To stop or not to stop disease modifying therapies in secondary progressive multiple sclerosis, that is the question

KEYWORDS:

• Multiple sclerosis
• secondary progressive multiple sclerosis
• DMT
• therapy
• outcome

The predominant clinical disease course of multiple sclerosis (MS) which can be treated today by a variety of different disease-modifying treatments (DMT) is characterized by reversible episodes of neurological disability (relapsing remitting form of MS (RRMS)), which frequently evolves into progressive neurological decline (secondary progressive multiple sclerosis (SPMS)) which cannot be treated by DMTs as well. Some MS patients (about 10%) may exhibit a disease course with progressive neurological decline since the onset and they are classified as primary progressive MS (PPMS). The clinical course of PPMS differ from SPMS; and postmortem studies showed that there is significantly more inflammation in SPMS (perivascular cuffing and cellularity in the brain tissue) than in PPMS disease [1]. Such data reinforce our approach to use the term MS as an umbrella term referring to a group of possible different disease entities.

Pathological studies have shown differences between RRMS and SPMS in terms of inflammatory environment, cellular responses, and the location of brain and spinal lesions. However, the debate is still open whether SPMS and RRMS should be considered as two different nosological entities or just two phases of the same disease. Today, the most supported theory is that RRMS and SPMS represent a continuum [2]. In acute RRMS, extensive axonal loss occurs in acute lesions; but the clinical deficits of these inflammatory relapses are mostly reversible, as the human brain has a remarkable ability to compensate for neuronal loss. With time and ongoing inflammatory activity, axonal loss can drive the conversion of RRMS to SPMS when the brain exhausts its capacity to compensate for further neuronal loss. However, entering in secondary progressive phase represents an insidious change for persons suffering from RRMS. Indeed, in SPMS the disability accrual becomes irreversible, and the ability to recover from clinical relapses begins to be frequently ineffective [3]. As we said long is the debate about to consider or not SPMS as the natural evolution of RRMS but no consensus is reached (see elsewhere, 4). The reality is that a majority of RRMS shifts to SPMS, even if they are treated with DMTs [3-5].

The introduction of DMTs since 1990s dramatically changes the natural history of RRMS, and in the last 5 years we witnessed the release of new and stronger biological therapies which showed impressive ability to impact the inflammatory activity in RRMS. Very recently, an observational study of patients with MS treated with autologous hematopoietic stem cell transplantation showed that almost half of them remained free from neurological progression for 5 years after transplant [6]. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline Expanded Disability Status Scale (EDSS) score were factors associated with better outcomes [6].

Overall, the efficacy of MS treatments seems to be higher in the earlier stages of RRMS and decreases over time. Frustrating results were collected about the treatment of progressive forms. Very recently, the scientific community was excited by the approval of the first drug for the treatment of PPMS, that is, ocrelizumab. It is a humanized monoclonal antibody who showed the ability in reducing by 24% the risk of 12-week confirmed disability progression in PPMS relative to placebo [7]. We are waiting for long-term clinical data.

In our clinical practice, we are faced with the phenomenon that our MS patients become chronically treated with DMT. The optimal duration of DMT use remains an open and controversial question. There are patients who stay on DMT as long as they tolerate the treatment and the DMT seems effective. Others switch between DMTs in order to find one that is more effective or more tolerable, and others who cannot tolerate any of the DMTs, or show any clinical effect by this treatment. Determining when DMT is no longer helpful is challenging, as we have no comparator intraindividually available. In addition, no studies have directly assessed the clinical challenge to continue versus discontinue DMT in different MS populations. Moreover, with the aging of persons with MS who lived in the industrialized countries, we are facing with a new query: are there any difference in terms of the treatment in old (more than 50 years old) and young persons with MS? We do not know; and there are no treatment recommendations for aging population with MS; which includes a great percentage of persons with SPMS [8].

The scarce literature data (mostly looking at RRMS population) have tried to divide the reasons for treatment withdrawal into: (1) physician’s decision: if disease is considered stable; (2) other reasons: patient’s wish, intolerance, side effects, desire for pregnancy, or comorbidities.

Recently, RRMS whose treatment was discontinued by physician were compared (in terms of experiencing new relapses or MRI lesion accrual) with those who discontinued treatment for other reasons. The difference between the two groups was not statistically significant [9].

Overall, it seems that most of RRMS treated with interferon beta, who discontinued therapy, had a return of their baseline disease activity after approximately 2 years [10]. However, it has been reported that untreated RRMS patients with an EDSS <3 (fully ambulatory patients) and a disease duration >10 years were still ambulatory in 83% of cases after 20 years follow-up [11]. MS-Base registry has not reported any relapses after discontinuation of DMT in 36.8% of treated patients with injectable DMTs (for >3 years and had no relapses for >5 years) [12]. They found younger age and lower disability to be predictive of relapsing after DMT discontinuation, but no MRI data could be included in their analysis. A recent study included 221 RRMS patients, who discontinued DMT after ≥12months and had documented follow-up ≥2years after discontinuation [12]. The authors identified the patients’ characteristics age ≥45years, DMT intake ≥4years without evidence of clinical or radiological disease activity as indicative to remain relapse-free after DMT discontinuation [13].

