FATIGUE IN RHEUMATOID ARTHRITIS

Transcription

1 FATIGUE IN RHEUMATOID ARTHRITIS RESEARCH STRATEGY MEETING REPORT 9th & 10th November 2008 Chancellor s Conference Centre, University of Manchester Arthritis Research Campaign Page 1

2 CONTENTS Summary... 3 Fatigue: a patient s perspective Turn the fog off... 3 SESSION 1: ASSESSMENT AND MEASUREMENT OF FATIGUE... 3 Workgroup 1: How to define and measure fatigue... 4 Workgroup 2: Laboratory and imaging assessment of fatigue... 5 Workgroup 3: Can fatigue be sub-grouped and what are the clinical predictors?... 5 SESSION 2: AETIOLOGY OF FATIGUE IN RA... 6 Physiology and pathophysiology of effort... 6 Psychological mechanisms... 7 Workgroup 4: Pathophysiology of fatigue... 7 Workgroup 5: Psychology of fatigue... 8 SESSION 3: NOVEL APPROACHES TO THERAPY... 9 Physiological approaches... 9 Psychological approaches... 9 Workgroup 6: Physiological approaches Workgroup 7: Psychological approaches Conclusions What was learnt? Where next? Major outcomes Appendix 1: Programme Arthritis Research Campaign Page 2

3 SUMMARY In November 2008 arc convened a research strategy workshop of over 20 research scientists from the fields of rheumatology, psychology, psychotherapy, physiotherapy, exercise physiology and sports science to discuss research needs in the field of fatigue in rheumatoid arthritis (RA). The main aims of the meeting were to Formulate a set of research priorities that are strategically important which hopefully would encourage research grant applications to arc Identify any specific areas that require ring-fenced investment The programme of the day covered several key areas (Appendix 1). FATIGUE: A PATIENT S PERSPECTIVE TURN THE FOG OFF The workshop opened with a patient describing her experience of fatigue in RA. A number of symptoms characterised her fatigue: heavy legs, difficult to move and movement was not effortless, sluggish, lacked energy, difficult to concentrate, and brain fog (when messages did not get in or out of the brain). The fatigue severely affected her quality of life. Other key points were: Fatigue was constantly in the background even when the arthritis was not in flare Bad pain days did not necessarily equate to bad fatigue days SESSION 1: ASSESSMENT AND MEASUREMENT OF FATIGU E Ernest Choy gave a brief introduction into this topic. Fatigue affects over 90% of RA patients and over 40% of them feel it is a clinically important problem, second only to pain. Patients are concerned about the effect fatigue has on their working life and find that fatigue continues even though their treatment for RA is successful (in terms of pain and joint damage etc.). How then do we measure fatigue? Should a uni-dimensional or multi-dimensional questionnaire be used? So far over 23 different scales have been used including: MAF, SF-36, FACIT-F, ordinal scales, POMS and VAS. Factor analysis of fatigue questionnaires identified 5 dominant factors: 1) psychological factors (anxiety/depression), 2) distress/cognition, 3) fatigue severity, 4) physical interference and 5) social interference. Studies of RA patients using the VAS score to measure fatigue have shown that fatigue is approximately normally distributed but the VAS is only useful in indicating overall severity. MAF predominately measured the impact of fatigue and the FACIT-F and MFSI were heavily weighted toward anxiety/depression and distress. Dr Choy also summarised data on the factors associated with fatigue. After multi-variate analysis these included: pain, modified HAQ (mhaq), erosive disease, methotrexate treatment (know to decrease fatigue), disease activity and depression. However the R 2 for this model was around 50% so a substantial component to the fatigue is still missing. Factors found to have no association with fatigue included: demography (age, gender), disease features such as Arthritis Research Campaign Page 3

