Accepted Article

DR MERVE BENLI (Orcid ID : 0000-0003-2191-113X)

PROFESSOR OLIVIER HUCK (Orcid ID : 0000-0002-7988-2290)

Article type : Review Article

Orofacial Manifestations and Dental Management of Systemic Lupus Erythematosus: a

review
Merve Benli1, Fareeha Batool2,3, Céline Stutz2, Catherine Petit2,3,4, Sophie Jung3,4,5, Olivier
Huck2,3,4

1 Istanbul University, Faculty of Dentistry, Department of Prosthodontics, Istanbul, Turkey

2 INSERM, UMR 1260 ‘Osteoarticular and Dental Regenerative Nanomedicine’, Faculté de
Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), France
3 Faculté de Chirurgie Dentaire, Université de Strasbourg, France
4 Pôle de Médecine et de Chirurgie Bucco-Dentaires, Hôpitaux Universitaires de Strasbourg,
France
5 CNRS UPR 3572 "Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT)", Institut
de Biologie Moléculaire et Cellulaire (IBMC), Strasbourg, France
Figure: 1
Tables: 5
Words: 8517
Corresponding author:
Prof. Olivier Huck, Dental Faculty, 8 rue Sainte-Elisabeth, 67000 Strasbourg, France;
@: o.huck@unistra.fr; Phone: +33(0)388116947

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/ODI.13271
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 Abstract
Accepted Article
Background: Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease with
numerous clinical manifestations. There is no consensus about the ideal oral management for this
group of patients to date. This review aimed to describe the broad spectrum of orofacial and
clinical manifestations and their therapeutic approaches.
Methods: Studies concerning orofacial manifestations of SLE and dental treatment modalities
were selected by a literature search (1978-2019) using Google Scholar, PubMed/MEDLINE
electronic databases.
Results: The initial search strategy provided a total of 129 articles, and of these, 30 were included
for qualitative synthesis. The reviewed studies revealed that SLE patients are more at risk of
compromised oral and dental health exhibiting increased risk of periodontal diseases and temporo-
mandibular joint disorders. The use of systemic drugs especially immunosuppressive and
anticoagulants in SLE patients may also influence their oral management.
Conclusion: Results emphasize the need to carry out, at an early stage of the disease, an
appropriate oral management of these patients to improve oral health related quality of life and to
prevent the need of more invasive therapeutics. A multidisciplinary approach is needed for dental
and medical management of such patients.

Keywords: systemic lupus erythematosus; orofacial manifestations; oral management;

autoimmune

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 Introduction
Accepted Article Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease with
an incompletely understood etiology inducing detrimental consequences on numerous organs and
connective tissue. The highest rates of SLE incidence and prevalence were detected in North
America (23.2:100 000 and 241:100 000 respectively) while the lowest in Africa (0.3:100 000)
(Rees et al., 2017). SLE affects preferentially the women with a sex ratio of 9:1 and is often
diagnosed between 20 to 40 years of age (Pons-Estel et al., 2017; Shaikh et al., 2017; Al-Rayes et
al., 2007). Diagnosis of SLE is based on clinical examination, clinical history and serological
markers detection (Garbett et al., 2017). Diagnosis criteria were proposed by the American
College of Rheumatology (Tan et al., 1982) and include the presence of oral ulcers, malar rash,
discoid rash, photosensitivity, non-erosive arthritis, hematologic, immunologic, renal and
neurologic disorders, pleuritic or pericarditis and positive antinuclear antibody (Table 1) (Garbett
et al., 2017). Fulfilling 4 of these 11 criteria is necessary for the diagnosis of SLE emphasizing the
importance of oral examination (Garbett et al., 2017). SLE is characterized by alternance of
quiescence and active phases (flares), that according to the symptoms, could be characterized
using dedicated tools such as systemic lupus erythematosus disease activity (SLEDAI-2K) or
systemic lupus activity measure (SLAM-R) scales (Romero-Diaz et al., 2011) .
Several biological mechanisms have been suggested to explain SLE pathophysiology.
Amongst them, a role for genetic and epigenetic sensitivity, hormonal and environmental factors,
and modulation of both adaptive and innate immunity have been described (Wahren-Herlenius and
Dörner, 2013). More than 100 genetic susceptibility loci have been described to date. Deficiencies
in apoptotic clearance with subsequent accumulation of apoptotic cell debris significantly
contributes to the development of SLE (Shao and Cohen,2011) as it may lead to the breakdown of
self-tolerance and the emergence of disease-specific antinuclear antibodies (Yamaguchi et al.,
2008). Specific roles for polyclonal B cells and T cells have been described (Tsokos et al., 2016;
Mohan and Putterman, 2015; Perl, 2016). In SLE, T cells are responsible for regulating B cells
activation (Moulton and Tsokos, 2011) and the release of disease-specific antinuclear antibodies
contributing to destruction of the infiltrated tissue (Yamaguchi et al., 2008).
SLE affects the cardiovascular, pulmonary, renal, hematologic, and ocular systems. The
most severe systemic involvement of SLE is lupus nephritis and its current treatment strategies are
not satisfactory (Croca et al., 2011; Sprangers et al., 2012). Symptoms of musculoskeletal system
are frequently observed in SLE patients, with joint pain being the first complain (Zoma, 2004).

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 Moreover, osteomyelitis, bone tuberculosis, and synovitis have also been reported (Mok et al.,
Accepted Article
2005; Rosa et al., 2011; Ribero et al., 2017). Therefore, the involvement of SLE in the bone-
related diseases and complications poses a risk for dentists in clinical procedures such as dental
implant placement or alveolar bone surgeries. Similarly, the neuropsychiatric manifestations
observed in several SLE patients can trigger anxiety or stress-related disorders such as bruxism
(Thomas et al., 2017; Haye Salinas et al., 2017; Mok et al., 2018). The aim of this review is to
provide an updated overview of orofacial manifestations affecting SLE patients and their impact
on the dental management.

