Medicine

Corticosteroids are used in all types of disease. In general, we use single short- term intravenous regimens for acute attacks. In RR patients with many attacks, multiple attacks with accumulating disability (RR-P) or chronic progressive disease, we use maintenance therapy (periodic boosters), either with corticosteroids, immunosuppressive therapy, or combinations thereof. We do not use long term oral steroids, alternate day steroid therapy, or oral steroid tapers. Patients who are steroid dependent are generally tapered off their steroids, often being treated instead with methylprednisolone boosters and/or immunosuppressive drugs.

Single Treatment

For acute attacks with prominent findings and significant functional impairment, methylprednisolone is given intravenously. This can be given either as inpatient or outpatient therapy, generally for 5 days, although occasionally we have used shorter, 3-day courses, or longer 7-day courses. Oral steroids are occasionally given for acute attacks in patients with relapsing-remitting or relapsing-remitting progressive disease.

Adverse effects of Single Treatment:

Repeated Treatments/Pulse Therapy 

In patients with CP disease or RR-P disease or breakthrough disease, pulsed intravenous methylprednisolone may be given. We initiate treatment with 5 days of methylprednisolone(1 g/day) either as inpatient or outpatient therapy followed by single 1 gram intravenous monthly boosters given on an outpatient basis. We currently give this over a 3 year period. If additional steroids are required greater than 3 times per year (especially in patients with RR-P disease), consideration is given to adding immunosuppressive therapy.

Adverse Effects of Pulse therapy 

Reconstitution and Infusion 

Methylprednisolone (Solumedrol): One gram of methylprednisolone reconstituted in 16 cc of sterile water and add to 150cc of 0.9% NS. Infuse over 1.5 hours.

Partners MS Center recommended monitoring for frequent or pulse methylprednisolone:

1. Adequate calcium (1200-1500mg/day), and vitamin D (400-800 units/day).(Two-three caltrate tabs daily).

2.Yearly bone density

3.Vitamin D (25-OH) level every 6 months. Supplement if below 30ng/ml

References [1-6]

Several studies have demonstrated some benefit of IVIG in relapsing-remitting MS, which was supported in a meta-analysis by Sorensen et al., EJN, 2002. However use of IVIG has been supplanted by the availability of FDA-approved disease modifying medications (Beta-interferons and glatiramer acetate) for the treatment of relapsing-remitting multiple sclerosis. A randomized placebo-controlled trial of monthly IVIG in RR MS was reported by Fazekas et al. in the Lancet in 1997. This placebo-controlled trial involved 150 patients over 2 years. In the placebo group there were 116 relapses compared to 62 in the IVIG group. 36% of the placebo group, were relapse free compared to 53% of the IVIG group with a significant p value of 0.03. Only 3 IVIG patients (4%) experienced side effects including cutaneous reactions and depression, although these were not unequivocally related to the IVIG. Therefore, IVIG may be indicated in only a small subset of patients.

A retrospective analysis describing the use of IVIG post-partum for the prevention of relapses, found some benefit when IVIG was administered both, during pregnancy and postpartum, as well as during the postpartum period alone (Achiron et al. J. Neurol 2004). However, further randomized double blind studies are needed to confirm these results.

Adverse effects:

Potential side effects of IVIG include infusion reactions, cutaneous reactions (alopecia, eczema), thrombotic disease, aseptic meningitis, increased susceptibility to infection, renal dysfunction and rarely renal failure.

Dosing regimen:

Our current dose regimen is 1000mg/Kg monthly for up to two years.

Partners MS Center Practice Guidelines for IVIG administration:

•    Baseline CBC+diff within first 3 months (rare cases of neutropenia)
•    Baseline – Check IgA, prior to first dosing (anaphylactic reactions)
•    Avoid sucrose preparations

References [1-6]

1. Fazekas, F., F. Deisenhammer, S. Strasser-Fuchs, G. Nahler, and B. Mamoli. (1997) Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet, 349(9052), 589-93.
2. Sorensen, P.S. (2003) Treatment of multiple sclerosis with intravenous immunoglobulin: review of clinical trials. Neurol Sci, 24 Suppl 4, S227-30.
3. Sorensen, P.S., F. Fazekas, and M. Lee. (2002) Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol, 9(6), 557-63.
4. Fazekas, F., P.S. Sorensen, M. Filippi, S. Ropele, X. Lin, H.W. Koelmel, O. Fernandez, C. Pozzilli, P. O’Connor, M.M. Enriquez, and O.R. Hommes. (2005) MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler, 11(4), 433-40.
5. Hommes, O.R., P.S. Sorensen, F. Fazekas, M.M. Enriquez, H.W. Koelmel, O. Fernandez, C. Pozzilli, and P. O’Connor. (2004) Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet, 364(9440), 1149-56.
6. Achiron, A., E. Pras, R. Gilad, I. Ziv, M. Mandel, C.R. Gordon, S. Noy, I. Sarova-Pinhas, and E. Melamed. (1992) Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting multiple sclerosis. Arch Neurol, 49(12), 1233-6.

