Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals’ perspective

Multiple sclerosis (MS) is a highly heterogeneous chronic disease characterized by a continuum of disease phenotypes, with a tendency to worsening. It is estimated that around 2.3 million people live with MS worldwide, with a higher prevalence in women [1]. The onset of MS is common in young adults, although pediatric and late-onset disease also occurs [1].

The different clinical courses have been classified according to disease activity and disability progression [1, 2], which are evaluated with an objective scale, the Expanded Disability Status Scale (EDSS) [3].

In 85–90% of MS patients, the disease is characterized by acute onset and relapses of neurological symptoms, followed by their remission, the so-called relapsing–remitting MS (RRMS) [4]. About 50–80% of patients experience conversion from RRMS to the secondary progressive multiple sclerosis form (SPMS) within 15–20 years from diagnosis [4]. SPMS is characterized by irreversible worsening of neurological symptoms and disability, irrespective of relapses [5]. Despite the numerous disease-modifying treatments (DMT) available for RRMS, the conversion to SPMS continues to be a frequently observed phenomenon. Early identification of RRMS patients at higher risk of conversion could allow the clinicians a more effective use of the available DMT. However, there is a lack of simple and reliable tools in clinical practice to allow the rapid identification of subjects at high risk of transition to SPMS [6]. Early and effective treatment of RRMS may help to tackle the progression of MS, as demonstrated by the study of Brown et al. on the effectiveness of early (i.e., within 5 years of disease onset) treatment of RRMS on conversion to SPMS [7].

Identifying the right timing of the transition from RRSM to SPMS is of pivotal importance for adequate and timely treatment, given the availability of an effective and safe drug for its active form, siponimod, which was approved by the US Food and Drug Administration (FDA) in March 2019 [8] and by the European Medicines Agency (EMA) in January 2020 [9]. The accurate identification of disease status is critical because patients with SPMS are also likely to require additional physical and cognitive rehabilitation and psychological treatment to cope with the long-feared progression of the disease [10, 11].

Despite the well-characterized neuropathological features of SPMS (extensive and confluent demyelinating lesions together with chronically active-expanding lesions throughout the brain and spinal cord [12, 13] and meningeal inflammation and white and gray matter atrophy [14]), the early recognition of SPMS patients is a paramount challenge for healthcare professionals (HCPs). This is due to the following: (i) the lack of diagnostic tests, standardized protocols, and criteria to identify the turning point leading from RRMS to SPMS [15, 16], (ii) the absence of specific symptoms indicating the progression [17], and (iii) the difficulties in reaching an effective interaction between the MS patient and the physician, often delaying the recognition of the transition phase. Indeed, due to the slow and insidious progression of the transition phase to SPMS, the worsening is not always evident in terms of EDSS scores and can go unnoticed both by patients and HCPs. Progression from RRMS towards SPMS can be masked by inflammatory processes, relapses, treatments, and compensatory mechanisms deserving the definition of “silent progression” [18]. Aging is another important risk factor for progression that should be considered, especially in elderly patients and in those with a late onset of the disease.

All of the abovementioned factors and difficulties in identifying early transition to SPMS contribute to the underestimation and delay of the diagnosis. Indeed, identification of SPMS patients is mostly retrospective, thus leaving a long period of uncertainty [17, 19].

In the present work, we review the current needs, gaps, and criticisms in SPMS and discuss the possible approaches suggested by a panel of experts in Italy, to implement the effective identification and management of SPMS.

The lack of a specific treatment for SPMS has been the main critical point in disease management. The available RRMS therapies may delay progression/conversion to SPMS by reducing brain damage, although evidence is conflicting [20]. The first DMT approved for the treatment of SPMS was mitoxantrone [21]. The efficacy of mitoxantrone is due to a broad mechanism of action, from decreasing the secretion of proinflammatory cytokines to inhibition of macrophage-mediated myelin degradation [22]. This type 2 topoisomerase inhibitor acts on neuroinflammation and has been shown to reduce the number of relapses and time to first relapse and improve EDSS and the ambulation index [21]. Its use is limited by unfavorable adverse effects, i.e., cardiotoxicity [23], hepatotoxicity, and hematologic malignancy [24]. Mitoxantrone remained the only FDA-approved drug for the treatment of SPMS until 2019.

Interferon-beta-1b is also approved for the treatment of SPMS, as a result of its antiviral, anti-inflammatory, antiproliferative, and immunomodulatory activities, although a 10-year follow-up of the European trial testing and its efficacy in SPMS patients did not convincingly support its long-term use [25].

