ALTERNATIVE THERAPIES FOR MAJOR APHTHOUS ULCERS IN AIDS PATIENTS M IC H A E L G L IC K ,
:
specific infectious pathogen for recurrent aphthous ulcers has not been characterized. : Instead, predisposing factors possibly combined w ith local traum a, are associated with ulcer development. An imm unopathogenic pathw ay may be ultim ately responsible for severe m ajor recurrent : aphthous ulcers. This article presents two alternate therapies for resista n t : major recurrent aphthous ulcers in p atients w ith significant im m une deficiency. Major recu rren t aphthous ulcers (MjRAU) differ from m inor recurrent aphthous i ulcers (MiRAU) in size, : duration, severity and sequelae, j Typical MjRAUs are larger th an 10 m illim eters in diam eter, and crateriform , w ith a deep, eroded base. These ulcers are present for more th a n th ree weeks and can be severely debilitating for the patient, interfering with norm al chewing and speaking.1 Usually, the affected site scars : upon healing. MjRAUs can be found on any oral mucosal surface including the heavily keratinized tissues, i which usually are not associated w ith MiRAU.1,2
B R IA N O. M U Z V K A , D .M .D .
ABSTRACT
Two a lte r n a te th er a p ie s for r e sista n t m ajor r ecu rren t ap h th o u s u lc e rs in p a tie n ts w ith sig n ific a n t im m u n e d e fic ie n c y are p resen ted . No cause has been im plicated for recurrent aphthous ulcers b ut m any theories suggest stress, vitam in deficiency, diet, horm onal changes, allergies, trau m a or im m une dysfunction as the ultim ate cause of these ulcers.3 No single cause is responsible for all the MjRAUs or the MiRAUs; consequently, several different, b u t variably successful tre a tm e n t m odalities have been used. Glucocorticosteroid and antim icrobial therapy constitute the traditional tre a tm e n t for both MjRAU and MiRAU. These medications have been adm inistered as topical pastes, m outhrinses, intralesional injections and system ically by oral route.1 O ther reported therapeutic modalities with some beneficial response include im m unom odulators such as
levamisole37 and colchicine, and other m iscellaneous agents such as dapsone, thalidom ide and monoamino oxidase inhibitors.8 MiRAUs have been reported in as m any as 60 percent of m em bers of professional groups while the incidence rate in the general population is about 20 percent.9 No prevalence studies among the general population with MjRAUs have been reported. Oral aphthous ulcers among individuals w ith AIDS, compared w ith im m unocom petent individuals, may be more p ersistent and severe and involve other areas of the gastrointestinal tra c t.1012 The prevalence of MjRAU in this p articular patien t population has been reported to range from 1.1 percent13to 4 percent.14 This correlates w ith our patien t population, where only four patients, among a population of 280 patients with AIDS, had MjRAU, suggesting an incidence ra te of 1.4 percent.15 *■ Case 1. A 60-year-old homosexual m an came to the Infectious Disease C enter at Temple U niversity D ental School com plaining of a painful JADA, Vol. 123, July 1992
61
ulcer on the left lateral border of his tongue. The ulcer had been present for 10 days. His medical history included m ultiple bouts of venereal diseases including gonorrhea and syphilis. He had a past h epatitis B viral infection, b ut a chronic carrier sta te did not develop. Three sequential HIV tests perform ed two years earlier had positive results but the p atien t had not developed any m ajor opportunistic infections or neoplasm s. The only H lV-associated disease was occasional intraoral Candida infections. The p a tie n t’s medication included Retrovir (Burroughs Wellcome), acyclovir and aerosolized pentam idine once a m onth. His CD4* cell count was 14 cells/mm3 (norm al 700 to 1,000 cells/mm3) and his white blood count was 3,200 cells/mm:i (norm al 4,500 to 11,000 cells/mm3). The p atien t had a crateriform ulcer, about 4 to 5 mm deep w ith a 20-mm diam eter, on th e left lateral border of his tongue. No red halo surrounded it. The patient said th a t sm all intraoral ulcers recurred for the past 30 years both on his tongue and on the upper and lower vestibular areas. These ulcers usually caused only slight discomfort and resolved spontaneously w ithin seven to 10 days. In spite of the lesion size, an excisional biopsy was performed. The hem atoxylin and eosin preparation showed inflam m atory infiltrate w ith eosinophils extending into skeletal muscle and submucosal tissue. No granulom atous disease or viral cytopathic effect was detected. 62
JADA, Vol. 123, July 1992
Figure 1. First sign of a shallow small ulcer on the right lateral border of the tongue.
