Outcomes

Baseline and follow up survey of IBD fatigue awareness, help seeking and services

• What is the current awareness of IBD fatigue among members and health care professionals?
• Does the project change the level of awareness of fatigue in our members and healthcare professionals?

Current awareness of IBD fatigue – health care professionals

To help us understand the level of awareness and information needs of fatigue in IBD among healthcare professionals, we distributed questionnaires at the BSG conference in 2011, and also sent the questionnaire to IBD nurses.

The survey has several limitations, particularly its self selected and relatively small sample (94 health care professionals). Despite this, the survey indicates a need for greater information on fatigue and IBD.

We asked health care professionals how often IBD patients report fatigue to them – 37% responded ‘sometimes’, 35% ‘often’ and 20% ‘very often’. Only 7% of respondents stated that patients rarely reported fatigue.

Most respondents’ usual course of action, when faced with a patient presenting with fatigue with IBD in remission would be to check the haemoglobin level and treat if low (92%). Other frequent responses chosen were referral for other diagnostic tests (41%), advice on diet (36%), advice to take more exercise (33%) and advice to get more rest or sleep (31%). Actions mentioned by respondents in the open ended response section of this question, included:

• Check disease activity and inflammatory markers
• Holistic interview identifying stressors
• Referral to IBD nurse, dietician or psychologist (the need for psychological support or referral was mentioned by many respondents)
• Check drug side effects
• Assess for depression

Despite 55% of respondents indicating that their patients often or very often report fatigue, and 92% of respondents indicating that patients report fatigue as a problem more frequently than ‘rarely’, the level of self rated knowledge among health care professionals was low:

• 27% indicated that they had poor knowledge of the likely causes of fatigue in IBD
• 59% rated their knowledge as ‘fair’
• only 14% rated their level of knowledge as good or excellent.

The survey results indicate that 40% of health care professionals who responded, actively raise the topic with their patients (often, very often or always). However, a third only raise the topic ‘sometimes’, 18% only ‘rarely’ raised the topic and 8% stated that they never raise fatigue with their patients. As the survey was filled out by a self selected group of respondents who are likely to have above average interest in fatigue, the results suggest that there is a need to increase the profile of fatigue to ensure that patients receive the best care.

A high percentage (68%) of health care professionals surveyed consider that IBD fatigue can be adequately treated in most or some patients. However, given the perception of it being a treatable condition, the reluctance to ask about fatigue in clinics is more perplexing. General comments included:

“I would like to receive some evidence based information to give advice to these patients”

“Fatigue is common and I think the approach should be multidisciplinary including dietician, psychologist, gastroenterologists”

“Its effects are underestimated and poorly understood.”

“It is the single most difficult symptom to manage as those who experience it don’t seem to get any benefit from current strategies.”

“I work with children and young adults, the latter in particular struggle with fatigue. It affects their ability to interact with their peers both at school and socially, this has long term implications for them in adulthood.”

“Complex, under-rated, no resources to deal with it, (psychologically) difficult to define, but common.”

“I believe that fatigue is a major issue but unfortunately still poorly recognised as a problem to IBD patients.”

“Very undertreated in primary care.”

The survey results indicated that healthcare professionals, as well as patients, would welcome greater understanding of fatigue. At the end of our first year of research, we extended the remit of our research to conduct some in-depth interviews with healthcare professionals to further understand their understanding of IBD fatigue.

We advertised for healthcare practitioners to come forward via the Crohn’s and Colitis UK charity newsletter and an IBD specialist nurses’ newsletter and used a snowballing method to identify other healthcare practitioners.  Twenty semi structured interviews were conducted with a range of practitioners (gastroenterologists, IBD nurses, general practitioners, dietitians, psychologists and pharmacists).

