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In-Depth Reviews
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TNF-α Bioactivity-Inhibiting Therapy in ANCA-Associated Vasculitis: Clinical and Experimental Considerations

Dennis Huugen, Jan Willem Cohen Tervaert and Peter Heeringa
CJASN September 2006, 1 (5) 1100-1107; DOI: https://doi.org/10.2215/CJN.02181205
Dennis Huugen
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Jan Willem Cohen Tervaert
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Peter Heeringa
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Abstract

Wegener’s granulomatosis, microscopic polyangiitis, idiopathic necrotizing crescentic glomerulonephritis, and Churg-Strauss syndrome are associated with the presence of ANCA with specificity for myeloperoxidase or proteinase 3. Current therapy consists mainly of corticosteroids and cyclophosphamide, but because this treatment regimen is associated with considerable morbidity, other treatment modalities remain desirable. There is compelling evidence that TNF-α plays an important role in the pathogenesis of ANCA-associated vasculitis. Consequently, inhibition of TNF-α bioactivity potentially results in attenuation of disease. This review discusses whether TNF-α bioactivity-inhibiting drugs are useful in the treatment of ANCA-associated vasculitis. The results of in vitro and in vivo experiments, as well as clinical studies, are evaluated. Although the importance of TNF-α during lesion development is evident, clinical trials that use TNF-α blockers in patients with ANCA-associated vasculitis give mixed results. Importantly, in a large-scale, randomized trial, treatment with etanercept was found not to be effective and resulted in an excess of treatment-related morbidity. It remains to be investigated whether inhibition of TNF-α bioactivity is effective in a subgroup of patients.

Wegener’s granulomatosis (WG), microscopic polyangiitis, idiopathic necrotizing crescentic glomerulonephritis (NCGN), and Churg-Strauss syndrome are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) (1). They are widely used as serum markers not only for the diagnosis of systemic vasculitis but also for follow-up, because ANCA levels predict disease reactivation in most patients (2). In vasculitis and glomerulonephritis, the main ANCA antigens are the myeloid enzymes myeloperoxidase (MPO) and proteinase 3 (PR3), but in a minority of patients, ANCA are specific for other neutrophil proteins, such as elastase.

To date, therapy for ANCA-associated disease consists mainly of immunosuppression with high-dose glucocorticoids and cyclophosphamide during the induction phase and azathioprine in combination with low-dosage steroids as maintenance therapy. This therapeutic regimen is associated with considerable morbidity and often proves to be insufficient for the induction of a sustained remission, because most patients develop relapsing disease activity during follow-up. Consequently, renal, pulmonary, and/or other organ damage is encountered (3).

In various immune-mediated diseases, including rheumatoid arthritis (4–6), Crohn’s disease (7), and ankylosing spondylitis (8,9), the efficacy of TNF-α–inhibiting treatment is well established. Also in several forms of vasculitis, such as Takayasu arteritis (10) and Behçet’s disease (11–13), there is evidence that inhibition of TNF-α bioactivity is beneficial.

Here, we review the literature on the role of TNF-α in ANCA-associated vasculitides. In vitro studies as well as in vivo experimental data and clinical trials on the feasibility of TNF-α bioactivity inhibition are discussed, as well as their consequences for the future use of this treatment modality in patients with ANCA-associated disease.

Role of TNF-α in ANCA-Associated Vasculitis: In Vitro Observations

A considerable amount of data that were obtained from in vitro experiments point toward a role for TNF-α in the pathogenesis of ANCA-associated disease. Importantly, ANCA-induced neutrophil activation is greatly enhanced by TNF-α, leading to an increased release of oxygen radicals and toxic granule constituents (14–18). The exact mechanism of this effect is uncertain, but several reports demonstrate an increased presence of MPO and/or PR3 on the outer membrane of neutrophils after incubation with TNF-α (16,17,19,20). This increases the availability of the ANCA antigens for binding of the autoantibodies. In addition, neutrophil priming with TNF-α causes upregulation of various molecules that are involved in adhesion of neutrophils to the endothelium (21), and it has been demonstrated convincingly that one of these molecules in particular, the β2 integrin CD11b/CD18 (CR3), is critically involved in ANCA-induced neutrophil activation (22). In vitro, TNF-α pretreatment of endothelial cells makes them more susceptible to damage that is induced by incubation with ANCA-stimulated neutrophils, in particular when those neutrophils also are preincubated with TNF-α (23,24). Moreover, pretreatment of human umbilical cord vascular endothelial cells with TNF-α is necessary for the establishment of firm adhesion of ANCA-stimulated neutrophils to those cells (25).

