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Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: Analysis of predisposing factors
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Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors Maria Sepulveda MD , Carmen Montejo MD , Sara Llufriu MDPhD , ´ Nuria Sola-Valls MD , David Reyes MD , Elena H. Martinez-Lapiscina MDPhD , Irati Zubizarreta MD , Irene Pulido-Valdeolivas MDPhD , ˜ MDPhD , Eugenia Martinez-Hernandez MDPhD , Helena Arino ˜ MDPhD , Albert Saiz MDPhD , Nuria Banos Yolanda Blanco MDPhD PII: DOI: Reference:
S2211-0348(19)30472-9 https://doi.org/10.1016/j.msard.2019.101483 MSARD 101483
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
15 July 2019 3 October 2019 27 October 2019
Please cite this article as: Maria Sepulveda MD , Carmen Montejo MD , Sara Llufriu MDPhD , ´ Nuria Sola-Valls MD , David Reyes MD , Elena H. Martinez-Lapiscina MDPhD , Irati Zubizarreta MD , Irene Pulido-Valdeolivas MDPhD , Eugenia Martinez-Hernandez MDPhD , ˜ MDPhD , Nuria Banos ˜ MDPhD , Albert Saiz MDPhD , Yolanda Blanco MDPhD , Helena Arino Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors, Multiple Sclerosis and Related Disorders (2019), doi: https://doi.org/10.1016/j.msard.2019.101483
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights:
3 (42%) patients suffered rebound after fingolimod cessation for pregnancy planning
Pregnancy failed to halt such exaggerated inflammatory activity
New-borns were delivered healthy despite using steroids throughout pregnancy
Lymphocyte count <300/ul was related to reappearance of activity disease
Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors
Maria Sepúlveda1, MD; Carmen Montejo1, MD; Sara Llufriu1, MD, PhD; Nuria SolaValls1, MD; David Reyes1, MD; Elena H. Martinez-Lapiscina1, MD, PhD; Irati Zubizarreta1, MD; Irene Pulido-Valdeolivas1, MD, PhD; Eugenia Martinez-Hernandez1, MD, PhD; Helena Ariño1, MD, PhD; Nuria Baños2, MD, PhD; Albert Saiz1, MD, PhD; Yolanda Blanco1, MD, PhD
1.
Center of Neuroimmunology, Service of Neurology, Laboratory of Advanced
Imaging in Neuroimmunological Diseases, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Universitat de Barcelona, Barcelona, Spain. 2.
BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital
Clínic and Hospital Sant Joan de Deu), Institut Clínic de Ginecologia, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona.
Correspondence: Yolanda Blanco MD, PhD, Service of Neurology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Phone: (34)932275414; Fax: (34)932275783; e-mail: [email protected] Word count: Abstract, 256; Text, 2,051; References, 21; Figures, 3; Tables, 1 Key words: pregnancy, multiple sclerosis, fingolimod, rebound, withdrawal.
ABSTRACT Background: Rebound of multiple sclerosis (MS) activity has been described after the withdrawal of high-efficacy drugs, but its impact during pregnancy is less known. We describe a series of cases of rebound syndrome after the cessation of fingolimod due to pregnancy planning. Methods: The clinical and radiological data of 7 MS patients who discontinued fingolimod therapy between May 2012 and March 2018 to plan a pregnancy was analysed. Results: Three (42.8%) of the 7 patients experienced a rebound effect, all of whom became pregnant. During pregnancy, the 3 patients had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids and/or immunoglobulin. These patients experienced a median increase of 3 points in the Expanded Disability Status Scale (range, 2-4), as well as a median increase of 27 new gadolinium-enhancing lesions (range, 9-40) and 38 new T2 lesions in a post-partum MRI (range, 21-70). The 3 pregnancies resulted in the delivery of healthy babies. A strong correlation was found between the lymphocyte count at fingolimod onset and the annual relapse rate in the period without therapy (r= -0.84, p=0.005). The time to first relapse was shorter in patients who had <300/μl lymphocytes at fingolimod onset (median time 46 vs 426 days, p=0.010). Conclusion: Rebound activity after fingolimod suspension represents a severe longlasting inflammatory syndrome that may affect up to 40% of female MS patient who discontinue therapy due to pregnancy planning. Lymphopenia (<300/μl) in the first 3 months of fingolimod onset may predispose patients to suffer earlier and higher disease activity upon cessation.
1.
Introduction
Pregnancy is considered a period of relative decrease of multiple sclerosis (MS) activity in untreated patients, or in those treated with low to moderately effective disease-modifying drugs (DMD)1,2 .This contrasts with the recent report of increased relapse during pregnancy in women who were on natalizumab and fingolimod prior to conception3,4. Disease reactivation after discontinuation of natalizumab, including rebound phenomenon or activity that exceeds that of the pretreatment period, has been reported in as many as one third of the patients5-7. Accordingly, different strategies have been proposed when planning pregnancy in women who are receiving natalizumab treatment. By contrast, little is known about the rebound activity upon ceasing fingolimod therapy for childbearing desire, and the information is limited to a few cases. Therefore, we aimed to describe the frequency of presentation, the clinical features, and outcome of a series of patients with rebound activity after fingolimod discontinuation for pregnancy planning. We also analyzed the possible predisposing factors associated with this increased activity.
2.
