Роль неизлечимой терапии восстановления с помощью кладрибинных таблеток в борьбе с повторным множественным склерозом у пожилых пациентов.

Key Summary Points

Adverse changes in the immune system occur with increasing age against a background of increased inflammation (“immunosenescence” and “inflammaging”) There is evidence that the efficacy of some disease-modifying therapies decreases as people with relapsing multiple sclerosis (RMS) become older Immune reconstitution therapy (IRT) with cladribine tablets (CladT) appears to be effective largely irrespective of age A successful response to IRT may provide long-term freedom from MS disease activity for these patients CladT may be effective as an “exit therapy”, facilitating the cessation of continuous DMT for older people with stable RMS

Adverse changes in the immune system occur with increasing age against a background of increased inflammation (“immunosenescence” and “inflammaging”) There is evidence that the efficacy of some disease-modifying therapies decreases as people with relapsing multiple sclerosis (RMS) become older Immune reconstitution therapy (IRT) with cladribine tablets (CladT) appears to be effective largely irrespective of age A successful response to IRT may provide long-term freedom from MS disease activity for these patients CladT may be effective as an “exit therapy”, facilitating the cessation of continuous DMT for older people with stable RMS

Introduction

The proportion of older people with relapsing multiple sclerosis (RMS) has increased in recent decades within the context of a general increase in longevity [ 1 , 2 ]. These trends have occurred especially within the populations of developed nations and the availability of a number of newer and more effective disease-modifying therapies (DMTs) for the management of RMS [ 1 , 2 ]. This demographic shift has important implications for the management of RMS. For example, the pathophysiology and clinical presentation of RMS differ importantly between older and younger populations: MS in older patients is characterised by less focal inflammation [ 3 , 4 ], fewer relapses [ 5 – 7 ], and alteration of the immune system [ 7 ] (these changes are described in more detail later in the review). The effects of DMTs in populations with RMS also vary with age, with evidence of lower efficacy at older ages for continuously applied DMTs. Pharmacological immune reconstitution therapy (IRT) in the management of RMS differs from these approaches in that continuous treatment is not required for the majority of patients [ 8 ]. Rather, two short courses of treatment, separated by 1 month, are given at the beginning of the first and second year of treatment. A marked reduction in B lymphocyte counts occurs, which repopulates over a period of months thereafter [ 9 ]. Effects on CD8 + T lymphocytes are modest, and there is little or no effect on components of the innate immune system [ 9 ]. A randomised Phase 3 trial (CLARITY) and real-world studies have shown that most patients are free from MS disease activity for a period of years after the initial 2-year treatment period [ 10 – 12 ]. Clinical benefits (lower MS disease activity and less accumulation of disability) were still apparent for initial treatment with CladT vs. placebo a decade later [ 13 ]. Retreatment with CladT may be effective if mild-to-moderate MS disease activity recurs 3–5 years after treatment initiation [ 14 – 16 ].

Available data suggest that the effects of pharmacological immune reconstitution therapies (currently cladribine tablets [CladT] and alemtuzumab) may be better maintained in older people with MS. These observations emphasise the need for individualised management of older people with this condition. In this narrative review, we consider the potential role of IRT within the management of RMS in older people.

This review article is based on previously conducted studies and the clinical expertise of the authors in treating patients with RMS. No new clinical studies were performed by the authors. No patient-specific efficacy or safety data were reported; therefore, institutional review board (IRB)/ethics approval was not required.

Methods

This is a narrative review. Clinical studies of potential interest regarding the effects of IRT according to age were identified from a PubMed search – ( "multiple sclerosis" OR RMS OR MS) AND (cladribine [ti] OR alemtuzumab [ti] OR "immune reconstitution" [ti]) AND (age OR elderly OR older )

( "multiple sclerosis" OR RMS OR MS) AND (cladribine [ti] OR alemtuzumab [ti] OR "immune reconstitution" [ti]) AND (age OR elderly OR older )

– limited to Clinical Trial, Randomized Clinical Trial, Observational study, Meta-Analysis, Case Reports, Comparative Study, or Systematic Review. Reference lists of identified publications and authors’ literature collections were additional sources of material. Priority was given to consideration of randomised trials and systematic reviews/meta-analyses where these were available.

