Oral-Genital Lichenoid Reaction:

A Rare Hypersensitives to Drug, A Review


Nanda Rachmad Putra Gofur1, Aisyah Rachmadani Putri Gofur2,

Rizki Nur Rachman Putra Gofur3, Mega Kahdina3, Hernalia Martadila Putri2, Soesilaningtyas4

1Department of Health, Faculty of Vocational Studies, Universitas Airlangga, Indonesia.

2Narizma Healthcare, Surabaya, Indonesia.

3HVA Hospital, Pare Kediri, East Java.

4Deptartment of Dental Nursing, Politeknik Kesehatan Kementrian Kesehatan, Indonesia.

*Corresponding Author E-mail: nanda.rachmad.gofur@vokasi.unair.ac.id



Background: Lichenoid reaction as the result of hypersensitivity from drug might be had similir clinical appearance to idiopathic lichen planus. Lichenoid drug reaction is termed as a condition of the oral cavity having an identifiable etiology, which is clinically and histologically similar to oral lichen planus and also manifest on genital. A number of drugs have been described as a causative factor of those reactive lesions. Objectives : The aim of this study is to finding mechanism of oral-genital lichenoid reaction caused by drugs. Problem Statement: Potential Pathway of Oral-genital lichenoid reaction caused by drugs. Discussion: Oral lichenoid lesions could be impact from medication and contact antigenic reaction. Clinical condition these two look similar to oral lichen planus, also its pathology. Studies of LDR caused by angiotensin-converting enzyme (ACE) inhibitors, antimalaria, antituberculosis, antitumor and non-steroidal anti-inflammatory drugs (NSAIDs) have been found. Conclusion: OLR is a disease condition with definite identifiable aetiology. Cell-mediated immune dysregulation has been associated with pathogenesis, explaining oral and genital manifestation.


KEYWORDS: Lichenoid Reaction, Oral-genital, Drug, Hypersensitives.




Lichen planus is a disease immune-mediated pathogenesis that resulting chronic inflammation. It usually involves the oral mucosa but can involve other sites, such as the skin, vulva and vaginal mucosa, glans penis, scalp, and nails. OLP is a chronic inflammatory, autoimmune oral mucosal disease mediated by T cells that invades stratified squamous epithelium with unclear antigen and multifactorial pathogenesis.


OLP is usually presented in several clinical morphologies which may appear alone or in combination: white/reticular stripes (Wickham's striae: erythematous-violet, polygonal, glossy, non-confluent, symmetrical papules on the surface with whitish streaks), white, plaque-like white papules, erosive/ erythematous/atrophic, ulcerative, bullous1.


Oral lichen planus is usually a persistent disorder and can persist for years despite several treatment strategies. Some medications can cause oral disorders that resemble lichen planus and are said to be reactions to oral lichenoid drugs. Oral lichenoid drug reactions are rare. Unlike true oral lichen planus, drug-induced oral lichenoid eruptions disappear after drug discontinuation. Lycenoid drug eruption rarely affects the buccal mucosa. A distinctive white lace pattern may be present. It is thought that drugs that cause the lichenoid reaction only reveal the latent disease of lichen planus or amplify2,3.

Oral Lichenoid Reaction (OLR) is a common side effect on the skin of several drugs with an incidence of 5%, such as NSAIDs (nonsteroidal anti-inflammatory drugs), malaria drugs, sedatives, gout and hypertension drugs. It is known by symmetric generalized eruptions in the extremities. However, the form of division between the two is also similar. Isolated genital involvement is rare but possible, reported with β-blockers, mitotane, antineoplastic drugs, and Nivolumab (fully human IgG4 anti-programmed cell death) protein 1 receptor antibody4,5.


Table 1. Potential Drug to cause Lichenoid Reaction1


Drug classification




Hyperuricemia and Gout Preparations












Analgesics (Non-opioid) and antipyretic





Antihypertensive agents

Angiotensin-converting enzyme inhibitors




Beta blockers










Other antihypertensives







Antacids, antireflux agents and antiulcerants




Disease-modifying anti-rheumatic drugs (DMARDs)







Lithium carbonate



Nonsteroid anti-inflammatory drugs (NSAIDs)




Antipsychotic drugs











Antidiabetic agents




Cancer immunotherapy




Oral Lichenoid can be analyzed by clinical and pathology appearance identifiable of Oral Lichen Planus (OLP). Lichenoid injuries as a rule related with Dental Amalgam, as deferred extreme touchiness reaction and creates after long-time period, in this can be a long time. Lichenoid response by and large appear sheterogeneous clinical appearances extending from white asymptomatic plaque injuries to atrophic, symptomatic reticular injuries, erosive injuries or indeed flaky lesions6,7.