4 duration, rheumatoid factor positivity (RF), nodules, treatment, concomitant diseases and other blood markers such as creatinine and haemoglobin. Possible causes for fatigue were discussed including: concomitant disease (depression, fibromyalgia), inflammation and cytokines (TNF, IL1, IL6), HPA axis and hormones, chronic pain (stress), metabolic (anaemia), muscular (prominent muscle wasting) and medications. The main conclusions were: Fatigue is common in RA and is an important independent driver of disability Fatigue is multi-factorial (inflammation, depression, pain etc) Fatigue is mostly central in RA Different instruments measure different aspects of fatigue The topic was explored in detail by three workgroups: WORKGROUP 1: HOW TO DEFINE AND MEASURE FATIGUE A number of points emerged: Fatigue is hard to define in exercise sciences is it muscle fatigue, tiredness or perception of a task? Psychologically patients describe fatigue as qualitatively different to just tiredness and tasks are perceived to be difficult What should we measure in fatigue? We can and should measure physical fatigue and we can measure cognitive function for mental fatigue. It is unlikely we can utilise one measurement tool to cover all due to individual variability. Currently there are no multi-dimensional measurement tools available. A multi-directional approach is required How do we define fatigue physical function vs. perception are different? Measurement we need a more detailed understanding of fatigue Better use of questionnaires or better designed questionnaires? Studies must include both a physical and cognitive assessment Conclusions Secondary analysis of published studies needs to be undertaken using approaches such as factor analysis to derive and better define the individual domains Full review of such data is needed to show the gaps in knowledge in relation to the specific domains identified Arthritis Research Campaign Page 4

5 WORKGROUP 2: LABORATORY AND IMAGING ASSESSMENT OF FATIGUE This group discussed what is known about imaging and laboratory measurement of fatigue in RA and overall it was felt that very little is certain in this area. There are no biomarkers for fatigue in RA compared to other diseases such as Chronic Fatigue Syndrome (CFS) and Multiple sclerosis. Although lessons can be learnt from other diseases it cannot be assumed that fatigue in RA is the same. There was much discussion about a role for IL-6 in RA fatigue which requires more study. One hypothesis is that the circadian variation of IL-6 in RA patients might be correlated with diurnal changes in fatigue. There were studies suggesting that brain imaging abnormalities may be identified as correlates with fatigue in other disorders but the data in RA was very limited. Key questions included: What are the core components of fatigue? Is fatigue the same when induced (by exercise)? Are there common co-factors for fatigue or are there specific factors for RA? Proteomic analysis to find a new bio-marker may be worthwhile maybe even mrna (but where to look?) There may be biomarkers for different domains in RA fatigue Core fatigue (baseline) + stress fatigue when fatigue is exacerbated Better imaging is required both post exercise and post stress How does physical exertion and sleep affect fatigue? Conclusions Need an adventurous approach Design of the study is critical and stimulation tests are important Biomarkers must be independent of disease activity Need an iterative process from phenotype to biomarker then retest biomarker to better categorise or finetune the phenotype WORKGROUP 3: CAN FATIGUE BE SUB-GROUPED AND WHAT ARE THE CLINICAL PREDICTORS? Fatigue is subjective and cannot be measured easily objectively Patients use a number of words to describe fatigue (weak, confused, brain fog, lethargic) There are mental and physical components to fatigue Arthritis Research Campaign Page 5

6 What is needed? o o Need a precise measure of fatigue Need to define the endo-phenotype (Latent trait analysis) Influenced by personality, severity, mood, sleep etc Also need a large number of patients o Need to specify the outcomes Differential effects Subjective experience of fatigue, disability, mood, pain and sleep Predictors Probably a large number of predictors including disease activity, co-morbidity, disability, beliefs and selfefficacy (catastrophic cognitions), mood, sleep, coping strategies, personality, demographic (age, disease duration, gender etc.) Conclusions Need large epidemiological studies (prospective, nested case-control) Multi-centre approach/studies (to ensure large number of patients) Multi-disciplinary teams needed Measure physiological, cognitive, behavioural, social and emotional responses SESSION 2: AETIOLOGY OF FATIGUE IN RA PHYSIOLOGY AND PATHOPHYSIOLOGY OF EFFORT Samuele Marcora introduced this subject on the physiology and pathophysiology of effort. The importance of understanding the basic physiology of fatigue was addressed. Fatigue needs to be studied as a perception/sensation as an increased perception of effort. Rating of perceived exertion (RPE) can be used as a cheap measure of exercise intensity using the Borg scale. A number of physiological factors can affect perception of effort including: physical fitness, age, gender, environment, sleep etc. Pathophysiological factors that affect perception include cardiorespiratory and muscular fitness, pain levels and anaemia. However improving these factors is not enough to treat/cure fatigue. Studies on the effect of chemotherapy on perception of effort in breast cancer patients have shown that post-treatment there is an increased perception of effort despite the fact that physiologically blood lactate remained at similar levels. Hypnosis has been shown to change perception of effort with changes in cerebral blood flow in different regions of the brain depending if the Arthritis Research Campaign Page 6

