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Transient hair loss during treatment with dimethyl-fumarate for Multiple Sclerosis
Abstract
Introduction:
Dimethyl-fumarate is a recently approved drug for relapsing-remitting Multiple Sclerosis in Italy.
Clinical case:
A 55-year-old woman started therapy with dimethyl-fumarate on June 2014; it was well-tolerated aside from moderate flushing. Starting September 2014 she noticed a progressive hair loss, that neither the dermatological examination nor clinical and medical history nor blood investigations could explain. The hair loss slowed down after two months and was followed by a hair growth back.
Discussion:
Transient hair loss is not a reported side effect of dimethyl-fumarate therapy but by excluding any known cause we attributed it to the beginning of the new therapy.
... There are also some recent reports about newly noticed rare adverse effects of this drug, including articular and musculoskeletal pain [49]. There aren't many reported skin changes associated with dimethyl fumarate use in patients with MS, just a newly reported case report about transient hair loss [50]. In addition, it is important to point out that this drug is nowadays being used for the treatment of dermatological diseases such as psoriasis and bullous pemphigoid [51,52]. ...
... Teriflunomide Drug -induced bullous pemphigoid [14], toxic epidermal necrolysis [40], nail loss [42], palmar pustular psoriasis [43], psoriasiform changes of fingernails [41] Dimethyl Fumarate Transient hair loss [50] Table: Cutaneous side effects of first/second line oral disease-modifying treatments. ...
Multiple sclerosis (MS) is a progressive autoimmune and sometimes disabling disease of the central nervous system (CNS), characterized by formation of white matter lesions in the CNS due to inflammation, demyelination and axonal loss. Disease-modifying treatments (DMTs) are being investigated as a treatment choice in patients with MS. Teriflunomide, fingolimod and dimethyl fumarate are the most popular oral forms of the DMTs that are used usually for relapsing forms of MS (RMS), the most common disease phenotype. In this complementary, we have compiled the reports about cutaneous adverse reactions associated with oral first or second line DMTs. There have been recently published rare cases to point out serious cutaneous adverse effects associated with fingolimod therapy such as Kaposi sarcoma, peripheral vascular adverse effects, ecchymotic angioedema-like cutaneous lesions, lymphomatoid papulosis. There are also a few case reports about cutaneous adverse effects of teriflunomide, such as eczema, rash and palmar pustular psoriasis. In addition, a recently published case report has demonstrated another serious adverse effect associated with teriflunomide; drug – induced bullous pemphigoid. However, there aren’t many reported skin changes associated with dimethyl fumarate use in patients with MS, just a newly reported case report about transient hair loss. By examining the specific clinical, pharmacological and safety features of all drugs, we tried to provide an overview. In addition, it is important to point out some immunosuppressants may trigger autoimmune diseases. These DMTs may also have led to similar autoimmune phenomenon, attending to the development of some cutaneous autoimmune reactions. The molecular mechanisms behind these reactions are still unknown and further studies are needed to reveal them.
... A single case study of a 55-year-old woman experiencing transient hair loss associated with dimethyl fumarate treatment was published in 2016. 23 Our findings indicate a surprisingly large number of alopecia reports for this drug (a total of 1675), rendering dimethyl fumarate as the second most reported DMT in association with alopecia. Additionally, odds ratio analyses show an increased odd of alopecia in females, but not males. ...
Background:
There is currently limited literature addressing the reporting of alopecia in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). Anecdotal reports of hair thinning from patients on various DMTs prompted further investigation of a large database.
Objective:
To analyze total reports, source of reporting, age distribution, and sex distribution of alopecia associated with DMTs.
Methods:
FDA Adverse Event Reporting System (FAERS) public dashboard and OpenFDA database were analyzed for alopecia reports between January 1, 2009, and June 30, 2020, attributed to usage in MS of FDA approved DMTs. The main outcomes included total reports for each drug, age, sex distribution, and reporting source. OpenFDA data was used for statistical analyses including reporting odds ratios (ROR) and information components.
Results:
8759 alopecia reports were identified among 44 114 adverse events in skin and subcutaneous tissue disorders (19.9%). 3701 (42.3%) with teriflunomide, 1675 (19.1%) with dimethyl fumarate, 985 (11.2%) with natalizumab, 926 (10.6%) with fingolimod, 659 (7.5%) with interferon beta-1a, 257 (2.9%) with glatiramer acetate, 243 (2.8%) with ocrelizumab, 124 (1.4%) with interferon beta-1b, 117 (1.3%) with alemtuzumab, 36 (.4%) with siponimod, 24 (.3%) with cladribine, and 12 (.1%) with rituximab. Reports were mostly made by patients (78.3%) and highest in fifth and sixth decades of life. OpenFDA analyses showed increased ROR (ROR 95% confidence interval) of alopecia in females with teriflunomide (18.00, 17.12-18.93), alemtuzumab (1.43, 1.16-1.76), dimethyl fumarate (1.26, 1.18-1.34), and ocrelizumab (1.28, 1.11-1.49). Increased ROR in males was associated with teriflunomide (24.65, 20.72-29.31).
Conclusion:
We identified many reports of alopecia for DMTs in addition to teriflunomide. Within the limitations of the database, increased RORs of alopecia were observed for females treated with alemtuzumab, dimethyl fumarate, and ocrelizumab. The source of reporting was largely driven by female patients. Possible alopecia, even if transient, should be considered during patient education when starting DMTs.
