Multiple sclerosis relapse after discontinuation of oral disease modifying therapies: Comparison of fingolimod and dimethyl fumarate

doi:10.21203/rs.3.rs-1982514/v1

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Multiple sclerosis relapse after discontinuation of oral disease modifying therapies: Comparison of fingolimod and dimethyl fumarate

https://doi.org/10.21203/rs.3.rs-1982514/v1

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Background: The discontinuation of oral disease modifying therapies before pregnancy, especially in the patients receiving fingolimod, may lead to disease relapse and progression. The intent of this study is to compare the number of attacks and EDSS scores after fingolimod and dimethyl fumarate cessation due to pregnancy.

Methods: This is a cross-sectional study on pregnant women with multiple sclerosis (MS) who were on fingolimod or dimethyl fumarate and discontinued the drugs before their pregnancy. Evaluation was done by a checklist and patients’ file. Disease attacks and expanded disability status scale (EDSS) scores before, during, and after pregnancy were evaluated.

Results: In our study, 13 people with MS (pwMS) using fingolimod and 16 pwMS using dimethyl fumarate discontinued their medication due to pregnancy. In the fingolimod and dimethyl fumarate groups, the median (range) number of attacks after drug withdrawal was 3 (0-4) and 0 (0-2), respectively. The median (range) six month post-delivery EDSS scores was 3.00 (1-8) in the fingolimod group and 1.5 (1-4) in the dimethyl fumarate group. Attacks were see 4.92 times more often after fingolimod cessation as compared to dimethyl fumarate discontinuation.

Conclusion: Fingolimod discontinuation due to pregnancy was linked to higher rates of attacks as compared to dimethyl fumarate cessation.

Multiple Sclerosis

Pregnancy

Fingolimod

Dimethyl Fumarate

Multiple sclerosis (MS), is and autoimmune and neuroinflammatory process mainly affecting the central nervous system. Pregnancy related aspects of the disease are of high-yield importance due to risk of attacks for the fetus and the limitation of therapies during pregnancy.(1) Several oral disease modifying therapies (DMTs) have been introduced to date for MS and none have been approved for pregnant women, therefore, such medications should be discontinued once pregnancy is confirmed or planned under the guidance of a neurologist. Various studies have reported different results for DMTs. (2) Interferon-β (IFN-β), glatiramer acetate and natalizumab were used in the pregnant women.(3) Fingolimod (Gilenya®) (FIN), a sphingosine-1-phosphate receptor modulator, is approved by United States Food and Drug Administration (FDA) as the first oral therapy for relapsing remitting MS (RRMS) with a recommended dosage of 0.5 milligrams/day.(4) Exposure to FIN during pregnancy increases the risk of major congenital anomalies, such as congenital heart disease, kidney disease, and musculoskeletal anomalies. Numerous studies showed that FIN can increase the risk of miscarriage and other congenital anomalies.(3) Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has also been approved by the FDA for the treatment of MS.(5, 6)

We evaluated the effect of discontinuation of two oral DMTs, FIN and DMF, on the rate of relapse in the pregnant people with MS (pwMS).

This cross-sectional study which was performed during 2021–2022 among all pregnant women with Multiple Sclerosis (MS) who were referred to Isfahan MS clinics and treated with FIN and DMF. A total of 560 patients with a history of DMF or FIN use were screened, of which 29 patients reported a history of pregnancy and drug discontinuation. Inclusion criteria were all women of childbearing age (18–40 years) who, were diagnosed with MS before pregnancy based on the revised McDonald Criteria 2017, were taking FIN or DMF before their pregnancy, and at least six months had passed their pregnancy. Exclusion criteria were women who did not consent to take part in the present research.

A predefined checklist was used for data collection. The checklist included three sections: demographic characteristics, pregnancy characteristics, and MS-related characteristics. The variables in three sections of this checklist are: age, gestational age, duration of MS, duration of FIN therapy, last FIN dose, recurrence of attacks, number of previous deliveries, abortions, number of previous pregnancies, use of assisted reproductive techniques, and the most common symptoms of MS. EDSS scores, and number of attacks before and six months after pregnancy were obtained from patients’ profile where applicable.

The obtained data were analyzed in SPSS software version 26. To describe quantitative variables, mean, standard deviation, median and interquartile ranges were used. Exclusively, when EDSS scores and number of attacks are reported, we used median and range. For qualitative data, Number and percentages were used. Comparison of medians was done using independent samples median test. When medians in a specific group were compared before and after the inciting event, one sample Wilcoxon signed-rank test was used. Comparison of the number of attacks between the two groups was done using Poisson distribution and log function. The total number of attacks after drug cessation was added as the dependent variable. FIN and DMF groups were included as factors. Covariates were age of pregnancy and the duration of DMT therapy in years. Exponential parameter estimates were also included in the analysis. All statistical test were done using a 95% confidence interval (CI) and a level of significance (p-value) of less than 0.05.

