Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients

Antibodies to periodontogenic bacteria are associated
                with higher disease activity in lupus patients
    H. Bagavant, M.L. Dunkleberger, N. Wolska, M. Sroka, A. Rasmussen, I. Adrianto*,
    C. Montgomery, K. Sivils, J.M. Guthridge, J.A. James, J.T. Merrill, U.S. Deshmukh
    Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, USA;
    Current affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, USA.

     Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE).
    In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the
     mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease
                                                   parameters in SLE patients.

     Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing
      bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the
        Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter
      actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga
    ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinical
     parameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement,
                                    and disease activity (SLEDAI and BILAG) were studied.

SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetem-
 comitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and
 they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal
         pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity.

Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients.
  These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to
                                                    lupus therapies.

                                                         Key words
                                    systemic lupus erythematosus, periodontitis, antibodies

                           Clinical and Experimental Rheumatology 2019; 37:Clinical
                                                                            106-111.and Experimental Rheumatology 2019
Periodontal bacterial exposure and lupus / H. Bagavant et al.

Harini Bagavant, MBBS, PhD                    Introduction                                 ing higher incidence of periodontitis
Micah L. Dunkleberger, BA                     Systemic lupus erythematosus is a            in SLE patients (11). In addition, a
Nina Wolska, MS                               complex autoimmune disorder affect-          recent report on the characterisation of
Magdalena Sroka, MS
                                              ing multiple organ systems such as the       the subgingival microbial community
Astrid Rasmussen, MD, PhD
Indra Adrianto, PhD                           skin, kidneys, heart, lung, and brain (1).   showed that compared to non-lupus
Courtney Montgomery, PhD                      The presence of autoantibodies against       controls, SLE patients have significant
Kathy Sivils, PhD                             multiple self-components is a hall mark      dysbiosis in the periodontal microbiota,
Joel M. Guthridge, PhD                        of SLE and the autoantibody specifici-       with a greater proportion of pathogenic
Judith A. James, MD, PhD                      ties are associated with distinct patho-     bacteria (12). Whether exposure to the
Joan T. Merrill, MD                           logic features of the disease. In addi-      periodontal bacteria affects disease ac-
Umesh S. Deshmukh, PhD
                                              tion to a strong genetic predisposition,     tivity in SLE is still not clear. The goal
Please address correspondence to:             environmental factors, particularly in-      of the present study was to determine if
Dr Harini Bagavant,
                                              fectious agents, can play a role in SLE      bacteria in the dental plaque influence
Research Associate Member,
Oklahoma Medical Research Foundation,         pathogenesis. In SLE, microbes hold          autoimmune features in SLE patients.
825 NE 13th Street,                           the potential to initiate and exacerbate     Since high titres of IgG antibodies to
Oklahoma City, OK 73104, USA                  autoimmunity, and modify the course          plaque bacteria indicate either an ongo-
E-mail:              of clinical disease by affecting multiple    ing infection or prior history of expo-
Reprints will not be available from the       pathways (2).                                sure (13-16), banked sera from a well
author.                                       The association between antibodies to        characterised SLE patient cohort were
Received on January 2, 2018; accepted         infectious agents and antibodies to self-    analysed for antibodies to a selected
in revised form on April 17, 2018.            proteins has been established in a wide      panel of oral bacteria. The associations
© Copyright Clinical and                      spectrum of autoimmune diseases (3, 4).      between anti-bacterial antibodies and
Experimental Rheumatology 2019.               Over the past several years, considera-      clinical disease were evaluated.
                                              ble attention has been directed towards
                                              investigating how viral exposures, such      Methods
                                              as Epstein Barr virus, influence the dis-    Patients and controls
                                              ease (5). However, bacterial infections      All experiments were performed in ac-
                                              affecting the respiratory tract, urinary     cordance with the Helsinki Declaration
                                              tract, and skin are often seen in SLE pa-    and approved by the Oklahoma Medi-
                                              tients (6). In addition to these anatomic    cal Research Foundation Institutional
                                              sites, the gingival mucosal surface is       Review Board. Banked serum samples
                                              continuously exposed to a plethora of        and clinical data were obtained from
                                              bacteria present in the dental plaque.       SLE patients seen from May 2002 to
                                              The interface between the dental plaque      October 2014 in the Oklahoma Lupus
                                              and the gingival epithelium represents       Cohort through the Oklahoma Rheu-
                                              a site of constant communication be-         matic Diseases Research Cores Cent-
                                              tween microbes and the innate immune         er. Patients who met the ≥4 American
                                              system (7). Further, these bacteria          College of Rheumatology (ACR) SLE
                                              have access to the systemic circulation      criteria, and were evaluated for disease
                                              through bleeding gums and through di-        activity (n=303) were studied. The de-
                                              rect invasion of the gingival epithelium     mographics of the patients in this study
                                              (8, 9). Previous work from our labora-       are shown in Table I. Sera from de-
                                              tory suggests that the dental plaque can     identified volunteers, who did not have
                                              offer a chronic source of autoantigen        SLE were also studied for anti-bacterial
                                              mimics (10). T cells reactive with a         antibodies (n=75).
                                              Sjögren’s syndrome and lupus-associ-
                                              ated autoantigen Ro60, can be activated      Clinical parameters of SLE
                                              by peptides derived from dental plaque       Anti-dsDNA antibody was measured
                                              bacteria. Thus, exposure of the immune       by the Crithidia luciliae indirect im-
Funding: this work was supported by           system to dental plaque bacteria in SLE      munofluorescence assay. Antibodies to
grants from the Oklahoma Center for the
                                              patients holds a significant potential to    other autoantigens including Sm pro-
Advancement of Science and Technology
(HR15-145), and the National Institutes       modulate the disease.                        tein with ribonucleoproteins (SmRNP),
of Health (P30GM110766,                       The knowledge of lupus patient re-           Sjögren’s syndrome antigen A (SSA/
U54GM104938, P30AR053483,                     sponses to dental plaque bacteria is lim-    Ro), and Sjögren’s syndrome antigen
P30GM103510, U19AI082714,                     ited. The indication that lupus patients     B (SSB/La) were measured using a
and U01AI101934).                             are exposed to these bacteria can be         bead-based assay. C3 and C4 comple-
Competing interests: none declared.           derived indirectly from reports show-        ment levels were determined at the

