The Spectrum of Wegener's Granulomatosis and Disease Relapse
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《新英格兰医药杂志》
Wegener's syndrome (Wegener's granulomatosis) is a rare systemic disorder, and because it involves multiple organs, affected patients may seek help from physicians in many specialties. It is classified as a type of primary systemic vasculitis, and the typical renal glomerular involvement is histologically identical to that seen in microscopic polyangiitis. However, Wegener's syndrome also involves multiple other organs. The clinical picture includes airway disease and skin, eye, and joint involvement, which therefore figure in the diagnostic criteria. Unlike microscopic polyangiitis, the lesions in Wegener's syndrome are largely granulomatous. Vasculitis and granulomata can occur in the same lesion, but they commonly appear separately, and it is unusual to see both in the same biopsy specimen. Wegener postulated from the outset that the disease initially takes the form of airway granulomata, which may suddenly develop into generalized systemic disease. Initial granulomatous disease may persist for a decade, sometimes masquerading as rheumatoid arthritis or another disease before declaring itself as systemic Wegener's granulomatosis. Indeed, one center has documented that a small percentage of cases remain localized even during extensive follow-up; in most cases, however, there is a conversion to systemic disease.
Although the airway granulomata were stressed in the original description of the condition, the systemic lesions — predominantly related to acute vasculitic inflammation — have since received more attention. Systemic Wegener's granulomatosis is noted for its severity and the high mortality associated with it. Before the introduction of immunosuppressive therapy, most patients died within two years after diagnosis. Initial clinical experience with cyclophosphamide demonstrated impressive benefits but not a long-term cure. Recent trials have provided further evidence of the benefits of cyclophosphamide and have shown that shorter courses are as effective as the longer ones previously used, with reduced toxicity. A remission rate of 90 percent can now be achieved regularly, although some patients still die relatively soon after diagnosis.
Thus, the initial response to immunosuppression with the best current therapy is impressive, but such treatment does not result in total clearance of the disease, and it is difficult to maintain a remission. Active disease can recur after 15 years of remission, perhaps because localized subclinical disease may persist during an apparent remission. Methotrexate may prolong control of the disease, but the relapse rate is high after early discontinuation of treatment. Blockade of tumor necrosis factor (TNF-) should have a place here, and observational studies suggest that it works best in granulomatous disease. It may be effective in acute vasculitis as well, insofar as it counteracts TNF-–induced endothelial-cell dysfunction. It is therefore disappointing that the recent large trial reported by Stone et al. in this issue of the Journal (pages 351–361) shows that the routine addition to therapy of long-term TNF blockade results in a negligible improvement in the maintenance of remission.
Relapse is now the primary clinical problem. It can occur even within the first 18 months of therapy and is seen in as many as 50 percent of patients by 5 years of follow-up. The relapse rate is higher with Wegener's granulomatosis than with a primary systemic vasculitis such as microscopic polyangiitis. Relapse is seen in limited (granulomatous) disease as well as in the severe systemic forms. Thus, it seems likely that relapse is generally related to granulomata. Relapse may even occur after "immune ablation" with hematopoietic stem-cell rescue, suggesting that the current immunosuppressive therapy has less effect on the granulomata than on the vasculitis. These may resolve and then develop again or, more likely, persist in a subclinical, inactive form. Experienced clinicians recognize the difficulties of distinguishing, without performing a biopsy, between "scar tissue" that remains in the airways after the induction of remission and persistent low-grade activity. Postmortem studies in patients with Wegener's granulomatosis also indicate that persistent airway inflammation is more common than has been appreciated clinically.
The concept that persistent granulomata can be at the root of relapses of Wegener's granulomatosis underscores the need to understand their pathogenesis as clearly as that of inflammatory vasculitis. Research has documented many of the immune mechanisms involved in the latter disorder. This research has focused particularly on antineutrophil cytoplasmic antibodies (ANCA). Neutrophil cytoplasmic granules move to the surface membrane in activated neutrophils, thereby becoming accessible to ANCA. Simultaneous binding to Fc receptors signals the release of neutrophil factors that are capable of causing the death of endothelial cells, with direct damage to the vessel wall (see diagram). By contrast, far less is known about the granulomatous component of Wegener's granulomatosis. Multiple types of cells are present (see diagram), but their precise roles are not well delineated. The histologic features are variable, indicating a dynamic process, but the mechanisms driving the persistence of granulomata or triggering the antibody-mediated vasculitic phase have not been determined.
