2. Comprehensive Approach to POMS Care
Confirmation of the diagnosis of POMS is followed by a comprehensive approach to address the needs of the patient and family, including long-term use of DMT, social and school support, cognitive assessment, lifestyle assessment and modification as needed, symptom management, and mental health assessment and treatment. Typically, a team-based approach is needed to address these lifelong concerns of the POMS patient [
6]. A POMS treatment team may include pediatricians, pediatric neurologists, neuroimmunologists, urologists, ophthalmologists, social workers, nurses, physical therapists, occupational therapists, neuropsychologists, health psychologists, cognitive therapists, nutritionists, and speech therapists. An MS Care Unit, a highly specialized treatment team, has been proposed due to the complexity of POMS DMT use and symptom management [
7]. Treatment goals of POMS are similar to AOMS, yet there are additional POMS concerns. These unique concerns of the POMS patient are long-term DMT efficacy and safety, neurodevelopmental stage, pediatric pharmacokinetics, and pharmacodynamics. Cognitive dysfunction needs to be assessed and addressed early in the POMS population due to the threat of disabling cognitive outcomes [
8]. Identification of the distinct injury and repair mechanisms unique to the younger patients may help to direct treatment paradigms and development of blood and imaging biomarkers, but for now the treatment recommendations vary widely.
4. Treatment Paradigms
The process of choosing a DMT should include a risk benefit discussion to clarify treatment goals of the provider, patient, and family. Clarifying individual’s priorities and trade- offs that may be acceptable to the patient and their family will focus the collective goals and risk tolerance. These priorities may be concordant or discordant between patient and provider and may depend on the patient and families’ understanding of the disease, neurocognitive status, and adherence to past medications [
12,
13]. Studies have shown the patient’s determinants of DMT choice include many variables: long term risk of disability, dosing, monitoring, cost, and safety of medication [
14]. General practice guidelines and recommendations exist for DMT use in POMS, but the best treatment strategy is not known and is fluid, as more DMTs are available for use [
15,
16,
17].
DMTs can be divided by their efficacy, mechanism of action, mode of administration, monitoring needs, safety, or by the length or frequency of the treatment [
16]. DMT use should commence when the diagnosis is confirmed. Studies show frequent delays in treatment initiation in POMS. Mean DMT initiation delay of 20 months was seen in one POMS database review, which likely can lead to worsening disability due to ongoing inflammation and subsequent damage while awaiting treatment initiation [
17,
18]. Historically, the first line therapies for POMS have been injectable therapies including interferon β and glatiramer acetate supported by the AOMS and observational studies in POMS [
19,
20]. Long-term injectable DMT for relapsing forms of MS was first approved in the 1990s, see
Table 1. From 2012–2019, nine new oral and infusion DMTs were approved for AOMS, enhancing the choices and pattern of use of DMTs for this population, see
Table 2 and
Table 3. The lack of randomized controlled trials (RCT) of DMT in POMS originally limited DMT use in POMS. One RCT has been completed in POMS, see
Table 4 and many are ongoing. Currently there are 17 FDA approved DMTs, (see
Table 5) for relapsing forms for AOMS and only one FDA approved DMT for POMS, and one FDA approved for adult onset primary progressive MS. EMA has approved Interferons and glatiramer acetate for patients 12 years of age and older. Canada has approved Fingolimod for POMS.
The pattern of use of DMT in POMS has changed with the availability of higher efficacy DMT. These previous “first line” therapies have frequent side effects, are more difficult, and have lower efficacy as compared to our newer DMT for AOMS [
20]. The sequence of DMT varies according to provider’s experience and goals, patient’s preference and goals, payor, patient location, and even variability within one country can affect DMT choice [
7]. The recent review of the United States’ Network of Pediatric MS Center’s database illustrated the change in pattern of DMT usage in POMS. The 2018 review included over 1000 POMS patients and the newer higher efficacy DMTs were used as first line in 42% of the POMS patients, the newer DMT included dimethyl fumarate (
n = 102), natalizumab (
n = 101), rituximab (
n = 57), fingolimod (
n = 37), daclizumab (
n = 5), and teriflunomide (
n = 3) showing the shift toward higher efficacy medications as first line for POMS in the US [
17]. The DMTs are approved for use in AOMS at varying levels internationally (see
Table 5 [
29]). There are locations in the European Union and various payors in the US that dictate DMT algorithms. The high efficacy therapy protocol has been evaluated in uncontrolled smaller series in POMS, such as a Natalizumab series in 20 POMS patients showing the use of first line high efficacy DMT for POMS [
30].