Im m unohistochem ical stains for cytomegalovirus and herpes simplex virus were negative, as was in situ hybridization for E pstein-B arr virus. Stains for hepatitis B virus surface and core antigens were also negative. Additional cytochemical stains were performed but were negative for syphilis and fungal infections. W ithin three days of the biopsy, another ulcer started to develop a t th e sam e site. M outhrinses w ith Miles’ m ixture (a liquid preparation containing 84,000 IU nystatin, 84 mg tetracycline and 1.04 mg hydrocortisone per 5 cc) and 2 percent viscous lidocaine, four tim es daily, enhanced ulcer healing. Three weeks after the biopsy, a small ulcer appeared on the p atien t’s right lateral tongue border (Figure 1). We institu ted initial therapy of intralesional injections with triam cinolone because of the p a tie n t’s prior extensive ulcer on the left lateral border of his tongue. Accum ulated doses of 1.2 cc were injected every three
days during a 12-day period. The patien t returned on the te n th day. He had a shallow ulcer th a t was 15 mm in diam eter a t the site of the initial right tongue ulcer (Figure 2). Miles’ m ixture and 2 percent viscous lidocaine were in stitu ted again, four tim es daily. Three weeks after the initial sign of the ulcer, the lesion had grown bigger (Figure 3) and was identical to the one on the patien t’s left lateral tongue border. We instituted a regim en of 50 mg of levamisole, adm inistered orally every eight hours for three days followed by an 11-day laten t period. After two such cycles, the ulcer resolved and healed with scarring. After four weeks of levamisole therapy, the p atien t’s white blood count was 3,400 cells/mm3 and his CD4+ count was 34 cells/mm3. ■■ Case 2—A 29-year-old homosexual m an w ent to IDC for treatm en t of m ultiple chronic intraoral ulcers. His medical history included
Figure 2. The ulcer grew bigger within 10 days after the initial sign appeared.
m ultiple bouts of syphilis 10 years earlier, hospitalization for
Pneumocystis carinii pneum onia and positive results from HIV tests performed 18 m onths earlier. M edications included Retrovir, acyclovir and aerosolized pentam idine once every m onth. His intraoral ulcers, present for 13 m onths, severely restricted chewing and speaking. Several biopsies did not im plicate any causative pathogen. The p a tie n t’s previous systemic glucocorticosteroid therapy had to be discontinued because of progressive low w hite blood counts. He had also received two blood transfusions after side effects from Retrovir therapy. The p atien t had a CD4+cell count of 37 cells/mm3 and a w hite blood count of 2,800 cells/mm3. B ilateral horizontal ulcers th a t were 5 mm wide, 2-3 mm deep and 40 mm long radiated from the m outh angles along the buccal mucosa. Three eroded areas, each 5-7 mm in
diam eter, were on the tip of his tongue. A crateriform ulcer, 25 mm in diam eter, was on the inside of his right lower lip. M outhrinses w ith Miles’ m ixture and 2 percent viscous lidocaine were in stitu ted four tim es daily. The ulcers resolved completely a fter 14 days. Deep scarring rem ained a t the ulcer sites. D IS C U S S IO N
To tre a t any disease or disease entity, first establish a diagnosis and determ ine the etiologic pathogen(s). RAUs are diagnosed by history and clinical presentation, and by excluding any known cause. RAU tre a tm e n t m ust be based on the known predisposing and local factors. Although no common immunologic pathogenic pathw ay has been documented in non-HIV-infected individuals, a clear correlation betw een severe systemic im m unosuppression and MjRAU occurrence is present in HIV-infected p a tie n ts.16 Studies
of RAU, in presum ably HIVnegative individuals, have indicated low CD4* helper cell levels in the perivascular area surrounding th e lesion during the ulcerative phase and a consequent increased level during the healing phase.17 Decreased CD47CD8^ cell count ratio has also been docum ented in individuals with RAU,18indicating imm une suppression. In all of our AIDS patients w ith MjRAU, th e peripheral CD4* cell count was below 50 cells/mm315 which corresponds with severe im m une deterioration. Q ualitative and quantitative deficiencies or dysfunctions of T lymphocytes, or both, are responsible for m any oral lesions in im m une suppressed individuals.19 Therefore, using immunom odulators to tre a t oral ulcers in these p atients m ay be beneficial. Levamisole, an immunopotentiating drug, restores both deficient phagocytic function and cutaneous delayed hyper sensitivity reactions, and increases both absolute and relative peripheral Tcell count.20 In our patient, levamisole therapy was not continued after the ulcer resolved. Thus, it was not possible to study the long term effect of this drug on the p atien t’s CD4+cell count. Levamisole is m ainly used to delay colon cancer recurrence in Dukes’ cancer patients. In some Dr. Glick is director, Infectious Disease
C en ter, and assoc iate professor,
D ep artm e n t of Oral M edicin e, Tem ple
University School of Dentistry, 3 2 2 3 N.
