Gwenny M. Verstappen

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

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 Sjögrens syndrome (SS).

Abatacept attenuates T follicular helper-cell-dependent B-cell hyperactivity in primary Sjögren's syndrome.

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 Sjögrens syndrome (SS).

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.

Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease

Brutons tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacologic BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity; conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We undertook this study to investigate BTK expression and activity in human B cells in the context of autoimmune disease.

Enhanced Bruton's tyrosine kinase activity in peripheral blood B lymphocytes of autoimmune disease patients

Brutons tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacologic BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity; conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We undertook this study to investigate BTK expression and activity in human B cells in the context of autoimmune disease.

Prevalence and predictors of over-the-counter medication use among pregnant women: a cross-sectional study in the Netherlands

BackgroundOver-the-counter-medication (OTC-medication) use during pregnancy can be potentially harmful for the fetus. To successfully counsel the patient it is important to know if the patient is at risk. In this study possible predictors for OTC-medication use were identified and a model was designed to predict OTC-medication use during pregnancy.MethodsWe performed a post-hoc analysis on data collected for a clustered clinical trial to study a screening strategy for Query fever. Pregnant women under supervision of a midwife were eligible for inclusion. These women filled out questionnaires during their pregnancy and post-partum. These questionnaires were used to determine the prevalence and to select possible predictors for OTC-medication use. These predictors were included in a prediction model using multivariate analysis. The discrimination and calibration of the model were assessed with Receiver Operating Characteristic analysis and the Hosmer and Lemeshow test.ResultsOf the 1348 women enrolling in the clustered clinical trial, we included 1246 women in this analysis. The prevalence of OTC-medication use was 12.5%. The predictors for OTC-medication use in our cohort were: nulliparity, use of prescription medication, the presence of a comorbidity, Body Mass Index between 26 and 30 kg/m2 and General Practitioner visits. These predictors were used to design a prediction model for OTC-medication use. The area under the Receiver Operating Characteristic-curve of the prediction model was 0.667 (95% CI 0.620-0.714 P<0.001) and the predictive probabilities ranged from 6.6% to 57.4%. The Hosmer and Lemeshow goodness-of-fit test indicated good calibration of the model (P = 0.640).ConclusionIt is possible to indicate women at risk for OTC-medication use during pregnancy, using five maternal characteristics that independently contribute to the prediction model. The predictors are easy to estimate and the model is easy to implement in daily practice.

The value of rituximab treatment in primary Sjögren's syndrome

The rationale for B cell depletion therapy with rituximab in primary Sjögrens syndrome relies upon the well-established role of B cell hyperactivity in immunopathogenesis. In line with this notion, several biomarkers of B cell activity are significantly affected by treatment, both in the target organs and periphery. In contrast to most biological outcomes, clinical outcomes are not consistent between studies. Although two large RCTs did not meet their primary endpoint, several beneficial clinical effects of treatment have been shown. As discussed in this review, differences in study design and patient characteristics could explain the variation in results. Interestingly, a newly developed composite endpoint of subjective and objective outcomes did show a significant effect of rituximab in one of the large RCTs. Response predictors need to be identified to define more targeted inclusion criteria and achieve precision medicine. The positive effects seen on biological and clinical parameters warrant future studies to investigate this promising treatment modality.

Pharmacotherapy for managing extraglandular symptoms of primary Sjögren’s syndrome

Introduction: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by impaired function of the exocrine glands. Many pSS patients also experience extraglandular symptoms. Effective therapeutic interventions for pSS patients are not yet approved. However, advances in understanding of the disease process have led to the development of promising therapeutic targets. Areas covered: This review provides an overview of current and presumed future strategies for the treatment of extraglandular symptoms in pSS patients, in relation to pathogenesis of the disease. In addition, future approaches for the evaluation of these symptoms in clinical trials will be discussed. Expert opinion: Of all clinical trials that have been conducted in pSS, only few evaluated the effect of treatment on extraglandular symptoms. This lack of data can be partially explained by: i) heterogeneity of extraglandular symptoms; ii) inclusion of patients with low systemic disease activity in clinical trials; and iii) the former lack of a validated outcome measure to evaluate the systemic disease activity. These methodological issues should be addressed in future clinical trials. The ultimate goal in the management of pSS is evidence-based and personalized treatment of the broad range of symptoms experienced by patients suffering from this disease, including extraglandular symptoms.

