Abstract
Objective
To dynamically compare the longitudinal (time axis) and transverse (between groups) differences of the salivary cytokines during thalidomide maintenance treatment of recurrent aphthous stomatitis.
Methods
A randomized, controlled, clinical trial was performed. After the initial prednisone treatment, thalidomide (50 mg/d vs. 25 mg/d) was used as a maintenance drug for 4 or 8 weeks. The salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ were dynamically detected with a cytometric bead array.
Results
Overall, the level of six elevated salivary cytokines after prednisone treatment was significantly downregulated, remained low during thalidomide maintenance, and rebounded at recurrence. The effect of 50 mg/d thalidomide on the salivary cytokines was not superior to 25 mg/d medication. The relapse-free period following drug withdrawal was the longest in the subgroup using 25 mg/d thalidomide for 8 weeks. The order of magnitude of IL-6 was the most obvious, and at week 8, only the level of IL-6 in the group (25 mg/d thalidomide for 8 weeks) continued to decline compared with the other groups.
Conclusion
Thalidomide maintenance treatment can effectively sustain low levels of salivary IL-4, 5, 6, 10, TNF-α, and IFN-γ of recurrent aphthous stomatitis patients. IL-6 displayed a good correlation with the disease and is expected to become an index for diagnosis and follow-up.
Clinical relevance
Low-dose long-term thalidomide maintenance treatment was supported for recurrent aphthous stomatitis.
Trial registration
Trial registration number of ChiCTR‐IPR‐16009759 at http://www.chictr.org/index.aspx.
Similar content being viewed by others
References
Al-Maweri SA, Halboub E, Al-Sharani HM, Shamala A, Al-Kamel A, Al-Wesabi M, Albashari A, Al-Sharani A, Abdulrab S (2021) Association between serum zinc levels and recurrent aphthous stomatitis: a meta-analysis with trial sequential analysis. Clin Oral Investig 25:407–415. https://doi.org/10.1007/s00784-020-03704-8
Zeng Q, Shi X, Yang J, Yang M, Zhao W, Zhao X, Shi J, Zhou H (2020) The efficacy and safety of thalidomide on the recurrence interval of continuous recurrent aphthous ulceration: a randomized controlled clinical trial. J Oral Pathol Medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 49:357–364. https://doi.org/10.1111/jop.12960
Harte MC, Saunsbury TA, Hodgson TA (2020) Thalidomide use in the management of oromucosal disease: a 10-year review of safety and efficacy in 12 patients. Oral Surg Oral Med Oral Pathol Oral Radiol 130:398–401. https://doi.org/10.1016/j.oooo.2020.06.009
Nasca MR, O’Toole EA, Palicharla P, West DP, Woodley DT (1999) Thalidomide increases human keratinocyte migration and proliferation. J Invest Dermatol 113:720–724. https://doi.org/10.1046/j.1523-1747.1999.00744.x
Schroder JM (1992) Chemotactic cytokines in the epidermis. Exp Dermatol 1:12–19. https://doi.org/10.1111/j.1600-0625.1992.tb00066.x
Deng Y, Wei W, Wang Y, Pan L, Du G, Yao H, Tang G (2022) A Randomized controlled clinical trial on dose optimization of thalidomide in maintenance treatment for recurrent aphthous stomatitis. J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 51:106–112. https://doi.org/10.1111/jop.13259
Aggour RL, Mahmoud SH, Abdelwhab A (2021) Evaluation of the effect of probiotic lozenges in the treatment of recurrent aphthous stomatitis: a randomized, controlled clinical trial. Clin Oral Investig 25:2151–2158. https://doi.org/10.1007/s00784-020-03527-7
Shao Y, Zhou H (2020) Clinical evaluation of an oral mucoadhesive film containing chitosan for the treatment of recurrent aphthous stomatitis: a randomized, double-blind study. J Dermatolog Treat 31:739–743. https://doi.org/10.1080/09546634.2019.1610548
Wei W, Sun Q, Deng Y, Wang Y, Du G, Song C, Li C, Zhu M, Chen G, Tang G (2018) Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol 126:142–151. https://doi.org/10.1016/j.oooo.2018.02.013
