trol of other GPA manifestations. The response to systemic therapy, including glucocorticoids, can be as low as 22–44% [49, 50]. Response to cyclophosphamide or rituximab seems limited (but these should still be considered and may help a subsequent proportion of patients). Thus, local treatment based on (repeated) dilation with bougies or balloons is often required, followed, at least for subglottic stenosis and main bronchi, by local injections of glucocorticoids. The use of lasers seems to lead to more adherent fbrous scars. Some groups also end the dilation session with local application of mitomycin. Stenting and laryngotracheal reconstruction with partial tracheal resection should only be performed in highly specialized centers and as a last resource. Surgical management of bronchial stenoses is limited to stenosis of the main bronchi, is hazardous, and is not standardized.

Adjuvant Measures and Prevention

of Treatment Adverse E ects

Maintenance of a good nutritional status during all treatment phases is essential, with nutritional supplementation, enteral or parenteral, if necessary. Physical therapy can help patients, especially those with PNS or CNS involvement [168]. Potential adverse effects of prolonged steroid therapy are numerous and require at least the prescription of calcium (500–1000 mg/day, depending on diet intake), vitamin D (2000 IU/day), and, often, bisphosphonates, according to updated recommendations by rheumatology societies. Pneumocystis jiroveci pneumoniae, annual vaccinations for in uenza ( u), COVID vaccination (and/or other agents to decrease to risk of severe COVID infection), and vaccinations every 3–5 years for Pneumococcus spp. and Haemophilus infuenzae should be considered in every patient, along with ensuring that all mandatory vaccines are up to date. There is no evidence suggesting that vaccinations could trigger a GPA onset or are. Conversely, in patients receiving high-dose prednisone and potent immunosuppressants, the effcacy of most vaccines remains unpredictable [169, 170], and, as usual, patients on immunosuppressive therapies should not receive live virus vaccines.

Managing traditional cardiovascular risk factors (smoking, dyslipidemia, diabetes, hypertension) is also essential, from the beginning of GPA treatment, to limit the cardiovascular consequences of glucocorticoid therapy in addition to specifc pro-atherothrombotic complications associated with GPA [91]. The risk of late neoplasia induced by treatments must be considered in treatment decisions [65] as well as that of infertility induced by some cytotoxic agents (when conceivable, sperm cryopreservation and egg preservation can be offered).

Principles of Treatment for Relapsing and Refractory GPA

New, persistent, or worsening symptoms during treatment of GPA should always raise suspicion of an infectious complication or, more rarely, a GPA mimicking condition, such as lymphoma, cancer, or cocaine-levamisole-induced vasculopathy.

Treatment of GPA relapse occurring during maintenance treatment or in patients off immunosuppressants should be based on conventional induction treatment strategies, as described previously. The RAVE study revealed that rituximab is more often effective than cyclophosphamide in patients with relapsing disease [41], which was further confrmed by the pre-enrollment phase of the RITAZAREM study (patients with relapsing GPA, all treated with rituximab for induction) [140].

In the rare case of a patient with truly refractory GPA to glucocorticoids and cyclophosphamide, a switch to the alternative agent (rituximab) should be made, or vice versa if rituximab was used for induction [171]. For patients with disease resistant to all of these treatments, administered at suffcient doses, at recommended intervals, and after having excluded all other conditions that can mimic vasculitis, other strategies must be considered on a case-by-case basis and in collaboration with reference centers for vasculitis.

Outcomes and Prognostic Factors

Survival and Causes of Deaths

With current therapies, the remission rate exceeds 80% and the overall mortality rate is <15% at 5 years. However, mortality remains higher than in the general population of similar age, with a standardized mortality ratio of 1.58 (95% CI 1.14–2.13), particularly among men (1.8 vs. 1.23 for women) [144]. The main causes of early mortality in recent studies have been infections and poor disease control. After the frst year post-diagnosis, the leading causes are cardiovascular complications, infections, and late cancers [118, 172, 173].

As mentioned previously, fve factors, present at the time of initial diagnosis of GPA, are associated with a poor prognosis/survival: serum creatinine ≥150 μmol/L, specifc cardiomyopathy, age >65 years, severe gastrointestinal involvement, and absence of ear, nose, and throat involvement [116]. Previous studies have reported a poor prognosis with renal failure (defned by a serum creatinine level >160 μmol/L or a granular fltration rate <15 mL/min) and/ or age >50–52 years, whereas ear, nose, and throat symp-

toms had a good prognostic value in terms of survival [118]. Pulmonary disease was identifed as a poor prognostic factor in one study [145]. Although alveolar hemorrhage may be responsible for massive and acute respiratory distress syndrome, it has not been clearly identifed to be associated with a poor prognosis with appropriate treatment. An analysis of patients from several trials of the European Vasculitis Society (EUVAS) group reported an increased, but not signifcant, risk of death in patients with alveolar hemorrhage (HR 1.35, 95% CI 0.70–2.64) [174].