The study has been approved by the university of Isfahan ethics committee (IR.MUI.MED.REC.1399.890).

A total of 560 female pwMS that were on FIN (170) and DMF (390) were screened of which 29 of reported a history of pregnancy and medication cessation (13 FIN and 16 DMF). Patients’ demographic features are presented in Table 1.

Table 1

Baseline characteristics of participants
Participant Group	FIN (N = 13)	DMF (N = 16)
Age (mean years ± SD)	33.38 ± 5.34	30.56 ± 4.32
Pre-EDSS (median, min-max)	2.5 (1–1.5)	1.5 (0–5)
Post-EDSS (median, min-max)	3 ( 1–8)	1.5 (1–4)
Duration of Therapy (mean years ± SD)	3.50 ± 2.39	2.88 ± 1.08
Age of Pregnancy (mean years ± SD)	29.69 ± 5.32	29.44 ± 4.25
DMF: Dimethyl fumarate EDSS: Expanded Disability Status Scale FIN: Fingolimod Pre-EDSS: EDSS before pregnancy Post-EDSS: EDSS six months after delivery

The median and range of EDSS scores in the FIN group before and six months after delivery was 2.50 (1–5) and 3(1–8), respectively. Median and range of attacks in the FIN group was 2 (1–4) before the onset of pregnancy, 0 (0–1) during pregnancy and 2 (0–4) six months after delivery. The median and range of attacks after discontinuation of FIN until six months after delivery was 3 (0–4). The median and range of EDSS scores in the DMF group before and six months after delivery was 1.5 (0–5) and 1.5(1–4), respectively. Median and range of attacks in the DMF group was 1.5 (1–4) before, and 0 (0–2) six months after delivery. No attacks were seen during pregnancy in the DMF group. The median and range of attacks after discontinuation of DMF until six months after delivery was 0 (0–2).

Attacks were observed more often when FIN was discontinued as compared to DMF (p-value < 0.001) using the independent-samples median test (figure-1). When a Poisson model was used, attacks were 4.92 times more likely to be seen after cessation of FIN as compared to DMF, a statistically significant result (p < .001, 95% CI 2.14–11.32) The number of disease relapses were also higher after FIN discontinuation during pregnancy and in the six-month period after delivery (p-value < 0.05 and 0.001, respectively). Although EDSS scores at the time of interview were lower in patients who were taking DMF before pregnancy, the difference was not statistically significant (p-value = 0.14)

Five patients who were being treated with FIN and experienced an attack during pregnancy. None of the patients who discontinued DMF had an attack during their pregnancy. Table 2 describes the characteristics of patients who had an attack during pregnancy due to the discontinuation of FIN.

Table 2

The characteristics of fingolimod-treated women with disease relapse after drug cessation during pregnancy
Patient	Age of pregnancy (years)	Symptom of attack	MS duration	Duration of therapy	Time to relapse (weeks)	Pre-EDSS	Post-EDSS	Number of attacks before pregnancy	Number of attacks in the six month post-delivery
1	22	Visual impairment	11	2	8	1	1	1	2
2	31	Limb paresis	7	6	20	3.5	3	4	2
3	36	Limb paresis	20	3	12	2.5	2.5	2	2
4	35	Imbalance	13	6	32	2.5	3	3	1
5	29	Paraplegia	4	1	8	1	1.5	2	0
EDSS: expanded disability status scale; FIN: Fingolimod; MS: Multiple Sclerosis; Pre-EDSS: EDSS before pregnancy; Post-EDSS: EDSS six months after delivery

We evaluated disease reactivation after FIN and DMF discontinuation in pregnant MS patients. There are several reports showing MS rebound after cessation of FIN, however, data regarding disease relapse after discontinuation of DMF is limited. In our study, 170 women were being treated with FIN and 390 were on DMF. Thirteen pwMS discontinued FIN due to pregnancy. Out of these 13 women, five (38.4%) reported disease relapse during pregnancy, especially during the first trimester. However, none of the patients who discontinued DMF experienced an attack during pregnancy, although, attacks were seen after delivery. Based on the results of our study, attacks were more likely to be seen (4.92 times) in pwMS who discontinued FIN as compared to DMF.

