Learning about the effects of B cell depletion

B cell depletion in other conditions, can it tells us how things work

D’Amico E, Zanghì A, Chisari CG, Fermo SL, Toscano S, Arena S, Patti F, Zappia M. Effectiveness and safety of Rituximab in demyelinating diseases spectrum: An Italian experience.Mult Scler Relat Disord. 2018 Oct 3;27:324-326. doi: 10.1016/j.msard.2018.09.041. [Epub ahead of print]

BACKGROUND: Rituximab (RTX), a monoclonal antibody targeting the CD20+ B lymphocytes, deserves major attention as therapeutic option in the treatment of demyelinating disorders of the central nervous system (DDCNS). We reported our clinical experience with the use of RTX in terms of efficacy and safety in persons suffering from DDCNS.
METHODS: An Italian single-center observational analysis of patients who underwent RTX treatment between 2011 and 2017 was performed at MS center of Catania, Italy. No evidence of disease activity (NEDA) was applied to evaluate the response to RTX. CD19+ and CD20+ counts were collected along therapy. RTX-related adverse events were recorded.
RESULTS: Eleven patients with MS, four with NMOSD and two with NMO were enrolled. Out of them, 4/17 were naïve to previous treatments. According to NEDA status, 11/17 got NEDA3 status at the follow-up. Six patients had relapses (two had a single relapse and four had multiple relapses). One patient with primary progressive MS and one with relapsing remitting MS stopped RTX, the last one for severe lymphopenia.
CONCLUSIONS: RTX showed efficacy to impact DDCNS worsening with an acceptable safety profile.

B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.

In humans CD20 is encoded by the MS4A1 gene.This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features . This gene encodes a B-lymphocyte surface molecule that plays a role in the development and differentiation of B-cells into plasma cells. Alternative splicing of this gene results in two transcript variants that encode the same protein..It is suspected that it acts as a calcium channel in the cell membrane. This perhaps why anti-CD20 antibody can kill B cells by causing apoptosis. This study looks at the effect of rituximab. But the lymphopenia was a worry. However what this this really means as the lymphocyte are a mixed bunch and despite normal lyphocyte numbers you can have severe lymphopenia of select subpopulations of B cells. That is propably why rituximab works.

The big question is if cladribine works in NMO, how does it do this? CD20 is not expressed by antibody producing plasma cells and it is believed that NMO is a problem of aquaporin-4 antibodies.
If rituximab is working how is it doing that. Rituximab targets the CD20 antigen on B-cells and decreases attack frequency and severity in people with NMO; however, it does not remove attacks, even when modifying treatment to achieve B-cell depletion. Therefore people continue to recieve rituximab. If you monitor repopulation of CD27+ memory B cells you can reduce dose frequency.

Valentino P et al. Aquaporin-4 antibody titration in NMO patients treated with rituximab.Neurol Neuroimmunol Neuroinflamm. 2017 Mar; 4(2): e317.

(1) In group analysis, AQP4-Ab titres correlated with the disease activity, showing higher titres during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titres and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab 
titres in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titres was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period.Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited.

Pellkofer HL, Krumbholz M, Berthele A, Hemmer B, Gerdes LA, Havla J, Bittner R, Canis M, Meinl E, Hohlfeld R. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology. 2011;76:1310-1315.

“Repeated treatment with rituximab led to sustained clinical stabilization in most patients with NMO. Disease activity correlated with B-cell depletion, but not clearly with AQP4-ab or levels of APRIL. BAFF levels increased after application of rituximab and indicated persisting efficacy of the drug but did not correlate with disease activity. Overall, rituximab was well-tolerated even after up to 5 consecutive treatment courses; however, we observed several severe adverse reactions”.

Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica.Brain. 2008;131:3072-3080.

“We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates”. 

Conversely, AQP4-Ab was detectable in 56/57 samples from eight patients during remission (>30 days from relapse onset), but the titres were low.

So antibody levels are controlled by rituximab so that asks the question what happens to childhood infection protection responses. You can’t have it both ways.

Marcinnò A, Marnetto F, Valentino P, Martire S, Balbo A, Drago A, Leto M, Capobianco M, Panzica G, Bertolotto A. Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders.Neurol Neuroimmunol Neuroinflamm. 2018 Sep 13;5(6):e498.

OBJECTIVE: To evaluate the long-term effects of rituximab (RTX) on total and specific immunoglobulins (Igs) in patients with neuromyelitis optica spectrum disorders (NMOSDs).
METHODS: Total IgG, IgA, and IgM levels were evaluated in 15 patients with NMOSDs treated with RTX (median follow-up 70 months). Anti-aquaporin 4 (AQP4)-IgG titration was performed on samples from 9 positive patients. Anti-tetanus (TET), anti-varicella-zoster virus (VZV), and anti-Epstein-Barr virus nuclear antigen (EBNA) IgGs were also tested in patients with NMOSDs and in 6 healthy controls (HCs).
RESULTS: RTX reduced total IgG by 0.42 g/L per year, IgA by 0.08 g/L per year, and IgM by 0.07 g/L per year. Hypogammaglobulinemia (Low antibody levels. hypo-IgG) (IgG < 7 g/L) developed in 11/15 patients. Severe hypo-IgG (IgG < 4 g/L) was found in 3/15 patients, of whom 2 patients developed serious infectious complications. (This is problem of contiuous immune suppression)  In group analysis, anti-AQP4 IgG titers were reduced by RTX over time, and a significant correlation between anti-AQP4 IgG titers and total IgG levels was found. The effects of RTX were observed on pathogen-specific IgGs as well. In particular, the levels of anti-TET IgG in patients were significantly lower than those in HCs. The half-life of anti-TET IgG was reduced by about 50% in patients compared with the general population.
CONCLUSIONS: Long-term RTX treatment is associated with the risk of hypo-Ig and reduction of anti-TET protection in patients with NMOSDs. Results obtained in this study suggest the importance of monitoring total and specific Ig levels before and during treatment with anti-CD20 drugs to prevent hypo-Ig-related complications and to optimize clinical management.

So understanding how rituximab works in NMO will tell us if cladribine has potnetial there and suggest how antibody levels can be targetted when the plasma cells are not directly targeted.

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  • "antibody levels can be targetted"

    Did you think about this?

    Because of the dramatic success of B-cell–
    depleting antibodies in limiting multiple sclerosis
    lesion formation and clinical disease activity,
    there is renewed attention on the role of B cells.36
    It has long been known that the CSF of most
    patients with multiple sclerosis harbors unique
    antibodies (oligoclonal bands) that are produced
    within the CNS. There is evidence that the antibody-
    producing function of B-lineage cells is
    important in some multiple sclerosis lesions.7
    However, because of the rapidity of the clinical

    response to B-cell depletion (as early as 8 to 12
    weeks), even before the reduction of circulating
    immunoglobulin, it seems more likely that other
    functions of B cells, including antigen presentation
    to helper T cells and cytokine production, are
    more relevant

    Multiple Sclerosis

    N Engl J Med 2018;378:169-80.
    DOI: 10.1056/NEJMra1401483

    Response to theraphy


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