Periodontal disease in pediatric rheumatic diseases

Abstracts

Gingivitis and periodontitis are immunoinflammatory periodontal diseases characterized by chronic localized infections usually associated with insidious inflammation. This narrative review discusses periodontal diseases and mechanisms influencing the immune response and autoimmunity in pediatric rheumatic diseases (PRD), particularly juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (C-SLE) and juvenile dermatomyositis (JDM). Gingivitis was more frequently observed in these diseases compared to health controls, whereas periodontitis was a rare finding. In JIA patients, gingivitis and periodontitis were related to mechanical factors, chronic arthritis with functional disability, dysregulation of the immunoinflammatory response, diet and drugs, mainly corticosteroids and cyclosporine. In C-SLE, gingivitis was associated with longer disease period, high doses of corticosteroids, B-cell hyperactivation and immunoglobulin G elevation. There are scarce data on periodontal diseases in JDM population, and a unique gingival pattern, characterized by gingival erythema, capillary dilation and bush-loop formation, was observed in active patients. In conclusion, gingivitis was the most common periodontal disease in PRD. The observed association with disease activity reinforces the need for future studies to determine if resolution of this complication will influence disease course or severity.

Gingivitis; Periodontitis; Periodontal diseases; Juvenile idiopathic arthritis; Childhood-onset systemic lupus; erythematosus; Juvenile dermatomyositis

Gengivite e periodontite são doenças periodontais imunoinflamatórias caracterizadas por infecções localizadas crônicas geralmente associadas a uma inflamação insidiosa. Essa revisão narrativa discute doenças periodontais e mecanismos que influenciam a resposta imune e a autoimunidade na área das doenças reumáticas pediátricas (DRP), particularmente a artrite idiopática juvenil (AIJ), lúpus eritematoso sistêmico juvenil (LESJ) e dermatomiosite juvenil (DMJ). Foi notada maior frequência de gengivite nessas doenças em comparação com controles sadios, enquanto casos de periodontite foram achados raros. Em pacientes com AIJ, a gengivite e a periodontite estavam relacionadas a fatores mecânicos, artrite crônica com incapacitação funcional, desregulação da resposta imunoinflamatória, dieta e medicamentos, principalmente corticosteroides e ciclosporina. Em pacientes com LESJ, a gengivite estava associada a períodos mais longos da doença, doses elevadas de corticosteroides, hiperativação dos linfócitos B e elevação da imunoglobulina G. São escassos os dados sobre doenças periodontais na população com DMJ; nos pacientes ativos, foi observado um padrão gengival singular, caracterizado por eritema gengival, dilatação dos capilares e formação arbustiforme. Em conclusão, gengivite foi a doença periodontal mais comum em pacientes com DRP. A associação observada com a atividade da doença reforça a necessidade de futuros estudos, com o intuito de determinar se a resolução dessa complicação irá influenciar o curso ou a gravidade da doença.

Gengivite; Periodontite; Doenças periodontais; Artrite idiopática juvenil; Lúpus eritematoso sistêmico juvenil; Dermatomiosite juvenil

Introduction

Gingivitis and periodontitis are immunoinflammatory periodontal diseases characterized by chronic localized infections usually associated with insidious inflammation.¹

Periodontal diseases (PD) can cause systemic inflammation, and it was demonstrated to be an essential underlying component of several inflammatory and immune mediated diseases, such as atherosclerosis,² diabetes mellitus³ and systemic autoimmune rheumatic diseases.⁴ In adults with rheumatoid arthritis (RA), PD was associated with disease activity and severity⁵ with a striking similarity between both diseases with regard to genetic susceptibility and pathogenesis.⁶

PD is also relevant for pediatric rheumatic diseases (PRD), since poor oral health is a risk factor for systemic infection and inflammation in general population and may be more important in patients with immune dysregulation under immunosuppressive drugs.⁷

Therefore, we performed a narrative review and we conducted a series of literature searches in the MEDLINE/PubMed database for English language articles focusing on PD in patients with PRD. The search strategy included a combination of medical subject headings and keywords. The search terms that we used were "periodontal disease", "gingivitis", "pediatric rheumatic diseases", "juvenile idiopathic arthritis", "juvenile rheumatoid arthritis", "juvenile systemic lupus erythematosus", "childhood-onset systemic lupus erythematosus" and "juvenile dermatomyositis". The search covered the period between 1970 and 2012, and included clinical studies, systematic reviews and animal studies. All articles identified were full-text papers.

