Warts and all

I have previously made the case that warts, both cutaneous and genital, are a relative contraindication to alemtuzumab therapy. I had one patient who has a torrid time with cutaneous warts after receiving alemtuzumab treatment. Fortunately, her immune system rejected them when it reconstituted and she is now fine.

At least with alemtuzumab and other IRTs (immune reconstitution therapies) you can rely on the immune system reconstituting; not so with continuous immunosuppressants.

I saw someone with MS yesterday who is on fingolimod with cutaneous warts, which are spreading, getting worse and causing a lot of discomfort. They were bleeding and were obviously causing her some distress. The bottom line is that the warts are unlikely to clear whilst she remains on fingolimod. Fingolimod is a drug that was repurposed from the solid-organ transplant field and is a chronic high-level immunosuppressant targeting both T and B cell responses of the immune system.

Warts on fingolimod is not a new problem; it is well described. In the case series below warts only responded to treatment and cleared when fingolimod was stopped. The problem is what to do about MS and MS rebound when you stop the fingolimod? In my opinion, the only solution is to go onto a DMT that is not a systemic immunosuppressive; these include interferon-beta, glatiramer acetate, teriflunomide and natalizumab. Another option is ocrelizumab as it selectively targets B-cells and leaves the T-cell compartment relatively intact, i.e. for the CD8+ cytotoxic T-cells to fight the viral infection that is causing warts.

Cutaneous warts (image from eMedicineHealth)

The main problem we have in the NHS is the NHS England’s handcuffs in terms of eligibility for specific DMTs. This particular patient has previously failed the injectables so she is not going back onto those, she would not eligible for natalizumab as she does not have rapidly-evolving severe MS, which leaves only teriflunomide and ocrelizumab as viable options. The advantage of teriflunomide is that it is an oral agent, it has known antiviral effects and has a reversible mode of action. In comparison, ocrelizumab is a more effective DMT on average than teriflunomide, but as ocrelizumab is a depleting monoclonal antibody its action is irreversible. Ocrelizumab is also immunosuppressive and there is a definite herpes zoster signal with ocrelizumab, compared to interferon-beta and placebo. Ocrelizumab may, therefore, affect T-cell antiviral responses to HPV to some degree. Therefore based on a scientific rationale I would think the best agent for this patient is teriflunomide and if she is not keen on a de-escalation strategy, i.e. dropping down to a less effective agent, then she should switch to ocrelizumab. Do you agree?

She should also see a virologist to get the human papillomavirus causing warts genotyped. If this genotype is one that is covered by the polyvalent HPV vaccine (Gardasil-9) she may be able to receive this vaccine to boost her immunity to the virus once she is off fingolimod and on teriflunomide.

Triplett et al. Warts and all: Fingolimod and unusual HPV-associated lesions. Mult Scler. 2018 Nov 14:1352458518807088.

BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster.

METHODS: We present five cases of chronic and treatment-refractory warts associated with fingolimod therapy.

RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod.

CONCLUSION: Cutaneous warts are associated with human papillomavirus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

CoI: multiple

Exercise, exercise, exercise ….

If you live in London it is impossible not to have gotten caught up in London-Marathon fever over the weekend.

Eliud Kipchoge won the London marathon in the second fastest recorded time (two hours two minutes 38 seconds). Interestingly, Kipchoge wears an electric blue band on his wrist, where four simple words are written: “No human is limited”. He has obviously not met someone with advanced MS who is disabled.

In the study below people with progressive MS used up to 2.81x times more energy on average, for simple mobility tasks, compared to control subjects. The progressive MSers in this study accumulated an oxygen deficit and experienced fatigue and exertion when repeating simple motor tasks such as rolling over in bed, moving from a lying to a sitting or a sitting to standing position, walking and climbing steps. Reasons for why MSers use more energy is complex but part of it is due to deconditioning, i.e. simply being unfit.

We don’t know how the brain perceives fatigue but a higher oxygen cost during physical activity is measured by the body and results in a greater perception of fatigue. The reason why Eliud Kipchoge can run mile after mile at a pace no man or woman has done before is that he is conditioned to do so and has trained his brain to not feel fatigue.

“The mind is what drives a human being, If you have that belief – pure belief in your heart – that you want to be successful then you can talk to your mind and your mind will control you to be successful. My mind is always free. My mind is flexible. That is why I wear this band on my wrist. I want to show the world that you can go beyond your thoughts, you can break more than you think you can break.” Eliud Kipchoge.

