| 1. Are glucocorticoids recommended for the treatment of active AAV? |
The treatment protocol for every AAV patient with active disease must include systemic glucocorticoids. The initial dose for prednisone or equivalent is 1 mg/kg/day (grade of recommendation C). Glucocorticoid therapy needs to be associated with an immunosuppressive agent or with a biological agent in patients with active AAV (grade of recommendation C). |
| 2. Is there any difference between oral and IV glucocorticoids in the induction therapy of AAV? |
There is no evidence that IV glucocorticoids are more efficient than oral glucocorticoids in AAV patients with active disease. However, patients with severe manifestations (i.e. life threatening disease with the involvement of vital organs) IV pulse therapy with methylprednisolone should be prescribed at 15 mg/kg/day or 0.5-1.0 g/day for 1-3 days when starting treatment (grade of recommendation D). |
| 3. What is the optimal dose and duration of oral glucocorticoids in the induction therapy of AAV? |
Treatment of patients with active AAV should be planned in an individualized basis. Prednisone or prednisolone is prescribed at an initial daily dose of 0.5-1.0 mg/kg/day (maximum 80 mg/day) for one to four weeks (grade of recommendation B) followed by tapering 10 mg every two to four weeks until 20 mg/day. Afterwards, dose reduction should be 2.5-5.0 mg every 2-4 weeks until complete withdrawal (grade of recommendation D). The duration of glucocorticoid therapy should be at least 6 months and in some instances, it may be up to 1 or 2 years. Longer glucocorticoid therapy could be necessary in relapsing patients (grade of recommendation B). |
| 4. What is the role of cyclophosphamide in the induction therapy of AAV? |
Cyclophosphamide is indicated in induction therapy in AAV patients with generalized disease or in those presenting life/organ-threatening disease (grade of recommendation A). Additionally, patients with less severe forms of AAV, such as localized disease and the early systemic form may benefit from cyclophosphamide therapy, especially in patients who do not respond to methotrexate therapy (degree of recommendation D). The duration of cyclophosphamide therapy in patients with AAV should be limited to 3-6 months in order to avoid adverse events due to its cumulative dose and cyclophosphamide should be switched to a less toxic maintenance therapy as soon as remission is accomplished (grade of recommendation A). |
| 5. Are there differences between oral and IV pulse therapy cyclophosphamide for therapy induction of AAV? |
In the short term, there are no differences in induction of remission rates between oral and IV pulse therapy of cyclophosphamide. Therefore, patients with active AAV may be treated with either oral cyclophosphamide at a dose of 2 mg/kg/day (maximum 200 mg/day) or IV pulse cyclophosphamide at a dose of 15 mg/kg (maximum 1.2 g per pulse) given 3 times in the first month with 2 weeks interval, and then within every 3 weeks up to 3-6 months or until remission is achieved (grade of recommendation A). In patients with renal insufficiency, cyclophosphamide dose should be corrected according to age and renal function. |
| 6. Is methotrexate indicated for remission induction in AAV? |
Methotrexate, 20-25 mg/week, is an alternative to cyclophosphamide for remission induction in AAV patients with non-organ threatening disease, i.e. localized or early systemic disease (grade of recommendation A). Methotrexate doses should be reduced by 50% in patients with GFR between 10 and 50 mL/min and it should not be used in end-stage renal disease (i.e. GFR under 10 mL/min) (grade of recommendation D). |
| 7. What is the role of rituximab in the induction therapy of AAV? |
Rituximab is an alternative to cyclophosphamide in the induction therapy in generalized forms of AAV, especially in patients with organ/life-threatening disease (grade of recommendation A). Rituximab (375 mg/m2 weekly for 4 weeks) is non-inferior to cyclophosphamide for induction therapy in AAV and it may be prescribed when there are contraindications for cyclophosphamide use, such as in patients with a high cumulative dose and in young patients of childbearing age without established offspring, or in AAV patients with relapsing disease (grade of recommendation A). Alternatively, rituximab can be used in two infusions at a dose of 1 g two weeks apart. |
| 8. Which precautions should be taken when prescribing rituximab? |
Before the infusion of rituximab in AAV patients, serology tests for HIV, HBV and syphilis should be checked. Patients with chronic HBV and HIV should only be treated with rituximab with concomitant prescription of antiviral therapy and the consultation from a specialist in infectious diseases (grade of recommendation C). Vaccination should be given prior to rituximab infusion whenever it is possible, especially for annual influenza, pneumococcal and HBV. Administration of other vaccines such as anti-tetanus and diphtheria or anti-meningoccocal is optional but immunization records should be updated (grade of recommendation D). Baseline serum immunoglobulin levels and B-cell count in peripheral blood are recommended to be measured before rituximab infusion and thereafter. It is important to measure serum immunoglobulins, especially serum IgG, prior to each administration of rituximab and 4-6 months after and to assess the need for replacement of IVIG (grade of recommendation C). In cases of severe hypogammaglobulinemia (IgG <500 mg/L) and infectious complications, the replacement of IVIG is required at a dose of 0.2-0.4 g/kg for 1 day, every 3-4 weeks, as required to maintain serum IgG levels above 500 mg/mL. Rituximab withdrawal should be considered if patient presents serum IgG persistently below 500 mg/dL and severe recurrent infections (grade of recommendation C). However, it should be to taken into account the balance between treatment benefits to control inflammatory activity and the risk of severe adverse events with rituximab therapy. |
