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Effect of MMP-13 levels on Disease Modifying Antirheumatic Drugs(DMARDS) and Corticosteroids on Rheumatoid Arthritis Patients with Chronic Periodontitis - A Biochemical Analysis
Abstract
To investigate the effect of anti-rheumatic DMARD and anti-inflammatory steroids in rheumatoid arthritis patients with chronic Periodontitis and also to estimate the levels of inflammatory biomarker MMP-13 in rheumatoid arthritis patients with chronic Periodontitis. A total of 90 subjects participated in the study. They were divided into three groups, Group I- 30 RA patients with CP who are consuming DMARD medications, Group II- 30 RA patients with CP who are consuming steroids and Group III- 30 population controls.The medications used by the rheumatoid arthritis patients were confirmed by a rheumatologist from the patients clinical records, based on the duration of the diseases, use of DMARDs, use of steroids , serological markers of RA, ACPA (anti-citrullinated peptide antibody), RF(rheumatoid factor) and no of swollen tender joints were determined. The Disease activity score (DAS 28) was calculated from the no of tender and swollen joints (28 joint count).Subsequent analysis for mmp-13 was done by enzyme linked immunosorbent assay (ELISA).The serum MMP -13 levels in the serum of the healthy control group had significantly lower mean and standard deviation when compared to group I and II. The MMP-13 levels were higher in patients taking DMARDs when compared with the patients on steroid medications, which were statistically significant (P <0.001). In our study, MMP-13 levels are raised in DMARD group and decreased in the corticosteroid group with an increase in the periodontal parameters such as pocket depth and CAL. The possibility of periodontal destruction would have happened much before and the treatment on steroids would have lead to remission, thereby reduction in the MMP 13 levels was noted.
Associations between periodontal disease (PD) and other diseases, including rheumatoid arthritis (RA), respiratory disease, and chronic kidney disease, have been reported. Patients with moderate to severe periodontitis have a high risk of suffering from RA and vice versa. This bidirectional relationship could be due to genetic (HLA-DR), dysregulation of the inflammatory response, and the role of Porphyromonas gingivalis (P. gingivalis), which stimulates anti-cyclic citrullinated peptide antibodies via citrullination. This review aims to identify associated factors that contribute to RA and PD relationship and to explore the effects of disease-modifying anti-rheumatic drugs (DMARDs) on PD. A literature search was performed using PubMed and Google Scholar to identify related articles published from the year 1990 to 2020 within the research interest using keyword combinations. Thirty-one articles that fit the research interest and address the research questions for both objectives were selected. As a result, the associated factors for RA and PD relationship, including genetic predisposition, immunoregulatory imbalance, and the role of P. gingivalis in the citrullination process as a risk factor of RA. Significant improvement was found in periodontal parameters in RA patients treated with biologic and synthetic DMARDs. This review reported common factors contributing to the RA and PD relationship and the benefits of DMARDs on periodontitis.
Associations between periodontal disease (PD) and other diseases, including rheumatoid arthritis (RA), respiratory disease, and chronic kidney disease, have been reported. Patients with moderate to severe periodontitis have a high risk of suffering from RA and vice versa. This bidirectional relationship could be due to genetic (HLA-DR), dysregulation of the inflammatory response, and the role of Porphyromonas gingivalis (P. gingivalis), which stimulates anti-cyclic citrullinated peptide antibodies via citrullination. This review aims to identify associated factors that contribute to RA and PD relationship and to explore the effects of disease-modifying anti-rheumatic drugs (DMARDs) on PD. A literature search was performed using PubMed and Google Scholar to identify related articles published from the year 1990 to 2020 within the research interest using keyword combinations. Thirty-one articles that fit the research interest and address the research questions for both objectives were selected. As a result, the associated factors for RA and PD relationship, including genetic predisposition, immunoregulatory imbalance, and the role of P. gingivalis in the citrullination process as a risk factor of RA. Significant improvement was found in periodontal parameters in RA patients treated with biologic and synthetic DMARDs. This review reported common factors contributing to the RA and PD relationship and the benefits of DMARDs on periodontitis.
RA is a chronic autoimmune inflammatory condition associated with increased cardiovascular morbidity and mortality. Endothelial dysfunction, a marker of early atherosclerotic disease, occurs in some inflammatory diseases but this relationship has not been previously explored within the microvasculature of patients with RA. We therefore assessed forearm microvascular endothelial function in patients with RA and determined its relationship to RA disease activity and inflammation.
A total of 128 RA patients with no previous history of cardiovascular disease were evaluated. Endothelium-dependent and -independent forearm skin microvascular function was measured using laser Doppler imaging after iontophoretic delivery of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Parameters of RA disease activity and inflammation were also checked.
