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Medically explained symptoms: A mixed methods study of diagnostic, symptom and support experiences of patients with lupus and related systemic autoimmune diseases

Authors:

Abstract

Objectives To explore patient experiences and views of their symptoms, delays in diagnosis, misdiagnoses, and medical support, to identify common experiences, preferences and unmet needs. Methods Following a review of LUPUS UK’s online forum, a questionnaire was posted online during December 2018. This was an exploratory mixed methods study with qualitative data analysed thematically and combined with descriptive and statistically analysed quantitative data. Results There were 233 eligible respondents. Mean time to diagnosis from first experiencing symptoms was 6 years 11 months. Seventy-six percent reported at least one misdiagnosis for symptoms subsequently attributed to their systemic autoimmune rheumatic disease. Mental health/non-organic misdiagnoses constituted 47% of reported misdiagnoses and were indicated to have reduced trust in physicians and to have changed future healthcare-seeking behaviour. Perceptions of physician knowledge and listening skills were highly correlated with patient ratings of trust. The symptom burden was high. Fatigue had the greatest impact on activities of daily living, and yet the majority reported receiving no or poor support in managing it. Assessing and treating patients holistically and with empathy was strongly felt to increase diagnostic accuracy and improve medical relationships. Conclusion Patient responses indicated that timely diagnosis could be facilitated if physicians had greater knowledge of lupus/related systemic autoimmune diseases and were more amenable to listening to and believing patient reports of their symptoms. Patient priorities included physicians viewing them holistically, with more emotional support and assistance in improving quality of life, especially in relation to fatigue.
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Medically explained symptoms: A mixed methods study of diagnostic, symptom and support
experiences of patients with lupus and related systemic autoimmune diseases
Melanie Sloan1 Rupert Harwood2 Stephen Sutton1 David D’Cruz3 Paul Howard4 Chris Wincup5
James Brimicombe1 Caroline Gordon6
1Behavioural Science Group, Institute of Public Health, University of Cambridge, Cambridge, UK
2Patient Co-investigator, Institute of Public Health
3The Louise Coote Lupus unit, Guys’ and St Thomas’ Hospital, London, UK
4LUPUS UK, St James’ House, Romford, Essex
5 Department of Rheumatology, University College London, London, UK
6Rheumatology Research Group, Institute of inflammation and ageing, College of Medical and Dental
Science, University of Birmingham, Birmingham, UK
Correspondence to:
Melanie Sloan
Behavioural Science Group
Institute of Public Health
University of Cambridge
Forvie Site
Robinson Way
Cambridge
CB2 0SR
UK
Email:mas229@medschl.cam.ac.uk
Abstract
Objectives
To explore patient experiences and views of their symptoms, delays in diagnosis, misdiagnoses, and
medical support, to identify common experiences, preferences and unmet needs.
Methods
Following a review of LUPUS UK’s online forum, a questionnaire was posted online during December
2018. This was an exploratory mixed methods study with qualitative data analysed thematically and
combined with descriptive and statistically analysed quantitative data.
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction
in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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Results
There were 233 eligible respondents. Mean time to diagnosis from first experiencing symptoms was
6 years 11 months. Seventy-six percent reported at least one misdiagnosis for symptoms
subsequently attributed to their systemic autoimmune rheumatic disease. Mental health/non-
organic misdiagnoses constituted 47% of reported misdiagnoses and were indicated to have reduced
trust in physicians and to have changed future healthcare-seeking behaviour. Perceptions of
physician knowledge and listening skills were highly correlated with patient ratings of trust. The
symptom burden was high. Fatigue had the greatest impact on activities of daily living, and yet the
majority reported receiving no or poor support in managing it. Assessing and treating patients
holistically and with empathy was strongly felt to increase diagnostic accuracy and improve medical
relationships.
Conclusion
Patient responses indicated that timely diagnosis could be facilitated if physicians had greater
knowledge of lupus/related systemic autoimmune diseases and were more amenable to listening to
and believing patient reports of their symptoms. Patient priorities included physicians viewing them
holistically, with more emotional support and assistance in improving quality of life, especially in
relation to fatigue.
Keywords: Systemic lupus erythematosus, patient-views, quality of life, patient-physician
interaction, misdiagnoses, symptoms, UCTD, diagnostic delays, medical support.
Key messages:
1. Diagnostic delays and misdiagnoses are common in SLE/CTD and can damage trust in
physicians.
2. SLE/CTD patients strongly value physicians taking a holistic view, listening and believing
patient- reported symptoms.
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3. More support is required with adapting after SLE/CTD diagnosis and in improving quality of
life.
Introduction
Systemic lupus erythematosus (SLE) is a chronic, inflammatory, autoimmune disease which can be
life threatening. With no definitive diagnostic tests for SLE and related diseases, and a diversity of
often non-specific presenting symptoms1, patients are largely reliant upon expert medical opinion
for a diagnosis, with delays in diagnosis and subsequent treatment commonly reported2,3,4. Multiple
studies indicate weaknesses in how medical training addresses SLE and other rheumatological
conditions5,6,7,8 and highlight a need for greater awareness amongst clinicians in order to aid faster
diagnosis9. In addition, there have been calls for more patient-focused research2.
The problem of undiagnosed lupus in the community was recognised over 20 years ago10. Despite
attempts to increase awareness of the disease, more recent studies report lengthy journeys to
diagnosis2,3,4 with many patients having accrued considerable damage to their health by the time
they reach diagnosis, and earlier treatment associated with better prognosis11,12,13. A 2014 survey of
over 2500 LUPUS UK members found that the mean time to diagnosis from initial symptom
awareness was 6.4 years, with approximately half reporting they were initially misdiagnosed2.
Diagnostic delays of over 3 years were also reported by 58% of lupus participants in the 2017 Rare
Autoimmune Rheumatic Diseases Alliance (RAIRDA) survey4.
Guidance for UK practitioners was lacking until the publication of the British Society for
Rheumatology guideline for the management of lupus in 201714. Research on patient experiences
and preferences is key to increasing the impact of the guideline as diagnosis and effective disease
management is likely to be strongly influenced by patient-physician interactions.
