[show abstract][hide abstract] ABSTRACT: Primary Sjogren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.Methods/design: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.
The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.Trial registration: UKCRN Portfolio ID: 9809 ISRCTN65360827.
[show abstract][hide abstract] ABSTRACT: Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, great efforts have been made to develop valid tools for the assessment of these both facets. Disease specific questionnaires such as Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptom Inventory (SSI) have been proposed for evaluation of patients' symptoms, whereas different composite indexes have been suggested for the assessment of systemic disease activity. After that, an international project supported by EULAR, emerged to develop consensus disease activity indexes: the EULAR Sjögren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. Both EULAR indexes have been developed in an international collaboration to be consensual. Both indices have now been validated in a large independent international cohort. They both have been shown to be feasible, valid and reliable instruments. Also, we have found that these two scores did not correlate, suggesting that these two indexes assess two different disease components that poorly overlap, but were complementary. The sensitivity to change of both scores has been assessed, they are both able to detect change, however, ESSDAI score, like other systemic score, is more sensitive to change than ESSPRI and other patient scores. Current work is ongoing to define disease activity levels and clinically important changes for defining significant clinical improvement with the systemic score ESSDAI, and ESSPRI. We hope that this increased knowledge on the way to assess patients with primary SS, along with the emergence of new targeted therapy, will put a great input in the improvement of conduction of clinical trials in pSS.
Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10(-114)), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10(-19)), STAT4 (Pmeta = 6.80 × 10(-15)), IL12A (Pmeta = 1.17 × 10(-10)), FAM167A-BLK (Pmeta = 4.97 × 10(-10)), DDX6-CXCR5 (Pmeta = 1.10 × 10(-8)) and TNIP1 (Pmeta = 3.30 × 10(-8)). We also observed suggestive associations (Pmeta < 5 × 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.
[show abstract][hide abstract] ABSTRACT: The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren's syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren's syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years.
Therapeutic advances in musculoskeletal disease 08/2013; 5(4):234-49.
[show abstract][hide abstract] ABSTRACT: Abstract
Objectives: EuroQoL-5 dimension (EQ-5D) is a standardised, preference-based tool for measurement of health-related quality of life and EQ-5D utility values can be converted to Quality Adjusted Life Years (QALY) to aid cost-utility analysis. This study aimed to evaluate the EQ-5D utility values of 639 primary Sjögren’s syndrome (PSS) patients from the UK PSS registry.
Methods: Prospective data collected using a standardised pro forma were compared to UK normative data. Relationships between utility values and the clinical and laboratory features of PSS were explored.
Results: The proportion (%) of PSS patients reporting any problem in mobility, self-care, usual activities, pain/discomfort & anxiety/depression were 42.2, 16.7, 56.6, 80.6 & 49.4 respectively, compared to 5.4, 1.6, 7.9, 30.2 & 15.7 for the UK general population. The median EQ-5D utility values was 0.691 (Interquartile range: 0.587-0.796, range: -0.239 to 1.000), with a bi-modal distribution. Bivariate correlation analysis revealed significant correlation between EQ-5D utility values and many clinical features of PSS but most strongly with pain, depression and fatigue (R values >0.5). After adjusting for age and sex differences, multiple regression analysis identified pain and depression asthe two most important predictors of EQ-5D utility values accounting for 48% of the variability. Anxiety, fatigue, and body mass index were other statistically significant predictors but accounting for <5% in variability.
Discussion: This is the first report on the EQ-5D utility values of PSS patients. PSS patients have significantly impaired utility values compared to the UK general population. EQ-5D utility values are significantly related to pain and depression scores in PSS.
Annals of the Rheumatic Diseases 04/2013; · 9.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: A new approach for the classification of patients with Sjögren's syndrome (SS) has been recently proposed. Although these new criteria substantially differ from the American European Consensus Group criteria, which have represented the gold standard for the last decade, when compared with each other the two sets show a high statistical degree of agreement. However, the fact that two different criteria to classify patient with SS could be available may introduce some additional difficulties in the scientific communication, making cohorts of patients selected by using different methods less than completely equivalent, and the results of epidemiological studies and therapeutic trials not entirely comparable. Consequently, to reach a consensus agreement on universally accepted classification criteria for SS seems to be a very desirable objective.
