Treatment Of Systemic Sclerosis Research Articles

The Use of Biological Feedback in Complex Treatment of Patients with Rheumatoid Arthritis and Systemic Sclerosis

There are significant emotional problems in patients with systemic sclerosis (SS) and rheumatoid arthritis (RA), including most expressed symptoms of anxiety and depression that complicate the process of social and psychological adaptation of patients, reduce the level of subjective control as an attribute of personal responsibility for controlling their disease. The effectiveness of the biofeedback (BFB) training inthe treatment of patients with rheumatoid arthritis and systemic sclerosis is analyzed. Analysis of the effectiveness of treatment was conducted by studying the dynamics of a number of psychological indices (the level of subjective control, reactive and personal anxiety, depression) and their comparison in patients of the main and control groups before and after the treatment. Correction of the psycho-emotional state of patients with SS and RA was carried out using biofeedback (BFB), based on the principle of self-regulation of body functions using external feedback systems. There was a significant reduction in anxiety and depressive reactions in patients, during the process of BFB therapy, accompanied by a significant decrease of scoresby Spielberger–Khanin and Beck psychological tests, noted a significant effect of increasing the level of subjective control that can improve the effectiveness of therapy and long-term disease prognosis. Thus, the additional application of BFB training in complex treatment of SS and RA patients promoted the improvement of the efficiency of the treatment and rehabilitation carried out and the improvement of the patients’ quality of life.
 Keywords: BFB training, systemic sclerosis, rheumatoid arthritis, rheumatic diseases, reactive anxiety, personality anxiety, depression, level of subjective control

Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis.

Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous “damage-associated” ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases.

Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts

Tyrosine kinase inhibitors have emerged as a therapeutic option for rheumatic diseases such as systemic sclerosis (SSc). Because tyrosine kinases like c-Abl kinase are important for fibroblast activation and fibrosis development in SSc, the c-Abl inhibitor imatinib was proposed for SSc treatment. Transporters for organic cations have become increasingly recognized as an important determinant for uptake and efficacy of tyrosine kinase inhibitors. Therefore, we investigated the role of organic cation transporters in the uptake of imatinib. Moreover, the influence of important SSc pathogenetic factors, like PDGF and Notch pathway activation on these uptake processes, has been studied. We showed that organic cation transporters OCT1-3, novel organic cation transporters OCTN1/2, and the multidrug and toxin extrusion protein MATE1 are expressed in healthy dermal and SSc fibroblasts. Decreased expression levels of MATE1 and decreased imatinib uptake were measured in SSc fibroblasts. In small interfering RNA experiments, MATE1 was identified as key transporter for imatinib uptake and biological effect in dermal fibroblasts. Furthermore, PDGF reduced imatinib uptake by decreasing MATE1 expression in SSc fibroblasts, but not in healthy fibroblasts. Blocking the Notch pathway in SSc fibroblasts increased MATE1 transporter expression and imatinib uptake. In conclusion, MATE1-mediated transport governs therapeutic efficacy of imatinib in SSc.

An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Use of tocilizumab in systemic sclerosis: A brief literature review

The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomized clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS.

Utilización de tocilizumab en la esclerosis sistémica: breve revisión de la literatura

The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomised clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS.

All-Trans Retinoic Acid Induces CD4+CD25+FOXP3+ Regulatory T Cells by Increasing FOXP3 Demethylation in Systemic Sclerosis CD4+ T Cells.

Background Retinoic acid (RA) is an active metabolite of vitamin A and has been reported to improve the clinical symptoms of patients with systemic sclerosis (SSc). However, the mechanism of RA in the prevention of SSc remains unclear. Regulatory T cells (Tregs) are a subpopulation of T cells with immunosuppressive activity. The quantitative and functional defects of Tregs may mediate the immune dysfunction in SSc. The addition of all-trans retinoic acid (ATRA) to human naïve CD4+ cells could promote the maturation of Tregs and increase the stable expression of Foxp3. In this study, we explored the role of RA on Tregs in SSc CD4+ T cells and its possible epigenetic mechanisms, so as to further understand the mechanisms of RA on SSc. Methods CD4+ T cells were isolated from peripheral blood of SSc and treated with or without ATRA and/or transforming growth factor-β (TGF-β). The percentage of CD4+CD25+FOXP3+ Tregs was counted by flow cytometry. FOXP3 mRNA and protein levels were measured by quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. Bisulfite sequencing was performed to determine the methylation status of the FOXP3 proximal promoter sequences. Results The expression of Tregs and FOXP3 in CD4+ T cells from patients with SSc increased in response to ATRA. Moreover, combined stimulation with ATRA and TGF-β resulted in the enhancement of these effects. Further studies revealed that stimulation with ATRA increased the expression of FOXP3 in SSc CD4+ T cells by downregulating FOXP3 promoter methylation levels. Conclusions ATRA acts as an inducer of Treg response in SSc CD4+ T cells via demethylation of the FOXP3 promoter and activation of FOXP3 expression. This may be one of the molecular mechanisms for ATRA, and therefore, RA can be used for the treatment of SSc.

