*Article* **Recommendations for the Diagnosis and Treatment of Multiple Sclerosis Relapses**

**Cristina Ramo-Tello 1,\*, Yolanda Blanco 2, Luis Brieva 3, Bonaventura Casanova 4, Eva Martínez Cáceres 5, Daniel Ontaneda 6, Lluís Ramió-Torrentá 7,8 and Àlex Rovira <sup>9</sup>**

	- <sup>8</sup> Department of Medical Sciences, University of Girona, 17004 Girona, Spain
	- <sup>9</sup> Section of Neuroradiology, Radiology Service, Vall d'Hebron Universitary Hospital, 08035 Barcelona, Spain; alex.rovira.idi@gencat.cat
	- **\*** Correspondence: cramot.germanstrias@gencat.cat

**Abstract:** Minimizing the risk of relapse is essential in multiple sclerosis (MS). As none of the treatments currently available are capable of completely preventing relapses, treatment of these episodes remains a cornerstone of MS care. The objective of this manuscript is to reduce uncertainty and improve quality of care of this neurological process. This article addresses definitions of key concepts, recommendations for clinical examination, classification criteria, magnetic resonance imaging, biomarkers, and specific therapeutic counsels including special populations such as pregnant and breastfeeding women, and children. An algorithm for treating MS relapses is also provided.

**Keywords:** multiple sclerosis; relapse; pseudo-relapses; methylprednisolone; treatment algorithm

#### **1. Introduction**

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). It is characterized by inflammation (clinically expressed in the form of relapses), multifocal demyelination, axonal loss, and gliosis in both the white and gray matter. Currently, the cause of MS remains unknown. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, myelin-specific T cells are believed to play a crucial role in pathogenesis [1]. Much has been published on the role of disease-modifying therapies (DMTs) in reducing annualized relapse rates and relapse severity in MS, but there is comparatively less evidence, or consensus on how relapses should be diagnosed or treated. Early detection and optimal management of relapses will help ensure appropriate control of the disease. A panel of eight experts in the management of MS (the authors) —six neurologists, a neuroradiologist, and an immunologist—was formed to develop this report on the diagnosis and treatment of MS relapses. The aim was to provide a framework to help reduce variability in clinical practice.

#### **2. General Principles**

#### *2.1. Relapse*

A relapse is the consequence of an immune-mediated attack on the CNS. A patient is suspected of having a relapse when the person reports or is objectively observed to

**Citation:** Ramo-Tello, C.; Blanco, Y.; Brieva, L.; Casanova, B.; Martínez Cáceres, E.; Ontaneda, D.; Ramió-Torrentá, L.; Rovira, À. Recommendations for the Diagnosis and Treatment of Multiple Sclerosis Relapses. *J. Pers. Med.* **2022**, *12*, 6. https://doi.org/10.3390/ jpm12010006

Academic Editor: Viviana Nociti

Received: 5 November 2021 Accepted: 16 December 2021 Published: 22 December 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

have evidence of a typical acute inflammatory demyelinating event in the central nervous system. Relapses are defined as clinical episodes lasting at least 24 h, in the absence of fever, infection or acute concurrent medical illness [2]. Relapses are also referred to as episodes, bouts, attacks, flares, flare-ups, or exacerbations.

The typical onset of a relapse in MS is subacute with intensity increasing over days, although cases of rapid onset have been described. In most cases, symptoms peak for about 1 to 2 weeks and then typically remit over the next 2 to 4 weeks without treatment. Based on the above time frames, for a relapse to be considered a second distinct event (second episode of CNS inflammatory activity), symptoms must occur at least 30 days after the start of the most recent flare and the new, recurring, or worsening symptoms must last for at least 24 h.

Agreement exists that the appearance of new symptoms within 30 days of initial onset corresponds to worsening of an existing episode, not a new episode. If the symptoms during this period are different to those at onset, the episode is considered to be multifocal. Other conditions, such as spinal cord compression, cerebrovascular disease, pseudo-relapses, and functional syndromes, must always be ruled out when a MS relapse is suspected.

#### *2.2. Pseudo-Relapses*

A pseudo-relapse is a clinical episode presenting with signs and symptoms similar to those observed in a previous relapse but in the absence of new inflammatory activity is due to systemic factors that can cause worsening of pre-existing neurologic symptoms. Its onset and resolution typically coincide with the triggering event. The possibility of relapse must be considered in patients whose symptoms persist after resolution of the triggering event or are more severe than prior episodes.

The main triggers of pseudo-relapses are infection (normally urinary or upper respiratory tract), stress, and increased body temperature due to external factors (e.g., a hot shower or high temperatures) or internal factors (e.g., fever or exertion) [3]. Worsening of symptoms caused by an increase in body temperature is known as Uhthoff's phenomenon.

Misdiagnosis of pseudo-relapses often leads to inappropriate corticosteroid treatment or changes to DMT or immunosuppressive therapy, resulting in unnecessary risks and adverse effects.

#### *2.3. Paroxysmal Symptoms*

Paroxysmal symptoms are less common manifestations of MS. Paroxysmal symptoms are characterized by their sudden onset, brevity (usually seconds to a few minutes) [4], frequency (from 10 to 20 times per day up to a few hundred times per day), stereotyped fashion, relatively long clinical course (at least 24 h) and typically respond to carbamazepine [5].

Classic paroxysmal symptoms include trigeminal neuralgia, Lhermitte's sign, clusters of tonic spasms, itching, paroxysmal diplopia, paroxysmal dysarthria with ataxia, paroxysmal paresthesia, and paroxysmal hemiparesis or hemitonic spasms. They are not accompanied by altered consciousness or changes in electroencephalographic activity.

When these symptoms occur in isolation, and particularly when they present for the first time, they may be the result of inflammatory activity indicative of a first relapse [6]. If they have occurred previously, they could reflect ephaptic transmission from an existing demyelinating plaque rather than acute disease activity. It is important to recognize and treat them with corticosteroids or carbamazepine as appropriate.

Epileptic seizures, aphasia, and other manifestations of cortical lesions are not considered paroxysmal symptoms in this context.

#### *2.4. Relapse Triggers to Keep in Mind*

Relapse rates are higher during the first three months postpartum [7]. Although the evidence is inconclusive, infections [8] including SARS-CoV-2 [9], vaccines [10] and stress [11] may trigger MS relapses too. Withdrawal of an effective DMT [12], monoclonal antibodies targeting tumor necrosis factor alpha (TNF-*α*) [13], gonadotropin-releasing hormone antagonists (used in the treatment of infertility, hormone-sensitive breast and prostate cancers, certain gynecological disorders and as part of hormone therapy in transgender patients) can also increase the risk of MS relapse [14].

#### *2.5. Relapse Phenotypes*

Relapse symptoms are readily identified when they are the result of acute inflammation in the optic nerve, spinal cord or brainstem/cerebellum.

There is increasing evidence that cognitive impairment (e.g., reduced performance at school or work) and psychiatric alterations could be due to an isolated cognitive relapse [15] or non-reactive depression [16]. Therefore it is recommended to quantify all new symptoms using appropriate tests or scales that permit follow-up and comparisons over time.

Relapse presentation tends to be monofocal, but patients can develop multifocal symptoms involving different functional systems as well.

#### *2.6. Relapse Severity*

There is currently no validated tool on how to assess the severity of a MS relapse. Physical exam is the most important tool for assessing the severity of MS relapse, the authors stress the importance of using the Expanded Disability Status Scale (EDSS) and recording it in the patient's medical record.

