Original Article
Effect of Topical Cyclosporine Rinse on Oral Lichen Planus — A Double-Blind Analysis
N Engl J Med 1990; 323:290-294August 2, 1990
- Abstract
- Abstract
Background.
Oral lichen planus is a relatively common disorder of the mouth that can be debilitating. It is frequently palliated with topical or systemic corticosteroids and retinoids. These treatments require prolonged use, however, and are not always effective.
Methods.
In a double-blind trial, 16 patients with symptomatic oral lichen planus were randomly assigned to receive either topical cyclosporine or its vehicle. The patients swished and expectorated 5 ml of medication (containing 100 mg of cyclosporine per milliliter) three times daily.
Results.
After eight weeks, the eight recipients of cyclosporine had marked improvement in erythema (P = 0.003), erosion (P = 0.02), reticulation (presence of white lace-like lesions; P = 0.007), and pain (P = 0.002), whereas the eight recipients of vehicle had no change or minimal improvement. After a switch to cyclosporine for eight weeks, the vehicle-treated patients had improvement similar to that seen in the patients who initially received cyclosporine. There were no systemic side effects. In most cases blood cyclosporine levels were low or undetectable. Cyclosporine levels present in specimens of oral mucosa at the end of therapy four hours after the patients swished were similar to the levels previously reported in psoriatic lesions after treatment with systemic cyclosporine (14 mg per kilogram of body weight per day).
Conclusions.
As a topical preparation, cyclosporine may be useful in the treatment of oral lichen planus and possibly other cutaneous disorders. (N Engl J Med 1990; 323:290–4.)
Media in This Article
Figure 1
Comparison of the Effects of Cyclosporine (C) and Vehicle (V) on Oral Lichen Planus during the Double-Blind Phase.Figure 2
Mean (±SE) Improvement during the Double-Blind Phase (Open Circles) and the Open Phase (Solid Circles) during Eight Weeks of Cyclosporine Therapy.Article Activity
- Article
Oral lichen planus is a relatively common disorder affecting up to 2 percent of the general population.1 Any oral mucosal site may be involved, and there are usually multiple areas of involvement. Although reticular and papular lesions occur most frequently, they are usually asymptomatic and require no treatment.2 However, the erythematous and erosive forms of the disease can be a source of morbidity.
In comparison with the cutaneous form of lichen planus, oral lesions are more resistant to therapy and less likely to undergo spontaneous remission. The primary goal of therapy for all forms of lichen planus is palliative.
Three letters published recently in medical journals have suggested, on the basis of nonblinded evaluations, that topical cyclosporine might improve oral lichen planus.3 4 5 To make an objective assessment, we conducted a double-blind study of topical cyclosporine as compared with its vehicle in oral lichen planus. In this article we report that cyclosporine administered as a swish-and-spit medication produced marked improvement in this oral condition, with minimal systemic absorption.
Methods
Sixteen patients with oral lichen planus proved on biopsy were enrolled in our study. All the patients were symptomatic and had no evidence of cutaneous lichen planus. In addition to reticulated lesions (including lace-like networks of lines, papules, and plaques as described by Andreasen6), all the patients had various degrees of erythema or erosion. Topical medications previously prescribed for the treatment of lichen planus were stopped two weeks before the start of the study, and systemic medications four weeks before.
Informed consent was obtained from all patients alter the nature of the study and its procedures were explained; the protocol and consent form were approved by the University of Michigan institutional review board, and notification of a physician-sponsored investigation was filed with the Food and Drug Administration.
The patients were assigned to one of two groups with use of a table of random numbers. One group received cyclosporine in a formulation designed for peroral systemic administration and containing 100 mg per milliliter (Sandimmune, Sandoz Research Institute, E. Hanover, N.J.) for eight weeks, whereas the other group received Sandimmune vehicle only. During the initial eight weeks, neither the physician responsible for evaluating the patients nor the patients knew the identity of the medications dispensed, which were identical in appearance and taste. All the patients were instructed to swish 5 ml of solution (500 mg of cyclosporine for the patients receiving active medication) in the mouth and expectorate the solution after five minutes. All patients were repeatedly told not to swallow any medication. No eating or drinking was permitted for 30 minutes after application, and the process was repeated three times daily. The patients were seen every two weeks for evaluation.
