Friday, 11 August 2017

Taking out the rubbish: proteasome inhibitor for NMO

Neuromyelitis Optica (NMO) is an autoimmune inflammatory disease of the CNS in which antibodies directed against nerve cells - usually against a water channel called aquaporin-4 - lead to inflammatory lesions affecting mainly the optic nerves and the spinal cord.  Around 1/2 to 1/4 of people with NMO don't respond to aggressive immunomodulating drugs like azathioprine and rituximab. 

A drug that has been suggested as a possible option in NMO is bortezomib (Velcade). Bortezomib is a relatively new anti-cancer drug which is most often used in multiple myeloma, a disease caused by uncontrolled production of antibody by abnormal B cells. Interestingly it is also being trialled in Lupus, another B-cell-driven autoimmune disorder, We don't really understand how bortezomib works. On a subcellular level, it binds to and inhibits the function of the proteasome - the cellular machinery responsible for degrading proteins. So bortezomib prevents waste disposal.

How does this killl B cells? Bortezomib kills cells most effectively when they are producing lots of immunoglobulin. This suggests that cells making lots of protein are especially dependent on effective waste disposal via the proteasome, and that inhibiting the proteasome allows waste products to accumulate and kill the cell.

A study published last month in JAMA neurology found 5 people with refractory NMO despite full medical therapy. They gave these people 4 cycles of bortezomib. Each cycle consisted of 4 days of injections spaced out over about a fortnight. The cycles were 10 days apart. People were allowed to continue using steroids or azathioprine alongside. 

4 out of the 5 people in the study were relapse-free for one year despite previously having very active disease. There was an overall reduction in mean EDSS scores at 1 year - a measure of disability from 5.5 to 4. Bortezomib was associated with a drop in the serum antibody levels and serum total and plasma B cell counts. 

Obviously this study is too small to support routine use of bortezomib for people with NMO. But it certainly supports designing a phase 2 trial to test whether this drug is more effective than standard therapy for highly-active NMO.

What does this mean for MS? Well, we think that B cells are incredibly important in MS: it is not entirely clear which subsets are involved and this may differ from person to person. We think plasma cells probably play a role, but they don't seem to be the main driver of the disease as they are in NMO, myeloma, and Lupus. Once we understand more about the role of plasma cells in MS, it may be appropriate to trial bortezomib in selected people with plasma cell-driven disease. Until then, I don't think bortezomib will add much to our current arsenal of DMTs in MS, but it will teach us a lot about basic B cell biology in autoimmune disease and cancer. 


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The paper:
In neuromyelitis optica spectrum disorder (NMOSD), enhanced plasma cell activity contributes to antiaquaporin-4 autoantibody (AQP4-ab) production.1 Longitudinal data indicate that 25% to 66% of patients with NMOSD who are treated with azathioprine, rituximab, and other immune-modifying therapies still experience relapses.2 Here we assess the safety and efficacy of bortezomib, a selective inhibitor of the 26S proteasome subunit, among patients with highly relapsing NMOSD.
Methods
This is a registered longitudinal study from the National Institutes of Health (NCT02893111) that was conducted from December 2015 to January 2017. Five Chinese female patients who satisfied the 2015 diagnostic criteria of NMOSD were enrolled.3 The study protocol and supporting documentation were approved by the ethical committee of Tianjin Medical University General Hospital. Written informed consent was obtained from each patient or a legally acceptable surrogate. The characteristics of patients and their responsiveness to prior therapies were collected and illustrated in the Table. Study patients received 4 cycles of subcutaneous bortezomib at a dosage of 1 mg/m2 of body surface area on days 1, 4, 8, and 11 per cycle followed by a 10-day treatment-free interval. This intervention was concurrent with an oral corticosteroid or azathioprine regimen.
Relapses, Expanded Disability Status Scale scores, and pain levels (visual analog scale) were assessed by 2 experienced neurologists who were blinded to the study. Serum AQP4-ab titers were tested by a green fluorescent protein–AQP4 fluorescence immunoprecipitation assay. Peripheral B cells and plasma cell counts were measured by flow cytometry with anticluster of differentiation (CD) 19 (allophycocyanin; Biolegend) and anti-CD138 (fluorescein isothiocyanate; Biolegend), respectively. Descriptive values are given as medians (interquartile range [IQR]) for continuous variables.
Results
Despite undergoing vigorous therapies (Table), all the patients experienced at least 2 relapses in the previous 6 months or 3 relapses throughout the years (Figure, A). After initiating bortezomib treatment, 4 of the 5 patients, including patient 2, were relapse-free during the 1-year follow-up. A myelitis relapse was only observed in patient 1 when the patient experienced slight paraplegia 10 months following the onset of bortezomib. Magnetic resonance imaging with gadolinium enhancement showed a new lesion in the 12th thoracic–first lumbar segment of the spinal cord. Prompt treatment with intravenous methylprednisolone (500 mg/d) for 5 days ameliorated her symptoms.
None of the 5 patients experienced further neurological deterioration at the conclusion of the study. The median Expanded Disability Status Scale scores reduced from a median (IQR) of 5.50 (3.75-6.25) at baseline to 3.50 (0.75-4.25) after 1-year follow-up (Figure, B). Their visual analog scale scores also declined from a median (IQR) of 6.0 (5.0-6.75) on study entry to 3.0 (2.25-3.75) after 12 months. Compared with the baseline, serum AQP4-ab titers reduced from a median (IQR) of 66.4nM (35.7-147.3) to 27.1nM (18.7-34.9) after 1 year (median reduction, 59.2%) (Figure, C). Peripheral CD19+ B cell counts declined from a median (IQR) of 230/μL (175-390) to 41/μL (21-158) and CD138+ plasma cell counts decreased from 7/μL (6-13) to 2/μL (1-3) after 1 year. Finally, the observed adverse effects related to bortezomib were mild and transient (Table).
Discussion


The reason that a proportion of patients with NMOSD treated with rituximab still experience attacks may be derived from resistance to CD20 devoid of long-lived plasma cells that are resistant to depletion.4,5 Bortezomib can deplete long-lived plasma cells.6Our results support this notion and suggest that bortezomib could serve as a promising escalation therapy for highly active NMOSD that does not respond well to or does not tolerate current immunosuppressive treatments. In addition, clinical improvements among the 5 patients were closely associated with the reduction of autoimmune activity, reflected by a decrease in serum AQP4-ab titers, peripheral plasma cell count, and precursor B cells with proteasome inhibition. However, this study is limited by a small and heterogeneous sample size of Asian women. Large-scale randomized clinical trials are further required to generate definitive evidence.

1 comment:

  1. Here in Brazil it is very common the first treatment of NMO are either azathioprine or mycophenolate mofetil. Plasmapheresis is done when they do not respond. In the hospital where I am monitoring MS there is no case in treatment with Rituxiamb.

    If the NMO appears to have an antibody acting against a specific antigen why is its treatment still so ineffective?

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