You are on page 1of 16

Oral Diseases (2016) doi:10.1111/odi.

12507
2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved
www.wiley.com

REVIEW ARTICLE

The spectrum of orofacial manifestations in systemic


sclerosis: a challenging management
S Jung1,2,3, T Martin4,5,6, M Schmittbuhl7, O Huck1,2,8
1
ole de Medecine et de Chirurgie Bucco-Dentaires, H^opitaux Universitaires de Strasbourg, France; 2Faculte de Chirurgie Dentaire,
P^
Universite de Strasbourg, France; 3Center of Chronic Immunodeciency (CCI), Medical Center, Faculty of Medicine, University of
Freiburg, Germany; 4Service dImmunologie Clinique, H^opitaux Universitaires de Strasbourg, France; 5Faculte de Medecine,
Universite de Strasbourg, France; 6CNRS UPR 3572 Immunopathologie et Chimie Therapeutique, Institut de Biologie Moleculaire et
Cellulaire (IBMC), Strasbourg, France; 7Faculte de Medecine Dentaire, Universite de Montreal, Centre de Recherche du Centre
Hospitalier de lUniversite de Montreal (CHUM), Montreal, QC, Canada; 8INSERM, UMR 1109 Osteoarticular and Dental
Regenerative Nanomedicine, Faculte de Medecine, Federation de Medecine Translationnelle de Strasbourg (FMTS), France

Systemic sclerosis (SSc) is a rare multisystem connec- increased mortality with a 5-year survival rate estimated to
tive tissue disorder characterized by the triad fibrosis, be around 85% (Ioannidis et al, 2005). The incidence of
vasculopathy and immune dysregulation. This chronic SSc ranges from 0.6 to 2.4 per million per year in adult pop-
disease has a significant impact on the orofacial region ulation (Chifot et al, 2008). There are geographic dispari-
that is involved in more than two-thirds of the cases. ties in SSc prevalence, the latter being higher in the USA
SSc patients can show a wide array of oral manifesta- than in Europe for instance (Mayes et al, 2003; Chifot
tions, which are usually associated with a severe impair- et al, 2008; Ranque and Mouthon, 2010). Differences are
ment of the quality of life. They often present a also observed according to ethnicity, African Americans
decreased the salivary flow and a reduced mouth open- having a higher prevalence in comparison with European
ing that contribute substantially to the worsening of the Americans (Mayes et al, 2003). SSc occurs most commonly
oral health status. Therefore, SSc patients require speci- during the fth decade and preferentially affects women
fic and multidisciplinary interventions that should be ini- with a mean sex ratio around 3 to 1 (Chifot et al, 2008).
tiated as early as possible. The identification of specific
radiological and clinical signs at the early stage will Clinical manifestations and classications
improve the management of such patients. This study Diagnosis of SSc is mainly based on medical history and
reviews the wide spectrum of orofacial manifestations clinical examination. Patients can exhibit a wide range of
associated with SSc and suggests clues for the oral man- clinical features including skin thickening, calcinosis, lung
agement that remains challenging. brosis, arthralgia, myocardial lesions and renal insuf-
Oral Diseases (2016) doi:10.1111/odi.12507 ciency (Table 1). Raynauds phenomenon is almost
always the rst clinical manifestation of the disease
Keywords: systemic sclerosis; oral management; orofacial (Hachulla and Launay, 2011).
manifestations; fibrosis Despite the great phenotypic variability of the disease,
skin involvement is observed in the majority of SSc
patients (Krieg and Takehara, 2009). Pathological accumu-
lation of connective tissue components within the dermis
Introduction leads to the loss of cutaneous elasticity followed by
sclerosis i.e. thickening and hardening of the skin. The
Systemic sclerosis (SSc) is a rare multisystem connective skin becomes atrophic and is often tightly tethered to the
tissue disorder of unknown origin characterized by three underlying tissue (Czirjak et al, 2008). Sclerosis usually
main pathological features: extended brosis, vasculopathy, starts in the ngers, with progressive exion and retraction
and immunological abnormalities. SSc patients have a (sclerodactyly) (Poole, 1994). The modied Rodnan skin
decreased quality of life (Almeida et al, 2015) and an score (mRSS) is an approved tool that is widely used to
quantify skin involvement in SSc (Czirjak et al, 2008;
Krieg and Takehara, 2009). Cutaneous thickening is
Correspondence: Sophie Jung, P^ole de Medecine et de Chirurgie Bucco- assessed by palpation of the skin in 17 areas of the body,
Dentaires, H^opitaux Universitaires de Strasbourg, 1 place de lH^opital, which are scored from 0 to 3 (0 = normal, 1 = weak,
67091 Strasbourg, France. Tel: +33 3 88 11 69 56, Fax: + 33 3 88 11 69
17, E-mail: s.jung@unistra.fr 2 = intermediate and 3 = severe skin thickening), giving a
Received 27 April 2016; revised 10 May 2016; accepted 16 May 2016 possible range from 0 to 51. Fibrotic manifestations have
Orofacial manifestations in systemic sclerosis
S Jung et al

2
Table 1 Organ involvement in systemic sclerosis 2001 (LeRoy and Medsger, 2001). Internal organ involve-
ment can also be observed in the absence of skin thicken-
Organ/system ing in a rare form called SSc sine scleroderma (LeRoy and
involved Clinical manifestations
Medsger, 2001; Hachulla and Launay, 2011). The Ameri-
Skin and mucous Sclerosis (skin and mucosa) can College of Rheumatology/European League Against
membranes Atrophy (skin and mucosa) Rheumatism (ACR/EULAR) has developed a new set of
Pigmentation disorders (skin and mucosa) criteria that show high sensitivity and specicity, allowing
Calcinosis (subcutaneous calcications) an earlier diagnosis in particular of forms with very limited
Peripheral vascular Raynauds phenomenon or no skin brosis (Van den Hoogen et al, 2013).
system Telangiectasia
Ischemic ulcers (digital ulcers. . .)
Pathophysiology
Osteoarticular Polyarthralgia/arthritis
system Tenosynovitis, tendon retractions Fibrosis is the distinguishing hallmark of SSc (Ho et al,
Bone resorption 2014). Although the exact etiology is still unknown, accu-
Muscular system Myalgia mulation of extracellular matrix components is thought to
Myositis result from abnormal interactions between endothelial
Nervous system Trigeminal neuralgia cells, immune cells and broblasts leading to the produc-
Carpal tunnel syndrome tion of proinammatory and probrotic cytokines (e.g.,
Digestive system Esophagus: dysphagia, esophagitis, reduced TGF-b, IL-6, TNF-a) in a context of vascular hyper-reac-
peristalsis, gastroesophageal reux tivity and tissue hypoxia (Tamby et al, 2003; Scala et al,
(GERD). . . 2004; Lafyatis, 2014). Van Bon et al (2014) have shown
Stomach: gastroparesis. . . that CXCL4, an anti-angiogenic and probrotic chemo-
Small bowel: reduced peristalsis, bacterial
overgrowth. . .
kine, can be used as a predictive biomarker as high
Intestinal pseudo-obstruction syndrome, CXCL4 levels are correlated with severe complications
malabsorption. . . such as lung brosis and pulmonary hypertension.
Lungs Pulmonary arterial hypertension Autoimmunity plays an important role as evidenced by
Pulmonary brosis the presence of several SSc-specic autoantibodies (Steen,
Fibrosing alveolitis 2005). Anti-centromere antibodies are associated with lim-
Heart Pericarditis ited SSc while anti-topoisomerase I antibodies (anti-Scl
Pericardial brosis 70) and anti-RNA polymerase III are rather found in
Heart block patients with diffuse SSc (LeRoy and Medsger, 2001;
Myocardial brosis
Cardiac insufciency Chung and Utz, 2004; Steen, 2005; Dumoitier et al,
2014). The complexity of SSc pathogenesis and the diver-
Kidneys Scleroderma renal crisis (SRC) with kidney
failure sity of clinical features argue for a multifactorial process
Nephrosclerosis (Nikpour et al, 2010). The implication of genetic factors
Proteinuria is supported by an increased risk to develop the disease in
relatives of SSc patients. Although a higher incidence of
some genetic polymorphisms and HLA class II associa-
long been considered as untreatable, but this view has tions have been found (Arnett et al, 2010), only few cau-
changed over the past few years. Promising strategies sative variants have been identied yet (e.g., CD247,
include high-dose immunosuppression with autologous STAT4, IRF5) (Dieude et al, 2009, 2011; Rueda et al,
hematopoietic stem cell transplantation (Van Laar and Sul- 2009; Radstake et al, 2010; Dumoitier et al, 2014). The
livan, 2013) and a large number of disease-modifying combination of several single-nucleotide polymorphisms
therapies targeting proinammatory and probrotic cytoki- (SNPs) in different genes may therefore be required (Mar-
nes such as TGF-b (Antic et al, 2013). tin and Fonseca, 2011). Moreover, the low concordance
The gastrointestinal tract is the second most affected rate among monozygotic twins (4.2%) (Feghali-Bostwick
organ system and digestive manifestations can range from et al, 2003) highlights the important role played by envi-
abdominal bloating, gastroesophageal reux (GERD) to ronmental factors. Occupational exposure to silica and
severe weight loss due to malabsorption. The latter can be organic solvents has been reported to be implicated in SSc
the consequence of small bowel bacterial overgrowth that pathogenesis (Dospinescu et al, 2013; Marie et al, 2014).
is promoted by reduced peristaltism (Savarino et al, 2014). Different epigenetic changes have also been implicated in
Systemic sclerosis is usually classied into two major SSc pathophysiology (Broen et al, 2014).
subsets based on the extent of skin brosis. In limited cuta- As orofacial involvement in SSc is frequently under-
neous SSc (lcSSc), skin involvement is restricted to face, diagnosed, our aim was to describe the wide spectrum of
neck and area distal to elbows and knees whereas in dif- clinical manifestations that can be observed and to give an
fuse cutaneous SSc (dcSSc), skin brosis also involves the update on the oral management of SSc patients.
proximal limbs and/or the trunk (LeRoy et al, 1988).
dcSSc is associated with a more severe clinical course
characterized by internal organ involvement. Criteria for an Materials and methods
additional early or limited subset of SSc (lSSc)character- Search strategy
ized by Raynauds phenomenon and SSc-specic autoanti- A literature search was performed using PubMed without language and
bodies but without skin manifestationswere proposed in time restriction. The following search strategy was used: (systemic