Methods
From May 2012 to May 2018 we retrospectively reviewed the demographic, clinical, radiological and analytical data of MS patients from our Multiple Sclerosis Unit that stopped fingolimod treatment when planning for pregnancy. It is worth noting that the approval for the use of fingolimod in our administrative region (Catalonia) was received in May 2012. All the patients recruited to this study were diagnosed with relapsingremitting MS (RRMS), according to the McDonald criteria 20108 , and the data collected included demographic data (age), clinical features (age at onset, disease duration, number of relapses, prior/ongoing therapies, wash-out period, MRIs) and data
concerning the outcome of pregnancy. Disability was recorded using the Expanded Disability Status Scale (EDSS), and relapses were defined as new neurological symptoms lasting at least 24 hours, accompanied by new findings on neurological examination and separated from a previous attack by at least 30 days. Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, and the development of multiple new or enhancing lesions exceeding baseline activity. An annual relapse rate (ARR) was calculated for each trimester in the year before and in the 18 months after fingolimod cessation. An ARR for each trimester was also calculated in the year before and during pregnancy, and in the year after delivery. Lymphocyte counts were obtained 1, 3 and 6 months after onset, and then every 6 months. Patients were recommended to maintain anti-conceptive treatment for two months before trying to conceive. Written informed consent for the use of clinical data for research purposes was obtained from all the patients.
2.1. Statistical analysis A correlation analysis between the ARR in the period without therapy and the lymphocyte count at the onset of fingolimod therapy was done using Pearson’s correlation coefficient. The lowest lymphocyte count in the first 3 months of therapy was considered as the lymphocyte count at the onset of fingolimod treatment. The time to first relapse after fingolimod withdrawal was analyzed using a Kaplan-Meier survival analysis and a Cox’s regression was used to assess the following independent variables: ARR 1 and 2 years before fingolimod withdrawal, duration of washout period, lymphocyte count at fingolimod onset, and lymphocyte count before fingolimod withdrawal. All analyses were carried out with SPSS version 21 software.
3. Results 3.1. Overall cohort From a total cohort of 62 MS patients, 21 (33.9%) abandoned fingolimod treatment during the study period for different reasons: 7 (33.3%) due to the desire to become pregnant, 4 (19.0%) due to breakthrough disease activity, 6 (28.6%) due to adverse events, 3 (14.2%) due to a sustained worsening of disability and 1 (4.8%) through the patient’s own decision. 3.2. Cohort of women with a desire to have a child The 7 patients who abandoned fingolimod due to the desire to bear a child were followed for a median (range) of 19.3 (10-47) months after suspension of the treatment. The main features of these patients are detailed in Table 1. Five of these 7 patients became pregnant, with a median time to pregnancy of 15 weeks (range, 0-32). In one patient it occurred in utero exposure to fingolimod for 21 days. The 5 patients had recurrence of the disease activity after fingolimod withdrawal. In 3 (42.8%) patients the disease exacerbation was compatible with a rebound phenomenon, and it involved the 3 trimesters of the pregnancy. One patient had two relapses prior to conception, and another suffered a relapse in the first month post-partum. The two patients that did not become pregnant did not experience any relapse: one patient was diagnosed with breast cancer 3 months after stopping fingolimod, and the second patient is still attempting to get pregnant 12 months after fingolimod suspension (see Figure 1). Interestingly, one of the patients that experienced a rebound of disease activity had experimented severe disease reactivation 2 years previously in an earlier attempt to become pregnant, one month after fingolimod withdrawal.
During pregnancy, the 3 patients who experienced a rebound phenomenon had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids (methylprednisolone, 1 g/day for 3 days) and/or immunoglobulin (0.4 g/Kg/day for 5 days). They had a median increase in their EDSS of 3 points (range, 2-4.5), and a median increase of 15 (range, 9-40) new gadolinium-enhancing lesions and 26 (range, 21-70) new T2 lesions detected on a magnetic resonance imaging performed within the first three weeks post-partum. Relapses suffered by Cases 1 and 2 during pregnancy are detailed in supplementary material. If we only consider the 5 patients who got pregnant, the relapse rate increased gradually during pregnancy, peaking in the second trimester and remaining elevated during the first trimester post-partum (see Figure 2a). When all 7 patients were considered, we observed an increase in the occurrence of relapses during the first trimester and a peak in the third trimester after the treatment was suspended (see Figure 2b). Two of the 3 patients with rebound activity received steroids during all three trimesters of pregnancy and the other two, during the second and third trimesters. Labour was induced in four of the five pregnancies, two for obstetric reasons (in the 38th and 40th weeks, vaginal delivery) and two for continuous and severe relapses (in the 35th week, caesarean section). All five pregnancies resulted in the delivery of healthy babies, with no congenital abnormalities, although the two new-borns delivered in the 35th week had a low birth weight. 3.2.1. Follow-up post-partum The 5 patients resumed MS treatment after a median (range) of 25 (6-42) days postpartum and all declined to breastfeed. Two of the patients who experienced a rebound initiated therapy with alemtuzumab, while the third resumed fingolimod therapy, as did the other two patients who did not suffer a rebound. In one of the patients treated with
alemtuzumab, a brain MRI performed 3 months after the first cycle showed 14 new T2 lesions (9 with gadolinium enhancement). The patient then remained free of clinical and radiological activity in the following 46 month follow-up period, with an EDSS score of 2.0. The other patient treated with alemtuzumab had persistent radiological activity and 2 relapses in the first year of treatment. Moreover, she suffered a new relapse two months after the second cycle of alemtuzumab along with a new enhancing lesion. Her EDSS score 11 months after the second cycle of alemtuzumab was 2.0. The third patient who resumed with fingolimod experienced 2 relapses, 3 and 7 weeks after initiating of the treatment, and the therapy was switched to rituximab. Since then, the patient has not experience any clinical or radiological activity for 16 months. 3.3. Analysis of prognostic factors A strong correlation was found between the lymphocyte count at the onset of fingolimod therapy and the ARR in the period without therapy (r= -0.84, p=0.005). The time to first relapse was shorter in those patients who had < 300/μl lymphocytes at fingolimod onset (median time 46 vs 426 days, p=0.010, Figure 3). No association was found in relation with the clinical activity or lymphocyte count before fingolimod suspension or the duration of the washout period.