Periodontal diseases in children and adolescents

Plaque-induced PD has been classified into three subtypes: healthy (absence of plaque induced PD), gingivitis (presence of gingival inflammation without loss of connective tissue attachment) and periodontitis (presence of gingival inflammation with loss of connective tissue and alveolar bone).⁸ Gingivitis is an inflammatory response to bacteria of the dental biofilm, without loss of dental attachment, and its prevalence among schoolchildren ranged from 40% to 100%.^9-12 Periodontitis is a widespread infection affecting the tooth support of 10%-15% of the general population.¹³ The incidence of periodontitis in pediatric population is generally 1%.¹⁴

Children and adolescents can develop PD as a consequence of a local or a systemic factor. Local factors include: plaque, calculus, orthodontic appliances and dental anomalies (such as: enamel projections, enamel pearls). Systemic factors include: malnutrition, gender, race, hormones, smoking, systemic diseases and immunosuppressive drugs.^15-17

The more common form of PD in pediatric population is gingivitis. This gingival abnormality is characterized by a local inflammatory response to microbial challenge without bone resorption. However, it is crucial to note that young subjects with overt gingival inflammation more frequently exhibit periodontal attachment loss than adolescents without gingival inflammation and gingivitis always appears to precede the development of periodontitis.^2,15

Most cases of periodontitis described in children and adolescents occur as manifestation of systemic diseases, such as Papillon-Lefevre syndrome, hypophosphatasia and leukocyte adhesion deficiency. These diseases induce an impaired immune system, that compromise microbial plaque response and increase the likelihood of periodontal bone loss and premature teeth loss associated with severe and generalized periodontitis during or immediately after eruption of the primary teeth.^15-17

Pathogenesis of PD

The tooth is an organ with peculiar characteristics in the organism. It is a hard structure that has one portion immersed in connective tissue and another part is exposed to the external environment, susceptible to bacterial colonization (Fig. 1). In addition, bacteria or their products continually interact with gingival epithelium to stimulate a host response.¹⁸ An inflammatory infiltrate (mainly comprised of neutrophils or polymorphonuclear leukocytes) is usually present, even in the absence of clinically obvious inflammation in order to maintain periodontal homeostasis.¹⁹

Fig. 1
Periodontal tissues anatomy. (A) Clinical examination of healthy gingiva; (B) Periodontal tissues; (C) Histological characteristics of gingival

The bacteria associated with PD comprise a group of Gram-negative anaerobic organisms, among which the socalled "red complex" pathogens, especially Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, are more prominent. The reasons for the host response fails to control periodontal infection or to inhibit disease progression are not well understood, but the disruption of host homeostasis by periodontal pathogens may be a major contributory factor.²⁰

Gingivitis pathogenesis is characterized initially by a vascular response with increased fluid and inflammatory cell infiltration in gingiva with perivascular lymphocytic infiltrate and macrophage cells deposition. Lymphocytes are predominantly T cells with a CD4:CD8 ratio of approximately 2:1.¹⁹ Clinical signs of oral inflammation including bleeding, swelling and redness of the gingiva may occur in these patients.

The persistence of this inflammatory response results in chronic gingivitis with collagen degradation but without any dental attachment loss. Gingivitis may progress to periodontitis, but this only occurs in 10% to 15% of the population and may be associated with environmental factors and/ or genetic susceptibility.¹⁹ The immunological mechanism underlying periodontal development involves a shift to a Bcell/plasma-cell response with high levels of interleukin-1 (IL-1) and interleukin-6 (IL-6) production, increased chemokine production by macrophages [IL-1b, tumor necrosis factor-alpha (TNF-α) and IL-17]^21,22 and a consequent enhanced osteoclastogenesis with connective tissue destruction and alveolar bone loss.²²

Cytokines may also modulate the action, differentiation, and survival of cells outside the immune system. In this regard, nervous system cells expressing neurotransmitters related to neurogenic inflammation²³ are known to allow neuroplastic changes that are observed in chronic pain. In fact, severe periodontal disease was reported by our group to be related to refractory craniofacial pain.²⁴

