Multiple sclerosis

Management
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By Anthony T Reder MD

TREATMENT OF SYMPTOMS. Primary symptoms are from CNS inflammation and damage. Secondary problems arise from social disruption, muscle deconditioning, and drug side effects. Many symptoms of multiple sclerosis can be treated (Schapiro 2003). Education of patients about the consequences of demyelination is an important first step. The second intervention should be to avoid drugs that cause fatigue, weakness, or confusion, or lifestyles that increase disease activity (eg, smoking). Exercise with cycling and elliptical machines is correlated with fewer multiple sclerosis symptoms and less fatigue (Huisinga et al 2011). Multiple dietary supplements are used by over 50% of multiple sclerosis patients (Bowling and Stewart 2004), including multivitamins, calcium, and B and D vitamins. Use should be evaluated along with prescription therapy. Healthy weight is important to increase mobility, to reduce fatigue and heat retention, and to reduce inflammatory cytokine production by fat cells. French fries (fat-fried potatoes) increase weight; yogurt, grains, nuts, and fruit reduce weight (Mozaffarian et al 2011). Yogurt thickens mouse fur and gives it a silky sheen.

Fatigue.  The most common complaint in multiple sclerosis is fatigue (discussed above in Clinical manifestations). Causes of “secondary fatigue” include temperature dysregulation, limitation of mobility and spasticity, deconditioning, sleep problems, itching, anxiety, pain, depression, infections, drugs, and other medical disorders (anemia, hypothyroidism) (Krupp and Christodoulou 2001). Initial therapy should remove these precipitants. In heat-sensitive patients, morning exercise in cool morning air, precooling before workouts, cooling vests, a glass of ice water, swimming in cool water, or wearing a hat while in sunlight can bring about astonishing improvements in fatigue and weakness, especially during the afternoon’s circadian rise in body temperature. Aspirin, which lowers temperature, can reduce heat-induced fatigue even if the patient is afebrile, eg, during the daily rise in body temperature in late afternoon. Two aspirin twice a day may reduce fatigue and prevent symptoms of premenstrual pseudo-exacerbations, likely by reducing temperature or inflammation.

Yoga and individual or group exercises improve fatigue caused by deconditioning; so do relaxation and energy conservation. Cognitive-behavioral therapy and mindfulness therapy (awareness of moment-to-moment experience) may help. Proper sleep hygiene, more sleep, and sometimes long-term use of sleep-inducing drugs are needed for this chronic problem.

Lassitude and severe tiredness caused by multiple sclerosis is often reduced with modafinil (100 to 200 mg in the morning), which activates histaminergic and certain noradrenergic nuclei. Amantadine (100 mg morning and noon) is effective in one half of patients. Some patients improve with methylphenidate (5 to 10 mg, 2 or 3 times a day; Ritalin, Methylin, Concerta) or its extended release form (20 mg per day), or with amphetamine, 75% dextroamphetamine/25% levoamphetamine (Adderall), and atomoxetine (norepinephrine reuptake inhibitor). Lisdexamfetamine (prodrug for dextroamphetamine; Vynase) is reputed to reduce abuse and may be effective for multiple sclerosis fatigue. Terbutaline (1.25 to 2.5 mg twice a day) is a beta-adrenergic agonist that reduces fatigue and also enhances suppressor T cell function. L-carnitine, one gram twice a day, may restore muscle energy metabolism (Smith and Darlington 1999) and may be more effective than amantadine. Pemoline (37.5 mg, 1 to 4 times a day) was withdrawn by the United States Food and Drug Administration in 2005 because of liver toxicity.

Fatigue in some patients improves, in descending order, with natalizumab, glatiramer acetate, and IFN-beta. Antidepressants such as venlafaxine, bupropion, sertraline, and fluoxetine sometimes reduce fatigue. Oral dehydroepiandrosterone (or 10% cream) and 4-aminopyridine reduce subjective fatigue.

A dermal absorption patch containing caffeine and histamine had a modest effect on fatigue in a small trial (but no effect on the course of multiple sclerosis) (Gillson et al 2002). Serum caffeine levels did not predict changes in fatigue. The histamine could affect wake-inducing neuronal pathways. There is potential immune benefit—histamine induces Th2 cells, reduces permeability of the blood-brain barrier, and inhibits experimental allergic encephalomyelitis; caffeine enhances adenosine signaling, and adenosine A2A receptors decrease Th1 cell function. However, histamine patches should be used with caution as histamine suppresses IFN-alpha production and has complex effects on IFN-gamma and on the Th1/Th2 ratio. Potentially related, modafinil activates the tuberomammillary nucleus, the sole source of histamine in the brain.

Vitamin B12 plus lofepramine (a norepinephrine uptake-inhibiting antidepressant) and L-phenylalanine (norepinephrine precursor) (the “Cari Loder regimen”) has nonsignificant trends for symptom improvement. Rantatolimod (Poly IC variant) is a type I interferon inducer and TLR3 agonist that reduces fatigue in chronic fatigue syndrome.

Cognition. Physical activity improves cognitive processing speed. Slowed cognition is temporarily ameliorated with glucocorticoid or adrenocorticotropic hormone treatment. However, long-term steroid exposure can damage hippocampal neurons.

IFN-beta-1b improved visual memory between years 2 and 4 of therapy on 2 of 4 neuropsychiatric measures that also correlated with MRI changes in the initial drug trial (Pliskin et al 1997). It possibly enhanced verbal memory in a retrospective study of treated versus untreated subjects (Selby et al 1998). IFN-beta-1a in early mild multiple sclerosis improved information processing and memory and showed trends for better visual-spatial and verbal abilities (Fischer et al 2000; Cohen et al 2002). IFN-alpha has dose-dependent benefit on cognition in relapsing-remitting multiple sclerosis (Cabrera-Gomez et al 2003). Analysis of long-term (16-year) effects of IFN-beta-1b and comparisons to the original Pliskin study suggest stable cognition (Lacy et al personal communication 2012).

In a 2-year study, glatiramer had no effect on cognition (Weinstein et al 1999). Differences in clinical severity between studies did not explain the lack of effect (Kurtzke scores were 3.0 to 4.9 for IFN-beta-1b, 2.3 for IFN-beta-1a, and 2.4 to 2.8 for glatiramer acetate).

Natalizumab improves cognition. Fingolimod does too, based on unpublished comments. In mice, both of these agents interfere with short- and long-term learning because they block IL-4 production by meningeal cells, which should otherwise induce BDNF (Derecki et al 2010). The therapeutic benefit in multiple sclerosis, at least in short-term studies, outweighs the concern from mice who fail the water maze test.

Donepezil had cognitive benefit in initial studies, but the same investigators later found no effect (Krupp et al 2011). In other studies, cognition improved in multiple sclerosis with cholinesterase inhibitors, from a baseline of 50 on a 100-point scale up to 70 (Reder unpublished). It also improved airplane pilots’ retention of complex skills in flight simulators. In Alzheimer disease, 23 mg/day is more effective than 10 mg/day, so 10 mg twice a day may aid cognition in multiple sclerosis (not formally tested). Memantine has occasional benefit in multiple sclerosis (Reder unpublished) and in healthy controls, and it is potentially neuroprotective. A study that titrated the memantine dose up to 30 mg/day was terminated because of side effects (the recommended dose is 20 mg per day). Rapid dose escalation also increases side effects. Combination of memantine with amantadine, a related compound, can induce out-of-the-body, psychedelic reactions. There are trends for amantadine > 4-amino-pyridine > modafinil and pemoline = 0 to improve cognition, and for amantadine to speed up evoked potentials and reaction times. Abstracts report improved cognition or no effect from ginkgo biloba. Cannabinoids can inhibit spatial learning and working memory. There is a marked cognitive increase with l-amphetamine, 30 mg/day, in memory-impaired multiple sclerosis patients (Sumowski et al 2011). Auditory/verbal memory improved in 49% of those treated, compared to 7% of placebos, and visual/spatial memory improved in 48% versus 0% of placebos. Nicotine, 15 mg transdermal patch, improves multiple memory measures in mild cognitive impairment and causes a 1.1 kg weight loss (Newhouse et al 2012).

Affective disorders. Antidepressants treat depression in multiple sclerosis, but may be even more effective for mood swings and pseudobulbar affect. For depressed patients with fatigue, a low dose of selective serotonin reuptake inhibitors can treat both problems (sertraline 50 mg every morning; paroxetine 10 to 20 mg; citalopram 20 mg; or fluoxetine 20 mg). In combination with nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors increase the risk of gastrointestinal bleeding 6-fold. For patients with insomnia and spastic bladder, amitriptyline (25 mg at bedtime) is helpful, but its anticholinergic activity can interfere with cognition. Correction of depression correlates with a fall in IFN-gamma production (ie, it may have immune benefit) (Mohr et al 2001). Another potential benefit of antidepressants is induction of brain-derived neurotrophic factor (BDNF) (Arnason 2005). Imipramine acetylates and methylates the BDNF gene, leading to increased BDNF levels (Tsankova et al 2007). Fluoxetine induces BDNF and restores plasticity in the visual cortex. It also reduced Gd+ MRI lesions 3-fold in a 40-person study (Mostert et al 2008).

Pseudobulbar affect and emotional lability is reduced with an oral combination of dextromethorphan and quinidine (AVP-923, formerly Neurodex, now Nuedexta). This is a fixed-dose combination of dextromethorphan, a sigma-1 receptor agonist, and quinidine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that raises serum concentrations of dextromethorphan. At 12 weeks, a mix of 40% multiple sclerosis and 60% amyotrophic lateral sclerosis patients on placebos had improvement of 3.0 fewer daily pseudobulbar episodes, whereas those on AVP-923 had 4.1 fewer episodes (p=0.005) (Pioro et al 2010). Antidepressants, which also reduce pseudobulbar episodes, were not compared to this drug.

Abulia, sometimes responsible for physical inactivity and social withdrawal, may be countered with dopamine agonists such as amantadine or bromocriptine. Pramipexole and ropinirole may be more effective for abulia, in this author’s opinion.

Anorexia can be countered with nutritional supplements, and possibly with some antidepressants and dronabinol.

Visual loss. Improve lighting at home and work, use glow-in-the-dark tape, adjust computer brightness, and increase size of print in reading material. Correct nystagmus.

Vertigo. Vertigo is sometimes severe and prolonged. It responds to vestibular suppressants (meclizine12.5 to 25 mg several times per day), memantine, or glucocorticoids. Head/eye movement exercises and gait training may help. Benign paroxysmal vertigo symptoms can overlap and can be treated with particle repositioning maneuvers. This vertigo is associated with torsional-upbeat nystagmus of short duration during the Hallpike maneuver (Frohman et al 2000). Brainstem auditory evoked potentials could help discriminate central from peripheral lesions.

Nystagmus and oscillopsia sometimes respond to dronabinol, memantine, and gabapentin, possibly because of specific receptors in cerebellar and extraocular pathways. The response to smoked marijuana is more rapid (2 to 3 minutes) than with oral dronabinol. Other potential therapies include baclofen, clonazepam, trimethobenzamide, and anticholinergics.

Lack of coordination and tremor. Cerebellar intention tremor and severe lack of coordination from multiple sclerosis are difficult to treat. Arm weights, braces, and friction devices reduce the amplitude of the movements. Clonazepam (a GABA-A blocker), baclofen (a GABA-B blocker), primidone, and dronabinol are occasionally helpful. Anecdotal reports suggest benefit from topiramate, memantine (30 to 40 mg per day) (Javed 2008), buspirone, gabapentin, levetiracetam, glutethimide, isoniazid, and odansetron. Essential tremor could amplify the multiple sclerosis tremor and is suppressed with ethanol and GABA-ergic drugs. Beta-adrenergic blockers (propranolol) are occasionally helpful but should be used with caution because of immune hyperreactivity to adrenergic drugs in multiple sclerosis (Karaszewski 1991). Piracetam and valproate reduce myoclonus but have not been tested in multiple sclerosis.

Thalamic stimulation or stereotaxic radiosurgery sometimes reduces tremor. These are not as effective as in Parkinson disease because multiple sclerosis plaques are diffusely distributed. Cooling the affected arm may reduce feedback from spindle afferents (Leocani and Comi 2000). A similar mechanism is likely in the improvement seen from customized botulinum toxin A injections for arm tremors in multiple sclerosis. Balance can improve with horseback riding (“hippotherapy”), a balance-master machine, standing “wobble boards” or Wii balance board, and exercises, including physical therapy, yoga, and tai chi.

Weakness. fMRI shows diffuse cortical activation, indicating that for a given action, energy expenditure in the multiple sclerosis brain is much greater than normal—but also that rewiring could compensate for damage. Patients with fatigue also have reduced maximal voluntary force, possibly from conversion to fatigable, deconditioned muscle fibers.

Weakness improves by cooling with ice packs, swimming, or environmental adjustment in heat-sensitive patients. Pre-cooling before therapy improves performance and reduces the transient deficits from a rise in core temperature.

Inpatient or outpatient rehabilitation, locomotor training, and exercise on land or in water reduce disability and improve quality of life in multiple sclerosis. Exercise can benefit general health, social function, mood, anxiety, depression, strength, and fatigue. Exercise programs can reverse deconditioning and muscle weakness that patients incorrectly perceive as multiple sclerosis progression (Schapiro 2003). Exercise, stretching, and strengthening should not be pushed to the point of severe fatigue because the fatigue will often persist, sometimes for days. Comprehensive moderate intensity programs improve walking speed. Patients report improved walking with round-bottom shoes (MBT; Reder).

Weight loss in corpulent patients will improve balance, lessen fatigue from moving heavy limbs, and allow better cooling on hot days (spheres retain heat efficiently). Crutches, braces, and bandage ankle supports can also improve function. Bone mineral density is low in multiple sclerosis, a consequence of less activity, use of steroids and antidepressants, and possibly abnormal vitamin D metabolism, low sun exposure, and elevated osteopontin levels. Weight-bearing exercise can prevent osteoporosis.

Some patients report increased leg strength from IFN-beta.

4-aminopyridine is a broad spectrum potassium channel blocker that enhances strength in 40% and also cognition, sensation, sexual and bladder function, and vision in occasional patients. Generalized seizures occur with high doses. Dalfampridine extended-release [ER] 4-aminopyridine (Ampyra; formerly Fampridine-SR) improves walking speed. This author provides an initial 2- to 4-week test dose because of its high cost ($1200 per month).

Spasticity. Spasticity can be relieved by stretching the affected muscles and by reducing pain and stress. Physical therapy, energy conservation, yoga, and tai chi improve both spasticity and fatigue.

Drug therapy includes baclofen (5 to 80 mg per day); lethargy and weakness are side effects at higher doses. Tizanidine (2 to 36 mg per day) causes less weakness than baclofen and may also reduce pain and blood pressure. Another alpha2-adrenergic agonist, clonidine, has more modest effects on spasticity. Side effects are dry mouth and sedation, especially if it is taken with meals. Second choices are diazepam (5 to 15 mg per day) and dantrolene (25 mg per day to start, with gradual increases and careful monitoring of liver function; seldom used due to hepatitis). Some patients report benefit from clonazepam (0.5 to 3 mg per day), gabapentin (100 to 2400 mg per day), dronabinol (5 to 15 mg per day; delta9-tetrahyocannabinol, Marinol) and smoked cannabis. A large study with cannabis and tetrahydrocannabinol in the United Kingdom showed subjective improvement in spasticity, pain, sleep, cachexia, and mood, as did a combination of delta9-tetrahyocannabinol (27 mg/ml) and cannabidiol (25 mg/ml) (Sativex). Nabilone (Cesamet, 1 mg) reduces nausea and vomiting associated with chemotherapy and should benefit multiple sclerosis. The endocannabinoid system is highly activated in multiple sclerosis plaques (Eljaschewitsch et al 2006). Cannabinoids reduce the Th1/Th2 cell ratio and have theoretical benefit on immunity. They suppress glutamate-induced excitotoxicity of neurons by inducing a protective phosphatase in microglial cells. However, they may interfere with cognition.

