EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees I t is the objective of the EULAR executive committee to promote actions and/or projects aimed at improving the knowledge and/or the recognition of musculoskeletal disorders.The chief aim is to contribute to the improvement of outcome of patients with rheumatic disorders. Apart from the projects devoted to education and research, projects aimed at facilitating the conduct of clinical studies or at improving the management of musculoskeletal disorders are welcome. Such studies can be categorised in four sections:
In order to define the effects and safety of cyclosporin A (CsA) in systemic lupus erythematosus (SLE), we conducted an open clinical trial with 16 SLE patients. During an observation period of up to 64 months and an average treatment period of 30.3 months, 16 SLE patients, who did not have adequate disease control or experienced side-effects with their previous immunosuppressive therapy, were treated with CsA (3-5 mg/kg). In 3/16 patients, CsA treatment was discontinued because of side-effects, in two because of inefficacy and in 2/16 because of a pregnancy. Four out of 16 patients had a flare of disease during CsA therapy 7, 24, 36 and 40 months after initial response to therapy; one patient stopped CsA treatment after 54 months of successful disease control. Four out of 16 patients are still on CsA. The best beneficial effect was observed in 10 patients with proteinuria, which decreased from 4.7 +/- 2.6 to 1.5 +/- 1.1 g/24 h. In 3/3 patients with thrombocytopenia and 3/3 patients with leucocytopenia, platelets and leucocytes returned to normal values. The most frequent side-effects were hypertension and deterioration of renal function (3/16) and hypertrichosis (5/16). According to the preliminary results of this study, CsA was well tolerated and able to control disease activity over an extended time period. These data should encourage investigators to perform a multicentre controlled trial on CsA therapy in SLE.
Three different classes of Fc receptors for IgG (Fc gamma R) are currently distinguished in humans, of which polymorphonuclear phagocytes (PMN) normally express both low-affinity receptor classes-- Fc gamma RII (CD32) and Fc gamma RIII (CD16). During therapy with granulocyte colony-stimulating factor (G-CSF), neutrophils from patients with various malignancies and different hematologic disorders were found to additionally express high levels of the receptor with high affinity for IgG (Fc gamma RI; CD64). For these patients, the relative fluorescence intensity (rFI) for Fc gamma RI was 5.3 (range, 1.7 to 10.3; n = 19), compared with 1.0 (range, 1.0 to 1.1; n = 8) for healthy donors. The expression of Fc gamma RI during G-CSF therapy could be confirmed by using a panel of six CD64-specific antibodies, and by showing mRNA for Fc gamma RI. So far, three genes for Fc gamma RI have been identified, encoding four distinct transcription products. By reverse transcriptase-polymerase chain reaction technology, transcripts for both membrane-associated isoforms (hFc gamma RIa and hFc gamma RIb2) could be detected. The functional activity of Fc gamma RI on PMN during G-CSF therapy was shown by measuring binding of monomeric human IgG and antibody-dependent cellular cytotoxicity (ADCC). Thus, Fc gamma RI-positive neutrophils displayed enhanced ADCC activity to glioma (A1207), squamous cell (A431), and ovarian (SK-ov3) carcinoma cell lines. The involvement of Fc gamma RI in this increased cytotoxic activity was shown by blocking Fc gamma receptors with monoclonal antibodies, and by using F(ab')2 x F(ab')2-bispecific antibodies with specificities against tumor-related antigens and Fc gamma RI, resulting in solely Fc gamma RI-mediated cytotoxicity. Therapeutically, this additional Fc receptor on PMN may increase the efficacy of experimental antibody therapy.
Analysis of somatic mutations revealed that induction of anti-dsDNA autoantibodies from SLE patients are antigen driven and thus T cell dependent. Since DNA per se has repeatedly been shown not to be immunogenic, various mechanisms leading to the production of anti-dsDNA-antibodies have been discussed including the role of oligonucleosomes. In the present study we demonstrate that the percentage of macrophage engulfing apoptotic cell material was significantly reduced in SLE as compared to control patients. These data suggest that, in contrast to a non-inflammatory clearance of apoptotic cell, phagocytosis of apoptotic cell material may be decreased in SLE patients, possibly leading to a presentation of autoantigens and thus possibly triggering an autoantibody response to nucleoproteins.
We have investigated the capacity of polymorphonuclear phagocytes (PMN) to lyse malignant B-cell lines using antibodies and antibody derivates to a range of different B-cell antigens. PMN were found to mediate lysis of all tested B-cell lines in the presence of HLA class II antibodies L227, L243, F3.3, and CR3/43. Target cell lysis was significantly enhanced when PMN isolated during granulocyte colony- stimulating factor (G-CSF) treatment were compared with PMN from healthy donors. Only G-CSF primed PMN, expressing Fc gamma RI (CD64), lysed B cells in the presence of monoclonal antibody (MoAb) 1D10 or Lym- 1 to HLA class II related epitopes. Remarkably, PMN were consistently unable to kill malignant B cells with antibodies to the B-cell related antigens CD19, CD20, CD21, CD37, and CD38. These target antigen restriction was not observed with mononuclear effector cells, which mediated cytotoxicity with antibodies to HLA class II, but also with mouse/human chimeric constructs to CD19, CD37, and CD38. Blocking studies with Fc gamma RI antibodies and reverse antibody-dependent cellular cytotoxicity (ADCC) experiments against Fc gamma R antibody expressing hybridoma targets confirmed the pivotal role of Fc gamma RI in enhanced killing by G-CSF primed neutrophils. Bispecific antibodies (BsAb) with one specificity for Fc gamma RI, and another for a tumor associated antigen, offer an interesting approach to improve effector cell recruitment for immunotherapy. In our studies, very effective lysis was observed with G-CSF primed PMN and an [HLA class II x Fc gamma RI] BsAb. The therapeutic implications of these findings and the possible use of BsAb in combination with G-CSF are discussed.
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