Annals of the rheumatic diseases 12/2012; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Primary Sjögren's Syndrome (pSS) is characterized by focal lymphocytic infiltration of secretory exocrine glands associated with severe dryness of eyes and mouth in particular. Systemic features such as disabling fatigue, cutaneous vasculitis, lung, neurological, haematological or other systemic involvement also occur. Conventional immunosuppressive therapies such as corticosteroids or disease-modifying drugs, have been used in some patients with these systemic features with variable benefit. Current therapy for dryness is principally symptomatic although medications to stimulate residual glandular secretion can be helpful for appropriate individuals. As the pathogenesis of the condition becomes better understood, particularly, in recent years, the role of systemic B-cell activation, biologic therapies specifically targeted against molecules involved in disease pathogenesis represent a more targeted approach to therapeutic intervention. The greatest experience in pSS is with rituximab, an anti-CD20 (expressed on a subset of B-cells) monoclonal antibody already in use for the treatment of some B-cell lymphomas and rheumatoid arthritis. Randomised placebo-controlled studies in pSS are currently underway. This review discusses the rationale for using biologic therapies in pSS, the current data on rituximab and the potential use of other biologic therapies in pSS in the future.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: To determine the prevalence of autonomic dysfunction (dysautonomia) among patients with primary Sjögren's syndrome (PSS) and the relationships between dysautonomia and other clinical features of PSS.METHODS: Multicentre, prospective, cross-sectional study of a UK cohort of 317 patients with clinically well-characterised PSS. Symptoms of autonomic dysfunction were assessed using a validated instrument, the Composite Autonomic Symptom Scale (COMPASS). The data were compared with an age- and sex-matched cohort of 317 community controls. The relationships between symptoms of dysautonomia and various clinical features of PSS were analysed using regression analysis.RESULTS: COMPASS scores were significantly higher in patients with PSS than in age- and sex-matched community controls (median (IQR) 35.5 (20.9-46.0) vs 14.8 (4.4-30.2), p<0.0001). Nearly 55% of patients (vs 20% of community controls, p<0.0001) had a COMPASS score >32.5, a cut-off value indicative of autonomic dysfunction. Furthermore, the COMPASS total score correlated independently with EULAR Sjögren's Syndrome Patient Reported Index (a composite measure of the overall burden of symptoms experienced by patients with PSS) (β=0.38, p<0.001) and disease activity measured using the EULAR Sjögren's Syndrome Disease Activity Index (β=0.13, p<0.009).CONCLUSIONS: Autonomic symptoms are common among patients with PSS and may contribute to the overall burden of symptoms and link with systemic disease activity.
Annals of the rheumatic diseases 05/2012; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, a core set of domains, which included sicca symptoms, objective measurements of tear and saliva production, fatigue, quality of life, disease activity and damage was indicated as essential for outcome assessment in this disorder. Afterwards, great efforts have been made to develop valid tools for the assessment of different domains. Specific questionnaires such as the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI) have been proposed as dedicated tools for the evaluation of patients symptoms, whereas different composite indexes have been suggested for the assessment of disease activity and damage. Some of these preliminary studies served as bases of an international project supported by EULAR, aimed at developing two consensus disease activity indexes: the EULAR Sjögren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. A detailed and critical review of all these indexes is provided in this article. Both EULAR indexes showed, in recent studies, to be feasible, valid, and reliable instruments. After their final validation, which is currently in process, they could be used as consensus outcome criteria in therapeutic trials and in clinical practice.
Journal of Autoimmunity 02/2012; 39(1-2):97-102. · 8.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: To compare adalimumab versus etanercept in patients with active rheumatoid arthritis (RA) to test the hypothesis that adalimumab was not inferior to etanercept in terms of drug continuation by a margin of 15% after 52 weeks of treatment.
Pragmatic, randomised, parallel group, multicentre, unblinded and non-inferiority trial. Randomisation stratified by baseline use of methotrexate.
125 adults with active RA despite treatment with two disease-modifying drugs (DMARDs), including methotrexate randomised (1 : 1) to adalimumab 40 mg alternate weeks or etanercept 50 mg weekly, added to existing medication.
The primary outcome was proportion of patients continuing treatment after 52 weeks. Secondary outcomes included: disease activity score using 28 joints (DAS28), treatment satisfaction (TSQM V.2), health status (Euroqol-5D), drug toxicity and persistence with therapy after 2 years.
Persistence with therapy was 65% for adalimumab versus 56.7% for etanercept (one-sided 95% CI for proportion still taking adalimumab minus proportion on etanercept ≥-7.9%); demonstrating non-inferiority at the 15% margin. After 2 years these figures were: adalimumab 58.3% and etanecept 43.3% (CI ≥-1.7%). The proportion of good, moderate and non-responders based on DAS28-C reactive protein, after 52 weeks, were 26.3%, 33.3% and 40.4%, respectively, for adalimumab versus 16.7%, 31.7% and 51.7%, respectively, for etanercept (p=0.158). Baseline median EQ-5D scores improved from 0.52 to 0.69 for adalimumab and from 0.52 to 0.64 for etanercept (p=0.046) after 52 weeks. Global satisfaction, effectiveness, side effects and convenience scores based on the TSQM were similar for both drugs. Fourteen serious adverse events occurred including two deaths from myocardial infarction, one patient with ovarian cancer and one with acute myeloid leukaemia.
