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Behçet's disease: a case report
Clin Podiatr Med Surg 19 (2002) 519 – 525
Behcßet’s disease: a case report Eric A. Barp, DPMa, Vincent J. Mandracchia, DPM, MSb,*, Marc R. House, BSc a
Broadlawns Medical Center, Des Moines, IA 50314, USA Department of Surgery, Broadlawns Medical Center, Department of Podiatric Medicine, College of Podiatric Medicine and Surgery, Des Moines University-Osteopathic Medical Center, Des Moines, IA 50314, USA c Des Moines University-Osteopathic Medical Center, Des Moines, IA 50314, USA b
Behcß et’s disease is a multisystem, inflammatory, relapsing, chronic disorder that may include mucocutaneous, ocular, genital, articular, vascular, central nervous system (CNS), and gastrointestinal (GI) involvement with exacerbations in the lower extremity [1,2]. It was originally described as a triad of recurrent oral ulcerations, genital ulcerations, and uveitis affecting young male adults. The cause is unknown and speculation leads toward an autoimmune-mediated disease or one with a genetic component, with perhaps an aspect of each. Immunologic (including autoimmune), viral causes, and an HLA-related immunogenetic predisposition (HLA-B51) associated with cases in Japan and the Mediterranean have been suggested. Histopathologic vasculitic changes are common to all involved organs [2]. The syndrome generally begins in the third decade, typically around the age of 21, and occurs twice as often in men as in women [2]. Occasional cases have been reported in children. The disease is more common along the ancient silk route in Mediterranean and Asian countries, especially Japan, earning the name Old Silk Route disease. Hulusi Behcßet, a Turkish dermatologist, originally described the disease in 1937 [3 – 5]. Some sources indicate that Hippocrates may have originally described the disease [4]. Although uncommon in the United States, Behcßet’s disease must be considered, especially in patients with a history of oral and genital ulcers and unexplained ocular disease with suspect manifestations of the lower extremity.
* Corresponding author. Address reprint requests to Broadlawns Medical Center, 1801 Hickman Avenue, Des Moines, IA 50314. E-mail address: [email protected] (V.J. Mandracchia). 0891-8422/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 9 1 - 8 4 2 2 ( 0 2 ) 0 0 0 3 5 - 6
520
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
Symptoms Oral ulcerations Almost all patients have recurrent painful oral ulcers resembling those of aphthous stomatitis or canker sores; in most patients, these ulcers are the first manifestations of the disease. These recurrent oral ulcerations alone are sometimes described as Sutton’s disease. Sutton’s disease is not considered a contagious disease, but also believed to be of autoimmune in nature. Of the oral ulcerations, 80% are considered the minor form and leave no lasting scar; however, 10% of the ulcers may form on the hard palate with resultant scar formation and are termed aphthous major ulcerations. The remaining 10% will form herpetiform ulcerations [2]. As stated previously, the oral ulcerations are typically the first manifestation of the disease; however, in up to 20% of patients there may be a preulceration period, with the formation of very episodic ulcerations and occasional gastrointestinal involvement. Sporadic cases of the oral ulcerations progressing to granuloma have also been documented [6].
Genital ulcerations In men, ulcers resembling the oral ulcerations occur on the penis and scrotum, where they are painful. In females, however, the ulcers may develop in the vulva and vagina, where they may be either painful or asymptomatic. Sexual intercourse has been implicated to trigger genital ulcerations. Urethritis is not a symptom of Behcßet’s disease and may help distinguish the disease from Reiter’s disease [2]. There are also intermittent reports of ‘‘kissing ulcerations’’ developing along the inner thigh from contact with the scrotum. Other symptoms follow in days to years. The symptoms often do not occur concomitantly, making the diagnosis of the disease difficult. Furthermore, this often precludes early intervention to manage the symptoms, leading to the potential development of more serious effects of the disease.