Intravenous immunoglobulins prevents experimental fibrosis in a murine model of systemic sclerosis

Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by an extensive multi-organs fibrosis. Immunosuppressants are effective in some extent but their incomplete efficacy is hampered by a higher infection risk. Intravenous immunoglobulins (IVIG) have a good safety profile, exhibit immunomodulatory and antifibrotic properties and hence could be a relevant treatment for SSc. The purpose of this study was to investigate the effects of IVIG in an experimental model of SSc. Materiels et methodes SSc was induced in 6 weeks old Balb/c mice by subcutaneous injections of HOCl five days a week during six weeks (n = 20), whereas control mice received subcutaneous injections of PBS (n = 20). Human IVIG was administrated intravenously by single retro-orbital injection at a dose of 2 g/kg the first day of HOCl administration (n = 20). A control group received an injection of 2% maltose (n = 20). Skin thickness was assessed during the protocol until the sacrifice (day 42). Skin tissues were collected in 4% PFA and processed for histological analysis. Dermal thickness was measured by performing a May-Grunwald–Giemsa staining of 4 μm skin sections; collagen deposition was assessed by performing a Picrosirius red-staining and quantified by using a color deconvolution method. In addition, immunostaining of skin sections was performed in order to evaluate the α-smooth muscle actin (α-SMA) expression. Frozen skin tissues were analyzed to also assess the mRNA expression of main inflammatory and pro-fibrotic genes (by quantitative reverse transcription polymerase chain reaction). Collagen deposition was also evaluated by measuring the content of hydroxyproline in 10 mg of frozen tissue. Resultats Mice exposed to HOCl developed a diffuse cutaneous SSc with higher dermal thickness compared to the PBS group. IVIG significantly reduced dermal thickness and collagen deposition in HOCl-receiving mice. The amount of α-SMA positive cells evaluated by immunofluorescence was reduced in the HOCl treated mice receiving IVIG. The mRNA expression profile of various markers of fibrosis (fibronectin, TGFβ) or inflammation (TNFα, IL-1β, IL-6) were also significantly decreased in the skin of HOCl mice treated with IVIG compared to HOCl-treated mice receiving 2% maltose. Conclusion These results demonstrate the efficacy of IVIG in preventing experimental fibrosis in a HOCl murine model of SSc.

Humanistic and cost burden of systemic sclerosis: A review of the literature.

Systemic sclerosis (SSc), or systemic scleroderma, is a chronic multisystem autoimmune disease characterised by widespread vascular injury and progressive fibrosis of the skin and internal organs. Patients with SSc have decreased survival, with pulmonary involvement as the main cause of death. Current treatments for SSc manage a range of symptoms but not the cause of the disease. Our review describes the humanistic and cost burden of SSc. A structured review of the literature was conducted, using predefined search strategies to search PubMed, Embase, and the Cochrane Library. Grey literature searches also were conducted. In total, 2226 articles were identified in the databases and 52 were included; an additional 10 sources were included from the grey literature. The review identified six studies reporting relevant cost estimates conducted in five different countries and four studies that assessed the humanistic burden of SSc. Total direct annual medical costs per patient for Europe varied from €3544 to €8452. For Canada, these costs were reported to be from Can$5038 to Can$10,673. In the United States, the total direct health care costs were reported to be US$17,365 to US$18,396. Different key drivers of direct costs were reported, including hospitalisations, outpatients, and medication. The total annual costs per patient were reported at Can$18,453 in Canada and varied from €11,074 to €22,459 in Europe. Indirect costs represented the largest component of the total costs. EQ-5D utility scores were lower for patients with SSc than those observed in the general population, with reported mean values of 0.49 and 0.68, respectively. The average value of the Health Assessment Questionnaire for patients with SSc was significantly higher than the control population (0.94), and the average value of the SF-36 was significantly lower than the control population: 49.99 for the physical dimension and 58.42 for the mental dimension. Overall, there is a paucity of information on the burden of SSc. Nonetheless, our review indicates that the quality of life of patients with SSc is considerably lower than that of the general population. In addition, SSc places a considerable economic burden on health care systems and society as a whole.