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 Materials and methods
Accepted Article
Search strategy
This review was conducted according to PRISMA guidelines. A literature search related to
dental management and orofacial manifestations of SLE was performed using Google Scholar and
PubMed/MEDLINE online databases, encompassing studies from 1978 until 2019. The following
keywords were used in various combinations: ‘systemic lupus’ OR ‘lupus’, and, ‘orofacial’,
‘mouth’, ‘oral’, ‘dental prosthesis’, ‘dental implant’, ‘oral mucosa’, ‘periodontal outcomes’,
‘temporomandibular joint’, ‘prosthodontics’, ‘salivary gland’, ‘xerostomia’, ‘dental treatment’,
‘dental material’, ‘therapeutics’. For all appropriate studies, full-text articles were obtained and
evaluated separately by independent reviewers.

Eligibility criteria
The inclusion criteria included English-language papers, studies involving patients who
had suffered from SLE, studies reporting one or more orofacial manifestation, studies assessing
performed oral/dental treatment by validated methods. Review articles, editorial letters, opinions,
brief communications, conferences, duplicates, studies with inadequate information or
incompatible methodology, studies not dealing with SLE patients, studies involving SLE patients
with concurrent systemic and/or syndromic diseases were excluded.

Data collection
The following parameters obtained from the articles were assessed according to the study
design: groups, sample size (number of SLE patients), patient’s characteristics, time from SLE
diagnosis, drug treatment, oral involvement, oral rehabilitation method, main results and main
conclusions. The data collected were presented as tables.

Bias risk assessment

Previously described methodology described in Baccaglini et al. was followed for bias risk
assessment (Baccaglini et al., 2007). The risk of bias assessment of the included studies was
conducted independently by two reviewers and disagreements were solved through discussion by
reaching a consensus. An independent review for the selected articles was conducted to assign the
evidence levels of the articles for classifying them as A, B, C, D, and F. The studies that were out
of the scope of this study were labeled with ‘F’ and excluded from the study. Remaining labels A,

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 B, C and D were designated by considering the evidence quality of the articles (Baccaglini et al.,
Accepted Article
2007). Quality of evidence was evaluated by using the following items: allocation concealment
(selection bias), random sequence generation, blinding of personnel and participants (performance
bias), incomplete outcome data (attrition bias), blinding of outcome assessment (detection bias),
selective reporting (reporting bias), and other sources of bias (absence of the description of
findings, patient profile, time from diagnosis or drug use). This evaluation included methodologic
quality, heterogeneity, the directness of evidence and risk of publication bias (Table 2).

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 Results and Discussion
Accepted Article The performed search strategy provided a total of 129 articles. After initial evaluation
through titles and abstracts, the number of eligible articles was reduced to 64. At the end of the
review process, 30 articles met all the inclusion criteria and were included in this review (Figure
1).
Orofacial manifestations
Oral lesions occur in more than 40% of SLE patients and can strongly impact oral health-
related quality of life. Therefore, prevention and management of oral diseases is of crucial
importance (Urman et al., 1978; Ahola et al., 2015). Orofacial manifestations are frequently left
underdiagnosed, and the corresponding symptoms are often hidden by other systemic symptoms
(Abrão et al., 2016; Corrêa et al., 2018).
Oromucosal lesions
Mucocutaneous lesions are one of the most reported oral manifestations of SLE and, in
some cases, can be the only lesion observed in SLE patients (Tan et al., 1982; Schiødt, 1984). Oral
lesion prevalence in these patients varies depending on the treatment received and the stage of the
disease (Aliko et al., 2010). These lesions may occur in different shapes and sizes, such as plaques
or blemishes on the mucosa at different sites such as palate, tongue and lips (Table 3) (Abrão et
al., 2016). The classical oral lesion of SLE is white plaques with erythema in the center and
sometimes telangiectasia with keratotic striae in the periphery (Lourenço et al., 2007).
Morphology of oral lesions can vary according to the type of disease making the definition criteria
of these oral lesions in different forms of SLE rather difficult (Muñoz-Corcuera et al., 2009;
López-Labady et al., 2007). They generally include oral ulcers, lichenoid lesions, leukoplakic
plaques, petechiae, raised keratotic plaques, purpura, and erythematous areas that are commonly
seen on the labial or buccal mucosae in conjunction with cutaneous manifestations (Petri et al.,
2012; Grimaldo-Carjevschi et al., 2011). In some cases, lesions can be similar to those observed in
oral lichen planus and can cause oral soreness and chronic burning (Mays et al., 2012; Khudhur et
l., 2014). In addition, discoid lesions that are similar to ones found on sun-exposed skin may be
found on the vermillion border with evident cheilitis (Callen,1997).
The presence of oral ulcers is common in SLE correlating well with the underlying disease activity
and included into classification criteria proposed by the American College of Rheumatology to
categorize a patient as having SLE (Petri et al., 2012; Mays et al., 2012). The “non-responders to
treatment” of oral ulcers carry a risk for malignant transformation into squamous cell carcinoma

