Plasma Exchange for Severe ANCA-Associated Vasculitis (AAV)?

There has been lots of new data in the AAV literature of late. We have new nomenclature, including the dropping of Freidrich Wegeners name for the more generic but descriptive granulomatosis plus angiitis (GPA), by the Chapel Hill consensus conference. A large genome wide association study by the European Vasculitis Genetics Consortium has reported genetic variants associated with AAV and show that polymorphism segregate with ANCA specificity (Anti-MPO and Anti-PR3). A recent follow-up to the RAVE study demonstrates non-inferiority of rituximab as compared to oral cyclophosphamide for severe AAV. Moreover, among patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression, at least for the first year.

Removing pathogenic antibodies via plasma exchange (PE) is an attractive, if crude, treatment option for severe AAV and is generally recommended for severe alveolar hemorrhage (although without much evidence). In patients without severe lung involvement, it has gained a role in attempting to prevent ESRD in patients with severe renal disease at presentation, due largely to the MEPEX trial. MEPEX was published in 2007 and included patients with AAV who required dialysis at presentation or had a serum creatinine >500 µmol/L (5.8 mg/dL). This study included 137 patients who were randomized to 7 PE treatments or IV methlyprednsiolone pulse therapy. Both groups received oral steroids and cyclophosphamide. PE was associated with a risk reduction of ESRD of 24% at 1 year. Patient survival and severe adverse event rates were similar in the 2 groups. A follow up to MEPEX has been published in Kidney International this month where the original patients were followed for a median of 3.95 years. During this follow-up, over a half of patient died and almost two-thirds had either died or developed ESRD (the composite primary outcome), with no significant difference between the groups. Also, there was no significant differences in relapse rate.

It must be noted that the original MEPEX trial was designed to examine rate of ESRD alone and demonstrated a benefit with PE at 1 year. The current study looks at a composite of ESRD & death at 4 years. If the early effect on ESRD if real, it would be intuitive that later mortality would be improved which it seems is not. Overall this study questions the benefit of PE in severe AAV and certainly dampens our enthusiasm for its use in this sick patient cohort. A criticism of MEPEX is that IV methlyprednisolone is considered a standard of care in initial treatment of severe AAV and not an alternative to PE. In the real world, patients would receive IV methylprednisolone plus PE. It is also very possible that a beneficial effect of PE exists in cases of AAV earlier in their natural history before significant scarring has occurred, as suggested by a meta-analysis. At this point, PE can certainly be considered as part of the armamentarium of AAV treatment but its exact indication is unclear. The ongoing PEXIVAS trial is planned to enroll 500 patients and will hopefully clarify the role of PE, if any, in severe AAV.

Does nephrology need personalized medicine?

Systems biology is one of science’s growth areas. Sequencing technologies and software tools developed on the back of the human genome project have reduced the cost of, and therefore increased access to, large and complex datasets (ending in -ome) of genome sequences (genomics), gene expression (transcriptomics) and proteins and metabolites (proteomics and metabolomics). Systems biological techniques integrate these datasets and provide insights into how phenotypes may emerge from interacting biological processes rather than isolated genes or proteins.

A recent editorial in the journal Nephrology Dialysis Transplantation examined this field in general and its relevance to nephrology. The authors mention that –omic datasets have been useful in modeling “self-organized highly interconnected networks”, and that such networks have implicated unexpected candidates in disease pathogenesis (see for example, this paper on cardiac hypertrophy). 

The review goes on to suggest that using the tools of systems biology to finely phenotype individuals will usher in an era of truly personalized medicine. However, it is not clear to me that a definite sequel to this type of analysis will be the personalization of treatment or even that the concept of personalized medicine is particularly suited to our current view of what constitutes clinical evidence.

Diseases such as the ANCA-associated vasculitides (AAV) are now known to exhibit genomic variability. Randomised controlled trials (RCTs) in AAV (such as here and here) have been hampered by: 

1. Short follow-up times 
2. Inter-group heterogeneity which may have affected outcomes. These factors have contributed to ongoing debate about the applicability of the results of these trials (see correspondence here). 
3. Additionally a recent trial in membranous nephropathy, likely to represent another disease with distinct –omic subsets, was marked by slow recruitment. 

 

All these points together suggest that it may be difficult to conduct meaningful clinical studies of distinct –omic subtypes in nephrological diseases. Currently, primacy is given to RCTs when evaluating the efficacy of new treatments; and in nephrology the community is finally beginning to produce the RCTs which have been absent historically. 

If the focus is to switch away from RCTs with their large, well-matched study groups and towards splitting groups up by some -omic fingerprint I am able to envisage a time when one has to choose between giving more credence to the results of larger, “non-personalised” trials or smaller studies featuring –omic data but lacking the controlled element of RCTs.  Would this represent progress?