What is a disease flare in RA? A medical student’s perspective

Introduction: This guest article was written by Anca Smyth, who is currently a fourth year medical student at Queen’s University Belfast. She wrote an essay during her ‘special study component’ three week attachment in Altnagelvin hospital and later submitted it to the Irish Society for Rheumatology. Anca not only won the prestigious Bernard Connor Prize at the 2016 conference, but she was invited to present her paper to the Society. So congratulations to Anca and best wishes for the future! – Philip Gardiner

“When it comes to our health most of us are guilty of thinking that we are invincible. Imagine waking up one morning with excruciating pain, having stiff, swollen joints and weakness which markedly interfere with your ability to carry out the normal activities of daily living. To a rheumatoid arthritis (RA) sufferer such debilitating symptoms may constitute ‘a significant disease flare’, an episodic exacerbation of this chronic, symmetrical, small joint inflammatory condition. Or does it?

Unlike the ACR/EULAR classification criteria for RA [1] which is based on objective measurements of serological parameters, acute phase reactants, numbers and sites of swollen or tender joints and symptom duration, there has been no standard definition of what constitutes a RA flare or how it can be objectively assessed and classified according to severity. Apart from measuring the efficacy and safety of novel pharmacological agents used in the treatment of RA by means of randomised controlled clinical trials, a valid definition and classification of a flare would prove to be an invaluable tool in guiding clinical care and monitoring disease outcome.

When a patient is experiencing a flare, a significant increase in the disease activity so that it requires a change of treatment [2], there is often discrepancy in the interpretation of the severity of signs and symptoms between the doctor and the patient [3]. This may lead to inappropriate treatment, patient dissatisfaction and non-adherence to therapeutic interventions [4, 5]. Such discordance is due to the heterogeneous nature of the patient experience during this acute episode, which not only affects objectively measured clinical parameters but also generates self-reported symptoms such as pain, weakness, sleeplessness or fatigue [6, 7]. From the patient’s perspective the experience of a flare is also about functional impairment, disability and social participation [8, 9] which interfere with the patient’s quality of life and psychological well-being.

There is also variation between RA sufferers regarding what constitutes a significant disease flare. Reasons for this include the fact that patients report the severity of a flare according to their baseline disease activity and previous experiences with the disease [10], thus what seems a severe flare to an early RA patient may be classified as a normal fluctuation of disease activity by someone who has been living with this disease for an extended period of time. Additional factors in defining a significant flare include the level of a patient’s tolerance to worsening of signs and symptoms, health beliefs and coping skills [11, 12].

Current methods of assessing RA patients include measuring the disease activity in 28 joints using the DAS28 score and evaluating physical disability by means of a Health Assessment Questionnaire (HAQ28) and patient’s global health status by employing a 10cm Visual Analogue Scale (VAS).  However, none of these approaches are without flaws. Two of the main determinants of the patient’s global health are pain and fatigue [13], subjective symptoms which cannot be measured accurately and which are influenced by many factors including mental health status and co-morbidities [14]. Considering the ACR/EULAR disease remission criteria of a score of 1 or less on the patient’s global assessment scale of 0-10 such targets may be difficult to achieve accounting for the fact that many RA patients suffer from depression [15] or chronic pain syndrome [16].

The HAQ tool, limited by its ‘ceiling effect’ due to lack of adequate sensitivity in detecting a worsening of disability towards its upper limits or assessing lower limb function [17] does not accurately evaluate the severity of a RA flare. The DAS 28 score, a weighted composite of the number of swollen joints, level of the inflammatory marker ESR (erythrocyte sedimentation rate) and patient global assessment score is currently employed in clinical practice to classify disease activity, guide therapeutic treatment and function as an outcome measure in the treat-to-target approach [18]. Limitations of this approach include a misleadingly low DAS28 score if the flare predominantly affects the patient’s feet, which are not included in the DAS28 joint count, or if it is concentrated on a single joint, causing debilitating pain and rendering the patient unable to work. Conversely, a high DAS28 score based on a large number of swollen joints in the absence of pain or elevated ESR may initiate an unnecessary escalation in therapeutic treatment [19]. Some studies have used the inverse of the improvement criteria based on the DAS28 score to assess the severity of a flare but such a correlation seems inappropriate [20].

