Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. Tolle, Scheibenbogen et al. 2020

[John Mac]

Abstract
(1) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmunological disease. There is evidence for an autoimmune mechanism for ME/CFS with an infection-triggered onset and dysfunction of ß2-adrenoreceptor antibodies (ß2AR-AB). In a first proof-of-concept study, we could show that IA was effective to reduce ß2AR-AB and led to improvement of various symptoms.

(2) Five of the ME/CFS patients who had clinical improvement following treatment with a five-day IA were retreated in the current study about two years later with a modified IA protocol. The severity of symptoms was assessed by disease specific scores during a follow-up period of 12 months. The antibodies were determined by ELISA.

(3) The modified IA treatment protocol resulted in a remarkable similar clinical response. The treatment was well tolerated and 80–90% decline of total IgG and ß2AR-AB was achieved. Four patients showed a rapid improvement in several clinical symptoms during IA therapy, lasting for six to 12 months. One patient had no improvement.

(4) We could provide further evidence that IA has clinical efficacy in patients with ME/CFS. Data from our pilot trial warrant further controlled studies in ME/CFS.

https://www.mdpi.com/2077-0383/9/8/2443

 

[Legend]

I'm sorry to ask. But what is a modified IA protocol?

 

[Trish]

I'm sorry to ask. But what is a modified IA protocol?

In the full paper they explain: 'Patients who had responded to the first IA (IA1) were retreated with a modified IA protocol (IA2) about two years later. Here, IA cycles were given with longer intervals.'
So the immunoadsorption was done on days 1, 2, 3, 6, 7 on the first version, and days 1, 2, 4, 6, 8 on the modified version.

 

[hinterland]

I'm sorry to ask. But what is a modified IA protocol?

IA = Immunoadsorption.

From Wikipedia:

Immunoadsorption is an alternative blood purification technique[1] used to eliminate pathogenic antibodies.[2][3][4]

It may be used as an alternative to plasma exchange in certain conditions.[5] Evidence of benefit is lacking in those with kidney problems.[6] Concerns include that it is expensive.[6]

 

[butter.]

looks placeboish

 

[John Mac]

looks placeboish

A placebo controlled trial should answer that. The researchers suggest that.

Data from our pilot trial warrant further controlled studies in ME/CFS.

80–90% decline of total IgG and ß2AR-AB was achieved

Just because there is a fall in a biological measurement doesn't mean that it is the cause of the symptom improvement, it could easily just be placebo.

 

[Jonathan Edwards]

An 80-90% decline in total IgG sounds seriously bad news to me. We used to worry if there was a 50% reduction with rituximab. Unless there is some good reason why this is considered acceptable, perhaps in the short term, I would not recommend continuing to study this protocol.

 

[Jaybee00]

You mean they would be very vulnerable to contracting/dying from an infection with that much IgG depletion?

 

[wigglethemouse]

An 80-90% decline in total IgG sounds seriously bad news to me. We used to worry if there was a 50% reduction with rituximab. Unless there is some good reason why this is considered acceptable, perhaps in the short term, I would not recommend continuing to study this protocol.

They are removing them from the plasma only so it's a bit different to Rituximab I believe. How quickly do they come back? By the way, Fig 3 shows the values for all patients normalised to 1 at the start. I think the square data points are total values.
Full text PDF : https://www.mdpi.com/2077-0383/9/8/2443/pdf

 

[Jonathan Edwards]

You mean they would be very vulnerable to contracting/dying from an infection with that much IgG depletion?

The point is that they might be. Resistance to infection is complicated and some people manage on low IgG levels but an 80-90% reduction puts someone into seriously risky territory.

 

[Jonathan Edwards]

They are removing them from the plasma only so it's a bit different to Rituximab I believe.

Plasma is the only relevant compartment for antibodies so it is the same as for rituximab. They are not affecting B cells but the relevance of affecting B cells is only through the knock on effect on plasma antibodies in both situations.

 

[Jonathan Edwards]

How quickly do they come back?

I have only had a quick look at the paper but it seems only to give us IgG and antibody levels for 9 days. This is completely meaningless from my perspective since to be any use one would want antibodies to go down for months at least.

(The paper is published in something I have never heard of called Journal of Clinical Medicine, which sounds to me like one of the new journals that will publish anything. Peer review should have insisted on longer term Ig levels - that is if I am right that these are not given.)

The key point is that treatment aimed at reducing antibody levels is only a reasonable idea if there is some specificity that lasts over months. Rituximab is useful because for reasons we do not fully understand there is very useful specificity. It does not look as if there is any here.