Corticosteroid inhibits chemokines production in systemic sclerosis patients

In this study, we evaluated glucocorticoids (GC) effects on cytokine/chemokine levels in serum samples and peripheral blood mononuclear cell (PBMC) production from systemic sclerosis (SSc) patients. We evaluated cytokine and chemokine levels in serum samples from SSc patients taking or not taking systemic glucocorticoids. PBMCs response to methylprednisolone (MP) was examined from 15 SSc patients and 8 healthy control subjects following PBMC stimulation with anti-CD3/CD28. Cytokine (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17A) and chemokine (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in serum and in PBMC culture supernatants by CBA or ELISA. Compared with patients not taking corticosteroids, we did not observe any significant differences in cytokines/chemokines serum levels in patients using systemic corticosteroids. After stimulation with anti-CD3/CD28, PBMCs treated with MP (100μM), showed a significant reduction of CCL2/MCP-1 (p=0.001), CCL5/RANTES (p=0.04), and CXCL8/IL-8 (p=0.003) levels in SSc patients. In PBMC from healthy controls, we observed decreased IFN-γ, TNF, IL-2, and IL-10 levels after MP treatment, compared with stimulated condition (p<0.01 for all). However in SSc patients, we did not find any significant reduction in these cytokine levels after MP treatment. In conclusion, CCL2/MCP-1, CCL5/RANTES, and CXCL8/IL-8 are chemokines that are potentially modulated by corticosteroids in vitro in SSc patients, but no effect was observed on IL-2, IL-4, IL-6, IL-10, IL-17A, TFN, and IFN-γ secretion. These results suggest a potential effect of GCs on SSc treatment and may reflect the benefit of their use in some patients.

Pathogenesis of systemic sclerosis-current concept and emerging treatments.

Systemic sclerosis (SSc) is an intractable multifaceted disease with high mortality. Although its pathogenesis is not fully understood, recent studies have advanced our knowledge on SSc. The cardinal pathological features of SSc are autoimmunity, vasculopathy, and fibrosis. The B cells in SSc are constitutively activated and lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. In addition to these autoantibodies, which are valuable for diagnostic criteria or biomarkers, many other autoantibodies targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, are known to be functional and induce activation or apoptosis of endothelial cells. The autoantibody-mediated endothelial cell perturbation facilitates inflammatory cell infiltration, cytokine production, and myofibroblastic transformation of fibroblasts and endothelial cells. Profibrotic cytokines, such as transforming growth factor β, connective tissue growth factor, interleukin 4/interleukin 13, and interleukin 6, play a pivotal role in collagen production from myofibroblasts. Specific treatments targeting these causative molecules may improve the clinical outcomes of patients with SSc. In this review, we summarize recent topics on the pathogenesis (autoantibodies, vasculopathy, and fibrosis), animal models, and emerging treatments for SSc.

Photopheresis: Advances and Use in Systemic Sclerosis.

Extracorporeal photochemotherapy (photopheresis, ECP) is a cell-based immunomodulatory treatment that separates leukocytes from peripheral blood, exposes them to a photosensitizing agent followed by ultraviolet A light, and then reinfuses them back into the patient. ECP has been found to be effective for graft versus host disease, transplant rejection, and various autoimmune diseases. The mechanism is not well understood but studies have shown clinical benefit in the treatment of systemic sclerosis (SSc). This review examines the ECP technique, advances in our knowledge of its mechanism, and the data supporting its use in SSc-like fibrosing diseases and in SSc itself. Multiple lines of evidence support ECP use in SSc. ECP generates apoptotic cells and dendritic cells, induces production of anti-inflammatory cytokines, and increases regulatory T cell numbers. Clinical studies have generally demonstrated improvement, especially the skin, in SSc patients receiving ECP. ECP may be an effective and safe procedure for the treatment of SSc.

Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis.

Systemic sclerosis (SSc), an autoimmune disease, may cause significant osteopenia due to activation of the IL4Rα/mTOR pathway. Mesenchymal stem cell transplantation (MSCT) can ameliorate immune disorders in SSc via inducing immune tolerance. However, it is unknown whether MSCT rescues osteopenia phenotype in SSc. Here we show that MSCT can effectively ameliorate osteopenia in SSc mice by rescuing impaired lineage differentiation of the recipient bone marrow MSCs. Mechanistically, we show that donor MSCs transfer miR-151-5p to the recipient bone marrow MSCs in SSc mice to inhibit IL4Rα expression, thus downregulating mTOR pathway activation to enhance osteogenic differentiation and reduce adipogenic differentiation. Moreover, systemic delivery of miR-151-5p is capable of rescuing osteopenia, impaired bone marrow MSCs, tight skin, and immune disorders in SSc mice, suggesting that miR-151-5p may be a specific target for SSc treatment. Our finding identifies a previously unrecognized role of MSCT in transferring miRNAs to recipient stem cells to ameliorate osteopenia via rescuing a non-coding RNA pathway.

