Plasma Exchange in ANCA-Associated Vasculitis: For Whom (If Any)?
Authors: Michael Walsh
Journal: Journal of the American Society of Nephrology (2022)

ANCA-associated vasculitis (AAV) is a multisystem disease. Patients with AAV are frequently treated by a variety of specialists so it is not surprising different specialty groups each produce guidelines for AAV. Despite publishing several guidelines at similar times (shortly after publication of major trials ), there are notable differences in recommendations around plasma exchange (PLEX) as an adjuvant treatment for AAV ranging from conditionally recommending against the routine use of PLEX for any patient to considering use in patients with a serum creatinine >5.7 mg/dl (500 µmol/L) to considering PLEX as second-line therapy in patients with serum creatinine >5.7 mg/dl.12–3 The apparent discordance in recommendations seems to stem from the interpretation of the most recent randomized, controlled trial, PEXIVAS, comparing PLEX with standard therapy and its contrasting results to the MEPEX trial that strongly influenced previous guidelines.4,5 PEXIVAS enrolled 704 patients with an eGFR<50 ml/min (including those receiving dialysis) or with lung hemorrhage, and after a median follow-up of 2.9 years, it was unable to find a benefit of adjuvant PLEX on the composite outcome of ESKD or death (hazard ratio [HR], 0.86; 95% confidence interval [95% CI], 0.65 to 1.13). MEPEX enrolled 137 patients with a creatinine >500 µmol/L or receiving dialysis and found that PLEX substantially reduced the risk of dialysis dependency at 12 months (HR for ESKD, 0.46; 95% CI, 0.24 to 0.91). Importantly, PEXIVAS enrolled 205 participants who generally met the MEPEX inclusion criteria, but it did not find a benefit of PLEX in this subgroup (HR, 0.85; 95% CI, 0.59 to 1.22). The recommendations from Kidney Disease Improving Global Outcomes and AFSA seem to interpret these differing results as PLEX being beneficial for patients from MEPEX but not from PEXIVAS. The ACR recommendations, conversely, seem to interpret this as an overall failure to show benefit in any patient group. Differing interpretations could arise from the belief that PLEX has qualitatively different effects in those with versus without severe kidney involvement (i.e., effect modification or interaction) or that there is in fact an overall benefit but the benefit is only worthwhile in absolute terms for individuals at high risk of the outcome (i.e., the relative effect of PLEX is consistent across levels of kidney function, but only those with very poor kidney function are at risk of ESKD and/or death and are, therefore, the only ones likely to experience benefits that outweigh the risks). The study by Nezam et al.6 attempts to elucidate this issue to a degree using a nationwide cohort of 425 French patients with AAV. Using modern statistical approaches to try to circumnavigate the biases and confounding inherent in observational studies estimating treatment effects, they found that PLEX did not reduce the risk of death or ESKD in the overall cohort (relative risk, 0.77; 95% CI, 0.47 to 1.25). However, estimating a treatment effect from a subgroup of patients with a better than expected outcome after PLEX suggested that PLEX may reduce the risk of death or ESKD in some patients. Those patients who may benefit, identified with a prognostic score that incorporates renal biopsy information, appeared to differ largely in that their serum creatinine was almost double that of the group in which PLEX was not recommend. Importantly, the estimated relative effects of PLEX were roughly the same across the groups (relative risk, 0.65 in the PLEX not recommended group and relative risk, 0.69 in the PLEX recommended group). Conceptually, this blurs the distinction as to whether PLEX is recommended group is based on effect modification or whether this group is simply at high risk of ESKD and therefore accrued enough events to reliably detect the effect of PLEX (which highlights the reason randomized, controlled trials often enrich their study population with high-risk individuals). In either case, it does not support the argument that PEXIVAS did not find an effect of PLEX by including an excess of patients with sclerotic kidneys since sclerotic class biopsies were almost twice as common in the PLEX-recommended group. The data of Nezam et al.6 may or may not be sufficiently compelling to convince clinicians whether PLEX is beneficial or not. Adding confidence to the results of this study is the consistency of the overall estimated effect on the composite of death and ESKD at 12 months with PEXIVAS and MEPEX. However, their approach highlights at least two important issues outside of estimating treatment effects from observational data. First, the degree to which differing study results are attributable to random error rather than systematic differences between them (like the enrolled populations or specific treatment regimens that might create effect modification but also, outcome definitions, possible biases, etc.) needs to be distinguished. Although there is no simple way to do this, it should be noted that true effect modification seems uncommon, and an instrument exist to help determine when they truly exist.7 The second issue is that when considering a treatment that is believed to have a beneficial effect, the degree to which an individual patient might expect benefits (and harms) depends on their baseline risk. This is important in diseases where the baseline risk varies substantially between patients and when there are important potential consequences to treatment. Engaging in informed decision making requires clinicians to estimate that patient's baseline risk (as best they can) and apply the best estimate of the relative treatment effects to provide that patient with expected benefits and harms (in absolute terms).8 Recommending treatments on the basis of obtaining sufficient precision to detect an absolute effect in a subgroup will systematically bias recommendations away from smaller, lower-risk subgroups on the basis of arbitrary thresholds and would not be consistent with the ideals of shared decision making. Although differing guideline recommendations on the use of PLEX in AAV remain to be clarified by further studies, careful observational studies, like that of Nezam et al.,6 will add to the evidence and help define more nuanced treatment approaches in the future. Disclosures M. Walsh reports Research Funding: Canadian Institutes of Health Research, National Health and Medical Research Council, Health Research Council, British Heart Foundation, National Institute of Health Research, and Vifor; and Advisory or Leadership Role: Bayer, Novo Nordisk, and Otsuka. Funding None.