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 Table of Contents  
REVIEW ARTICLES
Year : 2021  |  Volume : 13  |  Issue : 3  |  Page : 207-213

The association between pemphigus and pemphigoid with periodontitis: A systematic review and meta-analysis with trial sequential analysis


1 College of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
2 University of Malaya, Kuala Lumpur, Malaysia
3 College of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia; Dental Department, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia

Date of Submission19-Nov-2020
Date of Decision06-Jan-2021
Date of Acceptance23-Jan-2021
Date of Web Publication18-Jun-2021

Correspondence Address:
Dr. Fathima Fazrina Farook
King Saud Bin Abdulaziz University for Health Sciences, Preventive Dental Science Department, 11426 Riyadh.
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jioh.jioh_333_20

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  Abstract 

Aim: Ample evidence is available regarding the potential synergistic and bidirectional association between periodontal disease and systemic inflammatory diseases. However, the link between periodontal disease and autoimmune bullous diseases remains unclear in the literature. The present review aimed to investigate the association between periodontal disease and two major subgroups of autoimmune bullous diseases—pemphigus and pemphigoid. Materials and Methods: We performed a systematic review and meta-analysis on data extracted according to PRISMA. Relevant articles were selected from a literature search using MEDLINE, EMBASE, and CENTRAL from inception until December 7, 2020. Both randomized and non-randomized controlled studies were included. Non-systematic reviews and trials published as abstract, case series, and case reports were excluded. The meta-analysis was conducted with RevMan 5.3. Results: Three articles (199 subjects) were included for the analysis. Of the 199 participants, 99 patients with bullous disease were compared with 100 healthy controls. In comparison to the healthy cohort, the group with bullous disease had a statistically significant increase in clinical attachment loss (mean difference (MD) 0.82, 95% confidence interval (CI): 0.21–1.43, ρ=0.008, I2 = 92%) and probing depth (MD 0.79, 95% CI: 0.71–0.87, ρ<0.00001, I2 = 0%). No difference was demonstrated in the plaque index (MD 20.57, 95% CI: ‒3.35–44.5, ρ= 0.09, I2 = 98%) and gingival index (MD 6.87, 95% CI: ‒6.15–19.89, ρ=0.3, I2 = 98%) for both bullous and healthy groups. Conclusion: Both autoimmune bullous diseases, pemphigus and pemphigoid, are significantly associated with periodontal disease. However, the findings need to be interpreted cautiously as there is significant heterogeneity. Additional prospective studies are required to strengthen the evidence.

Keywords: Bullous Disease, Pemphigoid, Pemphigus, Periodontal, Periodontitis, Vesiculobullous Lesions


How to cite this article:
Farook FF, Al Meshrafi AA, Alshammari A, Nuzaim M N, Al-Nomay NS. The association between pemphigus and pemphigoid with periodontitis: A systematic review and meta-analysis with trial sequential analysis. J Int Oral Health 2021;13:207-13

How to cite this URL:
Farook FF, Al Meshrafi AA, Alshammari A, Nuzaim M N, Al-Nomay NS. The association between pemphigus and pemphigoid with periodontitis: A systematic review and meta-analysis with trial sequential analysis. J Int Oral Health [serial online] 2021 [cited 2021 Oct 22];13:207-13. Available from: https://www.jioh.org/text.asp?2021/13/3/207/318454




  Introduction Top


Periodontitis, a multifactorial and complex inflammatory disease in tooth-supporting tissues, is categorized by loss of periodontal tissue support.[1],[2] In adults, the main cause of tooth loss, periodontitis, is a significant global public health problem. Periodontitis is initiated by the microbial plaque biofilm but develops due to an intensified host immune-inflammatory response.[3]The host response depends on several factors including genetic make-up, lifestyle choices, and environmental factors.[4]

The prevalence figures of periodontal disease vary according to race and geographic region.[5]Though slowly progressing periodontitis is prevalent, advanced disease is diagnosed in approximately 5–20% of the adult population globally.[6] Chronic periodontitis, known as periodontitis according to the new classification for periodontal diseases and implant conditions, is considered the second most prevalent oral disease globally.[7],[8]

Ample evidence is available in literature regarding the potential synergistic and bidirectional association between periodontal disease and systemic immune inflammatory disorders.[9],[10],[11],[12],[13],[14],[15],[16],[17] The link between autoimmune bullous diseases and periodontitis is more evident with the subtypes, pemphigus vulgaris (PV) and mucous membrane pemphigoid (MMP),[18],[19],[20],[21],[22],[23] both affecting predominantly the oral mucosa. These rare pemphigus and pemphigoid diseases are characterized by anti-desmosomal and anti-hemidesmosomal autoantibody-induced intraepithelial and sub-epithelial split formation. The clinical manifestations include blisters and erosions on the skin and mucous membranes. The pathophysiology underlying this association could be an indirect effect based on the build-up of plaque from reduced oral hygiene due to pain, infrequent dentist visits for checkup and cleaning, or a reduced immune response to periodontal pathogens due to taking immunosuppressive treatment. A more direct cause is possibly shared pathogenic mechanisms between autoantibody-induced and inflammatory tissue damage due to bacteria.[23],[24] The potential association between periodontal disease and autoimmune bullous diseases is still unknown.