The trial of Fingolimod versus interferon β-1a in POMS is the first double blind, active comparator trial completed in POMS showing superior efficacy of fingolimod over interferon β-1a in reducing relapses in children and adolescents ages 12 to <18. The median duration of the trial regimen was 1.6 years. This trial confirmed POMS relapse rates were 2–3 times higher than AOMS [
31]. The incidence of serious adverse events was higher in the fingolimod group as compared to the interferon β-1a group, serious infections were reported with fingolimod (see
Table 6). Typical influenza-like symptoms were seen in the interferon group. There were 7 seizures reported in the trial, 6 with fingolimod, and 1 on interferon. Seizures have been reported more commonly in pediatric central nervous system demyelination syndromes, but this risk needs further monitoring. There were no reports of skin carcinoma that were seen in the AOMS trials with Fingolimod. Rebound disease, MS activity after cessation of fingolimod, has been reported in AOMS, yet not in POMS to date [
32]. The discontinuation rates were lower for fingolimod as compared to interferon β-1a, half of the interferon β-1a. Discontinuation was commonly related to disease activity. The discontinuation rates related to adverse events were overall low: (Fingolimod 4.7 vs. IFN 2.8%) [
2]. The fingolimod versus interferon β-1a trial is the first completed RCT in POMS and provides needed data addressing unique features of treatment issues in POMS.
Infusion therapies for MS have a longer lasting immune effect compared to oral DMT medications with variable windows of immune changes, natalizumab’s effects may last 4–16 weeks [
26]. Alemtuzumab and Natalizumab have shown similar effects on relapse rates, and yet disability progression was less in Natalizumab as compared to Alemtuzumab, no controlled data in POMS [
33]. Alemtuzumab has had effective pediatric use in heart and kidney transplants with known risks including immunosuppression and autoimmunity [
34,
35], and is currently being investigated as escalation therapy for POMS (
ClinicalTrials.gov Identifier: NCT03368664). Rituximab has been assessed in a class 1 phase II study in AOMS showing significant improvement in relapse rate and MRI lesion load [
36]. A reduction in relapse rate was shown in adolescents with POMS administered Rituximab [
37]. The risk of severe infections including PML justifies randomized evaluation of these infusion therapies in POMS to clarify the long-term risk of these products in this unique population.
The dosing of certain pharmaceutical products in pediatric patients must take into account the unique absorption, distribution, metabolism, and elimination (ADME) of this age group [
38]. The level of hepatic metabolizing enzymes may be significantly different in various age ranges and can differ between sexes as well. The renal glomerular filtration rate reaches adult values at 1 year of age and is therefore less of a concern [
38]. The pharmacokinetics of a particular agent and potential differences according to the age of the child or adolescent must be taken into account due to variability. Pharmacodynamic studies in POMS are recommended as efficacy may be influenced by the differences in efficacy and tolerability according to the level of the developing immune system [
38].
6. Escalation of Therapy
The optimal sequence of DMT is not known; there is lack of clarity on treatment sequencing in AOMS and POMS. There are uncontrolled studies of DMT used in the context of POMS showing similar efficacy as in the AOMS population. The terminology of first line versus second line is being replaced with the concepts of escalation and induction, as well as individualized therapy [
4]. A 2011 open label multicenter series of POMS patients showed 55.8% of the patients with disease stability who therefore did not need to escalate therapy, while the rest of the patients needed 2–4 further DMT in 2 years due to refractory disease. The rate of change was similar if the patients started with Interferon or glatiramer [
17]. The pattern of “first line” DMT choice is changing over time due to observational and controlled studies suggesting higher efficacy of newer DMT as compared with lower efficacy early approved DMT in AOMS and POMS, see primary and secondary outcomes of RCT in various DMT, see
Table 7. The unique features of POMS have not been studied in all DMT [
19]. The concept of utilizing high efficacy treatment in POMS from the disease onset has been proposed, the long term outcomes of which are not yet known [
39]; the concern for long term disability in this population validates this proposal [
40].