To judge on treatment discontinuation in SPMS patients, the situation is even more complicated as no current licensed DMTs seem to influence the clinical evolution that is attested by the failure of such treatments in several completed randomized controlled clinical trials [14]. Here, over 6000 patients were enrolled and immune-modulator DMTs (Interferon beta 1-a, 1-b, and Glatiramer Acetate), several immunosuppressant drugs (Azathioprine, Ciclosporin, Cyclophosphamide, Linomide, Mitoxantrone, and Cladribine), monoclonal antibodies [anti-CD20 monoclonal antibody (Rituximab), Natalizumab, and Alemtuzumab] were tested [14]. For example, the European and North American placebo-controlled study of Interferon beta-1b in SPMS showed not significant results in delaying disability progression, while slight significant positive effects were reached on relapses and MRI-related endpoints [15]. Such results underline how disease progression and experiencing new relapse and MRI activity may be dissociated in SPMS. Alemtuzumab showed the same conflicting results, with no benefit in terms of EDSS progression or rate of brain atrophy in MRI [16]. Recent results of the randomized, placebo-controlled, phase 3 ASCEND trial have shown that Natalizumab could not delay disease progression in SPMS [17]. Such failure could be explained by drugs’ mechanisms of action; in fact, Alemtzumab and Natalizumab are very potent ‘peripherally acting immunological’ drugs. That is probably not the issue in most people with secondary progressive MS; where we probably have ongoing inflammation that is occurring within the central nervous system itself and would need ‘centrally acting immunological’ drugs.

The most important and encouraging results for SPMS treatment have recently been shown for Siponimod, an oral S1P modulator as Fingolimod (after initial agonist effects, they cause down-modulation of the S1P receptors and functional antagonism) [18]. There was a 21% reduction in 3-month confirmed disability progression in the Siponimod group (hazard ratio [HR], 0.79; p = .013). The secondary end point of 6-month confirmed disability progression was reduced by 26% (HR, 0.74; p = .006). About MRI data, the percentage brain volume change from baseline was 23.4% lower (over 12 and 24 months) in the siponimod group (p = .0002) [18]. However, looking at the subgroup analysis, positive effects are more prominent in younger patients with shorter disease duration, less disability, more recent relapses, and MRI activity. Such category of persons with SPMS could be defined on transition from relapsing to SPMS and have some inflammatory features, which could explain the described benefits.

Several other clinical trials in SPMS are currently ongoing (see at https://clinicaltrials.gov/ct2/results?term=secondary+progressive+multiple+sclerosis&Search=Search).

However, we have to mention that the actual design of clinical trials (use of placebo-controlled trials to demonstrate efficacy and safety of new therapeutic interventions) problematic to transfer results into clinical practice. What could be the placebo effect in the SPMS reality? What is the individual response to therapy? How could we define SPMS responders or nonresponders?

The clinical trials so far are too short and, the investigated anti-inflammatory therapies have been developed to modify the damaged neuronal pathways, but with a therapeutic lag that may take years to be clinically manifest [19].

The clinical dilemma about stopping or not DMTs in SPMS remains unsolved. We neither have clinical guidelines nor randomized trials comparing these approaches [20].

The decision to discontinue DMTs is still extremely personal and individual. Currently, MS neurologists have to base their decision on clinical judgment and EDSS changes for measuring disability. However, because the EDSS is largely driven by mobility assessment, we have no data on other functions such as upper limb function and cognitive impairments. In the clinical practice, other validated measures of health status in MS that incorporate more function domains [MS Quality of Life-54 (MSQOL-54, the Functional Assessment of Multiple Sclerosis (FAMS), and the Multiple Sclerosis Quality-of-Life Inventory (MSQLI)] are frequently not administered in the real life assessment, because they are too much time consuming. Without adequate measures of quality of life, balancing the benefits of DMTs against harms becomes challenging, especially across different drug regimens. Patients with long-standing established SPMS (with no clinical or radiological activity) represent a silent percentage of progressive MS whom predictors of harms or benefits in withdrawal therapy are not identified because our measures of therapeutic efficacy in the clinical practice are still based on inflammatory parameters (relapse, gadolinium lesions).

To answer these important questions, we dramatically need a better characterization of SPMS cohorts (in the real life and in the clinical trials) to better address our therapeutic efforts [21,22].

Using prospective population-based design and standardized data collection methods would assist us to understand the clinical characteristics of SPMS populations, as well as other factors that may influence clinical outcomes, such as socioeconomic status, access to care, and comorbidities. Since the pharmaceutical industry would not benefit from studies focusing on DMTs discontinuation, other funding sources need to be identified.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.