Uveitis Ocular disease occurs in most cases, especially in the male patients [2,7]. Anterior uveitis presents as neutrophil accumulation often resulting in a hypopyon. The most common is a relapsing iridocyclitis, which often presents as pain, photophobia, and hazy vision. The posterior segment of the eye may also be involved, with choroiditis, retinal vasculitis, and papillitis. Anterior uveitis often occurs with posterior uveitis. Untreated posterior uveitis may cause blindness. Behcß et’s disease is the second leading cause of blindness in Japan and is very common in other Asian and Mediterranean countries [8]. In Japan, ocular involvement occurs in 69% of patients with Behcßet’s disease [7,8].
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
521
Skin lesions Various skin lesions occur in 80% of cases [2]. Pustules and acneiform lesions are the most common. Variability is again a common finding with Behcßet’s disease, and other forms of vesicles, folliculitis, and pyoderma gangrenosum –type lesions have been reported [1– 3]. Particularly suggestive are erythema nodosum –like lesions and other slow-healing lesions that leave cicatrix formation. In about 40% of patients, inflammatory reactions to minor trauma occur (eg, needle punctures). This is known as pathergy and occurs in a relatively small percentage of the Behcßet’s population. Its presence, however, is a strong indicator of the disease. Associated symptoms Relatively mild, self-limiting, and nondestructive arthritis involving the knees and other large joints occurs in 50% of patients [2]. Recurrent superficial or deep migratory thrombophlebitis develops in 25% and may lead to obstruction of the vena cava [9]. The literature frequently makes the distinction between Behcßet’s syndrome and a neuro-Behcßet’s syndrome [10,11]. This again emphasizes the diffuse nature and complexity of the disease. Headaches are a frequent neurologic component of the disease, with the causative mechanism being attributed to the vasculitis. Involvement of the central nervous system (18%) may present as chronic meningoencephalitis, benign intracerebral hypertension, cerebral aneurysm [9,11], or life-threatening brain stem and spinal cord lesions [10]. Gastrointestinal manifestations vary from nonspecific abdominal discomfort to a syndrome resembling regional enteritis, such as Crohn’s disease or colitis [12]. A review of the literature revealed that the ulcerations have been reported throughout the gastrointestinal system, beginning with the oral ulcerations and progressing to the esophagus [2,6,12,13] and lower alimentary tract. Sporadic cases of ulcerations and stenosis in the pharynx have also been reported [6,13 – 15]. Inflammatory vasculitis may cause aneurysms or thrombosis and may also involve the kidneys with an asymptomatic focal glomerulonephritis. Some studies have indicated a close association of mitral valve prolapse and Behcßet’s disease, citing the vasculitis as the causative mechanism [3,4,16]. In rare cases, the lungs are involved, with vasculitis and aneurysms of the pulmonary arteries. Diagnosis Diagnosis is clinical and may require months. Differential diagnoses include Reiter’s syndrome, Stevens-Johnson syndrome, systemic lupus erythematous (SLE), regional enteritis (Crohn’s disease), ulcerative colitis, ankylosing spondylitis, and herpes simplex infection, especially with recurrent aseptic meningitis. Behcßet’s disease does not have any specific findings that exclude all alternative possibilities, but it is often distinguished by a relapsing course and multiple organ involvement. Laboratory abnormalities are nonspecific but characteristic of inflammatory disease (elevated ESR and mild leukocytosis).
