ASQoL scores (mean ASQoL ± S.D. = 7.5 ± 5.12 and 9.0 ± 3.54, respectively) than those reporting patterns A or C (mean ASQoL ± S.D. 5.2 ± 5.12 and 2.8 ± 1.71, respectively) (Table 3). There was also an association between the pattern for the overall disease course and Overall Back Pain in the preceding week (P = 0.033), which was low in those reporting Pattern C (mean ± S.D. = 3.3 ± 3.40) and high in those reporting patterns A, B or D (mean ±S.D. = 4.5 ± 2.51, 4.8 ± 2.76 and 4.9 ± 2.23, respectively). There were no significant associations between the pattern in the past year and any of the health status measures (Table 3).


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  		TABLE 3. Associations between pattern of disease and disease health status measures

 
When the data were stratified according to whether symptoms were constant, (Pattern B or D) or intermittent (Pattern A or C), those with constant symptoms for the overall disease course showed significantly worse BASDAI (P = 0.029), BASFI (P = 0.013), ASQoL (P = 0.007) and Overall Back Pain (P = 0.025) than those with intermittent symptoms (Table 4). For the pattern in the past year, BASDAI and ASQoL were significantly worse in patients with constant symptoms (P = 0.049 and 0.033, respectively).


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  		TABLE 4. Associations between pattern of disease activity and health status stratified by those who have intermittent or constant symptoms

 
There were no significant associations between reported disease patterns and either age of symptom onset or disease duration since onset (P-values range from 0.370 to 0.947; Tables 3 and 4Go). There were also no significant differences in the proportions of males and females reporting each pattern or patterns with intermittent vs constant symptoms (P-values from 0.238 to 0.791).

Test–retest reliability of recording pattern of disease
Comparing the pattern reported for the entire disease course in the subset of 20 patients, the {kappa}-value of 0.391 indicates that reliability was poor (P = 0.015). However, an examination of the data indicates that of the seven people whose answers differed between initial questioning and 24 h later, six changed between patterns characterized by constant symptoms (B–D or vice versa) and only one between patterns with intermittent and constant symptoms (in this case, Pattern B to Pattern A). Reliability for pattern in the past year was fair with a {kappa}-value of 0.559 (P = 0.008). Of the 15 patients who responded to the question on both occasions, three gave different answers between initial questioning and 24 h later, and in all cases the change was from Pattern B to Pattern D or vice versa.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
In this study, we have found that (i) the majority of AS patients experience flares, (ii) the use of a novel visual technique to record patient-perceived disease patterns in AS has defined two main types of pattern, (iii) patterns characterized by constant symptoms are associated with worse health status measures, (iv) there were no associations between the occurrence of flares and gender or age and (v) there were no associations between disease pattern and gender, age of symptom onset or disease duration since symptom onset. Disease pattern over the full disease course and the contrast between constant and intermittent symptoms seem to be the key features with respect to health status, as they yielded the clearest associations with health status measures.

The literature concerning the definition and nature of flares in AS is limited. Longitudinal studies of disease activity typically examine trends over a number of years [23–26], and measure disease activity too infrequently to allow the characterization of shorter term variability. A previous focus-group study that attempted to elucidate patients’ concepts of flares suggested that they were a common occurrence affecting all AS patients in one form or another [2]. However, it did not consider in detail the level of disease activity between flares and variability in symptoms over time. The results have been interpreted by some as implying that there is no disease activity between flares although this is neither stated nor implied by the authors, and this is not our impression. Data to substantiate either viewpoint have not previously been available, but the results of this study suggest that for the majority of AS patients the disease is characterized by flares on a background of constant disease activity. This has major implications for economic modelling of the cost utility of treatments for AS.

This is the first study to attempt to define disease patterns and the impact of flares in disease activity in AS from the patients’ perspective using a visual aid. A strength is the use of this novel instrument, the Flare Illustration, to facilitate patients’ own description of the temporal variation in symptoms they experience. It is a very feasible tool, is easy for patients to understand and provides data in a form which can be easily assessed for associations with health status measures. Furthermore, there is potential for the Flare Illustration to be applied to outcome domains other than disease activity, such as pain levels or functional impairment, and it can also be directly applied to other diseases. However, further validation of this instrument may be required to test its full psychometric properties.

A weakness is that the study was cross-sectional and based on patient recall. Test–retest analysis suggested that patient recall may be unreliable, or that when patients reflect on the illustration they may understand it better and change their mind regarding their disease pattern. The results implied that the distinction between patterns with (B or D) and without (A and C) constant symptoms is valid, but the Flare Illustration will require further validation to improve reliability.

The results of this cross-sectional pilot study also need to be substantiated by more frequent, regular BASDAI completion to see whether patients’ perception of their disease activity is borne out by the prospectively collected data, or whether other patterns emerge. This work is currently underway with our cohort.