Pain anywhere in the body often amplifies spasticity. Non-steroidals and cyclooxygenase II inhibitors can reduce spasticity and severe spasms associated with pain. Abstracts suggest improvement with cyproheptadine (4 to 12 mg per day) and threonine. Local spasticity can be reduced with injection of botulinum toxin. Intrathecal baclofen pumps are beneficial in intractable cases. This pump improves function in the affected arm after strokes and could reduce spasticity from asymmetric multiple sclerosis symptoms. It improves quality of life in multiple sclerosis.

Tonic spasms. Tonic spasms are reduced with antispasticity agents (baclofen, tizanidine, benzodiazepines), antiepileptics (carbamazepine, phenytoin, valproate, gabapentin), and carbonic anhydrase inhibitors (acetazolamide, possibly topiramate). Episodic visual problems may also respond to these drugs.

Myoclonus and restless legs. Myoclonus is inhibited by clonazepam or primidone. Cramps can be ameliorated with temperature reduction, anti-spasticity drugs, and with magnesium oxide (400 mg twice a day). Many other paroxysmal symptoms respond well to carbamazepine, oxcarbazepine, phenytoin, gabapentin (up to 2000 mg per day), and acetazolamide (250 mg, twice a day). Some respond to cannabinoids, L-dopa, bromocriptine, and quinine. Restless legs improve with dopamine agonists, benzodiazepines, and narcotics. Serum calcium, magnesium, and electrolytes should be checked.

Spastic bladder. The bladder is usually small and spastic in multiple sclerosis. Anticholinergics such as tolterodine (1 to 2 mg twice a day or 4 mg extended release; night administration may be best), oxybutynin (5 mg 2 or 3 times a day or 10 to 20 mg extended release per day, also transdermal), hyoscyamine, flavoxate, solifenacin (M3 blocker), darifenacin (M3 blocker, at 7.5 to 15 mg per day), troposium, amitriptyline (25 mg at bedtime), and intravesicular botulinum toxin injections relieve urinary frequency. These agonists cause bladder distention and urinary retention at excessive doses. Desmopressin (DDAVP), an antidiuretic hormone analogue, decreases nighttime micturition (Andrews and Husmann 1997). Cannabinoids attenuate urgency and nocturia. Infections can amplify bladder spasticity.

Urinary retention, with a post-void residual of greater than 100 mL, should be evaluated with a cystometrogram. Retention and hesitancy from a tight external sphincter is occasionally reduced with baclofen (10 to 20 mg), terazosin (1 to 10 mg per day; also doxazosin, tamsulosin, and alfuzosin), clonidine, phenoxybenzamine, or cannabinoids. Applying a vibrator over the bladder or mowing the lawn can stimulate contraction. Clean intermittent self-catheterization is essential if urinary retention occurs, and helps prevent infections. Urine should be acidified (cranberry or blueberry juice, can be sugar-free; vitamin C).

Sexual function. Sexual function improves with physical exercise, a romantic environment, lubricants (Astroglide, K-Y jelly), vacuum tumescence (men), the Eros device (women), alternative forms of stimulation (oral sex, vibrator), pelvic floor (Kegel) exercises and biofeedback, and emptying the bladder before sex. Discontinuing agents that interfere with sexual function such as antidepressants, antihypertensives, and smoking is helpful.

Phosphodiesterase-5 inhibitor therapy is effective in men and occasionally in women (sildenafil 50 to 100 mg; tadalafil 10 mg; vardenafil 10 mg). These drugs cause vasodilation in the presence of high levels of nitric oxide. Potentially important, nitric oxide is elevated in multiple sclerosis plaques, but sildenafil promotes remyelination and prevents axonal loss in experimental allergic encephalomyelitis.

Intracorporeal injections of alprostadil (PGE1) or intraurethral pellets of prostaglandin sometimes help.

Alprostadil cream, a vasodilator applied to female genitalia showed benefit in a 2005 abstract (www.medscape.com/viewarticle/515150).

In men, testosterone 1% gel, 50 mg, applied to the skin (with monitoring of prostate and prostate-specific antigen) has been used in men with low libido. In women, testosterone levels are lower with clinically active multiple sclerosis. Supplementation (testosterone patch, 300 ug/day) may increase interest in sex and orgasms (Davis et al 2008). Slight hair growth and possible breast cancer are side effects.

Constipation. Constipation is sometimes relieved with bowel training (diary, external sphincter, and puborectalis strengthening) and “scheduling”; more or less bulk/fiber in the food; more fluids; stool softeners; enemas; laxatives (lactulose 10 mL per day); and polyethylene glycol (macrogol, Miralax, and others). Physical exercise, coffee, large intestine self-massage, electrical stimulation, and an external vibrator to stimulate the colon are also helpful. Methylnaltrexone, an opiate antagonist, is potentially effective.

Sensory loss. Sensory loss is sometimes reversible with cooling or 4-aminopyridine. Vitamin B12 levels are low in some patients with multiple sclerosis (Reynolds 1992), although estimates of B12 deficiency may have been high because of referral bias in this study. Deficiency is easily treated. Some patients report increased energy and improved proprioceptive sensation after receiving monthly B12 injections; however, the effect has not been studied in a controlled trial (see synergy with interferon, below). Knee or ankle wraps add proprioceptive input (orthotic feedback) and can improve balance. Gabapentin, carbamazepine, acetazolamide, or bromocriptine usually prevent paresthesias.

Pain. Pain is a problem in two thirds of multiple sclerosis patients at some time. Reduction of skeletal muscle and bladder spasticity, constipation, malpositioning, and pressure sores is essential. Neurogenic pain responds to gabapentin (100 to 2400 mg per day), oxcarbazepine (75 to 600 mg), carbamazepine (25 to 400 mg, some multiple sclerosis patients are very sensitive to this drug), phenytoin (50 to 300 mg), topiramate (15 to 200 mg), lamotrigine (25 to 200 mg), levetiracetam (125 to 1500 mg), tiagabine (2 to 12 mg), duloxetine (20 to 60 mg), and a combination of delta9-tetrahyocannabinol (27 mg/ml) and cannabidiol (25 mg/ml) (Sativex nasal spray). Modest additional benefit is seen from tizanidine, baclofen plus amitriptyline, lidocaine/mexiletine, nonsteroidal anti-inflammatory drugs, and glucocorticoids. Long-term treatment with opioids is sometimes effective but often leads to tolerance and drug-seeking. Intrathecal opiates and triamcinolone alleviate pain. Vitamin D (2000-3000 U/day) is described as effective in the pain literature, and levels are low in those with musculoskeletal pain.

Trigeminal neuralgia (tic douloureux) shows dramatic improvement with misoprostol (200 µg 4 times a day), even in cases refractory to other drugs such as carbamazepine and phenytoin (Reder and Arnason 1995). This prostaglandin analogue elevates cAMP, and may deactivate pain-facilitating microglia by interfering with inflammatory TLR4 signaling and by inducing anti-inflammatory Th2 cells and elevating IL-4 and IL-10. cAMP induction has important anti-inflammatory effects in monocytes (Feng et al 2002b) and has neuroprotective effects after facial nerve damage (Wainwright et al 2008). TLR3, 7, and 9 are expressed on dorsal root ganglion cells. They contribute to inflammation, blood-brain barrier disruption, and pain and also may be therapeutic targets. Case reports also suggest benefit from botulinum toxin injected into muscles near the site of pain. Gamma knife radiosurgery had apparent benefit in an uncontrolled study. Vascular surgery is less effective in multiple sclerosis (plaques are in central V nerve pathways) than in older hypertensive patients with tortuous blood vessels (that compress peripheral V nerve).

TREATMENT OF THE UNDERLYING DISEASE. The course of multiple sclerosis can be modified. However, there is no cure, and no treatment completely halts the disease. Smoking cessation should prevent some exacerbations.

Generalized immunosuppression. Chemotherapy is sometimes beneficial in early inflammatory multiple sclerosis, but not in progressive multiple sclerosis. Long-term benefits are unclear. Neuronal destruction, brain atrophy, and deleterious effects on cells that secrete neurotrophins are possible. These agents increase the risk of progressive multifocal leukoencephalopathy (PML) in patients who are later started on natalizumab.

Azathioprine (Imuran) only modestly reduces progression in relapsing-progressive multiple sclerosis, although it reduces enhancing MRI lesions by 64% (uncontrolled study).

Cladribine (Mylinax, 2-chloro-2’-deoxyadenosine) binds to DNA in lymphocytes but largely spares other hematopoietic cells. CD4 and CD8 cells are depleted by 80% after therapy. Twenty-five percent to 30% crosses the blood-brain barrier. The injectable form reversed progression in 2 of 3 studies. In the third study, MRI improved but clinical scores did not. In a fourth study, brain volume continued to diminish during therapy. Side effects included injection site reactions, upper respiratory infections, and herpes zoster.

Oral cladribine, in a phase III trial showed reduction in Gd+ MRI (86% to 88%), relapse rate (55% to 58%), and progression (31% to 33%). There were minimal side effects, with only suggestions of an increase in cancer and herpes zoster skin lesions; long-term follow-up will tell the risk of these potential long-term complications. Unknown risks of cladribine led to denial by the United States Food and Drug Administration. Despite earlier approval in several countries, it was abruptly removed from the international market.

Cyclophosphamide’s benefit is hotly debated. It may be most effective in relapsing multiple sclerosis (Weiner and Cohen 2002) and severe refractory disease. After intense immunosuppression, cells recover at different rates, starting with red cells and platelets (3 weeks) and then lymphocytes (3 months). CD4 cells and CD8+CD28- suppressor T cells can take a year to recover.

Cyclosporin A had a modest benefit in relapsing-remitting multiple sclerosis and trends in early progressive multiple sclerosis. Renal side effects were significant.

Methotrexate caused slight improvement on a composite score of neurologic function.

Mitoxantrone (12 mg/m 2 every 3 months; Novantrone) significantly reduces relapses, progression, and MRI lesions in multiple studies. This anthracenedione inhibits proliferation of T and B cells and macrophages, kills antigen-presenting cells, and inhibits migration of monocytes and to some extent T and B cells. It reduces secretion of IFN-gamma, TNF-alpha, and IL-2. It has 3 major side effects: (1) a fall in the white blood cell count, (2) acute myelogenous leukemia (approaching 1% of treated patients, with 30% dying), and (3) cardiotoxicity that increases with cumulative doses greater than 140 mg (approximately 2.5 years of therapy) and sometimes earlier. There is a 12% risk of impaired left ventricular ejection and a 0.4% risk of congestive heart failure. Measurement of left ventricular ejection fraction with echocardiography or multiple gated radionucleotide angiography (MUGA) is recommended before each dose. Iron chelation with dexrazoxane has suppressed cardiotoxicity. Reversal of the low leukocyte count with granulocyte colony stimulating factor (G-CSF) is unnecessary and can cause exacerbations. A 3-month induction with this drug before starting glatiramer and IFN-beta is more effective than either of the other agents alone. (See Combinations, below.)

Glucocorticoids and adrenocorticotropic hormone (ACTH) reduce edema, inflammation, and oligoclonal bands and temporarily ameliorate symptoms and MRI signs of multiple sclerosis. Glucocorticoids shorten the duration of exacerbations, but do not alter the course of multiple sclerosis. High-dose intravenous methylprednisolone (1 g per day for 3 days) lessened recurrences after first attacks of optic neuritis and delayed the subsequent development of multiple sclerosis (Beck et al 1993). With long-term follow-up, however, the groups did not differ. An alternative to intravenous glucocorticoids is oral dexamethasone (96 mg twice a day for 3 days) or 1 g of methylprednisolone powder from a vial sprinkled into an iced fruit drink (approximately 4 oz) or chocolate pudding to mask bitterness. Oral and intravenous absorption are equivalent.

Concomitant aspirin and nonsteroidal anti-inflammatory drugs should be completely avoided to prevent gastrointestinal bleeding. Experience with lupus, possibly with acute disseminated encephalomyelitis, and with experimental allergic encephalomyelitis suggests that a prolonged prednisone taper is prudent after high-dose steroid therapy (Reder et al 1994a). In multiple sclerosis, however, positive or even negative effects of a taper are unknown, and a 3-day pulse without taper is commonly used.

Beneficial effects of steroids on MRI last longer when patients are taking interferons, but intermittent high-dose steroid pulses added to interferon have no clinical benefit (Cohen et al 2009). Glucocorticoids and interferons both trigger apoptosis of activated T cells. However, some steroid-resistant inflammatory CD4+,CD25intermediate cells can survive repeated courses of steroids.

High-dose glucocorticoids cause apoptosis of neurons and neural precursor cells in the hippocampus (Sapolsky 1999) and retina (Diem et al 2003), delay remyelination after ethidium bromide toxicity in rodents (Chari et al 2006), possibly cause brain atrophy, and can enhance production of proinflammatory cytokines (MacPherson et al 2005). Therapy should be started soon after the onset of the attack because this coincides with immune activation. In experimental optic neuritis, dexamethasone, given before and early after onset of inflammation, prevents retinal ganglion cell loss (Dutt et al 2010). Late administration, however, causes apoptosis of the ganglion cells. Five days of therapy leads to declarative memory loss at day 6; it is reversible by day 60 (Uttner et al 2005). Memory loss resembles that of post-traumatic stress disorder. Muscle loss (possibly worse with dexamethasone than methylprednisolone), hyperglycemia, weight gain, aseptic necrosis of bone, and a plethora of other side effects must be considered in light of mere short-term clinical benefit.

Adrenocorticotropic hormone was replaced by glucocorticoids because of its mineralocorticoid side effects, but it occasionally benefits patients who are resistant to glucocorticoids. ACTH induces only moderate levels of cortisol, but has additional complex effects. It induces cAMP to inhibit lymphocytes (eg, less IFN-gamma production), facilitates sodium channel redistribution in demyelinated axons, and is a neuroprotectant. ACTH may prevent osteoporosis by activating osteoblasts and VEGF induction or bone blood vessels.

Failures in therapeutic trials.

Abatacept (Ig fused to CTLA-4, binds to B-7/CD80, CD86; Orencia) had no effect on multiple sclerosis or its immune abnormalities.

Anti-CD154 (CD40 ligand) caused thromboemboli.

Anti-CCR2 failed.

Anti-chlamydial drugs have not had dramatic benefit.

Cladribine was withdrawn, although trials showed efficacy. (Discussed above.)

CTLA-4-Ig fusion protein (abatacept; Orencia) and antibodies to LFA-1 (to all isoforms of CD11/CD18) had no clinical or immunological benefit.

Anti-viral drugs have not had dramatic benefit, but viruses trigger multiple sclerosis exacerbations.

Hyperbaric oxygen has significant side effects and lacks efficacy.