Methotrexate is an immunosuppressive agent approved for use in rheumatoid arthritis. A published report by Goodkin et al, Ann Neurology, 1995, suggests that methotrexate may be efficacious in helping hand function in chronic progressive disease at a dose of 7.5 mg per week orally. Methotrexate has been shown to be effective when used in combination with Beta-interferon in patients experiencing breakthrough relapses (Calabrese et al. Neurology 2002). We currently use methotrexate primarily for RR-P patients, although we have also used the drug in RR patients with frequent attacks and in active CP patients. Our protocol involves the use of 20 mg subcutaneously once per week or 7.5mg up to 20mg per week orally. As yet, we have no formal data that establishes the efficacy of this regimen in MS. Nonetheless, we view it as a treatment option, especially in younger patients who do not wish the more severe toxicity associated with cyclophosphamide or older slowly progressive patients for whom cyclophosphamide may not be of benefit. It is also easier to administer. A recent open-label study has demonstrated that addition of methotrexate to beta-interferons may be beneficial in patients experiencing relapses while on beta-interferon alone (Calabrese et al., Neurology 2002).

Adverse Effects:

Methotrexate should not be used in patients with total pre-treatment WBC counts <3500, or in patients with renal failure (creatinine clearance <60ml/min) or pre-existing hepatotoxicity. Occasional adverse effects include nausea, vomiting and diarrhea, headaches, dizziness, mouth sores, skin rash, bruising, decreased healing ability, joint aches, hair thinning and menstrual irregularities. More serious side affects include hepatotoxicity, allergic pneumonitis, pancytopenia, birth defects and infertility. Methotrexate is pregnancy category X.

Partners MS Center Guidelines for Methotrexate Administration:

1. Prior to initiating treatment, we obtain blood work (consisting of CBC with differential and platelet count, PT, PTT, liver and renal function tests), urinalysis and a CXR.
2. Once treatment is started, we monitor for toxicity with CBC’s and liver function tests monthly and renal function is tested at least every 3 months. Liver biopsy may be performed after 2 years of treatment, but this is not mandatory.
3. There are also several potential drug interactions and the following drugs should be avoided:
   • a. alcohol which increases the risk of hepatotoxicity
   • b. sulfa containing antibiotics which have been associated with several cases of megaloblastic anemia through folic acid inhibition
   • c. nonsteroidal anti-inflammatory agents which may decrease the glomerular filtration rate or compete with methotrexate for renal tubular excretion
   • d. salicylates, sulfonamides (antibacterial, hypoglycemic, diuretics), and phenylbutazone which increase toxicity by displacing methotrexate from serum albumin
   • e. anticoagulants
4. Administer 20mg subcutaneously weekly. Most patients can be taught to self-administer or have their spouse or a visiting nurse perform the injection. Alternately, 7.5mg up to 20mg orally weekly can be given.
5. Co-administration with folic acid 1mg/day has been reported (Morgan et al, Arthritis Rheum, 1990), to decrease adverse effects of methotrexate without altering efficacy.

References:

1. Goodkin, D.E., R.A. Rudick, S. VanderBrug Medendorp, M.M. Daughtry, K.M. Schwetz, J. Fischer, and C. Van Dyke. (1995) Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol, 37(1), 30-40.
2. Calabresi, P.A., J.L. Wilterdink, J.M. Rogg, P. Mills, A. Webb, and K.A. Whartenby. (2002) An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. Neurology, 58(2), 314-7.
3. Goodkin, D.E., R.A. Rudick, S. VanderBrug Medendorp, M.M. Daughtry, and C. Van Dyke. (1996) Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology, 47(5), 1153-7.
4. Morgan, S.L., J.E. Baggott, W.H. Vaughn, P.K. Young, J.V. Austin, C.L. Krumdieck, and G.S. Alarcon. (1990) The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum, 33(1), 9-18.

NOVANTRONE(R) (Mitoxantrone for injection concentrate) was recommended to slow the worsening of neurologic disability and to reduce the relapse rate in patients with clinically worsening forms of relapsing-remitting and secondary progressive multiple sclerosis (MS), by the U.S. Food and Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Panel. Clinical results presented by Immunex demonstrate that NOVANTRONE had a statistically significant impact on reduction of relapse rate and delay in disability progression in these patients. In a Phase III trial, there was a 65% reduction in annual relapse rate with NOVANTRONE compared to placebo and a 64% reduction in 1-point Expanded Disability Status Scale (EDSS) deterioration confirmed at 6 months. Positive magnetic resonance imaging (MRI) data were also presented that corroborate these clinical findings. NOVANTRONE, at a dose of 12 mg/m(2), was administered by short IV infusion once every three months for two years.