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

3
sclerosis OR scleroderma, systemic) AND, respectively, orofacial, chewing, and also makes oral hygiene and dental
oral, mouth, microstomia, oral mucosa, xerostomia, resorption, treatment challenging because of the limited access. A
temporomandibular joint, periodontal disease, periodontal ligament,
caries, dental treatment, implant. smaller interincisal distance was found to be signicantly
correlated with the overall disease activity, extent of
cutaneous involvement, and presence of anti-
Orofacial manifestations topoisomerase I antibodies (Baron et al, 2014b).
Systemic sclerosis has a major impact on the orofacial
region that is affected in approximately 80% of SSc Telangiectases. Telangiectases that are the consequence of
patients. However, orofacial involvement remains under- the dilatation of small vessels in the skin manifest as
diagnosed and the corresponding symptoms are often small red macular areas and reect abnormal
overshadowed by severe systemic manifestations (Del neoangiogeneis. They represent a characteristic feature of
Rosso and Maddali-Bongi, 2014). SSc as they frequently (7087.5%) affect facial skin,
especially cheeks, nose, and lips (Figure 1), but also the
Skin and mucosa oral mucosa (lateral border of tongue and buccal mucosa
Facial appearance. Skin brosis affects rapidly the face, of cheek) (Nagy et al, 1994; Vincent et al, 2009; Chu
leading to changes in personal appearance (Sticherling, et al, 2011).
2012a). Subcutaneous collagen deposition in facial skin
results in a smooth, tight, expressionless mask-like facies Intra-oral mucosal manifestations. Submucous brosis
with disappearance of wrinkles, perioral furrows and atrophy induces atrophy and subsequent fragility and sensitivity of
of nasal alae (pinched nose) (Figure 1) (Albilia et al, 2007; the oral mucosa (including gingiva and taste buds) that
Sticherling, 2012a). Hence, facial changes belong to the most becomes pale and sclerotic. Certain manifestations of the
worrying aspects of the disease as they affect esthetics and disease such as denutrition, GERD, vitamins B9 and B12
can lead to the loss of individual physiognomy (Amin et al, deciencies, exocrine pancreatic insufciency, or small
2011; Del Rosso and Maddali-Bongi, 2014). SSc patients bowel involvement associated with bacterial overgrowth
frequently have a very similar appearance and one of the can worsen mucosal atrophy (Alantar et al, 2011). SSc
most challenging aspect is the self-perception of their patients frequently complain of burning mouth syndrome
modied appearance that may have a negative impact on or dysesthesia. Flattening of the palate, shortening of the
their social interactions (Amin et al, 2011). Other common uvula, mucosal crenations, and impaired tongue mobility
skin manifestations include hypo- and hyperpigmentation of due to tongue brosis or to lingual frenum abnormalities
certain cutaneous areas, hypohidrosis, and modications of (reduced length and increased thickness) can also be
the lip color (Krieg and Takehara, 2009). observed (Eversole et al, 1984; Vincent et al, 2009;
Sticherling, 2012a,b; Frech et al, 2016). Furthermore, the
Microstomia. Sclerosis of lips and of skin around the tongue can be affected by Raynauds phenomenon (Casey
mouth leads to reduced mouth opening (microstomia) and and Lawton, 1971; Bridges and Kelly, 2002).
width (microcheilia) (Figure 1). The decrease of the
interincisal distance was conrmed in a large cohort of Salivary gland involvement
163 SSc patients compared with 231 controls (37.7 mm vs Xerostomia that represents the subjective sensation of a
44.3 mm, P < 0.0001) (Baron et al, 2014a). Microstomia dry mouth (Nape~nas et al, 2009) is a common feature of
interferes considerably with oral functions, especially SSc with a prevalence varying from 25% to 71.2% (Wood
and Lee, 1988; Nagy et al, 1994; Avouac et al, 2006; Sal-
liot et al, 2007; Vincent et al, 2009; Chu et al, 2011;
Kobak et al, 2013). In SSc, xerostomia is not only a sub-
jective sensation, but it is usually the consequence of an

Figure 1 Typical facial features in a patient with diffuse SSc. Mask-


like facies with disappearance of wrinkles and atrophy of nasal alae
(pinched nose) secondary to subcutaneous collagen deposition in facial
skin, reduced mouth opening (microstomia) and width (microcheilia) due
to sclerosis of the lips and telangiectases, especially on nose and cheeks Figure 2 Xerostomia, mucosal atrophy of the tongue, and angular
that are the consequence of the dilatation of small vessels in the skin cheilitis (candidiasis) in a patient with diffuse SSc

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

4
objective reduction in the quantity of the saliva produced. 2007). When it is associated with Sjogrens syndrome,
SSc patients salivary ow was assessed in different stud- SSc seems to be less severe. Indeed, Sjogrens syndrome
ies (Andonopoulos et al, 1989; Nagy et al, 1994; Chu is more frequently observed in patients with limited SSc
et al, 2011; Kobak et al, 2013; Baron et al, 2014a,b). The (Avouac et al, 2006; Salliot et al, 2007; Vincent et al,
largest cohort study (163 SSc patients vs 231 controls), 2009). Lung brosisone of the most severe complica-
performed recently by the Canadian Scleroderma Research tions of limited SScaffects only 11% of the patients
Group, revealed that the disease was associated with a with both SSc and Sjogrens syndrome (vs more than 30%
lesser saliva production (63.19 mg min 1 vs of patients with SSc alone) (Salliot et al, 2007). The asso-
1
147.52 mg min ) (Baron et al, 2014a). SSc patients have ciation of Sjogren syndrome with SSc could reect a
lower stimulated and resting salivary ow rates than unaf- spreading of autoimmunity as those patients are more
fected individuals and also lower salivary pH values. This prone to develop a third autoimmune disease (e.g., pri-
might be responsible for an increased caries risk, difcul- mary biliary cirrhosis) (Salliot et al, 2007). Some studies
ties in wearing prostheses, altered taste sensation, and also report an enlargement of the parotid gland in about
pathological conditions such as burning mouth syndrome, 20% SSc patients (Andonopoulos et al, 1989; Nagy et al,
mucosal atrophy, or candidiasis (Figure 2) (Chu et al, 1994).
2011). However, decreased saliva production has not been
correlated with disease severity (Wangkaew et al, 2006; Bone resorption and temporomandibular joint involvement
Baron et al, 2014b). Xerostomia can be exacerbated by Involvement of bones and joints is common in SSc
GERD, severe microstomia, especially when patients are patients but in the jaws, only the mandible is affected.
unable to close their lips, and by certain medications (e.g., Mandibular osteolysis can be observed in 6.6 to 46.7% of
antidepressants). SSc patients (Seifert et al, 1975; Marmary et al, 1981;
Salivary defense system also seems to be affected (Knas Wood and Lee, 1988; Rout et al, 1996; Marcucci and
et al, 2014). Increased production of reactive oxygen spe- Abdala, 2009; Vincent et al, 2009; Leung et al, 2011;
cies can be responsible for the direct activation of brob- Dagenais et al, 2015). There is no clear correlation
lasts and the stimulation of TGF-b secretion. Moreover, it between the incidence of the mandibular resorption and
can also worsen the development of brosis by altering the severity or the progression of the disease (Marmary
the balance between proteases and anti-proteases et al, 1981; Wood and Lee, 1988; Baron et al, 2015a,b).
(Zalewska et al, 2014). Mason et al have observed an Although this condition tends to affect patients with a
increased mast cell population in the salivary glands from longer disease mean time (7.29 years) (Marcucci and
SSc patients. Their products are able to stimulate brob- Abdala, 2009), it can occur at any time during the course
last proliferation and collagen synthesis. Changes in the of SSc (Seifert et al, 1975; Benitha et al, 2002). The
expression of TGF-b isoforms by glandular broblasts gonial angles are the most frequently affected sites
were also found with a downregulation of TGF-b3 that (37.6%), followed by the condylar heads (20.8%), the
normally limits the deposition of brous tissue during coronoid processes (20.0%), and the posterior border of
healing process (Shah et al, 1995; Mason et al, 2000). the ramus (14.4%). Bilateral condylysis can be found in
Hebbar et al have shown that E-selectinan adhesion 713.7% of the cases (Haers and Sailer, 1995; Rout et al,
molecule specic to activated endothelial cellswas 1996; Vincent et al, 2009; Doucet and Morrison, 2011).
expressed in the salivary glands of patients with Ray- Temporomandibular joint (TMJ) disorders are also fre-
nauds phenomenon before the onset of clinical skin quently associated with the disease (Vincent et al, 2009;
changes. TNF-a secretion by mast cells that also inltrate Matarese et al, 2016; Pischon et al, 2016) and can be the
the salivary tissues at the early onset of the disease con- consequence of mandibular resorption. The prevalence of
tributes to endothelial cell activation (Hebbar et al, 1995, clinical signs of TMJ dysfunction (pain, TMJ sounds,
1996, 1998). impairment of mandibular movements. . .) and characteris-
Xerostomia in SSc seems to be due to the brotic pro- tic magnetic resonance imaging (MRI) ndings (disk,
cess rather than to lymphocytic sialadenitis, the latter articular surface and bone changes) is higher in SSc
being a typical feature of Sj ogrens syndrome. In SSc, patients compared to healthy controls (Matarese et al,
salivary gland brosis develops around capillaries and 2016; Pischon et al, 2016).
excretory ducts. Capillary wall sclerosis induces functional The pathogenesis of bone resorption in SSc is not well
abnormalities by reducing vascular permeability whereas understood yet. The current hypothesis is that osteolysis
periductal brosis impairs salivary excretion (Hebbar et al, could be the consequence of a multifactorial process due
1994; Avouac et al, 2006). Sj ogrens syndrome is found to the combination of microvasculopathy with pressure
in only 14% to 33.9% of SSc patients, depending on the ischemia secondary to skin thickening and muscular atro-
diagnostic criteria (Cipoletti et al, 1977; Osial et al, 1983; phy (Benitha et al, 2002; Auluck et al, 2005). Osteolytic
Coll et al, 1987; Drosos et al, 1988; Hebbar et al, 1994; lesions coincide with the attachment zones of the facial
Avouac et al, 2006; Kobak et al, 2013). It is an autoim- muscles such as condyles (lateral pterygoid insertion),
mune epithelitis (Skopouli and Moutsopoulos, 1994) that coronoid processes (temporal muscle insertion), and, espe-
can either occur alone (primary Sj ogrens syndrome) or cially, mandibular angles (masseter insertion) (Benitha
can be associated with other autoimmune disorders (sec- et al, 2002; Doucet and Morrison, 2011) that are usually
ondary Sj ogrens syndrome). Salliot et al have demon- the last areas affected by the physiological resorption pro-
strated that Sjogrens syndrome is not secondary to SSc cess (Pogrel, 1988; Auluck et al, 2005). Ramon et al sug-
but can be associated with the disease (Salliot et al, gested that SSc vasculopathy may preferentially affect the

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

5
Table 2 Summary of the studies reporting tooth decay in SSc patients

Number of missing Number of decayed Caries experience Number of lled


Study Groups teeth teeth DMFT/S teeth

Wood and Lee (1988) SSc: n = 31 ND 3.2  4.3 DMFS: 95  37 ND


Controls: n = 30 1.8  2.6 DMFS: 77  35
SSc with xerostomia: n = 24 4.9  6.1 DMFS: 101  36
Nagy et al (1994) SSc: n = 25 ND ND DMFT: 21.9  6.5 ND
Controls: n = 15 DMFT: 18.7  6.1
Chu et al (2011) SSc: n = 40 4.1  5.5 (ns) 2.1  2.4 DMFT: 10.5  7.8 4.3  4.2
Controls: n = 40 4.9  5.5 1.5  2.5 DMFT: 11.6  7.0 5.2  4.2
Baron et al (2014a) SSc: n = 163 7.9  9.4 (ns) 0.9  1.8 ND 11.2  6.1
Controls: n = 261 5.7  7.0 0.6  1.8 11.8  5.8
Pischon et al (2016) SSc: n = 58 5.5 (2.010.0) (a) ND DMFT: 17.66  6.00 ND
Controls: n = 52 5.0 (0.58.5) DMFT: 18.12  6.85

Values are indicated as mean  standard deviation except for (a) where they are indicated as median (interquartile range). Statistically signicant results
are highlighted in bold.
ND: not determined; ns: not signicant.