Salivary Gland Stem Cells Age Prematurely in Primary Sjögren's syndrome

A major characteristic of the autoimmune disease primary Sjögrens syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.

Sjogren's syndrome, should we sign?

Type I interferons (IFNs) play a significant role in the pathogenesis of primary Sjögren’s syndrome (pSS). Derailed IFN production may contribute to overactivation of the innate and adaptive immune system, finally leading to B-cell hyperactivity, autoimmunity, and dysfunctioning of the glandular tissue. In pSS patients many IFN-stimulated genes and proteins are overexpressed, resulting in a so-called IFN signature. Although initially mainly type I inducible genes were believed to be overexpressed in pSS patients, more recent evidence indicates that also type II IFN genes can be overrepresented. Not all pSS patients seem to exhibit an IFN signature and the key question that remains to be answered is whether the presence of a type I and/or type II IFN signature reflects merely a more severe variant or more active phase of the disease or that it identifies a distinct subgroup of patients with a different etiopathogenesis. Type I IFNs have been implicated in the pathogenesis of several systemic autoimmune diseases, including pSS.[1] pSS is characterized by a chronic inflammatory process of the salivary glands and lacrimal glands, leading to the dominant complaints of dry mouth and dry eyes. The disease is, however, certainly not restricted to exocrine glands as reflected by complaints of fatigue and pain and a wide range of extraglandular manifestations, explaining the diverse clinical presentation of pSS patients. Type I IFN comprises a large group of subtypes of IFNs of which IFNα and IFNβ are the most studied proteins. These subtypes share similar functions. Type I IFNs are prevalently induced by the binding of (viral) DNA/RNA to transmembrane pattern recognition receptors (Toll-like receptors (TLRs) in particular TLR3, TLR7, and TLR9) or to cytosolic sensors (e.g. RIG-1, MDA-5). Most body cells, including epithelial cells of exocrine glands, can produce IFNβ, whereas plasmacytoid dendritic cells (pDCs) are specialized to produce large amounts of IFNα, but also produce other subtypes; pSS patients express higher serum levels of type I IFN (IFNα) compared to healthy controls.[2] Other studies, however, detected serum IFNα only in a small proportion of pSS patients.[3] IFNα producing pDCs are found in the glandular infiltrates from pSS patients.[3,4] Not only microbial-derived nucleic acids, but also autologous nucleic acids and immune complexes composed of autoantibodies directed to RNA binding proteins are strong stimulants of IFNα production by pDCs in pSS patients.[3] These autoantigens (mostly SSA/SSB) are possibly derived from the intrinsically activated epithelial cells.[5] In turn, IFNs can upregulate the expression of these autoantigens by the epithelial cells. Furthermore, B-cells from patients with pSS can stimulate directly the secretion of IFNα by pDCs.[6] IFN production is regulated by various IFN regulatory factors (IRFs) and type I IFN production by pDCs is dependent on the transcription factors IRF5 and IRF7. [7] The importance of IRF5 in pSS is illustrated by genome-wide association studies that identified a polymorphism in IRF5 associated with pSS.[8] Another pSS-associated gene polymorphism is stat4, a transcription factor involved in the signaling of type I IFN, after binding to its receptor the type I IFN receptor (IFNAR). This receptor is widely expressed by many different cell types and binds all isoforms of type I IFNs.[9] IFNAR signaling results in the transcription of several genes that renders the cells with a kind of antiviral state, in order to protect the body from viral infections. Many other genes that are stimulated by type I IFN modulate both innate and adaptive immune responses, for example by increased antigen presentation, cytokine and chemokine production, and stimulation of effector Tand B-cell responses. Indeed, most evidence for a crucial role of (type I) IFN in pSS comes from studies analyzing mRNA transcripts and protein expression levels of genes stimulated by IFN. Measuring the expression of IFN-inducible genes also overcomes the problem that there are several type I IFN subtypes, as a result of which assessment of a single subtype I IFN does not provide clues about the overall type I IFN activity.[10] Initial microarray analysis of mRNA extracted from minor salivary gland tissue of pSS patients revealed an upregulated expression of many IFN-stimulated genes, the so-called IFN signature, compared to nonpSS sicca patients.[4,11] The finding that the increased expression of many (type I) IFN-stimulated genes can also been observed in circulating monocytes, peripheral blood mononuclear cells, and whole EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2016 VOL. 12, NO. 4, 365–367 http://dx.doi.org/10.1586/1744666X.2016.1130624