Assessment of clinician adherence to Fingolimod instructions and its effect on patient safety.

OBJECTIVES: To assess clinicians' adherence to fingolimod's effective use according to the prescribed recommendations to reduce safety risk, identify the consequences, and highlight areas for improvement to policy makers for the benefit of both patient and care-giver. METHODS: A retrospective observational study conducted at a tertiary hospital targeting multiple sclerosis patients on fingolimod from January 2017 to December 2021. The physicians' adherence to the manufacturer's instructions was assessed and categorized into good, moderate, and poor based on adherence to fingolimod instructions and monitoring measures. Four monitoring measures were assessed: bradycardia observation, ophthalmic examination, liver enzymes, and infections. In addition, the impact of adherence on patient safety was also assessed. RESULTS: A total of 140 patients were included. Seventy-twopatients (51.4%) had physician with poor adherence (followed only one instruction or none). Sixty-five patients (46.4%) had 2-3 manufacture recommendations where physician's adherence was moderate. Three patients (2.10%) had all manufacturer's recommendations. In terms of fingolimod complications, 18 patients found to have bradycardia after the first does, macular oedema and infections was reported in 4 patients, and the elevation in hepatic enzymes was reported in 6 patients. Poor physician's adherence has resulted in treatment incompleteness and highest fingolimod discontinuation or switching to other treatment options. CONCLUSION: Adherence to fingolimod instructions was poor among physicians which resulted in highest drug switching or discontinuing rate.

Intracerebral haemorrhage in multiple sclerosis: assessing the impact of disease-modifying medications.

Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial haemorrhage (ICH) is a rare but highly morbid complication, more common CNS complications include progressive multifocal leukoencephalopathy (PML) and other CNS infections. This severe form of stroke, known for its high morbidity and mortality rates, presents a critical challenge in the management of MS. The use of disease-modifying drugs (DMDs) in treating MS introduces a nuanced aspect to patient care, with certain medications like Dimethyl Fumarate and Fingolimod showing potential in reducing the risk of ICH, while others such as Alemtuzumab and Mitoxantrone are associated with an increased risk. Understanding the intricate relationship between these DMDs, the pathophysiological mechanisms of ICH, and the individualised aspects of each patient's condition is paramount. Factors such as genetic predispositions, existing comorbidities, and lifestyle choices play a crucial role in tailoring treatment approaches, emphasising the importance of a personalised, vigilant therapeutic strategy. The necessity for ongoing and detailed research cannot be overstated. It is crucial to explore the long-term effects of DMDs on ICH occurrence and prognosis in MS patients, aiming to refine clinical practices and promote patient-centric, informed therapeutic decisions. This approach ensures that the management of MS is not only comprehensive but also adaptable to the evolving understanding of the disease and its treatments.

Clinical and magnetic resonance imaging outcomes in pediatric-onset MS patients on fingolimod and ocrelizumab.

BACKGROUND: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. OBJECTIVE: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. METHODS: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. RESULTS: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions. CONCLUSION: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.

Effect of Prior Treatment With Fingolimod on Early and Late Response to Rituximab/Ocrelizumab in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Real-life studies noted that the risk of disease activity in multiple sclerosis (MS) after switching to rituximab (RTX) or ocrelizumab (OCR) may be unequal depending on prior disease-modifying therapy (DMT), with a higher risk associated with fingolimod (FING). METHODS: We performed a retrospective analysis of a structured prospective data collection including all consecutive patients with relapsing MS who were prescribed RTX/OCR in the MS center of Marseille. Cox proportional hazards models were applied to clinical and MRI outcomes. RESULTS: We included 321 patients with a median (interquartile range [IQR]) follow-up of 3.5 years (1.5-5) after RTX/OCR initiation. At the first RTX/OCR infusion, the mean (SD) age of patients was 37 (10) years, and the median (IQR) disease duration was 8 years (3-15): 68 patients did not receive treatment before RTX/OCR and 108 switched from FING, 47 from low efficacy therapy, and 98 from natalizumab. For statistical analysis, the group "FING" was divided into "short-FING" and "long-FING" groups according to the median value of the group's washout period (27 days). On Cox proportional hazards analysis, for only the "long-FING" group, the risk of relapse within the first 6 months of RTX/OCR was increased as compared with patients without previous DMT (hazard ratio [HR]: 8.78; 95% CI 1.72-44.86; p < 0.01). Previous DMT and washout period duration of FING had no effect on B-cell levels at 6 months. Beyond the first 6 months of RTX/OCR, age <40 years was associated with increased risk of relapse (HR: 3.93; 95% CI 1.30-11.89; p = 0.01), male sex with increased risk of new T2 lesions (HR: 2.26; 95% CI 1.08-4.74; p = 0.03), and EDSS ≥2 with increased risk of disability accumulation (HR: 3.01; 95% CI 1.34-6.74; p < 0.01). Previous DMT had no effect on the effectiveness of RTX/OCR beyond 6 months after initiation. DISCUSSION: For patients switching from FING to RTX/OCR, the risk of disease reactivation within the first 6 months of treatment was increased as compared with patients with other DMT or no previous DMT only when the washout period exceeded 26 days. Neither FING nor other previous DMT reduced the effectiveness of RTX/OCR beyond the first 6 months of treatment.

