Volume 86 • Number 4
Letters to the Editor To the Editor: Re: Saliva and Serum Levels of Pentraxin-3 and Interleukin-1b in Generalized Aggressive or Chronic Peri¨ zc ¨, ¨mu ¨sx P, Nizam N, Nalbantsoy A, O odontitis. Gu xaka O Buduneli N. (J Periodontol 2014;85:e40-e46.) We have read with great interest the published article by Gu ¨ mu ¨ sx et al.1 They have evaluated saliva and serum levels of pentraxin-3 (PTX3) and interleukin-1b (IL-1b) in patients with generalized chronic periodontitis (CP) or aggressive periodontitis (AgP) and periodontally healthy individuals and concluded that salivary PTX3 might be suggested to be related to periodontal tissue inflammation. However, there are some points that need to be clarified. PTX3 is an acute-phase protein and produced in response to inflammatory conditions in vivo.2 There are various situations that likely affect PTX3 levels. The authors defined exclusion criteria as individuals with medical disorders, such as diabetes mellitus, and immunologic disorders and those who had received antibiotic or periodontal treatment in the last 6 months. In addition to these conditions, PTX3 levels vary in several inflammatory or infectious diseases such as rheumatologic diseases, vasculitis, chronic obstructive pulmonary disease, asthma, pneumonia, and ulcerative colitis.3 In this regard, simple laboratory tests such as C-reactive protein, erythrocyte sedimentation rate, complete blood count, and routine biochemistry tests could have been performed in addition to PTX3 and IL-1b evaluation to make selection of participants for the study more reliable. Previous studies showed that angiotensin-converting enzyme inhibitors, glucocorticoids, and statins affect serum PTX3 levels.4 In addition, dietary supplements such as omega-3 fatty acid, vitamin D, vitamin A, and vitamin E could affect PTX3 levels.5 Bailey et al. reported that supplement use was reported by 49% of the United States population.6 In this regard, the authors should state whether the participants use these kinds of dietary supplements. Obesity is another confounding factor for PTX3 measurement. Witasp et al.7 reported that PTX3 levels positively correlate with obesity. Therefore, body mass indexes of participants should be defined. Lastly, although the authors expressed that not selecting sex-matched individuals was a limitation, we would go further in stating that it is not acceptable. Yamasaki et al.8 showed that there was a significant difference between the sexes in terms of PTX3. Also, we wonder if there is a plausible explanation as to why 486
the authors did not obtain serum samples of control groups. This situation leads to lack of strength of the study. In conclusion, we believe this study contributes valuable information to the medical literature. However, the explanation of our concerns will certainly provide clearer information for readers. Mehmet Agilli, Department of Biochemistry, Agri Military Hospital, Agri, Turkey; Fevzi Nuri Aydin, Department of Biochemistry, Sirnak Military Hospital, Sirnak, Turkey; Tuncer Cayci and Yasemin Gulcan Kurt, Department of Medical Biochemistry, Gulhane Military Medical Academy, Ankara, Turkey. The authors report no conflicts of interest related to this letter. REFERENCES
€ xaka O, € Buduneli 1. Gu ¨ mu ¨ sx P, Nizam N, Nalbantsoy A, Ozc N. Saliva and serum levels of pentraxin-3 and interleukin-1b in generalized aggressive or chronic periodontitis. J Periodontol 2014;85:e40-e46. 2. Yaman H, Cakir E, Akgul EO, et al. Pentraxin 3 as a potential biomarker of acetaminophen-induced liver injury. Exp Toxicol Pathol 2013;65:147-151. 3. Bonacina F, Baragetti A, Catapano AL, Norata GD. Long pentraxin 3: Experimental and clinical relevance in cardiovascular diseases. Mediators Inflamm 2013;2013: 725102. doi:10.1155/2013/725102. 4. Iwata A, Miura S, Tanaka T, et al. Plasma pentraxin-3 levels are associated with coronary plaque vulnerability and are decreased by statin. Coron Artery Dis 2012;23:315-321. 5. Røsjø E, Myhr KM, Løken-Amsrud KI, et al. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol 2014;271:60-65. 6. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-266. 7. Witasp A, Carrero JJ, Michae¨lsson K, et al. Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss. Obesity (Silver Spring) 2014;22:1373-1379. 8. Yamasaki K, Kurimura M, Kasai T, Sagara M, Kodama T, Inoue K. Determination of physiological plasma pentraxin 3 (PTX3) levels in healthy populations. Clin Chem Lab Med 2009;47:471-477. Submitted August 18, 2014; accepted for publication August 18, 2014. doi: 10.1902/jop.2015.140480
Authors’ Response: We appreciate the opportunity to respond to the letter by Drs. Agilli, Aydin, Cayci, and Kurt. The authors raise some methodologic points to be clarified
Letters to the Editor
J Periodontol • April 2015