Clinical and Experimental Rheumatology 2019                                                                                      107
Periodontal bacterial exposure and lupus / H. Bagavant et al.

Table I. Oklahoma Lupus Cohort patient

                                SLE patients

Total, n                        303
Female, n (%)                   279 (92.1)
Age in years, median (range)     40 (16-71)
Duration of disease in years,     2 (0-39)
 median (range)
Race, n (%)
Caucasian                       165   (54.5)
African American                 62   (20.5)
Asian                            12   (3.9)
American Indian                  41   (13.5)
Mixed (2 or more)                22   (7.2)
Pacific Islander                  1   (0.3)
ACR SLE criteria, median (range) 6    (4-11)
SLEDAI, median (range), n         6   (0-24), 300
BILAG total, median (range), n 11     (0-42), 303

Diagnostic Laboratory of Oklahoma.
Clinical assessments of SLE were done
using the modified SELENA - Sys-
temic Lupus Erythematosus Disease
Activity Index (SLEDAI) (17) and the
British Isles Lupus Assessment Group
(BILAG-2004) Index (18).

Bacterial strains
Bacterial strains residing in the sub-
gingival plaque in the oral cavity were
used as antigens for ELISA, and were
obtained from ATCC (Manassas, VA,
USA). These include: red complex or-
ganisms implicated in chronic periodon-
tal disease: Prophyromonas gingivalis
(ATCC 33277) and Treponema denticola
(ATCC 35405); a periodontal pathogen
associated with aggressive periodontal
disease: Aggregatibacter actinomycet-
emcomitans serotype b (ATCC 28522);
and commensal bacteria: Streptococcus
gordonii (ATCC 51656) and Capnocy-
tophaga ochracea (ATCC 33596).

