Abstract
Background: Rheumatoid arthritis (RA) and periodontal disease (PD) are both characterized by an inflammatory reaction. Anti-cyclic citrullinated peptide (anti-CCP) is a common diagnostic test for RA. Anti-CCP is proposed to be used as a serological biomarker to detect PD in patients with RA.
Methods: A case-control study was designed for 94 subjects; 42 patients with RA and 52 without RA. PD and its types were investigated among these subjects. An enzyme-linked immunosorbent assay (ELISA) test was used to measure anti-CCP levels in these subjects.
Results: Subjects were recategorized into four groups after PD diagnosis: group 1 for RA with PD (34.04%); group 2 for RA only (10.63%); group 3 for PD only (30.85%); and group 4 for individuals without RA and PD (24.46%). Anti-CCP may be considered an effective biomarker for predicting the development of PD in RA patients based on five current results found in group 1 compared to other groups. These included the detection of significantly higher anti-CCP levels, a high sensitivity (63.15%), low specificity (50%), higher cut-off value (58.53 U/ml), high positive predictive value (94.73%), and low negative predictive value (8.69%) of anti-CCP. Chronic periodontitis is the most common and has a significant association with elevated levels of anti-CCP.
Conclusion: Measuring the anti-CCP level in RA patients may be a good indicator for PD diagnosis based on the suggested cut-off value. The sensitivity of the test is sufficiently reliable to produce true positive results. Anti-CCP may also be useful in the diagnosis of PD type, especially chronic periodontitis.
Rheumatoid arthritis (RA) is the most common type of autoimmune inflammatory disease of uncertain cause that influences the synovial membranes of multiple joints.1 Its prevalence is estimated to be between 0.5% and 1% worldwide.2 Periodontal disease (PD) is another inflammatory disease whose stages are characterized by the destruction of the supporting structures of the teeth, including the periodontal ligament and alveolar bone.3 The actual number of epidemiological distributions of PD is not identified, as most dental public health activities focus on dental caries.4
Anti-cyclic citrullinated peptide (anti-CCP) or anti-citrullinated protein antibodies (ACPA) are mainly produced through citrullination. Citrullination is the result of converting arginine to citrulline by the enzyme peptidylarginine deiminase.5 Anti-CCP will be produced as a response to this type of conversion.6 It is one of the autoantibodies induced during the development of RA7 and plays an important role in the diagnosis and prognosis of RA.8 Recently, the anti-CCP has been incorporated as a criterion into the new 2010 RA classification criteria.5 The anti-CCP is inspected as a serological significance test with a specificity of 96% to detect RA using an enzyme-linked immunosorbent assay (ELISA).9 On the other hand, the suitability of the anti-CCP for PD diagnosis is not entirely confirmed. High levels of anti-CCP are observed in untreated PD patients relative to healthy individuals, and this level has decreased after treatment.10 Harvey11 found the anti-CCP can be used for diagnosing PD when it is higher. In contrast, other studies do not support the application of anti-CCP in the diagnosis of PD, since most PD patients have a normal anti-CCP value.12,13
Sharing the production of anti-CCP in any of RA and PD or under other conditions may encourage testing possible diagnosis of PD in patients with RA by measuring anti-CCP levels. In the aspect of diagnosis of RA in PD patients, the RA prognosis is not expected to occur in a patient with PD unless two specific conditions are present. The first is chronic exposure to citrullinated proteins of infected bacteria in the periodontal region.14,15 The second is patients with PD should be genetically susceptible to autoantibody initiation and RA development.14
A different aspect, which is the aim of this study, is assessment using anti-CCP as a viable option to diagnose PD in patients with RA. This is a challenge due to the similarity in the inflammatory reaction between RA and PD, and it is difficult to find a diagnostic tool to differentiate between them. Using anti-CCP may be the solution. Stimulating the production of anti-CCP in patients with RA is mainly triggered by the interaction of genetic and environmental factors, while it is triggered in PD patients by bacterial infection.6,14,16 Porphyromonas gingivalis is one of the causative agents of PD with the capability to carry out a citrullination process.16 This bacterial process in patients with PD increases anti-CCP levels with a potential reason for initiation of RA.14,15 In contrast, this bacterium has no role in increasing anti-CCP or developing PD in patients with RA.17
Of the 509 different types of bacteria that live in gingival crevices and cause PD,18 Porphyromonas gingivalis is the one most associated with the onset of RA disease.15,16 Based on the review by Araújo et al.,19 seven studies illustrated evidence of the role of this bacterium in RA and PD by the shared presence of citrullinated proteins and their antibodies (antibodies to P. gingivalis, and P. gingivalis peptidyl-arginine deiminase. The title of antibodies against P. gingivalis bacterium may also play a role in the diagnosis of the relationship between anti-CCP levels and PD in patients with RA. The levels of IgG and IgM anti-P.gingivalis were found to be higher in RA patients with severe PD compared to those with only severe PD.20 DNA from bacteria in periodontal areas is detected in the serum and synovial fluid of patients with RA and PD.12
The adequacy of the anti-CCP test for the diagnosis of PD in patients with RA compared to those without RA or PD is the main aim of this study. Determination of the sensitivity, specificity and cut-off value of anti-CCP in patients with RA and PD is another aim.
