- Email: [email protected]
Clinical features of Behçet's disease
Clinical features of Behqet’s disease Report of four cases Thomas N. Helm, h4D,a Charles Camisa, IVD,~ Carl Allen, DDS,b and Careen Lowder, iUD,c Cleveland and Columbus, Ohio CLEVELAND
CLINIC
FOUNDATION
AND OHIO STATE UNIVERSITY
Behget’s disease is a multisystem inflammatory disorder of unknown etiology. The unifying histologic reaction pattern is a leukocytoclastic vasculitis that affects predominantly the skin, oral mucosa, and eyes. Many other sites of involvement have been reported but are inconsistently found in individual patients. Early recognition and treatment of Behpet’s disease may help prevent devastating permanent sequelae such as blindness. Because oral involvement is often the first manifestation of this disorder, dental practitioners are in a unique position to help these patients. We report four cases of Behpet’s disease in North American patients. Diagnostic criteria and treatment options are reviewed. (ORAL SURC ORAL MED ORAL PATHOL 1991;72:30-4)
I
n 1937 Hulusi Behqet’ described two patients with oral ulcers, genital ulcers, and loss of vision. Other reports of patients with this symptom complex, many from Asia and Asia Minor, subsequently appeared in the world’s literature. Although these patients fit Behqet’s original description, they had numerous other signs of disease, such as erythema nodosum, acneiform skin eruptions, pathergy, nondestructive asymmetric arthritis, thrombophlebitis, aneurysm formation, spastic paresis, impaired memory, and glomerulonephritis.* Becauseof its protean manifestations, the diagnosis of Behcet’s diseasemay be difficult to make. Various diagnostic criteria have been proposed to help classify individual patients.*-s Criteria suggested at the Fifth International Conference on Behqet’s Disease93‘() include oral aphthous-like ulcers, not otherwise explained, that have recurred at least three times during a l-year period, and two of the following four manifestations not otherwise explained: (1) recurrent genital ulcerations; (2) retinal vasculitis, anterior uveitis, or posterior uveitis; (3) erythema nodosumlike skin lesions or acneiform lesions; and (4) a positive pathergy test result read by a physician 1 to 2 days after oblique insertion of a 20-gauge needle into the skin. Connective tissue disease, Reiter’s syn-
“Department
of Dermatology,
bScction of Diagnostic Services, University, Columbus. CDepartment of Ophthalmology, 7/13/28237 30
Cleveland Clinic College Cleveland
Foundation. of Dentistry, Ohio State Clinic
Foundation.
drome, and inflammatory bowel disease should be ruled out before BehGet’sdiseaseis diagnosed. Other features considereduseful in confirming a diagnosis of Beheet’s diseaseby the International Behget’s Study Group9* I0 include deep venous thrombosis, subcutaneous thrombophlebitis, epididymitis, arthritis, gastrointestinal ulceration, and arteritis or aneurysm formation. Becausethe diagnosis of Behget’s disease is not easily made, one must be familiar with its many manifestations. The following report outlines the varied clinical histories and presentations of four patients whose final diagnoses were of Behqet’s disease. CASE REPORTS Case 1 A 71-year-old black woman was first seen in February 1986 for evaluation of painful oral ulcerations of recent on-
set. The patient claimed that she had never had ulcerations of this type before, and she denied any other skin or mucosal involvement. Clinical examination showed a cluster of shallow ulcers, 2 to 5 mm in diameter, involving the maxillary right labial mucosa (Fig. 1). No vesicle formation was seen, and no epithelial separation was observed. Minor aphthous stomatitis was suspected, but because the problem was of recent onset, a biopsy was performed. Microscopic examination of the lesional tissue revealed an ulcer with vasculitis; these findings were believed to be consistent with aphthous ulceration. The patient was given topical corticosteroids, with some improvement. One year later the patient was seen for the evaluation of persistent oral ulcerations. The patient reported that recurrent episodes of these lesions had bothered her for several months and that she had been hospitalized elsewhere for this problem without a specific diagnosis. She also had sores in the perineum.
Volume Number
Clinical features of Behqet’s disease
72 I
31
Fig. 1. Case 1, Right labial mucosa with shallow aphthous-like ulcerations.
3. Case 1. Punched-out ulcers on labia majora and perineum.
Fig. Fig.