Lessons from elite marathon runners and the findings from this study suggest that rehabilitation interventions that increase endurance during physical tasks will help reduce fatigue in people with progressive MS. The question now is to get NHS resources allocated to setting-up a National exercise and training programme for MS-related fatigue and to get MSers to buy into the benefits of regular exercise no matter how disabled they are. I know this is easier said than done, but that is no excuse not to get it done; it needs to be done.

Please note, it is also not only about exercise, but how you live your life.

Kipchoge’s believes that “living simply sets you free”. For nearly 300 days a year, he lives and trains at a simple training centre in Kaptagat, a tiny village in the Kenyan highlands. He is known as the “boss man” by his training partners but that doesn’t stop him cleaning the toilets or doing his share of the daily chores. If you are interested in being inspired please watch ‘Breaking2’ a Nike sponsored project to see if the 2-hour barrier for the marathon could be broken. It is not that Kipchoge came so close to breaking the two-hour barrier, missing it by a mere 25 seconds, but his philosophy on how to live that is so inspiring. I am in awe!

Devasahayam et al. Oxygen cost during mobility tasks and its relationship to fatigue in progressive Multiple Sclerosis. Arch Phys Med Rehabil. 2019 Apr 23. pii: S0003-9993(19)30257-6.

OBJECTIVE: To compare the oxygen costs of mobility tasks between individuals with progressive MS using walking aids and matched controls and to determine whether oxygen cost predicted fatigue.

DESIGN: Cross-sectional descriptive.

SETTING: A rehabilitation research laboratory.

PARTICIPANTS: 14 adults with progressive MS (54.07+8.46 years of mean age) using walking aids and 8 age/sex-matched controls without MS.

INTERVENTIONS: Participants performed five mobility tasks (rolling in bed, lying to sitting, sitting to standing, walking and climbing steps) wearing a portable metabolic cart.

OUTCOME MEASURE(S): Oxygen consumption (V̇O2) during mobility tasks, maximal V̇O2 during graded maximal exercise test, perceived exertion and task-induced fatigue measured on a visual analogue scale before and after mobility tasks.

RESULTS: People with progressive MS had significantly higher oxygen cost in all tasks compared to controls (p<0.05): climbing steps (3.60 times more in MS), rolling in bed (3.53), walking (3.10), lying to sitting (2.50), and sitting to standing (1.82). There was a strong, positive correlation between task-induced fatigue and oxygen cost of walking, (rs(13)=0.626, p=0.022).

CONCLUSIONS: People with progressive MS used 2.81 times more energy on average for mobility tasks compared to controls. People with progressive MS experienced accumulation of oxygen cost, fatigue and exertion when repeating tasks and higher oxygen cost during walking was related to greater perception of fatigue. Our findings suggest that rehabilitation interventions that increase endurance during functional tasks could help reduce fatigue in people with progressive MS who use walking aids.

Extinction-Rebellion

If you live in London you may have had your life interrupted over the last two weeks by the Extinction Rebellion protests. This is a serious environmental movement that wants us to act now to save the planet from environmental catastrophe.

As part of the protest, my daughters have been giving me a hard time about my carbon footprint. They want to know if I am offsetting my air miles, which I do occasionally, that is when I personally book my flights. But in general, I am sure that most of my air miles are not offset. However, there is one initiative I am proud of that is addressing climate change and that is TriMS.online.

triMS-online is a virtual online conference for people interested in MS. The original idea of triMS-online came from this blog; thank you.

The aims of triMS-online are multiple. The objective is to do punchy, short, themed MS-related conferences online that can be viewed as a live event, or asynchronously, i.e. when you have the time. This is particularly useful for people who can’t travel for family reasons, for example, you may have young children or you are a carer. Or you simply don’t have the time and/or resources to travel to large international meetings.

triMS-online is environmentally friendly; imagine how many air miles we are avoiding by not having to fly people to conferences?

The other advantage of triMS-online is that it takes high-quality MS research and education to resource-poor environments across the globe. We want a new generation of MS researchers and HCPs to have access to the latest MS research and teaching.

