Medications have been increasingly used by patients for the treatment of their systemic diseases. However, many drugs have been reported to induce oral lichenoid lesions (OLL) (1, 2). Recent studies reported that low red cell folate levels were found in patients with oral lichen planus (OLP), stomatitis, glossitis, and burning tongue (3, 4). OLL is an oral lesion that is histopathologically similar to OLP, which makes it very difficult to distinguish between these two lesions (2). OLP/OLL patients commonly complain of pain, irritation, burning sensation, or taste disturbance. OLP is the most common chronic oral mucosal disease involving a cell mediated immune response with an unclear etiology, whereas OLL has specific known causes (5). Oral lichenoid drug reaction (OLDR) is caused by drugs such as Allopurinol, Carbamazepine, Chloroquine, Dapsone, Ketoconazole, NSAIDs, Propanolol, and Tetracycline (6). Both OLP and OLDR are very difficult to treat because of their chronic nature (5, 7). In addition, there is another lichen-like lesion known as oral lichenoid contact lesion (OLCL), which is caused by contact with materials such as amalgam or mercury. However, there is insufficient evidence to support the routine removal of amalgam restorations or replace amalgam filling to confirm the diagnosis or management of OLCL (8, 9). The oral lichenoid lesions in graft-versus-host disease (OLL-GVHD) are lesions that arise in recipients of allogeneic hematopoietic stem cell or bone marrow transplantations. Unclassified OLL is an oral lesion presenting as erythematous changes to the gingiva without the signs of “classic” OLP elsewhere in the oral cavity, or lesions that have a lichen planus-like aspect, but lack one or more characteristic clinical features, such as a bilateral presentation (10).
OLDR can be treated and its diagnosis confirmed by eliminating its cause, such as by withdrawing the suspected drug (1, 11). The presence of white striae with or without erythematous or ulcerative areas, histopathologic examination, and patients’ medication history may not be sufficient to confirm the diagnosis of OLDR. In our study, we focused on oral lesions erupting in patients taking medications without withdrawing their medications. Moreover, the patients were taking multiple drugs and those drugs could not be withdrawn to confirm the diagnosis of OLDR. A recent report mentioned that some lesions such as lichenoid drug reaction may present asymptomatically initially but become symptomatic years later and then the relationship between the start of drug use and development of lesion is difficult to confirm for the diagnosis (12). Therefore, when patients taking medication had persistent lesions, we used the term OLL related drug instead.
Because medications have been increasingly used in patients with systemic diseases, treatment of OLP and OLL related drug should be carefully concerned. Appropriate treatment of such lesions will be helpful to improve the quality of life in those patients. Therefore, the aim of our study was to investigate the relationship between OLL related drug, medications, and folate and vitamin B12 levels which have not been investigated before. Hence, our findings will be useful for the clinician judgement in the treatment of OLL related drug.
Patients and methods
Twenty patients who enrolled in the Oral Medicine clinic at the Faculty of Dentistry, Chulalongkorn University were included in this study. Their oral lesions were diagnosed by oral examination and the diagnoses were confirmed by histopathological evaluation. The duration of their oral lesion, type of lesion, medications, and systemic diseases were recorded. The study group comprised 15 females and 5 males with ages ranging from 40–76 (mean+ SD = 58.3 +10.55) years. Oral examinations found 2 cases of ulcerative lesions and 18 cases of atrophic lesions. The control group consisted of 24 healthy volunteers (F=15, M=9) with no oral lesions apart from dental caries and gingivitis. The ages of the control group ranged from 36–59 years with a mean+ SD = 47.92 +7.63 years.
The study protocol was approved by the Ethics Committee for the use of human subjects, Faculty of Dentistry, Chulalongkorn University. Informed consent was obtained from the patients and the control subjects before they participated in the study. Venous blood was drawn between 9.00 am and noon to minimize any effects of diurnal variation.
The laboratory investigation included a complete blood count, hemoglobin typing, and serum and red cell folate and vitamin B12 levels determination as previously described (3). The complete blood count was performed by a standard method using a Coulter counter and the hemoglobin typing was analyzed by electrophoresis. Serum folate, red cell folate, and serum vitamin B12 levels were determined by competition binding radio assays. A red cell folate level below 100 ng/ml was defined as folate deficient, 100-120 ng/ml as folate deficient erythropoiesis, and 120-160 ng/ml as folate depletion (13). A serum vitamin B12 level less than 150 pg/ml was defined as low (14). Anemia was defined as a hematocrit of less than 39% for males and less than 36% for females. The macrocyte was defined as a mean corpuscular volume (MCV) above 100 fl, normocyte as MCV 80-96 fl and microcyte as MCV less than 80 fl (15).
