Clinical improvement in the nine patients treated with anti-CD20 during the follow-up times (3, 6, 12, 18, 24 and 36 months). well tolerated and SSc individuals experienced an improvement of the skin score and of medical symptoms. The obvious fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the end result after B cell depletion. Trial sign up ISRCTN77554566. Introduction Even though pathogenesis of systemic sclerosis (SSc) remains unknown, the B cell abnormalities characterized by autoantibody production , hyper–globulinemia and polyclonal B cell hyperactivity  are thought to play an important part in the disease. It has been previously explained that SSc individuals possess unique abnormalities of blood homeostasis and B cell compartments, characterized by expanded na?ve cells and activated, but diminished, memory space B cells . Furthermore, the manifestation of CD19, a critical transmission transduction molecule of B cells that regulates autoantibody production, is definitely significantly improved in memory space and na?ve B Rabbit polyclonal to PPP5C cells in SSc individuals [3,4]. Analysis of DNA microarrays of cutaneous Cefotaxime sodium biopsies from diffuse SSc (dSSc) individuals demonstrated a higher manifestation of clusters of genes of CD20-positive cells . In the tight-skin mice, a genetic model of human being SSc, the CD19 signaling pathway appeared to be constitutively triggered Cefotaxime sodium [6, 7] and the loss of CD19 manifestation significantly up-regulated surface IgM manifestation, completely abrogated hyper–globulinemia and autoantibody production, and also inhibited IL-6 production . Additionally, with this animal model, the down-regulation of B cell function led to a decrease in pores and skin fibrosis during the disease onset . Likewise, inside a bleomycin-induced SSc mouse model, another animal model that shares many characteristics with human being SSc, CD19 deficiency inhibited the development of pores and skin and lung fibrosis, hyper–globulinemia, and autoantibody production . Therefore, B cells could have a relevant impact on Cefotaxime sodium the development of fibrotic changes as reported in the mouse scleroderma models [6-9] and also in CCl4-induced liver injury, in an antibody- and T cell-independent manner . In several studies focusing on the pathogenesis of SSc, the improved levels of IL-6 in the skin, serum, and bronchoalveolar lavage fluid of SSc individuals suggest a role of this cytokine in promoting fibrosis by enhancing swelling [11-13]. Furthermore, immunohistochemistry data shown an over-expression of IL-6 on Cefotaxime sodium endothelium and fibroblasts of involved pores and skin of scleroderma individuals compared with normal pores and skin . SSc dermal fibroblasts constitutively create about a four-fold increase in IL-6 levels with respect to healthy settings fibroblasts  and secretion of IL-6 from lung fibroblast is definitely induced by SSc lung-derived B cells . Recently, it has been reported that B-cell activating element (BAFF), an essential component of B cell homeostasis and a potent B-cell survival element associated with autoimmune disease in humans, is improved in SSc individuals compared with healthy settings . In the tight-skin mice, BAFF antagonist augmented anti-fibrogenic cytokines and inhibited the development of pores and skin fibrosis. Finally, after BAFF activation, B-cells experienced a significantly enhanced ability to create IL-6 . Two recent open-label studies reported the security of anti-CD20 treatment in SSc individuals; despite both studies describing a decrease in myofibroblast score on serial pores and skin biopsies after treatment, only one reported an improvement in pores and skin score [19,20]. In these two studies, lung function remained stable during follow up, whereas a case report suggested a possible beneficial part of rituximab on lung involvement in scleroderma disease . The primary aim of the current prospective study was to evaluate the changes in the skin score from baseline to at least 6 up to 36 months of follow up after anti-CD20 therapy. Secondary aims were to assess the potential effectiveness of rituximab on lung function, to investigate the changes in IL-6 and BAFF serum levels as biological guidelines of disease activity, and to correlate the medical characteristics with the immune cell infiltrate recognized by immunohistochemistry. Materials and methods Individuals and treatment Nine individuals with progressive cutaneous SSc involvement, who showed a worsening of pores and skin score higher than 10% after the standard cyclophosphamide therapy  (up to 6 g), were treated with rituximab, two.