CladT and alemtuzumab are currently the only two pharmacological therapies believed to act as IRTs that are not administered continuously in responders to treatment, as described above. The use of alemtuzumab has been restricted in some countries by the appearance of potentially serious adverse events. Finally, autologous haemopoietic stem cell transplantation is a non-pharmacological IRT but requires access to specialist centres. For these reasons, this review focusses mainly on CladT as an exemplar of IRT, although the other approaches listed above are considered where appropriate. Unless specified otherwise, data presented here represent the therapeutic use of a cumulative dose of CladT of 3.5 mg/kg given via two annual courses, as per the product label.

The Burden of MS in Older Patients

Incidence and Prevalence of MS by Age

The mean age of diagnosis of MS is relatively low (often described as about 30 years [ 17 ]). However, improved longevity of people with MS and additional diagnoses occurring in older people have led to a significant burden of MS falling on older age groups. For example, in the USA, the prevalence of MS is now highest among 45–64-year olds [ 18 ]. In England, the highest prevalence of MS per decade of life occurs at 50–59 years for both genders, and 28% of women with MS and 27% of men with MS are aged > 65 years [ 19 ]. The median ages of women and men with MS were in the 55–59-year age group [ 19 ]. In Italy, the mean age of onset of MS increased from 26 to 35 years between 1991 and 2021 [ 20 ]. A population-based study from Norway reported that 11.9% of diagnoses of MS occurred at ages > 50 years in 2010 compared with only 2.6% before 1970 [ 21 ].

The proportion of older people with MS in Middle Eastern/Arabian Gulf countries appears to be variable, although data are limited. For example, 23% of people with MS were aged > 40 years in a survey in Saudi Arabia conducted in 2020 [ 22 ]. A study from Kuwait reported a substantial minority of older people among its MS population (Fig.  1 ) [ 23 ]. Lower proportions of people aged > 40 years have been described in chart reviews in other Gulf states, such as 7% in Qatar [ 24 ] and 2–3% in the United Arab Emirates [ 25 , 26 ]. Systematic reviews found that the mean age of onset of MS in several Gulf states [ 27 ] or the broader Middle East/North Africa Region [ 28 , 29 ] varied from 25–33 years, which is broadly similar to the global estimate of ~ 30 years, described above [ 17 ]. Interestingly, from a study cited above, 20/128 new cases of MS in the UAE arose in people aged 35–54 years [ 26 ]. Fig. 1 Prevalence of multiple sclerosis (MS) according to age from a study in Kuwait. Drawn from data presented in Ref. [ 23 ]

Prevalence of multiple sclerosis (MS) according to age from a study in Kuwait. Drawn from data presented in Ref. [ 23 ]

Increasing Age and the MS Phenotype

Older patients with MS differ significantly from younger patients in important ways, some of which are summarised below. This section does not cover the important effects of older age on the efficacy and safety of DMTs for MS, which is dealt with in detail later in the article.

Immunosenescence and inflammaging

The term “cellular senescence” relates to a natural consequence of aging in which cells of the body become unable to replicate [ 30 ]. Within this context, “immunosenescence” refers to deleterious changes in both the adaptive and immune systems in older people [ 1 , 30 , 31 ]. While immunosenescent cells no longer divide, they remain metabolically active. Senescent immune cells promote a proinflammatory phenotype and secrete abnormally high levels of inflammatory mediators (especially various interleukins and TNFα). A complex interaction occurs that involves multiple cell types and physiological systems, including altered proportions and naïve and memory T and B lymphocytes, thymic involution (shrinking of the thymus), altered function of haematopoietic stem cells, impaired responses to new antigens and metabolic stress, epigenetic modification of key genes, and persistent antigen stimulation. Immunosenescence has been justifiably termed “the twilight of the immune system” [ 31 ], as the net result is a chronically inflammatory phenotype (“inflammaging”) and reduced immune function.

There is evidence that the natural age-related phenomena that underlie immunosenescence, including increased inflammation and impaired remyelination of nerve fibres, become amplified and accelerated in MS, with appearance at a younger age [ 32 , 33 ]. For example, one study associated MS with an imbalance between the expression of the costimulatory molecule CD226 by immune cells (which is associated with impaired immune function [ 34 ]) and immunomodulatory signals from CD8 + T cells, which results in a proinflammatory phenotype characteristic of immunosenescence and inflammaging [ 35 ]. Other data show that the accumulation of senescent CD8 + T cells bearing receptors associated with natural killer cells mediates cytotoxic effects in the central nervous system [ 36 ]. Exacerbation of inflammatory responses in microglia associated with senescence may be associated with the “smouldering MS” phenotype that is believed to underlie the progression of MS independently of relapses [ 1 ].

