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
To investigate whether the protective effects of the 70-kDa heat shock protein (hsp70) extend to the apoptotic mode of cell death, we transfected Jurkat T cells with the gene for the human hsp70 and challenged the cells with an anti-Fas mAb or with two different murine anti-CD3 mAbs. The anti-Fas mAb-triggered apoptotic cell death and the anti-CD3 mAb-mediated activation-induced cell death were significantly enhanced in the gene-transfected Jurkat cells overexpressing hsp70 compared with the unmanipulated and the vector-transfected cells. On the other hand, the well-established protective effect that this protein offers to the cells was unaffected, as determined by enhanced viability of gene-transfected cells exposed to a lethal heat shock. To investigate the mechanisms that are responsible for the increased susceptibility of the gene-transfected cells to apoptotic death, we studied the TCR/CD3-initiated events that showed a significant down-regulation of the protein tyrosine phosphorylation levels and the cytoplasmic free Ca2+ responses. As for the Fas/Apo-1/CD95-mediated early events, the activity of protein serine/threonine phosphatases was markedly increased in the cells overexpressing hsp70. Our study demonstrates that hsp70 overexpression offers thermoprotection but enhances TCR/CD3- and the Fas-induced apoptotic cell death. This phenomenon is associated with a down-regulation of the Ag receptor-initiated early signal transduction pathways and with an up-regulation of Fas-mediated early metabolic events.
BackgroundBoth epidemiology and planning of health care puts high demands on the ability to record and monitor data. Disease registries have contributed significantly the previous years, however, an enormous amount of healthcare data is spread among hospitals, primary care providers, researchers, health insurers, with each of these usually acting as a silo, preventing effective use of data.ObjectivesSince Greece is among the first countries that developed an extensive electronic prescription system, we aimed to identify all patients with prescribed pharmacological treatment for RA, SLE and SSc among 7.742.629 Greek citizens (72% of the population, >99% Caucasians) who were included in the system during the first semester of 2014.MethodsThe database of the electronic prescription platform of the Greek National Organization for Provision of Healthcare Services (EOPYY) was used to provide analytics on these patients (date of birth and gender based on the unique citizens' social security numbers and the relevant ICD-10 codes). Permission for use of anonymized data was obtained by the administration of EOPYY together with the positive recommendation of the General Secretariat for Public Health of the Ministry of Health of Greece, in accordance to the national legislation on the Protection of Individuals and Personal Data.ResultsThis “Big Data” analysis revealed that RA prevalence is 0.84%, SLE prevalence is 0.075% and SSc prevalence is 0.016%. Female:male ratio is approximately 4:1 in RA, and 9:1 in both SLE and SSc, with slight differences across age groups (15-24, 25-34, 35-44, 45-54, 55-64, 65-74, 75+). The peak RA prevalence is observed after the age of 75 years; in contrast, the peak prevalence of SLE and SSc is observed between 45-54 and 55-64 years, respectively, which is compatible with the earlier/higher mortality of these patients compared to RA. The highest female preponderance (94%) is noted in patients older than 74 years with SSc, supporting the previously suspected earlier mortality of men compared to women in SSc.ConclusionsThese data provide reliable estimates of the epidemiology of both common and rare autoimmune rheumatic diseases. Analysis of such large databases overrides any incorrect diagnosis-associated limitations that an electronic prescription system may have. However, a proportion of patients may be missed because of mild disease or not receiving (prescribed) treatment, therefore, the true prevalence is likely to be higher than that calculated. Further analyses of data deriving from the second semester of 2014 which covers 95% of the Greek population should confirm these results and reveal the distinct pharmacological approaches, including biologic agents, as well as the co-morbidities. These analyses are in progress.Disclosure of InterestNone declared
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 efficacy and safety of RTX in SSc compared to standard treatment.MethodsFifty 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).ResultsPatients 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.ConclusionsOur 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 InterestNone declared
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