Broad St., P hiladel
phia 1 9 1 4 0 . Address reprint requests to Dr. Glick.
JADA, Vol. 123, July 1992
63
early studies, w here im m unocom petence was not evaluated, levamisole therapy improved healing and the ulcer recurrence ra te reduced when used for p a tie n ts w ith recurrent aphthous ulcers.3'7 O ther studies did not corroborate these findings.20'22 The potential significant side effect of levamisole, agranulocytosis,23 outweighed th e beneficial response to the drug, and th is therapeutic m odality was discontinued. Side effects to th is drug occur more frequently in patients w ith and a t risk for autoim m une disorders.24 In patien ts w ith severe T-cell im m une suppression, there is no risk of autoim m une disease developm ent; imm une stim ulatory drug therapy, which could include levamisole, is indicated pathophysiologically. Close m onitoring of patien ts’ white blood cell counts during levamisole therapy helps to avoid the onset of serious side effects. Therapy w ith M iles’ solution and viscous lidocaine has far less of a systemic influence on th e patient th an does levamisole. Components in th is m ixture will have prim arily a local effect. Tetracycline reduces th e bacterial flora of and surrounding the lesion, while n y statin stops fungal growth and glucocorticosteroids reduce inflam m ation. Oral topical glucocorticosteroid therapy has not been indicated
Dr. M u zy k a is
a ssistant professor, D e p a rtm e n t o f Oral M edic in e, Te m p le
U niversity School of D entistry,
Philadelphia.
64
JADA, Vol. 123, July 1992
Figure 3. A deeply eroded, crateriform, painful ulcer developed within three weeks of the initial manifestation.
in im m une suppression25but enhances aphthous ulcer healing. Adding viscous lidocaine will improve the compliance ra te of the patient by reducing oral discomfort during chewing and speaking. P atien ts w ith RAUs need to be m ade aw are of th e empirical natu re of any proposed therapy. The severe discomfort and disabling characteristics of MjRAUs in patients w ith AIDS require prom pt and effective therapeutic intervention w ithout fu rth e r compromising the patients. The use of less toxic therapeutic m odalities a t an early stage when the lesions do not have aggressive tissue destruction is recommended. More invasive and potentially cytotoxic therapy m ay be in stitu ted later if necessary. T reating HIV-infected patients poses m any challenges to the dental care provider. Of utm ost im portance is the patien ts’ overall health and im m une sta tu s.26 Im proper antibiotic use m ay lead to
opportunistic oral fungal infection, which will assault the p a tie n ts’ already debilitated im m une system . Using systemic glucocorticosteroid therapy in AIDS p atients m ay cause hum oral im m une suppression, leaving the patients susceptible to even more opportunistic bacterial infections, as well as potentially inducing adrenal insufficiency.27 Therapeutic interventions discontinued in the pre-AIDS era need to be re-evaluated for tre a tm e n t of resista n t lesions in HIV-infected patients. C O N C L U S IO N
M any oral lesions, described in HIV-infected individuals, are early signs of immune deterioration and disease progression.28 D ental care providers m ust recognize these signs and communicate these findings to the patien ts’ physicians. Early HIV disease detection will enable prom pt institu tio n of anti-retroviral therapy, which may prolong the p atien t’s life. ■
Figure 4. The ulcer resolved completely with deep scarring, after two cycles of levamisole administration.
