Coastal Neurological
Medical Group, Inc.

Multiple Sclerosis Immunological and Clinical Concepts
BY DEE E. SILVER M.D.

Multiple sclerosis can be considered to have significant immunological aspects and the treatments now are immunomodulatory and we need to understand the mechanisms of action of these various drugs that are used to modify this disease. We also need to understand the clinical features of MS and understand some of the clinical trials. MS is an autoimmune disorder with demyelinization, inflammation and axonal and neuronal loss. It is a very clinically heterogeneous syndrome but also it has significant heterogeneity in various areas of the brain where the pathology exists. The differential diagnosis can be extensive but it is a disease of multiple anatomical site involvement clinically and on MRI and it is a disease of exacerbations and remissions. The clinical diagnosis is supported not only by the history but by the physical, which helps determine multiple anatomical site involvement but also by supportive tests such as MRIs with enhancement and spinal fluid analysis and rarely tests such as VERs and MRIs of the cervical spine. This disease is probably never or rarely benign. The most important concept over the last 10 years since 1995, when Betaseron was released, is that we should diagnose the disease early and treat it as early as possible. Many people feel now, because of the known axonal and neuronal loss that occurs outside the demyelinating plaque area, that this is probably a neurodegenerative disease. Multiple sclerosis is certainly a chronic disorder of the central nervous system and impairment and disability will increase over a period of time. There are 4 clinical presentations and they are:

  1. Relapsing MS.
  2. Secondary progressive MS.
  3. Progressive MS.
  4. Progressive relapsing MS.

The relapsing MS is a form in which there is complete or incomplete recovery following an acute exacerbation and if there is a cumulative disability it is considered to be a secondary progressive MS. MS is probably one of the most common causes of neurological disability in young adults in the United States. The typical concept of demyelinization in MS occurs in the axon where there is acute demyelinization and then there is chronic demyelinization in some areas with later degeneration and loss of axons and neuronal loss. Axonal damage is directly related to the progressive disability in MS patients or to permanent neurological disability. It is thought that oftentimes this is seen in areas where there is not "black holes" or where there is not demyelinating plaques. There is T cell mediated inflammation with probably proinflammatory cytokine release and there is significant transection of the axons and demyelinization.

The natural history of MS is that of a subclinical period where there may be minimal or no clinical features and the MRI activity may occur and be picked up incidentally. There are probably demyelinating plaques with hyperintensity on T1 and there may be enhancement with gadolinium administration. The MRI changes are frequent during the subclinical and early part of the relapsing disease. As this occurs there is frequent MRI activity and total T2 lesion burden is certainly increased with time and as time progresses there is in the early part of the disease usually frequent relapses and impairment and then there is an associated brain atrophy. The numbers of relapses usually reduce as the disease goes into the secondary progressive form and MRI activity generally is less; however, the burden of disease of MRI total T2 lesion area increases and atrophy increases on the MRI. The immunological aspect of multiple sclerosis is quite complex. In the periphery there usually is a foreign molecule, some type of protein or antigen, which is present and may have its origin from a viral insult. This foreign molecule is engulfed by an antigen presenting cell (APC).

This engulfment by the APC cell, which is usually a macrophage or some other peripheral cell in the blood, often has an external groove where the antigen is present. With the combination of the foreign molecule in the APC the term major histocompatibility complex (MHC) is determined. This MHC is recognized by a T cell and that T cell can have its activation increased by CD40. This CD40 has clonal expansion and there is then differentiation into the TH1 and TH2 cells. The TH1 cell is a proinflammatory T cell and the TH2 cell is an anti-inflammatory T cell. There is a cytokine imbalance in multiple sclerosis. In normal people there is a balance between inflammatory and anti-inflammatory cytokines but in MS there is an excessive amount of pro-inflammatory environment which is a TH1 cell and anti-inflammatory cells are oftentimes reduced. Inflammatory markers (IFNy) are IL-12 and TNF. Anti-inflammatory cytokines are IL-4, IL-10 and PGFß. The goal in the treatment of MS is to either maintain a balance between the TH1 and TH2 cells or to shift the T cells to an anti-inflammatory bias which would be more TH2 cells.

Glatiramer acetate (GA) and the interferons (IFN) are 2 different classes of drugs and they have 2 different mechanisms of actions (MOA). In the cerebrospinal fluid IFN effect appears passive but it probably has its benefit by not allowing the basement membrane of the vascular system to allow inflammatory cells to go into the brain. GA's effect is due to GA reactive T cells that combine with the APC and shift the T cell balance to TH2 anti-inflammatory. GA probably does not have a great deal of effect on the blood-brain barrier (BBB) as compared to steroids and IFNs and cladribine. This most likely is the reason that when treating with GA there is not a robust reduction in enhancement of the MRIs in the first several months. It is thought, however, that GA has a robust immunological activity early.

