S. Bowman

Primary Sjögren’s syndrome: too dry and too tired

Chronic fatigue is one of the most prevalent and debilitating symptoms in primary SS (pSS). Approximately 70% of pSS patients suffer from disabling fatigue, which is associated with reduced health-related quality of life. In this article, we review the instruments used for evaluating pSS-related fatigue, our current understanding of the underlying psychosocial and physiological mechanisms of fatigue in pSS and the therapeutic strategies that have been studied in the management of fatigue in pSS.

United Kingdom Primary Sjögren's Syndrome Registry—a united effort to tackle an orphan rheumatic disease

Primary SS (pSS) is a multi-system autoimmune disease with a prevalence and health economic impact that are comparable with RA. However, pSS research has been relatively poorly supported. The creation of a large cohort of clinically well-characterized pSS patients will provide a catalyst and valuable resources to promote high-quality pSS research. In this review, we will describe the creation of such a cohort and the associated research biobank that is currently being established in the UK--entitled United Kingdom Primary Sjögrens Syndrome Registry (UKPSSR). We will discuss the strengths and weaknesses of the design of the registry and highlight the key challenges in the establishment of the registry and the strategies that we employ to overcome these barriers. Finally, we will consider the future development of the UKPSSR including utilization and maintenance of the cohort.

Cardiovascular risk factors in women with primary Sjögren's syndrome: United Kingdom primary Sjögren's syndrome registry results

To determine the prevalence of traditional cardiovascular risk factors using established definitions in a large cohort of clinically well‐characterized primary Sjögrens syndrome (SS) patients and to compare them to healthy controls.

[Accepted Manuscript] Randomized Controlled Trial of Rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's Syndrome.

To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögrens syndrome (SS).

Potential diagnostic utility of anti-centromere antibody in primary Sjögren’s syndrome in the UK

Dear Editor, Anti-centromere antibody (ACA), an antibody classically associated with systemic sclerosis (SSc), particularly limited cutaneous SSc or CREST syndrome [1], has attracted considerable attention recently in the context of Primary Sjogrens Syndrome (pSS) [2, 3]. We therefore read with interest the recent article in this journal by Kitagawa et al. [4] describing the clinical features of ACA-positive pSS patients and their proposal to include ACA in then classification criteria for pSS. Under the American European consensus group (AECG) classification criteria, positive biopsy of the minor salivary glands (MSG) is essential for the classification of pSS patients who are negative for the SSA (Ro) and SSB(La) antibodies. However, MSG biopsy is an invasive procedure and if ACA testing can mitigate the need for MSG biopsy in patients with suspected pSS, measuring ACA will have considerable diagnostic utility in clinics. The UK Primary Sjögrens Syndrome Registry (UKPSSR) is an on-going cohort of clinically well-characterised pSS patients from 30 centres across the UK [5]. All patients fulfilled the AECG classification criteria for pSS and were tested for the presence of a panel of autoantibodies including ACA. Thus, the UKPSSR provides a unique opportunity to explore the impact of the inclusion of ACA in the classification criteria for pSS. As of February 2012, complete immunology datasets were available for 549 patients. The clinical characteristics of the patients are summarised in (Table 1). Only 154 (27.6 %) of patients had a MSG biopsy, with 462 (84.2 %) positive for either SSA(Ro) and/ or SSB(La) antibodies. A mere seven (1.3 %) patients were ACA-positive, and of these, only three were negative for SSA(Ro) and SSB(La) antibodies. Therefore, if ACA were incorporated in the classification criteria, only 3 out of 87 (3.4 %) SSA(Ro)/SSB(La)-negative patients could have avoided MSG biopsy in this cohort. This is in marked contrast to the figure reported by Kitagawa and colleagues (15.6 % of SSA(Ro)/SSB(La) pSS patients were ACA in their study). Indeed, the reported frequencies of ACA positivity range from 3.7 to 27.6 %. The reasons for the discrepant findings are not clear but may reflect the differences in autoantibody profiles among pSS patients from different ethnic origins or places of residence and differences in the classification criteria used in these studies [2, 3, 6]. Another plausible explanation is that in previous studies, patients were recruited from single centres, whereas 30 recruitment centres are involved in the UKPSSR and therefore arguably has greater ecological validity. Furthermore, our cohort is considerably larger than those reported in the literature to date. Given the association between ACA and scleroderma, some of the ACA patients reported in these studies may have secondary rather than primary Sjögrens syndrome. In the UKPSSR cohort, patients with secondary Sjögrens syndrome are excluded and the mean disease duration of ACA patients was 11.6 years (range 4–20). We have also determined the frequency of other autoantibodies in our cohort (Table 2). Eight patients were Scl-70 K. Collins (*) :W. F. Ng (*) Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK e-mail: k.s.collins@ncl.ac.uk e-mail: wan-fai.ng@ncl.ac.uk

