- Email: [email protected]
“Nail loss after teriflunomide treatment: A new potential adverse event”
Author’s Accepted Manuscript “Nail loss after teriflunomide treatment: a new potential adverse event” L. Mancinelli, P. Amerio, M. di Ioia, V. Di Tommaso, G. De Luca, M. Onofrj, A. Lugaresi www.elsevier.com/locate/msard
PII: DOI: Reference:
S2211-0348(17)30240-7 http://dx.doi.org/10.1016/j.msard.2017.09.029 MSARD668
To appear in: Multiple Sclerosis and Related Disorders Received date: 27 June 2017 Revised date: 29 August 2017 Accepted date: 24 September 2017 Cite this article as: L. Mancinelli, P. Amerio, M. di Ioia, V. Di Tommaso, G. De Luca, M. Onofrj and A. Lugaresi, “Nail loss after teriflunomide treatment: a new potential adverse event”, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. 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.
“Nail loss after teriflunomide treatment: a new potential adverse event” Mancinelli L.1, Amerio P.2, di Ioia M.3, Di Tommaso V.3, De Luca G.4, Onofrj M.3 Lugaresi A.1, 5* 1
Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater
Studiorum – University of Bologna, ITALY 2
Department of Dermatology and Venereology, University “G. d’Annunzio” Chieti-
Pescara, ITALY 3
Department of Neuroscience Imaging and Clinical Science, University “G. d’Annunzio”
Chieti-Pescara, ITALY 4
UOC Clinica Neurologica, PO “SS. Annunziata” Chieti, ITALY
5
IRCCS Istituto delle Scienze Neurologiche – "UOSI Riabilitazione Sclerosi Multipla" –
Bologna, ITALY *Corresponding Author: Alessandra Lugaresi - IRCCS Istituto delle Scienze Neurologiche c/o Ospedale Bellaria – PAD Tinozzi – "UOSI Riabilitazione Sclerosi Multipla" - Via Altura, 3 – 40139 Bologna (Italy). Phone: +39 051 4966216 Fax: +39 0514966222 Luca Mancinelli: [email protected] Paolo Amerio: [email protected] Maria di Ioia: [email protected] Valeria Di Tommaso: [email protected] Giovanna De Luca: [email protected] Marco Onofrj: [email protected] [email protected]
Abstract Nail loss might represent a new, reversible, adverse event associated with teriflunomide treatment. It shares close analogies with hair loss and thinning, known adverse events of teriflunomide. MS specialists should be aware of this possibility and evaluate treatment discontinuation.
1. Introduction Teriflunomide is a recent therapeutic option for Relapsing Remitting Multiple Sclerosis (RR-MS), showing a similar efficacy to subcutaneous Interferon β-1a (IFNB1a) 3-times weekly in the phase three clinical trial “TENERE”.
The molecule represents the
principal active metabolite of the Rheumatoid Arthritis approved drug leflunomide, and acts by reversible inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), required for de novo pyrimidine synthesis in rapidly dividing lymphocytes; it thereby limits the proliferation of activated T and B cells, which are thought to cross the blood–brain barrier and participate in the damaging inflammatory processes associated with MS within the Central Nervous System [1]. One of the known and frequent (13,5% at the 14 mg/day dose), reversible effects of teriflunomide is hair thinning, which, in pooled extension studies led to treatment discontinuation in 1.3% of patients in the 14 mg/day group [2]. Hair and nails are both predominantly epithelial structures derived from primitive epidermis and made up of keratinous fibrils embedded in a sulfur-rich matrix. There is a number of hereditary and acquired conditions that can selectively affect hair follicle and nail apparatus [3].
