Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers

Stüve, Olaf; Soerensen, Per Soelberg; Leist, Thomas; Giovannoni, Gavin; Hyvert, Yann; Damian, Doris; Dangond, Fernando; Boschert, Ursula

doi:10.1177/1756286419854986

Cited by 82 publications

(117 citation statements)

References 41 publications

(64 reference statements)

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“…6A). 10,11 This selectivity can be explained by virtue of the drug's biology and the distribution of deoxycytidine kinase (DCK), which activates CLAD by phosphorylation and is highly expressed in lymphocytes. 14 Moreover, we show that some of the immunological changes are more pronounced or exclusively in the second year, which can be seen as a consequence of the second annual treatment cycle.…”

Section: Discussionmentioning

confidence: 99%

“…9 The flow cytometric analysis of immune cells in peripheral blood of MS patients treated with CLAD revealed a rapid reduction of CD16 + /CD56 + cells (nadir at week 5), a marked reduction in CD19 + B cells (nadir at week 13) and a less-pronounced effect on CD4 + (week 13 nadir) and CD8 + T cells (nadir at week 24), respectively. 10 Of note, there are distinct recovery kinetics. B cells return to threshold values by week 84 and CD4 + T cells by week 96.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, there is no or little effect on neutrophils and monocytes. 10,12 Characterization of immune cell alterations occurring during the disease course and in response to treatment may support a better understanding of MS pathogenesis and the mechanism of action (MoA) of disease-modifying therapies (DMT). From a therapeutic viewpoint, DMTs may be more effective and associated with lesser extent of side effects if they can specifically correct these detrimental immune processes.…”

Section: Introductionmentioning

confidence: 99%

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Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Moser

Schwenker

Seiberl

et al. 2020

Ann Clin Transl Neurol

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Objectives: To expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short-term effects on peripheral immune cell subsets. Methods: In this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD. The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry. Results: We found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper-repopulation of maturing B cells. Counts of classical (À65%) and various nonclassical TH17 cells (À84% to À87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of classswitched memory B-cell phenotypes (À87% to À95%). The nadir of TH cells was more pronounced in the second treatment year. We observed a proportional surge of CD20 T-cell subsets and an expansion of regulatory T, B and NK cells. Natural killer T cells (NKT) were only depleted in year two and did not recover. Interpretation: Peripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD. While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course. Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease-modifying effect of CLAD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Moser

Schwenker

Seiberl

et al. 2020

Ann Clin Transl Neurol

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“…It will likely be incompatible with the live-attenuated and possibly viral vector vaccines. It might be relatively safer compared with alemtuzumab owing to its oral route of administration and lesser effect on T cells [98]. Although the oral route is safer compared with intravenous DMTs from the exposure risk standpoint, the need for periodic laboratory monitoring still carries a high exposure risk at the medical laboratory or with home collection personnel.…”

Section: Potential Relevance To the Covid-19 Pandemic And Possible Rimentioning

confidence: 99%

Multiple Sclerosis Disease-Modifying Therapy and the COVID-19 Pandemic: Implications on the Risk of Infection and Future Vaccination

et al. 2020

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The coronavirus 2019 (COVID-19) pandemic is expected to linger. Decisions regarding initiation or continuation of diseasemodifying therapy for multiple sclerosis have to consider the potential relevance to the pandemic. Understanding the mechanism of action and the possible idiosyncratic effects of each therapeutic agent on the immune system is imperative during this special time. The infectious side-effect profile as well as the route and frequency of administration of each therapeutic agent should be carefully considered when selecting a new treatment or deciding on risk mitigation strategies for existing therapy. More importantly, the impact of each agent on the future severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) vaccine should be carefully considered in treatment decisions. Moreover, some multiple sclerosis therapies may have beneficial antiviral effects against SARS-CoV-2 while others may have beneficial immune-modulating effects against the cytokine storm and hyperinflammatory phase of the disease. Conventional injectables have a favorable immune profile without an increased exposure risk and therefore may be suitable for mild multiple sclerosis during the pandemic. However, moderate and highly active multiple sclerosis will continue to require treatment with oral or intravenous high-potency agents but a number of risk mitigation strategies may have to be implemented. Immune-modulating therapies such as the fumerates, sphinogosine-1P modulators, and natalizumab may be anecdotally preferred over cell-depleting immunosuppressants during the pandemic from the immune profile standpoint. Within the cell-depleting agents, selective (ocrelizumab) or preferential (cladribine) depletion of B cells may be relatively safer than non-selective depletion of lymphocytes and innate immune cells (alemtuzumab). Patients who develop severe iatrogenic or idiosyncratic lymphopenia should be advised to maintain social distancing even in areas where lockdown has been removed or ameliorated. Patients with iatrogenic hypogammaglobulinemia may require prophylactic intravenous immunoglobulin therapy in certain situations. When the future SARS-CoV-2 vaccine becomes available, patients with multiple sclerosis should be advised that certain therapies may interfere with mounting a protective immune response to the vaccine and that serological confirmation of a response may be required after vaccination. They should also be aware that most multiple sclerosis therapies are incompatible with live vaccines if a live SARS-CoV-2 vaccine is developed. In this article, we review and compare disease-modifying therapies in terms of their effect on the immune system, published infection rates, potential impact on SARS-CoV-2 susceptibility, and vaccine-related implications. We propose risk mitigation strategies and practical approaches to disease-modifying therapy during the COVID-19 pandemic.

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“…26% of patients and grade 4 in 0.7% [27]. The absolute numbers of monocytes and neutrophils remained unchanged following cladribine treatment [28][29][30][31][32].…”

Section: Cladribinementioning

confidence: 99%

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

et al. 2020

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Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.

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Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers

Cited by 82 publications

References 41 publications

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS

Multiple Sclerosis Disease-Modifying Therapy and the COVID-19 Pandemic: Implications on the Risk of Infection and Future Vaccination

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

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