The authors th a n k A rth u r S. Miller, D.M.D., and Jo h n S. J. Brooks, M.D., for their assistance in evaluating and in terpreting the biopsy specimens. 1. Regezi JA, Sciubba J J . O ral pathology: clinical-pathologic correlations. Philadelphia: Saunders; 1989:46-53. 2. Lynch MA, B rightm an V J, G reenberg MS. B urket’s oral medicine. Diagnosis and treatm en t. 8th ed. PhiladelphiarLippincott;1984:181-5. 3. Verhagen H, DeCree J , B rugm ans J. T reatm en t of aphthous stom atitis. Lancet 1973;2:842. 4. Symoens J , B rugm ans J. T reatm ent of recu rren t aphthous stom atitis and herpes w ith levamisole. Br Med J 1974;4:592. 5. M ohammad AR, R uprecht A. U nusual chronic recu rren t aphthous sto m atitis treated w ith levamisole. J O ral Med 1983;38:164. 6. D rinnan A, Fischm an S. Randomized double-blind study of levamisole in recurrent aphthous stom atitis. J O ral Pathol 1978;7:414-7. 7. Zissis NP, H atzioti AJ, A ntoniadis D. T herapeutic evaluation of levamisole in recu rren t aphthous stom atitis. J O ral Med 1983;38:161-3. 8. Scully C, P orter SR. R ecurrent aphthous stom atitis: cu rren t concepts of etiology, pathogenesis and m anagem ent. J O ral Pathol Med 1989;18:21-7. 9. Ship II. Epidemiologic aspects of recu rren t aphthous ulcerations. O ral Surg O ral Med Oral Pathol 1972;33:400-6. 10. Bach MC, Howell DA, V alenti AJ, e t al. A phthous ulceration of th e g astrointestinal tra c t in p atients w ith th e acquired immunodeficiency syndrom e (AIDS). Ann
Intern Med 1990;112:465-7. 11. D retler RH, R ausher DB. G iant esophageal ulcer healed w ith steroid therapy in a patien t w ith AIDS. Rev In f Dis 1989;11:768-9. 12. Bach MC, V alenti AJ, Howell DA, e t al. Odynophagia from aphthous ulcers of the pharynx and esophagus in the acquired immunodeficiency syndrom e (AIDS). Ann Intern Med 1988;109:338-9. 13. P helan JA, Eisig S, Freedm an PD, e t al. Major aphthous-like ulcers in p atien ts w ith AIDS. O ral S urg Oral Med O ral Pathol 1991;71:68-72. 14. B arr C, Croxson T, Dobles A, e t al. HIVassociated oral lesions: immunologic and salivary p aram eters (Abstract no. 1443). J D ent Res 1990;69:289. 15. M uzyka BC, Glick M. A lternate treatm en t for m ajor aphthous ulcerations in AIDS p atien ts (Abstract). NYC: Third International Symposia on O ral AIDS, Nov. 23, 1991. 16. M acPhail LA, G reenspan D, Feigel DW, et al. R ecurrent aphthous ulcers in association w ith HIV infection. O ral Surg
O ral Med O ral Pathol 1991;71:678-83. 17. P edersen A, K lausen B, Hougen HP, et al. T-lymphocyte subsets in recu rren t aphthous ulcerations. J O ral Pathol Med 1989;18:59-60. 18. L andesberg R, Fallon M, Insel R. A lterations of T helper/inducer and T suppressor/inducer cells in p atien ts w ith recurrent aphthous ulcers. O ral S urg Oral Med O ral Pathol 1990;69:205-8. 19. G arfunkel AA, Glick M. Common oral findings in two different diseases - leukem ia and AIDS. Compendium (In press). 20. Levo Y, R otter V, Ram ot B. Restoration of cellular im m une response by levamisole in p atien t w ith Hodgkin’s disease. Biomed 1975;23:198-200. 21. M iller MF, S ilvert ME, L aster LL. Effect of levamisole on the incidence and prevalence of recu rren t aphthous stom atitis. J Oral Pathol 1978;7:387-92. 22. Olson JA, Silverm an S. Double-blind study of levamisole th erap y in recurrent aphthous stom atitis. J O ral Pathol 1978;7:393-9. 23. R osenthal M, T rab ert U, M uller W. Leucocytotoxic effect of levamisole. Lancet 1976;1:369. 24. Diez RA. HLA-B27 and agranulocytosis by levamisole. Immunology Today 1990;11:270. 25. Plem ons JM , Rees TD, Zachariah NY. Absorption of a topical steroid and evaluation of adrenal suppression in p atien ts with erosive lichen planus. O ral S urg Oral Med Oral Pathol 1990;69:688-93. 26. Glick M. Clinical protocol for treatin g patients w ith HIV disease. Gen D ent 1990;38:418-25. 27. Glick M. Glucocorticosteroid replacem ent therapy: a lite ra tu re review and replacem ent therapy. O ral S urg O ral Med Oral Pathol 1989;67:614-20. 28. Glick M. E valuation of prognosis and survival of the HIV infected patient. Oral Surg Oral Med O ral Pathol (In press).