It would be helpful to apply the criteria followed in some clinical trials according to which a relapse can be considered to be mild when there is an EDSS increase of less than 1 point, moderate when there is an increase of 1 to 2.5 points, and severe when there is an increase of 3 or more points [17]. If pre-relapse information is not available in the medical record, a score of 2 or higher in the visual, brainstem, or pyramidal functional systems is required for optic neuritis, myelitis, or brainstem relapse respectively. In the case of relapse in an uncertain location, a score of at least 2 points in the EDSS is necessary [18,19].

The authors consider that it is important to quantify the severity and apply the proposed therapeutic algorithm (Figure 1) until more evidence is available. In this way, the EDSS at the time of relapse can be compared with the previous EDSS allowing to quantify the increase in disability related to the relapse (EDSS score on relapse minus previous EDSS score).

#### *2.7. Relapse Recovery*

Remission is not a synonym of recovery. Recovery is considered to occur when the patient's disability levels return to pre-relapse levels. Patients who do not recover prerelapse function and disability levels (measured by EDSS) within 6 months of treatment are considered to usually have permanent sequelae.

Some authors have postulated that severe relapses and longer duration are associated with a greater risk of sequelae [20]. There is some evidence that recovery after 12 weeks of treatment with methylprednisolone (MP) is determined by pre-relapse EDSS scores rather than relapse severity, with lower remission rates observed in patients with a pre-relapse score of over 3.0 [21].

#### **3. Clinical Examination**

The author's recommendations for the evaluation of patients in relapse are summarized in Table 1.

**Figure 1.** Therapeutic algorithm of MS relapse.

**Table 1.** Recommendations for the Assessment of Patients with Suspected Relapse.

#### **Recommendations for the Assessment of Patients with Suspected Relapse**

Mandatory:


Optional:


#### **4. Treatment**

The treatment goals for patients with a MS relapse are to shorten the duration and severity of the episode, relieve symptoms and increase recovery.

#### *4.1. Which Types of Relapse Should Be Treated?*

Corticosteroids relieve and shorten the duration of relapse symptoms but do not prevent sequelae and do not modify the disease course of MS over time [22]. It is therefore recommended not to treat mild relapses (increase in EDSS < 1 point), sensory relapses in particular, unless they have a significant impact on quality of life, and unless the potential benefits of treatment outweigh the potential adverse effects (AEs). Patients with remitting symptoms are often not treated.

#### *4.2. Therapeutic Window*

Patients should be made aware of the importance of informing their MS specialist team as soon as they suspect a relapse to ensure prompt evaluation, exclusion of a pseudo-relapse, and initiation of high-dose corticosteroids where appropriate.

#### *4.3. Corticosteroid Treatment*

The standard first-line treatment for relapses is corticosteroid therapy using highdoses of methylprednisolone (MP). The UK NICE (National Institute for Health and Care Excellence) guidelines [23] recommend administering at least 500 mg of oral MP every 24 h for 5 consecutive days. An alternative is to recommend 1 g of oral MP for 3 to 5 consecutive days [18,24,25] even for optic neuritis [26] given scientific evidence available to date.

The oral formulation offers greater convenience: enables treatment during weekends, prevents the patient from having to go to an outpatient clinic (a significant advantage during the SARS-COVID-19 pandemic) and results in considerable savings in terms of healthcare costs and prevents work productivity loss. As the vast majority of countries do not have access to oral commercial formulations of high-dose MP, hospital pharmacies need to prepare these formulations or request the manufacturers to produce tablets of various doses. Ideally, patients should be prescribed 500 mg tablets to enable the administration of 500-mg/24 h for 5 consecutive days or 1000 (500 + 500) mg/24 h for 3–5 consecutive days. The US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) have not approved MP for oral use.

1 g of intravenous MP for 3 to 5 consecutive days can be administered if preferred by the physician or patient, in cases where oral MP has failed or is not tolerated, and if hospitalization is required due to severe symptoms, or to monitor other medical or psychological conditions such as diabetes and depression.

There is evidence suggesting that tapering doses of oral corticosteroids following high-dose administration does not offer benefits [27] and there is no significant risk of adrenal suppression.

Patients must be informed that they should expect to see an improvement within an average of 1 to 2 weeks of starting the first course of MP.

Patients with moderate relapses who do not tolerate MP could be candidates for adrenocorticotropic hormone therapy [28] administered as an intramuscular or subcutaneous injection at 80–120 units for 14–21 days. A growing number of studies report favorable results in this setting. However, ACTH gel is significantly more expensive than steroids.

#### *4.4. Inadequate Response to MP*

The authors agreed that the definition of inadequate treatment response included worsening of the EDSS within 2 weeks of MP initiation. If the increase in EDSS is moderate (1–2.5 points), a second course of MP should be given as per the recommendations in the section on corticosteroid treatment. If the increase is substantial (≥3 points), treatment with plasmapheresis should contemplated. Plasmapheresis is the only second-line treatment for steroid-resistant exacerbations supported by solid clinical evidence [29]. The procedure is performed every other day to reach a total of five sessions, although a shorter may be used in patients showing an optimal response.

Patients with a suboptimal response after five plasmapheresis exchanges or patients in whom MRI shows persistent acute inflammatory activity should be started on a thirdline therapy. Options include (1) cytotoxic therapy with myeloablative agents such as cyclophosphamide (200 mg/kg/d for 4 days intravenously) [30], or (2) an initial high loading dose of rituximab (2000 mg intravenously) divided into 2 infusions given 2 weeks apart to attack antibody-secreting B lymphocytes [31], or (3) a single dose of natalizumab (300 mg intravenously) to prevent lymphocytes from crossing the blood-brain barrier [32]. These third-line treatments, which can also be used for fulminant or tumefactive demyelination, are not supported by strong evidence, but are commonly used in severe cases.

Data suggest that intravenous immunoglobulin therapy is not useful [32–34], but it could be a suitable option for patients with severe relapses who do not have access to a center with plasmapheresis.

Patients with severe relapses who are intolerant toMP should be treated with plasmapheresis.

#### *4.5. Adverse Effects of Methylprednisolone*

Patients must be warned that they may experience immediate adverse effects (AEs) during treatment with high-dose MP. AEs are generally mild or moderate. The most common AEs are insomnia, mood changes (irritability, euphoria and depression), gastrointestinal disorders, palpitations, weight gain, edema, acne, headache, musculoskeletal pain, and a metallic taste in the mouth. Patients should also be warned about the risk of infections, such as herpes, sepsis, pneumonia, arthritis, bursitis, and complicated urinary infections.

The need for prophylactic treatment of AEs should be assessed on a case-by-case basis. Examples are insomnia medication and gastroprotective drugs for patients with a history of peptic ulcers, acid reflux, or hiatal hernia. Diabetic patients should be advised to monitor their blood sugar levels closely, and despite the lack of evidence, non-diabetic patients should undergo capillary blood glucose testing at their primary care center or local pharmacy. Blood pressure should also be monitored in patients with hypertension.

Serious events are rare. The most common serious event are psychosis, depression, and mania. There have been very few reports of reactivation of latent infections to date, but caution is warranted as patients on immunosuppressive DMT are at an increased risk. There are no data showing that high-dose MP significantly increases the risk of latent chronic infections.

High doses of MP are considered to be immunosuppressive. MP should not be administered 8 weeks before or 8 weeks after the administration of live or attenuated live vaccines because of the increased risk of complications due to viral replication [35]. Vaccines containing inactivated or killed organisms may be used, although response may be diminished.