4. Discussion The main findings of this study were that up to 40% of the patients who discontinued fingolimod therapy due to pregnancy planning experienced a rebound of MS activity. This increased MS activity appeared shortly after fingolimod withdrawal and pregnancy did not halt the associated inflammatory process. However, new-borns were delivered healthy despite using immunosuppressant drugs (corticosteroids) throughout the gestational period. Finally, we found that a low lymphocyte count (<300/µl) in the first
three months after the initiation of fingolimod therapy was the only risk factor related to the rapid reappearance of clinical activity after discontinuation of the drug. The severity and persistence of disease activity post-partum emphasizes the importance of resuming a high-efficacy DMD that has a rapid effect onset in the immediate period after delivery. Although there are a few reports of rebound of MS activity after fingolimod discontinuation9-14 , the post-hoc analysis of the Phase III FREEDOMS and FREEDOMS II trials did not observe a greater risk of a higher-than-expected recurrence of disease activity in patients who discontinued such treatment15. These contradictory results could be explained by the heterogeneity of the cohorts analysed, the use of different definitions of the rebound phenomenon and the existence of different followup periods. Similar to the rebound associated with natalizumab discontinuation5-7, we found that clinical activity appeared soon after fingolimod withdrawal (in the first three months), and pregnancy did not prevent the exaggerated inflammatory activity. Information on MS activity during pregnancy after stopping fingolimod is limited to two case reports9,12 , and one involving a patient who suffered a severe disease course that resulted in the death of the patient. The disease severity in the setting of pregnancy is evidenced by the high clinical activity that our patients had during the 3 gestational trimesters (a median of 5 relapses), and the need for intensive treatment with steroids and immunoglobulin. Importantly, the therapies did not apparently have negative consequences for the new-borns and probably contributed to a decrease in the neurological sequelae in the patients. The main factors related to the appearance of rebound after fingolimod cessations are unclear. In one study, a higher ARR and lower EDSS scores before commencing fingolimod therapy were identified as predisposing factors16, and in another it was a
lymphocyte count below 500/µL at the time of discontinuing fingolimod17 . By contrast, we found a strong correlation between the total lymphocyte count at fingolimod onset (within the 3 first months) and the clinical activity after discontinuation. Moreover, patients with less than 300/μl lymphocytes in these first 3 months of onset of fingolimod had a shorter time to first relapse, although this will need to be confirmed in larger cohorts. The mechanisms underlying the post-fingolimod rebound are not well known but they have been related to rapid lymphocyte reconstitution. In an animal model, this rebound was preceded by S1P1 overexpression in lymph node-entrapped lymphocytes, which was correlated with subsequent massive lymphocyte egression and CNS immune infiltration18. However, peripheral lymphocyte reconstitution after fingolimod withdrawal is not homogeneous and it is not correlated with age, treatment duration, or the pre- or on-treatment lymphocyte count19. Currently, it is not clear what the best strategy is for patients treated with fingolimod that want to get pregnant. In contrast to natalizumab, the options of maintaining fingolimod therapy throughout pregnancy or of avoiding the wash-out period of two months before conception are problematic due to the teratogenic effects of fingolimod20. Similarly, it is not clear what measures are appropriate to prevent post-partum relapses, but given the severity and the length of the rebound activity, the initiation of a high efficacy DMD soon after delivery is advisable. In this sense, it is noteworthy that disease activity may persist in some patients after initiating rituximab10 or alemtuzumab therapy21. In fact, in our series one of the patients still presented notable radiological inflammatory activity and 2 relapses during the first year post-partum despite having commenced alemtuzumab therapy.
Our study is limited by the small sample size and the retrospective review of the data, although it does provide valuable information that can be useful when planning pregnancy in patients treated with fingolimod. In conclusion, discontinuation of fingolimod treatment carries a notable risk of disease reactivation and of a rebound during pregnancy, a possibility that should be discussed with women treated with this drug. However, the best strategy to adopt regarding discontinuing fingolimod in women who are planning a pregnancy remains unclear.
Declaration of interest Maria Sepúlveda received speaker honoraria from Novartis, Genzyme and Biogen and travel reimbursement from Genzyme and Biogen. Carmen Montejo, David Reyes, Eugenia Martinez-Hernandez, Helena Ariño and Nuria Baños declare no conflict of interest. Sara Llufriu received speaker honoraria from Biogen, Novartis, TEVA, Genzyme and Merck. Nuria Sola-Valls received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen, Merck Serono and Bayer-Schering. Elena H. Martinez-Lapiscina received speaker honoraria from Biogen, Genzyme, Novartis and Roche. Irati Zubizarreta received compensation for consulting services from Bayer-Schering and received travel reimbursement from Genzyme, Biogen, Merck for national and international meetings over the last 3 years. Irene Pulido-Valdeolivas has received travel reimbursement from Roche and GenzymeSanofi for international and national meetings over the last 3 years; she holds a patent for an affordable eye tracking system to measure eye movement in neurologic diseases and holds stock options in Aura Innovative Robotics; she has received travel reimbursement from European Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis. Albert Saiz received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen, Genzyme-Sanofi, TEVA, Novartis, and Roche. Yolanda Blanco has received speaker honoraria from Novartis, Roche, Genzyme-Sanofi and Biogen.
Funding This work was suported in part by Red Española de Esclerosis Múltiple (RD 16/0015/0002; AS) integrated in the Plan Estatal de Investigación Científica y Técnica de Innovación I+D+I and co-funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa"); Departament de Salut de la Generalitat de Catalunya (SLT002/16/00354, MS); and Instituto de Salud Carlos III (JR16/00006, EHM-L; JR17/00012, EMH; CM16/00136, HA).
