Hendrika Bootsma

EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome

Objective To develop a disease activity index for patients with primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) Sjögrens syndrome disease activity index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true. Conclusions The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

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.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012–2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that ‘treating-to-target’ can and will be applicable to the care of patients with SLE.

Changes in antibodies to C1q predict renal relapses in systemic lupus erythematosus

The presence of elevated plasma levels of autoantibodies against C1q, a subcomponent of the first component of complement in sera of patients with systemic lupus erythematosus (SLE) has been found to be associated with renal involvement. The purpose of this study was to determine whether increases in anti-C1q antibodies (anti-C1q) precede renal involvement in SLE. Forty-three SLE patients were studied longitudinally to determine the relationship between manifestations of the disease and levels of anti-C1q as well as to identify antibodies against double-stranded DNA (anti-dsDNA). Increased levels of anti-C1q were detected in all 14 of the patients who developed proliferative lupus nephritis out of 17 patients with renal relapses, which was significantly more frequent (P < 0.005) than in patients with nonrenal relapses (six of 16 patients) or with inactive disease (two of 10 patients). Increased anti-dsDNA levels were observed in 14 of 17 patients with renal relapses compared with 15 of 16 patients with nonrenal relapses and five of 10 patients with inactive disease. Significant increases in anti-C1q levels prior to the relapse occurred in 10 of 14 patients who developed proliferative nephritis and in three of 16 patients with nonrenal relapses. Significant increases in anti-dsDNA levels occurred in 11 patients of the former group and in nine patients of the latter group. No significant increases in anti-C1q or anti-dsDNA levels were observed in the patients with inactive disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Levels of soluble VCAM-1, soluble ICAM-1, and soluble E-selectin during disease exacerbations in patients with systemic lupus erythematosus (SLE); a long term prospective study

Active SLE is characterized by immune deposits and subsequent vascular inflammation in many organs. Expression and up‐regulation of adhesion molecules is basic to migration of inflammatory cells into the tissues. Recently, soluble isoforms of these molecules have been described which might be an expression of their up‐regulation in the tissues and, as such, of disease activity. The purpose of this study was to evaluate whether changes in levels of soluble adhesion molecules reflect disease activity. We analysed serial sera in a 6‐month period preceding 22 consecutive exacerbations of SLE for levels of soluble vascular cell adhesion molecule‐l (sVCAM‐1). soluble intercellular adhesion molecule‐l (slCAM‐1), and sE‐selectin. Levels were related to clinical disease activity (SLEDAI). and levels of anti‐dsDNA and complement. At the time of maximal disease activity, levels of sVCAM‐1 in patients with SLE were higher than those in controls (P < 0.0001), levels in patients with renal involvement being higher than in those without (P < 0.02). Levels of sVCAM‐1 correlated with SLEDAI scores (P < 005) and, inversely, with levels of C3 (P = 0.01). In addition, in the presence of anti‐dsDNA, levels of sVCAM‐1 tended to correlate with levels of these autoantibodies (P < 0.1). Levels of sICAM‐1 were normal and sE‐selectin levels even decreased compared with controls. Levels of sVCAM‐l were higher at the moment of relapse (P = 0.001) than at 6 months before this time point. This rise correlated with the rise in SLEDAI score (P < 0.02). Levels of sICAM‐l and sE‐selectin did not rise, and remained in the normal range in all exacerbations studied. In conclusion, in contrast to sICAM‐1 and sE‐selectin, levels of sVCAM‐l are increased, rise parallel to disease activity during exacerbations in SLE, and are associated with decreasing levels of complement factors. This favours the hypothesis of immune deposit formation, activation of the complement cascade and activation of endothelial cells. Concurrent up‐regulation of vascular adhesion molecules may thus result in transmigration of activated inflammatory cells inducing tissue damage.

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.

Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus.