IFN effect on the periphery reduced BBB disruption and penetration and reduced the influx of inflammatory cells into the central nervous system and reduces the matrix metalloproteinase (MMP) activity. Interferons also play a role in reducing the trafficking of inflammatory cells into the central nervous system by down-regulating the adhesion molecules and reduce inflammatory cells' influx into the brain. Also IFNs affect the expression of chemokines and hence reduce the influx of CSF cells. GA has a high affinity for the MHC groove and this leads to generation of a GA specific T cell. This GA T cell is predominantly predisposed to have a TH2 bias or anti-inflammatory bias. This is known because it can be injected in mice and it prevents EAE. GA probably does not inhibit trafficking of T cells through the blood-brain barrier. What GA does is to shift the bias toward TH2 cells and this causes reduced CNS inflammation because when there is presentation of myelin components by microglia and macrophages there is a reactivation of the GA T cells and this causes more TH2 cells and results in a release of anti-inflammatory cytokines. This is called bystander suppression.

The treatment of MS is summarized with the concept of understanding the drugs that are available and the clinical disease. The following triangle should be used to evaluate all drugs but especially drugs used for MS. The triangle has 3 points, efficacy, tolerability and safety. Importantly, in the treatment of MS the diagnosis should be made early and treatment should be done early and it does appear in the interferons that dose treatment matters. Patients need to be monitored carefully and serial MRIs need to be done. Many symptoms need to be monitored; not just spasticity, gait and vision, but also symptoms such as fatigue, pain, depression, dementia and sleep disorders should be carefully monitored. It is considered by most that it is important to switch drugs if there is progression but never to completely stop any of the immunomodulators and adjunctive therapy is a key if the disease progresses. There is always nonpharmacological therapy that can be used in patients and there is pharmacological therapy. Adjunctive therapy using multiple drugs with different mechanisms of action is going to be an important key in the treatment of this disease.

The diagnosis is one of multiple anatomical site involvement and exacerbations and remissions both looking at this clinically and from the MRI. Most patients are between the ages of 10 and 50 with their onset. They have CNS white matter disease, the lesions on the MRI are disseminated in time and space and there are objective abnormalities. The patient's time course usually is that of exacerbations which last usually greater than 24 hours, usually documented for at least 48 and they occur at various times. There can be a step-wise progression in these clinical symptoms. A differential diagnosis is extraordinarily important to consider. It is important to make the diagnosis early because therapeutic considerations must be made. The patient should be informed, lifestyle changes may be important and followup is needed and early treatment is by most people mandatory. Clinical diagnosis by history and physical should be supported by laboratory testing, especially by enhanced and nonenhanced MRIs.

Relapsing/remitting MS is about 55% of the cases of MS. Secondary progressive is approximately 30%, with primary progressive only about 10% and progressive relapsing about 5%.

MRIs in MS are very important and an MRI of the brain is more sensitive than spinal MRIs; however, spinal MRIs may be very important when the diagnosis is uncertain and more lesions need to be determined. Spinal MRI is sometimes more specific in people over the age of 50. The majority of MRI lesions, probably 10 of every 11, are silent. There is no definite marker for the diagnosis of MS. MRI is probably the closest and the white matter lesions usually should be greater than 9 but sometimes fewer are significant when the history and physical is definite. The lesions usually should be greater than 3 mm in diameter, predominantly in the white matter. They are often ovoid, perpendicular to the ventricle and in the corpus callosum. They are usually in the cerebral white matter but also infratentorial and oftentimes they are juxtacortical. Corpus callosum lesions are very, very helpful in making the diagnosis and some lesions will have an open ring enhancement and enhancing lesions are always helpful in the diagnosis especially when they come and go. Black holes, of course, are also helpful in the diagnosis, especially when it is obvious that they have evolved from a previous T2 lesion or when they disappear. Thirty percent of the T2 lesions will become black holes. Histopathological correlation of black holes definitely has shown significant axonal loss and it is said that strongly hypointense lesions have about 20% loss of their axons. Mildly hypointense lesions have about 60% loss of their axons. There has been a definite correlation between T1 lesion load and cerebral atrophy and the marker for clinical progression in patients with MS. The accumulation of hypointense lesions (black holes) on T1 MRI correlates with disease progression in MS. Brain atrophy and the relationship between black holes and disease duration and clinical disability has been documented in several studies.

