Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies
Abstract
:1. Introduction
2. Comprehensive Approach to POMS Care
3. Treatment Goals
4. Treatment Paradigms
5. Monitoring Treatment in POMS
6. Escalation of Therapy
7. Immune Reconstitution
8. Clinical Trials in POMS
9. Compliance and Adherence
10. Biomarkers in MS
11. Neuroregeneration in POMS
12. Conclusions
Funding
Conflicts of Interest
References
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Interferon Β 1a | |
Mechanism of Action | Shifts cytokine balance to a more anti-inflammatory profile; reduces trafficking of inflammatory cells across the blood brain barrier |
Dosing | Dose titration to start 22 or 44 µg sq three times weekly; 30 µg im weekly; or 125 µg sq every other week |
Side effect | injection-site erythema, influenza-like illness, pyrexia, headache, myalgia, chills, injection-site pain, injection-site pruritus, arthralgia and asthenia |
Monitoring | CBC and LFT at baseline and q 6 months |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
Adverse events | depression |
elevated transaminases and thyroid abnormalities | |
Neutralizing antibodies to interferons | |
POMS publications | [21] |
POMS RCT | Ongoing, ClinicalTrials.gov Identifier: NCT03870763 |
Interferon β-1b | |
Mechanism of Action | Shifts cytokine balance to a more anti-inflammatory profile; reduces trafficking of inflammatory cells across the blood brain barrier |
Dosing | 0.25mg sq every other day |
Side effects | See Interferon β-1a |
Monitoring | |
Adverse events | |
POMS publications | [22] |
POMS RCT | none |
Glatiramer Acetate | |
Mechanism of action | Modulates function of antigen-presenting cells; induces differentiation of CD4 + T cells into Th2 cells |
Dosing | 20 mg sq every day or 40 mg sq three times a week |
Side effects | injection-site reactions, chest pain, rash, dyspnea, and vasodilation |
Monitoring | No blood work required |
Adverse events | Lipoatrophy, skin necrosis |
POMS publications | [23] |
POMS RCT | none |
Daclizumab | |
Mechanism of action | Humanized monoclonal antibody to alpha subunit of IL-2 receptor, reducing IL–2-mediated activation of lymphocytes |
Dosing | 150 mg sq once monthly |
Side effects | influenza, bronchitis, eczema, lymphadenopathy, nasopharyngitis, upper respiratory tract infection, rash, and dermatitis. Rash (7% to 11%), depression (7% to 10%), upper respiratory tract infection (9% to 17%), pharyngitis (25%), and elevated ALT levels (5% to 6%) http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761029s000lbl.pdf |
Monitoring | Assess for Hepatitis B and C, Daclizumab is contraindicated in Hepatitis B and C |
Assess for LFT at baseline, preexisting hepatic disease or impairment (ALT or aspartate transaminase ≥2 times the upper limit) or history of autoimmune hepatitis is contraindicated | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
Adverse events | Autoimmune Encephalitis (removed from US market 2018) |
Colitis | |
Elevated Liver enzymes | |
POMS publication | [24] |
POMS RCT | none |
Fingolimod | |
Mechanism of Action | Sphingosine 1 phosphate receptor modulator |
Dosing | 0.25 or 0.5 mg by mouth once a day |
Side effects | Headache |
Back pain | |
Diarrhea cough | |
AE | Low ALC |
QTc prolongation | |
Respiratory Infection | |
High ALT | |
Rebound disease activity | |
Rare PML | |
Bradycardia | |
First- and second-degree block | |
Rebound disease sinusitis back pain first-dose monitoring requirement, contraindications in heart disease, risk of macular edema skin cancers | |
Monitoring | contraindications in heart disease |
VZV serum titer, pre FDO | |
OCT pre and 3 months post FDO use with caution with other medications that prolong QTc interval | |