There has been important patient perspective research in recent years, including research reporting
access to healthcare, diagnostic delays, and frequency of misdiagnoses 2,3,4,9. However, significant
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gaps in the literature remain, particularly with regards to ascertaining patient views of the reasons
for, and impacts of, diagnostic delays and misdiagnoses. This study addresses these gaps, as well as
investigating patient perceptions of their symptoms, support received from clinicians and patient
suggestions for improvements in diagnosis and care.
Methods
Data Collection
Following a review of patient priorities on the LUPUS UK web-based forum and discussions with
patients, LUPUS UK, and rheumatologists, a questionnaire (supplementary material, section
Questionnaire, available at Rheumatology Advances in Practice online) was designed to collect
quantitative and qualitative data. The main survey sections included: perceptions of support,
symptoms and reasons for misdiagnoses/delays. Open questions to elicit qualitative responses
included: misdiagnoses experiences, advice to doctors on improving diagnosis and care, and an
invitation at the end of the questionnaire to give any further patient-views. The questionnaire was
pre-tested and then made available, with an accompanying information sheet, for 3 weeks in
December 2018 for completion online using Qualtrics, on the LUPUS UK online forum and ‘Lupus UK
sufferers’ Facebook group. The supplementary material section Methodology, available at
Rheumatology Advances in Practice online, provides more in-depth description of data collection,
analysis and study limitations. This study complies with the declaration of Helsinki, the Cambridge
psychology research ethics committee approved the research [PRE 2018-84] and informed consent
was obtained from all respondents.
Inclusion criteria: Age 18 years +, reporting a diagnosis of lupus, undifferentiated or mixed
connective tissue disease (UCTD, MCTD), Sjögren’s syndrome or overlap condition on their clinic
letters, and listing symptoms that were supportive of these diagnoses; including, in the case of those
reporting a diagnosis of SLE, symptoms that were supportive of a diagnosis made in-line with the
American College of Rheumatology (ACR) and/or Systemic Lupus International Collaborating Clinics
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(SLICC) classification criteria15,16.The 2% reporting ‘probable’ lupus were also included, as their
reported symptoms met the criteria.
Analysis
Following data cleaning and removal of ineligible participants, quantitative data from 233
participants was analysed using SPSS version 25. Qualitative responses were provided by 182
respondents on the questionnaire, with a further 24 providing information by contacting the
research team.
Qualitative data were combined and analysed thematically17 using NVivo 12 to assist with coding and
classification. Briefly, analysis involved 1) immersion in the data 2) developing and agreeing an initial
coding scheme 3) coding the data 4) refining and re-coding 5) identifying commonly occurring
themes17. Once provisional themes had been identified, the LUPUS UK forum moderator (PH) posed
several questions18,19,20 to the online community to confirm that emerging themes reflected the
wider community views, and to allow the lead researcher (MS) to probe responses in more depth.
Validity of the findings was also strengthened by member checking21,22, by comparing emerging
themes with forum discussions and by examining deviant cases23. Further triangulation occurred by
the integration of qualitative and quantitative data24,25.
Participants
Participant characteristics are shown in Table 1. There were 78% of respondents reporting a
diagnosis of SLE, 10% with UCTD, and 12% with other related autoimmune conditions. The vast
majority of respondents were white and female, and 70% were resident in England.
Results
Areas identified from thematic analysis to improve diagnosis and care were: The importance of
listening and belief, holistic viewpoint and knowledge acquisition and transfer.
Delays and misdiagnoses
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The average time to diagnosis from first experiencing lupus/CTD symptoms was 6 years 11 months
(mean) and 4 years (median), with 24% of respondents reporting that diagnosis took over 10 years
and 22% reporting that they were diagnosed within one year. At least one misdiagnosis was
reported by 76% of respondents, with 47% of all misdiagnoses being of ‘non-organic aetiology’,
psychological, mental health (MH) or medically unexplained symptoms (MUS), the combined
category referred to henceforth as MH/MUS. Misdiagnoses were most frequent amongst
respondents with UCTD, with 95% reporting receiving one or more.
Misdiagnoses are summarised in Figure 1 with health anxiety the most frequent, followed by
misdiagnoses of alternative rheumatic diseases, most commonly rheumatoid arthritis.
Over 80% of the respondents who reported receiving a MUS/MH misdiagnosis (often referred to by
participants and forum members as an in your head’’ misdiagnosis) indicated that it had both
reduced their future trust in physicians and altered their healthcare seeking behaviour, with the
impact of these misdiagnoses illustrated in the following quote:
‘The misdiagnosis of stress, unexplained etc is the most dangerous misdiagnosis and it completely destroys
trust, feels like you are not being listened to, like you are explaining it wrong, doing something wrong, doing
this to yourself and it causes guilt, mistrust and makes you question yourself’ (Female, 30s, England)
The majority (60%) of respondents reported these MUS/MH misdiagnoses had made them less likely
to seek medical help and report symptoms in the future. For others (27%), these misdiagnoses made
them more likely to seek help, often detailing how they ‘’knew’’ their ‘’own bodies’’ and continued
to seek clarity for continuing symptoms in the face of medical disbelief of an organic aetiology.
Table 2 summarises patient views of the key influences on delays and misdiagnoses. The most
commonly experienced symptoms before diagnosis were often non-specific (rashes, fatigue, joint
pain and oral ulcers) and difficult to attribute to a single disease unless viewed in the context of a
systemic illness.
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Patients reporting atypical serology, especially permanently negative ANA, experienced much
greater diagnostic delays (mean delay of 13 years for permanently negative ANA participants) than
ANA positive patients, with 92% [Exact Binomial 95% CI 62% to 100%] of seronegative respondents
taking over 4 years to be diagnosed, compared to 55% [95% CI 44% to 66%] with positive ANA and
65% [95% CI 48% to 78%] with intermittently positive ANA. No seronegative participants were
diagnosed within one year, compared to 26% of ANA positive patients [95% CI 17% to 37%]. Using
Fisher’s Exact test between seronegative, ANA intermittently positive and ANA positive groups there
was a significant difference (p=0.0386) in the percentages taking over 4 years to be diagnosed.
