Cytokines, cortisol, and nitric oxide as salivary biomarkers in oral lichen planus: a systematic review

HUMBERTO, Janaina Silva Martins; PAVANIN, Jefferson Veronezi; ROCHA, Maria José Alves da; MOTTA, Ana Carolina Fragoso

doi:10.1590/1807-3107bor-2018.vol32.0082

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Systematic Review, Stomatology • Braz. oral. res. 32 • 2018 • https://doi.org/10.1590/1807-3107bor-2018.vol32.0082 copy

Cytokines, cortisol, and nitric oxide as salivary biomarkers in oral lichen planus: a systematic review

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Abstract

The etiopathogenesis of oral lichen planus (OLP) is still not fully elucidated, and it is believed that its development could involve a neuro-immune-endocrine profile. This systematic review investigated the relationship between cytokines, cortisol, and nitric oxide (NO) in the saliva of OLP patients. An electronic search was conducted in Pubmed/Medline, Scopus, LIVIVO, and Web of Science databases with no restriction of language to identify studies published up to December 2017. Data extraction was performed using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. A total of 140 articles were retrieved, and 32 articles fulfilled the inclusion criteria (cytokines = 17; cortisol = 9; NO = 6). The most studied cytokines in the saliva of OLP patients were interleukins IL-4, IL-6, IL-8, IFN-ү, and TNF-α, which were higher in OLP patients than in healthy controls (HC). Salivary cortisol was found to be higher in OLP than in HC in most (55.5%) of the selected studies, and all studies related to NO found higher levels of this marker in OLP than in HC. Despite controversial results, our review suggests that OLP patients have an increased inflammatory response, as indicated by the proinflammatory profile of salivary cytokines. In addition, we conclude that salivary cytokine and NO measurements may have significant diagnostic and prognostic potential for monitoring disease activity and therapeutic responses in OLP.