2. Case 1. Acneiform pustule on chin.
Examination showednumerous ulcers, 3 mm in diameter, identical to the initial lesions involving the mandibular labial mucosa and the mucosa of the lateral dorsal aspect of the tongue. A pustule on the chin (Fig. 2), and several “punched out” ulcers involving the labia majora and perineal skin (Fig. 3) were present. Viral cultures were negative. Biopsy of a genital lesion showed microscopic features similar to the oral lesion. Findings of direct and indirect immunofluorescence studies were negative. A diagnosis of Behqet’s syndrome was rendered because of the oral and genital ulcers and the facial acneiform lesion. The patient was treated with colchicine, 0.6 mg twice daily, and had complete resolution of her disease.
for areas of hyperemia in the cecum, transverse colon, and sigmoid colon. Biopsy of the colon showed chronic inflammation, whereas histologic sections of a tongue lesion demonstrated ulceration and polymorphonuclear leukocyte infiltration without vasculitis. Cultures for herpes simplex virus were negative. During the course of his hospitalization, punched-out ulcers of the scrotal and perianal skin developed. A sterile pustule that developed at the site of a tuberculin skin test (Fig. 6) was believed to represent a manifestation of pathergy. The patient’s oral ulcers, genital ulcers, and pathergic response were consistent with a diagnosis of Behqet’s disease.He was treated with colchicine, 0.6 mg twice daily, and prednisone, 40 mg/day, with good results.
Case 2
Case 3
A 25-year-old white man was referred for evaluation of painful oral lesions of 1 year’s duration. He had headache, intermittent diarrhea, sore throat, and dysphagia. Examination of the oral mucosa showed clusters of aphthous-like lesions involving the tip of the tongue (Fig. 4) and the posterior of the soft palate (Fig. 5). Ophthalmologic examination did not reveal uveitis. Laboratory investigation was remarkable for guaiacpositive stool. Findings of colonoscopy were normal except
A 37-year-old black man was seen in 1986 with a l-year history of episodic oral ulcerations. Evaluation revealed one small ulcer on the tip of the tongue. Ulcers later developed on the left side of the tongue and prevented eating, because of pain. He had one or two bouts of such oral ulcerations every month thereafter. The lesions would last up to 10 days before they healed. Despite using sucralfate (Carafate) paste and diphenhydramine (Benadryl), he noted no improvement.
32
Fig.
Helm et al.
4. Case 2. Aphthous-like’resions on tip of tongue.
Fig. 5. Case 2. Aphthous-like ulcers on posterior soft palate.
Recurrent aphthous stomatitis was initially diagnosed. A small ulcer in the urethra near the meatus developed in February 1988. Cultures for herpes simplex virus were negative. Urinalysis revealed pyuria, but culture for Neisseria gonorrhea was negative. Results of an ophthalmologic examination were unremarkable. Nine months later herpesvirus cultures from the scrotum were negative. Ulcers developed on the scrotum, and pustules appearedon the thighs. A diagnosis of Behqet’sdisease was made. The patient started treatment with colchicine, 0.6 mg twice daily, which resulted in control of the symptoms. When he later discontinued the drug on his own, many new lesions developed. Prednisone, 30 mg/day, and colchicine, 0.6 mg twice daily, were reinstituted with initial success in controlling the symptoms. However, the oral and genital ulcers recurred during therapy; azathioprine was started at a dosageof 100 mg/day. The prednisone dosage was tapered, and his condition has remained stable with colchicine and azathioprine treatment for the past 3 months. Case
4
A 46-year-old white woman was seenat the ophthalmology department in September 1989 for a secondopinion re-
ORAL WRG
ORAL
MED ORAL PATHOL July 1991
Fig. 6. Case 2. Pathergy phenomenon at site of tuberculin skin test.
garding loss of vision in the left eye. Redness and blurred vision had developed 2 years before her visit. Her vision improved somewhat spontaneously, and she did not see an ophthalmologist until 1 year after her visual problems began, at which point she was treated with a short course of prednisone and unknown topical medicaments. Her vision continued to deteriorate to the point where she could detect only hand motions with the left eye. Examination revealedvision of 20/20 in the right eye and 3/200 in the left eye. Occlusive vasculitis and intraretinal hemorrhages were seen in the peripheral portion of the inferior nasal portion of the right retina. The left eye had severevitritis with many inflammatory cells that had coalescedinto large fluffy aggregates.The vesselswere obliterated (Fig. 7) and a macular hole (Fig. 8) had developed as a result of the chronic inflammation. The fluorescein angiogram showed extensive capillary nonperfusion. On careful questioning the patient reported problems with arthritis of the hands and arthralgias of the shoulders and neck. She also was found to have unexplained episodic oral ulcerations. For the past 2 years tender pretibial nodules had developed. On examination the oral lesion was aphthous-like and the leg lesions suggesteda diagnosis of erythema nodosum, but the possibility of subcutaneous polyarteritis nodosa was also considered. Biopsy of a representative nodule suggested a focal necrotizing vasculitis, and the patient was first treated with methotrexate, 12.5 mg/wk, with some improvement in the oral ulcers and leg nodules. However, serial ophthalmologic examination showed progressionof ocular vasculitis. A second deep incisional biopsy of a new inflamed nodule on the leg revealed lobular panniculitis. Special stains for fungi and bacteria were negative. On review, the previous biopsy specimen was also believed to be consistent with a diagnosis of panniculitis. The findings of recurrent oral aphthae, erythema nodosum-like skin lesions, posterior uveitis, and retinal vasculitis were consistent with the diagnosis of Behqet’s disease. The patient was given colchicine, 0.6 mg twice daily, and prednisone, 60 mg/day, with good control of symptoms. No new oral ulcers or nodules developed on the legs with this regimen. Her ocular diseaseinitially remained