522
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
In 1990 the International Study Group (ISG) [17] devised the following criteria for the diagnosis for Behcßet’s disease [2,17]. First, recurrent oral ulceration occurring at least three times in a 12-month period was the only requirement the group deemed essential. A patient must have two of the following: genital ulcerations, uveitis, or skin involvement. The urate crystal test has also been proposed as a more sensitive test than the pathergy test [2]. With injection of urate crystals under the skin, the person with Behcßet’s disease will have a more pronounced and, more specifically, a longer duration of inflammatory reaction than a person without [2] (Table 1). It must be mentioned that these criteria were originally set forth to have a means of standardization for inclusion in research studies of the disease. These criteria were not intended for use in the diagnosis and treatment of individual patients seen in the clinical setting. It was stressed that the disease is highly variable and the patient and each symptom should be treated on a clinical basis [17]. Some authors have also recommended that the disease be divided into two forms. The first to be termed Behcßet’s disease would include those of the genetic makeup from the original area of the old silk route. The second would be termed Behcß et’s syndrome. This classification would be reserved for patients of other ancestry presenting with compilations of symptoms that describe Behcßet’s disease. One larger study included 230 patients suspected of having Behcßet’s disease. Only 6% of the population set was of an ancestry from the old silk route and fell into the author-defined category of ‘‘definite.’’ The balance of the ‘‘definite’’ were native Caucasians of European descent. With a higher prevalence of the disease among people of these old silk route regions, a strong genetic basis for the disease was thought. This study, however, indicates that there may be alternate forms of the disease, supporting the need for a separation of the disease with a classification system to distinguish those who have a genetic predisposition for the disease from those who have acquired it by some other means [2]. There has been a recent association between the HLA-B51 allele and the presence and severity of the disease. It is generally believed to have a higher prevalence among persons with Behcßet’s, but there seems to be some disagreeTable 1 International Study Group criteria for Bechet’s syndrome Clinical presentation
Criteria
Recurrent oral ulcerations
Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient which recurred at least three times in one 12-mo period
Plus two of the following: Recurrent genital ulceration Eye lesions
Skin lesions
Aphthous ulceration or scarring observed by physician Anterior uveitis, posterior uveitis, or cells in vitreous on slit lam examination or retinal vasculitis observed by physician Erythema nodosum observed by physician or patient; pseudofolliculitis, papulopustular lesions, or acneiform nodules observed by physician
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
523
ment on its association with the severity of the disease [18,19]. One study found an increase in the severity of the disease among those persons positive with the HLA-B51 allele. A later study, however, stated that the presence of the allele was not predictive for the severity of the disease, but rather that the age of onset and the male sex were stronger predictors of the severity of the disease. Prognosis and treatment The syndrome is generally chronic and manageable. Remission and relapse may last from weeks to years and even extend over several decades. Blindness, vena cava obstruction, and paralysis, however, may complicate the course; the occasional fatalities usually are associated with neurologic, vascular, and GI involvement. Symptomatic treatment is reasonably successful. Colchicine 0.5 mg twice a day or three times a day may decrease the frequency and severity of oral and genital ulcers. Needle punctures provoke inflammatory skin lesions and should be avoided when possible. Topical corticosteroids may temporarily relieve ocular and oral disease [8]. Topical or systemic corticosteroids, however, do not alter the frequency of relapses. Occasional patients with severe uveitis or CNS involvement respond to high-dose systemic corticosteroids (prednisone 60 to 80 mg/d). Patients with posterior uveitis who do not respond to prednisone should be treated initially with cyclosporine 5 mg/kg/d, increased incrementally if needed to 10 mg/kg/d until