Deng Y, Yao Y, Du G, Liu W (2022) Changes in Th1/Th2-related cytokine expression in the saliva of patients with recurrent aphthous stomatitis before and after prednisone treatment. Clin Oral Investig 26:1089–1093. https://doi.org/10.1007/s00784-021-04349-x
Habibzadeh S, Sheikh Rahimi M, Edalatkhah H, Piri H, Maleki N (2021) Effectiveness of booster dose of tetanus and diphtheria toxoids (Td) vaccine in management of recurrent aphthous stomatitis: a prospective, randomized, triple-blind and placebo-controlled clinical trial. J Dermatolog Treat 32:361–366. https://doi.org/10.1080/09546634.2019.1654597
Saikaly SK, Saikaly TS, Saikaly LE (2018) Recurrent aphthous ulceration: a review of potential causes and novel treatments. J Dermatolog Treat 29:542–552. https://doi.org/10.1080/09546634.2017.1422079
Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O (2010) Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis. Medicine 89:176–182. https://doi.org/10.1097/MD.0b013e3181dfca14
Liu WZ, He MJ, Long L, Mu DL, Xu MS, Xing X, Zeng X, Liao G, Dan HX, Chen QM (2014) Interferon-gamma and interleukin-4 detected in serum and saliva from patients with oral lichen planus. Int J Oral Sci 6:22–26. https://doi.org/10.1038/ijos.2013.74
Abdel-Haq A, Kusnierz-Cabala B, Darczuk D, Sobuta E, Dumnicka P, Wojas-Pelc A, Chomyszyn-Gajewska M (2014) Interleukin-6 and neopterin levels in the serum and saliva of patients with Lichen planus and oral Lichen planus. J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 43:734–739. https://doi.org/10.1111/jop.12199
Kaur J, Jacobs R (2015) Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis. J Korean Assoc Oral Maxillofac Surg 41:171–175
Lamster EKIB (2002) The diagnostic applications of saliva–a review. Crit Rev Oral Biol Med 13:197–212
Kawai T, Watanabe N, Yokoyama M, Arai K, Oana S, Harayama S, Yasui K, Oh-Ishi T, Onodera M (2013) Thalidomide attenuates excessive inflammation without interrupting lipopolysaccharide-driven inflammatory cytokine production in chronic granulomatous disease. Clin Immunol 147:122–128. https://doi.org/10.1016/j.clim.2013.03.004
Paravar T, Lee DJ (2008) Thalidomide: mechanisms of action. Int Rev Immunol 27:111–135. https://doi.org/10.1080/08830180801911339
Mohty M, Stoppa AM, Blaise D, Isnardon D, Gastaut JA, Olive D, Gaugler B (2002) Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide. J Leukoc Biol 72:939–945
Moreira AL, Tsenova-Berkova L, Wang J, Laochumroonvorapong P, Freeman S, Freedman VH, Kaplan G (1997) Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis. Tuber Lung Dis 78:47–55. https://doi.org/10.1016/s0962-8479(97)90015-0
Yang S, Zhang B, Shi Q, Liu J, Xu J, Huo N (2017) Association of IL-6-174 G/C and IL10-1082 G/A polymorphisms with recurrent aphthous stomatitis risk: a meta-analysis. Medicine 96:e9533. https://doi.org/10.1097/MD.0000000000009533
Chen L, Ke Z, Zhou Z, Jiang X, Zhao Y, Zhang J (2018) Associations of IL-1, 6, and 10 gene polymorphisms with susceptibility to recurrent aphthous stomatitis: insights from a meta-analysis. Genet Test Mol Biomarkers 22:237–245. https://doi.org/10.1089/gtmb.2017.0072
Zhou Y, Wu J, Wang W, Sun M (2019) Association between interleukin family gene polymorphisms and recurrent aphthous stomatitis risk. Genes Immun 20:90–101. https://doi.org/10.1038/s41435-018-0019-y
Yamamoto T, Yoneda K, Ueta E, Osaki T (1994) Serum cytokines, interleukin-2 receptor, and soluble intercellular adhesion molecule-1 in oral disorders. Oral Surg Oral Med Oral Pathol 78:727–735. https://doi.org/10.1016/0030-4220(94)90087-6
Boras VV, Lukac J, Brailo V, Picek P, Kordic D, Zilic IA (2006) Salivary interleukin-6 and tumor necrosis factor-alpha in patients with recurrent aphthous ulceration. J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 35:241–243. https://doi.org/10.1111/j.1600-0714.2006.00404.x
Shen C, Ye W, Gong L, Lv K, Gao B, Yao H (2021) Serum interleukin-6, interleukin-17A, and tumor necrosis factor-alpha in patients with recurrent aphthous stomatitis. J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 50:418–423. https://doi.org/10.1111/jop.13158
