Dermatológica 150: 163-168 (1975)
Behcet’s Disease: Etiology and Treatment S. H aim Department of Dermatology, Rambam University Hospital and Aba Khoushi School of Medicine, Haifa
Key Words. Behçet's disease • Etiology • Treatment • Venous occlusion • Fibrinolytic activity Abstract. The etiology and treatment of Behçet’s diseases are still undecided. There are three principal etiological hypotheses: viral, autoimmune and defective fibrinolytic activity. Accordingly, antiviral, immunosuppressive and fibrinolytic enhancing agents have been tried. Corticosteroids, however, still constitute conventional therapy. Follow-up of cases has so far revealed that none of the above therapeutic measures fundamentally alters the course of the disease, and serious complications may occur and progress during their administration.
Received: December 12, 1974; accepted: January 8, 1975.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
In 1937, Behçf.t [I] described a chronic triple symptom complex of orogenital ulceration and ocular inflammation. It has now become apparent that the disorder is a systemic process of diverse symptomatology [2, 3]. In addition to the original triad, a variety of other manifestations may be en countered, including prominent skin lesions [4], arthritis [5], encephalopathy [6, 7], colitis [8], involvement of veins [9, 10] and arteries [11]. As the etiology and treatment of this disease remain speculative, we think it of interest to review the various etiological hypotheses and to discuss the different therapeutical measures tried to date. This review is partly based on our own experience with 36 cases of the malady. At present, there are three main etiological hypotheses designed to ex plain Behçet’s disease: viral, autoimmune and defective fibrinolytic activity. The viral etiology was supported by several authors. As early as 1945, A lm
H aim
and O berg [12] injected rabbits intrathecally with cerebrospinal fluid from patients with the disease and produced encephalitis, optic neuritis, uveitis, keratitis and conjunctivitis. In 1953, Sezer [13] reported the successful culture of a virus from the eye, blood and urine of a patient with Behcet’s disease. He was also able to produce encephalitis in mice by injecting this cultured virus intrathecally [14]. Moreover, he showed that intraocular in oculation of the virus in rabbits produced a disease similar to that seen in man. E vans et al. [15] were able to repeat Sezer’s work. Indirect support for a viral etiology was furnished by the finding of elevated neuraminic acid levels during exacerbations of the disease [16]. R ubinstein and U rich [17] dem onstrated histological changes in the brain similar to those found in other viral diseases. S ugiura et al. [18] studied serum levels of antibodies against various pathogenic agents, such as adenovirus, measles, EB virus, and Chlamydia, in patients with Behget’s disease. Significant levels of comple ment fixing antibody were found in 42.8% of 73 patients. This rate was higher than the 5.8% seen in age-matched control subjects. The investigators as sumed that Chlamydia may be associated etiologically or immunologically with the disease in some patients. Treatment administered in 10 of our 36 patients included serum taken and prepared from a patient during the florid stage of the disease, the antiviral agent (jV-methylisatin thiosemicarbazone; marboran, Burroughs Wellcome) as well as antibiotics. All were ineffective during the florid stage and did not alter the course of the disease. In 1966, we reported a favorable, although transient, response to fresh blood and plasma transfusions in six cases [19]. The most obvious was a case complicated by encephalomyelitis which caused persistent headache and hiccups, refractory to oral prednisone, analgesics and chlorpromazine. Transfusion of 500 ml fresh blood, however, was followed on two occasions by an immediate remission of all symptoms. In 1971, O 'D uffy et al. [20] reported, likewise, a case complicated by colitis in which immediate re mission of symptoms, lasting several months, followed blood transfusion. In a further case, a leukocyte transfusion brought a temporary suppression of aphthous ulcers which had been refractory to prednisone and infusion of plasma. The authors concluded that the useful component in the blood is unknown. It might be either an antibody that could neutralize an infectious agent or a cell-bound substance, such as transfer factor that could stimulate the patient’s lymphocytes to attack a foreign substance. They thought that a study both of the role of virus infection and of the components of blood, which were helpful in these cases, might establish the site of action of an active therapeutic agent.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
164
