Andrea Richards

Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study

Objective: Primary Sjögren syndrome (pSS) causes significant systemic symptoms including fatigue as well as glandular dysfunction. There are currently no effective systemic therapies; however, open label series have suggested that rituximab may be beneficial for systemic and glandular manifestations. Therefore, we performed a double blind, placebo-controlled, randomised pilot study of the efficacy of rituximab in reducing fatigue in pSS. Methods: A total of 17 patients with pSS and a score on fatigue visual analogue scale (VAS) >50 were randomised to receive either 2 infusions of rituximab 1 g or placebo; patients also received oral and intravenous steroids. Outcome measures included: the proportion of patients with >20% reduction in fatigue VAS, changes in pSS related symptoms, health related quality of life and immunological parameters of pSS. These were measured 6 months after therapy. Results: There was significant improvement from baseline in fatigue VAS in the rituximab group (p<0.001) in contrast to the placebo group (p = 0.147). There was a significant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to significant difference in the mental health domain score of SF-36 (p = 0.06). There was one episode of serum sickness in the rituximab treated group. Conclusions: This is the first double blind study of rituximab in pSS to show benefit; further studies are justified.

Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögrens syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0–10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

Patient-reported outcomes in primary Sjögren's syndrome: comparison of the long and short versions of the Profile of Fatigue and Discomfort—Sicca Symptoms Inventory

OBJECTIVES The long-form 64-item Profile of Fatigue and Discomfort--Sicca Symptoms Inventory (PROFAD-SSI) questionnaire was developed as a patient-reported assessment tool for use in primary SS (PSS) and other rheumatic disorders. In this study, we assess whether the (shorter and more practical) 19-item PROFAD-SSI-SF (short form) gives similar results and whether a still briefer version using visual analogue scales (VASs) is feasible. METHODS Questionnaire surveys comprising the long and short versions of the PROFAD-SSI were mailed to 43 patients with PSS and 50 patients with RA, who were asked to complete these contemporaneously as well as repeating the process 1 month later. PSS patients also completed a series of VASs comprising fatigue and sicca domains of the SSI. RESULTS Surveys were returned from 35 PSS patients and 35 RA patients. All domains of the long- and short-form PROFAD-SSI showed strong correlations (Spearman rho between 0.779 and 0.996, P < 0.01). Factor analysis generally confirmed the previously validated domain structure with Cronbachs alpha = 0.99. The PROFAD-SF somatic fatigue domain correlated more strongly with a fatigue VAS than did the mental fatigue domain. The SSI-SF domain scores correlated with equivalent VAS scores. CONCLUSION The long- and short-form PROFAD-SSI questionnaires correlate closely suggesting that the PROFAD-SF is valid as an outcome tool. Preliminary data also suggest that an even briefer form with compression of the domains into single VAS is also feasible.

Estimating Indirect Costs in Primary Sjogren's Syndrome

Objective. To estimate the indirect costs associated with primary Sjögren’s syndrome (pSS) compared with rheumatoid arthritis (RA) and community controls. Methods. 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. Results. Using a conservative model, the estimated total annual indirect costs (95% CI) were £7677 (£5560, £9794) for pSS, £10,444 (£8206, £12,681) for RA, and £892 (£307, £1478) for controls. Using a model that maximizes the estimates, the equivalent figures were £13,502 (£9542, £17,463), £17,070 (£13,112, £21,028), and £3382 (£2187, £4578), respectively. These were all significantly greater at p < 0.001 for patient groups than for the control group. Conclusion. 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.

Squamous-Cell Carcinoma of the Tongue

A 73-year-old woman presented with a persistent ulcer and white patch on the right margin of the tongue. Intraoral examination revealed a superficial ulcer with a homogeneous base, an indurated upper border, and an adjacent speckled red and white patch at the lower border.

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy

Objectives To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. Trial registration number 65360827, 2010-021430-64; Results.

Management of oral Graft versus Host Disease with topical agents: A systematic review

Background Oral Graft-versus-Host Disease (oGvHD) is a common complication of haematopoietic stem cell transplantation. Choosing the right topical application to be used intra orally can be a challenge. Consequently, the aim of this work is to review the effectiveness and safety of topical agents currently used in the management of the inflammatory mucosal lesions encountered in oGVHD. Material and Methods We carried out electronic searches of publications up to May 2015 of the databases Pubmed, National Library of Medicine’s Medline, Embase and the Cochrane Central Register of Controlled Clinical trials to identify potentially relevant studies (keywords: “oral”, “graft”, “versus”, “host”, “disease” and “treatment”). The main inclusion criterion was the reported use of a topical agent which was not intentionally swallowed when used for the treatment of oGVHD. A 3-point grading system, described by the Swedish Council on Technology Assessment in Health Care and the Centre for Reviews and Dissemination, University of York, was used to rate the methodological quality of the papers. Results From the 902 entries identified in the search, 7 studies qualifying for inclusion were analysed. Overall, there is limited evidence with regards to the effectiveness of topical steroids for oGVHD. However, the studies showed some effect of Budesonide alone and when combined with dexamethasone. Topical tacrolimus also appears to have some effect and clobetasol propionate mouthwash had a significantly better clinical response than dexamethasone mouthwash in treating oGVHD. Conclusions As the number of clinical trials conducted is limited, there is little evidence to support the use of topical therapies to treat the inflammatory mucosal lesions found in oGVHD. High quality randomised control trials are needed in order to measure the effectiveness of any topical application for the treatment of the inflammatory mucosal lesions found in oGVHD. Key words:Oral, graft versus host disease, topical, therapy.