Oral interferon, oral myelin, and oral glatiramer acetate had no side effects, but no benefit. Inhaled interferon may have caused pulmonary fibrosis.

Linomide/roquinimex induces tumor necrosis factor, but it reduces clinical and MRI activity. However, it caused heart attacks—a local inflammatory reaction in serous membranes, possibly idiosyncratic to multiple sclerosis. Laquinimod, a related compound with less toxicity, reduces Gd+ MRI lesions by 44% in 24 weeks and is under study.

MBP analogues and altered peptide ligands that bind the T cell receptor have failed (Jones et al 2004). The Tovaxin vaccine against myelin antigens was remarkably unimpressive (Lublin personal communication 2008). Myelin peptides and altered peptide ligands, however, have caused exacerbations. This suggests that specific anti-CNS responses are responsible for some multiple sclerosis exacerbations.

Plasmid DNA that encodes full-length human myelin basic protein (BHT-3009) could induce tolerance to brain antigens. Preliminary data show that low-dose injections reduce MRI lesions, but higher doses increase lesions in some patients, possibly because the vector contains immunostimulatory DNA (Garren et al 2008).

Tolerization with intravenous myelin basic protein for progressive multiple sclerosis failed in a phase III trial. MBP82-98 at high doses was given intravenously, a potent route for generating tolerance (Gaur et al 1992). In phase II studies of HLA-DR2- and DR4-positive multiple sclerosis patients (62% of all patients), the peptide suppressed autoantibodies against myelin basic protein, caused a shift to Th2 cells, and slowed progression.

Intermittent high-dose steroid pulses or methotrexate added to interferon had no additional clinical benefit in a well-designed trial (ACT) (Cohen et al 2009).

Sulfasalazine, used to treat Crohn disease, caused early improvement at 1 year but showed no benefit at 2 years. This argues against short trials in multiple sclerosis.

Soluble tumor necrosis factor receptor-immunoglobulin fusion protein (a TNF blocker; Lenercept) precipitated clinical disease (even though MRIs improved). Peripheral immune activation, loss of normal apoptosis by feral T cells, blockade of tumor necrosis factor-induced remyelination, and lack of penetration into the brain by these agents are potential problems. Related drugs include etanercept, infliximab, and adalimumab.

Anti-TNF antibodies and blockers occasionally induce demyelinating diseases when they are used to treat connective tissue disease. TNF inhibits formation of interferon-producing plasmacytoid dendritic cells and reduces IFN-alpha levels (Palucka et al 2005), perhaps amplifying a preexisting interferon signaling defect in multiple sclerosis (Feng et al 2002a).

Total lymphoid irradiation has significant side effects and lacks efficacy.

Ustekinumab (anti IL-12/23 p40) had no effect on multiple sclerosis MRI lesions, although it was beneficial in experimental allergic encephalomyelitis.

VLA-4 inhibitor CDP323 is an oral agent with a natalizumab-like mechanism of action that was effective in experimental allergic encephalomyelitis and safe in humans, but failed in phase II multiple sclerosis trials.

Somewhat-specific immunosuppression or other alteration of immunity. Within the past 20 years, 7 approved therapies have altered the course of multiple sclerosis: IFN-beta-1a intramuscular and subcutaneous, IFN-beta-1b, glatiramer acetate, mitoxantrone, natalizumab, and fingolimod (Goodin et al 2001). These therapies are important advances for patients and for understanding the cause of multiple sclerosis, but they are expensive and only partially effective on average. Many of these agents function differently in animal models and have unexpected mechanisms of action in multiple sclerosis.

Interferon. Interferon beta (IFN-beta-1a [Avonex, Rebif]; IFN-beta-1b [Betaferon, Betaseron, Extavia]) and probably IFN-alpha and IFN-tau alter the course of relapsing-remitting multiple sclerosis. Benefits last for at least 5 years on study (Reder 1997), and recent data show clinical benefit over 21 years of therapy. IFN-beta reduces Gd+ MRI lesions by 85%, prevents severe relapses by up to 50%, and slows progression; interferon beta-1b extends life by at least 6 years. Interferons also improve quality of life and cognition (Pliskin et al 1997), sometimes dramatically (“I read the first book of my life;” “I could finish my PhD thesis”).

IFN-beta is most effective in relapsing-remitting forms of multiple sclerosis, especially in early disease on several clinical measures. In clinically isolated demyelinating syndromes, there is a 50% lower chance of developing clinically definite multiple sclerosis with IFN-beta-1b treatment (BENEFIT trial) (Kappos et al 2007), 50% to 60% fewer new MRI lesions, and 40% less progression. In 2-year studies, IFN-beta slows progression by 27% in relapsing-progressive multiple sclerosis (Kappos et al 2001), but not in patients with later, progressive forms of multiple sclerosis or in primary progressive disease (Goodkin 2000; Javed and Reder 2006). However, in a 7-year study of primary progressive multiple sclerosis, with 2 years of IFN-beta-1b versus placebo and then 5 years off drug, there was delayed benefit on 9-hole peg test of arm function, on word list generation measures of cognition, and on magnetization transfer MRI (Tur et al 2011). IFN therapy is comprehensively reviewed in (Applebee and Panitch 2009). (MRI is discussed below with biological markers.)

Increasing the interferon dose beyond current levels (6 to 12 million units of IFN-beta-1a weekly or 8 to 16 MU of IFN-beta-1b every other day) does not significantly improve clinical outcomes in stable relapsing-remitting multiple sclerosis. There are suggestions, however, that higher doses of subcutaneous IFN-beta-1a reduce relapses, slow progression, and also improve cognition (Ebers and PRISMS Study Group 1998). Benefit of the higher dose is more pronounced when Kurtzke scores are greater than 3.5. The odds ratio of cognitive decline over 3 years is 0.51 for thrice weekly 44 ug versus 22 ug of IFN-beta-1a (Patti et al 2010) (COGIMUS). Sixteen MU of IFN was better than 8 MU or glatiramer at reducing number and percent of new lesions that became permanent black holes (Filippi et al 2011).

Arguments for early treatment are as follows:

  • Axonal destruction starts early, with the first exacerbations, and cannot be reversed. With a 2-year delay before starting IFN-beta-1a, lost function is not regained.
  • Clinically isolated first symptoms, with concomitant evidence of multiple old and new MRI lesions, are less likely to progress to clinically defined multiple sclerosis if therapy is begun early (Coyle and Hartung 2002).
  • Children treated with IFN-beta have few side effects and a good prognosis (Banwell et al 2006).
  • Interferons reduce the chance that MRI T1 black holes will develop, ab initio.
  • Immune activity becomes more difficult to control with time. The early inflammatory character is most responsive to current therapies.
  • IFN-beta has little benefit in secondary progressive multiple sclerosis (Panitch et al 2004).
  • IFN-beta-1b prevents death from multiple sclerosis (see below).

Caveats to early treatment include:

  • Diagnosis should be definite before therapy is begun.
  • Justification for instituting expensive therapy with a partially effective agent is difficult, even though the alternative is worsening of multiple sclerosis. Starting therapy is less important when multiple sclerosis has been stable, clinically and on MRI, for years.

Long-term treatment is beneficial:

  • With each exacerbation, 40% have persistent neurologic deficit (Lublin et al 2003), and therapy prevents attacks.
  • In the 16- and 21-year long-term follow-up IFN-beta-1b studies, interferon use during the original 5-year study led many years later to no significant adverse events, frequent loss of neutralizing antibodies, fewer relapses, 50% less conversion to secondary progressive multiple sclerosis, and a 47% reduction in mortality (Reder 2010; Reder et al 2010).

Sixteen years after the start of the 5-year pivotal trial, 88% of 375 relapsing-remitting patients who had begun to receive IFN-beta-1b approximately 8 years after the onset of disease were evaluated. Annualized relapse rate for those remaining on interferon versus those on therapy for less than 10% of the time was 36% lower at 5 years, 35% lower at 10 years, and 40% lower at 16 years. Patients with the longest time on IFN-beta had less progression and 50% less transition to a progressive course, compared to those on minimal IFN-beta (Ebers et al 2010), which may partly explain the effect on survival. Note that “responders” would tend to remain on interferon, leading to more apparent benefit in this correlation. However, deaths were not included in the progression data and would strongly bias data in the other direction. Finally, these quite active patients entered the trial 8 years after their first multiple sclerosis symptoms, much later than current practice, again biasing against a significant effect of IFN therapy.

In follow-up of the hypothesis-generating 16-year study, a pre-specified analysis of all-cause death at primary outcome in a more complete 21-year study showed that the pivotal 5-year treatment with IFN-beta reduced mortality by 47% (p < 0.017) (Goodin et al 2012a). There were 37 deceased in the placebo-treated group, 22 in the 1.6-million unit group, and 22 in the IFN-beta-1b 8-million unit group. Excess deaths were largely from pneumonia, perhaps from poor swallowing and weak respiration in progressed patients. The number needed to treat (NNT) in order to prevent a death was only 8, which is a huge biological effect. The 5-year randomization and over 98% ascertainment, the equivalent use of multiple sclerosis therapies in all groups after study end, statistically rigorous intent-to-treat analysis, and the “hard outcome”—death—makes this a powerful prospective study showing that IFN-beta-1b prevents death. The mechanism is unexplained but may be from delayed time to progression, prevention of viral or bacterial infections, or reversal of an endogenous interferon signaling defect (Feng et al 2002a) potentially affecting multiple metabolic paths.

Interferon immunology. IFN-beta was initially anticipated to kill the “multiple sclerosis virus.” Current thinking is that interferon modifies immunity in multiple ways to ameliorate multiple sclerosis. It reduces adenovirus infections, and treatment reduces the chance that a virus infection will lead to an exacerbation (Panitch 1994). It also decreases relapses during periods of severe air pollution (Oikonen and Eralinna 2008) (see aryl hydrocarbon receptor, above).

IFN-beta has pleiotropic effects on immunity. Interferon generates some proinflammatory products as well as immunoinhibitory and neurotrophic products.

Proinflammatory and neurotoxic effects of IFN-beta are part of its antiviral and anticancer properties, and include:

  • Increase in thymic export of Trec cells could enhance or inhibit immunity; studies conflict. IFN-beta induces both anti- and pro-inflammatory cytokines, especially with the initial injections (Byskosh and Reder 1996; Duddy et al 1999; Feng 2001). Type I interferons increase long-lived central memory Th1 and CD8 cells, but decrease Th2 cell differentiation. These reports contest the putative reduction of Th1 inflammatory cytokines.
  • Transient induction of IFN-gamma, TNF-alpha, nitric oxide; reduction of TGF-beta.
  • Type I interferons plus antigen stimulate IFN-gamma and antibody production in rodents (IgM, IgG1, 2a, 2b, 3, and 4). Interferon exposure prior to antigen inhibits antibody production, but interferon exposure before or with antigen enhances antibody production (Le Bon et al 2001). This may affect antibody responses to newly released brain antigens during CNS destruction. IgG3 levels are not induced in patients by IFN-beta-1a.
  • Enhanced macrophage, cytolytic T cell, and natural killer cell function.
  • Enhances expression of CD14, CD80, and CD86 on monocytes.
  • Reduced production of IL-10 by activated monocytes.
  • Induces immature dendritic cells to become immunostimulatory DC1.

Anti-inflammatory effects of IFN-beta with potential benefit in multiple sclerosis include:

  • Lymphopenia (especially of natural killer cells). Some of the lymphopenia is from sequestration of lymphocytes in lymph nodes, akin to the effect of fingolimod.
  • Increase in a suppressor subpopulation of natural killer cells that may be low in untreated multiple sclerosis. Induction of CD56bright suppressor NK cells (Martin et al 2010).
  • Increased thymic export of Trec cells that become regulatory T cells and enhanced Treg function (Korporal et al 2008), identical to effects of glatiramer seen by the same lab (Haas et al 2009).
  • Reversal of the CD8 suppressor T cell (Noronha et al 1990) and CD4 regulatory T cell (Venken et al 2008) defects in multiple sclerosis.
  • A shift from Th1 to Th2 cells in Japanese patients, but not in Caucasians (Ochi et al 2004) where there is a paradoxical increase in Th1 cells.
  • Increased CD4,CD25 Treg function.
  • Increase in IFN-gamma receptors on lymphocytes, possibly allowing activated T cells to die through IFN-gamma-mediated apoptosis (Ahn et al 2004).
  • More activated T cell production of anti-inflammatory IL-10 in serum and CSF (below).
  • Decrease in IL-2, IL-17, osteopontin, TNF-alpha, and IFN-gamma levels, as well as IFN-gamma- and IL-4-secreting cells with prolonged therapy.
  • Reduction of inflammatory Th17 cells and IL-17 (Durelli et al 2009) by induction of IL-27.
  • Decrease in production of most chemokines, including CXCL8/IL-8.
  • Increase in RGS-1, a G-protein coupled receptor that inhibits chemokines and migration in mononuclear cells.
  • Reduction of B7-1 (CD80) costimulatory molecules on B cells (Genc et al 1997) and also reduction of CD40, which is needed for B cell differentiation.
  • Increase in the subnormal expression of the inhibitory immunoglobulin-like transcript-3 (ILT3) on monocytes and dendritic cells (Jensen et al 2010). ILT3 induces CD8 suppressor cells and increases their expression of beta2-adrenergic receptors.
  • Elevated soluble CD14, a macrophage product, may be a biomarker; significance is unknown.
  • Induction of survival of dendritic cells, increasing production of type I interferons. This may reverse the defective plasmacytoid dendritic cell dysfunction in multiple sclerosis.
  • Induction of mature dendritic cells to inhibit Th1 cells.
  • Induction of myeloid dendritic cells (mDC) to produce IL-6 and IL-10 (reversing the low level of production in multiple sclerosis).
  • Increased dendritic cell expression of PD-L1, an inhibitor of T cell activation, and decreased expression of costimulatory proteins.
  • Apoptosis in mature mDC, and decreasing their number.
  • Induction of plasmacytoid dendritic cells to produce more IFN-beta and less IFN-alpha.
  • Reduction of IL-23, a product of dendritic cells and macrophages, which induces Th17 cells.
  • Elevation of serum soluble vascular cell adhesion molecules (potentially blocking T cell-endothelial cell adhesion, although serum levels may be too low). These molecules (ICAM-1, VCAM-1) are shed from endothelial cells, making them less attractive to T cells.
  • Serum from IFN-beta-treated patients reduces permeability of the blood-brain barrier in a model system.
  • Increase in CD73 on endothelial cells to increase immunoinhibitory adenosine and cAMP levels. CD73 is on endothelial cell and lymphocytes that produce adenosine, which is anti-inflammatory and possibly neuroprotective. However, CD73 may increase passage of cells through the choroid plexus into the brain.
  • Inhibition of T cell migration through the blood-brain barrier, preferentially blocking Th1 cell migration more than Th2 cell migration in a model system (Prat et al 2005). Block of CD4, but not CD8, cell migration and MMP-9 production, from high pre-therapy levels in CD4 cells (Dressel et al 2007).
  • Blocks neutrophil infiltration into the CNS (in rats).
  • Reduction of the toxic effects of H2O2 and TNF-alpha on brain endothelial tight junctions (Javed and Reder 2006).
  • Blocks matrix metalloprotease secretion (MMP-9) and enhances tissue inhibitor of metalloprotease secretion (TIMP).
  • Suppression of production of glutamate and superoxide by activated microglia.
  • Blocks the ability of IFN-gamma and LPS to induce nitric oxide in astrocytes and, in turn, prevents damage to nearby neurons.
  • May reduce new HHV-6 infections, possibly linked to progression of multiple sclerosis.