Given the complexity of patient experiences and heterogeneity of assessment tools that affect the interpretation of a significant disease flare, there is no ‘one size fits all’ approach to monitoring a flare. In an era of demedicalisation, there is an emphasis on treating the individual in the community, with medical care providers offering evidence based patient education and counselling regarding management of flares or side-effects of medication in the form of leaflets, telephone consultation with various members of the multi-disciplinary team or telecare services for people to report and be advised on their flares [21]. Such a model of care not only promotes self-efficacy and helps achieve an internal locus of control but it also increases accessibility and reduces travelling time for patients in the rural communities.

Since RA is a chronic condition, the patient may be the expert in monitoring their condition and self-management of a flare by means of non-pharmacological (such as exercise, bed rests, applying ice or heat packs or via complementary and alternative therapies) or pharmacological interventions (by increasing the dose of glucocorticoids, analgesics or non steroidal anti-inflammatory medication alongside a fixed-dose of disease modifying anti-rheumatic drugs) seems to be the approach employed by most RA sufferers [22]. There are times, however, when self-management of a flare is ineffective and the patient decides to seek medical help. Although the threshold at which such a decision is made is unknown, the doctor must adopt a holistic approach in assessing the patient and based on shared-decision making determine an appropriate change in treatment.

In conclusion, the concept of a significant disease flare in RA is complex, non-standardised and its interpretation depends on interplay between a patient’s physical and psychological parameters, previous disease experience and health beliefs. Monitoring of this acute episode should occur in the community, with health professionals providing ongoing patient education and counselling and facilitating timely review by the clinician when the patient seeks medical help.”

References

[1]. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burnester GR et al. 2010 Rheumatoid Arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis and Rheumatism 2010; 62(9): 2569-2581.

[2]. Alten R, Pohl C, Choy EH, Christensen R, Furst DE, Hewlett SE, Leong A, May JE, Sanderson TC, Strand V, Woodworth TG and Bingham CO. Developing a Construct to Evaluate Flares in Rheumatoid Arthritis: A Conceptual Report of the OMERACT RA Flare Definition Working Group

[3]. Studenic P, Radner H, Smolen JS and Aletaha D. Discrepancies Between Patients and Physicians in Their Perceptions of Rheumatoid Arthritis Disease Activity. Arthritis and Rheumatism 2012; 64(9): 2814-2823.

[4]. Van den Bemt BJF, van den Hoogen FHJ, Benraad B, Hekster YA, van Riel PLC, van Lankveld W. Adherence Rates and Associations with Nonadherence in Patients with Rheumatoid Arthritis Using Disease Modifying Antirheumatic Drugs. The journal of Rheumatology 2009; 36: 2164-2170.

[5]. Matteo MR. Variations in patients’ adherence to medical recommendations: a quantitative review of 50 years of research. Medical Care 2004; 42: 200-209.

[6]. van Tuyl LHD and Boers M. Patient’s Global Assessment of Disease Activity: What Are We Measuring? Arthritis and Rheumatism 2012; 64(9): 2811–2813.

[7]. Kalyoncu U, Dougados M, Daures JP, Gossec L. Reporting of patient-reported outcomes in recent trials in rheumatoid arthritis: a systematic literature review. Annals of the Rheumatic Diseases 2009; 68: 183–190.

[8]. Benka J, Nagyova I, Rosenberger J, Marcejova Z, Lazurova I, van der Klink JL, Groothoff JW and van DijkJP. Social participation in early and established rheumatoid arthritis patients. Disability and Rehabilitation 2015; 19: 1-8.
[9]. Sverker A, Ostlund G, Thyberg I, Valtersson E and Bjork M. Dilemmas of participation in everyday life in early rheumatoid arthritis: a qualitative interview study. Disability and Rehabilitation 2015; 37(14): 1251-1259.
[10]. Seror R, Tubach F, Baron G, Guillemin F, Ravaud P. Measure of function in rheumatoid arthritis: individualised or classical scales? Annals of the Rheumatic Diseases. 2010; 69(1): 97–101.