Lichenoid ejections may well be affect from a few drugs with clinical appearance erythematous, level, intersecting, polygonal papules on trunk or limits, which comparable to lichen planus. Another uncommon clinical sign are Desquamative Gingivitis (DG). Common sign of a few pathologies, begun from mucocutaneous maladies as vesiculo, bullous to unfavorably susceptible responses to a number of allergens (Al-Hashimi et al, 2007). Conceivable relationship between the nearness of oral-genital lichenoid response related with safe illnesses, comparable instruments was found in pathogenesis. Microorganisms biofilm actuate safe framework, which coming about provocative reactions such as cytosines and Metalloproteinases8,9.


Lichen planus could be a common constant provocative clutter, influencing the skin, oral and genital mucosa, scalp and nails. Lichenoid responses are a associated substance, the term alluding to a lichen planus-like hasty activated by systemic presentation. Drugs such as allopurinol stands close to numerous classes of drugs included, such as nonsteroidal anti-inflammatory drugs (NSAIDs), B-blockers, Pro inhibitors, thiazide diuretics as well as a few antibiotics10,11. This article review oral and genital lichenoid response caused hyepersensitivity of the sedate.



Therefore, the aim of this study is to finding mechanism of oral-genital lichenoid reaction caused by drugs.



Etiology of Lichenoid Reaction:

The etiology of OLR, including dental substance hypersensitivity, systemic drug adverse event, as a manifestation of SLE, GVHD. OLR is a term used to identify oral lesions induced by contact allergy of restoration and hypersensitivity of the drug, which may mimic OLR both clinically and histoptahologically. The restoration of amalgam is an alloy consisting of a mixture of roughly equal parts of 50 percent liquid mercury and a powder of Ag / silver. In almost all situations, mercury is one of the metal allergens caused by sensitized patients' direct interaction with the oral mucosa in amalgam restoration12,13.


Clinical Manifestation of Lichenoid Reaction:

On the other hand, oral manifestations in the form of a lichenoid reaction to the drug, although frequently quoted, are rare, and have only been reported twice in the literature. The clinical presentation in all reported cases was painful mouth ulceration. The lesions are mainly described as white striae, white plaques, along with erosions and ulcerations. Common lesions are found bilaterally on the buccal mucosa, on the edge of the tongue, and possibly on the lower lip mucosa. Then a biopsy was performed which also described lichen planus in more detail14.


The diagnosis of drug-induced lichenoid lesions may be difficult, as they may have the same aspects found in idiopathic oral lichen planus, both clinically and histopathologically. It is important to make a distinction between the two conditions, as lichen planus is usually treated with corticosteroids or immunomodulatory agents, whereas drug-induced lichenoid lesions are treated with withdrawal of the causative agent. The difficulty of diagnosis also lies in the fact that skin and / or oral lesions may occur after a variable latency period of introduction of the intrusive drug. In this case, several weeks of allopurinol therapy was sufficient to observe oral lesions. Keratotic lesions involve the buccal mucosa and lower lip, with focal erythema and areas of ulceration. Other possible locations are the lateral border of the tongue, and the median anterior area15.


Histopathology revealed stratified squamous epithelium with focal atrophy and hidden parakeratosis. The superficial chorion contains a dense band-like inflammatory infiltrate, consisting mostly of lymphocytes and macrophages, with very rare eosinophils. Apoptotic keratinocytes in the basal layer are observed. This feature is consistent with active lichen planus or drug-induced lichenoid reactions16.



Figure 1. Clinical Manifestation of Oral Lichenoid Reaction1,17


Pathophysiology of Lichenoid Reaction:

Mechanism of lichenoid drug reaction still not discussed well; but inflammatory reaction from T cell induce cytokines believed as responses.  Moreover, case report found that genetic factors might be play a. Various drugs was found associated with lichenoid drug eruption, such as ACE inhibitors, thiazide diuretics, antimalarials, beta-blockers, gold salts, and penicillamine18.