There was a significant negative correlation between the level of inflammation measured by log(10)CRP and maximum vasodilatation measured by peak ACh response (r(2) = -0.209, P = 0.018, Pearson correlation test). In a multiple regression model, age (beta = -0.449, P < 0.0001) and log(10)CRP (beta = -0.193, P = 0.026) were independently negatively associated with ACh responses. When RA patients were sub-divided according to their systemic inflammatory status (CRP > 10 mg/l vs CRP </= 10 mg/l), the high CRP group showed lower vasodilator responses to ACh [P = 0.018, analysis of variance (ANOVA)] and SNP (P = 0.05, ANOVA) than the low CRP group.
In this large cross-sectional study, we found for the first time systemic inflammation (CRP) to be independently associated with microvascular dysfunction in patients with RA. This strong correlation was independent of other conventional vascular risk factors.
The efficacy of oral prednisone as bridge therapy in rheumatoid arthritis (RA) was studied. Forty patients starting aurothioglucose were randomized to receive either prednisone or placebo for 18 weeks. The dose was 10 mg/day in the first 12 weeks, 7.5 mg/day in weeks 13 and 14, 5 mg/day in weeks 15 and 16, and 2.5 mg/day in weeks 17 and 18. Patients were followed for 44 weeks. We found that disease activity was significantly lower in the prednisone group as early as week 1 and continued up to week 12. Response to prednisone was noticed in 60% of the patients. After tapering prednisone, a rebound deterioration was noticed at weeks 20 and 24 in 58% of the responders. No significant differences in X-ray progression were found between the two groups. We concluded that oral prednisone (10 mg/day) significantly reduces short-term disease activity in 60% of patients with active RA. The rebound deterioration after tapering the dose means that bridge therapy with prednisone using this dose-reduction scheme is not recommended.
Oral glucocorticoids are widely used to treat patients with rheumatoid arthritis, but their effect on joint destruction, as assessed radiologically, is uncertain.
We conducted a randomized, double-blind trial comparing oral prednisolone (7.5 mg daily for two years) with placebo in 128 adults with active rheumatoid arthritis of less than two years' duration. Except for systemic corticosteroids, other treatments could be prescribed. The primary outcome variables were the progression of damage as seen on radiographs of the hand after one and two years, as measured by the Larsen index, and the appearance of erosions in hands that had no erosions at base line. The radiographs were viewed jointly by a radiologist and a rheumatologist who were unaware of the treatment assignment and the time point at which the films were obtained.
The statistical analysis of radiologically detected changes was based on 106 patients for whom there were films obtained at base line and two years later. After two years, the Larsen scores increased by a mean of 0.72 unit in the prednisolone group, indicating very little change, and by 5.37 units in the placebo group, indicating substantial joint destruction (P = 0.004). Of the 212 hands of these patients, 147 (69.3 percent) had no erosions at the start of the study. At two years, 15 of the 68 such hands in the prednisolone group (22.1 percent) and 36 of the 79 such hands in the placebo group (45.6 percent) had acquired erosions (difference, 23.5 percentage points; 95 percent confidence interval, 5.9 to 40.7; P = 0.007). The patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months; for pain at 6 months; and for disability at 6, 12, and 15 months (all P < 0.05). There was no difference between groups in standardized scores for the acute-phase response. The adverse events were typical of those encountered with antirheumatoid drugs.
In patients with early, active rheumatoid arthritis, prednisolone (7.5 mg daily) given for two years in addition to other treatments substantially reduced the rate of radiologically detected progression of disease.
Periodontal inflammation is characterized by irreversible degradation of periodontal ligament collagen fibers leading to loss of tooth attachment. Cultured gingival keratinocytes and fibroblasts express, in vitro, various matrix metalloproteinases (MMPs) which can degrade fibrillar collagens. We hypothesized that several MMPs are also synthesized in vivo by sulcular epithelium, and analyzed the collagenolytic MMPs (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in gingival tissue specimens and gingival crevicular fluid from adult and localized juvenile periodontitis patients by in situ hybridization, immunohistochemistry, and Western immunoblotting. MMP-2, -7, -8, and -13 were expressed in gingival sulcular epithelium. MMP-7 and -13 were also located in fibroblasts and macrophages, and MMP-8 in neutrophils. MMP-8- and -13-positive cells/mm2 were higher in periodontitis gingiva when compared with healthy control tissue (p < 0.01). In periodontal diseases, gingival sulcular epithelium expresses several, rather than a single, collagenolytic MMPs, and this proteolytic cascade is evidently responsible for the tissue destruction characteristic of adult and juvenile periodontitis.
Matrix metalloproteinases (MMPs) participate in extracellular matrix degradation in physiological and pathological conditions. The available evidence suggests that MMP-13 plays a significant role in both the initiation and progress of bone resorption. The aim of our study was to identify the presence of MMP-13 in adult patients with untreated chronic periodontitis. We also determined the activity of MMP-13 present in lesions undergoing episodic attachment loss in gingival crevicular fluid (GCF) samples.