Taken together, in vitro data point toward a mechanism in which TNF-α and ANCA together induce the activation of neutrophils. These activated neutrophils attach to the endothelium, release their toxic granule constituents and oxygen radicals, and thereby cause vascular damage.

TNF-α in Animal Models of Autoimmune Crescentic Glomerulonephritis

In crescentic glomerulonephritis, the role of TNF-α has been investigated most thoroughly in animal models of anti–glomerular basement membrane (GBM) glomerulonephritis. In these models, heterologous antibodies to the GBM are administered to mice or rats, respectively, either with (in the accelerated model) or without (in the heterologous model) preceding immunization with unspecific heterologous antibodies. This results in crescentic glomerulonephritis that is characterized by massive early neutrophil influx and an abundance of immune complexes.

Le Hir et al. (26) studied the role of TNF-α in the accelerated model of anti-GBM glomerulonephritis using TNF-α knockout (TNF-α−/−) mice and found that TNF-α deficiency led to attenuation but no complete inhibition of disease as reflected by delayed onset of proteinuria and attenuation of histopathologic and immunohistochemical alterations. Importantly, no significant decrease in early neutrophil influx could be observed in the TNF-α−/− mice.

Whereas TNF-α−/− mice are only partially protected from disease in the accelerated model of anti-GBM GN, treatment with daily doses of a soluble TNF-α receptor (sTNFr) from day −1 onward completely prevents the development of crescents in the heterologous rat model of anti-GBM GN (27). An explanation for the discrepancy between this study and the study in TNF-α−/− mice by le Hir et al. is not provided, but it is conceivable that TNF-α plays a more profound role in the heterologous, neutrophil-dependent, than in the accelerated model of anti-GBM disease. Alternatively, TNF-α−/− mice, because of their lifelong lack of endogenous TNF-α, may have developed a compensatory mechanism for this deficiency, thereby increasing the levels of alternative proinflammatory cytokines that play a role in the development of anti-GBM GN. It is interesting that in the rat model, treatment of established anti-GBM disease (from day +4 onward) with sTNFr resulted in a marked attenuation of disease 10 d after disease induction, reflected by reduced proteinuria, crescent formation, fibrinoid necrosis, and glomerular influx of monocytes and cytotoxic T cells (27). This suggests that TNF-α plays a role not only in the initial phase of disease development but also in maintaining the disease, a notion that is supported further by a more recent study from the same group, in which the effect of a TNF-α–inhibiting mAb on the course of (heterologous) anti-GBM GN was studied in rats that were followed for as long as 28 d (28). In this study, treatment of established anti-GBM GN with anti–TNF-α mAb from day 4 or day 14 until the rats were killed at day 28 significantly attenuated disease as measured by glomerular and tubulointerstitial scarring and serum creatinine level.

Investigation of the role of TNF-α in ANCA-associated GN long has been hampered by the lack of an animal model in which the pathogenicity of ANCA could be demonstrated convincingly. In a mouse model of spontaneous crescentic glomerulonephritis in SCG/Kj mice (29), TNF-α levels were shown to be elevated compared with healthy C57Bl/6 mice (30). Although MPO-ANCA are detected in these mice, they also display massive glomerular immune complex depositions and elevated titers of anti-nuclear autoantibodies (31). Therefore, the contribution of MPO-ANCA to the pathology that is observed in this model is questionable.

