- Email: [email protected]
Teeth loss after teriflunomide treatment: Casual or causal? A short case series
Accepted Manuscript
Teeth loss after teriflunomide treatment: casual or causal? A short case series Veria Vacchiano , Nicola Frattaruolo , Luca Mancinelli , Matteo Foschi , Antonio Carotenuto , Cinzia Scandellari , Maurizio Piattelli , Vincenzo Brescia Morra , Alessandra Lugaresi PII: DOI: Reference:
S2211-0348(18)30196-2 10.1016/j.msard.2018.06.018 MSARD 873
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
28 December 2017 18 June 2018 28 June 2018
Please cite this article as: Veria Vacchiano , Nicola Frattaruolo , Luca Mancinelli , Matteo Foschi , Antonio Carotenuto , Cinzia Scandellari , Maurizio Piattelli , Vincenzo Brescia Morra , Alessandra Lugaresi , Teeth loss after teriflunomide treatment: casual or causal? A short case series, Multiple Sclerosis and Related Disorders (2018), doi: 10.1016/j.msard.2018.06.018
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Highlights: Teriflunomide, a safe and effective drug for RRMS, is a mild immunosuppressant The loss of periodontal host–microbe homeostasis causes caries and periodontitis Poor oral hygiene might contribute to dental pathology, mainly in advanced MS cases Whether teriflunomide might favour teeth loss in predisposed individuals is uncler Dental care prior to and during teriflunomide therapy is recommended
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT Teeth loss after teriflunomide treatment: casual or causal? A short case series Veria Vacchianoa, Nicola Frattaruolob, Luca Mancinellia, Matteo Foschia, Antonio Carotenutob, Cinzia Scandellaric, Maurizio Piattellid, Vincenzo Brescia Morrab, Alessandra Lugaresia.c. a
Department of Biomedical and Neuromotor Sciences (DIBINEM) – Alma Mater Studiorum – University of Bologna –
Bologna. Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and
Odontostomatology, Federico II University - Naples. c
IRCCS Institute of the Neurological Sciences of Bologna (ISNB) – Bologna.
d
CR IP T
b
AN US
Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio of Chieti-Pescara, Chieti, Italy
The authors state that the content of the submitted manuscript has not been published previously and has not been submitted elsewhere for review. There is no financial support received in
M
conjunction with the generation of this submission. Conflicts of interest are stated. The Authors
ED
certify that this manuscript is a unique submission and is not being considered for publication with
PT
any other source in any medium. The Authors have nothing to declare and disclosures are reported.
CE
Correspondence to: Alessandra Lugaresi, MD, PhD c/o UOSI Riabilitazione Sclerosi Multipla – Padiglione Tinozzi, Ospedale Bellaria, Via Altura, 3A
AC
– 40139 Bologna
Tel. +39 051 4966211 e-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. Case reports: Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from
CR IP T
interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine.
Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and
AN US
periapical bone loss in several residual roots. Investigating retrospectively the patient’s dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss.
M
Case 2: a 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced
ED
the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued
PT
and the accelerated elimination procedure with cholestyramine was performed.
CE
Case 3: a 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility
AC
of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure.
Discussion: Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth
ACCEPTED MANUSCRIPT loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. Conclusions: We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment.
CR IP T
Keywords: teriflunomide; periodontitis; dental caries; leflunomide; multiple sclerosis.
