infiltrate the tissues, particularly early in the disease, and induce the changes related to the disorder. This is brought about by cytokine release, oxygen-free radicals, and fibrogenic growth-factors leading to fibroblast stimulation and causing glycosaminoglycan deposition, cell growth, and preadipocyte transformation (6,7).

CHANGING PARADIGMS IN THE TREATMENT

OF INFLAMMATION: THE RHEUMATOLOGIC

APPROACH

Our experience in working with rheumatologists has made us aware of the changing approach to the management of rheumatologic disorders (as presented by Shojania in this symposium). Traditionally, diseases in this specialty have been treated in a pyramidal fashion, beginning with nonspecific anti-inflammatories, such as salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs), moving up the ladder to disease-modifying treatments, such as antimalaria drugs, gold, methotrexate, and sulfadiazine, and more recently to drugs that target specific cytokines. The general shift, as noted in this symposium, has been to invert the pyramid and use more specific or aggressive therapy early in the course of the disease.

DIRECTED TREATMENTS OF DISTINCT ORBITAL INFLAMMATIONS

The recent trend in the management of rheumatologic disorders has prompted our unit to use their approach in managing certain orbital inflammations, thereby introducing more specific treatment for several disorders. This has led to improved results in the management of some complex inflammations. For instance since 1994, we have been treating newly diagnosed sclerosing inflammation with a combination of cytolytic doses of corticosteroids (intravenous methylprednisolone), T-cell inhibitors such as cyclosporine or methotrexate, and in some instances other immunosuppressive drugs.

This has led to significant improvement in some advanced cases and no recurrences or progression so far in eight patients treated following a biopsy-proven primary diagnosis of sclerosing inflammation of the orbit. Recently, in the instance of AAPOX, we have applied the same principle to attack the cytotoxic T-cells and have had several successes.

A recent case of a patient with AAPOX summarizes the role of immune mediation in establishing and promoting the disorder. This 46-year-old man presented with bilateral orbital involvement of AAPOX, which was associated with significant infiltration of the subcutaneous tissues of his cheek. He had an antecedent lymphoproliferative disorder and adultonset asthma, signifying an immunoregulatory problem as the basis for his manifestations. The AAPOX heretofore had been unresponsive to corticosteroids alone. He was placed on cyclosporine, pulsed steroids, and immunosuppressives, which led to significant improvement of his periorbital and subcutaneous facial disease. Recently, he developed Burkitt’s lymphoma that was treated with aggressive chemotherapy and autologous bone marrow transplantation, leading to further improvement of his orbital disease almost to the point of disappearance. Approximately 10 weeks after his bone marrow transplant, he developed an acute orbital infiltrate as his body repopulated with its own lymphocytes, which underlines the role of these cells and their cytokines in this specific inflammatory disease.

We have also encountered two different instances of myositis that were treated on the basis of the cellular infiltrate. One patient, previously unresponsive to corticosteroids, was found on biopsy to have a dominance of T-cells and responded well to methotrexate and cyclosporine. The second patient had a dominance of CD20 cells and responded to Rituximab, a specific chimeric drug directed against CD20 cells.

In review of the literature and from our own experience, T-cells and their mediators are now implicated in fibrotic responses in asthma, systemic sclerosis, sarcoidosis, murine viral myocarditis, thyroid orbitopathy, wound healing, lung

Figure 3 This diagram illustrates the inflammatory pathway and intermediaries that lead to fibroblast proliferation in collagen synthesis, emphasizing the multiple sites at which the process could be altered.

fibrosis, liver fibrosis, sclerosing inflammation, and retroperitoneal fibrosis, as well as AAPOX and Erdheim–Chester disease, which is reported in this symposium (8–21). In addition, fibroblasts isolated from conditions of pathologic fibrosis often display a persistently abnormal phenotype, which is apparently independent of exposure to initiating pathologic stimulus (22). This leads to the possibility of treating desmoplastic inflammatory diseases at many different points in their pathogenetic pathway (Fig. 3). This paradigm will define the future of management of inflammatory disease. In fact, the shift in our knowledge of inflammatory disease from nonspecific to specific is now allowing us to identify cytologic and molecular targets that will alter the fundamental approach to inflammatory disorders. Moreover, it emphasizes a need to define inflammatory disorders with greater specificity and accuracy.

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