2. Case report R. D. R. is a 55 years old woman who was referred to the Multiple Sclerosis Centre of Chieti in September 2013, following an episode, 3 months earlier, of acute optic neuritis treated with intravenous methylprednisolone. A few years before the patient presented progressive paraparesis, leading to the diagnosis of lumbar canal stenosis and subsequent surgical intervention in March, 2012. The patient has a familial history for Multiple Sclerosis (mother). At first evaluation in our centre, she was able to walk without help and rest for about 1 kilometer and Expanded Disability Status Scale (EDSS) step was 3.0. The diagnosis of MS was confirmed in January 2014, based on the revised McDonald’s criteria. The patient started treatment with IFNB1a. In April 2015 treatment was discontinued due to clinical and radiological lack of efficacy (despite negative neutralizing antibodies to IFNB1a), and within a month teriflunomide was initiated. The drug was initially well tolerated, not causing either hepatotoxicity nor arterial hypertension but only rare mild nausea after intake. On August 7 th 2015 the patient reported worsening of paraparesis, at least partly attributable to hot weather. In that occasion she also complained for the first time of hair loss, described as mild by the patient and scarcely noticeable at examination. On October 22 nd the patient phoned us reporting that she had been noticing progressive loss of finger nails in the past four weeks. At examination two finger nails in her right hand had dropped off (one of these presenting in a regrowth phase), whereas two in the left hand presented lack of growth with consequent onichomadesis (fig. 1). Some of the remaining nails in both hands showed thinning and progressive detachment from their bed. The patient reported persistent hair loss as well. She denied new drugs intake, use of different
soap, cream and other cosmetic products. She had only applied her usual nail polish, after the appearance of the first signs of the effect. Moreover, an expert dermatologist (PA) to whom we referred the patient excluded nail mycosis, psoriasis and other possible etiologies of nail dystrophy, and confirmed that the hypothesis of a causal relationship with teriflunomide was highly probable. Hence, the drug was discontinued and, because of its very long half-life, the patient underwent the accelerated removal procedure with oral colestiramine. After removal treatment her blood teriflunomide level was equal to 0,36 mg/l. The patient started dimethyl-fumarate a few weeks after teriflunomide discontinuation. At subsequent visits the patient’s nails showed progressive regrowth and normalization (fig. 2), strengthening the cause/effect relationship with teriflunomide. The patient has provided written permission to this publication, including pictures. 3. Discussion To our knowledge there are no published reports of nail loss under teriflunomide treatment. With reference to the mechanism of action of teriflunomide, it is thought that some of the proliferating cells of the body (i.e. gastrointestinal or epithelial cells) express lower levels of DHODH and are not specifically stimulated for rapid expansion; therefore, teriflunomide is far less able to inhibit their proliferation. [4] Teriflunomide usually is reported to induce hair thinning and loss of hair. The mechanism underlying this condition is still not known, however is thought not to be related directly to the drug. The hair thinning and shedding has been described by the manufacturer as a form of telogen effluvium. Telogen effluvium has been describes as a “nonspecific reaction
pattern” in which the main symptom is the increased shedding of telogen hairs developing 3-4 months after the causing event. Its pathogenesis is very heterogeneous and little is known about the mechanism of induction. However, drugs could be involved in this type of condition. [5] Because nail and hair growth are under the same influences, an arrest in hair growth is often mirrored in the nails. We think that our patient had a drug induced telogen effluvium associated with the involvement of the nails, with an atypical presentation of what is usually called beau’s lines. Beau’s lines are the result of nail growth arrest and appear as transversal lines or absence of nail from the lunula as in our patient. The timing of the hair shedding after drug introduction describes the induction of synchronization of “telogen“ phase in hair growth with subsequent shedding. The involvement of the nails follows this “shock” to the hair growth, inducing a “stop” of nail growth and subsequent developing the lesions showed by our patient. As further clues to ascribe the effect to the drug we underline the absence of any other change in the patient’s life such as new drugs, new diet, new cosmetics; the exclusion of other possible etiologies by our dermatologist and, finally, reversibility at drug discontinuation. 4. Conclusion MS specialists should be aware of this potential adverse event, which might represent a new cause of teriflunomide discontinuation.
Figure 1: second and fourth fingers of the left hand showing onichomadesis (arrows)
Figure 2: particular of the patient’s right hand (second to fifth fingers) showing nails in the regrowht phase, better evident at the fourth finger (arrow)
Conflict of interest_Lugaresi.docx Prof Lugaresi has served as a Bayer, Biogen, Genzyme/Sanofi, Merck Serono, Novartis, Teva Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Genzyme, Merck Serono, Novartis, Sanofi and Teva and her institution received research grants from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi and Teva. Prof Lugaresi has also received travel and research grants from the Associazione Italiana Sclerosi Multipla.
References 1. Bar-Or A, et al. “Teriflunomide and Its Mechanism of Action in Multiple Sclerosis” Drugs 2014; 74(6): 659–674. doi: 10.1007/s40265-014-0212-x 2. Comi G, et al. “Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions” Mult Scler Relat Disord 2016 Jan;5:97-104. doi: 10.1016/j.msard.2015.11.006. Epub 2015 Nov 10 3. Baran R, Dawber RP, Haneke E “Hair and nail relationship” Skinmed 2005 JanFeb;4(1):18-23 4. Löeffler M, et al. “Dihydroorotate dehydrogenase mRNA and protein expression analysis in normal and drug-resistant cells” Nucleosides Nucleotides Nucleic Acids 2004 Oct;23(8-9):1281-5 5. Rebora A. “Proposing a Simpler Classification of Telogen Effluvium” Skin Appendage Disord 2016 Sep;2(1-2):35-38. Epub 2016 May 18
Highlights •
Nail loss following teriflunomide treatment
•
The effect was reversible at drug discontinuation
•
An expert dermatologist excluded other etiologies for the adverse event
•
Nail loss might represent a new rare adverse event of teriflunomide
PII: DOI: Reference:
S2211-0348(17)30240-7 http://dx.doi.org/10.1016/j.msard.2017.09.029 MSARD668
To appear in: Multiple Sclerosis and Related Disorders Received date: 27 June 2017 Revised date: 29 August 2017 Accepted date: 24 September 2017 Cite this article as: L. Mancinelli, P. Amerio, M. di Ioia, V. Di Tommaso, G. De Luca, M. Onofrj and A. Lugaresi, “Nail loss after teriflunomide treatment: a new potential adverse event”, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j.msard.2017.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. 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.
