D. Daoussis

Targeting CD40L: a Promising Therapeutic Approach

The activation of lymphocytes is a central event of the adaptive immune response. Physiologically, this activation is carefully controlled. Productive stimulation of T cells is necessary for all T-cell-dependent immune responses and requires two distinct intracellular signals. The first signal is

SAT0222 B Cell Depletion Therapy in Systemic Sclerosis Associated Interstitial Lung Disease. A Multicenter, Open Label, Comparative Study with A Follow up of 94 Patient-Years

Background We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To assess long term efficacy and safety of RTX in SSc compared to standard treatment. Methods Fifty one patients with SSc associated interstitial lung disease were recruited and treated with RTX (n=33) or standard treatment (n=18). RTX cycles were repeated every 6 months throughout follow up apart from 6 patients where RTX was discontinued following 2 years of continuous treatment. Mean follow up was 2.9 years (range 1–7). Standard treatment consisted of azathioprine (n=2), methotrexate (n=6) and mycophenolate (n=10). Results Patients in the RTX group showed an increase in FVC during the first year of treatment (mean ± SEM of FVC: 80.60 ± 3.69 vs 83.02 ± 3.37 at baseline vs 1-year, respectively, p=0.13); this beneficial effect was further augmented at 2 years (86.90 ± 4.72, p=0.04 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow up. At 2 years, the RTX group was numerically better than the control group; however, differences tended but did not reach statistical significance (p=0.063). At the 7 year time point patients in the RTX group had higher FVC compared to baseline (mean ± SEM of FVC: 91.60 ± 6.62, p=0.15 compared to baseline) in contrast to patients in the control group where FVC deteriorated (p<0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group (p=0.013). DLCO also improved following 2 years of RTX treatment (mean ± SEM of DLCO: 59.22 ± 3.16 vs 61.51 ± 4.02 at baseline vs 2-years, respectively, p=0.05). In the standard treatment group DLCO constantly deteriorated throughout follow up. In 6 patients where RTX was stopped following 2 years of continuous treatment a decline in PFTs was evident. Improvement of skin thickening was found in both the RTX and the standard treatment group, however, direct comparison between groups strongly favored RTX at all time points (p=0.002, 0.015, 0.002, 0.053 0.029 for the 1, 2, 3, 4 and 5-year time point, respectively). In the RTX group, six cases of respiratory infection requiring hospitalization, one case of hepatitis B reactivation and one case of herpes zoster were recorded. Two patients were diagnosed with cancer (lung and prostate). Five deaths were recorded: end stage respiratory failure (n=2), lung cancer (n=1), sudden death (n=1), unknown (n=1). In the control group, five patients with respiratory and four patients with urinary infection were hospitalized. In four cases, infections were recurrent. Two deaths were reported due to respiratory infection. Conclusions Our data indicate that continuous treatment with RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Treatment was well-tolerated. Randomized controlled studies are highly needed. Disclosure of Interest None declared

SAT0450 Rituximab in Systemic Sclerosis. Results of an up to Seven Years, Open Label, Multicenter Study with a Follow-up of 89 Patient-Years

Background We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To assess long term data on efficacy and safety of RTX in SSc Methods Thirty patients with SSc were recruited from three rheumatology departments. Patients were treated at baseline, 6, 12 and 18 months. Beyond two years, retreatment with RTX was decided by the treating physician. Follow-up data exist for 30, 16, 13, 6 and 4 patients at 1, 2, 3, 5 and 7 year time points, respectively. Results Patients were predominantly female (n=22) with a median age of 56 and median disease duration of 4 years. Data from serology, concomitant treatment, skin involvement, PFTs, transthoracic echocardiogram, high resolution lung CT and undesirable effects were recorded. FVC showed significant improvement at 1 year compared to baseline (mean ± SEM: FVC: 83.5±3.4 vs 78.2±3.6 respectively, p<0.001), with a further significant improvement at 2 years (86.2±5.5 p=0.018) and a stabilization thereafter (84.3±6.5 at 5 years, p=0.04). DLco significantly improved at two years compared to baseline (62.4±4.5 vs 57.3±3.2 respectively, p=0.012). Three patients who had initially shown improvement or stabilization of their PFTs with continuous treatment, showed deterioration of PFTs after RTX cessation at three years; these patients did not respond to RTX retreatment later on. Skin thickening (MRSS) improved significantly early (p<0,001 at all time points compared to baseline). During the follow-up period, six cases of respiratory infection requiring hospitalization, one case of hepatitis B reactivation, one case of herpes zoster and two cases of mild infusion reactions were recorded. One patient was diagnosed with lung cancer and another one with prostate cancer. Five deaths were recorded. Two patients died because of end stage respiratory failure, one patient of lung cancer, one of sudden death while the cause of death in the fifth patient is unknown. Conclusions Our data indicate that continuous treatment with RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Treatment was generally well-tolerated. Randomized controlled studies are highly needed. Disclosure of Interest None declared

