Once considered an untreatable neurological condition, multiple sclerosis (MS) can today be managed with a diverse range of therapeutic approaches [1]. A multitude of treatments, mostly addressing focal inflammatory processes, has contributed to radically improving the natural history of MS [2]. While disease modifying therapies (DMTs) act in different ways, they all impact the immune system of people with MS [3]. Consequently, most of these drugs are associated with an increased risk of infection to varying degrees compared to the general population [4].
Long-standing evidence indicates that first-line injectable DMTs like interferon beta and glatiramer acetate do not pose an increased risk of infection [5]. In contrast, newer and more effective DMTs may heighten the risk of certain infections due to their more potent effect on the immune system [6].
When discussing treatment options, individuals with MS and healthcare providers share the decision process, weighing the benefits against the risks of different drugs. Current treatment guidelines recommend selecting a therapy – from low- to high-efficacy – after a thorough discussion with the person with MS about individual characteristics and comorbidities, the severity of the disease, and the drug’s safety profile and accessibility [7].
A major concern when evaluating the risks is the possibility of treatment-related infections. Professor Fredrik Piehl from the Karolinska University Hospital in Stockholm tells us, “We have had a new treatment modality since about 5-6 years ago: the B-cell depleting therapies. These therapies are highly effective for suppressing inflammatory MS disease activity, but we need to gather more data on the risk of infection associated with longer exposure. Here randomised control clinical trials often have limited follow-up times and tend to exclude individuals with comorbidities. Furthermore, if individuals with MS develop severe infections while receiving a treatment in a clinical trial, physicians will, of course, take them off the treatment. Therefore, to better understand whether B-cell therapies are associated with an increased risk of infection, we analysed real-world data.
We linked the Swedish MS register to national care registries to evaluate this risk in people with relapsing-remitting MS treated with various DMTs: the B-cell depleting therapy rituximab, highly effective natalizumab and fingolimod, as well as the traditional first line therapies interferon beta and glatiramer acetate. Here we found that rituximab was indeed associated with higher rate of infections requiring hospitalization, while natalizumab and fingolimod were not different from the traditional therapies. On the other hand, natalizumab and fingolimod, but not rituximab, were linked to a higher use of antiherpetic drugs [3]. In sum, a particular MS drug may increase the risk of certain infections, but not others”.
Early use of high efficacy treatments can lead to better clinical outcomes [8]. Individuals who receive high efficacy treatments within 2 years of MS onset have less long-term disability compared to those who start the same therapies 4-6 years after onset [8]. These therapies are highly effective at suppressing focal inflammatory processes within the central nervous system [1]. Over a 2-year period, ocrelizumab was associated with significantly lower rates of disease activity compared to interferon beta-1a, reducing lesions by 95% in individuals with relapsing-remitting MS [9]. Recent studies suggest prioritising high-efficacy therapies as the primary treatment in pediatric-onset MS [10]. These therapies are linked to a sustained reduction in disease activity over 5 years, better tolerance, and a lower rate of treatment switching in children with MS [10].
However, long-term safety studies are still needed [10]. Additionally, prevention and monitoring strategies are crucial for the early identification and management of potential infections [11].
Reducing the risk of infections
Additional real-world evidence corroborates earlier findings suggesting that long-term exposure to B-cell depleting therapies can increase the risk of infections [12]. But to what extent may infections impact MS outcomes? A recent study leveraging a large cohort from the Swedish MS Registry compared individuals treated with rituximab – commonly used off-label – with those receiving interferon beta or glatiramer acetate. The study found that rituximab was indeed associated with more than double the risk of developing infections requiring hospitalisation [12]. However, individuals with relapsing-remitting MS on platform therapies were more likely to experience lasting disability worsening following severe infections compared to those treated with rituximab. This worsening was also more commonly associated with magnetic resonance imaging (MRI) activity in those on platform therapies than in those on rituximab [12]. Notably, in individuals with progressive MS, regardless of the treatment they were on, a hospital-treated infection was linked to an increased risk of disability worsening compared to matched individuals without an infection [12].
Professor Piehl shares with us, “We need to personalise treatment and evaluate the pros and cons for each person with MS. Initially, some people I visit are very focused on preventing relapses and may not be overly concerned about the risk of infections. However, this perspective often changes after 3 or 5 years of treatment, when they may start to become tired of getting infections more frequently than before. As physicians, we must aim to optimise long-term outcomes. And one outcome that is particularly challenging to predict is the long-term effect of treatment on risk of infections.
Still, in most cases B-cell therapies may have a favorable risk-benefit balance for a young person with MS. However, as people age, reducing infections becomes even more important, which can alter this balance. Equally important, there is limited evidence that B-cell therapies are significantly more effective than other drugs for individuals with MS who are 50 years old or older. If you look at randomized control trials and stratify participants by age, you will see that most of the benefits of high-efficacy drugs are observed in people under 40, with less relative benefit in those older than 40. While we aim for high effectiveness early in treatment, long-term safety remains a priority”.
