Internal Medicine II: Disease-Modifying Therapies and Adverse Effects

Mary Ann Picone

Constantine J. Pella

Introduction

Disease-modifying therapies (DMTs) are at the forefront of treatment for the progression of multiple sclerosis (MS). It is important for the internist and nonneurologist to understand the administration of DMTs and the adverse effects and infection risks associated with some of the newer DMTs. For more information on the mechanism of action of DMTs, please refer to the Immunology chapter.

As you can see from Figure 6.1, there are multiple DMTs available now with different mechanisms of actions. Table 6.1 shows the stratification of the different therapies organized by efficacy. These are approved for relapsing forms of MS, and ocrelizumab is approved also for primary progressive MS. The challenge in choosing treatment is trying to do the best to individualize treatment for a heterogeneous disease. Choosing the optimal individualized treatment regimen involves evaluating patient lifestyle, comorbidities, support system, benefits and risks of treatment, timing of pregnancy, and prognostic disease profile and encouraging the patient to
have realistic expectations of what the therapies can do. Although none of the treatments are cures, the goal is to achieve as close to what is referred to as NEDA, no evidence of disease activity. This refers to no new activity noted on magnetic resonance imaging (MRI), no relapses, and no clinical disease progression. Considering the higher-efficacy agents available today, there is a lower threshold to keep a patient on a therapy that may be suboptimal. It is important that patients are followed closely, particularly early on in the disease course and when new therapies are initiated to monitor for efficacy and adverse events. We have no biomarkers at present to predict which patients will respond to a certain therapy; however, neurofilament light protein is a proposed biomarker for MS disease activity and treatment response. This is a structural component of neurons and axons. Neurofilaments are released into the cerebrospinal fluid (CSF) after axonal injury. Levels increase during relapse, and initial CSF levels may help to predict disease course. These are still investigational at this point.

Figure 6.1. Time plot showing the evolution of different disease-modifying therapies for the treatment of MS. *Voluntary withdrawal from market announced March 2018. Republished with permission of Intellisphere, LLC from Owens GM. Managed care aspects of managing multiple sclerosis. Am J Manag Care. 2013;19 (16 Suppl):s307-s312; permission conveyed through Copyright Clearance Center, Inc. See eBook for color figure. **Recently received FDA approval March 2019.

Injections

Copaxone (Glatiramer Acetate)

This is an immunomodulator used for patients with relapsing-remitting MS. It consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: l-glutamic acid, l-alanine, l-tyrosine, and l-lysine. Designed to mimic a protein in myelin, Copaxone binds to major histocompatibility complex molecules and competes with myelin antigens for T cells, which induces specific suppressor cells of

the T helper 2 (Th2) type that migrate to the brain where they express the anti-inflammatory cytokines interleukin 10 and transforming growth factor beta, in addition to brain-derived neurotrophic factor.¹ Recent evidence suggests that Copaxone directly inhibits dendritic cells and monocytes, both of which are circulating antigen-presenting cells.⁷ There is no required blood work monitoring with Copaxone.