FRI0513 Decreased Skin Expression but Normal Circulating Levels and Function of Dickkopf-1 in Patients with Systemic Sclerosis

Background The critical question of what drives fibroblast activation in systemic sclerosis (SSc) remains unanswered. The Wnt pathway, a known regulator of osteoblastogenesis, has also emerged as a crucial mediator of the fibrotic process. It was recently reported that Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway, is absent from scleroderma skin1. No data exist on circulating levels and function of Dkk-1 in patients with SSc. Objectives To assess: i) circulating levels and function of Dkk-1 in patients with SSc and ii) skin expression of Dkk-1 in SSc and investigate potential correlations with clinical and demographic characteristics. Methods Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 healthy subjects, age and sex matched, using an established solid phase immunoassay. The functional integrity of Dkk-1 was assessed by a functional ELISA which measures only Dkk-1 bound to LRP6 receptor. Skin biopsies were obtained from 12 patients with SSc and 5 healthy subjects and Dkk-1 skin expression was assessed by immunohistochemistry Results Patients were predominantly female (84%) with a mean age (±SEM) of 57.3 (±2.1) years. Most had diffuse disease (64%) with a mean MRSS (±SEM) of 17.1 (±1.2) and a mean (±SEM) disease duration of 8 (±1.3) years. Circulating levels of Dkk-1 did not differ significantly in patients with SSc compared to healthy subjects (mean ±SEM: 1603±154 pg/ml vs 1889±95 pg/ml for patients with SSc and healthy subjects, respectively, p=0.1). We found no correlation of circulating Dkk-1 levels with age, gender, disease duration, disease type, MRSS, HAQ-DI, inflammatory markers and PFTs. Patients with SSc had similar functional Dkk-1 levels compared to healthy subjects (mean ± SEM: 257.8±89.5 pg/ml vs 325±74.9 pg/ml for patients with SSc and healthy subjects, respectively, p=ns). In all skin biopsies obtained from healthy subjects, Dkk-1 was expressed at the epidermis, appendices and spindle like cells in the dermis. In sharp contrast, no Dkk-1 expression could be detected in spindle-like cells in the dermis in all patients with SSc; only 2 patients exhibited a weak expression at the epidermis. Conclusions Circulating levels and function of Dkk-1 are not impaired in patients with SSc despite the striking lack of skin expression. These data indicate that local factors suppress Dkk-1 expression in scleroderma skin References Akhmetshina et al. Nat Commun 2012. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4078

FRI0514 Upregulation of Dickkopf-1 Skin Expression following B Cell Depletion Therapy Associates with Enhanced Resolution of Skin Fibrosis in Patients with Systemic Sclerosis