7 hypnosis was to invoke up-hill or down-hill cycling. More imaging studies need to be done to examine neural activity in the brain and how this changes with induced fatigue. PSYCHOLOGICAL MECHANISMS Sarah Hewlett reviewed the psychological mechanisms of fatigue. Constructs for fatigue include beliefs, feelings and behaviour. Illness beliefs do not always correspond with the facts. Cross-sectional studies have so far given conflicting results, however no associations have been found with CRP, ESR, cortisol, age or anaemia and we may need models rather than single factors to study fatigue. Longitudinal studies of long-term predictors of fatigue in RA, of which there have been five, have shown that several factors increase the risk of fatigue: history of depression or anxiety, fatigue at baseline, bad consequence beliefs, low self-efficacy at baseline and avoidant coping. There are fewer studies of short-term predictors of fatigue but published studies so far have shown that it cannot be predicted by any day of the week and over 30% have a diurnal fatigue pattern. Fatigue can also be predicted by perceived quality of sleep and positive/negative mood. Conclusions A fatigue algorithm is need for RA (cancer already has one) Need to strengthen the research evidence currently available on mood, self-efficacy and consequence beliefs Research is required to address if different types of fatigue have different causes? Need to know how do patients perceive the cause of their fatigue and are these perceptions accurate? Prospective, large cohort studies (physical, psychological and behavioural) are required to unravel the longterm and short-term predictors of fatigue The topic was explored in detail by two workgroups: WORKGROUP 4: PATHOPHYSIOLOGY OF FATIGUE Little is understood about the pathophysiology of fatigue in RA and it is not appropriate just to assume from other disease models. May not be relevant to extrapolate from normal subjects to RA patients Need to separate out the psychological and physical components Mismatch between perceived and expended effort simple experiment is required. This mismatch is most replicated finding in CFS no studies done in RA. Controlling for depression is important studies need mental fatigue without depression (exclude those at severe end of depressive scale) Perception of fatigue and actual fatigue and how does fatigue relate to mood? Longitudinal studies of disease markers are required Arthritis Research Campaign Page 7

8 Drug response does this change the fatigue? Shift of importance of symptoms fatigue will be forgotten if pain levels are high Experimental models what is the relevance in people with RA? Importance of peripheral mechanisms Cognitive fatigue in patients with RA Research Priorities What interventions are acceptable to the patient? Fatigue in normal people is poorly understood. More research in this area may require support from other funders Do biological therapies such as anti-tnf influence fatigue? Requires a questionnaire on fatigue at baseline and follow-up What is the diurnal variation in fatigue? Should formulate hypotheses with predictions to test in these different interventions, time series measurements or stimulation studies Study design is important as correlation may not be causative Sub-maximal exercise does this induce fatigue in a way that can be tolerated in RA patients (i.e. does not cause pain)? WORKGROUP 5: PSYCHOLOGY OF FATIGUE Although muscle fatigue is understood the psychology of fatigue is less so. Priorities The lack of a gold standard to measure fatigue is a problem Questionnaires with new fatigue scales add to the problem of having lots of imperfect scales but incrementally should make development of an optimal scale closer Standard database of levels of fatigue and their psychological predictors in RA is needed but adding to a clinician s workload is problematic Need evidence such as how physiotherapist / behavioural approaches can influence fatigue. Further evidence from clinical practice is required and data on the success of psychological interventions is required Health economist is required to add to weight of evidence as fatigue is a major factor in RA patients giving up work Arthritis Research Campaign Page 8