The mean and range of the serum folate, red cell folate, and vitamin B12 levels in the drug related OLL and control groups are shown in Table 1. Folate analysis indicated that one subject in the OLL group had a folate deficiency (67 ng/ml). The red cell folate levels in the OLL related drug group ranged from 67–718 ng/ml with a mean + SD =289+144.78 ng/ml. In the control group, the red cell folate levels ranged from 260–576 ng/ml with a mean+SD = 399.38 + 85.8 ng/ml. However, there was no significant difference in red cell folate levels between the groups (p>0.05). We found that only one subject in the OLL related drug group demonstrated low serum folate (3.5 ng/ml) and there was no significant difference in serum folate levels between the groups (p>0.05). Serum vitamin B12 levels were within normal ranges in both groups.
NS = no significance
Seven cases in OLL related drug and two cases in the control group showed low hemoglobin. Four subjects in OLL related drug group and three cases in the control group had low hematocrit, less than 36%, and these subjects were defined as anemic. Antihypertensives and hypolipidemics were the most common medications taken by patients with OLL related drug as shown in Table 2.
* One patient taking more than one medication ** Others: alendronate, antacid, antihistamine, antimycobacterial, antiviral, glucosamine etc.
The histopathological examination of patients with OLL related drug found that the histopathological diagnoses of the oral lesions were varied with 7 subjects diagnosed with OLP/OLDR consistent with OLP in 5 cases, and with OLP in 3 cases, 3 subjects diagnosed with chronic nonspecific inflammation, 1 subject each with OLDR or normal mucosa with hyperplastic (Table 3).
When diagnosing the oral lesions in our study, most of our patients could not remember the exact onset of their systemic diseases, the names of the medications they were taking or any alternative medications prescribed by their physicians. The diagnosis of OLDR can be confirmed by withdrawing the suspected drug. However, in our study, the diagnosis of OLDR could not be confirmed and the term OLL related drug was used instead. Indeed, it is impossible or very difficult to withdraw a suspected drug because of ethical considerations and furthermore, in the present study the patients were taking multiple drugs. The subjects in the study group had their diagnoses confirmed by both oral and histopathological examination. The histopathological findings in most cases were consistent with OLP or OLP/OLDR. The histopathological sections demonstrated oral mucosa covered by parakeratinized stratified squamous epithelium with basal cell degeneration. A band-like infiltration of lymphocytes with a few plasma cells and macrophages were observed within the subjacent fibrous connective tissue. A recent study revealed that the histopathology of OLL showed more eosinophils, plasma cells, and granulocytes in OLL compared with OLP (16). Therefore, to establish the histopathological diagnosis of OLP and OLL, it should be mandatory to define the type of cells in the mononuclear infiltrate, which can be associated more accurately with the patient’s history and clinical features. One subject whose oral lesion was reported as normal mucosa with hyperplastic epithelium might be due to partial remission from topical steroid treatment.
In the present study, we only found one OLL related drug subject with an atrophic lesion and folate deficiency (67 ng/ml); however, her serum folate and vitamin B12 were normal. This subject had a history of hypertension for more than 3 years. The histopathological examination and direct immunofluorescence from this subject’s oral lesion, which was negative, resulted in a diagnosis lichenoid mucositis, consistent with lichen planus. At the time of blood withdrawal, she was taking amlodipine, hydralazine HCl, and losartan. Two years later, this subject was diagnosed with hyperthyroidism and was treated with propylthiouracil and propanolol. However, her complete blood profile and hemoglobin pattern were within normal limits.
A recent study of medications in Thai patients with oral lichen planus or oral lichenoid drug reaction showed that most of the patients with oral lesions took more than one medication. Antihypertensive drugs were the most commonly used drugs by Thai patients with oral lesions (17). Our study also showed that most of our patients were taking multiple drugs rather than a single drug, particularly antihypertensives and hypolipidemics, which are the most common medications taken by patients with OLL. Regarding hypolipidemics, all 12 cases of OLL related drug in our study used statin group. Our cases are similar to the previous reports that statin has been implicated in causing cutaneous and oral mucosal involvement such as OLL (18-20). However, it is difficult to definitely conclude a relationship between the oral lesions and these medications. The relationship between taking antihypertensives or hypolipidemics and OLL related drug should be investigated in a large group study.
Interestingly, all the patients in the present study showed normal vitamin B12 levels. These findings may reflect that the medications taken by the patients in our study do not affect the pathway of cobalamin metabolism.
Four cases in OLL related drug and 3 cases in the control group had anemia but their red cell folate, serum folate and vitamin B12 were within normal limits. We define normal Hb level for males is 14-18 g/dl; that for females is 12 -16 g/dl. All 7 female cases had shown low hematocrit less than 36%. However, there was no significant difference in anemia between the two groups. A large group study is needed to clarify the folate, vitamin B12, and anemia related medications.