Increased Risk of Infections

Impaired immune function with immunosenescence would be expected to result in an increased risk of infections. This certainly occurs during natural aging: an analysis of hospitalisations for infections in the USA (1998–2006) showed the rate increasing from about 7/10,000 individuals at age 20 years to about 38/10,000 at age 65 years and then to about 98/10,000 at age 80 years [ 37 , 38 ]. The severity of infections may also be higher in older vs. younger people [ 39 ].

People with MS are at increased risk of infection [ 40 ]. Eight years of follow-up of 6602 people with MS in Sweden revealed an increased risk in those with MS compared to those without MS for bacterial, viral, and fungal infections of the skin, respiratory system, throat, and lungs [ 41 ]. The risks (incidence rate ratios) for MS vs. no MS were 1.61 (95% CI 1.52–1.71) for a first nonserious infection and 2.54 (95% CI 2.28–2.83) for a first serious infection in this study. Progressive MS and higher disability, more commonly seen in older patients, appear to confer a greater risk of infection than RMS and lower disability, respectively [ 42 ]. A reduced immune response to vaccination has also been associated with age-related immunosenescence [ 43 ].

The use of DMTs other than interferons or glatiramer acetate for MS is also associated with an increased risk of infections; this may be especially true for DMTs that act via continuous immunosuppression, which have also been shown to reduce the efficacy of vaccinations, including for COVID-19 [ 44 – 48 ]. Nevertheless, it is generally accepted that people with MS receiving DMTs benefit from vaccination and should receive it [ 49 , 50 ]. People treated with natalizumab for MS who become seropositive for John Cunningham virus (JCV) are at increased risk of developing progressive multifocal leukoencephalopathy (PML), a potentially life-threatening opportunistic infection [ 51 ]. A study of 238 cases of PML on natalizumab found that older age and prior immunosuppressive therapy were the main drivers of increased risk of PML: age > 50 years more than doubled the risk of PML (hazard ratio 2.11) [ 52 ]. PML has also been observed during treatment of people with MS with other DMTs [ 53 ]. The risk of infections during treatment with CladT is discussed in detail separately below.

Increasing Comorbidity with Age

The risk of many health conditions increases as individuals age, and people with MS are no exception to this. People with MS develop age-related comorbidities, such as cardiovascular pathology, psychiatric disorders, diabetes, or cancer, which worsen prognosis and complicate the design of the MS treatment regimen [ 54 ]. Some age-related comorbidities overlap with MS, such as cognitive impairment or physical disability [ 55 ]. A meta-analysis of trials in populations with MS showed that almost half of all patients reported at least one comorbidity, with depression and hypertension being the most common [ 56 ]. Concerningly, this analysis suggested that people with comorbidities may be under-represented in clinical trials, so that their populations may not truly reflect the real-world, routine care population of people with MS to a full extent. Another meta-analysis showed that a higher burden of comorbidity predicted higher MS disease activity [ 57 ].

Effects of Immune Reconstitution Therapy on Older People with MS

Efficacy of Cladribine Tablets According to Age

A post hoc analysis stratified the population of the CLARITY study and its extension according to various demographic and disease characteristics at baseline, including age ≤ 40 years ( N  = 508) vs. > 40 years ( N  = 362) [ 58 ]. For patients aged ≤ 40 years, the annualised relapse rate (ARR) was 0.38 for placebo and 0.16 for CladT, representing a relative risk reduction (RRR) of 57.9% for CladT vs. placebo. The ARR was lower in both treatment groups for the cohort aged > 40 years (0.28 for placebo and 0.12 for CladT), with an essentially identical RRR of 57.1%. Older people with MS will likely include individuals who have received treatment for longer: CladT was effective in reducing the ARR in people diagnosed < 3 years previously (RRR vs. placebo 65.9%), 3–10 years previously (RRR vs. placebo 67.6%), and > 10 years (RRR vs. placebo 46.4%). Older people with MS may also have received previous DMT, and the CladT was also effective irrespective of receipt (RRR for CladT vs. placebo 61.3%) or non-receipt of a prior DMT (RRR vs. placebo 45.0%).

