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Effect of dosage reduction on peripheral blood lymphocyte count in patients with multiple sclerosis receiving long-term fingolimod therapy
Journal of Clinical Neuroscience 63 (2019) 91–94
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Effect of dosage reduction on peripheral blood lymphocyte count in patients with multiple sclerosis receiving long-term fingolimod therapy Kazuya Takahashi ⇑ Department of Neurology, Hokuriku Brain and Neuromuscular Disease Center, National Hospital Organization Iou Hospital, Kanazawa, Japan
a r t i c l e
i n f o
Article history: Received 21 August 2018 Accepted 28 January 2019
Keywords: Fingolimod Multiple sclerosis Progressive multifocal leukoencephalopathy John Cunningham (JC) virus Adverse drug reaction Lymphocyte
a b s t r a c t Of the 19 cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) reported worldwide by the end of 2017, 4 cases were from Japan. This may indicate that fingolimod sensitivity is higher in the Japanese population than in the western population because the fingolimod dosage used for the prevention of multiple sclerosis (MS) is the same in both populations. Therefore, the laboratory data of nine patients with MS receiving fingolimod treatment for more than 2 years were retrospectively collected. Moreover, the effect of drug holiday was compared between five patients who underwent at least 3 months of dosage reduction via drug holiday after receiving fingolimod for more than 2 years and three patients who underwent drug holiday after receiving fingolimod for less than 2 years. The total, CD3(+), CD4(+), C19(+) lymphocyte counts, the CD4(+)/CD8(+) cell ratio, and the serum IgG concentrations were similar between Japanese patients with MS receiving fingolimod for more than 2 years and Western patients from the previous reports. Recovery of lymphocyte counts in the peripheral blood after fingolimod dosage reduction was worse in some MS patients who received long-term fingolimod treatment than in MS patients who received short-term fingolimod treatment. My findings indicate that the currently used fingolimod dosage may be too high for some Japanese MS patients receiving long-term fingolimod treatment. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Multiple sclerosis (MS) is considered as a Th1-mediated autoimmune disease of the central nervous system (CNS), and is characterized by phases of remission and relapse. Fingolimod, the first oral drug approved for relapsing-remitting MS, is a functional antagonist of sphingosine-1-phosphate receptor and is widely used globally, including in Japan. By the end of 2017, over 200,000 MS patients received fingolimod worldwide. Progressive multifocal leukoencephalopathy (PML) is a rare and fatal demyelinating CNS disease caused by John Cunningham virus (JCV). It occurs exclusively in individuals with a weakened immune system, including in patients with acquired immune deficiency syndrome and patients taking immunosuppressive medications. The first case of fingolimod-associated PML without prior natalizumab treatment was reported in 2015 [1], and subsequently, 19 fingolimod-associated PML cases without prior natalizumab treatment have been reported worldwide to date. Overall, the inci⇑ Address: Department of Neurology, Hokuriku Brain and Neuromuscular Disease Center, National Hospital Organization Iou Hospital, Ni73-1, Iwade-machi, Kanazawa 920-0192, Japan. E-mail address: [email protected] https://doi.org/10.1016/j.jocn.2019.01.034 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
dence of fingolimod-associated PML is estimated to be 0.069 per1000 patients [2]. However, in Japan, 4 cases of fingolimodassociated PML have already been registered by the Progressive Multifocal Leukoencephalopathy Surveillance Committee, despite the number of patients receiving fingolimod being less than 6000. This indicates that the fingolimod-associated PML rate in Japan is about ten times higher than the fingolimod-associated PML rate in the rest of the world. However, the reason for this discrepancy is unclear and warrants further investigation. JCV infection, which can cause PML in immunocompromised individuals, is latent and non-pathogenic in individuals with normal immune function. The prevalence of anti- JCV antibody is generally 50–70% worldwide, although it varies by country [3], and 45% of anti-JCV antibody-positive MS patients have a JCV antibody index of >1.5, which indicates the highest risk for natalizumabinduced PML [4]. The anti-JCV antibody prevalence in the Japanese population is 69.5%, and 52.4% of MS patients have a JCV antibody index of >1.5 [5]. Although these values are still on the higher end of the global range, the incidence of fingolimod-related PML is not high in MS patients in the other countries with a higher prevalence of JCV infection. This result indicates that the anti-JCV antibody prevalence and index alone cannot explain the differences in incidence of fingolimod-related PML. These results may indicate that
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the current fingolimod dosage constitutes an overdose for Japanese MS patients, although the same dosage is used in all countries where fingolimod has been approved for MS treatment. In addition, fingolimod treatment for more than 2 years and age over 40 years are considered risk factors of fingolimod-associated PML [2]. In the present study, I first evaluated lymphocyte counts in Japanese MS patients who received fingolimod for more than 2 years. Next, to determine if fingolimod dosage may be too high for some Japanese MS patients, I compared the difference in the effect of drug holiday in Japanese MS patients who had received fingolimod treatment for more than or less than 2 years.