Evidence of disease activity during pregnancy and post-partum in MS patients treated with high-efficacy therapies.

BACKGROUND: Multiple sclerosis (MS) predominantly affects women of childbearing age. Due to the risk of teratogenicity, women with active multiple sclerosis (MS) who require high-efficacy therapies (HET) may need to discontinue treatment during pregnancy. Fingolimod and Natalizumab withdrawal increases the risk of disease reactivation, a risk not commonly associated with anti-CD20 therapies. However, comparative data are limited during pregnancy and post-partum. Our aim was to compare evidence of disease activity during pregnancy and post-partum in women treated with HET (anti-CD20 therapies, Natalizumab or Fingolimod) before conception, whether or not exposed during pregnancy. METHODS: In this single-center retrospective study, we included consecutive pregnancies of relapsing-remitting MS patients and classified them in three groups according to the last HET used before conception: « anti-CD20 ¼ « Natalizumab (NTZ) ¼ and « Fingolimod (FGD) ¼. The main outcome was annualized relapse rate (ARR) during pregnancy and post-partum. RESULTS: We included 66 pregnancies: 21, 24 and 21 in anti-CD20, NTZ and FGD groups respectively. Overall, mean ARR (SD) increased from 0.36 (0.6) during the preconception year to 0.60 (1.3) during pregnancy and to 1.03 (2.0) in the first 3 months post-partum. Mean ARR in anti-CD20 group (0.09 (0.3)) during pregnancy and the first 3 months post-partum was lower compared with NTZ (0.48 (0.6); p = 0,09) and FGD (1.50 (1.8); p = 0.001) groups. Proportion of pregnancies with radiological activity during pregnancy and post-partum in anti-CD20 group (5.2 %) was lower compared with NTZ (63.1 %; p < 0.001) and FGD (72.2 %; p < 0.001) groups. There was no significant difference in the evolution of EDSS score from conception to post-partum between each group (p = 0.75). CONCLUSION: Evidence of disease activity was significantly lower in patients exposed to anti-CD20 therapies before conception. This study suggests that use of anti-CD20 therapies is an efficient option to prevent disease reactivation during pregnancy and post-partum.

A case of early disease rebound after fingolimod discontinuation in a patient with multiple sclerosis and SARS-CoV-2 infection.

Fingolimod is approved in Italy as a second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse.

Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Risk of cardiovascular disease in patients with multiple sclerosis treated with fingolimod compared to natalizumab: A nationwide cohort study of 2095 patients in Denmark.

BACKGROUND: Fingolimod may be associated with risk of developing cardiovascular disease (CVD). Studies including reference groups and long follow-up are scarce. OBJECTIVES: We hypothesized that patients treated with fingolimod would be at higher risk of developing CVD compared to patients treated with natalizumab. METHODS: A nationwide 12-year cohort study linking individual-level data from the Danish Multiple Sclerosis Registry with health registries on 2095 adult patients with multiple sclerosis (MS) without any health records of CVD at follow-up start. Exposure to fingolimod and natalizumab was defined by the first treatment of at least 3 months. Cohort entry was from 2011 to 2018. We defined CVD as a composite measure, including hypertension, ischemic heart disease, atrial fibrillation, heart failure, and stroke. We used multivariable adjusted Cox regression. RESULTS: There were 28.8 and 17.4 CVD events per 1000 person-years in fingolimod and natalizumab groups, respectively. Compared to natalizumab-treated patients, fingolimod-treated patients had a higher risk of CVD (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.18-2.08). Hypertension comprised 200 of 244 CVD events. CONCLUSION: We found an increased risk of CVD in patients with MS treated with fingolimod. This increased risk was mainly due to hypertension.

