Major recurrent oral ulcers in AIDS; report of three cases
Gustavo Reyes-Terdn\ Velia Ramirez-Amador', Estela De la Rosa^ Martha Gonzalez-Guevara^ and Samuel Ponce de Leon^ Departments of 'Infectious Diseases. Instituto Nacional de la Nutricidn 'Saivador ZubirAn\ 'Health Care. Universidad Autdnoma Metropolitana-Xochimilco. M6x/co City, Mexico
Reyes-Teran G, Ramirez-Amador V, De la Rosa E, Gonzalez-Guevara M, Poncede-Leon S: Major recurrent oral uleers in AIDS: report of three eases, J Oral Pathol Med 1992; 21: 409-411. We report the eases of three AIDS patients who developed major recurrent oral ulcers with severe odynophagia and weight loss. Tbe patients were treated successfully with systemic steroids. Within the first week of prednisone therapy (40 mg/day), the symptoms improved and the lesions entirely healed. We suggest, on the bases of reeent literature, that superantigens and the eytokine network eould be involved and they should be eonsidered in the immunopathogenic mechanisms of this type of ulcers.
Oral uleers of non-specific origin have been described in association with human immunodefieiency virus (1 3). The elinical appearance and behavior of these non-infectious or neoplastic ulcerations is similar to reeurrent oral uleers of minor, major and herpetiform type, but with increased severity and frequency. Major recurrent ulcers appear larger (10 mm or more), more painful and persistent than the minor variety, being one to 10 in number (4). In contrast to the minor type these ulcers tend to heal with the formation of scars, may show raised borders and a craterifonn appearanee (5). The sites involved inelude the tonsillar area, soft palate, labial and buccal mucosa, floor of the mouth, ventral aspect of tongue, and esophagus (1-5). This condition has been known as "Sutton's aphthae" and "periadenitis mucosa necrotica reeurrens" (6). This latter name has been eonsidered a misname by some authors (4). Herein, we report the eases of three AIDS patients who developed iTiajor reeurrent oral ulcers with severe odynophagia and weight loss. We describe the clinical characteristics of the patients and our experieticc with the management of this condition which consisted in systemic prednisone (40 mg/day first k, and 20 mg/day second week).
Patient 1
In May 1990, a 26-yr-old homosexual man with AIDS was hospitahzed with
a 10 kg weight loss, fever, and severe, progressive odynophagia related to two large uleers on the soft palate. Current medication included therapy with zidovudine. He received courses of acyclovir and ketoconazole without benefit. In addition he was treated with topical steroids, tetracycline and metronidazole without healing of the uleers. Cultures and two biopsies showed no evidence of infeetious agents. Within the first week after prednisone therapy (20 mg bid) was started in December 1990, pain deereased dramatieally and the lesions rapidly healed over the next 2 wk. Patient 2
In February 1990 a .'^l-yr-old homosexual man with HlV-1 infection and a CD4+ T eell count of 425 mm' started with a painful large oral ulcer localized on the soft palate (Fig. 1) which lasted approximately 10 days and showed spontaneous remission. One month later new ulcers appeared and persisted, despite the fact that he was receiving zidovudine. In May "91, the patient exhibited more severe ulcerative lesions on the soft palate and gastric-esophagus junction, with increasing odynophagia and wasting syndrome. At this time the CD4-I- T cell count was 26 mm'. Biopsies and brushing showed no fungus or virus and there was no response to therapy with acyclovir, ketoconazole, chlorhexidine, tetracycline, and metronidazole. A trial of oral prednisone therapy
Key words: AIDS: HIV infection: mouth diseases: oral recurrent ulcers V, Ramirez-Amador. Camino Sta Teresa 277-9, 14010 M6xico DF, Mexico Accepted for publication May 12. 1992
was begun but was discontinued because of nausea and vomiting. Three weeks later, when the oral ulcer involved also the uvula (Fig. 2), a new trial of prednisone, 20 mg bid, was intended with improvement of symptoms within 3 days and healing of the soft palate uleers.