Materials and Methods
Patients
A case-control study was designed consisting of 94 subjects, which included 42 patients suffering from RA and 52 subjects without RA. The study was conducted on subjects attending Al-Najaf Rehabilitation Centre for Disabled Persons, Sports Medicine, and Physiotherapy of Al Sadder Medical City in Al-Najaf from September 2019 to February 2020. The age of the RA patients ranged from 20 to 73 years, consisting of 11 males (30 to 73 years) and 31 females (20 to 68 years). Individuals without RA included 19 males (27 to 54 years) and 23 females (20 to 70 years). They were verified to have no history or clinical evidence of RA without any apparent abnormalities. All clinical criteria for RA were diagnosed by hospital rheumatologists based on modified diagnostic criteria referred to by the American College of Rheumatology/European League against Rheumatism Collaborative Initiative (ACR/EULAR).21 RA patients had a long history of experiencing this type of autoimmune disease, and cases ranged from moderate-stage to severe-stage of RA. Non-steroidal anti-inflammatory drugs (NSAIDs) were frequently used to reduce the clinical severity of RA. The gender and ethnicity of subjects had been included.
In all participants, PD was evaluated by specialized dentists at the Centre for Dentistry and Surgery in Al-Najaf. Radiography was performed to determine the types of PD by showing any damage in the gum as gingivitis (non-specific grade) or bone tissue as chronic periodontitis (CP). Excluded patients included those who have other than RA autoimmune diseases and who are under specific treatment or taking a drug for RA before blood collection. Patients without teeth were also excluded.
Anti-CCP Measurement
Blood samples were taken from implicated individuals. The ELISA assay was used as a serological assay to measure the anti-CCP titer by human anti-cyclic-citrullinated-peptide-(CCP) ELISA Kit (Biobase, China). Anti-human IgG-horseradish peroxidase was used as a conjugate reagent to react with a substrate of chromogen solution. The color of the final solution was read at 450 nm using a BioTek ELx800 ELISA reader (U.S.A) for 15 minutes. Based on the manufacture’s manual, the level < 20 U/ml of anti-CCP is considered the normal value. Anti-CCP concentrations were categorized into four groups; 21-40 U/ml moderate, 41-60 U/ml high, 61-80 U/ml higher, and 81-100 U/ml highest.
Ethical Approval
The study was carried out according to the Declaration of Helsinki and was approved by the local ethics committee of the authors’ college in No. 32 on June 19, 2020. All patients provided written informed consent before enrolling in this study.
Statistical Analysis
Data from all tests were expressed in the form of mean ± SD. Values were statistically calculated using one-way analysis of variance (ANOVA) of the Excel application in Windows 10. The equivalent or low level of P at 0.05 concerts is significant. The cut-off value of anti-CCP was determined using a 95% confidence interval (CI) of the mean (mean ± 2SD).