165
In 1963, O shima et al. [21] demonstrated circulating antibodies against oral mucosa in 17 of 40 patients with Behçet’s disease. They also found elevated serum y-globulin and mucoprotein levels during the active stage of the disorder. Therefore, autoimmune or hyperimmune etiology was suggested. Lehner [22-24] confirmed these findings, but he pointed out that the anti bodies were not only in cases of Behçet’s disease but also in those with recurrent aphthous ulceration, and that there was a poor correlation between the antibody titer and the activity of the disease. In both processes he found a slight rise in serum IgA levels, but the salivary IgA concentration was raised only in cases with Behçet’s disease. Using the indirect immuno fluorescence technique, O ’D uffy et at. [20] demonstrated anticytoplasmic antibodies in the serum of all five patients with the disease so tested. 20 normal control sera lacked these antibodies. There was no relationship between the intensity of staining and the activity of the disorder, and the authors attributed no etiological importance to this finding. On the assumption that the etiology could be autoimmune, immuno suppressive agents were tried in this disease, and the more recent literature reveals some encouraging reports on their effect on the activity of the disease [25, 26]. However, not all relevant reports are favorable [27], and according to M amo and A zzam [25] aphthous ulceration has persisted despite chlor ambucil in a daily dose of 0.1-0.2 mg/kg body weight. While the association between Behçet’s disease and venous thrombosis is clear [28], the pathogenesis of the thrombotic process is not fully elucidated. Stasis does not appear to be a relevant factor [29], whereas changes in the vascular endothelium were clearly demonstrated histologically [24, 30]. The question remains if there are additional factors which may predispose the thrombotic diathesis. To date, no satisfactory evidence of a hypercoagulable state was demonstrated, and anticoagulants are of no value in these cases. Hyperfibrinogenemia is a frequent finding in most patients with Behçet’s disease, especially during the active phase. Elevation of fibrinogen levels is, however, commonly seen in many inflammatory diseases in which there is no tendency to thrombosis. C unliffe [31] was the first to report impaired systemic and local fibrinolysis in patients with cutaneous vasculitis, and these patients improved clinically when treated with the fibrinolytic en hancing agents, phenformin and ethylestrenol. C unliffe and M enon [32] used these successfully in a case of Behçet’s disease with anticoagulant resistant thrombosis and pulmonary emboli. Although the patient had no demonstrable impairment of his fibrinolytic activity, he developed no further thrombotic episodes while on fibrinolytic enhancement therapy. K irk and
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
Behçet’s Disease: Etiology and Treatment
166
H aim
H andley [33] reported similar results in three cases with Behçet's disease. In 1973, C hajek and F ainaru [34] described two cases complicated by thrombosis of the superior vena cava, in which defective fibrinolysis was observed as evaluated by the euglobulin lysis time (ELT). Subsequently we studied eleven patients with active Behçet’s disease [35]. The results revealed no clear correlation between the ELT and the occurrence of thrombosis. The problem is further complicated by the observation by Steel et al. [36] of shortened platelet survival in patients with idiopathic, recurrent, anti coagulant resistant venous thrombosis. As yet, no comprehensive studies are available on platelet survival in Behçet’s disease. Therefore, we may conclude that, although there is no clear evidence of impaired systemic fibrinolysis in this disorder, a deficiency of a venous endothelial tissue fibrinolysis activator may exist, and that fibrinolytic enhancement therapy may be of value of in managing this complication. The above therapeutic trials have not altered the fact that corticosteroids, both topical and systemic, are still the treatment of choice in Behçet’s disease. According to K atzenellenbogen [37], these agents have changed the prognosis of the disease, and none of his patients treated with corticosteroids has lost his sight. This experience, however, has not been mirrored in our cases. The recurrent course of the disorder does not seem to be affected fundamentally by any kind of therapy tried so far. Corticosteroids and other modalities of treatment may suppress many of the inflammatory features of the malady, and may shorten the duration of its exacerbation. They do not seem, however, to prevent progression of uveitis, and serious complications of the disease may begin and progress during their administration.