2. Methods 2.1. Patients selection This study was approved by the Ethics Committee of the Iou Hospital (IOU2018-02). Nine MS patients who received 0.5 mg fingolimod daily for more than 2 years and who regularly visited Iou hospital at the end of 2017 were enrolled in this study. Moreover, among these nine MS patients, five had undergone fingolimod dosage reduction for more than 3 months via intermittent drug holidays (0.5 mg 6 days/week with no drug on Fridays) after receiving fingolimod for more than 2 years and three had undergone dosage reduction via drug holidays after receiving fingolimod for less than two years. These two patient groups were compared to investigate the effect of drug holidays during short- and longterm fingolimod therapy. Patients with other autoimmune disease, cancer, infectious disease, and immunosuppressive medications including steroids, were excluded from this study.
2.2. Laboratory data The data on total, CD3(+), CD4(+), CD8(+), and CD19(+) lymphocyte count, and serum immunoglobulin G (IgG) concentration were collected retrospectively. Data for each patient were classified as data collected within 2 years after the initiation of fingolimod treatment (within ST) and data collected more than 2 years after the initiation of fingolimod treatment (after LT), and the average cell counts were calculated by excluding data during dosage reduction and for 3 months after a change in fingolimod dosage.
2.3. Analysis of recovery of lymphocyte counts after reduction of fingolimod dosage via intermittent drug holidays Fingolimod dosage was reduced via drug holiday within ST in three cases and after LT in five cases. In all three cases of dosage reduction within ST, the dosage was reduced again after LT. We compared peripheral blood lymphocyte counts before and after fingolimod dosage reduction. Recovery of lymphocyte counts was calculated by subtracting lymphocyte counts in the peripheral blood just before dosage reduction from lymphocyte counts in the peripheral blood 3 months after dosage reduction.
2.4. Statistical analysis The Mann–Whitney U test or Kruskal–Wallis test was used for between-group comparison of data. P-values < 0.05 were considered significant. All quantitative data are presented as mean (standard deviation). Statistical calculations were performed using SPSS 18.0 software (IBM, Armonk, NY, USA).