regarding our study.1 We thank the authors for their critical reading, and we believe this letter, written by four MDs from departments of biochemistry, clearly emphasizes the importance of collaboration between clinical and laboratory branches since laboratory findings may not provide the whole clinical picture and vice versa. A more holistic approach is expected to combine the clinical and laboratory data as much as possible. The authors suggest selecting participants for our study after simple laboratory tests such as C-reactive protein (CRP) and erythrocyte sedimentation rate. We strongly disagree with them on this point because such a methodology would create bias and lead readers to biased data. Moreover, CRP is a component of the pentraxin superfamily,2 and it is already stated in our manuscript that circulating CRP levels have been reported to be associated with periodontal disease3,4 and that significantly higher CRP levels were found in a group of patients with aggressive periodontitis (AgP) compared to a group with chronic periodontitis,4,5 possibly arising from the rapid rate of disease progression in AgP.6 Therefore, we believe a meticulous patient history is more reliable for unbiased study outcomes. The authors refer to a study that suggests dietary supplements such as omega-3 fatty acid, vitamin D, vitamin A, and vitamin E could affect pentraxin-3 (PTX3) levels.7 However, the study by Røsjø et al.7 was accepted for publication on March 17, 2014, whereas the date of acceptance for our study was July 17, 2013, and it was published in March 2014. Therefore, the data published by Røsjø et al. can be of use for studies planned or at least conducted/continued after March 2014. Furthermore, the authors of the letter refer to a study by Bailey et al.8 reporting the frequency of dietary supplement use as 49% in the United States population. Every population/race has its own dynamics and characteristics, including dietary habits. Therefore, each study deserves to be judged within the realities of the particular ethnic population involved in the study. Although we could not find a study reporting the prevalence of dietary supplement usage in the Turkish population, it is estimated to be much lower than that in the United States. In their letter, Agilli et al. report that obesity is another confounding factor for PTX3 measurement and suggest defining body mass indexes of the participants. However, they refer to a study that was published in May 2014,9 which is 2 months later than our study was published. To the best of our knowledge, there was no published study such as this one when our manuscript was written or even accepted for publication. Therefore, even though these studies provide evidence against published studies or blur published data, they can only enlighten the pathway for future studies rather than being used as a background to discuss previously published studies.
It is also stated that matching sex between the study groups is of utmost importance because Yamasaki et al.10 reported significant differences between the sexes in PTX3 levels. Contrary to that study, Kume et al.11 found similar circulating PTX3 levels in males and females, and we believe that at present there are not enough studies to draw conclusions about such a relationship since the published data are conflicting. As already stated in our paper, the individuals in the healthy control group were free of any periodontal disease, and few of them volunteered for blood sampling. Therefore, serum analysis could not be performed in this group. Science is an ever-evolving field, and facts can significantly change in time. Furthermore, a biomarker requires truly strong evidence coming from numerous studies and preferentially should be verified in hundreds of patients/individuals before being termed a biomarker.12 Chronic conditions such as cardiovascular diseases have similar complexity as periodontal diseases, and despite the application of even greater expenditure and manpower, recent reports reveal that previously lauded vascular risk factors such as CRP and N-terminal proB-type natriuretic peptide are, in fact, not useful.13 In the case of PTX3, it is still too early to conclude not only whether it is affected by parameters like sex, dietary supplements, or various systemic diseases but also the nature of the possible effects. At present, the published data are conflicting, and we look forward to further studies to better clarify functions of PTX3 as well as its complex interactions with various demographic parameters. € un € xaka, and € us € x, Nejat Nizam, Ozg € Ozc Pınar Gum Nurcan Buduneli, Department of Periodontology, School of Dentistry, Ege University, I_zmir, Turkey; Aysxe Nalbantsoy, Department of Bioengineering, School of Engineering, Ege University. The authors report no conflicts of interest related to this letter. REFERENCES
€ xaka O, € Buduneli 1. Gu ¨ mu ¨ sx P, Nizam N, Nalbantsoy A, Ozc N. Saliva and serum levels of pentraxin-3 and interleukin1b in generalized aggressive or chronic periodontitis. J Periodontol 2014;85:e40-e46. 2. Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med 2005;2: 29-36, quiz 58. 3. Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PM, van der Velden U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 2000;71: 1528-1534. 4. Salzberg TN, Overstreet BT, Rogers JD, Califano JV, Best AM, Schenkein HA. C-reactive protein levels in 487
Letters to the Editor
5.
