Study on thyroid autoimmunity of oral lichen planus and oral lichenoid mucositis

Abstract

Context:

Oral lichen planus (OLP) and oral lichenoid mucositis (OLM) are immune-mediated mucosal conditions with multifactorial etiology, with similar clinical and histological characteristics. Diagnosis should be confirmed considering both clinical and histological aspects. Some subsets are associated with immune-mediated thyroid dysfunction due to anti-thyroid peroxidase antibody (TPO) and anti-thyroglobulin antibody (TGA).

Aims:

To ascertain the presence of thyroid autoantibodies in a cohort of patients with OLP and OLM from a South Indian population.

Methods and Materials:

This observational study comprised 21 patients with 7 cases of OLP (Group I) and 14 cases of OLM (Group II) who reported from 2021–2023 for 2 years. Serum anti-thyroid antibodies including TPO and TGA was estimated using chemiluminescence immunoassay technique along with clinical and histological aspects. Altered levels of serological parameters were compared with respect to these auto-immune conditions.

Results:

Increased level of thyroid autoantibodies was observed in three (42%) of the seven cases of OLP. Two cases had elevated TPO (3-4 folds) and TGA (6-38 folds) and the subjects were above 50 years. Seven (50%) of the 14 OLM cases exhibited increased thyroid autoantibody levels and were above 50 years, predominantly females. TPO levels were increased in the range of 12 to 178 and TGA from 2 to 136 folds. Duration of these lesions were more than a year.

Conclusions:

Increased thyroid autoantibodies observed in both OLP and OLM represent an underlying autoimmune response. Long-term monitoring will enable the clinicians to correlate the antibody levels with the management of these lesions.

INTRODUCTION

Oral lichen planus (OLP) and oral lichenoid mucositis (OLM) are associated with altered cell-mediated immunity.[1,2] OLP is a mucocutaneous chronic inflammatory disease with an unknown etiology and associated contributory factors that are genetic, infections, metabolic, and psychological.[3,4,5,6] The risk for malignant transformation, particularly the erosive clinical subtype of OLP, is 1.4%.[6] OLM or interface mucositis may be associated with medications (OLM-drug), restorations (OLM-dental), allergens (OLM-contact stomatitis), and altered immune dysfunction.[7,8] OLM has features overlapping OLP clinically and histopathologically.[2] Both these chronic conditions require long-term follow-up.[9]

OLP involves a dysregulated immune response to antigens by innate immune cells, CD8⁺ lymphocytes, CD4⁺ Th subsets-Tregs, Th17, cytokines, and chemokines that lead to keratinocyte apoptosis and basement membrane destruction.[10] OLM represents a delayed hypersensitivity reaction with mast cells contributing to the pathogenesis. Tumour necrosis factor (TNF)α produced by the degranulation of mast cells triggers T cells to secrete MMPs causing the destruction of the basement membrane.[11]

Subsets of OLP and OLM present with autoimmune endocrine disorders. Studies have shown an association between OLP and thyroid dysfunction.[12,13,14,15] Coexistence of OLP with autoimmune thyroid disease suggests that the circulatory thyroid autoantibodies may be associated with an organ-specific autoimmune response in the oral mucosa or skin.[16,17,18] Autoimmune thyroid dysfunction is characterised by cellular and humoral autoimmunity due to anti-thyroid peroxidase antibody (TPO) and anti-thyroglobulin antibody (TGA).[19] This observational study was designed to ascertain the presence of thyroid autoantibodies in a cohort of patients with OLP and OLM from a South Indian population.

SUBJECTS AND METHODS

A total of 21 patients who reported from 2021–2023 for 2 years were included in the study. A detailed clinical and histopathological examination was conducted. The modified World Health Organization (WHO) diagnostic criteria for OLP and OLM[20] were used.

The study comprised 7 cases of OLP (Group I) and 14 cases of OLM (Group II). A routine hemogram and levels of serum anti-thyroid antibodies including TPO and TGA using the chemiluminescence immunoassay (CLIA) technique were conducted. Ethical clearance was obtained from the Institutional Ethics Committee (IEC no. 20180732) and informed consent was procured from all participants.

RESULTS

Demographics

The age range in OLP was between 38 and 70 years, with 4 (58%) females and 3 (42%) males. In OLM, the age ranged from 45 to 71 years with 10 (71%) females and 4 (29%) males. The duration of these lesions varied from a minimum of 3 months to a year or more [Table 1].

Table 1.