Requires FDO < 6 h of observation with first dose with hourly vitals | |
EKG before and after FDO | |
CBC with diff baseline, 3 months then every 6 months | |
JC index | |
Avoid live vaccines while on Fingolimod and for 2 months after it is stopped. | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
POMS publications | [9] |
POMS RCT | Completed [2] |
FDA approved in POMS | Approved in POMS 2018 |
Dimethyl Fumarate | |
Mechanism of Action | Increase Nuclear factor erythroid 2 (NF-E2)-related factor 2 |
Dosing | 120 mg oral twice a day × 7 days then 240 mg oral twice a day |
Side effects | Flushing, diarrhea, nausea, vomiting, and abdominal pain |
Adverse events | Low absolute lymphocyte count |
Rare PML case | |
Monitoring | Baseline CBC with diff and LFT then q 12 months |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
POMS publications | [25] |
POMS RCT | Yes, ongoing BG00012, ClinicalTrials.gov Identifier: NCT02283853 |
ClinicalTrials.gov Identifier: NCT03870763 | |
FDA approved for POMS | No |
Teriflunomide | |
Mechanism of Action | Inhibits pyrimidine biosynthesis |
Dosing | 7 mg or 14 mg oral once a day |
Side effects | Diarrhea |
Nausea | |
Headache | |
Adverse events | Decreased hair density |
Elevated Alanine aminotransferase | |
Increased blood pressure | |
Paresthesia in the upper extremities | |
Major birth defects and embyrolethality in animal studies relatively long half-life of approximately 19 days, elimination can take >8 months | |
Monitoring | CBC with diff, LFT baseline, LFT q month × 6, Blood pressure monitoring |
Effective birth control compliance in male and female patients | |
Contraindicated in severe hepatic impairment and those of child bearing potential not using effective birth control (http://products.sanofi.us/aubagio/aubagio.pdf) | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
Rapid elimination due to long half life | If drug-induced liver injury or pregnancy is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or activated charcoal |
POMS Publications | None |
POMS RCT | Yes, ongoing ClinicalTrials.gov Identifier: NCT02201108 |
FDA approved for POMS | None |
Natalizumab | |
Mechanism of Action | Inhibits the transmigration of immune cells across the blood-brain barrier thus inhibiting inflammation in the central nervous system. |
Dosing | 300 mg Intravenous every 4 weeks or 3–5 mg/kg IV every 4 weeks |
Side effects | Infusion reactions |
Headaches | |
Fatigue | |
Adverse events | PML |
Infections | |
Neutralizing antibodies | |
JC antibodies | |
Rebound disease | |
Encephalitis | |
Meningitis | |
Acute retinal necrosis due to herpes infection | |
Monitoring | Risk evaluation mitigation strategy due to risk of PML |
Monitor for the risk of PML while on Natalizumab and at least 6 months after stopping Natalizumab | |
Monitor patients for signs or symptoms of PML, if any concerning signs, hold treatment and evaluate the patient as needed, clinically, MRI and possibly cerebrospinal fluid for JC virus DNA | |
John Cunningham virus index q 3 months | |
CBC and LFT q 6 months | |
Natalizumab antibodies | |
Monitor 1 h after infusion | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
PML | Progressive Multifocal Leukoencephalopathy risk factors:
|
POMS publications | [26,27,28] |
POMS RCT | none |
FDA approval in POMS | none |
Alemtuzumab | |
Mechanism of action | monoclonal antibody against CD52 and leads to depletion of mature lymphocytes |
Dosing | 12 mg IV daily × 5 year 1 then 12 mg IV daily × 3 in year 2 and then as needed depending on disease activity |
Side effects | Infusion reactions rash, headache, vomiting, nausea, diarrhea, flushing, abdominal pain, pyrexia, nasopharyngitis, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infections, arthralgia, extremity pain, back pain, sinusitis, oropharyngeal pain, paresthesia, and dizziness |