[11]. Rohekar G and Pope J. Test-Retest Reliability of Patient Global Assessment and Physician Global Assessment in Rheumatoid Arthritis. The Journal of Rheumatology 2015; 36(10): 2178-2182.

[12]. Sanderson TC, Hewlett SE, Flurey C, Dures E, Richards P and Kirwan JR. The impact triad (severity, importance, self-management) as a method of enhancing measurement of personal life impact of rheumatoid diseases. The Journal of Rheumatology 2011; 38: 191-194.

[13]. Bartlett SJ, Bykerk VP, Cooksey R, Choy EH, Alten R, Christensen R, Furst DE et al.  Feasibility and Domain Validation of Rheumatoid Arthritis Flare Core Domain Set: Report of the OMERACT 2014 RA Flare Group Plenary. The Journal of Rheumatology 2015; 42(11): 2185-2189.

[14]. Barton JL, Imboden J, Graf J, Glidden D, Yelin EH and Shillinger D. Patient-Physician Discordance in Assessments of Global Disease Severity in Rheumatoid Arthritis. Arthritis Care and Research 2010; 62(6): 857–864.

[15]. Khan NA, Spencer HJ, Abda E, Aggarwal A, Alten R and Ancuta C. Determinants of discordance in patients’ and physicians’ rating of rheumatoid arthritis disease activity. Arthritis Care Research 2012; 64: 206–14.

[16]. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize RA patients with fibromyalgia. J Rheumatol 2004; 31: 695–700.

[17]. Gardiner PV, Sykes HR, Hassey GA and Walker DJ. An evaluation of the health assessment questionnaire in long term longitudinal follow-up of disability in Rheumatoid Arthritis. British Journal of Rheumatology 1993; 32: 724-728.
[18]. Ward MM, Guthrie LC and Alba MI. Clinically important changes in individual and composite measures of rheumatoid arthritis activity: thresholds applicable in clinical trials. Annals of the Rheumatic Diseases 2013; 1: 205079.
[19]. Pincus T, Yazici Y and Sokka T. Quantitative measures of rheumatic diseases for clinical research versus standard clinical care: differences, advances and limitations. Best Practice and Research Clinical Rheumatology 2007; 21(4): 601-628.

[20]. Leeb BF, Sautner J, Leeb BA, Fassl C, Rintelen B. Lack of agreement between patients’ and physicians’ perspectives of rheumatoid arthritis disease activity changes. Scandinavian Journal of Rheumatology 2006; 35: 441-446.

[21]. National Institute for Health and Care Excellence. Commissioning for people with rheumatoid arthritis. NICE commissioning guides [CMG51], 2013.

[22]. Hewlett S, Sanderson T, May J, Alten R, Bingham CO, Cross M, March L, Pohl C, Woodworth T and Bartlett SJ. ‘I’m hurting, I want to kill myself’: rheumatoid arthritis flare is more than a joint count- an international patient perspective on flare where medical help is sought. Rheumatology 2012; 51:69-76.

When is a DAS28 NOT a disease activity score?

I’m a big fan of the Disease Activity Score (DAS) and if you’re interested at all you should check out this excellent article in ‘The Rheumatologist’ about how Piet van Riel and Desiree van der Heijde developed the score. As much as I like this tool, I think people need to be aware of its limitations in clinical settings. There is no such thing as a perfect disease activity score, and similar problems arise with other scores. I use the DAS28 (ESR) regularly in clinic, and for the majority of patients it is a very useful tool that matches what the patient and physician think is happening to disease activity. I am written this article mainly for clinical health professionals in Rheumatology.