Because all data for the statistical analysis had been obtained by the end of the first eight weeks of therapy, we elected to reveal the identity of the assigned medications and conclude the double-blind phase of the study. The patients who had received cyclosporine stopped therapy. The patients who had received vehicle subsequently received cyclosporine (100 mg per milliliter) for eight weeks. In this article, we report the data from the double-blind study as well as those obtained during the open phase of treatment of these patients, who were seen every two weeks, but we have not included the open-phase data in the statistical analysis.
At each visit, each patient's whole-blood cyclosporine level was measured by high-performance liquid chromatography one to four hours after swishing and expectorating, and the complete blood count, blood urea nitrogen, serum levels of electrolytes, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, triglycerides, and cholesterol, and a urinalysis were obtained.
Clinical evaluations were performed by the same physician before therapy and biweekly thereafter, Each patient's oral lichen planus was classified on a scale of 0 to 3, with 0 indicating no clinical disease and 3 representing severe clinical disease. According to this scale, the degrees of erosion, erythema, and reticulation of each individual lesion were quantified. Subsequently, a mean score for erosion was calculated for each patient by totaling all assigned erosion scores and dividing the total by the number of lesions with erosion present. Similarly, mean scores for erythema and reticulation were obtained. At each visit the patients performed self-evaluations, grading their symptoms on a scale of 0 to 3, with 0 indicating no pain and 3 representing severe discomfort.
At the final visit, a global score was determined on the basis of the evaluating physician's assessment of the patient's lichen planus, taking into consideration the degrees of erythema, reticulation, and erosion. In the double-blind phase of the study, the global score was based on a comparison with the patient's clinical condition before the initiation of therapy; in the subsequent phase, it was based on a comparison with the patient's status after completion of the course of vehicle administration and just before the receipt of cyclosporine. The scale of global scores was as follows: worse, - 1; no change to minimal improvement (less than approximately 20 percent), 0; moderate improvement (approximately 20 to 49 percent), 1; marked improvement (50 to 80 percent), 2; almost complete or complete improvement (81 to 100 percent), 3.
The changes in erosion, erythema, reticulation, and symptoms for each patient were examined by comparing the scores before therapy and at the final (eight-week) evaluation in the patients receiving either cyclosporine or vehicle, with a two-tailed Mann-Whitney test. Mean erosion scores for the entire group of patients before and after therapy were obtained by adding each patient's mean erosion scores and dividing by the number of patients with such lesions. The scores for erosion incorporate the data for eight patients, the total number with erosions at any time during this study. Similarly, mean scores for erythema and reticulation were calculated before and after therapy. Mean pain scores were calculated by adding each patient's mean pain score and dividing by the total number of patients. When appropriate, means are reported with a confidence interval of ±1 SE.
At the conclusion of cyclosporine therapy in six patients, 6-mm punch biopsies of the full thickness of the posterior two thirds of the buccal mucosa were obtained four hours after the medication was swished to determine cyclosporine levels in tissue. Each specimen was frozen in liquid nitrogen and ground to form a powder. Cyclosporine was measured in the powdered tissue by a modification of the method of Annesley et al.7 In brief, the tissue was added to 2 ml of 0.1 M hydrochloric acid, and 5 ml of methyl terl-butyl ether containing 250 ng of cyclosporine D was added. After 10 minutes of gentle mixing, the tubes were centrifuged at 500Xg for 5 minutes. The upper organic phase was transferred to a second tube containing 2 ml of 0.1 M sodium hydroxide. After vigorous mixing for five minutes, the tubes were centrifuged and the upper organic phase transferred to a third tube for evaporation. The residue was suspended in 50 μl of acetonitrile-water-methanol (49:25:26 by volume) and 100 μl of heptane. After vortexing, the tubes were centrifuged, and 20 μl of the lower layer was injected onto a Beckman Ultrasphere C8 column (2 mm by 25 cm). Separation was performed at 70°C with an average flow rate of 0.35 ml per minute; the effluent was monitored at 230 nm. Powdered tissue from the control samples was added to standard tubes containing 200, 400, and 600 ng of cyclosporine and subjected to the same procedures. The measurement of cyclosporine was based on the ratio of the peak areas of cyclosporine and of cyclosporine D.