After monitoring at 2 and 4 months, 21 patients showed destructive periodontitis (periodontally affected sites presenting at least two sites with > or =2 mm clinical attachment loss), and GCF samples were collected both from active and inactive sites (21 GCF samples, each). GCF was collected during a 30-second interval using a paper strip, and an immunofluorescence assay was performed to determine the basal activity of MMP-13 and the relationship between 4-aminophenylmercuric acetate (APMA)-activated total MMP-13 and basal MMP-13 activity. Gingival tissues from five patients were fixed in formalin and MMP-13 expression was demonstrated using immunohistochemistry and in situ hybridization. MMP-13 molecular forms were examined by Western immunoblotting with monoclonal antibodies.
MMP-13 was found in 100% of GCF samples from patients with chronic periodontitis. Active sites, associated with tissue destruction, had significantly higher proportions of active MMP-13 and MMP-13 activity levels than their inactive counterparts (1.49 versus 1.17 ng fluorescent product, respectively; P <0.05). Western blot, immunohistochemical staining, and in situ hybridization confirmed the presence of MMP-13 in periodontal disease, with observable differences between periodontitis and healthy subjects. MMP-13 immunoreactivities were seen mainly as 55 and 48 kDa, corresponding to partially and fully activated forms, respectively, and a smaller proportion of 60-kDa proenzyme form.
MMP-13 activity in GCF samples was significantly increased in active sites from progressive periodontal disease, supporting its role in the alveolar bone loss developed in this disease.
Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.
Background
The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs.
Objectives
To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and non-steroidal, anti-inflammatory drugs in patients with rheumatoid arthritis.
Search strategy
Medline Silverplatter, The Cochrane Controlled Trials Register, reference lists and a personal archive. Date of last search May 2002.
Selection criteria
All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a non-steroidal, anti-inflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. For adverse effects, long-term trials and matched cohort studies were also selected.
Data collection and analysis
Decisions on which trials to include were made independently by two observers based on the methods sections of the trials. Standardised mean difference (random effects model) was used for the statistical analyses.
Main results
Ten studies, involving 320 patients, were included. Prednisolone had a marked effect over placebo on joint tenderness (standardised mean difference 1.30, 95% confidence interval 0.78 to 1.83), pain (1.75, 0.87 to 2.64) and grip strength (0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than non-steroidal, anti-inflammatory drugs on joint tenderness (0.63, 0.11 to 1.16) and pain (1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable.
Reviewers' conclusions
Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.
Plain language summary
Synopsis
Low dose corticosteroids relieve the symptoms of rheumatoid arthritis, with a low risk of adverse effects even in the long term.
Corticosteroid drugs can relieve inflammation, and in high doses they have a dramatic effect on the symptoms of rheumatoid arthritis. They are used only temporarily, however, because of serious adverse effects during longterm use. The review found that corticosteroids in low doses are very effective. They are more effective than usual anti-arthritis medications (non-steroidal anti-inflammatory drugs, or NSAIDs). The risk of adverse effects is relatively low, even with long-term use.
Safety data come from a number of sources. Randomized clinical trials tend to be relatively short, exclude patients with significant comorbidity, have limited numbers of subjects and are primarily powered for efficacy. The most useful post-marketing data come from large national registries, such as Britain's BSRBR, Sweden's ARTIS, Germany's RABBIT, France's DANBIO, Spain's BIODASER and North America's CORRONA. Among the most commonly used non-biologic DMARDs, MTX is associated with risks of hepatotoxicity and cytopenia, as well as pneumonitis, particularly during the first year of treatment. Regarding TNF inhibitors, there is an increased risk of infection (including serious infections) by bacterial pathogens, atypical fungi and opportunistic pathogens. When possible, pneumococcal and influenza vaccines should be given before initiation of treatment with any biologic DMARD. Screening for latent tuberculosis is recommended for all TNF inhibitors, and has been shown to reduce the risk of reactivation. Evidence from registries suggests that there is no increased risk of solid tumours with TNF inhibitor treatment; however, non-melanoma skin cancers are more common. Specific risks with other biologic DMARDs include gastrointestinal perforation with tocilizumab, progressive multifocal leucoencephalopathy with rituximab and pulmonary infections with abatacept. Overall, the safety of biologic and non-biologic DMARDs appears to be reasonable, particularly compared with the risks associated with the disease itself. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA.
Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included.
Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1-1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found.
The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.
Risk factors play an important role in an individual's response to periodontal infection. Identification of these risk factors helps to target patients for prevention and treatment, with modification of risk factors critical to the control of periodontal disease. Shifts in our understanding of periodontal disease prevalence, and advances in scientific methodology and statistical analysis in the last few decades, have allowed identification of several major systemic risk factors for periodontal disease. The first change in our thinking was the understanding that periodontal disease is not universal, but that severe forms are found only in a portion of the adult population who show abnormal susceptibility. Analysis of risk factors and the ability to statistically adjust and stratify populations to eliminate the effects of confounding factors have allowed identification of independent risk factors. These independent but modifiable, risk factors for periodontal disease include lifestyle factors, such as smoking and alcohol consumption. They also include diseases and unhealthy conditions such as diabetes mellitus, obesity, metabolic syndrome, osteoporosis, and low dietary calcium and vitamin D. These risk factors are modifiable and their management is a major component of the contemporary care of many periodontal patients. Genetic factors also play a role in periodontal disease and allow one to target individuals for prevention and early detection. The role of genetic factors in aggressive periodontitis is clear. However, although genetic factors (i.e., specific genes) are strongly suspected to have an association with chronic adult periodontitis, there is as yet no clear evidence for this in the general population. It is important to pursue efforts to identify genetic factors associated with chronic periodontitis because such factors have potential in identifying patients who have a high susceptibility for development of this disease. Many of the systemic risk factors for periodontal disease, such as smoking, diabetes and obesity, and osteoporosis in postmenopausal women, are relatively common and can be expected to affect most patients with periodontal disease seen in clinics and dental practices. Hence, risk factor identification and management has become a key component of care for periodontal patients.