Lu J, Zhang N, Wu C (2020) LncRNA CASC 2 is upregulated in aphthous stomatitis and predicts the recurrence. BMC Oral Health 20:12. https://doi.org/10.1186/s12903-019-0993-0
Garbers C, Heink S, Korn T, Rose-John S (2018) Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov 17:395–412. https://doi.org/10.1038/nrd.2018.45
Anderson KC (2005) Lenalidomide and thalidomide: mechanisms of action–similarities and differences. Semin Hematol 42:S3-8. https://doi.org/10.1053/j.seminhematol.2005.10.001
Shannon E, Noveck R, Sandoval F, Kamath B, Kearney M (2007) Thalidomide suppressed interleukin-6 but not tumor necrosis factor-alpha in volunteers with experimental endotoxemia. Transl Res 150:275–280. https://doi.org/10.1016/j.trsl.2007.05.003
Li J, Luo S, Hong W, Zhou Z, Zou W (2002) Influence of thalidomide on interleukin-6 and its transmission in multiple myeloma patients. Zhonghua Zhong Liu Za Zhi 24:254–256
Shah K, Guarderas J, Krishnaswamy G (2016) Aphthous stomatitis. Ann Allergy Asthma Immunol 117:341–343. https://doi.org/10.1016/j.anai.2016.07.005
Natah SS, Hayrinen-Immonen R, Hietanen J, Malmstrom M, Konttinen YT (2000) Immunolocalization of tumor necrosis factor-alpha expressing cells in recurrent aphthous ulcer lesions (RAU). J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 29:19–25. https://doi.org/10.1034/j.1600-0714.2000.290104.x
Sun A, Wang JT, Chia JS, Chiang CP (2006) Levamisole can modulate the serum tumor necrosis factor-alpha level in patients with recurrent aphthous ulcerations. J Oral Pathol Med : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 35:111–116. https://doi.org/10.1111/j.1600-0714.2006.00383.x
Chaudhuri K, Nair KK, Ashok L (2018) Salivary levels of TNF-alpha in patients with recurrent aphthous stomatitis: a cross-sectional study. J Dent Res Dent Clin Dent Prospects 12:45–48. https://doi.org/10.15171/joddd.2018.007
Hegde S, Ajila V, Babu S, Kumari S, Ullal H, Madiyal A (2018) Evaluation of salivary tumour necrosis factor-alpha in patients with recurrent aphthous stomatitis. Eur Oral Res 52:157–161. https://doi.org/10.26650/eor.2018.543
Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G (1993) Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177:1675–1680. https://doi.org/10.1084/jem.177.6.1675
Mubeen K, Siddiq MA, Jigna VR (2009) Thalidomide: an emerging drug in oral mucosal lesions. Clin J Gastroenterol 2:149–155. https://doi.org/10.1007/s12328-009-0089-5
Xiao X, Deng Y, Long Y, Liu W, Shi H (2023) Evaluation of cytokines as diagnostic and therapeutic indicators for recurrent aphthous stomatitis: a statistical study. J Dent Sci 18:883–888. https://doi.org/10.1016/j.jds.2022.10.013
Mazzoleni DS, Mazzoleni F, Mazzoleni LE, Francesconi CFM, Milbradt TC, Uchoa DM, Birnfeld HR, Andrighetto LV, Ries S, Simon D, Talley NJ (2022) Helicobacter pylori and other factors in recurrent aphthous stomatitis: a cross-sectional study. Oral Dis 28:390–397. https://doi.org/10.1111/odi.13765
Acknowledgements
We thank International Science Editing for editing this manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (82205200, 82101008).
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by Yiwen Deng, Yufeng Wang, Hui Yao, and Guanhuan Du. Analyses were conducted by Wei Wei. The first draft of the manuscript was written by Wei Wei and Yiwen Deng, and all authors commented on previous versions of the manuscript. Guanhuan Du and Guoyao Tang provided methods, reviewed drafts of the paper, and approved the final draft. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics approval
This study was approved by the Institutional Review Board of Shanghai Ninth People’s Hospital (SH9H-(2016)01).
Consent to participate
Informed consent was obtained from all the subjects.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wei, W., Deng, Y., Wang, Y. et al. Dynamic salivary cytokine profile of recurrent aphthous stomatitis patients in thalidomide maintenance treatment. Clin Oral Invest 28, 140 (2024). https://doi.org/10.1007/s00784-024-05531-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00784-024-05531-7