Clinical features of Behqet’s disease 33
Volume 72 Number I
7. Case 4. All blood vesselsnasal to optic nerve head are obliterated.
8. Case4. Full-thickness hole is present in macula of left eye.
Fig.
Table I. Summary
Fig.
of four casesof Behqet’s disease Case I
Clinical findings Oral ulceration Genital ulceration Ocular disease (uveitis or retinal vasculitis) Skin lesions (erythema nodosum-like lesions or papular-pustular lesions) Pathergy reaction (read by physician at 24-48 hr) Treatment
Case 2
+ +
+ +
+
Colchicine, prednisone
stable, and prednisone dosagewas tapered to 10 mg twice daily. DISCUSSION
These four casesare typical of Behqet’s disease in that all patients had oral ulcers before any other signs of diseasehad developed (Table I). At some point in the course of their disease,99% of patients with Behget’s diseasewill have oral ulcers; these are the presenting sign of Behqet’s disease in 67% of casesand typically precede skin, eye, genital, or joint involvement.2 Findings of cultures and laboratory tests were negative in our patients. Biopsy of lesional tissue helped rule out autoimmune blistering diseasessuch as pemphigus vulgaris and bullous pemphigoid and directed the evaluation toward Behqet’s disease when neutrophilic infiltrations were found. A neutrophilic vascular reaction seemsto be the fundamental histologic change in the lesions of Behcet’s disease.” This reaction pattern is not specific for Behcet’s diseaseand can also be seen
Case 4
+ +
+ +
+
+
-
+ Colchicine
Case 3
Azathioprine, prednisone
Colchicine, prednisone
in aphthous stomatitis. It is not clear how this reaction pattern develops. Genetic studies have linked HLA-BS and -Bw51 to Behqet’s disease.‘* Other researchers have suspected that infection with herpes simplex virus is important in the pathogenesis of Behqet’s disease.l3 Interestingly, herpesvirus infection can lead to the production of heat shock proteins, which cross-react with oral mucosa. Other agents such as Streptococcus sanguis may share crossreacting epitopes, thereby explaining the seemingly diverse and unrelated agents suspectedin the pathogenesis of Behqet’s disease.14The way in which all these findings relate to one another is unclear, but people who are genetically susceptible people may respond to a variety of infectious agents by producing a leukocytoclastic tissue reaction. 13 Direct immunofluorescence sometimes reveals the presence of immune complexes in lesional skin. Whether these immune complexes precipitate
the lesions of Behqet’s
diseaseor are merely an epiphenomenon has not been shown. Documented immune aberrations such as in-
34
Helm et al.
creasedinterleukin-6 activity with T-cell suppression and B-cell stimulation15 again suggest that Behget’s diseaseis an autoimmune process.Although biopsy of lesions for routine histologic and direct immunofluorescencestudies may show changes that are suggestive of Behcet’s disease, biopsy is most useful to exclude diagnoses of autoimmune diseasesor infectious causes. The diagnosis of Behcet’s disease can best be made by relying on the clinical criteria set forth by the International Study Group for Behcet’s Disease.‘, ’ o The treatments for Behcet’s disease that have shown the greatest efficacy are immunomodulatory rather than antimicrobial. Successful treatment consists of anti-inflammatory agents that modify neutrophi1 activity. Topical corticosteroids such as 0.1% triamcinolone (Kenalog in Orabase) are helpful for controlling localized disease in the mouth. Topical anesthetics such as viscous lidocaine and agents that coat ulcers such as sucralfate (Carafate) and tannic acid in alcohol (Zilactin) are said to make patients more comfortable, but we have found these to be of limited use. Colchicine may be helpful if topical therapy cannot control symptoms.16Colchicine may be effective because of interference with neutrophil chemotaxis. 17The dosethat can be given is limited by gastrointestinal side effects. Prednisone therapy is also useful in dosesranging from 40 to 60 mg/day, but the chronic nature of Behcet’s diseaseoften necessitates the addition of steroid-sparing agents such as azathioprine (Imuran),18 cyclosporine,19 cyclophosphamide (Cytoxan), chlorambucil,20 and thalidomide13 for long-term therapy. Although patients may be bothered most by the painful oral lesions of Behcet’s disease, the insidious nature of the ocular disease often dictates the need for more aggressive treatment. Azathioprine has recently been shown to be effective for the ocular manifestations of Behcet’s diseaseand may prevent progression of ocular disease if instituted early. ‘* New treatments for ocular inflammatory diseasesuch as methotrexate2’ also offer exciting possibilities for the treatment of Behcet’s disease. The diverse manifestations of Behcet’s diseaseoften make early diagnosis difficult, but oral ulceration is the most frequent and usually the first manifestation of the disease.Dental practitioners are therefore in an advantageousposition to help diagnose Behcet’s disease by suspecting the diagnosis, asking the relevant historical questions, and obtaining appropriate dermatologic and ophthalmologic consultations. In this way patients at risk for ocular diseaseand resulting blindness may be identified and treated as early as possible.