Clinicians choosing a first tumour necrosis factor inhibitor for active RA, despite trying two DMARDs including methotrexate, may choose either adalimumab or etanercept in the knowledge that these drugs are similarly effective.
EU Clinical Trials Register 2006-006275-21/GB.
[show abstract][hide abstract] ABSTRACT: In primary Sjögren’s syndrome (SS), clinical features can be divided into two facets: the benign subjective but disabling
manifestations such as dryness, articular and muscular pain, and fatigue, and the systemic manifestations such as synovitis,
vasculitis, skin, lung, renal and neurological involvement, or lymphoma. Great efforts have been made to develop valid activity
indexes needed to assess the effectiveness of new therapies. First, for evaluation of patients’ symptoms: the Profile of Fatigue
and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI) then for systemic features: the SS Disease Activity Index (SSDAI)
and Sjögren’s Systemic Clinical Activity Index (SCAI). The development of these indexes served as bases of an international
collaborative project promoted by European League Against Rheumatism (EULAR). Thirty-nine primary SS experts were involved
in the development of these two consensus disease activity indexes: the EULAR Sjögren’s Syndrome Patients Reported Index (ESSPRI),
a patient-administered questionnaire to assess subjective features, and the EULAR Sjögren’s Syndrome Disease Activity Index
(ESSDAI), a systemic activity index to assess systemic complications. Both indexes have good correlations with existing scores
and also global evaluation of disease activity by physician for ESSDAI and by patient for ESSPRI. In addition, ESSDAI had
a good sensitivity to change and detects changes more accurately, when compared to other scores. These both indexes are simple
and aimed to be used for both clinical trials and clinical practice. They are currently being validated for that purpose.
KeywordsPrimary Sjögren’s syndrome-Disease activity index-Patient-reported outcome-Outcome assessment-Systemic activity
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: Primary Sjögren's syndrome (PSS) is a relatively common immune-mediated condition characterized by oral and ocular dryness, fatigue, musculoskeletal pain and poor health-related quality of life. Other extra-glandular organs can also be affected and PSS is associated with a markedly increased risk of lymphoma. Furthermore, the health-economic cost for PSS is substantial. There is currently no effective treatment available. With better understanding of the pathophysiology of PSS and advances in technologies, it is now possible to develop biological therapies to target specific molecules or molecular pathways that are important in PSS pathogenesis. Indeed, a limited number of biological therapies have already been tested in PSS with mixed successes. AREAS COVERED: Published data on the use of biological therapies in PSS, the possible roles for other biological therapies and the potential challenges for their use. EXPERT OPINION: The use of biological agents targeting key cellular and molecular pathways in PSS pathogenesis represents a promising therapeutic strategy. Clinical trials assessing the efficacy of biological therapies in PSS should be encouraged but patient selection and outcome measures used in these studies must be carefully considered to ensure that the true effects of biological therapies on the outcomes of PSS are being appropriately evaluated.
[show abstract][hide abstract] ABSTRACT: Early therapy improves outcomes in rheumatoid arthritis (RA). It is therefore important to improve predictive algorithms for RA in early disease. This study evaluated musculoskeletal ultrasound, a sensitive tool for the detection of synovitis and erosions, as a predictor of outcome in very early synovitis.
58 patients with clinically apparent synovitis of at least one joint and symptom duration of ≤3 months underwent clinical, laboratory, radiographic and 38 joint ultrasound assessments and were followed prospectively for 18 months, determining outcome by 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism criteria. Sensitivity and specificity for 1987 RA criteria were determined for ultrasound variables and logistic regression models were then fitted to evaluate predictive ability over and above the Leiden rule.
16 patients resolved, 13 developed non-RA persistent disease and 29 developed RA by 1987 criteria. Ultrasound demonstrated subclinical wrist, elbow, knee, ankle and metatarsophalangeal joint involvement in patients developing RA. Large joint and proximal interphalangeal joint ultrasound variables had poor predictive ability, whereas ultrasound erosions lacked specificity. Regression analysis demonstrated that greyscale wrist and metacarpophalangeal joint involvement, and power Doppler involvement of metatarsophalangeal joints provided independently predictive data. Global ultrasound counts were inferior to minimal power Doppler counts, which significantly improved area under the curve values from 0.905 to 0.962 combined with the Leiden rule.