Patient 3
A 30-yr-old homosexual man with AIDS, presented with increasing odynophagia and weight loss. Small uleers in the oral mueosa were observed during examination. The patient had a history of painful reeurrent uleers of the tongue, the palate, and the pharynx. In April 1991 while he was taking zidovudine, acyclovir, ketoeonazole, and cotrimoxazole, a major ulcer on lower labial mueosa was noted. One month later, new painful minor and major ulcers appeared on the lips, the tongue, and the pharynx. Repeated cultures were negative, and biopsy specimens revealed acute and chronic inflammation with no evidence of neoplasia or infectious agents. A course of systemic prednisone, 20 mg bid, was given and his symptoms improved in 48 to 72 h. The lesions entirely healed within 7 days.
Discussion
In HIV-infected patients the prevalence of major recurrent uleers has been 1%
410
REYES-TteRAN et at.
vestigations have suggested that these patients may have inherent local imbalances in immunoregulation (2). CD4-IT cells, C D 8 + T cells, NK cells, monocyte/macrophage, and polymorphonuclear leucocytes have been identified in the infiltrate of these ulcers, in different proportions varying with the duration of the lesion (X 10). Cell-mediated cytotoxicity (CMC) and antibodydependent cellular cytotoxicity (ADCC) responses have been found in patients Fig. I Patient 2. Large crateriform ulcer (10 with reeurrent oral ulcers, and these two mm) with irregular borders, edema and sur- types of immune responses have been rounded by an erythematous area. suggested as responsible for the eytotoxic mechanism for oral epithelial cells in these patients (10 11). However, the to 4% (3). In our experience of 161 HIV- factors that trigger the activation of T infected patients (7), we have seen major cells to induce self-damage to the oral recurrent ulcers in 9 patients (b"/n) either epithelial cells, and the mechanisms at first or subsequent oral examination, which control the migration of different of whom the three described here have populations of lymphocytes to the sites been treated successfully with systemic of the uleer formation remain unknown. steroids, after trying local treatments We suggest, on the basis of recent with tetracycline mouthrinses and/or literature, that exogen superantigens topical steroids. (12) could be the factor that activates The diagnostic criteria followed in T cells and consequently the cytokines this work for major recurrent ulcers in- network (13) whieh could mediate the cluded a non-infectious or neoplastic cytotoxic effects and finally the formaetiology identified by cytologic smears tion of the ulcer. Probably, interleukin and/or biopsy. The clinical features 2 (IL-2), interferon gamma (IFN-gamconsidered were size (10 mm or more), ma), and tumor neerosis factor (TNF) duration (more than 10 days) and sever- eould be the main cytokines involved in ity. In some eases the ulcers healed with the immunopathogenic mechanisms of recurrent major oral uleers. There is eviscarring, and sometimes they showed raised margins. Although oral ulcers ex- dence that T N F and IFN gamma acting synergistically, increase the class I and hibiting these characteristics have been II major histocompatibility complex called "periadenitis mucosa necrotica recurrens', we considered the term ma- (MHC), IL-I and surface adhesion moljor reeurrent uleers implying as other ecules, promoting, in eoneert with IL(4), this condition represent an exagger- 2, the CMC (14). Presumably, various possibilities could be considered to exated form of the minor type. Because the pathogenesis of this type plain the cytotoxic effect of TNF: by of ulcers is not completely understood, direct (apoptosis and neerosis) (15) or the treatment of recurrent oral ulcers indirect effect through the chemotaxis has been empirical and based primarily and activation of neutrophils, with reon symptom management. Recent in- active oxygen intermediates and neutral proteases liberation (14, 15), and by the release of IL-8, a chemotractant of T cells and neutrophils (16).
Fig. 2. P a t i e n t 2 . S u b s e q u e n t l y , liic u v i i u i w ; i s
totally involved and covered by a white-grayish pseudomembrane.