As founding chair of the scientific committee of triMS-online, I wanted to use the opportunity to shake things up a bit. When you go to ECTRIMS it is generally the same-old faces and KoLs on the platforms; the English refer to this as the ‘Old Farts’ syndrome, which includes me. We, therefore, invited a diverse group of ‘young’ MS academics from across the globe to run triMS-online and we made a strategic decision of having at least an equal number of women on the steering committee; in fact, 6 out of 10 of members are women.

The following is our second triMS-online programme, which addresses paediatric MS. We plan to run about 2-3 triMS.online conferences a year and have many ambitious plans for the triMS-online platform going forward. One idea is to host regional meetings on the platform, for example, a Latin American meeting in Spanish. Why not one in Polish or for that matter any other language?

I urge you to register for the next meeting and to submit posters. The platform is like a real conference with meeting rooms, social events and exhibition spaces.

We will be need feedback, including suggestions for future meetings. Don’t be shy and join the revolution, even though it may not be a rebellion.

We would encourage young academics, in particular, those who are from under-represented groups to submit posters for this next meeting.

CoI: multiple

Old age; how is it going to affect me?

Is ageing a disease? It is if you have MS.

We have been making the argument for moving our treatment target in MS to focus on old age; i.e. how do we your HCPs get you to old age with enough brain to deal with the ravages of age-related cognitive impairment?

It is clear that your brain and cognitive reserves are what protects you from the ‘normal age-related neuronal drop-out’, which occurs as part of normal life. We know that MS shreds both brain (size) and cognitive (synapses) reserve and hence it should bring forward age-related cognitive impairment in MSers. The latter was a hypothesis, but the study below shows it is not necessarily a hypothesis anymore. In summary, older MSers are more likely to be cognitively impaired (77%) compared to younger MSers (43%). The challenge is to prevent this. How? Early effective treatment to stop the shredder and to make sure we tackle smouldering MS.

Do you need any more evidence? Please ask your neurologist if you have NEDA is there any evidence of smouldering MS? He/She may want to know what smouldering MS is. You can then tell them it is what is happening at the bottom of the treatment pyramid that is out of sight of our routine monitoring. This is the reason why you need to self-monitor and if you are getting worse you need to ask what can be done about it.

Branco et al. Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Neurol Sci. 2019 Apr 23. doi: 10.1007/s10072-019-03875-7.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group.

OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients.

METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains.

RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70).

CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

CoI: multiple

Yellow Fever Vaccine Alert

In the past, I have made the claim that vaccinations, including vaccination with live attenuated viruses such as yellow fever, are relatively safe post-IRTs (immune reconstitution therapies) such as alemtuzumab, cladribine and HSCT.

I even have two Alemtuzumabers on my books who have both had yellow fever vaccines before travelling to Ecuador and the Galapagos Islands. who I frequently mention in talks who had no problems with the vaccine. I will have to retract that advice. HCPs have just been sent the following warning from the MHRA (Medicines and Healthcare products Regulatory Agency).

Yellow fever vaccine (Stamaril) and fatal adverse reactions: extreme caution needed in people who may be immunosuppressed and those 60 years and older

“We have recently received 2 reports of fatal adverse reactions to the yellow fever vaccine (Stamaril). Due to an increased risk of life-threatening reactions, the vaccine must not be given to anyone with a medical history of thymus dysfunction or who is immunosuppressed. In addition, extreme caution must be used and a careful risk assessment conducted before vaccination of people aged 60 years and older due to a substantially increased risk of such adverse reactions in this age group.”

This is particularly relevant to Alemtuzumabers in that there is recent data that has been presented that it damages the thymus. If you are HCP who works with MSers please read the advice on the MHRA’s website.

Foot drop

The study below tried to compare the clinical effectiveness of ankle-foot orthoses (AFOs) and functional electrical stimulation (FES) and whether or not they were cost effective. The high drop-out rate (38%) made the study inconclusive.

When we, at Barts-MS, did a clinical audit a few years ago we showed that the best predictor of falls was the need to use a walking aid; e.g. walking stick, chair, AFO or FES. Falls in MSers are a major cause of morbidity and in fact mortality and are the 3rd or 4th most common reason why MSers need urgent, or unplanned, hospital admissions. Falls lead to head injuries and frequently cause fractures. For example, in the last 4 weeks, I have seen three patients who sustained fractures as a result of falls; one a fractured scaphoid bone in the wrist, another a fractured ankle and the third a fractured humerus and clavicle.

If you are tripping and/or falling please ask your neurologist or MS nurse to assess you to see if you need a physio assessment to reduce your risk of falls. Prevention is better than having to deal with the consequences of falls.

