TNF-α Blocker Therapy and Solid Malignancy Risk in ANCA-Associated Vasculitis

Abstract

ANCA-associated vasculitides (AAV) are small vessel systemic vasculitis syndromes associated with the potential for high morbidity and mortality. This group includes granulomatosis with polyangiitis (Wegener´s, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). The standard treatment consists of a combination of glucocorticoids and potent immunosuppressant drugs. These have broad mechanisms of action as well as important adverse effects. Efforts have been made to investigate novel agents with better-defined and narrower mechanisms of action, such as biologics, including TNF-α blockers. Etanercept, a well-known TNF-α blocker evaluated for GPA in the Wegener's Granulomatosis Etanercept Trial (WGET), was associated with an increase in the development of solid malignancies in comparison to placebo during that trial period. A 5-year follow-up after the WGET trial showed a sustained increase in incidence of solid malignancies, but this could no longer be solely attributed to etanercept exposure. These studies raised concerns about the use of the family of TNF-α blockers in AAV. Here, we review the evidence about the association between therapeutic inhibition of tumor necrosis factor (TNF-α) by etanercept and other TNF-α blockers with the development of solid malignancies in GPA and other AAV.

ANCA-Associated Vasculitis: Advancement in Pathogenesis, Clinical Features and Management

“…Currently, the monoclonal antibodies, rituximab, and mepolizumab have been reported as novel drugs in AAVs treatment [11,12]. Our previous data confirmed that TNF-α blockers in rheumatic diseases e. g. rheumatoid arthritis compromised the disease activity [13] whereas, TNF-α blocker, etanercept characterized by increasing solid malignancies development [14].…”

Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies

“…These data suggest a unique functional role for domain III, which may be employed as a ligand receiving pocket such as EGFR, HER3, and HER4. Ligand-induced activation of EGFR involves a marked change in the extracellular region from a 'tethered' (inactive) to an 'extended' (active) configuration, 27 in which an exposed 'dimerization arm' in domain II drives the formation of receptor dimers. 28 In tethered EGFR, the dimerization arm is occluded by auto-inhibitory intramolecular interactions between domains II and IV, which are also observed in unliganded ErbB3 and ErbB4 but are absent in ErbB2.…”

Merkel cell carcinoma in a patient treated with infliximab: Beware of the subcutaneous nodule

“…It is proposed that TNF-alpha inhibitors enhance malignant growth via the blockage of TNF-alpha and its anti-tumoral mechanisms. [12][13][14] An experimental animal tumour model demonstrated that anti-TNF alpha antibodies hindered anti-tumour immune responses and promoted the growth of immunogenic rat colon tumours that were rejected by immunocompetent untreated rats.…”