Physical fatigue characterises patient experience of primary Sjögren's syndrome.

OBJECTIVES: Besides ocular and oral dryness, fatigue is a major symptom in patients with primary Sjögren's syndrome (pSS). Our aim was to investigate the importance of fatigue in relation to other symptoms experienced as well as to evaluate the effect of rituximab treatment on fatigue in pSS patients with active disease. METHODS: This analysis was based on data from our open-label rituximab study in 28 pSS patients. Symptoms of dryness, physical fatigue, pain, and mental fatigue were scored on 0-10 scales (according to ESSPRI). Systemic disease activity was assessed with ESSDAI. RESULTS: At baseline, 24 (86%) patients rated physical fatigue as the complaint most eligible for improvement (median importance of 10), followed by pain, dryness, and mental fatigue. After rituximab treatment, physical fatigue showed maximum improvement of 2.5 points and 31% in median values at group level, and 10 (36%) patients reached physical fatigue score<5 representing patient-acceptable symptom state (PASS). In comparison, systemic disease activity improved 5.5 points and 73% at group level, and 22 (79%) patients reached ESSDAI<5 representing low disease activity. GEE analysis over time revealed that physical fatigue was significantly associated with absolute number of B cells, dryness and mental fatigue, but not with ESSDAI, IgG levels and IgM-RF. CONCLUSIONS: Physical fatigue characterises patient experience of pSS. Rituximab treatment resulted in significant improvement of patient-reported symptoms. However, the large majority of patients still experienced physical fatigue at an unsatisfactory level, above the cut-off value for PASS. Therefore, attention for optimal management of this prominent symptom is warranted.

Abatacept treatment of patients with primary Sjögren's syndrome results in a decrease of germinal centres in salivary gland tissue.

OBJECTIVES: The aim of this study was to assess the histopathological changes in parotid gland tissue of primary Sjögren's syndrome (pSS) patients treated with abatacept. METHODS: In all 15 pSS patients included in the open-label Active Sjögren Abatacept Pilot (ASAP, 8 abatacept infusions) study parotid gland biopsies were taken before treatment and at 24 weeks of follow up. Biopsies were analysed for pSS-related histopathological features and placed in context of clini- cal responsiveness as assessed with EULAR Sjögren's syndrome disease activity index (ESSDAI). RESULTS: Abatacept treatment resulted in a decrease of germinal centres (GCs)/ mm2 (p=0.173). Number of GCs/mm2 at baseline was associated with response in the glandular domain of ESSDAI (Spearman ρ=0.644, p=0.009). Abatacept treatment did not reduce focus score, lymphoepithelial lesions, area of lymphocytic infiltrate, amount of CD21+ networks of follicular dendritic cells, and numbers of CD3+ T-cells or CD20+ B- cells. Number of IgM plasma cells/mm2 increased (p=0.041), while numbers of IgA and IgG plasma cells/mm2 were unaffected during abatacept treatment. CONCLUSIONS: Abatacept affects formation of GCs of pSS patients in parotid glands, which is dependent on co-stimulation of activated follicular-helper-T-cells. Herewith, local formation of (autoreactive) memory B-cells is inhibited. Presence of GCs at baseline predicts responsiveness to abatacept in the ESSDAI glandular domain.

Development of the ClinESSDAI: a clinical score without biological domain. A tool for biological studies.

OBJECTIVE: To develop and validate ClinESSDAI (Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index), ie, ESSDAI without the biological domain. PATIENTS AND METHODS: The 702 fictive vignettes derived from 96 real cases of primary Sjögren's syndrome of the ESSDAI development study were used. As for ESSDAI development, the physician assessment of disease activity (0-10 scale) was used as the 'gold standard' in a multivariate model for weighting domains, after removing the biological domain. The reliability, assessed by intraclass correlation coefficient (ICC) between ClinESSDAI and ESSDAI, explored if ClinESSDAI was equivalent to ESSDAI. Its psychometric (ie, measurement) properties were compared with that of ESSDAI in an independent cohort. Also, its use was evaluated on data of two clinical trials. RESULTS: In multivariate modelling, all 11 domains remained significantly associated with disease activity, with slight modifications of some domain weights. Reliability between clinESSDAI and ESSDAI was excellent (ICC=0.98 and 0.99). Psychometric properties of clinESSDAI, disease activity levels and minimal clinically important improvement thresholds and its ability to detect change over time in clinical trials were very close to that of ESSDAI. CONCLUSIONS: ClinESSDAI appears valid and very close to the original ESSDAI. This score provides an accurate evaluation of disease activity independent of B-cell biomarkers. It could be used in various circumstances: (i) in biological/clinical studies to avoid data collinearity, (ii) in clinical trials, as secondary endpoint, to detect change independent of biological effect of the drug, (iii) in clinical practice to assess disease activity for visits where immunological tests have not been done.

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI).

OBJECTIVES: To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). METHODS: For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. RESULTS: Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. CONCLUSIONS: This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

Development of the Sjögren's Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy.