IFN-beta therapy increases IL-10 in the CSF (Rudick et al 1998); samples may have contained lysed CSF T cells. This IL-10 is likely produced by T cells, and possibly by astrocytes (Hulshof et al 2002), because IFN-beta reduces IL-10 production by activated monocytes yet elevates production by activated T cells (Feng et al 2002b; Hamamcioglu and Reder 2007). However, plaques have a typical 20:1 monocyte:T cell ratio. IFN-beta could have immunostimulatory effects in plaques because it reduces IL-10 in activated monocytes--which produce 10-fold more IL-10 than T and B cells (Feng et al 2002b). This is not borne out on MRI, as IFN prevents T1 black hole formation.

IFN-beta induces proteins with neurotrophic effects:

  • Induction of neurotrophic and gliotrophic factors such as adrenocorticotropin (ACTH) (Reder 1992), enkephalins, and beta-endorphin in immune cells during active multiple sclerosis (Gironi et al 2000).
  • BDNF by T cells (Hamamcioglu and Reder 2007). BDNF increases in clinical responders to IFN-beta therapy.
  • Insulin-like growth factor-1 (IGF-1, along with IGF-binding proteins that block its effect) in relapsing-remitting, but not in secondary progressive multiple sclerosis (Hosback et al 2007).
  • Leukemia inhibitory factor (LIF) in mononuclear cells (also involved in stem cell growth) (Byskosh and Reder 1996).
  • Nerve growth factor (NGF) by astrocytes (Boutros et al 1997) and endothelial cells (Biernacki et al 2005).
  • Four to eight hours after the first intramuscular injection, there is a rise in serum ACTH, cortisol, prolactin, and growth hormone and a 1.5 degree C rise in body temperature (Then Bergh et al 2007). After 3 months, these hormones do not increase, body temperature rises by only 0.6 degrees, and there is a trend for increased serum testosterone.
  • Alternate transcription of genes, converts an estrogen receptor-binding protein to a neurotrophic factor during IFN-beta therapy (Croze et al 2009). Exon shuffling may be important in neurotrophic genes, which often have complex regulation.
  • Induction of a large number of genes involved in cytoprotection and energy metabolism after years of therapy, but not after acute administration (Croze et al 2012).
  • Differentiation of neural precursor cells to neurons [with a high dose of IFN-beta-1b, 1000 U/ml (Arscott et al 2011)].
  • Diminished neurite outgrowth and maturation of neural precursor cells, but only at very high doses (100 to1000 units/ml) that are presumably not reached during multiple sclerosis therapy (Wellen et al 2009); 10 U/ml had no effect.
  • Prevention of mitochondrial respiratory chain damage in neurons by IFN-treated astrocytes.
  • Augmentation of neocortical neuronal activity and excitability.
  • Improved axonal integrity and NAA increases on MRI spectroscopy (Narayanan et al 2001).
  • Less astrocyte gliosis and scarring.
  • Dose-dependent induction of Schwann cell myelination.
  • IFN-beta, but not IFN-alpha, prevents demyelination in the Theiler virus mouse model.
  • Indirect neuroprotection by reducing inflammation, conferring 22% survival in retinal ganglion cells during optic neuritis (Sattler et al 2006). 50% survival was imparted by erythropoietin and by CNTF.

Interferon dysregulation is present in multiple sclerosis before interferon therapy. Endogenous IFN-alpha/beta production and immune cell responses to type I interferon in multiple sclerosis are subnormal (Feng et al 2002a; Billiau et al 2004; Stasiolek et al 2006). Plasmacytoid dendritic cells (pDC) produce less IFN-alpha (Stasiolek et al 2006), and toll-like receptor agonists (TLR7 and TLR9) induce less IFN-alpha than in controls, although some get opposite results. In immune cells from untreated patients, microarrays show the IFN-alpha/beta pathway is surprisingly more dysregulated than the Th1 and Th2 pathways (Yamaguchi et al 2008). Low endogenous type I interferon in multiple sclerosis may lead to a propensity to generate more IL-17 and less IL-10. Interferon therapy could compensate for the defect.

The interferon signaling pathway differs between mice and men. IFN-gamma is protective in experimental allergic encephalomyelitis, yet IFN-gamma causes multiple sclerosis exacerbations. IFN-beta ameliorates or worsens experimental allergic encephalomyelitis in a large number of conflicting studies. Mice also have deletions in the STAT interferon signaling molecule.

Interferon posology. With the same total interferon dose in a week, daily low doses are more effective than a weekly high dose at inhibiting tumor growth (Slaton et al 1999), virus infections, and cytokine production (Rothuizen et al 1999). This high-dose and frequency effect is also true with early inhibition of MRI Gd enhancement and multiple sclerosis relapses. Thrice-weekly versus weekly subcutaneous IFN-beta-1a is better at reducing new MRI lesions over 2 years in clinically isolated syndromes, but trends for fewer clinical attacks are nonsignificant. Lower doses of interferon diminish clinical efficacy—seen with cognition and relapse rate from IFN-beta-1a, 22 µg < 44 µg subcutaneous weekly; with IFN-beta-1b, 1.6 < 8 million units subcutaneously every other day; plus no effect on MRI with once a week IFN-beta-1a, 22 µg or 44 µg at 6 months, although a similar weekly dose of intramuscular IFN-beta-1a reduces MRI lesions. Reduction of dose and frequency provokes attacks in crossover studies. Importantly, in the pivotal trial of weekly intramuscular IFN-beta-1a there was significant slowing of progression.

There is a maximum “ceiling” effect of weekly IFN-beta-1a injections in reducing relapses; 60 µg is no better than 30 µg. Doubling every-other-day high dose IFN-beta-1b treatments also had little or no additional clinical benefit on stable multiple sclerosis, but did reduce conversion of new lesions to T1 MRI black holes (below).

Interferon pharmacodynamics.Interferon injections initiate multiple phenomena:

  • Serum IFN-beta levels peak at less than 1 hour, followed by a second burst of interferons alpha and beta several hours later (Khan and Dhib-Jalbut 1998; van Boxel-Dezaire et al 2006; Feng et al 2012b).
  • Biological response markers are induced for several days (MxA, 2’,5’-oligoadenylate synthetase, neopterin, and beta-2 microglobulin and remain elevated. Levels fall slightly after a year of therapy (Byskosh and Reder 1996). Intramuscular IFN-beta induces neopterin and beta2-microglobulin with a peak at 24 to 48 hours and a return to baseline by 6 days. Subcutaneous and intramuscular interferon effects are similar. Elevated TRAIL (tumor necrosis factor-related apoptosis inducing ligand) is associated with good clinical response.
  • Alterations in cytokines, chemokines, and immune cell function.
  • Gradual shifts occur in immune cell subset survival and distribution over months, especially in immune-suppressive NK cells (Perini et al 2000). Cortisol is not induced. IFN-alpha induces cortisol and has more side effects than IFN-beta.
  • There is more bone growth and osteoclasts don’t proliferate—thus, less osteoporosis.
  • A local depot effect causes red skin and vasodilatation for weeks, suggesting immune cells are also stimulated for a prolonged time.

Importantly, temporal differences are seen in therapeutic responses to IFN-beta in MRI enhancement (one week), relapses (3 to 6 months), progression (more than 1 year), and possibly neuroprotection. Clinical activity correlates better with immune markers (r = 0.5 to 0.79 in immune suppressor T cell assays) than with MRI T2 lesions (r = 0.25) (Feng et al 2002a).

Markers of biological responses to IFN-beta. A biological marker that predicts efficacy would aid in therapy. Before therapy, patients with high T cell proliferation to mitogen (PHA) or to anti-CD2/CD28 are more likely to be clinical responders to interferon (88% vs. 16% in this dichotomy) (Killestein et al 2002a) (see CD58, above). High pre-therapy serum IL-17F and IFN-beta (Axtell et al 2010) and MxA mRNA (Reder 2010; van der Voort et al 2010), low IL-10 and IL-12 RNA (van Boxel-Dezaire et al 2000), and more old and active MRI lesions (Hesse et al 2010) also predict later poor response.

Before interferon therapy, high serum IL-17F and IFN-beta levels predicted poor response to IFN-beta therapy in approximately 20% of patients (Axtell et al 2010). So did high levels of baseline interferon-stimulated genes (Comabella et al 2009) and MxA (Reder 2010; van der Voort et al 2010). High on-therapy responses to IFN-beta are also associated with poor clinical response (Rudick et al 2011). Importantly, however, the majority of multiple sclerosis patients have low serum interferon levels before therapy (Feng et al 2012a) and low responses to IFN-beta therapy (Feng et al 2002a). This majority may respond to interferon therapy.

During therapy, patients are more likely to relapse when they have high mitogen-induced lymphocyte proliferation, high IFN-gamma plus low IL-10 production, and no decline in serum immunoglobulin. Relapses also occur when ongoing injections do not induce MxA protein (Kracke et al 2000; Reder et al 2011).

Interferon therapy induces MxA protein in lymphocytes; IFN-beta-1b is the most potent in this regard. This suggests pharmacokinetics differ between IFN-beta-1a and beta-1b, or that there is an ongoing conformational change from inactive to active molecules in the high protein load of IFN-beta-1b. High levels of MxA in white blood cells after starting interferon therapy correlate with fewer relapses (Kracke et al 2000). Approximately 10% of patients have poor MxA induction, regardless of neutralizing antibody status. Black patients, compared to whites, are less likely to respond to IFN-alpha therapy for hepatitis C (Kimball et al 2001), and allelic variations in several genes control interferon responses. In the EVIDENCE trial, black patients had poorer response to IFN-beta-1a than white patients (Cree et al 2006). Interferon inhibitory activity from soluble interferon receptors, virus-induced proteins, drugs such as statins, or intrinsic resistance to interferon signaling are possible causes.

On MRI, interferons rapidly reduce the number of enhancing MRI lesions. IFN-beta reduced new and enlarging T2 lesions by a median of 71% versus placebo (Sormani et al 2005); however, 7% were “non-responders.” The heterogeneity of responses to interferon in this study suggests that MRI poorly predicts future treatment failure. In serial studies, 50% are early MRI non-responders, but some later become MRI responders (Chiu et al 2009).

Prevention of contrast-enhancing MRI lesions after 1 year of therapy generally prevents new lesions from becoming “black holes” in the first place and predicts lower T1 black hole volume in the next 2 years of therapy, as well as less brain atrophy. In a large study with 8 MU of IFN-beta-1a, the number of permanent black holes from new lesions was 0.3/year and the proportion evolving to black holes was 21.6% (Filippi et al 2011). This is less than 0.43 per year (p=0.05) and 23.5% (p=0.2, NS) with glatiramer. In smaller series, brain atrophy also slows in patients who completed 2 years of IFN-beta-1a therapy. It may slow development of T1 holes compared to placebo in progressive multiple sclerosis (Barkhof et al 2001). However, others find no effect on T1 MRI in secondary progressive multiple sclerosis (Brex et al 2001) and relapsing-remitting multiple sclerosis (Simon et al 2000). Once black holes develop, therapy does not enhance repair on MRI.

Continuing atrophy during therapy predicts worse clinical outcome, as does clinical progression on therapy. Suppression of new white matter lesions in later, progressive multiple sclerosis does not slow brain atrophy or disability. Changes in MRI and relapses alone (compared to MRI-, relapse-, and progression-negative) did not predict response to IFN-beta therapy over months 12 to 36. However, a combination of relapses and MRI worsening had an odds ratio of 8.3 for new relapses and 4.4 for progression. With relapse, MRI, plus progression, the odds ratios were 9.8 for predicting new relapses and 6.5 for progression (Río et al 2009).

It is unclear if there are truly separate groups of responders and non-responders. It is unknown if nonresponsive patients would be even worse without treatment. Accurate measurement of activity before therapy versus activity after randomized therapy would separate these 2 models.

Neutralizing antibodies. All interferon therapies induce neutralizing antibodies. Neutralizing antibodies cross-react with all forms of recombinant IFN-beta, but not with IFN-alpha. The incidence of neutralizing antibodies is highest with frequent (every other day) and subcutaneous IFN-beta-1b (30%), lower with subcutaneous IFN-beta-1a (15%), and lowest with weekly intramuscular IFN-beta-1a (2%) (Ross et al 2000; Bertolotto et al 2002). Assays differ: a titer of 1:400 with IFN-beta-1b is comparable to a titer of 1:100 with IFN-beta-1a. Thus, IFN-beta blocking ability at a given titer will also differ.

Low doses of IFN-beta-1b and IFN-beta-1a are stronger inducers of neutralizing antibodies than high doses of the same interferon. Concomitant glucocorticoid therapy reduces formation of neutralizing antibodies. Antibodies usually appear within 1 to 2 years of IFN-beta-1b treatment, but they eventually disappear (Rice 1997). Neutralizing antibodies tend to persist during IFN-beta-1a therapy.

With high-titer neutralizing antibodies, interferon-induced biological response markers fall, and so do side effects. The blocking effect is most visible with low doses of IFN-beta and with high titers of neutralizing antibodies. In patients who have neutralizing antibodies, a double dose of IFN-beta induces twice as much MxA protein. During the neutralizing antibody-positive period, some MRI enhancement reappears, and biological markers such as serum beta2-microglobulin, MxA, neopterin, viperin, IFIT-1, and 2,5-OAS fall. However, other markers such as IL-10 secretion are less affected. The differential gene responsiveness to neutralizing antibodies is partially explained by the huge variability in interferon response between patients (Reder et al 2008). Treatment effects are restored after patients revert back to antibody-negative.

Neutralizing antibodies correlate with reduced efficacy of interferon therapy (Sorensen et al 2003; 2005; 2006; Francis et al 2005) and partial loss of benefit on MRI (Pachner et al 2009). This logical relationship has not been clinically proven. With several studies, IFN-beta-1b-antibody-positive patients do at least as well as antibody-negative patients (Goodin et al 2007a; 2007b; 2012).

Rate of progression tends to improve in neutralizing antibody-positive patients, but the mechanism is unexplained. Antibodies to interferons have complex effects, some of which could enhance interferon signaling (Reder 2007; Moll et al 2008). In the first year of therapy, patients destined to become neutralizing antibody positive (but not yet positive), have a better clinical response to interferon therapy in all published trials. It is possible that binding antibodies, induced early, enhance interferon signaling or prolong its half-life. Neutralizing antibodies could also have a non-specific effect on Fc receptors, paralleling the inhibition induced by intravenous immunoglobulin therapy. Forty-three percent of the patients in the pivotal IFN-beta-1b trial were antibody positive, and therefore, one would expect even higher frequencies in any population with clinical worsening. However, only 12% of patients with worsening multiple sclerosis have high titers of neutralizing antibodies (greater than 1:100 dilution), and only 21% have detectable antibodies (1:20) (Goodin et al 2007a; 2007b).

Certain patients are predisposed to the development of neutralizing antibodies (NAb) (Reder 2007). Before starting interferon, this subgroup of patients tends to have higher pokeweed mitogen (PWM)-induced immunoglobulin secretion (Oger et al 1997), high serum ApoE (immunosuppressive), more exacerbations (Petkau et al 2004), and possibly more enhancing lesions on MRI (Calabresi et al 1997). Patients with these active responses are predestined to have a worse course of multiple sclerosis.