small muscular branches of the internal maxillary artery tomography (CBCT) approach in a patient with diffuse
that provide vascularization of the sites commonly SSc (Jung et al, 2013).
involved by bone resorption. Those vascular abnormalities
could therefore account for the observed ischemic oste- Dental involvement
olytic lesions (Ramon et al, 1987). Muscles that often Xerostomia and GERD are responsible for a decrease of
become atrophic and bulkier secondary to increased bro- the salivary pH. Indeed, a low pH compromises the
sis exert a permanent pressure on the bone (Auluck et al, buffering capacity of the saliva and can induce enamel
2005). Skin hardening may also amplify pressure ischemia and dentin erosion. It also induces a modication of the
with subsequent bone resorption, especially of the oral microora that becomes pathogenic, increasing caries
mandibular angles (Pogrel, 1988; Auluck et al, 2005). susceptibility (Albilia et al, 2007). The Canadian Systemic
This hypothesis is supported by the recent work of Baron Sclerosis Oral Health study, which describes the largest
et al that showed an inverse correlation between interden- SSc cohort, reveals that SSc patients had signicantly
tal distance and the number of erosions (Baron et al, more decayed teeth compared to healthy controls (0.88 vs
2015a). Severe resorption can, in some cases, induce pain- 0.59, P = 0.0465) (Baron et al, 2014a). Two other studies
ful trigeminal neuropathy due to the compression of the (Wood and Lee, 1988; Chu et al, 2011) also reported
inferior alveolar nerve (Fischoff and Sirois, 2000). Ero- more untreated decayed teeth in SSc patients than in con-
sions of the condyles can also lead to degenerative disease trols (respectively 3.2 vs 1.8 and 2.1 vs 1.5), but the dif-
of the TMJ that is frequently associated with pain and ference was only signicant for patients with associated
dysfunction (Haers and Sailer, 1995; Mugino and Ike- xerostomia (4.9 vs 1.8; P < 0.05) (Wood and Lee, 1988)
mura, 2006; Doucet and Morrison, 2011; Delantoni and (Table 2).
Matziari, 2015; MacIntosh et al, 2015). Regarding tooth loss, no study highlighted a statistical
difference between SSc patients and healthy controls (Chu
Calcinosis et al, 2011; Baron et al, 2014a; Pischon et al, 2016).
Dystrophic calcinosis is a common nding in SSc. However, a trend toward an increased number of missing
Although it is usually associated with the limited form of teeth has been observed in recent studies (Baron et al,
the disease, about 25% of all SSc patients are affected 2014a; Pischon et al, 2016). Interestingly, Baron et al
(Boulman et al, 2005; Reiter et al, 2011). Calcinosis is found a relationship between reduced manual dexterity
characterized by the deposition of hydroxyapatite and (sclerodactyly) and the number of missing teeth (Baron
amorphous calcium phosphate nodules in the skin, subcu- et al, 2014a,b). Indeed, limitation in mouth opening, espe-
taneous tissues, and periarticular regions (Boulman et al, cially when it is associated with sclerodactyly, may impair
2005; Reiter et al, 2011). Calcications are also frequently dental hygiene and result in a rapid deterioration of oral
observed at sites that are exposed to recurrent microtrauma health.
and where tissue integrity has been compromised (Puga-
shetti et al, 2011; Reiter et al, 2011). To our knowledge, Periodontal involvement
only 4 SSc patients presenting with calcinosis in the facial Periodontal disease. SSc is associated with an impaired
area have been reported so far (coronoid process of mand- periodontal health (Wood and Lee, 1988; Chu et al, 2011;
ible, along mandibular arch, nose, TMJ) (Temekonidis and Leung et al, 2011; Mayer et al, 2013; Baron et al, 2014a;
Drosos, 2001; Alp oz et al, 2007; Chikazu et al, 2008; Elimelech et al, 2015; Pischon et al, 2016). Most of the
Nestal-Zibo et al, 2009). Calcications within the peri- studies showed that SSc patients have higher periodontal
odontal ligament space (PDL) and the pulp chamber that indices (probing depth (PD), plaque index (PI), gingival
may also be related to the general spectrum of dystrophic index (GI), and bleeding on probing (BOP)) than controls
calcinosis have been evidenced by cone-beam computed (Leung et al, 2011; Mayer et al, 2013; Baron et al,

Oral Diseases
6

Oral Diseases
Table 3 Summary of the studies reporting periodontal disease in SSc patients

Community
Gingival Clinical Attachment Periodontal Index
Study Groups Pocket Depth (PD) Bleeding Inammation Plaque Loss (CAL, mm) (CPI)

Wood and SSc: n = 29 PD score (a): Gingivitis score ND Plaque score (c): ND ND
Lee (1988) 10.1  8.9 mm (b): 8.8  4.2 13.2  8.5
Controls: n = 28 PD score: Gingivitis Plaque
3.9  5.3 mm score: 5.4  5.6 score: 12.3  9.0
Nagy et al SSc: n = 25 2.8  0.7 mm ND Gingivitis score PI% (d): 82  15 ND ND
(1994) Controls: n = 15 2.4  0.8 mm (%): 65  22 PI%: 68  25
Gingivitis score
(%): 58  27
Chu et al SSc: n = 40 % with >3 mm: 76 ND ND ND ND CPI 0: 0%, CPI 12:
(2011) Controls: n = 40 % with >3 mm: 55 23%, CPI 34: 77%
CPI 0: 0%, CPI 12:
45%, CPI 34: 55%
Leung et al SSc: n = 36 2.52  0.58 mm BOP%:78.4  19.6 ND PI% (d): 65  12.5 3.19  0.94 ND
(2011) Controls: n = 36 1.92  0.44 mm BOP%:49.3  22.6 PI%: 69.3  18.0 3.17  1.29
S Jung et al
Orofacial manifestations in systemic sclerosis

Mayer et al SSc: n = 12 3.74  0.36 mm FMBS%: 37.83  13.5% GI: 1.51  0.53 PI: 1.45  0.54 ND ND
(2013) Controls: n = 12 3.47  0.33 mm FMBS%: 30.08  16.9% GI: 1.21  0.67 PI: 1.41  0.82
Baron et al SSc: n = 163 Nb with PD>3 mm ND ND ND ND ND
(2014a) or
CAL 5.5 mm:
5.23  5.63
Controls: n = 231 Nb with PD>3 mm
or
CAL 5.5 mm:
2.94  4.11
Elimelech SSc: n = 20 3.74  0.32 mm BOP%: 37  14.8 GI: 1.53  0.34 PI: 1.47  0.40 ND ND
et al (2015) Controls: n = 20 3.35  0.31 mm BOP%: 27  90 GI: 1.12  0.54 PI: 1.24  0.61
Pischon et al SSc: n = 58 2.99  0.59 mm BOP: 0.29 (0.20.45) (e) GI: 0.16 (0.070.40) (e) PI: 0.88 (0.461.73) (e) 4.01  1.04 mm ND
(2016) Controls: n = 52 3.16  0.58 mm BOP: 0.41 (0.230.58) GI: 0.49 (0.260.73) PI: 0.35 (0.201.58) 3.4  0.89 mm

Values are indicated as mean  standard deviation unless stated otherwise. Statistically signicant results are highlighted in bold. (a) PD scores of 0, 1, or 2 were allocated for gingival sulcus depths of
less than 3 mm, 3 mm, or greater but less than 5 mm, and 5 mm or greater, and the scores were summed (b) sites were scored as 1 or 0 depending on gingival bleeding after periodontal probing and the
scores were summed; (c) sites were scored as 1 or 0 depending on the presence or absence of visible plaque and the scores were summed; (d) sites with detectable plaque (%); (e) values are indicated as
median (interquartile range). BOP: bleeding on probing (%); CAL: clinical attachment loss; CPI: Community Periodontal Index (CPI 0 = healthy, CPI 1 = gingivitis, CPI 2 = calculus, CPI 3 = pockets
45 mm, CPI 4 = pockets 6 mm); FMBS: Full-mouth bleeding score (%); GI: Gingival Index (GI); ND: not determined; ns: not signicant; PI: Plaque Index (02).
Orofacial manifestations in systemic sclerosis
S Jung et al

7
Table 4 Summary of the studies reporting widening of the periodontal ligament space (PLS) in SSc patients

Number of patients Number/percentage of teeth


Study Groups PLS widening (mm) with PLS widening with PLS widening

White et al (1977) SSc=35 ND n = 13 (37%) ND


Rowell and Hopper SSc: n = 30 ND 30% ND
(1977) Controls: n = 30
Marmary et al (1981) SSc: n = 19 0.15 n = 19 (100%) ND
Objective Controls: n = 8 0.08
measurements
Alexandridis and SSc: n = 26 Maxilla: 65% SSc patients 32 to 35% of PLS around teeth in
White (1984) Controls: n = 26 0.295  0.053 have a mean PDL patients with progressive SSc are >
Objective 0.224  0.021 width > controls controls
measurements Mandibula:
0.290  0.043
0.219  0.020
Mean: 0.292  0.048
0.220  0.019
Janssens et al (1987) SSc: n = 47 ND 59.2% ND
Controls: n = 359 (SLE+RA patients) 0% (SLE)-4% (RA)
Wood and Lee (1988) SSc: n = 24 0.18  0.05 mm ND ND
Objective SSc with mandibular erosions: n = 6 0.22  0.22 mm
measurements Controls: n = 28 0.11  0.01 mm
Rout et al (1996) SSc: n = 21 ND 33% 14/214 teeth (7.5%)
Vincent et al (2009) Limited SSc: n = 20 ND n = 7 (35%)
Diffuse SSc: n = 10 n = 3 (30%)
Leung et al (2011) SSc: n = 36 (236 teeth) 0.360  0.057 ND ND
Objective Controls: n = 36 (240 teeth) 0.330  0.032
measurements
Jagadish et al (2012) SSC: n = 6 ND 66% ND
Dagenais et al (2015) SSc: n = 159 Mean: 0.16  0.06 n = 52 (37.96%) 1.08  2.57
Objective Controls: n = 222 0.15  0.04 n = 24 (11.11%) 0.16  0.49
measurements Periapical PLS: (1 tooth)
0.2  0.1
0.15  0.04

Values are indicated as mean  standard deviation. Statistically signicant results are highlighted in bold.
ns, not signicant; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

2014a; Elimelech et al, 2015; Pischon et al, 2016) diffuse form of SSc and/or an impaired manual dexterity
(Table 3). Three recent studies found a positive has been observed (Yuen et al, 2014). In contrast, the
correlation between SSc and periodontitis (increased large casecontrol study of Baron et al did not found
number of teeth with PD >3 mm or clinical attachment any relationship between periodontal disease and global
level 5.5 mm, increased PD, and increased periodontal disease severity, reduced saliva secretion or decreased
attachment loss, respectively) (Leung et al, 2011; Baron mouth opening, and sclerodactyly that could impede
et al, 2014b; Pischon et al, 2016). Periodontal disease oral hygiene (Baron et al, 2014b). Pischon et al
and SSc share many common features. They are demonstrated very recently a higher periodontal clinical
characterized by a comparable disease course (prominent attachment loss that remained statistically signicant
acute inammation during early stages and brosis, after adjustment for age, gender, education, smoking
atrophy, and tissue destruction during more advanced status, and alcohol consumption but also after
stages) and by similar etiopathogenic pathways adjustment for plaque accumulation (PI) (Pischon et al,
(microvascular alterations, brosis, and inammation with 2016). This observation suggests that the impaired oral
increased serum levels of proinammatory cytokines) hygiene may only partially account for the higher
(Scala et al, 2004; Elimelech et al, 2015). The etiology prevalence of periodontal disease in SSc patients.
of periodontal disease in SSc is most likely multifactorial Despite the higher periodontal attachment loss, the other
but remains elusive (Baron et al, 2014b). Indeed, various clinical parameters (PD, BOP, and GI) were not
disease-related factors, such as xerostomia that promotes increased. Chronic brosis and microvascular alterations
the development of dental plaque, impaired oral hygiene that are hallmarks of the disease may mask the signs of
due to reduced manual dexterity and mouth opening or acute inammation, making the diagnosis of periodontal
microvascular alterations that can lead to tissue ischemia disease more difcult in SSc patients (Pischon et al,
could account for the higher prevalence of periodontal 2016). Fibrosis, in particular when it involves the frena,
disease in SSc patients (Yuen et al, 2014). According to can promote gingival recession (Eversole et al, 1984;
Yuen et al, a correlation between gingivitis and the Jagadish et al, 2012).