1 B e h c e t , II.: Über rezidivierende, aphthöse, durch einen Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Derm. Wschr. 105: 1152-1157 (1937). 2 Berlin , C.: Behcet’s disease as a multiple symptom complex: Report of ten cases. Archs Derm. 82: 73-79 (I960). 3 H aim, S.: Behcet's syndrome as a generalized systemic disease. Harefuah 78: 63-65 (1970). 4 N azaro, P .: Cutaneous manifestations of Behcet’s disease. Symposium on Behcet’s disease, pp. 15-41 (Karger, Basel 1966). 5 Strachan , R.W. and W igzell, F.W .: Polyarthritis in Behcet's multiple symptom complex. Ann. rheum. Dis. 22: 26-36 (1967). 6 W olf, S.W .; S chotland , D.L., and P hillips, L.L.: Involvement of nervous system in Behcet’s syndrome. Archs Neurol., Chicago 12: 315-325 (1965).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
References
Behçet’s Disease: Etiology and Treatment
167
8 Boe, J.; Dolgaard, J.B., and Scott, D.: Mucocutaneous ocular syndrome with in testinal involvement. A clinical and pathological study of four fatal cases. Am. J. Med. 25: 857-867 (1958). 9 H aim, S.; Barzilai, D., and H azani, E.: Involvement of veins in Behçet’s syndrome. Br. J. Derm. 84: 238-241 (1971). 10 C arr, G.R.: Cellulitis and thrombophlebitis in Behçet's syndrome. Lancet //: 358-359 (1957). 11 E noch , B.A.: Gangrene in Behçet’s syndrome. Br. med. J. ii: 54-55 (1969). 12 A lm, L.andOBERG,L.: Djugorsok VidS.R. Behçet’s syndrome. Nord. Med. 25: 603-604 (1945). 13 S ezer, N.: Isolation of virus as a cause of Behçet's disease. Am. J. Ophthal. 36: 301-315 (1953). 14 S ezer, N.: Further investigations on the virus of Behçet’s disease. Am. J. Ophthal. 41: 41-55 (1956). 15 E vans, H.D.; P alus , G.A., and S pillane, J.D.: Involvement of nervous system in Behçet’s syndrome. Report of three cases and isolation of virus. Lancet ii: 349-353 (1959). 16 S himuzu , T.; K agami, T.; M atsumata, T., and M atsumuria, M.: Clinical studies on Behçet’s syndrome. Analysis of epidemiology and attacks predisposing factors. Medicine, Niaka 12: 526-534 (1963). 17 R ubenstein, L.J. and U rich , H. : Meningoencephalitis of Behçet’s disease. Case report with pathological findings. Brain 86: 151-160 (1963). 18 S ugiura , S.; A oki, K.; F ujioka, K., and K ono, M.: Serum antibodies to various pathogenic agents and lymphocytic transformation in Behçet’s disease. Acta Soc. ophthal. jap. 76: 635-641 (1972). 19 H aim, S. and S herf, K.: Behçet’s disease. Presentation of 11 cases and evaluation of treatment. Israel J. med. Scis 2 : 69-74 (1966). 20 O 'D uffy, J.D.; C arney, J.A., and D eodhar, S.: Behçet’s disease. Report of 10 cases, 3 with new manifestations. Ann. intern. Med. 75: 561-570 (1971). 21 O shima, Y.; S himizu , T.; Y okohari, R.; M atsumato, T.; K ano, K.; K agami, T.; N agaya, H., and M arugama, R.: Clinical study on Behçet’s syndrome. Ann. rheum. Dis. 22: 36-45 (1963). 22 L ehner, T. : Characterization of mucosal antibodies in recurrent aphthous ulceration and Behçet’s syndrome. Archs oral Biol. 14: 843-853 (1969). 23 L ehner, T. : Behçet’s syndrome and autoimmunity. Br. med. J. i: 465-467 (1967). 24 L ehner, T. : Immunological aspects of recurrent oral ulcers. Oral Surg. 33: 80-85 (1972). 25 M amo, J.G. and A zzam , S.A.: Treatment of Behçet's disease with chlorambucil. Archs Ophthal., N.Y. 84: 446-450 (1970). 26 R osselet, E.; Saundan, Y. et Z enklusen, G.: Les effects de l’azothioprine (Imuran) dans la maladie de Behçet’s. Premiers résultats thérapeutiques. Ophthalmologica, Basel 156: 218-226 (1968). 27 W ong , V.G.: Immunosuppressive therapy of ocular inflammatory diseases. Archs Ophthal., (N.Y.) 81: 628-637 (1969).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
7 Strouth , J.C. and D yken, M.: Encephalopathy of Behçet’s disease. Report of a case. Neurology, Minneap. 14: 794-805 (1964).
