Rheumatology 2001; 40: 1180-1188
© 2001 British Society for Rheumatology
Report |
Revisiting Sjögren's syndrome in the new millennium: perspectives on assessment and outcome measures. Report of a workshop held on 23 March 2000 at Oxford, UK
Rheumatology Department, Division of Immunity and Infection, The Medical School, University of Birmingham, UK,
1 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA,
2 Broegelmann Research Laboratory, University of Bergen, Norway,
3 Neuroscience Centre, National University Hospital, Righospitalet, Hornbaek, Denmark,
4 Piombino Hospital, Piombino, Italy,
5 Sjögren's Syndrome Research Centre, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden and
6 Centre for Rheumatology, University College London, UK
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Introduction |
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The past decade has seen the development and validation of widely accepted outcome measures for use in randomized controlled trials and longitudinal observational studies in the autoimmune rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [1]. This has generated criteria by which the effectiveness of specific therapy can be judged [2] and has allowed the results of different studies to be compared directly with each other. Furthermore, the underlying concepts, such as those of disease activity, damage and functional impairment, provide a framework to develop similar measures for related conditions.
Although proposals for the assessment of disease status [3] and damage [4] have been developed for primary Sjögren's syndrome, there are no internationally agreed and validated measures and so we have adopted the approach used previously in an EC Concerted Action Programme to develop disease activity assessment measures for RA [5].
Following discussions at the VIIth International Symposium on Sjögren's Syndrome, held in Venice in December 1999, it was decided to hold a 1-day workshop during the European Rheumatology Research Workshop (ERRW) in Oxford, UK in March 2000 to start developing a preliminary core set of outcome measures for use in randomized controlled trials and longitudinal observational studies in primary Sjögren's syndrome.
This paper describes the first phase of this approach in which a consensus opinion of the specialists involved in the workshop process was obtained, as to which clinical and serological features of primary Sjögren's syndrome are sufficiently important to include in any assessment instrument. The performance of such an instrument can then be evaluated prospectively in the next phase of this project, which is to follow. The data set out in this paper, however, define the key features of the syndrome that were felt by the participants to be important for inclusion in such an instrument and hence provide a critical insight into the perspective of specialists involved in the care of patients with Sjögren's syndrome.
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Materials and methods |
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Thirty-four individuals attending the International Symposium in Venice who had expressed an interest in participating in the workshop, or were thought likely to be attending the ERRW, were sent a brief questionnaire setting out the core measures used in RA and SLE [1, 6] and asking them to rate on a four-point scale (no use, some use, quite useful and extremely useful), potential components of a multisystem involvement activity/damage index and potential outcome domains for Sjögren's syndrome. Twenty-six completed pre-conference postal questionnaires were received, two of which represented the combined views of two individuals.
On arrival at the workshop, each of the participants was provided with a pack containing background materials and objectives relevant to each of the three stages of the workshop.
Part 1. Session objectives: to achieve a consensus on core outcome domains
The materials contained a descriptive summary of the core domains used in RA and SLE, a definition of activity (inflammation=reversible), damage (permanent=irreversible=duration>6 months), a description of health status/loss of function and quality of life instruments and copies of papers describing similar work in SLE [6, 7]. Following an introduction that covered these issues, the 18 participants at this stage of the workshop dispersed into three discussion groups of five to seven participants each. Each of these three discussion groups was led by a facilitator (SJB, RJ, SP) whose role was to encourage free discussion and work towards a consensus. At the end of the discussion group deliberations, each member of the group was asked to divide 100 points as they wished between the domains they felt should be included in the core set of outcome domains. Each group then elected a ‘rapporteur’ who presented the group's consensus to the plenary discussion session.
Part 2. Session objectives: to determine a core set of questions and simple measures to evaluate surface exocrine glandular disease in the non-specialist out-patient setting
The materials contained a questionnaire asking for ratings of the usefulness of specific sicca symptoms, signs and measures (incorporating 30 oral features, 20 ocular features and 10 features of other dryness complaints [8–10; Anne Field, personal communication]). Following an introduction to this session, the participants were asked to complete the questionnaire individually using the same four-option rating scale used in the pre-workshop questionnaire.
Part 3. Session objectives: to develop activity/damage/status measure(s)
The materials contained information about the Copenhagen assessment model [3] and data from a cohort of SLE patients and primary Sjögren's syndrome patients using the SLICC damage index for SLE, modified for Sjögren's syndrome by adding an oral component [4]. In addition, copies of SLAM [11], BILAG [12], SLEDAI [13], ECLAM [14], BVAS [15] activity measures used in SLE/vasculitis and a copy of the vasculitis damage index [16] (derived from the SLICC damage index) were also provided along with the results from the multisystem component of the pre-workshop questionnaire. Following a summary of the Copenhagen model and proposals for a modified SLICC damage index, the participants were asked to modify further a prototypic SLICC–Sjögren's damage index, which incorporated the results of the pre-workshop questionnaire.