JADA, Vol. 123, July 1992
65
:
specific infectious pathogen for recurrent aphthous ulcers has not been characterized. : Instead, predisposing factors possibly combined w ith local traum a, are associated with ulcer development. An imm unopathogenic pathw ay may be ultim ately responsible for severe m ajor recurrent : aphthous ulcers. This article presents two alternate therapies for resista n t : major recurrent aphthous ulcers in p atients w ith significant im m une deficiency. Major recu rren t aphthous ulcers (MjRAU) differ from m inor recurrent aphthous i ulcers (MiRAU) in size, : duration, severity and sequelae, j Typical MjRAUs are larger th an 10 m illim eters in diam eter, and crateriform , w ith a deep, eroded base. These ulcers are present for more th a n th ree weeks and can be severely debilitating for the patient, interfering with norm al chewing and speaking.1 Usually, the affected site scars : upon healing. MjRAUs can be found on any oral mucosal surface including the heavily keratinized tissues, i which usually are not associated w ith MiRAU.1,2
B R IA N O. M U Z V K A , D .M .D .
ABSTRACT
Two a lte r n a te th er a p ie s for r e sista n t m ajor r ecu rren t ap h th o u s u lc e rs in p a tie n ts w ith sig n ific a n t im m u n e d e fic ie n c y are p resen ted . No cause has been im plicated for recurrent aphthous ulcers b ut m any theories suggest stress, vitam in deficiency, diet, horm onal changes, allergies, trau m a or im m une dysfunction as the ultim ate cause of these ulcers.3 No single cause is responsible for all the MjRAUs or the MiRAUs; consequently, several different, b u t variably successful tre a tm e n t m odalities have been used. Glucocorticosteroid and antim icrobial therapy constitute the traditional tre a tm e n t for both MjRAU and MiRAU. These medications have been adm inistered as topical pastes, m outhrinses, intralesional injections and system ically by oral route.1 O ther reported therapeutic modalities with some beneficial response include im m unom odulators such as
levamisole37 and colchicine, and other m iscellaneous agents such as dapsone, thalidom ide and monoamino oxidase inhibitors.8 MiRAUs have been reported in as m any as 60 percent of m em bers of professional groups while the incidence rate in the general population is about 20 percent.9 No prevalence studies among the general population with MjRAUs have been reported. Oral aphthous ulcers among individuals w ith AIDS, compared w ith im m unocom petent individuals, may be more p ersistent and severe and involve other areas of the gastrointestinal tra c t.1012 The prevalence of MjRAU in this p articular patien t population has been reported to range from 1.1 percent13to 4 percent.14 This correlates w ith our patien t population, where only four patients, among a population of 280 patients with AIDS, had MjRAU, suggesting an incidence ra te of 1.4 percent.15 *■ Case 1. A 60-year-old homosexual m an came to the Infectious Disease C enter at Temple U niversity D ental School com plaining of a painful JADA, Vol. 123, July 1992
61
ulcer on the left lateral border of his tongue. The ulcer had been present for 10 days. His medical history included m ultiple bouts of venereal diseases including gonorrhea and syphilis. He had a past h epatitis B viral infection, b ut a chronic carrier sta te did not develop. Three sequential HIV tests perform ed two years earlier had positive results but the p atien t had not developed any m ajor opportunistic infections or neoplasm s. The only H lV-associated disease was occasional intraoral Candida infections. The p a tie n t’s medication included Retrovir (Burroughs Wellcome), acyclovir and aerosolized pentam idine once a m onth. His CD4* cell count was 14 cells/mm3 (norm al 700 to 1,000 cells/mm3) and his white blood count was 3,200 cells/mm:i (norm al 4,500 to 11,000 cells/mm3). The p atien t had a crateriform ulcer, about 4 to 5 mm deep w ith a 20-mm diam eter, on th e left lateral border of his tongue. No red halo surrounded it. The patient said th a t sm all intraoral ulcers recurred for the past 30 years both on his tongue and on the upper and lower vestibular areas. These ulcers usually caused only slight discomfort and resolved spontaneously w ithin seven to 10 days. In spite of the lesion size, an excisional biopsy was performed. The hem atoxylin and eosin preparation showed inflam m atory infiltrate w ith eosinophils extending into skeletal muscle and submucosal tissue. No granulom atous disease or viral cytopathic effect was detected. 62
JADA, Vol. 123, July 1992
Figure 1. First sign of a shallow small ulcer on the right lateral border of the tongue.