Adverse events | Autoimmune conditions |
Infections | |
Possible cancer | |
Premedication needed for infusion | |
Antiviral needed for risk of viral infection until CD4 > 200 cells/u/L | |
Monitoring | Varicella Zoster virus titers before infusion, vaccinate as needed |
All necessary immunizations, including varicella zoster vaccine, should be completed at a minimum of 6 weeks prior to administration of alemtuzumab | |
risk evaluation mitigation strategy program due to risk of serious adverse reactions | |
Continuous observation × 2 h after infusion | |
Labs and urine month × 5 years after last infusion | |
CD4 | |
Risk management strategy | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
POMS Publications | none |
POMS RCT | Yes, ongoing (ClinicalTrials.gov Identifier: NCT03368664) |
FDA approval in POMS | none |
Ocrelizumab | |
Mechanism of Action | Humanized form of the CD20 monoclonal antibody |
Dosing | 300 mg IV repeated in 2 weeks then 600 mg IV every 6 months. |
Pretreatment with IV steroids and Benadryl | |
Side effects | Infusion reaction |
Adverse events | Upper respiratory tract infections (40% to 49%), lower respiratory tract infections (8% to 10%), infusion reactions (34% to 40%), and infection of the skin and/or subcutaneous tissue (14%) https://www.gene.com/download/pdf/ocrevus_prescribing.pdf [Reflist] |
Monitoring | Risk evaluation mitigation strategy due to risk of autoimmune disorder risk and cancer risks |
Screen for Tuberculosis and Hepatitis B prior to use | |
Vaccinate at least 6 weeks prior to therapy | |
Monitor 1 h after infusion | |
Infection | |
Possible breast cancer | |
Pregnancy test prior to use, it is not recommended to get pregnant or nurse while on this product | |
POMS Publications | None |
POMS RCT | None |
FDA approval in POMS | None |
POMS outcomes Age 10–17 [2] | Interferon β-1a | Fingolimod |
---|---|---|
n | 108 | 107 |
Dosing | interferon β-1a at a dose of 30 μg per week | 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg |
Adverse events | 95.3% serious AE n = 7 (infection, supraventricular tachycardia) | 88%serious AE n = 18, 16.8% (infection, leukopenia) |
Convulsions n = 1, 0.9% | Convulsions n = 6, (5.6%) | |
AE > 10% | AE > 10% | |
Nervous system disorder 42% | Leukopenia | |
Eye disorder | ||
Psychiatric 10.3 | Gastrointestinal disorders 34% | |
Headache 29% | Infection and infestation 59% | |
Influenza 11% | ||
Respiratory tract upper 15.9% | ||
Nervous system disorder 43% | ||
Headache 31.8% | ||
Psychiatric 18.7% | ||
Skin disorders 16.8% | Skin disorders 18.7% | |
Completed trial 87.4% | 88 (81.5%) | 100 [93.5%] |
Primary End Point, Adjusted Annualized Relapse Rate | 0.67 | 0.12, 82% decrease compared with IFN B-1a, P < 0.0001 |
MRI | New T2 lesion, 53% absolute difference | |
Secondary End Point Annualized Rate of New or Newly Enlarging T2 Lesions | 9.27 | 4.39 relative difference, 53%; P < 0.001 |
Reasons for Permanent Discontinuation of Medication | N = 11, lack of treatment effect | Elevated liver aminotransferase levels, macular edema, cardiac arrhythmias or electrocardiographic (ECG) abnormalities, and pregnancy |
DMT | FDA | EMA | Canada | Australia |
---|---|---|---|---|
Interferons AOMS | 1995, 2002, 2009, 2012, 2013, 2014 (pegylated) | 1995 | 1995 | 1996 |
1997 | ||||
1998 | ||||
2008 | ||||
2014 | ||||
Interferons POMS | Age 12–adult | |||
Glatiramer Acetate AOMS | 1996, 2014 | 2002 | 1997 | 1997 |
2015 | ||||
Glatiramer Acetate POMS | Age 12–adult | |||
Fingolimod AOMS | 2010 | 2010 | 2011 | 2011 |
Fingolimod POMS | 2018 Age 10–17 | 2018 Age 10–17 | ||
