ClinicSpeak: macrophages infiltrates after alemtuzumab in a patient with NMO

What does the pathology of a case of NMO teach us about alemtuzumab? #MSResearch #MSBlog #ClinicSpeak

"The case report below is of a patient with anti-aquaporin-4 NMO who was treated with alemtuzumab. Unfortunately the patient died and at post-mortem the pathology showed extensive innate immune activation, i.e. extensive macrophage infiltration, with very little lymphocytes. It is clear this patient did not respond to alemtuzumab in that she had a recurrent attack and died from a large lesion and extensive lesion involving the brain stem and brain. The brain MRI lesions of this patient are very atypical for NMO and I wonder if she may have succumbed to another condition, for example progressive multifocal leukoencephalopathy or PML; the pathological description does not mention tests to exclude PML. Outside the context of MS alemtuzumab has been linked to PML, typically in patients with leukaemias and lymphomas. This poor woman had a very stormy course with multiple urinary tract infections, septicaemia, herpes zoster, a deep venous thrombosis in the leg, haematomas following plasma exchange, a broken femur after falling out of her wheelchair and an episode of Clostridium difficile colitis. She finally required a tube inserted for feeding directly into her stomach; i.e. a so called gastrostomy tube, before being discharged home."

"The interesting question is did alemtuzumab work in this patient and dos it work in NMO?  We have previously reported on the association between thyroid autoimmunity and the MS mimics, NMO (neuromyelitis optica) and TM (transverse myelitis), compared to MS in the past and I have speculated that alemtuzumab may not suitable for treating autoantibody mediated conditions such as NMO. This may relate to how alemtuzumab works and its complications; i.e. it may trigger and stimulate autoantibody production."

"Alemtuzumab's putative mode of action is via depleting your immune system and allowing it to recover spontaneously. Alemtuzumab kills or bursts open white blood cells, or leukocytes, by binding to a specific protein CD52 on the surface of the cell. When alemtuzumab binds to the cells it attracts a large number of other proteins, called complement, to the surface of the cells and these proteins pierce a hole in the cell causing it to burst. Complement is the family of proteins the immune system uses to kill damaged or cancerous cells and invading organisms. When the white cells burst they release their contents into the bloodstream; some of these substances are proteins that mediate the effects of inflammation on the body, which is why alemtuzumab causes an infusion reaction with a raised temperature, chills, rigors and a skin rash in most treated patients. To dampen down the infusion reactions we pretreat patients who are about to receive alemtuzumab with steroids, paracetamol and anti-histamines."

"Alemtuzumab is given as short courses on a yearly basis; daily for 5 days in the first year and then daily for 3 days in the second and subsequent years. Subsequent courses are only given if your MS has been shown to reactivate, i.e. you have relapses or develop new or enhancing lesions on MRI. The majority of MSers (two-thirds) only require 2 courses to go into long-term remission. A minority of MSers will require 3, 4 or very rarely 5 courses of alemtuzumab. Please note that reactivation of your MS after alemtuzumab does not mean that you have failed to respond to alemtuzumab it simply means you need another course, this is different to maintenance therapies (give continuously) were disease reactivation is an indication of non or suboptimal response."

"After each course the white cells recover by dividing or proliferating. When the immune system recovers there have been questions about whether or not it is competent to fight infections, cancers and whether or not it can remember the vaccines you have had in the past. A small study has shown that when the immune system recovers post-alemtuzumab it is competent and does remember the vaccinations you have had in the past. Another observation that tells us the immune system post-alemtuzumab is competent, or nearly competent, is the lack of so called opportunistic infections in alemtuzumab-treated MSers."

"There is one major caveat; when the white blood cell counts post-alemtuzumab are very low, or have not yet fully recovered MSers are at risk of herpes virus reactivation. Unfortunately, the lady below had herpes zoster. Once infected with herpes viruses they persist in the body in a dormant state and can reactivate when the immune system is stressed or compromised. To prevent this from occurring we prescribe prophylactic anti-viral drugs for about 6 weeks to prevent herpes virus reactivation. Despite doing this there is an approximately 1 in 50 chance of developing shingles after alemtuzumab treatment. In the clinical trials the majority of shingles cases were mild or moderate. It is also reassuring to know that shingles can be treated with anti-viral drugs."