3. Results 3.1. Peripheral blood lymphocyte counts of Japanese MS patients after long-term fingolimod treatment The total lymphocyte, CD3(+) T cell, CD19(+) B cell, CD4(+) lymphocyte, and CD8(+) lymphocyte counts, the CD4(+)/CD8(+) cell ratio, and the serum IgG concentration are shown in Fig. 1. Although the average total lymphocyte count decreased significantly after LT compared to the average baseline value before fingolimod treatment (2124 (563)/mm3; p < 0.001), the average total lymphocyte count within ST (489 (140)/mm3) was not significantly different from that after LT (506 (153)/mm3; p = 0.938; Fig. 1a). Compared with the average baseline serum IgG concentration before fingolimod treatment, the serum IgG concentration in both the ST and LT groups was significantly lower (ST; p = 0.035; LT; p < 0.001), and furthermore it was significantly lower in the LT group than in the ST group (p = 0.185; Fig. 1b). The average T cell count, B cell count, CD4(+) lymphocyte count, and CD4(+)/CD8(+) cell ratio in the peripheral blood of MS patients after LT (T cell; 339(179)/mm3, B cell; 46(33)/mm3, CD4(+)cell; 83(52)/mm3, CD4 (+)/CD8(+) cell ratio; 0.35(0.17)) (T cell; p = 0.001, B cell; p = 0.002, CD4(+) cell; p = 0.001, CD4(+)/CD8(+) cell ratio; p = 0.001) were significantly lower than the average baseline values in MS patients before fingolimod treatment (T cell; 1168 (217)/mm3, B cell; 280(102)/mm3, CD4(+) cell; 555(73)/mm3, CD4(+)/CD8(+) cell ratio; 1.6(0.19); Fig. 1c, d, e, g). The average CD8 positive lymphocyte count in the peripheral blood of Japanese MS patients after LT (281(120)/mm3) was not significantly different from that in the peripheral blood of Japanese MS patients before the initiation of fingolimod treatment (353(82)/mm3; p = 0.157; Fig. 1f) 3.2. Trend of recovery of lymphocyte counts after reduction of fingolimod dosage via intermittent drug holidays When fingolimod dosage was reduced via intermittent drug holidays within ST, total lymphocyte counts in the peripheral blood increased rapidly at 3 months after dosage reduction in all cases (Fig. 2). In contrast, when fingolimod dosage was reduced via intermittent drug holidays after LT, recovery of lymphocyte counts in the peripheral blood did not change or decreased in three cases at 3 months after dosage reduction (Fig. 2). Although the recovery of lymphocyte counts in the peripheral blood increased in the other two cases, they were also lower than the recovery of lymphocyte counts in the peripheral blood when fingolimod dosage was reduced via intermittent drug holidays within ST. Moreover, when fingolimod was reduced after LT, the recovery of lymphocyte counts in the peripheral blood of two (Case 1 and 3) of three patients (Case 1–3) who had experienced intermittent drug holidays both within ST and after LT was worse than the recovery of lymphocyte counts when fingolimod was reduced within ST (Fig. 2). 4. Discussion Previous studies revealed changes in lymphocyte counts after the initiation of fingolimod treatment [6–9]. However, since most of these studies investigated changes in lymphocyte counts within 1 year after the initiation of fingolimod treatment, the effect of long-term fingolimod treatment on lymphocyte counts remains unclear. The lymphocyte counts in the peripheral blood of MS patients receiving long-term fingolimod therapy in this study are similar to the values reported by Saida et al. [9]. The T cell, B cell, and CD4(+) lymphocyte counts, and the CD4(+)/CD8(+) cell ratio
K. Takahashi / Journal of Clinical Neuroscience 63 (2019) 91–94
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Fig. 1. Changes in lymphocyte counts in the peripheral blood after long-term fingolimod treatment. Absolute lymphocyte counts (a), serum IgG concentration (b), CD3(+) T cell counts (c), CD19(+) B cell counts (d), CD4(+) lymphocyte counts (e), CD8(+) lymphocyte counts (f), and CD4(+)/CD8(+) lymphocyte ratio (g) in the peripheral blood of MS patients before fingolimod treatment (Pre), within 2 years after the initiation of fingolimod treatment (ST), and more than 2 years after the initiation of the fingolimod treatment (LT). Data are presented as mean ± standard deviation.
are also similar to the findings of Song et al. [8], although their results were obtained from blood samples collected up to 1 year after the initiation of fingolimod therapy. These results indicate that the effect of fingolimod on lymphocyte counts, including T, and B cell counts, and CD4/8 lymphocyte ratio, is stable without fluctuation over a long period.
