Wednesday, February 19, 2014

What prognostic group do you fall into?

A dirty fact: "You can't predict the prognosis of MS early in the course of the disease."

What prognostic group do you fall into?

An accurate prognosis in MS is a difficult call. It depends on several factors and it will never be accurate. In other words it is an actuarial science. In the same way as actuaries working in the insurance industry we need have to calculate a prognosis and give you a rough idea what to expect. An actuarial calculation is an average with a wide range of possibilities. This is the reason why I try and keep it simple and classify MSers into three prognostic categories; poor, indeterminate or good. Poor in this context simply means if you leave MS to its own devices and let it run it natural course the average person in this category will do badly. To be honest with you given sufficient time the majority of MSers will do badly, this is why I am an active treater. Why take the risk of untreated MS if you don’t have to?

The following is a list of factors that have been linked to poorer prognosis. I suggest you add up how many you have and if you have four or more factors you are less likely to have benign MS.

  1. Older age of onset (greater than 40 years) 
  2. Male sex 
  3. “Multifocal“ onset (more than one site in the nervous system involved) 
  4. Efferent system affected (motor, cerebellar, bladder) 
  5. Partial or no recovery from initial relapses 
  6. High relapse rate in the first 2 years (more than 2 relapses) 
  7. Disability after 5 years (EDSS > 3.0) 
  8. Abnormal MRI with large lesion load (more than 9 lesions on MRI) 
  9. Posterior fossa lesions (lesions in the back of the brain) 
  10. Brain atrophy (shrinkage of the brain) 
  11. CSF positive for OCBs (oligoclonal IgG bands) 
  12. Low vitamin D levels 
  13. Raised neurofilament levels in your spinal fluid (this test is not part of routine care unless you live in Sweden) 
  14. Smoker (smokers with MS do worse than non-smokers) 
  15. Co-morbidities (e.g. diabetes, hypertension and raised cholesterol) 
  16. Genomic factors (e.g. ApoE4; this is risk factor for Alzheimer's disease and some other degenerative brain diseases; not everyone in the field accepts this as a poor prognostic factor) 
Humans have an interesting psychology in that the exception is the rule. Gamblers don’t enter a casino to lose; they always believe they are going to win. When a person with lung cancer starts chemotherapy they believe they going to one of the 10% who are cured. When some with MS is diagnosed they believe they going to be in the 30% with benign disease. The current dogma is that 30% of untreated MSers will have benign disease. This definition of benign MS is based on having no, or little disability at 15 years; i.e. an EDSS of 3.0 or less (no visible disability). The problem with this is when you interrogate benign MSers you find that more than 50% of them have hidden symptoms of depression, anxiety and cognitive impairment. Can we really justify this definition of benign MS? What is more when you follow benign MSers past 15 years only 15% remain as benign at 25 years and only 5% after 30 years. If you get to 40 years follow-up with benign MS half will become disabled over the next 10 years. Time is the killer. Some of you will state that these figures are out of date and there are newer and better figures, which show MS is a more benign disease. You may be right. In population based studies the proportion of subjects with benign MS is greater than those in hospital or clinic-based studies; for example in the Ohlmstead, Mayo Clinic, population about 45% have benign disease at 15 years. The reason for this is that MSers with benign disease often drop-out of hospital follow-up and show up in population based studies and the wider use of DMTs is beginning to change its course.

I don’t think it is worth arguing over the exact figures; the message is that most MSers will not turn out have benign MS. Please note I say turn-out. We simply cannot make an accurate call on this early in the course of the disease. What we should be focusing on is how can we maximise your chances of having benign disease? Treating MSers with DMTs is one way of doing this and making sure that MSers adopt a healthy lifestyle is other strategy that can be done in parallel. The following figure illustrates what we are trying to do with DMTs. We are simply trying to move you to the left into a more favourable prognostic group. In other words we are trying to make sure you have benign MS.

MS classified by disease activity prior to DMTs

The aim of wide adoption of DMTs; to shift as many MSers into a more benign prognostic category. 

Some would argue that this approach is defeatist and that we should be trying to cure you of having MS. That is easier said than done. To find a cure for MS we have to find the cause. Part of finding the cause is showing a treatment cures you of the disease. At present most in the field believe that MS is an autoimmune disease; in other words your immune system goes awry and instead of doing what it was designed to do, i.e. fight infections and cancers, it turns on itself and attacks the myelin and nerve processes in the central nervous system. The only way to cure people of autoimmune diseases is to destroy your immune system and replace it with a new immune system that hopefully does not have any autoimmune cells. Therefore the only DMTs or treatment strategies that can potrntially cure you of MS at present are the ones that reboot your immune system. These are part of the so called induction therapies and include alemtuzumab, cladribine, mitoxantrone, bone marrow transplantation and possibly selective B cell depleting agents (anti-CD20 and anti-CD19). To prove someone is cured of MS you have wait a long time to see if the disease comes back or not. This has similarities to cancer cures; how long do you have to wait to say you are cured from a cancer? The oncologists have stopped using the term cure and simply state that there is no evidence of detectable disease or NEDD. For certain cancers if you have NEDD at 5-years after completing your treatment your likelihood of a cure is very high say 80%; in other words 20% will relapse after 5 years. In MS we don’t have this type of data yet as we have not had induction therapies for very long. What we have done is stolen the terminology from oncology and we have started to talk about no evident disease activity or NEDA. If you have NEDA after induction therapies how long do we need to wait say you are cured of MS? I am not sure, only time will tell. However, I have proposed a working definition of a cure as being NEDA at 15 years. How good are we at inducing a state of NEDA? Not good at all. One of the reasons for this is that we are not measuring NEDA very well. At present we include relapses, disease progression and MRI activity in the definition. Most studies have been including the baseline MRI as the comparator, this is a mistake. Most DMTs take weeks to months to start working hence any activity that takes place during the first few weeks or months of starting should not be counted. Therefore I am trying to promote the need to rebaseline MSers before starting the NEDA clock. The rebaselining will depend be DMT specific; the longer it takes for a DMT to start working the longer you need to wait to rebaseline. For the interferons, mitoxantrone, natalizumab, fingolimod, teriflunomide and BG-12 3-6 months would be appropriate. For GA rebaseling should be at 9 months and for alemtuzumab 18 to 24 months. Why so long? Alemtuzumab is an induction therapy and there is little to be gained by assessing whether or not there is evident disease activity until after you have had the full treatment course; i.e. two annual cycles of treatment. Therefore the current NEDA figures that have been published are not very helpful.

Time answers many questions:
  1. Do I have benign MS?
  2. What is my longterm prognosis?
  3. If post-induction therapy, I am rendered with no evident disease activity for 20 years, have I been cured of MS?
  4. If post-induction therapy, I am rendered with no evident disease activity, will I come back with SPMS? 
What we can't do is turn back time to make a different decision in the beginning.