Highlights:
Teriflunomide, a safe and effective drug for RRMS, is a mild immunosuppressant
-
The loss of periodontal host–microbe homeostasis causes caries and periodontitis
-
Poor oral hygiene might contribute to dental pathology, mainly in advanced MS cases
-
Whether teriflunomide might favour teeth loss in predisposed individuals is uncler
-
Dental care prior to and during teriflunomide therapy is recommended
ED
M
AN US
-
PT
Background
CE
Teriflunomide is a once-daily oral immunomodulant approved for the treatment of relapsingremitting multiple sclerosis (RRMS). Teriflunomide is the active metabolite of leflunomide, a drug
AC
used to treat rheumatoid arthritis since 1998. Teriflunomide inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in de novo pyrimidine synthesis, resulting in a cytostatic effect on proliferating activated T and B lymphocytes. Long-term extension studies have shown efficacy on clinical outcomes and Magnetic Resonance Imaging (MRI) parameters and a consistent safety profile. Pooled safety data from four placebo-controlled teriflunomide studies and their extensions showed that the most common adverse events were alanine aminotransferase increase, headache, diarrhea, hair thinning, and nausea (Comi et al, 2016). Tooth disorders, but not serious tooth
ACCEPTED MANUSCRIPT diseases, have been reported during teriflunomide treatment, most frequently toothache and teeth infections (EMA, Summary of product characteristics, 2018). We describe three cases of multiple teeth loss during teriflunomide treatment. Case reports Case 1: a 39-year-old woman, with RRMS, disease onset in 2004, treated for almost 10 years with
CR IP T
interferon beta. In October 2016, due to poor tolerability and compliance, she was switched to teriflunomide treatment.
At the beginning of teriflunomide treatment she experienced only mild alopecia. Four months later she complained of mandibular pain without gingival swelling, bleeding or dental abscess. After a
AN US
few days she experienced the sudden loss of 2 upper incisors without bleeding or trauma. In the following days she lost a molar in the maxillary dental arch, and another molar in the lower arch. The patient denied any other change in her life such as new drugs, new diet or different lifestyle.
M
She did not report nocturnal bruxism or smoking habit. Dental scans performed from 2009 to 2017 showed progressive dental pathology, poor oral hygiene and scarce therapeutic interventions.
ED
A dental assessment including orthopantomography and a subsequent dental computed tomography (CT) scan in fact revealed missing incisors, premolars and molars, several residual roots with
PT
periapical lesions, or periapical endodontic treatment and upper canines predisposed for transient,
CE
fixed prosthesis with possible thermal damage; distal class II and class III periodontitis in the lower arch, and profuse amounts of dental plaque.
AC
Suspecting a causal role of teriflunomide, we discontinued treatment and started the accelerated elimination procedure with cholestyramine. Investigating the patient’s dental medical history, we discovered that she had already performed other orthopantomographies in 2009, 2011 and 2014. These scans showed a parodontopathy with progressive dental loss/extraction in the absence of recent dental symptomatology. Case 2: a 52-year-old woman affected by MS since 1988. She had been previously treated with interferon beta for five years. She asked to be switched to an oral drug, due to poor tolerability of
ACCEPTED MANUSCRIPT injections. She started teriflunomide in October 2016 with no adverse events in the first period. After 1 year of treatment she experienced the sudden loss of five teeth (two canines and three premolars), in the absence of trauma or bleeding. The patient denied nocturnal bruxism or smoking habit. Dental assessment and orthopantomography showed profuse amounts of dental plaque and moderate chronic periodontisis. Teriflunomide was discontinued and the accelerated elimination
CR IP T
procedure with cholestyramine was performed. Case 3: a 56-year-old woman diagnosed with MS in 1988. She was treated with interferon beta for fifteen years, discontinued due to poor injection tolerability. She started teriflunomide in april 2016.
AN US
For eighteen months she did not report any adverse event. She subsequently experienced
hypermobility of several teeth without gum inflammation or pain, but she did not seek dental consult nor report the fact. After a few weeks she referred the loss of five teeth, followed by other seven teeth two days later, without traumatic events. She also denied smoking habit or nocturnal
M
bruxism. Teriflunomide was discontinued but the patient refused to undergo the accelerated
ED
elimination procedure.