SAT0242 How good are the eular sjögren’s syndrome disease activity index (ESSDAI), and EULAR sjögren’s syndrome patients reported index (ESSPRI) in predicting health status in primary sjögren’s syndrome?

Background Over the past 2 years, the EULAR Sjogren’s syndrome study group have developed 2 new instruments, ESSDAI and ESSPRI to measure systemic disease activity and overall symptom burden. The ESSPRI also generates an EULAR sicca score (ESS) which measures the overall symptom of dryness. These instruments are designed to be used as standardised outcome measures for clinical studies and trials. Therefore it is useful to investigate how well these instruments predict the health status of patients with primary Sjogren’s syndrome (PSS). EQ-5D is a generic instrument that measure health outcome, the value sets can be converted to Time Trade Off (TTO) values representing the time a patient would be willing to give up to be freed from a reduced health state. In this study, we examined the relationship between ESSDAI and ESSPRI and the TTO values derived from EQ-5D. Objectives To evaluate the relationship between the two new instruments for the assessment of PSS (ESSDAI and ESSPRI) and health status of PSS patients. Methods Data including ESSDAI, ESSPRI and EQ-5D were prospectively collected from 633 PSS patients who have participated in the UK PSS registry (UKPSSR) using a standardised pro forma as previously described (1). TTO values were derived from the UK reference data provided by EuroQoL (the developer of the EQ-5D instrument) which has been transformed so that the values range from -1 to 1, with 1 being the number of years in perfect health state, 0 being dead and negative values representing health states worse than being dead. The relationships between the derived TTO values based on the health state of the patients and ESSDAI, ESSPRI as well as ESS were determined. Results The mean±SD TTO value of the PSS cohort was 0.624±0.301, with a range of -0.239 to 1. There were statistically significant correlations between TTO and ESSDAI, ESSPRI and ESS; TTO values decreased with increased ESSDAI, ESSPRI and ESS values (p<0.001 for all three). The strength of correlation was strongest with ESSPRI (R=-0.64), followed by ESS (R=-0.29) and ESSDAI (R=-0.15). Conclusions The recently developed EULAR PSS outcome assessment tools, in particular the ESSPRI, are useful predictors of the health status of PSS patients. Other UKPSSR collaborators: Moots R, Chadravarty K, Gendi N, Hamburger J, Richards A, Rauz S, Mulherin D, Kitas GD, Lloyd M, Lawson C, Clunie G, Knight S, Symmons D, Carr A, Carrozzo M, Figuereido F, Macleod I, Tarn JR, Foggo H, Edgar S,Young-Min S, Field A, Kaye S, Mewar D, Akil M, Dasgupta B, Fedele S, Porter S, Li C, Hall F. References Ng WF et al, Rheumatology, 2011;50:32-9. Disclosure of Interest None Declared

FRI0448 Evaluating health status of 620 patients with primary sjÖgren’s syndrome using EQ-5D