Siponimod AOMS | 2019 | |||
Siponimod POMS | none | |||
Daclizumab AOMS | 2016, removed from market 2018 | 2016 | xx | xx |
Teriflunomide AOMS | 2012 | 2013 | 2013 | 2016 |
Teriflunomide POMS | none | |||
Dimethyl fumarate AOMS | 2013 | 2014 | 2013 | 2017 |
Dimethyl fumarate POMS | none | |||
Cladribine AOMS | 2019 | 2017 | 2017 | 2010, removed from market 2011 |
Reapproved 2019 | ||||
Cladribine POMS | none | |||
Natalizumab AOMS | 2004, returned to market in 2006 | 2006, 2011 SC | 2006 | 2006 |
Natalizumab POMS | none | |||
Alemtuzumab AOMS | 2014 | 2013 | 2013 | 2015 |
reserved for those with inadequate | ||||
responses to 2 or more MS medications | ||||
Alemtuzumab POMS | none | |||
Ocrelizumab AOMS | 2017 | 2018 | 2017 | 2017 |
RRMS | RRMS | |||
PPMS | PPMS | |||
Ocrelizumab POMS | none |
Natalizumab | Progressive Multifocal Encephalopathy (PML) |
Contraindicated if history of PML. | |
Teriflunomide | Contraindicated in patients with pre-existing acute or chronic liver disease |
contraindicated in women of childbearing potential | |
Hepatotoxicity and risk of teratogenicity | |
Alemtuzumab | Risks of serious and sometimes fatal autoimmune conditions, infusion reactions, and various malignancies. |
It is contraindicated in human immunodeficiency virus due to CD4 + lymphocyte count reductions | |
Daclizumab | Daclizumab is contraindicated in Hepatitis B and C or liver impairment |
Removed from US market due to Autoimmune encephalitis | |
Risk of severe liver injury and immune-mediated disorders, such as skin reactions, lymphadenopathy, and noninfectious colitis | |
Fingolimod | Fingolimod is contraindicated: if there is a cardiac event or vascular event like a stroke or TIA, irregular heart rate in the past 6 months and or medication that slows the QTc |
Siponimod | Patients with a CYP2C9*3/*3 genotype (4) |
In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure (4) | |
Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker (4) |
Reduction in ARR | Relative Risk Reduction to Placebo | Reduction in Sustained Disability | Reduction in MRI New T2 Lesions | Reduction in New Gad Enhancing Lesions | |
---|---|---|---|---|---|
Alemtuzumab | Not tested vs placebo | ||||
Dimethyl fumarate [41] vs. placebo | 53,48% | 44% | 34%, 38% | 85% | 90% |
Fingolimod [42] | See Table 6 for POMS data | 23% | |||
Natalizumab | 68% | 42% | 83% | ||
Daclizumab (removed from the market willingly by Biogen) | 45% compared with IFN β 1a | 45–54% | 54% new or new enlarging T2 | ||
Ocrelizumab [43,44] | 44, 46% compared with IFN β 1a | 46–47% | Slow disability in PPMS | ||
Teriflunomide [45] | 31% | 29% | 69% against placebo | Free from gad lesions 89% compared with placebo | |
Cladribine [46] | 66% | Slowed 3-month disability 33% | 86% |
Product | Potential Biomarker |
---|---|
Interferon | Neutralizing antibody |
Natalizumab | Natalizumab antibody |
JC index | |
L Selectin | |
Neurofilament light chain | |
Fingolimod | VZV status |
Alemtuzumab | interleukin (IL)-21 |
CD4 | |
CD19 | |
DMF | ALC |
All | Neurofilament light chain |
Chitinase3-like 1 | |
Glial fibrillary acidic proteins |
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Rensel, M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children 2019, 6, 73. https://doi.org/10.3390/children6060073
Rensel M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children. 2019; 6(6):73. https://doi.org/10.3390/children6060073
Chicago/Turabian StyleRensel, Mary. 2019. "Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies" Children 6, no. 6: 73. https://doi.org/10.3390/children6060073
APA StyleRensel, M. (2019). Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children, 6(6), 73. https://doi.org/10.3390/children6060073