| 9. Is plasma exchange indicated in the treatment of patients with active AAV? |
Plasma exchange is indicated in AAV patients with rapidly progressive glomerulonephritis with serum creatinine >5.8 mg/dL, since it leads to improvement in renal survival when associated with glucocorticoids and cyclophosphamide (grade of recommendation A). Plasma exchange is prescribed in a 7-session schedule on alternate days at a 60 mL/kg volume exchange on each occasion, volume replacement needs to be done with 5% albumin and occasionally with fresh frozen plasma at the end of the procedure to replenish coagulation factors (grade of recommendation A). There is still insufficient evidence to support plasma exchange to treat patients with AAV presenting alveolar hemorrhage, possibly these patients may benefit from plasma exchange (grade of recommendation D). |
| 10. Is IVIG as an alternative therapy for the induction therapy of AAV? |
IVIG is an alternative for the induction therapy of AAV patients with active disease at an immunomodulatory dose (i.e. 2 g/kg divided in 2-5 days), in specific scenarios such as in infected AAV patients with persistent disease activity and in patients refractory to standard treatment with glucocorticoids and cyclophosphamide (grade of recommendation B). Additionally, AAV patients with persistent and active disease who present contraindications to cyclophosphamide or rituximab may also benefit from IVIG therapy (grade of recommendation D). |
| 11. Is mycophenolate mofetil (MMF) indicated for the induction therapy of AAV? |
To date, there is not enough evidence to recommend the use of MMF in AAV induction therapy, it should be reserved as an alternative to cyclophosphamide, rituximab or methotrexate, since small studies have shown some benefits over cyclophosphamide in AAV patients with active disease (grade of recommendation C). |
| 12. Is there any place for anti-TNFα agents in the induction therapy of AAV patients? |
The TNF receptor blocker agent etanercept is not recommended in the induction therapy of AAV patients (grade of recommendation A). Other anti-TNFα agents have not been studied properly in AAV.
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| 13. Is azathioprine indicated for the induction therapy of AAV patients? |
Azathioprine is not indicated for induction therapy of AAV patients with active disease (grade of recommendation D). |
| 14. How subglottic stenosis should be approached in GPA patients? |
GPA patients presenting SGS in the presence of systemic disease activity should be treated with glucocorticoids and immunosuppressive agents according to disease severity in association with local treatment. In case of SGS in GPA patients in remission, we recommend only local treatment (grade of recommendation D). As first line local therapy, mechanical intratracheal dilation associated with intralesional injection of a long-acting glucocorticoid (e.g. methylprednisolone acetate or triamcinolone) is recommended, sometimes requiring repeated procedures (grade of recommendation C). In refractory cases and in patients presenting severe manifestations of SGS, open surgery with laryngotracheal reconstruction or permanent tracheostomy should be performed. Indeed, tracheostomy should be reserved only as an urgent intervention for life-threatening situations (grade of recommendation D). |
| 15. Is prophylaxis for pneumocystis pneumonia indicated in AAV patients during induction therapy? |
Prophylaxis for PCP with 400 mg/80 mg dose/day or 800 mg/160 mg three times a week of SMT-TMP is indicated to AAV patient undergoing induction therapy with glucocorticoids and cyclophosphamide or rituximab (grade of recommendation A). Patients with a total lymphocyte count below 300 cells/mm3 must also receive prophylactic treatment for PCP regardless of the immunosuppressive therapy prescribed (grade of recommendation B). If GFR is between 15 and 30 mL/minute, SMT-TMP dose should be reduced to 400 mg/80 mg three times a week. In AAV patients presenting terminal renal failure, during methotrexate therapy or in sulfa allergy, inhaled pentamidine at 300 mg/month should be preferred (grade of recommendation C). |
| 16. What should be considered regarding vaccination in patients with AAV receiving induction therapy? |
Whenever it is possible, patients with AAV should be vaccinated prior to starting immunosuppressive treatment, ideally three weeks before. Influenza vaccine seems to be safe and effective for AAV patients in remission and it should be given annually (grade of recommendation B). Considering the high frequency of pulmonary infections in AAV patients, pneumococcal vaccine should also be administered (grade of recommendation D). Immunization schedule in AAV patients should follow the Immunization Guide published by the Brazilian Society of Immunization/Brazilian Society of Rheumatology. |