MPO-ANCA + GPA is rare and is associated with increased mortality as compared with anti-PR3+ GPA (which, in contrast, may be associated with a better survival but an increased risk of relapse) [118]. A high rate of PR3-­ ANCAs at diagnosis has been associated with a lower survival rate as well as anemia because of in ammation, alveolar hemorrhage, and/or renal failure [118].

Relapse

The high risk of relapse, sometimes on multiple occasions in the same patient, has been a hallmark of GPA. The rate of relapse-free survival did not exceed 42–57% at 5 years with conventional treatments (i.e., induction with cyclophosphamide and maintenance with azathioprine or methotrexate), but it has dramatically improved in the past decade, especially since the wider use of rituximab for maintenance [137, 144].

Relapse may occur more frequently in PR3 than in MPO-­ ANCAs or ANCA-negative GPA [175–177]. The predictive value of monitoring ANCA titers during treatment is controversial. The persistence of ANCA titers during treatment, especially when switching to conventional, non-rituximab-­ based maintenance therapy, was found to be associated with a high relapse rate, 86%, as compared with 20% with ANCA results that became negative in one study and a relative subsequent risk of relapse 2.6 times higher in another study [178]. However, these results emphasize that relapses are not systematic, even with persistent ANCA positivity [179]. Conversely, relapses can occur in patients negative for ANCAs [180]. An increase in the titer or a recurrence of ANCA positivity has been observed in about 40% of patients with relapse within the following weeks or months (6 months) [181]. The magnitude of the increase in ANCA titers was believed to improve the predictive value of this factor, with a relative risk of relapse of 14.5 with ANCA titers increased by more than four times the previous value [179]. However, 29% of patients with increased PR3-ANCA titers did not experience relapse [182]. A meta-analysis concluded that an increase in titers or persistence of ANCA positivity during remission only modestly predicted future disease relapse,

and, thus, serial ANCA measurements during disease remission had limited or no value in guiding non-rituximab-based treatment decisions [183]. The value of PR3-ANCA monitoring might be greater in patients with renal vasculitis and/or in those receiving rituximab maintenance (see section on “Maintenance Therapy for Systemic/Severe/Generalized Forms”) [184]. However, not all patients with PR3-ANCA-­ positive GPA become ANCA-negative while on rituximab therapy. In the MAINRITSAN 2 study, 37% of patients were persistently ANCA-positive after 28 months of maintenance with systematic reinfusions of rituximab every 6 months [141]. In the MAINRITSAN 3 study, 50% of patients who had a relapse had become ANCA-positive again and only one patient with persistent ANCA negativity had a relapse [151]. However, 15% of those who did not relapse also had become ANCA-positive again. The addition of CD19+ B-cell count monitoring may not only add to the predictive value of serial ANCA monitoring but also to its cost. After (or during) rituximab therapy, relapses are rare in patients with both negative ANCA and CD19+ B-cell counts, with only one such case in the RAVE trial and none in the MAINRITSAN 3 study [132]. However, in the MAINRITSAN 2 study, 18% of the patients who relapsed were both ANCA-negative and B-cell-depleted at the time of their relapses.

Several other clinical factors have been identifed as potentially predicting relapse in different patient cohorts. The most reproducible factors are the presence of a cardiac disease at diagnosis, a “less intense” initial treatment (defned by a cumulative dose of cyclophosphamide <10 g after the frst 6 months of treatment and/or a decrease in the dose of glucocorticoids <20 mg/day before the third month), a previous relapse, and pulmonary and/or ear, nose, and throat [175, 176, 181] diseases. Conversely, the presence of more severe renal disease (and/or serum creatinine level >100 μmol/L at diagnosis) is associated with a lower risk of relapse. These results suggest a greater association of relapse in predominantly granulomatous GPA forms (i.e., with ear, nose, and throat involvement, pulmonary nodules, orbital tumors) than predominantly “vasculitic” manifestations (i.e., with glomerulonephritis and/or pulmonary capillaritis), which, by contrast, carry a high mortality rate. A longer duration of low-dose glucocorticoids (about 5 mg/day after 1 year post-­diagnosis) may be associated with a low risk of relapse, but, this observation, as mentioned previously (cf. Treatment), remains controversial [122, 124].

Studies are under way to identify new and more useful biological factors to help differentiate between infections and disease ares, assess disease activity, and predict relapse, as are studies of cytokine profles and genomic investigations [185].