After discontinuation of fingolimod, it takes about 4–8 weeks for lymphocyte counts to recover [10]. The present study confirmed that lymphocyte counts in MS patients recovered within 3 months when the fingolimod dosage was reduced within ST. However, when the dosage was reduced after LT, recovery of lymphocyte counts was clearly suppressed in some MS patients. Gha-
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Funding This work was supported by the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health and Labour Sciences Research Grants, The Ministry of Health, Labour and Welfare, Japan. Declarations of interest None. Appendix A. Supplementary data Fig. 2. Recovery of lymphocyte counts after the reduction of fingolimod dosage via intermittent drug holidays. Recovery of lymphocyte counts were calculated by subtracting the lymphocyte counts in the peripheral blood just before intermittent dosage reduction of 0.5 mg/week (from 0.5 mg daily to 0.5 mg 6 days/week) from the lymphocyte counts in the peripheral blood at 3 months after intermittent dosage reduction of 0.5 mg/week. Dosage was reduced by intermittent drug holidays within 2 years after the initiation of fingolimod treatment in three cases (ST) and more than 2 years after the initiation of fingolimod treatment in five cases (LT).
diri et al. [11] also reported that lymphocyte counts do not recover completely at 3–4 weeks after fingolimod discontinuation in some MS patients receiving long-term fingolimod treatment. However, the proportion of patients with recovered lymphocyte counts in their study was higher than that observed in the Japanese patients in the present study [11]. Although fingolimod is used globally at a standardized dosage of 0.5 mg/day, several recent studies have investigated the effects of fingolimod dosage reduction [12–14]. The daily dosage of fingolimod can’t be adjusted because it is produced as 0.5 mg hard capsules, which are recommended to be taken orally once a day. Therefore, drug holidays are usually given when fingolimod dosage reduction is considered. Moreover, a fingolimod dosage of <0.5 mg/day has not yet been tested in clinical trials on adult MS patients, although a dosage of 0.25 mg/day was approved by the United States Food and Drug Administration for MS treatment in children with a body weight of <40 kg. However, all the patients enrolled in the present study had a body weight of >40 kg. Notably, the lymphocyte counts were almost the same in patients receiving a fingolimod dose of 0.5 mg/day and those receiving 1.25 mg/day [9]. These results indicate that the relationship between the fingolimod dosage and lymphocyte counts in peripheral blood is not linear, which makes it difficult to determine the optimum dosage of fingolimod. Although the present study had a small sample size, the results indicate that the currently used fingolimod dosage might be too high, at least for some Japanese MS patients receiving long-term fingolimod treatment. These findings indicate that clinicians may have to consider decreasing the fingolimod dosage in Japanese patients with MS. Acknowledgement I would like to thank Editage (www.editage.jp) for English language editing.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.01.034. References [1] FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs, http://www.fda.gov/Drugs/ DrugSafety/ucm456919.htm; 2015 [accessed 4 August 2018]. [2] Berger JR, Cree BA, Greenberg B, Hemmer B, Ward BJ, Dong VM, et al. Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology 2018;90:e1815–21. [3] Bozic C, Subramanyam M, Richman S, Plavina T, Zhang A, Ticho B. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol 2014;21:299–304. [4] Hegen H, Auer M, Bsteh G, Di Pauli F, Plavina T, Walde J, et al. Stability and predictive value of anti-JCV antibody index in multiple sclerosis: a 6-year longitudinal study. PLoS One 2017;12:e0182462. [5] Aoyama S, Mori M, Uzawa A, Uchida T, Masuda H, Ohtani R, et al. Serum antiJCV antibody indexes in Japanese patients with multiple sclerosis: elevations along with fingolimod treatment duration. J Neurol 2018;265:1145–50. [6] Henault D, Galleguillos L, Moore C, Johnson T, Bar-Or A, Antel J. Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis. Neurology 2013;81:1768–72. [7] Rudnicka J, Czerwiec M, Grywalska E, Siwicka-Gieroba D, Walankiewicz M, Grafka A, et al. Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients preliminary study. Cent Eur J Immunol 2015;40:354–9. [8] Song ZY, Yamasaki R, Kawano Y, Sato S, Masaki K, Yoshimura S, et al. Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod. PLoS One 2015;10:e0124923. [9] Saida T, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Ueda K, et al. Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study. BMC Neurol 2017;17:17. [10] Yoshii F, Moriya Y, Ohnuki T, Ryo M, Takahashi W. Neurological safety of fingolimod: an updated review. Clin Exp Neuroimmunol 2017;8:233–43. [11] Ghadiri M, Fitz-Gerald L, Rezk A, Li R, Nyirenda M, Haegert D, et al. Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult Scler 2017;23:1225–32. [12] Zecca C, Merlini A, Disanto G, Rodegher M, Panicari L, Romeo MAL, et al. Halfdose fingolimod for treating relapsing-remitting multiple sclerosis: observational study. Mult Scler 2018;24:167–74. [13] Tanaka M, Kinoshita M, Tanaka K. Intermittent drug holidays in fingolimod therapy for multiple sclerosis. Mult Scler 2018;24:236–7. [14] Tanaka M, Kinoshita M. Daily fingolimod administration may cause lymphopenia but alternate-day administration may be too little to inhibit disease activity. J Neuroimmunol 2015;288:69.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Effect of dosage reduction on peripheral blood lymphocyte count in patients with multiple sclerosis receiving long-term fingolimod therapy Kazuya Takahashi ⇑ Department of Neurology, Hokuriku Brain and Neuromuscular Disease Center, National Hospital Organization Iou Hospital, Kanazawa, Japan
a r t i c l e
i n f o
Article history: Received 21 August 2018 Accepted 28 January 2019
Keywords: Fingolimod Multiple sclerosis Progressive multifocal leukoencephalopathy John Cunningham (JC) virus Adverse drug reaction Lymphocyte
a b s t r a c t Of the 19 cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) reported worldwide by the end of 2017, 4 cases were from Japan. This may indicate that fingolimod sensitivity is higher in the Japanese population than in the western population because the fingolimod dosage used for the prevention of multiple sclerosis (MS) is the same in both populations. Therefore, the laboratory data of nine patients with MS receiving fingolimod treatment for more than 2 years were retrospectively collected. Moreover, the effect of drug holiday was compared between five patients who underwent at least 3 months of dosage reduction via drug holiday after receiving fingolimod for more than 2 years and three patients who underwent drug holiday after receiving fingolimod for less than 2 years. The total, CD3(+), CD4(+), C19(+) lymphocyte counts, the CD4(+)/CD8(+) cell ratio, and the serum IgG concentrations were similar between Japanese patients with MS receiving fingolimod for more than 2 years and Western patients from the previous reports. Recovery of lymphocyte counts in the peripheral blood after fingolimod dosage reduction was worse in some MS patients who received long-term fingolimod treatment than in MS patients who received short-term fingolimod treatment. My findings indicate that the currently used fingolimod dosage may be too high for some Japanese MS patients receiving long-term fingolimod treatment. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Multiple sclerosis (MS) is considered as a Th1-mediated autoimmune disease of the central nervous system (CNS), and is characterized by phases of remission and relapse. Fingolimod, the first oral drug approved for relapsing-remitting MS, is a functional antagonist of sphingosine-1-phosphate receptor and is widely used globally, including in Japan. By the end of 2017, over 200,000 MS patients received fingolimod worldwide. Progressive multifocal leukoencephalopathy (PML) is a rare and fatal demyelinating CNS disease caused by John Cunningham virus (JCV). It occurs exclusively in individuals with a weakened immune system, including in patients with acquired immune deficiency syndrome and patients taking immunosuppressive medications. The first case of fingolimod-associated PML without prior natalizumab treatment was reported in 2015 [1], and subsequently, 19 fingolimod-associated PML cases without prior natalizumab treatment have been reported worldwide to date. Overall, the inci⇑ Address: Department of Neurology, Hokuriku Brain and Neuromuscular Disease Center, National Hospital Organization Iou Hospital, Ni73-1, Iwade-machi, Kanazawa 920-0192, Japan. E-mail address: [email protected] https://doi.org/10.1016/j.jocn.2019.01.034 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