9 SESSION 3: NOVEL APPROACHES TO THERAPY In the final session the question of the most promising approaches to treating fatigue were discussed. PHYSIOLOGICAL APPROACHES Peter White introduced this area with a presentation on the physiological approaches that have been used in CFS. Key question was the choice between a complex intervention or to treat a single factor that has systemic effects? The mismatch between perceived and actual effort is the most replicated finding in CFS (10-15 studies) Of the potential approaches, Graded exercise therapy (GET), as tested in CFS, should be tried in RA. The steps behind GET are: explain and educate assess physical capacity establish baseline activity individual home exercise increase duration before increasing the intensity target heart rates feedback to the patient In five trials (3 UK, Australia and New Zealand) the percentage of patients that had improved was at least twice that of controls after three months of treatment. The physiological improvements included an increase in peak V0 2 with over a quarter improving in strength but this was not associated with feeling better. The sense of effort normalises after GET treatment i.e. it changes the brain more than the body and perception changes first. Studies in RA have been less successful as they have been training programmes rather than GET, better results can be achieved with graded exposure. This behavioural change must be maintained so exercise must be continued and this is more likely if an inhome exercise is established rather than a high or moderate intensity training design. Summary GET needs further exploration in RA fatigue Its efficacy may be more brain therapy not reconditioning Examining biomarkers before and after treatment may help us to learn more about RA fatigue PSYCHOLOGICAL APPROACHES Trudie Chalder discussed how cognitive behavioural therapy had been used to treat chronic fatigue syndrome (CFS) in which both fatigue and disability are perpetuated by fearful cognitions and avoidance behaviour. Disruptive sleep can lead to symptom focusing and lead to low mood leading to muscle pain. Three studies on the efficacy of CBT in fatigue have all shown that fatigue and physical functioning was improved in patients with CFS after treatment (CBT). There is also evidence that fatigue after serious infections (not common URTIs) can be reduced by CBT. Lengthy convalescence, being less fit or active and psychological co-morbidity can predict chronic ill health. An RCT was conducted to test the hypothesis that a brief psycho-educational package, administered by a research nurse shortly Arthritis Research Campaign Page 9

10 after onset of Glandular Fever would reduce fatigue symptoms. Intervention consisted of: one face to face session followed by two telephone sessions two weeks apart with a nurse. Sessions were reinforced with a booklet and lifestyle management (advice on return to work, gentle grading of activity and planned rest). After six months there was less fatigue in the treated group. Psychoeducation has also shown positive results in reducing fatigue in chronic diseases (cancer). The most frequent behavioural strategies used to cope with fatigue in RA are: rest, pacing according to energy levels, avoiding or limiting activities and distraction. One open study has shown that CBT can change a number of outcomes in RA patients including fatigue. A tailored CBT for people with early RA who were already psychologically distressed showed that effects were found on primary outcomes of fatigue, depression & perceived social support. Summary CBT needs to be targeted A model needs to be specified An a-priori hypothesis with specific outcome needs to be stated There is some evidence for a cognitive behavioural model of fatigue syndromes (not just CFS) with beliefs and avoidance behaviour playing a key role CBT or a modified form of CBT is an effective treatment for fatigue syndromes in general Where now for RA fatigue? Catastrophic beliefs can perpetuate fatigue in CFS, this has not been tested in RA Examine the relationship between cognitive behavioural responses and fatigue / social adjustment in RA prospectively A cognitive behavioural intervention for people with RA fatigue is already being tested (arc grant, Hewlett et al) RCTs are required The workgroups were then asked to consider the following questions Do we know what the best interventions are? Which groups should they be applied to? How can we assess how people respond? What are the research priorities? WORKGROUP 6: PHYSIOLOGICAL APPROACHES There are a number of potential physiological approaches from work in CFS: GET Drugs (cytokine blockage) Gabapentin to look at pain pathways Tocilizumab role of IL-6 in exercise, studies in breast cancer patients Modafenil CNS stimulant Nutritional supplements Complementary therapies Arthritis Research Campaign Page 10