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 (Grimaldo-Carjevschi et al., 2011). Additionally, an association between the increased risk for
Accepted Article
development of malignancy (squamous cell carcinoma, Hodgkin and non-Hodgkin lymphomas)
and SLE has also been reported (Bernatsky et al., 2005& 2007; Menzies et al., 2018). In the study
performed by Orteu et al., honeycomb plaques (scarred plaques, silvery white) and cheilitis have
been described in SLE patients in addition to the general oral manifestations of the disease (Orteu
et al., 2001; Chi et al., 2010). Desquamative gingivitis and mouth burning have also been reported
as secondary oral symptoms as well (Brennan et al., 2005). Previous studies reported higher
incidence of herpes zoster due to immune dysregulation and immunosuppression in SLE patients
contributing to the variety of oral symptoms (Chakravarty et al., 2013; Rondaan et al., 2014). Oral
lesions in SLE typically respond well to systemic immunosuppressive therapy, and systemic
antimalarial drugs and topical corticosteroids may be used in patients with oral mucosal lesions
and limited skin disease (Jessop et al., 2009). However, the influence of risk factors, for instance
smoking, should be investigated.
Caries, periodontal manifestations and tooth loss
In a recent study, high counts of cariogenic bacteria genus (Streptococcus sobrinus and
Streptococcus mutans) have been detected in supragingival plaque samples of the patients with
SLE (Loyola Rodriguez et al., 2016). In the study by Moori et al., the prevalence of dental caries
was 100% in patients with active SLE and 85% in patients with inactive SLE (Moori et al., 2016).
It is obvious that saliva pH and salivary flow rate contribute to this high risk of caries (Loyola
Rodriguez et al., 2016). SLE patients exhibit periodontal manifestations, however, studies
assessing periodontal involvement in this patient group are scarce (Rhodus and Johnson, 1990)
and only a few case reports and clinical studies about periodontal diseases in SLE are available in
the literature (Table 4) (Jaworski et al., 1985; Novo et al., 1999; Fernandes et al., 2007, Kobayashi
et al., 2007). Indeed, diagnosis of acute necrotizing ulcerative gingivitis (ANUG), periodontitis,
and gingivitis was mentioned in case reports with SLE (Jaworski et al., 1985; Nagler et al., 1999).
Among them, a greater predisposition to periodontal diseases was measured in patients with SLE
compared to healthy controls (Novo et al., 1999; Fernandes et al., 2007; Kobayashi et al., 2007).
Recently, a decrease in SLE activity has been correlated to the improvement of periodontal
parameters and it has been shown that periodontal treatment was associated with a better response
to immunosuppressive drugs in SLE patients (Fabbri et al., 2014). However, some contradictory
results could be found where no significant differences in terms of plaque or gingival indices were
observed (Mutlu et al., 1993). Tooth loss is an important feature of oral health as a reduced

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 number of teeth will directly impact oral health related quality of life. Correa et al. showed that
Accepted Article
SLE patients exhibit more tooth loss than healthy population. This finding was explained by both
the severity of SLE and by the presence of periodontal diseases and/or dental caries (Corrêa et al.,
2018).
Salivary glands involvement and xerostomia
A reduced salivary flow rate of 0.61ml/min and 3.25ml/5min has been shown in active
SLE patients (Loyola Rodriguez et al., 2016). Although xerostomia is a common feature of SLE,
there is not much data about salivary glands involvement (Menzies et al., 2018; Vitali et al., 2002).
They might be affected directly by the disease or by Sjögren syndrome (SS), a frequently
associated feature of SLE (Grennan et al., 1977). SS is seen in 14.0%–17.8% of SLE cases (Pasoto
et al., 2019). However, some studies have shown that both diseases may have different
characterizations and SLE presents distinctive histomorphological features (Fernandes et al., 2010;
Scheinfeld, 2006; Ben-Aryeh et al., 1993). Indeed, SS is primarily characterized by focal
lymphocytic sialadenitis in salivary gland, while this finding was not observed in salivary gland
samples of SLE (Fernandes et al., 2010; Fisher et al., 2015; Bologna et al., 2018) supporting a
specific impact of SLE on salivary glands (Bologna et al., 2018; Skopouli et al., 1991).
Interestingly, in Bologna et al. study, all SLE patients exhibited xerostomia but only 13.05% of
them presented a significant reduction in salivary production (≤0.1ml/min unstimulated salivary
flow rate) (Bologna et al., 2018), whereas, in the study by Leite et al., 79% of SLE patients
suffered from hyposalivation (Leite et al., 2015). Interestingly, salivary flow rate and the pH of the
saliva were found to be lower in flare up periods compared to remission phases of the disease
(Moori et al., 2016; Qin et al., 2017).
Temporomandibular joint involvement
Involvement of temporomandibular joint (TMJ) in patients with SLE was described to be
often found within the first years of the disease and less frequent later (Aceves-Avila et al., 2013).
A previous study showed that 2/3 of SLE patients had severe symptoms with potential
involvement of TMJ (Jonsson et al., 1983). This high rate of TMJ disorders was also observed in
another study where 20% of SLE patients had symptoms (Aceves-Avila et al., 2013). The most
frequent finding is regular pain while other reported symptoms are TMJ sounds (especially
crepitation), difficulty in mouth opening, and reduced mouth opening (Aliko et al., 2011). A recent
study evaluated clinical outcomes of TMJ reconstructions in patients with various
autoimmune/connective tissue diseases and found that SLE patient group presented an