There are reports of autoimmune thyroiditis, systemic lupus erythematosus, and rheumatoid symptoms with IFN-alpha therapy, usually in subjects with preexisting autoantibodies. However, there is little or no increase over background incidence of autoantibodies with IFN-beta therapy.

Table 2 compares the putative effect of neutralizing antibodies on interferon efficacy. This is a hypothetical comparison of different populations (varied placebo and treated groups), drug doses, and trial designs. It could be argued that with these large populations, drug and antibody effects on relapsing-remitting multiple sclerosis are more important than minor differences in study populations and trial design.

Table 2. Therapeutic Calculus of Multiple Sclerosis Treatments: Effect of Nab Titer vs. Nab Duration

Pivotal trial data

Relapses:

% fewer

vs. PL

Progression:

% less vs.

PL

T2

MRI: %

benefit

vs PL

 

Gd+ MRI: % benefit vs PL

Avonex

6 MU per wk (a)

 

32

21°

61***

52***

Avonex ITT

 

18

37°

xxxxx

xxxxx

Betaseron

1.6 MU every other day

 

16

0°

75

 

Betaseron

8 MU @ 2y

 

34

29°                 31 °°
 

75

 

Rebif

22 mcg 3

times a week

 

27

22°

67

 

Rebif

44 mcg 3

times a week

(b)

 

33

30°

78

84

Copaxone

20 mg per day

 

29

12°

30****

29

Tysabri

300 mg each

month

68

42°

83

92

° Confirmed (Data from pivotal trials)
°° Unconfirmed; significant in both Betaseron & Copaxone; not used below for putative effect of NAb (Data from pivotal trials)
*** 61 and 52 are subsets of the total study population
**** 30 = percentage of new lesions vs placebo (PL) at 9 months

Relapses: Nab effect x frequency of NAb
[Pivotal relapse rate-{pivotal relapse rate x % blocking x % NAb positive}]

 

100% block

(change in RRate)

 

50% block

(change in RRate)

33% block

(change in RRate)

Avonex

6 MU each week (a)

 

1 x 0.05 (d)

(30.4)

0.5 x 0.05

(31.2)

0.33 x 0.05

(31.5)

Avonex ITT

1 x 0.05

(17.1)

 

0.5 x 0.05

(17.6)

0.33 x 0.05

(17.7)

Betaseron

1.6 MU @ 2y

 

1 x 0.385

(9.84)

0.5 x 0.385

(12.9)

0.33 x 0.385

(14.0)

Betaseron

8 MU @ 2y

(NAb peak)

 

1 x 0.365

(21.6)

0.5 x 0.365

(27.8)

0.33 x 0.365

(29.9)

Betaseron

8 MU @ 4y (c) (NAb falling)

 

1 x 0.10

(30.6)

0.5 x 0.10

(32.3)

0.33 x 0.10

(32.9)

Rebif

22 mcg 3 times a week

 

1 x 0.238

(20.6)

0.5 x 0.119

(22.5)

0.33 x 0.22238

(24.9)

Rebif

44 mcg 3 times a week (b)

 

1 x 0.125

(28.9)

0.5 x 0.125

(30.9)

0.33 x 0.125

(31.6)

Copaxone

20 mg each day

 

No effect

(benefit?)

 

(X)

 

(X)

Tysabri/Antegren

300 mg each month

1 x 0.06

(63.9)

 

(X)

 

(X)

Progression: NAb effect x frequency of NAb (e)

 

100% block

(change in progression)

50% block

(change in progression)

33% block

(change in progression)

 

Avonex

6 MU each week (a)

 

1 x 0.05 (d)

(20.0)

0.5 x 0.05

(20.5)

0.33 x 0.05

(20.7)

Avonex ITT

1 x 0.05

(35.2)

 

0.5 x 0.05

(36.1)

0.33 x 0.05

(36.4)

Betaseron

1.6 MU @ 2y

 

1 x 0.385

(0)

0.5 x 0.385

(0)

0.33 x 0.385

(0)

Betaseron

 8.0 MU @ 2y (NAb peak)

 

1 x 0.365

(18.4)

0.5 x 0.365

(23.7)

0.33 x 0.365

(25.5)

Betaseron

 8.0 @ 4y (c)

(NAb falling)

 

1 x 0.10

(26.1)

0.5 x 0.10

(27.6)

0.33 x 0.10

(28.0)

Rebif

22 mcg 3 times a week

 

1 x 0.238

(16.8)

0.5 x 0.119

(18.3)

0.33 x 0.22238

(20.3)

Rebif

44 µg 3 times a week (b)

 

1 x 0.125

(26.3)

0.5 x 0.125

(28.1)

0.33 x 0.125

(28.8)

Copaxone

20 mg each day

 

NA

(benefit?)

 

(X)

 

(X)

Tysabri/Antegren

300 mg each month

1 x 0.06

(39.5)

 

(X)

 

(X)

Adversities: Relative importance (f)

 

Flu-like Sx

LFT/WBC

IPIR

Skin

 

Avonex

6 MU each week (a)

+ (early)

+

0

Redness: 0

Lumps: 0

Necrosis: 0

 

Betaseron

1.6 MU @ 2y

 

+

+/-

0

 

Betaseron

8.0 MU @ 2y

++ (early)

+

0

Redness: ++ (most)

Lumps: + (in 5%)

Necrosis: +++ (in 2%)

 

Rebif

22 mcg 3 times a week

 

 

 

 

 

Rebif

44 µg 3 times a week (b)

++ (early)

+

0

Redness: ++ (most)

Lumps: 0

Necrosis: +++ (rare)

 

Copaxone

20 mg each day

0

0

++ (1/1000)

Redness: + (most)

Lumps: 0

Necrosis: 0

 

Tysabri/Antegren

300 mg each month

0

0

+

 

(a) Based on subset of 2-year completers (164/272); instead of all subjects entered (272) and comparisons with intent-to-treat analysis (ITT).

(b) Faster therapeutic onset with high dose IFNs may be important in very active multiple sclerosis.

(c) Effect at 2 years (at peak NAb positivity) and at then 4 years (when most on IFN-beta-1b return to NAb-negative status). Two-year values are used for putative 4-year calculations. Interferon-beta-1a induces higher and more persistent titers than IFN-beta-1b. Measured titers can be off by 3-fold, depending on the subtype of interferon used to spike the assay (Files et al 2007).

(d) NAb % age (5%=0.005) is not from pivotal trial (22%); but from experience with later Avonex product. Danish data show 20% NAb development in relapsing-remitting multiple sclerosis with 2 attacks/2y.

(e) Effects on progression are unclear; several studies suggest NAbs have a beneficial effect on progression. NAb could affect innate immunity or the NAb+ subgroup may be immunologically unique--and predestined to behave differently, regardless of NAb status.

(f) Convenience is important to some. An international airline stewardess may not want frequently-dosed, refrigerated drugs. Ataxic patients may require the easiest injections. Compliance increases with tolerability and convenience.

CBC = complete blood count, IPIR = immediate post-injection reaction, LFT = liver function tests, Nab = neutralizing antibody, PL = placebo, Tysabri/Antegren based on Phase II and II studies.

Note: Cross-study comparisons are not valid. Nonetheless, these large studies provide well-controlled large-population data.

Withdrawal of interferons leaves a window of safety from multiple sclerosis activity that lasts weeks to months. A small series shows no MRI lesions for 6 to 10 months after discontinuation. Occasionally, however, patients who were deemed “interferon failures” have exacerbations or rapid progression several weeks after discontinuation of interferon. Thus, therapy had been partially effective, even in patients with some clinical symptoms during treatment.

Side effects with IFN-beta are relatively rare and are largely from induced cytokines. Acute toxicities include transient influenza-like symptoms, headache, increased temperature (sometimes prolonged) and heart rate, fatigue, maculopapular rash (rare), and sometimes spasticity, coincident with preexisting cord lesions. At 24 hours blood lymphocytes diminish, but monocytes rise. Flu-like symptoms correlate with induced levels of IL-6 and prostaglandins. IL-6 levels and temperature rise most with evening injections. Side effects are comparable in children, although those younger than 10 years old are more likely to develop elevated liver function tests. Flu-like side effects are diminished by gradual upward titration when staring therapy. They improve with time and with acetaminophen, aspirin, hydration, and other interventions (Walther and Hohlfeld 1999). A personalized nursing program increases adherence to therapy.

Chronic toxicities appear in a small percentage of patients and include weight loss (approximately 2 kg), a mild fall in white blood cell count and neutrophils that usually disappears by 4 months, increased liver function tests peaking at 1 to 2 months after start of high-dose therapy (dosage reduction normalizes values), an increase in triglycerides, yet a decrease in cholesterol (Byskosh and Reder 1996; Tremlett and Oger 2004). There have been several cases of serious liver injury, autoimmune hepatitis, pancreatitis, and focal segmental glomerulosclerosis with IFN-beta-1a, often on a background of associated autoimmune markers. De novo thyroid dysfunction and autoantibodies are not a problem with IFN-beta (Reder et al 2010). Patients on IFN-alpha and, occasionally, IFN-beta therapy for hepatitis C develop cotton-wool spots (from retinal hypoperfusion) and retinal hemorrhage. One quarter treated with IFN-alpha (for hepatitis B) have slowed visual evoked potentials. However, visual evoked potentials actually improved with IFN-beta-1b in a small study (Pliskin et al 1997). Some women, often with a prior history, develop menstrual disorders with weekly IFN-beta-1a, but IFN-beta-1b seems to reduce complaints. Rare patients, often with a history of depression, complain of worsening depression. In large controlled studies, however, depression was not induced. Selective serotonin reuptake inhibitor antidepressants or a switch to glatiramer or other agents may be needed.

A 2 cm warm red macule often appears at the injection site. The pain from subcutaneous IFN-beta-1a injections can be ameliorated by injecting room-temperature interferon solution, possibly pre-cooling the skin with ice, allowing an air bubble to enter as the last part of the injection.

Skin necrosis and panniculitis occasionally develop with subcutaneous IFN-beta-1b. The rate has decreased with better patient education, vertical as opposed to oblique injections, interferon-free needle techniques, an auto-injector apparatus, and rubbing the site after injections. The skin necrosis rate over 2 years was 1% in 3 of 292 patients (Kappos et al 2007). Necrosis is less common with subcutaneous IFN-beta-1a and glatiramer acetate, and is not seen with intramuscular interferon injections. Japanese patients, who are 15 kg lighter and who have different diets than American patients, had 14% necrosis rates over 2 years with IFN-beta-1b.

Skin Langerhans cells could be activated by interferon aggregates. Interferon may prevent angiogenesis and wound healing by decreasing IL-8. (IFN-beta induces IP-10/CXCL10, which downregulates IL-8 and also induces migration of T cells into the lesion; interferon-induced MCP-1/CCL2 promotes macrophage migration.) There is strong synergy between interferon and lipopolysaccharide to induce tristetraprolin, a protein that shortens the half-life of many cytokines (Sauer et al 2006). It is likely that any systemic infection (dental procedures, periodontal disease, surgery, cystitis, and smoking with bronchitis) could potentiate a localized interferon bolus. Following dental procedures, skipping one interferon dose or a taking a short course of antibiotics before the next interferon injection may be advisable (Arnason personal communication 2006).

Primary Sjögren syndrome, lupus manifestations, and dermatomyositis have appeared after IFN-beta therapy. Lupus erythematosus and Sjögren syndrome have a marked “interferon signature” unlike the hypo-response to interferon that characterizes multiple sclerosis (Javed and Reder 2006). It is possible that a rise in interferon levels provokes these diseases that are rarely associated with multiple sclerosis.

Cancer may be reduced in patients treated with IFN-beta.

Fertility is enhanced by interferons, perhaps by improved implantation of the ovum. Type I IFN-tau in ungulates enhances implantation, similar to human chorionic gonadotrophin. IFN-beta is a category C drug and not advised during pregnancy. Eighty-eight women who remained on IFN-beta for an average of 5 weeks while pregnant had smaller, shorter babies (114 g and 1.2 cm less), but no excess of spontaneous abortions or developmental abnormalities (Amato et al 2010).

During breastfeeding, interferon therapy is not recommended. However, a huge dose, 30 million units, of intravenous interferon-alpha-2b only slightly elevates milk interferon levels (from 1249 to 1551 IU/ml) (Kumar et al 2000), and most of this should be eliminated in the baby’s gastrointestinal system. Pumping and disposing of milk for 5 hours after the injection is another option, as most interferon should be cleared, but this would be “off-label” use. Delaying interferon therapy for the first few days after delivery allows the baby to ingest colostrum.

Glatiramer acetate. Glatiramer acetate, 20 mg subcutaneously daily, reduces exacerbations by one third. Effects are most pronounced in early multiple sclerosis with minimal disability. Glatiramer reduces the chance of developing clinically definite multiple sclerosis after a first attack by 45% compared to placebo (PreCISe study). In a well-designed study, cognition was not affected, but the placebo control group did not decline over time. Doubling the daily dose has no additional benefit in stable relapsing-remitting patients. Anecdotal reports claim benefit in childhood-onset multiple sclerosis. Clinical effects of glatiramer in mice are rapid and dramatic; in man they appear at 3 months. This suggests that the mechanism of action differs between mice and men.

Every-other-day drug was equivalent to everyday dosing in 30 patients (Khan personal communication 2008). Long-term follow-up of the original trial showed low relapse rates and low rates of progression. However, only 43% of the patients were identified, so the majority may or may not have stopped therapy because of worsening. Direct comparisons with IFN-beta-1a and -1b are described below.

Mechanism of action of glatiramer acetate. Glatiramer alters immunity in many ways. It binds with high affinity to some major histocompatibility proteins on antigen-presenting cells, possibly acting as an altered peptide ligand or a competitor to pathogenic antigens and suppresses immune responses to brain antigens. HLA-DR2 patients may respond best to glatiramer. Glatiramer inhibits expression of activation molecules on monocytes and also transforms them to type II monocytes. These cells release fewer inflammatory monokines, but more IL-10, and induce deviation to Th2 cells (Weber et al 2007b).

Glatiramer acetate induces a Th2-biased response in 40% of patients. Th2 cells penetrate the blood-brain barrier more easily than Th1 cells and are present in CSF by 12 months after therapy is begun. Polarization of T cells to Th2 cells, in turn, induces immunosuppressive type 2 monocytes and microglia (and B cells), which further amplify the Th2 deviation (Kim et al 2004). Therapy reduces elevated IL-12, but not IL-10, in mononuclear cells. Glatiramer induces IL-27 in macrophages, which then lowers levels of IL-17. Glatiramer increases thymic export of Trec cells that are regulatory T cells and boosts their function (Haas et al 2009), identical to effects of IFN-beta seen by the same lab (Korporal et al 2008). Glatiramer elevates numbers of regulatory CD4 T cells in relapsing-remitting multiple sclerosis (Venken et al 2008). Glatiramer acetate and cross-stimulating myelin antigens (Stapulionis et al 2008) induce secretion of Th2 cytokines, including large amounts of neuroprotective BDNF in blood and brain. Th2 cells induce elevated titers of IgG4 and of IgG1, greater than IgG2 (no IgM or IgE). Antibodies to glatiramer are mostly IgG1 (a Th2-induced subtype). They do not block function and actually appear to enhance efficacy. Gene expression is increased for apoptosis and class I MHC antigen presentation pathways and decreased for adhesion and inflammation.