Background Experimental and clinical data indicate that B cells may actively participate in the fibrotic process in the context of systemic sclerosis (SSc). Recently the Wnt pathway has emerged as a crucial regulator of fibrosis. In scleroderma skin, the Wnt pathway is highly activated; this is linked to the fact that Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway, is virtually absent from scleroderma skin1 Objectives To assess the effect of B cell depletion therapy on Dkk-1 skin expression Methods Skin biopsies were obtained from 8 patients with SSc, prior to and 6 months following RTX administration. Skin biopsies were also obtained from 3 additional patients with SSc at baseline and at 6 months for control purposes (2 patients receiving cyclophosphamide and 1 no treatment). These patients were enrolled in a clinical study assessing the efficacy of RTX in SSc2. All biopsies were taken from lesional skin of the forearm. Skin involvement was assessed both clinically by applying the MRSS tool and histologically. Collagen accumulation was assessed by Massons thrichrome and computerized image analysis was used to quantify the results. Dkk-1 skin expression was assessed by immunohistochemistry. Circulating Dkk-1 levels were measured using an established solid phase immunoassay Results In all baseline biopsies Dkk-1 had no expression in spindle like cells in the dermis; a single patient showed a weak staining at the epidermis. However, following RTX administration, 4 patients exhibited a significant upregulation of Dkk-1 expression in spindle like cells. In sharp contrast, in the control biopsies Dkk-1 was undetectable in spindle like cells at 6 months. In the subgroup of patients which exhibited upregulation of Dkk-1 skin expression, an enhanced clinical response, in terms of resolution of skin fibrosis, was found. In these patients, histologic analysis revealed that Dkk-1 upregulation associated with a significant decrease in collagen accumulation in the upper dermis by a mean ± SEM 49.47±10.63% compared to 18.18±6.67% in patients which did not exhibit Dkk-1 upregulation (p=0.04). Histologic data matched the clinical data; MRSS at 1 year (following 2 cycles of RTX treatment; at baseline and at 6 months) decreased by mean ± SEM 57.31±10.37% compared to 29.59±7.71% decrease in the subgroup with undetectable Dkk-1 (p=0.07). PFTs improved following RTX treatment, irrespective of Dkk-1 skin expression. Circulating levels of Dkk-1 did not change following RTX treatment (mean ± SEM of OD: 0.17±0.04 vs 0.19±0.03 for patients with SSc and healthy subjects, respectively, p=ns). Conclusions Upregulation of Dkk-1 skin expression associates with an enhanced resolution of skin fibrosis following B cell depletion therapy. RTX may mediate its beneficial effects on fibrosis by increasing Dkk-1 skin expression. This could potentially downregulate the Wnt pathway, a well known driver of fibrosis References Akhmetshina et al. Nat Commun 2012. Daoussis et al. Rheumatol (Oxford) 2010. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4088

THU0455 Acth is Effective and Safe for the Treatment of Acute Calcium Pyrophosphate Crystal Arthritis in Hospitalized Patients

Objectives To evaluate the efficacy and safety of adrenocorticotropic hormone (ACTH) for the treatment of acute calcium pyrophosphate (CPP) crystal arthritis in hospitalized patients. Experimental data indicate that ACTH is not just a “steroid releasing” hormone but has an intrinsic anti-inflammatory effect related to its ability to bind and stimulate melanocortin receptors. Methods We retrospectively identified 14 cases of acute CPP crystal arthritis where ACTH was used as first line treatment; the hospital medical files of these patients were fully reviewed. Data recorded were: 1) age, 2) sex, 3) admission and discharge diagnosis 4) history of major comorbidities that represent contraindications to non steroidal anti-inflammatory drugs (NSAIDs), steroids or colchicine use 4) site(s) of joint involvement, 5) presence of chondrocalcinosis on x-rays and 6) fasting glucose and potassium levels (where available) and blood pressure (BP) at baseline and the 1st and 2nd day following ACTH administration, in order to explore “steroid-related” metabolic side effects. All patients were subjected to arthrocentesis; diagnosis was verified by CPP crystal detection whereas synovial fluid cultures were negative. Response to treatment was defined as i) resolution of arthritis and ii) no use of steroids, NDAIDs, colchicine or analgesics for 4 days following the attack. Patients were treated with 1 mg of synthetic ACTH intramuscularly. Results Patients had a mean ± SD age of 80.29 ± 3.87 years with equal gender distribution. All patients had at least one comorbidity that represents a contraindication to NSAIDs, steroids or colchicine use. The most common site of joint involvement was the knee (n=9), followed by the ankle (n=3), elbow (n=1) and wrist (n=1); in all cases the attack was monoarticular. The majority of patients (n=10) had a diagnosis of osteoarthritis. A dramatic response was seen in 13 patients with attenuation of signs of inflammation within 24 hours without the use of NSAIDs, colchicine or steroids. One patient had a partial response and received a second ACTH injection the day following the first injection; response with complete resolution of arthritis was seen. No patient suffered a rebound attack during hospitalization. No adverse events could be related to ACTH administration. Patients treated with ACTH showed a non statistically significant increase in fasting glucose the day following the injection compared to baseline (mean ± SEM: 153.70 ± 73.09 vs 130 ± 34.22 mg/dl, respectively, p=0.34, data available from 9 patients). BP and potassium levels remained stable the 1st and 2nd day following ACTH administration. Conclusions This study provides evidence supporting the use of ACTH as first line treatment for acute CPP crystal arthritis in hospitalized patients; our data indicate that ACTH is effective and most importantly safe. The latter is of particular interest, since patients with acute CPP crystal arthritis are usually of advanced age and suffer from multiple comorbidities and are therefore poor candidates for NSAIDs, colchicine or steroid administration. Disclosure of Interest None Declared