Results
Double-Blind Phase
During the eight-week, double-blind phase of the study, eight patients (six women and two men) 45 to 70 years of age (mean, 63) received only cyclosporine, and eight patients (five men and three women) 57 to 71 years of age (mean, 61) received vehicle. At the conclusion of this phase, all eight patients receiving cyclosporine had improved in all categories evaluated (Fig. 1Figure 1
Comparison of the Effects of Cyclosporine (C) and Vehicle (V) on Oral Lichen Planus during the Double-Blind Phase.). Mean (±SE) scores for erythema declined from 1.8±0.2 before therapy to 0.3±0.1 after eight weeks of cyclosporine treatment, as compared with a change from 1.9±0.3 to 1.8±0.3 for the patients receiving vehicle (P = 0.003). Mean scores for erosion declined from 1.9±0.1 to 0.3±0.1 during cyclosporine treatment, as compared with 1.6±0.8 to 1.7±0.4 during vehicle administration (P = 0.02). Mean scores for reticulation decreased from 1.7±0.2 to 0.8±0.1 as compared with 1.9±0.3 to 1.8±0.3 (P = 0.007).Before the study, all the patients reported various degrees of oral discomfort from their lichen planus. The average pain scores decreased from 1.8±0.2 before therapy to 0.4±0.2 after eight weeks of cyclosporine treatment, as compared with a change from 1.7±0.2 to 1.6±0.3 in the patients receiving vehicle (P = 0.002).
Of the eight patients receiving vehicle, one had moderate improvement with respect to erythema and erosion, five remained essentially unchanged, and two had ulcerative flare-ups requiring them to withdraw from the double-blind phase after receiving vehicle for six weeks. The effects of vehicle on all eight patients were included in the statistical analysis.
Open Phase
In the open phase, the eight patients who received cyclosporine after the administration of vehicle had clinical responses and a decline in mean pain scores that were equivalent to the responses in the patients who received only cyclosporine during the double-blind phase. Mean scores for erythema declined from 1.8±0.3 before cyclosporine therapy to 0.3±0.1 after eight weeks of treatment. Mean scores for erosion and reticulation declined from 1.7±0.4 to 0.1±0.1 and from 1.8±0.3 to 1.0±0.2, respectively. Average pain scores decreased from 1.6±0.3 to 0.2±0.1 after eight weeks of cyclosporine.
The responses of all patients to cyclosporine therapy are shown in Table 1Table 1
Clinical Improvement of Oral Lichen Planus in 16 Patients after Eight Weeks of Topical Cyclosporine Therapy.. In the global evaluation, marked improvement or better was noted in 14 of the 16 patients. In all 16 patients, improvement was noted with cyclosporine treatment as early as one week after the start of therapy, but it generally became obvious by the fourth to sixth week. Four patients had no relief from pain until the final two weeks of therapy. The time course of improvement over eight weeks in the double-blind and open phases is shown in Figure 2Figure 2Mean (±SE) Improvement during the Double-Blind Phase (Open Circles) and the Open Phase (Solid Circles) during Eight Weeks of Cyclosporine Therapy.. In general, reticulated lesions on the buccal mucosa and lips responded better than lesions on the tongue and gingiva.Follow-up
Twelve of 16 patients were available for periodic examination after treatment with cyclosporine ended. One month after the end of therapy, four patients had exacerbations of approximately the same severity as their initial presentation before therapy. These patients have since responded to conventional topical therapy. Four patients remained free of disease for three to six months after therapy. Lesions that arose after remission were milder than those before therapy, and they resolved readily with topical therapy. The remaining four patients have had total remissions for six to eight months after the end of therapy.