To determine whether short-term, oral low dose prednisolone (< or = 15 mg daily) is superior to placebo and non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis.
Meta-analysis of randomised trials of oral corticosteroids compared with placebo or a non-steroidal anti-inflammatory drug.
Trials conducted anywhere in the world.
Patients with rheumatoid arthritis.
Joint tenderness, pain, and grip strength. Outcomes measured on different scales were combined by using the standardised effect size (difference in effect divided by SD of the measurements).
Ten studies were included in the meta-analysis. Prednisolone had a marked effect over placebo on joint tenderness (standardised effect size 1.31; 95% confidence interval 0.78 to 1.83), pain (1.75; 0.87 to 2.64), and grip strength (0.41; 0.13 to 0.69). Measured in the original units the differences were 12 (6 to 18) tender joints and 22 mm Hg (5 mm Hg to 40 mm Hg) for grip strength. Prednisolone also had a greater effect than non-steroidal anti-inflammatory drugs on joint tenderness (0.63; 0.11 to 1.16) and pain (1.25; 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31; -0.02 to 0.64). Measured in the original units the differences were 9 (5 to 12) tender joints and 12 mm Hg (-6 mm Hg to 31 mm Hg). The risk of adverse effects during moderate and long term use seemed acceptable.
Prednisolone in low doses (< or = 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means.
Major challenges in periodontology include understanding the pathophysiology, the interplay between various components of the host response, parallels with other diseases and identifying biomarkers of the disease.
Four reviews were compiled with the aim of better understanding: (1) the role of polymorphic nuclear leucocytes (PMNs), i.e. neutrophils; (2) the function of cytokine networks in the host response; (3) whether parallels exist with rheumatoid arthritis (RA); and (4) whether useful biomarkers currently exist to help in the management of periodontal disease.
Based on the focused questions, electronic and manual searches were conducted for human, animal and cellular studies on the above topics.
Papers fulfilling the inclusion criteria were selected and reviews were written and reviewed and corrected before the academy meeting to produce consensus statements.
The following consensus statements were produced. PMNs are important in the pathophysiology of periodontal disease but there is limited evidence on their much quoted destructive potential. Cytokine networks are enormously complex and we are really at the beginning of understanding their role in the disease process. RA has both similarities and marked differences to periodontal disease although the existing utilization of anti-cytokine therapies and other molecules in its treatment may have importance in periodontal disease therapy. Biomarkers for periodontal disease have yet to be completely defined but the ratio of receptor activator of NF-κB ligand to osteoprotegerin appears to be a biomarker test with utility for detecting bone destruction.
Several studies have indicated a relationship between rheumatoid arthritis and periodontal disease. The aim of this study was to investigate the association between the circulating proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta, prostaglandin E(2), serotonin, rheumatoid factor, and periodontitis in patients with rheumatoid arthritis.
Nineteen patients, 17 women and two men, with rheumatoid arthritis were included. These patients had been examined repeatedly (average of three times) with regard to inflammatory markers and mediators from blood samples. Their teeth, excluding third molars, were examined with regard to number, clinical attachment level (CAL), probing depth (PD), and gingival bleeding on probing (BOP). Assessment of furcation involvement and increased tooth mobility was also made. All patients were non-smokers. Thirty healthy individuals, 20 women and 10 men, were included as a reference regarding TNF-alpha.
Patients with high levels of time-averaged TNF-alpha from repeated plasma samples had a higher frequency of BOP as well as increased CAL and PD compared to those with low levels.
Gingivitis and periodontitis are related to high levels of circulating TNF-alpha in patients with rheumatoid arthritis.
Periodontal conditions among an adult population of 161 dentate patients with rheumatoid arthritis (RA) were compared with those of an age and sex-matched random sample of non-rheumatic subjects. The number of teeth and prevalence of dental plaque, calculus, gingivitis, and deepened periodontal pockets were recorded. Alveolar bone breakdown and the distribution of subjects according to severity of periodontal disease were also registered. There was a tendency towards better periodontal conditions among RA-patients, severe periodontal breakdown occurring less frequently among RA-patients (12%) than among the controls (16%). The RA-patients had less plaque and calculus than the control group, a finding which could indicate a difference in periodontal care.