Demographics of OLP and OLM (n=21)

Case no.	Age/gender	Clinical diagnosis	Histological diagnosis	Clinical symptoms	Duration	Location
1	61/F	LP	LP	Burning sensation	≥1 year	Buccal mucosa
2	70/M	LM	LP	Erythematous mucosa, white patch	≥1 year	Buccal mucosa, gingiva
3	57/F	LP	LP	Burning sensation	5 M	Buccal mucosa
4	52/M	LP	LP	Burning sensation	≥1 year	Buccal mucosa
5	63/F	LM	LP	Erythematous mucosa	≥1 year	Buccal mucosa
6	38/M	LP	LP	Burning sensation	≥1 year	Buccal mucosa
7	40/F	LP	LP	Burning sensation	8 M	Buccal mucosa
8	46/F	DG	LM	Burning sensation	3M	Gingiva premolar
9	55/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar
10	58/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar
11	71/M	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar
12	57/F	LM	LM	Burning sensation	≥1 year	Gingiva premolar
13	60/F	LM	LM	Burning sensation	≥1 year	Buccal mucosa
14	45/M	DG	LM	Erythematous gingiva	6 M	Gingiva premolar
15	62/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva-molar
16	68/M	DG	LM	Erythematous gingiva	≥1 year	Gingiva-molar
17	49/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva PM/M
18	62/F	ELP	LM	Generalised mucositis	≥1 year	Buccal mucosa
19	50/M	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar
20	62/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar
21	56/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar

*DG, desquamative gingivitis, ELP=erosive lichen planus, LM=lichenoid mucositis, LP=lichen planus. Cases with altered thyroid autoantibodies.

Clinical characteristics

In all, in seven (100%) OLP cases, the buccal mucosa was involved. One case had multiple site involvement affecting the buccal mucosa and gingiva. The chief complaint was a burning sensation. Five (72%) of the seven cases were clinically diagnosed as lichen planus. The remaining two (18%) cases were clinically diagnosed as lichenoid mucositis as they presented with an erythematous mucosa.

OLM cases predominantly involved the gingiva with 12 (86%) and 2 (14%) in the buccal mucosa. The clinical symptom was a burning sensation of the mouth with erythematous gingiva affecting more than one quadrant. A clinical diagnosis of desquamative gingivitis (DG) was given for 11 (78%) of the 14 cases. The case with a lesion on the buccal mucosa was diagnosed as erosive lichen planus.

Serological and histopathological characteristics

Increased level of thyroid autoantibodies was observed in three (42%) of the seven cases of OLP. Two of the three cases had elevated TPO (3-4 folds) and TGA (6-38 folds) from normal. TPO levels were raised in the remaining one case (three-fold). In three cases, subjects were above 50 years (2 males and 1 female) [Table 2]. The case with a 38-fold increase in TGA and a 3-fold rise in TPO had erythematous mucosa in addition to a white patch on the buccal mucosa and was clinically diagnosed as lichenoid mucositis. Histopathologically, this case had a parakeratinised epithelium with a demarcated basement membrane and a sub-epithelial dense diffuse lymphocytic infiltrate in the connective tissue [Table 3].

Table 2.

Clinical characteristics and altered serological parameters in OLP (n=3)

Case no.	Age/gender	Clinical diagnosis	Histo. Diagnosis	Clinical symptom	Duration	Location	TPO value (IU/mL)	Increase in folds from normal	TGA value (IU/mL)	Increase in folds from normal
2	70/M	LM	LP	Erythematous mucosa, White patch	≥1 year	Buccal mucosa, Gingiva	18.69	3	156.62	38
3	57/F	LP	LP	Burning sensation	5 M	Buccal mucosa	19.7	4	26.3	6
4	52/M	LP	LP	Burning sensation	≥1 year	Buccal mucosa	18.17	3	3.27	0

Table 3.

Histopathological characteristics of altered serological cases in OLP (n=3)

Case no.	Age/gender	Type of keratinisation	Thickness	Rete ridges	Basal cell degeneration	Artefactual separation	Basement Membrane	Inflammation mild/dense	Diffuse/focal	Type of inflammatory cells	Location	Vasculitis
2	70/M	Para	Normal	Pointed	Absent	Present	Demarcated	Dense	Diffuse	Lymphocytes	SE	Absent
3	57/F	Para	Atrophic	Flat	Present	Absent	Effacement	Dense	Diffuse	Lymphocytes	SE	Absent
4	52/M	Para	Normal	Pointed	Present	Absent	Demarcated	Dense	Focal	Lymphocytes + plasma cells	SE	Absent

*SE=sub-epithelial

Seven (50%) of the 14 patients with OLM exhibited increased thyroid autoantibody levels. Four of them had raised TPO and TGA, two had elevated TGA alone, and one with increased TPO. TPO levels were increased in the range of 12 to 178 and TGA 2-136 folds. Those with increased TGA alone were in the range of 4–9 folds and the one with only TPO had 38-fold raised levels [Table 4].