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

8
Using capillaroscopy, Scardina et al reported microvas- pathogenic pathways in the skin and in the periodontal
cular abnormalities in the gingival tissues of SSc tissues (Elimelech et al, 2015).
patients. Although the number of capillaries was reduced, The combination of those factors with impaired oral
they were characterized by an increased diameter and hygiene, due to reduced mouth opening and manual dex-
tortuosity (Scardina et al, 2005). Ozcelik et al have terity, may lead to a more rapid progression of periodonti-
shown that the histological inammatory inltrate is tis in SSc patients (Elimelech et al, 2015). Further studies
more intense in gingival biopsy samples from SSc are needed to better characterize the association between
patients than in controls whereas the expression of vascu- SSc and periodontal disease.
lar endothelial growth factors (VEGF) is signicantly
lower (Ozcelik et al, 2008). Conversely, Matarese et al Periodontal ligament widening. Thickening of the
(Matarese et al, 2012) observed an increased VEGF periodontal ligament (PDL) was rst described in SSc
expression in gingival tissue and periodontal samples patients by Stafne and Austin in 1944 (Stafne and Austin,
from SSc patients and suggested that this chronic overex- 1944). Periodontal ligament space (PLS) widening is one
pression could impair the formation of new vessels of the most common radiologic ndings in SSc
(Koch and Distler, 2007; Matarese et al, 2012). Despite (Figures 3a,b and Table 4). Indeed, it can be observed in
being contradictory, these observations demonstrate that more than one-third of the patients (Rowell and Hopper,
the defective vascularization, which is characteristic of 1977; White et al, 1977; Marmary et al, 1981; Janssens
the disease, also involves the periodontal tissues and can et al, 1987; Wood and Lee, 1988; Rout et al, 1996;
therefore play a role in the pathogenesis of periodontal Vincent et al, 2009; Leung et al, 2011; Jagadish et al,
diseases, impairing the inammatory response against 2012; Dagenais et al, 2015). However, most of the
periodontal pathogens and decreasing the healing capaci- descriptions are based on case reports or on subjective
ties. Higher TNF-a levels have been measured in gingi- analysis of X-rays (Rowell and Hopper, 1977; White
val crevicular uid from SSc patients (Mayer et al, et al, 1977; Janssens et al, 1987; Rout et al, 1996;
2013; Elimelech et al, 2015). The latter were not corre- Vincent et al, 2009; Anbiaee and Tafakhori, 2011;
lated with periodontal parameters but with modied Rod- Jagadish et al, 2012; Bali et al, 2013). To our knowledge,
nan skin score, suggesting the existence of similar there are few studies presenting objective PLS
measurements in SSc patients (Marmary et al, 1981;
Alexandridis and White, 1984; Wood and Lee, 1988;
Leung et al, 2011; Dagenais et al, 2015). Leung et al
showed that SSc patients have a signicant widening of
the PLS compared to healthy controls (0.360  0.057 mm
in SSc patients vs 0.330  0.032 mm in controls;
P = 0.005). However, the main limitation of this study is
related to the measurements that have been performed on
panoramic radiographs, known to be prone to image
distortion (Leung et al, 2011). In the recent Canadian
study that assessed 159 SSc patients and 222 controls,
PLS widening affected at least one tooth in 38% of SSc
patients compared with 11.1% of controls. The difference
remains signicant after adjustment for age, gender,
ethnicity, education, and smoking status, in particular in
premolars and molars (Dagenais et al, 2015). PLS
thickening can be observed in every group of teeth but
posterior areas are more frequently involved (Stafne and
Austin, 1944; White et al, 1977; Marmary et al, 1981;
Alexandridis and White, 1984; Anbiaee and Tafakhori,
2011; Dagenais et al, 2015).
Although the exact mechanisms still remain unclear,
different hypotheses have been suggested. The width of
the roots is equivalent in SSc patients and control sub-
jects, suggesting that PLS widening occurs at the
expense of the alveolar bone (Wood and Lee, 1988).
According to Auluck et al, the masticatory muscles
become bulkier secondary to brosis leading to increased
occlusal forces (occlusal trauma), which may result in
PLS widening (Auluck, 2007). This hypothesis could
explain the increased prevalence of PLS widening around
posterior teeth. However, an opposite hypothesis has also
Figure 3 Cone-beam computed tomography (CBCT) of a patient with
diffuse SSc: mandibular axial (a) and cross-sectional (b) views showing been proposed, suggesting that increased brosis of the
periodontal ligament space widening that affects particularly premolars masticatory muscles and of the supplying vessels, that is
(black arrows) and molars responsible for muscular atrophy, rather reduces the

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

9
mastication forces leading to PLS widening (Mehra, 1982; Hagen et al, 1990; Amaral et al, 2013). In their retro-
2008). Indeed, occlusal traumatisms can induce angular spective analysis on 442 SSc patients, Farrel and Medsger
bone defects and tooth mobility that are usually not described an association with TN in 4% of cases (16
observed in teeth affected by PLS enlargement during patients) (Farrell and Medsger, 1982). TN can be associated
SSc (Wood and Lee, 1988; Mehra, 2008; Jagadish et al, with limited or with diffuse SSc (Jimenez-Moreno et al,
2012). The lamina dura and the gingival attachment are 1998; Mohyuddin et al, 2009) and may occur prior to the
intact in most cases (Anbiaee and Tafakhori, 2011). development of SSc clinical signs, as suggested by Scardina
Baron et al (2015a) found a signicant correlation et al (2002), who reported four cases with medical history
between the number of teeth affected by PLS thickening containing past TN preceding the onset of SSc by several
and the global disease severity. The enlargement of the years.
ligament may therefore reect the generalized overpro- Sensory involvement is predominant in TN that rarely
duction of collagen and the brotic process observed in affects the muscles of mastication. It usually involves the
SSc (Baron et al, 2015a). The PDL contains mainly col- V2 (maxillary) and V3 (mandibulary) nerves (Farrell and
lagen bers and also cells including broblasts. As in Medsger, 1982), but it can sometimes affect all three divi-
the other connective tissues, broblast dysfunction can sions of the trigeminal nerve. TN can be uni- or bilateral
lead to an excessive collagen production with subsequent (Jimenez-Moreno et al, 1998; Mohyuddin et al, 2009) and
resorption of the alveolar bone around the roots, leading is frequently associated with pain, dysesthesia or even
to the enlargement of the PLS (Baron et al, 2015a). anesthesia that can involve the oral cavity (Denton and
PLS widening can be one of the rst radiographic signs Ong, 2004).
of SSc (Anbiaee and Tafakhori, 2011). Baron et al Neuropathy may result from ischemic lesions of the
(2015a) found a correlation between short disease duration peripheral nerves. Some authors suggested that small arter-
and enlarged PDL, suggesting that the increased width of ies providing blood supply to peripheral nerves can be
PLS could be more important during the early stages of affected as microvascular lesions may alter nerves func-
the disease. Further studies are needed to assess whether tion (Lee et al, 1984; Denton and Ong, 2004). Autoimmu-
this radiographic sign could be used as a potential diag- nity could also play a role with the production of specic
nostic marker and in particular to determine a cutoff value. autoantibodies that may target the nervous system (Denton
In the absence of any other clinical manifestations, alterna- and Ong, 2004). Moreover, autoimmune response against
tive aetiologies of PLS widening such as occlusal trauma, basement membrane antigens could account for vascular
recent orthodontic treatment, or periapical disease should injury, leading to peripheral nerves dysfunction (Jimenez-
be of course considered (Prasad and Pai, 2012). Moreno et al, 1998; Denton and Ong, 2004). Jimenez-
To our knowledge, there are no clinical consequences Moreno et al propose that TN could be regarded as an
of PLS widening and the affected teeth require no inter- entrapment neuropathy due to the inammatory response
vention. Indeed, Baron et al (2015a) did not evidence any with edema (Jimenez-Moreno et al, 1998; Ribeiro et al,
correlation between thickening of the PLS and periodontal 2009). Local compressive nerve damage should also be
disease or the number of missing teeth. However, considered in the pathogenesis of some TN cases as sug-
unawareness of this specic radiographic feature or confu- gested by Fischoff et al who described a case of severe
sion with other pathological processes (endodontic infec- mandibular resorption resulting in a painful neuropathy
tion, severe periodontal disease. . .) can lead to diagnosis due to the compression of the inferior alveolar nerve
and treatment misconducts (unwarranted teeth extractions), (Fischoff and Sirois, 2000). On the other side, Farrell and
increasing the mouth handicap. Medsger found that the proportion of patients with severe
facial brosis is equivalent in both groups with TN or
Neurologic involvement without TN, suggesting that the neuropathy may not be
Neurologic manifestations were previously considered as the consequence of direct extension of brosis to the
rare events and rather as complications of other organs trigeminal nerve (Farrell and Medsger, 1982).
damage. However, evidence of primary nervous system
involvement in SSc is currently increasing (Amaral et al, Oral cancer risk
2013). Moreover, neurologic manifestations may be under- Systemic sclerosis has been associated with an increased
diagnosed as they can be easily confused with symptoms risk of cancer, especially of the lung, liver, bladder, and
related to skin hardening (Ribeiro et al, 2009). hematologic system (Derk et al, 2006; Kuo et al, 2012;
Trigeminal neuropathy (TN), a chronic condition affect- Szekanecz et al, 2012; Onishi et al, 2013). Men have a
ing the fth cranial nerve, is the most frequently reported higher risk than women (Onishi et al, 2013). Organs
peripheral nervous system manifestation. Indeed, the 73 TN affected by extensive brosis such as lungs may be prone
associated with SSc that have been documented in the litera- to cancer development whereas increased risk for lympho-
ture account for more than 15% of all reported peripheral proliferative diseases (non-Hodgkins lymphomas) may
nervous system events (Amaral et al, 2013). However, the rather be the consequence of chronic B-cell activation
literature addressing TN during SSc principally consists of (Szekanecz et al, 2012). Derk et al (2006) demonstrated
case series and case reports (Teasdall et al, 1980; Jimenez- elevated standardized incidence ratio (SIR) for oropharyn-
Moreno et al, 1998; Fischoff and Sirois, 2000; Mohyuddin geal cancer in a cohort of 769 SSc patients (SIR 9.63
et al, 2009; Ribeiro et al, 2009; Vincent et al, 2009), and [95% CI 2.9716.29]). They found a highly signicant
the link between the two conditions has only been investi- increase in the incidence of tongue squamous cell carci-
gated in a small number of studies (Farrell and Medsger, noma associated with the diffuse form of the disease