In the pathogenesis of rheumatoid arthritis, locally produced antibodies complex with an inciting antigen, yet to be identified, within the joint and activate the complement system, resulting in articular inflammation mediated primarily by polymorphonuclear leukocytes and their products. Chronic inflammatory cells then produce soluble factors that induce both tissue destruction and inflammation. A major issue is how and why apparently normal immune responses in the acute stage progress to chronic inflammation in subsequent months to years. Although it is often assumed that the initial etiologic agent, persisting in the joint or at an extra-articular site, is responsible for continued synovitis, this need not be the case. It is possible that once the inciting agent is cleared from the joint through a normal immune response, the presence of activated cells rich in surface class II histocompatibility (Ia) antigens could, under the influence of multiple genetic or environmental factors, become the target of autoimmune attack. Alternatively, the process might result from the interactions of synovial lining cells and their products with T cells assuming a secondary role. Further research into the relative contributions of soluble products, T helper and suppressor subsets, synoviocytes, and antigen determine which model is correct.
Osteoclasts resorb the extracellular matrix of bone by secreting protons and enzymes into a circumpherentially sealed compartment between the osteoclast and the bone surface. Although the lysosomal cysteine proteinases play a major role in matrix degradation by osteoclasts, collagenase (matrix metalloproteinase-1, EC 3.4.24.7) is also required for osteoclastic bone resorption, and may be directly involved in collagen degradation in the hemivacuole. We assessed the effects of inhibitors of cysteine proteinases and collagenase on bone resorption by osteoclasts isolated from rodent bone. We found that while inhibition of cysteine proteinases strongly suppressed osteoclastic resorption, inhibitors of collagenase were without effect on the number, size, or demineralised fringe of excavations. We could find no evidence of expression of mRNA for collagenase in rat osteoclasts by in situ hybridisation, but found that it was expressed by chondrocytes, bone surface cells and osteocytes adjacent to osteoclasts. The distribution of these cells, and the correlation between increased collagenase production and increased stimulation of osteoclastic resorption in vitro by bone cells, suggests that these cells might be involved in the regulation of bone resorption in situ, and that collagenase production might play a role in this process.
Capture ELISAs with biotinylated monospecific antibodies were developed to detect both C-reactive protein (CRP) and haptoglobin (Hp) in serum of adult periodontitis (AP) patients and normal subjects. Each acute-phase reactant was significantly increased in serum from AP patients with CRP at 9.12 +/- 1.61 mg/l versus 2.17 +/- 0.41 mg/l (P < 0.001) and Hp at 3.68 +/- 0.37 g/l versus 1.12 +/- 0.78 g/l (P < 0.001). Assessment of clinical characteristics of the patients' periodontal disease indicated that CRP and Hp levels were significantly increased in patients with the most frequent disease active episodes (P < 0.02 and P < 0.001, respectively). Longitudinal examination of the Hp levels showed a significant decrease following scaling and root planing (3.68 versus 2.38 g/l; P < 0.01). After a 2-year administration of 50 mg/b.i.d. Flurbiprofen (a non-steroidal anti-inflammatory drug), significantly decreased Hp levels were noted (P < 0.005). CRP levels declined by 35-40% after 1-2 years of treatment with the drug (P < 0.05). The findings indicated that localized infections resulting in increased inflammation and tissue loss in the periodontium elicit systemic host changes manifest by increases in two acute-phase reactants. The conclusions are that either these molecules are formed locally and distributed to the serum, or these presumably localized infections impact upon the systemic components of the host protective responses.
To quantify periodontal disease in rheumatoid arthritis (RA) patients and controls, and to correlate the degree of destruction from periodontal disease and from RA.
Fifty RA patients were matched for age, sex, smoking status, and oral hygiene with 101 controls. Correlations between indices of chronic destruction in periodontal disease (gingival attachment loss) and in RA (Larsen radiographic score) were determined.
Patients with longstanding active RA (mean +/- SD 13 +/- 8 years) who were receiving treatment with disease-modifying antirheumatic drugs (n = 46), corticosteroids (n = 38), or nonsteroidal antiinflammatory drugs (n = 43) had a higher rate of gingival bleeding (increased by 50%), greater probing depth (increased by 26%), greater attachment loss (increased by 173%), and higher number of missing teeth (increased by 29%) compared with controls. No correlation was found between the Larsen radiographic score and gingival attachment.
Patients with longstanding active RA have a substantially increased frequency of periodontal disease, including loss of teeth, compared with controls. Antiinflammatory treatment interferes with periodontal disease and might have masked a possible correlation between the indices of chronic destruction in RA and periodontal disease.