OP0242 Serum Indian Hedgehog (IHH) Levels Are Increased in Patients with Ankylosing Spondylitis (AS). Anti-TNF a Treatment Decreases Serum IHH Levels in Patients with as and Affects the Expression of Functional Target Genes in a Cell Line Model

Background The molecular pathways involved in the process of new bone formation in ankylosing spondylitis (AS) are not entirely known. However, data suggests that this process is linked to the reactivation of developmental pathways. It was recently shown that the Hedgehog pathway (HH) is involved in osteophyte formation in osteoarthritis. Moreover, it appears to be the main controller of endochondral ossification, a process already known to participate in new bone formation in AS. The ligand that activates the HH pathway in the skeleton is Indian Hedgehog (IHH). Objectives To assess i) serum levels of IHH in patients with AS compared to healthy subjects and patients with rheumatoid arthritis (RA) ii) the effect of anti-TNFα treatment on IHH levels in patients with AS and RA and iii) the effect of serum of patients with AS on HH pathway activation Methods Serum samples were obtained from 59 patients with AS (36 on anti-TNFα treatment), 70 patients with RA (30 on anti-TNFα treatment) and 53 healthy subjects. IHH levels were measured using an established solid phase immunoassay. The effect of serum from patients with AS on HH pathway activation was evaluated using an experimental model based on osteoblast-like, Saos-2 cells. On day 0, 2X106 Saos-2 cells were cultured in EMEM/10%FBS; on day 2, 10% of serum was added and on day 3 cells were lysed and mRNA was extracted. RT-PCR was used to assess the expression of two HH pathway target genes (Ptch-1 and glypican 3). Results IHH levels were significantly increased in AS patients not receiving anti TNF- treatment compared to healthy subjects (mean±SEM of OD: 0.37±0.02 vs 0.28±0.02, respectively, p=0.03). Patients with AS on anti-TNF treatment had significantly lower IHH levels compared to AS patients not on such treatment (mean±SEM: 0.28±0.02 vs 0.37±0.02, respectively, p=0.02). Interestingly, the exact opposite was true for patients with RA; patients on anti-TNF treatment had higher levels of IHH compared to patients not on such treatment (mean±SEM: 0.38±0.03 vs 0.27±0.02, respectively, p=0.01). In order to explore whether the differences in IHH levels found in AS patients have a functional effect, we assessed HH pathway activation in Saos2 cells following incubation with serum obtained form 2 AS patients prior to and 3 months following anti-TNF treatment. We found that the expression of both target genes (Ptch-1 and glypican 3) declined following anti-TNF treatment. Conclusions IHH levels are increased in patients with AS and decrease following anti-TNF treatment; taking into account the critical role of this pathway in the bone forming process this finding may have pathogenic and clinical implications. Disclosure of Interest None Declared

THU0342 Anti-TNF Treatment Reduces Serum Serotonin Levels in Patients with Ankylosing Spondylitis and Downregulates Serotonin Signaling in an Experimental Cell Line Model