As a separate exercise, the participants were asked to rate the components of a more detailed questionnaire on multisystem involvement derived from the Copenhagen assessment model [3] and the 1988 workshop [9], applying the same four-point rating scale used previously. At the end of this process, an open discussion was held to discuss how the concepts of disease-specific activity and status apply to patients with primary Sjögren's syndrome, how any such measures should be scored and their role in measuring outcome in primary Sjögren's syndrome. Following the workshop, the results were distributed to all contributors/participants with further proposals to modify the multisystem (non-surface exocrine) and modified SLICC damage components in light of the results of the workshop questionnaires. Twenty-nine replies were received, representing the views of 31 individuals (the 28 participants of the pre-workshop phase and three additional individuals from the same departments who had expressed a desire to be involved in the process at this later stage). These results were then collated and are presented below.
Where data were missing, the results were corrected up to reflect the total number of participants at each phase of the process. Minitab© version 12 (Minitab Inc, PA, USA) was used for statistical analysis. The Wilcoxon signed rank confidence interval was used to determine the 95% confidence interval of the estimated median score generated in this test for each item studied.
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Results |
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TopIntroductionMaterials and methodsResultsDiscussionReferences |
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Core domains
The domains proposed in the pre-conference questionnaire were rated as being ‘quite useful’ or ‘extremely useful’ by between 12 (health economic) and 25 (generic quality of life) participants (data not shown). This information was provided in the workshop packs to each of the 18 participants at the beginning of the workshop.
Following the three discussion group meetings, 16 of the 18 participants provided individual domain weighting scores, which were summed using an approach similar to that previously used in SLE [6]. Four domains emerged with the highest scores and received some points from at least 10 participants: disease activity (388), damage (338), generic quality of life (212) and health status/loss of function/health-related quality of life (194) (Table 1
). This was reflected in the group presentations. Toxicity/adverse events (120) and health economics (119) each received points from 12 of the 16 individuals and were felt to have relevance in specific circumstances, particularly randomized controlled trials. Six individuals proposed that fatigue could be a domain in its own right rather than a component of an activity domain and, largely as a result of one contribution of 50 points, this reached a total of 109 points. Additional independent comments from the pre-workshop questionnaire and discussion group presentations included: (1) recommendation of the SF-36 as a health status/health-related quality of life measure by six participants (and the Health Assessment Questionnaire by two); (2) recommendation of the Nottingham Health Profile and WHOQoL by two participants each and EUROQoL and AQoL by one participant each as generic quality of life measures. The subdivision of the disease activity domain into combinations of serology, symptom questionnaires, fatigue and salivary and lachrymal gland function measurements was proposed by one discussion group. The inclusion of pregnancy outcome/congenital heart block as a specific outcome domain and combining activity and damage measures into a status measure were both proposed by one discussion group. No other potential domain received more than 15 points or was proposed by more than one individual.
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Assessment of sicca features (surface exocrine disease)
The mean scores and standard deviation for each sicca feature are listed in Table 2. These ranged from 0.412±0.507 (median 0, interquartile range 0–1) (bad breath) to 2.824±0.529 (median 3, interquartile range 3–3) (salivary gland enlargement). Thirteen oral, eight ocular and seven other sicca features had a mean score of 2 (quite useful) or more. An additional six oral and one ocular feature had an estimated median of 2 or more using the Wilcoxon signed rank confidence interval. Other items with mean/median scores between 1 and 2 (some use) are also listed, while four items scored less than 1 (oral intolerance of air conditioning, bad breath, difficulty in focusing and difficulty in night driving). Some of the items were near duplicates: salivary gland enlargement (2.824±0.529; median 3, interquartile range 3–3) vs swelling of salivary glands over the face (2.333±0.976; median 3, interquartile range 2–3); difficulty in swallowing dry food (2.5±0.516; median 2.5, interquartile range 2–3) vs difficulty in swallowing (2.176±0.728; median 2, interquartile range 2–3) and difficulty in swallowing certain foods (1.647±0.931; median 2, interquartile range 1–2). This illustrates the preference for using specific formulations of questions and there are a number of examples of this in Table 2. All six of the EU classification items and both unstimulated salivary flow rate, rose bengal staining and Schirmer's test had a mean score above 2 with estimated medians of 2.5 or above. It was pointed out that other dyes such as lissamine green or fluorescein are used as an alternative to rose bengal in many units.
