Description of the condition

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system, characterised by inflammation, demyelination, and variable degrees of axonal loss and gliosis.

The aetiology of MS is not completely understood. We know that inflammation, which is considered a crucial component of MS etiopathogenesis, involves both T and B cells, with myelin sheath loss and the activation of inflammatory cascade and olygodendrocytes (Bhise 2016). Neurodegeneration is also an essential process in MS, closely linked to inflammation (Koudriavtseva 2016), which develops during the early stages of MS, and is related to disability accumulation and disease progression.

MS is the most frequently occurring demyelinating disease, particularly among young people (Miller 2012), with a prevalence that varies considerably, from high levels in North America and Europe (more than 100 per 100,000 population) to low rates in Eastern Asia and sub‐Saharan Africa (2 per 100,000 population; GBD 2016). This leads to a significant economic burden on society and on the healthcare system.

MS is more prevalent in women than men, with a female:male ratio that varies by geographic region from 2:1 to 3:1, and has increased in the past decades (Golden 2017). Substantial epidemiological evidence supports the role of Epstein‐Barr virus (EBV) infection (Laurence 2017), and smoking (Hedstrom 2019), as risk factors, while the role of vaccines, stress, and traumatic events has not been confirmed. Several epidemiological, immunological, and genetic studies have reported an association between vitamin D and MS, but the supplementation with vitamin D has not shown significant clinical benefit in people with MS (Jagannath 2018). It is also important that the likelihood of an individual developing MS is strongly influenced by ethnic background and family history, suggesting that genetic susceptibility is a key determinant of risk. The association between HLA‐DRB1*15:01 and a high risk of MS has been known for decades and, more recently, over 100 loci have been firmly associated with susceptibility to developing MS (Hollenbach 2015).

MS‐related neurological symptoms vary significantly among patients, and include visual disturbances, numbness/tingling sensations, weakness, bladder and bowel dysfunction, cognitive impairment, fatigue, and dizziness. Based on symptom onset and disease evolution, four MS phenotypes were initially described. The most frequent form (85%) is relapsing‐remitting (RR‐MS), where patients experience periods of new symptoms or relapses, which last at least 24 hours, followed by quiet periods of disease remission. More than 50% of people with RR‐MS can develop a steady progression of symptoms over 15 years, with or without periods of remission, known as secondary‐progressive MS (SP‐MS; Lublin 1996; Weinshenker 1989). Some people with MS (15%) experience a gradual onset and steady progression of signs and symptoms, which is known as primary progressive (PP‐MS). Finally, in some cases the MS clinical course can be relapsing‐progressive (RP‐MS). This classification has been recently reviewed: the RP‐MS phenotype has been eliminated and the clinically isolated syndrome (CIS) has been added into the classification (Lublin 2014). CIS is a central nervous system demyelinating clinical event, isolated in time, that is compatible with the possible future development of MS. There is a subgroup of people with RR‐MS who have a more aggressive disease course characterised by a rapid accumulation of disability, despite treatment with one or more disease‐modifying drugs. In the past, this disease phenotype was called 'aggressive' MS, and more recently has been called highly active MS (HAMS). It is generally agreed that the severe nature of this phenotype requires different treatment decisions. Unfortunately, there is no consensus on the definition of HAMS or on the treatment algorithm (Díaz 2019). MS prognosis is extremely variable and uncertain. In this regard, factors that may contribute to clinical evolution are age, sex, subtype of MS, magnetic resonance imaging (MRI) distribution of demyelinating lesions and spinal cord atrophy (Schlaeger 2014).

There is no definitive cure for MS. Steroid treatment during the relapse phase can accelerate clinical recovery, without a significant impact on long‐term MS disability (Ciccone 2008). However, a wide range of immunomodulatory therapies or disease‐modifying drugs have become available over the last few years. These drugs are promising, in light of the results of clinical trials, in reducing the possibility of relapses and the risk of disability progression. Currently disease‐modifying drugs for MS approved by the European Medicine Agency (EMA 2017) include beta interferons, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, alemtuzumab, natalizumab, and more recently ocrelizumab and cladribine. The introduction of oral medications such as dimethyl fumarate, fingolimod, teriflunomide, and cladribine has been a crucial step in the history of this disease, allowing many patients an immediate improvement in terms of injection‐related discomfort and day‐to‐day management and, possibly, reducing the costs of administering them.

A major objective at the time of the initial diagnosis is to arrest the disease at the early inflammatory stage, in the hope that this will also delay disease progression and minimise future disability. The new treatments have many indication for RR‐MS, although there are relatively few options for progressive MS, that is, ocrelizumab for people with PP‐MS. Other treatments for MS include symptomatic therapies focused on alleviating symptoms such as pain, fatigue, numbness, spasticity, and urinary disturbances.

Description of the intervention

Cladribine is a purine nucleoside analogue, which selectively depletes peripheral lymphocytes without a major impact on the innate immune system, in particular with a low level of influence on the activity of natural killer cells, eosinophils, macrophages and basophils. Chemically it mimics the nucleoside adenosine, but it is relatively resistant to de‐amination by the enzyme adenosine deaminase. Cladribine undergoes intracellular phosphorylation by deoxycitidine kinase (DCK) and its active metabolite, cladribine triphosphate, accumulates within the cells and interferes with cellular metabolism, inducing DNA damage and apoptosis. Cladribine preferentially targets lymphocytes, producing rapid and sustained reductions in CD4+ and CD8+ cells, with rapid but more transient effects on CD19+ cells (Giovannoni 2017), relatively sparing other immune cells.