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

10
(Derk et al, 2005). A nationwide population study also Health Impact Prole-49 (OHIP-49) is the most widely
revealed increased SIR for cancer of the oral cavity and used questionnaire to measure oral health-related quality
pharynx (SIR 3.67 [95% CI 1.836.56]) (Kuo et al, of life (HRQoL) in patients with oral diseases. Baron et al
2012). Diagnosis of oral cancer is particularly challenging have recently demonstrated, using OHIP-49 instrument,
in SSc patients as the symptoms of sclerosis can poten- that both global health-related quality of life (HRQoL)
tially overshadow certain manifestations of malignant dis- and oral HRQoL of life are severely impaired in their
eases and as microstomia may limit access to the oral large cohort of 163 SSc when compared to the 231
 cek et al, 2015).
cavity (Co healthy controls (Baron et al, 2014a). They found a statis-
tically signicant association between oral HRQoL and
Treatment-related adverse effects global HRQoL (Baron et al, 2014b). In 2007, Mouthon
Certain medications may be responsible for adverse et al developed and validated a disease-specic question-
effects involving the oral cavity (Alantar et al, 2011). Cal- naire quantifying mouth disability in SSc: the Mouth
cium-channel blockers, commonly used to treat Raynauds Handicap in Systemic Sclerosis Scale (MHISS) (Mouthon
phenomenon, can induce gingival hyperplasia (Shah and et al, 2007). It contains a total of 12 items, with 5 levels
Wigley, 2008). Different immunosuppressive drugs such of answer per item (score 04) and a total score ranging
as cyclophosphamide or mycophenolate mofetil can be from 0 to 48. A higher value indicates a more important
prescribed to SSc patients. Corticosteroids are usually functional impairment. This questionnaire is divided into
used with caution and at low dosage as they are associ- three parts that explore, respectively, the handicap related
ated with an increased risk of scleroderma renal crisis to mouth-opening limitation, to xerostomia, and to esthetic
(Denton et al, 2009). Among the many adverse effects concerns (Mouthon et al, 2007). The MHISS has been
that can be observed, such therapies are associated with developed in French and validated in French, Italian, and
increased risk of infections (Alantar et al, 2011). All Dutch (Mouthon et al, 2007; Maddali-Bongi et al, 2012;
patients should have a dental and radiographic examina- Schouffoer et al, 2013). Vitali et al created the Sclero-
tion prior to initiating immunosuppressive treatment in derma Logopedic Scale (SLS) to assess the oropharyngeal
order to remove potential sources of odontogenic infec- area disorders in SSc patients (Vitali et al, 2010). This 58-
tion, and a regular follow-up is recommended. Oral ulcer- items scale is divided into ve subscales (Impairment,
ations are frequent in patients receiving methotrexate Swallow, Voice, Multield and Quality of life) but seems
immunomodulator therapy, prescribed for muscular, joint, more difcult to use in the daily practice.
and skin manifestations, and may appear at any time dur-
ing the treatment (Kalantzis et al, 2005). Folate supple-
mentation can help to reduce mucosal toxicity and may Oral management
avoid the need to discontinue methotrexate. Local treat- Systemic sclerosis requires a specic oral management that
ments (e.g., topical analgesics or steroids, covering agents, involves a multidisciplinary team (dentist, oral surgeon,
chlorhexidine gluconate mouthwashes) can also be used physiotherapist. . .). However, SSc patients often encounter
but they only provide symptomatic relief (Kalantzis et al, some difculties in nding a dentist who agrees to treat them
2005). Penicillin should be avoided in combination with (Leader et al, 2014).
methotrexate as it may increase the hematologic toxicity.
Baron et al also mentioned that 76.3% of SSc patients
use medications that are known to be associated with Prevention measures and oral hygiene
mouth dryness (e.g., anticholinergic antidepressants for A regular follow-up with appropriate preventive mea-
psychiatric symptoms) and can enhance a preexisting sures is essential to maintain adequate oral health in SSc
xerostomia (Baron et al, 2014a). Sicca syndrome should patients (Cazal et al, 2008). Prevention of dental caries,
be considered before the initiation of antibiotic treatment gingival inammation, and tooth loss can only be
to prevent the risk of associated oral candidiasis (Alantar achieved by patient education (Poole et al, 2010) and by
et al, 2011). the development of tailor-made oral hygiene techniques.
For example, in patients with impaired manual dexterity,
Oral health-related quality of life an electric toothbrush or a toothbrush with a foam ergo-
Systemic sclerosis is associated with an impaired quality nomic handle can be proposed. Indeed, Balzer showed
of life. Outcome measurements are commonly used to that the use of adaptive oral hygiene devices (oscillat-
evaluate SSc patients (Pope, 2011). Global disability and ingrotating toothbrush and osser with a toothbrush-like
quality of life are usually measured by the Health Assess- handle) combined to exercises designed to increase
ment Questionnaire (HAQ) (Poole and Steen, 1991) or by mouth opening and therefore facilitate oral hygiene
its modied version (sHAQ for scleroderma HAQ) (Steen allows the improvement of gingival health in SSc
and Medsger, 1997) that has been specically developed patients compared to the use of more traditional oral
for SSc patients. HAQ and sHAQ are self-reported ques- hygiene devices (manual toothbrush and nger-held den-
tionnaires, sHAQ also including visual analog scales (e.g., tal oss) (Balzer, 2012). All kinds of preventive mea-
for pain or organ involvement evaluation) (Poole and sures such as regular periodontal maintenance with
Steen, 1991; Steen and Medsger, 1997). SSc has a strong scaling or topical uorides applications (uoride tooth-
impact on oral functions and therefore on oral health- pastes, varnishes, etc) should be encouraged. The treat-
related quality of life, emphasizing the need for quantify- ment of GERD may also help in maintaining a normal
ing the handicap related to mouth disability. The Oral pH (Alantar et al, 2011).

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

11
Cessation of tobacco use is strongly recommended, as it receptors and may be contraindicated in patients with
can worsen mucosal involvement (hyperkeratosis, xerosto- chronic respiratory, cardiovascular, or renal disease.
mia. . .) and increase the risk of malignant transformation Anetholtrithione (25 mg, 3 times a day) could be an alter-
(Alantar et al, 2011) native to pilocarpine chlorhydrate as it exhibits less side
effects (Vincent et al, 2009; Alantar et al, 2011).
Dental treatment and prosthodontics
Teeth preservation is crucial as limited access to the oral Microstomia
cavity can make the dental treatment challenging, espe- Reports of surgical interventions to enlarge the oral orice
cially when prosthetic rehabilitation is needed. Conven- such as bilateral commissurotomy or commissuroplasty
tional dental care can be performed in SSc patients but have been described but represent very invasive proce-
short sessions with regular breaks should be favored dures (Johns et al, 1998; Mehra et al, 1998; TerzIo glu
(Alantar et al, 2011). The use of sectional impression et al, 2002; Koymen et al, 2009). Active (placing the
techniques as well as of sectional or exible removable thumbs in opposite corners of the mouth and pulling out-
prosthesis can be really helpful in patients with restricted wards) or passive (using tongue depressors inserted
oral access. Midline hinges and stud attachment may facil- between the posterior teeth) mouth-stretching exercises,
itate insertion and removal of the fractionated denture facial grimacing, connective tissue massage, Kabats tech-
(Yenisey et al, 2005; Dikbas et al, 2007; Prithviraj et al, niques, or kinesitherapy can be proposed as an initial
2009). However, exible prostheses are often difcult to non-surgical alternative to improve mouth opening, oral
adapt and show a reduced retention (Alantar et al, 2011). functions, and skin elasticity (Pizzo et al, 2003; Maddali-
To date, less than 20 reports and only one systematic Bongi et al, 2011; Wada and Ram, 2013). Encouraging
review on dental implant rehabilitation in SSc patients SSc patient to perform exercises since the earliest phases
have been published (Reichart et al, 2016). No evidence- of the disease will help to limit the extension of skin
based recommendations are currently available and further brosis. TheraBite Jaw Motion Rehabilitation System
studies are strongly needed. Although data are only avail- (Atos Medical AB, Malmo, Sweden) that is based on
able for 28 patients and 165 implants, implant survival repetitive and passive stretching could also be used to
rates seem to be comparable in patients with and without increase mouth width. It has been shown to be efcient in
SSc (Reichart et al, 2016). However, implantprosthetic patients with head and neck cancer suffering from trismus
treatment in SSc patients is challenging. An interdisci- and in case of myogenic temporomandibular disorder
plinary consultation with assessment of the individual (Kraaijenga et al, 2014; Pauli et al, 2015). Recently,
risk-benet balance is required. Several parameters need autologous fat transplantation and adipose-derived stromal
to be considered such as the disease severity, microvascu- cells (ADSCs) injections have been performed in the peri-
lar impairment, ongoing medications (especially bisphos- oral region. Both therapeutic approaches appear to be
phonates), limitation in mouth opening, decreased salivary promising as they allowed the improvement of mouth
production, and reduced ability to perform oral hygiene opening (Del Papa et al, 2015; Onesti et al, 2016). Del
that can favor the occurrence of peri-implantitis (Alantar Papa et al have even noticed the induction of a signicant
et al, 2011; Reichart et al, 2016). neovascularization (Del Papa et al, 2015).

Xerostomia Telangiectases
Spicy food and acidic products should be avoided. Telangiectases are usually not treated except in case of
Patients are encouraged to drink water regularly and eat bleeding or aesthetic concerns (Alantar et al, 2011). Both
preferentially solid food that require more mastication intense pulse light and laser seem to be effective treat-
effort and provide a mechanical stimulation of the salivary ments. Pulse dye laser has better outcomes in terms of
ow. A broad range of saliva substitute such as sprays, appearance, whereas intense pulsed light has fewer side
gels, mouthwashes, or special toothpastes are also avail- effects (Dinsdale et al, 2014).
able. They help in maintaining moisture of the oral
mucosa, but they must be applied frequently during the Bone resorption and TMJ involvement
day. Oxygenated glycerol triester saliva substitute sprays Resorption of the mandible is in most cases asymp-
show evidence of effectiveness compared to electrolyte tomatic and is therefore usually a fortuitous nding dur-
sprays. Different saliva stimulants (e.g., sugar-free sweets, ing routine radiographic examination (Dagenais et al,
chewing gums) can also be used during the day by 2015). A regular follow-up is still required, such lesions
patients with residual secretion in order to increase sali- being potentially associated with a signicant risk of
vary production (Furness et al, 2011). The use of pathological fracture (Mugino and Ikemura, 2006). The
parasympathicomimetic drugs such as pilocarpine that management of condylar resorption ranges from conser-
stimulates saliva secretion was mainly studied for treat- vative approaches with only functional appliances (Mug-
ment of dry mouth in patients with Sj ogrens syndrome ino and Ikemura, 2006) to maxillary and mandibular
(Vivino et al, 1999) but it can also be tried for SSc asso- osteotomies (Haers and Sailer, 1995) or condylar resec-
ciated xerostomia (5 mg, 34 times a day) (Alantar et al, tion (Doucet and Morrison, 2011) with genioplasty.
2011). However, this cholinergic agonist is responsible for Recently, the replacement of destroyed temporomandibu-
several adverse affects (e.g., excessive sweating, vasodi- lar condyles with costochondral grafts in two SSc
latation) related to its non-selective action on muscarinic patients has been described with long-term functional