Adverse Effects:

In the Phase III study, treatment with NOVANTRONE resulted in generally manageable side effects that were primarily mild to moderate. During the two-year trial, the most frequent side effects reported by patients treated in the 12 mg/m(2) arm were nausea, alopecia (hair loss), upper respiratory tract infection, urinary tract infection, menstrual disorder, and transient neutropenia (a reduced number of white blood cells). Although 2% of patients experienced a decrease in left ventricular ejection fraction <50%, no congestive heart failure was reported. Because of the potential for functional cardiac changes, Immunex has recommended that MS patients receiving NOVANTRONE should have cardiac monitoring prior to each infusion and that treatment should be discontinued at a cumulative dose of 140 mg/m(2). Longterm follow-up studies have demonstrated that a small proportion of patients treated with Mitoxantrone may be at risk for developing secondary leukemia or lymphoma. Mitoxantrone causes a bluish discoloration of urine. Mitoxantrone is pregnancy category D.Partners MS Center Practice Guidelines for Administration of Mitoxantrone: 

• Baseline and every 3-month 2D echocardiograms must be checked prior to the administration of each 3-month dose.
• Baseline CBC, PT, PTT, Chem-20
• Baseline and yearly MRI
• CBC with differential before infusion
• Premedication: 24mg Zofran IV, 10mg oral Compazine.
• If WBC falls below 1.5, the dose of Mitoxantrone is held.
• Annual cardiac echos indefinitely (per FDA guidelines)
• Annual CBC with diff, even after Mitoxantrone discontinued
• If possible, one should consider prior vaccination with influenza, H1N1, zostavax varicella vaccine 1 month prior to beginning immunosuppressive infusion.
   

References:

[1-9]

1. Ridge, S.C., A.E. Sloboda, R.A. McReynolds, S. Levine, A.L. Oronsky, and S.S. Kerwar. (1985) Suppression of experimental allergic encephalomyelitis by mitoxantrone. Clin Immunol Immunopathol, 35(1), 35-42.
2. Noseworthy, J.H., M.B. Hopkins, M.K. Vandervoort, S.J. Karlik, D.H. Lee, M. Penman, et al. (1993) An open-trial evaluation of mitoxantrone in the treatment of progressive MS. Neurology, 43(7), 1401-6.
3. Bastianello, S., C. Pozzilli, F. D’Andrea, E. Millefiorini, M. Trojano, S. Morino, et al. (1994) A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci, 21(3), 266-70.
4. Millefiorini, E., C. Gasperini, C. Pozzilli, F. D’Andrea, S. Bastianello, M. Trojano, et al. (1997) Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol, 244(3), 153-9.
5. van de Wyngaert, F.A., C. Beguin, M.B. D’Hooghe, G. Dooms, F. Lissoir, H. Carton, et al. (2001) A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurol Belg, 101(4), 210-6.
6. Hartung, H.P., R. Gonsette, N. Konig, H. Kwiecinski, A. Guseo, S.P. Morrissey, et al. (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet, 360(9350), 2018-25.
7. Krapf, H., S.P. Morrissey, O. Zenker, T. Zwingers, R. Gonsette, and H.P. Hartung. (2005) Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology, 65(5), 690-5.
8. Nadeau, S.E. (2006) Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology, 66(9), 1457-8; author reply 1457-8.
9. Brassat, D., C. Recher, E. Waubant, E. Le Page, F. Rigal-Huguet, G. Laurent, et al. (2002) Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology, 59(6), 954-5.

Natalizumab is an FDA-approved treatment for relapsing forms of multiple sclerosis. Tysabri (natalizumab) is a humanized monoclonal antibody directed against alpha-4-integrin, an adhesion molecule present on inflammatory cells including T cells and B cells, and effectively blocks the transmigration of these cells into tissues, including the central nervous system (CNS). Tysabri is administered by monthly intravenous infusions.

Tysabri was initially approved for the treatment of relapsing remitting MS by the FDA in 2004, however was withdrawn from the market in February 2005, after the post-marketing detection of two cases of progressive multifocal leukoencephalopathy (PML), a potentially fatal viral disease affecting the CNS. Subsequent to withdrawal, a 3rd case of PML was detected in a Crohn’s patient postmortem. Tysabri was re-approved for the treatment of relapsing-forms of multiple sclerosis in June 2006, under the guidelines of the TOUCH prescribing program in which, prescribing physicians and facilities undergo a specialized training, and patients receiving Tysabri are registered and followed closely. Tysabri is administered only as monotherapy, and the use of concomitant immunosuppressive drugs with the exception of steroids is contraindicated. Two new cases of PML were identified in August 2008. Several new cases have since been identified, bringing the second post-marketing total of PML cases to 13 (August 2009). The estimated risk of PML is still approximately 1/1000.