Key findings of this research were that:

• Healthcare practitioners found it hard to quantify fatigue  and know if it was a specific symptom of IBD.
• Patients and their healthcare practitioners often use different words to describe fatigue which makes it difficult to establish whether patients and health care practitioners are speaking the same language when talking about fatigue
• Estimates of how many people with IB fatigue ranged from 0-100% with some healthcare practitioners not recognising IBD as a significant symptom of IBD Fatigue.
• We found that there was ‘don’t ask don’t tell approach which meant that many healthcare professionals don’t ask patients about their fatigue, and many patients don’t raise the issue with their healthcare practitioner.
• Some healthcare practitioners were reticent to raise the issue of fatigue with patients in the absence of evidence based options for treatment.
• Healthcare practitioners have a limited understanding of how fatigue impacts on lives of people with IBD
• Financial constraints were repeatedly mentioned as a reason for not being able to offer an optimal service.
• Healthcare practitioners mentioned a variety of blood tests that could be done to assess reasons for fatigue but there was no systematic checklist or pathway for referral.  There was a sense of healthcare practitioners referring patients to each other with no clear objective or idea of what can be offered to the patient.
• Some felt that a fatigue rating scale would be very useful, others felt it would be another piece of paper that would not be used.
• Many healthcare practitioners expressed a desire for better education and information sources on IBD-fatigue.

Current awareness/experience of IBD fatigue in Crohn’s and Colitis UK members

In January 2013, as part of the development of a fatigue rating scale, we contacted members of Crohn’s and Colitis UK to assess their level of awareness of the IBD fatigue project and their views on the usefulness of the newly developed IBD-fatigue assessment scale.

We randomly selected and approached over 2100 Crohn’s and Colitis UK members, 605 agreed to take part in the study, and 464 returned the completed questionnaire. From those who responded 51% were aware of the project and 90% were aware that IBD could cause fatigue. Despite the high level of awareness only 54% of patients had discussed fatigue with a healthcare professional and only 38% had asked for help. Of those patients who had asked for help only 27% (48 patients) were offered treatment and 5% were referred to sources of further information. We would hope that when the IBD-fatigue assessment scale is available, that we will see a greater number of patients discussing fatigue with their healthcare professionals.

The members who took part in the survey were sent a draft version of a new IBD-fatigue assessment scale, which had been developed by our research team, as part of extensive testing with patients, and 64% of patients said that the IBD-fatigue scale would make them more likely to seek help from a doctor or an IBD nurse in the future.

When asked how they would use the IBD-fatigue assessment scale, 86% said they would use it to assess their current level of fatigue, 88% would use it to monitor their fatigue levels over time. It was also considered a useful tool for opening up a dialogue about fatigue with healthcare professionals – as 69% said they would take the fatigue rating scale to their GP consultations, and 76% said they would take it to their consultations with a gastroenterologist. It was also considered a valuable tool for discussing fatigue with family and friends (49%) and for evidence when applying for disability benefits allowance (40%).

The overall value of the project and the fatigue assessment scale were given a positive endorsement, with 68% saying that the project in IBD-fatigue had increased their knowledge of IBD-fatigue and 72% stating that the fatigue scale will make them feel more confident in discussing problems related to fatigue.

The fatigue rating  is available here (add in link) with a self scoring facility. A paper is also in development for publication to raise awareness of the IBD-fatigue assessment scale among healthcare professionals.

Description of IBD-related fatigue.

• What is the experience of fatigue reported by people with IBD?
• What coping mechanisms are used by people who live with IBD-related fatigue?

The experience of fatigue

In  July 2010 flyers were sent out in NACC news (the Crohn’s and Colitis UK newsletter) asking Crohn’s and Colitis UK members to contact us if they were interested in being part of the research project.  We had an overwhelming response, receiving interest from nearly 600 participants in only 3 weeks.  We finally had to close the project to further interest on 26 July 2010. Our lead researcher, Wladzia Czuber-Dochan at King’s College selected a purposive sample of 20 interviewees across the country suitable for in-depth interview.

The purpose of this qualitative part of the study was to

1. Describe the experience of IBD-fatigue as reported by people with IBD
2. Describe the impact of IBD-fatigue on people’s life
3. Identify coping mechanisms used by people with IBD-fatigue

Many participants in our research had difficulty to describe and put into words what fatigue is like, and it feels different to different people. It can also be very unpredictable, varying day by day or even hour by hour and can come on suddenly and out of the blue, like hitting a brick wall.