Background The mechanisms involved in new bone formation in ankylosing spondylitis (AS) are incompletely understood. Evidence suggests that gut-derived serotonin is an inhibitor of bone formation; serotonin binds to the serotonin receptor Htr1b on osteoblasts, inhibits Creb phosphorylation and decreases osteoblast proliferation. Objectives To assess i) serum serotonin levels in patients with AS, a prototype bone-forming disease, compared to patients with osteoporosis (OP) and healthy subjects ii) the effect of anti-TNFa treatment on serum serotonin levels in patients with AS and iii) the effect of serum of AS patients on serotonin signaling, in an experimental model. Methods Serum serotonin levels were measured in 37 patients with AS (19 on anti-TNFa treatment), 8 patients with OP and 29 healthy subjects by RIA methodology. The effect of serum on serotonin signaling was assessed using an experimental model based on osteoblast-like, Saos2 cells. On day 0, 2X106 Saos2 cells were cultured in EMEM/10%FBS; on day 2, 10% of serum was added and on day 3 cells were lysed, protein was extracted and expression of phospho-Creb and GAPDH were assessed by Western blot. We assessed the effect of serum from 11 patients with AS (5 on anti-TNFa), 6 patients with rheumatoid arthritis (RA) (2 on anti-TNFa) and 9 healthy subjects. Proliferation of Saos2 cells was evaluated using MTT assay. Results Serum serotonin levels were similar in patients with AS, OP and healthy subjects (mean±SEM ng/ml: 106.3±11.65, 99.19±31.77, 115.6±17.48, respectively, p=ns for all comparisons). However, serotonin levels were significantly lower in patients with AS on anti-TNFa treatment compared to patients with AS not on such treatment (mean±SEM: 140.1±17.11 vs 71.16±10.66 for patients, respectively, p=0.002). In order to explore if these differences in serotonin levels have a functional effect on serotonin signaling, we assessed phospho-CREB expression in Saos2 cells. We found that phospho-CREB expression in Saos2 cells treated with serum from AS patients on anti-TNF treatment was significantly higher compared to AS patients not on such treatment (mean±SEM of densitometric intensity ratio pCREB/GAPDH:0.80±0.14 vs 0.34±0.13, respectively, p=0.04). We next assessed the effect of serotonin on Saos2 proliferation; we found that serotonin at 75ng/ml (a concentration relevant to that of human serum) suppresses Saos2 proliferation (mean±SEM:0.23±0.01 vs 0.18±0.01, for cells not treated and treated, respectively, p=0.002). Conclusions Serum serotonin levels decrease following anti-TNF treatment in patients with AS. Accordingly, expression of phospho-CREB is higher in Saos2 cells treated with sera from AS patients receiving TNF blockers compared to sera from AS patients not on such treatment. Taking into account the critical role of serotonin as an inhibitor of bone formation, our findings may have both pathogenetic and clinical implications. Disclosure of Interest None Declared

FRI0408 Rituximab treatment reduces circulating th2 cells and il4 expression in the skin of patients with systemic sclerosis.

Background Evidence suggests that B cells play a key role in the pathogenesis of Systemic Sclerosis (SSc). B cell depletion therapy has been used in the treatment of SSc with favorable results in lung function and skin fibrosis. However its mechanism of action remains to be elucidated. Objectives We investigated the effect of RTX on T-helper 1 (Th1), T-helper 2 (Th2) and T-helper 17 (Th17) cells as well as on serum cytokines, aiming at exploring the potential mechanisms of action of RTX. Methods We assessed 14 patients with SSc prior to and 6 months following RTX administration and 3 patients with SSc on standard treatment at the same time points. CD4 cells were separated from peripheral blood, stimulated with PMA and Ionomycin, stained for intracellular cytokines and measured using Flow Cytometry. Th1, Th2 and Th17 cells were defined as CD4 cells stained positive for Interferonγ (INFγ), Interleukin 4 (IL4) and Interleukin 17 (IL17) respectively. Serum levels of IL4 were measured by employing a quantitative ELISA method. IL4 expression in the skin was assessed using immunohistochemistry in skin biopsies obtained from 12 patients with SSc prior to and 6 months following RTX treatment and 3 control SSc patients. Immunohistochemical assessment was performed using computerized image analysis. Statistical analysis was performed by employing the paired t-test. Results were expressed as mean ± SEM. Results We found a significant decrease in circulating Th2 cells in all 14 patients following RTX treatment (mean±SEM: 13.9±4.2% vs 9.3±3.7 prior to and following RTX administration respectively, p=0.016). RTX had no effect on Th1 (mean±SEM: 3.47±0.68 vs 2.79±0.93 prior to and following RTX administration respectively, p=NS) and Th17 cells (mean±SEM: 0.25±0.07 vs 0.19±0.04 prior to and following RTX administration respectively, p=NS). We found no changes in serum levels of IL4 in all 14 patients. The 3 patients who were not treated with RTX exhibited no differences in Th1, Th2 and Th17 cells. A decrease in IL4 expression in the skin was small but significant in all 12 patients following RTX treatment both in the papillary (mean±SEM: 1.95±0.28% vs 1.15±0.164 prior to and following RTX administration respectively, p=0.004) and the reticular dermis of the skin (mean±SEM: 1.78±0.26 vs 1.15±0.15 prior to and following RTX administration respectively, p=0.008) while no differences were found in IL4 expression in the skin of controls. Immunostaining for IL4 was almost exclusively found in skin infiltrating mononuclear cells. Conclusions Our study shows that RTX reduces circulating Th2 cells and IL4 expression in the skin. Th2 cells are currently thought as strongly related with fibrosis. Further studies on the mechanisms of RTX action in patients with SSc are warranted. Disclosure of Interest None Declared