Defect in skin was reported over a year caused by causative drug, and rash development within 6 months. Lichenoid drug eruptions might be limited and cured between weeks to months recovery after stopping the drug. Additional clinical development side effect during treatment was found as pruritis. Stratified squamous epithelium has been found in histopathological examination. Focal atrophy and discreet parakeratosis was also found. Another finding was superficial chronic inflammatory infiltrate, contain macrophages lymphocytes, also eosinophils. Apoptotic keratinocytes were also found in the basal layer19,20.


Figure 2. Histopathology of Oral-Genital Lichenoid Reaction17


Pathogenesis of lichen planus reaction associated with a lymphotoxicity reaction against basal membrane. Drugs also could modify the peripheral metabolism of steroids by directly suppressing secretion of the adrenal cortex. The administration of antihypertension alters the extra-adrenal metabolism in humans, leading to a decline of measurable 17-hydroxy corticosteroids, even without decrease in plasma corticosteroids. Increase formation of 6-beta-hydroxy cholesterol and directly interacts with lipid membranes by intercalation of drugs. into phospholipidic bilayers impacting on membrane21.


The study found that different routes of antigen presentation may be a major factor in the development of OLR. Penicilline can convert the antigen and sulfhydryl groups of the captopril change enzyme system. This can trigger an immune response to epithelial antigens leading to the development of OLR. In a comprehensive review of drug reactions in the oral mucosal tissue resulted that the pharmacological pathways that cause the same drug give rise to different clinical manifestations. Other studies have also found that the counter-behavior of some drugs belonging to the same family (such as antimalarial) both produces lichenoid reactions22,17.


Through the immune response, cell-mediated immune dysregulation has been linked to the pathogenesis of OLR. There are recently published data showing that OLP is a T cell-mediated autoimmune disease in which auto-cytotoxic CD8 + T cells stimulate oral epithelial cell apoptosis. But in OLR, considering it as an outgrowth of OLP, the evidence seems to support a variety of mechanisms. Expression of keratinocyte antigen is probably induced by systemic drugs (lichenoid drug eruption). CD8 + cytotoxic T cells can induce apoptosis of keratinocytes through cell activation by antigens associated with major histocompatibility complex (MHC) class I in basal keratinocytes. In addition, the activity of any drug can be on the network as well as at the site of node23,24.


There was autoantibodies and plasma cells found infiltrate. If there is a direct effect on the B lymphocytes, this also happens in the peripheral blood and regional lymph nodes. Many drugs, however, are able to act locally in the tissues and for cause mast cell degranulation or perhaps local release of neuropeptides which act directly on mast cells. The subsequent release of TNF-α and other cytokines must cause lesion progression and persistence25,26,27,28.


Multiple cases of LDR were diagnosed in allied military personnel in the Pacific, the southern European and the Indo-Burman theatres in World War II, who were taking prophylactic antimalarial drugs, but reports were suppressed until after the cessation of hostilities. In LDR, there is a latent period right from ingestion of the drug to the appearance of the symptom. This latent period depends on the type of drug. Common medications which are known to produce LDE. NSAIDs especially fenclofenac, fenylbutazone and Salsalate are known to cause LDR, specially the erosive type. Antihypertensives causing the lesion are propranolol, methyldopa, practolol, oxprenolol. LDR are also reported to occur after use of antimicrobials penicillin, tetracycline, cyclosporine, indomethacin, prednisolone29,30,31.


Recent reports regarding Imatinib mesylate STI571 causing the lesions is being published. It is an oral cancer drug that selectively inhibits several protein tyrosine kinases associated with human malignancy32,33. The drug is used for the treatment of chronic myeloid leukaemia (CML), malignant gastrointestinal stromal tumors, and some other conditions. Because of the excellent clinical response in CML the drug has recently been approved as a first line treatment for CML patients. Moreover, Carbamazepine which is a drug with GABAnergic properties and blocker of N-methyl D-aspartate (NMDA) receptor and with potential to induce the appearance of LDR type lesions, reports show that the appearance of LDR in oral and genital generally occurs a long time after the patient has started the use of the medication34,35,36.



OLR is a disease condition with definite identifiable aetiology. Cell-mediated immune dysregulation has been associated with pathogenesis, explaining oral and genital manifestation. The pathway also finding potential risk of malignant transformation in OLR makes this entity of more clinical significance and thereby increases the need of proper understanding of its diagnosis and management.



The authors declare no conflict of interest.



