Ocrelizumab’s known-unknowns

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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

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.

20 comments

  • As Alem is out of the equation beeing bumped to third line and continuously administered Ocrelizumab/Rituximab has some serious AEs, Clad is looking better every day…

    • even better if JCV- : natalizumab – the longest running high efficacy drug with the highest number of patient-years and most know-unkowns established (less surprises).

      It seems the debate is evolving progressively to Tysabri vs HSCT …

  • 2 questions
    Based on the above story what are your thoughts on receiving ocrelizumab after supposedly failing on alemtuzumab,?

    You mention basiliximab which reminds me that some years ago I was given mycophenolate which did not agree with me but was obviously and off-label drug which may help progressive MS. Is this still used,?

  • “It was i leclerc”

    Than post this 2 days ago 😉

    “the patient did not show signs of MS activity or disability progression, possibly owing to the immunosuppressive effects of basiliximab and tacrolimus”

    This is interresting ,since tacrolimus MOA is mainly on t cells, and without virtualy no B cells

    The patient had a double wammy, this may lend to the hyphotesis of T cell depletion being important after all

    😉

    “Tacrolimus is a macrolide calcineurin inhibitor. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T-cells (NF-AT), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.[18]”

    https://en.wikipedia.org/wiki/Tacrolimus

  • I am interested in your thoughts as to why anyone with progressive MS would take Ocrevus or siponimod/Mayzent with such adverse reactions?

    If one takes away the “active” progressive MS patients from their selection bias loaded trials, which majority of progressive MS patients are not, then you have these drugs with no statistical significance above placebo just as the FDA has noted in progressive MS.

    Clearly, immunosuppressive neuroinflammatory medications working on B and T-cells have been an absolute failure in progressive MS. Dr. Burt found this as well in his HSCT trials as did Coles and Compton with alemtuzumab. This was found in rituximab as well. These drugs have hit a dead-end but Pharma continues to cash in with very minimal or no effect above placebo when bias in trials are removed.

    • You obviously have not been following our length-dependent axonopathy posts. The trials in these populations have been negative because of poor trial design and therapeutic lag, which is why we are doing ORATORIO-HAND and CHARIOT-MS with an upper limb primary outcome measure. When your MS is too advanced in the legs you can’t see a treatment effect because the outcome measure is poorly responsive.

        • At best it is about delay, is it not? I know you want to promote trials, but I think no one should ever promote hypothesis as fact. I speak as someone with PPMS.

      • I have read for a long time about your length-dependent axonopathy and therapeutic lag theories/hypothesis. I really do wish you were right but it is wishful thinking that is obliterated as one ages. At best, a progressive patient will get to the same miserable endpoint just maybe slightly slower.

        FDA has read through these loaded trials and stated that ocrezulimab and siponomimod make absolutely no difference about placebo in non active progressive MS patients.

        Better question is what immunosuppressant do you currently prescribe your non-active progressive patients?

        • “I thought that what we’d see was that more severe relapses resulted in long-term disability driven by cumulative injury.

          “But in our dataset, we did not find that link. Instead, many disability events seemed to occur completely independently of relapses… and even if the patient was showing signs of increased disability, they often had no change of disease activity on the MRI.”

          https://journals.lww.com/neurotodayonline/Fulltext/2019/04180/In_MS,_Progression_of_Disease_Activity_Is_Often.2.aspx?fbclid=IwAR0h7p86C9feOkoTMe9YGjdREFCajkgZ2vARCUaKoAh4MinxieEz2Kq7GIk

          • Mushroom food….what do people think creates the environment for progression to occur? Based on this view it is not relapses but stop relapses early and do you get less progression. This mindset of relapses are not important to progression shows that there is no thought to biology. Yes the nuber of relapses are not the issue animal studies show this, so mice go progressive after one attack others take two others four, but the origin of progression is the inflammaotry response.

            Teh say
            “Long-term disease progression in patients with relapsing-remitting multiple sclerosis (RRMS) occurs independently of relapse activity and is associated with accelerated brain atrophy, researchers reported. They proposed using the term, silent progression, to describe the accumulating disability in patients with RRMS.

            A new 10-year study of patients with relapsing-remitting multiple sclerosis (RRMS) found that while relapses were associated with disability progression over the course of a year, relapses did not contribute to long-term disability progression. Most markedly, the results found that no evidence of disease activity (NEDA) at two years did not predict long-term stability”. Instead, the researchers said, disability progression was associated more with brain atrophy, leading them to recommend more aggressive treatment for atrophy much earlier to address this “silent progression” aspect of the disease timeline.”

            Yes treat aggressively much earlier get grid of the silent destroyer and bin the CRAB drugs. Treat with combinations. This X (2 year NEDA) predicts Y in ten years approach has been the basis of countless boring clinical studies that say very little for the individual

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