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 improvement of maximal incisal opening without pain (Mehra et al., 2018). The social and
Accepted Article
psychological status of patients with SLE is suggested to be a possible risk factor for TMJ
disorders due to the common prevalence of muscle hyperactivity, stress, anxiety and depression in
these patients (Hanly et al., 2005; Rollman and Gillespie, 2000). Chronic use of corticosteroids in
SLE patients may also have effects on condylar changes, including erosions, flattening, sclerosis,
and osteophytes (Liebling and Gold, 1981; Gerbracht and Shapiro, 1982; Caramaschi et al., 2012).
Therefore, inflammatory process of the SLE is not accepted as the sole reason for the TMJ
changes and associated manifestations in these patients (Aliko et al., 2011).
Oral management and treatment-related adverse effects
Dental treatment of SLE patients is challenging due to missing teeth, advanced carious
lesions, inadequate bone quality and/or quantity and side effects of therapeutic agents used in SLE
and multidisciplinary intervention is needed (Corrêa et al., 2018; Drew et al., 2018). Therapeutic
strategies for SLE aim to control disease activity while minimizing damages related to both active
disease and drug-related adverse effects. Treatment goals include prevention of long-term
morbidity and mortality (SLE patients mostly die of long-term complications) as well as
improvement of health-related quality of life. Considering the wide spectrum of clinical and
biological manifestations, SLE patients require a tailored management. Currently, therapeutic
approaches range from antimalarials (hydroxychloroquine, known to block TLR-7 and TLR-9
signaling in plasmacytoid dendritic cells) that are recommended in almost all SLE patients to non-
steroidal anti-inflammatory drugs, glucocorticoids, sometimes in addition to one or a combination
of conventional immunosuppressive agents (cyclophosphamide, methotrexate, azathioprine,
mycophenolate mofetil), or more recently to targeted therapies such as belimumab (monoclonal
antibody directed against B-cell activating factor (BAFF)) or rituximab (anti-CD20 monoclonal
antibody that depletes B cells) (Fanouriakis et al., 2019; Kaul et al., 2016; Gatto et al., 2019).
Nevertheless, different emerging targeted therapies are currently under clinical development
(Felten et al., 2018). Several medications may be responsible for adverse effects involving the oral
cavity and should be taken into consideration in case of invasive dental procedures. For example,
methotrexate that is usually prescribed for joint involvement may be associated with the
development of mouth ulcers. Bisphosphonates are frequently prescribed to patients under
prolonged glucocorticoid therapy to prevent osteoporosis and are associated with an increased risk
of medication-related osteonecrosis of the jaws (Nicolatou-Galitis et al., 2019). In addition,
patients receiving immunosuppressants, biological agents or corticosteroids have an increased risk

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 of infection, particularly, oral infection including oral candidiasis. The higher risk of opportunistic
Accepted Article
infections related to the mean daily doses of medicaments has been confirmed in SLE patients
(Yang et al., 2018). The reported infections in this group of patients are fungal infections
(disseminated candidiasis, pneumocystosis, aspergillosis, cryptococcosis, and zygomycosis),
mycobacterium infection (tuberculosis, extrapulmonary tuberculosis, and non-tuberculous
mycobacteria), cytomegalovirus, varicella or herpes zoster, non-typhoid salmonella, and
Pneumocystis carinii pneumonia (Yang et al., 2018; Danza and Ruiz-Irastorza, 2013; Tektonidou
et al., 2015).
A thorough medical consultation should be carried out, especially before prescribing new drugs
for dental and medical management of SLE patients, to avoid the risk of organ damage and
interaction of drugs. Commonly prescribed drugs by dental practitioners such as NSAIDS,
penicillin, tetracycline, cephalosporins and acetylsalicylic acid have a predominant kidney-
dependent elimination and their use in these patients should be carefully evaluated due to potential
nephrotic syndrome and organ damage (Mok et al., 2018; Hajji et al., 2017; Albilia et al., 2007,
Fessler and Boumpas, 1995; Weening et al., 2004). Instead of using these types of medication,
clindamycin, acetaminophen and narcotics are suggested. It is also recommended to assess the
renal function of the patient and decrease dosage along with an increase of dose intervals if the
renal function is affected (Albilia et al., 2007).
Considerations for dental treatment
Regular oral examination is recommended to provide treatment and diagnose SLE due to
specific symptoms of the disease. A regular follow-up is also strongly recommended and invasive
dental procedures require expert advice. However, it is imperative to consider the medication used
by the patient in order to improve treatment strategy while minimizing the risk of complications.
Prophylactic antibiotics/ antifungals
Preventive dental care and effective monitoring systems with pertinent specialists should
be implemented for SLE patients having a predisposition to severe infections. These infections are
difficult to detect owing to their silent characterization and require a detailed clinical examination
to allow an early diagnosis (Albilia et al., 2007). The use of prophylactic antibiotic treatment
should be discussed with the medical team if invasive dental treatments are necessary. Indeed, the
risk of infective endocarditis should be discussed as recent invasive dental procedure has been
demonstrated as a risk factor for infective endocarditis in SLE patients (Chang et al., 2017).
Prophylactic antifungal treatment may also be necessary in some cases because of the increased

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 prevalence of opportunistic fungal infections in SLE patients (Zuber et al., 1997). Importantly, the
Accepted Article
use of antifungals should be considered, if possible, prior to the use of anticoagulants due to their
potential interactions and subsequent risk of over coagulation as observed with coumarin (Visser
et al., 2002).
Anticoagulants/ antithrombotic agents
An important consideration for dental treatment is the use of anticoagulants as SLE
patients have a high risk for thromboembolic events like myocardial infarction or stroke,
especially in association with antiphospholipid antibody syndrome (Fessler and Boumpas, 1995;
Watad et al., 2018). Therefore, coagulation tests such as international normalized ratio (INR) and
prothrombin time should be performed in order to evaluate preoperatively the bleeding risk
associated to dental surgery (Albilia et al., 2007). According to laboratory test results, appropriate
local hemostatic measures should be taken (e.g. sutures, collagen sponges, tranexamic acid
solution applications) as mentioned by current recommendations for the management of patients
under antithrombotic medications (van Diermen et al., 2013).
Immunosuppressive drugs
The silent characterization of infections in patients with SLE comes from the chronic use
of immunosuppressive drugs and their anti-inflammatory and immunosuppressive effects, that
mask infection clues (Lehman,1995). Furthermore, the rapid progression of infection can be seen
in SLE due to therapy-related immunosuppression and the disease itself with the paucity of pain
and swelling (Albilia et al., 2007). The use of general immunosuppressive drugs is a common
treatment for patients with SLE and it has some adverse effects on the oral cavity (Moulton et al.,
2017). Helkimo's index (subjective symptoms index for TMJ disorders) was found higher in
patients with SLE who were taking one or more immunosuppressive drugs (Fernandes et al.,
2007). Immunosuppressive treatment associated with lymphopenia has been defined as a major
risk factor for herpes zoster infection in children with SLE (Ferreira et al., 2016). SLE patients
who received immunosuppressive treatment have been shown to have TMJ impairment due to
complications of corticosteroid treatment and also thought to be induced by SLE itself (Fernandes
et al., 2007; Jonsson et al., 1983). Furthermore, patients treated with these drugs are at increased
risk of developing systemic complications from dental infections (Foster and Fitzgerald, 2005).
Notably, corticosteroid drugs are widely used in SLE management due to their
immunosuppressive and anti-inflammatory effects. However, they are associated with several
long-term adverse effects such as myopathies and osteoporosis (Abdwani et al., 2008; Stichweh