When it comes to ankle-foot orthoses (AFOs) or functional electrical stimulation (FES) they both do the job equally well. Some people can’t tolerate AFOs (too bulky and unsightly) and others can’t tolerate FES devices (too finicky and/or painful). In addition, to these two options, there is a multitude of other options for MS-related foot drop that are available to you. If you don’t ask you won’t find out.

If you are at risk of falls you need to look into your bone health. This requires a bone density or DEXA scan. MSers are at high risk of having thin bones (osteopaenia or osteoporosis) and may need medication to try and reverse this.

Renfrew et al. The clinical- and cost-effectiveness of functional electrical stimulation and ankle-foot orthoses for foot drop in Multiple Sclerosis: a multicentre randomized trial. Clin Rehabil. 2019 Apr 11:269215519842254. doi: 10.1177/0269215519842254.

OBJECTIVE: To compare the clinical- and cost-effectiveness of ankle-foot orthoses (AFOs) and functional electrical stimulation (FES) over 12 months in people with Multiple Sclerosis with foot drop.

DESIGN: Multicentre, powered, non-blinded, randomized trial.

SETTING: Seven Multiple Sclerosis outpatient centres across Scotland.

SUBJECTS: Eighty-five treatment-naïve people with Multiple Sclerosis with persistent (>three months) foot drop.

INTERVENTIONS: Participants randomized to receive a custom-made, AFO ( n = 43) or FES device ( n = 42).

OUTCOME MEASURES: Assessed at 0, 3, 6 and 12 months; 5-minute self-selected walk test (primary), Timed 25 Foot Walk, oxygen cost of walking, Multiple Sclerosis Impact Scale-29, Multiple Sclerosis Walking Scale-12, Modified Fatigue Impact Scale, Euroqol five-dimension five-level questionnaire, Activities-specific Balance and Confidence Scale, Psychological Impact of Assistive Devices Score, and equipment and National Health Service staff time costs of interventions.

RESULTS: Groups were similar for age (AFO, 51.4 (11.2); FES, 50.4(10.4) years) and baseline walking speed (AFO, 0.62 (0.21); FES 0.73 (0.27) m/s). In all, 38% dropped out by 12 months (AFO, n = 21; FES, n = 11). Both groups walked faster at 12 months with device ( P < 0.001; AFO, 0.73 (0.24); FES, 0.79 (0.24) m/s) but no difference between groups. Significantly higher Psychological Impact of Assistive Devices Scores were found for FES for Competence ( P = 0.016; AFO, 0.85(1.05); FES, 1.53(1.05)), Adaptability ( P = 0.001; AFO, 0.38(0.97); FES 1.53 (0.98)) and Self-Esteem ( P = 0.006; AFO, 0.45 (0.67); FES 1 (0.68)). Effects were comparable for other measures. FES may offer value for money alternative to usual care.

CONCLUSION: AFOs and FES have comparable effects on walking performance and patient-reported outcomes; however, high drop-outs introduces uncertainty.

What, I don’t have MS?

In the study below approximately 1 in 5 people diagnosed with MS don’t have MS. This is so much higher than previous studies. I have always quoted the Danish post-mortem studies that sugget only 1 in 20 MSers are misdiagnosed. Maybe Danish neurologists are simply better at diagnosing MS compared to their American colleagues?

There is no one test that can be done to diagnose MS. MS is diagnosed by combing a set of clinical and MRI findings, electric or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria the Healthcare professional (HCP) or neurologist makes a diagnosis of MS.

The underlying principle of making a diagnosis of MS is showing dissemination of lesions in space and time and excluding other possible diagnoses that can mimic MS. The diagnostic criteria have evolved over time from being based purely on clinical attacks to those including electrical and spinal fluid tests to the modern era in which we use MRI to help confirm dissemination in time and space.

Dissemination in time means to attacks or MS lesions occurring at least 30 days apart. Dissemination in space means lesions occurring in different locations, for example, the optic nerve and spinal cord.

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular pathway. They can be useful to show the effects of lesions in pathways that are not evident on neurological examination or seen on MRI. The EPs can also show slow electrical conduction which is one of the hallmarks of diseases that affect myelin, the insulation of nerves that are responsible for speeding up electrical conduction.