An alternative mouse model of MPO-ANCA–associated vasculitis is provided by Xiao et al. (32), who showed that transfer of IgG or splenocytes from murine MPO-immunized MPO knockout (MPO−/−) mice to wild-type or immune-deficient mice induces disease manifestations similar to those observed in human MPO-ANCA–associated disease. Using the passive transfer model of anti-MPO IgG-induced glomerulonephritis, we recently demonstrated that a “second hit” with LPS significantly increased the severity of anti-MPO IgG-induced lesions (33). Furthermore, in this accelerated model of MPO-ANCA–induced GN, we found that administration of a single dose of TNF-α bioactivity-inhibiting mAb 1 d before disease induction led to a significant decrease but no complete inhibition of renal disease as measured by the degree of urinary abnormalities and the percentage of crescentic glomeruli. This study suggests that TNF-α plays an important, although not pivotal, role in the pathogenesis of NCGN induced by anti-MPO IgG and LPS. However, the fact that these results are obtained after preemptive anti–TNF-α treatment might limit their applicability for the clinical situation.

It is interesting that the effect of TNF-α bioactivity-inhibiting therapy also was investigated recently in a novel rat model of MPO-ANCA–associated NCGN. In this model, the immunization of WKY/NCrlBR rats with human MPO leads to the generation of anti-human MPO antibodies that cross-react with rat MPO, resulting in pulmonary vasculitis and pauci-immune NCGN in some animals (34). In addition, treatment of established disease with a TNF-α–inhibiting mAb strongly reduced albuminuria and completely reversed crescent formation (35).

Taken together, data obtained from animal models of anti-GBM as well as MPO-ANCA–associated NCGN clearly indicate that TNF-α plays an important role in disease induction and progression and suggest a beneficial role for TNF-α bioactivity inhibition in humans. Due caution should be taken, however, when extrapolating the results from animal experiments to the human situation.

TNF-α Inhibition: Human Studies

The efficacy of two TNF-α–inhibiting drugs has been investigated in patients with ANCA-associated NCGN. First, etanercept (Enbrel, Wyeth Pharmaceuticals, Madison, NJ) is a fusion protein of two p75 subunits of the TNF-α receptor, linked to the Fc portion of human IgG1. Second, infliximab (Remicade, Centocor, Horsham, PA) is a chimeric IgG1 mAb that binds and inhibits soluble as well as membrane-bound TNF-α. The efficacy of both treatments in patients with rheumatoid arthritis seems to be comparable (36), but in patients with Crohn’s disease, etanercept, in contrast to infliximab, seems not to be effective (37). The role of adalimumab (Humira, Abbott, Chicago, IL), a novel, fully human TNF-α–inhibiting mAb (38) that has been shown to be effective in rheumatoid arthritis and Crohn’s disease when the response to etanercept or infliximab is lost (39,40), in the treatment of ANCA-associated vasculitis remains to be established.

From the in vitro and in vivo studies on the role of TNF-α in ANCA-associated vasculitis discussed above, it may be hypothesized that an effect of anti–TNF-α treatment would be the result of inhibition of TNF-α–induced preactivation of neutrophils. This would lead to decreased membrane expression of the ANCA antigens, which makes it impossible for the autoantibodies to exert their pathogenic effect.

Several clinical studies provide indirect evidence for a role of TNF-α in ANCA-associated vasculitis. First, plasma levels of TNF-α are increased in patients with ANCA-associated GN, and increased amounts of TNF-α can be found by immunohistochemistry (41). Second, the fractional excretion of TNF-α is increased in patients with ANCA-associated GN, suggesting local production by renal cells or infiltrating leukocytes (42). Third, response to treatment with intravenous Ig is accompanied by a decrease in serum TNF-α level (43). Finally, it has been shown in rheumatoid arthritis that TNF-α is pivotally involved in a tightly regulated network of proinflammatory cytokines and is responsible for the increased production of IL-1, IL-6, and IL-8 and GM-CSF (reviewed in reference [44]). Consequently, inhibition of TNF-α bioactivity in patients with ANCA-associated vasculitis also would result in decreased levels of those cytokines and thereby decrease vascular inflammation.

The human studies on TNF-α bioinhibition in ANCA-associated vasculitis are summarized briefly in Table 1. In the first study, infliximab was added in an uncontrolled manner to standard treatment that consisted of corticosteroids and cyclophosphamide in six patients with treatment-resistant WG (45). In five cases, this led to remission that lasted for 6 to 24 mo. Addition of infliximab to standard immunosuppressive therapy also led to remission in a more recently published case of Wegener’s disease (46).

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Table 1.