Tysabri has been shown to be effective in reducing relapse rate by 67% when used as monotherapy (AFFIRM trial), and by 56% in patients who were treated with dual Avonex/Tysabri therapy (SENTINEL trial). Tysabri effectively suppressed new lesion formation by MRI in both studies, and was effective in slowing the accumulation of disability, by 42% in the AFFIRM study and 24% in the SENTINEL trial. Tysabri is classified as pregnancy category C.

Side effects:

Common:

1. increased risk of infections — UTI, URTi, pneumonia, GI infections, herpes infections
2. Infusion reactions including anaphyaxis or anaphylactoid reactions, headache, dizziness, fatigue, rigors, urticaria, pruritis
3. Development of neutralizing antibodies to Natalizumab
4. Cholelithiasis
5. Arthralgias, extremity pain
6. Liver damage

Rare:

1. Progressive multifocal leukoencephalopathy: risk based on available data is 1:1000
2. Cryptosporidial gastroenteritis was observed in 1 patient
3. Other opportunitistic infections rarely observed
4. Non-bacterial meningitis, herpes encephalitis
5. Melanoma

Partners MS Center Practice Guidelines for administration of Natalizumab (Tysabri):

In compliance with the TOUCH prescribing program, we have developed the following guidelines for use of Tysabri.

• LFTs at baseline and then every 6 months
• MRI at baseline every 6 months
• Regarding infusion premedication for allergy – Hold unless symptoms; if mild symptoms develop (i.e. itching), add Claritin/Benadryl on a regular basis at that time
• Baseline dermatology evaluation and subsequently annual exam (group decided not to wait for Tysabri start pending initial dermatology consult but consult should be arranged and done within reasonable time frame)
• Ophthalmology screening exam (then no need for annual unless area identified that requires monitoring for conversion to ocular melanoma)
• At two years strongly consider lumbar puncture to assay for the presence of JC Virus.
• If possible, one should consider prior vaccination with influenza, H1N1, zostavax varicella vaccine 1 month prior to beginning immunosuppressive infusion.

References:

[1-8]

1. Yednock, T.A., C. Cannon, L.C. Fritz, F. Sanchez-Madrid, L. Steinman, and N. Karin. (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature, 356(6364), 63-6.
2. Adelman, B., A. Sandrock, and M.A. Panzara. (2005) Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med, 353(4), 432-3.
3. Berger, J.R. and I.J. Koralnik. (2005) Progressive multifocal leukoencephalopathy and natalizumab–unforeseen consequences. N Engl J Med, 353(4), 414-6.
4. Kleinschmidt-DeMasters, B.K. and K.L. Tyler. (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med, 353(4), 369-74.
5. Langer-Gould, A., S.W. Atlas, A.J. Green, A.W. Bollen, and D. Pelletier. (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med, 353(4), 375-81.
6. Van Assche, G., M. Van Ranst, R. Sciot, B. Dubois, S. Vermeire, M. Noman, J. Verbeeck, K. Geboes, W. Robberecht, and P. Rutgeerts. (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med, 353(4), 362-8.
7. Polman, C.H., P.W. O’Connor, E. Havrdova, M. Hutchinson, L. Kappos, D.H. Miller, J.T. Phillips, F.D. Lublin, G. Giovannoni, A. Wajgt, M. Toal, F. Lynn, M.A. Panzara, and A.W. Sandrock. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med, 354(9), 899-910.
8. Rudick, R.A., W.H. Stuart, P.A. Calabresi, C. Confavreux, S.L. Galetta, E.W. Radue, F.D. Lublin, B. Weinstock-Guttman, D.R. Wynn, F. Lynn, M.A. Panzara, and A.W. Sandrock. (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med, 354(9), 911-23.
9. Mullen, J.T., T.K. Vartanian, and M.B. Atkins, Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med, 2008. 358(6): p. 647-8.

Rituximab is a chimeric monoclonal antibody directed against CD20 receptors of B-lymphocytes. Blockade of this CD20 receptor causes antibody dependent cellular cytotoxicity and complement dependent tumor cell lysis. Rituximab was initially approved for the treatment of CD20 positive lymphomas. However autoimmune disorders are mediated at least in part by B-cells, and elimination of autoreactive B-cell clones is a rationale for use of Rituximab in these diseases. Rituximab is now approved for use in patients with moderate to severe rheumatoid arthritis with inadequate reponse to other therapies.