Disseminated tuberculosis associated with fingolimod treatment in a patient with multiple sclerosis.

Fingolimod is a sphingosine-1-phosphate receptor modulator approved as a disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS). A woman in her 30s was treated with fingolimod for relapsing-remitting MS. After 7 years of treatment, she presented with non-productive cough, night sweats, breathlessness and unintentional weight loss. She had a negative interferon-gamma release assay (IGRA). A high-resolution CT thorax showed innumerable miliary opacities in both lungs. Bronchoalveolar lavage was positive for Mycobacterium tuberculosis complex PCR. An MRI head showed multiple small punctate contrast-enhancing lesions most typical for tuberculomas. We describe the first reported case of disseminated tuberculosis (TB) associated with fingolimod treatment. Patients who are receiving DMT must be closely observed for the development of opportunistic infections, and IGRA results should be interpreted with caution. Screening for latent TB prior to commencing fingolimod should be considered on an individual basis. The management of TB in MS patients on DMT requires an interdisciplinary approach.

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

BACKGROUND AND OBJECTIVES: It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. METHODS: We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised ß-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. RESULTS: We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). DISCUSSION: Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

Teaching NeuroImage: Cryptococcus in a Woman With Multiple Sclerosis on Fingolimod.

A 33-year-old woman with relapsing remitting multiple sclerosis who was on fingolimod for 5 years presented with a solitary skin lesion on her abdomen (Figure 1) for 2 months, which was unresponsive to antibiotics. The neurologic examination was normal. She denied having infectious symptoms, chest pain, shortness of breath, recent travel, trauma to the area, or animal exposure. Her most recent absolute lymphocyte count was 0.22 × 109/L (reference 1.2-4.0 109/L). The differential diagnosis included skinfold friction, dermatofibroma, pyoderma gangrenosum, and basal cell carcinoma. Although a dermatologist did not initially recommend a biopsy because the lesion was not ulcerated, she obtained one based on the recommendation of her neurologist. Shave biopsy revealed cryptococcal fungal infection (Figure 2). There was no evidence of asymptomatic disseminated cryptococcus. The proposed mechanism for the lesion involves a latent infection while immunocompetent with reactivation once immunocompromised.1 Cryptococcus infections are associated with immunosuppression, most often due to human immunodeficiency virus infection, and only 6 fingolimod-associated cutaneous infections have been reported in the literature.2 Patients with MS on immunosuppressant medication should be carefully screened for cutaneous infections.

Switching to ozanimod as a strategy to adjust fingolimod-related lymphopenia.

INTRODUCTION: Fingolimod is a disease-modifying therapy for multiple sclerosis (MS) that modulates sphingosine 1-phospate receptors, impeding the egress of lymphocytes from lymphnodes and thus causing lymphopenia. Severe lymphopenia should lead to fingolimod discontinuation. We aim to evaluate whether switching from fingolimod to ozanimod can adjust fingolimod-related lymphopenia while maintaining clinical efficacy. METHODS: In this real-world observational study, we included 18 people with MS (47.7 ± 7.6 years of age, 77.8 % of women, 13.9 ± 6.9 years of disease duration, median EDSS 3.0) at the time of fingolimod discontinuation due to lymphopenia. We collected laboratory (lymphocyte absolute count on the same hematological counter) and clinical variables at fingolimod discontinuation, at ozanimod prescription, and 6 months after ozanimod prescription. RESULTS: From 13 cases of grade 3 and 4 lymphopenia at the time of fingolimod discontinuation, we observed only 2 cases of grade 3 and no cases of grade 4 lymphopenia after 6 months of ozanimod treatment. On paired t-tests, absolute lymphocyte count at fingolimod discontinuation were lower than ozanimod prescription (p<0.001), and after 6 months (p<0.001). We observed no clinical changes. DISCUSSION: People with MS who have severe fingolimod-related lymphopenia and are clinically stable, can exhibit increased absolute lymphocyte counts when switched to ozanimod, while preserving clinical stability.

Frequency and risk factors of rebound after fingolimod discontinuation - A retrospective study.