The laboratory tests are typically done to exclude other diseases that can mimic MS. One test that is useful in helping to make the diagnosis of MS is examining the spinal fluid for the presence of oligoclonal immunoglobulin G or IgG bands (OCBs), which are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. Please note OCBs can are found in infections of the nervous system and other autoimmune diseases, therefore, the presence of OCBs are not diagnostic on their own.

I have spent some time explaining this all to you as we neurologists get the diagnosis wrong in approximately 5% of the time and if this paper below is correct may be in even a higher number of patients. In other words, at least 1 in 20 people who have a diagnosis of MS in life don’t have MS when their brains are studied at postmortem.

Why is getting the correct diagnosis of MS so important? Firstly, some of the treatments for MS have life-threatening complications; you don’t want to expose people without MS to these complications. Some diseases that mimic MS can be made worse by MS DMTs. This latter is particularly relevant for NMO or neuromyelitis optic. Patients with NMO misdiagnosed as having MS get worse on many of the MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications for people. Just having a diagnosis of MS, even if you turn out to have benign disease, has implications for the person concerned. For example, it may affect your life choices and may impact on your ability to get insurance cover to name to obvious examples. I would, therefore, advise you to make sure you have MS and not an MS mimic.

The most common MS mimics:

The evolving definition of MS based on diagnostic criteria:

Clinical criteria only:

Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.

Clinical, EPs and CSF analysis:

Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.

Clinical, EPs, CSF analysis and MRI:

Kaisey et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019 May;30:51-56.

BACKGROUND: Multiple Sclerosis (MS) specialists routinely evaluate misdiagnosed patients, or patients incorrectly assigned a diagnosis of MS. Misdiagnosis has significant implications for patient morbidity and healthcare costs, yet its contemporary incidence is unknown. We examined the incidence of MS misdiagnosis in new patients referred to two academic MS referral centers, their most common alternate diagnoses, and factors associated with misdiagnosis.

METHODS: Demographic data, comorbidities, neurological examination findings, radiographic and laboratory results, a determination of 2010 McDonald Criteria fulfillment, and final diagnoses were collected from all new patient evaluations completed at the Cedars-Sinai Medical Center and the University of California, Los Angeles MS clinics over twelve months.

RESULTS: Of the 241 new patients referred with an established diagnosis of MS, 17% at Cedars-Sinai and 19% at UCLA were identified as having been misdiagnosed. The most common alternative diagnoses were migraine (16%), radiologically isolated syndrome (9%), spondylopathy (7%), and neuropathy (7%). Clinical syndromes and radiographic findings atypical for MS were both associated with misdiagnosis. The misdiagnosed group received approximately 110 patient-years of unnecessary MS disease-modifying therapy.

CONCLUSION: MS misdiagnosis is common; in our combined cohort, almost 1 in 5 patients who carried an established diagnosis of MS did not fulfill contemporary McDonald Criteria and had a more likely alternate diagnosis.

Ocrelizumab’s known-unknowns

Below is the first case report of fulminant hepatitis owing to echovirus 25 in an MSers on ocrelizumab.

Please note continuous anti-CD20 therapy takes out your B-cells and prevents you from forming germinal centres (where B-cells get educated to make antibodies, i.e. the B-cell’s Universities) in lymph nodes and the spleen. In other words, ocrelizumab treatment causes functional splenectomy. The latter causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted.

This echovirus infection on ocrelizumab is a known-unknown; severe enteroviral infections have previously been reported after B-cell depletion, mainly in patients with haematological conditions.Meningoencephalitis is the most common manifestation, but there have been 3 other cases of fulminant hepatitis reported.

This case is a warning to be careful about infections on ocrelizumab. I predict that both the FDA and EMA will both have their say in relation to ocrelizumab’s adverse event profile in the future; maybe even an article 20 moment. The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels tells us there will be, or there are, infectious complications on ocrelizumab.

So if you are on ocrelizumab please be vigilant and take care.

Nicolini et al. Fulminant Hepatitis Associated With Echovirus 25 During Treatment With Ocrelizumab for Multiple Sclerosis. JAMA Neurol. 2019 Apr 8. doi: 10.1001/jamaneurol.2019.0522.

….. A 44-year-old woman with RRMS received 600 mg of ocrelizumab intravenously every 24 weeks for 4.5 years as part of the OPERA II trial….

