Maintenance Immunotherapy in MOGAD: Early Steroid Benefit, Dose Thresholds, and Disability Risk - Part 2

In the second episode of this series, Dr. Justin Abbatemarco and Dr. Benjamin P. Trewin discuss what was found in non-steroidal maintenance therapies. 

Read more about this abstract on the AAN website.  

Show transcript: 

Dr. Justin Abbatemarco:

Hello and welcome back. This is Justin Abbatemarco from the Cleveland Clinic. And we're joined by Ben Trewin on his abstract maintenance immunotherapy and MOGAD, early steroid benefit, dose thresholds and disability risk. Ben, in our first episode we really talked about corticosteroids, but your paper and abstract looked at other therapies. What did you find in those non-steroidal maintenance therapies?

Dr. Benjamin Trewin:

In addition to looking at oral corticosteroid therapies, we also looked at B-cell depleting therapies, namely rituximab and ocrelizumab, and intravenous immunoglobulin and steroid-sparing therapies, namely azathioprine and mycophenolate predominantly, I suppose a couple on methotrexate. Now, what we found, it's important to note that we were able to tease apart the effects of all these drugs with our Cox proportional hazard model chops up, follow up into distinct intervals with different combinations and permutations of these medications and their different doses in a more granular way than is allowed by previous techniques like incident rate ratios when we compare pre and post annualized relapse rate, and we think this is a strength of the study. With this methodological strength, we were able to see that steroid-sparing therapies, despite 334 patient years of data, do not appear to have any independent benefit with respect to time to next relapse.

The estimate of effect there was 1.06. And then for time to confirm sustained disability, there was also no confidence signal, the confidence interval being 0.15 to 1.4, that it actually prevented any disability despite a wealth of data, which I think is an important thing to note. And I think previous studies, particularly looking with incident rate ratios, have been a little more optimistic with that. And I think there might be misattributing some of the benefit of concomitant steroids to the steroid-sparers, but it's more complex than that, of course. And then with respect to B-cell depleting therapies, we did have 48 of 261 patients exposed, which is reasonable, but not quite enough to get the signal we're looking for. However, we found something quite interesting, because when we compared the Liverpool data to the Australasian data, the two big study groups involved, we saw that it wasn't quite as effective in Liverpool as it was in Australasia in this subgroup analysis.

And so we dug a little deeper, as one should, and found that the dosing is actually different. And in Australasia, we have a tendency to just give two grams of rituximab up front, or 600 milligrams of ocrelizumab. And then six-monthly, you give a gram of rituximab without fail, without trying to watch the B cells or trying to muck around with doses in any way. And when we looked at that, the threshold dosing, as we termed it, as compared to below threshold dosing, there actually was weak evidence at a PVA of 0.08 that threshold dosing is superior to below threshold dosing. And that needs to be reproduced, but I think that was an important signal. And finally, I would say IVIG, of course, has some very strong data in this area. And I think it's important from this study at least to remain a little agnostic on that as we only had 31 patients on IVIG, and so I absolutely wouldn't say it's not effective. I would say unfortunately, we had insufficient data to make any big claims about that.

Dr. Justin Abbatemarco:

I think some really great data to help pick apart here and help inform practice. I think your point about looking at the previous literature and trying to tease apart these steroid-sparing agents, that corticosteroids they're not uniformly addressed, and so it's difficult to think about at those previous data points, so I appreciate that. And then this dose response to the B-cell therapies, there's been questions in the literature, because I think we've gotten a lot of mixed results on B-cell therapies. And so this to me is one of the larger studies that really help answer this question that maybe B-cell therapies are effective and maybe we need to be a little more sensitive to dose, which is the same theme we saw on IVIG. IVIG, maybe at higher doses, could be more effective for MOGAD. What do you think about that comparison?

Dr. Benjamin Trewin:

I like where you're going with that because we're quite interested in these dose responses as we introduce this 12.5 milligram per day oral corticosteroid dose or 0.16 milligrams per kilograms per day in kid. And so we're quite interested. And, of course, that work by Dr. Chen and Dr. Mariner has revealed that IVIG also has quite a sensitive dose threshold there at one gram every four weeks. And we followed that precinct because that research was so strong. So it's nice to feel like we're building on previous studies and then perhaps even detecting another dose threshold with respect to rituximab. And I must say, it was a little bit of a surprise, we came in and saw why is the Liverpool data moving that way and the other one moving this way? So it was a nice data-driven evolution of our multi-variable model.

Dr. Justin Abbatemarco:

So helpful. And I'll ask everyone to come back for the final episode, where we try to put this all together. We're going to put Ben on the spot and really understand how he approaches these cases in clinical practice. Ben, thank you.

Dr. Benjamin Trewin:

Thanks very much, Justin.