dence of fingolimod-associated PML is estimated to be 0.069 per1000 patients [2]. However, in Japan, 4 cases of fingolimodassociated PML have already been registered by the Progressive Multifocal Leukoencephalopathy Surveillance Committee, despite the number of patients receiving fingolimod being less than 6000. This indicates that the fingolimod-associated PML rate in Japan is about ten times higher than the fingolimod-associated PML rate in the rest of the world. However, the reason for this discrepancy is unclear and warrants further investigation. JCV infection, which can cause PML in immunocompromised individuals, is latent and non-pathogenic in individuals with normal immune function. The prevalence of anti- JCV antibody is generally 50–70% worldwide, although it varies by country [3], and 45% of anti-JCV antibody-positive MS patients have a JCV antibody index of >1.5, which indicates the highest risk for natalizumabinduced PML [4]. The anti-JCV antibody prevalence in the Japanese population is 69.5%, and 52.4% of MS patients have a JCV antibody index of >1.5 [5]. Although these values are still on the higher end of the global range, the incidence of fingolimod-related PML is not high in MS patients in the other countries with a higher prevalence of JCV infection. This result indicates that the anti-JCV antibody prevalence and index alone cannot explain the differences in incidence of fingolimod-related PML. These results may indicate that
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the current fingolimod dosage constitutes an overdose for Japanese MS patients, although the same dosage is used in all countries where fingolimod has been approved for MS treatment. In addition, fingolimod treatment for more than 2 years and age over 40 years are considered risk factors of fingolimod-associated PML [2]. In the present study, I first evaluated lymphocyte counts in Japanese MS patients who received fingolimod for more than 2 years. Next, to determine if fingolimod dosage may be too high for some Japanese MS patients, I compared the difference in the effect of drug holiday in Japanese MS patients who had received fingolimod treatment for more than or less than 2 years.
2. Methods 2.1. Patients selection This study was approved by the Ethics Committee of the Iou Hospital (IOU2018-02). Nine MS patients who received 0.5 mg fingolimod daily for more than 2 years and who regularly visited Iou hospital at the end of 2017 were enrolled in this study. Moreover, among these nine MS patients, five had undergone fingolimod dosage reduction for more than 3 months via intermittent drug holidays (0.5 mg 6 days/week with no drug on Fridays) after receiving fingolimod for more than 2 years and three had undergone dosage reduction via drug holidays after receiving fingolimod for less than two years. These two patient groups were compared to investigate the effect of drug holidays during short- and longterm fingolimod therapy. Patients with other autoimmune disease, cancer, infectious disease, and immunosuppressive medications including steroids, were excluded from this study.
2.2. Laboratory data The data on total, CD3(+), CD4(+), CD8(+), and CD19(+) lymphocyte count, and serum immunoglobulin G (IgG) concentration were collected retrospectively. Data for each patient were classified as data collected within 2 years after the initiation of fingolimod treatment (within ST) and data collected more than 2 years after the initiation of fingolimod treatment (after LT), and the average cell counts were calculated by excluding data during dosage reduction and for 3 months after a change in fingolimod dosage.
2.3. Analysis of recovery of lymphocyte counts after reduction of fingolimod dosage via intermittent drug holidays Fingolimod dosage was reduced via drug holiday within ST in three cases and after LT in five cases. In all three cases of dosage reduction within ST, the dosage was reduced again after LT. We compared peripheral blood lymphocyte counts before and after fingolimod dosage reduction. Recovery of lymphocyte counts was calculated by subtracting lymphocyte counts in the peripheral blood just before dosage reduction from lymphocyte counts in the peripheral blood 3 months after dosage reduction.
