#ClinicSpeak: blistering skin disease and MS

Have you heard of bullous pemphigoid? If you have been treated with alemtuzumab this post is for you. #ClinicSpeak #ResearchSpeak

Bullous pemphigoid is an acute or chronic autoimmune disease of the skin, involving the formation of blisters in the skin layers. It is can be a very disabling disease  and is unsightly. As a general medical registrar I remember looking after several patients with severe BP. One patient died under our care with secondary infection and septicaemia. On occasions when the disease is extensive with many lesions that slough patients can lose a lot of liquids and salts or electrolytes through the lesions, which adds to difficulties in managing them. 

The Danish registry study shows a surprising association between BP and MS; pwMS are almost 10x more likely to develop BP than the general population. Why? 

I have another interest in BP in that it is one of the potential secondary autoimmune diseases that may develop post-alemtuzumab. I am aware of one pwMS who developed BP after being treated with alemtuzumab. So please be vigilant if you have had alemtuzumab treatment and develop any blistering of the skin please seek medical attention ASAP. The cause of BP is an auto-antibody that binds to a particular protein in the skin. BP is therefore another one of the many emerging auto-antibody mediated secondary autoimmune diseases that may develop post-alemtuzumab. 

It is a great pity we didn’t test our hypothesis of trying to prevent autoimmune disease post-alemtuzumab; i.e. with a small dose of rituximab, or using teriflunomide, after alemtuzumab. If successful can you imagine what a difference it would have made regarding the use and uptake of alemtuzumab as a treatment for MS? We have had to abort our ideas of doing any trials of this nature; with the emergence of the next generation of DMTs, i.e. ocrelizumab and oral cladribine, it is likely that most patients will not choose alemtuzumab as a treatment. I predict alemtuzumab will become the MS treatment of last resort, being used just prior to HSCT.

Kibsgaard et al. Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid. Br J Dermatol. 2017 Jun;176(6):1486-1491.

BACKGROUND: Bullous pemphigoid (BP) is a disease of the elderly and may be associated with neurological and cardiovascular diseases and diabetes. Mortality rates strongly exceed those of the background population. 

OBJECTIVES: To investigate the frequency of comorbidities and their temporal relation to BP.

METHODS: A register-based matched-cohort study on all Danish patients with a hospital-based diagnosis of BP (n = 3281). The main outcomes were multiple sclerosis (MS), Parkinson disease (PD), Alzheimer disease (AD), stroke, diabetes types 1 and 2, malignancies, ischaemic heart disease (IHD), hypertension and eventually death.

RESULTS: At baseline, patients with BP had increased prevalences of MS [odds ratio (OR) 9·7, 95% confidence interval (CI) 6·0-15·6], PD (OR 4·2, 95% CI 3·1-5·8), AD (OR 2·6, 95% CI 1·8-3·5) and stroke (OR 2·7, 95% CI 2·4-2·9). Furthermore, malignancies, cardiovascular disease and diabetes were over-represented among patients with BP: type 1 diabetes (OR 3·1, 95% CI 2·5-3·8), type 2 diabetes (OR 2·3, 95% CI 2·0-2·6), malignancies (OR 1·3, 95% CI 1·1-1·4), IHD (OR 1·7, 95% CI 1·5-1·9) and hypertension (OR 2·0, 95% CI 1·8-2·2). During follow-up, the risk of MS was significantly higher among patients with BP [hazard ratio (HR) 9·4, 95% CI 4·9-18·0], even if events during the first year after diagnosis of BP were excluded (HR 5·1, 95% CI 2·3-11·3). Patients with BP had an average increased mortality rate of 2·04 (95% CI 1·96-2·13).

CONCLUSIONS: We discovered a significantly increased frequency of MS among patients with BP. At the time of diagnosis, patients with BP had an excessive number of comorbidities and an increased mortality rate over the following years.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


Leave a Reply to halcncod Cancel reply

    • Kudos for posting my comment above. I had doubts….

      Guys: we love your work, but you should really reconsider your editorial policy: Quantity v.s. quality.

      The comment above is a flagrant case-in-point.

    • Not at all; technological innovation drives creative destruction. If a DMT with similar efficacy to alemtuzumab with a better safety profile, and less monitoring, is licensed and green-lighted by NICE it will displace alemtuzumab. At the moment a lot of pwMS are being forced to choose alemtuzumab because that is what we have. In a few months time they will, hopefully, have two other options.

      Last week's post referred to the here and now, today's post is referring to the future.

  • Why does Alemztumab seem to normalise brain atrophy better than cladribine (from the data out there)?

    What's Alemztumab doing that Cladribine can't? Cladribine should, in theory, be better, because it's small enough to get into the CNS. Yet it does not normalise brain atrophy, it only reduces it, unlike Alemzutumab.

  • Why does Alemtuzumab do better on brain atrophy than Cladribine?