Background EQ-5D is a standardised tool for measurement of health status and is an increasingly popular health-related quality of life instrument but has not been applied to patients with primary Sjögren’s syndrome (PSS). EQ-5D provides a simple descriptive profile, a single index value for health status and a visual analogue score (VAS). The key advantages of EQ-5D are that the instrument is preference-based, easy to complete and the value sets can be easily converted to Quality Adjusted Life Years (QALY) to aid cost-utility analysis. Objectives To evaluate the health status of a large cohort of patients with primary Sjogren’s syndrome in the UK using EQ-5D. Methods We evaluated the health status of 620 clinically well characterised PSS patients from the UK PSS registry (UKPSSR) who fulfil the American European Consensus Group classification criteria 2002. All data were collected prospectively using a standardised pro forma as previously described (1). Data were compared to the UK normative data provided by the EuroQoL. In addition, the relationship between the health status of PSS patients and various clinical and patient reported outcome measures of PSS were examined. Results The proportion of PSS patients reporting any problem in mobility, self-care, usual activities, pain/discomfort & anxiety/depression were 42.4, 16.9, 56.7, 81.1 & 49.6 (%) respectively compared to 5.4, 1.6, 7.9, 30.2 & 15.7 (%) in the general UK population. The mean±SD VAS score was 59.9±21.2, compared to 81.3±16.8 for the general UK population. Univariate correlation analysis showed that EQ-5D VAS correlated with many clinical features of PSS but most strongly with fatigue, depression and pain with R values >0.5. Among the laboratory measures, only IgG levels, paraproteins and C3 correlated with EQ-5D VAS. Hierarchical cluster analysis showed that depression and fatigue are the most important determinants of variations in health status in this PSS cohort. Conclusions To our knowledge, this is the first report on the health status of PSS patients using EQ-5D. PSS patients have significantly impaired health status compared to the UK general population. Depression and fatigue are the key determinants of health status in PSS. Our data adds to the growing body of evidence that effective management of fatigue is key to improving the health status of PSS patients. References Ng WF et al, Rheumatology, 2011;50:32-9. Other UKPSSR collaborators: Moots R, Chadravarty K, Gendi N, Hamburger J, Richards A, Rauz S, Mulherin D, Kitas GD, Lloyd M, Moore L, Lawson C, Clunie G, Knight S, Symmons D, Carr A, Carrozzo M, Figuereido F, Macleod I, Tarn J, Foggo H, Mann S, Young-Min S, Field A, Kaye S, Mewar D, Akil M, Dasgupta B, Fedele S, Porter S, Li C, Hall F. Disclosure of Interest None Declared

A7.5 A whole blood micro-RNA signature for primary SjÖgren’s syndrome-related lymphoma

Background/Purpose Micro RNAs (miRNAs) are 18–25 nt non-coding RNAs that bind target/complementary sequences within the 3’UTR of RNA molecules steering them towards degradation or translational repression, and play a key role in the regulation of gene expression. Better understanding of the expression pattern of miRNAs in diseases may improve our understanding of the biological basis of the disease and identify potential biomarkers. The role of miRNAs in primary Sjögren’s syndrome (PSS) and PSS-related lymphoma remains poorly understood. The aim of this project is to identify a miRNA signature for PSS-related lymphoma. Methods We profiled the expression of miRNAs in whole blood (PaxGene) total RNA preparations using the Exiqon miRCURY LNA array which encompasses >1400 miRNAs and other small non-coding RNAs. A discovery cohort comprised of 36 samples from the United Kingdom Primary Sjögren’s Syndrome Registry (UKPSSR) (12 PSS patients with lymphoma, 12 PSS patients without lymphoma, 12 healthy controls) were used in the initial analysis. We also explored different normalisation strategies and developed an approach, which we considered most appropriate for analysing these data. Real-Time PCR was used to validate the most highly differentially expressed miRNAs between groups. A miRNA signature for PSS-related lymphoma was identified using cluster analysis followed by validation with a second independent cohort of 36 patients and controls. Results The initial miRNA array profiling revealed a clear clustering of the 3 subject groups. Between patient groups with and without lymphoma association, 44 miRNAs were differentially expressed. RT-PCR was used to validate 3 out of 9 of the most highly differentially expressed miRNAs. A 5-miRNA signature for pSS-associated lymphoma was identified using clustering analysis followed by validation with a second independent cohort of 36 patients and controls. The sensitivity and specificity of the signature is excellent with an area under the ROC curve of 0.92. Conclusion We have identified 5 miRNAs that are differentially expressed in peripheral blood between PSS patients with lymphoma and those without lymphoma. Identifying the mRNA targets of these miRNAs in PSS may improve our understanding of the pathogenesis of PSS-related lymphoma. Furthermore, miRNAs may be useful biomarkers for PSS-related lymphoma.