Escalation therapy refers to starting with low efficacy product and increasing the efficacy of the DMT depending on the NEDA status and tolerability. Comparison of the DMT AOMS studies has inherent limitations; multiple comparisons have been reported including a value based comparison from the Institute for Clinical and Economic review, ICER, looking at the strength of the evidence, patient goals, and costs for each FDA approved DMT products [
47]. A standardized ICER evaluation of all MS DMT concluded the newest FDA AOMS approved product, ocrelizumab dominating the other DMTs when cost was compared with supportive care for the AOMS patient, showing it as the best value in the US market or as cost effective as a first line treatment for RRMS [
27]. There is no similar ICER evaluation for DMT use in POMS. In the AOMS DMT ICER analysis Alemtuzumab dominated as the second line DMT over the other defined second line products: natalizumab, fingolimod and ocrelizumab for RRMS, providing more quality due to high efficacy and lower cost, while the other DMTs were similar in terms of cost and health outcomes. Maintaining up-to-date education on the changing landscape of DMT and risk tolerance also likely plays a role in the rate and timing of escalation therapy in various providers [
28]. There has been global concern over the cost and access to DMTs, especially financial barriers to the patients and their families.
7. Immune Reconstitution
Immune reconstitution (IR) therapy, a “resetting” of the immune system, intermittent or noncontiguous therapy, applies to various medications and procedures. There have been suggestions that these noncontiguous AOMS therapies may indeed be cost effective, as well as improve quality of life [
48]. Autologous stem cell transplantation for severe cases of POMS has been an early example of this type of IR therapy. Concerns over IR treatment related mortality in early studies predominated, yet there was evidence of long-lasting (3 years), change in the T cell repertoire as well as clinical stability in AOMS patients following autologous stem cell transplantation [
49,
50]. A recent AOMS randomized trial of myeloablative stem cell therapies (SCT) in relapsing AOMS showed delayed time to disease progression when compared to other DMT [
51]. Mesenchymal stem cells (MSC) are present in various tissues including bone marrow, adipose and umbilical cord blood, and their immune altering capabilities have been exploited in various disease states. MSC are reported to have minimal known risk, potential immune alteration, and CNS regeneration, yet the lack of controlled studies in POMS precludes their current use in this population [
52]. Pediatric neurologic conditions treated with MSC include autism, cerebral palsy, and spinal muscular atrophy (SMA). MSC use in pediatric SMA was noted to be low risk yet not long-lasting, as there was recurrence of symptoms in SMA. The recurrence of symptoms in pediatric SMA may mean that MSC may indeed be a “maintenance” therapy after all [
53].
10. Biomarkers in MS
Biomarker is an objective measure of a biologic process or the pharmacologic response to a therapeutic intervention. Biomarkers may play a role in the DMT choice, DMT risk management, and predicting treatment response. Biomarkers would therefore help to effectively and efficiently tailor the care POMS patient and guide the caregiver and family. There are proposed biomarkers for the diagnosis of MS, the DMT choice, and DMT maintenance of the various disease modifying products, yet the majority of the data is in the AOMS (see
Table 8 below). Neutralizing antibodies to the interferons have been known to lessen efficacy and are used to guide therapy with the current recommendation to stop interferons due to high titers of neutralizing antibody [
60]. John Cunningham visual index, or JC index is used to gauge the safety of using Natalizumab due to risk of Progressive multifocal encephalopathy or PML. JC status, prior use of immunosuppressive products, and length of use of Natalizumab increase the risk of PML. If Biomarkers range from blood to CSF tests and include neutralizing antibodies leading to less efficacy of the DMT to serum or CSF evidence of neurotrauma, as that seen with Neurofilament light chain (NFL), a marker of white matter axonal injury. Glial fibrillary acidic proteins at elevated levels can also be seen in AOMS and in the future may be used as a biomarker of disease activity. POMS study showed high levels of NFL in the CSF of pediatric cases with acquired CNS demyelination [
61]. A low cost, simple test, such as a blood test, to predict and/or monitor the treatment response which could enhance the long-term outcomes of the patient due to enhanced active monitoring of the MS activity would be welcome as it could minimize patient discomfort due to tests, as well as minimize their cost.
There are possible biomarkers to guide therapy choice and to determine disease activity; neurofilament light chain (NFL) is one such biomarker. NFL and glial fibrillary acidic protein (GFAP) concentrations in the serum and CSF have correlated with overall disease activity, reflecting a recent relapse, disease progression, or MRI activity with a new or active lesion and may reflect axonal injury [
62,
63]. A blood test as a means of MS disease assessment would be a novel and effective way of managing a chronic disease that now relies on expensive MRIs for assessment of subclinical disease activity.