Side Effects and Changes in Laboratory Values
In no patient did clinical side effects or alterations in laboratory values require the withdrawal of cyclosporine. The side effects reported by all patients were limited to a transient burning sensation of the mucosal surfaces during the swishing of the medication. Twelve of the 16 patients receiving cyclosporine and 3 of the 8 patients receiving vehicle noted a precipitation of the solution during use, resulting in waxy particles that were easily expelled from the mouth.
In only one patient did the laboratory values during therapy differ substantially from those before therapy; the patient's serum creatinine level, which was 110 μmol per liter (1.3 mg per deciliter) at base line, remained unchanged until the eighth week, when it rose to 150 μmol per liter (1.7 mg per deciliter). The patient had been taking a diuretic agent throughout treatment; his blood cyclosporine level was 70 ng per milliliter on the day the creatinine level measured 150 μmol per liter. Two weeks after he discontinued medication, his creatinine level returned to 110 μmol per liter.
Whole-Blood Cyclosporine Content
During the eight weeks of cyclosporine treatment, 7 of the 16 patients had undetectable levels of the drug in their blood (lower limit of detection, 10 ng per milliliter). In the remaining nine patients, cyclosporine levels of 30 to 151 ng per milliliter were recorded; in these patients, more than half of all measurements during the study were below 60 ng per milliliter. There was no correlation between patients' clinical responses and their blood levels of cyclosporine. None of the patients had detectable drug levels during the administration of vehicle.
Cyclosporine Content of the Buccal Mucosa
The amount of cyclosporine present in the healed lesions of the buccal mucosa in patients with oral lichen planus at the end of cyclosporine therapy, four hours after the patient swished the medication, was 2.1±0.3 ng per milligram of tissue (wet weight) and 17.7±3.9 ng per milligram of protein. By comparison, skin plaques of patients with psoriasis contained 2.3±0.3 ng of cyclosporine per milligram of tissue and 13.5±3.2 ng per milligram of protein after seven days of systemic administration of cyclosporine at 14 mg per kilogram of body weight per day.8
Discussion
The treatment of oral lichen planus can be challenging and frustrating. Systemic retinoid and corticosteroid agents are of benefit in recalcitrant cases, although the cessation of therapy typically results in relapses and the long-term use of these agents is limited by their potential toxicity. Systemic griseofulvin had no beneficial effect in seven patients with oral lichen planus.9 Anecdotal reports have suggested that dapsone10 and temarotene,11 a new retinoid, may be effective in oral lichen planus, but these reports have not been confirmed in formal clinical trials. Corticosteroids applied topically or injected into lesions remain the most effective and frequently used therapy.12
This study demonstrates that topical cyclosporine treatment significantly improves oral lichen planus. Erosions and erythema, which have been shown to correlate with oral symptoms,2 were each improved by more than 50 percent in 87 percent of the patients (Table 1). Furthermore, in our patients relief from pain followed the improvement of these lesions.
The administration of cyclosporine may result in a relatively prolonged remission in patients with lichen planus. Eight of our 12 patients had remissions lasting three to eight months. Pigatto et al. recently reported a six-month remission in six of eight patients with cutaneous lichen planus after peroral treatment with cyclosporine.13 In contrast, patients treated with systemic cyclosporine for psoriasis, atopic dermatitis, and alopecia areata had relapses shortly after discontinuing medication.14
The goal of the present study was to evaluate efficacy. It is unlikely that the regimen we employed will be used by itself to treat oral lichen planus over the long term. Despite the low systemic absorption and therefore the relative safety of topical cyclosporine, the large dose and volume of medication used would be prohibitively costly in practice. The cost of therapy with a potent topical steroid averages 25 to 50 cents per day, as compared with $60 to $70 per day for a cyclosporine rinse. Our excellent response with a high-dose rinse, however, suggests a potential for therapeutic benefit at lower dose and cost. Furthermore, Frances et al.3 and Balato et al.,4 in open studies, demonstrated improvement in oral erosive lichen planus with topically applied cyclosporine at 1/15 the dose we used. If cyclosporine becomes available at a lower price, perhaps in an appropriate concentration or vehicle designed for intraoral use, or if double-blind studies confirm the efficacy of lower-dose topical cyclosporine, then the therapy could become cost effective.
