Key messages

• Compared with placebo, cladribine likely reduces the risk of relapse, and it may reduce the number of new lesions seen on brain scans in people with multiple sclerosis after almost two years of treatment, but the evidence is very uncertain. Cladribine may result in little to no difference in slowing the progression of disability after almost two years of treatment. Compared with placebo, cladribine may not change the risk of serious side effects, but the evidence is very uncertain.

• Longer and better-quality studies are needed to assess the benefits and harms of cladribine acting on the immune system in multiple sclerosis. Future research should compare cladribine with other medicines used in this disease, focusing on effects that are most important to patients, such as quality of life and the ability to complete everyday tasks. Future studies should also include vulnerable populations.

What is multiple sclerosis?

Multiple sclerosis (MS) is an uncommon disease caused by inflammation of the brain and spinal cord, leading to damage that impairs important everyday activities over time, such as walking and self-care. People with MS experience symptoms such as visual disturbances, numbness/tingling, weakness, bladder and bowel dysfunction, problems with mental abilities, fatigue, and dizziness. These symptoms may worsen and lead to dependence upon others. The reappearance of symptoms is called 'relapse'. The most common form of MS is called 'relapsing-remitting MS', where symptoms come and go. Over time, relapses become more frequent, with more troublesome symptoms and shorter periods of well-being in between. MS is a particularly burdensome condition; it typically affects young people, mainly women, in the most active stage of their lives.

How is multiple sclerosis treated?

MS is currently treated with 'disease-modifying' medicines (e.g. interferon beta, glatiramer acetate, natalizumab, fingolimod, alemtuzumab, teriflunomide, and dimethyl fumarate). These medicines can slow but not stop disease progression.

What did we want to find out?

The exact causes of MS are not fully understood, but we know that inflammation, driven by certain immune cells (T and B cells), plays an important role. Cladribine works by reducing some of these immune cells in the blood and brain, which may help lower inflammation and slow down the course of the disease. We wanted to know if cladribine can slow or stop the worsening of disability in people with MS, with no increase in unwanted events.

What did we do?

We searched for studies comparing cladribine with no treatment, placebo (dummy treatment), or any 'disease-modifying' medicines in people with any type of MS. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods, number of participants, and precision of the results.

What did we find?

We included 15 studies with the following designs.

• Nine randomised controlled trials (RCTs, where participants are assigned randomly to two or more treatment groups) that followed 2571 participants for one to two years.

• Four open-label extension trials (OLEs, where participants from RCTs are offered continued access to the study treatment) that followed participants for another two to 10 years.

• Two observational studies (using 'real-life' data) that compared cladribine with other 'disease-modifying' medicines in 4111 people over one to three years.

Important outcomes for patients, such as quality of life and thinking or memory problems, were not reported in any study.

Results from RCTs suggest cladribine probably reduces the risk of new relapses compared to placebo. It may also lower the number of new lesions seen on magnetic resonance imaging (MRI) scans of the brain, although the evidence is very uncertain. However, cladribine may have little or no effect on whether disability gets worse. There may be little or no difference between cladribine and placebo in the number of people with serious unwanted events and who stop using treatment, and cladribine may increase the risk of other unwanted events, but our confidence in these results is very low.

Results from OLEs suggest cladribine may increase the proportion of people who show no signs of the disease worsening at four years compared to placebo. It may reduce relapses and the number of new MRI lesions, but the evidence is very uncertain. It may have little to no effect on whether disability gets worse, whether people experience unwanted events, or whether they stop using treatment, but we have very little confidence in these results.

From observational studies comparing cladribine with other medicines, results were mixed: cladribine may be better than some medicines (dimethyl fumarate, teriflunomide, and fingolimod at three years) for reducing relapses, but its effects on this outcome compared with fingolimod, natalizumab, and interferon beta at one year remain unclear.

What are the limitations of the evidence?

Our confidence in the effects of cladribine is limited by poor-quality research and loss of focus on affected people's needs. Most studies were performed by the cladribine manufacturing company. There is concern that their interests may have influenced reporting of study results.

How up-to-date is this evidence?

The evidence is current to February 2025.