Lichen Planus, Oral; Saliva; Biomarkers

Studies	Cytokines	Study design	Number of patients/studies	Method	Main results	Level of evidence	Grade of recommendation
Pezelj-Ribaric et al. (2004)⁴⁰40. Pezelj-Ribaric S, Prso IB, Abram M, Glazar I, Brumini G, Simunovic-Soskic M. Salivary levels of tumor necrosis factor-alpha in oral lichen planus. Mediators Inflamm. 2004 Apr;13(2):131-3. https://doi.org/10.1080/09629350410001688530 https://doi.org/10.1080/0962935041000168...	TNF-α	Case-control study	40 OLP/20 HC	ELISA	Salivary TNF-α levels were higher in OLP than in HC and showed positive correlation with the clinical form: higher levels in erosive/ulcerative than in reticular form.	3b	B
Rhodus et al. (2005b)¹⁵15. Rhodus NL, Cheng B, Myers S, Miller L, Ho V, Ondrey F. The feasibility of monitoring NF-kappaB associated cytokines: TNF-alpha, IL-1alpha, IL-6, and IL-8 in whole saliva for the malignant transformation of oral lichen planus. Mol Carcinog. 2005 Oct;44(2):77-82. https://doi.org/10.1002/mc.20113 https://doi.org/10.1002/mc.20113...	TNF-α, IL-1α, IL-6, and IL-8	Case-control study	13 OLP/13 HC	ELISA	Higher salivary TNF-α, IL-1α, IL-6, and IL-8 levels in OLP than in HC.	3b	B
Rhodus et al. (2006)²⁰20. Rhodus NL, Cheng B, Bowles W, Myers S, Miller L, Ondrey F. Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone. Oral Dis. 2006 Mar;12(2):112-6. https://doi.org/10.1111/j.1601-0825.2005.01165.x https://doi.org/10.1111/j.1601-0825.2005...	TNF-α, IL-1α, IL-6, and IL-8	Open non-randomized trial	13 OLP/13 HC	ELISA	Lower salivary TNF-α, IL-1α, IL-6, and IL-8 levels after topical dexamethasone compared with baseline.	2c	B
Tao et al. (2008)⁴²42. Tao X, Li C, Rhodus NL, Xia J, Yang X, Cheng B. Simultaneous detection of IFN-gamma and IL-4 in lesional tissues and whole unstimulated saliva from patients with oral lichen planus. J Oral Pathol Med. 2008 Feb;37(2):83-7. doi: 10.1111/j.1600-0714.2007.00593.x.	IL-4 and IFN-y	Case-control study	19 OLP (10 eOLP and 9 rOLP)/7 HC	ELISA	Higher salivary IFN-y levels in eOLP compared to HC. No differences for IL-4.	3b	B
Zhang et al. (2008)⁵⁶56. Zhang Y, Lin M, Zhang S, Wang Z, Jiang L, Shen J et al. NF-kappaB-dependent cytokines in saliva and serum from patients with oral lichen planus: a study in an ethnic Chinese population. Cytokine. 2008 Feb;41(2):144-9. https://doi.org/10.1016/j.cyto.2007.11.004 https://doi.org/10.1016/j.cyto.2007.11.0...	TNF-α, IL-6, and IL-8	Case-control study	30 OLP (16 eOLP and 14 rOLP)/ 30 HC	ELISA	Higher salivary TNF-α, IL-6, and IL-8 levels in OLP compared to HC, either between the RT form or the ES form with the HC, separately.	3b	B
Liu et al. (2009)⁴4. Liu W, Dan H, Wang Z, Jiang L, Zhou Y, Zhao M et al. IFN-gamma and IL-4 in saliva of patients with oral lichen planus: a study in an ethnic Chinese population. Inflammation. 2009 Jun;32(3):176-81. https://doi.org/10.1007/s10753-009-9118-2 https://doi.org/10.1007/s10753-009-9118-...	IL-4 and IFN-y	Case-control study	79 OLP (58 eOLP and 21 rOLP)/41 HC	ELISA	Lower IFN-γ and higher IL-4 levels in saliva of OLP than in HC, respectively; IL-4 higher in eOLP than in rOLP form.	3b	B
Ghallab et al. (2010)²¹21. Ghallab NA, el-Wakeel N, Shaker OG. Levels of salivary IFN-gamma, TNF-alfa, and TNF receptor-2 as prognostic markers in (erosive) oral lichen planus. Mediators Inflamm. 2010;2010:847632. https://doi.org/10.1155/2010/847632 https://doi.org/10.1155/2010/847632...	IFN-γ, TNF-α, and sTNFR-2	Open non-randomized trial	20 OLP/20 HC	ELISA	Higher salivary IFN-y, TNF-α, and sTNFR-2 levels in OLP at baseline compared to HC and after treatment with prednisone.	2c	B
Dan et al. (2011)³⁵35. Dan H, Liu W, Wang J, Wang Z, Wu R, Chen Q et al. Elevated IL-10 concentrations in serum and saliva from patients with oral lichen planus. Quintessence Int. 2011 Feb;42(2):157-63.	IL-10 and IFN-y	Case-control study	79 OLP (58 eOLP and 21 rOLP)/41 HC	ELISA	Higher salivary IL-10 levels and lower IFN-y in OLP than in HC. No significant difference of salivary cytokines levels between erythematous and reticular form.	3b	B