TABLE 6.1 VARIOUS DISEASE-MODIFYING TREATMENTS (DMTS) STRATIFIED BY EFFICACY

DMT	Route of Administration	Dosage	Monitoring	Adverse Effects
Low Efficacy
Interferon-ß (Betaseron, Extavia, Rebif, Avonex, Plegridy)	SC/IM	Depends on type of interferon therapy	Every 6 mo: CBC, LFTs Every 12 mo: TSH	Injection site reaction, flulike symptoms, headache, lymphopenia, hepatotoxicity, depression, spasticity
Glatiramer acetate (Copaxone)	SC	20 mg/mL daily or 40 mg/mL twice a week (˜48 h apart)	–	Immediate postinjection reaction, uncommon idiosyncratic reaction, lipoatrophy
Teriflunomide (Aubagio)	PO	7.0 and 14.0 mg daily	Once per month for 1st 6 months LFTs Every 6 mo: CBC, LFTs	Diarrhea, nausea, alopecia, bone marrow suppression, hepatotoxicity, peripheral neuropathy, teratogenicity
Medium Efficacy
Dimethyl fumarate (Tecfidera)	PO	Titrated up from 120 mg twice a day to 240 mg twice a day	Every 6 mo: CBC, LFTs	Dyspepsia, nausea, vomiting, abdominal pain, diarrhea, flushing, PML
Fingolimod (Gilenya)	PO	0.5 mg daily	In 3 mo: repeat CBC with diff, LFTs, Macula Eval. Every 6 mo: LFTs, CBC with diff	Headache, hypertension, transaminitis, lymphopenia, HSV, macular edema, bradycardia, PML, dermatological cancers
High Efficacy
Natalizumab (Tysabri)	IV	300 mg every 4 wk	Every 3 months, CBC with diff, LFTS. Every 6 mo: JCV Ab, MRI. After 6 mo: natalizumab neutralizing antibodies	Infusion reactions, hepatotoxicity, PML, HSV, encephalitis, headache
Alemtuzumab (Lemtrada)	IV	12 mg/d 5 consecutive days followed by 12 mg/d for 3 consecutive days 1 y later	Every 3 mo: TSH. Yearly skin examination, GYN, MRI	Secondary autoimmunity, infusion reactions, malignancies, infections, pneumonitis
Ocrelizumab (Ocrevus)	IV	600 mg every 6 mo^a	Hepatitis B screen before use, yearly MRI	Infusion reactions, reactivation of hepatitis B and tuberculosis, possible malignancy, PML, upper respiratory infections
Adapted with permission from Mahajan KR, Rae-Grant A. New American Academy of Neurology Disease-Modifying Treatment Guidelines: Impact on Clinical Practice. In: Practical Neurology. Bryn Mawr Communications III, LLC; 2018;17(6):22-27.
Patients are premedicated with IV solumedrol or an equivalent corticosteroid and an antihistamine before the infusion.
APC, antigen presenting cells; BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; Cr, creatinine; ECG, electrocardiography; GYN, gynecological screening for HPV; HSV, herpes simplex virus; IM, intramuscular; IV, intravenous; JCV, John Cunningham virus; LFT, liver function test; MRI, magnetic resonance imaging; OCT, optical coherence tomography; PML, progressive multifocal leukoencephalopathy; PO, orally, dihydro-orotate dehydrogenase; SC, subcutaneous; TSH, thyroid stimulating hormone; UA, urine analysis.

Interferon

Interferons as a class need to have complete blood count (CBC) with differential and liver function profile monitored generally every 6 months. Depression has been reported with interferons, although in clinical trials versus noninterferon therapy, no increased risk of depression was noted in patients treated with interferon. Flulike symptoms are the most common side effects, but dose titration can help to mitigate flulike symptoms. Injection-site reactions can also be seen, particularly with subcutaneous injections. Seizures have also been reported in patients given interferon therapy. Dosing with interferons (for adults) varies based on the brand:

1. Interferon beta-1b (Betaseron, Extavia): Initial: 0.0625 mg every other day, increase dose by 0.0625 mg every 2 weeks to target dose of 0.25 mg every other day.²

2. Interferon beta-1a

a. Avonex: 30 µg administered intramuscularly once weekly or 7.5 µg once weekly to reduce flulike side effects, increasing dose in increments of 7.5 µg once weekly till target dose of 30 µg a week is reached.

b. Rebif: Target dose either 22 or 44 µg administered subcutaneously three times weekly.³

c. Plegridy: A pegylated version of Avonex that allows for longer-lasting binding to interferon receptor sites; thus, this only needs to be administered subcutaneously twice monthly. Initial dose 63 µg on day 1, 94 µg on day 15. Maintenance 125 µg every 14 days beginning on day 29.⁴

Oral Therapies

Aubagio (Teriflunomide)

As the active metabolite of leflunomide, it acts as an immunomodulatory agent by inhibiting pyrimidine synthesis and disrupts T cells from interacting with antigen-presenting cells.⁵ It is approved for the treatment of relapsing forms of MS in adults and is available in 7- and 14-mg doses. No titration is needed. Side effects include hair thinning,
abdominal pain, diarrhea, and often soft stools. Liver enzymes have to be monitored monthly for the first 6 months and then periodically thereafter. Aubagio can cause increased blood pressure, and although this is not considered a contraindication for use of the drug, patients with a history of high blood pressure should be monitored closely.⁵ If a patient needs to stop the drug abruptly because of tolerability issues or pregnancy considerations, an elimination procedure can be undertaken with the use of cholestyramine or activated charcoal to quickly decrease serum levels of Aubagio.⁵ Pediatric use is being evaluated in clinical trials.

Gilenya (Fingolimod)

This is a sphingosine 1-phosphate receptor modulator indicated and approved for the treatment of relapsing forms of MS.⁶ It binds to sphingosine receptors to block the egress of lymphocytes (B cells, central memory and naïve T cells) from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. Gilenya does not destroy lymphocytes but does sequester them in lymphoid tissue; thus, CBC testing will demonstrate lymphopenia, often with absolute lymphocyte counts below 0.2 × 109/L.⁷ This is an expected finding. Within 8 weeks of discontinuation of fingolimod, lymphocyte counts usually return to the normal range, but CD4 and CD8 central memory cells decrease and remain decreased over time. It was recently approved for pediatric use.