6.
7.
8. 9.
488
patients with aggressive periodontitis. J Periodontol 2006;77:933-939. Chopra R, Patil SR, Kalburgi NB, Mathur S. Association between alveolar bone loss and serum C-reactive protein levels in aggressive and chronic periodontitis patients. J Indian Soc Periodontol 2012;16:28-31. Orozco A, Gemmell E, Bickel M, Seymour GJ. Interleukin1beta, interleukin-12 and interleukin-18 levels in gingival fluid and serum of patients with gingivitis and periodontitis. Oral Microbiol Immunol 2006;21: 256-260. Røsjø E, Myhr KM, Løken-Amsrud KI, et al. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol 2014;271:60-65. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-266. Witasp A, Carrero JJ, Michae¨lsson K, et al. Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss. Obesity (Silver Spring) 2014; 22:1373-1379.
Volume 86 • Number 4
10. Yamasaki K, Kurimura M, Kasai T, Sagara M, Kodama T, Inoue K. Determination of physiological plasma pentraxin 3 (PTX3) levels in healthy populations. Clin Chem Lab Med 2009;47:471-477. 11. Kume N, Mitsuoka H, Hayashida K, Tanaka M. Pentraxin 3 as a biomarker for acute coronary syndrome: Comparison with biomarkers for cardiac damage. J Cardiol 2011;58:38-45. 12. Buduneli N, Kinane DF. Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. J Clin Periodontol 2011; 38 (Suppl. 11):85-105. 13. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009; 302:49-57. Submitted September 10, 2014; accepted for publication October 14, 2014. doi: 10.1902/jop.2015.140518
Letters to the Editor To the Editor: Re: Saliva and Serum Levels of Pentraxin-3 and Interleukin-1b in Generalized Aggressive or Chronic Peri¨ zc ¨, ¨mu ¨sx P, Nizam N, Nalbantsoy A, O odontitis. Gu xaka O Buduneli N. (J Periodontol 2014;85:e40-e46.) We have read with great interest the published article by Gu ¨ mu ¨ sx et al.1 They have evaluated saliva and serum levels of pentraxin-3 (PTX3) and interleukin-1b (IL-1b) in patients with generalized chronic periodontitis (CP) or aggressive periodontitis (AgP) and periodontally healthy individuals and concluded that salivary PTX3 might be suggested to be related to periodontal tissue inflammation. However, there are some points that need to be clarified. PTX3 is an acute-phase protein and produced in response to inflammatory conditions in vivo.2 There are various situations that likely affect PTX3 levels. The authors defined exclusion criteria as individuals with medical disorders, such as diabetes mellitus, and immunologic disorders and those who had received antibiotic or periodontal treatment in the last 6 months. In addition to these conditions, PTX3 levels vary in several inflammatory or infectious diseases such as rheumatologic diseases, vasculitis, chronic obstructive pulmonary disease, asthma, pneumonia, and ulcerative colitis.3 In this regard, simple laboratory tests such as C-reactive protein, erythrocyte sedimentation rate, complete blood count, and routine biochemistry tests could have been performed in addition to PTX3 and IL-1b evaluation to make selection of participants for the study more reliable. Previous studies showed that angiotensin-converting enzyme inhibitors, glucocorticoids, and statins affect serum PTX3 levels.4 In addition, dietary supplements such as omega-3 fatty acid, vitamin D, vitamin A, and vitamin E could affect PTX3 levels.5 Bailey et al. reported that supplement use was reported by 49% of the United States population.6 In this regard, the authors should state whether the participants use these kinds of dietary supplements. Obesity is another confounding factor for PTX3 measurement. Witasp et al.7 reported that PTX3 levels positively correlate with obesity. Therefore, body mass indexes of participants should be defined. Lastly, although the authors expressed that not selecting sex-matched individuals was a limitation, we would go further in stating that it is not acceptable. Yamasaki et al.8 showed that there was a significant difference between the sexes in terms of PTX3. Also, we wonder if there is a plausible explanation as to why 486
the authors did not obtain serum samples of control groups. This situation leads to lack of strength of the study. In conclusion, we believe this study contributes valuable information to the medical literature. However, the explanation of our concerns will certainly provide clearer information for readers. Mehmet Agilli, Department of Biochemistry, Agri Military Hospital, Agri, Turkey; Fevzi Nuri Aydin, Department of Biochemistry, Sirnak Military Hospital, Sirnak, Turkey; Tuncer Cayci and Yasemin Gulcan Kurt, Department of Medical Biochemistry, Gulhane Military Medical Academy, Ankara, Turkey. The authors report no conflicts of interest related to this letter. REFERENCES