ORAL SURCORAL MED ORAL PATHOL July 1991 REFERENCES 1. Behqet H. iiber rezidivierende, aphthose, durch ein Virus ver-
ursachte Geschwilre am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr 1937;105:1152-7. 2. Shimizu T, Ehrlich GE, Inaba Cl, Hayashi K. Behpet disease (Behqet syndrome). Semin Arthritis Rheum 1979;8:223-60. 3. O’Duffy JD. Summary of international symposium on Beh9et’s disease. J Rheumatol 1978;5:229-33. 4. Mason RM, Barnes CG, Behcet’ssyndrome with arthritis. Ann Rheum Dis 1969;28:95-103. 5. Mizushima Y. Recent research into Behcet’s diseasein Japan. Int J Tissue React 1988;10:59-65. 6 O’Duffy JD. Suggested criteria for diagnosis of Behqet’s disease. [Abstract]. J Rheumatol 1974;l: 18. 7 Zhang X-Q. Chin J Intern Med 1980;19:15-20(in Chinese). 8. Dilsen N, Konice M, Aral 0. Our diagnostic criteria of BehGet’sdisease: an overview-1986. In: Lehner T, Barnes CG, eds. Recent advances in Behcet’s disease. London: Royal Society of Medicine Services 1986;103:177-80, International Congress Series. 9. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behpet’s disease.Lancet 1990;335:1078-80.(Additional information from this group was presentedat the Fifth International Conference on Behqet’s Disease; Rochester, Minn, Sept 14-15, 1989.) 10 Jorizzo JL, Rogers RS. Behqet’s disease:an update based on the International Conference held in Rochester, Minnesota, September 14 and 15, 1989. J Am Acad Dermatol 1990;23: 738-41. 11. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol 1988;19:983-1005. 12. Arbesfeld SJ, Kurban AK. Behcet’s disease:new perspectives on an enigmatic syndrome. J Am Acad Dermatol 1988;19: 767-79. 13. Jorizzo JL. Behcet’s disease:an update based on the 1985 International Conference in London. Arch Dermatol 1986; 122:556-g. 14. Lehner T, Fortune F, Studd M. T-cell immunoregulation in Behcet’s disease and consideration of microbial aetiology invohing herpes simplex virus, heat shock protein and streptococcal antigens. Fifth International Conference on Behcet’s Disease; Rochester, Minn, Sept 14-15, 1989. 15 Sakane T. Significance of immune abnormalities in the pathophysiology of Behcet’s disease.Presentedat the Fifth International Conference on Behcet’s Disease;Rochester, Minn, Sept 14-15, 1989. 16. Miyachi Y, Shinkichi T, Ozaki M, Horio T. Colchicine in the treatment of the cutaneous manifestations of Behpet’s disease. Br J Dermatol 1981;104:67-9. 17. Aram H. Colchicine in dermatologic therapy. Int J Dermatol 1983;2:566-9. 18. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behcet’s syndrome. N Engl J Med 1990; 322:281-5. 19. Busch R, Ruzicka TH, Donhauser G. Cyclosporin-A therapie des morbus Behcet. Hautarzt 1990;41:229-31. 20. Schilling H, Bornfeld N, Windeck R, Wessing A, Kirch W. Cytostatic and immunosuppressivetreatment of ocular Behcet syndrome. Klin Monatsbl Augenheilkd 1990;192:62-9. 21. Schmitt MA, Lowder CY, Wilke WS, et al. Low dose methotrexate therapy for ocular inflammatory disease [Abstract]. Presentedat Association for Research in Vision and Ophthalmology; Sarasota, Fla, May 1990. Reprint requests:
Thomas N. Helm, MD Department of Dermatology Cleveland Clinic Foundation One Clinic Center Drive 9500 Euclid Ave. Cleveland, OH 44195-5032
CLINIC
FOUNDATION
AND OHIO STATE UNIVERSITY
Behget’s disease is a multisystem inflammatory disorder of unknown etiology. The unifying histologic reaction pattern is a leukocytoclastic vasculitis that affects predominantly the skin, oral mucosa, and eyes. Many other sites of involvement have been reported but are inconsistently found in individual patients. Early recognition and treatment of Behpet’s disease may help prevent devastating permanent sequelae such as blindness. Because oral involvement is often the first manifestation of this disorder, dental practitioners are in a unique position to help these patients. We report four cases of Behpet’s disease in North American patients. Diagnostic criteria and treatment options are reviewed. (ORAL SURC ORAL MED ORAL PATHOL 1991;72:30-4)