Multiple participants who lacked visible symptoms and/or consistent positive serological markers,
commented on the sense of invalidation and physician disbelief when test results did not reflect the
severity of their symptoms, as articulated by this participant:
‘The rheumatologist sent me to see a psychiatrist because I complained that I felt ill even though the blood
results were OK. The previous results were positive. Psychiatrist said that I was OK and I should get a new
rheumatologist who knew more about lupus(Female, 50s, England)
Additional evidence of the greater diagnostic/care difficulties experienced by the permanently ANA
negative group was their very high rate of MH/MUS misdiagnoses (92%). However, those reporting
positive anti-dsDNA still had a mean diagnostic delay of 6 years 2 months, and 54% reported a
MH/MUS misdiagnosis.
Missed and Misdiagnoses after diagnosis
A quarter of participants felt that diagnoses provided for new symptoms arising post SLE diagnosis
were incorrect. A quarter of these perceived that they were misdiagnosed with fibromyalgia; 25%
with anxiety or mental health issues; and 8% with functional disorders, either gastrointestinal or
neurological; and, as instanced in the following quote, many participants had been subject to
multiple misdiagnoses:
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‘Myriad of patronising psychological assumptions including health fixation disorder, anxiety and fibromyalgia.
All while flaring with eventual proven pathology’ (Female, 50s, Australia)
Other participants expressed concern that new symptoms were too quickly attributed to their SLE,
with other potential causes not appropriately investigated, as this participant details:
‘I had to have my gall bladder removed quite suddenly and my GP had been telling me that lupus caused
digestive problems so didn’t investigate it’ (Female, 30s, England).
Conversely, this participant, in common with others, reported feeling that some symptoms were not
correctly attributed to the disease; leading to greater anxiety over the possible aetiology:
‘Not understanding what is happening to your body is distressing and scary. One of the symptoms I have
(difficulty swallowing food/choking) has never been connected to lupus but I am sure this is the case’ (Female,
60s, England)
Symptoms, serology and disease burden
As figure 2 demonstrates, the symptom burden was high. Fatigue was reported to be present all or
most of the time by 82% of respondents and specified by the majority to be the symptom impacting
their life the most, followed by pain, and then cognitive dysfunction. The invisibility of these
symptoms to society and physicians generates an additional challenge of feeling ‘’disbelieved’’, as
highlighted by this respondent:
‘The fatigue and the pain really is life changing. It’s not easy to see, but it’s there and very real’ (Female, 30s,
England)
Interestingly, only 3% of patients responded that organ involvement had the most significant impact,
including those with lung, heart, brain or kidney involvement, who predominantly also considered
fatigue or pain to be most impactful.
The life-changing impact of these multiple, largely invisible symptoms was highlighted by many,
including the reduction in physical and cognitive abilities, greatly reduced quality of life, impact on
families, social life and employment. The majority (77%) had stopped working, reduced hours or
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changed jobs at some stage as a result of their disease; with 34% of participants not currently
working due to their health issues.
Support
Figure 3 displays that approximately half of respondents perceived they were receiving good or
excellent support overall and from their rheumatologist. Mean scores (1-5, with 1 being no support
to 5 being excellent support) for overall support were less for UCTD (2.6) and patients in Wales (2.7),
and slightly higher for anti-dsDNA positive participants (3.5) than the overall mean (3.3).
The need for much greater support with adapting, accepting and coping mentally with the disease
was supported by the qualitative findings and a key element of the holistic viewpoint theme
identified. This theme encompasses the indicated patient belief that physicians should improve
diagnosis by viewing symptoms together; and improve treatment by providing care for every aspect
of the patient affected by the disease. It was commonly expressed that this care should include
more support and empathy; consideration of mental as well as physical health; and help with
improving quality of life and with learning to live with a life-changing disease. Aspects of this theme
are reflected in the following participant quote:
‘I have treatment for the disease but not as a person who has lost so much. It’s a devastating illness…Delays in
diagnosis are damaging physically and mentally, There is a clear pattern of grief coming to terms with a
massive loss of quality of life. I’ve had no emotional support’ (Female, 40s, England).
Clinician support – knowledge, trust and listening skills
Respondents were asked to rate the different types of clinicians they had consulted for their
SLE/CTD for: listening skills, knowledge of lupus and the level of trust the patient felt for that type of
doctor. The options provided were ‘very poor’, ‘poor’, ‘moderate’, ‘good’ or ‘very good’.
Clinicians consulted by more than 15% of respondents included (in descending order of quantity
consulting) GP, rheumatologist, lupus specialist, A&E doctor, specialist nurse, physiotherapist,
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neurologist, dermatologist, cardiologist, nephrologist, psychologist/ counsellor, haematologist and
immunologist.
Non-rheumatology specialists’ ratings were analysed separately by speciality, but were largely
similar so were combined in Figure 4, with any significant differences reported individually.
The clinicians considered to have the poorest knowledge of lupus were A&E doctors, GPs and
neurologists, with respective ratings for poor/very poor knowledge being 66%, 50% and 51%.There
was a mean of 36% poor/very poor ratings for all specialist physicians’ knowledge, excluding
rheumatology clinicians.
Knowledge – acquisition and exchange, was a major theme identified. Physician knowledge
acquisition was felt to be of prime importance for diagnosis, whereas knowledge exchange becomes
a patient priority post-diagnosis. This theme included patients wanting physicians to provide them
with more information, especially at the diagnostic appointment. It also included physicians being
more amenable to patients sharing their – often extensive - knowledge of the disease and their
individual manifestations. The importance of physicians admitting limited disease-specific
knowledge and referring more quickly for appropriate testing and consultations with specialists was
also identified within this theme. Many patients reported feeling that MH/MUS misdiagnoses were
due to lack of physician knowledge of immune dysfunction and not listening/believing a patient’s
symptoms.