168
H aim
S. H aim, MD, Head, Department of Dermatology, Ministry of Health, Rambam Uni versity Hospital, Aba Khousky School of Medicine, Haifa (Israel)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
28 H aim, S.: Contribution of ocular symptoms in the diagnosis of Behcet’s disease. Study of 23 cases. Archs Derm. 98: 478-480 (1968). 29 K ansu, E.; O zkr, F.L.; A kalin, F.; G ules, Y.; Sileli, T.; T anman, F.; K aplaman, E., and M uftuogla, E .: Behcet's syndrome with obstruction of venae cavae. Q. Jl. Med. 41: 151-168 (1972). 30 F rance, R.; Buchanan , R.M.; W ilson, M.W., and S heldon, M.B.: Relapsing iritis with recurrent ulcers of mouth and genitalia (Behcet’s syndrome). Review of literature with report of additional case. Medicine, Baltimore 30: 335-355 (1951). 31 C unliffe, W.J.: An association between cutaneous vasculitis and decreased blood fibrinolytic activity. Lancet i: 1226-1228 (1968). 32 C unliffe, W.J. and M f.non , I.S.: Treatment of Behcet's syndrome with phenformin and ethyloestrenol. Lancet /: 1239-1240 (1969). 33 K irk , J. and H andley, A.D.: Experience in the use of fibrinolytic agents in Behcet’s syndrome. Aust. J. Derm. 13: 5-10 (1972). 34 C hajek, T. and F ainaru , M.: Behcet's disease with decreased fibrinolysis and superior vena caval occlusion. Br. mcd. J. i: 782-783 (1973). 35 H aim, S.; Sobel, J.D., and F reidman-B irnbaum, R.: Thrombophlebitis. A cardinal symptom of Behcet’s syndrome. Acta derm.-vener., Stockh. 54: 299-301 (1974). 36 Steel, P.P.; W eily, H.S., and G anton, B.: Platelet survival and adhesiveness in recurrent venous thrombosis. New Engl. J. Med. 288: 1148-1152 (1973). 37 K atzenellenbogen, I.: Survey of 22 cases of Behcet’s disease; in the significance of a specific skin hyperactivity. 13th Int. Congr. Dermatol., Miinchen 1967, pp. 321-324 (Springer, Berlin 1968).
Behcet’s Disease: Etiology and Treatment S. H aim Department of Dermatology, Rambam University Hospital and Aba Khoushi School of Medicine, Haifa
Key Words. Behçet's disease • Etiology • Treatment • Venous occlusion • Fibrinolytic activity Abstract. The etiology and treatment of Behçet’s diseases are still undecided. There are three principal etiological hypotheses: viral, autoimmune and defective fibrinolytic activity. Accordingly, antiviral, immunosuppressive and fibrinolytic enhancing agents have been tried. Corticosteroids, however, still constitute conventional therapy. Follow-up of cases has so far revealed that none of the above therapeutic measures fundamentally alters the course of the disease, and serious complications may occur and progress during their administration.