Use of Rituximab in multiple sclerosis is off-label. Ongoing phase II/III studies are examining the role of Rituximab in relapsing remitting and primary progressive multiple sclerosis. Rituximab has also been studied in a small group of patients with neuromyelitis optica (NMO or Devic’s disease) (Cree, Neurology 2005) and larger studies in this area are now ongoing.

Side effects and adverse reactions:

Side effects reported in patients treated with Rituximab:

1. Gastrointestinal System: nausea, vomiting. Rare — reactivation of hepatitis B infection.
2. Central and Peripheral nervous system: headache, fever, chills, dizziness
3. Hematologic: leucopenia, thrombocytopenia, neutropenia
4. Cardiovascular: hypotension, arrhthmyias
5. Respiratory system: cough, rhinitis, dyspnea, bronchospasm
6. Metabolic: tumor lysis syndrome, severe mucocutaneous reactions
7. Renal: Acute renal failure
8. Infection: Increased susceptibility to common infections; two cases of progressive multifocal leukoencephalopathy have recently been reported in lupus patients treated with Rituximab.
9. Severe infusion reactions have been described in patients treated with Rituximab for malignancies.
10. Pregnancy category C.

Partners MS Center Practice Guidelines for Rituximab Infusion:

Rituximab is administered at 1000mg intravenously once every 2 weeks for a total of two doses, which results in a suppression of circulating B cells (CD19, CD20 cell counts) for 6-9 months. Rituximab 1000mg iv is typically infused over 4-5 hours.

Suggested medication monitoring

• Baseline CBC with diff, CD19 and CD20 count (particularly for re-treatment)
• CBC with differential and CD19, CD20 counts q3 months
• If CD19/20 counts remain low at 9 months, consideration should still be given to retreatment
• Premedicate with Benadryl (50mg) IV and Tylenol (1g), methylprednisolone 1 gram.
• MRI brain at baseline and every 6 months
• If possible, one should consider prior vaccination with influenza, H1N1, zostavax varicella vaccine 1 month prior to beginning immunosuppressive infusion.

References:

[1-5]

• Cross, A.H., J.L. Stark, J. Lauber, M.J. Ramsbottom, and J.A. Lyons. (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol, 180(1-2), 63-70.
• Monson, N.L., P.D. Cravens, E.M. Frohman, K. Hawker, and M.K. Racke. (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol, 62(2), 258-64.
• Petereit, H.F. and A. Rubbert. (2005) Effective suppression of cerebrospinal fluid B cells by rituximab and cyclophosphamide in progressive multiple sclerosis. Arch Neurol, 62(10), 1641-2; author reply 1642.
• Stuve, O., S. Cepok, B. Elias, A. Saleh, H.P. Hartung, B. Hemmer, et al. (2005) Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol, 62(10), 1620-3.
• Cree, B.A., S. Lamb, K. Morgan, A. Chen, E. Waubant, and C. Genain. (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology, 64(7), 1270-2.

Daclizumab (Zinbryta) was approved by the FDA in May 2016 as a new medication for the treatment of relapsing remitting MS.  Originally developed as a prophylactic agent against solid organ allograft rejection, this humanized monoclonal antibody selectively binds to the high-affinity interleukin-2 receptor subunit (CD25), which is expressed at abnormally high levels on T cells in patients with MS.

How effective is it?

Subcutaneous daclizumab therapy led to a 50% or more reduction in annual MS disease relapse and MRI activity compared to placebo or interferon beta in clinical trials.

How is it administered?

The drug is given by self-administered subcutaneous injection once a month.

Which patients should be considered?

Daclizumab should generally be used only in patients who have had an inadequate response to two or more MS drugs because daclizumab has serious safety risks, including liver injury and immune conditions.

What are the risks associated with daclizumab?

Hepatic Injury

The new label contains a boxed warning, cautioning that drug can cause severe, potentially fatal, liver injury. Health care professionals should check a patient’s liver function prior to starting daclizumab, and continue to check monthly before each dose, and for up to six months after the last dose.

Daclizumab can cause life-threatening severe hepatic injury, including liver failure and autoimmune hepatitis. In clinical trials, serum transaminase elevations occurred during treatment and up to 4 months after the last dose of daclizumab. Serious events, including acute hepatic failure and hepatitis including autoimmune hepatitis, were observed in 1% of patients.

Immune mediated disorders

Immune mediated disorders including skin reactions, lymphadenopathy, and noninfectious colitis can occur in patients treated with daclizumab. Overall, in clinical trials, serious immune mediated conditions were observed in 5% of patients.

