Written by: Medical College of Wisconsin Rheumatology Fellows
Topic Overview
Vasculitides are a group of diverse diseases that cause inflammation in the vasculature, with protean manifestations of potentially serious, life-threatening complications. Often categorized by size of the affected vasculature, small vessel vasculitides can be further characterized by those associated with positive ANCA serologies, such as GPA and MPA—two very important diseases in the world of rheumatology that have unique clinical, laboratory, and histopathologic findings. Early recognition is key to preventing morbidity and mortality, and induction therapy consists of high dose steroids and immunosuppressive therapy. However, sometimes the sequela is so dire that this is not enough, especially with respect to pulmonary hemorrhage and renal failure. In the face of complicated and high-risk clinical situations, we, as clinicians do everything to preserve a patient’s life and limit morbidity. Yet, by doing this, can we potentially be causing more harm, and is the approach “less is more” actually better?
For the first time, the PEXIVAS landmark study addressed this very question, as studies before had never assessed if plasma exchange can improve survival and reduce severe complications. Through a large (>700 patients involved!), multi-center, randomized, two by two trial conducted over 16 countries, the study set out to answer two main questions in cohorts of patients with severe ANCA-associated vasculitis:
- Does plasma exchange reduce all cause death and progression to end stage renal disease (ESRD)?
- Are reduced dose steroids non-inferior to standard dose steroids?
The patients were randomized 1:1:1:1 to receive plasma exchange with standard dose steroids, plasma exchange with reduced dose steroids, no plasma exchange with standard dose steroids or no plasma exchange with reduced dose steroids. All patients received induction treatment with IV cyclophosphamide, PO cyclophosphamide or IV rituximab, followed by maintenance treatment with azathioprine. The results did not demonstrate that plasma exchange reduced the incidence of death from any cause or end stage renal disease in severe ANCA associated vasculitis. Additionally, reduced dose steroids were found to be non-inferior to standard dose steroids.
Implications for patients, providers, and researchers
Current implications: We, as rheumatologists, are always seeking management options that are both effective and safe, and yet sometimes, the crux of the matter is that a lot of our therapeutic options have significant side effects and potential toxicities. We think that this trial is important as it addresses main safety sectors including death and adverse events.
The results of the study demonstrated that there was no reduced incidence of death or ESRD in patients receiving plasma exchange compared to those who did not.
Furthermore, low-dose steroids yielded non-inferior results to standard doses, and most importantly, they demonstrated overall reduced risk of serious infections. We can rapidly and cumulatively (almost by 60%!) taper steroids in our patients without losing efficacy while also reducing the risk of infections. A common theme at the ACR conference this year was reduction of steroids, and this study further corroborated this idea that we can actively act upon to decrease infectious burden. The very cornerstone of rheumatologic interventions is steroids, and so we think this result is indeed a game changer!
Future implications: One could argue that a limitation of the study was in the patient cohort itself, as while the study was aimed to assess the sickest in vasculitis, in truth, the patient panel was not entirely representative of the most severe forms of diffuse alveolar hemorrhage or acute renal failure. More severe ANCA vasculitis patients were underrepresented in this trial; thus, future studies can further assess and incorporate the more ideal patient group to expound on the results. Additionally, azathioprine was used as maintenance treatment in this study, instead of rituximab. We know from the MAINRITSAN trial that using rituximab for maintenance treatment in ANCA vasculitis prevented relapses more so than with azathioprine. Therefore, it is possible that the results of PEXIVAS may have been different if rituximab was used for maintenance therapy.
Will it win first round?
The PEXIVAS trial was strongly designed via the two-by-two factorial design, which enabled four different groups to be analyzed. The study was also large, conducted over a long duration, and spanned across multiple countries which makes the results more universal and applicable.
While the ADVOCATE study is indeed interesting and important as a new drug to help sustain remission in vasculitis, we just do not think that the trial is as impressive as PEXIVAS. We now know that plasmapheresis does not alter morbidity and mortality, while also gaining insight that we can use a lower cumulative dose of steroids with equal efficacy and mitigation of serious infections. Though the ADVOCATE trial shows promise for avacopan in the remission in ANCA vasculitis, this may not be readily available for use.
Will PEXIVAS win at all?
While we do find overall strengths in this trial, we still would like to comment on some of its weaknesses. For one, it was an open-label study, and the choice of induction therapy was made prior to randomization. In theory, this could have created biases in treatment favoring cyclophosphamide over rituximab for induction if plasma exchange was given or not. The largest issue with this study is as iterated above, was that patients with severe vasculitis were hardly represented ( <10%), and thus, this study cannot be easily applied to patients with life threatening clinical manifestations. While there are weaknesses, overall, we feel that its strengths outweigh them.
The overall winner in the competition is challenging as this assertion is sort of comparing apples to oranges as all the clinical investigations in this competition are so monumental. However, we do feel that on the strength of our arguments, the PEXIVAS team can match and perhaps even surpass any scouting report in this competition. We anticipate a stiff competition from more fashionable diseases in rheumatology such as the investigations looking at gout, lupus nephritis and the harmful effects of short-term steroids. In the end, the PEXIVAS team will always contend that the prevention of harm to the patient is worth more than any new discoveries other trials may or may not show. Through the very nature of steroids being the cornerstone of rheumatologic interventions, we do believe this study has huge implications, both in the realm of vasculitis and likely through extension to other systemic inflammatory conditions. If we can control disease through less steroid exposure, and mitigate cumulative risk and toxicity, this can have an extensive ripple effect in potentially reducing infections, osteoporosis, avascular necrosis, and more steroid sequela as we begin to study it across other rheumatologic conditions. Let the best team win!
References:
- Walsh M, et al; PEXIVAS Investigators. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631.
- Jayne DRW, et al; ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609.
- Pagnoux C, Guillevin L; French Vasculitis Study Group; MAINRITSAN investigators. Rituximab or azathioprine maintenance in ANCA-associated vasculitis. N Engl J Med. 2015 Jan 22;372(4):386-7.
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