Human studies on TNF-α inhibitiona

A large, prospective, but also uncontrolled trial among patients with MPO- or PR3-ANCA–positive vasculitis was published in 2004 (47). Addition of infliximab to standard therapy at initial presentation, during relapse, or during persistent disease activity was followed by a clinical response in 28 of 32 patients, as measured with the Birmingham Vasculitis Activity Score (48) and reflected by a decrease in C-reactive protein, serum creatinine, and required steroid dosage. Unfortunately, however, many adverse effects were observed, including several cases of infection, thrombotic events, and a case of B cell lymphoma, complicating clinical response. In addition, despite ongoing treatment with infliximab, relapses were observed frequently. This suggests an escape mechanism that might be mediated partly by the development of anti-infliximab antibodies (6,49–52), although this was not investigated in detail. In an accompanying paper, the administration of infliximab significantly improved endothelial function in 10 patients with active ANCA-associated disease, as measured by endothelium-dependent vasodilation, and also in these patients, a clinical response was observed (53).

Until now, studies have focused mainly on the addition of infliximab to standard immunosuppressive therapy, and there is only limited information on infliximab replacing standard treatment. In an uncontrolled study on 10 patients with conventional therapy-resistant systemic vasculitis, seven of whom had WG, Bartolucci et al. (54) found that treatment with corticosteroids and infliximab led to a considerable resolution of disease symptoms and corticosteroid requirement at 42 d and 6 mo. Although limited in size and uncontrolled, this study encourages further research into the replacement of conventional treatment by infliximab in individuals who have ANCA-associated vasculitis and fail to enter remission under standard therapy. A case report in which remission induction was achieved in a patient with microscopic polyangiitis after primary treatment with prednisolone, cotrimoxazole/trimethoprim, and four infusions of infliximab supports this notion (55).

In contrast to data on the use of infliximab, the effect of etanercept in patients with WG is less promising. In the only double-blind, placebo-controlled, multicenter trial on the use of TNF-α–inhibiting therapy in ANCA-associated vasculitis presented thus far, the Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group investigated the efficacy of the addition of etanercept to standard therapy (56). Patients with limited and severe disease, either newly diagnosed or relapsing, were enrolled. Standard treatment for limited and severe disease consisted of glucocorticoids and of methotrexate or cyclophosphamide, respectively; etanercept or placebo was randomly added to this as experimental treatment. Between the etanercept and placebo groups, no significant differences were found in remission rates; disease flares; and disease activity, damage, or quality-of-life scores. Remarkably, during follow-up, six cases of cancer were identified in the etanercept group, whereas no such events were seen in the control group. No significant differences were found in the incidence and the severity of other adverse events.

The results of the etanercept study are surprisingly negative and seem to be in remarkable contrast to the data that were obtained from animal studies and clinical trials using infliximab. A discrepancy between the effect of etanercept and infliximab was observed previously in another granulomatous disease, Crohn’s disease (37), and potentially could be explained from differences in the working mechanism of the drugs. First, infliximab binds soluble and membrane-bound TNF-α much better than etanercept, resulting in an increased capacity of infliximab to inhibit TNF-α–mediated cytotoxicity and TNF-α–induced endothelial cell activation (57). Second, infliximab but not etanercept can induce an anti-inflammatory response by reverse signaling through membrane-bound TNF-α (58). Finally, infliximab and etanercept exert different effects on T lymphocytes (59,60) and monocytes (61).

Limitations to TNF-α–Inhibiting Therapy

From the studies on TNF-α inhibition in ANCA-associated vasculitis, as well as from similar studies that were performed in patients with other autoimmune diseases, several lessons can be drawn with respect to safety issues regarding this therapy. Generally, TNF-α–inhibiting therapy can lead to infusion reactions, such as headache, irritation at the site of injection, dizziness, nausea, chest pain, dyspnea, and pruritus. In addition, treatment with infliximab is associated with a higher rate of infections (6,49), in particular with an increased risk for reactivation of tuberculosis (62). In line with these findings, treatment with infliximab in patients with ANCA-associated vasculitis resulted in infections in 22% of the patients (47). However, in patients who had WG and were treated with etanercept (56), as well as in several controlled trials on infliximab in rheumatoid arthritis (5) and ankylosing spondylitis (8), the incidence of infection was similar in the treatment and control groups.