€ xaka O, € Buduneli 1. Gu ¨ mu ¨ sx P, Nizam N, Nalbantsoy A, Ozc N. Saliva and serum levels of pentraxin-3 and interleukin-1b in generalized aggressive or chronic periodontitis. J Periodontol 2014;85:e40-e46. 2. Yaman H, Cakir E, Akgul EO, et al. Pentraxin 3 as a potential biomarker of acetaminophen-induced liver injury. Exp Toxicol Pathol 2013;65:147-151. 3. Bonacina F, Baragetti A, Catapano AL, Norata GD. Long pentraxin 3: Experimental and clinical relevance in cardiovascular diseases. Mediators Inflamm 2013;2013: 725102. doi:10.1155/2013/725102. 4. Iwata A, Miura S, Tanaka T, et al. Plasma pentraxin-3 levels are associated with coronary plaque vulnerability and are decreased by statin. Coron Artery Dis 2012;23:315-321. 5. Røsjø E, Myhr KM, Løken-Amsrud KI, et al. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol 2014;271:60-65. 6. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-266. 7. Witasp A, Carrero JJ, Michae¨lsson K, et al. Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss. Obesity (Silver Spring) 2014;22:1373-1379. 8. Yamasaki K, Kurimura M, Kasai T, Sagara M, Kodama T, Inoue K. Determination of physiological plasma pentraxin 3 (PTX3) levels in healthy populations. Clin Chem Lab Med 2009;47:471-477. Submitted August 18, 2014; accepted for publication August 18, 2014. doi: 10.1902/jop.2015.140480
Authors’ Response: We appreciate the opportunity to respond to the letter by Drs. Agilli, Aydin, Cayci, and Kurt. The authors raise some methodologic points to be clarified
Letters to the Editor
J Periodontol • April 2015
regarding our study.1 We thank the authors for their critical reading, and we believe this letter, written by four MDs from departments of biochemistry, clearly emphasizes the importance of collaboration between clinical and laboratory branches since laboratory findings may not provide the whole clinical picture and vice versa. A more holistic approach is expected to combine the clinical and laboratory data as much as possible. The authors suggest selecting participants for our study after simple laboratory tests such as C-reactive protein (CRP) and erythrocyte sedimentation rate. We strongly disagree with them on this point because such a methodology would create bias and lead readers to biased data. Moreover, CRP is a component of the pentraxin superfamily,2 and it is already stated in our manuscript that circulating CRP levels have been reported to be associated with periodontal disease3,4 and that significantly higher CRP levels were found in a group of patients with aggressive periodontitis (AgP) compared to a group with chronic periodontitis,4,5 possibly arising from the rapid rate of disease progression in AgP.6 Therefore, we believe a meticulous patient history is more reliable for unbiased study outcomes. The authors refer to a study that suggests dietary supplements such as omega-3 fatty acid, vitamin D, vitamin A, and vitamin E could affect pentraxin-3 (PTX3) levels.7 However, the study by Røsjø et al.7 was accepted for publication on March 17, 2014, whereas the date of acceptance for our study was July 17, 2013, and it was published in March 2014. Therefore, the data published by Røsjø et al. can be of use for studies planned or at least conducted/continued after March 2014. Furthermore, the authors of the letter refer to a study by Bailey et al.8 reporting the frequency of dietary supplement use as 49% in the United States population. Every population/race has its own dynamics and characteristics, including dietary habits. Therefore, each study deserves to be judged within the realities of the particular ethnic population involved in the study. Although we could not find a study reporting the prevalence of dietary supplement usage in the Turkish population, it is estimated to be much lower than that in the United States. In their letter, Agilli et al. report that obesity is another confounding factor for PTX3 measurement and suggest defining body mass indexes of the participants. However, they refer to a study that was published in May 2014,9 which is 2 months later than our study was published. To the best of our knowledge, there was no published study such as this one when our manuscript was written or even accepted for publication. Therefore, even though these studies provide evidence against published studies or blur published data, they can only enlighten the pathway for future studies rather than being used as a background to discuss previously published studies.