PT
Discussion and conclusions
Odontogenic infections (periodontal disease and dental caries) are the commonest cause of teeth
CE
loss (Costalonga and Herzberg, 2014). The breakdown of oral tissue homeostasis favours the proliferation of pathobionts (i.e. P. gingivalis, T. denticola, Tannerella forsythia, and
AC
Aggregatibacter Actinomycetemcomitans for periodontitis and Streptococcus mutans and Lactobacillus for caries) and may be facilitated by congenital or acquired defects in host immunoregulatory mechanisms. Aging, systemic diseases (e.g. rheumatoid arthritis, multiple sclerosis, type 1 diabetes, osteoporosis, cardiovascular disease, obesity), environmental factors (e.g. smoking, diet and stress), and epigenetic modifications in response to environmental factors, alone or in combination, can contribute to unfavorable changes in the homeostatic balance (Hajishengallis, 2014). Dental caries cause progressive destruction of dental hard tissue, then affect
ACCEPTED MANUSCRIPT the pulp and eventually cause crown destruction. Periodontitis causes the destruction of the periodontal ligaments and the progressive loss of the alveolar bone around the teeth. If left untreated, both dental caries and periodontitis can lead to loss of teeth. Concomitant bruxism, common in many neurological conditions including MS, might play a role, but was not reported by our patients.
CR IP T
Despite alveolar bone resorption has never been associated with teriflunomide, tooth infections are considered common side effects of this drug; only in 1 female case in 2015 periodontitis was reported in association with teriflunomide treatment (EMA, Summary of product characteristics, 2018). Considering that in Case 1 medical history revealed a pre-existent dental pathology with
AN US
multiple caries and periodontitis, it is conceivable that, at least in this case, teriflunomide favoured local inflammation and subsequent dental loss in a predisposed subject.
Details about the dental medical history of the other 2 patients are not available. It is conceivable
M
that, but impossible to establish whether, the dental pathology was pre-existent to teriflunomide treatment. As symptom and teeth loss dynamics are similar, the presence of a neglected dental
ED
pathology is highly probable.
According to a recent review article about the effects of different disease modifying drugs,
PT
including leflunomide, of which teriflunomide is the active metabolite, on periodontal pathology in
CE
reumathoid arthritis patients (Romero-Sanchez, et al. 2017) methotrexate combined with leflunomide exhibits a higher extension of clinical attachment loss, which refers to the pathological
AC
detachment of collagen fibers from cemental surface, whereas anti-TNF-alpha therapy associated with methotrexate would be associated with a lower extension of clinical attachment loss. The authors speculate that the strong anti-proliferative activity of combined methotrexate and leflunomide treatment could reinforce immunosuppression and its impact on the gingival microbiota, concluding that this drug combination could have a deleterious effect on bone loss. This study suggests that leflunomide does not show a protective effect on periodontal disease, unlike anti-TNF-alpha treatment. In fact patients treated with leflunomide can present a worsening
ACCEPTED MANUSCRIPT of the clinical attachment loss, a sign of destructive periodontal disease. Similarly teriflunomide might play a role both in favouring dental pathology and hampering restorative mechanisms. In conclusion oral hygiene is critical in subjects treated with immunomodulant or especially immunosuppressive drugs. Even if further investigations are warranted to clarify the putative role of teriflunomide in dental loss, we recommend to assess and monitor possible concomitant tooth
AC
CE
PT
ED
M
AN US
CR IP T
morbidity, before and during teriflunomide treatment.
ACCEPTED MANUSCRIPT Bibliography Comi G. et al, 2016. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 5:97-104. http://dx.doi.org/10.1016/j.msard.2015.11.006. (Epub 2015 Nov 10).
CR IP T
Costalonga M, Herzberg MC. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol Lett. 2014;162:22-38. doi: 10.1016/j.imlet.2014.08.017. Epub 2014 Nov 8. Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol. 2014 Jan;35(1):3-11. doi: 10.1016/j.it.2013.09.001. Epub 2013 Oct 23.
AN US
Review. PMID:24269668
Romero-Sanchez C. et al, 2017. Is the Treatment with Biological or Non-biological DMARDS a Modifier of Periodontal Condition in Patients with Rheumatoid Arthritis? Curr Rheumatol Rev.
M
13(2):139-151. doi: 10.2174/1573397113666170407161520.