a therapeutic effect is observed; trough levels (lowest levels within therapeutic range) of cyclosporine should be maintained between 50 and 200 ng/mL (42 and 166 nmol/ L) [8]. Other reported but still incompletely evaluated therapies include thalidomide (in patients with no possibility for pregnancy) and pentoxifylline. Case report A 21-year-old male presented to Broadlawns Medical Center Emergency Department with an acutely inflamed and painful left ankle joint. He stated that these symptoms had been present for a couple of days without any relief. Past medical history was significant for Sutton’s disease, which is an autoimmune disease that manifests as recurrent oral ulcerations. He stated that his mother, who is from Japan, also suffers from Sutton’s disease. He also stated that he has a history of unusual skin lesions that spontaneously present and resolve, several of which had been excised. He reported that he had been hospitalized in the past for reasons unknown and had nasogastric tube placement. Review of systems was significant for photophobia, recent loss of consciousness, and watery stools for the last three days. He stated that the only medication that he takes is depakote for severe recurrent headaches. Physical examination revealed a lethargic male with a left ankle that was edematous and erythematous with an increase in calor. Range of motion in the sagittal plane elicited pain and was limited compared to that of the contralateral limb. Pustular lesions 2 mm in diameter were noted on the anterior left ankle. Upon
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E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
further physical examination, the patient also complained about the bright lights in the emergency room and was wearing dark sunglasses. Ankle joint aspirate demonstrated no bacteria and rare neutrophils, indicating that an infectious process was not present. It was decided to admit the patient for further observation and empiric intravenous antibiotic therapy. The second hospital day the patient reported that he was feeling better. The left ankle was once again tapped, revealing no bacteria and mild neutrophilia. The anterior ankle joint developed several pustular lesions that broke open. Cultures from the pustular lesions demonstated many neutrophils and the presence of Staphylococcus aureus. On the third hospital day, it was decided to change the antibiotic from Zosyn to Clindamycin because of no resolution at the ankle joint. The patient has also developed acneform lesions on the anterior thighs, which remain the course of 24 hours and then resolve spontaneously. Upon consultation with internal medicine, a possible diagnosis of arachnid bite was made. The lesion, however, does not appear to fit with an insect bite. Reviewing literature, the patient was questioned about sexually transmitted diseases, and a search for the symptoms was made with an indication toward Crohn’s disease or inflammatory bowel disease with extragastrointestinal manifestations of the oral ulcerations and inflammatory arthritis. After reviewing symptoms expressed by the patient, a diagnosis of Behcßet’s disease was made. The patient fit most of the diagnostic criteria with the exception of the absence of genital ulcerations. It is important to note that the diagnosis for Behcßet’s disease should be based clinically and not solely on the ISG diagnostic criteria. The inflamed ankle joint resolved and the range of motion increased after the fourth day of intravenous antibiotics. Upon discharge, the patient was referred to a GI specialist for follow-up of the other symptoms.
Conclusion While Behcßet’s disease is an uncommon presentation to a podiatric clinical setting it is nonetheless a fascinating and poorly understood disease as demonstrated by the current and historical research available about the topic. Much debate remains about the disease cause, course and treatment goals, only through further research into the specific components of this multisystem disease will medicine be more fully able to address the needs of the patient. This discussion should offer the podiatric physician an overview of the disease as well as available treatment options. It is important for the podiatrist to not exclude the disease from a differential diagnosis in the presence of unusual skin lesions or an acute inflammatory arthritis presentation. The importance of this is emphasized by the isolated presentation of the symptoms, which delays diagnosis in many patients. This further emphasizes the need for a complete and detailed history and physical exam in the presence of the aforementioned symptomatology.
