Slow and steady wins the race?

I mentioned in my post about supplements that I had “heard” but not “researched” a claim that slower immune system recovery correlated with better alemtuzumab outcomes.

This claim appears to stem from this paper: Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis.

In this study, 56 patients were followed for a median period of 39.5 months after treatment with alemtuzumab. They were monitored to identify speed of immune recovery and rate of relapse. The purpose was to identify whether immune recovery could be used as a biomarker to identify which patients might be at higher risk of relapse and therefore which might benefit from repeated treatments.

OK, quickly back-to-school for a biology lesson.

  • The immune system is made up of a bunch of things. One key element is the white blood cells, or leukocytes.
  • Leukocytes come in two basic categories – phagocytes and lymphocytes.
  • Lymphocytes come in different types, too – each type having a specific role in the immune system.

The white blood cells which “remember” bad guys they have seen before (in order to better respond to a future attack from the same pathogen) are the lymphocytes known as “helper T-cells”. The aim of alemtuzumab treatment is to kill of the helper T-cells in order to “wipe” this immune memory.

The aspect of immune recovery measured in this study was specifically CD4+, CD8+, and CD19+ recovery. These are three different types of lymphocyte. (CD4+ cells are helper T-cells. CD8+ cells are killer T-cells. CD19+ is a B-cell.) There was no correlation between recovery of either CD8+ or CD19+ and risk of future disease activity. But there was a correlation between CD4+ recovery and risk of future disease activity. It was therefore suggested that CD4+ counts after treatment might be a viable bio-marker. Remember, the CD4+, the helper T-cells, are the “memory cells” targeted by alemtuzumab treatment. So it is plausible that how they re-populate, including the time it takes, could be relevant to how successfully they were “wiped”.

It is worth emphasising that the sample here was very small. A total of 56 patients, only 14% of whom (8 people) had any disease activity*. While the results were considered statistically significant, it’s a really small sample size!

(* Great news, huh! A reason to be cheerful.)

A follow-up study was done by revisiting the data from the original Cambridge trials to see if the same correlation could be seen.

The name of the paper contains a spoiler: Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity.

Based on reviewing data for 108 patients, lymphocyte recovery did not significantly correlate with either disease activity or disability accumulation.

So much for that idea. As the data in the smaller study was not replicated in a larger data set, it seems that the correlation may have been coincidence after all. Ho hum.

The other question is whether the rate of lymphocyte recovery might be correlated with another outcome of interest – the risk of serious side effects. With alemtuzumab the serious side effects all relate to development of new auto-immune conditions.

It turns out that this has also been investigated. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.

This study looked at CD4 and CD8 recovery in 87 patients and found no correlation between the rate of lymphocyte recovery and the incidence of autoimmunity.

In conclusion, there seems to be no significant evidence of any correlation between speed of immune recovery and either disease activity, disability accumulation or side effect risk.

Of course, even if there were evidence of a correlation, this is not the same as causation. In other words, there would be no reason to conclude – even from a proven correlation between speed of lymphocyte recovery and treatment outcome – that deliberately slowing the immune system recovery (e.g. by avoiding immune-supportive vitamins or other supplements) would cause a better treatment outcome. There is a correlation between rain falling from the sky and use of an umbrella – but that doesn’t mean you can make it rain by putting up an umbrella.

When you think about it, if lymphocyte recovery were simply a signal that could be used to check how successfully lymphocytes were wiped,  it seems unlikely that anything you do after the wipe to affect speed of lymphocyte recovery could possibly affect the success of the wipe. Either they were wiped right, or they weren’t. If slowing down or speeding up lymphocyte recovery happens after the wipe, it is difficult to see how it could affect anything. It really is like putting up your umbrella and hoping it will rain.

Which means, for me, that I’m going to chill out even more about those multivitamins!

UPDATE: 15 June 2017.

MS-UK article (Previously unpublished data may explain Lemtrada’s efficacy and side effects) explains further findings relating to the speed of recovery of T-cells and B-cells. It’s all terribly complicated. Assuming I have understood this right, I believe this is a fair summary of the position –

  • Analysis of the previously unpublished data focussed on the CD19+ B-cells. B-cells make antibodies, and the population is regulated by T-cells.
  • The data analysis showed that if the B-cells recover dramatically (due to the lack of regulating T-cells), then there is a risk that they will start making alemtuzumab antibodies, reducing the effectiveness of the treatment.
  • It may also affect the safety of the treatment, as there is a suggestion that auto-immunity may arise as a result. (Not sure why!)
  • There is a suggestion therefore that treatments aimed at slowing the “hyperpopulation” of CD19+ might improve the safety and effectiveness of the treatment.

So there may be more to it than the earlier studies I referred to. Maybe that third study into the incidence of auto-immunity should have looked at CD19 as well as CD4 and CD8?

What isn’t clear is what treatment might be offered to slow down specifically the B-cell repopulation. We do know that Vitamin D deficiency is linked to an enhanced immune response and specifically that there is a evidence of a direct relationship between Vitamin D and B-cells. (Source) So ensuring adequate levels of Vitamin D could be one avenue to explore. But it’s all cutting edge stuff and there is little that can be said with certainty, it seems.

It’s all very interesting but there is nothing in it that tells the beleaguered alemtuzumab patient what to do – other than to keep taking you D vitamins, of course! As we were, then…



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