Trust was highest in lupus specialists, specialist nurses and physiotherapists. For all physician
categories, trust was strongly positively correlated with both perception of listening skills (mean
r=0.83) and knowledge (mean r=0.79). The correlation between trust and knowledge was lowest for
psychologists (r=0.58) and GPs (r=0.72). Several participants reported that their expectations of
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knowledge in these clinicians is not high, but that they valued their support and listening skills. One
participant, for example, wrote:
‘I have a very amazing GP, she listens to me each time I see her. I guess it can be harder for GPs to have the
full knowledge as they see so many illnesses on a daily basis. For me just being listened to is a good feeling. My
GP cannot fix me but she has really helped me so much in this battle’ (Female, 30s, England)
Most clinicians, including rheumatologists, had approximately 30% of ratings in the poor/very poor
categories for listening, with the exception of lupus specialists, immunologists and specialist nurses
who received fewer ratings of poor/very poor (16-20%) and A&E doctors who received the most
poor/very poor ratings for listening (56%).
The overarching qualitative theme was the importance of listening and belief in patient symptom
reporting, in terms of being essential in linking multiple diverse symptoms for a quicker diagnosis
and identifying flares, in validating patients’ subjective experiences and building a supportive
relationship with the patient, as explained by this patient:
He (lupus specialist) said he believed everything I was saying and asked me what life is like living with this? It
was very emotional for me because I felt listened to’ (Female, 30s, England)
Further sub-themes and patient quotes can be found in Supplementary Table S1, available at
Rheumatology Advances in Practice online.
Discussion
This mixed methods study has identified a number of commonly occurring patient experiences, both
before and after a diagnosis of SLE/CTD. As far as we are aware this is the first study to ascertain the
opinions of SLE/CTD patients regarding causes of delays/misdiagnoses and perceptions of support,
including impact upon future healthcare behaviour.
With 76% of respondents reporting at least one misdiagnosis and 24% having taken over 10 years to
reach diagnostic certainty, the diagnostic challenges identified by earlier studies2,3,4 remain of key
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importance to address. Although diagnostic difficulties are partially due to challenging and varied
presentations of the disease, the importance of listening to and believing patients is highlighted by
this study, with many patients reporting early symptoms being dismissed and around 30% of all
ratings for clinician’s listening skills being in the poor/very poor categories. Viewing symptoms – and
patients- holistically and physicians acquiring and sharing knowledge were also key areas identified
to improve diagnosis and care.
MUS/MH misdiagnoses were reported as damaging to mental health, trust in physicians and
healthcare seeking behaviour, occurring in almost half of misdiagnosed participants before
diagnosis. This propensity for early psychological misdiagnosis in systemic autoimmunity is in line
with a recent US study of over 3000 SLE patients where over 50% were initially told there was
nothing wrong or their symptoms were psychological.3 Misdiagnoses were also reported to occur
after diagnosis with SLE/overlap disease in 25% of our respondents; these were largely non-organic
pain, fatigue or MH related co-diagnoses, which respondents and forum members generally felt
were caused by -and should be attributed to - their CTD.
Our findings highlight that fatigue is a prevalent and debilitating symptom in keeping with a number
of previous studies2,9,26,27 and remains a problem even when the disease is not obviously clinically or
serologically active28. Despite limited understanding or consensus on mechanisms and an absence of
proven biomarkers29, fatigue is clearly a major unmet need with >70% of participants reporting no or
poor support with managing fatigue in our study and others30. This affects those with UCTD or non-
organ involvement SLE as much as those with severe SLE.
In terms of between-groups differences, participants with UCTD and participants resident in Wales
had the poorest perception of overall medical support. Great concerns over local barriers to
accessing specialist care were detailed by those living in Wales.
The first physicians likely to be assessing these patients are those rated by over 50% of patients as
having very poor/poor knowledge of SLE (predominantly GPs and A&E clinicians), with correct
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testing, referrals to specialists and treatment often reported to be delayed. Many of the patients in
this study were disadvantaged by a presentation of ‘multiple symptoms, multiple systems, multiple
times’ often being attributed to MH/MUS, especially if there are no presenting visible symptoms or
organ involvement. Tschudi-Madsen et al reported that the hypothesis prevalent in current
literature is that multisymptomatology and MUS are closely related and found a strong correlation
between physicians’ assessment of MUS and number of symptoms reported 31. Although it can be
difficult for a non-specialist to identify lupus, and investigating the underlying cause of symptoms is
often delayed by logistical and time constraints in primary care, and stringent criteria for referrals,
multiple diverse symptoms should also be considered a red flag for considering an autoimmune
multi-system disease.
One of the barriers to diagnosis is from physicians mistakenly considering ANA and anti dsDNA
positivity as essential for referral to rheumatology/diagnosis, also sometimes failing to interpret or
test for other relevant haematological or immunological abnormalities, as specified in the BSR and
other guidelines14,15,16. Although self-reported, the 8% of seronegative and the 32% of SLE patients
with a combination of historic positive and negative ANA results in this study, is in line with expert
opinion and recent research findings. Autoantibody profiles can change over time, can vary in titre
and positivity independent of disease activity, are heavily influenced by which test individual
laboratories use, can become negative over time/due to medication and symptoms may occur prior
to development of autoantibodies32,33,34,35,36. Whilst ‘true’ seronegativity (permanently negative ANA
and anti dsDNA) is often estimated at 5-8% of the SLE population, this only includes those who have
achieved diagnosis. The much greater diagnostic delay in seronegative patients in this study (>4
years for 92% compared to 55% for seropositive and 65% for intermittently ANA positivity) was
statistically significant (p=0.0386) and suggests that the actual percentage is much higher, with many
potentially remaining undiagnosed and untreated.
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Despite anti-dsDNA positive participants having the most specific biomarker for SLE, they still
experienced considerable diagnostic delay, with a mean time to diagnosis of 6 years and 2 months,
and with 54% reporting having received an MUS/MH misdiagnosis. Although these figures were
better than those for permanently seronegative participants (for whom the mean time to diagnosis
was 13 years and 92% of whom reported an MH/MUS misdiagnosis), they still raise the question of
whether there is sufficient knowledge and early testing of autoantibodies in primary care
Multiple respondents report, in common with other studies, feeling disbelieved when typical
serological / other test results did not reflect their symptoms. There is a perceived over-reliance on
certain test results, rather than also considering subjective symptoms37,38, and a need for more
widespread use and understanding of a broader range of haematological and immunological tests14.
This study also highlights the need for more support, empathy and communication in managing all
symptoms, regardless of serology or- often conflicting and still evolving - views of their aetiology.
