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Is there a role for TNF? blockade in ANCA-associated vasculitis and glomerulonephritis?

ABSTRACT: Tumour necrosis factor alpha (TNF?) is a cytokine that is pivotal in the inflammatory response. Blockade of TNF? has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNF? in the pathophysiology of disease, including increased expression of TNF? mRNA in leucocytes and in renal tissue. Importantly, TNF? can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNF? enhances glomerular injury and TNF? blockade using soluble TNF? receptor or anti-TNF? antibody ameliorates disease. Mice deficient in TNF? are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNF? antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNF? antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNF? antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNF? antibody. There are several clinical studies demonstrating a response to anti-TNF? antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNF? antibody was the only change in treatment. We suggest that further investigation of TNF? blockade in AAV is warranted.

SUBMITTER: McAdoo SP

PROVIDER: S-EPMC5837332 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis?

McAdoo Stephen P SP Pusey Charles D CD

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 20170101 suppl_1

Tumour necrosis factor alpha (TNFα) is a cytokine that is pivotal in the inflammatory response. Blockade of TNFα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFα in the pathophysiology of disease, including increased expression of TNFα mRNA in leu ...[more]

PMID: 28391344

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Project description:Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.

Project description:BACKGROUND:Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS:We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS:Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS:Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

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Is there a role for TNF? blockade in ANCA-associated vasculitis and glomerulonephritis?

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Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis?

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