PD and systemic diseases

Regarding periodontal pathogens, the dental plaque is a complex biofilm with a relevant role in the pathogenesis of PD and can serve as a reservoir of microbes with local and systemic consequence.²⁵ The systemic exposure to periodontal pathogens, their toxins, and periodontal derived/elicited inflammatory mediators may have a deleterious effect in different organ or systems. Three mechanisms by which periodontal infection may influence systemic health have been described: metastatic infection (caused by translocation of Gram-negative bacteria from the periodontal pocket to the bloodstream), metastatic injury (such as vascular lesions from the effects of circulating microbial toxins and pro-inflammatory mediators) and metastatic inflammation (due to the immunological response to the periodontal pathogens and their toxins).²⁵

Indeed, pathogen manipulation may perturb otherwise homeostatic host-bacterial interactions, thereby leading to non-protective and non-resolving chronic inflammation.²⁶ This condition can cause systemic inflammation that has been recognized as an essential component of different multifactorial diseases, including chronic inflammatory rheumatic diseases.²⁷

Gingivitis and periodontitis may also induce a variety of immunological alterations with circulating immune complexes due to the failure of autoimmune regulation and tolerance, contributing the onset and progression of systemic autoimmune and rheumatic diseases.⁴

Periodontal diseases in pediatric rheumatic diseases

Reports of PD in PRD are restricted to juvenile idiopathic arthritis, childhood-onset systemic lupus erythematosus and juvenile dermatomyositis.

Tables 1 and 2 include clinical studies of periodontal diseases in pediatric rheumatic diseases.

Table 1
Clinical studies of periodontal diseases in juvenile idiopathic arthritis

Diseases	Country	Number of patients and healthy controls	Clinical and immunological findings
Walton et al., 200028	UK	Review	Negative impact of poor oral health
Miranda et al., 200337	Brazil	32 JIA patients and 24 controls	JIA adolescents presented more periodontal attachment loss than healthy controls
Welbury et al., 200335	UK	149 JIA patients and 149 controls	Increased level of poor oral hygiene and dental decay in JIA
Savioli et al., 200432	Brazil	26 JIA patients and 13 controls	Gingivitis in JIA patients associated with upper limb disability
Ahmed et al., 200431	UK	55 patients and 55 controls	Gingivitis score was significantly higher in JIA compared to controls
Miranda et al., 200555	Brazil	38 JIA patients and 29 controls	Increased serum IL-18 and IL-1p in JIA patients increased susceptibility to PD
Havemose-Poulsen et al., 200538	Denmark	10 JIA, 23 RA, 45 aggressive periodontitis patients and 25 controls	Peripheral blood cytokine profile and citokine secretion pattern were showed in by JIA, RA and generalized aggressive periodontitis
Miranda et al., 200633	Brazil	18 JIA adolescents and 14 controls	No clinical or laboratory differences in periodontal inflammation were found in JIA patients and controls
Havemose-Poulsen et al, 200639	Denmark	10 JIA, 23 RA, 45 aggressive periodontitis patients and 25 controls	Elevated levels of traditional markers of inflammation were observed in generalized aggressive periodontitis, JIA and RA.
Reichert et al, 200636	Germany	78 JIA patients and 75 controls	JIA was not a risk factor for periodontitis
Reichert et al., 200743	Germany	110 JIA patients (50 of them generalized aggressive periodontitis),102 JIA with chronic periodontitis and 102 controls	HLA-DRB3n was common risk indicator for JIA and chronic periodontitis in females
Havemose-Poulsen et al, 200740	Denmark	10 JIA, 23 RA, 45 aggressive periodontitis patients and 25 controls	Variation of alleles of the IL-1 gene cluster modified the cytokine profiles of patients with aggressive periodontitis and chronic arthritis
Synodinos et al, 200829	Ireland	Review	Caries and periodontal disease related to diet, disease activity and similar inflammatory process pattern
Leksel et al, 200834	Sweden	41 JIA patients and 41 controls	JIA patients showed worse periodontal condition compared to controls
Silva et al, 201248	Brazil	16 JIA patients and 11 controls	Lower alveolar bone density in JIA patients

• JIA, juvenile idiopathic arthritis; RA, rheumatoid arthritis; PD, periodontal disease; UK, United Kingdom; USA, United States of America.