Thus, our hypothesis eould explain the reasons why drugs such as steroids (2-4), and thalidomide (17) might produce remission of these lesions. The effects of systemic steroids is by inhibiting some of the cytokines as IL-1 and TNF (14), and there is evidence that thalidomide selectively inhibits T N F (18). Our cases were interesting because they showed the chronicity, severity and difficulties in the treatment of reeurrent major ulcers in HIV-infected patients and the dramatic clinical response to corticosteroid therapy. We feel this is an
area that requires further studies directed to the seareh of possible exogen superantigens and their relation with the eytokines network to understand better the pathogenesis of this eondition, in order to define the most adequate management and improve the quality of life of these patients. Acknowledgement We want to thank the Department of Pathology, INNSZ, in particular Dr. Edgardo Reyes, for their collaboration. References 1. BA< M MC, VALKNTI AJ, Howi:i i DA,
SMiru TJ. Odynophagia from aphlhous ulcers of the pharynx and esophagus in the acquired immunodclicicncy syndrome (AIDS). Ann Intern Med 1988; 109: .138 9. 2. MACPHAIL L A , GRHKNSPAN D , FTIGAL DW, LKNNHTTE E T , GRI:I-NSPAN JS. Re-
y.
4.
5.
6.
current aphthou.s ulcers in association with HIV infection. Oral Surg Oral Med Oral Pathol 1991: 71: 678-8.'!. Piiii AN JA, Eisici S, F-Rt:f:i)MAN PD, NiwsoMF N, Ki.FiN RS. Major aphthotis-like ulcers in patients with AIDS. Oral .Swg Oral Med Oral Pathol 1991; 71: 68 72. LiiiNiR T. Progress report. Oral ulceration and Behget syndrome. Gut 1977; 18: 491 511. TYIDHSLKY WR. Oral medicine for the dental practitioner. 4. Recurrent ulcers. Br Dent J 1973; 135: 537 41. PiNi)H()R(i JJ. Atlas de enfermedades de hi muco.ia oral. 3° ed. Barcelona: Salvat 1981; 170.
7. RAMIREZ V, GONZAI.KZ A, GONZALEZ M ,
el at. Patologia bucal en 161 pacientes VIH-positivos asintomaticos y sintomaticos. Rev Invest Clin 1992: 44: 4.^ 52. 8. LANr)i:SBKRCi R, FAI.LON M . INSH R . Al-
terations of T helper/indticer and T suppressor/inducer cells in patients with recurrent aphthous ulcers. Oral Surg Oral Med Oral Pathol 1990: 69: 205 8. 9. Srui.i.Y C, POKIER SR. Recurrent aphthous stomatitis: current concepts ol etiology, pathogenesis and management, ,/ Oral Pathol Med 1989; 18: 21 7. 10. THOMAS DW, BACK; J, WALKER D M .
Characterization of the effector eells responsible lor the in vitro cytotoxicity of Hlood leucocytes from aphlhous ulcer patients for oral epithelial cells. 0'"' 1990: M: 294 9. 11. BiiRNitT PR. WRAY D, l.ylic effecis of serum antl moiionucleai" leukocytes on oral epithelial cells in recurrent aphlhous stomatitis, Clin Itttmunol tmmtinopaihol 1985; 34: 197 204, 12. JANIWAY C A . Self superantigens? Celt 1990: 63: 659 61. 13. STREET N E , MOSMANN TR. Functional
diversity of T lymphocytes due to secre-
Major recurrent oral ulcers 411 tion of different cytokine patterns. EASEB J 1991; 5: 171-7. 14. BEUTLKR B , CERAMI A. The common me-
diator of shock, cachexia, and tumor necrosis. .4dv Itnmunol 1988; 42: 213 31. 15. LARRKK
JW, WRIGHT
SC.
Cytotoxic
mechanism of tumor necrotic factor-a. FASEBJ 1990; 4; 3215-23.
16. BAGGIOLINI M , WAIZ A, KUNKEL SL,
successful treatment with thalidomide. J Atn Acad Dermalol 1990; 23; 523 5.
