Treatment of Pulmonary Vasculitis

Benjamin Terrier, MD, PhD; Loïc Guillevin, MD


Semin Respir Crit Care Med. 2018;39(4):504-510. 

In This Article

Induction Therapy


Prednisone (or prednisolone) is required in all cases and is usually prescribed at an initial dose of 1 mg/kg/d for 2 to 4 weeks. For severe patients (FFS ≥1), especially those with renal involvement and/or lung involvement requiring high oxygen or mechanical ventilation, methylprednisolone pulses can be administered at a dose of 7.5 to 15 mg/kg/d for 1 to 3 days, at onset of treatment.

While initial dose is consensual, treatment duration and tapering schedules are not, and differ between protocols and local practice. Meta-analysis on the effects of duration of glucocorticoid therapy on relapse rate in AAV showed that glucocorticoid regimen was the most significant variable explaining the variability between the proportions of patients with relapses, even if none of the studies included was directly comparing the glucocorticoids regimen. In this analysis, studies with longer courses of glucocorticoids were associated with fewer relapses.[3]

However, long-term glucocorticoid use was shown to cause many adverse events and long-term damage,[4] explaining why recent studies tend to use short-term glucocorticoids regimen for a duration ranging from 4.5 to 12 months.[5–7] For instance, we demonstrated for patients older than 65 years that during induction regimen, prednisone and CYC doses could be reduced by at least one-third to achieve remission while limiting adverse events.[6]

Along this line, the results of the PEXIVAS trial were just released, providing major data on the optimal glucocorticoid dose during induction regimen.[8] This trial aimed to determine the efficacy of therapeutic plasma exchanges (TPEs) in addition to glucocorticoids and immunosuppressive therapy, and the noninferiority of a reduced-dose glucocorticoid regimen, in reducing death and end-stage renal disease (ESRD). Patients with severe vasculitis were included, defined by at least renal involvement with estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2, or pulmonary hemorrhage due to active vasculitis. In this trial, all patients received between 1 and 3 g of intravenous (IV) methylprednisolone over 1 to 3 days, then daily oral glucocorticoids administered through a weight-based protocol. All participants received either 50, 60, or 75 mg/d (based on weight) of oral glucocorticoids for 7 days, and then protocol differed in the standard dose group and the reduced dose group. Participants in the standard dose group continued at 50, 60, or 75 mg/d for 7 additional days and tapered to between 12.5 and 20 mg/d at 3 months and 5 mg/d at 6 months. Participants in the reduced-dose group continued at 25, 30, or 40 mg/d for 7 days and taper to between 6 and 10 mg/d by 3 months and 5 mg/d by 6 months. Overall, all patients were receiving 5 mg/d from 6 to 12 months after randomization. Results of the trial showed that reduced dose of glucocorticoids was noninferior to "standard" dose and resulted in fewer serious infections.


As indicated previously, severe patients (FFS ≥1) are treated using a combination of glucocorticoids and immunosuppressive agents. CYC was until 2010 the only immunosuppressive agent commonly used to control severe vasculitis. It can be prescribed orally or intravenously.[9,10]

The current trend to prescribe less frequently CYC than RTX in AAV comes from safety concerns with the former: sterility in case of high dose or prolonged treatment, and increased risk of cancer in the long term with CYC.[11,12] The recommended dose of CYC is 0.5 to 0.7 g/m2 or 15 mg/kg for each infusion which should be administered at days 0, 14, 28, and then every 3 weeks until obtaining the remission, usually after six pulses, in association with mesna to decrease bladder toxicity of CYC. Patients with renal insufficiency are usually treated with 0.5 g/m2 to decrease treatment toxicity.

Oral CYC is prescribed at the dose of 2 to 3 mg/kg for 3 to 6 months. The main inconvenience of oral route is to deliver a higher cumulative dose of CYC than with IV route.

