Difficult Vasculitis

At the "Challenges in Clinical Practice Session" on Wednesday, June 10 at EULAR 2015, Drs. Rodrigo Cartin Ceba and Ulrich Specks reviewed data from their own experience from the Mayo Clinic during a discussion on how to best manage a patient with recurrent granulomatosis with polyangiitis (GPA). Despite the beautiful weather and amazing sites to visit in Rome, the room was packed, with standing room only.

The session started with Dr. Rodrigo Cartin Ceba (Mayo Clinic) presenting the case of a 34 year old female with known GPA, who presented with pulmonary hemorrhage, renal failure and positive PR3-ANCA, requiring ICU admission.  She responded well to pulse IV MP, followed by PO cyclophosphamide for 4 months, and then was in clinical remission on monotherapy with azathioprine for 18m.   The patient then presented with new dyspnea, hemoptysis (diffuse alveolar hemorrhage), malaise, fever, migratory arthralgias and renal failure requiring renal replacement therapy.  After ruling out infection, she was treated with IV MP, RXN 375 mg/m2 x 4 and PLEX x 6.   With this, her renal function and pulmonary function improved and she was discharged home off therapy.   

After the stage was set with the case presentation, Dr. Ulrich Specks from the Mayo Clinic reviewed recent data on management of recurrent diffuse alveolar hemorrhage (DAH) with focus on the following questions.  

• Can we estimate the risk of progression of DAH to respiratory failure?

  • According to data from the Mayo Clinic (Cartin-Ceba, EULAR 2015), baseline high BVAS score, SpO2/FiO 2 < 450, percent neutrophils on BAL >30%, and CRP > 25 are all independent predictors that DAH will progress to respiratory failure. In patients presenting with any of these risk factors, aggressive immunosuppression should be initiated in a timely fashion.

• How soon should IV MP be started? Can we distinguish infection from inflammation?

  • From Picard et al (2010), there is a four-point score to determine the likelihood that DAH is due to inflammation rather than infection. If the score is > 4, there is a high probability that DAH is inflammatory, and there should not be a delay in initiating high-dose steroids.

• Which remission induction agent should be added in someone presenting with a flare? RXN, CYCLO, or both?

  • The RAVE trial showed that RXN is non-inferior to Cyclo to induce remission in patients with GPA. In patients with previous exposure to cyclophosphamide presenting with a disease flare, RXN was better than repeat Cyclo. Furthermore, in PR3-ANCA positive patients, RXN was superior to cyclo. In MPO-ANCA positive patients, there was no difference. However, patients who were intubated were excluded from the RAVE trial, suggesting that perhaps the data may not be applicable in all cases.

  • Dr. Specks then reviewed the RITUXVAS Trial (ARD 2015) which included intubated patients. Patients were randomized to either Cyclo IV x 2, then RXN (375/m2 x4) or Cyclo IV for 3-6m then azathioprine. There was no difference in outcomes at 24m between groups, suggesting that RXN is effective in severely ill, intubated patients. However, all patients in the RXN group received two doses of Cyclo. Furthermore, the mortality rate in both groups was very high. Based on this data, perhaps we need to use a combination of Cyclo and RXN in severely ill patients.

  • Dr. Specks then reviewed experience from their cohort at the Mayo Clinic (Cartin-Ceba EULAR 2015) where they found superiority of RXN (83% complete remission) over Cyclo (43% complete remission) in patients with severe DAH, including those who are intubated. This is not a randomized controlled trial, and could be subject to confounding by indication. Based on this experience, he concluded that RXN is superior to Cyclo in severely ill patients with DAH and that combination of Cyclo and RXN is not needed.

• What is the role of Plasma Exchange in patients with DAH?

  • Only 7 patients in the RAVE trial had PLEX with no difference in outcomes between groups.

  • Klemmer (AJKD 2003) did a retrospective analysis of all patients admitted to ICU with GPA. All received IV MP and PLEX. All survived and there were no complications suggesting PLEX is safe and may be of benefit.

  • At the Mayo Clinic (Cartin-Ceba, EULAR 2015), all patients received IV MP and 32 received PLEX (these patients had more severe disease). After adjusting for probability to receive PLEX and agent used (Cyclo or RXN), there was no difference in outcomes between those who received PLEX and those who did not. Their conclusion is that there is insufficient evidence for the benefit of PLEX in patients with DAH. The PEXIVAS trial is ongoing and will hopefully provide more clarity of the efficacy of plasma exchange.

Bottom Line: Rituximab gives us another option for managing patients with ANCA-associated vasculitis, particularly those who are younger, have previously received cyclophosphamide, or who have a contra-indication to cyclophosphamide. We know from two RCTs (RAVE, RITUXVAS) that it is non-inferior to cyclophosphamide for inducing remission, even in very sick patients. There are still clinical situations in which the optimal utility of rituximab is unknown. From the Mayo Clinic experience, there is no benefit in adding PLEX or using combination cyclophosphamide plus rituximab, but this has not been replicated in other cohorts or in RCTs. Furthermore, optimal dosing and timing of maintenance therapy remain controversial. Data from ongoing studies should be informative for clinical practice.

Share This Report

About the Author

Trending Reports From EULAR 2015