FIN withdrawal has been reported for a variety of reasons, including pregnancy, adverse effects, and low effectiveness, as well as switching to other DMTs. Following the termination of FIN, several reports of unanticipated progression of clinical disease activity and MRI lesions were published. reporting some tumefactive lesions on MRI. Although there are many clinical variabilities in these instances, a recent case series showed three distinct patterns of MRI lesions post-FIN cessation rebound: a pattern with tumefactive lesions, many small T2 and Gadolinium enhanced lesions, and most properties of classical MS. FIN rebound has been attributed to an acute infiltration of lymphocytes into the CNS upon medication withdrawal; this, however, does not seem to be mainly owing to peripheral lymphocytes proliferation, as rebound has been observed even when lymphocyte counts were relatively low. The withdrawal of FIN in animals increased the lymphocytic S1P1 receptor expression, which resulted in lymphocyte egress from lymph nodes and disease relapse and increased symptom severity. A further study revealed a rise in S1P1 immunoreactivity on hypertrophic astrocytes in tumefactive plaques in a case with a catastrophic relapse who died following cyclophosphamide treatment.(5–13) Discontinuation of FIN may have induced S1P1 astrocytic overexpression as well as a downstream inflammatory reaction mediated by activation of nuclear factor-kappa B (NF-jB) and production of nitric oxide and inflammatory cytokines. In a similar study by Bianco et al. that evaluated 785 patients, 3% of all patients stopped FIN treatment due to pregnancy, and the result of their study showed that relapses mainly occurred in the first trimester and in the first three months post-partum.(14) Another study conducted by Hemat et al. reported 156 patients who discontinued FIN due to pregnancy leading to disease relapse in a quarter of patients.(15) In a similar study in Japan, pwMS who stopped using FIN due to medication conversion to DMF were assessed. After stopping FIN, ten patients (52.6%) showed exacerbations in clinical disease or MRI findings. Those with disease exacerbation had substantially lower peripheral blood lymphocyte counts at the time of FIN discontinuation than those without exacerbation. They found that stopping FIN might cause a relapse or reactivation of clinical illness in MS patients, and that patients who stop taking the medication should be closely monitored.(16) Berger et al. reported in another research that significant disease relapse surpassing pre-treatment MS activity following medication withdrawal seems to be an uncommon, but dangerous event in FIN-treated individuals. Disease relapse occurred during the first several months following withdrawal in their case series, preceded by lymphocyte reintroduction into the bloodstream. As a result, they recommend that individuals with a history of high disease activity receive regular clinical and radiological monitoring after stopping FIN.(8) A further intriguing study examined the radiological and clinical data of seven MS cases who stopped taking FIN in a 6 year period in order to better prepare for pregnancy. Among the seven cases (42.8%), all of whom got pregnant, 3 exhibited a rebound effect. The three individuals experienced a mean ± SD of 5.3 (1.3) relapses during pregnancy. Postpartum, the patients had a median rise of 3 points (range, 2–4) on the Expanded Disability Status Scale, along with a median rise of 27 new gadolinium-enhancing lesions (range, 9–40) and 38 T2 lesions (range, 21–70). The three pregnancies all resulted in healthy infants. The lymphocyte count at the start of FIN treatment and the annual relapse rate after cessation of FIN were shown to be correlated; cases with lymphocyte counts of < 300/µl at the start of FIN treatment the first relapse was shorted when the drug was withdrawn (median time 46 vs 426 days, p-value < 0.05).(17)

We evaluated and compared FIN and DMF cessation results. Our results showed that FIN cessation is associated with higher risks of rebound compared to DMF cessation. One explanation can be the lymphopenia after the beginning of FIN treatment. No attack occurred during pregnancy after DMF cessation unlike in patients who discontinued FIN five of who experienced at least one attack.

Further studies to evaluate the effects of pregnancy on MS rebound and etiology of rebound after FIN cessation are recommended.

Ethics approval and consent to participate

The study has been approved by the university of Isfahan ethics committee (IR.MUI.MED.REC.1399.890). All methods were carried out in accordance with relevant guidelines and regulations and written informed consent was obtained from all participants.

Consent for publication

Written informed consent was obtained from all participants.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The author(s) declare(s) that they have no competing interests

Funding

No funding was received for the production of this manuscript.

Authors contributions

All authors supervised the entire study. M.E., Ma.S., Me.S. designed the study. A.AS. and F.F. wrote the primary and final drafts and collected relevant data. All authors reviewed the mauscript.

Acknowledgements

None.

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No competing interests reported.

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Multiple sclerosis relapse after discontinuation of oral disease modifying therapies: Comparison of fingolimod and dimethyl fumarate

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