11 Key challenges No gold standard Acute vs. chronic fatigue Which patients should be targeted as there are multiple facets to RA fatigue? Priorities for research Treatment algorithm tool to identify cause and level of fatigue in individuals Patient perspective Collect the correct data Common assessment tools that are RA specific, multi-dimensional and validated Health economics Constraints Health economy is it cost-effective? Lack of outcome tools need a reliable consistent set. Can arc help to guide development of them? Need consensus from experts on a core set Patient perspective drug vs. graded exercise Complexity of disease/confounding factors WORKGROUP 7: PSYCHOLOGICAL APPROACHES The focus group discussed how psychological approaches could be used in RA and what other therapies had been used. What evidence is there of treatments used? CBT (only one RCT) Emotional expression (expressive writing reduced fatigue in lupus) 2 x GET (1 trend, 1 positive) 2 education/self-management studies (1 positive, 1 trend) What needs to be done? Something that can be put into practice (briefer interventions / more intensive intervention / who should deliver the intervention?) Managing low mood / stress (as part of a CBT not a lone project) Sleep management (lack of sleep studies) Factorial design 4 groups (CBT, GET, GET + CBT, TAU) Lessons from CFS need modifying for exploration of their applicability in RA How can we achieve this? Mechanisms of change Can be measured in context of trial different mechanisms may be implicated with different treatments When to rest / exercise Acute versus chronic. Conflict of beliefs - need to exercise but too much can be harmful in RA and inflamed joints need to be rested Target health professionals Modify CBT / intervention according to patient need / target groups Control groups Arthritis Research Campaign Page 11

12 In psychological studies Disease controls Within disease sub groups Outcomes Multiple outcomes Disability Quality of life Qualitative studies to examine patient experience of intervention Health Economist Dr appointments More objective measures actometers, walking /step test Adverse events / serious adverse events CONCLUSIONS WHAT WAS LEARNT? Despite knowing about fatigue in other diseases such as CFS very little is known about fatigue in RA. It was felt that it would be important to understand the physiology behind fatigue as this would help research into fatigue in other diseases, not only RA, and this may be an area for other charities to invest in as well. Basics behind pathophysiology of fatigue in RA Literature review on questionnaires/fatigue scales Basic experiments in RA patients with fatigue to establish whether perceived effort for exercise is greater than actual effort required WHERE NEXT? The main outcome of the meeting was that is was important, as a first step, to establish some guidelines that could be used to assess and measure fatigue in RA and set outcome measures that could be used. This would be achieved by establishing a taskforce (led by Sarah Hewlett) with the support of arc. A further meeting was also popular as a number of participants were aware of a number of research studies that were due for publication and would have been published by the time the next meeting was held. MAJOR OUTCOMES Taskforce to establish set of guidelines for assessment and measurement of fatigue in RA and outcomes that could be used in research feed through to arc inflammatory diseases CSG Further meeting in 9 months to a year to discuss taskforce conclusions and new insights that have been published in this research area Arthritis Research Campaign Page 12

13 APPENDIX 1: PROGRAMME Final Programme Sunday 9 th November Wine reception Dinner Monday 10 th November Registration Introduction: Goals of the workshop Alan Silman Fatigue: a patient s perspective Pam Richards Session I: Assessment & Measurement of Fatigue (Marquis Suite) :20 Introduction Ernest Choy Break-out Groups (with tea/coffee) Group 1: How to define / measure fatigue Group 2: Laboratory / imaging assessment of fatigue Group 3: Can fatigue be sub-grouped / what are the clinical predictors Report back Session II: Aetiology of Fatigue in RA (Marquis Suite) Physiology and pathophysiology of effort Samuele Marcora Arthritis Research Campaign Page 13

14 Psychological mechanisms the clinician s Sarah Hewlett perspective Q & A LUNCH Break-out Groups (with tea/coffee) Group 4: Pathophysiology of fatigue Group 5: Psychology of fatigue Report back Session III: Novel Approaches to Therapy (Marquis Suite) Physiological Peter White Psychological Trudie Chalder Q & A Break-out Groups (with tea / coffee) Group 6: Physiological Approaches Group 7: Psychological Approaches Report back Closing summary Alan Silman Arthritis Research Campaign Page 14