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.<sup>4 Cronstein B.N. A novel approach to the development of anti-inflammatory agents: Adenosine release at inflamed sites J Invest Med 1995 ;  43 : 50-57

Haga clic aquí para ir a la sección de Referencias, 5 Cronstein B.N. Molecular therapeutics: Methotrexate and its mechanisms of action Arthritis Rheum 1996 ;  39 : 1951-1960  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> 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.<sup>4 Cronstein B.N. A novel approach to the development of anti-inflammatory agents: Adenosine release at inflamed sites J Invest Med 1995 ;  43 : 50-57

Haga clic aquí para ir a la sección de Referencias, 5 Cronstein B.N. Molecular therapeutics: Methotrexate and its mechanisms of action Arthritis Rheum 1996 ;  39 : 1951-1960  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> 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 <sup>1 Appel G.B., Gee B., Kashgarian M. , y al. Wegener's granulomatosis: Clinical–pathologic correlations and long-term course Am J Kidney Dis 1981 ;  1 : 27-37

Haga clic aquí para ir a la sección de Referencias, 2 Capizzi R.L., Bertino J.R. Methotrexate therapy of Wegener's granulomatosis Ann Intern Med 1971 ;  74 : 74-79

Haga clic aquí para ir a la sección de Referencias, 3 Choy D.S.J., Gould W.J., Gearhart R.P. Remission in Wegener's granulomatosis treated with steroids and azathioprine NY State J Med 1969 ;  69 : 1205-1209

Haga clic aquí para ir a la sección de Referencias, 48 Weiner S.R., Paulus H.E. Treatment of Wegener's granulomatosis Semin Respir Med 1989 ;  10 : 156-161  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> and polyarteritis nodosa successfully.<sup>12 Fraga A., Mintz G., Orozco J.H. Immunosuppressive therapy in connective tissue diseases other than rheumatoid arthritis J Rheumatol 1974 ;  1 : 374-391

Haga clic aquí para ir a la sección de Referencias, 31 Leib E.S., Restivo C., Paulus H.E. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa Am J Med 1979 ;  67 : 941-947  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 34 Mitchell M.S., Gifford R.H., Bertino J.R. , y al. The treatment of disseminated vasculitis with methotrexate Inflammation 1976 ;  1 : 285-295  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 40 Tannenbaum H. Combined therapy with methotrexate and prednisone in polyarteritis nodosa Can Med Assoc J 1980 ;  123 : 893-894

Haga clic aquí para ir a la sección de Referencias</sup> 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.<sup>9 Espinoza L.R., Espinoza C.G., Vasey F.B. , y al. Oral methotrexate therapy for chronic cutaneous rheumatoid arthritis ulcerations J Am Acad Dermatol 1986 ;  15 : 508-512  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 34 Mitchell M.S., Gifford R.H., Bertino J.R. , y al. The treatment of disseminated vasculitis with methotrexate Inflammation 1976 ;  1 : 285-295  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 43 Tiliakos N. Pulse methotrexate (MTX) therapy for intractable cutaneous ulcers Arthritis Rheum 1985 ;  28 (Suppl) : 37

Haga clic aquí para ir a la sección de Referencias, 44 Upchurch K.S., Heller K., Bress N.M. Low-dose methotrexate therapy for cutaneous vasculitis of rheumatoid arthritis J Am Acad Dermatol 1987 ;  17 : 355-359  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 50 Williams H.C., Pembroke A.C. Methotrexate in the treatment of vasculitic cutaneous ulceration in rheumatoid arthritis J R Soc Med 1989 ;  82 : 763

Haga clic aquí para ir a la sección de Referencias</sup> 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.