A more recent analysis from the CLARITY population used a cut-off value of 45 years to evaluate the influence of age on the effectiveness of CladT over the 96-week duration of the initial randomised phase and the subsequent extension phase of the study [ 59 ]. Once again, CladT was effective vs. placebo in reducing ARR and the number of MRI lesions in either age category (Fig.  2 ). Compared with placebo, CladT also increased the proportion of patients with no evidence of disease activity (NEDA; no relapses, no gadolinium-enhancing [GD +] T1 lesions, no active T2 lesions, and no progression of disability). Fig. 2 Efficacy of cladribine tablets according to age at baseline in the CLARITY study. # = number of, ARR  = annualised relapse rate, Gd+   gadolinium enhancing, NEDA  no evidence of disease activity. Bars are 95% CI for ARR and SE for MRI parameters. Drawn from data presented in Ref. [ 59 ]

Efficacy of cladribine tablets according to age at baseline in the CLARITY study. # = number of, ARR  = annualised relapse rate, Gd+   gadolinium enhancing, NEDA  no evidence of disease activity. Bars are 95% CI for ARR and SE for MRI parameters. Drawn from data presented in Ref. [ 59 ]

An observational study in 97 people with RMS who received CladT (35 were aged ≥ 50 years) reported that there was no difference between the older and younger cohorts for the time to appearance of MS disease activity (HR 0.73 [95% CI 0.18–2.91], p  = 0.657) [ 60 ]. Other real-world data have reported that age positively predicted the achievement of NEDA-3 following administration of CladT to people with RMS [ 61 ] or that age ≥ 40 years did not diminish the efficacy of CladT for reducing relapses [ 62 ].

Safety of Cladribine Tablets According to Age

Lymphopenia

IRT involves transient suppression, followed by recovery of lymphocytes, by definition. This means that lymphopenia is frequently recorded as a side effect of an IRT, including CladT. An integrated analysis of the CLARITY Study and its extension and the ORACLE trial in people with a clinically isolated syndrome evaluated the influence of age on the incidence and severity of lymphopenia in 1564 subjects followed for 96 weeks following the initiation of treatment with CladT [ 63 ]. Lymphocyte counts reach a nadir following CladT administration and then recover slowly afterwards, as expected [ 9 , 63 ]. The nadir (lowest) absolute lymphocyte counts or subsets of lymphocytes (CD19 + B cells, CD4 + T cells, or CD8 + T cells) were broadly similar between subjects aged ≤ 50 years or > 50 years following the first and second annual treatment courses (Fig.  3 ). The incidence of Grade 3 lymphopenia (0.2–0.5 × 10 9 cells/l) in the younger and older CladT groups was 8.3% and 10% in year 1 of treatment, respectively, and 18.7% and 20%, respectively, in year 2. The median time for recovery from Grade ≥ 3 to Grade ≤ 2 lymphopenia was 5.7 weeks for younger patients and 6.4 weeks for older patients. Fig. 3 Lowest lymphocyte counts (absolute lymphocyte count [ALC] and major lymphocyte subtypes) measured following the year 1 and year 2 courses of CladT according to age at baseline in an integrated analysis of clinical trials in people with relapsing multiple sclerosis or clinically isolated syndrome. Bars are 95% CI. Drawn from data presented in Ref. [ 63 ]

Lowest lymphocyte counts (absolute lymphocyte count [ALC] and major lymphocyte subtypes) measured following the year 1 and year 2 courses of CladT according to age at baseline in an integrated analysis of clinical trials in people with relapsing multiple sclerosis or clinically isolated syndrome. Bars are 95% CI. Drawn from data presented in Ref. [ 63 ]

Infections

The integrated analysis of randomised CladT trials reported a slightly higher incidence of any bacterial or viral infection in older vs. younger patients who developed Grade 3 or higher lymphopenia after receiving CladT (Fig.  4 ) [ 63 ]. This was mostly explained by more cases of zoster in the older group, although the incidence of zoster in the older group was low (3.4 cases/100 patient-years). However, there was no correlation between age and lymphocyte counts after CladT treatment in the real-world study described above ( β  = 0.24, p  = 0.825) [ 61 ]. Fig. 4 Incidence of bacterial or viral infections according to age in an integrated analysis of clinical trials in people with relapsing multiple sclerosis or clinically isolated syndrome. Drawn from data presented in Ref. [ 63 ].

Incidence of bacterial or viral infections according to age in an integrated analysis of clinical trials in people with relapsing multiple sclerosis or clinically isolated syndrome. Drawn from data presented in Ref. [ 63 ].

Other Adverse Events

In a real-world study cited above [ 60 ], age > or < 50 years did not influence the risk of adverse events following treatment with CladT (OR 0.84 [95% CI 0.24–2.93], p  = 0.791).