‘It’s very strange to put your finger on it’ (Roger, 64, CD)

“physical heaviness … just a general lethargy and can’t-be-bothered-ness. It’s like a kind of physical depression … feeling under the weather‘(Julie, 47 UC)

‘ just feeling very, very weary, and no inner energy … I’m bone weary is the old way of describing it… An unfamiliar emptiness, a lack of wanting to do things’ (Robert, 82, CD)

‘My body feels two tonnes of weight … All my limbs feel very heavy’ (Vicky, 24, CD)

‘Overwhelming heaviness … you feel like lead … you just feel like you’re twice the weight you are…you just suddenly feel your arms are like lead and your hair’s heavy’ (Catherine, 49, UC)

“ very similar to like minor flu symptoms really. … this fuzziness … the tiredness is so heavy, it’s not an ordinary tiredness it’s so heavy and fluffy and strange’ (Sue, 58, CD)

’Fighting your head to try and get it to work … the brain fog’ (Sophie, 37, CD)

‘Head feels very like cotton woolly, very like fuzzy and I feel really, really tired’ (Fiona, 21, CD) ‘It’s just like an aura round you where you don’t want to do anything … and your brain is a bit addled’ (Roger, 64, CD)

‘Too exhausted to think’ (Ruby, 50, CD)

‘The brain fog feeling’ (Harry, 45, CD)

‘Being very woolly in my thinking’ (Gary, 51, CD)

’The cogs of your brain have all suddenly gone’ (Hugh, 39, CD)

We found that Fatigue can have an effect on all aspects of life. Some  people find it difficult to function at all when their IBD is active, both because of bowel symptoms but also fatigue.  Research and surveys suggest that fatigue may affect the lives of people with IBD in a number of different ways:

• Physical activity
  The low energy levels caused by fatigue can make it very hard to take part in physical activities such as sport.  Some people find that they do not even have the energy to carry out everyday tasks such as driving, housework, or collecting the children from school.

• Memory and concentration
  Some people find that fatigue can make it difficult to think logically and had difficulty with concentration and memory.  Some people reported that when they are very fatigued, they have trouble speaking and may stumble over their words. Some people call this ‘brain fog’.

• Social Activities
  Because of its unpredictable nature fatigue can make it very difficult to take part in social activities.  This may mean that people with IBD fatigue find it difficult to go on holiday, travel, socialise, or even take part in hobbies or interests.

• Emotions
  Fatigue had an impact on people’s emotions. Participants reported that they cannot do as much as they  would like, and often felt frustrated and angry. Some people may feel isolated and lonely if they find it difficult to get out and socialise with friends. This can lead to depression and low confidence.

• Relationships
  Some people find that fatigue has a negative effect on their relationships with friends and family.  For example, some people may feel that, because their condition cannot be seen, people do not believe them and think that they are being anti-social. People living with IBD fatigue report feeling guilty if their partner or family have to do extra things to help, or if they miss out on doing things together.

• Work and education
  Our study found that fatigue can have a direct affect on employment and education.  Whereas some people with IBD fatigue may be able to manage a full time job, others may struggle with such a commitment. Some experience fatigue so badly that they have to give up work. Working part time or reducing the number of hours worked can sometimes help manage fatigue. However, this can have major financial implications. Students with fatigue may find studying difficult, and may worry that their fatigue has limited their achievements and job aspirations.

The Coping Mechanisms Used by People with IBD-Fatigue

People in our study reported a number of different ways that they managed their fatigue. Things which work for some people may not work for others.  Examples of coping mechanisms which people with IBD have found useful to reduce their fatigue included:

• Frequent breaks and rest
• Good quality sleep
• Alternative therapies such as acupuncture, yoga or homeopathy
• Planning head and reducing stress
• Physiotherapy and exercise
• Flexible working hours

We also found that people found it difficult to talk about fatigue or for others to understand it,  and that having a conversation about fatigue with a health care professional or a family member can be the first step towards recognising the problem and dealing with it.

Several of our research participants found that even taking part in the study had helped them to realise the impact that fatigue had had on their lives.

Literature review to identify instruments/items suitable for use with people with IBD

• Which fatigue scales may be suitable for use with IBD patients and which approaches to management are successful in other conditions?

A literature review was commissioned by Crohn’s and Colitis UK as part of the Big Lottery-funded IBD-fatigue project, and conducted by the researchers from King’s College London (KCL). The aims of the review were to describe IBD-fatigue, to examine what factors contribute to it, and what methods are currently being used to manage fatigue by healthcare professionals and patients.

After an extensive literature search, twenty eight academic papers were included in the review. Most papers were not really focussed on fatigue and measured fatigue as a secondary outcome; therefore information on fatigue was at times limited. The lack of research papers is surprising given the importance of fatigue as a symptom to people living with IBD.