The cause of oral lichen planus is unknown. The efficacy of immunomodulatory agents such as corticoSteroids and systemic psoralen and intraoral ultraviolet A (PUVA)15 in its treatment supports the role of the immune system in its pathogenesis. The dermal infiltrate in lichen planus is composed primarily of activated T lymphocytes, and it has been suggested that through their production of interferon gamma, an inflammatory response is initiated that leads to damage to keratinocytes.16 The mechanism by which cyclosporine improves oral lichen planus is unknown. The drug selectively inhibits the proliferation and function of T lymphocytes, however, and reduces the rate of production of lymphokines such as interferon gamma.17 18 19 This may account for the clinical effects seen in our patients.
Cyclosporine has been shown to be efficacious in the treatment of many inflammatory dermatoses when given systemically. No consistently beneficial response has been observed in alopecia areata20 or psoriasis21 , 22 after topical application, however. Recently, Grattan el al. treated four patients with cutaneous lichen planus with topical cyclosporine under occlusion and observed slight improvement.23 However, since the cyclosporine measured in lesional skin-biopsy specimens was undetectable,23 the possibility that occlusion alone may have been responsible for the observed changes cannot be excluded. The greater absorption potential of the mucosa relative to skin may relate directly to the benefit derived from topical cyclosporine in our study and others,3 , 4 in comparison with its failure in the topical treatment of psoriasis and alopecia areata. The cyclosporine levels measured in oral mucosa in our study were comparable to those found in lesional specimens of patients with psoriasis after the systemic administration of high-dose cyclosporine.8 Our work provides substantive evidence that cyclosporine may be used as a topical regimen. Since the potential toxicity of systemic cyclosporine may limit its use in dermatologic disorders, a topical preparation that penetrates the skin is a desirable alternative that warrants further investigation in other cutaneous disorders.
Unlike the peripheral-blood lymphocytes in patients with cutaneous lichen planus, which are predominantly T-helper/inducer (CD4+, CD8-) cells, the T-lymphocyte subgroups in the peripheral blood of patients with oral lichen planus are no different from those of healthy controls.24 On the basis of this and other immunologic findings, the cause of oral lichen planus may be a local and not a generalized immunologic defect involving the oral mucosa.24 Although a concomitant systemic effect of cyclosporine cannot be excluded, seven of our patients (all of whom improved) had undetectable blood cyclosporine levels, thereby strengthening the hypothesis that a local, immunologically mediated process, when inhibited, was responsible for the clinical improvement.
Supported in part by the Babcock Dermatologic Endowment to the University of Michigan and the British Association of Dermatologists' Dowling Traveling Fellowship (to Dr. Griffiths). Cyclosporine was provided by Sandoz Research Institute, E. Hanover, N.J.
Two of the authors (Dr. Voorhees and Dr. Ellis) are consultants to the Sandoz Pharmaceutical Corporation.
We are indebted to Harrold Carter for professional photography; to Ted Hamilton, M.S., for statistical analysis of the data; to Dr. Thomas Annesley for performing some of the cyclosporine assays; and to Cyndi Slam for assistance with the study.
Source Information
From the Dermatopharmacology Unit, Department of Dermatology, University of Michigan Medical Center, 1910 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109–0314, where reprint requests should he addressed to Dr. Voorhees.
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