Im m unohistochem ical stains for cytomegalovirus and herpes simplex virus were negative, as was in situ hybridization for E pstein-B arr virus. Stains for hepatitis B virus surface and core antigens were also negative. Additional cytochemical stains were performed but were negative for syphilis and fungal infections. W ithin three days of the biopsy, another ulcer started to develop a t th e sam e site. M outhrinses w ith Miles’ m ixture (a liquid preparation containing 84,000 IU nystatin, 84 mg tetracycline and 1.04 mg hydrocortisone per 5 cc) and 2 percent viscous lidocaine, four tim es daily, enhanced ulcer healing. Three weeks after the biopsy, a small ulcer appeared on the p atien t’s right lateral tongue border (Figure 1). We institu ted initial therapy of intralesional injections with triam cinolone because of the p a tie n t’s prior extensive ulcer on the left lateral border of his tongue. Accum ulated doses of 1.2 cc were injected every three
days during a 12-day period. The patien t returned on the te n th day. He had a shallow ulcer th a t was 15 mm in diam eter a t the site of the initial right tongue ulcer (Figure 2). Miles’ m ixture and 2 percent viscous lidocaine were in stitu ted again, four tim es daily. Three weeks after the initial sign of the ulcer, the lesion had grown bigger (Figure 3) and was identical to the one on the patien t’s left lateral tongue border. We instituted a regim en of 50 mg of levamisole, adm inistered orally every eight hours for three days followed by an 11-day laten t period. After two such cycles, the ulcer resolved and healed with scarring. After four weeks of levamisole therapy, the p atien t’s white blood count was 3,400 cells/mm3 and his CD4+ count was 34 cells/mm3. ■■ Case 2—A 29-year-old homosexual m an w ent to IDC for treatm en t of m ultiple chronic intraoral ulcers. His medical history included
Figure 2. The ulcer grew bigger within 10 days after the initial sign appeared.
m ultiple bouts of syphilis 10 years earlier, hospitalization for
Pneumocystis carinii pneum onia and positive results from HIV tests performed 18 m onths earlier. M edications included Retrovir, acyclovir and aerosolized pentam idine once every m onth. His intraoral ulcers, present for 13 m onths, severely restricted chewing and speaking. Several biopsies did not im plicate any causative pathogen. The p a tie n t’s previous systemic glucocorticosteroid therapy had to be discontinued because of progressive low w hite blood counts. He had also received two blood transfusions after side effects from Retrovir therapy. The p atien t had a CD4+cell count of 37 cells/mm3 and a w hite blood count of 2,800 cells/mm3. B ilateral horizontal ulcers th a t were 5 mm wide, 2-3 mm deep and 40 mm long radiated from the m outh angles along the buccal mucosa. Three eroded areas, each 5-7 mm in
diam eter, were on the tip of his tongue. A crateriform ulcer, 25 mm in diam eter, was on the inside of his right lower lip. M outhrinses w ith Miles’ m ixture and 2 percent viscous lidocaine were in stitu ted four tim es daily. The ulcers resolved completely a fter 14 days. Deep scarring rem ained a t the ulcer sites. D IS C U S S IO N
To tre a t any disease or disease entity, first establish a diagnosis and determ ine the etiologic pathogen(s). RAUs are diagnosed by history and clinical presentation, and by excluding any known cause. RAU tre a tm e n t m ust be based on the known predisposing and local factors. Although no common immunologic pathogenic pathw ay has been documented in non-HIV-infected individuals, a clear correlation betw een severe systemic im m unosuppression and MjRAU occurrence is present in HIV-infected p a tie n ts.16 Studies
of RAU, in presum ably HIVnegative individuals, have indicated low CD4* helper cell levels in the perivascular area surrounding th e lesion during the ulcerative phase and a consequent increased level during the healing phase.17 Decreased CD47CD8^ cell count ratio has also been docum ented in individuals with RAU,18indicating imm une suppression. In all of our AIDS patients w ith MjRAU, th e peripheral CD4* cell count was below 50 cells/mm315 which corresponds with severe im m une deterioration. Q ualitative and quantitative deficiencies or dysfunctions of T lymphocytes, or both, are responsible for m any oral lesions in im m une suppressed individuals.19 Therefore, using immunom odulators to tre a t oral ulcers in these p atients m ay be beneficial. Levamisole, an immunopotentiating drug, restores both deficient phagocytic function and cutaneous delayed hyper sensitivity reactions, and increases both absolute and relative peripheral Tcell count.20 In our patient, levamisole therapy was not continued after the ulcer resolved. Thus, it was not possible to study the long term effect of this drug on the p atien t’s CD4+cell count. Levamisole is m ainly used to delay colon cancer recurrence in Dukes’ cancer patients. In some Dr. Glick is director, Infectious Disease
C en ter, and assoc iate professor,
D ep artm e n t of Oral M edicin e, Tem ple
University School of Dentistry, 3 2 2 3 N.