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References [1] Ohno S. Behcß et’s disease in the world. In: Lehner T, Barnes CG, editors. Recent advances in Behcet’s disease. London: Royal Society of Medicine Services; 1986. p. 181 – 6. [2] Pickering MC, Haskard DO. Behcßet’s syndrome. J R Coll Physicians Lond 2000;34:169 – 77. [3] Cheng TO. Behcßet’s disease (‘‘Silk Route disease’’) and mitral valve prolapse [letter]. Cardiology 1998;89:306. [4] Cheng TO. Behcßet’s disease [letter]. N Engl J Med 2000;342:588. [5] Shimizu T, Ehrlich GE, Inaba G, et al. Behcet’s disease (Behcet’s syndrome). Semin Arthritis Rheum 1979;8:223 – 60. [6] Yashiro K, Nagasako K, Hasegawa K. Esophageal involvement in intestinal Behcß et’s disease. Endoscopy 1986;18:57 – 60. [7] Mishima S, Masuda K, Izawa Y, et al. Behcßet’s disease in Japan: ophthalmologic aspects. Trans Am Ophthalmol Soc 1979;76:225 – 79. [8] Okada AA. Drug therapy in Behcßet’s disease. Ocul Immunol Inflamm 2000;8:85 – 91. [9] Nakasu S, et al. Cerebral aneurysms associated with Behcß et’s disease: a case report. J Neurol Neurosurg Psychiatry 2001;70(5):682 – 4. [10] Abraham S, Rajeev E, Girijaa S. Neuro-Behcß et’s disease. J Assoc Physicians India 2000; 48(8):838 – 41. [11] Weiner SM, Otte A, Schumacher M, et al. Neuro-Behcßet’s syndrome in a patient not fulfilling criteria for Behcet’s disease: clinical features and value of brain imaging. Clin Rheumatol 2000;19:231 – 4. [12] Kim JS, Lim SH, Choi IJ, et al. Prediction of the clinical course of Behcßet’s colitis according to macroscopic classification by colonoscopy. Endoscopy 2000;32:635 – 40. [13] Mori S, Yoshihira A, Kawamura H, Takeqchi A, Hashimoto T, Inaba G. Esophageal involvement in Behcßet’s disease. Am J Gastroenterol 1983;78:548 – 53. [14] Brooks GB. Pharyngeal stenosis in Behcßet’s Syndrome: the first reported case. Arch Otolaryngol 1983;109:338 – 40. [15] Gustafson RO, McDonald TJ, O’Duffy JD, Goellner JR. Upper aerodigestive tract manifestations of Behcßet’s disease: review of 30 cases. Otolaryngol Head Neck Surg 1981;89:409 – 13. [16] Morelli S, Perrone C, Ferrante L, et al. Cardiac involvement Behcßet’s disease. Cardiology 1997; 88:513 – 7. [17] International Study Group for Behcßet’s Disease. Criteria for diagnosis of Behcßet’s disease. Lancet 1990;335:1078 – 9. [18] Sakane T, Takeno M, Suzuki N, Inaba G. Behcßet’s disease. N Engl J Med 1999;341:1284 – 91. [19] Yazici H, Chamberlain MA, Scheuder I, D’Amaro J, Muftuoglu M. HLA antigens in Behcßet’s disease: a reappraisal by a comparative study of Turkish and British patients. Ann Rheum Dis 1980;39:344 – 8.
Behcßet’s disease: a case report Eric A. Barp, DPMa, Vincent J. Mandracchia, DPM, MSb,*, Marc R. House, BSc a
Broadlawns Medical Center, Des Moines, IA 50314, USA Department of Surgery, Broadlawns Medical Center, Department of Podiatric Medicine, College of Podiatric Medicine and Surgery, Des Moines University-Osteopathic Medical Center, Des Moines, IA 50314, USA c Des Moines University-Osteopathic Medical Center, Des Moines, IA 50314, USA b
Behcß et’s disease is a multisystem, inflammatory, relapsing, chronic disorder that may include mucocutaneous, ocular, genital, articular, vascular, central nervous system (CNS), and gastrointestinal (GI) involvement with exacerbations in the lower extremity [1,2]. It was originally described as a triad of recurrent oral ulcerations, genital ulcerations, and uveitis affecting young male adults. The cause is unknown and speculation leads toward an autoimmune-mediated disease or one with a genetic component, with perhaps an aspect of each. Immunologic (including autoimmune), viral causes, and an HLA-related immunogenetic predisposition (HLA-B51) associated with cases in Japan and the Mediterranean have been suggested. Histopathologic vasculitic changes are common to all involved organs [2]. The syndrome generally begins in the third decade, typically around the age of 21, and occurs twice as often in men as in women [2]. Occasional cases have been reported in children. The disease is more common along the ancient silk route in Mediterranean and Asian countries, especially Japan, earning the name Old Silk Route disease. Hulusi Behcßet, a Turkish dermatologist, originally described the disease in 1937 [3 – 5]. Some sources indicate that Hippocrates may have originally described the disease [4]. Although uncommon in the United States, Behcßet’s disease must be considered, especially in patients with a history of oral and genital ulcers and unexplained ocular disease with suspect manifestations of the lower extremity.