CD8 suppressor cells are a major target of this therapy. Before treatment, CD8 cells proliferate poorly to glatiramer acetate; proliferation normalizes after 1 year of therapy (Karandikar et al 2002). Glatiramer induces oligoclonal proliferation of CD8 T cells (Karandikar et al 2002). These CD8 cells secrete IFN-gamma, TNF-alpha, and transforming growth factor-beta. CD8+high,CD28-,CD57+ suppressor cells kill pathogenic activated Th1 CD4 cells linked with monocytes in a CD8/CD4/APC interaction (Tennakoon et al 2006) and are an important therapeutic target. Glatiramer reduces the excessive levels of the activating zeta chain of the T cell receptor on CD4 cells and increases levels on CD8 cells (Khatibi and Reder 2008). It also reverses a defect in the small human population of CD4+,CD25+ regulatory/suppressor T cells. Glatiramer induces regulatory B cells in animal models of multiple sclerosis, potentially very important in antigen-specific immunity (Genc et al 1997b).

Glatiramer acetate reduces new and enlarging MRI lesions. These effects were weaker and delayed compared to interferon therapy in the pivotal trials, but were equivalent in large face-to-face studies. Gd+ lesions do not discriminate between clinical responders and non-responders to glatiramer. However, glatiramer facilitates repair of T1 black holes from acute lesions on MRI (Filippi et al 2001). Brain atrophy slows over 18 months of glatiramer therapy. On MR spectroscopy, the N-acetyl aspartate/creatinine ratio increases after 1 year of therapy, possibly from a neuroprotective effect. Microglial activation measured with 11C-R-PK11195 on positron emission tomography is reduced by 3% after glatiramer therapy.

Although brain inflammation is not desirable, activated T cells do produce neurotrophic factors. Activation of T cells, B cells, and monocytes with myelin or glatiramer acetate will induce BDNF, insulin-like growth factor, platelet-derived growth factor, and other neurotrophic factors (Hohlfeld et al 2000). Glatiramer enhances Th2, but not Th1, cell migration across human brain microvascular endothelium in vitro (Prat et al 2005). Glatiramer acetate, injected in complete Freund adjuvant, induces murine T cells that protect against neuronal damage from multiple causes (Schori et al 2001). It is hoped that oral glatiramer induces neurotrophic factors in multiple sclerosis plaques. Glatiramer also directly interacts with neurons and prevents stress-induced death. Additionally, it prevents prion infection of cells (Cashman personal communication 2000).

Side effects of glatiramer include injection site erythema (reduced by 5 minutes of skin pre-warming), skin pigmentation, and rare lymphadenopathy. Atrophy of subcutaneous fat occurs in nearly half of patients. Lipoatrophy is most common in thin, red-headed women (Edgar et al 2004). The panniculitis includes infiltrating polymorphonuclear neutrophils, eosinophils, CD8 cells, B cells, and formation of germinal centers. Suggestions to prevent injection site reactions include warm compresses, and suggestions to prevent atrophy include rotating sites and never injecting cold solution. The package insert cautions against rubbing the injection site, but there is no rationale given for this; firm massage reduces skin reactions to IFN-beta.

There is an “immediate post-injection reaction” (IPIR) in 1 in 1000 to 1 in 3000 injections. This reaction consists of chest tightness and shortness of breath, palpitations, dizziness, flushing, and anxiety. It may be from abrupt influx of a bolus of intravenous glatiramer into the lungs.

Glatiramer versus interferon, glatiramer plus interferon, and comparison with natalizumab. Patients who have disease activity despite IFN-beta treatment had fewer relapses after switching to glatiramer (Wolinsky 2004), but there was no non-switch control group. In another study of 101 patients with some disease activity, switches, and likely regression to the mean, reduce disease activity over 4 years as follows: all forms of IFN-beta at a baseline frequency of 42% relapse-free become 53% relapse-free after a switch to glatiramer; glatiramer to interferon, 12% become 87% relapse-free; and (predominantly) intramuscular IFN-beta-1a to subcutaneous IFN-beta-1a or IFN-beta-1b, 41% become 67% relapse-free (Gajofatto et al 2009). Changing again was even more effective.

Two large trials in patients with stable relapsing-remitting multiple sclerosis showed that high-dose, high-frequency IFN-beta and glatiramer had very similar effects on relapse rates and T2 MRI lesions. Glatiramer reduced the relapse rate as well as IFN-beta-1b, 250 or 500 ug every other day (BEYOND trial), and as well as subcutaneous IFN-beta-1a, 44 ug thrice weekly (REGARD trial). There were no MRI differences between glatiramer and IFN-beta when using triple-dose gadolinium in a 3T magnet, a technique perhaps so sensitive that unquenched low-level MRI activity was detected with both drugs. High-dose IFN-beta-1b had less evolution to black holes than glatiramer. Glatiramer had more troublesome skin reactions, but no flu-like symptoms. The COMBIRx study of glatiramer versus weekly intramuscular IFN-beta-1a versus the combination showed no benefit over either monotherapy.

The combination of glatiramer and natalizumab in 55 patients over 20 weeks was safe. It reduced new T2- and Gd-enhancing MRI lesions by 3-fold compared to glatiramer alone in the GLANCE study.

Natalizumab. Natalizumab is an antibody to a late activation antigen (VLA-4) expressed on activated T cells and monocytes. It prevents adhesion of activated T cells to endothelial cells. Six monthly intravenous infusions caused a 10-fold drop in Gd+ MRI lesions and a 50% decline in relapses compared to placebo (Miller et al 2003). There was also benefit in the one third of patients with progressive disease. A large phase III trial showed 83% fewer new and 92% fewer enhancing MRI lesions, 42% less conversion of MRI T2 lesions to T1 holes, 66% reduction in relapse rate, 43% slowing in progression, less visual loss, improvement in quality of life, and less fatigue. This drug prevents axonal damage, measured by normalization of neurofilament light chain levels in the CSF (Gunnarsson et al 2011), and improves visual and sensory evoked potential function.

After stopping therapy, there was no clinical rebound in the controlled trials, and suggestions of long-term benefit remained (O’Connor et al 2011). Several small series later found many new MRI lesions or more clinical activity after stopping therapy in some patients. Because many on therapy had highly active multiple sclerosis before treatment, it was not clear if this was a true rebound or simply a return to baseline high activity.

Many patents switching to this therapy have active multiple sclerosis despite other treatments. However, discontinuation of the other agents is often followed by abrupt worsening. This author recommends no more than a 1-week gap between discontinuation of interferon or glatiramer and start of anti-VLA-4 therapy.

Six percent of patients develop persistent neutralizing antibodies that block efficacy. If these neutralizing antibodies persist, the therapy should be stopped.

Progressive multifocal leukoencephalopathy (PML) was seen in 2 patients on the interferon and natalizumab combination in the pivotal trials, but this was not statistically different from the 0 patients in the natalizumab-only group. To prevent PML, however, natalizumab monotherapy is advised. As of July 3, 2012, there were 264 cases of PML: 157 of 54,000 treated in Europe, 95 of 54,000 treated in the United States, and 12 of 7500 in the rest of the world (Biogen).

The overall risk of PML during natalizumab therapy is generally assumed to be approximately 1/1000. The risk is actually 1/415 after the first year of therapy, and other factors change the risk. The incidence of PML is 4-fold higher with prior chemotherapy. Because approximately 50% of the population is John Cunningham virus (JCV)-positive, the risk for PML doubles in JCV-positive patients. If JCV-negative, the risk of PML is low--approximately 1/30,000 per year assuming 1% conversion to JCV-positive per year and 2% false negative on the JCV titer test. Assume the overall risk is 1/1000. After 11 years of therapy, it is 1/100. If JCV-positive, the risk of PML rises from 1/1000 to 1/360. If JCV-positive with prior chemotherapy, it increases to 1/125 per year. Importantly, these risks are for each year, so after a total of 11 years on therapy, the risks are approximately 1/100 for all patients, 1/36 (3%) for JCV-positive patients, and 1/12.5 (8%) for JCV-positive patients with prior chemotherapy.

Occasional cases of CNS lymphoma and toxoplasmosis may be related to drug use.

Fingolimod. Fingolimod (FTY720; Gilenya), is a sphingosine 1-phosphate receptor agonist that is derived from the ascomycete metabolite ISP-1 (myriocin). It interferes with S1P receptor function and prevents egress of lymphocytes from lymphoid organs. The quarantined cells become tolerized or suppressed, possibly by lymph node stromal cells. Cells affected are T>B, CD4>CD8, T-helper>T-regulatory, and T-naïve>T-central memory. Central memory cells in the blood, including Th17 cells, are reduced by 90%. S1P receptors are upregulated in Sjögren syndrome, suggesting that doses may need to be modified in the face of some concurrent diseases. This drug prevents leukocytes from entering the CNS (Kowarik et al 2011). CSF white blood cells fall to one fifth of baseline levels after fingolimod or natalizumab.

Oral FTY720 compared to placebo reduced relapses by 54%, reduced MRI lesions (0.2/scan vs. 1.1/scan in placebos), and slowed progression (17.7% vs. 24.1% in placebo) [phase III FREEDOMS trial of nearly 1300 patients (Kappos et al 2010)]. There was slower atrophy on MRI. Oral FTY versus intramuscular IFN-beta-1a had similar benefit on relapses, some reduction in MRI lesions, and no difference in progression (Cohen et al 2010). The 0.5 mg dose was approved by the United States Food and Drug Administration in 2010 as first-line therapy for relapsing forms of multiple sclerosis.

Side effects include slowing of heart rate only at the first dose, moderately elevated liver enzymes, possible increase in DNA virus infections, and macular edema--0.5% in trials, potentially more in the general population where diabetes is more common. Diabetes, smoking, and past uveitis increase the risk of macular edema. Use is prohibited during pregnancy. There was no increase in cancer in treated patients in these short-term studies. Of note, the mandated chest CT scans that were part of the U.S. study have an expected risk of 1:2000 cases of cancer in younger multiple sclerosis patients.

FTY720 readily crosses the blood-brain barrier. FTY720 dose- and time-dependently stimulates neuronal and oligodendroglial growth, and enhances astrocyte support of neurons. In oligodendrocytes, lower doses facilitate growth and survival; higher doses are toxic, and S1P5 and S1P1 receptors are involved (Eskan et al 2008; Miron et al 2008). Experimental allergic encephalomyelitis studies suggest that the FTY benefit is more from effects on astrocytes than on T cells. FTY720 induces IFN-beta secretion (Eskan et al 2008). Interferons may synergize with FTY in preventing egress by increasing immune cell expression of CD69--linked to the sphingosine 1-phosphate receptor. S1P1 receptors enhance prion dissemination among secondary lymphoid organs; this drug could modify the process.

Glatiramer and interferons induce some invading immune cells that suppress inflammation or promote CNS repair, such as suppressor/regulatory CD8 and CD4 cells, and lymphocytes and monocytes secreting neurotropic factors. This mechanism could be prevented by natalizumab and fingolimod. Thus, short- and long-term effects may differ between the 4 therapies.

Plasmapheresis and plasma exchange. Plasmapheresis had no effect in a series of studies in the 1980s, although in a study of 200 chronic progressive multiple sclerosis patients, many of the 139 patients followed for 3 years improved (Khatri et al 1991). The number of dropouts precludes firm conclusions, and a later Canadian study found no benefit. There was some benefit in a mixed population of demyelinating diseases in patients who have fulminant severe motor deficits and have not recovered with steroid therapy (Weinshenker and Lucchinetti 1998; Keegan et al 2002). Similar responders to plasma exchange typically show Lucchinetti pathological pattern II, but not patterns I and III, in brain-lesion biopsies (Keegan et al 2005).

Intravenous immunoglobulin. Intravenous immunoglobulin (IVIG) had unimpressive effects in most North American and Danish studies. A large randomized trial in Austria showed benefit on relapse rate that was comparable to interferons and glatiramer acetate (Fazekas et al 1997), but a follow-up study was negative (Fazekas et al 2008). IVIG may reduce the probability of developing definite multiple sclerosis after the first attack (Achiron et al 2004). The number of enhancing MRI lesions is the same with IVIG therapy, but their volume is reduced, suggesting a suppressive effect at the margin of the lesions. IVIG may prevent CNS atrophy. In interferon- or glatiramer-treated patients (45% black, 55% white) with optic neuritis who had failed glucocorticoids (only 13% improved), IVIG led to improvement in 78% (Tselis et al 2008). Differences between IVIG studies may lie in plasma donor populations from different centers, in formation of aggregates in the commercial preparations, or in Fc receptor polymorphisms in the patients.

IVIG has many effects on immunity relevant to multiple sclerosis. Aggregated immunoglobulin induces suppressor T cells or prostaglandin-secreting monocytes. IVIG may also block endogenous cytokines, or transport Ig-bound cytokines into the recipient. Intravenous immunoglobulin binds to Fc receptors. Fc receptor allotypes are correlated with disease course in multiple sclerosis (Vedeler et al 2001). Novel Fc-based ligands that block the excitatory Fc receptor can potently prevent T cell and macrophage activation before the cells enter the brain (White et al 2001). The immunostimulatory high-affinity Fc gamma receptor I is downregulated by IFN-beta, especially in multiple sclerosis (Van Weyenbergh et al 1998), suggesting additive effects of IVIG and IFN-beta.

Whether to treat. Expert clinicians debate about when to treat. Multiple sclerosis has a variable course; some forms of multiple sclerosis are less responsive to therapy than others, and treatments are not perfect.

Some argue for caution because 17% of cases are benign at 10 years, 40% are progressive and not very responsive to therapy, reduction of brain atrophy is not dramatic, neutralizing antibodies could appear, and some therapies could permanently change the immune system. Treatment is avoided in those with low disability at 5 years, little MRI activity, progressive disease and inactive MRI, and clinically mild disease (Pittock et al 2006).

In the pro-treatment camp, it is argued that most axonal damage occurs in the first year, the drugs have benefit, most patients will (unpredictably) develop significant disability, and any delay in therapy causes more MRI and clinical disability. These authors suggest the earliest reasonable treatment (Frohman et al 2006).

Once treatment is started, discontinuation is highest in patients who have more disability, those who feel the drug is not efficacious, and those who have side effects. Appropriate patient expectations, plus dose escalation, smaller needles, access to medical personnel in clinic or a drug hotline, clean needle injections, and analgesics such as acetaminophen or long-acting non-steroidals can enhance drug compliance (Frohman et al 2002). Simply counseling patients on the importance of strict compliance, or close to it, is an effective way to increase adherence to therapy.

Experimental therapies. Therapies being tested to change the course of multiple sclerosis include antibodies and small proteins that destroy T cells (anti-CD52) and B cells (anti-CD20), or block T cell receptors, inflammatory cytokines (anti-IL-1, anti-IL-12, anti-IFN-gamma), chemokines, costimulatory proteins (anti-CD80/CD86, B7-1/B7-2), or adhesion molecules (anti-LFA-1/anti-CD18 and anti-VLA-4 oral small molecules or intravenous antibodies).