Detection of antibody to
bacterial strains
An ELISA-based assay to measure anti-
bacterial antibodies was used as previ-
ously described (19). Sera from the
Oklahoma Lupus Cohort were tested
at 1:500 dilution. Serial dilutions of a            Fig. 1. Presence of anti-dsDNA antibody in SLE patients is associated with higher antibody titres
pooled serum sample were included as                against A. actinomycetemcomitans, P. gingivalis, T.denticola and C. ochracea.
                                                    (A-E) SLE patients were stratified into autoantibody positive or autoantibody negative groups based
a calibrator for each plate. A standard             on reactivity to dsDNA, SmRNP, SSA/Ro, and SSB/La respectively and anti-bacterial antibody titres
curve was constructed and anti-bacte-               were compared using Kruskal Wallis test. Dunn’s post-test was used to compare anti-bacterial antibod-
rial antibody titres (units/ml) were cal-           ies between autoantibody positive and negative groups for each specificity. Anti-bacterial antibody
culated for each sample. Samples with               titres are plotted as units/ml (median+interquartile range); (n) number of patients in each group.
                                                    (F-I) Correlation between anti-dsDNA titres and anti-bacterial antibody titres calculated by Spearman
OD readings higher than the calibration             method.
curve were re-tested at higher dilutions.

108                                                                                                       Clinical and Experimental Rheumatology 2019
Periodontal bacterial exposure and lupus / H. Bagavant et al.

Table II. Association of antibodies to periodontal bacteria and disease activity by SLEDAI.                 tients, anti-A. actinomycetemcomitans
                                                                                                            antibodies showed the strongest cor-
Bacteria            Antibody titres (n)                             SLEDAI SCORES
                                                                                                            relation (Spearman rho=0.57; p10      p-value*    with anti-dsDNA antibody titres (Fig-
A.actino-                median                   1618              2021#            2318##       0.011     ure 1f). Anti-P. gingivalis (rho=0.42;
mycetemcomitans           range                 17-14520         275-21855         456-60160                p=0.005), anti-T. denticola (rho=0.43;
                            (n)                    (63)             (184)              (53)                 p=0.004) and anti-C. ochracea
P. gingivalis            median                   2823              3616             6062###     0.0095     (rho=0.34; p=0.04) also showed statis-
                          range               525-13550000       268-48470         225-88350
                            (n)                    (62)             (179)              (52)                 tically significant, albeit more modest
T. denticola             median                   7524              8505              9903        0.15      correlations (Fig. 1g-i).
                          range                 894-94190        845-149900       1046-172500
                            (n)                    (61)             (179)             (51)                  Antibodies to specific periodontal
C.ochracea               median                   3929              4668              4383        0.07      pathogens correlate with indicators of
                          range                 943-24030        677-122500        714-107800
                            (n)                    (54)             (160)              (37)                 higher disease activity in SLE patients
S.gordonii               median                   9999              9848              9562        0.86      SLE patients were categorised based
                           range               1393-30840        1630-45610        1826-32980               on disease activity into mild (SLEDAI
                            (n)                    (62)             (179)              (52)                 ≤2), moderately severe (SLEDAI 3-9)
*by   Kruskal Wallis test; #p=0.04,   ##
                                           p=0.007, ###p=0.0047 by Dunn’s post-test.                        and severe (SLEDAI ≥10) groups. As
                                                                                                            shown in Table II, a comparison of anti-
Table III. Association of antibodies to periodontal bacteria and disease activity by BILAG.                 bacterial antibody titres between these
                                                                                                            3 groups showed a statistically signifi-
Bacteria                    Antibody titres (n)                             TOTAL BILAG                     cant association between increased dis-
		  Mild Mod. Severe to severe p-value                                                                      ease activities with higher anti-A. actin-
		 (C/D)    (≥3B or ≥1A)                                                                                    omycetemcomitans antibody (p=0.011)