The literature review highlights a lack of clarity in the terms used and a lack of consistency on the definition of IBD-fatigue. Researchers in the reviewed studies used terms such as ‘fatigue’, ‘tiredness’, ‘reduced energy’ and ‘declined vitality and vigour’. None of the reviewed studies asked patients for the description of their experience of fatigue. Our researcher at Kings College London has also conducted in-depth interviews with patients, and has asked them to describe their fatigue, so that we have a clearer picture of what fatigue means for people living with IBD. This will be the subject of a separate paper, and is also helping us develop a fatigue assessment scale.

IBD-fatigue was reported by 22%-41% of people with IBD in remission and by 44%-86% in moderate to active disease. The prevalence data are obtained from the total of 6165 IBD patients, from sixteen different studies. The prevalence rates for IBD-fatigue are comparable with rates in other chronic conditions, for example, 41%-76% in rheumatoid arthritis, 75%-78% in multiple sclerosis and 40%-89% in cancer. Despite high prevalence, fatigue in IBD is not as well recognised and managed as in other conditions.

The review identified that nine different scales were used to measure fatigue in IBD, however only one was found to be previously tested in IBD. Five scales measured the type of fatigue and the remaining four scales measured the functioning affected by fatigue. This disparity between the scales makes comparison between different types of fatigue difficult. We are currently in the process of developing a new IBD-fatigue specific assessment tool that will be available to both patients and clinicians in the second half of 2013. The new fatigue scale will be available on our website, for patients to self score and take to their GP, IBD Nurse or Consultant, or to monitor their level of fatigue. Numerous factors associated with fatigue were identified in the review, and these can be categorised to physical, psychological and lifestyle factors; but only disease activity (physical factor) and anxiety and depression (psychological factors) were consistently associated with presence and severity of fatigue. Out of lifestyle factors, it has been identified that people with better social networks and support report lower levels of IBD-fatigue.

The review did not identify any studies looking at ways of managing fatigue which are currently used by people with IBD themselves. There were three studies testing two non-drug related interventions (stress management and problem solving therapy), but the studies were small, and there is a need for bigger, more comprehensive studies. Some medications (e.g. infliximab and adalimumab) were identified as having a positive effect on the level of fatigue, however only patients with Crohn’s disease were included in the studies.

The details of the full literature review paper are: Czuber-Dochan W, Ream E & Norton C (2013) Review article: description and management of fatigue in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. DOI: 10.1111/apt.12205.

Psychometric testing of the new IBD specific fatigue measure

• Can an IBD fatigue assessment scale measure fatigue and its impact in IBD patients?

Our interviews with our volunteers confirmed that fatigue was a big issue that had a severe impact on many areas of life.  It also confirmed a need for a way of measuring fatigue to enable people with IBD to discuss fatigue with their health care professionals and test interventions.

Fatigue scales had been used in many other conditions, to help patients and doctors measure levels of fatigue, however there was no scale that had been developed specifically for IBD.

Our fatigue scale was rigorously tested with 70 of our volunteers for the study. We then contacted 2,132 Crohn’s and Colitis members at random in October 2012 asking for volunteers to test the questionnaire, 605 people offered their help, and were then posted a booklet of questionnaires, including our new IBD Fatigue rating scale (IBD-F), 469 questionnaires were returned (a response rate of 77.5%).

In testing our IBD-fatigue scale performed well against two other fatigue scales widely used in other chronic conditions (MFI and MAF), however our study participants had a clear preference for our new scale.

Our fatigue scale, which can be accessed and scored online or printed from our website as a PDF, will enable:

• Patients to self-assess their fatigue and the impact is has on their functioning
• Patients to more easily raise their fatigue symptoms with healthcare professionals.
• Healthcare professionals to assess measure and monitor patients’ fatigue over time.

All the items and wording in the questionnaire have been developed with close participation of patients at each stage. The strength of IBD-F lies in the robust and rigorous development process, grounded in the experience of fatigue as reported by patients.

Further Reading: For a more in-depth analysis of the methodology of the fatigue rating scale development see Measure your Fatigue

Develop and evaluate two interventions to improve fatigue in IBD

• Will either or both tested interventions improve fatigue in IBD?