Skin Reactions: Occurred in 18% of daclizumab treated patients compared to 13% of placebo patients. The most common skin reactions were dermatitis and eczema

Lymphadenopathy: In a controlled trial 6% of daclizumab treated patients developed lymphadenopathy compared to 1% of Avonex treated patients

Noninfectious colitis: An increased incidence of serious colitis (< 1%) was reported in patients treated with daclizumab compared with placebo and Avonex in clinical trials

The most common adverse reactions reported by patients receiving daclizumab in the clinical trial that compared it to Avonex include cold symptoms (nasopharyngitis), upper respiratory tract infection, rash, influenza, dermatitis, throat (oropharyngeal) pain, eczema, and enlargement of lymph nodes.

The most common adverse reactions reported by patients receiving daclizumab when compared to placebo were depression, rash, and increased alanine aminotransferase

Mycophenolate mofetil (MMF) is a selective inhibitor of inosine-5’-monophosphate dehydrogenase type II, the enzyme responsible for the synthesis of the purine nucleotide guanine. It is cytostatic for T cells, B cells and macrophages, and may also affect inflammatory cell migration. MMF is administered orally. Over the last 5 years, there have been several reports of the use of MMF as a primary or secondary therapeutic agent in a variety of autoimmune conditions such as lupus, psoriasis, hemolytic anemia and Crohn’s disease as well as neurological disorders including chronic inflammatory demyelinating polyneuropathy and polymyositis.

Several open label studies have demonstrated that MMF is well tolerated, and may be effective in suppressing relapses and new gadolinium lesion formation in patients with multiple sclerosis.

Side effects and adverse reactions:

Common:

1. diarrhea
2. nausea, abdominal pain
3. insomnia, dizziness
4. increased susceptibility to infections
5. leucopenia
6. increased liver function tests

Rare:

1. increased risk of lymphoproliferative malignancies (lymphoma) – 0.4-1% incidence in controlled trials of renal, hepatic and cardiac transplant patients treated with other immunosuppressive agents.  (The risk of lymphoma in the general population is approximately 0.05%)
2. fetal malformations – Cellcept is contraindicated in pregnant women
3. neutropenia
4. GI bleeding
5. Herpes virus infections

Cellcept dosing regimen:

1. Baseline CBC with differential, LFT, SMA-7
2. We use escalating oral dosing depending on tolerability:
3.      Start at 250mg bid for 1 week
4.      Then 500mg bid for 1 week

iii.     Then 750mg bid for 1 week

1.      Then 1000mg bid for 1 week
2. Check CBC with differential, LFT, SMA-7 weekly for the first month, twice monthly for months 2-3, and then once a month.

References:

[1-3]

1. Ahrens, N., A. Salama, and J. Haas. (2001) Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurol, 248(8), 713-4.
2. Frohman, E.M., K. Brannon, M.K. Racke, and K. Hawker. (2004) Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol, 27(2), 80-3.
3. Vermersch, P., T. Stojkovic, and J. de Seze. (2005) Mycophenolate mofetil and neurological diseases. Lupus, 14 Suppl 1, s42-5.

Overview:

Fingolimod is Sphingosine-1-Phosphate (S1P) receptor modulator.  The Sphingosine 1-phosphate receptors  (type 1) are located on T and B cells in the lymph node and promotes lymphocyte egress from lymphoid organs.  Fingolimod induces internalization of this G-protein coupled receptor. This correlates with inhibition of lymphocyte egress and results in a 20-30% reduction in peripheral lymphocyte counts due to sequestration of lymphocytes in lymphoid tissues. 

FREEDOMS study: This studied two doses of Fingolimod compared to placebo for a period of 24 months. Fingolimod significantly reduced the annualized relapse rate to 0.18 in the patients receiving 0.5 mg qd and to 0.16 in the patients receiving 1.25 mg qd as opposed to 0.40 in placebo group. Both doses of Fingolimod are found to be effective in reducing the risk of disability progression over 24 months.

TRANSFORMS study: TRANSFORMS was a comparative study between IFN-beta 1a and Fingolimod oral in the patients of RRMS for a 12-month period. Fingolimod significantly reduced the annualized relapse rate to 0.16 and 0.2 in the patients receiving 0.5 mg and 1.25 mg per day as opposed to 0.33 in the IFN-beta-1a arm for the period of 12 months. A non-significant trend was found between Fingolimod and IFN-beta 1a regarding disability progression at the 0.5mg p=0.06.

Fingolimod effectively suppressed new lesion formation by MRI in both the studies.  One fatal varicella and one fatal herpes infection were seen in the 1.25mg fingolimod group in association with high dose steroid use.