Spectrum of Wegener's Granulomatosis.
The pathogenic mechanisms of the vasculitis (left) — which are related to the role of antineutrophil cytoplasmic antibodies (ANCA) — are well established. The principal cell involved is the polymorphonuclear leukocyte. By contrast, the granuloma (right) presents a variable histologic picture involving multiple types of cells whose specific roles are not clear. LPS denotes lipopolysaccharide.
The available epidemiologic data indicate that several factors may be involved. The predominance of airway disease led Wegener to postulate the involvement of inhaled agents, and several studies have since pointed to inorganic chemicals such as silica or hydrocarbons as possible factors. The individual statistical associations are not strong, but it is well established that silica in particular has the potential to stimulate granuloma formation through its effects on macrophage function. Macrophages do feature in Wegener's granulomatosis, with scant formation of giant cells, but the typical palisading of epithelioid cells is infrequent.
The seasonal incidence suggests that infection may also have a role. Central aggregates of necrotic polymorphonuclear leukocytes are seen in the granulomata occasionally, and granule release here could trigger ANCA formation. In the granulomata of "rheumatoid lung," dust and infection both appear to be involved in the pathogenesis. Infection could trigger new activity in a previously stable but chronic dust-induced lesion. Nasal carriage of Staphylococcus aureus, which is also associated with an increased rate of relapse, could play a similar role. Whether the mechanism involved is direct infection or the induction, by certain organisms, of immune deviation requires examination, since a shift from a type 1 helper T-cell response to a type 2 helper T-cell response has been associated with the abrupt development of systemic disease in patients with mycobacterial infections.
The stromal cells in the local environment, including the fibrocytes, have also been shown to influence local T-cell differentiation in chronic immune diseases such as rheumatoid arthritis. Linked investigations of immune status and the effects of external agents are required in order to elucidate the underlying molecular mechanisms. T cells are commonly present, but research has only recently begun to focus on their differentiation and cytokine secretion. Early data indicate that different subgroups of T cells predominate in localized Wegener's granulomatous and vasculitic lesions — a finding that should be pursued. Uncovering the driving forces behind both the persistence of granulomata and the shift from localized to systemic disease is a major challenge, but fresh approaches are required if the problems with the current therapies are to be solved. Such basic research on the granulomatous aspects of Wegener's granulomatosis should lead to the identification of new drug targets that may finally make the long-term maintenance of remission as effective as the current regimens for the induction of remission.
Dr. Bacon reports having served as a paid consultant for Wyeth and Merck Sharp & Dohme.(Paul A. Bacon, M.D.)
Although the airway granulomata were stressed in the original description of the condition, the systemic lesions — predominantly related to acute vasculitic inflammation — have since received more attention. Systemic Wegener's granulomatosis is noted for its severity and the high mortality associated with it. Before the introduction of immunosuppressive therapy, most patients died within two years after diagnosis. Initial clinical experience with cyclophosphamide demonstrated impressive benefits but not a long-term cure. Recent trials have provided further evidence of the benefits of cyclophosphamide and have shown that shorter courses are as effective as the longer ones previously used, with reduced toxicity. A remission rate of 90 percent can now be achieved regularly, although some patients still die relatively soon after diagnosis.
Thus, the initial response to immunosuppression with the best current therapy is impressive, but such treatment does not result in total clearance of the disease, and it is difficult to maintain a remission. Active disease can recur after 15 years of remission, perhaps because localized subclinical disease may persist during an apparent remission. Methotrexate may prolong control of the disease, but the relapse rate is high after early discontinuation of treatment. Blockade of tumor necrosis factor (TNF-) should have a place here, and observational studies suggest that it works best in granulomatous disease. It may be effective in acute vasculitis as well, insofar as it counteracts TNF-–induced endothelial-cell dysfunction. It is therefore disappointing that the recent large trial reported by Stone et al. in this issue of the Journal (pages 351–361) shows that the routine addition to therapy of long-term TNF blockade results in a negligible improvement in the maintenance of remission.