Cladribine was initially developed following research into the pathogenesis of the genetic disease adenosine deaminase deficiency (ADA), a severe immunodeficiency in children, resulting from the accumulation of deoxyadenosine nucleotides in lymphocytes (Beutler 1992). Cladribine has been extensively used for decades, in a variety of haematological disorders, such as hairy cell leukaemia (Saven 1998), and B‐cell chronic lymphocytic leukaemia (Juliusson 1996). The drug has also been investigated for several other autoimmune disorders.

Considering the role of inflammation in MS, involving both B and T cells, and cladribine's action of depleting lymphocytes in the periphery and in the central nervous system, this treatment began to be evaluated (initially with parenteral administration), in people with relapsing and progressive forms of MS. Three randomised, double‐blind, placebo‐controlled, phase II‐III trials have been conducted at the Scripps Research Institute (Beutler 1996; Rice 2000; Romine 1999), with promising results for reduction of relapses and disability progression. After these studies with parenteral cladribine administration, an oral tablet form was introduced. Cladribine has preferential and sustained activity in CD4+ and CD8+ T lymphocytes and B lymphocytes for more than 10 months following the last oral dose, probably affecting both resting and actively‐dividing lymphocytes, including quiescent progenitor cells (Guarnaccia 2008). This allows the use of an annual short‐course schedule. Its reduced effect on innate immune cells should preserve relative immunocompetence.

Over recent years many trials have been conducted with oral cladribine, involving people with different forms of MS. Trials such as ORACLE (investigating cladribine in people with CIS/early MS; Leist 2014), CLARITY (people with RR‐MS; Giovannoni 2010; Giovannoni 2011), and CLARITY extension (a two‐year extension of the CLARITY study; Giovannoni 2018), have shown encouraging results for relapse rates, disability progression, and MRI endpoints.

How the intervention might work

The cladribine molecule (also known as 2‐CdA) is an adenosine analogue, acting as a prodrug. Its activity is dependent on the intracellular accumulation of its active triphosphate, which occurs preferentially in certain cell types. Three intracellular enzymes play a key role in determining the availability of its active form.

1. DCK (catalyses the first of three phosphorylation steps required to convert cladribine into its biologically‐active nucleotide triphosphate, 2‐CdATP);

2. 5’nucleotidase (5’NTase; catalyses the reconversion of phosphorylated cladribine to the cladribine nucleoside);

3. ADA (catabolic pathway trough de‐amination, even though cladribine is quite resistant to this enzymatic process).

The accumulation of the active 2‐CdATP is dependent on the ratio of DCK, which creates it, to 5’NTase, which breaks it down (Kawasaki 1993).

The levels of DCK and the DCK:5’NTase ratio are high in T cells (CD4+, CD8+), B cells and dendritic cells. This results in selective accumulation of CdATP in lymphocytes, allowing cladribine to preferentially target these cells. As the active compounds increase within lymphocytes, there is inhibition of DNA synthesis and repair, disruption of cellular proliferation in actively‐dividing lymphocytes, and apoptosis or autophagy, or both, of quiescent lymphocytes (Saven 1998). Alteration of cytokine patterns and induction of T‐helper T‐related cytokines may also contribute to the sustained effects of cladribine seen in clinical trials (Korsen 2015).

MS is an autoimmune inflammatory disorder of the central nervous system. Even if the pathogenesis is not completely clear, inflammation is considered to be an essential component of this disease, involving both T cells and B cells. Targeted reduction of cladribine‐related lymphocyte subtypes is the basis of a possible new therapeutic approach.

Why it is important to do this review

Cladribine was approved in August 2017 in Europe for the treatment of highly‐active RR‐MS (EMA 2017), and in March 2019 in USA by the Food and Drug Administration (FDA; FDA 2019).

The EMA and the FDA withheld approval of this medication in 2010 to 2011 because of safety concerns (an increase in the frequency of cancer) in the CLARITY trial (NCT00213135; Giovannoni 2010). The ORACLE trial (Leist 2014), was terminated early by the study sponsor because of the negative regulatory decision on the CLARITY data. Results from the most recent trials resolved cladribine's initial problems, reassuring on safety and tolerance or tolerability profile. Data from the oral cladribine extension trial (Giovannoni 2018), and from the safety register, from the PREMIERE trial (NCT01013350), and re‐analysis of the pivotal phase III CLARITY trial (Cook 2011; Pakpoor 2015), have indicated that oral cladribine is unlikely to be associated with an increased short‐ or medium‐term risk of secondary malignancy. There may be a risk of Herpes Zoster infection, which is more frequently observed in those treated with cladribine tablets than with placebo, particularly in people with higher grades of lymphopenia (Cook 2009; Giovannoni 2010; Giovannoni 2013).

Even if this new treatment seems to be both effective and with a manageable side‐effects profile, it is now important to evaluate the risk‐benefit ratio of cladribine for people with MS, and to verify if this is confirmed in the long term. It is also essential to consider the risk‐benefit ratio for cladribine in the different subtypes of MS. Only a few studies have investigated cladribine in CIS/early MS stages (the transition phase from CIS to MS in the ORACLE trial) and progressive MS (Beutler 1996; Rice 2000). Difficulties in distinguishing the precise clinical MS subtype in the early stage of this disease result in some cases in a delayed or inappropriate prescription of disease‐modifying drugs. The possibility of finding a treatment that could be effective in different MS subtypes would be very valuable in the daily clinical approach to people with MS.