METHOTREXATE USE IN SYSTEMIC VASCULITIS - 11/09/11
Résumé |
The primary systemic vasculitides are a heterogeneous group of disorders that are characterized by diverse patterns of blood vessel involvement, organ manifestations, histologic features, and disease severity. Despite their differences, the vasculitides share the characteristics of inflammation of the vessel wall that may lead to compromise of the lumen and ischemia, or attenuation of the vessel wall, aneurysm formation, and possible hemorrhage. Although the pathophysiology of vasculitis remains poorly understood, immunologic mechanisms appear to play a critical role in the induction of vasculitic lesions. Support for such mechanisms has come not only from an increasing body of in vitro and in vivo evidence but also from the effectiveness of immunosuppressive therapy in the management of many vasculitic diseases.
Within the vasculitides there exist differing degrees of therapeutic responsiveness to individual immunosuppressive regimens. Although high-dose glucocorticosteroids (GS) alone are efficacious in treating some forms of vasculitis, others require the use of a cytotoxic agent in addition to GS. This is best exemplified by the focal segmental necrotizing glomerulonephritis that occurs in Wegener's granulomatosis, which was historically untreatable until the introduction of combined therapy with GS and cyclophosphamide (CYC).
Although GS and CYC have been the two agents that have provided the main therapeutic foundation for most severe forms of vasculitis, extended experience with these agents has raised significant concerns about their long-term toxicities. These concerns have motivated the pursuit of therapeutic alternatives for systemic vasculitis.
The initial investigation of methotrexate (MTX) as a therapeutic agent for vasculitis was supported by its theoretic mechanisms of action as well as encouraging results from early case reports. Mechanistically, MTX is thought to have several potential suppressive effects on both cellular and humoral immunity.4, 5 In addition to its immunosuppressive properties, it has been postulated that MTX has anti-inflammatory activity that is related to its effects on adenosine metabolism. At pharmacologic concentrations, MTX has been found to increase adenosine accumulation and release from cultured fibroblasts and endothelial cells, which in turn diminishes neutrophil adhesion to these cells.4, 5 This has particular relevance to the treatment of vasculitis because neutrophil adhesion to endothelial cells may be an important step in the pathogenesis of these diseases. Before the first reported prospective studies with CYC and GS, MTX had been used to treat a small number of patients with Wegener's granulomatosis 1, 2, 3, 48 and polyarteritis nodosa successfully.12, 31, 34, 40 Throughout this period the experience with MTX in rheumatoid arthritis (RA) grew, and beneficial results also were reported in individual patients who had cutaneous rheumatoid vasculitis.9, 34, 43, 44, 50 With this background, standardized prospective trials subsequently were initiated to study the efficacy of MTX in vasculitis. The three forms of systemic vasculitis in which MTX has been investigated most extensively to date include Wegener's granulomatosis, Takayasu's arteritis, and giant cell (temporal) arteritis.
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Vol 23 - N° 4
P. 841-853 - novembre 1997 Retour au numéro
Article précédent
- METHOTREXATE IN THE TREATMENT OF JUVENILE RHEUMATOID ARTHRITIS AND OTHER PEDIATRIC RHEUMATIC AND NONRHEUMATIC DISORDERS
- Bernhard H. Singsen, Rafaela Goldbach-Mansky
- METHOTREXATE USE IN MISCELLANEOUS INFLAMMATORY DISEASES
- William S. Wilke
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