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 and Pascual, 2005). In the study of Buckley, prolonged systemic corticosteroid treatment was
Accepted Article
demonstrated to have an association with the bone loss, which has a rapid and progressive
characterization (Buckley, 2000). Systemic corticosteroid therapy has also been reported to cause
alterations in the release of growth hormone, induce muscle atrophy and enhance the severity of
the malocclusion type by causing insufficient craniofacial and dentoalveolar growth (Dias and
Gleiser, 2009; Pedersen, 2001; Kumar and Nandlal, 2012). As a result of anti-inflammatory and
immunosuppressive effects, prolonged corticosteroid therapy predisposes to the development of
infection and tend to mask its clinical signs (Lehman, 1995). Rodriguez et al. reported the side
effects of disease-modifying antirheumatic drugs (prednisone, methotrexate, chloroquine,
hydroxychloroquine) on dental caries, glandular damage, salivary flow, and oral streptococci in
patients with SLE who had different treatment protocols (Loyola Rodriguez et al., 2016). In
another clinical study, the long-term use and cumulative doses of prednisone (corticosteroid) were
associated with an increased incidence of gingivitis (Fernandes et al., 2007). The authors suggest
that this is due to the predisposing effect of chronic use of corticosteroids to infection as a result of
their anti-inflammatory and immunosuppressive effects (Fernandes et al., 2007). A thorough
dental examination including dental radiography, is therefore, required before the initiation of a
treatment with immunosuppressive drugs, biological agents and/or bisphosphonates.
Screening for potential malignancies
During the regular oral examination and follow-up recommended for the treatment and the
diagnosis of SLE due to specific oral manifestations of the disease, mucosal examination should
be especially performed owing to the high prevalence of oral lesion such as oral ulcers. Refractory
oral ulcers that do not respond to treatment should undergo histopathological examination to
detect malignant transformations (Menzies et al., 2018).
Considerations for oral rehabilitation
Oral lesions and hyposalivation can cause problems while removing and placing dental
prostheses in mouth (Leite et al., 2015; Kam et al., 2006). Oral health related quality of life has
been shown to be affected negatively in SLE patients who wear removable dentures (Corrêa et al.,
2018). Accordingly, fixed prosthesis can be a more useful alternative and artificial saliva can be
used in these patients. Thus, dental implants can be a treatment choice for these patients (Strietzel
et al., 2019). Before implant placement procedures, the risk of avascular necrosis (osteonecrosis)
secondary to steroid use and decreased bone quality and/or quantity should be considered
(Caramaschi et al., 2012; Fernandes et al., 2010). Although SLE activity has an influence on bone

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 quality, there is some evidence reporting successful implant placement in SLE and a systematic
Accepted Article
review reported 100% implant survival rate (Table 5) (Drew et al., 2018; Li et al., 2004; Ergun et
al., 2010). However, the present data is scarce and more clinical trials should be performed
(Strietzel et al., 2019).
Another recommendation for oral management of SLE patients is that dental practitioners
should be careful in selecting dental materials in the oral rehabilitation of SLE patients because
high risk of metal delayed-type hypersensitivity (Type IV allergy) has been presented in these
patients, including nickel, gold, mercury, chromium, palladium or titanium (Bjørklund et al.,
2018). Occlusal splints should also be provided these patients to protect dental restorations from
the effect of bruxism, as these patients have increased frequency of stress (Hogan et al., 1991).
Nevertheless, as photosensitivity is common in SLE and can exacerbate symptoms such as fatigue,
joint pain and cutaneous lesions, precautions should be taken regarding exposure to fluorescent
light such as surgical lighting. Indeed, a case-report described the flaring of SLE consecutive to
dental procedure (Tiao and Werth, 2015). Therefore, the use of UV-blocking filters over the
surgical light source and double-enveloped light bulbs should be considered (Tiao and Werth,
2015; Moseley and Ferguson, 2011). Other factors that may trigger SLE include exposure to
infections, certain hormones, and drugs which may activate the innate and adaptive immune
system, resulting in inflammation, cytotoxic effects, and clinical symptoms (Fernandez and Kirou,
2016).
Limitations
The main limitation of this review consisted in the lack of prospective follow-up studies
and the heterogeneity among studied populations. The need of prospective studies appears
mandatory to clearly determine the etiology of the association between SLE and oral diseases.
Future studies should determine the specific role of the immunological features of SLE in oral
diseases onset, notably through evaluation of involved molecular pathways.
Conclusion
SLE is a multisystem autoimmune disease with a wide spectrum of clinical presentations,
partly linked to treatment-related adverse effects, but also related to the disease itself. Orofacial
involvement plays an important role in the disease course, both for diagnosis and treatment. Dental
practitioners have the responsibility to treat these patients according to the special conditions
associated to the disease. The help of a specialist in oral dermatology or immunologist for
assistance in the management of SLE associated lesions will be of importance for the dentist.

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 Also, the role of the specialist in Oral Medicine and Oral Pathology is one of aid or assistance,
Accepted Article
principally in the management of oral mucosa lesions. The dentist ought to become familiar with
inter-consultation and referral of patients, as required. The findings presented in this review article
highlighted that a multidisciplinary approach is needed for dental and medical management of
SLE patients.

Conflict of interest
Authors have no conflicts of interest related to this study.