Neutrophil-activating peptide-1 /interieukin 8, a novel cytokine that activates 18. SAMPAIO EP, SARNO EN, GALILLY R , neutrophils. ./ Clin Invest 1989; 84: CoHN ZA, KAPLAN G . Thalidomide se1045 9. lectively inhibits tumor necrosis factor 17. RADEEE B , KtiiTER R, SAMSON J. Recurproduction by stimulated human monorent aphthous ulcer in patient infected cytes. J E.xp Med 1991; 173: 699 703. with human immunodeficiencv virus:
Gustavo Reyes-Terdn\ Velia Ramirez-Amador', Estela De la Rosa^ Martha Gonzalez-Guevara^ and Samuel Ponce de Leon^ Departments of 'Infectious Diseases. Instituto Nacional de la Nutricidn 'Saivador ZubirAn\ 'Health Care. Universidad Autdnoma Metropolitana-Xochimilco. M6x/co City, Mexico
Reyes-Teran G, Ramirez-Amador V, De la Rosa E, Gonzalez-Guevara M, Poncede-Leon S: Major recurrent oral uleers in AIDS: report of three eases, J Oral Pathol Med 1992; 21: 409-411. We report the eases of three AIDS patients who developed major recurrent oral ulcers with severe odynophagia and weight loss. Tbe patients were treated successfully with systemic steroids. Within the first week of prednisone therapy (40 mg/day), the symptoms improved and the lesions entirely healed. We suggest, on the bases of reeent literature, that superantigens and the eytokine network eould be involved and they should be eonsidered in the immunopathogenic mechanisms of this type of ulcers.
Oral uleers of non-specific origin have been described in association with human immunodefieiency virus (1 3). The elinical appearance and behavior of these non-infectious or neoplastic ulcerations is similar to reeurrent oral uleers of minor, major and herpetiform type, but with increased severity and frequency. Major recurrent ulcers appear larger (10 mm or more), more painful and persistent than the minor variety, being one to 10 in number (4). In contrast to the minor type these ulcers tend to heal with the formation of scars, may show raised borders and a craterifonn appearanee (5). The sites involved inelude the tonsillar area, soft palate, labial and buccal mucosa, floor of the mouth, ventral aspect of tongue, and esophagus (1-5). This condition has been known as "Sutton's aphthae" and "periadenitis mucosa necrotica reeurrens" (6). This latter name has been eonsidered a misname by some authors (4). Herein, we report the eases of three AIDS patients who developed iTiajor reeurrent oral ulcers with severe odynophagia and weight loss. We describe the clinical characteristics of the patients and our experieticc with the management of this condition which consisted in systemic prednisone (40 mg/day first k, and 20 mg/day second week).
Patient 1
In May 1990, a 26-yr-old homosexual man with AIDS was hospitahzed with
a 10 kg weight loss, fever, and severe, progressive odynophagia related to two large uleers on the soft palate. Current medication included therapy with zidovudine. He received courses of acyclovir and ketoconazole without benefit. In addition he was treated with topical steroids, tetracycline and metronidazole without healing of the uleers. Cultures and two biopsies showed no evidence of infeetious agents. Within the first week after prednisone therapy (20 mg bid) was started in December 1990, pain deereased dramatieally and the lesions rapidly healed over the next 2 wk. Patient 2
In February 1990 a .'^l-yr-old homosexual man with HlV-1 infection and a CD4+ T eell count of 425 mm' started with a painful large oral ulcer localized on the soft palate (Fig. 1) which lasted approximately 10 days and showed spontaneous remission. One month later new ulcers appeared and persisted, despite the fact that he was receiving zidovudine. In May "91, the patient exhibited more severe ulcerative lesions on the soft palate and gastric-esophagus junction, with increasing odynophagia and wasting syndrome. At this time the CD4-I- T cell count was 26 mm'. Biopsies and brushing showed no fungus or virus and there was no response to therapy with acyclovir, ketoconazole, chlorhexidine, tetracycline, and metronidazole. A trial of oral prednisone therapy
Key words: AIDS: HIV infection: mouth diseases: oral recurrent ulcers V, Ramirez-Amador. Camino Sta Teresa 277-9, 14010 M6xico DF, Mexico Accepted for publication May 12. 1992
was begun but was discontinued because of nausea and vomiting. Three weeks later, when the oral ulcer involved also the uvula (Fig. 2), a new trial of prednisone, 20 mg bid, was intended with improvement of symptoms within 3 days and healing of the soft palate uleers.