"Whether or not MSers treated with alemtuzumab are at increased risk of developing secondary cancers is at present unknown. There have been too few MSers treated with alemtuzumab, and the ones who have been treated have been followed for too short a time, to answer this question. Therefore the increased cancer risk is a theoretical risk at present. In my opinion the cancer risk is low as we have not seen many of the so called indicator cancers, i.e. those cancers associated with drugs that target the immune system, in any of the MSers treated with alemtuzumab in the phase 3 trials. But on balance it is too early to make any judgement on this."

"The one risk from being treated with alemtuzumab is the development of secondary antibody-mediated autoimmune diseases that occur months to years after the last course of alemtuzumab. Autoimmune thyroid disease is the commonest disease and occurs in ~30% of treated MSers. The second most common is immune mediated thrombocytopenia, or ITP, that occurs in 2-3% of treated subjects. In ITP the immune system destroys the platelets or cells that help stop bleeding. A much more rare disease is so called Goodpasture's disease when the immune system makes antibodies that can damage the kidney. This last two diseases can be serious, but if detected early and treated most people make a good recovery. These autoimmune complications of alemtuzumab are why MSers who have been treated with the drug need to be monitored with monthly blood and urine tests for at least 4 years after the last course of treatment. Therefore if you are eligible for alemtuzumab and you want to be treated with this drug you are going to have to be adherent to the monitoring programme. If not and MSers die, or have near-death experiences, from these treatable complications the regulatory authorities may restrict alemtuzumab's use in the future. This would be unfair on those MSers who may wish to be treated with the drug in the future."

"The real advantage of alemtuzumab is the fact that it is an induction therapy; i.e. you get treated with the drug and you don't have to have it continuously. This has advantages for MSers who can't tolerate daily injection or oral therapies. Another advantage is the long-term remission that the majority of MSers go into after a two courses. Woman wanting to fall pregnant and start a family will find this attribute of the drug very appealing. What has been played down is that a large number of MSers who have disabilities find that they improve spontaneously after alemtuzumab. I don't think this is because alemtuzumab is a neurorestorative drug, but it simply reflects that when you suppress and stop inflammation in the brain and spinal cord you allow spontaneous recovery to occur. This is why I don't believe we need drugs to promote remyelination in MS; remyelination will occur spontaneously if we suppress inflammation with sufficiently effective therapies early in the disease course; a similar observation occurs with natalizumab or Tysabri. An important point regarding the spontaneous improvement post-alemtuzumab is the observation that it is more likely to occur early in the course of the disease, before the demyelinated axons die and there is sufficient reserve capacity to allow recovery. You can't remyelinate an axon that is not there; and this is why alemtuzumab has not be as effective in MSers in with secondary progressive MS."

Gelfand et al. Massive CNS monocytic infiltration at autopsy in an alemtuzumab-treated patient with NMO.Neurol Neuroimmunol Neuroinflamm. 2014 Oct 9;1(3):e34.

OBJECTIVES: To describe the clinical course and neuropathology at autopsy of a patient with neuromyelitis optica (NMO) treated with alemtuzumab.

RESULTS: A 61-year-old woman with aquaporin-4 immunoglobulin G antibody seropositive NMO had 10 clinical relapses in 4 years despite treatment with multiple immunosuppressive therapies. Alemtuzumab was administered and was redosed 15 months later. For the first 19 months after the initial alemtuzumab infusion, the patient did not experience discrete clinical relapses or have evidence of abnormally enhancing lesions on brain or spinal cord MRI. However, she experienced insidiously progressive nausea, vomiting, and vision loss, and her brain MRI revealed marked extension of cortical, subcortical, and brainstem T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. She died 20 months after the initial alemtuzumab infusion. Acute, subacute, and chronic demyelinating lesions were found at autopsy. Many of the lesions showed marked macrophage infiltration with a paucity of lymphocytes.

CONCLUSIONS: Following alemtuzumab treatment, there appeared to be ongoing innate immune activation associated with tissue destruction that correlated with nonenhancing T2/FLAIR hyperintensities on MRI. We interpret the cessation of clinical relapses, absence of contrast-enhancing lesions, and scarcity of lymphocytes at autopsy to be indicative of suppression of adaptive immunity by alemtuzumab. This case illustrates that progressive worsening in NMO can occur as a consequence of tissue injury associated with monocytic infiltration. This observation may be relevant to multiple sclerosis (MS) as well as NMO and might explain why in previous studies of secondary progressive MS alemtuzumab did not seem to inhibit disability progression despite a dramatic decline in contrast-enhancing lesions.

CoI: multiple

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