Received: December 12, 1974; accepted: January 8, 1975.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
In 1937, Behçf.t [I] described a chronic triple symptom complex of orogenital ulceration and ocular inflammation. It has now become apparent that the disorder is a systemic process of diverse symptomatology [2, 3]. In addition to the original triad, a variety of other manifestations may be en countered, including prominent skin lesions [4], arthritis [5], encephalopathy [6, 7], colitis [8], involvement of veins [9, 10] and arteries [11]. As the etiology and treatment of this disease remain speculative, we think it of interest to review the various etiological hypotheses and to discuss the different therapeutical measures tried to date. This review is partly based on our own experience with 36 cases of the malady. At present, there are three main etiological hypotheses designed to ex plain Behçet’s disease: viral, autoimmune and defective fibrinolytic activity. The viral etiology was supported by several authors. As early as 1945, A lm
H aim
and O berg [12] injected rabbits intrathecally with cerebrospinal fluid from patients with the disease and produced encephalitis, optic neuritis, uveitis, keratitis and conjunctivitis. In 1953, Sezer [13] reported the successful culture of a virus from the eye, blood and urine of a patient with Behcet’s disease. He was also able to produce encephalitis in mice by injecting this cultured virus intrathecally [14]. Moreover, he showed that intraocular in oculation of the virus in rabbits produced a disease similar to that seen in man. E vans et al. [15] were able to repeat Sezer’s work. Indirect support for a viral etiology was furnished by the finding of elevated neuraminic acid levels during exacerbations of the disease [16]. R ubinstein and U rich [17] dem onstrated histological changes in the brain similar to those found in other viral diseases. S ugiura et al. [18] studied serum levels of antibodies against various pathogenic agents, such as adenovirus, measles, EB virus, and Chlamydia, in patients with Behget’s disease. Significant levels of comple ment fixing antibody were found in 42.8% of 73 patients. This rate was higher than the 5.8% seen in age-matched control subjects. The investigators as sumed that Chlamydia may be associated etiologically or immunologically with the disease in some patients. Treatment administered in 10 of our 36 patients included serum taken and prepared from a patient during the florid stage of the disease, the antiviral agent (jV-methylisatin thiosemicarbazone; marboran, Burroughs Wellcome) as well as antibiotics. All were ineffective during the florid stage and did not alter the course of the disease. In 1966, we reported a favorable, although transient, response to fresh blood and plasma transfusions in six cases [19]. The most obvious was a case complicated by encephalomyelitis which caused persistent headache and hiccups, refractory to oral prednisone, analgesics and chlorpromazine. Transfusion of 500 ml fresh blood, however, was followed on two occasions by an immediate remission of all symptoms. In 1971, O 'D uffy et al. [20] reported, likewise, a case complicated by colitis in which immediate re mission of symptoms, lasting several months, followed blood transfusion. In a further case, a leukocyte transfusion brought a temporary suppression of aphthous ulcers which had been refractory to prednisone and infusion of plasma. The authors concluded that the useful component in the blood is unknown. It might be either an antibody that could neutralize an infectious agent or a cell-bound substance, such as transfer factor that could stimulate the patient’s lymphocytes to attack a foreign substance. They thought that a study both of the role of virus infection and of the components of blood, which were helpful in these cases, might establish the site of action of an active therapeutic agent.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
164
165