Extending the dosing intervals
Reducing the frequency of dosing may reduce the risk of infections. Extending the dosing intervals of natalizumab by 1 to 2 weeks can largely reduce the risk of developing progressive multifocal leukoencephalopathy (PML), a rare but potentially lethal brain infection [13]. However, too long intervals can also lead to a recurrence of symptoms, with increased severity and duration once the cycle is over [14]. This does not seem to be the case with extended intervals of rituximab and ocrelizumab [15, 16].
Dr Chiara Starvaggi Cucuzza, from the Karolinska University Hospital, tells us, “During the COVID-19 pandemic, we started prolonging the infusion intervals of rituximab from every 6 months to 12-24 months or more from the second infusion. We then utilised two ongoing prospective observational trials, COMBAT-MS and MultipleMS, with 718 individuals with relapsing-remitting MS. Participants were exposed to extended dosing intervals ranging from a minimum of 8 months to up to 18 months. We did not observe an increased risk of relapses compared to the standard 6-month dosing interval”.
Monitoring the therapeutic activity of a drug may help tailor interval dosing for each individual while effectively controlling disease activity [17].
Dr Adil Maarouf, from the Hôpital de la Timone in Marseille, and his co-authors showed that extended interval dosing of rituximab results in a substantial reconstitution of circulating B cells. The study included 247 individuals mostly with a relapsing form of MS (81%). 41% of participants had high disease activity before starting the treatment. Dr Maarouf tells us, “Anti-CD20 therapy to deplete B cells is an outstanding treatment for MS, but it is associated with a higher risk of infections, particularly pulmonary, urinary tract, and ENT (ear, nose, and throat) infections [18]. We have also observed skin infections linked to rituximab. To reduce the risk of infections and increase the efficacy of vaccines in individuals with MS, we extended the interval of rituximab dosing and regularly monitored the repopulation of circulating B-cell subsets [19]. We observed that disease activity did not differ between the standard (6-month) and extended interval (up to 24 months) dosing and remained very low in most patients. Only 5 patients experienced renewed disease activity. Interestingly, during the extended dosing period, disease activity remained stable despite substantial B-cell reconstitution [19]. With an extended interval dosing we avoid depleting individuals with MS of circulating lymphocytes B for their entire life. Additionally, individuals with MS feel more comfortable as they need less infusions.
With extended intervals we can restore a certain level of immune response, while controlling the disease activity. Indeed, we observed that individuals with extended interval dosing have a reduced risk of complications in case of COVID infection and a better response to vaccination. Before scheduling a vaccination or a surgery, we can verify that the B lymphocyte levels are normal to optimise the immune response. Early extended-interval dosing of rituximab or ocrelizumab is effective and safe also in paediatric population [20]. Finally, an effective way to prevent infections related to anti-CD20 therapies is to screen for neurogenic bladder – a bladder dysfunction caused by nervous system conditions – and manage it appropriately. This approach can significantly reduce the risk of pyelonephritis – a serious kidney infection”.
Anti-CD20 treatments can lead to low levels of immunoglobulin, a condition known as hypogammaglobulinemia [21]. A review of 39 articles found that 11% of 20,501 individuals with MS on anti-CD20 treatments developed hypogammaglobulinemia. The rates varied by drug: 18% individuals on rituximab, 11% on ocrelizumab, and 2% on ofatumumab [21]. Additionally, a study involving 188 individuals with MS treated with rituximab showed that the risk of reduced immunoglobulin G levels increases with age and is linked to a higher risk of infections [18]. Therefore, monitoring immunoglobulin levels in people with MS who are receiving anti-CD20 treatments is important to help lower the risk of infections.
Multidisciplinary approach: a key strategy
When discussing treatment options, neurologists need to anticipate the possible risk of infections linked to each drug and talk with the person with MS about ways to reduce these risks [11]. A multidisciplinary approach involving MS experts, as well as preventive medicine and infectious disease specialists, is advised to successfully implement risk mitigation strategies [22].
An initial assessment is recommended before starting the treatment to identify and treat any latent or chronic infections. This should include reviewing the history of past infections and evaluating the current vaccination status. Immunisation is a key strategy to prevent infections [22]. Throughout the treatment, patients should be closely monitored to ensure that any infectious complications are detected and treated promptly [22]. Finally, risk mitigation strategies should be carefully personalised for individuals who are more at risk, such as children, pregnant women, people with comorbidities, and people living in areas with endemic infections [5].
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Written by Stefania de Vito
Special thanks to Professor Fredrik Piehl (Karolinska University Hospital), to Dr Adil Maarouf (Hôpital de la Timone), and to Dr Chiara Starvaggi Cucuzza (Karolinska University Hospital) for their insights.
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