The role of TNF-α in carcinogenesis is complex and incompletely understood (63). The effect of anti–TNF-α therapy on the development of malignancies has been studied predominantly in rheumatoid arthritis, a disease that is associated with a higher incidence of malignancies (64). In this disease, a large case series (65), a controlled retrospective study (66), a large prospective study (64), and a controlled trial (6) suggest that treatment with infliximab or etanercept makes patients more prone to the development or recurrence of cancer, in particular lymphomas. Conversely, Lipsky et al. (5) found in a large prospective study that the incidence of malignancies in patients who had arthritis and were treated with infliximab was similar to background levels. In the WGET, the treatment of WG with etanercept increased the incidence of solid cancer (56), whereas one of 32 patients with ANCA-associated vasculitis was reported to have developed a B cell lymphoma during treatment with infliximab (47). Therefore, the link between TNF-α inhibition and malignancies should be investigated in more detail before any conclusion can be drawn with respect to this issue.

The high incidence of venous thromboembolic complications entails a new potential threat for patients with Wegener’s disease (67). Bearing this in mind, it is of particular concern to gather information on the thrombogenic effects of TNF-α–inhibiting therapy. Whereas TNF-α generally is thought to be prothrombotic in vivo (reviewed in reference [68]), the putative anticoagulant effect of TNF-α inhibition is challenged by the finding that anti–TNF-α can have a prothrombotic effect in chimpanzees (69). In addition, it has been shown that treatment with infliximab or etanercept can induce the formation of potentially prothrombotic anticardiolipin autoantibodies (70). In the WGET, however, no prothrombotic effect of etanercept was found (56).

Treatment with infliximab as well as etanercept has been associated with increased levels of autoantibodies and/or a lupus-like autoimmune disease (reviewed in reference [71]). This has been studied most extensively in patients with rheumatoid arthritis (5,6,70,72–75), but anti–TNF-α treatment also was shown to induce autoimmunity in ankylosing spondylitis (75), Crohn’s disease (51,52), and mixed connective tissue disease (76). The development of autoantibodies in these patients only very rarely leads to a (usually mild) lupus-like syndrome that resolves after discontinuation of anti–TNF-α therapy. However, anti–TNF-α therapy was complicated by the development of more severe glomerulonephritis in five patients who had rheumatoid arthritis and were treated with etanercept, infliximab, or adalimumab (77). In the WGET (56), as well as in the infliximab study (47), the incidence of autoimmunity was not reported. Nevertheless, autoimmunity that is induced by anti–TNF-α therapy remains an issue of concern in patients with ANCA-associated vasculitis as well.

Conclusion

Taken together, in vitro data support the notion that TNF-α plays an important role in the pathogenesis of ANCA-associated vasculitis and NCGN. Consequently, TNF-α bioactivity-inhibiting therapy might be effective in this disease. This is supported further by several studies in animal models of crescentic GN, although caution should be taken when translating animal studies to the clinical situation. In the only controlled study on TNF-α bioinhibition in patients with ANCA-associated vasculitis, addition of etanercept to standard immunosuppressive therapy did not lead to improvement and was associated with the occurrence of serious adverse effects. It remains to be seen whether other approaches will be effective. In future studies, patients whose disease is refractory to current treatment strategies should be tested in a controlled manner, and infliximab should be tested instead of etanercept as additional therapy to standard immunosuppressive regimens. Thus far, only 65 patients with ANCA-associated renal disease have been reported to be treated with anti–TNF-α therapy. Lack of control subjects, publication bias, and the short-term nature of the reports severely limit any conclusions regarding efficacy. Therefore, patients should receive anti–TNF-α treatment only in a randomized, controlled manner or in the case of life-threatening disease, when no alternative therapeutic options are available. The incidence of potential adverse effects, such as infections, malignancies, thromboembolic complications, and autoimmunity, should be of specific concern.

Acknowledgments

D.H. and P.H. are supported by the Dutch Kidney Foundation (C01.1927) and the Dutch Wegener's Foundation. P.H. is supported by a grant from The Netherlands Organization for Scientific Research (NWO VIDI grant 917.66.341).