Zhang et al. (2012)³⁶36. Zhang Y, Liu W, Zhang S, Dan H, Lu R, Wang F et al. Salivary and serum interleukin-18 in patients with oral lichen planus: a study in an ethnic Chinese population. Inflammation. 2012 Apr;35(2):399-404. https://doi.org/10.1007/s10753-011-9327-3 https://doi.org/10.1007/s10753-011-9327-...	IL-18	Case-control study	103 OLP/48 HC	ELISA	Higher salivary IL-18 levels in OLP than in HC.	3b	B
Cheng et al. (2014)⁵⁵55. Lisa Cheng YS, Jordan L, Gorugantula LM, Schneiderman E, Chen HS, Rees T. Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. J Periodontol. 2014 Jul;85(7):956-65. https://doi.org/10.1902/jop.2013.130320 https://doi.org/10.1902/jop.2013.130320...	IL-6 and IL-8	Case-control study	18 OSCC/20 CP/21 aOLP/20 iOLP/21 HC	ELISA	Highest salivary IL-6 and IL-8 levels in OSCC; higher salivary IL-6 and IL-8 in aOLP than in CP and HC.	3b	B
Abdel-Haq et al. (2014)⁴¹41. Abdel-Haq A, Kusnierz-Cabala B, Darczuk D, Sobuta E, Dumnicka P, Wojas-Pelc A et al. Interleukin-6 and neopterin levels in the serum and saliva of patients with Lichen planus and oral Lichen planus. J Oral Pathol Med. 2014 Nov;43(10):734-9. https://doi.org/10.1111/jop.12199 https://doi.org/10.1111/jop.12199...	IL-6	Case-control study	46 OLP/10 CLP/16 OLP + CLP /56 HC	ELISA	Salivary IL-6 levels were higher in OLP than in HC, especially in atrophic-erosive form.	3b	B
Liu et al. (2014)³⁹39. Liu WZ, He MJ, Long L, Mu DL, Xu MS, Xing X et al. Interferon-γ and interleukin-4 detected in serum and saliva from patients with oral lichen planus. Int J Oral Sci. 2014 Mar;6(1):22-6. https://doi.org/10.1038/ijos.2013.74 https://doi.org/10.1038/ijos.2013.74...	IFN-α, IL-4	Case-control study	60 OLP/40HC	ELISA	Higher IL-4 levels and low IFN-α in OLP patients.	3b	B
Lu et al. (2015)¹⁹19. Lu R, Zhang J, Sun W, Du G, Zhou G. Inflammation-related cytokines in oral lichen planus: an overview. J Oral Pathol Med. 2015 Jan;44(1):1-14. https://doi.org/10.1111/jop.12142 https://doi.org/10.1111/jop.12142...	IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IFN-γ, TGF-β, and TNF-α	Literature review	145 studies	Miscellaneous	High salivary IL-1, IL-6, IL-18 and TNF-α levels in OLP patients.	5	D
Wang et al. (2015)³⁷37. Wang K, Miao T, Lu W, He J, Cui B, Li J et al. Analysis of oral microbial community and Th17-associated cytokines in saliva of patients with oral lichen planus. Microbiol Immunol. 2015 Mar;59(3):105-13. https://doi.org/10.1111/1348-0421.12232 https://doi.org/10.1111/1348-0421.12232...	IL-17 and IL-23	Case-control study	30 OLP/15 HC	ELISA	Higher salivary IL-17 levels in OLP than in HC. No differences for IL-23.	3b	B
Malakzadeh (2015)³⁸38. Malekzadeh H, Robati M, Yousefimanesh H, Ghafourian Boroujerdnia M, Nadripour R. Salivary Interferon Gamma and Interleukin-4 levels in patients suffering from oral lichen planus. Cell J. 2015;17(3):554-8.	IFN-γ and IL-4	Case-control study	63OLP/63 HC	ELISA	Higher salivary IL-4 and IFN-γ in OLP than in HC	3b	B
Jeong et al. (2016)⁴³43. Jeong SH, Na HS, Park SH, Ahn YW, Chung J. Topical sulfasalazine for unresponsive oral lichen planus. Quintessence Int. 2016 Apr;47(4):319-27.	IL-1b and IL-8	Open non-randomized trial	21 OLP/30 HC	ELISA	High levels of IL-1b and IL-8 in OLP than in HC; No changes of salivary IL-1b and IL-8 levels after topical sulfasalazine compared to baseline.	2c	B
Mozaffari et al. (2017)⁴⁴44. Mozaffari HR, Ramezani M, Mahmoudiahmadabadi M, Omidpanah N, Sadeghi M. Salivary and serum levels of tumor necrosis factor-alpha in oral lichen planus: a systematic review and meta-analysis study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Sep;124(3):e183-9. https://doi.org/10.1016/j.oooo.2017.06.117 https://doi.org/10.1016/j.oooo.2017.06.1...	TNF-α	Systematic review	7 studies	Miscellaneous	Higher salivary TNF-α in OLP than HC	3a	B

