Introduction

Oral lichen planus (OLP) is a chronic disorder with an inflammatory nature, its pathogenesis includes a T-cell-mediated response against epithelium due to unidentified antigen(s). It affects 0.1–4% of the population all over the world [1]. Patients’ follow-up is mandatory to identify malignant changes into squamous cell carcinoma, taking place nearly in 0.2–4% of patients according to World Health Organization (WHO) reports [2].

OLP is twice as common in women as in men, and it is often manifested in the fifth and sixth decades of life. Clinical types of OLP include plaque-like, papular, reticular, bullous, erosive, and atrophic ulcerative lesions. OLP is typically found symmetrically on both sides of the cheek mucosa. It is not as much common on the tongue, lips, and gingival tissues. The white keratotic form has no symptoms thus not requiring treatment. However red lesions associated with pain and burning sensation need management [3].

OLP has been treated with a diversity of therapeutic approaches. It is difficult to employ a distinct, comprehensive therapeutic treatment method since disease activity is changing between remissions and exacerbations. The main goals of current therapy approaches are to lessen mucosal ulcerations and pain sensations. Because of the illness’s refractory nature, current medications are still unable to fully treat it. The management of OLP includes a combination of topical and systemic therapeutic techniques. Up until now, corticosteroids have been the standard treatment for OLP symptoms; however, chronic use of these medications has resulted in a number of undesirable side effects, comprising atrophy of the mucosal tissues, overgrowth of the candida, suppression of adrenal glands, elevated blood pressure, gastrointestinal distress, and elevated blood glucose levels. Corticosteroids are mostly administered systemically or intralesionally but still, their effect is frequently inadequate [4].

Topical steroid resistance in OLP appears to require an alternative effective therapeutic approach with the fewest adverse effects, as it is becoming unsatisfactory for various patients [5].

Sulfasalazine works well for immune-related inflammatory diseases such as Behcet’s disease, rheumatoid arthritis, and Crohn’s disorder, and it is also widely utilized in the management of inflammatory bowel disease. Notwithstanding its efficacy, the anti-inflammatory mechanism remains unclear. Sulfasalazine taken orally breaks down in the gut into 5-aminosalicylic acid (5-ASA) and sulfapyridine. It is well-recognized that sulfapyridine has antibacterial properties [6] whereas 5-ASA possesses anti-inflammatory properties [7]. Dermatological conditions for instance psoriasis, alopecia areata, and even lichen planus (LP) can be effectively treated with sulfasalazine [8].

For the treatment of LP, sulfasalazine has been recommended as a therapeutic alternative with few side effects [9]. Nevertheless sulfasalazine oral delivery has no effect on mucosal LP, and thus topical use of this medication has been tried showing its efficacy in management of OLP refractory cases [10].

To the authors’ knowledge, the influence of topical sulfasalazine with corticosteroid in management of OLP has not been studied. Therefore, in the current contemplation, we evaluated the efficiency of topical sulfasalazine in combination with topical corticosteroids in individuals with symptomatic OLP versus using topical corticosteroids alone. The study was based on the null hypothesis that there are no differences in effectiveness of different treatments used between the two study groups.

Materials and methods

Results

The research was conducted on 46 randomly and equally allocated cases to each study group. There were nine males and fourteen females with a mean age of 48.04 (± 8.56) years in the test group, and ten males and thirteen females with a mean age of 48.30 (± 8.93) years in the control group. Age and gender distribution did not significantly differ between the two groups (p > 0.05) as shown in Table 1. No unwanted reactions or complications with topical use of sulfasalazine have been reported in both groups.

As indicated in Tables 2 and 3, there was a significant decrease in sign score and pain scale by time (p < 0.001) among both groups. Values evaluated at baseline were considerably more than those assessed at other times (p < 0.001) in the control group, according to post hoc pairwise comparisons for sign scores. Moreover, the findings revealed that values found one week later were considerably greater than those obtained at subsequent times (p < 0.001). The values evaluated at later intervals beginning with one week, as shown in Table 2, did not, however, differ significantly.

All post hoc pairwise evaluations were statistically significant (p < 0.001) for the sign scores measured in the test group and for the pain scale values measured in both groups, as indicated in Tables 2 and 3.

There was no significant difference in the sign scores and pain scale between the two groups when comparing the study groups from baseline to two weeks (p > 0.05). But at the third week, the scores of the test group were significantly lesser than those of the control group (p < 0.001), as indicated in Tables 2 and 3.

Concerning the percentage of change, starting from 2 weeks, the reduction from baseline in the test group was higher, yet it was only statistically significant for the sign score values starting from 3 weeks (p < 0.001). On the other hand, as indicated in Table 4, the test group experienced a significantly higher reduction in pain scale recordings beginning at 2 weeks (p < 0.001). This is presented in Figures 1 and 2.

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Figure 1. 