OBJECTIVES: To determine which outcome measures detected rituximab efficacy in the Tolerance and Efficacy of Rituximab in Sjögren's Disease (TEARS) trial and to create a composite endpoint for future trials in primary SS (pSS). METHODS: Post hoc analysis of the multicentre randomized placebo-controlled double-blind TEARS trial. The results were validated using data from two other randomized controlled trials in pSS, assessing rituximab (single-centre trial in the Netherlands) and infliximab, respectively. RESULTS: Five outcome measures were improved by rituximab in the TEARS trial: patient-assessed visual analogue scale scores for fatigue, oral dryness and ocular dryness, unstimulated whole salivary flow and ESR. We combined these measures into a composite endpoint, the SS Responder Index (SSRI), and we defined an SSRI-30 response as a ≥30% improvement in at least two of five outcome measures. In TEARS, the proportions of patients with an SSRI-30 response in the rituximab and placebo groups at 6, 16 and 24 weeks were 47% vs 21%, 50% vs 7% and 55% vs 20%, respectively (P < 0.01 for all comparisons). SSRI-30 response rates after 12 and 24 weeks in the single-centre rituximab trial were 68% (13/19) vs 40% (4/10) and 74% (14/19) vs 40% (4/10), respectively. No significant differences in SSRI-30 response rates were found between infliximab and placebo at any of the time points in the infliximab trial. CONCLUSION: A core set of outcome measures used in combination suggests that rituximab could be effective and infliximab ineffective in pSS. The SSRI might prove useful as the primary outcome measure for future therapeutic trials in pSS.

Health-related quality of life, employment and disability in patients with Sjogren's syndrome.

OBJECTIVE: To compare health-related quality of life (HR-QOL), employment and disability of primary and secondary SS (pSS and sSS, respectively) patients with the general Dutch population. METHODS: HR-QOL, employment and disability were assessed in SS patients regularly attending the University Medical Center Groningen (n = 235). HR-QOL, employment and disability were evaluated with the Short Form-36 questionnaire (SF-36) and an employment and disability questionnaire. Results were compared with Dutch population data (matched for sex and age). Demographical and clinical data associated with HR-QOL, employment and disability were assessed. RESULTS: Response rate was 83%. SS patients scored lower on HR-QOL than the general Dutch population. sSS patients scored lower on physical functioning, bodily pain and general health than pSS patients. Predictors for reduced HR-QOL were fatigue, tendomyalgia, articular involvement, use of artificial saliva, use of anti-depressants, comorbidity, male sex and eligibility for disability compensation (DC). Employment was lower and DC rates were higher in SS patients compared with the Dutch population. CONCLUSION: SS has a large impact on HR-QOL, employment and disability.

Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjögren's Syndrome.

OBJECTIVE: To assess the effect of abatacept (CTLA-4Ig), which limits T cell activation, on homeostasis of CD4+ T cell subsets and T cell-dependent B cell hyperactivity in patients with primary Sjögren's syndrome (SS). METHODS: Fifteen patients with primary SS treated with abatacept were included. Circulating CD4+ T cell and B cell subsets were analyzed by flow cytometry at baseline, during the treatment course, and after treatment was completed. CD4+ effector T cell subsets and Treg cells were identified based on expression of CD45RA, CXCR3, CCR6, CCR4, CXCR5, programmed death 1, inducible costimulator (ICOS), and FoxP3. Serum levels of anti-SSA/anti-SSB and several T cell-related cytokines were measured. Expression of ICOS and interleukin-21 (IL-21) protein was examined in parotid gland tissue at baseline and after treatment. Changes in laboratory parameters and associations with systemic disease activity (EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI]) over time were analyzed using generalized estimating equations. RESULTS: Abatacept selectively reduced percentages and numbers of circulating follicular helper T (Tfh) cells and Treg cells. Other CD4+ effector T cell subsets were unaffected. Furthermore, expression of the activation marker ICOS by circulating CD4+ T cells and expression of ICOS protein in parotid gland tissue declined. Reduced ICOS expression on circulating Tfh cells correlated significantly with lower ESSDAI scores during treatment. Serum levels of IL-21, CXCL13, anti-SSA, and anti-SSB decreased. Among circulating B cells, plasmablasts were decreased by treatment. After cessation of treatment, all parameters gradually returned to baseline. CONCLUSION: Abatacept treatment in patients with primary SS reduces circulating Tfh cell numbers and expression of the activation marker ICOS on T cells. Lower numbers of activated circulating Tfh cells contribute to attenuated Tfh cell-dependent B cell hyperactivity and may underlie the efficacy of abatacept.

Detailed Analysis of the Articular Domain in Patients with Primary Sjögren Syndrome.