In 1963, O shima et al. [21] demonstrated circulating antibodies against oral mucosa in 17 of 40 patients with Behçet’s disease. They also found elevated serum y-globulin and mucoprotein levels during the active stage of the disorder. Therefore, autoimmune or hyperimmune etiology was suggested. Lehner [22-24] confirmed these findings, but he pointed out that the anti bodies were not only in cases of Behçet’s disease but also in those with recurrent aphthous ulceration, and that there was a poor correlation between the antibody titer and the activity of the disease. In both processes he found a slight rise in serum IgA levels, but the salivary IgA concentration was raised only in cases with Behçet’s disease. Using the indirect immuno fluorescence technique, O ’D uffy et at. [20] demonstrated anticytoplasmic antibodies in the serum of all five patients with the disease so tested. 20 normal control sera lacked these antibodies. There was no relationship between the intensity of staining and the activity of the disorder, and the authors attributed no etiological importance to this finding. On the assumption that the etiology could be autoimmune, immuno suppressive agents were tried in this disease, and the more recent literature reveals some encouraging reports on their effect on the activity of the disease [25, 26]. However, not all relevant reports are favorable [27], and according to M amo and A zzam [25] aphthous ulceration has persisted despite chlor ambucil in a daily dose of 0.1-0.2 mg/kg body weight. While the association between Behçet’s disease and venous thrombosis is clear [28], the pathogenesis of the thrombotic process is not fully elucidated. Stasis does not appear to be a relevant factor [29], whereas changes in the vascular endothelium were clearly demonstrated histologically [24, 30]. The question remains if there are additional factors which may predispose the thrombotic diathesis. To date, no satisfactory evidence of a hypercoagulable state was demonstrated, and anticoagulants are of no value in these cases. Hyperfibrinogenemia is a frequent finding in most patients with Behçet’s disease, especially during the active phase. Elevation of fibrinogen levels is, however, commonly seen in many inflammatory diseases in which there is no tendency to thrombosis. C unliffe [31] was the first to report impaired systemic and local fibrinolysis in patients with cutaneous vasculitis, and these patients improved clinically when treated with the fibrinolytic en hancing agents, phenformin and ethylestrenol. C unliffe and M enon [32] used these successfully in a case of Behçet’s disease with anticoagulant resistant thrombosis and pulmonary emboli. Although the patient had no demonstrable impairment of his fibrinolytic activity, he developed no further thrombotic episodes while on fibrinolytic enhancement therapy. K irk and
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
Behçet’s Disease: Etiology and Treatment
166
H aim
H andley [33] reported similar results in three cases with Behçet's disease. In 1973, C hajek and F ainaru [34] described two cases complicated by thrombosis of the superior vena cava, in which defective fibrinolysis was observed as evaluated by the euglobulin lysis time (ELT). Subsequently we studied eleven patients with active Behçet’s disease [35]. The results revealed no clear correlation between the ELT and the occurrence of thrombosis. The problem is further complicated by the observation by Steel et al. [36] of shortened platelet survival in patients with idiopathic, recurrent, anti coagulant resistant venous thrombosis. As yet, no comprehensive studies are available on platelet survival in Behçet’s disease. Therefore, we may conclude that, although there is no clear evidence of impaired systemic fibrinolysis in this disorder, a deficiency of a venous endothelial tissue fibrinolysis activator may exist, and that fibrinolytic enhancement therapy may be of value of in managing this complication. The above therapeutic trials have not altered the fact that corticosteroids, both topical and systemic, are still the treatment of choice in Behçet’s disease. According to K atzenellenbogen [37], these agents have changed the prognosis of the disease, and none of his patients treated with corticosteroids has lost his sight. This experience, however, has not been mirrored in our cases. The recurrent course of the disorder does not seem to be affected fundamentally by any kind of therapy tried so far. Corticosteroids and other modalities of treatment may suppress many of the inflammatory features of the malady, and may shorten the duration of its exacerbation. They do not seem, however, to prevent progression of uveitis, and serious complications of the disease may begin and progress during their administration.