Impact of Age on the Therapeutic Profile of Other DMTs for RMS

Alemtuzumab

An 8-year post hoc analysis of the Phase 3 Care clinical trials programme showed that the efficacy of alemtuzumab on reducing ARR and MRI activity, and improving disability outcomes, was similar for patients aged 18–25 years, 25–35 years, 35–45 years, and 45–55 years [ 64 ]. This analysis also showed that the proportion of patients with serious adverse events increased with age (36% and 51% for the lowest and highest age categories, respectively) in the integrated analysis of the CARE programme, described above. There were also more cases of serious infection (5.1% vs. 12.8%) and malignancies (2.2% vs. 8.1%). Another study showed that alemtuzumab is more effective in patients with RMS older than 23 years vs. younger patients [ 65 ].

Other DMTs

Stratification of the populations of randomised Phase 3 studies by age has demonstrated lower efficacy on treatment outcomes (relapse rates, slowing of the accumulation of MS-related disability, or achievement of no evidence of disease activity) in older vs. younger people with MS who received first-line/platform DMTs [ 66 – 68 ] or high-efficacy DMTs, including anti-trafficking agents (S1P modulators or natalizumab) [ 69 – 74 ] or anti-CD20 agents [ 75 – 77 ]. Meta-analyses have confirmed these observations [ 71 , 78 ]. A retrospective, observational study in elderly people with RMS (age > 60 years) found that stopping a DMT did not provoke MS relapses or worsening of disability during a 2-year follow-up period [ 79 ].

De-risking: Options for Managing Older People with RMS

Continuing Existing DMT (Fig.  5 )

Summary of options for de-risking care for an older patient with relapsing MS. a In responders. b When withdrawing anti-trafficking DMTs. See text for evidence to support statements

Continuing with the older person’s current DMT is probably the option associated with the least risk of MS disease recurrence (assuming the patient’s MS is well controlled). However, the DMT may be becoming less effective over time, as discussed above. This option may render the patient susceptible to side effects associated with continuous immunosuppression from some DMTs. Also, the patient must continue to take the medication regularly and follow monitoring requirements, which vary considerably between DMTs [ 80 ].

Withdrawing Existing DMT (Fig.  5 )

The frequency of relapses usually decreases and some patients with stable disease may be able to discontinue their DMT altogether [ 81 ]. This approach effectively removes the burden of treatment and issues with adherence (especially important for people with cognitive impairment [ 82 ]) and may greatly reduce the monitoring burden (depending on the type of DMT involved [ 80 ]).

The randomised DISCOMS trial evaluated this strategy (vs. continued DMT) in a population of 259 people with MS aged > 55 years who had not experienced a recent clinical relapse (last 5 years) or MRI lesion (last 3 years) [ 83 ]. More in the discontinuer group reported a relapse or new/expanding brain MRI lesion within 2 years compared with the group that continued DMT (12.7% vs. 4.2%, respectively). In another study, 2-year observational data from 221 people with MS who discontinued their DMT showed that age > 45 years, absence of relapses during at least 4 previous years of DMT, and absence of contrast-enhancing lesions were significant predictors of absence of relapses during follow-up. A study of discontinuation of platform DMTs in a MS population with mean age 53 years and at least 5 years free of clinical or radiological MS activity was stopped early because of the appearance of MS disease activity in the discontinuer group [ 84 ]. MS disease reactivation was more common following discontinuation of natalizumab or fingolimod compared with other DMTs in a large registry study [ 85 ]. Discontinuing DMT for older persons with very stable MS is therefore feasible, but not without risk of recurrence of MS disease activity, especially regarding discontinuation of anti-lymphocyte tracking agents.

IRT for Older People with MS

Practical Issues

CladT is administered as two 4–5-day courses of treatment, given 1 month apart, at the beginning of each of the first and second years of treatment (the posology of alemtuzumab is similar) [ 80 ]. Importantly, no further treatment is required if the patient’s MS is well controlled after the year 2 course. Thus, the successful application of IRT means that MS disease activity (relapses, MRI lesions) will be controlled, often for years, without the need for any continuous DMT. Accordingly, as for withdrawal of DMT, this approach avoids issues relating to the impact of comorbidities on continuously applied DMTs or issues with long-term adherence to therapy.