Data Statement The data that support the findings of this study are available from the corresponding author, upon request.
References 1. Confavreux, C., et al., 1998. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 339, 28591. 2. De Las Heras, V., et al., 2007. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler. 13, 981-4. 3. Alroughani, R., et al., 2018. Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology. 90, e840e846.
4. Portaccio, E., et al., 2018. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 90, e832-e839. 5. Miravalle, A.,et al., 2011. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 68, 186-91. 6. Sorensen, P.S., et al., 2014. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. J Neurol. 261, 1170-7. 7. Vidal-Jordana, A., et al., 2015. Significant clinical worsening after natalizumab withdrawal: Predictive factors. Mult Scler. 21, 780-5. 8. Polman, C.H., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69, 292-302. 9. Sempere, A.P., et al., 2013. Rebound of disease activity during pregnancy after withdrawal of fingolimod. Eur J Neurol. 20, e109-10. 10. Hatcher, S.E., et al., 2016. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 73, 790-4. 11. Gündüz, T., et al., 2017. Severe rebound after withdrawal of fingolimod treatment in patients with multiple sclerosis. Mult Scler Relat Disord. 11, 13. 12. Novi, G., et al., 2017. Dramatic rebounds of MS during pregnancy following fingolimod withdrawal. Neurol Neuroimmunol Neuroinflamm. 4, e377. 13. Sánchez, P., et al., 2018. Tumefactive multiple sclerosis lesions associated with fingolimod treatment: report of 5 cases. Mult Scler Relat Disord. 25, 95-98.
14. Frau, J., et al., 2018. Clinical activity after fingolimod cessation: disease reactivation or rebound?. Eur J Neurol. 25, 1270-1275. 15. Vermersch, P., et al., 2017. A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo. Mult Scler J Exp Transl Clin. 3, 2055217317730096. 16. Uygunoglu,U., et al., 2018. Factors predictive of severe multiple sclerosis disease reactivation after fingolimod cessation. Neurologist. 23, 12-16. 17. Sato, K., et al., 2018. Disease exacerbation after the cessation of fingolimod treatment in japanese patients with multiple sclerosis. Intern Med. 57, 26472655. 18. Cavone, L., et al., 2015. Dysregulation of sphingosine 1 phosphate receptor1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound. Brain Behav Immun. 50, 78-86. 19. Ghadiri M., et al., 2017. Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult Scler. 23, 1225-1232. 20. Thöne, J., et al., 2017. Treatment of multiple sclerosis during pregnancy safety considerations. Expert Opin Drug Saf. 16, 523-534. 21. Willis, M., et al., 2017. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 4, e320.
Table 1. Clinical and demographic characteristics of MS patients who stopped fingolimod due to pregnancy planning n=7 Age at onset,y; median (range) DD at FYD onset, y; median (range) Previous DMT, median (range) ARR preFYD, median (range) Duration of FYD, mo; median (range) L count within 1st mo from FYD onset (x/uL), mean (SD) L count 3 months after FYD suspension (x/uL), mean ARR last year before stopping FYD, median (range) EDSS at FYD stop, median (range) Pregnancy Time to conception, wk; median (range) Duration washout period, mo; median (range) Time to first relapse after FYD stop, wk; median (range) Total relapses during FYD washout period From FYD stop to conception During pregnancy Postpartum (6 mo) EDSS 1mo after delivery, median (range)
Case 1
Case 2
Case 3
Case 4
Case 5
22 9.3 IFNb 0.3 14
23 8.2 IFNb 0.6 42
24 4.3 IFNb;NTZ 1.2 49
33 1.2 none 3.3 15
19 2.6 IFNb 1.6 14
100
125
800
300
400
430
600
1000
1200
1500
ND
1800
ND
0.14 (0-1.0) 1.5 (1.0-2.5) 5/7 15 (0-32)
0 1.0 yes 0
0 1.0 yes 10
0 1.5 yes 31
0 2.0 yes 16
1.0 1.5 yes 15
0 1.5 no -
0 2.5 no -
11.6 (3.0-17.9)
7.2
11.6
17.9
14.0
13.9
3.0
11.0
11.5 (4.3-60.8)
4.3
15.4
30.3
60.9
7.6
-
-
3 15 4 3.5 (1.5-5.5)
0 5 1 5.5
0 6 0 4.0
1 4 2 3.5
0 0 1 2.0
2 0 0 1.5
-
-
-
-
23 (19-33) 6.5 (1.2-11.4) 0.9 (0.3-3.3) 28.6 (13.7-80) 393 (244) 1375
ND
Case 6
Case 7
22 27 11.4 6.6 GA IFNb;NTZ 0.5 0.9 80 14
Brain MRI Time from FYD stop to MRI, mo, median (range) New T2 lesions, mean (SD) Gd+ lesions, mean (SD) Gestational age of newborns, wk; median (range) Therapy postFYD
9.9 (7.0-16.8) 29.3 (29.4) 16 (17.1) 38 (35-41) -
7.0 70 40
10.5 21 9
16.8 26 15
ND
ND
35 Alem
35 Alem
38 Ritux
39 FYD
41 FYD
ND
9.4 0 0 -
Alem : alemtuzumab ; ARR : annualized relapse rate ; DD : disease duration, DMT : disease modifying therapies ; EDSS : expanded disability status scale ; FYD : fingolimod ; GA : glatiramer acetate ; Gd+ : gadolinium-enhancing lesions ; IFNb : beta-interferon ; L : lymphocyte ; mo : months ; MRI : magnetic resonance image ; ND : not done ; NTZ : natalizumab ; Ritux : rituximab ; wk : weeks ; y : years
-
Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors Maria Sepulveda MD , Carmen Montejo MD , Sara Llufriu MDPhD , ´ Nuria Sola-Valls MD , David Reyes MD , Elena H. Martinez-Lapiscina MDPhD , Irati Zubizarreta MD , Irene Pulido-Valdeolivas MDPhD , ˜ MDPhD , Eugenia Martinez-Hernandez MDPhD , Helena Arino ˜ MDPhD , Albert Saiz MDPhD , Nuria Banos Yolanda Blanco MDPhD PII: DOI: Reference:
S2211-0348(19)30472-9 https://doi.org/10.1016/j.msard.2019.101483 MSARD 101483
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
15 July 2019 3 October 2019 27 October 2019
Please cite this article as: Maria Sepulveda MD , Carmen Montejo MD , Sara Llufriu MDPhD , ´ Nuria Sola-Valls MD , David Reyes MD , Elena H. Martinez-Lapiscina MDPhD , Irati Zubizarreta MD , Irene Pulido-Valdeolivas MDPhD , Eugenia Martinez-Hernandez MDPhD , ˜ MDPhD , Nuria Banos ˜ MDPhD , Albert Saiz MDPhD , Yolanda Blanco MDPhD , Helena Arino Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors, Multiple Sclerosis and Related Disorders (2019), doi: https://doi.org/10.1016/j.msard.2019.101483
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights:
3 (42%) patients suffered rebound after fingolimod cessation for pregnancy planning
Pregnancy failed to halt such exaggerated inflammatory activity
New-borns were delivered healthy despite using steroids throughout pregnancy
Lymphocyte count <300/ul was related to reappearance of activity disease
Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: analysis of predisposing factors
Maria Sepúlveda1, MD; Carmen Montejo1, MD; Sara Llufriu1, MD, PhD; Nuria SolaValls1, MD; David Reyes1, MD; Elena H. Martinez-Lapiscina1, MD, PhD; Irati Zubizarreta1, MD; Irene Pulido-Valdeolivas1, MD, PhD; Eugenia Martinez-Hernandez1, MD, PhD; Helena Ariño1, MD, PhD; Nuria Baños2, MD, PhD; Albert Saiz1, MD, PhD; Yolanda Blanco1, MD, PhD
1.
Center of Neuroimmunology, Service of Neurology, Laboratory of Advanced
Imaging in Neuroimmunological Diseases, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Universitat de Barcelona, Barcelona, Spain. 2.
BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital
Clínic and Hospital Sant Joan de Deu), Institut Clínic de Ginecologia, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona.
Correspondence: Yolanda Blanco MD, PhD, Service of Neurology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Phone: (34)932275414; Fax: (34)932275783; e-mail: [email protected] Word count: Abstract, 256; Text, 2,051; References, 21; Figures, 3; Tables, 1 Key words: pregnancy, multiple sclerosis, fingolimod, rebound, withdrawal.
ABSTRACT Background: Rebound of multiple sclerosis (MS) activity has been described after the withdrawal of high-efficacy drugs, but its impact during pregnancy is less known. We describe a series of cases of rebound syndrome after the cessation of fingolimod due to pregnancy planning. Methods: The clinical and radiological data of 7 MS patients who discontinued fingolimod therapy between May 2012 and March 2018 to plan a pregnancy was analysed. Results: Three (42.8%) of the 7 patients experienced a rebound effect, all of whom became pregnant. During pregnancy, the 3 patients had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids and/or immunoglobulin. These patients experienced a median increase of 3 points in the Expanded Disability Status Scale (range, 2-4), as well as a median increase of 27 new gadolinium-enhancing lesions (range, 9-40) and 38 new T2 lesions in a post-partum MRI (range, 21-70). The 3 pregnancies resulted in the delivery of healthy babies. A strong correlation was found between the lymphocyte count at fingolimod onset and the annual relapse rate in the period without therapy (r= -0.84, p=0.005). The time to first relapse was shorter in patients who had <300/μl lymphocytes at fingolimod onset (median time 46 vs 426 days, p=0.010). Conclusion: Rebound activity after fingolimod suspension represents a severe longlasting inflammatory syndrome that may affect up to 40% of female MS patient who discontinue therapy due to pregnancy planning. Lymphopenia (<300/μl) in the first 3 months of fingolimod onset may predispose patients to suffer earlier and higher disease activity upon cessation.
1.
Introduction
Pregnancy is considered a period of relative decrease of multiple sclerosis (MS) activity in untreated patients, or in those treated with low to moderately effective disease-modifying drugs (DMD)1,2 .This contrasts with the recent report of increased relapse during pregnancy in women who were on natalizumab and fingolimod prior to conception3,4. Disease reactivation after discontinuation of natalizumab, including rebound phenomenon or activity that exceeds that of the pretreatment period, has been reported in as many as one third of the patients5-7. Accordingly, different strategies have been proposed when planning pregnancy in women who are receiving natalizumab treatment. By contrast, little is known about the rebound activity upon ceasing fingolimod therapy for childbearing desire, and the information is limited to a few cases. Therefore, we aimed to describe the frequency of presentation, the clinical features, and outcome of a series of patients with rebound activity after fingolimod discontinuation for pregnancy planning. We also analyzed the possible predisposing factors associated with this increased activity.
2.