Author contributions
All authors contributed to the development of the drafts, revision and refinement of the
manuscript. All authors reviewed the final version of the manuscript.

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Figures and tables legends

Figure 1: Flow-chart of the study

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 Table 1: Clinical and Immunologic Standard of the Systemic Lupus International Collaborating
Accepted Article
Clinics (SLICC) Classification Criteria. *Fulfilling 4 of these criteria (at least one of the
immunological and at least one clinical) or histologically diagnosed lupus nephritis is necessary
for classification as SLE.
Table 2: Risk of bias assessment
Table 3: Summary of the studies reporting oral mucosal lesions in SLE patients. NR: Not
reported, CLE: Cutaneous lupus erythematosus, CCL: Chronic cutaneous lupus, DLE: Discoid
lupus erythematosus, SS: Sjögren’s syndrome, RA: Rheumatoid arthritis, SSC: Systemic
sclerosis, NSAIDs: Non-steroidal anti-inflammatory drugs, D: Dermatomyositis, LA: Lichen
actinicus, S: Sarcoidosis.
Table 4: Summary of the studies reporting orofacial involvement and drugs used in SLE patients
and clinical tips.
Table 5: Summary of the studies reporting dental implant treatment in SLE patients

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Table 1: Clinical and Immunologic Standard of the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria 5,6. *Fulfilling 4

of these criteria (at least one of the immunological and at least one clinical) or histologically diagnosed lupus nephritis is necessary for classification as

SLE.

Clinical criteria Immunological criteria

Acute cutaneous lupus (including malar rash)
Chronic cutaneous lupus (including classical discoid
rash)
Oral ulcers (palate, buccal, tongue or nasal)
Nonscarring alopecia
Synovitis (≥2 joints), tenderness (≥2 joints), morning
stiffness (≥ 30 min) (characterized by swelling or
effusion)
Serositis (typical pleurisy or pericardial pain,>1 day)
Renal (urine protein/creatinine or 24h urine protein,
>0.5 g)
Neurologic (e.g., seizures, psychosis)
Hemolytic anemia
Leukopenia (< 4000/mm3) or lymphopenia (<
1000/mm3)
Thrombocytopenia (<100000/mm3)
ANA above laboratory reference range
Anti-dsDNA above laboratory reference range (except
ELISA)
Anti-Sm
Antiphospholipid antibody (lupus anticoagulant, false-
positive RPR, medium or high titer anticardiolipin, anti-
β2 glycoprotein I)
Low complement (C3, C4, or CH50)
Direct Coombs test (in the absence of hemolytic
anemia)
Table 2: Risk of bias assessment

Study Bias grade

Grennan et al (1977) B
Urman et al (1978) A
Jonsson et al (1983) A
Jonsson et al (1984) B
Burge et al (1989) A
Skopouli et al (1991) B
Jorizzo et al (1992) C
Ben-Aryeh et al (1993) B
Mutlu et al (1993) A
Jensen et al (1999) B
Novo et al (1999) A
Meyer et al (2000) B
Bernatsky et al (2005) A
Fernandes et al (2007) A
Lourenço et al (2007) B
López-Labady et al (2007) A
Kobayashi et al (2007) B
Figueredo et al (2008) A
Xu et al (2010) B
Aliko et al (2010) A
Fernandes et al (2010) C
Khatibi et al (2012) B
Aceves-Avila et al (2013) A
Fabbri et al (2014) A
Leite et al (2015) A
Loyola Rodriguez et al (2016) A
Bahloul et al (2017) B
Menzies et al (2018) A
Del Barrio-Díaz et al (2019) B
Correa et al (2018) A
 Table 3: Summary of the studies reporting oral mucosal lesions in SLE patients. NR: Not reported, CLE: Cutaneous lupus erythematosus, CCL: Chronic

cutaneous lupus, DLE: Discoid lupus erythematosus, SS: Sjögren’s syndrome, RA: Rheumatoid arthritis, SSC: Systemic sclerosis, NSAIDs: Non-

steroidal anti-inflammatory drugs, D: Dermatomyositis, LA: Lichen actinicus, S: Sarcoidosis.

Study Groups Findings Site of finding Patient Time from Drug treatment
description diagnosis

Urman et al SLE:n=182 Oral ulcer (26%) Hard palate NR NR Corticosteroid therapy

(1978) Gingiva Antimalarial drug
Buccal mucosa Salicylate

Jonsson et SLE:n=51 Discoid type lesions Hard palate NR NR NR

al (1984) or erythemas (45%) Buccal mucosa
Oral ulcer (13.04%) Vermillion
border

Burge et al SLE:n=53 Oral ulcer (36%) Hard palate NR SLE: 3 months-31 Chloroquine
(1989) CCL:n= 68 Cheilitis (6%) Vermillion years Prednisolon
Oral plaques (3%) border CCL: 6 months- Hydroxchloroquine
Soft palate 54 years Azathioprine
Lower lip

Jorizzo et SLE:n=10 Oral ulcer (70%) Palate NR 1-36 years Prednisone

al (1992) Erythema (60%) Buccal mucosa Plaquenil
Discoid lesions Gingiva Atabrine
(30%) Tongue Cyclophosphamide
Methotrexate
Jensen et al SLE:n=20 Minor mucosal Palate 35% smokers 0.5-28 years Prednisolone
(1999) lesion (84%) Tongue 65% non- Antimalarial drug
Telangiectasia (55%) smokers Azathioprine
Erythema (25%) Methothrexate
Median rhomboid
glossitis (10%)
Epithelial
hyperplasia (5%)

Bernatsky SLE: n= 9547 Hodgkin’s NR NR 1 - ≥20 years NR

et al (2005) lymphoma (2.63-
4.93%)
Non-Hodgkin’
lymphoma (0.75-
5.51%)

Fernandes JSLE:n= 48 Erythema/discoid Hard palate Juvenile 4 -104 month Chloroquine

et al (2007) Controls:n=48 lesions (41.6%) Oral mucosa Hydroxchloroquine
Oral ulcer (6.25%) Immunosuppressants