There are some concerns relating to fingolimod adverse reactions that should be noted by the internist. Bradycardia and atrioventricular (AV) block can occur. Six-hour first-dose electrocardiogram (EKG) monitoring is required for Gilenya for monitoring of bradycardia and risk of first-degree AV block at the initiation of dosing and at the 6-hour mark, along with hourly blood pressure and heart rate monitoring.⁶ Ophthalmological evaluation before the first dose, 3 to 4 months after therapy initiation, and yearly thereafter for macular edema is also required.

There is an increased risk of macular edema if the patient has underlying diabetes or uveitis. If noted, macular edema is reversed once Gileny is discontinued.⁷ Gilenya can elevate liver enzymes; thus, patients need to have liver enzymes monitored periodically. Progressive multifocal leukoencephalopathy (PML) cases have been reported with Gilenya, not thought to be related to lymphopenia.⁸ The age of the patient may play a role in increased PML risk. Other opportunistic infections also have occurred; these include pulmonary tuberculosis (TB), asymptomatic pulmonary cryptococcus, and cutaneous cryptococcus, and also a case of disseminated cryptococcus, ocular and cerebral toxoplasmosis, visceral leishmaniasis, Kaposi sarcoma, and Merkel cell carcinoma.

Respiratory and herpetic infections also can occur. If patients have frequent herpetic infections, they may not be ideal candidates for Gilenya use; however, there can be consideration of maintaining the patient on low-dose acyclovir or famvir while on Gilenya. Drug-drug interactions between Gilenya and other medications that have the potential to prolong QT interval have to be considered. The following is not an exhaustive list but includes some of the more frequently used classes of drugs that can prolong QT interval and should be avoided with Gilenya use⁶:

Antimicrobials: Levofloxacin, ciprofloxacin, erythromycin, ketoconazole, azithromycin, chloroquine, clarithromycin, fluconazole, moxifloxacine, pentamidine
Antidepressants: Amitriptyline, desipramine, imipramine, fluoxetine, sertraline, venlafaxine, escitalopram, citalopram
Antipsychotics: Haloperidol, quetiapine, chlorpromazine, thioridazine
Others: Sumatriptan, zolmitriptan, methadone, ondansetron, propofol, donepezil, droperidol
Antiarrhythmics: Amiodarone, quinidine, procainamide

Tecfidera (Dimethyl Fumarate)

Tecfidera is indicated for relapsing forms of MS. It is a twice-daily oral medication, recommended usually to be taken with breakfast and dinner. In the 2-year DEFINE trial, comparing Tecfidera with placebo, there was a 49% relative risk reduction of relapses compared with placebo.⁹ Taking Tecfidera with food decreases flushing and abdominal pain. Flushing and abdominal pain seen with Tecfidera are most common within the first month of use and then significantly decrease thereafter. Non-enteric-coated aspirin before dosing also decreases flushing. CBC with differential and liver function tests (LFTs) should be drawn before Tecfidera use and repeated at least every 6 months. If someone has a serious infection, then it is important to hold treatment with Tecfidera until infection is resolved.

In the clinical trials, mean lymphocyte counts decreased about 30% during the first year of treatment. If lymphocyte count is less than 500 and persists greater than 6 months, then the drug should be discontinued. Repeat lymphocyte testing should be performed until counts return to normal. Tecfidera should not be used during pregnancy or breastfeeding. If anyone does become pregnant while taking Tecfidera, she should discontinue treatment and enroll in Tecfiderapregnancyregistry.com. Increased LFTs have been observed with Tecfidera, and because of this it is important to check LFTs periodically, on average every 6 months. Tecfidera may cause liver injury. PML cases have been seen with Tecfidera and seem to be associated with lower lymphocyte counts. Infections other than PML appear to be rare with Tecfidera.

Monoclonal Antibodies (Infusion Therapies)

Lemtrada (Alemtuzumab)

This is a monoclonal antibody given in two treatment cycles. Year 1 it is administered 5 days in a row and then year 2, 3 days in a row. Lemtrada targets the CD52 molecule expressed on T and B leukocytes. Because intravenous administration of Lemtrada causes lysis of these cells, infusion reactions can occur as a result of these cells being depleted, causing cytokine release syndrome. Pretreatment with steroids and antihistamines helps to decrease these reactions. Once the immune system starts to reconstitute, secondary autoimmunity can occur. Monthly CBC with differential to monitor for autoimmune thrombocytopenia, and urinalysis and serum creatinine to monitor for Goodpasture syndrome, is required monthly up to 4 years after the last infusion. The urine protein to creatinine ratio needs to be obtained before starting the drug and at periodic intervals up to 48 months after last infusion. Thyroid function testing is required every 3 months. Human immunodeficiency virus testing before starting the drug is also required by the US Food and Drug Administration (FDA). Hepatitis B and hepatitis C carriers who receive Lemtrada may be at risk of irreversible liver damage relative to potential virus reactivation. Yearly skin examination is also required because of increased risk of melanoma. Annual HPV screening is recommended for women. Before starting Lemtrada the following tests are recommended:

TB screen
Varicella zoster titer
CBC with differential
Urinalysis
Thyroid function profile
Serum creatinine
Urine protein to creatinine ratio

If a woman is of childbearing potential, it is important to make sure that she is not pregnant before initiating treatment. Contraceptive therapy is recommended, and patients should not try to get pregnant for at least 6 months after Lemtrada infusion. Anyone who has any active infection should not proceed with the infusion but should wait until the infection is cleared before treating. Tattoos also should be avoided for at least 8 weeks after infusion to help prevent infection. Acyclovir must be given at the start of treatment and continued for at least 2 months. If the CD4 count is still below 200 at that time, acyclovir needs to be continued until the count is 200 or above. Regarding lymphopenia, even though repopulation
of cells occurs, 20% of patients had below normal lymphocyte counts after 12 months. The following are certain infections and other safety precautions with Lemtrada that should be recognized:

Acute acalculous cholecystitis was seen in eight patients who received Lemtrada for relapsing MS. Seven developed acute acalculous cystitis during or shortly after receiving Lemtrada, and one person developed it 6 to 7 weeks after infusion. Frequency of this risk is estimated at 0.2%¹⁰
Acute coronary syndrome is possible. A young otherwise healthy woman developed cardiac ischemia midway through a Lemtrada infusion. The mechanism may have been related to increased endothelial and myocyte membrane permeability and vasodilation via cytokine release syndrome and could lead to an increased demand and ischemia of the myocardium. This underscores the need for monitoring of vital signs during infusion and vigilance for potential cardiac events. EKG monitoring at this point is not required but may be up to the discretion of the treating neurologist¹¹
Listeria was first reported with Lemtrada use in 2008.Dietary precautions are important to emphasize to patients, particularly avoiding uncooked meats and fish, unpasteurized soft cheeses, dairy products, and juices for at least 4 months after infusion. The risk of Listeria meningitis is the highest in the first month after each Lemtrada cycle. However, owing to the concern that patients may not follow dietary precautions, preventive treatment with sulfamethoxazole-trimethoprim is now recommended in the United Kingdom. If it is unlikely that the patient will be compliant with diet, co-trimoxazole 960 mg three times weekly for 1 month is recommended. If patients are adherent to following a Listeria-free diet, another treatment option is 8 days of amoxicillin 1 g three times daily or co-trimoxazole 960 mg twice daily, which would eliminate Listeria colonization before treatment
Hemophagocytic lymphohistiocytosis occurred in two patients treated with Lemtrada for leukemia, but this was not seen in MS
Pulmonary nocardia beijingensis infection
Pneumonitis
Ischemic and hemorrhagic stroke and cervicocephalic arterial dissection is a rare but serious complication that can occur shortly after Lemtrada use. Health care providers need to advise patients at every Lemtrada infusion to seek emergency medical attention if they have symptoms of numbness, or weakness, visual symptoms, sudden difficulty with walking or balance, or sudden severe headache or neck pain¹²

Ocrevus (Ocrelizumab)

Ocrevus is a B cell-directed humanized monoclonal antibody, targeting the CD20 antigen expressed on mature B cells. It is the first FDA-approved therapy for primary progressive MS and FDA approved for relapsing forms of MS. It targets pro-B cells in the bone marrow but spares CD20-negative plasma cells that produce antibodies. The main effect of the anti-CD 20 therapy seems to maintain adequate antibody levels but reduces antigen presenting and cytokine secreting functions of B cells. Compared with rituximab, Ocrevus has a higher capacity for direct, antibody-dependent cell toxicity.

In the OPERA study comparing ocrelizumab with interferon beta-1a, the infection rate was 58.4% in the Ocrevus-treated group and 52.4% in the interferon beta-1a group. Main infections noted were upper respiratory tract infections and nasopharyngitis. Most infections were considered mild to moderate. There were no deaths related to infection in OPERA, which analyzed relapsing patients, and in the ORATORIO study, which analyzed progressive patients and compared ocrelizumab with placebo, there were two deaths, due to pneumonia, one of which was aspiration pneumonia, not thought to be related to ocrelizumab. Since ocrelizumab has been FDA approved there have been six cases of PML reported all in patients who had transitioned to Ocrevus from Tysabri who were John Cunningham virus (JCV) antibody positive. Ocrevus can cause reactivation of hepatitis B infection, and hepatitis panel is required before its use.

Only gold members can continue reading. Log In or Register to continue