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Copyright © 2006 by the American Society of Nephrology

References

  1. Franssen CF, Stegeman CA, Kallenberg CG, Gans RO, De Jong PE, Hoorntje SJ, Cohen Tervaert JW: Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Kidney Int57 :2195– 2206,2000
  2. Cohen Tervaert JW, Huitema MG, Hene RJ, Sluiter WJ, The TH, van der Hem GK, Kallenberg CG: Prevention of relapses in Wegener’s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet336 :709– 711,1990
  3. Slot MC, Cohen Tervaert JW, Franssen CF, Stegeman CA: Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. Kidney Int63 :670– 677,2003
  4. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK: A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med343 :1586– 1593,2000
  5. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med343 :1594– 1602,2000
  6. St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D: Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum50 :3432– 3443,2004
  7. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med337 :1029– 1035,1997
  8. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J: Treatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trial. Lancet359 :1187– 1193,2002
  9. Gorman JD, Sack KE, Davis JC Jr: Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med346 :1349– 1356.2002
  10. Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P: Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum50 :2296– 2304,2004
  11. Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G: Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behcet’s disease with refractory uveoretinitis. J Rheumatol31 :1362– 1368,2004
  12. Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V, Yazici H: Short-term trial of etanercept in Behcet’s disease: A double blind, placebo controlled study. J Rheumatol32 :98– 105,2005
  13. Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gul A: Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet’s disease: An open-label trial. Arthritis Rheum52 :2478– 2484,2005
  14. Falk RJ, Terrell RS, Charles LA, Jennette JC: Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A87 :4115– 4119,1990
  15. Franssen CF, Huitema MG, Muller Kobold AC, Oost-Kort WW, Limburg PC, Tiebosch A, Stegeman CA, Kallenberg CG, Cohen Tervaert JW: In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis. J Am Soc Nephrol10 :1506– 1515,1999
  16. Hess C, Sadallah S, Schifferli JA: Induction of neutrophil responsiveness to myeloperoxidase antibodies by their exposure to supernatant of degranulated autologous neutrophils. Blood96 :2822– 2827,2000
  17. Kettritz R, Schreiber A, Luft FC, Haller H: Role of mitogen-activated protein kinases in activation of human neutrophils by antineutrophil cytoplasmic antibodies. J Am Soc Nephrol12 :37– 46,2001
  18. Rarok AA, Limburg PC, Kallenberg CG: Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies. J Leukoc Biol74 :3– 15,2003
  19. Porges AJ, Redecha PB, Kimberly WT, Csernok E, Gross WL, Kimberly RP: Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol153 :1271– 1280,1994
  20. Harper L, Radford D, Plant T, Drayson M, Adu D, Savage CO: IgG from myeloperoxidase-antineutrophil cytoplasmic antibody-positive patients stimulates greater activation of primed neutrophils than IgG from proteinase 3-antineutrophil cytoplasmic antibody-positive patients. Arthritis Rheum44 :921– 930,2001
  21. Condliffe AM, Chilvers ER, Haslett C, Dransfield I: Priming differentially regulates neutrophil adhesion molecule expression/function. Immunology89 :105– 111,1996
  22. Reumaux D, Vossebeld PJ, Roos D, Verhoeven AJ: Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: Relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies. Blood86 :3189– 3195,1995
  23. Savage CO, Pottinger BE, Gaskin G, Pusey CD, Pearson JD: Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol141 :335– 342,1992
  24. Ewert BH, Jennette JC, Falk RJ: Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney Int41 :375– 383,1992
  25. Radford DJ, Luu NT, Hewins P, Nash GB, Savage CO: Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum44 :2851– 2861,2001
  26. Le Hir M, Haas C, Marino M, Ryffel B: Prevention of crescentic glomerulonephritis induced by anti-glomerular membrane antibody in tumor necrosis factor-deficient mice. Lab Invest78 :1625– 1631,1998
  27. Karkar AM, Smith J, Pusey CD: Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumour necrosis factor-alpha. Nephrol Dial Transplant16 :518– 524,2001
  28. Khan SB, Cook HT, Bhangal G, Smith J, Tam FW, Pusey CD: Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis. Kidney Int67 :1812– 1820,2005
