Andreea Coca

Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor

IntroductionAs a group, rheumatoid arthritis (RA) patients exhibit increased risk of infection, and those treated with anti-tumor necrosis factor (TNF) therapy are at further risk. This increased susceptibility may result from a compromised humoral immune response. Therefore, we asked if short-term effector (d5-d10) and memory (1 month or later) B cell responses to antigen were compromised in RA patients treated with anti-TNF therapy.MethodsPeripheral blood samples were obtained from RA patients, including a subset treated with anti-TNF, and from healthy controls to examine influenza-specific responses following seasonal influenza vaccination. Serum antibody was measured by hemagglutination inhibition assay. The frequency of influenza vaccine-specific antibody secreting cells and memory B cells was measured by EliSpot. Plasmablast (CD19+IgD-CD27hiCD38hi) induction was measured by flow cytometry.ResultsCompared with healthy controls, RA patients treated with anti-TNF exhibited significantly decreased influenza-specific serum antibody and memory B cell responses throughout multiple years of the study. The short-term influenza-specific effector B cell response was also significantly decreased in RA patients treated with anti-TNF as compared with healthy controls, and correlated with decreased influenza-specific memory B cells and serum antibody present at one month following vaccination.ConclusionsRA patients treated with anti-TNF exhibit a compromised immune response to influenza vaccine, consisting of impaired effector and consequently memory B cell and antibody responses. The results suggest that the increased incidence and severity of infection observed in this patient population could be a consequence of diminished antigen-responsiveness. Therefore, this patient population would likely benefit from repeat vaccination and from vaccines with enhanced immunogenicity.

Macrophage activation syndrome: Serological markers and treatment with anti-thymocyte globulin

Two patients presented at the University of Rochester Medical Center with a febrile illness, cytopenias, organ failure (liver failure or respiratory failure), and markedly elevated serum ferritin and sIL-2R. A diagnosis of probable macrophage activation syndrome was made. Both patients failed initial therapy with steroids and cyclosporine, either due to toxicity or lack of efficacy. Both patients responded dramatically to rabbit anti-thymocyte globulin (ATG).

Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren's syndrome.

Purpose of reviewLast year was marked by important clinical and mechanistic studies that improved our understanding of B-cell immunotherapy for systemic lupus erythematosus (SLE) and Sjogrens syndrome. Here, we will highlight the most relevant studies published in the last 18 months. Recent findingsThe highlight of the year was the approval of belimumab on the basis of two major trials. On the flip side, the disappointing results of rituximab in lupus nephritis provided a clinical and mechanistic counterpoint in SLE. Still, major limitations in the LUpus Nephritis Assessment with Rituximab (LUNAR) trial, positive subset analysis and new open studies and registries continue to provide hope for and major insights into the use of B-cell depletion. In Sjogrens syndrome, the role of B-cell depletion has been further investigated, both for glandular and extraglandular manifestations of the disease with mixed results in a disease in which outcomes are notoriously hard to measure. SummaryThe approval of anti-B cell activating factor therapy and an increasing body of open studies with rituximab as well as subset studies and secondary analysis of the Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus (EXPLORER) and LUNAR trials provide hope for B-cell immunotherapy and significant insight into its mechanisms of action and utilization in a selected subset of patients. Ongoing clinical trials of other B-cell targeting agents are eagerly anticipated.

Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus.

Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE.

Salivary anti-Ro60 and anti-Ro52 Antibody Profiles to Diagnose Sjögren’s Syndrome

Simple and non-invasive saliva-based diagnostics may be useful for the identification, understanding, and monitoring of autoimmune and infectious diseases. Previously, Luciferase Immunoprecipitation Systems (LIPS) were used for sensitive detection of patient serum autoantibodies in Sjögren’s Syndrome (SjS), a chronic autoimmune disease affecting the salivary and lacrimal glands. Here we explored the ability of LIPS to diagnose SjS based on IgG autoantibodies in patient saliva. From LIPS testing, anti-Ro60 autoantibodies were detected in the saliva of 70% (19/27) of SjS patients with 96% specificity. Positive anti-Ro60 autoantibodies were also found in 70% of the matched serum samples (96% specificity). LIPS detected Ro52 autoantibodies in the saliva and serum of 67% of SjS patients with 100% specificity. Overall, the autoantibody titers in saliva were approximately 4000-fold lower by volume than serum, but still distinguished seropositive patients from controls. These results suggest that LIPS salivary-based testing for SjS autoantibodies is a practical alternative to serum and compatible with point-of-care testing.