1.      Schmouchkovitch A, Herry H, Thuillier P, Kerlan V, Fleuret C, Le Toux G, et al. 2017. Oral and vulvo-vaginal lichenoid reactions due to mitotane (Lysodren): A case report. Medicine (Baltimore) 2017;96:e5075.

2.      Sarode SC, Sarode GS, Kalele K. 2012. Oral lichenoid reaction: A review. Int J Oral Maxillofac Pathol 2012;3:17-26

3.      A. Tamil Selvan, C. Jothibaskara Mohan, S. Karpagam Kumara Sundari, R. Suthakaran. Study on Role of Postmarketing Surveillance in New Drug Development. Asian J. Management 4(1): Jan.-Mar. 2013 page 12-15

4.      Evaluation of plasma drug concentration of Vasavaleha. Asian J. Pharm. Ana. 3(1): Jan.-Mar. 2013; Page 01-02.

5.      Nagaraj T, Saxena S, Nigam H, Biswas A, Sahu P. 2018. Oral lichenoid reaction on right buccal mucosa: A case report. J Adv Clin Res Insights 2018;5:56-57

6.      Kamath VV, Setlur K, Yerlagudda K. 2015. Oral lichenoid lesions - a review and update. Indian J Dermatol. Jan-Feb;60(1):102. doi: 10.4103/0019-5154.147830. PMID: 25657414; PMCID: PMC4318020.

7.      Sushil D. Patil, Prajkta Varpe, Sayali Chaure, Sanjay Kshirsagar. Comparison Study of Conventional and Microwave Assisted Force Degradation by RP-HPLC Method of Pharmaceutical Drug and Dosage form. Asian J. Pharm. Ana. 2017; 7(4): 218-224.

8.      P Ravi Kumar, Y Padmavathi , P Niveditha , N. Raghavendra Babu.. Development and Validation of Difference Spectrophotometric Method for the Quantitative Estimation of Mesalamine in Bulk Drug and Dosage forms. Asian J. Pharm. Ana. 2017; 7(4): 225-228.

9.      Ismail SB, Kumar KS, Zain RB. 2007. Oral lichen planus and lichenoid reactions: etiopathogenesis, diagnosis, management and malignant transformation. J Oral Sci 2007;49:89- 106

10.   Bäckman K, Jontell M. 2007. Microbial-associated oral lichenoid reactions. Oral Dis 2007;13:402-6

11.   Santosh V. Gandhi, Parag L. Khairnar1, Atul P. Chaudhari. Application of Multivariate Calibration Methods for Simultaneous Determination of Drugs in Fixed Dose Combination.Asian J. Pharm. Ana. 2018; 8(1):01-06

12.   Tomasz W. Kamiński, Małgorzata Karbowska, Dariusz Pawlak. A Review of the Pharmacological properties of potential drugs for the treatment of stuttering from the past to the future. Asian J. Pharm. Res. 2018; 8(2):104-109.

13.   Sugerman PB, Savage NW, Walsh LJ, Zhao ZZ, Zhou XJ, Khan A, Seymour GJ, Bigby M. 2002. The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med 13, 350-365.

14.   Amy DPD, Akram Shalabi, Ori Finfter, Yonatan Birenzweig, Yehuda Zadik. 2020. Severe chronic nonlichenoid oral mucositis in pembrolizumab-treated patients: new cases and a review of the literature, Immunotherapy, 10.2217/imt-2019-0162, (2020).

15.   Saurat, J.-H.; Lipsker, D.; Thomas, L.; Borradori, L.; Lachapelle, J.-M. 2017. Dermatologie Et Infections Sexuellement Transmissibles, 6th ed.; Elsevier-Masson: Paris, France.

16.   Lombardi, T.; Küffer, R. 2016.  Concept actuel du lichen plan oral. Le diagnostic facile au début, peut devenir très difficile dans les lichens anciens. La Presse Médicale 2016, 45, 227–239

17.   Guggina LM, Yanes DA, Choi JN. 2017. Inverse lichenoid drug eruption associated with nivolumab. JAAD Case Rep 2017;3:7-9.

18.   Giuliani, M.; Troiano, G.; Cordaro, M.; Corsalini, M.; Gioco, G.; Muzio, L.L.; Pignatelli, P.; Lajolo, C. 2019. Rate of malignant transformation of oral lichen planus: A systematic review. Oral Dis. 2019, 25, 693–709

19.   Helen McParland and Saman Warnakulasuriya. 2012. “Oral Lichenoid Contact Lesions to Mercury and Dental Amalgam—A Review,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 589569, 8 pages. https://doi.org/10.1155/2012/589569.