THU0323 Predictors of Disease Severity, Lymphoma and Death: Prevalence in Patients Registered on The United Kingdom Primary Sjögren's Syndrome Registry

Background There has been much research aimed at elucidating key biological and clinical features which predict severity of disease and development of lymphoma in patients with primary Sjögrens syndrome (pSS). Key biological predictors identified include the presence of leukopenia or lymphopenia, hypocomplementaemia, cryoglobulinaemia, monoclonal gammopathy; key clinical predictors include younger age at time of symptom onset or diagnosis, peripheral neuropathy, salivary gland enlargement and skin involvement (particularly palpable purpura) [1–4]. The UK Primary Sjögrens Syndrome Registry (UKPSSR) is a MRC funded patient cohort, devised to facilitate research into pSS to improve understanding of the condition. Objectives Ascertain the prevalence of putative clinical predictors amongst UKPSSR patients. Explore the relationship between demographics, clinical parameters, disease severity and lymphoma development. Methods Patients were identified on the UKPSSR (n=868), those with insufficient data were excluded from analysis (n=36). Frequency of the predictors was calculated for remaining 832 patients. Patients were assigned a value for each predictor: 1 for present, 0 for absent. These values were then added to provide the prevalence of each predictor within the cohort, and a cumulative score for each patient. Each patient had 2 cumulative scores: one for disease severity and risk of death, the other for risk of lymphoma. Patients with a recorded age of pSS symptom onset (n=739) were analysed to investigate the relationship between age of onset and development of lymphoma. SPSS used for statistical analysis. Results Pearson Chi-squared analysis found a statistically significant (p=0.004) increased incidence of lymphoma in patients presenting with symptoms of pSS before the age of 35. Predictors of lymphoma development were more common in patients whose symptoms started between age 20–34 (p=0.05). Patients with diagnosed lymphoma had a higher cumulative lymphoma risk score than patients who did not have lymphoma (p=0.05). Predictors of severe disease were found to be more common in patients whose symptoms began before age 35 (p=0.05). Conclusions This analysis corroborates the findings of previous research showing an increased lymphoma prevalence in patients presenting with pSS at a younger age [4]. It also finds a statistically significant link between poor prognostic features and development of lymphoma as described in the literature [2,3]. Further statistical analysis will aim to establish the link between each predictor and the development of systemic manifestations of pSS, baseline and cumulative ESSDAI scores and lymphoma. References Brito-Zeron, P., et al., Systemic activity and mortality in primary Sjögren syndrome. Ann Rheum Dis. Luciano, N., et al., One year in review 2015: Sjögrens syndrome. Clin Exp Rheumatol. Nocturne, G. and X. Mariette, Sjögren syndrome-associated lymphomas. BJH. Ramos-Casals, M., et al., Systemic involvement in primary Sjögrens syndrome evaluated by the EULAR-SS disease activity index. Rheumatology. Disclosure of Interest None declared

Serum Free Light Chains are Associated with Clinical Disease Activity of Primary Sjögren's Syndrome in the Cutaneous, Biological and Renal Domains

Background: Cognitive impairment in primary Sjogren’s syndrome (PSS) has been identified in several small studies using self-reported measures. Objectives: To quantify cognitive impairment symptoms in a large cohort of 150 PSS patients compared with controls and to explore the relationship between cognitive impairment with fatigue, pain and mood symptoms. Methods: PSS patients fulfilling the American European Consensus Criteria were recruited from 12 sites in England. They completed the Cognitive Failures Questionnaire (CFQ) as well as measures of mood (Hospital Anxiety and Depression Scale), fatigue (visual analogue scale (VAS)), dryness (VAS) and pain (VAS). CFQ scores were compared with data from controls. Completion of the CFQ yields a possible score between 0 and 100. The higher the score the greater the impairment. Results: One hundred and fifty PSS patients and 198 controls completed the CFQ. Cognitive symptoms were worse in the PSS group (43.7 ± 17.8 vs 35.9 ± 12.9; P < 0.001). This difference persisted (P < 0.001) following analysis of covariance adjusting for age and gender. There were significant correlations with pain, fatigue, anxiety, depression and subjective dryness scores with CFQ scores. In order to partition the variability in CFQ scores into its component parts, we performed a multiple regression analysis. This confirmed that anxiety was the most important predictor of CFQ scores (P = 0.004). Conclusion: Cognitive symptoms are common in PSS and independently associate with anxiety. Clinicians should give consideration to cognitive failure and anxiety in the management of PSS patients.