Erythemato-
ulcerative plaque
(46%)
White plaque types NR
(54%)
*Valid for SLE NR
Lourenço et group Buccal mucosa
al (2007) SLE: n=13 Lower lip NR
 CLE: n=33 Upper lip

López- SLE:n=38 Oral ulcer (5.5%) Hard palate NR NR Immunosuppressants

Labady et CLE:n=52 Red macula (4.4%) Buccal mucosa
al (2007) Red plaque (6.6%) Upper lip
White plaque (1.1%) Lower lip

Xu et al
(2010) SS/SLE:n= 41 Oral ulcer: NR NR SS/SLE:113.8± Corticosteroid therapy
SLE:n= 214 14.6% (SS/SLE) 84.0 months
12.1% (SLE) SLE: 44.9±18.0
months

Aliko et al SLE:n=22 Red lesions (35.5%) Palate SLE:9.1%smoker SLE:6.6±7.0 Oral steroids
(2010) RA:n=88 White lesions (7.3%) Labial/buccal RA:14.8% years NSAIDs
SSC:n=14 Red-white mucosa smoker RA: 9.5±8.2 years Methylprednisolone
lesions(6.5%) Tongue SSC: SSC: 9.4±8.1 Methotrexate
Nodular Alveolar 7.1%smoker years
lesions(5.6%) mucosa/gingiva
Ulcerative lesions Sulci
(8.9%) Vermilion
Vesicullo-bullous border/lips
lesions(0.8%) Comissures
Pigmented Floor of the
lesions(3.2%) mouth
Other(4%)

SLE: n=188 Oral ulcer (28.1%) Buccal mucosa 27.2 % smokers <3->12 months Corticosteroid therapy
Khatibi et Erythema (white Lower lip 72.8 % non- Azathioprine
al (2012) speckles/striae) Upper lip smokers Hydroxychloroquine
(13.8%) Cyclophosphamide
Erythema (9.5%)
White plaque (2.6%)

SLE:n=30 Oral ulcer (25%) Lip NR NR Prednisone

Bahloul et RA:n=4 Hyperpigmentation Gum Antiaggregants
al (2017) D: n= 5 (13.3%) Mucosa Oral anticoagulants
LA:n=1 Hydroxychloroquine
S: n=1

Menzies et SLE: n=11 Oral ulcers (23%) Hard palate 45% smokers 1-26 years Oral prednisolone
al (2018) CCL: n=11 Erosions (23%) (38%) 14% ex-smokers Steroid inhaler
DLE: n= 20 Erythema (19%) Labial mucosa 29% nonsmokers Antibiotic
White plaque (19%) Buccal mucosa 12% unknown
Others (16%) Gingiva
Alveoler ridge

Del Barrio- SLE:n= 58 White streaks (59%) Palate NR NR NR

Díaz et al CLE:n=92 Brown macules Gingiva
(2019) Control:n=151 (63%) Jugal mucosa
Red macules (60%)
Telangiectases
(100%)
 Table 4: Summary of the studies reporting orofacial involvement and drugs used in SLE patients and clinical tips.

Study Groups Peridontal Saliva Dental TMJ Drug therapy Risky effect Results
involvement caries/Tooth involvement
loss
Grennan SLE:n=32 - Xerostomia:12.5% - - NR Concomitant Overlap
et al Gland abnormality: Sjögren’s syndromes can
(1977) 65% syndrome can be affect saliva
found in SLE capacity
patients
Jonsson SLE:n=37 - - - Severe NR TMJ is a frequent More clinical
et al C: n=37 dysfunction:1 involvement in attention should
(1983) 4% SLE and shows be paid in TMJ
TMD radiographic for SLE patients
signs:41% change
Skopoul SLE:n= 72 - Xerostomia: 17% - - NR Concomitant Perivascular
i et al Perivascular Sjögren’s lymphocytic
(1991) lymphocytic syndrome may infiltration of
infiltration:24% have effects in salivary gland
salivary gland in may be initial
SLE lesion of
Sjögren’s
syndrome in
SLE
Ben- SLE:n=22 - Flow:0.25±0.15 - - Prednisone Significantly high Alterations in
Aryeh et C: n= 27 ml/min NSAIDS levels of IgA and the salivary
al IgA:10.45 + 7.10 Cytotoxic drugs IgM were composition
(1993) mg/100 ml Antihypertensive detected in may show
IgM:0.36±0.39 drugs patients with SLE subclinical
mg/100 ml salivary gland
 IgG:1.68±1.64 mg/100 involvement in
ml SLE