Different clinical trials have investigated the efficacy and safety of other approved MS treatments on progressive MS. Clinical studies focusing on the efficacy of anti-CD20 antibodies (rituximab and ocrelizumab) and S1P receptor modulators (fingolimod and siponimod) enrolled primary progressive MS (PPMS) and SPMS patients. B-cell-depleting therapy with rituximab or ocrelizumab showed some benefits for the treatment of young PPMS patients with inflammatory lesions, slowing disease progression up to 120 weeks [26, 27]. Despite PPMS and SPMS sharing some pathophysiological features, benefits from the treatment with rituximab and ocrelizumab have not yet been demonstrated in a representative SPMS population. As regards other RRMS-approved DMTs, fingolimod did not reduce disease progression in PPMS in the INFORMS phase 3 clinical trial [28], while natalizumab failed to show an improvement based on the EDSS scale in SPMS patients in the ASCEND phase 3 trial [29].

The most encouraging results for the treatment of SPMS came from the EXPAND study, a phase 3 RCT investigating the role of siponimod in delaying disability progression. In this study, siponimod, a more selective modulator of the S1P receptor than fingolimod, showed that intervention reduced the relative risk of 3-month and 6-month confirmed disability progression (CPD) by 21% (p = 0.01321) and 26% (p = 0.0058), respectively [30]. Moreover, pre-defined patient’s subgroup analysis of the primary endpoint (3-month CDP) indicated greater efficacy of siponimod in younger patients, with lower EDSS and shorter disease duration (i.e., baseline age of 20–30 years, EDSS score at baseline ≤ 5, and duration of MS since first symptoms of 10 years — early phase SPMS) [30]. The analysis of the secondary endpoint (6-month CDP) in the overall population and in specific subgroups defined by relapse activity and disease progression supported this finding [30]. Siponimod is now approved and marketed for the therapy of SPMS with active disease as evidenced by relapses or imaging features of inflammatory activity. No DMTs have so far been approved for the treatment of the inactive form of SPMS, even if the recent 2021 update of the European Academy of Neurology (EAN)/European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) guidelines suggests the use of siponimod both in patients with active and non-active SPMS [31].

Research and clinical studies have been performed in the past, and are still ongoing, to target, among others, molecular mechanisms involved in MS progression, such as oxidative stress [32], brain atrophy [33], demyelination [34], and lack of remyelination [35].

The unavailability of safe and effective therapies for SPMS often causes the discontinuation of DMTs in patients with RRMS experiencing disability progression, as patients and caregivers deal with the difficulties associated with the transition awareness process and communication with physicians [36].

The reactions to the communication of progression vary greatly across patients. In some cases, the patient realizes that the disease is slowly progressing even before the physician does. Indeed, a recent study demonstrated that patients realize SPMS conversion on average 2.7 years before the confirmation from the neurologist [37]. Some patients accept the progression, while others experience a denial phase towards identifying SPMS [36], ignoring the availability of a specific treatment and fearing potential loss of motor function. Some patients may be reluctant to share information related to worsening of symptoms because they fear there will be no chance of further treatment [36].

To avoid anxiety, fear, and delay in the intervention, timely and sensitive communication between physicians and patients is paramount [36]. Technical terms related to the pathology may generate confusion among patients, who should be able to express their concerns about their everyday life without hesitancy in discussing progression issues [36]. The timing of information delivery should be carefully considered by the physician; communication soon after the diagnosis may imply a negative reaction by the patient, but postponing the topic would reduce the acceptance of the situation and might fail to engage the patient in the treatment positively.

Communication of shifting into the progressive phase should always be accompanied by the perspective of the newly available treatments [36]. Defining the disease as a continuum, more than as a sequence of phases, using patient-friendly language, might help to increase patient-physician trust, creating awareness towards the pathology and encouraging engagement in the treatment.

The ManTra (Managing the Transition to SPMS) study was a mixed-method research project conducted in Italy and Germany to gather insights into the patient perspective concerning the transition period. The project used an online survey to assess the experience of patients newly identified with SPMS, verifying their needs and exploring patients’ perspectives about their transition phase to SPMS. The results of the project showed that around 40% of patients were not aware of their progressive condition [37]. This situation is particularly common in the southern regions of Italy, thus indicating that sociocultural biases influence the phenomenon, and that the necessary improvement of the physician-patients communication must be tailored to different geographic areas.