The main tolerability issues with CladT are transient lymphopenia, which does not appear to be more severe in older persons, and opportunistic infections, especially where lymphopenia is severe (both described above). Patients should be screened carefully for latent infections and vaccinated for zoster and other potential opportunistic infections before treatment, and careful monitoring of lymphocyte counts is needed during the 2-year administration of CladT. Beyond this time, the monitoring burden for CladT is relatively low compared with other high-efficacy DMTs [ 80 ].

There are two sub-populations of older people with MS: people presenting with newly diagnosed MS at a relatively advanced age (the minority) and people with long-standing MS that has likely been managed previously with several DMTs (the majority). The management of these populations will be discussed separately below.

IRT for Newly Diagnosed Older People with MS (Fig.  5 )

An older individual presenting with clinical or radiological MS disease activity has active MS, by definition, and may be a candidate for DMT. The choice of DMT, if prescribed, is guided by the individual patient characteristics. An individual with a substantial period of active life ahead of them needs to be protected from the insidious effects of MS disease progression, as does a younger patient. Ideally, suppression of MS disease activity should be achieved without exacerbating the already increased risks of infections or other important comorbidities associated with older age, as described above. For this reason, IRT may be a better fit for some of these patients than immunosuppressive therapies for some of these patients. This strategy is also in line with the increasing trend towards earlier use of high-efficacy DMTs in the management of RMS, including in DMT-naïve individuals [ 86 , 87 ].

IRT is also convenient, given that responders to treatment remain free of the need for regular DMT. Patient support programmes are available in some countries to increase adherence to the CladT regimen, which has resulted in a high level of adherence and persistence to the 2-year administration period of CladT [ 88 , 89 ]. The absence of regular DMT means that longer term issues with adherence to therapy are avoided entirely.

Ageing People with Long-Standing MS (Fig.  5 )

As described above, withdrawing a DMT is an option for “de-risking” the long-term management of an older individual with stable RMS. CladT has been shown to be effective in people with MS switching from other high-efficacy DMTs, including anti-CD20 agents, natalizumab and fingolimod, including in older patients and those with high MS disease activity, with a low rate of rebound MS disease activity following a switch from an anti-trafficking agent [ 16 , 90 – 103 ]. Indeed, one of these real-world studies demonstrated that CladT was effective and safe as a “last therapy” for elderly people with RMS [ 93 ]. Older age at the time of switching to CladT was associated with a reduced risk of MS relapses in another observational study [ 90 ]. Minimising washout periods between stopping and anti-trafficking agent and starting CladT is important to minimise the risk of rebound MS disease activity [ 12 ]. In practice, IRT provides an opportunity to withdraw an existing DMT while still providing a period of protection from MS disease recurrence. Accordingly, CladT may be the last DMT that the patient needs, where long-term freedom from MS disease activity occurs: in this case, CladT may be considered an “exit therapy” for older people with stable RMS [ 2 ].

Identifying Non-responders to CladT

A switch to an alternative high-efficacy DMT is recommended if moderate or severe MS disease activity recurs after treatment with CladT, especially following completion of the full, 2-year course [ 16 ]. This should apply irrespective of age, although real-world data from Italy suggested that older patients were less likely to receive a new DMT in the event of recurrence of MS disease activity after an initial treatment with CladT [ 104 ].

Limitations of this Review

The main limitation of this review is its narrative approach, although we did use a structured search approach to identify key articles for discussion, as described above. There is a lack of randomised, controlled trials in older people with MS, especially head-to-head comparisons of DMTs: this necessitates reliance on observational data with varying durations of follow-up, which is a general limitation of the evidence base in this area. In addition, we have discussed the phenomenon of immunosenescence from the perspectives of aspects that are directly relevant to the management of people with RMS (e.g. infections, effects on the actions of DMTs) to preserve the main focus of our review; however, it should be remembered that the clinical consequences of immunosenescence are many and wide ranging, both within and beyond the clinical presentation of RMS.

Conclusions

The pathophysiology and presentation of RMS differ importantly between younger and older patients. IRT with CladT appears to be effective and well tolerated irrespective of age, and achieving long-term freedom from MS disease activity is feasible. Switching to CladT is a rational option for reducing the dual burdens of continuous treatment (including side effects associated with continuous immunosuppression with some DMTs) and monitoring for older people with RMS. This includes possible use as an “exit therapy”, beyond which some patients may not need pharmacological therapy for their RMS in the future. The accumulation of further long-term real world data in older people with RMS will facilitate identification of the optimal use of CladT in this increasingly important population.