I
n 1937 Hulusi Behqet’ described two patients with oral ulcers, genital ulcers, and loss of vision. Other reports of patients with this symptom complex, many from Asia and Asia Minor, subsequently appeared in the world’s literature. Although these patients fit Behqet’s original description, they had numerous other signs of disease, such as erythema nodosum, acneiform skin eruptions, pathergy, nondestructive asymmetric arthritis, thrombophlebitis, aneurysm formation, spastic paresis, impaired memory, and glomerulonephritis.* Becauseof its protean manifestations, the diagnosis of Behcet’s diseasemay be difficult to make. Various diagnostic criteria have been proposed to help classify individual patients.*-s Criteria suggested at the Fifth International Conference on Behqet’s Disease93‘() include oral aphthous-like ulcers, not otherwise explained, that have recurred at least three times during a l-year period, and two of the following four manifestations not otherwise explained: (1) recurrent genital ulcerations; (2) retinal vasculitis, anterior uveitis, or posterior uveitis; (3) erythema nodosumlike skin lesions or acneiform lesions; and (4) a positive pathergy test result read by a physician 1 to 2 days after oblique insertion of a 20-gauge needle into the skin. Connective tissue disease, Reiter’s syn-
“Department
of Dermatology,
bScction of Diagnostic Services, University, Columbus. CDepartment of Ophthalmology, 7/13/28237 30
Cleveland Clinic College Cleveland
Foundation. of Dentistry, Ohio State Clinic
Foundation.
drome, and inflammatory bowel disease should be ruled out before BehGet’sdiseaseis diagnosed. Other features considereduseful in confirming a diagnosis of Beheet’s diseaseby the International Behget’s Study Group9* I0 include deep venous thrombosis, subcutaneous thrombophlebitis, epididymitis, arthritis, gastrointestinal ulceration, and arteritis or aneurysm formation. Becausethe diagnosis of Behget’s disease is not easily made, one must be familiar with its many manifestations. The following report outlines the varied clinical histories and presentations of four patients whose final diagnoses were of Behqet’s disease. CASE REPORTS Case 1 A 71-year-old black woman was first seen in February 1986 for evaluation of painful oral ulcerations of recent on-
set. The patient claimed that she had never had ulcerations of this type before, and she denied any other skin or mucosal involvement. Clinical examination showed a cluster of shallow ulcers, 2 to 5 mm in diameter, involving the maxillary right labial mucosa (Fig. 1). No vesicle formation was seen, and no epithelial separation was observed. Minor aphthous stomatitis was suspected, but because the problem was of recent onset, a biopsy was performed. Microscopic examination of the lesional tissue revealed an ulcer with vasculitis; these findings were believed to be consistent with aphthous ulceration. The patient was given topical corticosteroids, with some improvement. One year later the patient was seen for the evaluation of persistent oral ulcerations. The patient reported that recurrent episodes of these lesions had bothered her for several months and that she had been hospitalized elsewhere for this problem without a specific diagnosis. She also had sores in the perineum.
Volume Number
Clinical features of Behqet’s disease
72 I
31
Fig. 1. Case 1, Right labial mucosa with shallow aphthous-like ulcerations.
3. Case 1. Punched-out ulcers on labia majora and perineum.
Fig. Fig.