Side Effects:

• Most common adverse events during first dose:

o   Cardiovascular Events- Transient Bradycardia (4%)

o   Atrio-ventricular Block (rare)

o   Transient elevations in Blood Pressure

• Adverse events (general):

o   Headache (25% vs. 23% in placebo)

o   Diarrhea (12% vs. 7% in placebo)

o   Back pain (12% vs. 7%)

o   Mild to moderate Infections including Nasopharyngitis, Influenza

o   Lower Respiratory Tract Infections

o   Shortness of breath (5%)

o   Macular edema (0.4% at the 0.5mg dose vs. 0.1% placebo). There is an increased risk of macular edema in patients with a history of uveitis or diabetes.

o   Increased ALT levels equal to or greater than 3 times the normal level (8%)

o   Lymphopenia and leukopenia

Administration Guidelines:

• Fingolimod is approved for relapsing forms of MS at a dose of 0.5mg orally daily

Prior to initiation in all patients:

• Perform a baseline MRI within 3 months prior to starting
• Obtain baseline CBC with differential, LFT’s
• Ophthalmologic exam to establish a baseline.  Caution is patients with diabetes or a history of uveitis.
• EKG with specific attention to PR interval
• Document history of chicken pox  or varicella vaccination.  If neither obtain VZV titer.  Antibody negative patients should receive VZV vaccination, with a 1-month delay to therapy.
• Avoid live attenuated vaccines.

During first dose

• 6-hour observation period with pulse and BP prior to dosing, and pulse hourly.  Intravenous access should be obtained in case atropine is needed for symptomatic bradycardia.
• Observation should be repeated if patients miss more than 2 weeks of Gilenya.

Follow-up monitoring:

• Ophthalmologic exam at 3 months
• LFTs and CBC with differential every 6 months
• Avoid live attenuated vaccines
• Progessive multiple leukoencephalopathy (PML) has been reported in fingolimod treated patients.  Other opportunistic infections such as Cryptococcus have been reported.  As such, we recommend:-          CBC with differential, LFT, JC virus, VZV IgGIf patient is JC negative: Repeat CBC (diff) and LFT every 6 month.  Repeat JCV annually, advise patients if seroconversion occurs.If patient is JC positive:-          Repeat CBC (diff) every 6 month. If an absolute lymphocyte count of < 200 is obtained consider dosing interruption. If persistent low lymphocyte after 6 month consider fingolimod discontinuation.
• –          MRI brain at least once per year
• JC virus:
• Baseline lab work prior to starting fingolimod:

Pregnancy Category C:

• There are no adequate and well-controlled studies in pregnant women. Animal studies demonstrated fetal toxicity. Women taking this medication should practice adequate birth control.
• Fingolimod should be stopped for at least 2 months prior to conceiving.

References:

1. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med;362:387-401.
2. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med;362:402-415.
3. Francis G et al, Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Multiple Sclerosis Journal, 2014, Vol. 20(4) 471 –480.
4. Eric M. Williamson and Joseph R. Berger. Infection Risk in Patients on Multiple Sclerosis Therapeutics. CNS Drugs (2015) 29:229–244.
5. Franz Fazekas. Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group.Wien Med Wochenschr (2012) 162:354–366.

Aubagio (teriflunomide) is a once a day oral pill that was approved by the FDA September 12, 2012 for use in relapsing forms of multiple sclerosis.  It is a reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis for DNA replication.  As a result, it reduces T and B cell activation, proliferation, and function.   In a phase III trial, TEMSO, compared to placebo the higher dose of Aubagio (14mg) reduced relapse rate 31%, 3-month disability progression 30%, and total MRI lesion volume 67%.  Patients taking this drug were potentially more susceptible to hair loss (13% vs 3% in placebo), diarrhea (18% vs. 9% in placebo) and nausea (14% vs. 7% placebo) and mild liver function test abnormalities (57% vs. 36% placebo).  Serious effects on the fetus have been seen with a drug similar to Aubagio, leflunomide, which might apply to Aubagio as well.  For this reason the FDA has recommended that men or women do not to try to conceive a child within two years of taking Aubagio unless a charcoal or cholestyramine wash out procedure is performed.

Suggested medication monitoring

• A PPD should be planted to exclude tuberculosis prior to starting this drug.

• A CBC and LFT’s should be checked prior to starting teriflunomide and  then monitored monthly for six months.  For patients at our center, we also enroll them in the CLIMB study.

• Patients (both men and women) should be advised to use birth control when on Aubagio and for up to 2 years after use.

References

1. Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, Olsson TP, Miller A, Benzerdjeb H, Li H, Simonson C, O’Connor PW; Teriflunomide MultipleSclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012 ;78:1877-1885.
2. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, Truffinet P, Wang L, Miller A, Freedman MS; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293-1303.