Methods
From May 2012 to May 2018 we retrospectively reviewed the demographic, clinical, radiological and analytical data of MS patients from our Multiple Sclerosis Unit that stopped fingolimod treatment when planning for pregnancy. It is worth noting that the approval for the use of fingolimod in our administrative region (Catalonia) was received in May 2012. All the patients recruited to this study were diagnosed with relapsingremitting MS (RRMS), according to the McDonald criteria 20108 , and the data collected included demographic data (age), clinical features (age at onset, disease duration, number of relapses, prior/ongoing therapies, wash-out period, MRIs) and data
concerning the outcome of pregnancy. Disability was recorded using the Expanded Disability Status Scale (EDSS), and relapses were defined as new neurological symptoms lasting at least 24 hours, accompanied by new findings on neurological examination and separated from a previous attack by at least 30 days. Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, and the development of multiple new or enhancing lesions exceeding baseline activity. An annual relapse rate (ARR) was calculated for each trimester in the year before and in the 18 months after fingolimod cessation. An ARR for each trimester was also calculated in the year before and during pregnancy, and in the year after delivery. Lymphocyte counts were obtained 1, 3 and 6 months after onset, and then every 6 months. Patients were recommended to maintain anti-conceptive treatment for two months before trying to conceive. Written informed consent for the use of clinical data for research purposes was obtained from all the patients.
2.1. Statistical analysis A correlation analysis between the ARR in the period without therapy and the lymphocyte count at the onset of fingolimod therapy was done using Pearson’s correlation coefficient. The lowest lymphocyte count in the first 3 months of therapy was considered as the lymphocyte count at the onset of fingolimod treatment. The time to first relapse after fingolimod withdrawal was analyzed using a Kaplan-Meier survival analysis and a Cox’s regression was used to assess the following independent variables: ARR 1 and 2 years before fingolimod withdrawal, duration of washout period, lymphocyte count at fingolimod onset, and lymphocyte count before fingolimod withdrawal. All analyses were carried out with SPSS version 21 software.
3. Results 3.1. Overall cohort From a total cohort of 62 MS patients, 21 (33.9%) abandoned fingolimod treatment during the study period for different reasons: 7 (33.3%) due to the desire to become pregnant, 4 (19.0%) due to breakthrough disease activity, 6 (28.6%) due to adverse events, 3 (14.2%) due to a sustained worsening of disability and 1 (4.8%) through the patient’s own decision. 3.2. Cohort of women with a desire to have a child The 7 patients who abandoned fingolimod due to the desire to bear a child were followed for a median (range) of 19.3 (10-47) months after suspension of the treatment. The main features of these patients are detailed in Table 1. Five of these 7 patients became pregnant, with a median time to pregnancy of 15 weeks (range, 0-32). In one patient it occurred in utero exposure to fingolimod for 21 days. The 5 patients had recurrence of the disease activity after fingolimod withdrawal. In 3 (42.8%) patients the disease exacerbation was compatible with a rebound phenomenon, and it involved the 3 trimesters of the pregnancy. One patient had two relapses prior to conception, and another suffered a relapse in the first month post-partum. The two patients that did not become pregnant did not experience any relapse: one patient was diagnosed with breast cancer 3 months after stopping fingolimod, and the second patient is still attempting to get pregnant 12 months after fingolimod suspension (see Figure 1). Interestingly, one of the patients that experienced a rebound of disease activity had experimented severe disease reactivation 2 years previously in an earlier attempt to become pregnant, one month after fingolimod withdrawal.
During pregnancy, the 3 patients who experienced a rebound phenomenon had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids (methylprednisolone, 1 g/day for 3 days) and/or immunoglobulin (0.4 g/Kg/day for 5 days). They had a median increase in their EDSS of 3 points (range, 2-4.5), and a median increase of 15 (range, 9-40) new gadolinium-enhancing lesions and 26 (range, 21-70) new T2 lesions detected on a magnetic resonance imaging performed within the first three weeks post-partum. Relapses suffered by Cases 1 and 2 during pregnancy are detailed in supplementary material. If we only consider the 5 patients who got pregnant, the relapse rate increased gradually during pregnancy, peaking in the second trimester and remaining elevated during the first trimester post-partum (see Figure 2a). When all 7 patients were considered, we observed an increase in the occurrence of relapses during the first trimester and a peak in the third trimester after the treatment was suspended (see Figure 2b). Two of the 3 patients with rebound activity received steroids during all three trimesters of pregnancy and the other two, during the second and third trimesters. Labour was induced in four of the five pregnancies, two for obstetric reasons (in the 38th and 40th weeks, vaginal delivery) and two for continuous and severe relapses (in the 35th week, caesarean section). All five pregnancies resulted in the delivery of healthy babies, with no congenital abnormalities, although the two new-borns delivered in the 35th week had a low birth weight. 3.2.1. Follow-up post-partum The 5 patients resumed MS treatment after a median (range) of 25 (6-42) days postpartum and all declined to breastfeed. Two of the patients who experienced a rebound initiated therapy with alemtuzumab, while the third resumed fingolimod therapy, as did the other two patients who did not suffer a rebound. In one of the patients treated with
alemtuzumab, a brain MRI performed 3 months after the first cycle showed 14 new T2 lesions (9 with gadolinium enhancement). The patient then remained free of clinical and radiological activity in the following 46 month follow-up period, with an EDSS score of 2.0. The other patient treated with alemtuzumab had persistent radiological activity and 2 relapses in the first year of treatment. Moreover, she suffered a new relapse two months after the second cycle of alemtuzumab along with a new enhancing lesion. Her EDSS score 11 months after the second cycle of alemtuzumab was 2.0. The third patient who resumed with fingolimod experienced 2 relapses, 3 and 7 weeks after initiating of the treatment, and the therapy was switched to rituximab. Since then, the patient has not experience any clinical or radiological activity for 16 months. 3.3. Analysis of prognostic factors A strong correlation was found between the lymphocyte count at the onset of fingolimod therapy and the ARR in the period without therapy (r= -0.84, p=0.005). The time to first relapse was shorter in those patients who had < 300/μl lymphocytes at fingolimod onset (median time 46 vs 426 days, p=0.010, Figure 3). No association was found in relation with the clinical activity or lymphocyte count before fingolimod suspension or the duration of the washout period.