Some prognostic factors predicting transition to SPMS have been identified. Lesions in the gray matter, spinal cord, and infratentorial regions and high inflammatory activity at the disease onset and in the following 5 years are well-known risk factors for future progression [38]. Thus far, biological markers with a reliable prognostic value are missing and are definitively needed. Here, we report the most promising biomarkers deserving attention in the research settings, which still need to be validated through standard procedures before implementation into routine clinical practice.

Developing models to identify MS patients at risk of progression has been the focus of many studies. Manouchehrinia and colleagues generated a nomogram showing high predictive value for the risk of progression to SPMS over 10–20 years, based on year of birth, sex, age at onset, EDSS score, and age at the first EDSS score [61]. Another study employed both quantitative and qualitative approaches through a multivariate analysis of observational study data that identified discriminating factors between RRMS and SPMS arising from interviews with patients and HCPs that explored impacts associated with transition [17]. These tools would provide support to clinicians in everyday practice, without substituting the clinician experience and the need for instrumental examinations.

The MS Progression Discussion Tool (MSProDiscuss) is another model created by clinicians to facilitate interactions between HCPs and patients and to get insights into the patient’s perspective of MS. It includes quantitative and qualitative assessments and may help close monitoring of patients’ symptoms and impacts during transition [62]. However, it still needs to be validated in routine clinical practice.

Given the delayed detection and the lack of standardized tools to identify patients, the SPMS population in Italy is likely to be underestimated. A panel of 12 Italian MS experts, six from the Campania region and six from Sicily, took part in two virtual round tables (due to COVID-19 policy restrictions), to discuss the needs and the gaps in SPMS identification and management in this area of Italy and the possible ways to anticipate diagnosis and start the appropriate treatment promptly. Such issues, although with slight differences among the different regions, are common to the whole country. Board members were selected within these regions giving the proximity of the areas and the similarity in clinical and patient care organization. Inclusion criteria for the healthcare professionals were the 10-year experience in clinical neurology, their involvement in MS clinical research and patient treatment, and their publishing record related to MS.

Before the first meeting, the participants reviewed the literature with a particular focus on the most recent publications (from 2019 to 2021) searching PubMed with specific keywords (Multiple Sclerosis progression AND patient-reported outcome OR patient communication; Multiple Sclerosis progression — all fields AND biomarkers — Title and Abstract; Multiple Sclerosis progression AND diagnostic tools), concerning the three topics reported below:

Literature search identified 142 items for the first query, 365 and 56 for the second and third, respectively. Participants were assigned to one of the three groups, and each one selected around 10 articles to be used as a starting point for their discussion within the group. The flow chart followed for paper selection is reported in Fig. 1.

During the first meeting, the current state of the art was presented. The experts discussed the three topics, highlighting possible solutions to the gaps identified. The result of the discussion was shared in plenary session at the end of the first meeting. On the basis of the output of the first meeting, one of the organizers devised three statements for each topic, on a 4-level Likert scale, to be administered to all the participants.

In the second meeting, the panel reviewed the proposed solutions and undertook further discussion on the statements in plenary session, to find agreement on actions to be applied in clinical practice. This methodology allowed an extensive and productive discussion among the expert panel.

The outcome of the expert panel is summarized as follows, with pinpointed sentences, percentage of agreement on each sentence, and main discussion points.

Observation of slow worsening of symptoms can be facilitated by telemedicine, which allows more frequent visits and is appreciated, especially by patients with reduced mobility. The use of digital tools for monitoring progression (e.g., eSDMT) should be encouraged. A wrist-held dynamometer may help to get an objective insight into motor capabilities, although an improvement in the detecting ability of the device is wanted.

To summarize the joint work of the expert panel, these are the core points that were identified as central for the management of patients with MS experiencing the first suspected symptoms of progression:

SPMS is poorly identified, and its incidence and prevalence are underestimated in Italy, owing to the lack of reliable diagnostic tools. Thus far, the lack of a specific, effective, and safe treatment discouraged MS professionals from a timely and clear communication of the transition phase to the patient, even after the progression to SPMS was confirmed. Now that a therapeutic option is available, there is the need for adequate education both for patients, regarding the evolution of the disease and the possibility of a specific treatment, and for MS professionals, to train them to interact with the patients effectively and sensitively. The use of digital tools to detect signs of progression and support the patients during the disease course must be increased. Earlier communication means earlier identification of progression, which accounts for early and more effective treatment.

Early active SPMS may represent an important therapeutic window where early treatment has been shown to increase the time taken to reach higher disability milestones, finally preserving the patient’s QoL.