Studies	Study design	Number of patients	Method	Main findings	Level of evidence	Grade of recommendation
Rodstrom et al. (2001)⁴⁵45. Rödström PO, Jontell M, Hakeberg M, Berggren U, Lindstedt G. Erosive oral lichen planus and salivary cortisol. J Oral Pathol Med. 2001 May;30(5):257-63. https://doi.org/10.1034/j.1600-0714.2001.300501.x https://doi.org/10.1034/j.1600-0714.2001...	Case-control study	10 OLP/10 HC	RIA	No difference for salivary cortisol levels was found between OLP and HC; highest concentrations of salivary cortisol in early morning.	3b	B
Koray et al. (2003)¹³13. Koray M, Dülger O, Ak G, Horasanli S, Uçok A, Tanyeri H et al. The evaluation of anxiety and salivary cortisol levels in patients with oral lichen planus. Oral Dis. 2003 Nov;9(6):298-301. https://doi.org/10.1034/j.1601-0825.2003.00960.x https://doi.org/10.1034/j.1601-0825.2003...	Case-control study	40 OLP/40 HC	ELISA	Higher salivary cortisol levels in OLP than in HC.	3b	B
Shah et al. (2009)⁴⁷47. Shah B, Ashok L, Sujatha GP. Evaluation of salivary cortisol and psychological factors in patients with oral lichen planus. Indian J Dent Res. 2009 Jul-Sep;20(3):288-92. https://doi.org/10.4103/0970-9290.57361 https://doi.org/10.4103/0970-9290.57361...	Case-control study	30 OLP/30 HC	ELISA	Higher salivary cortisol levels in 56.6% (17/30) of OLP patients, and there was positive correlation between level of depression and cortisol	3b	B
Girardi et al. (2011)⁴⁶46. Girardi C, Luz C, Cherubini K, de Figueiredo MA, Nunes ML, Salum FG. Salivary cortisol and dehydroepiandrosterone (DHEA) levels, psychological factors in patients with oral lichen planus. Arch Oral Biol. 2011 Sep;56(9):864-8. https://doi.org/10.1016/j.archoralbio.2011.02.003 https://doi.org/10.1016/j.archoralbio.20...	Case-control study	31 OLP/31 HC	RIA	No difference was found between OLP and HC.	3b	B
Nosratzehi et al. (2014)⁵⁰50. Nosratzehi T, Fateme AK, Saeedeh SE. The evaluation of psychological factor and salivary cortisol and IgA levels in patients with oral lichen planus. Zahedan J Res Med Sci. 2014;16(7):4.	Case-control study	20 OLP/20 HC	ELISA	No difference was found between OLP and HC	3b	B
Nadendla et al. (2014)⁴⁸48. Nadendla LK, Meduri V, Paramkusam G, Pachava KR. Association of salivary cortisol and anxiety levels in lichen planus patients. J Clin Diagn Res. 2014 Dec;8(12):ZC01-03.	Cross-sectional study	20 OLP/20 HC	ELISA	Higher salivary cortisol levels in OLP patients than in HC.	2b	B
Pippi et al. (2016)²⁷27. Pippi R, Romeo U, Santoro M, Del Vecchio A, Scully C, Petti S. Psychological disorders and oral lichen planus: matched case-control study and literature review. Oral Dis. 2016 Apr;22(3):226-34. https://doi.org/10.1111/odi.12423 https://doi.org/10.1111/odi.12423...	Case-control study	20 OLP/14 HC	ELISA	Lower salivary cortisol levels than healthy controls, and hypocortisolism in the morning.	3b	B
Lopez-Jornet et al. (2016)²⁸28. Lopez-Jornet P, Cayuela CA, Tvarijonaviciute A, Parra-Perez F, Escribano D, Ceron J. Oral lichen planus: salival biomarkers cortisol, immunoglobulin A, adiponectin. J Oral Pathol Med. 2016 Mar;45(3):211-7. https://doi.org/10.1111/jop.12345 https://doi.org/10.1111/jop.12345...	Cross-sectional study	33 OLP/32 HC	CLIA	Higher salivary cortisol levels than HC.	2b	B
Karthikeyan and Aswath (2016)⁴⁹49. Karthikeyan P, Aswath N. Stress as an etiologic co-factor in recurrent aphthous ulcers and oral lichen planus. J Oral Sci. 2016;58(2):237-40. https://doi.org/10.2334/josnusd.15-0610 https://doi.org/10.2334/josnusd.15-0610...	Case-control study	30 RAS/30 OLP/30 HC	ECLIA	Higher salivary cortisol levels in RAS and OLP than in HC.	3b	B

