Sunday, 21 December 2014

Predicting Skin Reactions and Allergies to Natlizumab

de la Hera B, Urcelay E, Brassat D, Chan A, Vidal-Jordana A, Salmen A, Villar LM, Alvarez-Cermeño JC, Izquierdo G, Fernández O, Oliver B, Saiz A, Ara JR, Vigo AG, Arroyo R, Meca V, Malhotra S, Fissolo N, Horga A, Montalban X, Comabella M. Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles. Neurol Neuroimmunol Neuroinflamm. 2014;1(4):e47. doi: 10.1212/NXI.0000000000000047


OBJECTIVES:We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab.
METHODS: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration.
RESULTS: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 × 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. 
In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 × 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%.
CONCLUSIONS: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.

Antibodies are proteins and the immune system is particularly good at recognizing proteins and making antibodies against a foreign protein. The immune system aims to ignore your own protein.

If you take an human antibody an inject it into a mouse then an antibody response that reacts with the human protein within about 6 days and this tries and destroys the human protein. Humans do the same thing. Most therapeutic antibodies are originally made in a mouse, rat or rabbit, they are then re-engineered to remove the animal constant bits and replace them with human bits.
You can tell how much by the name.

RituXImab is chimeric, NataliZUmab is humanized, AlemtuZUmab is humanised..

The idea is that if you are injecting a human protein into humans it wont be rejected. You would think that if the antibody depletes the immune system you would think that there would be no immune response against it, but even alemtuzumab induces antibodies in some people. In natlizumab which is an antibody that does not deplete the immune system there is about a 5% risk that these antibodies against tysabri are generated. if they bind to the active bit of the tysabri molecule it will neutralise the therapeutic effect away. More worrying is that these ant-antibody responses can cause allergic or severe allergic reactions. If the allergy is caused by an anti-antibody that is called Immunoglobulin E, which sits in mast cells that release histamine when stimulated. This can cause your airways to constrict so you can't breath. This is an anaphylaxic reaction. Anaphylactoid reactions are similar and treated the same but are not immunoglublin E triggered and may be Immunoglobulin G triggered. This  can be life threatening and you can treat with Adrenaline (Ephinephrine). However, it does mean the end of taking the drug. This effect will not occur after the first infusion but may occur from the second infusion. 

One guess is if you have made antibodies against on humanised antibody, you could make it to another antibody.

In this study they look for risk factors. We know that one variant of the major histocompatibility complex is associated with susceptibility to MS. This is HLA-DR15. 


In this study, they show that if you have DR13 or DR14, then you have a nine times more likely chance to get antibodies. Having DR15, the main MS risk gene reduces this chance by 80%.

Do you know your DR-type?  In some labs in the US this was typed as matter of course. Through giving blood for MS research  i know mine...reduced chance of reacting to myelin oligodendrocyte glycoprotein and now at risk of having anaphylactoid response to tysabri.
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2 comments:

  1. I've been on Tysabri for 5 years. With every infusion I have skin eruptions ~7 mm in diameter for a week after my infusions. My antibody tests every year have been negative. What's going on, here?

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    Replies
    1. Skin reactions could be caused by T cell reactions and so not caused by antibodies, some people may have issues with injections or maybe something in the formulation, in one of our studies in beasties we found there was a problem with albumin a blood protein in the formulation of some MS drugs I presume the antibody is still working. There could be a number of explantions

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