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

12
improvement (MacIntosh et al, 2015). As TMJ involve- Almeida C, Almeida I, Vasconcelos C (2015). Quality of life in
ment is common in SSc patients, a careful examination systemic sclerosis. Autoimmun Rev 14: 10871096.
(including MRI exploration when necessary) should be Alpoz E, Cankaya H, G uneri P (2007). Facial subcutaneous cal-
performed during rheumatologic assessment (Matarese cinosis and mandibular resorption in systemic sclerosis: a case
report. Dento Maxillo Facial Radiol 36: 172174.
et al, 2016).
Amaral TN, Peres FA, Lapa AT, Marques-Neto JF, Appenzeller
S (2013). Neurologic involvement in scleroderma: a systematic
Trigeminal neuropathy review. Semin Arthritis Rheum 43: 335347.
So far, the pharmacological treatment of Trigeminal neu- Amin K, Clarke A, Sivakumar B et al (2011). The psychological
ropathy (TN) has not been evaluated in randomised con- impact of facial changes in scleroderma. Psychol Health Med
trolled trials. Corticosteroids alone or associated with 16: 304312.
other immunosuppressive drugs such as methotrexate are Anbiaee N, Tafakhori Z (2011). Early diagnosis of progressive
frequently used. However, symptoms are rarely improved systemic sclerosis (scleroderma) from a panoramic view: report
by such therapies. Amitriptyline, nortryptiline, carba- of three cases. Dento Maxillo Facial Radiol 40: 457462.
mazepine, oxcarbazepine, and gabapentin have been suc- Andonopoulos AP, Drosos AA, Skopouli FN, Moutsopoulos HM
(1989). Sjogrens syndrome in rheumatoid arthritis and pro-
cessfully used (Amaral et al, 2013), but further studies are
gressive systemic sclerosis. A comparative study. Clin Exp
required to establish guidelines. Rheumatol 7: 203205.
Antic M, Distler JHW, Distler O (2013). Treating skin and lung
Conclusion brosis in systemic sclerosis: a future lled with promise?
Curr Opin Pharmacol 13: 455462.
Although rare, SSc is a complex disease characterized by Arnett FC, Gourh P, Shete S et al (2010). Major histocompatibil-
a wide range of clinical features. The orofacial region is ity complex (MHC) class II alleles, haplotypes and epitopes
frequently involved and the multiple complications that which confer susceptibility or protection in systemic sclerosis:
can be observed tend to enhance the degradation of the analyses in 1300 Caucasian, African-American and Hispanic
quality of life. Dentists play a crucial role in the manage- cases and 1000 controls. Ann Rheum Dis 69: 822827.
Auluck A (2007). Widening of periodontal ligament space and
ment of this condition and should be integrated to the
mandibular resorption in patients with systemic sclerosis.
pluridisciplinary team. They should also be involved in Dento Maxillo Facial Radiol 36: 441442.
the diagnostic process, and therefore, they have to know Auluck A, Pai KM, Shetty C, Shenoi SD (2005). Mandibular
the specic orofacial manifestations, specically PLS resorption in progressive systemic sclerosis: a report of three
widening. The reinforcement of oral hygiene and teaching cases. Dento Maxillo Facial Radiol 34: 384386.
of facial exercises, along with a regular follow-up, are Avouac J, Sordet C, Depinay C et al (2006). Systemic sclerosis-asso-
essential measures to preserve oral health in SSc patients. ciated Sj
ogrens syndrome and relationship to the limited cuta-
neous subtype: results of a prospective study of sicca syndrome in
133 consecutive patients. Arthritis Rheum 54: 22432249.
Acknowledgements Bali V, Dabra S, Behl AB, Bali R (2013). A rare case of hidebound
disease with dental implications. Dent Res J 10: 556561.
Authors would like to thank Fareeha Batool for her help in the
Balzer J (2012). The use of adaptive oral hygiene devices and
preparation of the manuscript. This work has been supported by
orofacial exercise by adults with systemic sclerosis (sclero-
authors institutions, grant AAPJC 2014HUS no. 6026 and
derma) seems to improve their gingival health. J Evid-Based
EU-funded (ERDF) project INTERREG V RARENET.
Dent Pract 12: 9798.
Baron M, Hudson M, Tatibouet S et al (2014a). The Canadian
Author contributions systemic sclerosis oral health study: orofacial manifestations
and oral health-related quality of life in systemic sclerosis
All authors contributed to the development of the drafts, succes- compared with the general population. Rheumatol Oxf Engl
sive revision and renement of the manuscript. All authors 53: 13861394.
reviewed the nal version of the manuscript. Baron M, Hudson M, Tatibouet S et al (2014b). The Canadian
Systemic Sclerosis Oral Health Study III: relationship between
disease characteristics and oro-facial manifestations in systemic
Conict of interest sclerosis. Arthritis Care Res 12: 180186.
The authors declared that they have no conict of interest. Baron M, Hudson M, Dagenais M et al (2015a). The Canadian
Systemic Sclerosis Oral Health Study V: relationship between
disease characteristics and oral radiologic ndings in systemic
sclerosis. Arthritis Care Res 67: 681690.
References Baron M, Hudson M, Tatibouet S et al (2015b). The Canadian
Alantar A, Cabane J, Hachulla E et al (2011). Recommendations Systemic Sclerosis Oral Health Study II: the relationship
for the care of oral involvement in patients with systemic scle- between oral and global health-related quality of life in sys-
rosis. Arthritis Care Res 63: 11261133. temic sclerosis. Rheumatol Oxf Engl 54: 692696.
Albilia JB, Lam DK, Blanas N, Clokie CML, Sandor GKB Benitha R, Modi M, Tikly M (2002). Osteolysis of the cervical
(2007). Small mouths . . . Big problems? A review of sclero- spine and mandible in systemic sclerosis: a case report with
derma and its oral health implications. J Can Dent Assoc 73: computed tomography and magnetic resonance imaging nd-
831836. ings. Rheumatol Oxf Engl 41: 11981200.
Alexandridis C, White SC (1984). Periodontal ligament changes Boulman N, Slobodin G, Rozenbaum M, Rosner I (2005). Calci-
in patients with progressive systemic sclerosis. Oral Surg Oral nosis in rheumatic diseases. Semin Arthritis Rheum 34: 805
Med Oral Pathol 58: 113118. 812.

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

13
Bridges MJ, Kelly CA (2002). Raynauds phenomenon affecting IRF5 on disease susceptibility and related pulmonary brosis.
the tongue of a patient with scleroderma. Ann Rheum Dis 61: Arthritis Rheum 60: 24722479.
472. Dieude P, Boileau C, Allanore Y (2011). Immunogenetics of sys-
Broen JCA, Radstake TRDJ, Rossato M (2014). The role of temic sclerosis. Autoimmun Rev 10: 282290.
genetics and epigenetics in the pathogenesis of systemic scle- Dikbas I, Koksal T, Kazazoglu E (2007). Fabricating sectional-
rosis. Nat Rev Rheumatol 10: 671681. collapsible complete dentures for an edentulous patient with
Casey EB, Lawton NF (1971). Progressive systemic sclerosis microstomia induced by scleroderma. Quintessence Int Berl
presenting with Raynauds phenomenon in the tongue and Ger 1985: 1522.
sensory trigeminal neuropathy. Rheumatol Phys Med 11: 131 Dinsdale G, Murray A, Moore T et al (2014). A comparison of
133. intense pulsed light and laser treatment of telangiectases in
Cazal C, Sobral APV, Neves RFSN, Freire Filho FWV, Cardoso patients with systemic sclerosis: a within-subject randomized
AB, da Silveira MMF (2008). Oral complaints in progressive trial. Rheumatol Oxf Engl 53: 14221430.
systemic sclerosis: two cases report. Med Oral Patol Oral Cir Dospinescu P, Jones GT, Basu N (2013). Environmental risk fac-
Bucal 13: E114E118. tors in systemic sclerosis. Curr Opin Rheumatol 25: 179183.
Chifot H, Fautrel B, Sordet C, Chatelus E, Sibilia J (2008). Doucet J-C, Morrison AD (2011). Bilateral mandibular condyly-
Incidence and prevalence of systemic sclerosis: a systematic sis from systemic sclerosis: case report of surgical correction
literature review. Semin Arthritis Rheum 37: 223235. with bilateral total temporomandibular joint replacement.
Chikazu D, Mori Y, Saijo H et al (2008). A case of tumoural Craniomaxillofacial Trauma Reconstr 4: 1118.
calcinosis in the temporomandibular joint associated with sys- Drosos AA, Andonopoulos AP, Costopoulos JS, Stavropoulos
temic sclerosis. Int J Oral Maxillofac Surg 37: 190193. ED, Papadimitriou CS, Moutsopoulos HM (1988). Sjogrens
Chu CH, Yeung CMK, Lai IA, Leung WK, Mok MY (2011). syndrome in progressive systemic sclerosis. J Rheumatol 15:
Oral health of Chinese people with systemic sclerosis. Clin 965968.
Oral Investig 15: 931939. Dumoitier N, Lofek S, Mouthon L (2014). Pathophysiology of
Chung L, Utz PJ (2004). Antibodies in scleroderma: direct systemic sclerosis: state of the art in 2014. Presse Medicale
pathogenicity and phenotypic associations. Curr Rheumatol 43: e267e278.
Rep 6: 156163. Elimelech R, Mayer Y, Braun-Moscovici Y, Machtei EE, Balbir-
Cipoletti JF, Buckingham RB, Barnes EL et al (1977). Sj ogrens Gurman A (2015). Periodontal conditions and tumor necrosis
syndrome in progressive systemic sclerosis. Ann Intern Med factor-alpha level in gingival crevicular uid of scleroderma
87: 535541. patients. Isr Med Assoc J IMAJ 17: 549553.
 cek A, Hahn A, Ambrus M, Valesova M (2015). Complica-
Co Eversole LR, Jacobsen PL, Stone CE (1984). Oral and gingival
tions in the treatment of oropharyngeal carcinoma in patients changes in systemic sclerosis (scleroderma). J Periodontol 55:
with systemic sclerosis: a case report. Oncol Lett 9: 2528. 175178.
Coll J, Rives A, Gri~n o MC, Setoain J, Vivancos J, Balcells A Farrell DA, Medsger TA (1982). Trigeminal neuropathy in pro-
(1987). Prevalence of Sjogrens syndrome in autoimmune dis- gressive systemic sclerosis. Am J Med 73: 5762.
eases. Ann Rheum Dis 46: 286289. Feghali-Bostwick C, Medsger TA, Wright TM (2003). Analysis
Czirjak L, Foeldvari I, Muller-Ladner U (2008). Skin involve- of systemic sclerosis in twins reveals low concordance for dis-
ment in systemic sclerosis. Rheumatology 47: v44v45. ease and high concordance for the presence of antinuclear anti-
Dagenais M, MacDonald D, Baron M et al (2015). The Cana- bodies. Arthritis Rheum 48: 19561963.
dian Systemic Sclerosis Oral Health Study IV: oral radio- Fischoff DK, Sirois D (2000). Painful trigeminal neuropathy
graphic manifestations in systemic sclerosis compared with the caused by severe mandibular resorption and nerve compression
general population. Oral Surg Oral Med Oral Pathol Oral in a patient with systemic sclerosis: case report and literature
Radiol 120: 104111. review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
Del Papa N, Caviggioli F, Sambataro D et al (2015). Autolo- 90: 456459.
gous fat grafting in the treatment of brotic perioral changes Frech TM, Pauling JD, Murtaugh MA, Kendall K, Domsic RT
in patients with systemic sclerosis. Cell Transplant 24: 63 (2016). Sublingual abnormalities in systemic sclerosis. J Clin
72. Rheumatol Pract Rep Rheum Musculoskelet Dis 22: 1921.
Del Rosso A, Maddali-Bongi S (2014). Oral health in patients Furness S, Worthington HV, Bryan G, Birchenough S, McMil-
with systemic sclerosis. Rheumatol Oxf Engl 53: 13551356. lan R (2011). Interventions for the management of dry
Delantoni A, Matziari E (2015). Osteolysis affecting the jaws in mouth: topical therapies. Cochrane Database Syst Rev
systemic sclerosis: clinical and osseous changes based on a CD008934.
case presentation. Clin Med Insights Arthritis Musculoskelet Hachulla E, Launay D (2011). Diagnosis and classication of
Disord 8: 6567. systemic sclerosis. Clin Rev Allergy Immunol 40: 7883.
Denton CP, Ong VH (2004). Part VI. Other Conditions with Haers PE, Sailer HF (1995). Mandibular resorption due to sys-
Neurologic Involvement: Systemic sclerosis. The Neurologic temic sclerosis. Case report of surgical correction of a sec-
Involvement in Systemic Autoimmune Diseases, 1st Edition. ondary open bite deformity. Int J Oral Maxillofac Surg 24:
Amsterdam, Netherlands: Elsevier Science. 261267.
Denton CP, Lapadula G, Mouthon L, Muller-Ladner U (2009). Hagen NA, Stevens JC, Michet CJ (1990). Trigeminal sensory
Renal complications and scleroderma renal crisis. Rheumatol neuropathy associated with connective tissue diseases. Neurol-
Oxf Engl 48 (Suppl. 3): iii32iii35. ogy 40: 891896.
Derk CT, Rasheed M, Spiegel JR, Jimenez SA (2005). Increased Hebbar M, Janin A, Huglo D et al (1994). Xerostomia in sys-
incidence of carcinoma of the tongue in patients with systemic temic sclerosis: systematic evaluation by salivary scintigraphy
sclerosis. J Rheumatol 32: 637641. and lip biopsy in thirty-four patients. Arthritis Rheum 37:
Derk CT, Rasheed M, Artlett CM, Jimenez SA (2006). A cohort 439441.
study of cancer incidence in systemic sclerosis. J Rheumatol Hebbar M, Lassalle P, Janin A et al (1995). E-selectin expres-
33: 11131116. sion in salivary endothelial cells and sera from patients with
Dieude P, Guedj M, Wipff J et al (2009). STAT4 is a genetic systemic sclerosis. Role of resident mast cell-derived tumor
risk factor for systemic sclerosis having additive effects with necrosis factor alpha. Arthritis Rheum 38: 406412.