2.4. Statistical analysis The Mann–Whitney U test or Kruskal–Wallis test was used for between-group comparison of data. P-values < 0.05 were considered significant. All quantitative data are presented as mean (standard deviation). Statistical calculations were performed using SPSS 18.0 software (IBM, Armonk, NY, USA).
3. Results 3.1. Peripheral blood lymphocyte counts of Japanese MS patients after long-term fingolimod treatment The total lymphocyte, CD3(+) T cell, CD19(+) B cell, CD4(+) lymphocyte, and CD8(+) lymphocyte counts, the CD4(+)/CD8(+) cell ratio, and the serum IgG concentration are shown in Fig. 1. Although the average total lymphocyte count decreased significantly after LT compared to the average baseline value before fingolimod treatment (2124 (563)/mm3; p < 0.001), the average total lymphocyte count within ST (489 (140)/mm3) was not significantly different from that after LT (506 (153)/mm3; p = 0.938; Fig. 1a). Compared with the average baseline serum IgG concentration before fingolimod treatment, the serum IgG concentration in both the ST and LT groups was significantly lower (ST; p = 0.035; LT; p < 0.001), and furthermore it was significantly lower in the LT group than in the ST group (p = 0.185; Fig. 1b). The average T cell count, B cell count, CD4(+) lymphocyte count, and CD4(+)/CD8(+) cell ratio in the peripheral blood of MS patients after LT (T cell; 339(179)/mm3, B cell; 46(33)/mm3, CD4(+)cell; 83(52)/mm3, CD4 (+)/CD8(+) cell ratio; 0.35(0.17)) (T cell; p = 0.001, B cell; p = 0.002, CD4(+) cell; p = 0.001, CD4(+)/CD8(+) cell ratio; p = 0.001) were significantly lower than the average baseline values in MS patients before fingolimod treatment (T cell; 1168 (217)/mm3, B cell; 280(102)/mm3, CD4(+) cell; 555(73)/mm3, CD4(+)/CD8(+) cell ratio; 1.6(0.19); Fig. 1c, d, e, g). The average CD8 positive lymphocyte count in the peripheral blood of Japanese MS patients after LT (281(120)/mm3) was not significantly different from that in the peripheral blood of Japanese MS patients before the initiation of fingolimod treatment (353(82)/mm3; p = 0.157; Fig. 1f) 3.2. Trend of recovery of lymphocyte counts after reduction of fingolimod dosage via intermittent drug holidays When fingolimod dosage was reduced via intermittent drug holidays within ST, total lymphocyte counts in the peripheral blood increased rapidly at 3 months after dosage reduction in all cases (Fig. 2). In contrast, when fingolimod dosage was reduced via intermittent drug holidays after LT, recovery of lymphocyte counts in the peripheral blood did not change or decreased in three cases at 3 months after dosage reduction (Fig. 2). Although the recovery of lymphocyte counts in the peripheral blood increased in the other two cases, they were also lower than the recovery of lymphocyte counts in the peripheral blood when fingolimod dosage was reduced via intermittent drug holidays within ST. Moreover, when fingolimod was reduced after LT, the recovery of lymphocyte counts in the peripheral blood of two (Case 1 and 3) of three patients (Case 1–3) who had experienced intermittent drug holidays both within ST and after LT was worse than the recovery of lymphocyte counts when fingolimod was reduced within ST (Fig. 2). 4. Discussion Previous studies revealed changes in lymphocyte counts after the initiation of fingolimod treatment [6–9]. However, since most of these studies investigated changes in lymphocyte counts within 1 year after the initiation of fingolimod treatment, the effect of long-term fingolimod treatment on lymphocyte counts remains unclear. The lymphocyte counts in the peripheral blood of MS patients receiving long-term fingolimod therapy in this study are similar to the values reported by Saida et al. [9]. The T cell, B cell, and CD4(+) lymphocyte counts, and the CD4(+)/CD8(+) cell ratio
K. Takahashi / Journal of Clinical Neuroscience 63 (2019) 91–94
93
Fig. 1. Changes in lymphocyte counts in the peripheral blood after long-term fingolimod treatment. Absolute lymphocyte counts (a), serum IgG concentration (b), CD3(+) T cell counts (c), CD19(+) B cell counts (d), CD4(+) lymphocyte counts (e), CD8(+) lymphocyte counts (f), and CD4(+)/CD8(+) lymphocyte ratio (g) in the peripheral blood of MS patients before fingolimod treatment (Pre), within 2 years after the initiation of fingolimod treatment (ST), and more than 2 years after the initiation of the fingolimod treatment (LT). Data are presented as mean ± standard deviation.
