ORADE Grant Recipient Report – Dr. Lillian Barra

Dr. Lillian Barra was a 2017 recipient of an ORADE grant. In this article, Dr. Barra shares her learnings with members: 

I would like to thank the ORA for providing me with funding to attend and present my research at the 18th International Vasculitis Meeting and ANCA workshop in Tokyo, Japan.

This meeting had the very topical theme of “Diversity and Integration for Tomorrow” and consisted of several symposiums, workshops, abstract presentations and networking opportunities.

The following are key learnings from the conference:

Rituximab for remission maintenance in ANCA-associated vasculitis (AAV)

Dr. J. Stone provided an overview of the use of rituximab for the treatment of AAV and Dr. L. Guillevin presented several abstracts regarding the use of rituximab as maintenance therapy for AAV.

Current practice for maintaining remission in AAV patients after cyclophosphamide induction therapy generally consists of methotrexate or azathioprine for at least 18 months. However, relapse rates are at least 25% using these maintenance therapies.

The RAVE study (N Engl J Med. 2010;363:221) showed that rituximab was equivalent to cyclophosaphamide in inducing remission of AAV, but relapses remained high in the absence of maintenance therapy.

In the MAINRITSAN trial, (N Engl J Med. 2014;371:1771) rituximab was superior than azathioprine for maintaining remission after cyclophosphamide induction. The long-term analyses from this trial (60 months from study start with drug discontinuation at 18-22 months) showed relapse free survival of 58% and 37% in rituximab and azathioprine (p=0.012) with no significant differences in adverse events (abstract SY6_4).

Economic evaluations determined that the use of rituximab was cost-effective (abstract WS7_3). Optimal maintenance therapy after rituximab induction remains unclear.

The results of the RITAZAREM trial (rituximab vs. azathioprine after rituximab induction) are expected by December 2018.

Both MAINRITSAN and RITAZAREM used fixed dosing of rituximab.

The MAINRITSAN2 trial (abstract P2_136) investigated fixed dosing of rituximab vs. an individually tailored approach (rituximab given based on ANCA titer and/or reappearance of CD19 B cells). This trial found no significant difference between the 2 approaches: 17% vs. 10% relapse (p=0.2).

Take home message: rituximab is better than azathioprine at maintaining remission in AAV and is cost-effective; the optimal duration of maintenance therapy requires further study; individually-tailored vs. fixed dosing of rituximab for maintenance therapy is a viable option, but requires close follow-up with frequent laboratory testing.

Interstitial lung disease in Microscopic Polyangiitis (MPA)

MPA is a type of AAV, predominantly associated with anti-MPO antibodies. Lung involvement in this condition is common and is felt to be an unmet need with poor prognosis.

One of the challenges discussed at the symposium was the overlap of MPA with interstitial pulmonary fibrosis (IPF).

Three subtypes were discussed: MPA with co-existent IPF (with IPF preceding MPA in 30%), MPA with interstitial lung disease and other features of MPA, and lung-limited MPA. In addition, clinicians must consider IPF patients with false positive anti-MPO antibodies, which can occur with drug/ toxic exposures.

There are very few studies that have examined these different subtypes, but there are potential treatment implications given that IPF does not respond to immunosuppression and anti-fibrotic therapies may be indicated. CT scanning, bronchoscopy and/or lung biopsy were suggested for distinguishing the different groups.

Dr. K. Sugino et al. (SY3_1) reported from a retrospective study that the most common fibrosis pattern in MPA was UIP (15/20). The other 5 patients had a combined pattern with emphysema. Other series have reported some MPA patients with NSIP pattern. Most IPF patients had only fibrosis (78/132) and some had had a component of emphysema (54/132); therefore, there was some overlap in the 2 conditions. Prognosis of MPA with ILD (treated with immunosuppressants and/or cyclophosphamide) compared to IPF was similar, but patients from both groups with emphysematous changes did worse.

Dr. L. Flores-Suarez (SY3_5) noted that broncheoalveolar lavage from anti-MPO positive patients were more likely to contain eosinophils than antibody negative IPF patients.

Dr. T. Takemura (SY3_4) reported that most (11/12) of MPA ILD patients had inflammatory cysts present on lung biopsy which were not present in IPF.

Take home messages: MPA patients with lung involvement have poor prognosis despite immunosuppression, thus, identifying these patients is important; MPA can overlap with IPF: it is important to work closely with respirology to determine the best treatment approach; given that IPF can precede MPA, these patients should be monitored for the development of other MPA manifestations.

Improving steroid-sparing in vasculitis

Reducing exposures to corticosteroids is critical to decrease serious adverse events. Steroid-sparing has proven to be particularly difficult in eosinophilic polyangiitis with granulomatosis (EGPA) and large vessel vasculitis.

EGPA is the least common AAV, characterized by adult-onset asthma, rhinosinusitis and eosinophilia. It can also cause pulmonary-renal syndrome, significant neuropathy and severe cardiomyopathy. 84% of patients require chronic glucocorticoids (median dose of 13 mg daily) at 4 years follow-up, despite conventional steroid-sparing agents.

The preliminary results of the MIRRA trial (mepolizumab for relapsing EGPA) were presented at the meeting by Dr. R. Smith (SY6_1). Mepolizumab targets IL-5 which effects eosinophils. The primary outcome of this study was the Birmingham Vasculitis Activity Score = 0 + prednisone < 7.5 mg/day at 52 weeks follow-up; it was met by 28% in the active arm and 3% in the control arm. No other details of trial results were available at the time of the meeting.

The most common large vessel vasculitis is Giant Cell Arteritis (GCA). There are few options in GCA for steroid-sparing: methotrexate has a mild to moderate effect, other immunosuppressants have been poorly studied and anti-TNF agents do not have a significant effect.

Dr. J. Stone presented the results of the GiACTA trial (SY4_6). This trial investigated tocilizumab and the primary endpoint was sustained remission at 52 weeks. In this trial, tocilizumab + prednisone for 26 weeks was more effective at sustaining remission (60% of new and 53% of relapsing patients) compared to prednisone alone for 26 weeks (22% for new and 7% of relapsing patients). Adverse events were similar across groups.

Take home messages: mepolizumab may be an option for relapsing EGPA patients, but response rates remain low and other options should be investigated; in GCA, tocilizumab is effective at decreasing prednisone exposure in the short-term; optimal duration of tocilizumab therapy and its long-term benefit/ risk is unclear.