Table 2
Clinical studies of periodontal diseases in pediatric rheumatic diseases

Diseases	Country	Number of patients and healthy controls	Clinical and immunological findings
JDM
Ghali et al., 199960	USA	5 JDM patients	Gingival telangiectases
Marton et al., 200558	Hungary	34 JDM patients	Gingival telangiectases
Savioli et al., 201059	Brazil	26 JDM patients and 22 controls	Unique gingival pattern associated with cutaneous disease
C-SLE
Fernandes et al., 200764	Brazil	48 C-SLE patients and 48 children	C-SLE patients had inadequate oral hygiene, gingivitis and temporomandibular joint dysfunction
Figueredo et al., 200865	Brazil	16 C-SLE patients and 14 controls	Increased elastase activity suggested hyperactivity of neutrophils

• JDM, juvenile dermatomyositis; C-SLE, childhood-onset systemic lupus erythematosus; USA, United States of America.

Juvenile idiopathic arthritis (JIA)

There is a negative impact on oral health in JIA patients due to mechanical factors, chronic arthritis with functional disability, dysregulation of the immunoinflammatory response, diet and medications.^28-30

Several studies,^29-34 reporting that JIA could be a risk factor for gingivitis or periodontitis and these pediatric conditions were included in the current system classification of PD.⁸ In this regard, chronic arthritis with upper limb disability and reduced mandibular mobility due to temporomadibular joint involvement was reported to be an important contributing factor for PD in our JIA patients.³² Furthermore, a significant increased level of poor oral hygiene in patients with JIA was found.³⁵ On the other hand, one study showed that if cofactors (such as: age, gender and smoking) are included, the microbial plaque (and not the JIA diagnosis) is related to periodontitis.³⁶

It has been suggested that the association between JIA and periodontal disease might be caused by a common dysregulation of the immunoinflammatory response.³⁷ Increased values of IL-10, and TNF-α in unstimulated blood-cell culture and IL-1Ra in stimulated blood-cell culture were observed in generalized periodontitis, JIA and RA, indicating that these cytokines are shared by these diseases.³⁸ In the same way, patients with generalized periodontitis may present elevated levels of traditional markers of inflammation, such as neutrophils, leukocytes, CRP and ESR, similar to observed in patients with JIA and RA.³⁹

Moreover, allele variation of IL-1 gene cluster modify the cytokine profiles of patients with aggressive periodontitis as JIA, suggesting that this group shared genetic background for cytokines profiles.⁴⁰

In fact, the increased serum levels of IL-18 and IL-1β in JIA patients accompanied by a similar subgingival microbiota suggest that the increased frequency of incipient attachment loss observed in these patients might be due to their altered systemic inflammatory response, making them more susceptible to PD.³³

Additionally, for periodontitis,⁴¹ as well as for JIA,⁴² associations to HLA classes I and II alleles were reported, and HLA-DRB3 could be a common putative risk for JIA and chronic periodontitis among females.⁴³ In fact, the immune response to bacteria is influenced by human leucocyte antigen (HLA) polymorphism^44,45 and individual peptide binding capability of cell surface HLA receptors.⁴⁶ Furthermore, bacterial mimicry between bacteria and certain HLA molecules could lead to autoimmune reactions or to mechanisms of cross-tolerance.⁴⁷

Patients with JIA showed also lower alveolar bone density compared to healthy controls, without correlation with rheumatologic and periodontal clinical parameters.⁴⁸ The generalized bone loss in arthritis has been suggested to an increase of osteoclastic activity and a reduction in the process of bone formation. Reduced physical activity and inadequate calcium and vitamin D intake can influence this reduction in bone mineral density.^49,50

Microbial challenge, environmental immune response modifiers and host genetic variation can have local and systemic repercussion. These effects will induce changes in connective tissue and bone metabolism resulting in the clinical features observed in JIA with PD (Fig. 2).