The RNHRD is District General Hospital, which also acts as a tertiary referral centre, and receives both local and specialist referrals. Therefore, a proportion of the AS patients attending the hospital could be more severely affected and less likely to be asymptomatic between flares than the general AS patient population. However, our own data and previous studies of AS patients attending the RNHRD [19] suggest that patients show the full spectrum of disease activity and duration, from newly diagnosed to long-standing patients. In this study, BASDAI ranged from 0.0 to 8.3, BASFI from 0.0 to 8.8 and disease duration since the onset of symptoms from 5 to 53 yrs. Therefore, our cohort does represent a wide range of AS patients, but there may be some bias towards patients with more severe, long-standing disease.

The concept of a ‘flare’ may also need further clarification. Generalized pain, single joint pain or even iritis may define a flare for different patients [2]. The concept of flare held by physicians also requires greater clarification as this may differ from that of patients. Most studies rely on physician-defined concepts of flare, and none give an entirely satisfactory definition. Definitions based on changes in VAS scores, joint counts or biomarker levels necessarily involve an arbitrary element in selecting the threshold that defines a flare. Behavioural measures (patients seeking additional treatment) fail to take into account differences in treatment-seeking behaviour among individuals [17], whether current treatments are sufficiently effective to prompt such a response and fluctuations in symptoms that patients manage through alternative coping mechanisms but which still impact upon quality of life and may be clinically relevant.

Furthermore, in order to fully understand disease patterns in AS we may need to go beyond the concept of flares. Fluctuating symptoms have been described by patients with other conditions such as OA [27] and in other studies of AS without using the term flare [28, 29]. Whether this is considered equivalent to flares or to represent another level of symptom variability in this and other conditions requires further investigation.

In the absence of a biomarker of disease activity in AS, distinguishing between disease activity and chronic AS-related pain using questionnaire data is problematic. Patients may report continuing disease activity when this actually represents chronic pain and such patients may show poorer outcomes. This should be borne in mind when considering the results of this and other studies, but until a biomarker is identified they offer important insight into the disease.

Defining the pattern (or patterns) of disease activity in AS will have important implications for patient care especially if a biomarker of disease activity is identified that can predict a flare. It will enable clinicians to give better advice to individual patients regarding appropriate treatment. For example, our results imply the existence of two major patterns of AS symptoms, which are associated with differences in health status. This may be expected, since it is possible that some patients with intermittent symptoms were experiencing a symptom-free episode at the time of visiting the clinic. Identifying such patterns may enable us to define those patients who will benefit from biologic or other effective therapies and for whom the benefits of such treatments outweigh the drawbacks, and those who require less intensive treatment. This will help to prevent both over- and under-treatment of AS patients, improving the care they receive and also potentially preventing expenditure on unnecessary levels of treatment. This will best be achieved by future research focusing on the biological basis of flares.

An alternative approach may be to treat certain patients with anti-TNF drugs during flares to prevent longer term deterioration in health status. Although the treatment of AS with NSAIDs ‘on demand’ during flares has been shown to be less effective in reducing radiographic disease progression than constant NSAID use [30] this may be because, as we have shown in this study, for the majority of patients disease activity continues between flares and so spinal damage also continues to occur in these intervening periods. However, such intermittent treatment could still be appropriate in the minority of cases if patients report an absence of disease activity between flares.

The results of this study yield important new insights into the occurrence of flares in AS and their impact on outcome. This pilot study lays the foundations for future prospective studies to confirm our findings. The identification of patients who are most at risk of flares and the rigorous treatment of flares and persistently raised disease activity states between flares may lead to improved outcomes in this debilitating condition. Perhaps the greatest challenge of all is to understand the biological basis of flares, but the accurate documentation of their nature and occurrence in AS may provide some insight in this regard.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors would like to thank Paul Doherty for editorial assistance and two anonymous reviewers for insightful comments that helped to improve the manuscript.

Funding: Mrs Rivett and family in memory of the late Mr Rivett, a long-term sufferer of AS provided an unrestricted donation to the project. M.A.S. received a British Medical Association Doris Hillier Award in 2007 and a Cumming Visiting Professor Award in AS.

Disclosure statement: A.K. has received speaker fees and attended advisory boards for Abbott, Schering-Plough and Wyeth. A.K. has declared that Northwick Park Hospital rheumatology department has received research and service support from Abbott, Schering-Plough and Wyeth. M.S. has received speaker fees and attended advisory boards for Abbott, Schering-Plough and Wyeth. M.S. has declared that the Royal National Hospital for Rheumatic Diseases has received an unrestricted education grant from Wyeth for the Spondylitis program. All other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 14 December 2007; revised version accepted 3 April 2008.
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