                                                                                                            and higher anti-P. gingivalis antibody
A. actinomycetemcomitans           median                    1794                2534           0.043
                                    range                  17-16960           350-21855                     titres (p=0.0095).
                                     (n)                     (90)                 (43)                      The anti-A. actinomycetemcomitans an-
P. gingivalis                      median                    3408                5026           0.056       tibody titres in patients with the lowest
                                    range                 572-307000           307-88350                    disease activity scores were significant-
                                     (n)                     (90)                 (43)
                                                                                                            ly lower than the patients with moderate
T. denticola                       median                    8066                10565           0.23
                                    range                 893-149900          1922-80900                    (p=0.04) or highest activity (p=0.007).
                                     (n)                     (90)                 (42)                      Anti-P. gingivalis antibodies were sig-
C. ochracea                        median                    4197                 5369           0.08       nificantly lower in the patients with
                                    range                 943-122500           761-95120                    lowest disease activity compared to the
                                     (n)                     (76)                 (35)
                                                                                                            highest activity scores (p=0.0047).
S. gordonii                        median                   10012                 9907           0.46
                                    range                 1393-45610          3528-25180                    The British Isles Lupus Assessment
                                     (n)                     (90)                 (43)                      Group (BILAG) index uses different
                                                                                                            clinical measures for evaluation of dis-
Statistical analyses                                       based on the presence or absence of an-          ease activity based on individual organ
Graph Pad Prism 7.0 and Systat software                    tibodies to the major lupus-associated           involvement (18). The disease activity
were used to perform statistical analyses.                 autoantigens: dsDNA, Sm/RNP, SSA/                in each patient was classified as mild
Normality tests were performed on each                     Ro, and SSB/La. The anti-bacterial               (only C and D organ scores; n=90),
dataset and non-parametric tests were                      antibody titres in the antibody positive         moderate (1- or 2- B scores; n=168),
used for non-Gaussian distributions.                       and negative group for each autoantigen          and moderately severe to severe (≥3- B
Mann-Whitney test was used to compare                      were compared. As shown in Figure                or ≥1- A score; n=43). As shown in Ta-
two populations; Kruskal-Wallis test fol-                  1a-e, patients with anti-dsDNA have              ble III, the anti-A. actinomycetemcomi-
lowed by Dunn’s post-test for multiple                     higher antibodies to A. actinomycet-             tans antibody titres were significantly
comparisons. Correlations were deter-                      emcomitans, P. gingivalis, T. denticola,         higher in patients with moderately se-
mined by Spearman’s method. A p-value                      and C. ochracea, but not to S. gordonii,         vere to severe activity compared to the
of less than 0.05 at a 95% confidence in-                  when compared to patients lacking anti-          patients with mild disease (p=0.043).
terval was considered significant.                         dsDNA. The presence of anti-SmRNP                A similar trend was seen in anti-P.
                                                           antibodies was associated with higher            gingivalis antibody titres, although it
Results                                                    anti-bacterial antibody titres against all       failed to reach statistical significance
Higher anti-bacterial antibody titres                      the bacteria, while anti-SSA and anti-           (p=0.056). Associations were not seen
against specific bacteria are associated                   SSB failed to associate with antibodies          between disease activity and antibody
with the presence of anti-dsDNA                            to any of the periodontal bacteria.              titres to T. denticola, C. ochracea or S.
Patients were stratified into groups                       Among the anti-dsDNA positive pa-                gordonii.