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Assessment of multisystem involvement/disease activity
The results of a questionnaire on components of a multisystem involvement/activity measure completed by 16 participants (two of the original 18 participants were unable to participate due to other commitments) during the third part of the workshop are shown in Table 3. The results of this process were fed back to the 31 participants via a post-workshop phase, and two additional items (pleural effusion and other central nervous system involvement) were recommended for re-inclusion by between 18 and 26 of the 29 questionnaire replies at this stage of the process.
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Damage
The results of the assessment of a modified SLICC damage index proposed for use in primary Sjögren's syndrome are presented in Table 4. Two components of the existing SLICC damage index (premature gonadal failure and diabetes mellitus) had been removed prior to this exercise due to their low scores in the pre-workshop questionnaire. The participants were asked to remove items that they felt were not useful and suggest any additional items for inclusion. The results of this process were fed back to the participants in the post-workshop phase and a number of items were included at this stage. Items which scored A were proposed for removal by zero to three participants, B by four to five participants or were included during the post-workshop phase (recommended for re-inclusion by between 23 and 27 of 29 respondents). Items marked C were excluded by more than five participants.
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5 participants removed. Diabetes (11) and gonadal failure (10) were not included due to low pre-workshop questionnaire scores (other domains scored 17–67)
Open discussion
The final workshop session comprised an open discussion of the definition of disease activity in primary Sjögren's syndrome. Sixteen of the 18 participants from the earlier stages and three other individuals who were only able to join the workshop at this point participated. A number of proposals were agreed during this session. First, that disease activity in primary Sjögren's syndrome could be defined as any parameter that was potentially amenable to change, i.e. reversible. Damage could then be defined as any measure that was present for more than 6 months, i.e. analogous to the proposals of the SLICC group for SLE [17]. Separating out activity from damage in this way would still allow the formation of a status instrument combining both concepts. The second proposal was to adopt the concepts underpinning the Copenhagen model of multisystem involvement [3], i.e. defining the status of exocrine and non-exocrine disease features [which in that model also include further subdivisions into (A) surface, internal organ and monoclonal B-cell exocrine disease and (B) inflammatory vascular, non-inflammatory vascular, mediator induced and autoimmune endocrine non-exocrine disease] as the basis for a multisystem activity measure. Third, that the scoring of any such measure should include severity as well as activity. Previous approaches in Sjögren's syndrome and SLE have incorporated the concept of severity through several different means, e.g. is the abnormality severe enough to require treatment or not? [3], the degree of functional impairment caused by this abnormality [11], or a rating of severity in comparison with a previous time point [12]. The latter was felt to be difficult to apply to Sjögren's syndrome, but no decision was reached on the most appropriate alternative approach.
The workshop concluded by proposing that, following further post-workshop discussion of the results by the participants, a follow-up workshop should be arranged to take the proposals further and to set out the experimental approach to validating any proposed measures in patient groups.
Respondent variation
The mean and median scores for the exocrine and non-exocrine components from individual respondents ranged from a mean±standard deviation of 1.094±1.065 (median=1, interquartile range 0–2) to 2.7±0.702 (median=3, interquartile range 2.5–3). The mean scores were normally distributed. There was no obvious geographical or professional specialization pattern to account for this variation.
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Discussion |
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The concept that potentially reversible inflammatory activity leads over time to permanent damage and consequent functional impairment has been key to the development of measures to assess outcome in the inflammatory rheumatic disorders [1]. In conditions such as RA and SLE, the link between pathophysiological processes of inflammation and clinically based measurements is clear [2, 12]. By using this approach, disease activity, including short-lived exacerbations (flares), can be routinely recorded in a clinical setting differentially from features representing damage.
In primary Sjögren's syndrome these links are less clear-cut. Although biopsy of the exocrine glands demonstrates inflammatory lymphocytic aggregates and, in later disease, acinar destruction, the correlation between the degree of inflammation or damage on biopsy and the degree of functional impairment of the glands leading to symptoms and signs of dry eyes and mouth is modest [18, 19]. Clinical measurement of glandular function, e.g. Schirmer-I test or unstimulated salivary flow rate, cannot therefore be used to distinguish, sensitively or reliably, between the pathophysiological processes of inflammatory activity, acinar damage or acinar cell loss in the gland, any or all of which could be responsible for the functional impairment. This makes it very difficult at present to consider the activity of the surface exocrine component of the condition in pathophysiological terms.
