Current Understanding and Unknown Aspects of the Treatment of Granulomatosis with Polyangiitis (Wegener's Granulomatosis): Opportunities for Future Studies

Granulomatosis with polyangiitis (GPA) is a rare and systemic autoimmune disease, causing necrotizing vasculitis of small arteries and veins. The majority of diagnosed patients with GPA have circulating anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3). Here, we have reviewed the last findings and uncertainties regarding the treatment of GPA. Between the available treatments, in addition to corticosteroids, cyclophosphamide (CYP) is effective for remission-induction, while it is associated with some serious side effects, such as infertility and increased risk of malignancies. On the other side, rituximab (RTX) seems a safer alternative option and as effective as CYP. It could be used as both remission-induction and maintenance therapy in GPA patients, especially in women of childbearing age. Pregnant patients, who must not be exposed to the CYP and RTX could be well-managed with intravenous immunoglobulin (IVIg). Co-trimoxazole, which is widely used to treat certain bacterial infections or as prophylaxis in immunosuppressed patients, could be effective in preventing disease relapse. In the meantime, 15- deoxyspergualin, plasma exchange are other therapeutic options with a low level of evidence. Regarding potential treatments, ofatumumab, ocrelizumab, belimumab, atacicept, tabalumab, abatacept (CTLA4-Ig), and Janus kinase inhibitors seem to be effective. Renal involvement, older age, the presence of baseline organ damage, delayed-diagnosis of disease, rising in creatinine level, and higher neutrophil/lymphocyte ratio is associated with poor outcomes. Optimum doses of medications, prediction of treatment response and disease relapse, explaining lack of response in some patients, treating children with GPA, and management of GPA during the pregnancy are controversial issues, which need further studies.