  29. Kinjoh K, Kyogoku M, Good RA: Genetic selection for crescent formation yields mouse strain with rapidly progressive glomerulonephritis and small vessel vasculitis. Proc Natl Acad Sci U S A90 :3413– 3417,1993
  30. Ishida-Okawara A, Ito-Ihara T, Muso E, Ono T, Saiga K, Nemoto K, Suzuki K: Neutrophil contribution to the crescentic glomerulonephritis in SCG/Kj mice. Nephrol Dial Transplant19 :1708– 1715,2004
  31. Neumann I, Birck R, Newman M, Schnulle P, Kriz W, Nemoto K, Yard B, Waldherr R, Van Der Woude FJ: SCG/Kinjoh mice: A model of ANCA-associated crescentic glomerulonephritis with immune deposits. Kidney Int64 :140– 148,2003
  32. Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, Maeda N, Falk RJ, Jennette JC: Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest110 :955– 963,2002
  33. Huugen D, Xiao H, van Esch A, Falk RJ, Peutz-Kootstra CJ, Buurman WA, Tervaert JW, Jennette JC, Heeringa P: Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: Role of tumor necrosis factor-alpha. Am J Pathol167 :47– 58,2005
  34. Little MA, Smyth CL, Yadav R, Ambrose L, Cook HT, Nourshargh S, Pusey CD: Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood106 :2050– 2058,2005
  35. Little MA, Bhangal G, Smyth CL, Nakada MT, Cook HT, Nourshargh S, Pusey CD: Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis. J Am Soc Nephrol17 :160– 169,2006
  36. Hochberg MC, Tracy JK, Hawkins-Holt M, Flores RH: Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis62[Suppl 2] :ii13– ii16,2003
  37. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, Tremaine WJ, Johnson T, Diehl NN, Zinsmeister AR: Etanercept for active Crohn’s disease: A randomized, double-blind, placebo-controlled trial. Gastroenterology121 :1088– 1094,2001
  38. Rau R: Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: The initial results of five trials. Ann Rheum Dis61[Suppl 2] :ii70– ii73,2002
  39. Wick MC, Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF: Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): Results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol34 :353– 358,2005
  40. Papadakis KA, Shaye OA, Vasiliauskas EA, Ippoliti A, Dubinsky MC, Birt J, Paavola J, Lee SK, Price J, Targan SR, Abreu MT: Safety and efficacy of adalimumab (D2E7) in Crohn’s disease patients with an attenuated response to infliximab. Am J Gastroenterol100 :75– 79,2005
  41. Noronha IL, Kruger C, Andrassy K, Ritz E, Waldherr R: In situ production of TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis. Kidney Int43 :682– 692,1993
  42. Tesar V, Masek Z, Rychlik I, Merta M, Bartunkova J, Stejskalova A, Zabka J, Janatkova I, Fucikova T, Dostal C, Becvar R: Cytokines and adhesion molecules in renal vasculitis and lupus nephritis. Nephrol Dial Transplant13 :1662– 1667,1998
  43. Ito-Ihara T, Ono T, Nogaki F, Suyama K, Tanaka M, Yonemoto S, Fukatsu A, Kita T, Suzuki K, Muso E: Clinical efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis. Nephron Clin Pract102 :c35– c42,2006
  44. Feldmann M, Maini RN: Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med9 :1245– 1250,2003
  45. Lamprecht P, Voswinkel J, Lilienthal T, Nolle B, Heller M, Gross WL, Gause A: Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology (Oxford)41 :1303– 1307,2002
  46. Kleinert J, Lorenz M, Kostler W, Horl W, Sunder-Plassmann G, Soleiman A: Refractory Wegener’s granulomatosis responds to tumor necrosis factor blockade. Wien Klin Wochenschr116 :334– 338,2004
  47. Booth A, Harper L, Hammad T, Bacon P, Griffith M, Levy J, Savage C, Pusey C, Jayne D: Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol15 :717– 721,2004
  48. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D: Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM87 :671– 678,1994
  49. Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, Mayer L, Van Hogezand RA, Braakman T, DeWoody KL, Schaible TF, Van Deventer SJ: Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology117 :761– 769,1999
  50. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ: Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med340 :1398– 1405,1999
  51. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P: Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet359 :1541– 1549,2002
  52. Vermeire S, Noman M, Van Assche G, Baert F, Van Steen K, Esters N, Joossens S, Bossuyt X, Rutgeerts P: Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease: A prospective cohort study. Gastroenterology125 :32– 39,2003