2. Case 1. Acneiform pustule on chin.
Examination showednumerous ulcers, 3 mm in diameter, identical to the initial lesions involving the mandibular labial mucosa and the mucosa of the lateral dorsal aspect of the tongue. A pustule on the chin (Fig. 2), and several “punched out” ulcers involving the labia majora and perineal skin (Fig. 3) were present. Viral cultures were negative. Biopsy of a genital lesion showed microscopic features similar to the oral lesion. Findings of direct and indirect immunofluorescence studies were negative. A diagnosis of Behqet’s syndrome was rendered because of the oral and genital ulcers and the facial acneiform lesion. The patient was treated with colchicine, 0.6 mg twice daily, and had complete resolution of her disease.
for areas of hyperemia in the cecum, transverse colon, and sigmoid colon. Biopsy of the colon showed chronic inflammation, whereas histologic sections of a tongue lesion demonstrated ulceration and polymorphonuclear leukocyte infiltration without vasculitis. Cultures for herpes simplex virus were negative. During the course of his hospitalization, punched-out ulcers of the scrotal and perianal skin developed. A sterile pustule that developed at the site of a tuberculin skin test (Fig. 6) was believed to represent a manifestation of pathergy. The patient’s oral ulcers, genital ulcers, and pathergic response were consistent with a diagnosis of Behqet’s disease.He was treated with colchicine, 0.6 mg twice daily, and prednisone, 40 mg/day, with good results.
Case 2
Case 3
A 25-year-old white man was referred for evaluation of painful oral lesions of 1 year’s duration. He had headache, intermittent diarrhea, sore throat, and dysphagia. Examination of the oral mucosa showed clusters of aphthous-like lesions involving the tip of the tongue (Fig. 4) and the posterior of the soft palate (Fig. 5). Ophthalmologic examination did not reveal uveitis. Laboratory investigation was remarkable for guaiacpositive stool. Findings of colonoscopy were normal except
A 37-year-old black man was seen in 1986 with a l-year history of episodic oral ulcerations. Evaluation revealed one small ulcer on the tip of the tongue. Ulcers later developed on the left side of the tongue and prevented eating, because of pain. He had one or two bouts of such oral ulcerations every month thereafter. The lesions would last up to 10 days before they healed. Despite using sucralfate (Carafate) paste and diphenhydramine (Benadryl), he noted no improvement.
32
Fig.
Helm et al.
4. Case 2. Aphthous-like’resions on tip of tongue.
Fig. 5. Case 2. Aphthous-like ulcers on posterior soft palate.
Recurrent aphthous stomatitis was initially diagnosed. A small ulcer in the urethra near the meatus developed in February 1988. Cultures for herpes simplex virus were negative. Urinalysis revealed pyuria, but culture for Neisseria gonorrhea was negative. Results of an ophthalmologic examination were unremarkable. Nine months later herpesvirus cultures from the scrotum were negative. Ulcers developed on the scrotum, and pustules appearedon the thighs. A diagnosis of Behqet’sdisease was made. The patient started treatment with colchicine, 0.6 mg twice daily, which resulted in control of the symptoms. When he later discontinued the drug on his own, many new lesions developed. Prednisone, 30 mg/day, and colchicine, 0.6 mg twice daily, were reinstituted with initial success in controlling the symptoms. However, the oral and genital ulcers recurred during therapy; azathioprine was started at a dosageof 100 mg/day. The prednisone dosage was tapered, and his condition has remained stable with colchicine and azathioprine treatment for the past 3 months. Case
4
A 46-year-old white woman was seenat the ophthalmology department in September 1989 for a secondopinion re-
ORAL WRG
ORAL
MED ORAL PATHOL July 1991
Fig. 6. Case 2. Pathergy phenomenon at site of tuberculin skin test.
garding loss of vision in the left eye. Redness and blurred vision had developed 2 years before her visit. Her vision improved somewhat spontaneously, and she did not see an ophthalmologist until 1 year after her visual problems began, at which point she was treated with a short course of prednisone and unknown topical medicaments. Her vision continued to deteriorate to the point where she could detect only hand motions with the left eye. Examination revealedvision of 20/20 in the right eye and 3/200 in the left eye. Occlusive vasculitis and intraretinal hemorrhages were seen in the peripheral portion of the inferior nasal portion of the right retina. The left eye had severevitritis with many inflammatory cells that had coalescedinto large fluffy aggregates.The vesselswere obliterated (Fig. 7) and a macular hole (Fig. 8) had developed as a result of the chronic inflammation. The fluorescein angiogram showed extensive capillary nonperfusion. On careful questioning the patient reported problems with arthritis of the hands and arthralgias of the shoulders and neck. She also was found to have unexplained episodic oral ulcerations. For the past 2 years tender pretibial nodules had developed. On examination the oral lesion was aphthous-like and the leg lesions suggesteda diagnosis of erythema nodosum, but the possibility of subcutaneous polyarteritis nodosa was also considered. Biopsy of a representative nodule suggested a focal necrotizing vasculitis, and the patient was first treated with methotrexate, 12.5 mg/wk, with some improvement in the oral ulcers and leg nodules. However, serial ophthalmologic examination showed progressionof ocular vasculitis. A second deep incisional biopsy of a new inflamed nodule on the leg revealed lobular panniculitis. Special stains for fungi and bacteria were negative. On review, the previous biopsy specimen was also believed to be consistent with a diagnosis of panniculitis. The findings of recurrent oral aphthae, erythema nodosum-like skin lesions, posterior uveitis, and retinal vasculitis were consistent with the diagnosis of Behqet’s disease. The patient was given colchicine, 0.6 mg twice daily, and prednisone, 60 mg/day, with good control of symptoms. No new oral ulcers or nodules developed on the legs with this regimen. Her ocular diseaseinitially remained