#### *4.6. Symptomatic Treatment during MS Relapses*

It should be contemplated for pain, spasticity, and diminished sphincter control, as it can improve function, patient comfort, and quality of life.

The benefits of rehabilitation during acute relapse are not well established [36] but in general is recommended. Patients with fatigue and motor or sensory cord deficits may need to rest and be warned about the risk of falls, while those with sensory deficits for pain should be warned of the risk of injury.

#### *4.7. Relapse Treatment during Pregnancy*

The FDA does not classify MP as a pregnancy risk drug.

High-dose corticosteroids administered for short periods (3–5 days) appear to be safe during pregnancy, especially in the second and third trimesters.

There is conflicting evidence on the association between corticosteroid use during pregnancy and the risk of cleft lip and/or cleft palate [37]. There is little evidence that systemic corticosteroid use in pregnancy independently increases the risk of preterm birth, low birth weight, or preeclampsia. Currently, there is not enough evidence to determine whether systemic corticosteroids might contribute to gestational diabetes mellitus [38].

Intravenous immunoglobulins could be a suitable option for patients with severe relapses who do not respond to MP, although the risk of AEs such as cerebral venous thrombosis (which has an increased risk of occurring during pregnancy) must be contemplated [39]. Plasmapheresis performed under expert supervision can also be considered in such cases. The couple must always be involved in treatment decisions.

#### *4.8. Relapse Treatment during Breastfeeding*

Women with MS are at an increased risk of relapse in the postpartum period. Although the level of MP transfer into breast milk is very low, generally IVMP treatment is not advised during breastfeeding. If the mother wishes to continue breastfeeding, intravenous MP is preferable to oral, as it has a shorter peak effect. Patients should wait for 2–4 h before breastfeeding after administration of MP, as there is evidence that levels in infants after this time are lower than those in infants being treated with MP for another condition (0.25 mg/kg) [40]. Another option is to breastfeed only before receiving high doses of MP. Mothers can also use the approach of expressing milk using a breast pump, which can later be offered to the baby, before receiving MP.

#### *4.9. Relapse Treatment in Children*

Considering the lack of evidence regarding the treatment of MS relapses in the pediatric population, the recommendations in children are based on data from adult studies. MP is the most commonly selected first-line therapy for disabling MS relapses in children. The recommended treatment is intravenous MP 30 mg/kg/d (maximum 1000 mg/d) for 3–5 consecutive days [41]. Although equivalent studies have not been performed in children, it is assumed that high-dose oral corticosteroids will be similarly effective for the treatment of MS relapses in children and adults. Oral corticosteroid taper for the treatment of relapses is not a routine practice in pediatric MS. One exception is acute disseminated encephalomyelitis, where the recommended treatment is high-dose corticosteroids followed by an oral taper over 4–6 weeks with a starting dose of prednisone of 1–2 mg/kg/day. A taper period of 4–6 weeks is recommended as an increased risk of relapse has been observed with periods of 3 weeks or less [42].

As with adults, non-responders should be administered a second course of MP or treated with plasmapheresis [43].

The author's algorithm for treating MS relapses is summarized in Figure 1.

#### *4.10. Treatment of Asymptomatic Active Lesions on MRI*

It is difficult to evaluate the immediate or delayed effects of treatment initiated for acute lesions without clinical correlates. Magnetic resonance Imaging (MRI) studies have shown that focal signal abnormalities reflecting inflammatory activity can precede clinical manifestations by several weeks [44]. Because of this mismatch between imaging and clinical manifestations, it is possible that by the time a patient develops symptoms and is prescribed corticosteroid treatment, he or she may already have developed permanent residual disability due to demyelination and even axonal damage. There are neurologists who think that an asymptomatic new lesion on MRI should be treated accordingly [45] and others who think otherwise, as there is no evidence of the comparative effectiveness of these approaches [46,47].

There is also no evidence available on whether or not to treat large or numerous asymptomatic lesions involving the brainstem or spinal cord.

The authors recommend performing a more exhaustive examination (using the SDMT, the Nine-Hole Peg Test, or a fatigue scale) in patients with "asymptomatic" active lesions detected by MRI to establish whether lesions are truly subclinical.

#### **5. MRI Studies during Relapses**

MRI is the gold standard diagnostic test for MS but it is often impractical to obtain in a timely fashion in relation to relapse and can miss lesions for determined variety of reasons. Brain and spinal cord MRI scans are not necessary in patients with a clear diagnosis of MS relapse. They are, however, recommended in patients with an unclear or non-objectively observed clinical relapse and should be performed before starting corticosteroid treatment, as corticosteroids can reduce the time during which lesions show contrast uptake. MRI should be performed ideally within the first 72 h if steroid treatment is planned, and within 2 to 3 weeks of relapse onset in patients that do not receive steroid treatment because mean enhancement duration without treatment is 2–4 weeks [48].

A brain MRI study can demonstrate gadolinium-enhancing lesions when cognitive impairment, depression, or even excessive fatigue is suspected to be due to a new episode of inflammatory activity.

Sometimes a spinal cord MRI is deemed necessary to confirm a relapse likely related to spinal cord involvement. A brain MRI is also necessary in such cases, as active spinal lesions tend to be associated with active cerebral lesions, which are easier to identify. This combined strategy increases the likelihood of detecting active inflammatory lesions. However, adding spinal cord MRI to brain MRI in patients with relapses related to brain lesions does not appear to increase the sensitivity of MRI for detecting disease activity.

The abbreviated MAGNIMS (Magnetic Resonance Imaging in MS) MRI protocol should be followed at all times [49,50]. The contrast agent should be injected at least 5, and ideally 10, minutes before obtaining the T1 sequence. This wait time can be used to obtain other sequences included in the protocol (T2-FLAIR, T2).

MRI studies, particularly MRI conducted with contrast, should be avoided during the first trimester of pregnancy.

The author's recommendations for the MRI assessment of patients in relapse are summarized in Table 2.

**Table 2.** Recommendations for the MRI Assessment of Patients with Suspected Relapse.


#### **6. Biomarkers**

There have been reports of changes in lymphocyte subpopulations that can predict or support the occurrence of a relapse and that normalize after corticosteroid treatment [51,52]. There are, however, no immune related biomarkers currently available outside research applications.

Neurofilament light (NfL) chain protein is a cytoskeletal protein located in neuronal axons. Increased cerebrospinal fluid and blood NfL levels have been described in MS (following axonal injury) and other diseases. They have also been linked to aging. The possible value of NfL as a biomarker for MS relapses has been postulated in recent years, as increased levels have been associated with the presence of gadolinium-enhancing lesions on MRI [53]. In this context, in patients with early MS, the presence of both abnormal NfL and thin ganglion cell and inner plexiform layer in retinal optical coherence tomography (OCT) have been described as additive risk factors of disease activity [54].

More recently, wide metabolomic studies have shown metabolic perturbations during relapses, and several serum metabolites, mainly lysine and asparagine (higher in relapses), as well as isoleucine and leucine (lower in relapses), postulated as potential biomarkers useful to differentiate relapse from remission. Future metabolomics studies will need to prospectively include MRI scans to understand metabolic signatures and their relation with MRI-defined inflammation [55].

#### **7. Conclusions**

Diagnosis and particularly treatment of MS relapses varies greatly among clinicians. This document offers a series of simple and practical statements with recommendations that, although not reaching full consensus" reflect the realities of current clinical practice. They are easy to implement in daily practice and can be readily adapted to the specific needs of practitioners seeking to standardize care processes in MS. Further studies on larger cohorts are required to confirm the effectiveness of the interventions regarding relapses in MS.