  53. Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, Wilkinson IB: Infliximab improves endothelial dysfunction in systemic vasculitis. A model of vascular inflammation. Circulation109 :1718– 1723,2004
  54. Bartolucci P, Ramanoelina J, Cohen P, Mahr A, Godmer P, Le Hello C, Guillevin L: Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: An open pilot study on 10 patients. Rheumatology (Oxford)41 :1126– 1132,2002
  55. Zaenker M, Arbach O, Helmchen U, Glorius P, Ludewig S, Braasch E: Crescentic glomerulonephritis associated with myeloperoxidase-antineutrophil-cytoplasmic antibodies: First report on the efficacy of primary anti-TNF-alpha treatment. Int J Tissue React26 :85– 92,2004
  56. The Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group: Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med352 :351– 361,2005
  57. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C: Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther301 :418– 426,2002
  58. Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y, Otsuka J, Okamura S, Fujita S, Harada M: Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology128 :376– 392,2005
  59. Van den Brande JM, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, van Montfrans C, Hommes DW, Peppelenbosch MP, van Deventer SJ: Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology124 :1774– 1785,2003
  60. Agnholt J, Dahlerup JF, Kaltoft K: The effect of etanercept and infliximab on the production of tumour necrosis factor alpha, interferon-gamma and GM-CSF in in vivo activated intestinal T lymphocyte cultures. Cytokine23 :76– 85,2003
  61. Kirchner S, Holler E, Haffner S, Andreesen R, Eissner G: Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine28 :67– 74,2004
  62. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med345 :1098– 1104,2001
  63. Balkwill F: Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev13 :135– 141,2002
  64. Wolfe F, Michaud K: Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum50 :1740– 1751,2004
  65. Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM: Tumor necrosis factor antagonist therapy and lymphoma development: Twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum46 :3151– 3158,2002
  66. Geborek P, Bladstrom A, Turesson C, Gulfe A, Petersson IF, Saxne T, Olsson H, Jacobsson LT: Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis64 :699– 703,2005
  67. Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis JC Jr, Hoffman GS, McCune WJ, St Clair EW, Specks U, Spiera R, Petri M, Stone JH: Brief communication: High incidence of venous thrombotic events among patients with Wegener granulomatosis: The Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med142 :620– 626,2005
  68. Joseph L, Fink LM, Hauer-Jensen M: Cytokines in coagulation and thrombosis: A preclinical and clinical review. Blood Coagul Fibrinolysis13 :105– 116,2002
  69. van der Poll T, Levi M, van Deventer SJ, ten Cate H, Haagmans BL, Biemond BJ, Buller HR, Hack CE, ten Cate JW: Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood83 :446– 451,1994
  70. Jonsdottir T, Forslid J, van Vollenhoven A, Harju A, Brannemark S, Klareskog L, van Vollenhoven RF: Treatment with tumour necrosis factor alpha antagonists in patients with rheumatoid arthritis induces anticardiolipin antibodies. Ann Rheum Dis63 :1075– 1078,2004
  71. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P: Autoimmunity and anti-TNF-alpha agents. Ann N Y Acad Sci1051 :559– 569,2005
  72. Brion PH, Mittal-Henkle A, Kalunian KC: Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med131 :634– 569,1999
  73. Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN: Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: Findings in open-label and randomized placebo-controlled trials. Arthritis Rheum43 :2383– 2390,2000
  74. Shakoor N, Michalska M, Harris CA, Block JA: Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet359 :579– 580,2002
  75. Ferraro-Peyret C, Coury F, Tebib JG, Bienvenu J, Fabien N: Infliximab therapy in rheumatoid arthritis and ankylosing spondylitis-induced specific antinuclear and antiphospholipid autoantibodies without autoimmune clinical manifestations: A two-year prospective study. Arthritis Res Ther6 :R535– R543,2004
  76. Christopher-Stine L, Wigley F: Tumor necrosis factor-alpha antagonists induce lupus-like syndrome in patients with scleroderma overlap/mixed connective tissue disease. J Rheumatol30 :2725– 2727,2003
  77. Stokes MB, Foster K, Markowitz GS, Ebrahimi F, Hines W, Kaufman D, Moore B, Wolde D, D’Agati VD: Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant20 :1400– 1406,2005

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