THU0245 Rituximab has a beneficial effect on lung function and skin fibrosis in patients with systemic sclerosis. An open label study

Background Evidence suggests that B cells may play a role in fibrosis. We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To further assess efficacy and safety of RTX in SSc Methods Twenty five patients with diffuse SSc from two University Hospitals were recruited. All patients had evidence of lung involvement as indicated by findings in chest HRCT and pulmonary function tests (PFT). Patients received 4 weekly pulses of rituximab (375 mg/m2) at baseline and were retreated with the same scheme at 6 months. Lung function and skin thickening was assessed by PFTs and MRSS respectively, at baseline, 6 and 12 months. Data are presented as mean ± SEM, median (range) or percentages, as appropriate. Results Patients were predominately female (n=19) with a median age of 54.5 (32-77) and disease duration of 6 (1-28) years. All patients had diffuse SSc apart from 2 patients with CREST. Nine patients received concurrent immune based therapies (7 MMF, 1 MTX and 1 HCQ, all initiated at least 3 years prior to enrollment). At the 12 month evaluation time point (data available from 12 patients) a significant improvement of FVC and DLco was found (FVC: 69.1±5.6 vs 75.7±5.4 at baseline vs 12 months, respectively, p=0.001 and DLco: 54.8±5.6 vs 60.4±6 at baseline vs 12 months, respectively, p=0.008, n=12). Skin thickening improved significantly as well (mean MRSS ± SEMat 12 months: 8.75±1.6vs. 15.1±2.2at baseline, p=0.0001) an effect that was evident already at 6 months following RTX treatment (11.2±1.7, p=0.0001 vs. baseline). At the 6 month evaluation time point lung function parameters recorded a statistically significant yet perhaps a clinically questionable increase (mean FVC ± SEM: 78.6±4.4 vs 80.1±4.3 at baseline vs 6 months, respectively, p=0.047, n=25) while the improvement seen in DLco did not reach statistical significance (mean ± SEM, 60.9±3.4 vs 64±3.5 at baseline vs 6 months, respectively, p=0.13). Functional status improved as indicated by a decline in HAQ-DI (p<0.001, at 6 months compared to baseline). A beneficial effect on skin calcinosis in a patient with CREST was noted. RTX treatment was generally well tolerated. One case of respiratory tract infection requiring short term hospitalization, one case of Hepatitis B reactivation, one case of herpes zoster and two cases of mild infusion reactions were recorded. Conclusions Our data indicate that RTX can have a beneficial effect on skin fibrosis as well as lung function in patients with SSc. Skin involvement responds earlier than pulmonary function parameters; our preliminary data suggest that long-term treatment may be needed in order to enhance and sustain this effect. Treatment with RTX was well-tolerated and safe. A large-scale, randomized, controlled study is clearly needed. Disclosure of Interest None Declared