Results
Based on the PD assessment, the subjects were divided into four groups: 32 patients with RA and PD (group 1) (34.04%), with an age range of 30-73 years for males and 20-68 years for females; 10 patients with RA only (group 2) (10.63%) with an age range of 36-68 years for males and 30-61 years for females; 29 patients with PD only (group 3) (30.85%) with an age range of 24-50 years for males and 25-68 years for females; and 23 healthy control group (group 1) (24.46%) with an age range of 27-54 years for males and 20-70 years for females (Table 1). Females were more affected by RA with PD (27.65%) or PD alone (22.34%) than males (6.4% and 8.51%, respectively). Three types of PD were commonly diagnosed among all subjects: CP, gingivitis, and both CP with gingivitis. CP was more frequent than other types of PD, with a significantly higher level in group 1 than in group 3 (P=0.003). Gingivitis was also high in groups 1 and 3 (28.12% and 34.48%, respectively), but without significant difference (P=0.528). Many females participated in this study, making them more affected by all types of PD than males, with no significant differences between groups 1 and 3 (P=0.729)(Table 1).
Characters of patients and control group
The level of anti-CCP was measured in all subjects participating in the study to determine the differences among all groups. The anti-CCP concentration was significantly high and moderate (41-60 U/ml and 21-40 U/ml) in many patients in group 1 (18% and 10.63%, respectively) compared with group 2. Other higher concentrations of anti-CCP (greater than 61 U/ml) were observed only in group 1 patients (Table 2). Females in group 1 had significant moderate, high, and higher concentrations of anti-CCP compared to males. Alternatively, males in group 2 showed a higher concentration of anti-CCP (2.12%) than females (1%). There was no increase in anti-CCP levels in group 3 patients, making them similar to the control group (Table 2).
Anti-CCP level patients with RA and/or PD
Anti-CCP in group 1 showed elevated sensitivity (63.15%) with low specificity (50%) compared to that for other groups. The cut-off value of anti-CCP in group 1 was 58.53 U/ml and in groups 2 and 3 were 46.02 U/ml and 20.75 U/ml, respectively. The positive predictive value for anti-CCP levels in group 1 was 94.73% and it was 100% and 78.94% for groups 2 and 3, respectively. There was a consistent negative predictive value of 8.69% for all three groups (Table 3).
Cut-off value, sensitivity and specificity of anti-CCP level in patients with RA and/or PD
The relationship between PD type in RA patients and anti-CCP was determined based on anti-CCP measurement concentrations. A large number of patients with CP, as shown in Table 1, had elevated levels of anti-CCP (moderate, high, and higher levels), particularly in females (18.75%, 25%, and 3.12%, respectively). Gingivitis also exhibited elevated levels of anti-CCP in females with only one male at moderate levels (3.12%). RA patients with a combination of CP and gingivitis had only a high concentration of anti-CCP (41-60 U/ml), especially in females (6.25%) (Table 4).
Anti-CCP level in RA patients with the types of PD
Discussion
In this study, the concentration of anti-CCP (up to 60 U/ml) was significantly higher in a greater number of patients with both RA and PD, and four patients had equivalent or over 80 U/ml. Meanwhile, anti-CCP levels of up to 60 U/ml were found in only four patients with RA. Otherwise, the concentration of anti-CCP was normal in patients with PD alone. This leads us to suggest a greater increase in anti-CCP levels in patients with RA is an indication of the importance of clinical examination of PD development. A high cut-off value and positive predictive value of anti-CCP in the group of patients with RA and PD may also support this assumption. A patient who has both RA and PD may experience a doubling of inflammation rates and tissue destruction, which could result in higher levels of anti-CCP production. The correlation between RA and PD is first proposed after RA therapy has been found to reduce inflammation in the supporting tissues of teeth.22 This relationship is generally taken in two ways: the risk of initiating RA is higher in PD patients and PD may develop in RA patients.23 Both RA and PD have an inflammatory nature when RA is an autoimmune inflammatory disease, while PD is a chronic inflammatory disease of bacterial origin.19 The soft and hard tissues of the synovium in RA and periodontium in PD are usually destroyed as a result of an inflammatory response mediated by pro-inflammatory mediators.20 The differentiation between RA and PD depends mainly on the nature of inflammatory cells, micro-environmental and serum cytokines, matrix metalloproteinase and other mediator profiles, and osteoclast-mediated bone destruction.24
The present study found some RA patients had normal anti-CCP levels, which were supposed to be high as an indicator of RA severity. Many studies have documented the normal anti-CCP value in patients with RA, commonly referred to as false negative outcomes. Negative anti-CCP results were diagnosed in 27.2% of Korean patients with RA, although 12.4% of them had positive rheumatoid factor.25 A study of anti-CCP levels in patients with both RA and PD revealed that 10 out of 60 patients with severe cases of RA and PD had normal levels of anti-CCP.26 A similar study in patients with RA and PD revealed that 47% of 44 RA patients had normal levels of anti-CCP.27 While the PD in those patients who were determined based on clinical attachment loss showed negative results of anti-CCP in 21 patients, distributed between 15 out of 39 patients with mild clinical attachment loss and 6 out of 9 patients with moderate to severe clinical attachment loss.