Clinical and Experimental Rheumatology 2019                                                                                                       109
Periodontal bacterial exposure and lupus / H. Bagavant et al.

                                                    ing high titre of antibodies against or-      actinomycetemcomitans antibody titres
                                                    ganisms associated with periodontitis         and increased disease activity with both
                                                    in our cohort of SLE patients suggests        SLEDAI and BILAG indices. Higher
                                                    that the patients immune system was ex-       anti-P. gingivalis antibody titres were
                                                    posed to these oral pathogens.                also strongly associated with higher
                                                    The presence of anti-dsDNA antibody           SLEDAI scores. Anti-dsDNA antibod-
                                                    is a hallmark of SLE, and it showed           ies are a scoring criterion for SLEDAI,
                                                    strongest correlation with anti-A. ac-        and multivariate analyses showed that
                                                    tinomycetemcomitans. Although the             the SLEDAI association with anti-P.
                                                    precise specificity of anti-A. actinomy-      gingivalis antibodies was significantly
Fig. 2. Limited cross reactivity between anti-A.    cetemcomitans antibodies is not known,        driven by anti-dsDNA positivity. How-
actinomycetemcomitans and anti-dsDNA antibod-       they do not appear to cross-react with        ever, this fails to explain the trend be-
ies in SLE patients. IgG purified from five SLE     DNA. While absorption of anti-A. actin-       tween higher P. gingivalis antibodies
patients were pre-absorbed with A. actinomycet-
emcomitans, and the residual antibodies to A. ac-
                                                    omycetemcomitans IgG with A. actino-          and higher BILAG indices. Further,
tinomycetemcomitans (A) and dsDNA (B) were          mycetemcomitans significantly reduced         despite the comparable association of
measured by ELISA. Sera not pre-absorbed with       anti-bacterial reactivity, it failed to re-   anti-T. denticola antibodies with higher
A. actinomycetemcomitans were used as controls.
Each line connects control and A. actinomycet-
                                                    duce dsDNA reactivity (Fig. 2). These         anti-dsDNA as well as, C3 and C4 com-
emcomitans absorbed serum for the same patient.     data suggest that the A. actinomycetem-       plement depletion (Supplementary Fig.
p-values were calculated by paired t-test.          comitans mediated periodontal disease         2), there was a lack of association be-
                                                    process might contribute towards am-          tween anti-T. denticola antibodies and
Discussion                                          plifying anti-dsDNA in SLE patients.          either measure of disease activity. An
By using banked serum samples from                  This is highly plausible considering the      important factor to consider is that the
a well characterised cohort of SLE pa-              study by Konig et al which implicates A.      BILAG and SLEDAI are very different
tients, this study demonstrates that high           actinomycetemcomitans as a trigger for        kinds of measurement. While SLEDAI
titre of IgG antibodies against the perio-          rheumatoid arthritis (24).                    scores are more affected by global in-
dontal pathogen A. actinomycetemcom-                We had previously reported that bacte-        creases in disease activity, the BILAG
itans was significantly associated with             rial proteins from oral commensal bac-        index is more sensitive and fluctuates
higher disease activity in SLE patients.            teria, specifically C. ochracea were ca-      with changes even in an individual
Considered together with previous re-               pable of activating T cells reactive with     manifestation of the disease. Taken to-
ports investigating the association be-             the Sjögren and lupus associated autoan-      gether, these results suggest the need
tween periodontal disease and lupus                 tigen, SSA/Ro60. Therefore, the lack of       for additional studies to investigate the
(20-23), our study supports the notion              association between antibodies to peri-       contribution of exposure to P. gingivalis
that bacterial infections in the subgingi-          odontal bacteria and SSA and SSB was a        in SLE. The present study suggests that
val mucosa modulate SLE.                            surprising result. Since SSA and/or SSB       the relationship between SLE and peri-
In this study we used the presence of               antibody positivity was significantly as-     odontal disease is defined by the specif-
circulating anti-bacterial antibodies as            sociated with the history of sicca or dry     ic pathogen, A. actinomycetemcomitans
evidence for exposure to the bacteria.              mouth in our lupus patients (p=0.015,         driving the periodontal disease.
This strategy is well established and               n=299), anti-bacterial antibodies were        A unique characteristic of A. actinomy-
antibody titres against bacteria from the           compared between patients with or             cetemcomitans is their ability to induce
subgingival plaque have been used as                without sicca. As shown in Supplemen-         citrullination of host proteins. A recent
indicators for exposure to and burden of            tary Fig. 1, anti-bacteria antibody titres    report showed that Leukotoxin A, an
specific bacteria (13-16). A recent study           between patients with or without sicca        exotoxin produced by A. actinomycet-
showed a strong correlation between the             were not significant. These results sup-      emcomitans, induces permiabilisation
detection of antibodies to A. actinomy-             port previous literature showing lack         of the cell plasma membranes leading
cetemcomitans and its leukotoxin with               of association between clinical and           to an unregulated influx of calcium in
the presence of A. actinomycetemcomi-               microbiologic parameters of periodon-         toxin susceptible cells (24, 31). This
tans in the sub-gingival isolates from              tal disease and Sjögren’s syndrome, a         activates the endogenous protein argi-
individual patients (24). Further, anti-A.          disease characterised by reduced saliva       nine deiminase (PAD) enzymes in the
actinomycetemcomitans and anti-P. gin-              production and progressive loss of sali-      cytosol (PAD2) and the nucleus (PAD4)
givalis antibody titres reflecting expo-            vary gland function (27-29). In contrast      and causes hypercitrullination of self-
sure to those bacteria are known to per-            to periodontal disease, lack of saliva has    proteins, which in neutrophils, leads
sist for 15 years (25). A similar clinical          been found to be strongly associated          to cell death. Thus, exposure to A. ac-
observation was also made in another                with dental caries and supra-gingival         tinomycetemcomitans and not the other
study where elevated titres of anti-P.              bacteria, which are distinct from the         periodontal pathogens in lupus patients
gingivalis antibodies persisted when                periodontal bacterial populations (30).       holds the potential to amplify a patho-
monitored for 24 months even when the               Our clinical analyses showed a signifi-       genic autoimmune response through the
disease was inactive (26). Thus, detect-            cant association between higher anti-A.       release of modified self-antigens.