….. In July 2017, the patient and a person in close contact with her developed watery diarrhea. While the other person recovered quickly, the patient reported persistent febrile diarrhea (2 to 4 episodes/day) associated with a self-limiting maculopapular rash. For fever control, patient took 1000 mg of acetaminophen per day for 10 days. Two weeks thereafter, she was hospitalized. Blood tests showed increased alanine aminotransferase and aspartate aminotransferase levels (1847 and 2484 U/L, respectively; to convert either value to microkatals per liter, multiply by 0.0167), without cholestasis……

….. after admission, alanine and aspartate aminotransferase levels peaked to 6241 U/L and 9799 U/L, respectively, with increased bilirubin (total, 4 mg/dL; direct, 2.9 mg/dL; to convert either value to micromoles per liter, multiply by 17.104) and signs of coagulopathy (prothrombin time, 24%; international normalized ratio, 2.95). Owing to progression to liver failure, she received a liver transplant 11 days after admission……

….. In the patient’s native liver tissue, an HBV DNA test result was negative, while a test result for enterovirus RNA was positive. A phylogenetic analysis revealed that both serum and native liver samples harbored echovirus 25…..

….. ocrelizumab was permanently withdrawn, the patient did not show signs of MS activity or disability progression, possibly owing to the immunosuppressive effects of basiliximab and tacrolimus, which were given to prevent liver rejection…..

CoI: multiple

Hepatitis post-alemtuzumab

Another alemtuzumab-related post, this time in relation to alemtuzumab-associated liver injury, which has been also been included as a complication of alemtuzumab treatment in the EMA’s SmPC (summary of product characteristics).

Liver or hepatic injury can occur as part of a drug-induced injury as seen in case 2 below or as a delayed, presumably autoimmune, condition as in case 1 below. Please be aware autoimmune hepatitis has been described in association with all licensed MS DMTs including the original injectable therapies, i.e. interferon beta and glatiramer acetate. I have always considered this to be a simple association, i.e. pwMS are at risk of developing comorbid autoimmune hepatitis.

Again I think autoimmune hepatitis is a rare complication if it is a complication, of alemtuzumab treatment. You need to be vigilant of any new symptoms and get medical help immediately if you experience any of the following:

Yellow skin or eyes
Dark urine
Bleeding or bruising more easily than normal

El Sankari et al. Auto-immune hepatitis in a patient with multiple sclerosis treated with alemtuzumab. Acta Neurol Belg. 2018 Jun;118(2):331-333.

Case 1

25-year-old female patient was diagnosed with RR-MS in September 2011. The patient received two courses of ATZ in November 2014 and 2015 successively. She remained stable with an EDSS score of 4 and no recurrence of disease activity on brain MRI. Eleven months following the last ATZ course, laboratory assessments revealed hyperthyroidism attributed to Grave’s disease. l-thyroxin and thiamazol were initiated.

An increase in liver enzymes occurred 1 month later, while thyroid function was normalized. Despite the interruption of thiamazol, liver dysfunction persisted.

Liver biopsy showed a diffuse, severe and mixed inflammatory infiltrate, composed of lymphocytes, eosinophils and neutrophils, infiltrating the limiting plate, surrounding the portal triad, and sparing the biliary tract. A diagnosis of type 1 autoimmune hepatitis (AIH) was made.

Standard treatment, consisting of 1 mg/kg/day of prednisolone, was initiated, with a transient episode of encephalopathy, resolving after corticosteroid dose reduction (to 0.5 mg/kg/day). 1 month later, the patient improved clinically and her laboratory abnormalities resolved; prednisolone doses were then slowly decreased, and immunosuppressive treatment with azathioprine was introduced.

Beattie e al. Acute severe hepatitis with alemtuzumab and rechallenge after a year. J Clin Neurosci. 2019 Feb;60:158-160

Case 2

This patient developed severe hepatitis within two days of starting alemtuzumab, both initially and upon rechallenge. The alanine aminotransferase peaked at 577 units per litre and 426 units per litre after the initial dose of alemtuzumab and rechallenge respectively. The patient’s liver function tests improved significantly between doses of alemtuzumab and again normalised within three months of the second dose, with no clinical manifestations of acute hepatic failure.

CoI: multiple

Cry, the Beloved Country

This post has been moved to Medium. From now on Prof G will do all personal postings on Medium. He will continue to post on this platform but will be limiting his posts on the Barts-MS blog to factual content, no random personal musings and no off-beat MS topics.