Broad St., P hiladel
phia 1 9 1 4 0 . Address reprint requests to Dr. Glick.
JADA, Vol. 123, July 1992
63
early studies, w here im m unocom petence was not evaluated, levamisole therapy improved healing and the ulcer recurrence ra te reduced when used for p a tie n ts w ith recurrent aphthous ulcers.3'7 O ther studies did not corroborate these findings.20'22 The potential significant side effect of levamisole, agranulocytosis,23 outweighed th e beneficial response to the drug, and th is therapeutic m odality was discontinued. Side effects to th is drug occur more frequently in patients w ith and a t risk for autoim m une disorders.24 In patien ts w ith severe T-cell im m une suppression, there is no risk of autoim m une disease developm ent; imm une stim ulatory drug therapy, which could include levamisole, is indicated pathophysiologically. Close m onitoring of patien ts’ white blood cell counts during levamisole therapy helps to avoid the onset of serious side effects. Therapy w ith M iles’ solution and viscous lidocaine has far less of a systemic influence on th e patient th an does levamisole. Components in th is m ixture will have prim arily a local effect. Tetracycline reduces th e bacterial flora of and surrounding the lesion, while n y statin stops fungal growth and glucocorticosteroids reduce inflam m ation. Oral topical glucocorticosteroid therapy has not been indicated
Dr. M u zy k a is
a ssistant professor, D e p a rtm e n t o f Oral M edic in e, Te m p le
U niversity School of D entistry,
Philadelphia.
64
JADA, Vol. 123, July 1992
Figure 3. A deeply eroded, crateriform, painful ulcer developed within three weeks of the initial manifestation.
in im m une suppression25but enhances aphthous ulcer healing. Adding viscous lidocaine will improve the compliance ra te of the patient by reducing oral discomfort during chewing and speaking. P atien ts w ith RAUs need to be m ade aw are of th e empirical natu re of any proposed therapy. The severe discomfort and disabling characteristics of MjRAUs in patients w ith AIDS require prom pt and effective therapeutic intervention w ithout fu rth e r compromising the patients. The use of less toxic therapeutic m odalities a t an early stage when the lesions do not have aggressive tissue destruction is recommended. More invasive and potentially cytotoxic therapy m ay be in stitu ted later if necessary. T reating HIV-infected patients poses m any challenges to the dental care provider. Of utm ost im portance is the patien ts’ overall health and im m une sta tu s.26 Im proper antibiotic use m ay lead to
opportunistic oral fungal infection, which will assault the p a tie n ts’ already debilitated im m une system . Using systemic glucocorticosteroid therapy in AIDS p atients m ay cause hum oral im m une suppression, leaving the patients susceptible to even more opportunistic bacterial infections, as well as potentially inducing adrenal insufficiency.27 Therapeutic interventions discontinued in the pre-AIDS era need to be re-evaluated for tre a tm e n t of resista n t lesions in HIV-infected patients. C O N C L U S IO N
M any oral lesions, described in HIV-infected individuals, are early signs of immune deterioration and disease progression.28 D ental care providers m ust recognize these signs and communicate these findings to the patien ts’ physicians. Early HIV disease detection will enable prom pt institu tio n of anti-retroviral therapy, which may prolong the p atien t’s life. ■
Figure 4. The ulcer resolved completely with deep scarring, after two cycles of levamisole administration.