**Author Contributions:** Conceptualization, C.R.-T.; Validation, C.R.-T.; Visualization, Y.B., LB., B.C., E.M.-C., D.O., L.R.-T. and À.R.; Writing—original draft, C.R.-T.; Writing—review & editing, C.R.-T., Y.B., L.B., B.C., E.M.-C., D.O., L.R.-T. and À.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by NOVARTIS FARMACÉUTICA, SA, for the two expert panel meetings held and the recording and transcription of the content of the first meeting performed by the contract research organization, Dynamic.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors would like to thank Praneeta Raza and Susi Soler for editorial assistance with the manuscript.

**Conflicts of Interest:** Cristina Ramo-Tello has received personal compensation for scientific consultancy work and/or help with travel expenses for attending conferences from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Almirall, Brystol and Roche. The Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, where Ramo-Tello works has received grants from Novartis, Sanofi-Genzyme, Bristol, Roche and Almirall. Yolanda Blanco has received speaker honoraria from Novartis, Roche, Merck, Genzyme-Sanofi and Biogen. Luis Brieva has received support for research projects from his group as well as speakers' and consultancy fees and help with travel expenses for attending conferences from Bayer, Biogen, Roche, Merk, Novartis, Allmirall, and Sanofi. B. Casanova serves on scientific advisory boards for Novartis, Sanofi-Genzyme, and Roche, and has received speaker honoraria from Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd., Novartis, Roche, Celgene and Biogen. Eva Martinez-Cáceres has received personal compensation for scientific consultancy, speaker honoraria or help with travel expenses for attending conferences from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. D. Ontaneda has received research support from National Multiple Sclerosis Society, National Institutes of Health, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, and Genzyme. He has also received consulting fees from Biogen, Genentech/Roche, Genzyme, and Merck. Ll. Ramió serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Roche, Celgene and Almirall, and has received speaker honoraria from Roche, Biogen, Novartis, Sanofi-Genzyme, Merck, Celgene, Bayer and Teva Pharmaceutical Industries Ltd. Rovira serves on scientific advisory boards for Novartis, Sanofi-Genzyme, SyntheticMR, Bayer, Roche, Biogen, and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd., Novartis, Roche and Biogen. The funders had no role in the writing of the manuscript, or in the decision to publish it. The authors confirm that this manuscript complies with ethical standards.

#### **References**


### *Review* **Escalation vs. Early Intense Therapy in Multiple Sclerosis**

**Bonaventura Casanova 1,\*, Carlos Quintanilla-Bordás <sup>1</sup> and Francisco Gascón <sup>2</sup>**


**Abstract:** The treatment strategy of multiple sclerosis (MS) is a highly controversial debate. Currently, there are up to 19 drugs approved. However, there is no clear evidence to guide fundamental decisions such as what treatment should be chosen in first place, when treatment failure or suboptimal response should be considered, or what treatment should be considered in these cases. The "escalation strategy" consists of starting treatment with drugs of low side-effect profile and low efficacy, and "escalating" to drugs of higher efficacy—with more potential side-effects—if necessary. This strategy has prevailed over the years. However, the evidence supporting this strategy is based on short-term studies, in hope that the benefits will stand in the long term. These studies usually do not consider the heterogeneity of the disease and the limited effect that relapses have on the long-term. On the other hand, "early intense therapy" strategy refers to starting treatment with drugs of higher efficacy from the beginning, despite having a less favorable side-effect profile. This approach takes advantage of the so-called "window of opportunity" in hope to maximize the clinical benefits in the long-term. At present, the debate remains open. In this review, we will critically review both strategies. We provide a summary of the current evidence for each strategy without aiming to reach a definite conclusion.

**Keywords:** multiple sclerosis treatment; escalating strategy; he-DMT; diseases modifying therapies; early intense therapy

#### **1. Introduction**

*1.1. Multiple Sclerosis: A General Overview*

Multiple sclerosis (MS) is a disorder of remarkable heterogeneity that affects the central nervous system. It is characterized by inflammatory attacks to the myelin and axons, and by neurodegenerative cascade that give rise to progression of the disease independent of the initial inflammatory activity [1,2].

Based on these immunopathogenic mechanisms we can find two clinical forms of onset: bout-onset and progressive-onset disease. Bout-onset multiple sclerosis (BOMS) is characterized by relapses and remission (hence, relapsing-remitting MS (RRMS)). More than 50% of patients with BOMS will develop after variable time sustained progression of disability independent of the relapses, and hence, will convert to secondary progressive MS (SPMS). On the other hand, progressive-onset MS (POMS), is characterized by a sustained worsening of the disability since the beginning of the disease (hence, primary progressive MS [PPMS]) [3,4].

Relapses and progression are the main determinants of disability in MS [5]. However, natural history studies show that once progression becomes clinically evident, disability is no longer determined by the presence of previous relapses, and therefore is independent of the clinical form of onset (either BOMS or POMS). In fact, relapses have been shown to be minor contributors of progression of the disease. Specifically, short time between the first and second relapse and a sudden increase in the relapse rate in the preceding two years

**Citation:** Casanova, B.; Quintanilla-Bordás, C.; Gascón, F.

Escalation vs. Early Intense Therapy in Multiple Sclerosis. *J. Pers. Med.* **2022**, *12*, 119. https://doi.org/ 10.3390/jpm12010119

Academic Editor: Cristina M. Ramo-Tello

Received: 22 November 2021 Accepted: 1 January 2022 Published: 17 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

have been linked to the risk of developing SPMS, and yet they have little or no impact on disability once the progression has started [6,7].

At this point, two concepts must be introduced: relapse-associated worsening (RAW); the determinant of disability in RRMS, and steady progression independent of relapse activity (PIRA); the main determinant of disability in SPMS and PPMS [8–10]. Two other important considerations must be considered: the uncertainty of the real disease onset, and the lifelong duration of the disease. The diagnosis of MS is made based on the presence of relapses or sustained progression of disability in conjunction with typical magnetic resonance imaging and/or cerebrospinal fluid features. Therefore, it is important to recognize that the diagnosis may not truly mark the real onset of the disease, but rather the time at which the disease becomes clinically apparent and fulfills our established criteria to minimize the risk of misdiagnosis. Furthermore, BOMS is diagnosed around thirty years old, and SPMS and PPMS around forty-five years old. Considering life expectancy may be reduced by 5–7 years on average, it means that the average disease duration will be of 50 years for BOPMS and 35 years for POMS. These facts must be considered when analyzing clinical trials, as the apparent clinical disease duration may not be representative of the real disease duration, (thereby acting as a confounding factor)*,* and because the follow-up times of these trials are too short to evaluate the impact over the long-term of the disease [11].

Continuing with the uncertainty surrounding MS, one of the main problems we face in treating MS is whether there is activation of the innate immune system, which has been linked to the progression of disability, from the onset of the disease or whether it occurs at some point as a result of dysregulation of the acquired immune system joint to the phenomenon of antigenic spread. There is currently no answer to this question, but very early initiation with induction drugs that reset the immune system, such as Alemtuzumab, have given the best results in terms of long-term progressive secondary progressive progression, which may indicate that intense early treatment could prevents activation of the innate immune system and triggering of the innate immune-dependent mechanisms responsible for the progression of the disability.