4. Discussion The main findings of this study were that up to 40% of the patients who discontinued fingolimod therapy due to pregnancy planning experienced a rebound of MS activity. This increased MS activity appeared shortly after fingolimod withdrawal and pregnancy did not halt the associated inflammatory process. However, new-borns were delivered healthy despite using immunosuppressant drugs (corticosteroids) throughout the gestational period. Finally, we found that a low lymphocyte count (<300/µl) in the first
three months after the initiation of fingolimod therapy was the only risk factor related to the rapid reappearance of clinical activity after discontinuation of the drug. The severity and persistence of disease activity post-partum emphasizes the importance of resuming a high-efficacy DMD that has a rapid effect onset in the immediate period after delivery. Although there are a few reports of rebound of MS activity after fingolimod discontinuation9-14 , the post-hoc analysis of the Phase III FREEDOMS and FREEDOMS II trials did not observe a greater risk of a higher-than-expected recurrence of disease activity in patients who discontinued such treatment15. These contradictory results could be explained by the heterogeneity of the cohorts analysed, the use of different definitions of the rebound phenomenon and the existence of different followup periods. Similar to the rebound associated with natalizumab discontinuation5-7, we found that clinical activity appeared soon after fingolimod withdrawal (in the first three months), and pregnancy did not prevent the exaggerated inflammatory activity. Information on MS activity during pregnancy after stopping fingolimod is limited to two case reports9,12 , and one involving a patient who suffered a severe disease course that resulted in the death of the patient. The disease severity in the setting of pregnancy is evidenced by the high clinical activity that our patients had during the 3 gestational trimesters (a median of 5 relapses), and the need for intensive treatment with steroids and immunoglobulin. Importantly, the therapies did not apparently have negative consequences for the new-borns and probably contributed to a decrease in the neurological sequelae in the patients. The main factors related to the appearance of rebound after fingolimod cessations are unclear. In one study, a higher ARR and lower EDSS scores before commencing fingolimod therapy were identified as predisposing factors16, and in another it was a
lymphocyte count below 500/µL at the time of discontinuing fingolimod17 . By contrast, we found a strong correlation between the total lymphocyte count at fingolimod onset (within the 3 first months) and the clinical activity after discontinuation. Moreover, patients with less than 300/μl lymphocytes in these first 3 months of onset of fingolimod had a shorter time to first relapse, although this will need to be confirmed in larger cohorts. The mechanisms underlying the post-fingolimod rebound are not well known but they have been related to rapid lymphocyte reconstitution. In an animal model, this rebound was preceded by S1P1 overexpression in lymph node-entrapped lymphocytes, which was correlated with subsequent massive lymphocyte egression and CNS immune infiltration18. However, peripheral lymphocyte reconstitution after fingolimod withdrawal is not homogeneous and it is not correlated with age, treatment duration, or the pre- or on-treatment lymphocyte count19. Currently, it is not clear what the best strategy is for patients treated with fingolimod that want to get pregnant. In contrast to natalizumab, the options of maintaining fingolimod therapy throughout pregnancy or of avoiding the wash-out period of two months before conception are problematic due to the teratogenic effects of fingolimod20. Similarly, it is not clear what measures are appropriate to prevent post-partum relapses, but given the severity and the length of the rebound activity, the initiation of a high efficacy DMD soon after delivery is advisable. In this sense, it is noteworthy that disease activity may persist in some patients after initiating rituximab10 or alemtuzumab therapy21. In fact, in our series one of the patients still presented notable radiological inflammatory activity and 2 relapses during the first year post-partum despite having commenced alemtuzumab therapy.
Our study is limited by the small sample size and the retrospective review of the data, although it does provide valuable information that can be useful when planning pregnancy in patients treated with fingolimod. In conclusion, discontinuation of fingolimod treatment carries a notable risk of disease reactivation and of a rebound during pregnancy, a possibility that should be discussed with women treated with this drug. However, the best strategy to adopt regarding discontinuing fingolimod in women who are planning a pregnancy remains unclear.
Declaration of interest Maria Sepúlveda received speaker honoraria from Novartis, Genzyme and Biogen and travel reimbursement from Genzyme and Biogen. Carmen Montejo, David Reyes, Eugenia Martinez-Hernandez, Helena Ariño and Nuria Baños declare no conflict of interest. Sara Llufriu received speaker honoraria from Biogen, Novartis, TEVA, Genzyme and Merck. Nuria Sola-Valls received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen, Merck Serono and Bayer-Schering. Elena H. Martinez-Lapiscina received speaker honoraria from Biogen, Genzyme, Novartis and Roche. Irati Zubizarreta received compensation for consulting services from Bayer-Schering and received travel reimbursement from Genzyme, Biogen, Merck for national and international meetings over the last 3 years. Irene Pulido-Valdeolivas has received travel reimbursement from Roche and GenzymeSanofi for international and national meetings over the last 3 years; she holds a patent for an affordable eye tracking system to measure eye movement in neurologic diseases and holds stock options in Aura Innovative Robotics; she has received travel reimbursement from European Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis. Albert Saiz received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen, Genzyme-Sanofi, TEVA, Novartis, and Roche. Yolanda Blanco has received speaker honoraria from Novartis, Roche, Genzyme-Sanofi and Biogen.
Funding This work was suported in part by Red Española de Esclerosis Múltiple (RD 16/0015/0002; AS) integrated in the Plan Estatal de Investigación Científica y Técnica de Innovación I+D+I and co-funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa"); Departament de Salut de la Generalitat de Catalunya (SLT002/16/00354, MS); and Instituto de Salud Carlos III (JR16/00006, EHM-L; JR17/00012, EMH; CM16/00136, HA).
