Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients

Abstract

The results support that immune-monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.

Fingolimod Profoundly Reduces Frequencies and Alters Subset Composition of Circulating T Follicular Helper Cells in Multiple Sclerosis Patients

“…We found that transitional B cells are relatively increased during fingolimod treatment, which confirms previous reports (59,61). Transitional B cells have been described as regulatory IL-10-secreting Breg cells, and therefore, their strong relative increase upon fingolimod treatment as well as the relative increase of cTreg cells might suppress pathological conditions (41,62,63). Interestingly, the frequency of CCR6-expressing cTreg cells was particularly increased in the blood after fingolimod treatment.…”

“…Similar to T cells, the absolute number of B cells was decreased upon fingolimod treatment compared with HC and untreated MS patients (Fig. 5A), which is in line with previous studies (34,41,42). As some B cell subsets, especially memory B cells, were reported to act as pathogenic or proinflammatory B cells in MS and some as regulatory B (Breg) cells ( Supplemental Fig.…”

Fingolimod Profoundly Reduces Frequencies and Alters Subset Composition of Circulating T Follicular Helper Cells in Multiple Sclerosis Patients

“…We found that transitional B cells are relatively increased during fingolimod treatment, which confirms previous reports (59,61). Transitional B cells have been described as regulatory IL-10-secreting Breg cells, and therefore, their strong relative increase upon fingolimod treatment as well as the relative increase of cTreg cells might suppress pathological conditions (41,62,63). Interestingly, the frequency of CCR6-expressing cTreg cells was particularly increased in the blood after fingolimod treatment.…”

“…Similar to T cells, the absolute number of B cells was decreased upon fingolimod treatment compared with HC and untreated MS patients (Fig. 5A), which is in line with previous studies (34,41,42). As some B cell subsets, especially memory B cells, were reported to act as pathogenic or proinflammatory B cells in MS and some as regulatory B (Breg) cells ( Supplemental Fig.…”

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

“…Nevertheless, we could not prove an increased incidence of infectious adverse events in the lower vs. higher-level lymphopenia group. These data are in line with several studies presenting primarily mild to moderate infections during fingolimod ( 8 , 18 , 28 ) The most relevant infectious complication in fingolimod treated patients is defined by varicella-zoster virus (VZV) and herpes simplex virus (HSV) infection or reactivation ( 8 , 18 , 33 ). However, individual variation of VZV specific T cell responses are assumed to be more relevant for upcoming VZV activation rather than absolute lymphocyte counts ( 34 , 35 ).…”

Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population

“…Nevertheless, we could not find significant differences between patients with disease control and those with ongoing disease activity, in terms of EDSS worsening, relapses, MRI activity and NEDA-3 status. These findings support previous studies that found no association between disease activity and lymphocyte count [6,7,10], but are in contrast with some other reports [8,9,12,[17][18][19][20]. It is important to notice that all the studies finding an association between lymphocyte count and disease activity during FTY treatment analysed specific lymphocyte subsets and did not take into account total circulating lymphocytes.…”

Fingolimod Profoundly Reduces Frequencies and Alters Subset Composition of Circulating T Follicular Helper Cells in Multiple Sclerosis Patients

“…We found that transitional B cells are relatively increased during fingolimod treatment, which confirms previous reports (59,61). Transitional B cells have been described as regulatory IL-10-secreting Breg cells, and therefore, their strong relative increase upon fingolimod treatment as well as the relative increase of cTreg cells might suppress pathological conditions (41,62,63). Interestingly, the frequency of CCR6-expressing cTreg cells was particularly increased in the blood after fingolimod treatment.…”

“…Similar to T cells, the absolute number of B cells was decreased upon fingolimod treatment compared with HC and untreated MS patients (Fig. 5A), which is in line with previous studies (34,41,42). As some B cell subsets, especially memory B cells, were reported to act as pathogenic or proinflammatory B cells in MS and some as regulatory B (Breg) cells ( Supplemental Fig.…”

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

“…Nevertheless, we could not prove an increased incidence of infectious adverse events in the lower vs. higher-level lymphopenia group. These data are in line with several studies presenting primarily mild to moderate infections during fingolimod ( 8 , 18 , 28 ) The most relevant infectious complication in fingolimod treated patients is defined by varicella-zoster virus (VZV) and herpes simplex virus (HSV) infection or reactivation ( 8 , 18 , 33 ). However, individual variation of VZV specific T cell responses are assumed to be more relevant for upcoming VZV activation rather than absolute lymphocyte counts ( 34 , 35 ).…”

Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population

“…Nevertheless, we could not find significant differences between patients with disease control and those with ongoing disease activity, in terms of EDSS worsening, relapses, MRI activity and NEDA-3 status. These findings support previous studies that found no association between disease activity and lymphocyte count [6,7,10], but are in contrast with some other reports [8,9,12,[17][18][19][20]. It is important to notice that all the studies finding an association between lymphocyte count and disease activity during FTY treatment analysed specific lymphocyte subsets and did not take into account total circulating lymphocytes.…”

Fingolimod Profoundly Reduces Frequencies and Alters Subset Composition of Circulating T Follicular Helper Cells in Multiple Sclerosis Patients

“…We found that transitional B cells are relatively increased during fingolimod treatment, which confirms previous reports (59,61). Transitional B cells have been described as regulatory IL-10-secreting Breg cells, and therefore, their strong relative increase upon fingolimod treatment as well as the relative increase of cTreg cells might suppress pathological conditions (41,62,63). Interestingly, the frequency of CCR6-expressing cTreg cells was particularly increased in the blood after fingolimod treatment.…”

“…Similar to T cells, the absolute number of B cells was decreased upon fingolimod treatment compared with HC and untreated MS patients (Fig. 5A), which is in line with previous studies (34,41,42). As some B cell subsets, especially memory B cells, were reported to act as pathogenic or proinflammatory B cells in MS and some as regulatory B (Breg) cells ( Supplemental Fig.…”

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

“…Nevertheless, we could not prove an increased incidence of infectious adverse events in the lower vs. higher-level lymphopenia group. These data are in line with several studies presenting primarily mild to moderate infections during fingolimod ( 8 , 18 , 28 ) The most relevant infectious complication in fingolimod treated patients is defined by varicella-zoster virus (VZV) and herpes simplex virus (HSV) infection or reactivation ( 8 , 18 , 33 ). However, individual variation of VZV specific T cell responses are assumed to be more relevant for upcoming VZV activation rather than absolute lymphocyte counts ( 34 , 35 ).…”

Fingolimod and Dimethyl-Fumarate-Derived Lymphopenia is not Associated with Short-Term Treatment Response and Risk of Infections in a Real-Life MS Population

“…Nevertheless, we could not find significant differences between patients with disease control and those with ongoing disease activity, in terms of EDSS worsening, relapses, MRI activity and NEDA-3 status. These findings support previous studies that found no association between disease activity and lymphocyte count [6,7,10], but are in contrast with some other reports [8,9,12,[17][18][19][20]. It is important to notice that all the studies finding an association between lymphocyte count and disease activity during FTY treatment analysed specific lymphocyte subsets and did not take into account total circulating lymphocytes.…”