In patients older than 65 years, we demonstrated that giving IV 500 mg-fixed dose of CYC with the same schedule as described earlier reduced adverse events with a similar efficacy than standard dose of CYC.[6]


RTX, an anti-CD20 monoclonal antibody, has been approved by the European Medical Agency and Food and Drug Administration for the induction of remission of AAV. RTX noninferiority to CYC to induce remission of GPA and MPA was shown in the randomized, controlled, prospective, double-dummy Rituximab in ANCA-Associated Vasculitis (RAVE) trial in 197 patients with GPA or MPA patients. In this trial, oral CYC (2 mg/kg/d) for 3 to 6 months was compared with RTX (375 mg/m2 infused weekly) for 4 weeks. The remission rate with a prednisone dose of 0 mg at 6 months was 64% in the RTX group and 53% in the CYC group.[5] However, GPA and MPA patients with alveolar hemorrhage requiring mechanical ventilation or those with rapidly progressive renal failure with creatinine exceeding 350 μmol/L were excluded from this trial, indicating that RTX noninferiority may not be applicable to these severe patients.

RTX infusion of 1,000 mg at days 1 and 15 has been proposed and although it seems to be as effective in a retrospective study,[13] it needs to be evaluated in prospective trials.

Main adverse events are allergic reactions during infusion, infections, and trend toward lower immunoglobulin G (IgG) and immunoglobulin M levels. However, association between low immunoglobulin levels and infections remains controversial.

RTX may also be beneficial in severe refractory or relapsing EGPA, particularly for patients with positive ANCA, but these data are based on low-evidence-based open-label studies and case reports.[14–16] Our group is currently conducting two prospective randomized controlled trials comparing RTX-based regimen to conventional immunosuppressive agents based on the FFS, in the induction (REOVAS trial, NCT02807103) and maintenance (MAINRITSEG trial, NCT03164473) phase.

Therapeutic Plasma Exchanges

TPE have been proposed to treat severe vasculitis, especially patients with rapidly progressive crescentic glomerulonephritis and/or severe alveolar hemorrhage requiring mechanical ventilation. Their efficacy was proven in a randomized controlled trial focusing on patients with severe renal failure (creatininemia >500 μmol/L).[17] The results of the MEPEX trial showed that adding TPE to glucocorticoids and oral CYC was superior to pulses of methylprednisolone added to glucocorticoids and oral CYC to reduce the severity of renal impairment. However, the long-term analysis of patients included in this trial showed that both arms were similar for the primary composite outcome of death or ESRD, indicating that the long-term benefit of TPE remained unclear.

As indicated previously, the PEXIVAS trial evaluated the efficacy of TPE in addition to glucocorticoids and immunosuppressive therapy in patients with severe vasculitis, defined by at least renal involvement with eGFR <50 mL/min/1.73 m2, or pulmonary hemorrhage due to active vasculitis. Results of the trial showed that TPE did not significantly reduce the composite of mortality or ESRD, and all the secondary outcomes as well.[8]

Methotrexate and Azathioprine

Methotrexate (MTX) has been proposed as an induction regimen in nonsevere GPA without renal involvement.[18] In this randomized controlled trial (NORAM), patients with newly diagnosed AAV, with serum creatinine levels <150 μmoles/L, and without critical organ manifestations of disease were randomized to receive either standard oral CYC or oral MTX. Remission rate in patients treated with MTX was not inferior to that in patients treated with CYC. However, the MTX regimen was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment.

Azathioprine (AZA) was evaluated in combination with glucocorticoids to induce remission of patients with MPA, EGPA and PAN without poor-prognosis factors according to the FFS, and in the absence of alveolar hemorrhage–caused hemoptysis or respiratory distress. In this double-blind trial, patients were randomized to receive AZA or placebo for 12 months. Addition of AZA to glucocorticoids in these patients did not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.[7]

Intravenous Immunoglobulins

IV immunoglobulins (IVIgs) have been evaluated to induce remission, alone or in combination with other treatments, at a dose of 2 g/kg/course. IVIg effects have been assessed in AAV in two prospective trials. A first prospective, randomized, placebo-controlled trial investigated the efficacy of a single course of IVIg compared with placebo in previously treated AAV with persistent disease activity. Treatment response was more frequent in the IVIg group than in the placebo group (14/17 vs. 6/17, respectively). However, this effect was not maintained beyond 3 months.[19]

A second open-label observational study evaluated the safety and efficacy of IVIgs administered for 6 months to treat relapses of GPA or MPA occurring either under treatment or during the year following discontinuation of corticosteroids and/or immunosuppressants. IVIgs induced complete remissions in 13/22 patients at month 9 that persisted at month 24 in 57%.[20]