BACKGROUND: Fingolimod (FTY) rebound, a phenomenon of unexpectedly severe disease activity following FTY discontinuation, has been reported to occur in 5-43 % of patients. Only a few larger cohorts have been analyzed. We aimed to determine the frequency and risk factors of FTY rebound in our hospital district in Southern Finland with a population of 1.7 million. METHODS: We searched the Finnish MS-register for patients who were previous or current users of FTY for at least 6 months by November 2020. We assessed medical records and collected basic demographic data for the whole cohort. Criteria for a rebound were: (i) the most severe relapse in patient's history and an increase of at least 2 EDSS points during the relapse occurring within 6 months from FTY cessation, or (ii) more than one relapse within 6 months after FTY discontinuation, this being the highest relapse rate observed during the patient's lifetime. RESULTS: Among 3496 MS patients, we found 331 patients ever starting FTY and 283 of them had used FTY for at least 6 months. Among these 283 patients we discovered a total of 114 discontinuation events in 110 patients. Of the discontinuations, 32 (28 %) were followed by a relapse: 20 (17.5 %) were ordinary relapses not fulfilling rebound criteria, and 12 (10.5 %) were rebounds. The median time to an ordinary relapse and rebound were similar: 8.5 weeks (range 1.3-23) and 9.9 weeks (range 5.9-15.9), respectively. The rebound group was younger at diagnosis (p = 0.034) and had used FTY for a longer time (p = 0.048) before discontinuation compared to the group without a relapse. After discontinuation, rebound group had lower lymphocyte values as compared to both ordinary relapse group (p = 0.027) and no-relapse group (p = 0.006) and neutrophil to lymphocyte ratio (NLR) was increased compared to the no-relapse group (p = 0.019). CONCLUSION: In this study, 10.5 % of patients experienced a rebound, which is similar to the frequencies (10.3-12.5 %) obtained in other larger studies with >100 discontinuations. Relapses of any severity occurred in 28 % of patients discontinuing FTY, and therefore initiation of subsequent disease modifying therapies should occur promptly after discontinuation. Younger age at diagnosis, longer exposure to FTY and lower lymphocyte count as well as higher NLR after discontinuation were identified as risk factors for a rebound. The differences in blood leukocytes indicate that rebound might be a distinct pathophysiological phenomenon compared to an ordinary relapse.

Depression, anxiety, insomnia and dysmenorrhea in stressed fingolimod-treated women with multiple sclerosis.

OBJECTIVE: This study examined the prevalence and correlates of depression, anxiety, insomnia, and dysmenorrhea in stressed fingolimod-treated women with multiple sclerosis. METHODS: This cross-sectional study recruited female patients diagnosed with multiple sclerosis and high stress scores from Al-Bashir Hospital in Jordan. Depression was assessed by the Patient Health Questionnaire (PHQ-9); anxiety by the Generalized Anxiety Disorder (GAD-7) scale; insomnia by the Insomnia Severity Index (ISI-A) scale; and dysmenorrhea severity by a measure assessing working ability, location, intensity, days of pain, and miscellaneous dysmenorrhea symptoms (WaLIDD). RESULTS: A total of 129 patients were recruited for the study. Severe depression was reported in 55.8%, severe anxiety in 62.0%, severe insomnia in 36.4%, and severe dysmenorrhea in 23.3%. Multivariate analyses revealed that depressive symptoms were associated with dysmenorrhea (OR = 3.55, 95% CI = 1.56-8.12, p = 0.003); anxiety symptoms with "not using dysmenorrhea analgesics" (OR = 2.74, 95% CI = 1.16-6.46, p = 0.02) and dysmenorrhea symptoms (OR = 4.74, 95% CI = 1.94-11.59, p = 0.001); insomnia symptoms with age above 30 years (OR = 4.34, 95% CI = 1.64-11.51, p = 0.003); and dysmenorrhea symptoms with the presence of chronic diseases (OR = 4.21, 95% CI = 1.28-13.92, p = 0.02), anxiety symptoms (OR = 3.03, 95% CI = 1.18-7.73, p = 0.02), and insomnia symptoms (OR = 3.00, 95% CI = 1.18-7.64, p = 0.02). CONCLUSION: Stressed women with multiple sclerosis in Jordan experience high rates of depression, anxiety, insomnia, and dysmenorrhea. Characteristics related to these conditions may help clinicians to identify those at risk. Longitudinal studies are needed to determine the causal nature of these associations.

Cryptococcal meningoencephalitis in multiple sclerosis treated with fingolimod.

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.