Cladribine may not work well in everyone.


There are some people who do not respond to drugs. This can be for genetic reasons. There are people who do not deplete after treatment with alemtuzumab. There will be people that on’t respond well to rituximab/ocrelizumab and there are people that will not respond to cladribine. If you don’t deplete the lymphocytes, the drug may not work. So it is always improtant to monitor this after any depleting treatment.

Last year we reported that there are a number of people that do not appear to deplete their lymphocytes. What is the reason behind this. One imagines genetic reasons. In this report they suggest that a variant of adenosine diaminase is important.

They suggest a single nucleotide polymorphism is associated clinical characteristics. DNA is made up of 4 nucleotides: adenine A, cytosine C, thymine T and guanine G. The combination of three of these code for an animo acid and amino acids made proteins. A single nucleotide polymorphism (SNP), pronounced snip, is a gene variant. For example say that most people have T in the gene, some people have A, C or G. This is a SNP . This can be functional or non functional depending on where it is. But it acts as a marker of inheritence as you get one variant from your mum and one from your dad. The important gene may be nearby. Here they claim a variant of a SNP in the adenosine deaminase may influence how cladribine works.

If the gene variant causes a Loss of Function of adenososine diaminase, you don’t make lymphocytes. Are their variants that means that cladribine doesnt work? Cladribine has a chlorine molecule that means it can’t be broken down by adenosine diaminase and so it is activated to become a drug that kills lymphocytes. Therefore, the adenosine variant would have to be one that can break down cladribine. I will bet that the really important genetic variants lie elsewhere, but that’s another story

Stampanoni Bassi M, Buttari F, Simonelli I, Gilio L, Furlan R, Finardi A, Marfia GA, Visconti A, Paolillo A, Storto M, Gambardella S, Ferese R, Salvetti M, Uccelli A, Matarese G, Centonze D, De Vito F. A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment. Genes (Basel). 2020 Sep 30;11(10):E1152.

In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets.

We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced disability and increased CSF levels of TNF, IL-5 and RANTES was observed. In addition, lower CSF levels of the anti-inflammatory cytokine IL-10 were found. Finally, the presence of the C allele was associated with a tendency of increased lymphocyte count. In MS patients, ADA SNP rs244072 is associated with CSF inflammation and disability. The selective targeting of the ADA pathway through cladribine tablet therapy could be effective in MS by acting on a pathogenically relevant biological mechanism.

Genes | Free Full-Text | A Single Nucleotide ADA Genetic Variant Is  Associated to Central Inflammation and Clinical Presentation in MS:  Implications for Cladribine Treatment | HTML

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  • My lymphocytes have depleted following two treatment years of Cladribine but my MS has unfortunately worsened even further. Are there any other options for me to try to halt more deterioration? Thankyou.

  • Do you know if this genetic variant test is commercially available? Like you said earlier….pwms always have to be thinking about their next drug. Now if I can only get “the man” to approve subcutaneous clad. Thanks for sharing this study. 🧐

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