There are conflicting reports whether patients with rheumatoid arthritis (RA) are at a higher risk for periodontal disease (PD). Analogous mechanisms of tissue destruction have been reported for both diseases. This cross-sectional study should quantify PD in patients with longstanding RA and examine a possible association between the two diseases. It should also be investigated whether PD in RA patients could be the result of reduced functional capacity or be amplified by concomitant medical treatment. 50 RA patients were matched for age, sex, smoking and oral hygiene with 101 healthy controls. Data on the medication over the last three years was obtained by questionnaire. Among the rheumatological parameters recorded were a 28-joint-count, C-reactive protein (CRP), grip strength testing, upper extremity function (Keitel Index) and the Larsen-score of radiological joint destruction. The oral examination included the recording of individual oral hygiene measures and sicca symptoms, a modified Approximal Plaque- and Sulcus-Bleeding-Index (SBI), probing depths and clinical attachment loss and the Community Periodontal Index of Treatment Needs. The mean duration of RA was 13 (+/- 7.9) years. RA patients under treatment with disease modifying antirheumatic drugs (DMARDs, n = 46; 92%), corticosteroids (n = 38; 76%) and non steroidal antirheumatic drugs (NSAIDs, n = 43; 86%) had a higher rate of gingival bleeding (+ 50%), probing depth (+ 26%), clinical attachment loss (+ 173%) and number of missing teeth (+ 29%) compared with controls. While no correlation between the rheumatological variables (radiological destruction, functional capacity, grip strength) and the periodontal measurements (SBI, probing depth, clinical attachment loss) could be demonstrated, a positive correlation was observed between the CRP and the periodontal attachment loss (r = 0.32; p <0.05). In spite of a strong correlation between the duration of DMARD- and cortisone-medication and the Larsen-score (r = 0.48 and 0.64; p = 0.0005 and 0.0001, rsp.), no correlation between the duration of pharmacotherapy and the periodontal parameters could be established. Patients with long-term active RA present a substantially higher degree of PD including loss of teeth compared with controls. Functional impairment of the upper extremity might amplify present PD. The longterm use of NSAIDs, corticosteroids and DMARDs shows no connection with the severe PD observed in these patients. Oral hygiene amplifies PD severity and treatment need. Intensive prophylactic measures are required to prevent or reduce the damage of the periodontal tissues in RA patients.
The aim of this study was to determine and compare interleukin-6 (IL-6) levels in gingival crevicular fluid (GCF) and clinical periodontal findings in patients with rheumatoid arthritis (RA) and adult periodontitis (AP).
A total of 45 patients divided into 3 groups (15 patients with RA and AP, 15 patients with AP, and 15 periodontally healthy subjects) were included in this study. Plaque index (PI), gingival index (GI), sulcus bleeding index (SBI), probing depth (PD), and attachment level (AL) values for each patient were recorded. Enzyme-linked immunosorbent assay for quantitative detection of IL-6 in each GCF sample was employed.
No significant difference could be detected between the RA and AP groups in the mean clinical parameter data except PI. Although the mean GCF IL-6 level in the RA group was the highest, no significant difference could be found among the groups. There was only a strong negative correlation between GCF IL-6 levels and GI scores in the RA group.
In the patients with RA, despite increased local tissue destruction potential due to autoimmunity and higher PI levels than in the AP patients, our findings suggest that medication including corticosteroid and non-steroidal anti-inflammatory drugs may decrease gingival inflammation, but the synthesis and degradation of IL-6 in gingival tissue of RA patients may be different. To our knowledge, this study is the first report determining GCF IL-6 levels in RA patients.
Classification systems are necessary in order to provide a framework in which to scientifically study the etiology, pathogenesis, and treatment of diseases in an orderly fashion. In addition, such systems give clinicians a way to organize the health care needs of their patients. The last time scientists and clinicians in the field of periodontology and related areas agreed upon a classification system for periodontal diseases was in 1989 at the World Workshop in Clinical Periodontics. Subsequently, a simpler classification was agreed upon at the 1st European Workshop in Periodontology. These classification systems have been widely used by clinicians and research scientists throughout the world. Unfortunately, the 1989 classification had many shortcomings, including: (1) considerable overlap in disease categories, (2) absence of a gingival disease component, (3) inappropriate emphasis on age of onset of disease and rates of progression, and (4) inadequate or unclear classification criteria. The 1993 European classification lacked the detail necessary for adequate characterization of the broad spectrum of periodontal diseases encountered in clinical practice. The need for a revised classification system for periodontal diseases was emphasized during the 1996 World Workshop in Periodontics. In 1997 the American Academy of Periodontology responded to this need and formed a committee to plan and organize an international workshop to revise the classification system for periodontal diseases. The proceedings in this volume are the result of this reclassification effort. The process involved development by the Organizing Committee of an outline for a new classification and identification of individuals to write state-of-the-science reviews for each of the items on the outline. The reviewers were encouraged to depart from the preliminary outline if there were data to support any modifications. On October 30-November 2, 1999, the International Workshop for a Classification of Periodontal Diseases and Conditions was held and a new classification was agreed upon (Figure 1). This paper summarizes how the new classification for periodontal diseases and conditions presented in this volume differs from the classification system developed at the 1989 World Workshop in Clinical Periodontics. In addition, an analysis of the rationale is provided for each of the modifications and changes.