…when the patient has Fibromyalgia (as well as RA)

This one may be a bit obvious, but it can catch out the unwary. I have made this mistake more than once. As many of you know, the incidence of FMS is increased in chronic diseases like RA and SLE and it can seriously skew the DAS28. In a busy clinic we can be so busy doing the DAS28 and sorting out the patient’s problems that we don’t check for muscle tenderness in a patient with known RA. So how can we avoid this mistake? If you see a patient where the tender joint count and VAS scores are very high but the ESR and swollen joint counts are low/normal – look out! This is the typical pattern with FMS symptoms. A quick check for muscular tenderness will usually confirm your suspicions. Of course, the symptoms of pain and fatigue are genuine and need to be addressed, but just not with anti-TNF drugs or more Methotrexate! You are welcome to check out my little shared spreadsheet tool on Google Drive that shows the COMPONENTS of the DAS28 as slices in a pie chart. This tool uses the official formula for DAS28 (ESR) but splits up the components and allows you to experiment with different values and see the results. It makes it a lot easier to see when the Tender joint score and VAS score are dominating the DAS28.

…When the patient has more tender than swollen joints

I’m not going to make a big issue of this, but it is good to be aware that the DAS28 score puts twice as much emphasis on tender compared to swollen joints. This is good in that it makes the DAS28 more of a ‘patient reported outcome measure’ but not so good when you see a patient with quite a few swollen joints and an inappropriately low DAS28 score. And do remember that the DAS28 was not developed to be used in a system where there would be a clear incentive from having a higher score (i.e. access to biologic drugs) – it is open to some bias on the part of both patient and physician.

…When the patient has a low esr

The DAS scores were developed using data from clinical trials. With handy calculators around, most people don’t pause to check the formula. The ESR score is log-transformed to take account of the way an ESR rises. This is all very reasonable, but it has to be remembered that patients were selected for these clinical trials because they had very active disease with a lot of tender and swollen joints. In most of the trials the starting ESR was very high. The ESR during the trials fell significantly but often not to ‘normal’ levels. So the DAS28 was not really properly validated in the population of RA patients we see day to day in clinic: those with fewer active joints and low/normal ESRs.  Which do you think would cause a greater change in DAS28 score: a change in ESR from 40 to 20 or from 15 to 2mm/h? The change in DAS28 score is actually three time larger in the latter example – a reduction of 1.51 – greater than the NICE/BSR ‘response’ criterion for biologics. There is no cut-off for ESR values within the normal range, and even insignificant changes.

In the UK, NICE guidelines dictate which of our RA patients can get access to biologics. The ‘cut-off’ for access is a DAS28 score of over 5.1. This may be no problem for most patients, but for some men with particularly low ESRs this is an issue. I have a couple of patients who have definite ultrasound proven synovitis in multiple small joints but a low ESR of 2mm/h. Now I challenge you to try and get a DAS28 of 5.1 with that! Have a go on the DAS component spreadsheet. Try entering 15 tender, 15 swollen joints and a VAS score of 90. Now this doesn’t affect a lot of patients, but there’s a handful in our department who need treatment but can’t get it because of this.

…When the patient is in ‘Remission’ (DAS28 less than 2.6)

I would guess that most of you are already aware that the DAS28 doesn’t work too well when it comes to defining remission. This is partly because it completely misses out joints such as the feet and ankles which can be important to people with partly controlled arthritis. It is also partly because of the under-valuing of swollen joints (mentioned above). One of my patients had 5 swollen joints, no tender joints, ESR of 8, and VAS of 10. His DAS28 is 2.23 (i.e. in remission). I think it is better to use the new ACR/EULAR remission criteria.

…When it is done by someone inexperienced

Once people have learned how to examine the patient properly to complete the score and practiced using it regularly for a few weeks they will be able to get quite repeatable results. There is an instructional video on the official website http://www.das-score.nl/ and this site also contains a list of the ‘official’ reference articles on the various DAS scores. However, there are grey areas and there can be quite a bit of difference between observers. So if we’re checking DAS28 scores regularly in clinic, it is a good idea to have it checked by an experienced observer rather than a trainee. If we’re relying on a crucial result (e.g. to determine if a patient is to get biologic treatment or not) we need to make sure that the person doing it is experienced. To measure ‘response’ it is best for the observer to be the same person before and after.

So that’s it. All my moans about the DAS28 all in one page. Am I the only one who has these issues?