OBJECTIVE: We used the 28-joint Disease Activity Score (DAS28) and the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) articular domain to assess the effect of rituximab (RTX) and abatacept (ABA) on articular involvement in primary Sjögren syndrome (pSS). METHODS: Patients with pSS treated with RTX (n = 18) or ABA (n = 13) and having a DAS28 erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level ≥ 3.2 at baseline were selected. Generalized estimating equations were used to analyze the DAS28 and ESSDAI articular domain over time. RESULTS: In the RTX group, DAS28-ESR/CRP decreased significantly up to 48 weeks. In the ABA group, DAS28-ESR/CRP decreased significantly up to 24 weeks. DAS28 correlated significantly with ESSDAI articular domain. CONCLUSION: DAS28 is useful to evaluate the effect of biologicals on articular involvement in patients with pSS.

B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome.

OBJECTIVE: To assess the effect of B cell depletion therapy on effector CD4+ T cell homeostasis and its relation to objective measures of disease activity in patients with primary Sjögren syndrome (pSS). METHODS: Twenty-four patients with pSS treated with rituximab (RTX) and 24 healthy controls (HC) were included. Frequencies of circulating effector CD4+ T cell subsets were examined by flow cytometry at baseline and 16, 24, 36, and 48 weeks after the first RTX infusion. Th1, Th2, follicular Th (TFH), and Th17 cells were discerned based on surface marker expression patterns. Additionally, intracellular cytokine staining was performed for interferon-γ, interleukin (IL)-4, IL-21, and IL-17 and serum levels of these cytokines were analyzed. RESULTS: In patients with pSS, frequencies of circulating TFH cells and Th17 cells were increased at baseline compared with HC, whereas frequencies of Th1 and Th2 cells were unchanged. B cell depletion therapy resulted in a pronounced decrease in circulating TFH cells, whereas Th17 cells were only slightly lowered. Frequencies of IL-21-producing and IL-17-producing CD4+ T cells and serum levels of IL-21 and IL-17 were also reduced. Importantly, the decrease in circulating TFH cells was associated with lower systemic disease activity over time, as measured by the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index scores and serum IgG levels. CONCLUSION: B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.

Dental Implants in Patients with Sjögren's Syndrome.

BACKGROUND: Limited evidence is available for applying dental implants in Sjögren's syndrome (SS) patients. PURPOSE: This study aims to retrospectively assess clinical outcome of implant therapy in a cohort of well-classified patients with SS. MATERIALS AND METHODS: All SS patients attending the University Medical Center Groningen for follow-up (n = 406) were asked whether they had implants. In SS patients with implants peri-implant health and implant survival was recorded and compared with data from matched healthy controls. Patients' symptoms, health-related quality of life, oral functioning, and satisfaction were assessed using validated questionnaires. RESULTS: Of the responding SS patients (n = 335), 21% was provided with implants. Of these 69 SS patients, 50 SS patients were willing to join our study. In SS patients, peri-implant health was reasonably good with minor marginal bone loss and a peri-implantitis prevalence of 14%, comparable with healthy controls. Implant survival was 97% (median follow-up 46 months) [IQR 26;73], and overall patients' satisfaction was high. Oral functioning correlated negatively with dryness, patients' satisfaction, and chewing ability in SS patients. CONCLUSIONS: Implant therapy is common in our cohort of SS patients. In spite of shortcomings of our retrospective analysis, implants in SS patients seem to perform comparable with implants in healthy patients.

EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide.

The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS.

Treatment of primary Sjögren's syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point?

INTRODUCTION: In vitro and in vivo experimental data have suggested new immunopathogenic mechanisms in primary Sjögren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. Amongst these new treatment modalities, monoclonal antibodies specific for the B-cell surface molecule CD20 have been shown to be the most promising treatment option to date. AREAS COVERED: A search of the Pubmed, MEDLINE, EMBASE, Cochrane and Ovid databases was performed to review literature on the efficacy and safety profile of anti-CD20 therapy in pSS patients. EXPERT OPINION: A single course of the chimeric humanized anti-CD20 antibody rituximab was effective in reducing disease activity in pSS patients for about six to nine months. Retreatment of responders resulted in a similar effect to initial treatment. When combined with corticosteroids during infusion, rituximab was shown to be a safe drug to administer. Thus, anti-CD20 therapy can be considered an effective treatment option in pSS patients. However, large randomized controlled trials with anti-CD20 therapy, for example rituximab, are warranted in order to: 1) assess long-term effects of such treatment, 2) determine which pSS patients will benefit most from anti-CD20 treatment and 3) assess which retreatment schedule should be followed.

Pneumococcal septicaemia with Purpura fulminans in an 11-month-old child.

Purpura fulminans (PF) is a syndrome characterised by acute onset of rapidly progressive haemorrhagic necrosis of the skin due to dermal vascular thrombosis, mainly occurring during meningococcal sepsis. It occurs rarely in the course of infection with Streptococcus pneumoniae and most cases report Meningococcus as the causing agent. This is a case report of successful conservative limb-preserving management of PF and sepsis caused by Streptococcus pneumoniae in an 11-month-old girl.