Cellular immunity aberrations in patients with SLE are underscored by the abnormal early Ag receptor-mediated lymphocyte signal transduction pathway. To further characterize the T cell receptor (TCR)/CD3-initiated signaling defects, we studied 22 patients with SLE, 12 patients with other systemic rheumatic diseases, and 14 normal donors. The early (1 min) TCR/CD3-mediated tyrosine phosphorylation of cellular proteins with a molecular size between 36 and 64 kD was increased in 15 of 21 SLE patients, compared to normal or disease control subjects. The deficiency or absence of a band with a molecular size of approximately 16 kD in the immunoblots of SLE patients led us to investigate the expression of the TCRzeta chain. In immunoblots using anti-zeta antibodies we found that 10 of 22 lupus patients tested lacked the expression of TCRzeta, which was always present in control subjects (P < 0.001). Flow cytometric studies using permeabilized cells confirmed the deficiency or absence of the TCRzeta chain in lupus T cells. Using Northern blots we found that for eight patients tested, the TCRzeta mRNA was missing in three, decreased in three, and apparently normal in two patients (P < 0.003), but was always present in control subjects. Reverse transcriptase-PCR verified Northern blot results. We conclude that TCRzeta chain expression is either decreased or absent in the majority of patients with SLE, but not in patients with other systemic rheumatic diseases, regardless of disease activity, treatment status, or clinical manifestations. The previously described increases in TCR-initiated Ca2+ responses and the herein described increases in TCR-induced protein tyrosine phosphorylation and deficient TCRzeta expression may represent intrinsic defects modulating lupus T cell function.

To understand the molecular mechanisms that are responsible for the B cell overactivity that is observed in patients with SLE, we have conducted experiments in which the surface immunoglobulin (sIg)-mediated early cell signaling events were studied. The anti-sIgM-mediated free intracytoplasmic calcium (

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

Systemic sclerosis (SSc) is a complicated multisystem disease which is characterized by the highest standardized mortality ratio among all systemic rheumatic diseases with no approved therapies so far. From a pathogenetic point of view it is generally considered that autoimmunity, vasculopathy and fibrosis are the main pathophysiologic processes. In this opinion article/minireview we will discuss current and future options for SSc-related fibrotic manifestations (skin thickening and lung fibrosis). Based on the results of SLS II the best treatment option for skin involvement in SSc is mycophenolate mofetil (MMF). Methotrexate (MTX) is another option which is safe and of low cost but evidence supporting its use is weak. The standard of care for SSc-ILD nowadays is MMF. Patients not responding to MMF could be treated with rituximab (RTX) or cyclophosphamide (CYC) (tocilizumab [TCZ] could be an option as well but only for patients with increased inflammatory markers). Hematopoietic stem cell transplantation (HSCT) could be considered in patients with severe/life-threatening disease who have failed conventional treatment. The most promising therapeutic approach currently been evaluated in phase 3 trials is probably the combination of MMF plus pirfenidone.

BackgroundWe have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc).ObjectivesTo assess long term data on efficacy and safety of RTX in SScMethodsThirty 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.ResultsPatients 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.ConclusionsOur 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 InterestNone declared