Tocilizumab Treatment of Patients with Systemic Sclerosis: Clinical Data

Systemic sclerosis (SSc) is an immune-mediated disease characterized by progressive, and often severe, inflammation and fibrosis of the skin and internal organs, such as the lungs, heart, kidneys, and gastrointestinal tract. There is an unmet medical need to treat patients with SSc given the high SSc-related mortality rate. Furthermore, disease-modifying therapies are lacking, and current treatment options focus on the management of individual organ-specific complications associated with the disease. Immunosuppressive therapies are the mainstay of pharmacologic management of major SSc-associated complications, such as skin and lung manifestations, but their overall effectiveness is limited and toxicity issues are common. Advances in understanding of the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led to clinical research focusing on targeted immunotherapies, in an effort to develop much needed disease-modifying treatment options. The interleukin-6 receptor-alpha antagonist tocilizumab has demonstrated promising efficacy in a phase 2 trial and is being investigated in a phase 3 trial. This article provides an overview of current pharmacologic treatment options for the management of SSc-related complications and discusses tocilizumab for the treatment of SSc in clinical trials.

Adipose-Derived Cell Transplantation in Systemic Sclerosis: State of the Art and Future Perspectives

Systemic sclerosis (SSc) is one of the most complex connective tissue diseases. Although significant progress in the knowledge of pathogenic mechanisms and timely diagnosis, therapeutic options remain limited. The attempt to find new treatments for SSc has led researchers to investigate the potential of cellular therapies using autologous and allogeneic stem cells. Multipotent mesenchymal stromal cells (MSCs) are considered an attractive candidate for cell-based therapies. MSCs comprise a heterogeneous population of cells with multilineage differentiation potential that are preferentially able to home to the sites of damage, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. MSCs from bone-marrow have been first extensively characterized. Adipose tissue represents an additional abundant and accessible source of stem cells. Compared with BM-MSCs, adipose-derived stromal/stem cells (ASCs) offer several advantages, including ease of isolation, less donor morbidity, relative abundance, and rapidity of expansion. For all these reasons, at present ASCs are one of the most attractive and promising sources of adult stem cells for cell therapy, finding a field of application in the treatment of SSc, too. This review will focus on the current applications and possible future perspectives of adipose tissue-cell therapies in SSc.

Update of EULAR recommendations for the treatment of systemic sclerosis

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous...

Tenascin-C drives persistence of organ fibrosis.

The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc.

Cellular Therapies in Systemic Sclerosis: Recent Progress

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with a high mortality and morbidity. While progress has been made in terms of identifying high-risk patients and implementing new treatment strategies, therapeutic options remain limited. In the past few decades, various cellular therapies have emerged, which have been studied in SSc and other conditions. Here, we provide a comprehensive review of currently available cellular therapies and critically assess their merit as disease-modifying treatment for SSc. Currently, hematopoietic stem cell transplantation is the only cellular therapy that has demonstrated clinical effects on the immune system, neoangiogenesis, and fibrosis. Robust mechanistic studies as well as clinical trials are essential to move the field forward.

RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis

ABSTRACTBackground: Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. Methods: Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg−1·day−1) by oral gavage. Results: HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. Conclusions: Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.

B cell abnormalities and therapeutic strategies in systemic sclerosis.

One of the major roles of B cells is to generate antibodies to specific antigens. Secreted antibodies are the principal molecules involved in humoral immunity, with the capacity not only to neutralize pathogens, but also to enhance their elimination by activating phagocytosis or complement proteins. Recently, it has been highlighted that B cells exert important regulatory roles independent of their antibody producing function. These roles include efficiently presenting antigens to the T cells, secreting cytokines, and inducing immune cell differentiation. Thus, B cells have emerged as cells that play crucial roles in immune systems in addition to producing antibodies. Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis of several organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients display a variety of abnormal immune activation including the production of disease-specific autoantibodies. Previous studies have demonstrated that immune cells, mainly including B cells, play a critical role in systemic autoimmunity and disease expression, though the role of autoimmunity in generating the clinical and pathologic phenotype in SSc remains uncertain. SSc patients have B cell abnormalities characterized by chronic hyper-reactivity of memory B cells. Although distinct subsets of autoantibodies do not have a proven pathogenic role, they are selectively associated with unique disease manifestations. To date, the treatment of SSc has largely relied on cytotoxic immunosuppressants and corticosteroids. Although this has resulted in improved disease survival, these patients may still suffer severe adverse events and refractory disease to conventional immunosuppressive therapies. Recently, clinical trials involving the chimeric monoclonal antibody rituximab have raised high expectations. B cell depleting therapy with rituximab offers a promising treatment for the rheumatic autoimmune diseases including SSc. This article reviews the current knowledge of B cell biology and pathogenesis in SSc as well as the therapeutic approaches focusing on the targeting of B cell specific surface molecules and on the blocking of B cell activation and survival.