Table 4.

Clinical characteristics and altered serological parameters in OLM (n=7)

Case no.	Age/gender	Clinical diagnosis	Histo. diagnosis	Clinical symptom	Duration	Location	TPO value (IU/mL)	Increase in folds from normal	TGA Value (IU/mL)	Increase in folds from normal
8	46/F	DG	LM	Burning sensation	3 M	Gingiva premolar	81.02	14	8.15	2
11	71/M	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar	213.44	38	55.6	0
12	57/F	LM	LM	Burning sensation	≥1 year	Gingiva premolar	1000	178	17.11	4
13	60/F	LM	LM	Burning sensation	≥1 year	Buccal mucosa	184.39	33	29.44	7
18	62/F	ELP	LM	Generalised mucositis	≥1 Year	Buccal mucosa	50	0	39	9
20	62/F	DG	LM	Erythematous gingiva	≥1 Year	Gingiva premolar	1.43	0	431.5	4
21	56/F	DG	LM	Erythematous gingiva	≥1 year	Gingiva premolar	63.19	12	556.31	136

Patients of OLM with elevated thyroid antibodies were above 50 years and predominantly females (80%). Clinically, four of the seven patients presented as DG. The epithelium was atrophic (100%) with flat rete ridges (71%), basal cell degeneration (85%), and artefactual separation from the underlying connective tissue (85%). The other prominent feature was the effacement of the basement membrane (57%). The connective tissue showed a dense diffuse (100%), deep localisation of inflammatory cells (42%), and increased vascularity (57%).

The case with a 178-fold increase in TPO presented with a 4-fold rise in TGA with a lesion on the gingival premolar region and complaint of burning sensation for more than a year. Histologically, there was a dense plasma cell infiltrate in the deep connective tissue with increased vascularity.

The case with a 136-fold increase in TGA and a 12-fold rise in TPO was diagnosed clinically as DG. Histopathologically, the connective tissue exhibited diffuse, sub-epithelial lymphocytes and plasma cell infiltrate [Table 5].

Table 5.

Histopathological characteristics of altered serological cases in OLM (n=7)

Case no.	Age/gender	Type of keratinisation	Thickness	Re e ridges	Basal cell degeneration	Artefactual separation	Basement membrane	Inflammation mild/dense	Diffuse/focal	Type of inflammatory cells	Location	Vasculitis
8	46/F	Ortho	Atrophic	Pointed	Present	Absent	Demarcated	Dense	Diffuse	Lymphocytes	SE	Present
11	71/M	Ortho	Atrophic	Flat	Absent	Present	Demarcated	Dense	Diffuse	Lymphocytes	Deep	Present
12	57/F	Para	Atrophic	Flat	Present	Present	Demarcated	Dense	Diffuse	Plasma cells	Deep	Present
13	60/F	Para	Atrophic	Elongated	Present	Present	Effacement	Dense	Diffuse	Lymphocytes + plasma cells	Deep	Present
18	62/F	Para	Atrophic	Flat	Present	Present	Effacement	Dense	Diffuse	Lymphocytes + plasma cells	SE	Absent
20	62/F	Para	Atrophic	Flat	Present	Present	Effacement	Dense	Diffuse	Lymphocytes + plasma cells	SE	Absent
21	56/F	Para	Atrophic	Flat	Present	Present	Effacement	Dense	Diffuse	Lymphocytes + plasma cells	SE	Absent

*SE=sub-epithelial

DISCUSSION

OLP and OLM represent a spectrum of diseases resulting from either antigen-specific cell-mediated immunity or altered self-antigens.[8,9] The therapeutic approach depends on associated symptoms, clinical presentation, and histopathological confirmation.[21]