#### *1.2. The Selection of the Objective in Clinical Trials*

According to natural history studies and previous knowledge of the disease, the two main clinical endpoints chosen in phase III trials have been relapses and progression of disability [12]. When correlation between relapses and gadolinium-enhancing lesions (GEL) in the MRI was proven, it was also introduced as a surrogate marker of disease activity in phase II trials [13–16]. In fact, phase II trials have now replaced annualized relapses rate (ARR) with number of GEL as the primary endpoint, becoming the former a secondary endpoint, which has allowed trials to be shortened to six months. Meanwhile, phase III trials have maintained clinically defined primary endpoints: ARR for RRMS trials, and time to sustained progression confirmed in 3 or 6 months for PPMS trials [17].

Clinical secondary objectives in RRMS have been time to sustained progression of disability confirmed at 3 or 6 months. With the introduction of the MRI, T2 lesion number and volume, GEL number, and more recently, brain atrophy measures have been implemented in clinical trials [18]. However, it is important to consider the limited effect that these primary endpoints have in the natural history of the disease (i.e., development progressive course) and the potential confounding between relapse-related worsening and progressive disease [11]. This may explain the discrepancy observed between short-term efficacy of DMT on EDSS (mostly dependent on disability accumulation due to relapses) and the absence of effect to delay conversion to SPMS and to slow down progression of disability in PPMS and SPMS. An approach to deal with this problem has been to introduce the aforementioned concept of PIRA in clinical trials, as a way to distinguish progression of disability independent of relapses [19].

Also, scales other than EDSS such as the Multiple Sclerosis Functional Composite (MSFC), and other clinical and radiological variables, have been introduced to increase the sensitivity of progression of disability. However, uncertainty regarding the real clinical impact of these measures has limited their use [20,21].

Finally, care must be taken when assessing the clinical endpoint of a clinical trial. Firstly, the ARR may not harvest all the "focal" inflammatory activity. Secondly, ordinary brain MRI monitoring may fail to detect cortical lesions and ectopic meningeal follicles. Thirdly, progression measured by the EDSS is insensitive to minor clinical changes, especially when related to cognition [2].

For these reasons, treatment strategy in MS must be based on a judicious interpretation of the evidence from clinical trials. Special attention should be given to the actual results observed, as they may not reflect the reality of the disease and long-term effectiveness.

#### *1.3. Classification of Disease Modifying Therapies*

Before 1993, MS treatment was based on several immunosuppressive drugs, but it was with the approval of interferon (IFN) beta-1b (Betaferon®) that a new era of MS treatment began. Since then, nineteen drugs have been approved and four are already in the process of approval by the regulatory agencies. Obviously, each drug has a particular mechanism of action (MoA), level of effectiveness, and safety profile. According to the decrease in the ARR, DMT have been classified as moderate-intermediate efficacy and highefficacy therapies (HET). IFN, glatiramer acetate (GA), azathioprine, and the newer orals drugs teriflunomide and dimethyl fumarte (dimethyl fumarate) are usually considered as being of moderate efficacy. Fingolimod, other sphingosine-1-phosphate (S1P) receptor modulators and cladribine are usually considered as intermediate efficacy drugs. Finally, monoclonal antibodies (MoAb) such natalizumab, alemtuzumab and ocrelizumab, together with mitoxantrone (an antineoplastic agent) are usually considered HET. Daclizumab, a MoAb, is no longer considered as a treatment for MS due to severe and unacceptable secondary effects [22–34].

Aside to this classification, DMT have been also classified as "first-line" therapies and "second-line" therapies. The former, DMTs of moderate efficacy but low side effects profile such IFN, GA, teriflunomide and dimethyl fumarate are usually included. In the USA, fingolimod and cladribine are also considered as "first-line" DMT. "Second-line" therapies include the MoAb and mitoxantrone. The use of these terms is applicable for the treatment of RRMS, but not for PPMS and SPMS [35].

Classification of DMT into "lines" of treatment has been the most popular one, and this has determined the escalation-based treatment approach, despite the absence of clinical evidence and disparities in this classification. For example, fingolimod is considered as a "second-line" drug in Europe, but a first-line drug in the USA. On the other hand, dimethyl fumarate, despite having several cases of progressive multifocal leukoencephalopathy (PML), is considered a first-line therapy. Additionally, cladribine, which is approved in Europe for highly active RRMS, and in the USA also for relapsing forms SPMS, has not been robustly studied in either of these settings.

For more than 25 years, this absurd classification into lines of treatment that implies an escalation approach strategy has prevailed. The question arises as to whether this is the best approach when considering the long-term impact on the disease [36].

#### *1.4. The Concept of Treatment Failure*

The first double blind randomized placebo controlled clinical trial in RRMS, tested IFN-1b against placebo. After three years, the number of relapse-free patients was 17/123 (13.8%) in the placebo arm; and 27/124 (21.7%) in the treated-arm [37]. It was clear that almost 2/3 of patients had relapses despite treatment. Consequently, three lines of investigation were established: to identify non-responders; to define baseline characteristics of non-responders; and to study the consequences of a suboptimal response. All these lines of investigations prompted a definition of treatment failure (TF) or suboptimal response (RSO). Waubant et al. were the first authors to define TF, based on the relapse rate, and defining TF as an ARR similar to the previous year [38]. Rio et al. used different criteria to define TF, as it

included progression of EDSS, and a combination of clinical activity and MRI outcomes. However, progression of EDSS was a confounding factor, as IFN was not intended to treat progression. Sormani then modified these criteria (hence, the modified Rio-Sormani score), which remain as the most widely accepted definition of TF in current studies [39,40].

It is important to highlight that that the modified Rio-Sormani score has only been validated with IFN-1b treatment. If we want to apply these criteria in current clinical practice, we must consider the real value of a drug and the consequences of TF. For example, if a given drug is not intended to treat progression, it is reasonable that TF should not be considered when treatment has no effect on progression.

In agreement with this idea, it does not seem reasonable to consider TF when a progressive increases in disability are demonstrated under a determinate treatment, if the treatment have no effect over progression, at the same time, the presence of some inflammatory activity in form of relapses and/or MRI activity, are expected.

The short duration of clinical trials and observational studies has set the focus on the short-term effect of DMTs over disability, leading to the escalation strategy. However, long-term studies show DMT have a scarce effect on the risk of conversion to the SPMS and on disability once the progressive phase has started. This raises the question as to whether an escalation approach therapy is really appropriate [9,41].

Furthermore, if we follow the principle primum non nocere ("first, do no harm"), we should be cautious when escalating therapy, as HET initiation years after the disease increase the likelihood adverse events, but still do not change the long-term prognosis of the disease. HET have shown to have a greatest effect on the risk of conversion to SPMS when initiated early in the disease, during the so-called "window of opportunity". Still, early treatment with HET may expose young, healthy individuals with minor disability to serious side effects. Thus, the real debate should be whether the risks of early initiation HET outweigh the risks over the long term, and not where early intense therapy is "more efficacious" than escalation therapy.

#### **2. Escalation Therapy**

#### *2.1. Definition*

Escalation therapy must be clearly defined to compare studies and management strategies consistently. A European survey about MS management showed that treatment escalation or initiation based on relapses or new T2 lesions varied significantly between different countries, territories and even at institutions themselves [42]. There was a high agreement in switching to a HET when a patient experienced either two relapses, 5–8 new T2 lesions or two gadolinium enhancing lesions within a year [43]. However, this threshold is probably too high since these patients have a high probability to develop SPMS in the next two years. Hence, to evaluate the impact of treatment escalation, studies must clearly define previous DMTs, time evolution of the disease, and most importantly, the reason for treatment escalation. Otherwise, these studies may lead to paradoxical results, as was the case in the based on one of the largest registries of patients with multiple sclerosis, the MSBase registry, which used propensity score methodology, showed that patients starting on HET (fingolimod, alemtuzumab or natalizumab) had lower probability of conversion to SPMS when compared to patients starting on GA or IFN. In this series, time to treatment initiation was 6.5 years for HET vs. 5.1 years for GA or IFN. Furthermore, the authors reported a lower risk of conversion to SPMS when GA or IFN was started within 5 years versus later. In fact, treatment escalation after 5 years of evolution did not have a clear effect on the probability of converting to SPMS [43].

These evidence highlights the importance in defining to whom and to what DMT is being changed, as this is they are the only way to obtain clear conclusions from the escalation-based treatment strategy. It is not an academic question, as data shows that timing of treatment is crucial to impact significantly the probability to convert to SPMS, which might be related to effects of an aging immune system (i.e., immunosenescence) and

loss of a potential "window of opportunity", which evidence suggests is limited to around 5 years.

#### *2.2. Trials That Support Escalation Therapy*

The currently approved HET are: natalizumab, fingolimod, alemtuzumab, ocrelizumab and cladribine. However, only fingolimod, alemtuzumab and ocrelizumab have been studied in appropriate clinical trials and have class A evidence of superiority with respect to other first-line therapies.

#### 2.2.1. Fingolimod

The TRANSFORMS trial, fingolimod was assessed against IFN beta 1-a for one year in patients with RRMS between 18 and 55 years [44]. Patients had to have a relapse within the previous year, or two relapses within the previous two years, and a EDSS score between 0 and 5.5. 1292 patients were randomized: 426 to fingolimod 1.25 mg once a day; 431 to fingolimod 0.5 mg once a day-; and 435 to follow with IFN beta 1-a 30 μg i.m. weekly. The main clinical results were a reduction of the ARR of 0.16 in the 0.5 mg fingolimod arm, vs. 0.33 in the IFN beta 1-a arm; 82.6% of relapse-free patients in the 0.5 mg fingolimod arm vs. 69.3% in the IFN beta-1-a arm; and no differences with respect to progression of disability after one year. The main criticism of this trial (and other subsequent trials) is that the "active" treatment was continued even during a suboptimal response. Moreover, 45% of patients already had been treated with a previous DMT. Therefore, is difficult to draw conclusions about the effect of a treatment when is compared to another that has previously failed in these patients. Even so, the main clinical endpoint (progression of disability) was not met. Moreover, the extension trial at two years, despite having good results in MRI variables, still did not show any significant differences in progression of disability.

#### 2.2.2. Alemtuzumab

The second HET that was explored against an active comparator in naïve patients or that failed to a previous treatment was alemtuzumab. This was assessed in the two-phase III clinical trials: the CARE-MS I and the CARE-MS II. In the former, 581 naïve patients with RRMS were randomized in a 2:1 proportion to receive either alemtuzumab 12 mg or Rebif-44 3 days a week and followed up for two years. The main results were a reduction of the ARR of 0.18 in the alemtuzumab arm vs. 0.39 in the Rebif-44 arm, and 77.6% of relapses-free patients in the alemtuzumab arm vs. 58.7% in the Rebif-44 arm. There were no differences in sustained accumulation of disability confirmed over 6 months between groups, possibly due to the low baseline disability of patients. In the CARE-MS II trial, 636 RRMS patients with at least one relapse while on GA or IFN beta were randomized in 2:1 proportion to receive alemtuzumab 12 mg or Rebif-44. After two years, 65.4% in the alemtuzumab 12 mg arm remained relapse-free vs. 46.7% in the Tebif-44 arm. Unlike CARE-MS I, this trial showed a lower rate of sustained confirmed progression at 6 months in the alemtuzumab arm (13% vs. 20%). There was also a positive effect over the MSFC score and MRI measures. Hence, CARE-MS II, which used a population with higher inflammatory activity (previous treatment failure) and higher EDSS, did show a clear effect on disability accumulation [45,46].

#### 2.2.3. Ocrelizumab

The development phase III program of ocrelizumab in RRMS was done in two simultaneous and identical trials: OPERA-I and OPERA-II. Inclusion criteria required at least one relapse within the previous 2 years. These trials randomized a total of 1656 patients in a 1:1 ratio to receive ocrelizumab or Rebif-44. 71% and 73% were treatment naïve. The main results in the pooled analyses were a reduction in the ARR (0.16 in the ocrelizumab arm vs. 0.29 in the Rebif-44 arm), and a reduction in the proportion of patients reaching disability progression confirmed at 12 weeks (9.1% vs. 13.6%, respectively). However, subgroup analyses suggested that the reduction of progression of disability was not significant among

the 224 patients that were previously treated with a DMT, despite having a positive effect on the ARR. Similarly, subgroup analyses showed that the reduction of progression was not significant when considering patients with a body mass index of 25 or more. This example of "tortured-data", seems to suggest ocrelizumab may be more effective in lean than overweight patients [47,48].

#### *2.3. Summary*

The efficacy of escalation to HET has been evaluated in a myriad of observational studies, but level A evidence supporting this strategy is scarce. Although evidence shows that escalation therapy is useful to abrogate inflammatory activity, it has only showed a modest effect over the progression of disability. In fact, the longest observational studies still show that this strategy is futile to prevent conversion to SPMS. However, this does not prove that this strategy is not valid. We might consider it as a useful therapy to reduce relapses and the progression of disability in the beginning of the disease. Data suggest that beyond four or five years, the effect on relapses maintains, but not on accumulation of disability.

#### **3. High-Efficacy Therapy**

#### *3.1. Definition*

High-efficacy therapy (HET) refers to agents that have a greater impact on inflammation compared to moderately effective therapies [49]. Therefore, the classification of DMT as high-efficacy is based on favorable outcomes from clinical trials comparing that treatment usually to traditional DMTs (mostly inflammatory outcomes such as relapses and new lesions, although some experts prefer to evaluate lack of disability too) [49].

There is an agreement to consider natalizumab, antiCD20 therapy (rituximab and ocrelizumab), alemtuzumab, mitoxantrone, cyclophosphamide and autologous stem cell transplantation as HET. However, there is not a consensus regarding sphingosine-1-phosphate receptor modulators such as fingolimod (some consider it an intermediate efficacy therapy) and cladribine (as it has been compared to placebo, although it probably has an induction effect) [49] (Table 1).


**Table 1.** Early Intensive Therapy. \* There is not consensus regarding Cladribine and fingolimod (as some authors consider them HET and others not).

As opposed to escalation, where treatment starts with a low-risk and lower-efficacy treatment and only moves on to a more aggressive treatment if the ongoing approach fails, early aggressive therapy or Early Intensive Therapy (EIT) considers starting highefficacy treatment earlier in MS, mostly initially since its onset, to maximize the potential for preventing disability progression over time, assuming a higher-risk profile of adverse events [48,50].

Many consider that EIT as the best way to achieve long-term outcomes for people with MS, based on the following rationale: the ability to predict disease course at onset is limited, conventional imaging underestimates ongoing damage, irreversible nervous damage occurs very early and once neurological function is lost it cannot be regained. MS is rarely benign over the long term. Long term follow-up studies reveal the risks of

undertreatment. Safety profile of some HET may not differ from low-efficacy treatment and it is mainly early intervention that might substantively alter disease course and prevent irreversible progression, whereas later treatment might not confer much benefit [3–9]. Therefore, EIT is based on using highly effective treatments starting early, while on the therapeutic window, where they are more effective than when started later on the disease course in the escalation approach [51–57] (Table 2).