As part of our initial research application we set out to identify two interventions to see if they made any difference to IBD Fatigue, our review of the literature identified the areas of exercise and diet as being important areas for further research (these were also areas that patients had told us they wanted more guidance)

Exercise

Exercise emerged as an area that had shown to be effective in other conditions.

We looked at the literature surrounding cancer, multiple sclerosis, and rheumatoid arthritis – in total there were 1600 papers for cancer, 400 for MS and 200 for Rheumatoid arthritis.

The interventions that had been successful in treating fatigue in cancer and multiple sclerosis have been exercise-related and it was considered likely that exercise would be an effective intervention for IBD given the similarity of the description of IBD fatigue with cancer fatigue, in particular.

Our researcher at University College Hospital spoke with patients in clinic about their experience of exercise, and found that they were very eager to talk about this issue.  Many of the patients are active, even during flare ups, but considered they could do with further guidance.

Although research in managing cancer-related fatigue indicates that low grade exercise may be helpful in reducing and preventing fatigue at present there are no evidence based treatments for fatigue in IBD.

For individuals with cancer there has been a reversal of advice regarding exercise. Patients were previously advised to rest, however individually prescribed exercise is now acknowledged by medical experts as a treatment for fatigue. Our focus group participants were most frequently advised by health professionals to control their fatigue by taking rest and sleep.  We wanted to answer the question – is this also outdated advice for IBD patients?

The current research literature provides some indication that exercise is beneficial for individuals with inflammatory bowel disease.  There are currently no evidence-based guidelines for exercise and IBD.

Some recent studies have shown the following:

• Exercise is well tolerated in individuals with IBD
• A twelve-week walking programme elicited psychological benefits on the basis of a small number of patients.
• Improvements in quality of life were found in Crohn’s disease patients following a 3 month low grade walking programme, which required walking three times a week at 60% of maximum heart rate.
• Recent studies have  suggested that low to moderate activity is safe, and in general individuals with IBD should benefit from and increase exercise.
• Resistance training may particularly benefit the IBD population  in whom corticosteroid use and intermittent periods of inactivity may impair muscle mass and bone health.
• There are no studies in IBD patients that support the idea that low intensity exercise makes IBD symptoms any worse.
• Some individuals do present with gastrointestinal symptoms during high intensity exercise, but these are not common in low intensity exercise.

In addition to the literature review, our researcher sampled eleven patients from an IBD clinic who reported themselves as ‘exercising’

• Our case studies with patients found that only 3/11 of those we questioned reported doing exercise often, to work up a sweat.
• Aerobic exercise was the most common undertaken (by all eleven patients) but only two did resistance exercise regularly.
• Four of the patients felt that exercise helped them with fatigue, the effect of exercise was described as a ‘good kind of tiredness’
• Six patients reported having received no advice from healthcare professionals regarding exercise (6/11)
• All eleven of the exercising patients felt that exercise was beneficial and that ‘both children and adults with IBD should be encouraged to exercise’
• Patients felt there was a need for hospitals to offer exercise classes for people with mobility difficulties.
• There is no evidence that complete rest is advisable for patients with active disease or in remission.

Our preliminary research concluded that for patients to vary exercise levels according to their disease activity, effects of medication and severity of symptoms, there is a need to test individually prescribed exercise for the patient.

A trial of an individually prescribed exercise programme for IBD patients is currently underway at University College London Hospital.  Any current UCLH patient who is interested in taking part in the trial can email Angela McNelly:   angela.mcnelly.10@ucl.ac.uk

Diet

An intervention based on diet was also considered. It is hoped that this would enable an individual with IBD to reduce their fatigue by making suggested dietary changes. A number of options were considered, but after looking at the literature, it was felt that a useful study would be on increasing Omega 3 intake.

There have been studies in IBD focusing on disease activity and the immune system, but none on fatigue. Although benefits of increasing dietary omega 3 fatty acids in relation to fatigue in other diseases have been reported, more research in this area is required with IBD patients.

Evidence indicates that increasing omega 3 fatty acid intake could have a positive impact on cognitive and or physical aspects of fatigue in IBD.

Our focus group had indicated that patients experienced both physical and cognitive fatigue and randomised controlled studies using omega 3 supplements, have found positive effects on mood, depression, cognitive function and mental fatigue.  It has been suggested that the anti-depressive effects of Omega 3 fatty acids may relate to anti-inflammatory gut-brain mechanism and that these fatty acids could therefore improve mood and quality of life in individuals with IBD .