OLP with an estimated prevalence of 0.22 to 5%, is most often present in females from the fourth to eighth decades with buccal mucosal involvement.[1] All OLP cases in our study were observed on the buccal mucosa. OLM had a similar presentation with gingiva as the site of involvement (86%) comparable to a study by Lodolo et al.[22] The literature shows that the gingival involvement of OLP will be clinically manifested as DG[23] and it may be the only manifestation in 10% of OLP. This study had DG as a clinical presentation in 78% of OLM consequential to hypersensitivity reactions triggered by contact allergens such as mouthwashes or toothpaste.[24] The common symptom in both lesions was a burning sensation and the time of onset reported by the patients was more than a year.[25]

Histological examination is mandatory to give a confirmatory diagnosis for OLP and OLM. Basal cell degeneration with dyskeratotic keratinocytes/colloid bodies with lymphocytic infiltration and melanosis are hallmark features of OLP and OLM and exhibit perivascular inflammation with diffuse, mixed inflammatory cell infiltrate. OLP and OLM in our study exhibited parakeratinised epithelium with basal cell degeneration, which is in concordance with Carrozzo et al., 2019[9]; Cheng et al., 2016.[26] A diffuse, deep, perivascular, mixed inflammatory cell infiltrate, comprising eosinophil and plasma cells was observed in OLM, which is in concordance with Lodolo et al.[22] and Mravak et al.[27] and to recognise the lesion as drug-induced.[22]

Immunologic dysregulation plays an important role in the etiopathogenesis of oral lichenoid lesions. It is hypothesised that antigen-specific immunity and the response of epithelial cells to changes in antigenicity can elicit inflammation leading to sustained mucosal inflammation.[28] Autoimmune response to epithelial antigens or a dysregulated response to epithelial antigen is present in OLP, whereas local and systemic inducers of cell-mediated hypersensitivity are present in OLM.[29] Dendritic cells (DC), also known as Langerhans cells/antigen-presenting cells, play a key role in keratinocyte stimulation along with pro-inflammatory molecules, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and transcription factor nuclear factor-κB (NF-κB). DCs interact with antigen-specific T cells and produce specific immune responses.[10] Langerhans cells with the uniqueness of cross-presenting the antigens to cytotoxic T cells are responsible for the chronic inflammatory infiltrate and the recurrence.[30]

In the subset of OLP, the presence of systemic autoimmune thyroid disorders is attributed to humoral autoimmunity and circulating autoantibodies.[12,13] and it is speculated that these autoantibodies may have the ability to unmask the keratinocyte epitope, which may be recognised as target antigens by cytotoxic T cells.[16] Considering the dysregulated systemic autoimmunity, it is reasonable to presume that altered levels of thyroid autoantibodies may be responsible for the extensive duration of both OLP and OLM in our study.

Studies show that OLP has a higher prevalence of thyroid disease compared with controls.[14,16] In our study, two of seven OLP cases exhibited increased levels of TPO and TGA and one case with increased TPO alone, which is in concordance with the study by Rambhia et al.,[18] where 6 out of 13 cases of mucosal OLP had increased TGA. A study from China found significant increased levels of TPO (23%) and TGA (21%) in OLP (n = 320) cases.[31] Chang et al.[32] observed that 17.8% (n = 287) of erosive lichen planus cases had an increase in both TPO and TGA levels.

Clinically, severe forms of erosive lichen planus are found to have an abnormal increase in TPO autoantibody, suggesting that circulating thyroid autoantibodies may trigger an autoimmune response in the oral mucosa along with increased serum IL-8 in the study by Alikhani et al.[33] Their finding concluded that abnormal TPO levels are about four times more likely to develop erosive lichen planus. Our study showed a three to four-fold increase in TPO levels and 6–38-fold in TGA levels in OLP. OLP case with a 38-fold abnormal TGA was clinically diagnosed as lichenoid mucositis, indicating the severity of the lesion. The presence of autoantibodies in OLP indicates humoral immunity and aberrant T and B cell interaction along with isotope class switching are characteristics in recalcitrant erosive lichen planus.[34]

The finding in our study was the abnormal increase of 178-fold in TPO levels in OLM. Histopathology, this case had plasma cells in the connective tissue indicating immunoglobulin-mediated immunity. We found increased levels of thyroid autoantibodies in 7 out of 14 (50%) cases of OLM. Both serum TPO and TGA had an increased level in five cases and two had raised levels of TPO and TGA alone.

CONCLUSION

Increased thyroid autoantibodies were observed in both OLP and OLM, indicating the presence of the underlying autoimmune response. Further research necessitates the common pathogenic pathways involved in these autoimmune comorbidities and their clinical significance.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.