Tecfidera (BG12/dimethyl fumurate) is a twice daily oral pill that was approved by the FDA March 28, 2013 for use in relapsing forms of multiple sclerosis.  It works on the nrf2 antioxidant pathway.   In a phase III trial, DEFINE, compared to placebo Tecfidera 240mg twice daily reduced relapse rate 53%, 3 month disability progression 38%, and new or enlarging T2 lesions on MRI 85%.  A second study, CONFIRM, compared BG12 to placebo and found a reduction in relative relapse rate of 44% and disability progression of 21% and new or enlarging T2 lesions 71%.  In the CONFIRM study Copaxone (glatirimer acetate) was included as an active comparator.  When compared post hoc to Copaxone, differences were not significant except for new or enlarging T2-weighted hyperintense lesions (71% reduction for Tecfidera, 54% for Copaxone, p<0.01).  There was a reduction is annualized relapse rate of 44% with Tecfidera, 29% with Copaxone, but the result was non-significant (p=0.1).  No difference in time to disability progression was seen. Flushing can occur in about a third of patients taking the drug and may be attenuated with an aspirin taken 30 minutes prior to Tecfidera. Gastrointestinal side effects (diarrhea ~14%, nausea ~11%, abdominal pain ~10%, vomiting ~10%) also also were seen more frequently. Both flushing and gastrointestinal side effects tend to lessen over the course of the first month.  Leucopenia has been reported in some patients though rate of infection was not increased.  Tecfidera is introduced at half dose for the first week.  It should be taken with food.

Suggested medication monitoring 

Progressive multifocal leukoencephalopathy (PML) has been described in dimethyl fumarate treated patients.  Other opportunistic infections such as kaposi’s sarcoma and disseminated varicella infection have been described with similar fumarate agents.  As such, we recommend:

Baseline CBC with differential, LFT and JC virus antibody testing before starting Tecfidera. It may be of interest to check CD4 and CD8 levels, though it is currently unclear how it should affect decision making.

If a patient is JC negative: Repeat JC virus annually, advise patient if seroconversion occurs.  Repeat CBC (diff) and LFT annually.

If patient is JC positive:

–              MRI brain at least once per year.

–              Repeat CBC (diff) every 6 month. If absolute lymph count less than 600, consider dimethyl fumarate discontinuation.

References

1. Gold R, Kappos L, et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.  N Engl J Med. 2012;367:1098-1107.
2. Fox RJ, Miller DH,; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer inmultiple sclerosis. N Engl J Med. 2012;367:1087-1097.
3. Ontaneda D et al. Risk stratification and mitigation in multiple sclerosis. Mult Scler Relat Disord. 2014 September 1; 3(5): 639–649.
4. Ermis U et al. PML in a Patient Treated with Fumaric Acid. NEJM. 2013 April; 368; 17.
5. Nieuwkamp DJ et al. PML in a Patient without Severe Lymphocytopenia Receiving Dimethyl Fumarate. NEJM. 20135 April; 372; 15.
6. Hoepner R et al. Progressive multifocal leukoencephalopathy during fumarate monotherapy of psoriasis. Neurol Neuroimmunol Neuroinflamm 2015; 2:e85.
7. Dammeier D et al. Case report of a patient with progressive multifocal leukoencephalopathy under treatment with dimethyl fumarate. BMC Neurology (2015) 15:108
8. Nicholas JA et al. Design of oral agents for the management of multiple sclerosis: benefit and risk assessment for dimethyl fumarate. Drug Design, Development and Therapy 2014:8 897–908.

Pre-Ocrelizumab Checklist:

At our institution, we check the following labs prior to starting Ocrelizumab:

• Serum for hepatitis B surface antibody
• hepatitis B surface antigen
• hepatitis B core antibody
• CBC with differential
• SPEP

We may consider adding:

• JCV Ab titer
• LFTs
• CD19
• TB quantiferon
• HIV
• beta-HCG

Patients should also have appropriate breast cancer monitoring per USPST prior to starting therapy.  Additionally, patients should have received the appropriate vaccines for their age

Infusion Protocol:

In effort to potentially reduce infusion reactions, we commonly give the following pre-infusion medications:

• Methylprednisolone 100mg IV
• diphenhydramine 50mg IV
• acetaminophen 650mg PO

Labs prior to re-infusion:

• CBC with differential
• SPEP
• CD19

If a patient was on rituximab is to transition to ocrelizumab we recommend starting ocrelizumab at 600mg for the first dose and recurrently thereafter.  Transitions from other medications should be on a case-by-case basis.  Generally we would not recommend a “wash-out” but advise considering dosing late into a medication’s window of effect.  So, for example, when considering a transition between natalizumab and ocrelizumab we would recommend infusing 2-2.5 months after the last natalizumab infusion.