1 B e h c e t , II.: Über rezidivierende, aphthöse, durch einen Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Derm. Wschr. 105: 1152-1157 (1937). 2 Berlin , C.: Behcet’s disease as a multiple symptom complex: Report of ten cases. Archs Derm. 82: 73-79 (I960). 3 H aim, S.: Behcet's syndrome as a generalized systemic disease. Harefuah 78: 63-65 (1970). 4 N azaro, P .: Cutaneous manifestations of Behcet’s disease. Symposium on Behcet’s disease, pp. 15-41 (Karger, Basel 1966). 5 Strachan , R.W. and W igzell, F.W .: Polyarthritis in Behcet's multiple symptom complex. Ann. rheum. Dis. 22: 26-36 (1967). 6 W olf, S.W .; S chotland , D.L., and P hillips, L.L.: Involvement of nervous system in Behcet’s syndrome. Archs Neurol., Chicago 12: 315-325 (1965).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
References
Behçet’s Disease: Etiology and Treatment
167
8 Boe, J.; Dolgaard, J.B., and Scott, D.: Mucocutaneous ocular syndrome with in testinal involvement. A clinical and pathological study of four fatal cases. Am. J. Med. 25: 857-867 (1958). 9 H aim, S.; Barzilai, D., and H azani, E.: Involvement of veins in Behçet’s syndrome. Br. J. Derm. 84: 238-241 (1971). 10 C arr, G.R.: Cellulitis and thrombophlebitis in Behçet's syndrome. Lancet //: 358-359 (1957). 11 E noch , B.A.: Gangrene in Behçet’s syndrome. Br. med. J. ii: 54-55 (1969). 12 A lm, L.andOBERG,L.: Djugorsok VidS.R. Behçet’s syndrome. Nord. Med. 25: 603-604 (1945). 13 S ezer, N.: Isolation of virus as a cause of Behçet's disease. Am. J. Ophthal. 36: 301-315 (1953). 14 S ezer, N.: Further investigations on the virus of Behçet’s disease. Am. J. Ophthal. 41: 41-55 (1956). 15 E vans, H.D.; P alus , G.A., and S pillane, J.D.: Involvement of nervous system in Behçet’s syndrome. Report of three cases and isolation of virus. Lancet ii: 349-353 (1959). 16 S himuzu , T.; K agami, T.; M atsumata, T., and M atsumuria, M.: Clinical studies on Behçet’s syndrome. Analysis of epidemiology and attacks predisposing factors. Medicine, Niaka 12: 526-534 (1963). 17 R ubenstein, L.J. and U rich , H. : Meningoencephalitis of Behçet’s disease. Case report with pathological findings. Brain 86: 151-160 (1963). 18 S ugiura , S.; A oki, K.; F ujioka, K., and K ono, M.: Serum antibodies to various pathogenic agents and lymphocytic transformation in Behçet’s disease. Acta Soc. ophthal. jap. 76: 635-641 (1972). 19 H aim, S. and S herf, K.: Behçet’s disease. Presentation of 11 cases and evaluation of treatment. Israel J. med. Scis 2 : 69-74 (1966). 20 O 'D uffy, J.D.; C arney, J.A., and D eodhar, S.: Behçet’s disease. Report of 10 cases, 3 with new manifestations. Ann. intern. Med. 75: 561-570 (1971). 21 O shima, Y.; S himizu , T.; Y okohari, R.; M atsumato, T.; K ano, K.; K agami, T.; N agaya, H., and M arugama, R.: Clinical study on Behçet’s syndrome. Ann. rheum. Dis. 22: 36-45 (1963). 22 L ehner, T. : Characterization of mucosal antibodies in recurrent aphthous ulceration and Behçet’s syndrome. Archs oral Biol. 14: 843-853 (1969). 23 L ehner, T. : Behçet’s syndrome and autoimmunity. Br. med. J. i: 465-467 (1967). 24 L ehner, T. : Immunological aspects of recurrent oral ulcers. Oral Surg. 33: 80-85 (1972). 25 M amo, J.G. and A zzam , S.A.: Treatment of Behçet's disease with chlorambucil. Archs Ophthal., N.Y. 84: 446-450 (1970). 26 R osselet, E.; Saundan, Y. et Z enklusen, G.: Les effects de l’azothioprine (Imuran) dans la maladie de Behçet’s. Premiers résultats thérapeutiques. Ophthalmologica, Basel 156: 218-226 (1968). 27 W ong , V.G.: Immunosuppressive therapy of ocular inflammatory diseases. Archs Ophthal., (N.Y.) 81: 628-637 (1969).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 12:33:44 AM
7 Strouth , J.C. and D yken, M.: Encephalopathy of Behçet’s disease. Report of a case. Neurology, Minneap. 14: 794-805 (1964).
168
H aim
S. H aim, MD, Head, Department of Dermatology, Ministry of Health, Rambam Uni versity Hospital, Aba Khousky School of Medicine, Haifa (Israel)
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