Clinical features of Behqet’s disease 33
Volume 72 Number I
7. Case 4. All blood vesselsnasal to optic nerve head are obliterated.
8. Case4. Full-thickness hole is present in macula of left eye.
Fig.
Table I. Summary
Fig.
of four casesof Behqet’s disease Case I
Clinical findings Oral ulceration Genital ulceration Ocular disease (uveitis or retinal vasculitis) Skin lesions (erythema nodosum-like lesions or papular-pustular lesions) Pathergy reaction (read by physician at 24-48 hr) Treatment
Case 2
+ +
+ +
+
Colchicine, prednisone
stable, and prednisone dosagewas tapered to 10 mg twice daily. DISCUSSION
These four casesare typical of Behqet’s disease in that all patients had oral ulcers before any other signs of diseasehad developed (Table I). At some point in the course of their disease,99% of patients with Behget’s diseasewill have oral ulcers; these are the presenting sign of Behqet’s disease in 67% of casesand typically precede skin, eye, genital, or joint involvement.2 Findings of cultures and laboratory tests were negative in our patients. Biopsy of lesional tissue helped rule out autoimmune blistering diseasessuch as pemphigus vulgaris and bullous pemphigoid and directed the evaluation toward Behqet’s disease when neutrophilic infiltrations were found. A neutrophilic vascular reaction seemsto be the fundamental histologic change in the lesions of Behcet’s disease.” This reaction pattern is not specific for Behcet’s diseaseand can also be seen
Case 4
+ +
+ +
+
+
-
+ Colchicine
Case 3
Azathioprine, prednisone
Colchicine, prednisone
in aphthous stomatitis. It is not clear how this reaction pattern develops. Genetic studies have linked HLA-BS and -Bw51 to Behqet’s disease.‘* Other researchers have suspected that infection with herpes simplex virus is important in the pathogenesis of Behqet’s disease.l3 Interestingly, herpesvirus infection can lead to the production of heat shock proteins, which cross-react with oral mucosa. Other agents such as Streptococcus sanguis may share crossreacting epitopes, thereby explaining the seemingly diverse and unrelated agents suspectedin the pathogenesis of Behqet’s disease.14The way in which all these findings relate to one another is unclear, but people who are genetically susceptible people may respond to a variety of infectious agents by producing a leukocytoclastic tissue reaction. 13 Direct immunofluorescence sometimes reveals the presence of immune complexes in lesional skin. Whether these immune complexes precipitate
the lesions of Behqet’s
diseaseor are merely an epiphenomenon has not been shown. Documented immune aberrations such as in-
34
Helm et al.
creasedinterleukin-6 activity with T-cell suppression and B-cell stimulation15 again suggest that Behget’s diseaseis an autoimmune process.Although biopsy of lesions for routine histologic and direct immunofluorescencestudies may show changes that are suggestive of Behcet’s disease, biopsy is most useful to exclude diagnoses of autoimmune diseasesor infectious causes. The diagnosis of Behcet’s disease can best be made by relying on the clinical criteria set forth by the International Study Group for Behcet’s Disease.‘, ’ o The treatments for Behcet’s disease that have shown the greatest efficacy are immunomodulatory rather than antimicrobial. Successful treatment consists of anti-inflammatory agents that modify neutrophi1 activity. Topical corticosteroids such as 0.1% triamcinolone (Kenalog in Orabase) are helpful for controlling localized disease in the mouth. Topical anesthetics such as viscous lidocaine and agents that coat ulcers such as sucralfate (Carafate) and tannic acid in alcohol (Zilactin) are said to make patients more comfortable, but we have found these to be of limited use. Colchicine may be helpful if topical therapy cannot control symptoms.16Colchicine may be effective because of interference with neutrophil chemotaxis. 17The dosethat can be given is limited by gastrointestinal side effects. Prednisone therapy is also useful in dosesranging from 40 to 60 mg/day, but the chronic nature of Behcet’s diseaseoften necessitates the addition of steroid-sparing agents such as azathioprine (Imuran),18 cyclosporine,19 cyclophosphamide (Cytoxan), chlorambucil,20 and thalidomide13 for long-term therapy. Although patients may be bothered most by the painful oral lesions of Behcet’s disease, the insidious nature of the ocular disease often dictates the need for more aggressive treatment. Azathioprine has recently been shown to be effective for the ocular manifestations of Behcet’s diseaseand may prevent progression of ocular disease if instituted early. ‘* New treatments for ocular inflammatory diseasesuch as methotrexate2’ also offer exciting possibilities for the treatment of Behcet’s disease. The diverse manifestations of Behcet’s diseaseoften make early diagnosis difficult, but oral ulceration is the most frequent and usually the first manifestation of the disease.Dental practitioners are therefore in an advantageousposition to help diagnose Behcet’s disease by suspecting the diagnosis, asking the relevant historical questions, and obtaining appropriate dermatologic and ophthalmologic consultations. In this way patients at risk for ocular diseaseand resulting blindness may be identified and treated as early as possible.