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

14
Hebbar M, Gillot JM, Hachulla E et al (1996). Early expression Lee P, Bruni J, Sukenik S (1984). Neurological manifestations
of E-selectin, tumor necrosis factor alpha, and mast cell inl- in systemic sclerosis (scleroderma). J Rheumatol 11: 480
tration in the salivary glands of patients with systemic sclero- 483.
sis. Arthritis Rheum 39: 11611165. LeRoy EC, Medsger TA Jr (2001). Criteria for the classication
Hebbar M, Janin A, Lassalle P et al (1998). The correlation of early systemic sclerosis. J Rheumatol 28: 15731576.
between salivary endothelial expression of E-selectin and clini- LeRoy EC, Black C, Fleischmajer R et al (1988). Scleroderma
cal and biological parameters in systemic scleroderma. Rev (systemic sclerosis): classication, subsets and pathogenesis. J
Medecine Interne Fondee Par Societe Natl Francaise Rheumatol 15: 202205.
Medecine Interne 19: 537541. Leung WK, Chu CH, Mok MY, Yeung KWS, Ng SKS (2011).
Ho YY, Lagares D, Tager AM, Kapoor M (2014). Fibrosisa Periodontal status of adults with systemic sclerosis: case-con-
lethal component of systemic sclerosis. Nat Rev Rheumatol 10: trol study. J Periodontol 82: 11401145.
390402. MacIntosh RB, Shivapuja P-K, Naqvi R (2015). Scleroderma
Ioannidis JPA, Vlachoyiannopoulos PG, Haidich A-B et al and the temporomandibular joint: reconstruction in 2 variants.
(2005). Mortality in systemic sclerosis: an international meta- J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg
analysis of individual patient data. Am J Med 118: 210. 73: 11991210.
Jagadish R, Mehta DS, Jagadish P (2012). Oral and periodontal Maddali-Bongi S, Landi G, Galluccio F et al (2011). The reha-
manifestations associated with systemic sclerosis: a case series bilitation of facial involvement in systemic sclerosis: efcacy
and review. J Indian Soc Periodontol 16: 271274. of the combination of connective tissue massage, Kabats tech-
Janssens X, Herman L, Mielants H, Verbruggen G, Veys EM nique and kinesitherapy: a randomized controlled trial.
(1987). Disease manifestations of progressive systemic sclero- Rheumatol Int 31: 895901.
sis: sensitivity and specicity. Clin Rheumatol 6: 532538. Maddali-Bongi S, Del Rosso A, Miniati I et al (2012). The Ital-
Jimenez-Moreno J, Selva-OCallaghan A, Rovira-Ca~ nellas A ian version of the Mouth Handicap in Systemic Sclerosis scale
et al (1998). Trigeminal sensory neuropathy in systemic scle- (MHISS) is valid, reliable and useful in assessing oral health-
rosis. Br J Rheumatol 37: 587589. related quality of life (OHRQoL) in systemic sclerosis (SSc)
Johns FR, Sandler NA, Ochs MW (1998). The use of a triangu- patients. Rheumatol Int 32: 27852790.
lar pedicle ap for oral commisuroplasty: report of a case. J Marcucci M, Abdala N (2009). Clinical and radiographic study
Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg of orofacial alterations in patients with systemic sclerosis. Braz
56: 228231. Oral Res 23: 8288.
Jung S, Minoux M, Maniere M-C, Martin T, Schmittbuhl M Marie I, Gehanno J-F, Bubenheim M et al (2014). Prospective
(2013). Previously undescribed pulpal and periodontal liga- study to evaluate the association between systemic sclerosis
ment calcications in systemic sclerosis: a case report. Oral and occupational exposure and review of the literature.
Surg Oral Med Oral Pathol Oral Radiol 115: e47e51. Autoimmun Rev 13: 151156.
Kalantzis A, Marshman Z, Falconer DT, Morgan PR, Odell EW Marmary Y, Glaiss R, Pisanty S (1981). Scleroderma: oral mani-
(2005). Oral effects of low-dose methotrexate treatment. Oral festations. Oral Surg Oral Med Oral Pathol 52: 3237.
Surg Oral Med Oral Pathol Oral Radiol Endod 100: 5262. Martin J, Fonseca C (2011). The genetics of scleroderma. Curr
Knas M, Zalewska A, Waszkiewicz N et al (2014). Salivary: Rheumatol Rep 13: 1320.
ow and proteins of the innate and adaptive immunity in the Mason G, Hamburger J, Matthews J (2000). Mast cells, extracel-
limited and diffused systemic sclerosis. J Oral Pathol Med 43: lular matrix components, TGFb isoforms and TGFb receptor
521529. expression in labial salivary glands in systemic sclerosis. Ann
Kobak S, Oksel F, Aksu K, Kabasakal Y (2013). The frequency Rheum Dis 59: 183189.
of sicca symptoms and Sjogrens syndrome in patients with Matarese G, Isola G, Anastasi GP et al (2012). Immunohistochem-
systemic sclerosis. Int J Rheum Dis 16: 8892. ical analysis of TGF-b1 and VEGF in gingival and periodontal
Koch AE, Distler O (2007). Vasculopathy and disordered angio- tissues: a role of these biomarkers in the pathogenesis of sclero-
genesis in selected rheumatic diseases: rheumatoid arthritis and derma and periodontal disease. Int J Mol Med 30: 502508.
systemic sclerosis. Arthritis Res Ther 9(Suppl 2): S3. Matarese G, Isola G, Alibrandi A et al (2016). Occlusal and
Koymen R, Gulses A, Karacayli U, Aydintug YS (2009). Treat- MRI characterizations in systemic sclerosis patients: a prospec-
ment of microstomia with commissuroplasties and semidy- tive study from Southern Italian cohort. Joint Bone Spine 83:
namic acrylic splints. Oral Surg Oral Med Oral Pathol Oral 5762.
Radiol Endod 107: 503507. Mayer Y, Elimelech R, Balbir-Gurman A, Braun-Moscovici Y,
Kraaijenga S, van der Molen L, van Tinteren H, Hilgers F, Machtei EE (2013). Periodontal condition of patients with
Smeele L (2014). Treatment of myogenic temporomandibular autoimmune diseases and the effect of anti-tumor necrosis fac-
disorder: a prospective randomized clinical trial, comparing a tor-a therapy. J Periodontol 84: 136142.
mechanical stretching device (TheraBite) with standard phys- Mayes MD, Lacey JV, Beebe-Dimmer J et al (2003). Prevalence,
ical therapy exercise. Cranio J Craniomandib Pract 32: 208 incidence, survival, and disease characteristics of systemic
216. sclerosis in a large US population. Arthritis Rheum 48: 2246
Krieg T, Takehara K (2009). Skin disease: a cardinal feature of 2255.
systemic sclerosis. Rheumatology 48: iii14iii18. Mehra A (2008). Periodontal space widening in patients with
Kuo C-F, Luo S-F, Yu K-H et al (2012). Cancer risk among systemic sclerosis: a probable explanation. Dento Maxillo
patients with systemic sclerosis: a nationwide population study Facial Radiol 37: 183; author reply 184.
in Taiwan. Scand J Rheumatol 41: 4449. Mehra P, Caiazzo A, Bestgen S (1998). Bilateral oral commis-
Lafyatis R (2014). Transforming growth factor b-at the centre of surotomy using buccal mucosa aps for management of
systemic sclerosis. Nat Rev Rheumatol 10: 706719. microstomia: report of a case. J Oral Maxillofac Surg Off J
Leader D, Papas A, Finkelman M (2014). A survey of dentists Am Assoc Oral Maxillofac Surg 56: 12001203.
knowledge and attitudes with respect to the treatment of Mohyuddin A, Myers D, Guazzo E (2009). Bilateral trigeminal
scleroderma patients. J Clin Rheumatol Pract Rep Rheum neuralgia associated with limited systemic sclerosis. J Clin
Musculoskelet Dis 20: 189194. Neurosci Off J Neurosurg Soc Australas 16: 708710.