    Why does Alemtuzumab cause an initial increase in brain volume? No other DMT does this; HSCT does not do this.

    What is Alemtuzumab doing that Cladribine isn't? Cladribine gets into the CNS, whereas Alemtuzumab does not. Surely Cladribine should be better.

    • As profG memtions you would have to do a head to head.

      Also people in the alemtuzumab trials had very short disease duration of 2 years veres 7-10 years in CLAD trial, people were EDSS 2 (ALEM) verses EDSS 3 (CLAD) so the two are not really comparable.

      Also Alemtuzumab and cladribine deplete in different ways. With Alem it is explosive and rapid causing 90% infusion reactions. With CLAD the killing is slow taking 2-3 months to deplete, so you should re baseline to 3 months as was done with ocrelizumab to look at atrophy.

      T cells deplete by 95% and stay below 70% for two years with ALEM but for CLAD it is only 40% in year 1 and 60% in year 2, of course the question is how much and how long are the memory B cell depleted. You could optimise the dosing of CLAD for this.

      What is alemtuzumab doing that CLAD isn't…causing 50% of people to get secondary autoimmunities and more

    • That's actually a very good point about the disease duration of those studied. However, if you are leaving a large amount of 'corrupted' immune cells around they're probably going to cause ongoing damage until dealt with. A complete therapy (HSCT, Lemtrada comes close) would destroy the vast majority of them.

      Why do you think Alemtuzumab causes an initial increase in brain volume? Natalizumab causes an initial acceleration in atrophy, theorised to be 'pseudoatrophy' and as a result of bringing down inflammation. HSCT also causes an initial increase in atrophy, likely partly due to the toxic nature of the chemotherapy drugs used and partly due to a reduction in inflammation causing psuedoatrophy. Why Alem causes an initial brain volume increase confounds me.

  • Whoa… hang on a minute. I can't keep up. One minute highly efficacious DMTs and treatments 'should' be used as first line ('flip the pyramid'), now they'll be a last resort? Of course secondary AIs are less than ideal, but controlling disease activity, potentially permanently, is the primary goal and is a pretty powerful drawcard despite the low risk of secondary AIs (excluding the higher risk of thyroid disease).

    If I were to be given the choice between Ocrelizumab or Alemtuzumab today, I'd still choose Alemtuzumab. Why? a) because the brain atrophy data is impressive with alemtuzumab. There's a suspicious silence and lack of noise about Ocrelizumab's brain atrophy data, b) we really don't know what causes ms, so I'll cover more bases hitting both T and B cells and c) I'm hesitant to suppress my b-cells every 6 months indefinitely, it's like continually reopening the door for cancer to walk in. I understand these are theoretical assumptions, but given the inconsistency even on this blog about which DMT or induction treatment is the most efficacious, I'll go with a theory that stands until proven otherwise.

    • Re: 'Brain atrophy' – Alemtuzumab does better than cladribine on brain atrophy is because it is probably more effective than cladribine. However, wouldn't it be nice to do a head-2-head study of the two DMTs against each other? DrK tried to get this trial funded but it was turned down.

    • Re: 'Ocrelizumab or Alemtuzumab'

      Your comment is valid and we need to see the ocrelizumab brain atrophy data. But you make the point that it is about choice.

    • Induction therapy verses every 6 months….read our B cell paper for induction therapy capacity of ocrelizumab

    • I'm not convinced Alem's benefits can last forever even after 3 infusions over 3 years. Maybe there's a case for an initial course of Alem and then maintenance doses of Cladribine every year after that?

    • Halcncod – the extension data on the CARE-MS trials suggests that alemtuzumab can in fact cause long term remission.

    • I think we're at 6 years brain atrophy data for Alemzutumab, coming up on 7 years this year (seeing that data this year will be interesting – I await a blog post on it). Brain atrophy seems to still be normalised. Yes, it's very promising, yet at theoretical level I don't actually think it stops all auto-immune inflammation for the long term, I don't see a mechanism for that. Better safe than sorry.

      As a side note post-mortem studies done on people who have undergone HSCT show continued neuroinflammation and demyelination. There was one case of a woman having HSCT before she even started showing symptoms of MS (she was at the RIS stage and underwent HSCT for another condition) and they found continued neuroinflammation and demyelinating activity in the post-mortem done after she had died a few months after HSCT.

    • Halcnod – re maintenance cladribine after alemtuzumab – do you think this leaves one too immunosuppressed long term? More so being open to malignancy than infection?

    • I think people would have to evaluate their risk tolerance on that, but I don't think so. I think you would reduce the risk of secondary autoimmunity from Alem because Cladribine would keep B cell numbers from overshooting their mark. And you'd also only be doing 1 infusion of Alem rather than multiple infusions over multiple years as is normally the case.

By Prof G



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