20.   Sachin C Sarode, Gargi S Sarode, Ketki Kalele. 2012. Oral Lichenoid Reaction: A Review. International Journal of Oral and Maxillofacial Pathology; 2012:3(4):17-26.

21.   Moraes PC, Noce CW, Thomaz LA, Cintra ML, Correa ME. 2011. Pigmented lichenoid drug eruption secondary to chloroquine therapy: An unusual presentation in lower lip. Minerva Stomatol 2011;60:327-32. 

22.   Postlewait LM, Ethun CG, Tran TB, et al. 2016. Outcomes of adjuvant mitotane after resection of adrenocortical carcinoma: a 13-institution study by the US Adrenocortical Carcinoma Group. J Am Coll Surg 2016;222:480–90.

23.   Sciubba JJ. 2011. Autoimmune oral mucosal disease. Dent Clint North Am. 2011;5(1): 89-103

24.   Handono K, Gofur NRP, Nurdiana N, Kalim H. 2020. Gingivitis on Systemic Lupus Erythematosus (SLE) patients: A Pilot study Research J. Pharm. and Tech. 2020; 13(11):5466-5470. DOI: 10.5958/0974-360X.2020.00954.3

25.   Gofur NRP, Handono K, Nurdiana N, Kalim H. 2020. Association of Th – Tc Protein CD28+ and Periodontal Inflammation among Indonesian Women with SLE Disease. Sys Rev Pharm 2020; 11(6): 580 586

26.   Gofur NRP. 2020 Impact of SARS-CoV-2 on periodontal tissue manifestation. J Int Oral Health 2020;12:S90-2.

27.   Gofur NRP, Handono K, Nurdiana N and Kalim H. Periodontitis is associated with disease severity and anti-double stranded DNA antibody and interferon-gamma levels in patients with systemic lupus erythematosus, Journal of Taibah University Medical Sciences, 2019; 21;14(6):560-565. https://doi.org/10.1016/j.jtumed.2019.09.005

28.   Van der Meij E H, Schepman K P, Van der Waal I. 2003. The possible premalignant character of oral lichen planus and oral lichenoid lesions – A prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96: 164–171.

29.   Manohar D. Kengar, Kiran K. Patole, Akshay K. Ade, Sumesh M. Kumbhar, Chetan D. Patil, Ashutosh R. Ganjave. Introduction to Pharmacovigilance and Monitoring. Asian J. Pharm. Res. 2019; 9(2): 116-122.

30.   Al-Hashimi I, Schifter M, Lockhart PB, Wray D, Brennan M, Migliorati CA, et al. 2007. Oral lichen planus and oral lichenoid lesions: Diagnostic and therapeutic considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:1-12. 

31.   Dudhia BB, Dudhia SB, Patel PS, Jani YV. Oral lichen planus to oral lichenoid lesions: Evolution or revolution. J Oral Maxillofac Pathol [serial online] 2015 [cited 2019 Nov 22];19:364-70. Available from: http://www.jomfp.in/text.asp?2015/19/3/364/174632

32.   Hirota SK, et al. 2011. Analysis of a possible association between oral lichen planus and drug intake. A control study. Med Oral Patol Oral Cir Bucal 2011;16:e750–6.

33.   Akshay R. Yadav, Shrinivas K. Mohite. Cancer- A Silent Killer: An Overview. Asian J. Pharm. Res. 2020; 10(3):213-216.

34.   Sarika V. Khandbahale. A Review- Nanosuspension Technology in Drug Delivery System. Asian J. Pharm. Res. 2019; 9(2): 130-138.

35.   Sarika S. Lokhande. Microemulsions as Promising Delivery Systems: A Review. Asian J. Pharm. Res. 2019; 9(2): 90-96.

36.   Manisha Dhondising Rajput, Y. B. Rajput, L. D. Rajput. A Review on Adverse Drug Reaction. Asian J. Pharm. Res. 2020; 10(3):221-225.






Received on 05.02.2021            Modified on 15.05.2021

Accepted on 07.07.2021           © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(2):903-907.

DOI: 10.52711/0974-360X.2022.00151