To determine risk factors of accelerated atherosclerosis in patients with systemic lupus erythematosus (SLE), 72 patients with inactive disease and 36 ageand sex-matched controls were included. The intima-media thickness (IMT) of the common carotid artery was determined by ultrasound. Traditional risk factors and disease-related factors were recorded. Cardiovascular risk was estimated using SCORE (systematic coronary risk evaluation). Markers of inflammation, endothelial activation and vascular remodelling (matrix metalloproteinases (MMP-3, MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1)) were determined. IMT was increased in patients (0.67 mm 0.13 versus 0.61 mm 0.11,P 0.05). Prevalence of hypertension (33% versus 6%,P 0.001), SCORE (2.2 (1.7–4.2) versus 1.7 (1.3–2.1),P 0.001), as well as parameters of inflammation (CRP 1.8 (0.6–5.8) mg/L versus 0.6 (0.2–1.0) mg/L,P 0.001) and endothelial activation (VCAM-1 505 (389–683) ng/mL versus 374 (322–427) ng/mL,P 0.001) and von Willebrand factor (138 (59–208)% versus 48 (24–92)%,P 0.001), were increased in patients. Vascular remodelling was altered: MMP-3 and TIMP-1 were increased (18 (10–29) ng/mL versus 8 (5–11) ng/mL,P 0.001, and 275 (216–352) ng/mL versus 230 (197–268) ng/mL,P 0.001, respectively), and MMP-9 was decreased in SLE (266 (147–412) ng/mL versus 348 (226–530) ng/mL, P 0.05). Univariate analyses revealed that in patients IMT was associated with age, systolic blood pressure, SCORE and disease duration. In multivariate analysis, age and SCORE were independent predictors of IMT. In conclusion, SLE patients have an increased IMT, which is associated with traditional risk factors. Non-traditional risk factors, such as endothelial activation, altered vascular remodelling and disease duration, might play an additional role.

Treatment of primary Sjögren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment

We previously reported that B cell depletion therapy with rituximab (4 weekly infusions of 375 mg/m2, premedication: 25 mg prednisolone intravenously) in eight patients with early primary Sjogren syndrome (pSS) and seven patients with mucosa-associated lymphatic tissue (MALT)/pSS was effective in reducing subjective and objective symptoms after 12 weeks of follow-up.1 Three patients with early pSS developed serum sickness-like disease, of whom one patient declined to further participate. The MALT component of six of the seven patients with MALT/pSS was initially effectively treated with rituximab, one of these six patients was successfully retreated 9 months after the first treatment and all six patients are …

Clinical and Histologic Evidence of Salivary Gland Restoration Supports the Efficacy of Rituximab Treatment in Sjogren's Syndrome

OBJECTIVE To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögrens syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva. METHODS In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m(2)). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition. RESULTS Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients. CONCLUSION Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS.

The predictive value of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus. A prospective long term observation

OBJECTIVE This study investigated the predictive value of rises in IgM class antibodies against double stranded DNA (anti-dsDNA) for ensuing relapses in systemic lupus erythematosus (SLE) in comparison with rises in IgG class antibodies. In addition, it was analysed whether rises in IgM class anti-dsDNA were associated with specific clinical manifestations of SLE. METHODS Thirty four of a cohort of 72 SLE patients who were positive for IgM class anti-dsDNA at the start of the study or at the time of a relapse were analysed monthly for class specific anti-dsDNA levels during a median observation period of 19.6 months. Disease activity was scored according to the SLE Disease Activity Index. Anti-dsDNA were measured by IgM and IgG class enzyme linked immunosorbent assay (ELISA) and by Farr assay. RESULTS During the study 18 of 34 patients experienced 26 relapses. Twenty two (85%) of the relapses were accompanied by a positive test for IgM class anti-dsDNA by ELISA, 23 (89%) were positive for IgG class anti-dsDNA by ELISA, and 25 (96%) were positive by Farr assay. Patients with rises in IgG class anti-dsDNA by ELISA or in anti-dsDNA by Farr assay had a significantly higher cumulative risk for relapses than patients without those increases (p=0.04 and p=0.03, respectively). This was not the case for rises in IgM class anti-dsDNA (p=0.16). Moreover, a rise in IgM class anti-dsDNA before a relapse was not associated, expressed in terms of odds ratios, with specific clinical manifestations of SLE. CONCLUSION Relapses of SLE are frequently accompanied by IgM class anti-dsDNA. Rises of IgM class anti-dsDNA, in contrast with rises in IgG class anti-dsDNA, are not a sensitive tool for predicting a relapse and are not associated with specific clinical manifestations of SLE.