Patient 3
A 30-yr-old homosexual man with AIDS, presented with increasing odynophagia and weight loss. Small uleers in the oral mueosa were observed during examination. The patient had a history of painful reeurrent uleers of the tongue, the palate, and the pharynx. In April 1991 while he was taking zidovudine, acyclovir, ketoeonazole, and cotrimoxazole, a major ulcer on lower labial mueosa was noted. One month later, new painful minor and major ulcers appeared on the lips, the tongue, and the pharynx. Repeated cultures were negative, and biopsy specimens revealed acute and chronic inflammation with no evidence of neoplasia or infectious agents. A course of systemic prednisone, 20 mg bid, was given and his symptoms improved in 48 to 72 h. The lesions entirely healed within 7 days.
Discussion
In HIV-infected patients the prevalence of major recurrent uleers has been 1%
410
REYES-TteRAN et at.
vestigations have suggested that these patients may have inherent local imbalances in immunoregulation (2). CD4-IT cells, C D 8 + T cells, NK cells, monocyte/macrophage, and polymorphonuclear leucocytes have been identified in the infiltrate of these ulcers, in different proportions varying with the duration of the lesion (X 10). Cell-mediated cytotoxicity (CMC) and antibodydependent cellular cytotoxicity (ADCC) responses have been found in patients Fig. I Patient 2. Large crateriform ulcer (10 with reeurrent oral ulcers, and these two mm) with irregular borders, edema and sur- types of immune responses have been rounded by an erythematous area. suggested as responsible for the eytotoxic mechanism for oral epithelial cells in these patients (10 11). However, the to 4% (3). In our experience of 161 HIV- factors that trigger the activation of T infected patients (7), we have seen major cells to induce self-damage to the oral recurrent ulcers in 9 patients (b"/n) either epithelial cells, and the mechanisms at first or subsequent oral examination, which control the migration of different of whom the three described here have populations of lymphocytes to the sites been treated successfully with systemic of the uleer formation remain unknown. steroids, after trying local treatments We suggest, on the basis of recent with tetracycline mouthrinses and/or literature, that exogen superantigens topical steroids. (12) could be the factor that activates The diagnostic criteria followed in T cells and consequently the cytokines this work for major recurrent ulcers in- network (13) whieh could mediate the cluded a non-infectious or neoplastic cytotoxic effects and finally the formaetiology identified by cytologic smears tion of the ulcer. Probably, interleukin and/or biopsy. The clinical features 2 (IL-2), interferon gamma (IFN-gamconsidered were size (10 mm or more), ma), and tumor neerosis factor (TNF) duration (more than 10 days) and sever- eould be the main cytokines involved in ity. In some eases the ulcers healed with the immunopathogenic mechanisms of recurrent major oral uleers. There is eviscarring, and sometimes they showed raised margins. Although oral ulcers ex- dence that T N F and IFN gamma acting synergistically, increase the class I and hibiting these characteristics have been II major histocompatibility complex called "periadenitis mucosa necrotica recurrens', we considered the term ma- (MHC), IL-I and surface adhesion moljor reeurrent uleers implying as other ecules, promoting, in eoneert with IL(4), this condition represent an exagger- 2, the CMC (14). Presumably, various possibilities could be considered to exated form of the minor type. Because the pathogenesis of this type plain the cytotoxic effect of TNF: by of ulcers is not completely understood, direct (apoptosis and neerosis) (15) or the treatment of recurrent oral ulcers indirect effect through the chemotaxis has been empirical and based primarily and activation of neutrophils, with reon symptom management. Recent in- active oxygen intermediates and neutral proteases liberation (14, 15), and by the release of IL-8, a chemotractant of T cells and neutrophils (16).
Fig. 2. P a t i e n t 2 . S u b s e q u e n t l y , liic u v i i u i w ; i s
totally involved and covered by a white-grayish pseudomembrane.