To determine the cellular and molecular forms of MMP-8 (collagenase-2) and MMP-13 (collagenase-3) associated with chronic adult periodontitis by examining the species present in gingival crevicular fluid (GCF) and enzyme distribution in gingival tissue.
30-s GCF samples were collected directly from the periodontal pockets of 12 untreated patients using filter paper strips. After elution into buffer, the samples were examined by Western immunoblotting with polyclonal antibodies for MMP-8 and MMP-13 and quantification by scanning image analysis. Individual band intensities were expressed as a percentage of total sample absorbance and mean patient values were calculated. Gingival tissue from 6 patients was fixed in formalin and embedded in paraffin wax. MMP-8 and MMP-13 were localised using the same antibodies and an avidin-biotin-peroxidase detecting system. Double staining was performed with a contrasting substrate reaction.
The majority of MMP-8 staining in pre-treatment GCF was present in 80, 75 and 60 kD bands corresponding to prepro-, pro- and active forms of PMN-type enzyme. 43 and 38 kD bands evidently represented active, fibroblast-type MMP-8. Immunoreactivities at >100 kD and < or =30 kD were probably enzyme-inhibitor complex and degraded fragments, respectively. MMP-13 was seen mainly as 60 kD proenzyme with some 40 kD active enzyme and a small proportion of >100 kD complex. The percentages of MMP-8 PMN-type enzyme and MMP-13 proenzyme bands correlated significantly with gingival and bleeding indices (p<0.05). Immunohistochemistry demonstrated MMP-8 in PMNs, sulcular epithelial and also plasma cells in inflamed gingival connective tissue. MMP-13 immunoreactivity was detected in the sulcular epithelium and in macrophage-like cells.
Multiple species and elevated levels of both MMP-8 and MMP-13 from many rather than single cellular sources in the diseased periodontium are identified in untreated periodontitis GCF and active forms contribute to GCF collagenase activity.
Our aim was to compare the periodontal conditions in a group of juvenile idiopathic arthritis (JIA) patients with those in a control group of healthy subjects (CTR).
Thirty-two patients with JIA and 24 controls were selected. The measurements used to diagnose periodontal disease included plaque and bleeding scores, probing depths (PDs) and clinical attachment loss (CAL). Laboratory indicators of JIA activity included the erythrocyte sedimentation rate (ESR) and capsule-reactive protein (CRP). The Mann-Whitney test was used to evaluate the data (alpha = 0.05).
The mean ages were 15.9 (+/- 2.7) years and 14.7 (+/- 2.3) years for groups JIA and CTR, respectively. The median ESR was 42 mm/h 13 mm/h in the CTR group (p = 0.032) and the median CRP was 1.9 and 0.4 mg/l, respectively (p = 0.001). The prevalence of patients with a proximal attachment loss of 2mm or more in the JIA group was 25% and in controls it was 4.2%. The mean percentages of visible plaque and marginal bleeding were similar in the JIA (54 +/- 22 and 30 +/- 16, respectively) and CTR groups (44 +/- 18 and 29 +/- 11, respectively). The mean percentages of sites with PD > or = 4 mm were significantly higher in the JIA group (3 +/- 4.7) than in the CTR group (0.4 +/- 1.7) (p = 0.012). The mean percentages of sites with proximal CAL > or = 2 mm were 0.7 (+/- 1.4) in the JIA group and 0.001 (+/- 0.2) in the CTR group (p = 0.022).
Adolescents with JIA present more periodontal attachment loss than healthy controls, in spite of similar plaque and marginal bleeding levels.
Clinical effects of periodontal treatment on biochemical and clinical markers of disease severity in rheumatoid arthritis (RA) patients with periodontal disease were evaluated.
Forty-two patients were assigned to two groups, G1 (n=16) and G2 (n=26). G1 patients were submitted to oral hygiene instruction and professional tooth cleaning and G2 patients additionally had full-mouth scaling and root planing (SRP). Clinical periodontal measurements were obtained at baseline and 3 months after periodontal treatment. A Health Assessment Questionnaire (HAQ) was used to evaluate their performance on daily living. Rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and drug therapy were assessed.
Both groups presented a full-mouth improvement in all periodontal clinical parameters (p<0.05), with the exception of clinical attachment level (CAL) and probing pocket depth (PPD) >6 mm for G1. G2 showed greater mean reductions on PPD >4 mm than G1 (p<0.001). HAQ analyses showed a reduction on the degree of disability of G2, but not statistically significant. ESR was significantly reduced for G2 after SRP although RF did not show statistical reductions.
The data suggest that periodontal treatment with SRP might have an effect on the ESR reduction.
Cytokines play a key role in the pathogenesis of inflammatory diseases. An obvious question is whether patients with aggressive periodontitis, juvenile idiopathic arthritis, or rheumatoid arthritis share blood cytokine profiles distinguishing them from individuals free of disease.
