Clinical Pearls & Morning Reports
Published May 17, 2017
The cytokine interleukin-5 regulates eosinophil proliferation, maturation, and differentiation and is present at increased levels in patients with eosinophilic granulomatosis with polyangiitis. Mepolizumab is an anti–interleukin-5 monoclonal antibody that binds to interleukin-5 and prevents its interaction with its receptor on the eosinophil surface. Wechsler et al. investigated the efficacy and safety of mepolizumab versus placebo as add-on therapy in participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis over a period of 52 weeks.
Q. What are the characteristic features of eosinophilic granulomatosis with polyangiitis?
A. Eosinophilic granulomatosis with polyangiitis (formerly known as the Churg–Strauss syndrome) is characterized by asthma, sinusitis, pulmonary infiltrates, neuropathy, and eosinophilic vasculitis of one or more end-organs. Eosinophils are thought to induce pathogenic effects in patients with eosinophilic granulomatosis with polyangiitis by means of tissue and vascular infiltration and inflammation through a variety of mediators.
Q. How effective are glucocorticoids for the treatment of eosinophilic granulomatosis with polyangiitis?
A. Although systemic glucocorticoids form the cornerstone of treatment for eosinophilic granulomatosis with polyangiitis, most patients remain dependent on glucocorticoid therapy, and relapses are common. Furthermore, some patients do not have a sufficient response to glucocorticoids. Because recurrent relapses place the patient at risk for permanent tissue or organ damage, immunosuppressive agents are used for the induction and maintenance of remission in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis, despite a paucity of evidence supporting their efficacy in this context. Given the side effects that are associated with lengthy and high-dose use of glucocorticoids and immunosuppressive agents, there is a need for additional, more effective therapies.
A: In the trial by Wechsler et al., involving participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who were receiving standard-of-care therapy, mepolizumab treatment was associated with more accrued time in remission and with a lower frequency of relapse than was placebo, which allowed for reductions in the glucocorticoid dose in the mepolizumab group. Twenty-eight percent of the participants in the mepolizumab group, as compared with 3% of those in the placebo group, had remission for at least 24 weeks (odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001). A higher percentage of participants in the mepolizumab group than in the placebo group had remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001).
A: In the trial by Wechsler et al., although 81% of the participants in the placebo group had no accrued weeks of remission, 47% of those in the mepolizumab group did not have protocol-defined remission, either, which suggests that not all patients will have the same benefit. It remains unknown why mepolizumab was effective with regard to protocol-defined remission in approximately half the participants but not in the entire trial cohort. One consideration is that eosinophilic granulomatosis with polyangiitis is a heterogeneous disease with some manifestations being non–eosinophil driven. Another possibility is that some participants may have had long-standing, irreversible vasculitic damage that was refractory to anti–interleukin-5 therapy. Alternatively, although mepolizumab reduced blood eosinophils, the dose may have been insufficient to eliminate tissue eosinophils. Finally, adrenal insufficiency that was due to long-standing glucocorticoid use may have precluded adequate glucocorticoid tapering that would result in protocol-defined remission in some participants.