Rapid reduction of enhancement of T1 gadolinium-enhanced lesions is often seen when INFâ treatment is used or when steroids are used. When cladribine was used it was also documented that this reduced enhancement on T1 gadolinium. IV methylprednisolone at 1000 mg over 2-3 hours for 3 days with or without taper has been shown to be a dramatic reducer of gadolinium-enhanced lesions and can reduce it as much as 80% when monitored. New T1 gadolinium-enhancing lesions are also reduced and some T2 lesions will also disappear. Hence, IFNs, steroids are more likely to rapidly shut down gadolinium enhancement on MRI and GA will reduce these also but probably at a slower pace. GA has been noted to reduce the development of chronic T1 hypointensities after 7 months in several studies and this has been correlated to clinical disability.

CSF analysis in MS certainly is of benefit and can be helpful in making the clinical diagnosis. Cells can be increased, usually as lymphocytes, but also sometimes polymorphonuclear leukocytes in patients with MS. Protein certainly can be elevated but the IgG index synthetase rate certainly is important and initially 50 to 65% of patients with MS will have an elevated IgG index and ultimately it is 70 to 90%. Once it is positive, usually it stays positive. There are other diseases that will give elevated IgG index and IgG synthetase rate and false positives can be seen when there are very low CSF protein concentrations and also if there are high CSF protein concentrations. Myelin basic protein (MBP) is a nonspecific marker for CNS tissue damage and can be seen in MS but it fluctuates and has uncertain sensitivity. The cell count is usually below 50 white blood cells and is increased somewhat in 33% of cases of MS and the cells are usually mononuclear.

Clinical syndromes that suggest MS oftentimes are trigeminal neuralgia especially in young females, Lhermitte's sign and paroxysmal neurological attacks and evidence of weakness or worsening of the neurological symptoms with increased body heat or exercise or temperature (positive Guthrie's sign). There is also some benefit in the clinical feature of fatigue that is especially made worse by heat and also a positive Uhthoff's (loss of vision with increased body temperature). Other symptoms that are more nonspecific are often associated with MS and they are fatigue in 75%, depression in 50 to 75% of patients, sensory symptoms that can occur even as an initial symptom in 20 to 50%. Pain is present in 60%. Bladder symptoms, usually neurogenic bladder, is present in 75% of the cases, sexual dysfunction in about 50% and bowel difficulty in 40 to 50% and optic neuritis can occur in as much as 15 to 25% of cases initially or at some time in the initial presentation.

Unusual symptoms that usually indicate some other disease process are prominent fever, headache, abrupt paralysis or abrupt cranial nerve abnormality such as hearing loss or prominent longstanding pain that does not exacerbate or vary, or is global. Progressive myelopathy without bowel and bladder symptoms must be always carefully worked up as having another etiology other than MS and impaired levels of consciousness are usually not seen with MS unless it is fulminating.

Early treatment is really the standard approach at the present time and there are 2 studies; CHAMPS, using IFNß1A has shown that early treatment after the first clinical event with supportive MRI results, has shown that compared to no treatment at all there is a delay to definite diagnosis of MS when the patient is given an interferon as compared to no treatment at all. This study was reproduced essentially in the ETOMS trial using IFNß1A subcutaneously 3 times a week. Early treatment has been strongly supported because the underlying inflammatory immunological disease is ongoing and probably has been going on before the clinical events. Once the clinical disease becomes obvious there is a cascading pathological syndrome that involves inflammatory, demyelinating, and axonal and cell loss. Studies have shown that when MS patients are given disease modifying therapy versus placebo there is a significantly less likely chance of having a clinical attack and MRI activity is reduced.

Dose and frequency of the interferons may matter, however there disagreement on this topic. In prospective studies, such as the INCOMIN trial, IFNß1B was matched against IFNß1A IM 30 mcg for a week over a 2-year period and it was found that the frequent dosing of the IFNß1B on an every other day basis was superior to the 1A for reducing relapses and for the beneficial affects on the MRI parameters. It was however an open label trial, the groups were not well matched, and patients on IM once a week were older and had the disease longer. In the EVIDENCE trial comparing IFNß1A 44 mcg 3 times a week versus IFNß1A 30 mcg weekly IM, the IFNß1A was superior in reducing the number of relapses and also in MRI parameters. However, this was not a blinded trail, and the IM weekly group had more active lesions by 21%. Hence, these studies have documented along with the PRISM trial that dose and frequency matter.

In the EVIDENCE trial the percent of relapse-free patients at 24 weeks for Avonex was 63% and for Rebif was 75% with a P value of 0.001. At 48 weeks the percent accordingly was 52% and 62% with a P value of 0.009. The time to first relapse in the EVIDENCE trial was a difference of 4.8 months with Rebif delaying the time to first relapse. Avonex had a relapse average of 6.7 months and Rebif had an average of 11.5 months. There was a significant relative reduction in T2 active lesions at 48 weeks favoring Rebif and Rebif was favored in a reduction in the number of T2 active lesions at 48 weeks. There were a fewer people with Rebif that needed steroid treatments for relapses and time to progression by 1 point on the EDSS was reduced for Rebif as compared to Avonex. P values here were not as robust.