**Table 2.** Long-term outcomes of Early Intensive Treatments: Observational Studies.

However, when considering EIT, two main approaches arise. Firstly, Induction treatment (IT), also referred to as immune reconstitution therapy which is based on the use of HET with a sustained biological effect in naïve patients, followed or not by long-term maintenance treatment (generally with immunomodulatory agents) and secondly, sustained HET, which is based on the use of HET continuously, as their effect wanes when interrupting treatment [50–57]. Induction treatment includes mitoxantrone, cyclophosphamide, stem cell transplantation, alemtuzumab and cladribine, whereas the potential inductive effect of antiCD20 therapy is mild and of natalizumab and fingolimod is null (as their withdrawal is associated with reactivation of the disease) [50–56]. Induction treatments usually are associated with a higher risk profile but shorter in time as their administration is not sustained, while the use of continuous HET is associated with a risk profile sustained overtime. The rationale for induction therapy is to influence the inflammatory phase and to avoid the subsequent chronic phase resetting the immunological system to prevent the phenomenon of epitope spread [50–52]. The risk associated with treatment that is judged acceptable may vary with disease severity, however, disease severity might be underestimated, specially early at onset, and treatments are less effective as disease evolves [51,54–56]. It is known that MS patients treated early do better than those in whom treatment is delayed, but regarding the question does the potency of DMT truly matter, recent observational studies show better long-term outcomes on disability accumulation and risk of conversion to SPMS with EIT than escalation [57].

#### *3.2. Results over Inflammatory Activity, Progression, and Safety*

Natalizumab's original trial, AFFIRM study, showed a 68% reduction in ARR at year 1, 42% relative risk reduction in disability progression at 2 years, 83% reduction of new T2 lesions and 92% reduction in contrast enhancing lesions compared to placebo. The REVEAL study compared natalizumab to fingolimod with a lower cumulative probability of relapse and gadolinium-enhancing lesions 70% lower in the natalizumab group. Several observational studies comparing naive patients treated with natalizumab vs. injectables DMT have shown greater reductions in ARR and disability accrual, and others, when comparing escalation to Natalizumab to those switching to fingolimod have shown higher rates of NEDA with natalizumab. The TOP study at 5 years reported lower ARR in naive natalizumab patients than those who escalated to natalizumab from prior DMTs. Natalizumab main risk are infusion related reactions and PML risk [49,63].

Regarding Alemtuzumab, phase II CAMMS223 in naive RRMS showed better results on relapses, disability accumulation, MRI activity and atrophy compared to interferon at 3 years. In the CARE-MS I study with naive RRMS alemtuzumab reduced significantly ARR and MRI activity at 2 years but not disability progression compared to interferon-beta-1A, and in the CARE-MS 2 study with RRMS who failed to previous DMT, alemtuzumab reduced the ARR, MRI and disability progression at 2 years compared to interferon. Extension studies up to 6 years showed sustained benefits of alemtuzumab on clinical and MRI activity and progression of disability in a great proportion of patients, and interestingly the conversion rate to SPMS at 6 years was very low (3%). A cohort study comparing alemtuzumab effectiveness to natalizumab, fingolimod and interferons, up to 5 years, revealed similar reductions on ARR for alemtuzumab and natalizumab, but superior to fingolimod and interferons, however natalizumab seemed better than alemtuzumab in enabling recovery from disability. Alemtuzumab safety risks include infusion reactions, stroke and arterial dissection, severe infections including opportunistic ones such as herpetic and Listeria monocytogenes, and secondary autoimmune disorders (thyroid disorders, idiopathic thrombocytopenic purpura, and nephropathies among others) [49,50,63–66].

Cladribine was studied in the 2-year placebo-controlled phase 3 study CLARITY, with lower relapse rates, lower risk of 3 months sustained disability progression and significant reductions in brain lesions counts. Moreover, the 2-year extension study of CLARITY showed that patients that received cladribine during the core study followed by placebo during the third and fourth year had sustained benefits in terms of activity and progression (similar to 4 years with cladribine treatment). However, Cladribine may be slightly less effective than other HET, as an observational study revealed a significant reduction on ARR with cladribine compared to medium efficacy therapies and a similar reduction compared to fingolimod, but a lower reduction compared to natalizumab. Cladribine safety issues are related mainly to lymphopenia and herpes zoster infections [49,50,64].

Rituximab is used off-label in MS. Rituximab compared to placebo in a phase II trial showed a lower risk of relapse and greater reductions on MRI activity. Several observational studies, especially from Sweden, have confirmed these results. Moreover, an observational study revealed that switching from natalizumab (due to JCV positivity) to rituximab was related to lower clinical and MRI activity compared to switching to fingolimod. In a comparative study with a 4-year follow-up, initial treatment with rituximab demonstrated a significant lower rate of relapses and MRI activity compared to injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates compared with natalizumab and fingolimod. The OPERA I and II phase III studies compared ocrelizumab to interferonbeta-1a in RRMS patients with greater reductions in ARR, MRI activity and progression of disability at 3 and 6 months with ocrelizumab. The most common side effects of anti-CD20 therapy are infusion reactions and infections (including cases of herpes zoster, hepatitis B reactivation and PML), although bone marrow suppression and neutropenia have been described [66,67].

Mitoxantrone was compared to placebo in a French-British randomized controlled trial and to Interferon-beta in a 3-year pivotal trial, and was related to a significant lower relapse rate, MRI activity and disability worsening. Another study compared induction with mitoxantrone followed by glatiramer acetate maintenance therapy vs. glatiramer acetate, with a significant reduction on ARR and MRI activity in the first group. Long-term mitoxantrone effectiveness has been studied up to 5–10 years of follow-up with significant results on reduction of disability worsening, compared to medium efficacy DMTs, especially when followed by platform treatment maintenance. The risk of severe adverse events such as heart failure or leukemia or amenorrhea make mitoxantrone a less suitable treatment option nowadays [49,50,62,64].

Regarding Cyclophosphamide, the two-year randomized clinical trial of cyclophosphamide followed by interferon vs. interferon alone showed a significant reduction in clinical and MRI activity, and an observational study using induction with cyclophosphamide followed by maintenance therapy with glatiramer acetate showed similar results. However, its safety profile mainly related to infections and hemorrhagic cystitis and bladder cancer have reduced its use nowadays [50,62].

Autologous hematopoietic stem cell transplantation (AHSCT) has been used in aggressive RRMS. The phase II ASTIMS trial demonstrated AHSCT was superior to mitoxantrone reducing relapse rates and MRI activity without differences in the progression of disability between groups. An observational study showed an important proportion of progressionfree survival at 5 years of follow-up with AHSCT, with better outcomes with lower baseline EDSS. Another observational study revealed AHSCT is more suitable for aggressive RRMS as none of the RRMS experienced worsening of disability after a median follow-up of 5.4 years while 22.6% of SPMS experienced disability worsening. However, safety risks of AHSCT including infections and mortality, make AHSCT suitable only for aggressive RRMS patients refractory to high-efficacy conventional therapies and active disease with potential for disability accumulation. The BEAT-MS (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis) study is a 6-year ongoing study currently investigating AHSCT versus high-efficacy DMTs (natalizumab, alemtuzumab, ocrelizumab, or rituximab) with a primary endpoint of relapse-free survival up to 36 months [49,50,68].

Interestingly, a recent Norwegian observational study has compared the short-term effect of initial HET (with natalizumab, fingolimod and alemtuzumab) vs. medium efficacy treatment. Initial HET was associated with a greater proportion of NEDA at years 1 and 2 compared to initial medium efficacy treatment (OR 3.9, *p* < 0.001, at year 1) [69].

