Sunday, 21 December 2014

ClinicSpeak: predicting progression in MS

How predicting prognosis affects DMT decision making. #ClinicSpeak #MSBlog #MSResearch

"This study below is kind of what I do in clinical practice using a different technique. When looking at patients with early MS I put them into three categories; those with a active MS and a poor prognostic profile, those with active MS and an intermediate prognostic profile and those with inactive MS and a favourable prognostic profile. The latter patients are not eligible for DMTs under NHS England guidelines and are monitored to see if there disease become active, i.e. if they move into one of the other active categories. We tend to define activity as being clinical (relapses) or MRI (subclinical) activity in the last 12 months. Those patients in the active and poor prognostic category tend to have highly-active MS or rapidly-evolving severe MS and as a result tend to be offered access to highly-effective DMTs first-line; the latter is always in accordance with our NHS England prescribing guidelines. Those patients in the intermediate group are the most challenging and take the most time in clinic with regard to counselling. When you have a choice it always takes more time. We know if we leave you to face the natural history of MS the majority of you would end-up disabled; all it takes is sufficient time for this occur. We therefore offer you a choice of DMTs and more recently we have been able to include alemtuzumab for this groups of patients; please note alemtuzumab has a very liberal 1st-line license in the UK and Europe and therefore patients need to be told about its potential risks and benefits. Some neurologists disagree with this approach, but may change their practice once they get comfortable using alemtuzumab 1st-line. At the top of the decision making tree is the choice between an induction therapy and a maintenance-escalation approach; the philosophy of these two treatment approaches is so different that this decision should be made first. The whole aim of our treatment approach is to try and shift as many patients into the inactive, favourable prognostic groups using DMTs. Only be doing this will we reduce the overall burden of MS; the latter is what drives our treat-2-target approach of NEDA with zero-tolerance."

Scott et al. Relapsing multiple sclerosis patients treated with disease modifying therapy exhibit highly variable disease progression: A predictive model. Clin Neurol Neurosurg. 2014 Dec;127C:86-92.

OBJECTIVE: To describe a "new natural history" of multiple sclerosis (MS), characterizing three patterns of progression in Relapsing MS (RMS) patients during the "treatment era," using newly developed definitions. By utilizing our simple model we intend to predict which patients are most likely to reach an EDSS of 6.0.

METHODS: We stratified MS progression into three distinct patterns: aggressive MS (AMS), intermediate MS (IMS) and mild MS (MMS), based on Expanded Disability Status Scale (EDSS) score rate of change. These groups were compared for progression of EDSS before and after reaching these definitions.

RESULTS: The three groups remained significantly different in terms of disability throughout their disease courses p≤0.001; 98% of the patients used disease modifying treatments (DMTs). AMS patients represent a significantly more disabling and aggressive form of MS than the IMS group.

CONCLUSIONS: Transition from relatively mild MS to aggressive course may begin at any time in the first 15 years, despite DMTs. Our definition for AMS is unique and identifies a group of patients who become permanently disabled within two years after a variable amount of time in a benign phase, despite treatment with modern DMTs.

CoI: multiple

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.

Advent calendar-21

So we are talking about drug development we have shown that our drug is safe in animals and now we have to show that the drug is safe in humans.
So first studies in man/woman are called phase I studies. 

These are usually performed in healthy individuals in very well controlled environments, such as hospitals and usually specialise centres within the hospital setting so if things go wrong they are in the best place to deal with them. They are performed by specialist contract research organisations and they recruit volunteers for the study.
The people volunteering are often students and healthy males and they get paid for their time for volunteering, but they are all heroes or heroines.

It may be easy money if your drug, is safe like ours, but remember the "Elephant head" case where things went wrong. The gave a drug that was would cause white blood cells to grow like mad and release a lot of growth factors "cytokine storm" that caused the blood vessels to shut down causing loss of oxygen to the extremities and gangrene. Surprisingly, in toxicity studies this predicted problem was not seen, but animals like mice and rats are designed to live in dirty holes and tolerate all sorts of infections deal with "cytokine storms" humans can't.

Therefore we are grateful for to the brave people who take part in trials. Without  these people things will never progress.  

CoI We are developing a drug for people with MS