ED
EMA, Summary of product characteristics (last updated June 1, 2018) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
AC
CE
PT
_Product_Information/human/002514/WC500148682.pdf
Teeth loss after teriflunomide treatment: casual or causal? A short case series Veria Vacchiano , Nicola Frattaruolo , Luca Mancinelli , Matteo Foschi , Antonio Carotenuto , Cinzia Scandellari , Maurizio Piattelli , Vincenzo Brescia Morra , Alessandra Lugaresi PII: DOI: Reference:
S2211-0348(18)30196-2 10.1016/j.msard.2018.06.018 MSARD 873
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
28 December 2017 18 June 2018 28 June 2018
Please cite this article as: Veria Vacchiano , Nicola Frattaruolo , Luca Mancinelli , Matteo Foschi , Antonio Carotenuto , Cinzia Scandellari , Maurizio Piattelli , Vincenzo Brescia Morra , Alessandra Lugaresi , Teeth loss after teriflunomide treatment: casual or causal? A short case series, Multiple Sclerosis and Related Disorders (2018), doi: 10.1016/j.msard.2018.06.018
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 proof before it is published in its final 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.
ACCEPTED MANUSCRIPT Highlights: Teriflunomide, a safe and effective drug for RRMS, is a mild immunosuppressant The loss of periodontal host–microbe homeostasis causes caries and periodontitis Poor oral hygiene might contribute to dental pathology, mainly in advanced MS cases Whether teriflunomide might favour teeth loss in predisposed individuals is uncler Dental care prior to and during teriflunomide therapy is recommended
AC
CE
PT
ED
M
AN US
CR IP T
ACCEPTED MANUSCRIPT Teeth loss after teriflunomide treatment: casual or causal? A short case series Veria Vacchianoa, Nicola Frattaruolob, Luca Mancinellia, Matteo Foschia, Antonio Carotenutob, Cinzia Scandellaric, Maurizio Piattellid, Vincenzo Brescia Morrab, Alessandra Lugaresia.c. a
Department of Biomedical and Neuromotor Sciences (DIBINEM) – Alma Mater Studiorum – University of Bologna –
Bologna. Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and
Odontostomatology, Federico II University - Naples. c
IRCCS Institute of the Neurological Sciences of Bologna (ISNB) – Bologna.
d
CR IP T
b
AN US
Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio of Chieti-Pescara, Chieti, Italy
The authors state that the content of the submitted manuscript has not been published previously and has not been submitted elsewhere for review. There is no financial support received in
M
conjunction with the generation of this submission. Conflicts of interest are stated. The Authors
ED
certify that this manuscript is a unique submission and is not being considered for publication with
PT
any other source in any medium. The Authors have nothing to declare and disclosures are reported.
CE
Correspondence to: Alessandra Lugaresi, MD, PhD c/o UOSI Riabilitazione Sclerosi Multipla – Padiglione Tinozzi, Ospedale Bellaria, Via Altura, 3A
AC
– 40139 Bologna
Tel. +39 051 4966211 e-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. Case reports: Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from
CR IP T
interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine.
Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and
AN US
periapical bone loss in several residual roots. Investigating retrospectively the patient’s dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss.
M
Case 2: a 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced
ED
the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued
PT
and the accelerated elimination procedure with cholestyramine was performed.
CE
Case 3: a 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility
AC
of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure.
Discussion: Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth
ACCEPTED MANUSCRIPT loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. Conclusions: We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment.
CR IP T
Keywords: teriflunomide; periodontitis; dental caries; leflunomide; multiple sclerosis.
