Pulmonary Vasculitis Update / Review
Part 2: Treatment and Prognosis
(Go to Part 1: Clinical Features and Diagnosis)
Treatment of the ANCA-associated pulmonary vasculitides consists of systemic corticosteroids and cytotoxic therapies given in two phases, induction and maintenance, where the aggressiveness of the regimen is based on disease severity. The standard of care for induction therapy has been daily oral cyclophosphamide along with oral corticosteroids based on the landmark trial by Fauci and Colleagues at the NIH in 1983 where investigators achieved a 93% remission rate in granulomatosis with polyangiitis (GPA, formerly called Wegener’s). However, considering the substantial toxicity of oral cyclophosphamide (cytopenias, immune suppression, infertility, hemorrhagic cystitis, and bladder cancer) researchers have sought safer, less toxic, but equally efficacious alternatives, especially for milder disease and long-term maintenance therapy for pulmonary vasculitis.
Several scoring systems for disease activity and severity exist including the Five Factor Score (FFS), the Birmingham Vasculitis Activity Score (BVAS) (online calculator), and the Vasculitis Damage Index (VDI).
The European Vasculitis Study Group (EUVAS) classification system provides a well-characterized framework for disease severity and treatment decisions:
- Limited disease is non-life-threatening and limited to the upper airway.
- Early generalized disease has constitutional symptoms plus end-organ involvement without clear or immediate threat to organ function (e.g. GN with Cr < 1.4 or asymptomatic pulmonary nodules).
- Generalized active disease has clearly impaired or threatened organ function (e.g. GN with Cr 1.4 to 5.7 or symptomatic pulmonary disease).
- Severe disease has immediate threat of organ failure and/or death (e.g. GN with Cr > 5.7, DAH, or cardiomyopathy/CHF).
- Refractory disease is defined as failing conventional therapy.
- Remission means there is no evidence of ongoing vasculitic activity (BVAS = 0).
Few data here, but expert opinion suggests treatment with topical therapies, steroid monotherapy, and/or single moderate-potency cytoxic drugs (methotrexate, azathioprine, or mycofenolate mofetil).
Early Generalized Disease
Alternatives to cyclophosphamide induction in this group might be:
- Methotrexate (MTX) demonstrated similar 6 month remission rates compared to cyclophosphamide but slower time to remission and higher relapse rates in the NORAM study.
- Mycophenolate mofetil (MMF) was evaluated in a small case series of mild-moderate renal MPA patients with high remission rates. There is an ongoing RCT comparing MMF to cyclophosphamide.
- Azathioprine (AZA) has also been used, but with less evidence for the induction phase.
Generalized Active Disease
Alternatives to oral cyclophosphamide induction in this group include:
Intravenous cyclophosphamide produced similar remission rates as oral cyclophosphamide in the CYCLOPS trial along with lower rates of leukopenia and overall cyclophosphamide dose, but at the expense of a higher relapse rate (21 versus 39%). However, there were no differences in survival or renal function, and patients who fail induction with IV cyclophosphamide may still respond to oral.
Rituximab has been investigated as treatment for pulmonary vasculitis in two RCTs:
- In the RAVE trial, rituximab given weekly for 4 weeks was non-inferior to daily oral cyclophosphamide in 197 patients with GPA or MPA at inducing remission and successful taper of prednisone at 6 months (64% vs 53%, p<0.001).
- The RITUXVAS trial also found similar rates of remission in 44 patients with renal involvement between patients treated with IV cyclophosphamide or rituximab (IV cyclophosphamide was given along with rituximab on infusions one and three) (76% vs 82%, p=0.68).
Interestingly, rituximab was not clearly safer or better tolerated as was hoped; however, follow up in these trials was only 6 and 12 months, which may be too early to detect the longer term side effects of cyclophosphamide.
Induction therapy for severe disease similarly consists of steroids plus cyclophosphamide (IV or PO) with rituximab a potential alternative supported by the RAVE and RITUXVAS trials. The MEPEX trial provides evidence for also adding plasma exchange in patients with severe renal disease, demonstrating higher rates of dialysis-free survival at 3 months (69% vs 49%), and a case series supports its use in DAH.
Anti-thymocyte globulin, IVIG, infliximab, and deoxyspergualin have been used for refractory disease, but the authors emphasize that these patients are best treated in specialty centers experienced in treating pulmonary vasculitis.
Maintenance therapy is generally begun after induction of remission (usually after 3-6 months). Options include AZA, MTX, and MMF, although MMF has been associated with higher relapse rates compared to azathioprine and thus may be reserved for patients intolerant of AZA or MTX. The optimal duration of maintenance therapy is unknown, but is probably at least 18 months. The REMAIN study is currently comparing 24 months to 48 months. Steroids are generally tapered to the lowest tolerated dose or discontinuation during the maintenance phase. The optimal taper is unknown, but there is some evidence that continuing low dose steroids may reduce relapse rates. Finally, the optimal timing and choice of maintenance therapy in those who receive rituximab for induction therapy is unclear because the RAVE and RITUXVAS trials did not include maintenance therapy in the rituximab treatment groups.
Guidelines were recently published by the American College of Chest Physicians for the monitoring of immunosuppressive therapies. And don’t forget vaccinations and other considerations for patients on chronic steroids including bone health and PCP prophylaxis. Interestingly, TMP-SMX may not only prevent PCP, but also reduce relapse rates in GPA by reducing nasal carriage of Staph aureus.
Relapse and Complications
All forms of pulmonary vasculitis should be thought of as chronic diseases and many patients experience at least one episode of relapse. Other potentially life-threatening complications include infection, drug toxicities, and venous thromboembolism.
With much thanks to:
Stephen K Frankel, Marvin I Schwartz. The Pulmonary Vasculidities. AJRCCM 2012;186:216-224.