Although approximately 50% of respondents reported either good or excellent support for their
lupus overall and from their rheumatologist, there were common gaps in care identified. There is a
clearly expressed need for more support for patients in coming to terms with a life-changing chronic
disease and more consideration of psychosocial needs and quality of life. Empathetic listening and
belief in the patient’s subjective reporting of symptoms was highlighted as the top patient priority
for improvements for diagnosis and care – yet this aspect of consultations was often felt to be
unsatisfactory in this study and other studies of rheumatic diseases39. Listening was highly
correlated with trust, with positive views expressed about physicians, often GPs, who provided
support and compassion despite limited knowledge and diagnostic uncertainty.
The main limitation of this study was that participants were not demographically representative of
the SLE population, especially in terms of ethnicity, with patients of African and Asian origin under-
represented, as is common in rheumatological research40. Online support groups may also not be
representative of all patients in terms of age, education, severity of disease and satisfaction with
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medical support as they are actively seeking more peer support. We will address these concerns
with a prospective clinic-based study in the future. Although the research and questionnaire were
phrased neutrally, the study may have attracted a higher proportion with negative experiences. The
responses, including previous symptoms and serological results, may be subject to recall bias and
error due to self-reporting. The serological results may be skewed towards those with abnormal
results as these will have been more likely to be communicated to patients and be more memorable.
Mean diagnostic time and proportion in the ‘> 10 years to diagnosis’ group is likely to be greater
than reported as over 10% of responses were excluded due to non-numerical responses, usually for
lengthier timescales (e.g. ‘a long time’).The assessment of misdiagnoses were from the participants’
viewpoints. Some respondents may have had a concurrent MH condition alongside SLE, or MH
symptoms may have been a presenting part of their unrecognised developing systemic
autoimmunity.
Although a limitation is that diagnoses were self-verified, we mitigated against this by asking for the
diagnosis on their clinic letters and checking symptoms lists were indicative of these conditions. A
further check was that 91% of participants were currently taking at least one medication prescribed
to manage SLE and related conditions. Responses on a questionnaire are less likely to be subject to
social desirability bias and more open than responses given to physician questioning, especially
regarding reporting negative views about medical care. Analysing both quantitative and qualitative
data allows for greater depth and breadth of understanding24,25 and increases the validity, reliability
and credibility through the triangulation of results.
The large quantity of respondents sending additional qualitative information and expressing
gratitude for a study that gave them the opportunity to detail their experiences and opinions
demonstrates the importance of giving patients with chronic diseases a voice. In addition to the
research alerting policy makers and physicians to common, and possibly avoidable, negative
experiences, whilst gaining insight into best practice, the further benefits are that many of these
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patients reported feeling more empowered and hopeful of improvements in diagnosis and care for
patients in the future from being involved in the research.
In conclusion, physicians viewing symptoms/ patients holistically and listening to – and believing -
patients’ reports of their symptoms is felt to be of prime importance by patients in both achieving
diagnosis and in managing the disease post-diagnosis. More medical support could help improve the
reduced quality of life, especially in relation to fatigue where the majority of participants reported
receiving no or poor support. Improved knowledge of SLE amongst GPs and all physicians, regardless
of specialism, is required as the multi-system nature of the disease necessitates a multi-disciplinary
approach.
Figure legend
Figure 1 – Types and rates of misdiagnoses in order of decreasing frequency (n= 156 reporting a
misdiagnosis from N= 205 participants reaching this section of the questionnaire)
Figure 2 – Patient reported symptoms and serology (N=200) Only respondents stating they had a
diagnosis of SLE on their clinic letters and meeting ACR and/or SLICC criteria were included in the
serology categories (self-reported by those who knew their serological results, for example 111
participants for ANA)
Figure 3 – Perceived level of support (N=211) ordered in decreasing level of support
Figure 4 – Patient ratings for clinician knowledge, listening skills and trust (N=206) in order of
decreasing patient trust.
Funding: This work was supported by LUPUS UK
Disclosure statement: the authors have declared no conflicts of interest .
Acknowledgements: LUPUS UK, rheumatologists and many SLE patients greatly assisted with the
direction and development of the research question, designing the questionnaire, reviewing study
materials for accessibility, determining key messages from the results and providing regular input
throughout every stage of the study, including reviewing the draft manuscript. Particular thanks and
acknowledgement to expert patient representatives and LUPUS UK staff for their invaluable input:
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Michael Bosley, Moira Blane, Lynn Holloway, Colette Barrere and Chanpreet Walia. With thanks to
all the participants in this study and to James Brimicombe from the Cambridge Institute of Public
Health for data management support.
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43x27mm (300 x 300 DPI)
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30x28mm (300 x 300 DPI)
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33x29mm (300 x 300 DPI)
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44x27mm (300 x 300 DPI)
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Table 1 – Participant characteristics (N=233)
Characteristic
Number %
(rounded)
Diagnosis on clinic letters
SLE (may have listed additional diagnosis)
Undifferentiated or unspecified CTD
APS or Overlap syndrome
Sjögren’s syndrome
Discoid or cutaneous lupus
Probable lupus
MCTD
Country of residence
England
Scotland
Wales
USA/ Canada
Australia
Mainland Europe
Northern Ireland
Time delay to diagnosis
< 1 year
1-3 years
4-9 years
10+ years
Unsure or non-quantitative response
Missing
Age Band (years)
18-29
30-39
40-49
50-59
60-69
70+
Missing
Ethnic Group
White
Mixed
Asian
Black or African American
Other
Missing
Gender
Female
Male
Prefer not to say
Missing
181 78
23 10
8 3
7 3
5 2
5 2
4 2
163 70
33 14
20 9
7 3
5 2
4 2
1 <1
52 22
42 18
46 20
57 24
30 13
6 3
18 8
30 13
59 25
69 30
32 14
7 3
18 8
193 83
4 2
2 1
1 <1
1 <1
32 14
199 85
7 3
1 <1
26 11
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Education
None
GCSE/O level
A level
Degree
Postgraduate
Missing
Medications (Current or within the last
year)
Hydroxychloroquine
Oral steroids
Immunosuppressant (MMF, AZA or MTX)
Injected steroids
Biologics
Ciclosporin or tacrolimus
Cyclophosphamide
Percentage currently taking at least one
of the above medications = 91%
Note: medication percentages are
calculated from those reaching that part
of the questionnaire (198 Ppts)
2 1
37 16
55 24
68 29
36 15
35 15
143 72
96 48
85 43
52 26
12 6
7 4
6 3
Table 2 – Participants’ views of reasons for delays/misdiagnoses.
