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• Early apheresis and MOGAD attack outcomes: confounding by indication?
  Elias S Sotirchos
  Published on: 4 December 2024

• Published on: 4 December 2024

  Early apheresis and MOGAD attack outcomes: confounding by indication?

  • Elias S Sotirchos, Assistant Professor of Neurology Johns Hopkins University School of Medicine

  I read with great interest the article by Schwake et al, in which the authors performed a retrospective observational study evaluating clinical outcomes in 117 myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) attacks treated with apheresis.[1]

  One of the main findings and conclusions of the paper was that “apheresis was revealed to be most effective if started within 2 days of attack onset, with complete remission rates dropping radically afterwards”. Critically however, this finding may largely be due to selection bias (i.e., confounding by indication) rather than a true causal effect of apheresis timing.[2] As this was a retrospective study, assignment to first-line, second-line or third-line apheresis treatment was not random. Escalation to use of apheresis in the second-line or third-line groups would reasonably be expected to have occurred mainly due to persistent or worsening clinical deficits following treatment with high-dose corticosteroids. Conversely, in the early/first-line apheresis treatment, since the apheresis treatment was initiated as a first-line treatment (presumably concurrently with high-dose corticosteroids, though this is not explicitly stated by the authors in the article), it is quite possible that these attacks would have achieved complete remission even without the use of apheresis, either due to the effects of concomitant high-dose corticosteroids or due to the natural history of such attacks. Notably, demyelinati...

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  I read with great interest the article by Schwake et al, in which the authors performed a retrospective observational study evaluating clinical outcomes in 117 myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) attacks treated with apheresis.[1]

  One of the main findings and conclusions of the paper was that “apheresis was revealed to be most effective if started within 2 days of attack onset, with complete remission rates dropping radically afterwards”. Critically however, this finding may largely be due to selection bias (i.e., confounding by indication) rather than a true causal effect of apheresis timing.[2] As this was a retrospective study, assignment to first-line, second-line or third-line apheresis treatment was not random. Escalation to use of apheresis in the second-line or third-line groups would reasonably be expected to have occurred mainly due to persistent or worsening clinical deficits following treatment with high-dose corticosteroids. Conversely, in the early/first-line apheresis treatment, since the apheresis treatment was initiated as a first-line treatment (presumably concurrently with high-dose corticosteroids, though this is not explicitly stated by the authors in the article), it is quite possible that these attacks would have achieved complete remission even without the use of apheresis, either due to the effects of concomitant high-dose corticosteroids or due to the natural history of such attacks. Notably, demyelinating attacks of the central nervous system typically exhibit at least some spontaneous improvement, even in the absence of acute therapy, and the Optic Neuritis Treatment Trial (ONTT) failed to show a benefit of high-dose corticosteroids vs placebo on long-term clinical outcomes after acute optic neuritis, including in participants with severe attacks (visual acuity of 20/200 or worse at baseline), although the number of MOGAD participants in the ONTT was low.[3,4]

  This is a clear example of confounding by indication, and notably this bias is not isolated to this specific study, but has also been present in other studies that are cited as evidence that early apheresis influences clinical outcomes in neuromyelitis optica spectrum disorder (NMOSD).[5,6] This selection bias is further highlighted by the fact that in the present study disability outcomes (as determined by use of the Expanded Disability Status Scale) at last follow-up were better in those who did not receive apheresis compared to those who did, despite having similar demographic characteristics, annualized relapse rate, and disease duration. Interpreting this result in a consistent manner with the authors’ interpretation of their findings regarding early apheresis treatment would mean concluding that apheresis treatment is actually harmful, a conclusion that would be dismissed as being illogical and due to selection bias. However, the finding regarding early apheresis is not similarly scrutinized since it is consistent with a pre-conceived notion regarding the effectiveness of early apheresis, which is in turn based on similarly biased studies.

  Since the authors have information regarding attacks treated without apheresis, it would be very helpful to perform a comparison between outcomes of attacks treated with early apheresis and attacks treated without apheresis (accounting/matching for key variables, including time from attack onset to initial treatment, attack severity, use of disease-modifying therapy at the time of the attack, as well as demographic and other clinical characteristics), in order to assess whether early apheresis improved outcomes compared to high-dose corticosteroids alone. Use of appropriate causal inference methods, such as propensity score matching, can increase the robustness of such analyses.[7] Furthermore, no information is given in the article regarding the characteristics of the first-line, second-line, and third-line apheresis groups (such as attack phenotype, demographic and clinical characteristics). Presenting this information in a tabular format (similar to Table 1 that compares the characteristics of those who did vs did not receive apheresis) is critical for the reader to understand how comparable these groups are.

  Given the above issues, a randomized clinical trial of early (first-line) vs rescue (second-line) apheresis is warranted to assess whether early apheresis leads to better clinical outcomes in acute demyelinating attacks of the central nervous system. In this context, a multi-center, randomized-controlled, open-label, rater-blinded, pragmatic trial “Treatment of Inflammatory Myelitis and Optic Neuritis with Early vs Rescue Plasma Exchange (TIMELY-PLEX)”is planned to commence in the United States in 2025, comparing these two treatment approaches in severe optic neuritis and transverse myelitis.[8]

  References:
  1 Schwake C, Ladopoulos T, Häußler V, et al. Apheresis therapies in MOGAD: a retrospective study of 117 therapeutic interventions in 571 attacks. J Neurol Neurosurg Psychiatry. 2024;jnnp-2024-334863. doi: 10.1136/jnnp-2024-334863
  2 Kyriacou DN, Lewis RJ. Confounding by Indication in Clinical Research. JAMA. 2016;316:1818–9. doi: 10.1001/jama.2016.16435
  3 Beck RW, Cleary PA. Optic neuritis treatment trial. One-year follow-up results. Arch Ophthalmol. 1993;111:773–5. doi: 10.1001/archopht.1993.01090060061023
  4 Chen JJ, Tobin WO, Majed M, et al. Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4-IgG in Patients in the Optic Neuritis Treatment Trial. JAMA Ophthalmol. 2018;136:419–22. doi: 10.1001/jamaophthalmol.2017.6757
  5 Bonnan M, Valentino R, Debeugny S, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89:346–51. doi: 10.1136/jnnp-2017-316286
  6 Kleiter I, Gahlen A, Borisow N, et al. Apheresis therapies for NMOSD attacks. Neurol Neuroimmunol Neuroinflamm. 2018;5:e504. doi: 10.1212/NXI.0000000000000504
  7 Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011;46:399–424. doi: 10.1080/00273171.2011.568786
  8 Treatment of Inflammatory Myelitis and Optic Neuritis with Early Plasma Exchange (TIMELY-PLEX) | PCORI. 2024. https://www.pcori.org/research-results/2024/treatment-inflammatory-myeli... (accessed 12 November 2024)

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  Conflict of Interest:
  I am co-principal investigator for a multi-center, randomized-controlled, open-label, rater-blinded, pragmatic trial “Treatment of Inflammatory Myelitis and Optic Neuritis with Early vs Rescue Plasma Exchange (TIMELY-PLEX)” that is planned to commence in the United States in 2025, comparing first-line vs second-line use of apheresis in severe optic neuritis and transverse myelitis.

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