  • Antibodies (monoclonal antibodies):

- Alefacept (anti-CD2) reduces psoriasis in 50% of patients, but non-responders had increased expression of immune activation molecules. This mixed antagonist/agonist reduces effector memory T cells, but may also decrease regulatory T cells. In multiple sclerosis, CD2 binding is abnormal (Reder et al 1991); trials should be performed with caution.

- Alemtuzumab (CAMPATH; Lemtrada) is a monoclonal antibody against CD52. It depletes mature T cells for years. Since hematopoietic stem cells are said not to express CD52, other bone marrow cells or immune homeostasis are altered. After therapy, immune reconstitution is delayed at different rates--first B cells, then Treg and Th2 cells increase sequentially. Alemtuzumab therapy reduces MRI lesions and relapse rate for 18 months. Compared to a thrice-weekly IFN-beta-1a competitor, alemtuzumab reduced MRI lesion burden, and attack rate by 74%, progression by 71% and was effective in all subgroups (CAMMS223 Trial Investigators et al 2008); these differences were sustained for 5 years. However, in the 2-year, phase III CARE-MS trial, relapses were 49% less than with IFN-beta-1a, but there was no significant effect on progression (worsening in 8% vs. 11% on interferon). It is not effective in progressive multiple sclerosis.

There was a 33% incidence of (treatable) hypothyroidism in the initial study; the mechanism is unexplained. With thyroid disease, onset is after 10 months, and three fourths are Grave disease followed by return to normal or hypothyroidism; most require treatment. Autoimmune thrombocytopenic purpura (5 cases), glomerular basement membrane disease (1), and viral infections occurred (2-fold overall increase; occasional herpes simplex). Past smoking tripled risk of autoimmune disease.

- Atacicept blocks B cell activation by BLyS and APRIL. This study was stopped.

- Belimumab blocks BLyS (BAFF), a B cell activation factor.

- A modified anti-CD3 antibody induces tolerance and expands CD8 regulatory T cells.

- Daclizumab (Zenapax; similar to basiliximab, Simulect) binds to IL-2-receptor-alpha chain on T cells. It decreases relapses by 33% (or trends to do so) and MRI activity by 50% over 1 to 2 years; it decreases relapses by 78% from the prior rate in patients who failed interferon therapy. NK cells are elevated and may kill activated T cells. CD4 and CD8 cells decline. Daclizumab expands CD56bright suppressor NK cells in blood and CSF (Martin et al 2010). These NK cells have 100x higher expression of IL-2 receptors than T cells and can respond to quite low IL-2 levels. It depletes circulating CD4 Treg cells, calling into question the role of CD4 Treg in multiple sclerosis. Another phase IIb study is in progress. It is safe and partially effective in children with multiple sclerosis.

- DC2219 targets CD22 and CD19 on B cells and kills them.

- Epratuzumab (anti-CD22) targets an adhesion molecule that upregulates B cell receptors. It depletes 40% of B cells, but does not change antibody levels.

- Recombinant human IgM may engender remyelination.

- Antibodies to LINGO (BIIB033) may stop inhibition of remyelination and appear to be safe.

- Rituximab, an antibody against CD20 memory B cells, reduced relapses by 50% in relapsing-remitting disease (Hauser et al 2008). It was not submitted for FDA approval. It completely depletes B cells from the cerebral perivascular spaces and lowers CSF B cells by 95%, suggesting it would benefit progressive multiple sclerosis. A trial in progressive multiple sclerosis did not slow progression by 50% in the entire group, but there was benefit in younger patients who had a stronger inflammatory signature. Fc receptor polymorphisms affect drug responses. CSF B cell counts decrease by one half in 55% of patients. Ocrelizumab, a humanized form of rituximab, has had similar effects in early studies. Different B cell subsets are depleted, potentially with complex effects on immunity in multiple sclerosis and neuromyelitis optica.

Non-antibody experimental therapies include:

  • Adenosine 2A receptor agonists (ATL313) inhibit neuropathic pain.
  • Chemokine receptor blockade.
  • Chemotherapy. Antimetabolites (inhibitors of pyrimidine biosynthesis [FK778, gemcitabine, leflunomide, teriflunomide], inhibitor of inosine monophosphate dehydrogenase [VX-97]).
  • Anti-inflammatory cytokines (IL-4, IL-10, IFN-tau, alpha-melanocyte stimulating hormone) (Skurkovich et al 2001).
  • Estriol, the hormone that increases during the low-attack, later trimesters of pregnancy, has some benefit in early relapsing multiple sclerosis and reduces expression of costimulatory molecules. A combination study with glatiramer is in progress. High estradiol levels in men correlate weakly with clinical disability and more tissue damage on MRI (Tomassini et al 2005). Estriol inhibits experimental allergic encephalomyelitis in male and female mice.
  • Firategrast (oral anti-VLA-4; anti-alpha4 integrin) at high doses reduced new Gd+ MRI lesions by 50% at 6 months, but increased urinary tract infections. Low doses, however, increased MRI lesions by 80% versus placebo (Miller et al 2012).
  • Fish oil (cod liver oil), omega-3 fatty acids, and long-chain fatty acids (evening primrose oil, flaxseed oil) are anti-inflammatory. They have a modest or debatable benefit on relapses.
  • Fumarate (BG00012; BG12; Panaclar) is an oral agent used for psoriasis. It causes a Th1 to Th2 shift. It activates neuron, astrocyte, and oligodendrocyte Nrf2 antioxidant protein. In a multiple sclerosis phase II trial, it reduced new enhancing multiple sclerosis MRI lesions by 69% and had trends for a 32% fall in relapses, and possible neuroprotection with fewer new T1 MRI lesions. Flushing and red skin and gastrointestinal side effects occur in one third. Two phase III studies showed 50% reduced relapse rates versus placebo; effects on stemming progression appear to be significant in this 2 to 3 times per day oral medicine. This agent also suppresses HIV replication and HIV-induced neurotoxicity.
  • Glatiramer double-dose is being tested; preliminary reports show no added benefit.
  • Granulocyte-colony stimulating factor (G-CSF) reduces Th1 cytokines, and increases regulatory CD4 T cell and dendritic cell production of IL-10, TGF-beta, and IFN-alpha (Rutella et al 2005). IL-10 and IFN-alpha induce Treg cells in mice. However, there are reports of exacerbations from G-CSF in multiple sclerosis.
  • Granulocyte macrophage-colony stimulating factor (GM-CSF) blockade is under study.
  • Helminth ova (pork whipworm) to shift gut and then peripheral immunity from Th1 to Th2 (safety trial, Fleming personal communication).
  • Immune cell inhibitors. Blocking protein kinase cascades (Janus kinase [JAK], lymphocyte-specific cytoplasmic protein kinase [p56 Lck], mitogen-activated protein kinase [MAPK], protein kinase C [PKCtheta], TCRzeta chain associated protein [ZAP-70]), or nuclear factor of activated T cells [NFAT]).
  • Interferon conjugated to polyethylene glycol (PEG)-interferon, IFN-tau, and high-dose IFN-beta in relapsing and progressive multiple sclerosis.
  • IL-2 (see daclizumab).
  • IL-10 (through anti-inflammatory effects--but only in certain concentrations).
  • IL-12 blockade. Trials are on hold.
  • IL-17A blockade (AIN457 monoclonal antibody).
  • Laquinimod inhibits migration of CD4 T cells and macrophages into the spinal cord and causes a Th2 shift and reduces Th17 cells. It reduces active MRI lesions by 40% to 52%. The main side effect is elevation of liver enzymes. Phase III trial preliminary data show no change in annualized relapse rate, but significant slowing of progression and less fatigue and less cognitive decline in this once-a-day oral medicine. Roquinimex (Linomide), a related compound that enhances NK cell function, benefitted multiple sclerosis but caused serositis and myocardial infarctions.
  • Leukocytapheresis removes activated T cells instead of antibodies. It is potentially effective in Devic disease (Nozaki et al 2006) as well as multiple sclerosis (Bloom and Reder 2006).
  • Matrix metalloproteinase inhibitors including minocycline.
  • Methionine-enkephalin, intrathecal.
  • Minocycline deactivates microglia and possibly dendritic cells, monocytes, and T cells; may reduce antigen presentation and induce tolerance; and decreases inducible NO synthase, matrix metalloproteases, cyclooxygenases, and p38 mitogen-activated protein kinase (MAPK). In a small study, it dramatically reduced relapse frequency, and it may be additive with glatiramer acetate. However, it increases the rate of decline in amyotrophic lateral sclerosis, indicating it should not be used in multiple sclerosis until controlled trials are completed. Evaluation of doxycycline is in progress.
  • Myelin peptides, transdermally applied, are under study. (See failed MBP, above.)
  • Low-dose naltrexone, at 3 to 4.5 mg per day, improved several quality-of-life measures in controlled trials.
  • Opioid growth factor (Met5-enkephalin) inhibits experimental allergic encephalomyelitis.
  • Oxidized phospholipids (lecinoxoids, VB-201) are anti-inflammatory and inhibit experimental allergic encephalomyelitis.
  • Peroxisomal proliferator-activated receptor-gamma agonists (PPAR-gamma; oral agents for treating diabetes; also PPAR-alpha agonists, used for lowering cholesterol). Pioglitazone added to IFN-beta-1a had no clinical benefit, but reduced gray matter atrophy. Benefits and cautions should be evaluated in light of the interferon/statin interactions (below).
  • Statins are oral agents used to lower cholesterol. They also reduce inflammation in atherosclerotic plaques and possibly in multiple sclerosis (Neuhaus et al 2002). Statins inhibit experimental allergic encephalomyelitis, cause a Th1 to Th2 shift, reduce Th17 cells, may slow brain atrophy, and strengthen the blood-brain barrier. Synergy with natalizumab in this regard is unknown. Conversely, statins also increase matrix metalloprotease activity (Kieseier et al 2004), decrease coenzyme Q10 levels (possibly responsible for statin toxicity), and inhibit interferon signaling (Zamvil personal communication; Reder 2007).

Atorvastatin 80 mg versus placebo has modest benefit on MRI, but not exacerbations in clinically isolated syndromes (Waubant et al 2012) (STAyCIS). Statins alone appeared to reduce MRI lesions in several uncontrolled trials. However, in untreated patients with Gd-positive scans, the number of contrast-enhancing lesions falls at approximately the same rate, by 29% at 6 months (Zhao et al 2008). Other trials are in progress. (See statin and interferon combinations, below.)

  • Teriflunomide (Aubagio) is an immunosuppressant related to leflunomide that inhibits pyrimidine synthesis, mitochondrial dihydroorotate dehydrogenase, and calcium mobilization. It causes a Th2 shift. In relapsing multiple sclerosis versus placebo, it reduces MRI lesions by 60%, relapses by 30%, and progression by 30%. It is additive with IFN-beta therapy. Trials in clinically isolated syndromes and other forms of multiple sclerosis are in progress for this once-a-day oral med.
  • Testosterone is potentially neuroprotective in men. It induces BDNF and reduces delayed-type hypersensitivity immune responses. However, low serum testosterone levels correlate with more Gd+ MRI lesions in women (Tomassini et al 2005).
  • Vitamin A enhances regulatory T cell differentiation and potentiates IFN-beta signaling.
  • Vitamin D is sometimes anti-inflammatory and inhibits experimental allergic encephalomyelitis. High levels correlate with lower incidence of multiple sclerosis. In small trials, high-dose vitamin D2 had no MRI benefit. Trials with vitamin D3 suggest benefit on relapses and progression in multiple sclerosis. (See combination with interferon beta, below.) High-dose calcium and vitamin D can precipitate kidney stones.
  • Vitamin B12 (below, in combinations).

Other therapies and neurotrophic factors under study in multiple sclerosis. Neuroprotective and axonal-protective agents are the Holy Grail for many neurodegenerative diseases and would complement anti-inflammatory drugs in multiple sclerosis therapy. For instance, sodium- and calcium-channel blockers protect axons from cytokine-mediated degeneration (Kapoor et al 2003). Other therapies potentially treat multiple sclerosis symptoms.

Neurotrophic factors are produced by macrophages and T cells. They include brain-derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3, nerve growth factor, and leukemia inhibitory factor. IFN-gamma and TNF-alpha can inhibit stress responses and nitric acid excitotoxicity. IFN-beta induces nerve growth factor secretion in astrocytes and (acting through T cells) on endothelial cells. It stimulates growth of neurons, but may interfere with myelination in some CNS neurons. BDNF in T cells is increased in multiple sclerosis relapses by glatiramer therapy, by IFN-beta (in non-depressed patients) (Hamamcioglu and Reder 2007), by antidepressants (in depressed patients), and in mice who exercise--where it increases hippocampal cell proliferation and learning. Leukemia inhibitory factor, a member of the IL-6 superfamily, enhances oligodendrocyte survival and is induced by IFN-beta (Byskosh and Reder 1996). Some monoclonal IgM antibodies bind oligodendroglia and increase remyelination, glial-derived growth factor, and leukemia inhibitory factor. Erythropoietin is neurotrophic (below).