Table 2
Categories were pre-determined from literature review, forum analysis, patient, physician and LUPUS UK input. 5
options were given ranging from very unlikely to very likely with this section only completed by participants who
considered they had experienced delays and/or misdiagnosis (N=175). The 7 Pre-determined questionnaire
categories were found to duplicate responses so were condensed into 5 categories.
Perception of reason for
delays/ misdiagnosis
% of participants
indicating likely/
very likely this had
contributed to their
delay/ misdiagnosis
Example quotes from qualitative responses
The doctor/s initially
seeing and treating each
symptom separately and
not linking together as one
disease
80%
‘I used to go in with a long list of medical issues that screamed
of APS/lupus/ Sjögren’s, but not one GP joined the dots. Sadly
by the time I was diagnosed aged 45 it was too late. I’d had a
stroke, DVT, miscarriages and was struggling to work. I wish
I’d been diagnosed earlier and had help so much sooner’
(Female, 50s, Wales)
Symptoms disregarded or
disbelieved by the
doctor/s (merged with the
category of psychological/
‘all in your head’
misdiagnoses as the two
72%
‘I feel quite upset that I was diagnosed with ‘just anxiety’ by my
GP even to the point where I was lectured on the ‘worried well’
and prescribed a book on health anxiety! I read it diligently but
needless to say it didn’t make my symptoms disappear’ (Female,
50s, UK)
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were found to largely
duplicate)
‘I was unsupported for years after a rheumatologist told me my
symptoms were all in my mind and had I been sexually abused
as a child’ (Female, 50s, England)
The doctor/s not having
enough knowledge of the
disease (category merged
with those feeling they
were misdiagnosed due to
not having what doctor/s
considered the ‘right’ test
results or ‘typical’
symptoms)
69%
‘Neurologist said he didn’t believe in lupus and consultant
rheumatologist was not interested in discussing symptoms or
history as I haven’t lost my hair, didn’t have a malar rash and
I’m male. Thankfully he referred me to a lupus specialist’(Male,
40s, England)
‘I was dismissed by rheumatology having been told ‘there’s
nothing wrong’. This was 7 years before diagnosis of SLE by
blood test. In that time I suffered badly, had to reduce working
hours and long periods of being unable to work at all.
Symptoms can appear long before markers show in blood’
(Female, 30s, England)
Symptoms appearing
slowly over time
59%
‘The symptoms can be confusing, we did not link my previous
symptoms together as I just thought I was ageing badly’
(Female, 60s, England)
You not reporting or you
underplaying symptoms
39%
‘We underplay our symptoms as we get fed up with constantly
moaning about feeling unwell or rubbish’ (Female, 40s,
England)
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... In the present study, the discovery of lupus triggered a moment of emotional instability due to the difficulty in defining the diagnosis and accepting a new life condition imposed by limitations. Dealing with waiting for the definition of the diagnosis is a generating moment of anxiety and uncertainties (18)(19) . ...
... Living with lupus means being doomed to a daily struggle imposed by many difficulties since treatment adherence is not enough for disease stagnation. The recurrence of symptoms and the emergence of complications make this process tiring, leading to the experience of fatigue faced negatively by hindering adjustments in routine activities (18)(19) . However, knowing the psychological impacts that the disease can bring is incipient (22) . ...
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... In agreement with other studies [29] this lack of non-verbal interaction was found to be particularly detrimental to the eliciting and reporting of mental health concerns, although a minority of our participants (both clinician and patient) found it easier to discuss mental health and sensitive issues remotely. Demonstrations of listening and empathy, identified as of key importance to rheumatology patients in terms of satisfaction and behaviours [30][31][32], were perceived by our participants to be limited with telemedicine. This is in contrast to another study reporting that very few (<10%) clinicians and patients felt tele-rheumatology had a negative impact on the medical relationship [33]. ...
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... The potential comparison with some aspects of adverse childhood experiences (ACEs) 21 and other adverse life experiences 22 remains tentative, but highlights the severity of damage, and longer-term sequalae. Many 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 participants reported repeated AMEs, particularly dismissal, psychosomatic misdiagnoses and lack of physician knowledge, often on their arduous diagnostic journeys 15,16,23 , but also post-diagnosis. An unexpected finding in our study was that, although participants with AMEs had significantly lower satisfaction with many aspects of medical care, the non-adherence rate for the AME group as a whole was not significantly greater than the rate for the non-AME group. ...
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Objective We have developed a new conceptual model to characterise the signs and symptoms of SLE: the Type 1 and 2 SLE Model. Within the original model, Type 1 SLE consists of inflammatory manifestations like arthritis, nephritis and rashes; Type 2 SLE includes symptoms of fatigue, myalgia, mood disturbance and cognitive dysfunction. Through in-depth interviews, we explored how the Type 1 and 2 SLE Model fits within the lived experience of patients with SLE, with a focus on the connection between Type 1 and Type 2 SLE symptoms. Methods Semistructured in-depth interviews were conducted among adult participants meeting 1997 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria for SLE. Participants were purposefully selected for age, race, sex and nephritis history. All interviews were audio-recorded and transcribed. Data were analysed through episode profile and thematic analysis. Results Through interviews with 42 patients with SLE, two patterns of Type 2 SLE emerged: Intermittent (n=18) and Persistent (n=24). Participants with Intermittent Type 2 SLE described feeling generally well when Type 1 is inactive; these participants were younger and had more internal SLE manifestations. Participants with Persistent Type 2 described always experiencing Type 2 symptoms despite inactive Type 1, although the severity may fluctuate. Participants with Persistent Type 2 SLE experienced traditional lupus symptoms of joint pain, hair loss and rash, but less often had severe organ system involvement. Conclusions By listening to the stories of our patients, we found two underlying patterns of Type 2 SLE: Intermittent Type 2 symptoms that resolve in synchrony with Type 1 inflammatory symptoms, and Persistent Type 2 symptoms that continue despite remission of Type 1 symptoms.