* Corresponding author. Address reprint requests to Broadlawns Medical Center, 1801 Hickman Avenue, Des Moines, IA 50314. E-mail address: [email protected] (V.J. Mandracchia). 0891-8422/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 9 1 - 8 4 2 2 ( 0 2 ) 0 0 0 3 5 - 6
520
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
Symptoms Oral ulcerations Almost all patients have recurrent painful oral ulcers resembling those of aphthous stomatitis or canker sores; in most patients, these ulcers are the first manifestations of the disease. These recurrent oral ulcerations alone are sometimes described as Sutton’s disease. Sutton’s disease is not considered a contagious disease, but also believed to be of autoimmune in nature. Of the oral ulcerations, 80% are considered the minor form and leave no lasting scar; however, 10% of the ulcers may form on the hard palate with resultant scar formation and are termed aphthous major ulcerations. The remaining 10% will form herpetiform ulcerations [2]. As stated previously, the oral ulcerations are typically the first manifestation of the disease; however, in up to 20% of patients there may be a preulceration period, with the formation of very episodic ulcerations and occasional gastrointestinal involvement. Sporadic cases of the oral ulcerations progressing to granuloma have also been documented [6].
Genital ulcerations In men, ulcers resembling the oral ulcerations occur on the penis and scrotum, where they are painful. In females, however, the ulcers may develop in the vulva and vagina, where they may be either painful or asymptomatic. Sexual intercourse has been implicated to trigger genital ulcerations. Urethritis is not a symptom of Behcßet’s disease and may help distinguish the disease from Reiter’s disease [2]. There are also intermittent reports of ‘‘kissing ulcerations’’ developing along the inner thigh from contact with the scrotum. Other symptoms follow in days to years. The symptoms often do not occur concomitantly, making the diagnosis of the disease difficult. Furthermore, this often precludes early intervention to manage the symptoms, leading to the potential development of more serious effects of the disease.
Uveitis Ocular disease occurs in most cases, especially in the male patients [2,7]. Anterior uveitis presents as neutrophil accumulation often resulting in a hypopyon. The most common is a relapsing iridocyclitis, which often presents as pain, photophobia, and hazy vision. The posterior segment of the eye may also be involved, with choroiditis, retinal vasculitis, and papillitis. Anterior uveitis often occurs with posterior uveitis. Untreated posterior uveitis may cause blindness. Behcß et’s disease is the second leading cause of blindness in Japan and is very common in other Asian and Mediterranean countries [8]. In Japan, ocular involvement occurs in 69% of patients with Behcßet’s disease [7,8].
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
521
Skin lesions Various skin lesions occur in 80% of cases [2]. Pustules and acneiform lesions are the most common. Variability is again a common finding with Behcßet’s disease, and other forms of vesicles, folliculitis, and pyoderma gangrenosum –type lesions have been reported [1– 3]. Particularly suggestive are erythema nodosum –like lesions and other slow-healing lesions that leave cicatrix formation. In about 40% of patients, inflammatory reactions to minor trauma occur (eg, needle punctures). This is known as pathergy and occurs in a relatively small percentage of the Behcßet’s population. Its presence, however, is a strong indicator of the disease. Associated symptoms Relatively mild, self-limiting, and nondestructive arthritis involving the knees and other large joints occurs in 50% of patients [2]. Recurrent superficial or deep migratory thrombophlebitis develops in 25% and may lead to obstruction of the vena cava [9]. The literature frequently makes the distinction between Behcßet’s syndrome and a neuro-Behcßet’s syndrome [10,11]. This again emphasizes the diffuse nature and complexity of the disease. Headaches are a frequent neurologic component of the disease, with the causative mechanism being attributed to the vasculitis. Involvement of the central nervous system (18%) may present as chronic meningoencephalitis, benign intracerebral hypertension, cerebral aneurysm [9,11], or life-threatening brain stem and spinal cord lesions [10]. Gastrointestinal manifestations vary from nonspecific abdominal discomfort to a syndrome resembling regional enteritis, such as Crohn’s disease or colitis [12]. A review of the literature revealed that the ulcerations have been reported throughout the gastrointestinal system, beginning with the oral ulcerations and progressing to the esophagus [2,6,12,13] and lower alimentary tract. Sporadic cases of ulcerations and stenosis in the pharynx have also been reported [6,13 – 15]. Inflammatory vasculitis may cause aneurysms or thrombosis and may also involve the kidneys with an asymptomatic focal glomerulonephritis. Some studies have indicated a close association of mitral valve prolapse and Behcßet’s disease, citing the vasculitis as the causative mechanism [3,4,16]. In rare cases, the lungs are involved, with vasculitis and aneurysms of the pulmonary arteries. Diagnosis Diagnosis is clinical and may require months. Differential diagnoses include Reiter’s syndrome, Stevens-Johnson syndrome, systemic lupus erythematous (SLE), regional enteritis (Crohn’s disease), ulcerative colitis, ankylosing spondylitis, and herpes simplex infection, especially with recurrent aseptic meningitis. Behcßet’s disease does not have any specific findings that exclude all alternative possibilities, but it is often distinguished by a relapsing course and multiple organ involvement. Laboratory abnormalities are nonspecific but characteristic of inflammatory disease (elevated ESR and mild leukocytosis).