Based on the assumption that bullous disease is associated with periodontal disease, the main objective of this systematic review and meta-analysis was to determine the relationship between the two major bullous disorders, pemphigus and pemphigoid, with periodontal disease.


  Materials and Methods Top


The PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis) format was used to perform this review with meta-analysis, and the PICO (Participant, Intervention, Comparison and Outcomes) model was used to formulate the research question [Supplement 1]. The review protocol was registered on OSF at https://osf.io/2w8te.
Supplement 1: PICO table

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The primary outcome of the study was clinical attachment loss (CAL). Secondary outcomes included plaque index (PI), bleeding on probing (BOP), and probing depth (PD).

A systematic search from the databases MEDLINE, CENTRAL as well as EMBASE was conducted from its commencement until December 7, 2020. We conducted a search in trial registers (World Health Organization International Clinical Trials Registry and ClinicalTrials.gov) to identify unpublished and ongoing studies. In addition, a hand search was done for additional references. The search strategy used is presented in [Supplement 2]. We have limited our search to English language articles and English-translated version provided by the publishers. The authors were contacted to retrieve any missing data.
Supplement 2: Search strategy

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The inclusion criteria were patients with autoimmune bullous disease (≥18 years), matched with healthy controls. All observational studies investigating the association of periodontal disease in subjects with bullous disease matched with a healthy population were included in this review. We have excluded case reports, case series, systematic reviews, and abstract publications. Solo title and abstract reviews were screened by two reviewers. Disagreement between first and second reviewer was resolved by the third reviewer. The full texts of qualifying papers were then independently screened by the same two reviewers, and any discrepancies were discussed with the third reviewer for a final decision. We used the Newcastle Ottawa Scale, a star rating system, which comprises selection, comparability, and exposure to assess the quality of the case–control studies. Solo risk of bias assessment was done by two reviewers and a third author resolved any disagreements. The quality of evidence, GRADE assessment, and the summary of findings were assessed based on the Cochrane Handbook criteria.

A meta-analysis was conducted with the included studies assessing the association between autoimmune bullous disease and periodontitis using RevMan (Version 5.3).[25] The mean difference (MD) was the summary estimate in all three observational studies. To use the adjusted estimates as summary estimates, a generic inverse variance method was used. As the studies varied in their characteristics, a random-effects model and inverse variance method were used. We reported our findings as MD with 95% confidence interval (CI), and the heterogeneity between the studies was estimated using the I2 statistic. The interpretation of the I2 was based on the Cochrane Handbook with I2<40% categorized as not important, whereas 30–60%, 50–90%, and over 75% were considered as moderate, substantial, and considerable, respectively. The statistical significance of heterogeneity was signified by considering a two-sided ρ-value of <0.05. Although these categories overlap, the importance of the I2 value depends on the magnitude and direction of effects and the strength of heterogeneity.[26] We planned to use Funnel plots and an Egger regression test to evaluate the publication bias between the studies only if an adequate number of reports were available.

A trial sequential analysis (TSA) was performed using the Trial Sequential Analysis viewer version 0.9.5.5 Beta, Copenhagen Trial unit. This was done for our primary outcome, CAL, so as to avoid the risk of random error as well as the multiplicity phenomenon that may occur due to repeated significance testing in meta-analyses. For the TSA, we used a two-sided sequential analysis-adjusted random-effects model and power of 90% with 5% type 1 error risk, which provided the mandatory meta-analysis information size and adjusted significance thresholds.


  Results Top


In total, 235 citations were identified from the comprehensive literature search. Duplicates were removed. The resulting 235 citations were screened in terms of the title and abstract. Of the 235 citations, eight articles were selected for the assessment of full text. Out of the above, only three articles (199 subjects) were included in this review. The PRISMA flow diagram of our search process is displayed in [Figure 1]. The clinical characteristics of the three studies (n = 3) are presented in [Table 1] and characteristics of the excluded studies are given in [Supplement 3].
Figure 1: PRISMA flow chart

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Table 1: Clinical characteristics and outcomes of included studies

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Supplement 3: Characteristics of excluded studies

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The three observational studies were single-center studies with the objective to analyze the relationship between the two major autoimmune bullous diseases, pemphigus and pemphigoid, with periodontitis.