ORAL SURCORAL MED ORAL PATHOL July 1991 REFERENCES 1. Behqet H. iiber rezidivierende, aphthose, durch ein Virus ver-
ursachte Geschwilre am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr 1937;105:1152-7. 2. Shimizu T, Ehrlich GE, Inaba Cl, Hayashi K. Behpet disease (Behqet syndrome). Semin Arthritis Rheum 1979;8:223-60. 3. O’Duffy JD. Summary of international symposium on Beh9et’s disease. J Rheumatol 1978;5:229-33. 4. Mason RM, Barnes CG, Behcet’ssyndrome with arthritis. Ann Rheum Dis 1969;28:95-103. 5. Mizushima Y. Recent research into Behcet’s diseasein Japan. Int J Tissue React 1988;10:59-65. 6 O’Duffy JD. Suggested criteria for diagnosis of Behqet’s disease. [Abstract]. J Rheumatol 1974;l: 18. 7 Zhang X-Q. Chin J Intern Med 1980;19:15-20(in Chinese). 8. Dilsen N, Konice M, Aral 0. Our diagnostic criteria of BehGet’sdisease: an overview-1986. In: Lehner T, Barnes CG, eds. Recent advances in Behcet’s disease. London: Royal Society of Medicine Services 1986;103:177-80, International Congress Series. 9. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behpet’s disease.Lancet 1990;335:1078-80.(Additional information from this group was presentedat the Fifth International Conference on Behqet’s Disease; Rochester, Minn, Sept 14-15, 1989.) 10 Jorizzo JL, Rogers RS. Behqet’s disease:an update based on the International Conference held in Rochester, Minnesota, September 14 and 15, 1989. J Am Acad Dermatol 1990;23: 738-41. 11. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol 1988;19:983-1005. 12. Arbesfeld SJ, Kurban AK. Behcet’s disease:new perspectives on an enigmatic syndrome. J Am Acad Dermatol 1988;19: 767-79. 13. Jorizzo JL. Behcet’s disease:an update based on the 1985 International Conference in London. Arch Dermatol 1986; 122:556-g. 14. Lehner T, Fortune F, Studd M. T-cell immunoregulation in Behcet’s disease and consideration of microbial aetiology invohing herpes simplex virus, heat shock protein and streptococcal antigens. Fifth International Conference on Behcet’s Disease; Rochester, Minn, Sept 14-15, 1989. 15 Sakane T. Significance of immune abnormalities in the pathophysiology of Behcet’s disease.Presentedat the Fifth International Conference on Behcet’s Disease;Rochester, Minn, Sept 14-15, 1989. 16. Miyachi Y, Shinkichi T, Ozaki M, Horio T. Colchicine in the treatment of the cutaneous manifestations of Behpet’s disease. Br J Dermatol 1981;104:67-9. 17. Aram H. Colchicine in dermatologic therapy. Int J Dermatol 1983;2:566-9. 18. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behcet’s syndrome. N Engl J Med 1990; 322:281-5. 19. Busch R, Ruzicka TH, Donhauser G. Cyclosporin-A therapie des morbus Behcet. Hautarzt 1990;41:229-31. 20. Schilling H, Bornfeld N, Windeck R, Wessing A, Kirch W. Cytostatic and immunosuppressivetreatment of ocular Behcet syndrome. Klin Monatsbl Augenheilkd 1990;192:62-9. 21. Schmitt MA, Lowder CY, Wilke WS, et al. Low dose methotrexate therapy for ocular inflammatory disease [Abstract]. Presentedat Association for Research in Vision and Ophthalmology; Sarasota, Fla, May 1990. Reprint requests:
Thomas N. Helm, MD Department of Dermatology Cleveland Clinic Foundation One Clinic Center Drive 9500 Euclid Ave. Cleveland, OH 44195-5032