The study population consisted of Danish white adults, <35 years of age, diagnosed with localized aggressive periodontitis (LAgP; N = 18), generalized aggressive periodontitis (GAgP; N = 27), juvenile idiopathic arthritis (JIA; N = 10), or rheumatoid arthritis (RA; N = 23) and healthy individuals with no systemic or oral diseases (control [CTRL]; N = 25). Enzyme-linked immunosorbent assays were used to determine the levels of interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and lymphotoxin (LT)-alpha in peripheral blood (plasma) and unstimulated and stimulated whole blood cell cultures from the same blood collection. Autoantibodies (aAb) to IL-1alpha and IL-6 were quantitated by radioimmunoassay.
Similar patterns of slightly higher IL-10 levels in plasma were found for GAgP and RA patients and in unstimulated cultures for GAgP, RA, and JIA patients. Interestingly, unstimulated cultures also demonstrated similar patterns of higher TNF-alpha levels for these three groups of patients. Similar group patterns of periodontitis patients (LAgP and GAgP) included increased IL-1Ra levels in stimulated cultures, which also showed similar group patterns of arthritis patients (JIA and RA) with respect to higher IL-1alpha and lower LT-alpha levels. Low titers of aAb to IL-1alpha and IL-6 were found in almost all individuals.
Patients with aggressive periodontitis and types of arthritis presented with similar components of blood cytokine profiles distinguishing them from individuals free of disease.
This study was conducted to determine the component that causes the disease in rheumatoid arthritis (RA), which shows great resemblance to periodontitis in a pathologic context.
Within this study, the pathogen-specific IgG levels formed against Porphyromonas gingivalis FDC 381, Prevotella melaninogenica ATCC 25845, Actinobacillus actinomycetemcomitans Y4, Bacteroides forsythus ATCC 43047, and Prevotella intermedia 25611 oral bacteria were researched from the blood serum samples of 30 RA patients and 20 healthy controls with the enzyme-linked immunosorbent assay (ELISA) method.
The IgG levels of P gingivalis, P intermedia, P melaninogenica, and B forsythus were found to be significantly higher in RA patients when compared with those of the controls. Of the other bacteria antibodies, A actinomycetemcomitans was not found at greater levels in RA serum samples in comparison with the healthy samples.
The antibodies formed against P gingivalis, P intermedia, P melaninogenica, and B forsythus could be important to the etiopathogenesis of RA.
This study was undertaken to compare periodontal conditions, gingival crevicular fluid (GCF) levels of tissue-type plasminogen activator (t-PA), its inhibitor plasminogen activator inhibitor-2 (PAI-2), interleukin-1beta (IL-1beta), prostaglandin E(2) (PGE(2)) in rheumatoid arthritis (RA) patients and control groups.
Twenty-three RA patients, 17 systemically healthy patients with periodontal disease (PD), and 17 systemically and periodontally healthy subjects were recruited. GCF samples were obtained from two single-rooted teeth. Full-mouth clinical periodontal measurements were recorded at six sites/tooth. GCF samples were analysed using relevant ELISA kits. Data were tested statistically by appropriate tests.
Total amounts of t-PA, PAI-2 and PGE(2) in GCF samples of the healthy control group were significantly lower than the other groups (p<0.05). The RA group exhibited a higher total amount of t-PA in GCF samples than the PD group (p<0.05). PAI-2, IL-1beta and PGE(2) total amounts were similar in RA and PD groups (p>0.05).
The coexistence of RA and periodontitis does not seem to affect clinical periodontal findings or systemic markers of RA. Similar inflammatory mediator levels in RA and PD groups, despite the long-term usage of corticosteroids, non-steroidal anti-inflammatory drugs, suggest that RA patients may have a propensity to overproduce these inflammatory mediators.
To test for an association of periodontitis and tooth loss with rheumatoid arthritis (RA).
The third National Health and Nutrition Examination Survey (NHANES III) is a nationally representative cross-sectional survey of noninstitutionalized civilians. We included participants aged > or = 60 years who had undergone both musculoskeletal and dental examinations. RA was defined based on American College of Rheumatology criteria. Dental examinations quantified decayed and filled surfaces, missing teeth, and periodontitis. Periodontitis was defined as at least 1 site exhibiting both attachment loss and a probing depth of > or = 4 mm. We classified dental health status as (1) no periodontitis, (2) periodontitis, or (3) edentulous (i.e., complete tooth loss). We performed multivariate multinomial logistic regression models with dental health status as the dependent and RA as the independent variables.
The sample consisted of 4461 participants, of whom 103 were classified as having RA. Participants with RA had more missing teeth (20 vs 16 teeth; p < 0.001), but less decay (2% vs 4%; p < 0.001) than participants without RA. After adjusting for age, sex, race/ethnicity, and smoking, subjects with RA were more likely to be edentulous [odds ratio (OR) 2.27, 95% confidence interval (CI) 1.56 3.31] and have periodontitis (OR 1.82, 95% CI 1.04 3.20) compared with non-RA subjects. In participants with seropositive RA there was a stronger association with dental health status, in particular with edentulism (OR 4.5, 95% CI 1.2 17).
RA may be associated with tooth loss and periodontitis.
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