Another explanation for the normal levels of anti-CCP in RA patients and to the severity of RA is that anti-CCP levels can change during RA progression. In primary RA development, 22 patients out of 149 had false negative anti-CCP results even though they had positive levels of rheumatoid factor.8 After one year of follow-up of 141 of these patients, 3% of patients with positive anti-CCP levels turned negative, and 8% of those with negative results turned positive. Another study that analyzed the results of 5980 anti-CCP tests by ELISA from Korean patients with severe RA showed the levels of anti-CCP were below the recommended cut-off value by the manufacturer.28 These findings suggest the anti-CCP value could be altered in certain RA patients depending on various factors that may be related to the severity of the diseases or other disorders associated with RA.
Based on the findings of this study, the sensitivity of the anti-CCP assay for PD detection in patients with RA exceeded specificity, which means much more valuable positive results. Application of anti-CCP for diagnosis of RA usually showed more sensitivity and specificity than other serological tests like rheumatoid factor, C-reactive protein, and anti-citrullinated filaggrin antibody.10,25 Alternately, there are variable conclusions regarding the relevance of anti-CCP as an indicator of PD development, either alone or in patients with RA. An increase in anti-CCP levels is also demonstrated in patients with RA and PD in prior studies, which is significantly higher than in patients with PD or RA alone.29,30 It was also higher in people with RA or RA with PD than in healthy people or people with PD alone.31 Thus, a high level of anti-CCP may be a good indicator of the contribution of PD to RA pathogenesis or vice versa.32
The results of this study indicated the cut-off value for anti-CCP was higher in patients with RA and PD than in patients with RA or PD only. Such a high cut-off value for anti-CCP associated with RA and PD can be added to further evidence to support the assumption that PD may be predicted in patients with RA. The cut-off value of anti-CCP for RA diagnosis is usually between 1 and 5 U/ml.28 Stefanov et al.26 found the diagnosis of PD in patients with RA may require a higher cut-off value of anti-CCP but with no significant ability to differentiate the types of severity of periodontal lesions.
Chronic periodontitis in patients with RA of the current study demonstrated elevated levels of anti-CCP than any of the other two types of PD. Jarallah et al.33 also specify that the positive correlation between the serum anti-CCP and each of the plaque index, gingival index, or probing pocket depth, can be considered as an indicator of the connection between CP and RA. Ding et al.30 found patients with RA and CP have higher levels of anti-CCP than patients with RA or CP alone. The levels of anti-CCP were also found higher among RA patients with CP and gingivitis.34 However, this finding is not supported by other studies when none of the observed rates of CP or gingivitis has a significant level of anti-CCP compared to aggressive periodontitis.35 It is also noted generalized CP is not associated with an increase in anti-CCP levels.36 Otherwise, gingivitis has proven to be the most common type of PD in patients with RA with high levels of anti-CCP, especially in patients with local gingivitis.27 Evaluation of PD in patients with RA showed 52.3% had gingivitis with fewer other types of PD.27
Conclusions
Measurement of the anti-CCP level in patients with RA can be a good indicator for PD diagnosis. The reason for this conclusion is the cut-off value of anti-CCP was more elevated in patients who had both RA and PD (58.53 U/ml) than in those who had just RA (46.02 U/ml). The test has a sensitivity of 63.15% and a specificity of 50%, both of which are reliable enough to yield true positive results in patients with RA and PD. Anti-CCP can also help diagnose PD type, especially chronic periodontitis.
Footnotes
Disclosures: The authors declare they have no funding or competing interests for the work described in this article. Ethical approval (IRB) was obtained from the ethical committee of the first author college with a No. 32 in June 2020.
- Received November 4, 2023.
- Revision received August 5, 2024.
- Accepted August 19, 2024.
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