Of the 199 participants, a group of 99 patients with bullous diseases, pemphigus or pemphigoid, was compared with a healthy cohort (100 patients) to determine the association of periodontal disease with autoimmune bullous disease. The mean age of the group with bullous disease was 53.3±17.6 years and that of the healthy controls was 53.0±16.8 years, which was not statistically significant (P = 0.98) in all the studies. No conflict of interest was stated by the authors in the included studies. According to the New Castle Ottawa scale, all three studies had a low risk of bias [Supplement 4]. One study achieved a maximum of seven stars,[27] and the remaining two studies achieved a score of 8.[19],[28] The quality of evidence (GRADE) assessment with a summary of the findings are provided in [Supplement 5].
Supplement 4: Risk of bias assessment: Newcastle-Ottawa Quality Assessment Scale

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Supplement 5: Summary of Finding and Quality of Evidence (GRADE) Assessment

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A statistically significant increase in CAL in the bullous disease group compared with the control group was found (combined data, n = 199). [Figure 2]A demonstrates the pooled MD of the association between autoimmune bullous disease and periodontitis of 0.82 (95% CI: 0.21–1.43, ρ=0.008). A high magnitude of statistical heterogeneity (I2=92%) was observed across all studies. According to [Figure 3], though the mandated meta-analysis sample size was achieved, the cumulative Z curve crossed the conventional significance boundary and not the trial sequential significance boundary.
Figure 2: A: Forest plot of the MD in CAL between the bullous and control groups. B: Forest plot of the MD in probing depth between the bullous and control groups. C: Forest plot of the MD in bleeding on probing scores between the bullous and control groups. D: Forest plot of the MD in PI between the bullous and control groups

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Figure 3: TSA for CAL between bullous cases and healthy controls

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Compared with the control group, there was a statistically significant increase in the probing depth in the group with bullous disease (two studies, n = 159 subjects; MD 0.79, 95% CI: 0.71–0.87, ρ<0.00001 [Figure 2B]). A low statistical heterogeneity (I2=0%) was noted. In terms of bleeding on probing, there was no statistically significant difference between the two groups (three studies, n = 199 subjects; MD 6.87, 95% CI: ‒6.15–19.89, ρ=0.3 [Figure 2C]). Substantial heterogeneity (I2=98%) was found across the studies.

For the PI between the bullous disease group and the control group (three studies, n = 199 subjects; MD 20.57, 95% CI: ‒3.35–44.5, ρ= 0.09 [Figure 2D]), the finding was non-significant. There was significant statistical test of heterogeneity (I2=98%). Due to the insufficient number of studies (<10), a funnel plot was not created for the measured outcomes. Sensitivity analyses were conducted on all the outcomes. We detected no changes in the magnitude of the summary estimates by removing the most recent trials sequentially and re-analyzing the remaining data set. We also performed a sensitivity analysis for pemphigus and pemphigoid diseases, and no changes were detected in the summary estimates.


  Discussion Top


This is the first meta-analysis with TSA summarizing all available evidence related to the association between the two major autoimmune bullous diseases, pemphigus and pemphigoid, and periodontal disease. A thorough literature search was conducted, and the studies included went through a meticulous methodological assessment. However, a limited number of studies linking periodontitis and autoimmune bullous disease are available in literature. The studies examining the relationship between periodontitis and autoimmune bullous disease were restricted to PV and MMP due to the low incidence of other blistering diseases.[21],[22],[23]

Our meta-analysis showed that bullous disease was significantly associated with periodontal disease, specifically with regard to CAL and PD, but not for plaque and bleeding indices. However, it is noteworthy that the quality of the evidence for the chosen outcomes was low, due to a high degree of inconsistency and imprecision. The association of periodontitis with autoimmune bullous disease supports other studies on the same topic. Several case studies also proposed a link between bullous and gingival disease.[20]

Literature reported a relationship in the pathophysiological underpinning of bullous disease and periodontal disease, which includes the release of proinflammatory cytokines and the matrixins or matrix metalloproteinases and the release of reactive oxygen species.[29] It is accepted that periodontitis occurs as a result of hyperinflammatory or hyperimmune responses to plaque bacteria destroying the tooth supporting soft and hard tissues.[24],[30] The tissue injury mechanics include the release of proinflammatory cytokines (e.g.,interleukin IL-1, IL-6, IL-8, tumor necrosis factor-a) as well as matrix metalloproteinases (gelatinase B).[24] Pemphigoid diseases are caused by comparable inflammatory processes, including anti-hemidesmosomal autoantibody-induced cytokine production (e.g., IL-6 and IL-8), complement-mediated recruitment of matrix metalloproteinases (e.g., gelatinase B) as well as reactive oxygen species releasing leukocytes which damage the basal membrane zone components causing dermoepidermal splitting.[31]