#### *3.3. The Importance of Long-Terms Outcomes. Analysis of the Comparative Studies: Escalation vs. Early Intensive Treatment*

Initiating effective treatment early in the disease course in order to reduce relapse rate and the underlying inflammatory process may delay irreversible neurological damage and conversion to a secondary progressive course. The median time to conversion to a secondary progressive course is around fifteen years but can be shorter, especially in patients with aggressive disease [54]. The main goal of treatment must be to prevent accumulation of irreversible neurological disability and, in particular, to prevent conversion to a secondary progressive course [54].

However, clinical trials have short follow-up times, which might prevent detection of progression of disability and moreover disability worsening in these scenarios may reflect mainly disability accrual from relapses rather than true progression. Furthermore, extension phases have many biases that preclude long-term outcomes analysis, and moreover, clinical trials do not usually compare the escalation and EIT approach. Therefore, long-term outcomes that assess disability at five to ten years after treatment onset, and conversion to secondary progressive MS must be analyzed on real world experience.

Recent evidence from several observational studies, suggest that EIT provides a greater benefit than escalation treatment in decreasing the risk of developing SPMS and disability accrual at least in the medium-long term of 5 to 10 years [43,58–62].

A Danish observational study with 4 years follow-up showed that initial high efficacy treatment (with natalizumab, fingolimod, alemtuzumab, ocrelizumab or cladribine) compared to medium efficacy treatment in naive patients (using propensity score matched samples) was associated with a lower probability of 6-month confirmed EDSS worsening (16.7% vs. 30.1%, HR 0.53, *p* = 0.006) and of a first relapse (HR 0.50) up to 4 years. Although fingolimod was initially considered as HET, when reclassifying it as a medium DMT, comparable results as in the main study were found. When subgroup analysis of patients with high baseline disease activity was done, comparable results were found too [58].

Another real-life setting study showed long-term outcomes were more favorable following initial EIT (with natalizumab or alemtuzumab) vs. moderate-efficacy treatment (with interferons, glatiramer, teriflunomide, dimethyl fumarate and fingolimod). This cohort UK study that included 592 RRMS patients showed that EIT patients had a lower increase in EDSS score at 5 years than patients with the escalation approach (0.3 vs. 1.2, *p* = 0.002). Median time to sustained accumulation of disability was longer for the EIT, but no differences were found between the medium-efficacy DMT who escalated to highefficacy DMT and the EIT group. However, 60% of those who escalated to HET had already developed disability accumulation while still receiving initial moderate-efficacy treatment before escalation. Despite this, patients that received initial EIT had a more active disease (pretreatment ARR 1.7 vs. 0.7), it was this group that had better long-term outcomes. Interestingly, age at onset of first DMT was also related to EDSS change at 5 years [59].

An observational study with data from the Swedish MS and MSBase registries, assessed the efficacy of HET (natalizumab, rituximab, ocrelizumab, alemtuzumab or mitoxantrone) started early (0–2 years from onset) compared to later (4–6 years from onset) using propensity score. Although this study did not compare efficacy with the escalation approach (and escalation was allowed in both groups), it proved that early HET within 2 years of disease onset is associated with lower hazard of disability progression and lower disability accumulation at 6 to 10 years of follow-up compared to late HET (mean EDSS score at 10 years: 2.3 vs. 3.5, *p* < 0.0001) [60].

An Italian multicentric study that analyzed long-term trajectories up to 10 years of EIT vs. escalation in naive RRMS, starting treatment within the first year of disease onset, demonstrated EIT strategy is more effective than escalation in controlling disability progression over time. In this study EIT included patients that received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab or cladribine while escalation group received the high efficacy DMT after at least 1 year of treatment with glatiramer acetate, interferons, azathioprine, teriflunomide or dimethyl fumarate. Patients were followed for 10 years, and propensity score matched for characteristics at first DMT before analysis, all having at least one relapse on the previous year and baseline mean EDSS of 2.6. EIT was significantly associated with lower disability progression measured by mean annual EDSS change compared to baseline value in all time points, including at 5 and 10 years. This effect not only persisted but continued to increase over time despite all patients in the escalation group being escalated to a higher-efficacy DMT [61].

Regarding conversion to SPMS, EIT has been associated with a lower risk of conversion than escalation. A multicentric cohort study with 1555 patients, using propensity score matching, showed that EIT (initial treatment with alemtuzumab, natalizumab and fingolimod) was associated with a lower risk of conversion to SPMS than initial treatment with interferons and glatiramer (HR 0.66, *p* = 0.046; with a 5-year absolute risk 7% vs. 12%, median follow-up, 5.8 years). However, the probability of conversion to SPMS was lower when interferons or glatiramer were started within 5 years of disease onset versus later, and when platform treatments were escalated to fingolimod, alemtuzumab or natalizumab within 5 years versus later (HR 0.76, *p* < 0.001, 5-year absolute risk 8% vs. 14%, median follow-up 5.3 years), which may reflect that when using the escalation approach, treatment failure must be promptly detected [43].

In relation to long-term outcomes of specifically induction treatment in observational studies, most of available data is mainly related to the older induction treatments such as mitoxantrone or cyclophosphamide compared to injectable medium-efficacy treatment. Prosperini et al., compared effects and safety of initial induction treatment with mitoxantrone or cyclophosphamide vs. escalation treatment starting with interferons in active RRMS (with median ARR of 2 and 60% of patients with baseline contrast enhancing lesions) using propensity score match, and found that a significantly lower proportion of patients of the induction group reached the milestone of EDSS 6 at 10 years (28% vs. 38.7%, HR

0.48, *p* = 0.024). Younger age was related with better outcomes in the induction group, and adverse events were more frequent after induction. Notably, although induction was not compared with initial sustained HET, some of the induction patients required escalation to fingolimod or other monoclonal antibodies, however, in a lower proportion than the escalation group (34.7% vs. 53.4%) [62].

Data related to newer induction treatments such as alemtuzumab or cladribine are usually analyzed together with other HET versus the escalation approach, but no observational studies of long-term outcomes comparing initial induction versus initial sustained HET are available [62].

Therefore, real-world data show that the escalation approach may be inadequate to prevent long-term outcomes compared to EIT and that initial EIT is related to a lower risk of developing SPMS and to lower disability accumulation at 5 and 10 years. However, evidence comparing long-term outcomes of induction treatment vs. sustained HET is scarce [58–60,62].

#### **4. Future Evidence**

To assess the effectiveness of EIT vs. Escalation, two pivotal clinical trials are currently ongoing; the TREAT-MS (TRaditional versus Early Aggressive Therapy for MS) trial and the DELIVER-MS (Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS) trial. The primary endpoint in TREAT-MS is time to sustained disability progression and the primary endpoint in DELIVER-MS is normalized whole brain volume loss from baseline to month 36. Interestingly both clinical trials consider the sphingosine-1-P modulators as medium efficacy treatments, while the first one considers cladribine as an EIT and the last one as a medium efficacy treatment [49,61,62].

This work has been supported by a grant from the Health Institute Carlos III: PI20/01446.

Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

**Author Contributions:** Conceptualization, B.C. and F.G.; methodology, B.C., C.Q.-B. and F.G.; formal analysis, B.C.; investigation, B.C. and F.G.; writing—original draft preparation, B.C., C.Q.-B. and F.G.; writing—review and editing, C.Q.-B.; supervision, B.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by a grant from the Health Institute Carlos III: PI20/01446.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