... During DEFINE trial, the level of aminotransferase elevated about three or more times the upper limit of normal in 6% of treated patients but such elevation only occurred in 3% of the placebo group. There are also some recent case reports and case series about rare AEs associated with dimethyl fumarate therapy including severe articular and musculoskeletal pain [35] and transient hair loss [36] which give us new insights for other possible AEs. ...
Multiple Sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS) mostly affecting young adults. The exact mechanism and pathogenesis of MS remain still undiscovered but there have been useful treatments with different efficacy rates. Most of these therapies are divided into the first line, second line and third line, impact on the immune system and immune cells. These drugs are approved to be useful in MS, but like any other therapies, adverse effects (AE) are associated with these drugs. In this review, we continue the survey over mechanisms of actions and AEs of MS drugs. Physicians must be aware of such AEs and complications to choose the best drug for each patient.
... Hair loss can be triggered by emotional stress, diet, illness, underlying medical conditions, or exposure to medication; severe hair loss is often associated with chemotherapy or radiation treatments [3]. There have been reports of hair thinning in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs) [4][5][6][7][8]. ...
Introduction:
Hair thinning occurred in 10-14% of teriflunomide-treated patients in the teriflunomide multiple sclerosis clinical development program, compared with 5% of placebo-treated patients. Our objective was to examine the clinical course of hair thinning in patients in an observational real-world project.
Methods:
Patients with relapsing-remitting multiple sclerosis who reported hair thinning to healthcare professionals (HCPs) during treatment with teriflunomide were eligible for inclusion. During two office visits, one at onset of hair thinning and another at follow-up, HCPs and patients completed questionnaires that categorized hair thinning as mild, moderate, or severe, or from 0 (no hair thinning) to 10 (very severe hair thinning), respectively. At the follow-up visit, patients also rated the degree of recovery. Patients were photographed at both visits with a standardized protocol and camera.
Results:
Of the 38 patients who completed follow-up, most were women (97%) without prior history of hair thinning (87%), with the majority (68%) receiving concomitant medications potentially associated with hair thinning. The mean time to onset of hair thinning was 77 days after the first teriflunomide dose. HCPs classified the majority of hair thinning events as mild (63%) or moderate (34%), with one event classified as severe (3%). The mean patient severity perception was 5/10, and complete/near-complete resolution or marked improvement was reported by 79% of patients.
Conclusion:
Consistent with observations from the teriflunomide clinical program, hair thinning was usually mild and occurred within the first 3 months of treatment, with most patients fully recovering while remaining on teriflunomide treatment. As with any potential adverse event, it is important to ensure appropriate expectations through patient education before treatment.
Funding:
Sanofi.
After 2 weeks of treatment, a woman with multiple sclerosis treated with dimethyl fumarate developed alopecia. Considering the adverse events, the therapy was discontinued, leading to alopecia regression during the next 3 months. Although the precise mechanism has not been completely elucidated, glutathione depletion or downregulation of aerobic glycolysis are considered to be potential reasons for hair loss induction. The incidence and mechanism of this uncommon adverse reaction to dimethyl fumarate should be further investigated.
Introduction:
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the brain and spinal cord characterized by inflammation, demyelination, and axonal degeneration.
Area covered:
Even though the pharmacological armamentarium for MS treatment is considerably improved in the last 20 years, safety data especially for the second-line and innovative treatments are lacking. In order to analyze the safety profile of drugs used for the treatment of MS, a literature review of pre-marketing, post-marketing studies and case reports was performed.
Expert opinion:
Nowadays, the numerous drugs approved in the last years for the treatment of MS allow a better control of the disease and a better patient compliance. The main advantages of the new disease-modifying agents for MS (DMTs), in fact, derive from the new oral administration and the prolonged half-life with consequent improvement in compliance compared to first-line therapy which required subcutaneous administrations. However, DMTs can cause serious, sometimes life-threatening or fatal, drug adverse reactions.
Due to the lack of safety data and given the recent marketing approval of the last DMTS for MS, observational studies and post-marketing surveillance activities will be necessary in order to improve the knowledge about the safety profile of these drugs and the improvement of their use in clinical practice.
The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.
BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.
We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.
The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.
In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).
BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).
In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.
At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
Alopecia areata is a cosmetically very disfiguring clinical picture and can be a great emotional burden to the patient, especially when persisting for a longer period of time.
10 patients with an alopecia resistant to therapy were treated within the bounds of an open, non-placebo controlled pilot study with fumaric acid esters (FAE's, Fumaderm) for a period of six months and a maximum dose of 120 mg dimethylfumarate per day. The shortest space of time between persistent Alopecia areata and the start of the therapy with FAE was between six months and 17 years.
Six patients took benefit from the six months therapy with FAE. In three of them very good results could be observed, presenting an almost entire remission, one patient showed a good success with a focal remission. With two patients a mediocre to moderate outcome was observed with growth of partly diffuse spread or very thin hair. Four patients took no benefit from the FAE therapy at all.
FAE can be useful in the treatment of therapy-resistant Alopecia areata. This therapy approach should be validated in a multi-centre study.
Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.
One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.