“Nail loss after teriflunomide treatment: a new potential adverse event” Mancinelli L.1, Amerio P.2, di Ioia M.3, Di Tommaso V.3, De Luca G.4, Onofrj M.3 Lugaresi A.1, 5* 1
Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater
Studiorum – University of Bologna, ITALY 2
Department of Dermatology and Venereology, University “G. d’Annunzio” Chieti-
Pescara, ITALY 3
Department of Neuroscience Imaging and Clinical Science, University “G. d’Annunzio”
Chieti-Pescara, ITALY 4
UOC Clinica Neurologica, PO “SS. Annunziata” Chieti, ITALY
5
IRCCS Istituto delle Scienze Neurologiche – "UOSI Riabilitazione Sclerosi Multipla" –
Bologna, ITALY *Corresponding Author: Alessandra Lugaresi - IRCCS Istituto delle Scienze Neurologiche c/o Ospedale Bellaria – PAD Tinozzi – "UOSI Riabilitazione Sclerosi Multipla" - Via Altura, 3 – 40139 Bologna (Italy). Phone: +39 051 4966216 Fax: +39 0514966222 Luca Mancinelli: [email protected] Paolo Amerio: [email protected] Maria di Ioia: [email protected] Valeria Di Tommaso: [email protected] Giovanna De Luca: [email protected] Marco Onofrj: [email protected] [email protected]
Abstract Nail loss might represent a new, reversible, adverse event associated with teriflunomide treatment. It shares close analogies with hair loss and thinning, known adverse events of teriflunomide. MS specialists should be aware of this possibility and evaluate treatment discontinuation.
1. Introduction Teriflunomide is a recent therapeutic option for Relapsing Remitting Multiple Sclerosis (RR-MS), showing a similar efficacy to subcutaneous Interferon β-1a (IFNB1a) 3-times weekly in the phase three clinical trial “TENERE”.
The molecule represents the
principal active metabolite of the Rheumatoid Arthritis approved drug leflunomide, and acts by reversible inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), required for de novo pyrimidine synthesis in rapidly dividing lymphocytes; it thereby limits the proliferation of activated T and B cells, which are thought to cross the blood–brain barrier and participate in the damaging inflammatory processes associated with MS within the Central Nervous System [1]. One of the known and frequent (13,5% at the 14 mg/day dose), reversible effects of teriflunomide is hair thinning, which, in pooled extension studies led to treatment discontinuation in 1.3% of patients in the 14 mg/day group [2]. Hair and nails are both predominantly epithelial structures derived from primitive epidermis and made up of keratinous fibrils embedded in a sulfur-rich matrix. There is a number of hereditary and acquired conditions that can selectively affect hair follicle and nail apparatus [3].