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Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by an almost 10:1 female predominance, the presence of deleterious nuclear autoantibodies, a tendency for flare, and striking protean manifestations. Early diagnosis is associated with less damage accrual, lower costs and improved quality of life due to timely treatment. However, early disease may not uncommonly show nonspecific presentation, a single classification criterion, or an unusual organ involvement contributing to frequent, often substantial diagnostic delays. We reviewed the literature (1982-2022) to accumulate and classify all reports of rare, atypical and unusual presentations. These can involve almost every organ and system, and thus present to physicians in every discipline and setting. Increasing physicians’ awareness of the potential of occult SLE to appear in varied, diverse and unexpected presentations, may encourage the inclusion of SLE in the differential. Informed history and examination focusing on systemic and joint symptoms and mucocutaneous involvement, and basic tests (focusing on leukopenia, thrombocytopenia, and proteinuria; followed by antinuclear antibodies and complement levels) will correctly diagnose most patients on presentation or within the following months and enable timely treatment.
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Women's health, and what we know about it, are influenced by social factors. From the exclusion of women's bodies in medical research, to the silence and stigma of menstruation and menopause, to the racism reflected in maternal mortality, the relevance of social factors is paramount. After a brief history of research on women's health, we review selected patterns, trends, and inequalities in US women's health. These patterns reveal US women's poor and declining longevity relative to those in other high-income countries, gaps in knowledge about painful and debilitating conditions that affect millions of women, and deep inequalities that underscore the need to redress political and structural features of US society that enhance health for some and diminish it for others. We close by describing the challenges and opportunities for future research, and the promise of a social determinants of health approach for advancing a multilevel, intersectional, and biosocial understanding of women's health. Expected final online publication date for the Annual Review of Sociology, Volume 48 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Systemic lupus erythematosus (SLE) is a complex and unpredictable disease which varies greatly among patients and has a significant impact on an individual’s daily living and quality of life. A better understanding of the patients’ experiences with the disease is vital to the effective management of the disease. LUPUS UK, a national UK-registered charity supporting people with systemic and discoid lupus, conducted a UK-wide survey of individuals living with lupus in order to provide foundation information to support and identify gaps needing further research. An anonymous survey was sent to 5660 LUPUS UK members in order to obtain demographic, diagnosis, symptom and treatment information. A total of 2527 surveys were returned by 2371 females (mean age 56.9 years, SD 13.6) and 156 males, (mean age 60.9 years, SD 15.7). Individuals reported a mean (SD) time to diagnosis from the first symptom of 6.4 (9.5) years, with 47% (n = 1186) initially being given a different diagnosis prior to lupus. Fatigue/weakness (91%, n = 2299) and joint pain/swelling (77.4%, n = 1957) were the most common symptoms that interfere with daily activities, while 73% (n = 1836) noted having some problems that make them unable to carry out their usual daily activities. Thirty-two per cent (n = 806) were also seeking support beyond traditional pharmacological treatments, such as acupuncture and massage. This study highlights the range and frequency of symptoms difficult to live with on a daily basis and support areas needing further research to improve patients’ well-being.
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Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a prevalence of approximately 1 in 1000. Over the last 30 years, advances in treatment such as use of corticosteroids and immunosuppressants have improved life expectancy and quality of life for patients with lupus and the key unmet needs have therefore changed. With the reduced mortality from disease activity, development of cardiovascular disease (CVD) has become an increasingly important cause of death in patients with SLE. The increased CVD risk in these patients is partly, but not fully explained by standard risk factors, and abnormalities in the immune response to lipids may play a role. Invariant natural killer T cells, which are triggered specifically by lipid antigens, may protect against progression of subclinical atherosclerosis. However, currently our recommendation is that clinicians should focus on optimal management of standard CVD risk factors such as smoking, blood pressure and lipid levels. Fatigue is one of the most common and most limiting symptoms suffered by patients with SLE. The cause of fatigue is multifactorial and disease activity does not explain this symptom. Consequently, therapies directed towards reducing inflammation and disease activity do not reliably reduce fatigue and new approaches are needed. Currently, we recommend asking about sleep pattern, optimising pain relief and excluding other causes of fatigue such as anaemia and metabolic disturbances. For the subgroup of patients whose disease activity is not fully controlled by standard treatment regimes, a range of different biologic agents have been proposed and subjected to clinical trials. Many of these trials have given disappointing results, though belimumab, which targets B lymphocytes, did meet its primary endpoint. New biologics targeting B cells, T cells or cytokines (especially interferon) are still going through trials raising the hope that novel therapies for patients with refractory SLE may be available soon.
Article
Objective: Non-white racial/ethnic groups remain underrepresented in rheumatic disease-related research despite being disproportionately affected by these disorders. We aimed to systematically review the literature regarding underrepresented patients' perceptions of participation in rheumatic disease research and develop strategies to improve diversity. Methods: A systematic search of Embase, Pubmed-MEDLINE, PsycINFO, and Cochrane was performed through October 2018. Two independent reviewers identified 642 unique studies; seven met inclusion criteria (peer-reviewed articles, published in English in last 20 years, adult population, focus on underrepresented patients' participation in rheumatic research). Five coauthors provided final approval of included articles. Data abstraction was performed and common themes and key differences were determined and adjudicated. Results: The seven articles included (n=1,892 patients, range n=20-961) evaluated factors associated with research participation of underrepresented populations. Five related to lupus, two to rheumatoid arthritis and five focused on African American patients, one on Hispanic. Five of the studies provided quantitative data through surveys (n=3) and chart review (n=2), while two utilized qualitative analyses. Key themes regarding underrepresented patients' perceptions of participating in research included: 1) importance of trust in the patient-physician relationship, 2) understanding of heterogeneity within and between ethnic groups, 3) need for authentic academic-community partnerships, and 4) the implications of strict inclusion criteria on study participant diversity. Conclusion: Limited evidence exists regarding underrepresented patients' attitudes towards research participation in rheumatology and further investigation is warranted. The themes identified provide a starting point for future interventions that promote increased diversity in rheumatic disease-related research studies. This article is protected by copyright. All rights reserved.