Increased inflammatory mediators and acute-phase proteins due to periodontitis may contribute to the development of these diseases.[32] The pathophysiology mechanisms of MMP are dissimilar to PV. Autoantibodies, in PV, cause direct blister formation by binding to the surface antigens of epithelial cells. Gingival PV lesions may serve as a potential reservoir for plaque accumulation and, in this way, encourage periodontitis. Another possible explanation is that periodontitis-related local inflammatory processes may stimulate and prolong the autoimmune response (by presenting the antigenic epitopes in the damaged periodontium). A third mechanism could be tissue-specific autoimmunity, involved in causing the development of periodontitis, subsequent to PV. Oral hygiene becomes more ineffective due to the painful, slow-healing oral lesions, causing increasing plaque, a major factor in the development of periodontitis. Therefore, the long standing autoimmune bullous diseases are known to compromise oral hygiene which can lead to periodontitis secondarily.

The current study supports a review done by Jascholt et al.[29] However, the review included several studies, two studies with re-analysis of the same samples and others with selection bias. The finding has to be interpreted with caution as the search was done with only one database (PUBMED).

The findings of our review indicated that the autoimmune bullous group had a significantly higher level of CAL and PD when compared with the healthy controls. CAL is the most accurate index to detect periodontitis as it depends on a stable reference point,[33] and the longitudinal measurement of CAL is considered the gold standard for recording changes in the periodontal status.[34] Although the required meta-analytic sample size was achieved to detect a significant effect, our finding has to be interpreted with care due to a high degree of heterogeneity and an inconclusive TSA of CAL. The trial sequential boundaries (significance boundaries) and futility boundaries were not crossed. These adjustments were made to ensure that the total Type I and Type II errors remain at the level prescribed when the total evidence base achieves the calculated sample size. In addition, a number of confounding factors can have an effect on the severity of periodontal disease, including debridement of plaque, smoking, and glycemic control. One of the studies excluded smokers,[19] with the remaining two studies matched for smoking status.[27],[28] All studies excluded patients with diabetes mellitus, other systemic diseases, periodontal treatment received in the last 6 months, and pregnancy.

In comparison to the healthy cohort, our study showed no statistical significant difference between the two groups with regard to the bleeding on probing. We performed a TSA and the cumulative Z curve crossed the trial sequential significance boundary and reached the required meta-analysis sample size. However, the futility boundary was not crossed indicating that it cannot be inferred that patients with bullous disease did not differ significantly in terms of the bleeding on probing when compared with the healthy controls. Further studies are required to investigate this association. The finding is contrary to a study reporting a significant increase in gingival inflammation[27] and describing the increase as a pathophysiological similarity between MMP and periodontitis. Another study, a 5-year observation study by Schellinck et al.,[18] also reported increased gingival inflammation compared with the control group, but not an increased risk for the progression of the periodontal disease. Because there was no statistical difference in the mean bleeding scores between the groups, it provides evidence that the increased gingival inflammation in the group with MMP may not be due to inflammatory periodontal disease, but possibly to the MMP itself. The increase in the gingival index observed in the group with MMP should be interpreted with caution, because the MMP morphology could have introduced bias.

In the current study, there was no significant difference in the PI between the two groups. A high plaque score and increased gingival inflammation would suggest an increased risk of developing periodontitis. Although these findings raise awareness of the potential risk of periodontitis, the non-significant difference between the two groups does not exclude an association between autoimmune bullous disease and periodontitis.

There are several limitations, including unadjusted or uncontrolled confounding factors such as incomplete information regarding smoking status, the lack of correlation between the periodontal parameters and the development or the level of oral MMP/PV.[35] Comorbidities and drugs administered in the nature of the observational studies may have affected the outcomes of the studies. These factors are associated with increased bone loss resulting in greater probing depth and CAL. In addition, limitations include the small sample sizes, limited information regarding the characterization of patients in terms of their clinical and molecular status, poor design issues such as the medical condition and periodontitis being recorded at same time (do not know which came first) and the non-availability of standardized severity score indices for the bullous and periodontal diseases.


  Conclusion Top


There appears to be a positive association between bullous disease and periodontal disease within bounds of the available evidence. Additional, well-designed prospective studies are required to explore the true relationship between the two diseases.

Acknowledgements

We would like to acknowledge Dr Susanna Wright of King Abdullah International Medical Research Center for her assistance in editing the manuscript.

Financial support and sponsorship

Self-funding.

Conflicts of interest

The authors declare that they have no conflict of interests.

Author contributions

FF: literature search, collection and analyzed data, manuscript writing; AM: literature search, collected data, and manuscript editing; AA: literature search and manuscript editing; MNMN: literature search and manuscript editing; NSN: literature search and manuscript editing All authors read and approved the final manuscript.

Ethical policy and Institutional Review Board statement

Not applicable.

Patient declaration of consent

Not applicable.

Data availability statement

The data sets are available from the corresponding author on reasonable request.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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