Clinical response to levamisole in thirty-nine patients with erythema multiforme An open prospective study F. Lozada-Nur, UNIVERSITY

DDS, IVS,~ D. Cram, IWD,~ and M. Gorsky, DMD,’ San Francisco, CalijT

OF CALIFORNIA-SAN

FRANCISCO

Patients with erythema multiforme (EM) often have chronic or recurring oral lesions that cause intense pain and interfere with a variety of functions including eating and speech. Previous studies suggest that levamisole restores to normal the function of phagocytes and T lymphocytes, and activates the inflammatory response. In our previous double-blind study 8 of 13 patients with EM had a decrease in severity and frequency of attacks. The purpose of this open prospective study was to evaluate short-term and long-term clinical efficacy of levamisole in patients with mucocutaneous EM. Thirty-nine patients with mucocutaneous EM seen in the Oral Medicine Clinic, School of Dentistry, University of California-San Francisco, comprised our study group. Levamisole was used alone in 17 patients or in combination with prednisone in 22 patients and was given as a single dose of 150 mglday for 3 consecutive days. Thirty-one patients showed a complete response from levamisole (alone in 13 and in combination with prednisone in 18). Four showed a partial response of signs and symptoms, and four others had no benefits from levamisole whether alone or in combination. The most common side effects from levamisole were skin rash, tiredness, weakness, myalgia, taste change, and insomnia. (ORAL SURC ORAL MED ORAL PATHOL 1992;74:294-8)

P

atients with oral erythema multiforme (EM) often have chronic or recurring oral lesions that cause intense pain and interfere with a variety of functions including eating and speech.” 2 Although systemic treatment with corticosteroids is helpful, preexisting systemic disease and undesirable side effects may contraindicate their use.’ Levamisole has been effective in diseasesin which cellular immune deficiency is suspected, such as chronic and recurrent infections, primary and secondary immune deficiencies, allergic disorders, rheumatoid diseases,and cancer.4-8 Accumulated evidence from previous studies suggests that levamisole restores to normal the function of phagocytes and increasesthe magnitude of delayed “Clinical Professor, Department of Stomatology, School of Dentistry. bClinical Professor, Department of Dermatology, School of Medicine. ?Jisiting Postdoctoral Scholar, Department of Stomatology, School of Dentistry. 7/13/34571

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hypersensitivity or T cell-mediated immunity in human beings. Levamisole has been shown to activate the inflammatory response.9-‘2Recently levamisole has been found to promote oxidation of a precursor molecule to soluble immune responsesuppressorsubstance (the latter might explain someof levamisole’s benefits in patients with rheumatoid arthritis).r3 We found that in our previous study 8 of 13 patients with EM had a decreasein the severity and frequency of attacks after the administration of levamisole.9The purpose of this study was to evaluate the short-term and long-term clinical efficacy of levamisole in a larger group of patients with mucocutaneous EM. MATERIAL AND METHODS Patients

Thirty-nine patients with mucocutaneous EM seen in the Oral Medicine Clinic, School of Dentistry, University of California-San Francisco, comprised our study group. The clinical characteristics of this patient population are described in Table I. Diagnosis was confirmed by clinical findings and biopsy specimensprocessedby routine staining as described

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first month and once a month thereafter to record clinical responseand side effects; complete blood cell (CBC) counts were performed in all patients before beginning of therapy and on each visit to the clinic for as long as they were receiving levamisole, to monitor white blood cell (WBC) counts. The extension of the diseasewas noted, erythema and ulcers were rated according to the following scale: severe,moderate, mild, or absent. Severity of pain was rated according to a numbered scale ranging from 0 (absent) to 10 (worst). In addition, patients were given a chart to record periods free of diseaseand onset of new outbreaks, together with days when pills were taken. Clinical efficacy was defined as complete remission with 80% to 100% remission of signs and symptoms and a reduction in the frequency of the disease; as partial remission, ranging from mild (50%) to marked (75%) remission of signs and symptoms and a reduction in the frequency of the disease;or as no response or worsening of the disease. RESULTS Fig. 1. A, Fifty-nine-year-old white woman with 2-year history of recurrent palatal EM. Intraorally patient showed large erosions and irregular ulcers covered by pseudomembrane with crusting of vermilion border of lip. Case was previously misdiagnosed as candidiasis with dysplasia. B, Same patient after 4-week course of levamisole. Healing ulcer is observed on right posterior portion of hard palate. Patient has remained free of diseasefor more than 2 years.

previously. 2*l4 Patients participating in this study were those who either failed to respond to clinically

safe dosesof prednisone or could not tolerate associated side effects. All patients were asked to sign a human research consent form. Conventional therapy was offered to any patient who did not wish to continue in the study. Treatment

protocol

Levamisole, 150 mg/day for 3 consecutive days, was used alone or in combination with prednisone for as long as there was evidence of disease. Seventeen patients received levamisole alone, and 22 patients received levamisole together with prednisone. Prednisone, when used with levamisole, was given in dosesranging from 5 to 30 mg as a single dose in the morning. Prednisone dose was determined by severity of diseaseand history of side effects from prednisone. Patients were monitored once a week for the