It is also stated that matching sex between the study groups is of utmost importance because Yamasaki et al.10 reported significant differences between the sexes in PTX3 levels. Contrary to that study, Kume et al.11 found similar circulating PTX3 levels in males and females, and we believe that at present there are not enough studies to draw conclusions about such a relationship since the published data are conflicting. As already stated in our paper, the individuals in the healthy control group were free of any periodontal disease, and few of them volunteered for blood sampling. Therefore, serum analysis could not be performed in this group. Science is an ever-evolving field, and facts can significantly change in time. Furthermore, a biomarker requires truly strong evidence coming from numerous studies and preferentially should be verified in hundreds of patients/individuals before being termed a biomarker.12 Chronic conditions such as cardiovascular diseases have similar complexity as periodontal diseases, and despite the application of even greater expenditure and manpower, recent reports reveal that previously lauded vascular risk factors such as CRP and N-terminal proB-type natriuretic peptide are, in fact, not useful.13 In the case of PTX3, it is still too early to conclude not only whether it is affected by parameters like sex, dietary supplements, or various systemic diseases but also the nature of the possible effects. At present, the published data are conflicting, and we look forward to further studies to better clarify functions of PTX3 as well as its complex interactions with various demographic parameters. € un € xaka, and € us € x, Nejat Nizam, Ozg € Ozc Pınar Gum Nurcan Buduneli, Department of Periodontology, School of Dentistry, Ege University, I_zmir, Turkey; Aysxe Nalbantsoy, Department of Bioengineering, School of Engineering, Ege University. The authors report no conflicts of interest related to this letter. REFERENCES
€ xaka O, € Buduneli 1. Gu ¨ mu ¨ sx P, Nizam N, Nalbantsoy A, Ozc N. Saliva and serum levels of pentraxin-3 and interleukin1b in generalized aggressive or chronic periodontitis. J Periodontol 2014;85:e40-e46. 2. Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med 2005;2: 29-36, quiz 58. 3. Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PM, van der Velden U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 2000;71: 1528-1534. 4. Salzberg TN, Overstreet BT, Rogers JD, Califano JV, Best AM, Schenkein HA. C-reactive protein levels in 487
Letters to the Editor
5.
6.
7.
8. 9.
488
patients with aggressive periodontitis. J Periodontol 2006;77:933-939. Chopra R, Patil SR, Kalburgi NB, Mathur S. Association between alveolar bone loss and serum C-reactive protein levels in aggressive and chronic periodontitis patients. J Indian Soc Periodontol 2012;16:28-31. Orozco A, Gemmell E, Bickel M, Seymour GJ. Interleukin1beta, interleukin-12 and interleukin-18 levels in gingival fluid and serum of patients with gingivitis and periodontitis. Oral Microbiol Immunol 2006;21: 256-260. Røsjø E, Myhr KM, Løken-Amsrud KI, et al. Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol 2014;271:60-65. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-266. Witasp A, Carrero JJ, Michae¨lsson K, et al. Inflammatory biomarker pentraxin 3 (PTX3) in relation to obesity, body fat depots and weight loss. Obesity (Silver Spring) 2014; 22:1373-1379.
Volume 86 • Number 4
10. Yamasaki K, Kurimura M, Kasai T, Sagara M, Kodama T, Inoue K. Determination of physiological plasma pentraxin 3 (PTX3) levels in healthy populations. Clin Chem Lab Med 2009;47:471-477. 11. Kume N, Mitsuoka H, Hayashida K, Tanaka M. Pentraxin 3 as a biomarker for acute coronary syndrome: Comparison with biomarkers for cardiac damage. J Cardiol 2011;58:38-45. 12. Buduneli N, Kinane DF. Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. J Clin Periodontol 2011; 38 (Suppl. 11):85-105. 13. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009; 302:49-57. Submitted September 10, 2014; accepted for publication October 14, 2014. doi: 10.1902/jop.2015.140518