Comparison of ESSDAI and ClinESSDAI in potential optimisation of trial outcomes in primary Sjögren's syndrome: Examination of data from the UK Primary Sjögren's Syndrome Registry

OBJECTIVES To assess the use of the Clinical EULAR Sjögrens Syndrome Disease Activity Index (ClinESSDAI), a version of the ESSDAI without the biological domain, for assessing potential eligibility and outcomes for clinical trials in patients with primary Sjögrens syndrome (pSS), according to the new ACR-EULAR classification criteria, from the UK Primary Sjögrens Syndrome Registry (UKPSSR). METHODS A total of 665 patients from the UKPSSR cohort were analysed at their time of inclusion in the registry. ESSDAI and ClinESSDAI were calculated for each patient. RESULTS For different disease activity index cut-off values, more potentially eligible participants were found when ClinESSDAI was used than with ESSDAI. The distribution of patients according to defined disease activity levels did not differ statistically (chi2 p = 0.57) between ESSDAI and ClinESSDAI for moderate disease activity (score ≥5 and <14; ESSDAI 36.4%; ClinESSDA 36.5%) or high disease activity (score ≥14; ESSDAI 5.4%; ClinESSDAI 6.8%). We did not find significant differences between the indexes in terms of activity levels for individual domains, with the exception of the articular domain. We found a good level of agreement between both indexes, and a positive correlation between lymphadenopathy and glandular domains with the use of either index and with different cut-off values. With the use of ClinESSDAI, the minimal clinically important improvement value was more often achievable with a one grade improvement of a single domain than with ESSDAI. We observed similar results when using the new ACR-EULAR classification criteria or the previously used American-European Consensus Group (AECG) classification criteria for pSS. CONCLUSIONS In the UKPSSR population, the use of ClinESSDAI instead of ESSDAI did not lead to significant changes in score distribution, potential eligibility or outcome measurement in trials, or in routine care when immunological tests are not available. These results need to be confirmed in other cohorts and with longitudinal data.

THU0544 Auditing the Impact of the Application of the Proposed New 2014 International Criteria for Behçet's Disease

Background As there is no diagnostic test for Behçets Disease (BD), multidisciplinary assessment remains the gold standard for diagnosis In 2014, an international team from 27 countries (not including the UK), described the New International Criteria for Behçets disease. The Criteria were judged capable of “performing with good discriminatory potential (Sensitivity 94.8%, ISG 85%, specificity 90.5%, ISG 96%) regardless of country” and were felt to be “intuitive and easy to use in a wide variety of settings” [1]. The authors suggessted a role for for mass screening and identification of possible BD Objectives To assess the performance of the proposed new international criteria for Behcets Disease in a UK setting. Methods The following information was captured from the cohort: Patient demographics Frequency distribution of clinical characteristics of BD for patients with clinically confirmed BD, incomplete BD and a rejected diagnosis of BD. The proposed 2014 ICBD criteria were compared with the ISG 1990 in comparison to the gold standard multidisciplinary assessment at the Birmingham National Centre. Results There were 80 females and 39 males. 16 cases were clinically diagnosed following multidisciplinary review but failed to meet ISG 1990 criteria. All of these met the ICBD 2014 criteria. 12 cases were ISG+ but BD was not confirmed clinically (including 3 clinically rejected BD diagnosis). This increased to 14 cases for the ICBD 2014 criteria (including 5 clinically rejected BD diagnosis) Conclusions As expected the proposed ICBD 2014 criteria were more sensitive at picking up cases than ISG 1990 using the multidisciplinary assessment process as the gold standard Specificity was less than expected for both criteria, as in our hands some clinical features were not always judged either to be attributable to a possible BD diagnosis or confidently ascertained, though time and future follow up may improve performance. A more detailed expert gynaecology assessment has now been factored into service design Those patients with “Incomplete BD” form an interesting subgroup which may warrant more detailed examination e.g. those patients who present with posterior uveitis consistent with BD but fail to fulfil the classification criteria. Routine use of pathergy testing may enhance performance. ICBD may serve as a useful screening tool but in our hands in a mainly UK population (62% white British) may over diagnose BD Patients referred to the National Behçets Centres. Our three national centres represent an ideal setting to extend our study. References International Team for the Revision of the International Criteria for Behçets Disease (ITR-ICBD). The International Criteria for Behçets Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014;28:338-47. Disclosure of Interest None declared