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

15
Mouthon L, Rannou F, Berezne A et al (2007). Development Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline Dysp-
and validation of a scale for mouth handicap in systemic scle- nea Index (BDI) and Transition Dyspnea Index (TDI) (Mah-
rosis: the Mouth Handicap in Systemic Sclerosis Scale. Ann lers Index), Cambridge Pulmonary Hypertension Outcome
Rheum Dis 66: 16511655. Review (CAMPHOR), and Raynauds Condition Score (RCS).
Mugino H, Ikemura K (2006). Progressive systemic sclerosis Arthritis Care Res 63: S98S111.
with spontaneous fracture due to resorption of the mandible: a Prasad RS, Pai A (2012). Localized periodontal ligament space
case report. J Oral Maxillofac Surg Off J Am Assoc Oral Max- widening as the only presentation of sclerodermareliability
illofac Surg 64: 11371139. recheck. Dento Maxillo Facial Radiol 41: 440; author reply
Nagy G, Kovacs J, Zeher M, Czirjak L (1994). Analysis of the 441442.
oral manifestations of systemic sclerosis. Oral Surg Oral Med Prithviraj DR, Ramaswamy S, Romesh S (2009). Prosthetic reha-
Oral Pathol 77: 141146. bilitation of patients with microstomia. Indian J Dent Res Off
Nape~nas JJ, Brennan MT, Fox PC (2009). Diagnosis and treat- Publ Indian Soc Dent Res 20: 483486.
ment of xerostomia (dry mouth). Odontol Soc Nippon Dent Pugashetti R, Shinkai K, Ruben BS, Grossman ME, Maldon-
Univ 97: 7683. ado J, Fox LP (2011). Calcium may preferentially deposit
Nestal-Zibo H, Rinne I, Glukmann M, Kaha H (2009). Calci- in areas of elastic tissue damage. J Am Acad Dermatol 64:
nosis on the face in systemic sclerosis: case report and over- 296301.
view of relevant literature. J Oral Maxillofac Surg Off J Am Radstake TRDJ, Gorlova O, Rueda B et al (2010). Genome-wide
Assoc Oral Maxillofac Surg 67: 15301539. association study of systemic sclerosis identies CD247 as a
Nikpour M, Stevens WM, Herrick AL, Proudman SM (2010). new susceptibility locus. Nat Genet 42: 426429.
Epidemiology of systemic sclerosis. Best Pract Res Clin Ramon Y, Samra H, Oberman M (1987). Mandibular condylosis
Rheumatol 24: 857869. and apertognathia as presenting symptoms in progressive sys-
Onesti MG, Fioramonti P, Carella S, Fino P, Marchese C, Scud- temic sclerosis (scleroderma). Pattern of mandibular bony
eri N (2016). Improvement of mouth functional disability in lesions and atrophy of masticatory muscles in PSS, presum-
systemic sclerosis patients over one year in a trial of fat trans- ably caused by affected muscular arteries. Oral Surg Oral
plantation versus adipose-derived stromal cells. Stem Cells Int Med Oral Pathol 63: 269274.
2016: 2416192. Ranque B, Mouthon L (2010). Geoepidemiology of systemic
Onishi A, Sugiyama D, Kumagai S, Morinobu A (2013). Cancer sclerosis. Autoimmun Rev 9: A311A318.
incidence in systemic sclerosis: meta-analysis of population- Reichart PA, Schmidt-Westhausen AM, Khongkhunthian P,
based cohort studies. Arthritis Rheum 65: 19131921. Strietzel FP (2016). Dental implants in patients with oral
Osial TA, Whiteside TL, Buckingham RB et al (1983). Clinical mucosal diseases a systematic review. J Oral Rehabil 43:
and serologic study of Sjogrens syndrome in patients with 388399.
progressive systemic sclerosis. Arthritis Rheum 26: 500508. Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E
Ozcelik O, Haytac MC, Ergin M, Antmen B, Seydaoglu G (2011). Calcinosis cutis: part I. Diagnostic pathway. J Am
(2008). The immunohistochemical analysis of vascular Acad Dermatol 65: 112; quiz 1314.
endothelial growth factors A and C and microvessel density in Ribeiro RT, Fialho LMN, de Souza LT, Barsottini OGP (2009).
gingival tissues of systemic sclerosis patients: their possible Trigeminal sensory neuropathy associated with systemic scle-
effects on gingival inammation. Oral Surg Oral Med Oral rosis: report of three Brazilian cases. Arq Neuropsiquiatr 67:
Pathol Oral Radiol Endod 105: 481485. 494495.
Pauli N, Andrell P, Johansson M, Fagerberg-Mohlin B, Finizia C Rout PG, Hamburger J, Potts AJ (1996). Orofacial radiological
(2015). Treating trismus: a prospective study on effect and manifestations of systemic sclerosis. Dento Maxillo Facial
compliance to jaw exercise therapy in head and neck cancer. Radiol 25: 193196.
Head Neck 37: 17381744. Rowell NR, Hopper FE (1977). The periodontal membrane in
Pischon N, Hoedke D, Kurth S et al (2016). Increased periodon- systemic sclerosis. Br J Dermatol 96: 1520.
tal attachment loss in systemic sclerosis patients. J Periodontol Rueda B, Broen J, Simeon C et al (2009). The STAT4 gene
doi: 10.1902/jop.2016.150475. inuences the genetic predisposition to systemic sclerosis phe-
Pizzo G, Scardina GA, Messina P (2003). Effects of a nonsurgi- notype. Hum Mol Genet 18: 20712077.
cal exercise program on the decreased mouth opening in Salliot C, Mouthon L, Ardizzone M et al (2007). Sjogrens syn-
patients with systemic scleroderma. Clin Oral Investig 7: 175 drome is associated with and not secondary to systemic sclero-
178. sis. Rheumatol Oxf Engl 46: 321326.
Pogrel MA (1988). Unilateral osteolysis of the mandibular angle Savarino E, Furnari M, de Bortoli N et al (2014). Gastrointesti-
and coronoid process in scleroderma. Int J Oral Maxillofac nal involvement in systemic sclerosis. Presse Medicale 43:
Surg 17: 155156. e279e291.
Poole JL (1994). Grasp pattern variations seen in the scleroderma Scala E, Pallotta S, Frezzolini A et al (2004). Cytokine and che-
hand. Am J Occup Ther Off Publ Am Occup Ther Assoc 48: mokine levels in systemic sclerosis: relationship with cuta-
4654. neous and internal organ involvement. Clin Exp Immunol 138:
Poole JL, Steen VD (1991). The use of the Health Assessment 540546.
Questionnaire (HAQ) to determine physical disability in sys- Scardina GA, Mazzullo M, Messina P (2002). Early diagnosis of
temic sclerosis. Arthritis Care Res Off J Arthritis Health Prof progressive systemic sclerosis: the role of oro-facial phenom-
Assoc 4: 2731. ena. Minerva Stomatol 51: 311317.
Poole J, Conte C, Brewer C et al (2010). Oral hygiene in sclero- Scardina GA, Pizzigatti ME, Messina P (2005). Periodontal
derma: the effectiveness of a multi-disciplinary intervention microcirculatory abnormalities in patients with systemic sclero-
program. Disabil Rehabil 32: 379384. sis. J Periodontol 76: 19911995.
Pope J (2011). Measures of systemic sclerosis (scleroderma): Schouffoer AA, Strijbos E, Schuerwegh AJM, Mouthon L, Vliet
Health Assessment Questionnaire (HAQ) and Scleroderma Vlieland TPM (2013). Translation, cross-cultural adaptation,
HAQ (SHAQ), Physician- and Patient-Rated Global Assess- and validation of the Mouth Handicap in Systemic Sclerosis
ments, Symptom Burden Index (SBI), University of California, questionnaire (MHISS) into the Dutch language. Clin Rheuma-
Los Angeles, Scleroderma Clinical Trials Consortium tol 32: 16491655.

Oral Diseases
Orofacial manifestations in systemic sclerosis
S Jung et al

16
Seifert MH, Steigerwald JC, Cliff MM (1975). Bone resorption Van den Hoogen F, Khanna D, Fransen J et al (2013). 2013
of the mandible in progressive systemic sclerosis. Arthritis classication criteria for systemic sclerosis: an American
Rheum 18: 507512. college of rheumatology/European league against rheuma-
Shah AA, Wigley FM (2008). Often forgotten manifestations of tism collaborative initiative. Ann Rheum Dis 72: 1747
systemic sclerosis. Rheum Dis Clin N Am 34: 221238. 1755.
Shah M, Foreman DM, Ferguson MW (1995). Neutralisation of Van Laar JM, Sullivan K (2013). Stem cell transplantation in
TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF- systemic sclerosis. Curr Opin Rheumatol 25: 719725.
beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci Vincent C, Agard C, Barbarot S et al (2009). Orofacial manifes-
108: 9851002. tations of systemic sclerosis: a study of 30 consecutive
Skopouli FN, Moutsopoulos HM (1994). Autoimmune epitheli- patients. Rev Medecine Interne Fondee Par Societe Natl Fran-
itis: Sjogrens syndrome. Clin Exp Rheumatol 12(Suppl 11): caise Medecine Interne 30: 511.
S9S11. Vitali C, Borghi E, Napoletano A et al (2010). Oropharyngola-
Stafne E, Austin L (1944). A characteristic dental nding in ryngeal disorders in scleroderma: development and validation
patients with acrosclerosis and diffuse scleroderma. Am J of the SLS scale. Dysphagia 25: 127138.
Orthod Oral Surg 30: 25. Vivino FB, Al-Hashimi I, Khan Z et al (1999). Pilocarpine
Steen VD (2005). Autoantibodies in systemic sclerosis. Semin tablets for the treatment of dry mouth and dry eye symptoms
Arthritis Rheum 35: 3542. in patients with Sj
ogren syndrome: a randomized, placebo-con-
Steen VD, Medsger TA (1997). The value of the health assess- trolled, xed-dose, multicenter trial. P92-01 Study Group.
ment questionnaire and special patient-generated scales to Arch Intern Med 159: 174181.
demonstrate change in systemic sclerosis patients over time. Wada T, Ram S (2013). Limited mouth opening secondary to
Arthritis Rheum 40: 19841991. diffuse systemic sclerosis. Case Rep Dent 2013: e937487.
Sticherling M (2012a). Systemic sclerosis dermatological Wangkaew S, Kasitanon N, Sivasomboon C, Wichainun R,
aspects. Part 1: Pathogenesis, epidemiology, clinical ndings. Sukitawut W, Louthrenoo W (2006). Sicca symptoms in
JDDG J Dtsch Dermatol Ges 10: 705716. Thai patients with rheumatoid arthritis, systemic lupus ery-
Sticherling M (2012b). Systemic sclerosis focus on dermato- thematosus and scleroderma: a comparison with age-matched
logical aspects. Part 2: Diagnostics, therapy. JDDG J Dtsch controls and correlation with disease variables. Asian Pac J
Dermatol Ges 10: 783791. Allergy Immunol Launched Allergy Immunol Soc Thail 24:
Szekanecz E,  Szamosi S, Horvath A  et al (2012). Malignancies 213221.
associated with systemic sclerosis. Autoimmun Rev 11: 852855. White SC, Frey NW, Blaschke DD et al (1977). Oral radio-
Tamby MC, Chanseaud Y, Guillevin L, Mouthon L (2003). New graphic changes in patients with progressive systemic sclerosis
insights into the pathogenesis of systemic sclerosis. Autoim- (scleroderma). J Am Dent Assoc 1939: 11781182.
mun Rev 2: 152157. Wood RE, Lee P (1988). Analysis of the oral manifestations of
Teasdall RD, Frayha RA, Shulman LE (1980). Cranial nerve systemic sclerosis (scleroderma). Oral Surg Oral Med Oral
involvement in systemic sclerosis (scleroderma): a report of 10 Pathol 65: 172178.
cases. Medicine (Baltimore) 59: 149159. Yenisey M, K ul
unk T, Kurt S, Ural C (2005). A prosthodontic
Temekonidis TI, Drosos AA (2001). Subcutaneous calcication management alternative for scleroderma patients. J Oral Reha-
on the nose in a patient with scleroderma. Clin Exp Rheumatol bil 32: 696700.
19: 560. Yuen HK, Weng Y, Reed SG, Summerlin LM, Silver RM. Fac-
TerzIoglu A, Cigs ar B, Aslan G (2002). Surgical correction of tors associated with gingival inammation among adults with
microstomia in a patient with scleroderma. Ann Plast Surg 49: systemic sclerosis. Int J Dent Hyg 2014; 12: 5561.
222223. Zalewska A, Knas M, Gi ndzie
nska-Sieskiewicz E et al (2014).
Van Bon L, Affandi AJ, Broen J et al (2014). Proteome-wide Salivary antioxidants in patients with systemic sclerosis. J
analysis and CXCL4 as a biomarker in systemic sclerosis. N Oral Pathol Med 43: 6168.
Engl J Med 370: 433443.

Oral Diseases