Box plot for the percent of reduction values in sign score

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Figure 2. 

Box plot for the percent of reduction values in pain scale

A statistically significant positive correlation (rs = 0.770, p < 0.001) was observed between the two measured sign scores and pain scales as shown in Table 5.

The clinical improvement of OLP cases following the combined treatment using topical sulfasalazine with topical corticosteroids was recorded as shown in Figure 3.

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Figure 3. 

Improved case of oral lichen planus (OLP) affecting buccal mucosa. (A) Baseline; (B) after 4 weeks of combination treatment with topical sulfasalazine and topical corticosteroid

Discussion

Although the precise pathologic mechanism underlying OLP, a chronic inflammatory disease, is unknown, evidence suggests that OLP is a disorder with autoimmune origin driven by T cells [15]. In particular, topically applied steroids are regarded as the first-line for OLP management. There have been trials with other topical medications like tacrolimus, pimecrolimus, cyclosporine, and aloe vera [16]. These, however, did not have as much of an impact as corticosteroids. In light of the fact that topical steroid resistance can become inconvenient for certain patients, it appears that finding an effective treatment strategy with the fewest negative effects is still imperative [3].

In addition to being used to treat Crohn’s disease and ulcerative colitis, sulfasalazine is a second-line treatment for rheumatoid arthritis. Similarly, sulfasalazine is proposed as a therapeutic alternative for the treatment of LP because it does not have any serious adverse effects.

Sulfasalazine administered orally, however, had no effect on mucosal LP with any observed improvement in all LP patients; this was explained according to the assumption that cytokine expression is not precisely equivalent in these two clinical manifestations of the same disease [17, 18].

Accordingly, the existing trial was done to investigate the influence of topical application of sulfasalazine combined with topical corticosteroids in the management of OLP patients as a test group compared to those managed with only topical steroids as a control group.

Sulfasalazine employs its anti-inflammatory effect by controlling dysregulated arachidonic acid metabolism hindering lipoxygenase enzyme; this will result in decreased production of pro-inflammatory leukotrienes. It also impedes the production of various inflammatory mediators and the expression of some adhesion molecules contributing to the process of OLP pathogenesis, which explains the reduction of sign score and pain scale values in the current study over time. The patients in this contemplate reported decreased pain and burning sensation during the treatment period. This all was in line as explained by Jeong et al. [10].

The current research revealed a significant reduction in sign score and pain scale over time concerning both intragroup relations. Additionally, pain scale values were significantly changed in both control and test groups. Meanwhile, a significant improvement in sign score values was more obvious in the test group. As regards the percentage of change reduction of sign score and pain scale in the test group it was significant in comparison to the control group. These findings are in line with the data of the previous investigation done by Jeong et al. [10] regarding the pain scale. However, regarding the reduction of sign score the current study is against that one which showed a non-significant decrease in the sign score with topical sulfasalazine treatment. This can be attributed to the previous study’s limited sample size [10].

Besides, the findings of the current research are against the outcome of the previous trials showing that sulfasalazine treatment had no effect on mucosal lesions of LP [17, 18]. This may be attributed to the difference in route of administration between these investigations using systemic oral route compared to the topical application in the current study. When taken orally, sulfasalazine is broken down by the gut microbiota’s azoreductase enzyme into 5-ASA and sulfapyridine. A number of bacteria have azo-reductase activity, including Bifidobacterium lactis, Streptococcus salivarius, and Lactobacillus acidophilus [19]. Most oral microbiota in the oral cavity is made up of Streptococcus species, including S. salivarius [20]. Thus, a medication topically administered to the oral mucosa was proposed as a potential treatment for OLP.

Furthermore, Langerhans and endothelial cells in oral and cutaneous LP express certain adhesion molecules, including vascular cellular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin adhesion molecule 1 (ELAM-1). In rat heart transplants, sulfasalazine inhibits nuclear factor-κβ transcription, which lowers the expression of adhesion molecules (VCAM, ICAM, and ELAM). Additionally, this medication suppresses the production of interleukin-12 in macrophages, inhibits the production of interleukin-2 and lymphocyte proliferative responses, and stops the immunological response of T-helper1 cells [10].

To the authors’ knowledge, the present study assesses the efficacy of topical sulfasalazine with corticosteroid in management of OLP in a randomized clinical trial study design which has not been presented before.

The current study’s limitation was a short follow-up period relative to the chronic nature of OLP which is characterized by remission and exacerbation. Accordingly, depending on this study’s outcomes we recommend designing researches investigating only the effect of sulfasalazine in the management of OLP and more follow-up period. Despite the sample size calculation done for the number of patients to be recruited studies involving more number of the patients for conclusion generalization.

In conclusion, based on the data presented in this study, combination of topical ‎sulfasalazine with topical corticosteroids is an efficient treatment in management of OLP in ‎terms of decreasing pain scale and sign score values.