An alternative approach, proposed in this workshop, is to define organ-specific activity in Sjögren's syndrome on the basis of reversibility of functional impairment, irrespective of the exact pathophysiology or whether a proposed intervention directly affects these processes or simply bypasses them. Patient selection is clearly important—individuals with little residual function on maximal gland stimulation are less likely to respond to immunosuppression or glandular stimulation, but are entirely appropriate for inclusion in trials of replacement therapy.
Although therapeutic studies of improvement in oral and/or ocular function generally do include both patient-related sicca symptomatology and various combinations of physician/nurse-derived measures such as combinations of the Schirmer-I test, dye tests (e.g. rose bengal or an equivalent test) and unstimulated salivary flow rate [10, 20–23], a gold standard measure with agreed content and method of scoring (Likert or visual analogue scales) has not yet been developed. This makes inter-study comparisons difficult. Such a standard measure would facilitate the development of effective clinical trials for this condition. This workshop has begun this process, through a physician-derived approach, to identify the key clinical features of the syndrome that are important in assessing the disease (Table 2
). It is worth noting that the results demonstrated a bias towards the high scoring of the symptoms contained in the EU classification criteria [8], reflecting the pan-European contribution to this workshop.
The other main clinical feature of primary Sjögren's syndrome is the multisystem or systemic nature of the disease. This is identified serologically as autoantibody formation (particularly anti-Ro and anti-La antibodies), B-cell hyperactivity manifested primarily through hypergammaglobulinaemia and consequently a raised erythrocyte sedimentation rate (although other inflammatory markers can also be raised on occasion). Not all patients demonstrate these features. The prominent fatigue that affects many patients may, at least in part, arguably reflect these processes. Less controversy exists in relation to non-erosive arthritis (particularly of the hands and wrists) and arthralgia in this context, although severe polyarthritis is unusual and was rated much lower by the participants (Table 3). Unlike RA or SLE, however, disease flares of primary Sjögren's syndrome are less common and less severe, and the levels of total IgG and of anti-Ro/La antibodies are often relatively stable over periods of years in individual patients [24]. Clinical trials in Sjögren's syndrome of, for example, hydroxychloroquine or other immunosuppressants, have used improvement in symptoms of fatigue, joint involvement and serological parameters as outcome measures for systemic involvement [22, 23]. Measurements of serum complement levels and double-stranded DNA levels, widely used in the assessment of SLE activity, were not felt to be useful in the assessment of primary Sjögren's syndrome, nor were clinical features such as photosensitivity, carditis/chest pain or active nephritis (all important features of SLE). Although there is increasing interest in the role of anti-muscarinic antibodies in the pathogenesis of primary Sjögren's syndrome [18], autonomic features were also not felt to be useful for inclusion (Table 3). This may change in the future if this area of research progresses. Conversely, liver, skin and thyroid disease, interstitial pulmonary and peripheral neuropathic involvement, renal tubular acidosis and proteinuria were all rated highly for inclusion in an assessment instrument for primary Sjögren's syndrome.
This workshop was not able to address in detail how to score an instrument based on these assessments, whether to give additional weighting to individual components (e.g. fatigue) or to incorporate specific validated measures for some components (e.g. the Chalder fatigue scale [25]) or to develop entirely novel disease-specific measures for primary Sjögren's syndrome.
By using a definition of disease activity based on potential reversibility rather than proven pathophysiology, we can then use the complementary SLICC definition of damage [17] as irreversible features (or at least considered so once present for 6 months) occurring since disease onset. This makes it possible to split disease status (i.e. the combination of activity and damage features [3]) into each of these categories (Table 3 and 4). Although the level of systemic damage that occurs in primary Sjögren's syndrome appears to be less than that in SLE [4], there was felt to be utility in recording damage in long-term observational studies. This allows comparability with other rheumatic diseases and supports studies of health economic analyses and studies that may predict lymphoma development, this being one of the major long-term outcomes of primary Sjögren's syndrome [26]. Since the SLICC damage index has been used as the gold standard for recording damage in SLE and a variant has now been developed for vasculitis [16], it was logical to use this to develop a modified version for recording multisystem damage in primary Sjögren's syndrome. This has been proposed previously [4]. This previous work confirmed that primary Sjögren's syndrome patients rarely develop damage in certain organ systems and this workshop has developed this approach further. The consensus was (1) to retain the major organ system domains to enable comparability between diseases, (2) to remove SLE-specific items and organ system domains that were felt to be less relevant to Sjögren's syndrome and (3) to add Sjögren's syndrome-specific ones, e.g. lymphoma development.