  • ACE inhibitors.
  • Adrenocorticotropic hormone and analogues. This cAMP inducer facilitates a Th1 to Th2 shift, increases glucocorticoid receptor function, increases uptake of toxic glutamate by astrocytes, and is neurotrophic.
  • AMPA receptor antagonists can be neuroprotective.
  • Angiotensin-converting enzyme (ACE) inhibitors could inhibit autoimmunity by reducing Th1 and Th17 function and increasing Treg function.
  • Anticholinergic agents (promote neurogenesis) inhibit Th1, Th17, and leukocyte migration and increase Th2.
  • Antidepressants such as fluoxetine induce BDNF and restore visual plasticity.
  • Antioxidants (vitamins E and C).
  • Aspirin inhibits innate immune responses, potentially important in progressive multiple sclerosis.
  • Brain-derived neurotrophic factor (BDNF) is induced by glatiramer and interferon beta. Delivery with bone marrow stems cells is under study.
  • Ca++ channel blockers. N-type voltage-dependent calcium channels allow pathological influx of Ca++ and are increased on demyelinated axons and activated microglia. Blockade of these channels in rat models is protective.
  • Caffeine, through CD73, activates adenosine receptors and inhibits experimental allergic encephalomyelitis, possibly by increasing adenosine, cAMP, type I interferons, and IL-10.
  • Calpain inhibitors block this calcium-dependent protease and protect axons in experimental allergic encephalomyelitis.
  • Cannabinoids are anti-inflammatory and possibly neuroprotective (delta9-tetracannabinol [Marinol]; Sativex). CB1 receptor activation reduces release of inflammatory cytokines, inhibits microglial activation to protect nigrostriatal dopaminergic neurons against MPTP toxicity, has psychotropic effects, reduces norepinephrine release from sympathetic nerves, and may thereby increase bone density. CB2 receptors increase progenitor and mature oligodendrocyte survival, and also neural stem cell survival, and are anti-inflammatory. Dexanabinol (a tetrahydrocannabinol derivative) may reduce excitotoxicity.
  • Circumin at high doses inhibits inflammation and, at low doses, promotes neural stem cell growth.
  • Chondroitin sulphate (CS) binds to trophic factors. Also, CS proteoglycans inhibit differentiation of oligo progenitor cells in culture.
  • Coenzyme Q10 enhances mitochondrial function (serum levels are reduced by statins).
  • Cranial nerve noninvasive neuromodulation (CN-NINM; electrotactile stimulation) stimulates the tongue during other exercises. Mechanisms are theorized to be related to deep brain and vagus nerve stimulation as in other neurologic diseases (U Wisconsin).
  • Cyclic adenosine monophosphate (cAMP) agonists (beta2-adrenergic agonists; prostaglandins and analogues such as misoprostol) and phosphodiesterase IV inhibitors (mesopram) are strongly anti-inflammatory. They aid regeneration of spinal axons (blocked by myelin associated glycoprotein, MAG) (Qiu et al 2002) and may be neuroprotective (PGE2). Rolipram inhibits Th1/Th17 cell responses, but increases contrast-enhancing MRI lesions in multiple sclerosis. Ibudilast, a phosphodiesterase inhibitor, had no effect on inflammation, but reduced brain atrophy and conversion from Gd-enhancing lesions to MRI T1 holes (Barkhof et al 2010). This may be from a direct inhibition of microglia. Prostaglandin E, a cAMP agonist, induces IL-10 in monocytes (Feng et al 2002b).
  • L-cycloserine prevents synthesis of C16-ceramide. It blocks experimental allergic encephalomyelitis and the production of iNOS and TNF.
  • Desferrioxamine. Iron chelation may reduce toxicity of oxygen radicals to myelin.
  • Dextromethorphan and quinidine to treat central neuropathic pain in multiple sclerosis.
  • Dextromethorphan decreases glutamate excitotoxicity and may be neuroprotective.
  • Dimethylfumarate (BG12) reduces proinflammatory cytokines and induces Nrf2, a potential neuroprotectant. In early trials, it reduced progression and multiple sclerosis relapses.
  • Eliprodil, a sigma opioid receptor ligand, promotes myelination in neuronal-oligodendrocyte cultures.
  • Erythropoietin is a neurotrophic factor that has had substantial benefit in experimental allergic encephalomyelitis (Genc et al 2004). It prevents axonal degeneration and can synergize with glucocorticoids (Diem et al 2004) and insulin-like growth factor-1 to prevent neuronal damage.
  • Flavonoids (luteolin, quercetin) are antioxidants found in green tea that suppress experimental allergic encephalomyelitis.
  • Food additives are under study, including green tea (epigallocatechin-3-gallate), cumin, and vitamins B3 and D.
  • Fumarate is used treat psoriasis. An analogue is dimethylfumarate (see above).
  • Glutamate antagonists (Riluzole). Glutamate reduction is highly protective in anoxic and traumatic white matter models.
  • Human endogenous retrovirus (HERV) blockade.
  • Idebenone is an antioxidant that improves mitochondrial respiration.
  • Immunoglobulins sometimes enhance oligodendrocyte repair (M Rodriquez).
  • Inosine raises uric acid, a peroxynitrite scavenger; urate is low in multiple sclerosis.
  • Intrathecal glucocorticoids (triamcinolone acetonide).
  • Lactam antibiotics increase glutamate transporter expression.
  • Neuroprotective effects of interferons and glatiramer are discussed above.
  • Insulin-like growth factor-1 (IGF-1) is required for the survival of oligodendrocytes and is increased in serum by IFN-beta therapy.
  • IL-6-agonists. IL-6-positive cells in multiple sclerosis lesions correlate with oligodendroglial preservation (Schonrock et al 2000). IFN-beta directly induces IL-6 in astrocytes. However, IL-17 induction by TGF-beta plus IL-6 is a potential danger.
  • Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, blocks high excitotoxic concentrations of glutamate and increases BDNF in the limbic cortex.
  • Mesenchymal stem cells (see stem cells).
  • Metformin, an anti-diabetic drug that activates AMP-activating protein kinase, is anti-inflammatory and inhibits experimental allergic encephalomyelitis.
  • Modafinil is neuroprotective in Parkinson models. It may slow accumulation of disability in multiple sclerosis (Bibani et al 2012), but the data conflict within the paper and the non-randomized retrospective analysis could be biased by a metabolic effect of fatigue itself.
  • Myelin-associated glycoprotein, MAG, oligo-myelin glycoprotein, Nogo, LINGO, and jagged/Notch inhibit axonal growth and are present in gliotic plaques. Interference with these proteins is a possible treatment for neurodegeneration.
  • Na+ channel blockers. Flecainide protects axons from nitric oxide and electrical activity. Microglia and macrophages express excessive numbers of Na-v1.6 channels in multiple sclerosis and experimental allergic encephalomyelitis. Phenytoin ameliorates inflammation in experimental allergic encephalomyelitis by 75% (Craner et al 2005); sudden withdrawal provokes attacks. Lamotrigine reduced deterioration in the 25-foot walk, but decreased gait and balance and caused cerebral atrophy.
  • Neural precursor cells (Neurospheres).
  • Neuregulin-1 determines whether axons are ensheathed by Schwann cells.
  • Nicotine inhibits immunity (Nouri-Shirazi and Guinet 2012). After peripheral leg injury, nicotine prevents macrophage infiltration through the blood-brain barrier into the hippocampus and prevents ensuing cognitive decline. A nicotine patch is a potential therapy to block inflammation and benefit cognition in multiple sclerosis.
  • Paroxetine (Prozac) inhibits microglial activation and oxidative stress in MPTP-induced nigrostriatal damage.
  • Phenytoin may act as a neuroprotectant but could have toxic effects if suddenly withdrawn.
  • Phosphodiesterase (see cyclic AMP).
  • Potassium K+ channel blockers. K2P5.1 channels are overexpressed in multiple sclerosis and in activated CD4 and CD8 cells. Kv1.3 potassium channel blockade inhibits human effector memory T cells. Knockout mice have milder experimental allergic encephalomyelitis, with low interferon-gamma and IL-17, and elevated IL-10.
  • Prostaglandins (PGE2) are cAMP agonists that inhibit experimental allergic encephalomyelitis and stop pain from trigeminal neuralgia in multiple sclerosis (Reder and Arnason 1995).
  • Remyelination induction: insulin-like growth factor, nerve growth factor, transforming growth factor-beta.
  • Resveratrol, from red wine, ameliorates experimental allergic encephalomyelitis through activation of the aryl hydrocarbon and estrogen receptors.
  • Riluzole, a glutamate blocker, is neuroprotective. It slowed cervical atrophy and T1 degeneration on MRI but had no clinical effect in primary progressive multiple sclerosis in a small study (Kalkers et al 2002).
  • Sildenafil (Viagra) promotes remyelination and prevents axonal loss in experimental allergic encephalomyelitis.
  • Sirolimus (rapamycin; immune suppression) and CCI-779, an ester of Sirolimus, blocks T cell proliferation. However, K-506/tacrolimus (which inhibits calcium-dependent T cell activation) and mycophenolate mofetil (a purine synthesis inhibitor) are potentially dangerous as they inhibit regeneration of pancreatic beta cells after a toxic insult (Nir et al 2007), and their safety on oligodendrocyte precursors must be studied.
  • Sodium channel blockade could preserve compromise axons by reducing sodium and calcium overload and depolarization.
  • Stem cells (Martino et al 2010). Hematopoietic stem cells from bone marrow are transplanted in a multi-step process. Preconditioning with cyclophosphamide and G-CSF mobilizes large numbers of CD34+ hematopoietic stem cells from bone marrow into the peripheral blood. This influx causes fewer Th17 cells and a Th2 shift, and these Th2 cells secrete neurotrophic factors. Cells are harvested. Then, ablative chemotherapy destroys remaining peripheral immune cells, but also causes significant brain atrophy. Some protocols deplete T cells with anti-thymocyte globulin or alemtuzumab. Importantly, alemtuzumab is effective on its own and could be responsible for some or all of the reported benefit. Reinfused stem cells migrate to the thymus and generate a new T cell repertoire. Recipients of allogeneic stem cell transplants still have ongoing intrathecal lymphocyte activation, demyelination, and neurodegeneration, even though inflammation is suppressed. Some feel this is a reasonable therapy for aggressive multiple sclerosis. Autoimmune disorders occasionally follow stem cell transplants.

After bone marrow transplants, 0.1% of the 15 million Purkinje neurons in the brain are from donor stem cells, possibly from fusion with brain cells. The brain of rats injected with 6-hydroxydopamine to destroy the substantia nigra becomes neurotrophic for tyrosine hydroxylase-positive neural stem cells (Nishino et al 1990). It is possible that neural and oligodendroglial stem cells would also be attracted to multiple sclerosis plaques. These cells can also be engineered to deliver neurotrophic factors such as BDNF.

Mesenchymal stem cells (non-hematopoietic; CD73, CD90, and CD105 positive) may be able to home to areas of brain inflammation and replace neurons and oligodendroglia. Mesenchymal cells reside in the perivascular zone as pericytes, but can be isolated from peripheral blood. They secrete an altered form of chemokine, CCL2, thus inhibiting migration of cells into inflammation. They have complicated effects in immune regulation, with less Th1 but more Th17 response, and less IL-10 secretion. Immune effects may predominate, although they can transdifferentiate into neuroectodermal cells. Intravenous administration is safe. They inhibit experimental allergic encephalomyelitis, and in a proof of concept study provided modest benefit on the optic nerve in secondary progressive multiple sclerosis. A large study is ongoing.

Olfactory ensheathing cells are differentiated glial cells that resemble Schwann cells. They integrate into astrocytic scars and can remyelinate axons. Embryonic or autologous peripheral nerve Schwann cells, oligodendrocyte precursor cells, and neural stem cells are possible therapies.

  • Venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, suppresses proinflammatory cytokines and experimental allergic encephalomyelitis.
  • Xaliproden, an agonist of 5-HT1A receptors and multiple kinases, is neuroprotective and ameliorates experimental allergic encephalomyelitis.
  • Zonisamide, which is used in epilepsy, induces glutathione in astroglia, potentially protecting against oxidative stress.

Less traditional treatments are under evaluation, eg, magnets and bee stings. The mechanism in bee stings is proposed to be from modification of immunity or through an excitatory neurotoxin. Surprisingly few multiple sclerosis patients have had anaphylactic reactions to bee stings, perhaps because of a Th1 immune bias in multiple sclerosis. However, no evidence of clinical benefit exists.

Potentially dangerous drugs include any that amplify inflammation and are described at the end of the Prevention section of this clinical summary.

Combinations of therapies. Many small studies have described the safety of drug combinations. Unfortunately, few were designed to show efficacy. Combinations directed against the early inflammatory phase of multiple sclerosis are common. IFN-beta is being tested in combination with cAMP agonists, lamotrigine, matrix metalloprotease inhibitors, minocycline, statins, and vitamins B12 and D. In progressive disease, therapy will require neuroregeneration and reduction of chronic macrophage-mediated inflammation--perhaps with drugs such as cAMP agonists (prostaglandins, beta-adrenergics, or phosphodiesterase inhibitors) (Feng et al 2002b), thalidomide, or minocycline.

  • Alemtuzumab is a potential induction therapy for subsequent interferon or glatiramer.
  • Beta2-adrenergic agonists and glucocorticoids have synergistic anti-inflammatory effects.

Combinations with interferon include the following:

  • In a group of 10 IFN-beta failures, combination with cyclophosphamide reduced relapses, progression, and MRI activity (Patti et al 2004).
  • Relapsing patients with disease activity despite intramuscular IFN-beta-1a were treated with oral placebo, methotrexate, intravenous methylprednisolone, or both for one year (ACT trial) (Cohen et al 2009). Although the steroids reduced neutralizing antibody titers to interferon, there were no clinical differences between groups.
  • Minocycline plus IFN-beta inhibits murine experimental allergic encephalomyelitis and attenuates neuronal death.
  • Mitoxantrone induction for 3 months followed by glatiramer had better MRI and clinical outcome than glatiramer alone.
  • Mitoxantrone induction for 6 months followed by IFN-beta had better clinical outcome than IFN-beta alone.
  • Natalizumab plus intramuscular IFN-beta-1a was more effective than interferon alone, with 52% reduction in relapses and 24% less progression.
  • Phosphodiesterase inhibitors and interferon synergize in blocking the production of inflammatory cytokines.
  • Rituximab, added to ongoing therapy in patients who had some activity on interferon or glatiramer (numbers not clear), reduced Gd-enhancing lesions by 88%.
  • Statin combination with interferon requires caution. In a randomized, double-blind study, there was an excess of clinical or MRI worsening (1/10 on interferon alone vs. 10/15 on the combination) when patients who had been stable on thrice-weekly IFN-beta-1a were placed on high-dose atorvastatin (Birnbaum et al 2008). Similar trends were found in another study (Sorensen et al 2011) (SIMCOMBIN). Others state that statins do not affect clinical or molecular responses to intramuscular IFN-beta-1a (Rudick et al 2009). However, statins block interferon signaling in vitro (Dhawan et al 2007; Feng et al 2012b) and in vivo (Feng et al 2012b).
  • Teriflunomide added to ongoing IFN-beta therapy for a year reduces enhancing MRI lesions by over 80% and tends to reduce relapse rate.
  • Vitamin B12 methylates arginine on the STAT1 transcription factor and enhances IFN-beta signaling. The two synergistically reduce inflammation and increase oligodendroglia maturation in mice (Mastronardi et al 2004), but the equivalent human dose is 15 million units of interferon and 1 million micrograms vitamin B12. Nitrosocobalmin, which releases nitric oxide, synergizes 200-fold with IFN-beta in cancer therapy. The combination has enhanced antiviral effects and could potentiate IFN-beta in multiple sclerosis.
  • Vitamin D3 and murine interferon-beta synergize in protection against experimental allergic encephalomyelitis. In multiple sclerosis, 20,000 units of vitamin D3 per week added on to IFN-beta-1b reduced Gd-enhancing lesions and tended to reduce disability (Soilu-Hanninen et al 2012).

Combinations with glatiramer include the following:

  • When compared to glatiramer alone, glatiramer plus albuterol, a beta2-adrenergic agonist, increased neurologic function and time to next exacerbation and reduced secretion of IFN-gamma (Khoury et al 2010). However, 40% of the patients did not complete the study and IL-13, a Th2 cytokine, was decreased.
  • Weekly IFN-beta-1a plus glatiramer had no additive effect (CombiRx, 2012 AAN).
  • Mitoxantrone induction followed by glatiramer had better MRI outcome than glatiramer alone.

Critical issues in multiple sclerosis therapy:

  • Treatments that are more than 33% effective are being developed. Early treatment with current approved drugs elevates the response to 50% or 60%. This suboptimal “plateau” suggests that a second agent may be needed, perhaps one not directed against T cells.
  • Treating acute inflammation (relapses) versus chronic neurodegeneration (progression). There are no effective treatments for progressive forms at this time.
  • Switching therapy. Comparative trials without a “remain-on-drug” group can’t be evaluated because attack frequency tends to regress to the mean. Secondly, because multiple sclerosis is highly variable, a drug could reduce exacerbations in all multiple sclerosis patients, but some “partial responders” would still appear to be non-responders. It is also possible that some patients are true “non-responders.” (See figures “Response to Therapy A” and “Response to Therapy B” in Interferon immunology, above.)
  • Criteria for switching in increasing order of importance include same rate or more MRI lesions < relapses < progression < cognitive loss. Once progression starts, however, there are no good treatments.
  • Differentiating between subtypes of multiple sclerosis.
  • Biomarkers. MRI (Gd+, T2, and T1 lesions, and newer techniques), CSF immunoglobulins, antigens, and glial and neuronal products, and biological markers in the blood.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors