Therefore, dermal fibroblasts may be constitutively activated by autocrine TGF- in SSc lesional skin. in tocilizumab (an anti-IL-6 receptor antibody), rituximab (an anti-CD20 antibody), and fresolimumab (an anti-TGF- antibody). The analysis of gene expression profiles in skin lesions of SSc patients treated with tocilizumab or fresolimumab revealed a critical role of monocyte-macrophage lineage cells in the development of skin fibrosis and the involvement of IL-6 and TGF- in the activation of those cells. Considering that B cells modulate the differentiation and activation of macrophages, favorable clinical outcomes of rituximab treatment imply the central role of B cell/monocyte-macrophage lineage cell axis in the pathogenesis of SSc. This scenario may be relevant at least partly to other skin fibrotic conditions. In this review article, the currently available data on these drugs are summarized and the future directions are discussed. transgenic mice exhibit hypergammaglobulinemia and autoantibody production due to the abnormal activation of B O6BTG-octylglucoside cells [23]. Tight-skin mice show O6BTG-octylglucoside hypodermal fibrosis, hypergammaglobulinemia, and positivity of anti-nuclear antibody and anti-topoisomerase I antibody, but both O6BTG-octylglucoside CD19 loss and B cell depletion by anti-CD20 antibody result in the reduction of these abnormalities [24, 25]. Supporting these findings, it is generally O6BTG-octylglucoside accepted that in addition to antibody production, B cells play multifaceted functions in immune system, such as cytokine production, antigen presentation, macrophage differentiation and activation, and lymphoid tissue development [26]. Consistently, B cell depletion therapy broadly affects disease processes of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, antinuetrophil cytoplasmic antibody-associated vasculitis, dermatomyositis/polymyositis, and main Sj?grens syndrome as well as SSc [27]. The effect of rituximab on SSc In the first pilot study by Lafyatis et al. [28], 15 dcSSc patients with disease duration of <18?months were administered rituximab (1000?mg, twice, 2?weeks apart). In skin biopsy samples, the decrease in the number of myofibroblasts and skin-infiltrating B cells was obvious at week 24 despite no significant switch of altered Rodnan total skin thickness score (mRSS). In another pilot study reported by Smith et al. [29], 8 cases of dcSSc with disease duration of <4?years were administered rituximab (1000?mg, twice, 2?weeks apart) together with 100?mg methylprednisolone at each infusion. mRSS was significantly improved at week 24 compared with the baseline. Skin biopsy specimens taken at week 12 revealed the decrease in collage deposition and the number of myofibroblasts and skin-infiltrating B cells compared with those taken at the baseline. As a common obtaining in these two studies, no significant effect was detected on pulmonary function test results. On the other hand, Daoussis et al. [30] performed a randomized controlled study of rituximab on 14 dcSSc patients, in which 8 patients were treated with two cycles of rituximab at baseline and week 24 (each cycle consisted of 4 weekly infusions (375?mg/m2)) and 6 patients received standard treatment alone. A 12 months after the initiation of treatment, a significant reduction of mRSS was seen in the rituximab group, while not in the control group. More importantly, both of %FVC (forced vital capacity) and %DLco (diffusion capacity of the lungs for carbon monoxide) were significantly improved in the rituximab group, while no significant changes were seen in the control group. Comparable favorable efficacy was reported in a nested case-control study using the European Scleroderma Trial and Research (EUSTAR) database [31]. In 63 SSc patients treated with rituximab, mRSS was significantly improved compared with closely matched control individual group. As well, O6BTG-octylglucoside %FVC was stabilized in the rituximab group, while not in the placebo group. Comparable clinical effects of rituximab were recently reported by Daoussis et al. [32] in 51 SSc patients with interstitial lung disease (ILD). These three Igfbp2 studies documented a potential disease-modifying effect of rituximab on skin fibrosis and ILD of SSc. There is another.