Quantitative proteomics of parotid saliva in primary Sjögren's syndrome

The diagnosis of primary Sjögrens syndrome (pSS) is difficult due to the lack of specific laboratory and clinical tests. As an initial step for the global discovery of changes in the abundance of parotid salivary proteins in pSS, a pooled sample was compared to that from healthy control subjects by multidimensional protein identification technology (MudPIT). A total of 1246 proteins were identified by MudPIT. The abundance of 477 of these proteins did not change, 529 were only detected in either the pSS or HC sample, while 206 of these proteins were significantly upregulated ≥ twofold and 34 were downregulated ≤ 0.5. Ingenuity Pathway Analyses of differentially expressed proteins identified by MudPIT resulted in the identification of 100 significant pathways. The same samples were quantified in parallel using RP MS. Fifty‐eight of 71 proteins identified by RP overlapped with MudPIT results. Five proteins were further analyzed by targeted label‐free quantification to confirm the similar relative differential expression observed by RP and MudPIT approaches. The present study supports the use of MS for global discovery and validation of marker proteins for improved and early diagnosis of pSS.

Primary Sjögren's syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells.

The significance of distinct B cell abnormalities in primary Sjögrens syndrome (SS) remains to be established. We undertook this study to analyze the phenotype and messenger RNA (mRNA) transcript profiles of B cell subsets in patients with primary SS and to compare them with those in sicca syndrome patients and healthy controls.

B cell depletion in lupus and Sjögren's syndrome: an update.

PURPOSE OF REVIEW The critical role of B cells in the pathogenesis of systemic lupus erythematosus and Sjogrens syndrome has provided a strong rationale to specifically target B cells. This review summarizes recent advances in the field of B cell depletion in systemic lupus erythematosus and Sjögrens syndrome. RECENT FINDINGS Reports of successful B cell depletion therapy in refractory SLE have continued to surface over the last year. The accumulation of positive results therefore stands in stark contrast to the recent reports that two phase III randomized placebo controlled trials employing B cell depletion with rituximab in nonlupus and lupus nephritis (Explorer and Lunar, respectively) did not achieve. Multiple reasons, including trial design, limitations of outcome instruments and sort follow-up have been invoked to explain these disconcerting results. In the representative studies addressing B cell depletion in lupus in the last year, complete and partial remission in lupus nephritis has been achieved in 60-89% of cases. Improvements in the British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were associated with decrease in anti-dsDNA and increase in complement levels. B cell depletion seemed quite efficacious also in pediatric SLE. While more definitive studies are still lacking for primary Sjogrens syndrome, incidental reports indicating potential efficacy have also been recently published. SUMMARY Despite the disappointing results of Explorer and Lunar trials, other evidence continues to be published in support of the notion that B cell depletion could be useful for patients with refractory disease, including lupus nephritis, and antibody-mediated cytopenias, possibly in combination with other immunosuppressant medication.

Targeted biologic approaches to the treatment of systemic vasculitis.

The introduction of biological agents in the treatment of systemic vasculitis offers the promise of targeted therapy with greater efficacy and fewer side effects than conventional treatments. In this paper, we review the rationale for biological strategies in vasculitis and discuss the results of clinical studies to date. The biotherapies discussed include immune-cell-depleting agents, both B- and T-cell targeted; costimulatory blockade; and cytokine blockade. Although most of these agents remain unproven until ongoing randomized clinical trials are complete, their introduction heralds a new era of vasculitis treatment and has provided novel insights into disease pathogenesis.

Two negative randomized controlled trials in lupus: now what?

Recently, two large randomized controlled trials of distinct biologic therapies in systemic lupus erythematosus, B-cell depletion with rituximab and co-stimulatory blockade with CTLA4Ig (abatacept), failed to meet primary endpoints. Given the great need for new treatments in lupus, these results were met with disappointment and have left the rheumatology and immunology community searching for an explanation. Are these experimental agents ineffective in lupus or are there trial design issues or other considerations? In this commentary, we discuss our perspective on these results within the context of current understanding of the pathophysiology of lupus and the mechanism of action of biologic therapies.