522
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
In 1990 the International Study Group (ISG) [17] devised the following criteria for the diagnosis for Behcßet’s disease [2,17]. First, recurrent oral ulceration occurring at least three times in a 12-month period was the only requirement the group deemed essential. A patient must have two of the following: genital ulcerations, uveitis, or skin involvement. The urate crystal test has also been proposed as a more sensitive test than the pathergy test [2]. With injection of urate crystals under the skin, the person with Behcßet’s disease will have a more pronounced and, more specifically, a longer duration of inflammatory reaction than a person without [2] (Table 1). It must be mentioned that these criteria were originally set forth to have a means of standardization for inclusion in research studies of the disease. These criteria were not intended for use in the diagnosis and treatment of individual patients seen in the clinical setting. It was stressed that the disease is highly variable and the patient and each symptom should be treated on a clinical basis [17]. Some authors have also recommended that the disease be divided into two forms. The first to be termed Behcßet’s disease would include those of the genetic makeup from the original area of the old silk route. The second would be termed Behcß et’s syndrome. This classification would be reserved for patients of other ancestry presenting with compilations of symptoms that describe Behcßet’s disease. One larger study included 230 patients suspected of having Behcßet’s disease. Only 6% of the population set was of an ancestry from the old silk route and fell into the author-defined category of ‘‘definite.’’ The balance of the ‘‘definite’’ were native Caucasians of European descent. With a higher prevalence of the disease among people of these old silk route regions, a strong genetic basis for the disease was thought. This study, however, indicates that there may be alternate forms of the disease, supporting the need for a separation of the disease with a classification system to distinguish those who have a genetic predisposition for the disease from those who have acquired it by some other means [2]. There has been a recent association between the HLA-B51 allele and the presence and severity of the disease. It is generally believed to have a higher prevalence among persons with Behcßet’s, but there seems to be some disagreeTable 1 International Study Group criteria for Bechet’s syndrome Clinical presentation
Criteria
Recurrent oral ulcerations
Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient which recurred at least three times in one 12-mo period
Plus two of the following: Recurrent genital ulceration Eye lesions
Skin lesions
Aphthous ulceration or scarring observed by physician Anterior uveitis, posterior uveitis, or cells in vitreous on slit lam examination or retinal vasculitis observed by physician Erythema nodosum observed by physician or patient; pseudofolliculitis, papulopustular lesions, or acneiform nodules observed by physician
E.A. Barp et al / Clin Podiatr Med Surg 19 (2002) 519–525
523
ment on its association with the severity of the disease [18,19]. One study found an increase in the severity of the disease among those persons positive with the HLA-B51 allele. A later study, however, stated that the presence of the allele was not predictive for the severity of the disease, but rather that the age of onset and the male sex were stronger predictors of the severity of the disease. Prognosis and treatment The syndrome is generally chronic and manageable. Remission and relapse may last from weeks to years and even extend over several decades. Blindness, vena cava obstruction, and paralysis, however, may complicate the course; the occasional fatalities usually are associated with neurologic, vascular, and GI involvement. Symptomatic treatment is reasonably successful. Colchicine 0.5 mg twice a day or three times a day may decrease the frequency and severity of oral and genital ulcers. Needle punctures provoke inflammatory skin lesions and should be avoided when possible. Topical corticosteroids may temporarily relieve ocular and oral disease [8]. Topical or systemic corticosteroids, however, do not alter the frequency of relapses. Occasional patients with severe uveitis or CNS involvement respond to high-dose systemic corticosteroids (prednisone 60 to 80 mg/d). Patients with posterior uveitis who do not respond to prednisone should be treated initially with cyclosporine 5 mg/kg/d, increased incrementally if needed to 10 mg/kg/d until a therapeutic