110                                                                                                Clinical and Experimental Rheumatology 2019
Periodontal bacterial exposure and lupus / H. Bagavant et al.

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An interesting clinical study in SLE           11. RUTTER-LOCHER Z, SMITH TO, GILES I,                    tal disease. J Periodontol 1992; 63: 1110-6.
patients (n=49) showed that aggressive             SOFAT N: Association between systemic lupus        27. KURU B, McCULLOUGH MJ, YILMAZ S, POR-
                                                   erythematosus and periodontitis: a system-             TER SR: Clinical and microbiological studies
treatment of periodontitis resulted in a           atic review and meta-analysis. Front Immunol           of periodontal disease in Sjögren syndrome
significant improvement in the respons-            2017; 8: 1295.                                         patients. J Clin Periodontol 2002; 29: 92-102.
es to lupus therapy (23). This report          12. CORRÊA JD, CALDERARO DC, FERREIRA GA               28. LUGONJA B, YEO L, MILWARD MR et al.:
                                                   et al.: Subgingival microbiota dysbiosis in sys-       Periodontitis prevalence and serum antibody
complements our finding of higher lupus
                                                   temic lupus erythematosus: association with            reactivity to periodontal bacteria in primary
activity in patients with potential expo-          periodontal status. Microbiome 2017; 5: 34.            Sjögren’s syndrome: a pilot study. J Clin
sure to specific bacteria. Prevention of       13. PAPAPANOU PN, NEIDERUD AM, DISICK E,                   Periodontol 2016; 43: 26-33.
periodontal disease and management of              LALLA E, MILLER GC, DAHLÉN G: Longitu-             29. de GOÉS SOARES L, ROCHA RL, BAGORDA-
                                                   dinal stability of serum immunoglobulin G              KIS E, GALVÃO EL, DOUGLAS-de-OLIVEI-
periodontal health have been advocated                                                                    RA DW, FALCI SGM: Relationship between
                                                   responses to periodontal bacteria. J Clin Peri-
as simple tools for reducing morbidity in          odontol 2004; 31: 985-90.                              sjögren syndrome and periodontal status: A
debilitating systemic disease states (32).     14. CUNNINGHAM LL, NOVAK MJ, MADSEN M,                     systematic review. Oral Surg Oral Med Oral
Our study provides support for conduct-            ABADI B, EBERSOLE JL: A bidirectional rela-            Pathol Oral Radiol 2018; 125: 223-31.
                                                   tionship of oral-systemic responses: observa-      30. LE GALL M, CORNEC D, PERS JO et al.: A pro-
ing systematic clinical investigations             tions of systemic host responses in patients           spective evaluation of dental and periodontal
into periodontal disease in SLE and a              after full-mouth extractions. Oral Surg Oral           status in patients with suspected Sjögren’s
rationale for aggressive management of             Med Oral Pathol Oral Radiol 2014; 117: 435-            syndrome. Joint Bone Spine 2016; 83: 235-6.
periodontal health in SLE patients.                44.                                                31. KONIG MF, ANDRADE F: A critical reappraisal
                                               15. KUDO C, NARUISHI K, MAEDA H et al.:                    of neutrophil extracellular traps and NETosis
                                                   Assessment of the plasma/serum IgG test to             mimics based on differential requirements for
Acknowledgements                                   screen for periodontitis. J Dent Res 2012; 91:         protein citrullination. Front Immunol 2016; 7:
The assistance from Mr Stan Kamp                   1190-5.                                                461.
                                               16. DYE BA, HERRERA-ABREU M, LERCHE-                   32. CULLINAN MP, SEYMOUR GJ: Periodontal
and Ms Louise Williamson in compil-
                                                   SEHM J et al.: Serum antibodies to periodon-           disease and systemic illness: will the evidence
ing and submitting this manuscript is              tal bacteria as diagnostic markers of peri-            ever be enough? Periodontol 2000. 2013; 62:
gratefully acknowledged.                           odontitis. J Periodontol 2009; 80: 634-47.             271-86.

Clinical and Experimental Rheumatology 2019                                                                                                         111
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