Highlights:
Teriflunomide, a safe and effective drug for RRMS, is a mild immunosuppressant
-
The loss of periodontal host–microbe homeostasis causes caries and periodontitis
-
Poor oral hygiene might contribute to dental pathology, mainly in advanced MS cases
-
Whether teriflunomide might favour teeth loss in predisposed individuals is uncler
-
Dental care prior to and during teriflunomide therapy is recommended
ED
M
AN US
-
PT
Background
CE
Teriflunomide is a once-daily oral immunomodulant approved for the treatment of relapsingremitting multiple sclerosis (RRMS). Teriflunomide is the active metabolite of leflunomide, a drug
AC
used to treat rheumatoid arthritis since 1998. Teriflunomide inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in de novo pyrimidine synthesis, resulting in a cytostatic effect on proliferating activated T and B lymphocytes. Long-term extension studies have shown efficacy on clinical outcomes and Magnetic Resonance Imaging (MRI) parameters and a consistent safety profile. Pooled safety data from four placebo-controlled teriflunomide studies and their extensions showed that the most common adverse events were alanine aminotransferase increase, headache, diarrhea, hair thinning, and nausea (Comi et al, 2016). Tooth disorders, but not serious tooth
ACCEPTED MANUSCRIPT diseases, have been reported during teriflunomide treatment, most frequently toothache and teeth infections (EMA, Summary of product characteristics, 2018). We describe three cases of multiple teeth loss during teriflunomide treatment. Case reports Case 1: a 39-year-old woman, with RRMS, disease onset in 2004, treated for almost 10 years with
CR IP T
interferon beta. In October 2016, due to poor tolerability and compliance, she was switched to teriflunomide treatment.
At the beginning of teriflunomide treatment she experienced only mild alopecia. Four months later she complained of mandibular pain without gingival swelling, bleeding or dental abscess. After a
AN US
few days she experienced the sudden loss of 2 upper incisors without bleeding or trauma. In the following days she lost a molar in the maxillary dental arch, and another molar in the lower arch. The patient denied any other change in her life such as new drugs, new diet or different lifestyle.
M
She did not report nocturnal bruxism or smoking habit. Dental scans performed from 2009 to 2017 showed progressive dental pathology, poor oral hygiene and scarce therapeutic interventions.
ED
A dental assessment including orthopantomography and a subsequent dental computed tomography (CT) scan in fact revealed missing incisors, premolars and molars, several residual roots with
PT
periapical lesions, or periapical endodontic treatment and upper canines predisposed for transient,
CE
fixed prosthesis with possible thermal damage; distal class II and class III periodontitis in the lower arch, and profuse amounts of dental plaque.
AC
Suspecting a causal role of teriflunomide, we discontinued treatment and started the accelerated elimination procedure with cholestyramine. Investigating the patient’s dental medical history, we discovered that she had already performed other orthopantomographies in 2009, 2011 and 2014. These scans showed a parodontopathy with progressive dental loss/extraction in the absence of recent dental symptomatology. Case 2: a 52-year-old woman affected by MS since 1988. She had been previously treated with interferon beta for five years. She asked to be switched to an oral drug, due to poor tolerability of
ACCEPTED MANUSCRIPT injections. She started teriflunomide in October 2016 with no adverse events in the first period. After 1 year of treatment she experienced the sudden loss of five teeth (two canines and three premolars), in the absence of trauma or bleeding. The patient denied nocturnal bruxism or smoking habit. Dental assessment and orthopantomography showed profuse amounts of dental plaque and moderate chronic periodontisis. Teriflunomide was discontinued and the accelerated elimination
CR IP T
procedure with cholestyramine was performed. Case 3: a 56-year-old woman diagnosed with MS in 1988. She was treated with interferon beta for fifteen years, discontinued due to poor injection tolerability. She started teriflunomide in april 2016.
AN US
For eighteen months she did not report any adverse event. She subsequently experienced
hypermobility of several teeth without gum inflammation or pain, but she did not seek dental consult nor report the fact. After a few weeks she referred the loss of five teeth, followed by other seven teeth two days later, without traumatic events. She also denied smoking habit or nocturnal
M
bruxism. Teriflunomide was discontinued but the patient refused to undergo the accelerated
ED
elimination procedure.