Data Statement The data that support the findings of this study are available from the corresponding author, upon request.
References 1. Confavreux, C., et al., 1998. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med. 339, 28591. 2. De Las Heras, V., et al., 2007. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler. 13, 981-4. 3. Alroughani, R., et al., 2018. Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Neurology. 90, e840e846.
4. Portaccio, E., et al., 2018. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 90, e832-e839. 5. Miravalle, A.,et al., 2011. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 68, 186-91. 6. Sorensen, P.S., et al., 2014. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. J Neurol. 261, 1170-7. 7. Vidal-Jordana, A., et al., 2015. Significant clinical worsening after natalizumab withdrawal: Predictive factors. Mult Scler. 21, 780-5. 8. Polman, C.H., et al., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69, 292-302. 9. Sempere, A.P., et al., 2013. Rebound of disease activity during pregnancy after withdrawal of fingolimod. Eur J Neurol. 20, e109-10. 10. Hatcher, S.E., et al., 2016. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 73, 790-4. 11. Gündüz, T., et al., 2017. Severe rebound after withdrawal of fingolimod treatment in patients with multiple sclerosis. Mult Scler Relat Disord. 11, 13. 12. Novi, G., et al., 2017. Dramatic rebounds of MS during pregnancy following fingolimod withdrawal. Neurol Neuroimmunol Neuroinflamm. 4, e377. 13. Sánchez, P., et al., 2018. Tumefactive multiple sclerosis lesions associated with fingolimod treatment: report of 5 cases. Mult Scler Relat Disord. 25, 95-98.
14. Frau, J., et al., 2018. Clinical activity after fingolimod cessation: disease reactivation or rebound?. Eur J Neurol. 25, 1270-1275. 15. Vermersch, P., et al., 2017. A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo. Mult Scler J Exp Transl Clin. 3, 2055217317730096. 16. Uygunoglu,U., et al., 2018. Factors predictive of severe multiple sclerosis disease reactivation after fingolimod cessation. Neurologist. 23, 12-16. 17. Sato, K., et al., 2018. Disease exacerbation after the cessation of fingolimod treatment in japanese patients with multiple sclerosis. Intern Med. 57, 26472655. 18. Cavone, L., et al., 2015. Dysregulation of sphingosine 1 phosphate receptor1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound. Brain Behav Immun. 50, 78-86. 19. Ghadiri M., et al., 2017. Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult Scler. 23, 1225-1232. 20. Thöne, J., et al., 2017. Treatment of multiple sclerosis during pregnancy safety considerations. Expert Opin Drug Saf. 16, 523-534. 21. Willis, M., et al., 2017. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 4, e320.
Table 1. Clinical and demographic characteristics of MS patients who stopped fingolimod due to pregnancy planning n=7 Age at onset,y; median (range) DD at FYD onset, y; median (range) Previous DMT, median (range) ARR preFYD, median (range) Duration of FYD, mo; median (range) L count within 1st mo from FYD onset (x/uL), mean (SD) L count 3 months after FYD suspension (x/uL), mean ARR last year before stopping FYD, median (range) EDSS at FYD stop, median (range) Pregnancy Time to conception, wk; median (range) Duration washout period, mo; median (range) Time to first relapse after FYD stop, wk; median (range) Total relapses during FYD washout period From FYD stop to conception During pregnancy Postpartum (6 mo) EDSS 1mo after delivery, median (range)
Case 1
Case 2
Case 3
Case 4
Case 5
22 9.3 IFNb 0.3 14
23 8.2 IFNb 0.6 42
24 4.3 IFNb;NTZ 1.2 49
33 1.2 none 3.3 15
19 2.6 IFNb 1.6 14
100
125
800
300
400
430
600
1000
1200
1500
ND
1800
ND
0.14 (0-1.0) 1.5 (1.0-2.5) 5/7 15 (0-32)
0 1.0 yes 0
0 1.0 yes 10
0 1.5 yes 31
0 2.0 yes 16
1.0 1.5 yes 15
0 1.5 no -
0 2.5 no -
11.6 (3.0-17.9)
7.2
11.6
17.9
14.0
13.9
3.0
11.0
11.5 (4.3-60.8)
4.3
15.4
30.3
60.9
7.6
-
-
3 15 4 3.5 (1.5-5.5)
0 5 1 5.5
0 6 0 4.0
1 4 2 3.5
0 0 1 2.0
2 0 0 1.5
-
-
-
-
23 (19-33) 6.5 (1.2-11.4) 0.9 (0.3-3.3) 28.6 (13.7-80) 393 (244) 1375
ND
Case 6
Case 7
22 27 11.4 6.6 GA IFNb;NTZ 0.5 0.9 80 14
Brain MRI Time from FYD stop to MRI, mo, median (range) New T2 lesions, mean (SD) Gd+ lesions, mean (SD) Gestational age of newborns, wk; median (range) Therapy postFYD
9.9 (7.0-16.8) 29.3 (29.4) 16 (17.1) 38 (35-41) -
7.0 70 40
10.5 21 9
16.8 26 15
ND
ND
35 Alem
35 Alem
38 Ritux
39 FYD
41 FYD
ND
9.4 0 0 -
Alem : alemtuzumab ; ARR : annualized relapse rate ; DD : disease duration, DMT : disease modifying therapies ; EDSS : expanded disability status scale ; FYD : fingolimod ; GA : glatiramer acetate ; Gd+ : gadolinium-enhancing lesions ; IFNb : beta-interferon ; L : lymphocyte ; mo : months ; MRI : magnetic resonance image ; ND : not done ; NTZ : natalizumab ; Ritux : rituximab ; wk : weeks ; y : years
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