Relapse is now the primary clinical problem. It can occur even within the first 18 months of therapy and is seen in as many as 50 percent of patients by 5 years of follow-up. The relapse rate is higher with Wegener's granulomatosis than with a primary systemic vasculitis such as microscopic polyangiitis. Relapse is seen in limited (granulomatous) disease as well as in the severe systemic forms. Thus, it seems likely that relapse is generally related to granulomata. Relapse may even occur after "immune ablation" with hematopoietic stem-cell rescue, suggesting that the current immunosuppressive therapy has less effect on the granulomata than on the vasculitis. These may resolve and then develop again or, more likely, persist in a subclinical, inactive form. Experienced clinicians recognize the difficulties of distinguishing, without performing a biopsy, between "scar tissue" that remains in the airways after the induction of remission and persistent low-grade activity. Postmortem studies in patients with Wegener's granulomatosis also indicate that persistent airway inflammation is more common than has been appreciated clinically.
The concept that persistent granulomata can be at the root of relapses of Wegener's granulomatosis underscores the need to understand their pathogenesis as clearly as that of inflammatory vasculitis. Research has documented many of the immune mechanisms involved in the latter disorder. This research has focused particularly on antineutrophil cytoplasmic antibodies (ANCA). Neutrophil cytoplasmic granules move to the surface membrane in activated neutrophils, thereby becoming accessible to ANCA. Simultaneous binding to Fc receptors signals the release of neutrophil factors that are capable of causing the death of endothelial cells, with direct damage to the vessel wall (see diagram). By contrast, far less is known about the granulomatous component of Wegener's granulomatosis. Multiple types of cells are present (see diagram), but their precise roles are not well delineated. The histologic features are variable, indicating a dynamic process, but the mechanisms driving the persistence of granulomata or triggering the antibody-mediated vasculitic phase have not been determined.
Spectrum of Wegener's Granulomatosis.
The pathogenic mechanisms of the vasculitis (left) — which are related to the role of antineutrophil cytoplasmic antibodies (ANCA) — are well established. The principal cell involved is the polymorphonuclear leukocyte. By contrast, the granuloma (right) presents a variable histologic picture involving multiple types of cells whose specific roles are not clear. LPS denotes lipopolysaccharide.
The available epidemiologic data indicate that several factors may be involved. The predominance of airway disease led Wegener to postulate the involvement of inhaled agents, and several studies have since pointed to inorganic chemicals such as silica or hydrocarbons as possible factors. The individual statistical associations are not strong, but it is well established that silica in particular has the potential to stimulate granuloma formation through its effects on macrophage function. Macrophages do feature in Wegener's granulomatosis, with scant formation of giant cells, but the typical palisading of epithelioid cells is infrequent.
The seasonal incidence suggests that infection may also have a role. Central aggregates of necrotic polymorphonuclear leukocytes are seen in the granulomata occasionally, and granule release here could trigger ANCA formation. In the granulomata of "rheumatoid lung," dust and infection both appear to be involved in the pathogenesis. Infection could trigger new activity in a previously stable but chronic dust-induced lesion. Nasal carriage of Staphylococcus aureus, which is also associated with an increased rate of relapse, could play a similar role. Whether the mechanism involved is direct infection or the induction, by certain organisms, of immune deviation requires examination, since a shift from a type 1 helper T-cell response to a type 2 helper T-cell response has been associated with the abrupt development of systemic disease in patients with mycobacterial infections.
The stromal cells in the local environment, including the fibrocytes, have also been shown to influence local T-cell differentiation in chronic immune diseases such as rheumatoid arthritis. Linked investigations of immune status and the effects of external agents are required in order to elucidate the underlying molecular mechanisms. T cells are commonly present, but research has only recently begun to focus on their differentiation and cytokine secretion. Early data indicate that different subgroups of T cells predominate in localized Wegener's granulomatous and vasculitic lesions — a finding that should be pursued. Uncovering the driving forces behind both the persistence of granulomata and the shift from localized to systemic disease is a major challenge, but fresh approaches are required if the problems with the current therapies are to be solved. Such basic research on the granulomatous aspects of Wegener's granulomatosis should lead to the identification of new drug targets that may finally make the long-term maintenance of remission as effective as the current regimens for the induction of remission.
Dr. Bacon reports having served as a paid consultant for Wyeth and Merck Sharp & Dohme.(Paul A. Bacon, M.D.)