The authors th a n k A rth u r S. Miller, D.M.D., and Jo h n S. J. Brooks, M.D., for their assistance in evaluating and in terpreting the biopsy specimens. 1. Regezi JA, Sciubba J J . O ral pathology: clinical-pathologic correlations. Philadelphia: Saunders; 1989:46-53. 2. Lynch MA, B rightm an V J, G reenberg MS. B urket’s oral medicine. Diagnosis and treatm en t. 8th ed. PhiladelphiarLippincott;1984:181-5. 3. Verhagen H, DeCree J , B rugm ans J. T reatm en t of aphthous stom atitis. Lancet 1973;2:842. 4. Symoens J , B rugm ans J. T reatm ent of recu rren t aphthous stom atitis and herpes w ith levamisole. Br Med J 1974;4:592. 5. M ohammad AR, R uprecht A. U nusual chronic recu rren t aphthous sto m atitis treated w ith levamisole. J O ral Med 1983;38:164. 6. D rinnan A, Fischm an S. Randomized double-blind study of levamisole in recurrent aphthous stom atitis. J O ral Pathol 1978;7:414-7. 7. Zissis NP, H atzioti AJ, A ntoniadis D. T herapeutic evaluation of levamisole in recu rren t aphthous stom atitis. J O ral Med 1983;38:161-3. 8. Scully C, P orter SR. R ecurrent aphthous stom atitis: cu rren t concepts of etiology, pathogenesis and m anagem ent. J O ral Pathol Med 1989;18:21-7. 9. Ship II. Epidemiologic aspects of recu rren t aphthous ulcerations. O ral Surg O ral Med Oral Pathol 1972;33:400-6. 10. Bach MC, Howell DA, V alenti AJ, e t al. A phthous ulceration of th e g astrointestinal tra c t in p atients w ith th e acquired immunodeficiency syndrom e (AIDS). Ann
Intern Med 1990;112:465-7. 11. D retler RH, R ausher DB. G iant esophageal ulcer healed w ith steroid therapy in a patien t w ith AIDS. Rev In f Dis 1989;11:768-9. 12. Bach MC, V alenti AJ, Howell DA, e t al. Odynophagia from aphthous ulcers of the pharynx and esophagus in the acquired immunodeficiency syndrom e (AIDS). Ann Intern Med 1988;109:338-9. 13. P helan JA, Eisig S, Freedm an PD, e t al. Major aphthous-like ulcers in p atien ts w ith AIDS. O ral S urg Oral Med O ral Pathol 1991;71:68-72. 14. B arr C, Croxson T, Dobles A, e t al. HIVassociated oral lesions: immunologic and salivary p aram eters (Abstract no. 1443). J D ent Res 1990;69:289. 15. M uzyka BC, Glick M. A lternate treatm en t for m ajor aphthous ulcerations in AIDS p atien ts (Abstract). NYC: Third International Symposia on O ral AIDS, Nov. 23, 1991. 16. M acPhail LA, G reenspan D, Feigel DW, et al. R ecurrent aphthous ulcers in association w ith HIV infection. O ral Surg
O ral Med O ral Pathol 1991;71:678-83. 17. P edersen A, K lausen B, Hougen HP, et al. T-lymphocyte subsets in recu rren t aphthous ulcerations. J O ral Pathol Med 1989;18:59-60. 18. L andesberg R, Fallon M, Insel R. A lterations of T helper/inducer and T suppressor/inducer cells in p atien ts w ith recurrent aphthous ulcers. O ral S urg Oral Med O ral Pathol 1990;69:205-8. 19. G arfunkel AA, Glick M. Common oral findings in two different diseases - leukem ia and AIDS. Compendium (In press). 20. Levo Y, R otter V, Ram ot B. Restoration of cellular im m une response by levamisole in p atien t w ith Hodgkin’s disease. Biomed 1975;23:198-200. 21. M iller MF, S ilvert ME, L aster LL. Effect of levamisole on the incidence and prevalence of recu rren t aphthous stom atitis. J Oral Pathol 1978;7:387-92. 22. Olson JA, Silverm an S. Double-blind study of levamisole th erap y in recurrent aphthous stom atitis. J O ral Pathol 1978;7:393-9. 23. R osenthal M, T rab ert U, M uller W. Leucocytotoxic effect of levamisole. Lancet 1976;1:369. 24. Diez RA. HLA-B27 and agranulocytosis by levamisole. Immunology Today 1990;11:270. 25. Plem ons JM , Rees TD, Zachariah NY. Absorption of a topical steroid and evaluation of adrenal suppression in p atien ts with erosive lichen planus. O ral S urg Oral Med Oral Pathol 1990;69:688-93. 26. Glick M. Clinical protocol for treatin g patients w ith HIV disease. Gen D ent 1990;38:418-25. 27. Glick M. Glucocorticosteroid replacem ent therapy: a lite ra tu re review and replacem ent therapy. O ral S urg O ral Med Oral Pathol 1989;67:614-20. 28. Glick M. E valuation of prognosis and survival of the HIV infected patient. Oral Surg Oral Med O ral Pathol (In press).
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