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1.
Arthritis Rheum ; 56(6): 1985-93, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17530638

ABSTRACT

OBJECTIVE: Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients. METHODS: A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel. RESULTS: FMD%, the main end point, increased significantly from a mean +/- SD of 3.1 +/- 1.3% to 8.4 +/- 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4 +/- 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n = 5), the 4-week results remained unchanged. CONCLUSION: Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.


Subject(s)
Endothelin Receptor Antagonists , Endothelium, Vascular/physiopathology , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/physiopathology , Sulfonamides/therapeutic use , Administration, Oral , Adult , Aged , Bosentan , Brachial Artery/diagnostic imaging , Brachial Artery/physiology , Dose-Response Relationship, Drug , E-Selectin/blood , Endothelin-1/blood , Endothelium, Vascular/drug effects , Female , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/physiopathology , Intercellular Adhesion Molecule-1/blood , Male , Middle Aged , Prospective Studies , Regional Blood Flow/physiology , Scleroderma, Systemic/blood , Sulfonamides/administration & dosage , Ultrasonography , Vascular Endothelial Growth Factor A/blood , Vasodilation/physiology
2.
Clin Immunol ; 123(1): 66-73, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17275413

ABSTRACT

B cell depletion may affect T cell activation and costimulation status in rituximab-treated patients with SLE. We examined whether rituximab administration in patients with active lupus nephritis is related to changes in mRNA expression of genes that define regulatory T cells (Tregs) in peripheral blood lymphocytes, measured by real-time PCR. At the early phase of B cell depletion mRNA levels of CD25, CTLA-4, GITR and the bona fide Treg functional marker FOXP3 increased significantly in all 7 patients examined. In contrast, mRNA levels of the costimulatory/activation T cell molecule CD40L were profoundly reduced, while mRNA levels of TGF-beta, a cytokine contributing to Treg induction, increased significantly in all. During follow-up, increased FOXP3 mRNA persisted in those patients in clinical remission, while in those patients with active disease subsequent decreases were noted. Further studies should examine whether modulation of Tregs by therapeutic B cell depletion contributes and/or predicts lupus disease remission.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Forkhead Transcription Factors/biosynthesis , Immunologic Factors/therapeutic use , Lupus Nephritis/drug therapy , Lupus Nephritis/immunology , T-Lymphocytes, Regulatory/drug effects , Adolescent , Adult , Antibodies, Monoclonal, Murine-Derived , B-Lymphocytes/drug effects , CD40 Ligand/drug effects , CD40 Ligand/immunology , Female , Gene Expression/drug effects , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Depletion , Male , RNA, Messenger/analysis , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Rituximab , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/drug effects , Transforming Growth Factor beta/immunology
3.
Arthritis Rheum ; 52(2): 501-13, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15693003

ABSTRACT

OBJECTIVE: Autoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open-label study was undertaken to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of lupus nephritis. METHODS: Lupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m(2)) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein <500 mg. Partial remission was defined as >50% improvement in all renal parameters that were abnormal at baseline. RESULTS: B cell depletion lasted from 1 month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1-4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4. As early as 1 month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4+ T cells was decreased by 4-fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA-DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double-stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome. CONCLUSION: Following B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.


Subject(s)
Antibodies, Monoclonal/therapeutic use , B-Lymphocytes/immunology , CD40 Ligand/physiology , Lupus Nephritis/drug therapy , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antigens, CD/analysis , Antigens, Differentiation, T-Lymphocyte/analysis , CD4-Positive T-Lymphocytes/immunology , CD40 Ligand/analysis , Down-Regulation , Female , HLA-DR Antigens/analysis , Humans , Lectins, C-Type , Leukocyte Reduction Procedures , Lupus Nephritis/immunology , Male , Prednisolone/administration & dosage , Prospective Studies , Rituximab
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