In a longitudinal study, extended ultrasound joint evaluation significantly increased detection of joint involvement in all regions and outcome groups. Greyscale and power Doppler scanning of metacarpophalangeal joints, wrists and metatarsophalangeal joints provides the optimum minimal ultrasound data to improve on clinical predictive models for RA.
Annals of the rheumatic diseases 03/2011; 70(3):500-7. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: To develop a score for assessment of patients' symptoms in primary Sjögren's syndrome (SS): the EULAR SS Patient Reported Index (ESSPRI).
Dryness, pain, somatic and mental fatigue were identified as the main symptoms of patients with primary SS, in studies developing the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI). It was suspected that a single 0-10 numerical scale for each domain was sufficient to assess these symptoms. These four scales were gathered to form the ESSPRI. 230 patients, from 12 countries completed the ESSPRI, SSI and PROFAD questionnaires and a 0-10 patient global assessment (PGA). Correlations between each symptom and PGA were obtained. Multiple regression modelling, using PGA as 'gold standard' was used to select domains and estimate their weights.
PGA had good correlation with dryness, limb pain, fatigue and mental fatigue (r=0.49-0.59, all p<0.0001), but correlated less well with individual dryness features. In multivariate analysis, dryness, limb pain and fatigue, but not mental fatigue, were significantly associated with PGA; weights derived from the regression were identical for these three domains. Thus, ESSPRI was redefined as the mean of the three scales: dryness, limb pain and fatigue. Lastly, ESSPRI significantly correlated with PGA (r=0.70), PROFAD (r=0.73) and SSI (r=0.66).
ESSPRI is a very simple index designed to measure patients' symptoms in primary SS. It has good construct validity and is well correlated with SSI and PROFAD. ESSPRI should now be validated for use as an outcome measure in clinical trials.
Annals of the rheumatic diseases 02/2011; 70(6):968-72. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 Sjögren's 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.
[show abstract][hide abstract] ABSTRACT: To estimate the indirect costs associated with primary Sjögren's syndrome (pSS) compared with rheumatoid arthritis (RA) and community controls.
Data were obtained from 84 women patients with pSS as part of a study to develop a systemic activity measure, from 87 consecutive women patients with RA attending a hospital clinic, and from 96 women community controls on a general practice list. A modified economic component of the Stanford Health Assessment Questionnaire was used to assess lost productivity.
Using a conservative model, the estimated total annual indirect costs (95% CI) were 7677 pound sterling (5560 pound sterling, 9794 pound sterling) for pSS, 10,444 pound sterling (8206 pound sterling, 12,681 pound sterling) for RA, and 892 pound sterling (307 pound sterling, 1478 pound sterling) for controls. Using a model that maximizes the estimates, the equivalent figures were 13,502 pound sterling (9542 pound sterling, 17,463 pound sterling), 17,070 pound sterling (13,112 pound sterling, 21,028 pound sterling), and 3382 pound sterling (2187 pound sterling, 4578 pound sterling), respectively. These were all significantly greater at p < 0.001 for patient groups than for the control group.
pSS is associated with significantly increased indirect costs equivalent to 69%-83% of that for patients with RA. This needs to be taken into account when evaluating the overall economic consequences of pSS.
The Journal of Rheumatology 04/2010; 37(5):1010-5. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess and compare the sensitivity to change of the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) with that of other primary Sjögren's syndrome (SS) disease activity indexes.
We abstracted 96 patient profiles, including data on 3 successive visits (visits 1-3), from the medical charts of patients with primary SS. Patient profiles were scored with the ESSDAI, SS Disease Activity Index (SSDAI), and Sjögren's Systemic Clinical Activity Index (SCAI). Thirty-nine experts assessed 5 profiles for whether disease activity had improved, worsened, or remained stable at visits 2 and 3.
For improved patients, the standardized response means (SRMs) for all scores did not differ, and ranged from -1.08 to -1.38 between visits 1 and 2 and from -0.50 to -0.76 between visits 2 and 3. For patients with worsened activity, the SRMs between visits 1 and 2 and between visits 2 and 3 were +0.46 and +1.10 for the ESSDAI, -0.03 and +0.79 for the SSDAI, and +0.17 and +1.02 for the SCAI, respectively. For patients with stable activity, the SRMs between visits 1 and 2 and between visits 2 and 3 were 0.00 and -0.13 for the ESSDAI, -0.44 and -0.11 for the SSDAI, and -0.36 and +0.34 for the SCAI, respectively.
For patients with improved activity, the 3 disease activity indexes showed similar, large sensitivity to change. However, the ESSDAI seemed to detect changes in activity more accurately than other disease activity indexes. Notably, for patients with stable activity, the ESSDAI did not show erroneous improvement.