Article
Objectives: The spectrum of antinuclear antibodies (ANA) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change in terminology to anti-cellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anti-cellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort. Methods: Anti-cellular antibodies were detected by IIF on HEp-2000 substrate utilizing the baseline serum. Three serological subsets were examined: 1) ANA-positive (presence of either nuclear or mixed nuclear/CMP staining), 2) anti-cellular antibody-negative (absence of any intracellular staining), and 3) isolated CMP staining. The odds of being anti-cellular antibody-negative versus ANA or isolated CMP-positive was assessed by multivariable analysis. Results: 1137 patients were included; 1049/1137 (92.3%) were ANA-positive, 71/1137 (6.2%) were anti-cellular antibody-negative, and 17/1137 (1.5%) had isolated CMP. The isolated CMP group did not differ from the ANA-positive or anti-cellular antibody-negative group in clinical, demographic or serologic features. Patients who were older (OR 1.02 [95% CI: 1.00, 1.04]), of Caucasian race/ethnicity (OR 3.53 [95% CI: 1.77, 7.03]), or on high dose glucocorticoids at or prior to enrolment (OR 2.39 [95% CI: 1.39, 4.12]) were more likely to be anti-cellular antibody-negative. Patients on immunosuppressants (OR 0.35 [95% CI: 0.19, 0.64]) or with anti-SSA/Ro60 (OR 0.41 [95% CI: 0.23, 0.74]) or anti-UI-RNP (OR 0.43 [95% CI: 0.20, 0.93]) were less likely to be anti-cellular antibody-negative. Conclusions: In newly diagnosed SLE, 6.2% of patients were anti-cellular antibody-negative and 1.5% had isolated CMP. The prevalence of anti-cellular antibody-negative SLE will likely decrease as emerging nomenclature guidelines recommend that non-nuclear patterns should also be reported as a positive ANA. This article is protected by copyright. All rights reserved.
Article
Objective The expression of antinuclear antibodies (ANA) is considered almost constant in systemic lupus erythematosus (SLE), although recent experience has suggested that many subjects with SLE considered for clinical trials are ANA negative at screening. The objective of this study is to determine whether assay variation can influence ANA detection in patients with established SLE. Methods Sera from 103 patients with established SLE were tested using three different immunofluorescence assays (IFA) for ANA determination. ANA determinations were also performed by an ELISA and bead-based multiplex assay. Results With IFA kits, the frequency of ANA negativity varied from 5 to 23 of 103 samples (4.9%–22.3%). The ELISA and multiplex assays showed that 12 (11.7%) and 14 (13.6%) samples were negative, respectively. Samples positive in all assays differed from those with discordant assay results in the frequency of historical anti–double-stranded DNA positivity and low complement levels at the time of blood sampling. Discussion These findings indicate that ANA negativity occurs in patients with established SLE although the frequency varies depending on the assay kit. Given the range of negativity with well-validated assays, these findings raise questions about whether ANA positivity should be employed to determine eligibility for clinical trials.
Article
BACKGROUND: Early detection of antinuclear antibodies (ANA) in asymptomatic subjects is useful to predict autoimmune diseases years before diagnosis. ANA have been determined by indirect immunofluorescence (IIF) using human epithelial type 2 (HEp-2) cells, which is considered the gold standard technique. Multiplex technology (BioPlex ANA Screen) has been introduced for ANA evaluation in recent years. Nevertheless, concordance between BioPlex and IIF is low and there is no harmonization between both methods for detection of autoantibodies. This study has aimed to clarify the clinical significance of autoantibodies detected by BioPlex ANA Screen in subjects with undiagnosed clinical suspicion of autoimmune disease and to determine the predictive value of autoantibodies detected by BioPlex ANA Screen. METHODS: A 3-year follow-up study was performed of 411 subjects without a clear diagnosis of autoimmune diseases in whom autoantibodies were detected by BioPlex ANA Screen that were negative by IIF on HEp-2 cells. RESULTS: At 3 years of follow-up, 312 (76%) subjects were positive for autoantibodies by IIF and 99 subjects continued to be negative. A diagnosis of autoimmune disease was found in most of the subjects (87%). CONCLUSIONS: BioPlex ANA Screen has greater sensitivity than IIF on HEp-2 cells for autoantibodies detection. Early detection of these antibodies by BioPlex can predict possible development of autoimmune diseases.
Article
Objective The objective of this study was to assess the impact of systemic lupus erythematosus (SLE) on patients and carers. Methods Adults with SLE and carers of SLE patients completed a UK-specific online survey covering many aspects of the disease. Surveys were developed in collaboration with an NHS lupus unit and a lupus patient organization. Results A total of 121 patients and 31 carers completed the surveys. Of the 70% of patients initially misdiagnosed with another condition, 59% received treatment for the misdiagnosis. Fatigue was the most debilitating symptom, experienced daily by 79% of patients. The proportion of patients not reporting flares to healthcare providers varied with flare severity: mild flares (43%), moderate flares (15%) and severe flares (5%). Most patients (89%) reported reduced ability to socialize, and 76% had changed employment; of these, 52% stopped working completely. Over one-half (52%) of carers in paid employment missed time from work, and 55% of carers reported a worsened financial status. Most carers (87%) experienced interference with social activities. Conclusion SLE is commonly misdiagnosed and has a considerable impact on the physical, social and financial status of patients and carers. Increased awareness of the disease among healthcare providers and employers of patients and their carers is needed.
Article
Fatigue impacts 80-90% of patients with systemic lupus erythematosus (SLE), and an incomplete understanding of fatigue mechanisms limits effective treatment. Disease activity indices and laboratory markers inconsistently correlate with fatigue severity in SLE populations. Identification of fatigue biomarkers has important implications for understanding pathogenesis and defining novel therapeutic targets, but a paucity of evidence exists for fatigue biomarkers in SLE. The evidence for adipokines, reduced glutathione, iron deficiency, and vitamin D as potential biomarkers for SLE-related fatigue are reviewed. To address gaps in the SLE literature, the experience of each fatigue biomarker in other diseases is examined. Finally, biomarker associations with SLE pathogenesis and disease activity are discussed, as further rationale for investigation among SLE patients.