effect is observed; trough levels (lowest levels within therapeutic range) of cyclosporine should be maintained between 50 and 200 ng/mL (42 and 166 nmol/ L) [8]. Other reported but still incompletely evaluated therapies include thalidomide (in patients with no possibility for pregnancy) and pentoxifylline. Case report A 21-year-old male presented to Broadlawns Medical Center Emergency Department with an acutely inflamed and painful left ankle joint. He stated that these symptoms had been present for a couple of days without any relief. Past medical history was significant for Sutton’s disease, which is an autoimmune disease that manifests as recurrent oral ulcerations. He stated that his mother, who is from Japan, also suffers from Sutton’s disease. He also stated that he has a history of unusual skin lesions that spontaneously present and resolve, several of which had been excised. He reported that he had been hospitalized in the past for reasons unknown and had nasogastric tube placement. Review of systems was significant for photophobia, recent loss of consciousness, and watery stools for the last three days. He stated that the only medication that he takes is depakote for severe recurrent headaches. Physical examination revealed a lethargic male with a left ankle that was edematous and erythematous with an increase in calor. Range of motion in the sagittal plane elicited pain and was limited compared to that of the contralateral limb. Pustular lesions 2 mm in diameter were noted on the anterior left ankle. Upon
524
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further physical examination, the patient also complained about the bright lights in the emergency room and was wearing dark sunglasses. Ankle joint aspirate demonstrated no bacteria and rare neutrophils, indicating that an infectious process was not present. It was decided to admit the patient for further observation and empiric intravenous antibiotic therapy. The second hospital day the patient reported that he was feeling better. The left ankle was once again tapped, revealing no bacteria and mild neutrophilia. The anterior ankle joint developed several pustular lesions that broke open. Cultures from the pustular lesions demonstated many neutrophils and the presence of Staphylococcus aureus. On the third hospital day, it was decided to change the antibiotic from Zosyn to Clindamycin because of no resolution at the ankle joint. The patient has also developed acneform lesions on the anterior thighs, which remain the course of 24 hours and then resolve spontaneously. Upon consultation with internal medicine, a possible diagnosis of arachnid bite was made. The lesion, however, does not appear to fit with an insect bite. Reviewing literature, the patient was questioned about sexually transmitted diseases, and a search for the symptoms was made with an indication toward Crohn’s disease or inflammatory bowel disease with extragastrointestinal manifestations of the oral ulcerations and inflammatory arthritis. After reviewing symptoms expressed by the patient, a diagnosis of Behcßet’s disease was made. The patient fit most of the diagnostic criteria with the exception of the absence of genital ulcerations. It is important to note that the diagnosis for Behcßet’s disease should be based clinically and not solely on the ISG diagnostic criteria. The inflamed ankle joint resolved and the range of motion increased after the fourth day of intravenous antibiotics. Upon discharge, the patient was referred to a GI specialist for follow-up of the other symptoms.
Conclusion While Behcßet’s disease is an uncommon presentation to a podiatric clinical setting it is nonetheless a fascinating and poorly understood disease as demonstrated by the current and historical research available about the topic. Much debate remains about the disease cause, course and treatment goals, only through further research into the specific components of this multisystem disease will medicine be more fully able to address the needs of the patient. This discussion should offer the podiatric physician an overview of the disease as well as available treatment options. It is important for the podiatrist to not exclude the disease from a differential diagnosis in the presence of unusual skin lesions or an acute inflammatory arthritis presentation. The importance of this is emphasized by the isolated presentation of the symptoms, which delays diagnosis in many patients. This further emphasizes the need for a complete and detailed history and physical exam in the presence of the aforementioned symptomatology.
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