are also similar to the findings of Song et al. [8], although their results were obtained from blood samples collected up to 1 year after the initiation of fingolimod therapy. These results indicate that the effect of fingolimod on lymphocyte counts, including T, and B cell counts, and CD4/8 lymphocyte ratio, is stable without fluctuation over a long period.
After discontinuation of fingolimod, it takes about 4–8 weeks for lymphocyte counts to recover [10]. The present study confirmed that lymphocyte counts in MS patients recovered within 3 months when the fingolimod dosage was reduced within ST. However, when the dosage was reduced after LT, recovery of lymphocyte counts was clearly suppressed in some MS patients. Gha-
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K. Takahashi / Journal of Clinical Neuroscience 63 (2019) 91–94
Funding This work was supported by the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health and Labour Sciences Research Grants, The Ministry of Health, Labour and Welfare, Japan. Declarations of interest None. Appendix A. Supplementary data Fig. 2. Recovery of lymphocyte counts after the reduction of fingolimod dosage via intermittent drug holidays. Recovery of lymphocyte counts were calculated by subtracting the lymphocyte counts in the peripheral blood just before intermittent dosage reduction of 0.5 mg/week (from 0.5 mg daily to 0.5 mg 6 days/week) from the lymphocyte counts in the peripheral blood at 3 months after intermittent dosage reduction of 0.5 mg/week. Dosage was reduced by intermittent drug holidays within 2 years after the initiation of fingolimod treatment in three cases (ST) and more than 2 years after the initiation of fingolimod treatment in five cases (LT).
diri et al. [11] also reported that lymphocyte counts do not recover completely at 3–4 weeks after fingolimod discontinuation in some MS patients receiving long-term fingolimod treatment. However, the proportion of patients with recovered lymphocyte counts in their study was higher than that observed in the Japanese patients in the present study [11]. Although fingolimod is used globally at a standardized dosage of 0.5 mg/day, several recent studies have investigated the effects of fingolimod dosage reduction [12–14]. The daily dosage of fingolimod can’t be adjusted because it is produced as 0.5 mg hard capsules, which are recommended to be taken orally once a day. Therefore, drug holidays are usually given when fingolimod dosage reduction is considered. Moreover, a fingolimod dosage of <0.5 mg/day has not yet been tested in clinical trials on adult MS patients, although a dosage of 0.25 mg/day was approved by the United States Food and Drug Administration for MS treatment in children with a body weight of <40 kg. However, all the patients enrolled in the present study had a body weight of >40 kg. Notably, the lymphocyte counts were almost the same in patients receiving a fingolimod dose of 0.5 mg/day and those receiving 1.25 mg/day [9]. These results indicate that the relationship between the fingolimod dosage and lymphocyte counts in peripheral blood is not linear, which makes it difficult to determine the optimum dosage of fingolimod. Although the present study had a small sample size, the results indicate that the currently used fingolimod dosage might be too high, at least for some Japanese MS patients receiving long-term fingolimod treatment. These findings indicate that clinicians may have to consider decreasing the fingolimod dosage in Japanese patients with MS. Acknowledgement I would like to thank Editage (www.editage.jp) for English language editing.
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