PT
Discussion and conclusions
Odontogenic infections (periodontal disease and dental caries) are the commonest cause of teeth
CE
loss (Costalonga and Herzberg, 2014). The breakdown of oral tissue homeostasis favours the proliferation of pathobionts (i.e. P. gingivalis, T. denticola, Tannerella forsythia, and
AC
Aggregatibacter Actinomycetemcomitans for periodontitis and Streptococcus mutans and Lactobacillus for caries) and may be facilitated by congenital or acquired defects in host immunoregulatory mechanisms. Aging, systemic diseases (e.g. rheumatoid arthritis, multiple sclerosis, type 1 diabetes, osteoporosis, cardiovascular disease, obesity), environmental factors (e.g. smoking, diet and stress), and epigenetic modifications in response to environmental factors, alone or in combination, can contribute to unfavorable changes in the homeostatic balance (Hajishengallis, 2014). Dental caries cause progressive destruction of dental hard tissue, then affect
ACCEPTED MANUSCRIPT the pulp and eventually cause crown destruction. Periodontitis causes the destruction of the periodontal ligaments and the progressive loss of the alveolar bone around the teeth. If left untreated, both dental caries and periodontitis can lead to loss of teeth. Concomitant bruxism, common in many neurological conditions including MS, might play a role, but was not reported by our patients.
CR IP T
Despite alveolar bone resorption has never been associated with teriflunomide, tooth infections are considered common side effects of this drug; only in 1 female case in 2015 periodontitis was reported in association with teriflunomide treatment (EMA, Summary of product characteristics, 2018). Considering that in Case 1 medical history revealed a pre-existent dental pathology with
AN US
multiple caries and periodontitis, it is conceivable that, at least in this case, teriflunomide favoured local inflammation and subsequent dental loss in a predisposed subject.
Details about the dental medical history of the other 2 patients are not available. It is conceivable
M
that, but impossible to establish whether, the dental pathology was pre-existent to teriflunomide treatment. As symptom and teeth loss dynamics are similar, the presence of a neglected dental
ED
pathology is highly probable.
According to a recent review article about the effects of different disease modifying drugs,
PT
including leflunomide, of which teriflunomide is the active metabolite, on periodontal pathology in
CE
reumathoid arthritis patients (Romero-Sanchez, et al. 2017) methotrexate combined with leflunomide exhibits a higher extension of clinical attachment loss, which refers to the pathological
AC
detachment of collagen fibers from cemental surface, whereas anti-TNF-alpha therapy associated with methotrexate would be associated with a lower extension of clinical attachment loss. The authors speculate that the strong anti-proliferative activity of combined methotrexate and leflunomide treatment could reinforce immunosuppression and its impact on the gingival microbiota, concluding that this drug combination could have a deleterious effect on bone loss. This study suggests that leflunomide does not show a protective effect on periodontal disease, unlike anti-TNF-alpha treatment. In fact patients treated with leflunomide can present a worsening
ACCEPTED MANUSCRIPT of the clinical attachment loss, a sign of destructive periodontal disease. Similarly teriflunomide might play a role both in favouring dental pathology and hampering restorative mechanisms. In conclusion oral hygiene is critical in subjects treated with immunomodulant or especially immunosuppressive drugs. Even if further investigations are warranted to clarify the putative role of teriflunomide in dental loss, we recommend to assess and monitor possible concomitant tooth
AC
CE
PT
ED
M
AN US
CR IP T
morbidity, before and during teriflunomide treatment.
ACCEPTED MANUSCRIPT Bibliography Comi G. et al, 2016. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 5:97-104. http://dx.doi.org/10.1016/j.msard.2015.11.006. (Epub 2015 Nov 10).
CR IP T
Costalonga M, Herzberg MC. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol Lett. 2014;162:22-38. doi: 10.1016/j.imlet.2014.08.017. Epub 2014 Nov 8. Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response. Trends Immunol. 2014 Jan;35(1):3-11. doi: 10.1016/j.it.2013.09.001. Epub 2013 Oct 23.
AN US
Review. PMID:24269668
Romero-Sanchez C. et al, 2017. Is the Treatment with Biological or Non-biological DMARDS a Modifier of Periodontal Condition in Patients with Rheumatoid Arthritis? Curr Rheumatol Rev.
M
13(2):139-151. doi: 10.2174/1573397113666170407161520.
ED
EMA, Summary of product characteristics (last updated June 1, 2018) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
AC
CE
PT
_Product_Information/human/002514/WC500148682.pdf