It has been found that omega 3 fatty acids may improve physical performance of trained and untrained individuals by increasing blood flow to active muscles and reducing muscle soreness and inflammation after exercise.  Other reported effects include a reduction in heart rate and oxygen consumption during exercise.

There are indications that Omega-3 has been useful for fatigue in other conditions – for example in breast cancer survivors.  A study of Omega-2 supplementation in advanced lung cancer in combination with other treatments reported significantly reduced fatigue and inflammation.

We were particularly interested in a study which combined Omega- 3 fatty acids and Exercise. There has been recent research to study the mechanism by which exercise acts on the brain and it appears to enhance the effects of omega 3 fatty acids (DHA). The evidence to date would suggest that the combined effects of increasing omega-3 and exercise on fatigue could be more effective than exercise or omega- 3 intake alone.

A blinded trial of Omega 3  fish oil for IBD patients is currently underway at University College London Hospital.  Any current UCLH patient who is interested in taking part in the trial, and who has not taken an Omega-3 supplement in the last 12 weeks can email Angela McNelly:   angela.mcnelly.10@ucl.ac.uk

To determine if people with IBD-related fatigue have undiagnosed medical conditions that could be treated to improve their fatigue?

• Do people with IBD and fatigue have undiagnosed medical conditions that if treated could improve fatigue?

While fatigue is clearly linked to disease activity, worsening as inflammation increases and generally reducing when inflammation subsides or is treated, a substantial minority of patients (up to 40%) report that fatigue is present in remission. This fatigue has a negative impact on quality of life and limits both work and social activity.

Fatigue in IBD is likely to have several different underlying mechanisms and contributing factors, including raised inflammatory markers, dietary and nutritional deficiencies, and anaemia, as well as potentially being related to non-IBD factors such as thyroid function and depression.  However, there is no consensus on what should be assessed in a patient with IBD fatigue, except to investigate inflammation.

This study aimed to develop and pilot a format for screening of people with IBD fatigue when disease is apparently in remission seeking potentially reversible causes of  fatigue which might be amenable to treatment.

A consensus consultation was used to generate a checklist. Eight health care professionals with varied backgrounds in IBD (two gastroenterologists, four IBD nurses, one dietitian and one Psychiatrist) and two IBD patients met in a single focus group, facilitated by an employee of an IBD charity, to discuss the questions:

1. What are the potentially treatable/reversible medical causes of IBD fatigue?
2. What other non-IBD potential causes of fatigue should be considered in patients with IBD fatigue?

The facilitator led a discussion on these questions and at the end of the meeting the group was then asked to score on a scale of 1-10 how relevant they thought a range of tests and assessments were to assessing IBD fatigue. The checklist was drawn up by the analysis of the focus group data.

An audit of IBD patients attending routine outpatient appointments was carried out to determine how many patients with IBD who were believed to be in remission had potentially medically reversible causes for fatigue. Patients were screened during the period April-July 2013.

Once active inflammation was excluded or treated as a cause of IBD fatigue, assessment for causes or fatigue was agreed as taking a blood sample for urea and electrolytes; full blood count; liver function tests; iron studies (haemoglobin and ferritin); vitamin B12; folate; vitamin D; magnesium; testosterone; coeliac screen; thyroid function test; cortisol (serum cortisol at 7-8am); fasting glucose (to test for diabetes); zinc;  and selenium.

This study found a high level of consensus among professionals on what to look for if a patient with IBD in remission reports fatigue. It also found many patients (30%) attending a hospital outpatient IBD clinic and thought by clinicians to be in remission actually had raised inflammatory markers when tested.

Of those patients in remission, half reported fatigue and half did not. Of those reporting fatigue but with no evidence of active disease, half had biomedical abnormalities which showed on first line tests suggested by our focus group which might explain fatigue, but which had not been previously investigated. In this study we did not go on to investigate suggested second line tests, nor did we attempt to correct abnormalities and see if fatigue improved.

It is well known and unsurprising that people with active IBD experience fatigue. What is less well recognised is that this does not always resolve in remission and that a significant minority of people with apparently quiescent disease report often disabling levels of fatigue.