2. Case report R. D. R. is a 55 years old woman who was referred to the Multiple Sclerosis Centre of Chieti in September 2013, following an episode, 3 months earlier, of acute optic neuritis treated with intravenous methylprednisolone. A few years before the patient presented progressive paraparesis, leading to the diagnosis of lumbar canal stenosis and subsequent surgical intervention in March, 2012. The patient has a familial history for Multiple Sclerosis (mother). At first evaluation in our centre, she was able to walk without help and rest for about 1 kilometer and Expanded Disability Status Scale (EDSS) step was 3.0. The diagnosis of MS was confirmed in January 2014, based on the revised McDonald’s criteria. The patient started treatment with IFNB1a. In April 2015 treatment was discontinued due to clinical and radiological lack of efficacy (despite negative neutralizing antibodies to IFNB1a), and within a month teriflunomide was initiated. The drug was initially well tolerated, not causing either hepatotoxicity nor arterial hypertension but only rare mild nausea after intake. On August 7 th 2015 the patient reported worsening of paraparesis, at least partly attributable to hot weather. In that occasion she also complained for the first time of hair loss, described as mild by the patient and scarcely noticeable at examination. On October 22 nd the patient phoned us reporting that she had been noticing progressive loss of finger nails in the past four weeks. At examination two finger nails in her right hand had dropped off (one of these presenting in a regrowth phase), whereas two in the left hand presented lack of growth with consequent onichomadesis (fig. 1). Some of the remaining nails in both hands showed thinning and progressive detachment from their bed. The patient reported persistent hair loss as well. She denied new drugs intake, use of different
soap, cream and other cosmetic products. She had only applied her usual nail polish, after the appearance of the first signs of the effect. Moreover, an expert dermatologist (PA) to whom we referred the patient excluded nail mycosis, psoriasis and other possible etiologies of nail dystrophy, and confirmed that the hypothesis of a causal relationship with teriflunomide was highly probable. Hence, the drug was discontinued and, because of its very long half-life, the patient underwent the accelerated removal procedure with oral colestiramine. After removal treatment her blood teriflunomide level was equal to 0,36 mg/l. The patient started dimethyl-fumarate a few weeks after teriflunomide discontinuation. At subsequent visits the patient’s nails showed progressive regrowth and normalization (fig. 2), strengthening the cause/effect relationship with teriflunomide. The patient has provided written permission to this publication, including pictures. 3. Discussion To our knowledge there are no published reports of nail loss under teriflunomide treatment. With reference to the mechanism of action of teriflunomide, it is thought that some of the proliferating cells of the body (i.e. gastrointestinal or epithelial cells) express lower levels of DHODH and are not specifically stimulated for rapid expansion; therefore, teriflunomide is far less able to inhibit their proliferation. [4] Teriflunomide usually is reported to induce hair thinning and loss of hair. The mechanism underlying this condition is still not known, however is thought not to be related directly to the drug. The hair thinning and shedding has been described by the manufacturer as a form of telogen effluvium. Telogen effluvium has been describes as a “nonspecific reaction
pattern” in which the main symptom is the increased shedding of telogen hairs developing 3-4 months after the causing event. Its pathogenesis is very heterogeneous and little is known about the mechanism of induction. However, drugs could be involved in this type of condition. [5] Because nail and hair growth are under the same influences, an arrest in hair growth is often mirrored in the nails. We think that our patient had a drug induced telogen effluvium associated with the involvement of the nails, with an atypical presentation of what is usually called beau’s lines. Beau’s lines are the result of nail growth arrest and appear as transversal lines or absence of nail from the lunula as in our patient. The timing of the hair shedding after drug introduction describes the induction of synchronization of “telogen“ phase in hair growth with subsequent shedding. The involvement of the nails follows this “shock” to the hair growth, inducing a “stop” of nail growth and subsequent developing the lesions showed by our patient. As further clues to ascribe the effect to the drug we underline the absence of any other change in the patient’s life such as new drugs, new diet, new cosmetics; the exclusion of other possible etiologies by our dermatologist and, finally, reversibility at drug discontinuation. 4. Conclusion MS specialists should be aware of this potential adverse event, which might represent a new cause of teriflunomide discontinuation.
Figure 1: second and fourth fingers of the left hand showing onichomadesis (arrows)
Figure 2: particular of the patient’s right hand (second to fifth fingers) showing nails in the regrowht phase, better evident at the fourth finger (arrow)
Conflict of interest_Lugaresi.docx Prof Lugaresi has served as a Bayer, Biogen, Genzyme/Sanofi, Merck Serono, Novartis, Teva Advisory Board Member. She received travel grants and honoraria from Bayer, Biogen, Genzyme, Merck Serono, Novartis, Sanofi and Teva and her institution received research grants from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi and Teva. Prof Lugaresi has also received travel and research grants from the Associazione Italiana Sclerosi Multipla.
References 1. Bar-Or A, et al. “Teriflunomide and Its Mechanism of Action in Multiple Sclerosis” Drugs 2014; 74(6): 659–674. doi: 10.1007/s40265-014-0212-x 2. Comi G, et al. “Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions” Mult Scler Relat Disord 2016 Jan;5:97-104. doi: 10.1016/j.msard.2015.11.006. Epub 2015 Nov 10 3. Baran R, Dawber RP, Haneke E “Hair and nail relationship” Skinmed 2005 JanFeb;4(1):18-23 4. Löeffler M, et al. “Dihydroorotate dehydrogenase mRNA and protein expression analysis in normal and drug-resistant cells” Nucleosides Nucleotides Nucleic Acids 2004 Oct;23(8-9):1281-5 5. Rebora A. “Proposing a Simpler Classification of Telogen Effluvium” Skin Appendage Disord 2016 Sep;2(1-2):35-38. Epub 2016 May 18
Highlights •
Nail loss following teriflunomide treatment
•
The effect was reversible at drug discontinuation
•
An expert dermatologist excluded other etiologies for the adverse event
•
Nail loss might represent a new rare adverse event of teriflunomide