As shown in Table II, 31 patients showed a complete response,13 from levamisole alone (Fig. 1), and 18 with levamisole and prednisone. Four showed a partial responseof signs and symptoms (Fig. 2), and four others had no benefits from levamisole, whether alone or in combination. In those 22 patients who had used prednisone before the use of levamisole, the minimum effective dosagethat was neededfor disease control ranged from 40 to 90 mg/day; for equivalent control this was dramatically reduced to 5 to 30 mg/ day when combined with levamisole.

Seventeen patients took levamisole alone because of other medical complications (gastric ulcer), personal refusal to take prednisone, failure to respond to safe doses of prednisone, or side effects from prednisone. Six patients remained completely free of diseasefrom 1 to 3 years without taking more levamisole. All patients who responded to levamisole initially continued to do so whenever the drug was reinstated. Side effects from levamisole were skin rash (four patients); tiredness, weakness, and/or myalgia (three); taste change (one); and insomnia (one). No significant changeswere recorded in the WBC or differential counts. In patients whose WBC values were elevated initially (range 10,000 to 17,000 cells/m3 after week 2 of levamisole therapy), WBC counts re-

duced to normal ranges (4000 to 8000 cells/mm3. The time of response after therapy was initiated

ranged from 1 to 3 weeks.Responsesto treatment did not appear to be associated with site involvement.

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Fig. 2. Thirty-year-old white woman with 3-year history of recurrent mucocutaneous EM. Notice bilateral involvement of legs (A). Large ulcers covered by pseudomembrane with crusting on vermilion border of lips can be seen (B). Complete healing of skin lesions was seen after 1 month of therapy (C), and marked improvement of oral lesion was seen by second week of therapy (D).

Table I. Clinical characteristics of 39 patients with oral EM Gender Location of lesions

Patient No.

Oral Oral and lip Oral, lip, and skin Total

4 16 19 39

!

F 3 II 5 19

1

Type of disease M

I

1 5 14 20

Age at onset (ml 18-69 1I-14 18-76 17-76

Chronic* 2 10 4 16

Cyclic

Follow-up (Yd f

2 6 I5 23

1.3-2.0 .6-10 .lO-10.5 .6-10.5 (5.2)$

*Patients whose diseasehas been present for at least 1 month without any signs of spontaneousremission. TPatients were required to have a history of EM at least 6 months before entering study. $Mean follow-up in years for whole group.

DISCUSSION

This study demonstrated a significant beneficial effect from levamisole, whether used alone or in combination with prednisone, as shown by complete remission of the diseaseand by a change in the course of the disease, making it shorter and less frequent. As reported previously, systemic corticosteroids remains the most effective treatment to control EM; however, adverse side effects, especially in patients with chronic disease, makes its use sometimes difficult. Levamisole in previous studies proved to be effective not only in treating acute EM but in inducing a long-term beneficial effect by reducing severity and

frequency of the disease.The long-term beneficial effect of levamisole might be due to its effect on the inflammatory responseby leading to a sequestration or elimination of persistent antigen and by increasing interleukin-2 production by T lymphocytes.‘* Patients tolerated levamisole well; side effects occurred in nine patients but were not severe and disappeared when therapy was discontinued. Two patients who had fatigue, myalgia, and flulike symptoms were withdrawn from therapy until they recovered. These patients declined to reenter the study, so we do not know whether lower doses would have avoided the recurrence of flulike symptoms. It has beenreported previously that patients in whom flulike

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II. Treatment responsein 39 patients with oral EM Oral (n = 4)

Levamisole (n = 17) Levamisole-prednisone (n = 22) Total (n = 39)

Oral and lip (n = 16)

Oral, lip, and skin (n = 19)

CR

PR

NR

CR

PR

NR

CR

PR

NR

2 0

0 0

1

1

4 9

1 1

1 0

7 9

1 1

0 1

2

0

2

13

2

1

16

2

1

CR, Complete response(80% to 100%remission of signs and symptoms); NR, no response(unchanged or worsening of signs and symptoms); PR, partial response(50% to 75% remission of signs and symptoms).