Mutlu et SLE:n=53 PI:0.57±0.12 - - - Corticosteroid The effect of Long terrn

al C:n=48 GI:0.4±0.08 NSAIDS immunomodulato administration
(1993) PD:1.28±0.07 Immunosuppress ry drugs on the of NSAIDS or
ants periodontal immunosuppres
Antimalarial probing depths sive drugs
has a clinical contributes to
point. lower
periodontal
probing depths
Novo et SLE:n=30 Periodontitis:60 - - - NR Increased risk of Monitoring
al RA:n=30 % (SLE) periodontitis in patients for
(1999) C:n=20 SLE patients periodontal
health is
recommended
Jensen SLE :n=20 - Xerostomia: 85% - - Prednisone High rate of Most of the
et al C:n=20 Dry mouth:45% Antimalarials xerostomia and sicca complaints
(1999) Flow:0.24 (0.02– Azathioprin sicca symptoms in patients may
1.18)ml/min Methothrexate were shown in be attributed to
patients with SLE the SLE and not
to drugs
 High rate loss - Immunosuppress High rate of oral Attention to oral
Meyer et SLE: n=46 Gingival - (NR) ants and examination and
al inflammation periodontal setting regular
(2000) Periodontal lesions due to appointments
lesions immunodysregula should
tion performed
Fernand JSLE:n=4 - DMFTI:4.0 Impaired TMJ
es et al 8 PI:61.5 (0-14.0) (ns) function(23% Chloroquine Encouraging
(2007) C:n=48 BGI: 26.0 TMJ Hydroxchloroqui Higher incidence JSLE patients to
pain(58%)(ns ne of gingivitis, keep adequate
) Immunosuppress temporomandibul oral health and
Pain on ants ar joint to
mandibular dysfunction, frequently
movement inadequate oral consult the
(2%) (ns) hygiene dentist is
Mobility recommended
reduction
(8%)
Kobayas SLE+P:n= PD(mm):SLE+ - Tooth - Corticosteroid Increased Corticosteroid
hi et al 46 P: 2.3 – 0.1, loss:SLE+P:2. Bisphosphonate prevalence of and
(2007) SLE:n=25 SLE:1.8 – 0.1 5 – 0.4(ns) therapy periodontitis bisphosphonate
P:n=58 CAL(mm):SLE SLE: 1.3 – (64.8%) in SLE therapy may
C:n=44 +P: 2.7 – 0.1, 0.4(ns) patients reduce levels of
SLE:2.1 – 0.1 inflammation
BL:SLE+P:16. and destruction
4- of the
1.4%,SLE:10.0 periodontal
– 1.1% tissue
Figuered JSLE:n=1 PI: 33 (± 19) - - - Immunomodulat JSLE patients Tissue
o et al 6 GBI:33.2 (± 16) ory drugs have presented a degradation and
(2008) C:n=14 PD: 17 (± 16) probing depth of periodontal
mm greater or equal to attachment loss
AL:0.2 (± 0,6) 3 mm have been
mm linked to high
elastase activity

Fernand SLE:n=12 - Xerostomia:SLE:100 - - NR Risk of Salivary gland

es et al SS:n=16 % xerostomia and alterations in
(2010) IgGdeposit:58%(SLE) mild/moderate SLE patients
Mild/moderate sialedinitis have may be a
sialadenitis been detected in specific
patients with SLE manifestation of
the SLE (lupus
sialadenitis)
Xu et al SS/SLE - Xerostomia:SS/SLE:8 - - Corticosteroid SLE has It is clinically
(2010) :n= 41 5.4% Glucocorticoid distinctive important to
SLE :n= SLE: 6.1% Immunosuppress serological and discriminate this
214 ants clinical features subgroup of
with SS SLE due to its
effects
Aliko et SLE:n=22 - - - TMJ Oral steroids TMJ symptoms TMJ
al RA:n=88 sounds:36.4% NSAIDS were reported in examination
(2011) Pain:27.3% Anti-rheumatic SLE patients should be
Reduced drugs commonly, and encouraged in
mouth Methotrexate pain was the most clinics and pain
opening:4.5% Hydroxychloroqu frequent management
ine should be
provided
Aceves- SLE:n= 25 - - - TMD:20% NR TMD has been Although TMD
Avila et RA:n= 92 presented in the produces some
al AS:n= 33 first years of the severe
(2013) OA:n=21 disease more impairments,
frequently than in most of the
later. patients seem to
adapt it easily.
Fabbri et SLE:n=49 BGI: - - - Corticosteroid Periodontitis is an Periodontal
al %40.8±31.0 Cyclophosphami important factor disease
(2014) PD:1.7±1.8 mm de in the treatment has
PAL: 2.5±1.9 maintenance of beneficial effect
mm the inflammatory in
response that controlling
occurs in SLE. disease activity
in SLE.
Leite et SLE:n= 48 - Hyposalivation:7.29% - - Antihypertensive Hyposalivation in Active disease
al Anticonvulsant SLE patients is and age >27
(2015) Diuretic associated with decrease the
disease activity amount of saliva
and age. significantly in
SLE patients.
Loyola SLE: n= - Flow: 0.6 ml/min Frequency: - NR Increased risk of SLE activity has
Rodrigu 60 pH: 4.6 85% caries and high a positive
ez et al DMFT:12.6 ± counts of correlation with
(2016) 5.7 cariogenic salivary pH,
IDCI bacterias have flow and dental
:9.8 ± 5.9 been detected in caries.
patients.
Menzies SLE: - Dry mouth:16% - - Oral In SLE, Regular oral
et al n=11 prednisolone associated examination is
(2018) CCL: Steroid inhaler diseases such as warranted to
n=11 Antibiotic Sjogren’s identify oral
DLE: n= syndrome may lupus and
20 influence saliva. provide
treatment.
Bologna SLE:n=13 - Xerostomia:100%(SL - - NR Different kind of Xerostomia in
et al DLE:n=7 E) alterations from patients with
(2018) SCLE:n= Flow: 0.29 ml/min SS were shown in SLE may be one
3 Hyposalivation:13.05 minör labial of multisystemic
% salivary glands in presentations of
SLE. the disease.

Correa SLE: n=75 Periodontitis:68 Flow:≤0.3 DMFTI: 13.65 - NR SLE has a Interdisciplinary
et al C:n= 78 % ml/min(12%) (6.48%) negative impact intervention
(2018) on the oral health with follow-up
related quality of is needed for
life of patients SLE care.
with SLE.
Table 5: Summary of the studies reporting dental implant treatment in SLE patients (C: case report)

Study Study Number Mean Number Mean Survival Time from Drug therapy
type of age of follow up rate diagnosis
patients (years) implants (months) (years)
Li et al CR 1 50 5 36 100 35? Corticosteroid
(2004) Paracetamol
Azathioprine Methotrexate
Chloroquine
Paracetamol
Ergun et CR 1 49 6 24 100 30 Hydroxychloroquine
al Steroids
(2010)
Drew et CR 1 28 15 18 100 NR Glucocorticoid
al Immunomodulators
(2018)
Accepted Article

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