There are 3 IFNßs available. There IFNß1A which is Avonex which is given at 30 mcg IM weekly. There is IFNß1A Rebif given at 44 mcg SC 3 times a week and there is IFNß1B 250 mcg SC every other day which is Betaseron.

The PRISM trial showed that higher dose patients on Rebif had fewer relapses at 2 years and 4 years. Rebif doubled the time to first and second relapses and the effect on the MRI is seen with Rebif at 2 months with 44 mcg SC 3 times a week. Total T2 lesions were decreased mainly in patients who got Rebif 44 mcg 3 times a week from the start. At lower doses and those who got placebo early and then switched to Rebif, either a smaller dose or the full dose, still had the benefit of the reduction in the T2 lesion area seen on the MRI but the benefit was not as robust as seen with the full dose. There was definite evidence that Rebif delayed the progression to disability. Rebif 44 mcg was the most efficacious. Neutralizing antibodies (NAB) seem to play a role in interferons and they are present in all of the interferons but they are not present in GA or Copaxone. With Betaseron, at the end of 1 year 38% of patients developed neutralizing antibodies but most of these disappear by 12 years. With Avonex, 22% of the patients have antibodies at the end of year 2. Rebif also, at the end of 4 years, have antibodies in 14% of patients on the high dose and 24% on the lower dose. It does appear that these antibodies reduce the beneficial effect on the MRI and patients have a higher relapse rate. There is still a great deal of controversy on the importance of NAB's and how frequently they occur in the various IFNB'S and generally they are rarely obtained by the doctor.

QUASIMS (Quality Assessment In Multiple Sclerosis Therapy) was a group of patients that were not double blinded nor was the examiner blinded but the IFNß-1a and IFNß-1b efficacy was essentially the same. There were 7156 patients followed for 2 years. Initial therapy was important for best efficacy, as compared to switching therapies.

GA immunologically shifts the TH1 cells to the TH2 and this shift is significant at 1-3 months. It has been shown that it reduces T1 black holes at 7 months by 50% and it reduces relapse rate by 33% and the progression to EDSS is also reduced. At 10 years 64.4% of patients on GA or Copaxone are better or stable. In an 8-year data follow-up 65.3% of patients who were on GA were stable or better as compared to 50.4% of patients who had been on placebo and then switched to GA. Only 34.7% of the patients were worse on GA as compared to 50% who were on placebo to GA. The yearly EDSS change baseline was definitely better for patients on GA. Total number of enhancing lesions are reduced by the use of GA as is the total enhancing lesion volume and the total number of new enhancing lesions is reduced by 33% and the total number of new T2 lesions are reduced by 30% when using GA. If treating MS patients is delayed as compared to using GA initially there will be a significant amount of lost benefit on reducing enhancing lesions on the MRI.

Immunomodulatory therapy is a disease modifying therapeutic approach and it should be strongly considered that these drugs can be of significant benefit.

Adverse effects for GA are minor but there are some injection site reactions and there is sometimes loss of fatty tissue in the subcutaneous area. There is an unusual, infrequent (15%) immediate post-injection reaction that can occur that is associated with anxiety, sweating, tachycardia and sometimes some chest pressure. This usually does not recur. GA is a pregnancy category B drug and has no known abortigenic effects.

Interferons are pregnancy class C drugs and in animal models are shown to have abortigenic effects. They are also associated commonly with flu-like syndromes which can occur very frequently, as often as 70 to 80% but sometimes disappear with time and can be treated with anti-inflammatories or steroids. Injection site reactions can certainly occur and are common and 5% of patients will develop some necrosis of the skin. Depression has to be carefully monitored and anemia, neutropenia, thrombocytopenia and liver function abnormalities need to be carefully looked for and this requires frequent lab tests, probably about every 3 months.

MS is a disease that we can modify its clinical progression and the known treatments will reduce relapse rate, will reduce progression to disability and at the present time certainly have a robust benefit on the MRI, mainly reducing T1 gadolinium enhanced lesions, reducing black holes and reducing T2 burden.

It is important when using drugs for MS that we remember the triangle for the evaluation of all drugs, which are efficacy, tolerability and safety. We want to diagnose the disease early and treat it early. Dose and frequency of the interferons seem to matter. We need to monitor patients clinically and watch for progression and get serial MRIs and we want to carefully monitor for symptoms such as fatigue, pain, depression, dementia and sleep disorders. It appears that switching the immunomodulators may be important when the patient progresses but we probably never stop these drugs and that adjunctive therapy is oftentimes a major important consideration. There probably is not a clinical picture of benign MS. It should always be remembered that there is nonpharmacological and pharmacological treatment for MS.

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9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
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