Petra M. Meiners

Effectiveness of Rituximab Treatment in Primary Sjogren's Syndrome A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjögrens syndrome (SS) in a double-blind, randomized, placebo-controlled trial. METHODS Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of > or =0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. RESULTS Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. CONCLUSION These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.

Health-related quality of life, employment and disability in patients with Sjögren'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.

Abatacept treatment reduces disease activity in early primary Sjögren's syndrome (open-label proof of concept ASAP study)

Objective To assess the efficacy and safety of abatacept in patients with early and active primary Sjögrens syndrome (pSS). Methods All 15 patients (12 women, three men) included in the open-label Active Sjögren Abatacept Pilot study met the revised American-European Consensus Group criteria for pSS and were biological disease-modifying antirheumatic drug-naive. Patients were treated with eight intravenous abatacept infusions on days 1, 15 and 29 and every 4 weeks thereafter. Follow-up was conducted at 4, 12, 24 (on treatment), 36 and 48 weeks (off treatment). Disease activity was assessed with European League Against Rheumatism (EULAR) Sjögrens Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögrens Syndrome Patient Reported Index (ESSPRI). Several other functional, laboratory and subjective variables were analysed. Generalised estimating equations were used to analyse parameters over time. Results ESSDAI, ESSPRI, rheumatoid factor and IgG levels decreased significantly during abatacept treatment and increased post-treatment. Salivary and lacrimal gland function did not change during treatment. Fatigue and health-related quality of life (HR-QoL) improved significantly during treatment. No serious side effects or infections were seen. Conclusions In this open-label study, abatacept treatment is effective, safe and well tolerated, and results in improved disease activity, laboratory parameters, fatigue and HR-QoL in patients with early and active pSS. Trial registration number 2009-015558-40.

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 Sjögrens 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.

Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjögren's syndrome treated with rituximab

Objective To evaluate the responsiveness of the EULAR Sjögrens Syndrome Patient Reported Index (ESSPRI) and EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI) in patients with primary Sjögrens syndrome (pSS) treated with rituximab. Methods Twenty-eight patients with pSS treated with rituximab (1000 mg) infusions on days 1 and 15 were included in the study. Data were collected prospectively at baseline and 16, 24, 36, 48 and 60 weeks after treatment. Internal responsiveness was assessed using standardised response means (SRM) and effect sizes (ES). SRM and ES <0.5, 0.5–0.8 and >0.8 were interpreted as small, moderate and large, respectively. External responsiveness was assessed using Spearman correlation coefficients. Results Median (range) ESSPRI and ESSDAI scores at baseline were 6.7 (0.3–9.0) and 8 (2–18), respectively. Both indices improved significantly after treatment. SRM and ES values for ESSPRI and ESSDAI were ≥0.8 at week 16 and decreased afterwards, and were larger for ESSDAI than for ESSPRI. SRM and ES values for patients and physicians global disease activity (GDA) and rheumatoid factor broadly followed the pattern of those of ESSPRI and ESSDAI. SRM and ES for stimulated whole salivary flow were small at all time points. At baseline and for most change scores, moderate to good correlations were found between ESSPRI and patients GDA and between ESSDAI and physicians GDA. Poor association was found between ESSPRI and ESSDAI. Conclusions ESSPRI and ESSDAI are sensitive measures of change in disease activity after therapeutic intervention, which supports the usefulness of these indices for future clinical trials in patients with pSS. The responsiveness of ESSDAI was greater than that of ESSPRI.

B Cell Reconstitution and T Helper Cell Balance After Rituximab Treatment of Active Primary Sjogren's Syndrome A Double- Blind, Placebo-Controlled Study

Objective To assess the phenotype of reconstituting B cells after B cell depletion, and to assess the effect of reconstitution on the balance of Treg cells and effector T cells in patients with active primary Sjogrens syndrome (SS). Methods Twenty-eight patients with primary SS were treated on days 1 and 15 with either rituximab (n = 19) or placebo (n = 9). The frequencies and absolute numbers of circulating B cell subsets, Treg cells, and effector T cells were examined in fresh blood samples by 4-color flow cytometry at baseline and 5, 12, 24, 36, and 48 weeks after the first infusion. The results in rituximab-treated patients were compared with those in patients receiving placebo and with those in age- and sex-matched healthy controls (n = 10). Results At baseline, patients with primary SS displayed several abnormalities in B cell homeostasis, including a significant reduction of CD27+ B cells and expansion of CD27– B cells, compared with healthy controls. At week 48 after rituximab treatment, the majority of emerging B cells exhibited a phenotype of transitional B cells. Although recovery of CD27+ memory B cells was delayed after rituximab treatment, a significant increase in Ig class–switched memory B cells within the memory pool was observed. In addition, percentages and absolute numbers of Treg cells and effector T cells, as well as ratios of effector T cells to Treg cells, did not change significantly after rituximab treatment. Conclusion The characteristics of reconstituted B cells in patients with primary SS following depletion by rituximab treatment showed dominance of transitional B cells during the early recovery phase, which corresponds to bone marrow–derived repopulation. The depletion of B cells did not influence the balance of peripheral Treg cells and effector T cells.

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

The EULAR Sjögrens 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.

EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) is sensitive to show efficacy of rituximab treatment in a randomised controlled trial

Rituximab therapy is a promising treatment for primary Sjogrens syndrome (pSS).1 ,2 So far, treatment studies performed in patients with pSS lacked the use of a uniform outcome measure to monitor disease activity. Recently, the European League Against Rheumatism (EULAR) developed the EULAR Sjogrens Syndrome Disease Activity Index (ESSDAI).3 ESSDAI was shown to be able to monitor disease activity in patient profile and open-label studies.4 ,5 To further study the utility of ESSDAI for clinical studies, we assessed the responsiveness of ESSDAI after rituximab treatment in a randomised controlled trial (RCT) of patients with pSS.6 As the principal investigator (HB) was involved in the development of ESSDAI, the database of a single-centre, randomised, double-blind, placebo-controlled trial (see ref. 6 for details) was prospectively completed with regard to all ESSDAI domains, namely the cutaneous, respiratory, renal, articular, muscular, peripheral and central nervous system, haematological, glandular, constitutional, …

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 Sjögrens 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.

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 Sjögrens 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.