Fig. 2
Similarities between periodontal diseases and pediatric rheumatic diseases: Microbial challenge, environmental immune response modifi ers and genetic factors have critical role in pathogenesis of both diseases. The host infl ammation, with production of antibodies, polymorphonuclears (PMN), cytokines and metalloproteinase, has local and systemic effect and trigger changes in connective tissue and bone metabolism with remarkable clinical signs of diseases

The most important factor associated with PD in JIA is medication. In this regard, cyclosporine may result in gingival enlargement, ulceration or bleeding.^51,52 Long-term use of methotrexate in rats with PD enhanced alveolar bone destruction.⁵³ Glucocorticoids may have induced osteoporosis,⁵⁴ and this therapy may also delay wound healing and increased risk of gingival infection,²⁸ however the effect of this medication in alveolar bone is unknown in JIA. Despite the immunosuppressive treatment, the majority of JIA patients presented mild gingivitis without loss of connective tissue attachment, and periodontitis was rarely described.^32,37,55 In addition, JIA patients under anti-TNF blockage had a higher frequency of sites with increased probing depth and a lower frequency of sites with bleeding on probing,⁵⁶ however experimental studies suggested that these drugs might inhibit radiographic progression.⁵⁷

Juvenile dermatomyositis (JDM)

Periodontal diseases were rarely reported in JDM population, and the two most important factors present in these patients are: reduction of mandibular mobility and gingival alterations.^58,59

Alterations in the masticatory system have been identified in JDM patients, such as: hyposalivation, mucosal alterations, mainly in the form of telangiectasia,^58-63 and weakness of the masticatory muscles.⁵⁸ The reduction of mandibular mobility, particularly mouth opening in active JDM patients reinforces the possibility that this finding is an additional manifestation of JDM in the masticatory system and a consequence of muscle weakness.⁵⁹

One relevant aspect evidenced in JDM patients was a unique gingival pattern, characterized by gingival erythema, capillary dilation and bush-loop formation (similar to periungual capillary changes observed in nailfold capillaroscopy) associated with cutaneous disease activity. This finding reported by our group was distinct from PD, suggesting that gingiva is a possible target tissue for JDM.⁵⁹

Childhood-systemic lupus erythematosus (C-SLE)

PRD were also rarely reported in C-SLE population. One study observed that C-SLE patients had an inadequate oral hygiene with higher incidence of gingivitis and without periodontitis. The most important risk factors for gingivitis were longer disease duration and higher cumulative dose of prednisone.⁶⁴

In C-SLE patients, active elastase was observed in gingival crevicular fluid (GCF) from inflamed sites, even in the presence of significantly lower levels of IL-18 and IL-13. In contrast, the plasma levels of IL-18 and the erythrocyte sedimentation rate were significantly higher in this group of patients. The increased elastase activity suggests neutrophils hyperactivity in C-SLE patients, possibly induced by a priming effect caused by the high IL-18 plasma levels.⁶⁵

Conclusions

In conclusion, gingivitis was the most common periodontal disease in PRD. The underlying mechanism is multifactorial and includes mechanical factors, chronic arthritis with functional disability, dysregulation of the immunoinflammatory response, diet and medications, particularly corticosteroids. The observed common association with disease activity in all reported diseases reinforces the need for future studies to determine if resolution of this complication could influence disease course or severity. In addition, there are some evidence that gingiva may be a target tissue in pediatric autoimmune rheumatic disease.

Take-home messages

The most important periodontal disease observed in pediatric rheumatic diseases was gingivitis.

Periodontitis was rarely reported in pediatric rheumatic diseases.

Periodontal diseases in JIA patients are multifactorial related to mechanical factors, functional disability, dysregulation of the immunoinflammatory response, diet and medications.

A gingival pattern, characterized by gingival erythema, capillary dilation and bush-loop formation associated with cutaneous disease activity was observed in JDM.

Gingivitis associated with longer disease period and high doses of corticosteroids was observed in C-SLE patients.

Acknowledgments

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (grants 2008/582384 to CAS, 2009/51897-5 to EB and CAS, and 2010/12035-5 to GMCF), Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (301411/2009-3 to EB, and 472155/2012-1 to CAS), Federico Foundation (to EB and CAS) and by Núcleo de Apoio à Pesquisa "Saúde da Criança e do Adolescente" of USP to CAS.

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Publication Dates

• Publication in this collection
  Jul-Aug 2014

History

• Received
  04 Oct 2013
• Accepted
  23 Nov 2013