 

[wigglethemouse]

I have only had a quick look at the paper but it seems only to give us IgG and antibody levels for 9 days.

Okay, lost in the mass of text was a statement that they replaced IgG after IA. The focus was on removing damaging antibodies and partially replacing the good ones. However, I thought IgG infusions had a half life of 21 days......

In this study, the patients received a single IgG infusion at the end of IA protocol in order to partially restore the strong IgG depletion.

 

[wigglethemouse]

They are not affecting B cells but the relevance of affecting B cells is only through the knock on effect on plasma antibodies in both situations.

They say that IA reduced memory B cells as well

We also found a decrease of memory B cells following IA1 and significantly lower ß2AR-AB after six months, suggesting that IA may have an effect on autoreactive memory B cells as well

The frequency of memory B cells significantly decreased, whereas the frequency of plasma cells increased after a five-day IA cycle.

I'm not sure what they mean by frequency........... maybe lost in translation?

 

[Hutan]

Participant selection

Five of the ten participants of our first study in 2016 were included in the current study. These patients had a transient or long-lasting improvement of clinical symptoms after the first IA therapy.

In short, all of the patients fulfilled the Canadian Consensus Criteria [1], had increased ß2AR-AB levels, and an infection-triggered disease onset.

The 5 participants were regarded as responders to a previous trial of the therapy (IA1 in 2018). And all of the participants had increased B2AR-ABs. So, this is not a random sample. That's ok, but something to keep in mind.

Treatment

During the IA1 study, we learned that repeated IA can worsen fatigue. Four patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms. To improve the tolerability of the treatment, we extended the treatment period and reduced the dose of IgG replacement.

The treatment in IA1-2018 was 5 IA in 7 days, with assessment on day 8. Worsening fatigue but improvements in other symptoms doesn't sound that good - I think it would be difficult to assess improvement.

The IA2-2020 treatment schedule was 5 IA in 8 days, with assessment on day 9, with a lower dose of replacement IgG after the final IA session.

A citrate-based anticoagulation was used.

Assessment

We assessed the presence and severity of symptoms, as described in our previous study [23]. In short, the patients quantified the severity of symptoms of the Canadian consensus criteria using a questionnaire that was developed by Fluge et al. [17,18]. After the determination of a baseline value, patients stated the improvement or worsening of symptoms (0–3: worsening; 3: no change from baseline; 3–6: improvement). The patients filled this questionnaire daily during treatment and monthly during follow-up. Furthermore, patients evaluated fatigue and cognitive impairment monthly using FACT-F questionnaire [24].

The followup was done for 12 months.

 

[Hutan]

Results
Levels of IgG and of autoantibodies decreased during the treatment period.

Regarding IA1- 2018 and the long lasting improvements - only some of the ten patients seemed to improve in the short term. Two years later, the status of 5 'responders' was that, compared to the baseline before IA1-2018, 3 had an improved total symptom score, 1 had a similar score and 1 had a slightly worse score. I'm not sure that that is enough to suggest 'long term results'.

Figure 6 gives the symptoms scores for the 5 patients during 12 months of followup after each of IA1-2018 and IA2-2020. Each chart is for a patient for one of the 12 month periods. There are four symptom groups, the lines plot the change in symptom scores. Scores in the grey zone indicate no change or worsening. Bearing in mind that this is an unblinded study, the results are a bit underwhelming. It's possible that three patients got some benefit from the treatment.

Although some placebo-treated patients showed an improvement in randomized placebo-controlled trials (RCT) in ME/CFS [18,31], the reproducibility and the long lasting symptom improvement associated with a significantly decreased frequency of memory B cells, increased frequency of plasma cells, and lower autoantibody concentration six month after IA1 rather speaks against an unspecific effect. Further, although being considered unlikely, IgG replacement at the end of IA may have an immunomodulatory effect. Therefore, we have intentionally kept the IgG dose in the current study lower to minimize this potential effect.

The authors note that people with ME/CFS treated with a placebo have reported improvements (that's the Norwegian rituximab study), but suggest that this is not what is happening here. They suggest the reproducibility and the long lasting symptom improvement are arguments against that. I'm not so sure when I look at Figure 6 that reproducibility and long lasting symptom improvement were better than what might be expected from a placebo.

It's good that this group is looking at the auto-antibody possibility. I'd love that to be the answer. But I don't see convincing evidence here. Perhaps it is for a relatively small subset.