In conclusion, therefore, the workshop was organized on the basis that sufficient consensus exists to develop agreed assessment and outcome measures for randomized controlled trials and longitudinal observational studies. It was agreed that the concepts inherent in the international proposals for a core set of domains for longitudinal observational studies in rheumatological diseases [1] should be applied to primary Sjögren's syndrome (Table 1). On this basis, the content of measures to assess disease process [surface exocrine function (Table 2) and multisystem activity (Table 3)] as well as damage [modified SLICC damage index (Table 4)] were proposed, based on concepts set out previously in terms of overall disease status. The SF-36 has emerged as the most widely used measure of health status/loss of function/health-related quality of life in primary Sjögren's syndrome [4, 27]. It was agreed that health economic analysis, toxicity/adverse events and generic concepts of quality of life were useful concepts, although gold standard measures have yet to emerge [28].
Further work is required to flesh out the details of the concepts developed during this workshop and to devise assessment instruments whose usefulness can be evaluated in prospective studies involving patient-derived data.
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Acknowledgments |
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We would like to thank Professor G. Panayi, Ms T. Wenham and the organizing committee of the European Rheumatology Research Workshop held in Oxford in March 2000 for providing facilities for this workshop. We are grateful to Cibavision UK, Roche Pharmaceuticals and Schering-Plough for financial support for the workshop. Work related to this project at the University of Birmingham is supported by an ICAC and project grant from the Arthritis Research Campaign. SJB is supported by a Clinician Scientist Fellowship from the Medical Research Council. We are grateful to Professor M. Salmon for his helpful discussions of the manuscript and to T. Marshall and R. Hill for statistical advice.
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Notes |
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* Contributors and workshop participants
K. Asmussen MD PhD, University of Copenhagen, Denmark*
S. Bombardieri MD, University of Pisa, Italy
S. J. Bowman PhD FRCP, University of Birmingham, UK*
A. Bron FRCS FRCOphth, University of Oxford, UK*
B. Davidson MD MRCP, Freeman Hospital, Newcastle, UK*
C. Gordon MD FRCP, University of Birmingham, UK
T. Gordon MD PhD, Flinders Medical Centre, Adelaide, Australia
I. Griffiths BSc FRCP, Freeman Hospital, Newcastle, UK
J. Hamburger FDS FFDRCSI, University of Birmingham, UK
D. Isenberg MD FRCP, University College London, UK
R. Jonsson DMD PhD, University of Bergen, Norway*
Y. T. Konttinen MD PhD, University of Helsinki, Finland
M. J. Leandro MD, Middlesex Hospital, London, UK*
R. Manthorpe MD, University Hospital Malmö, Sweden*
T. Manthorpe MD, Slagelse County Hospital, Denmark*
X. Mariette MD PhD, Paris Hospital, France
P. Migliorini MD, University of Pisa, Italy*
D. Mulherin MD MRCPI, Cannock Chase Hospital, UK
P. Ostuni MD, University of Padova, Italy
C. T. Pease MD MRCP, Leeds General Infirmary, UK
Y. Pennec MD, Central University Hospital, Brest, France
S. Pillemer MD, National Institutes of Health, Bethesda, USA*
E. Price MD MRCP, Princess Margaret Hospital, Swindon, UK*
M. Rischmueller MD FRACP, Queen Elizabeth Hospital, Woodville, Australia
J. L. Rostron BDS FDSRCS, University of Liverpool, UK*
E. Rovenska MD PhD, University of Bratislava, Slovakia*
J. Rovensky MD DSc, University of Bratislava, Slovakia*
P. Shirlaw BDS FDSRCPS, Guy's Hospital, London UK*
B. Speculand FDS FRACDS, City Hospital, Birmingham, UK
S. Steinfeld MD, University of Brussels, Belgium*
N. Sutcliffe MD MRCP, University College London, UK*
E. Theander MD, University of Lund, Sweden*
A. G. Tzioufas MD, National University of Athens, Greece
C. Vitali MD, Piombino Hospital, Livorno, Italy*
C. Yeoman PhD FDSRCS, Royal Hallamshire Hospital, Sheffield, UK*
P. Youinou MD, Central University Hospital, Brest, France*
M. Zeher MD PhD, University Medical School, Debrecen, Hungary 
Correspondence to: S. J. Bowman.
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S. J. Bowman, D. A. Booth, and R. G. Platts Measurement of fatigue and discomfort in primary Sjogren's syndrome using a new questionnaire tool Rheumatology, June 1, 2004; 43(6): 758 - 764. [Abstract] [Full Text] [PDF]
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K. H. Asmussen and S. J. Bowman Outcome measures in Sjogren's syndrome Rheumatology, October 1, 2001; 40(10): 1085 - 1088. [Full Text] [PDF]
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