Thomas Dörner

Disturbed Peripheral B Lymphocyte Homeostasis in Systemic Lupus Erythematosus

In patients with active systemic lupus erythematosus (SLE), a marked B lymphocytopenia was identified that affected CD19+/CD27− naive B cells more than CD19+/CD27+ memory B cells, leading to a relative predominance of CD27-expressing peripheral B cells. CD27high/CD38+/CD19dim/surface Iglow/CD20−/CD138+ plasma cells were found at high frequencies in active but not inactive SLE patients. Upon immunosuppressive therapy, CD27high plasma cells and naive CD27− B cells were markedly decreased in the peripheral blood. Mutational analysis of V gene rearrangements of individual B cells confirmed that CD27+ B cells coexpressing IgD were memory B cells preferentially using VH3 family members with multiple somatic mutations. CD27high plasma cells showed a similar degree of somatic hypermutation, but preferentially employed VH4 family members. These results indicate that there are profound abnormalities in the various B cell compartments in SLE that respond differently to immunosuppressive therapy.

Rheumatoid factor revisited.

Purpose of reviewInitial studies of the pathogenesis of rheumatoid arthritis focused on the role of rheumatoid factor and immune complex–associated vasculitis and synovitis. Subsequent work has delineated T cell responses, the role of cytokines, chemokines, and the aggressive nature of rheumatoid synovitis. Recent findings underscore the importance of humoral immunity in this entity and are the subject of this review. Recent findingsBy the discovery of anti–cyclic citrullinated peptide, anti-RA33, and anti-GPI antibodies in the human and mouse systems, respectively, the impact of humoral autoimmunity in rheumatoid arthritis regained remarkable interest. This review summarizes recent insights into humoral autoimmunity in rheumatoid arthritis in the context of the generation of rheumatoid factors, including B cell activation via toll-like receptors and genetic predispositions that can trigger the induction of rheumatoid arthritis. The generation of rheumatoid factors that can also be found during host defense against infectious agents and under pathologic conditions, such as rheumatoid arthritis, Sjögren syndrome, and hepatitis C–associated mixed cryoglobulinemia after hepatitis C infection is likely the result of genetic predispositions and the intensity of the (primary) immune reaction. Models of the role of rheumatoid factors in health and disease, including related lymphomagenesis, will be discussed. SummaryIn patients with rheumatoid arthritis, the induction of rheumatoid factors can be taken as an indicator of severe disease with a striking involvement of B cell activation. Very recent clinical trials using B cell depletion support the concept that humoral immunity, as evidenced by the production of rheumatoid factors, plays a significant role in the course of the disease.

Prevalence of self-reported neuropathic pain and impact on quality of life: a prospective representative survey

Background: Data on the incidence of neuropathic pain (NeP) in Austria, its general characteristics and consequences for the quality of life (QOL) are still lacking. The prevalence in the United Kingdom is 8%.

The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets.

Our understanding of the role of B cells as part of the immune system has been remarkably expanded in the past few years. Autoimmunity, the production of autoantibodies or the activation and expansion of autoimmune T cells, is relatively common, whereas the development of autoimmune diseases with destruction of tissue is much less frequent. In rheumatoid arthritis, the autoantigen(s) involved in tissue damage and their role in disease have not been fully elucidated. Recent data suggest that the impact of B cells in rheumatoid arthritis may be of significance; therefore, a depleting anti-B cell therapy appears to be another therapeutic strategy. This review will focus on recent findings of the role of B cells in rheumatoid arthritis and the implications to target B cells in this disease.

Emerging cell and cytokine targets in rheumatoid arthritis

Despite major progress in the treatment of rheumatoid arthritis (RA), strong unmet medical need remains, as only a minor proportion of patients reach sustained clinical remission. New approaches are therefore necessary, and include manipulation of regulatory T cells, which might be able to restore the disturbed immune system and could even lead to a cure if this restored regulation were to prove sustainable. Logistical and conceptual problems, however, beset this attractive therapeutic approach, including difficulties with ex vivo expansion of cells, specificity of targeting and the optimal time point of administration. Therefore, alternative avenues are being investigated, such as targeting B-cell effector functions and newly identified proinflammatory cytokines. On the basis of success with B-cell depleting therapy using anti-CD20 agents, further treatment modalities are now exploring direct or indirect interference in B-cell-mediated immunity with the use of agents directed against other B-cell surface molecules. Novel approaches target intracellular B-cell signalling and regulatory B cells. New cytokine-directed therapies target important proinflammatory mediators such as GM-CSF, new members of the IL-1 family, IL-6 and its receptor, IL-17, IL-20, IL-21, IL-23 as well as synovium-specific targets. This article reviews these emerging cell and cytokine targets with special focus on biologic agents, some of which might reach the clinic soon whereas others will require considerable time in development. Nevertheless, these exciting new approaches will considerably enhance our repertoire in the battle against this potentially devastating disease.

Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls

Objective: B lymphocytes have been implicated in the pathogenesis of lupus and other autoimmune diseases, resulting in the introduction of B cell-directed therapies. Epratuzumab, a humanised anti-CD22 monoclonal antibody, is currently in clinical trials, although its effects on patients’ B cells are not completely understood. Methods: This study analysed the in vivo effect of epratuzumab on peripheral B cell subsets in 12 patients with systemic lupus erythematosus, and also addressed the in vitro effects of the drug by analysing anti-immunoglobulin-induced proliferation of isolated B cells obtained from the peripheral blood of 11 additional patients with lupus and seven normal subjects. Results: Upon treatment, a pronounced reduction of CD27– B cells and CD22 surface expression on CD27– B cells was observed, suggesting that these cells, which mainly comprise naïve and transitional B cells, are preferentially targeted by epratuzumab in vivo. The results of in vitro studies indicate additional regulatory effects of the drug by reducing the enhanced activation and proliferation of anti-immunoglobulin-stimulated lupus B cells after co-incubation with CD40L or CpG. Epratuzumab inhibited the proliferation of B cells from patients with systemic lupus erythematosus but not normal B cells under all culture conditions. Conclusions: Epratuzumab preferentially modulates the exaggerated activation and proliferation of B cells from patients with lupus in contrast to normal subjects, thus suggesting that epratuzumab might offer a new therapeutic option for patients with systemic lupus erythematosus, as enhanced B cell activation is a hallmark of this disease.

Immunopathogenesis of primary Sjögren's syndrome: implications for disease management and therapy.

Purpose of reviewRecent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögrens syndrome. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as their implications for clinical handling and therapeutic options. Recent findingsIt becomes increasingly apparent that certain disturbances of the immune system (i.e. B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator) play a central role in this entity. Whether this is a primary abnormality or the result of predisposing factors or infectious, e.g. viral, agents remains uncertain. New insights into the pathogenesis also provide candidates for better diagnosis and classification of disease severity, such as flow cytometric analysis, measurement of soluble cell surface molecules, autoantibodies, cytokines, and ligands (B-cell-activating factor/B-lymphocyte stimulator). Whether B-cell-directed therapies (i.e. blocking B-cell-activating factor/B-lymphocyte stimulator, anti-CD20 therapy) will have an impact on primary Sjögrens syndrome needs to be shown in clinical trials. Alternative therapeutic approaches such as organ-targeted gene transfer are in development but must be carefully evaluated for safety and efficacy in preclinical models that resemble human primary Sjögrens syndrome. SummaryThe pathogenesis of primary Sjögrens syndrome is complex and the factors initiating and driving autoimmunity in this entity are largely unknown. Recent studies provide new insights into potential pathogenetic mechanisms of the disease and, thereby, the chance for improved strategies in disease management and therapy.

New approaches of B-cell-directed therapy: beyond rituximab.

Purpose of reviewThis study reviews therapeutic approaches of direct and indirect B-cell targeting in autoimmune diseases and their impact on protective immunity. Recent findingsBeyond recent clinical experiences with rituximab as B-cell-depleting agent, other biologicals targeting CD20, such as ocrelizumab, ofatumumab, hA20, and TRU-015 mainly deplete B cells and are under clinical investigation in different entities. Moreover, anti-CD22 targeting as another approach that has been studied in clinical trials showed a modest depletion, but inhibition of B-cell activation. More indirect innovative B-cell-affecting therapies comprise blockade of cytokines, such as B-cell-activating factor (BAFF/BLyS), APRIL, and their receptors as well as blockade of costimulation. Although decreases of immunoglobulin levels were seen, so far no major increases in infections were reported. SummaryThe value of certain B-cell-depletion therapies as well as other therapies modulating B-cell functions needs to be further delineated, especially in the therapeutic regimen of rheumatoid arthritis, specific collagen vascular diseases and vasculitis. Long-term observations of protective immunity are also needed to further evaluate the rate of infections.

B-cell lymphoproliferation in chronic inflammatory rheumatic diseases

Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sjögrens syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.

New concepts in the pathogenesis of Sjögren syndrome: many questions, fewer answers.

Although a modified European–American consensus classification of Sjögren syndrome has been introduced during the last year, the etiopathogenesis of this disease characterized by chronic lymphocytic inflammation, impaired function, and, finally, destruction of the salivary and lacrimal glands as well as systemic manifestations remains to be elucidated. Recent insights into the pathogenesis of Sjögren syndrome resulting from immunogenetic, hormonal, and epidemiologic evaluations as well as animal and in vitro studies are highlighted by this review. Evidence confirms that lymphocytic disturbances, including ectopic germinal center formation and aberrations of cellular signaling play a significant role in Sjögren syndrome. Although some of these features are unique to Sjögren syndrome, others are also found in a number of systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. The underlying cause of Sjögren syndrome remains largely enigmatic. However, distinct characteristics may provide the basis for the classification of the disease entities. Finally, an enhanced risk of lymphomagenesis is a well-known hallmark of primary Sjögren syndrome, indicating the central role of derangement of lymphocyte regulation. As demonstrated by the introduction of the new targeted therapeutic approaches in rheumatoid arthritis, solid insights into the pathogenesis of Sjögren syndrome may pave the way toward new therapeutic approaches.