Study	Study design/level of evidence	Number of patients	Method	Main findings	Level of evidence	Grade of recommendation
Ohashi et al. (1999)⁵¹51. Ohashi M, Iwase M, Nagumo M. Elevated production of salivary nitric oxide in oral mucosal diseases. J Oral Pathol Med. 1999 Sep;28(8):355-9. https://doi.org/10.1111/j.1600-0714.1999.tb02053.x https://doi.org/10.1111/j.1600-0714.1999...	Case-control study	21 OLP/18 RAU/18 HC	Griess	Higher salivary NO levels in OLP and RAU than in HC.	3b	B
Sunitha and Shanmugam (2006)³⁰30. Sunitha M, Shanmugam S. Evaluation of salivary nitric oxide levels in oral mucosal diseases: A controlled clinical trial. Indian J Dent Res. 2006 Jul-Sep;17(3):117-20. https://doi.org/10.4103/0970-9290.29878 https://doi.org/10.4103/0970-9290.29878...	Case-control study	20 OLP/20 RAU/20 HC	Griess	Higher salivary NO levels in OLP and RAU than in HC.	3b	B
Japtap and Baad (2012)³¹31. Jagtap K, Baad RK. Estimation of salivary nitric oxide in recurrent aphthous ulcer and oral lichen planus patients with its clinical significance. J Contemp Dent Pract. 2012 Sep;13(5):623-6. https://doi.org/10.5005/jp-journals-10024-1198 https://doi.org/10.5005/jp-journals-1002...	Case-control study	20 RAU/15 OLP/30 HC	Griess	Higher salivary NO levels in OLP than in RAU and HC.	3b	B
Kapoor et al. (2013)²⁶26. Kapoor C, Wadhwan V, Vaidya S, Malik S. Triology of nitric oxide, mast cell and stress in pathogenesis of oral lichen planus. J Oral Maxillofac Pathol. 2013 May;17(2):156-62. https://doi.org/10.4103/0973-029X.119741 https://doi.org/10.4103/0973-029X.119741...	Case-control study	25 OLP/25 HC	Griess	Higher salivary NO levels in OLP than in HC.	3b	B
Panjwani et al. (2013)²⁹29. Panjwani S, Bagewadi A, Keluskar V, Malik R, Rai S, Misra D. Estimation and comparison of levels of salivary nitric oxide in patients with oral lichen planus and controls. Int J Prev Med. 2013 Jun;4(6):710-4.	Case-control study	30 OLP/30 HC	Griess	Higher salivary NO levels in OLP than in HC.	3b	B
Tvarijonaviciute et al. (2017)⁵²52. Tvarijonaviciute A, Aznar-Cayuela C, Rubio CP, Ceron JJ, López-Jornet P. Evaluation of salivary oxidate stress biomarkers, nitric oxide and C-reactive protein in patients with oral lichen planus and burning mouth syndrome. J Oral Pathol Med. 2017 May;46(5):387-92. https://doi.org/10.1111/jop.12522 https://doi.org/10.1111/jop.12522...	Case-control study	20 OLP/31 HC	Griess	Higher salivary NO level and nitrite in OLP than HC.	3b	B

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[1] Corresponding Author: Ana Carolina Fragoso Motta. E-mail: anacfm@usp.br