Treatment of granulomatosis with polyangiitis (Wegener’s)

Abstract

Granulomatosis with polyangiitis is a systemic necrotizing vasculitis characterized by granulomatous inflammation of small vessels and is associated with autoantibodies to neutrophil cytoplasmic proteases, mainly proteinase 3. Potentially lethal if not promptly diagnosed and treated, most patients with granulomatosis with polyangiitis can achieve remission with the current treatment modalities, with fewer side effects compared to three decades ago. However, the risk of relapse remains high, necessitating prolonged maintenance immunosuppressive therapy whose optimal duration remains undetermined. We review herein the treatment modalities for granulomatosis with polyangiitis and how they have evolved over the past decades. The findings of the most important and recently completed therapeutic studies, including on rituximab for maintenance, are summarized, before describing the main ongoing studies aimed at further optimizing treatment strategies.

Keywords:

• ANCA-associated vasculitis
• cyclophosphamide
• glucocorticoids
• granulomatosis with polyangiitis
• rituximab
• treatment

Financial & competing interests disclosure

L Guillevin reports receiving fees for serving on an advisory board from GlaxoSmithKline and lecture fees from Roche, Actelion, Pfizer, CSL Behring, LFB Pharma and Octapharma. As of January 2014, L Guillevin has no links of interest to disclose with pharmaceutical companies. C Pagnoux reports receiving fees for serving on advisory boards from Roche, Genzyme and GlaxoSmithKline and lecture fees and grant support from Roche, Bristol-Myers Squibb, EuroImmune, Roche and Terumo-BCT. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a systemic necrotizing vasculitis characterized by granulomatous inflammation of small vessels and associated with PR3-ANCA in 80% of patients.

• While PR3-ANCA could be implicated in the pathogenesis of GPA, multiple other immune system cells, cytokines and constituents are involved and may represent potential therapeutic targets.

• Since the advent of glucocorticoids and cyclophosphamide, the overall GPA mortality rate has fallen from nearly 100% at 6 months to 10–15% at 5 years.

• The current therapeutic modality for GPA is two staged, first with remission-induction therapy, based on the combination of glucocorticoids and cyclophosphamide or, in certain contexts, rituximab, followed by long-term maintenance therapy to limit the risk of relapse.

• The persistently high risk of relapse over the past decade remains one of the most frustrating and characteristic GPA features, despite long-term maintenance treatment with conventional immunosuppressants such as azathioprine or methotrexate.

• Data from recent studies, including the randomized-controlled MAINRITSAN trial, support using rituximab for maintenance because it was demonstrated to be superior to azathioprine at preventing major relapses.

• The optimal duration of maintenance therapy, with conventional immunosuppressants or rituximab, remains to be determined as does that of glucocorticoids. It should probably be decided, according to the characteristics of each patient’s disease, at least until a more reliable biomarker is identified.