symptoms develop are at higher risk of granulocytopenia. Therefore if a patient resumes levamisole therapy, the initial dose should be lower and WBC count should be monitored with a weekly CBC count. In rheumatoid arthritis patients taking levamisole leukopenia has beenreported to develop.‘5, l6 Patients with oral lichen planus receiving levamisole may be at risk of flulike symptoms (personal observation). Although this requires further study, caution should be used in treating patients with lichen planus with levamisole. In all patients CBC counts should be performed before starting therapy and within 4 hours after the first doseof levamisole, to evaluate any early changes in blood cell counts. Agranulocytosis might develop at any time up to 2 years after therapy. Therefore periodic CBC counts must be performed. Our criteria to determine whether a patient should receive levamisole alone or in combination with prednisone evolved from long-term systematic clinical observations. Patients with mild to moderate forms of the diseaseare more responsiveto levamisole, whereas patients with acute severe disease do better when prednisone is added to levamisole. A possible explanation is that although levamisole regulates the immune response, prednisone displays its anti-inflammatory effect. Whether levamisole has a synergistic effect on prednisone is not known; it is evident that these are only clinical observations and that a prospective double-blind study must be performed to evaluate levamisole and levamisole-prednisone therapies. Determination of the most appropriate dose for each patient is basedon clinical trials. An initial dosage of 150 mg/day for 3 consecutive days every week is recommended by the manufacturer. Different schedules should be tried in patients who do not respond to therapy or maintenance regimens.l7 To our knowledge no known data relate levamisole blood levels and clinical efficacy in patients with EM. However, once a patient responds to one of the two treat-

ment modalities, that modality should remain effective in future flare-ups. In summary, patients with chronic or frequent EM remain a therapeutic challenge to the clinician. Levamisole, when usedin patients with EM, has been shown to be effective and relatively safe as compared with prednisone. Most patients responded well and remained free of diseasefor prolonged periods of time. Levamisole is available to clinicians as an Investigational New Drug. As of July 1990 levamisole received approval by The Food and Drug Administration for the treatment of colon cancer. REFERENCES 1. Lozada F, Silverman S. Erythema multiforme: clinical characteristics and natural history in 50 patients. ORAL SURG ORAL MED ORAL PATHOL 1978;46:628-36.

2. Lozada-Nur F, Gorsky M, Silverman S Jr. Oral erythema multiforme: clinical observations in 95 patients. ORAL SURG ORAL MED ORAL PATHOL 1989;67:36-40.

3. Lozada-Nur F, Silverman S Jr, Migliorati C. Adverse side effects associated with prednisone in the treatment of patients with oral inflammatory ulcerated diseases.J Am Dent Assoc 1984;109:269-70. 4. Lozada F, Silverman S, Cram D. Pemphigus vulgaris: a study of six cases treated with levamisole and prednisone. ORAL SURG ORAL MED ORAL PATHOL 1982;54:161-5.

5. Olson J, Silverman S. Double-blind study of levamisole ther;p;9fn9ecurrent aphthous stomatitis. J Oral Path01 1978; 6. Lozada F. Levamisole in the treatment of erythema multiforme: a double-blind trial in 14 patients. ORAL SURG ORAL MED ORAL PATHOL 1982;53:28-3 1.

7. Schuemans Y. Levamisole in rheumatoid arthritis. Lancet 1975;l:lll. 8. Moertel C, Fleming T, MacDonald J, et al. Levamisole and fluorouracil for adjuvant therapy of resectedcolon carcinoma. N Engl J Med 1990;322:352-8. 9. Lozada F, Spitler L, Silverman S Jr. Clinical and immunologic responsesto levamisole in 13 patients with erythema multiforme. Int J Immunopharmacol 1980;2:63-8. 10. Lewinski U, Mavligib G, Hersh E. Cellular immune modulation after a single high doseof levamisole in patients with carcinoma. Cancer 1980;46:2185-94. 11. Tripodi D, Parks LC, Brugnans J, et al. Drug-induced restoration of cutaneousdelayed hypersensitivity in anergic patients with cancer. N Engl J Med 1973;289:353-7. 12. Redondo JM, Lopez-Guerrero JA, Fresno M. Potentiation of interleukin-2 activity by levamisole and imidazole. Immunol Lett 1987;14:111-6.

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September 1992 13. Salmon S. Immunopharmacology. In: Katzung BG. Basic and clinical pharmacology. Norwalk, Conn: Appleton & Lange, 1989:726-7. 14. Buchner A, Lozada F, Silverman S Jr. Histopathologic spectrum of oral erythema multiforme. ORAL. SURG ORAL MFD ORAL PATHOL 1980;49:221-8. 15. Williams GT, Johnson SAN, Dieppe PA, Huskesson EL. Neutropenia during treatment of rheumatoid arthritis with levamisole. Ann Rheum Dis 1978;37:366-9. 16. Hodinka L, G&her P, Meretey K, Gyodi E, Petrinyi G, Bozsbky S. Levamisole-induced neutropenia and agranulocytosis association with HLA B27 leucocyte agglutinating

and lymphocytotoxic antibodies. Arch Allergy Appl lmmunol 1981:65:460-4. 17. Veys E, Mielants H. Experience and recommendations for treatment schedule of levamisole to rheumatoid arthritis. J Rheumatol [Suppl] 1978:4:31-41. Reprint requests: F. Lozada-Nur, DDS, MS Department of Stomatology School of Dentistry University of California San Francisco, CA 94143