Thus, our hypothesis eould explain the reasons why drugs such as steroids (2-4), and thalidomide (17) might produce remission of these lesions. The effects of systemic steroids is by inhibiting some of the cytokines as IL-1 and TNF (14), and there is evidence that thalidomide selectively inhibits T N F (18). Our cases were interesting because they showed the chronicity, severity and difficulties in the treatment of reeurrent major ulcers in HIV-infected patients and the dramatic clinical response to corticosteroid therapy. We feel this is an
area that requires further studies directed to the seareh of possible exogen superantigens and their relation with the eytokines network to understand better the pathogenesis of this eondition, in order to define the most adequate management and improve the quality of life of these patients. Acknowledgement We want to thank the Department of Pathology, INNSZ, in particular Dr. Edgardo Reyes, for their collaboration. References 1. BA< M MC, VALKNTI AJ, Howi:i i DA,
SMiru TJ. Odynophagia from aphlhous ulcers of the pharynx and esophagus in the acquired immunodclicicncy syndrome (AIDS). Ann Intern Med 1988; 109: .138 9. 2. MACPHAIL L A , GRHKNSPAN D , FTIGAL DW, LKNNHTTE E T , GRI:I-NSPAN JS. Re-
y.
4.
5.
6.
current aphthou.s ulcers in association with HIV infection. Oral Surg Oral Med Oral Pathol 1991: 71: 678-8.'!. Piiii AN JA, Eisici S, F-Rt:f:i)MAN PD, NiwsoMF N, Ki.FiN RS. Major aphthotis-like ulcers in patients with AIDS. Oral .Swg Oral Med Oral Pathol 1991; 71: 68 72. LiiiNiR T. Progress report. Oral ulceration and Behget syndrome. Gut 1977; 18: 491 511. TYIDHSLKY WR. Oral medicine for the dental practitioner. 4. Recurrent ulcers. Br Dent J 1973; 135: 537 41. PiNi)H()R(i JJ. Atlas de enfermedades de hi muco.ia oral. 3° ed. Barcelona: Salvat 1981; 170.
7. RAMIREZ V, GONZAI.KZ A, GONZALEZ M ,
el at. Patologia bucal en 161 pacientes VIH-positivos asintomaticos y sintomaticos. Rev Invest Clin 1992: 44: 4.^ 52. 8. LANr)i:SBKRCi R, FAI.LON M . INSH R . Al-
terations of T helper/indticer and T suppressor/inducer cells in patients with recurrent aphthous ulcers. Oral Surg Oral Med Oral Pathol 1990: 69: 205 8. 9. Srui.i.Y C, POKIER SR. Recurrent aphthous stomatitis: current concepts ol etiology, pathogenesis and management, ,/ Oral Pathol Med 1989; 18: 21 7. 10. THOMAS DW, BACK; J, WALKER D M .
Characterization of the effector eells responsible lor the in vitro cytotoxicity of Hlood leucocytes from aphlhous ulcer patients for oral epithelial cells. 0'"' 1990: M: 294 9. 11. BiiRNitT PR. WRAY D, l.ylic effecis of serum antl moiionucleai" leukocytes on oral epithelial cells in recurrent aphlhous stomatitis, Clin Itttmunol tmmtinopaihol 1985; 34: 197 204, 12. JANIWAY C A . Self superantigens? Celt 1990: 63: 659 61. 13. STREET N E , MOSMANN TR. Functional
diversity of T lymphocytes due to secre-
Major recurrent oral ulcers 411 tion of different cytokine patterns. EASEB J 1991; 5: 171-7. 14. BEUTLKR B , CERAMI A. The common me-
diator of shock, cachexia, and tumor necrosis. .4dv Itnmunol 1988; 42: 213 31. 15. LARRKK
JW, WRIGHT
SC.
Cytotoxic
mechanism of tumor necrotic factor-a. FASEBJ 1990; 4; 3215-23.
16. BAGGIOLINI M , WAIZ A, KUNKEL SL,
successful treatment with thalidomide. J Atn Acad Dermalol 1990; 23; 523 5.
Neutrophil-activating peptide-1 /interieukin 8, a novel cytokine that activates 18. SAMPAIO EP, SARNO EN, GALILLY R , neutrophils. ./ Clin Invest 1989; 84: CoHN ZA, KAPLAN G . Thalidomide se1045 9. lectively inhibits tumor necrosis factor 17. RADEEE B , KtiiTER R, SAMSON J. Recurproduction by stimulated human monorent aphthous ulcer in patient infected cytes. J E.xp Med 1991; 173: 699 703. with human immunodeficiencv virus:
