Journal of the American Academy of Dermatology
Phillips et af.
ment of human cultured epithelial allografts by recipient cellsas evidenced by HLA class 1 antigen expression. Derrnatologica 1987;175:166-70. 48. Aubock J, Irschick E, Romani N, et a!' Rejection, after a slightly prolonged survival time, of Langerhans cell-free allogeneicculturedepidermis used for wound coveragein humans. Transplantation 1988;45:730-7. 49. Burt AM, PallettCD,Sloane JP, et a!' Survivalof cultured
allograftsin patientswith burns assessed with probespecific for Y chromosome. Br Med J 1989;298:915-7. 50. Knowlton RG, BrownVA, Braman JC, et a!. Use of highly polymorphicDNA probes for genotypicanalysis following bone marrow transplantation. Blood 1986;68:378-85. 51. Yam P, Petz LD, Ali S, ct al. Development of a singleprobe for documentation of chimerism following bone marrow transplantation. Am J Hum Genet 1987;41:867-81.
Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis Ichiro Katayama, MD, PhD, Kazunobu Otoyama, MD, Shigeo Kondo, MD, Kiyoshi Nishioka, MD, PhD, and Shigeo Nishiyama, MD, PhD Kanagawa, Japan Anticardiolipin antibody-positive patients withprogressive systemic sclerosis wereanalyzed. Elevated anticardiolipin antibody titers were observed in 13 of 40 cases (33%). Anticardiolipin antibody titerwassignificantly higher inpatients withprogressive systemic sclerosis type 1thanin those with type2or type 3.Occurrence ofanticardiolipin antibody wassignificantly more frequent in patients positive for anti-nRNP antilxx:lies, rheumatoid factor, or thrombocytopenia. In contrast, patients with proximal scleroderma, scarring, or esophageal hypomotility were positive foranticardiolipin antilxx:ly less frequently. These results suggest that anticardiolipin antibody might beclosely associated withlupuslike clinical manifestations in a subset of progressive systemic sclerosis or definite progressive systemic sclerosis with thrombocytopenia, rheumatoid factor, or anti-nRNP antilxx:lies. (J AM ACAD DERMATOL 1990;23:198-201.) Recent reports suggest that antiphospholipid antibodies, especially anticardiolipin antibody (ACL) play an important rolein the developmentof thrombotic lesions or of occlusive vascular lesions in systemic lupus erythematosus (SLE).1,2 The presence of antibodies also correlates with thrombocytopenia, a positive biologic false-positive test result for syphilis, or lupus anticoagulant activity.l? Malia et a1. 6 demonstrated that ACL titers are high in advanced progressive systemic sclerosis (PSS) and From theDepartment ofDermatology, Kitasato University School of Medicine. Accepted for publication Oct. 29, 1989. Reprint requests: Ichiro Katayama, MD, PhD, Department ofDermatology, Kitasato University School ofMedicine, 1-15-1. Kitasato Sagamihara, Kanagawa, Japan. ]6/]/]7819
198
show a good correlation with plasma factor VIIIrelated antigen or C1q level,which might reflect the involvement of vascular injury in tissue fibrosis in PSS. In this report we describe the clinical features of ACL-positive patients with PSS and their clinical significance in the management of PSS. PATIENTS AND METHODS
Forty patients (5 men, 35 women) who were studied between 1973 and 1988 were enrolled in thisstudy. Each met the diagnostic criteria for scleroderma proposed by American Rheumatism Association? and wereclassified into three clinical groups as proposed by Barnett et al} that is, Raynaud's phenomenon and sclerodactyly only (type 1), acrosclerosis (type 2), systemic scleroderma with diffuse skin change(type 3). American Rheumatism Association criteria for SLE9 and diagnostic criteria for mixed connective tissue disease proposed by Sharp'? were
Volume 23 Number 2, Part 1 August 1990
Anticardiolipin antibodies in PSS 199
"I
•
I •
20
...J
U 00;
• 10
•
I
.
• _.. -w ..
-
• -..-·
N
_
I
•• · _
-1-
•
.
..
n
m
- -- - -- ----_ _ - ..
..
( n=13)
Fig. 1. Distribution of ACL titer among threedifferent subgroups ofPSS. (Control vstype I,p > 0.05;control vstype H,p = 0.01; control vstype IH,p:::: 0.05; control vstotalpatients, p = 0,01.)
used.In addition, mixedconnective tissue disease wasexcluded when sclerotic change suggesting PSS wasdemonstrated histopathologically. Although some patients had thrombocytopenia, leukocytopenia, or an elevated anti-DNA titer, theydid not fulfill the diagnostic criteria for SLE nor did they have any cutaneous lesions or histopathologic findings to suggest SLE. Venous blood was obtained at the first visitand stored at -20 0 C. Control bloodsamples wereobtained from 45 healthy volunteers between the agesof 10 and 65years. ACL titerwasmeasured by enzyme-linked immunosorbent assay.'! The assay wasperformed in triplicate and referredto 10 normal standard seraas controls ineachassay. Normalvalue was calculated as mean ± 2 SD « 4 U) of 45 normal volunteers. RESULTS
Anticardiolipin antibody in progressive systemic sclerosis. The patients were subdivided into three groups according to the classification proposed by Barnett.! that is, PSS type I (n = 10), type 2 (N = 13), and type 3 (n =: 17). As shown in Fig. 1, 60% of patients with PSS type 1 had ACL and a lower incidenceof positive ACL was observed in patients with type 2 (30%) and type 3 (24%). However, a high titer of ACL (>8 U) was demonstrated in three cases of type 3 patients. No patient with type 2 had a high titer of ACL. Although immunoglob-
ulin isotype-specific ACL was not analyzed, the resultscorrelatedwith IgG class-specific ACL, which may reflectthat the major activity ofACL is derived from IgG (data not shown). Relationship of clinical manifestations and anticardiolipin antibody. The relationship between frequency of ACL and each clinical manifestation of PSS was analyzed. Althoughit was not statistically significant, ACL occurredless frequently in patients with proximalscleroderma, scarring, or esophageal hypomotility (TableI). In contrast, the patientswith proteinuriahad a high incidence of positive ACL titers. Patients with cutaneous ulcer or livedo reticularis did not have a high incidence of positive ACL titers.Thisfinding contradicts previous observations in anticardiolipin syndrome'? and might be attributable to the involvement of a different pathogenic mechanism in the development ofvascular lesions in PSS.13 Relationship between laboratory findings and ACL. ACL occurred in a higher incidence in patients positive for rheumatoid factor, anti-nRNP antibody, or thrombocytopenia (p < 0.05). Patients positive for anti-Scl-70 or anticentromere antibody had lower occurrence of ACL, althoughit was not statistically significant. In contrast, positive ACL correlated with the presence of leukocytopenia and
Journal of the American Academy of Dermatology
200 Katayama et al. Table I. Clinical manifestations in ACL-positive patients with PSS
Table II. Laboratory findings in ACL-positive patients with PSS % positive for ACL (n)
% positive for ACL (n)
+
Clinical manifestation
Proximal scleroderma Sclerodactyly Pitting scar Lung fibrosis Esophageal hypomotility Proteinuria Cutaneous ulcer or gangrene Livedo
28 33 33 31 28 55 25
Laboratory findings
(29) (39) (12) (16) (18) (11) (12)
50 (10) o (1) 50 (12) 33 (24) 55 (11) 24 (29) 37 (28)
27 (15)
36 (25)
a positive titer for anti-double-stranded DNA. Biologic false-positive syphilis test results was demonstrated in only two patients in this study, and both of them were negative for ACL (Table II). mSCUSSION Antiphospholipid antibodies including ACL, lupus anticoagulant, or anti-VDRL antibodies' have been demonstrated in close association with recurrent abortions, thrombotic lesions, or central nervous system disorders, especially in patients with SLE. 1,2 Other than SLE, ACL has been demonstrated in patients with cutaneous ulcers," severe livedo.P or occlusive vascular disorders such as cutaneous polyarteritis nodosa or Takayasu's arteritis." This situation has been termed anticardiolipin syndrome.F In PSS, microvascular injury has been thought to be one of the important events in the induction of fibrosis and subsequent progression of the disease. 17,18 Cutaneous ulcers or necrosis, telangiectasia, and Raynaud's phenomenon are regarded as clinical manifestations of vascular injury. Kahaleh et al. 13 reported the serum-derived factor that induced endothelial cell injury. Marks et al.'? also reported a similar factor. A factor reported by Kobayashi et al.'? had the capacity to suppress the growth of endothelial cells derived from guinea pig aorta. Malia et al.6 reported that, other than these cytotoxic or cytostatic factors, plasma factor VIIIrelated antigens are elevated in scleroderma and correlated with ACL titer. They raised the possibility that ACL might play some role in the development of vascular injury in scleroderma. In our patients we could not find any relationship between ACL titer and vascular lesions. This discrepancy may be attributable to the involvement of different
ANA Rheumatoid factor" Anti-RNP* Anti-Sm Anti-Scl-70
Anticentromere Anti-dsDNA Lupus erythematosus cell Indirect Coombs' Leukocytopenia Anemia Thrombocytopenia* BFP for syphilis
+ 32 (34) 44 (23) 50 (14) 100 (1) 17 (6) 0(4) 60 (5) 44 (9) 57 (7) 42 (14) 36 (11) 71 (7) 0(2)
33 (6) 13 (15) 15 (20) 33 (30) 31 (13) 33 (15) 32 (28) 29 (14) 50 (4) 27 (26) 31 (29) 24 (33) 34 (38)
BFP, Biologic false-positive test result. *p == 0.05.
pathogenic mechanisms, the assay methods, or racial differences. In our experience, occurrence of antiphospholipid antibody is variable among patients with SLE, that is, some patients are positive for ACL and lupus anticoagulant, and have a biologic false-positive result for syphilis whereas others show various combinations of these antibodies. Therefore we think that the epitope recognized by anti phospholipid antibody might be heterogenous so that different clinical manifestations are observed in these patients. Plasma platelet-derived factors such as factor IV, ,B-thromboglobulin, are elevated in pSS20,21 and platelet-derived growth factor has been reported to have a fibroblast growth activity in PSS.22 These results indicate that ACL might have the ability to modulate the platelet function that results in tissue fibrosis or vascular injury. Lynch and How23 reported that ACL-positive serum from the patients with SLE binds to the membranous fraction of platelets. Our preliminary data demonstrate that ACL-positive serum from patients with SLE or PSS bound the lipid fraction of platelets (unpublished observations). Clinically, ACL titer correlated with the degree of thrombocytopenia and proteinuria and responded to corticosteroid therapy in one case. This finding raises the possibility that ACL might be another marker for certain clinical manifestations in scleroderma, although controversial results have been reported in SLE.24 ACL-positive patients with scleroderma might constitute one subset of PSS in which distinct clinical features develop.
Volume 23 Number 2, Part I August 1990 REFERENCES I. Boey ML, Colaco GB, Gharavi AE, et al. Thrombosis in systemiclupuserythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med 1 1983;287:1021-3. 2. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J AM ACAD DERMATOL 1986;15:211-9. 3. Koike T, Sueishi H, Tomioka H, et al. Anti-phospholipid antibodies and biological false positive serological test for syphilisin patientswithsystemiclupuserythematosus. Clin Exp Immunol 191\4;56:193-9. 4. Harris EN, Loizou S, Englert H. Anticardiolipin antibodies and lupus anti-coagulant [Letter}. Lancet 1984; 2:1099. 5. Harris EN, Gharavi AE, Hedge Y, et al. Anticardiolipin antibodiesin autoimmunethrombocytopenic purpura. Br J Hematol 1985;59:231-4. 6. Malia RG, Greaves M, Rowlands AC, et al. AnticardioIipin antibodies in systemic sclerosis: immunological and clinical associations. Clin Exp Immunol 1988;73:456-60. 7. SubcommitteeforSclerodermaCriteriaofAmericanRheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90. 8. Barnett Al, Miller MH, LittlejohnGO. A survival studyof patients with scleroderma diagnosed over 30 years (19531983): the value of a simplecutaneous classification in the early stages of the disease. J Rheumatol 1988;15:276-83. 9. Tan FM, CohenAS, Fries JF, et al. The 1982revised classification of SLE. Arthritis Rheum 1982;25:1271-7. 10. Sharp GC. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibody. Amsterdam: Excerpta Medica, 1987:23-32. 11. Loizou 8, McCrea JD, Rudge AC, et al. Measurementof anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp ImmunoI1985;62:738-45.
Anticardiolipin antibodies in PSS 201 12. SontheimerRD. The anticardiolipin syndrome. Arch Dermatol 1987;123:590-5. 13. Kahaleh MB, Sherer OK, LeRoyEC, Endothelial cell injury in scleroderma. J Exp Med 1979;149:1326·35. 14. Dodd HJ, SarkanyI, O'Shaughnessy D. Widespread cutaneousnecrosis associated withthelupusanticoagulant. Clin Exp DermatoI1985;IO:581-6. 15. Weinstein C, MillerMH, Axtens R. Livedoreticularis associated withincreased titer ofanticardiolipin antibodies in systemic lupus erythematosus. Arch Derrnatol 1987; 123:596-600. 16. Katayama I, Masuzawa M, Nishioka K, et al.Anticardiolipin antibodies in Henoch-Schoenlein purpura. Arch DerrnatolRes 1989;281:296-8. 17. Marks RM, Czcrniecki M, Andrews BS, et al.The effect of scleroderma sera on human microvascular endothelial cells. Arthritis Rheum 1988;31:1524-34. 18. Cohen S, Johnson AR, Hurd E. Cytotoxity of sera from patients with scleroderma: effects on human endothelial cells and fibroblast in culture. Arthritis Rheum 1983;26: 170-8. 19. Kobayashi Y, Masuzawa M, Nishioka K, et al. Growth suppression of endothelial cells of the guinea pig aorta by the sera of patients with progressive systemic sclerosis. Nippon Hifuka Gakkai Zasshi 1984;94:1639-41. 20. Harper JH, WohlH, Harper E. Plateletfactor4:an inhibitor of collagenase. Science 1978;199:991-2. 21. Kahaleh MB, Osborn I, LeRoyEC. Elevated levels of circulating platelets aggregates and l3-thromboglobulin in scleroderma. Ann Intern Med 1982;96;610-l 22. Heldin CH, Ronnstrand L. Characterization ofthe receptor for platelet-derived growthfactoronhumanfibroblasts. J Bioi Chem 1983;258:10054-61. 23. Lynch DM, HowSE. Antigenic determinants inidiopathic thrombocytopenic purpura. Br J HematoI1986;63:301-8. 24. Kalunian KC, Peter 18, Middlekauff HR, et aJ. Clinical significance ofa single test foranti-cardiolipin antibodies in patients with systemic lupus erythematosus. Am 1 Med 1988;85:602-8.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS
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Phillips et af.
ment of human cultured epithelial allografts by recipient cellsas evidenced by HLA class 1 antigen expression. Derrnatologica 1987;175:166-70. 48. Aubock J, Irschick E, Romani N, et a!' Rejection, after a slightly prolonged survival time, of Langerhans cell-free allogeneicculturedepidermis used for wound coveragein humans. Transplantation 1988;45:730-7. 49. Burt AM, PallettCD,Sloane JP, et a!' Survivalof cultured
allograftsin patientswith burns assessed with probespecific for Y chromosome. Br Med J 1989;298:915-7. 50. Knowlton RG, BrownVA, Braman JC, et a!. Use of highly polymorphicDNA probes for genotypicanalysis following bone marrow transplantation. Blood 1986;68:378-85. 51. Yam P, Petz LD, Ali S, ct al. Development of a singleprobe for documentation of chimerism following bone marrow transplantation. Am J Hum Genet 1987;41:867-81.
Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis Ichiro Katayama, MD, PhD, Kazunobu Otoyama, MD, Shigeo Kondo, MD, Kiyoshi Nishioka, MD, PhD, and Shigeo Nishiyama, MD, PhD Kanagawa, Japan Anticardiolipin antibody-positive patients withprogressive systemic sclerosis wereanalyzed. Elevated anticardiolipin antibody titers were observed in 13 of 40 cases (33%). Anticardiolipin antibody titerwassignificantly higher inpatients withprogressive systemic sclerosis type 1thanin those with type2or type 3.Occurrence ofanticardiolipin antibody wassignificantly more frequent in patients positive for anti-nRNP antilxx:lies, rheumatoid factor, or thrombocytopenia. In contrast, patients with proximal scleroderma, scarring, or esophageal hypomotility were positive foranticardiolipin antilxx:ly less frequently. These results suggest that anticardiolipin antibody might beclosely associated withlupuslike clinical manifestations in a subset of progressive systemic sclerosis or definite progressive systemic sclerosis with thrombocytopenia, rheumatoid factor, or anti-nRNP antilxx:lies. (J AM ACAD DERMATOL 1990;23:198-201.) Recent reports suggest that antiphospholipid antibodies, especially anticardiolipin antibody (ACL) play an important rolein the developmentof thrombotic lesions or of occlusive vascular lesions in systemic lupus erythematosus (SLE).1,2 The presence of antibodies also correlates with thrombocytopenia, a positive biologic false-positive test result for syphilis, or lupus anticoagulant activity.l? Malia et a1. 6 demonstrated that ACL titers are high in advanced progressive systemic sclerosis (PSS) and From theDepartment ofDermatology, Kitasato University School of Medicine. Accepted for publication Oct. 29, 1989. Reprint requests: Ichiro Katayama, MD, PhD, Department ofDermatology, Kitasato University School ofMedicine, 1-15-1. Kitasato Sagamihara, Kanagawa, Japan. ]6/]/]7819
198
show a good correlation with plasma factor VIIIrelated antigen or C1q level,which might reflect the involvement of vascular injury in tissue fibrosis in PSS. In this report we describe the clinical features of ACL-positive patients with PSS and their clinical significance in the management of PSS. PATIENTS AND METHODS
Forty patients (5 men, 35 women) who were studied between 1973 and 1988 were enrolled in thisstudy. Each met the diagnostic criteria for scleroderma proposed by American Rheumatism Association? and wereclassified into three clinical groups as proposed by Barnett et al} that is, Raynaud's phenomenon and sclerodactyly only (type 1), acrosclerosis (type 2), systemic scleroderma with diffuse skin change(type 3). American Rheumatism Association criteria for SLE9 and diagnostic criteria for mixed connective tissue disease proposed by Sharp'? were
Volume 23 Number 2, Part 1 August 1990
Anticardiolipin antibodies in PSS 199
"I
•
I •
20
...J
U 00;
• 10
•
I
.
• _.. -w ..
-
• -..-·
N
_
I
•• · _
-1-
•
.
..
n
m
- -- - -- ----_ _ - ..
..
( n=13)
Fig. 1. Distribution of ACL titer among threedifferent subgroups ofPSS. (Control vstype I,p > 0.05;control vstype H,p = 0.01; control vstype IH,p:::: 0.05; control vstotalpatients, p = 0,01.)
used.In addition, mixedconnective tissue disease wasexcluded when sclerotic change suggesting PSS wasdemonstrated histopathologically. Although some patients had thrombocytopenia, leukocytopenia, or an elevated anti-DNA titer, theydid not fulfill the diagnostic criteria for SLE nor did they have any cutaneous lesions or histopathologic findings to suggest SLE. Venous blood was obtained at the first visitand stored at -20 0 C. Control bloodsamples wereobtained from 45 healthy volunteers between the agesof 10 and 65years. ACL titerwasmeasured by enzyme-linked immunosorbent assay.'! The assay wasperformed in triplicate and referredto 10 normal standard seraas controls ineachassay. Normalvalue was calculated as mean ± 2 SD « 4 U) of 45 normal volunteers. RESULTS
Anticardiolipin antibody in progressive systemic sclerosis. The patients were subdivided into three groups according to the classification proposed by Barnett.! that is, PSS type I (n = 10), type 2 (N = 13), and type 3 (n =: 17). As shown in Fig. 1, 60% of patients with PSS type 1 had ACL and a lower incidenceof positive ACL was observed in patients with type 2 (30%) and type 3 (24%). However, a high titer of ACL (>8 U) was demonstrated in three cases of type 3 patients. No patient with type 2 had a high titer of ACL. Although immunoglob-
ulin isotype-specific ACL was not analyzed, the resultscorrelatedwith IgG class-specific ACL, which may reflectthat the major activity ofACL is derived from IgG (data not shown). Relationship of clinical manifestations and anticardiolipin antibody. The relationship between frequency of ACL and each clinical manifestation of PSS was analyzed. Althoughit was not statistically significant, ACL occurredless frequently in patients with proximalscleroderma, scarring, or esophageal hypomotility (TableI). In contrast, the patientswith proteinuriahad a high incidence of positive ACL titers. Patients with cutaneous ulcer or livedo reticularis did not have a high incidence of positive ACL titers.Thisfinding contradicts previous observations in anticardiolipin syndrome'? and might be attributable to the involvement of a different pathogenic mechanism in the development ofvascular lesions in PSS.13 Relationship between laboratory findings and ACL. ACL occurred in a higher incidence in patients positive for rheumatoid factor, anti-nRNP antibody, or thrombocytopenia (p < 0.05). Patients positive for anti-Scl-70 or anticentromere antibody had lower occurrence of ACL, althoughit was not statistically significant. In contrast, positive ACL correlated with the presence of leukocytopenia and
Journal of the American Academy of Dermatology
200 Katayama et al. Table I. Clinical manifestations in ACL-positive patients with PSS
Table II. Laboratory findings in ACL-positive patients with PSS % positive for ACL (n)
% positive for ACL (n)
+
Clinical manifestation
Proximal scleroderma Sclerodactyly Pitting scar Lung fibrosis Esophageal hypomotility Proteinuria Cutaneous ulcer or gangrene Livedo
28 33 33 31 28 55 25
Laboratory findings
(29) (39) (12) (16) (18) (11) (12)
50 (10) o (1) 50 (12) 33 (24) 55 (11) 24 (29) 37 (28)
27 (15)
36 (25)
a positive titer for anti-double-stranded DNA. Biologic false-positive syphilis test results was demonstrated in only two patients in this study, and both of them were negative for ACL (Table II). mSCUSSION Antiphospholipid antibodies including ACL, lupus anticoagulant, or anti-VDRL antibodies' have been demonstrated in close association with recurrent abortions, thrombotic lesions, or central nervous system disorders, especially in patients with SLE. 1,2 Other than SLE, ACL has been demonstrated in patients with cutaneous ulcers," severe livedo.P or occlusive vascular disorders such as cutaneous polyarteritis nodosa or Takayasu's arteritis." This situation has been termed anticardiolipin syndrome.F In PSS, microvascular injury has been thought to be one of the important events in the induction of fibrosis and subsequent progression of the disease. 17,18 Cutaneous ulcers or necrosis, telangiectasia, and Raynaud's phenomenon are regarded as clinical manifestations of vascular injury. Kahaleh et al. 13 reported the serum-derived factor that induced endothelial cell injury. Marks et al.'? also reported a similar factor. A factor reported by Kobayashi et al.'? had the capacity to suppress the growth of endothelial cells derived from guinea pig aorta. Malia et al.6 reported that, other than these cytotoxic or cytostatic factors, plasma factor VIIIrelated antigens are elevated in scleroderma and correlated with ACL titer. They raised the possibility that ACL might play some role in the development of vascular injury in scleroderma. In our patients we could not find any relationship between ACL titer and vascular lesions. This discrepancy may be attributable to the involvement of different
ANA Rheumatoid factor" Anti-RNP* Anti-Sm Anti-Scl-70
Anticentromere Anti-dsDNA Lupus erythematosus cell Indirect Coombs' Leukocytopenia Anemia Thrombocytopenia* BFP for syphilis
+ 32 (34) 44 (23) 50 (14) 100 (1) 17 (6) 0(4) 60 (5) 44 (9) 57 (7) 42 (14) 36 (11) 71 (7) 0(2)
33 (6) 13 (15) 15 (20) 33 (30) 31 (13) 33 (15) 32 (28) 29 (14) 50 (4) 27 (26) 31 (29) 24 (33) 34 (38)
BFP, Biologic false-positive test result. *p == 0.05.
pathogenic mechanisms, the assay methods, or racial differences. In our experience, occurrence of antiphospholipid antibody is variable among patients with SLE, that is, some patients are positive for ACL and lupus anticoagulant, and have a biologic false-positive result for syphilis whereas others show various combinations of these antibodies. Therefore we think that the epitope recognized by anti phospholipid antibody might be heterogenous so that different clinical manifestations are observed in these patients. Plasma platelet-derived factors such as factor IV, ,B-thromboglobulin, are elevated in pSS20,21 and platelet-derived growth factor has been reported to have a fibroblast growth activity in PSS.22 These results indicate that ACL might have the ability to modulate the platelet function that results in tissue fibrosis or vascular injury. Lynch and How23 reported that ACL-positive serum from the patients with SLE binds to the membranous fraction of platelets. Our preliminary data demonstrate that ACL-positive serum from patients with SLE or PSS bound the lipid fraction of platelets (unpublished observations). Clinically, ACL titer correlated with the degree of thrombocytopenia and proteinuria and responded to corticosteroid therapy in one case. This finding raises the possibility that ACL might be another marker for certain clinical manifestations in scleroderma, although controversial results have been reported in SLE.24 ACL-positive patients with scleroderma might constitute one subset of PSS in which distinct clinical features develop.
Volume 23 Number 2, Part I August 1990 REFERENCES I. Boey ML, Colaco GB, Gharavi AE, et al. Thrombosis in systemiclupuserythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med 1 1983;287:1021-3. 2. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J AM ACAD DERMATOL 1986;15:211-9. 3. Koike T, Sueishi H, Tomioka H, et al. Anti-phospholipid antibodies and biological false positive serological test for syphilisin patientswithsystemiclupuserythematosus. Clin Exp Immunol 191\4;56:193-9. 4. Harris EN, Loizou S, Englert H. Anticardiolipin antibodies and lupus anti-coagulant [Letter}. Lancet 1984; 2:1099. 5. Harris EN, Gharavi AE, Hedge Y, et al. Anticardiolipin antibodiesin autoimmunethrombocytopenic purpura. Br J Hematol 1985;59:231-4. 6. Malia RG, Greaves M, Rowlands AC, et al. AnticardioIipin antibodies in systemic sclerosis: immunological and clinical associations. Clin Exp Immunol 1988;73:456-60. 7. SubcommitteeforSclerodermaCriteriaofAmericanRheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90. 8. Barnett Al, Miller MH, LittlejohnGO. A survival studyof patients with scleroderma diagnosed over 30 years (19531983): the value of a simplecutaneous classification in the early stages of the disease. J Rheumatol 1988;15:276-83. 9. Tan FM, CohenAS, Fries JF, et al. The 1982revised classification of SLE. Arthritis Rheum 1982;25:1271-7. 10. Sharp GC. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibody. Amsterdam: Excerpta Medica, 1987:23-32. 11. Loizou 8, McCrea JD, Rudge AC, et al. Measurementof anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp ImmunoI1985;62:738-45.
Anticardiolipin antibodies in PSS 201 12. SontheimerRD. The anticardiolipin syndrome. Arch Dermatol 1987;123:590-5. 13. Kahaleh MB, Sherer OK, LeRoyEC, Endothelial cell injury in scleroderma. J Exp Med 1979;149:1326·35. 14. Dodd HJ, SarkanyI, O'Shaughnessy D. Widespread cutaneousnecrosis associated withthelupusanticoagulant. Clin Exp DermatoI1985;IO:581-6. 15. Weinstein C, MillerMH, Axtens R. Livedoreticularis associated withincreased titer ofanticardiolipin antibodies in systemic lupus erythematosus. Arch Derrnatol 1987; 123:596-600. 16. Katayama I, Masuzawa M, Nishioka K, et al.Anticardiolipin antibodies in Henoch-Schoenlein purpura. Arch DerrnatolRes 1989;281:296-8. 17. Marks RM, Czcrniecki M, Andrews BS, et al.The effect of scleroderma sera on human microvascular endothelial cells. Arthritis Rheum 1988;31:1524-34. 18. Cohen S, Johnson AR, Hurd E. Cytotoxity of sera from patients with scleroderma: effects on human endothelial cells and fibroblast in culture. Arthritis Rheum 1983;26: 170-8. 19. Kobayashi Y, Masuzawa M, Nishioka K, et al. Growth suppression of endothelial cells of the guinea pig aorta by the sera of patients with progressive systemic sclerosis. Nippon Hifuka Gakkai Zasshi 1984;94:1639-41. 20. Harper JH, WohlH, Harper E. Plateletfactor4:an inhibitor of collagenase. Science 1978;199:991-2. 21. Kahaleh MB, Osborn I, LeRoyEC. Elevated levels of circulating platelets aggregates and l3-thromboglobulin in scleroderma. Ann Intern Med 1982;96;610-l 22. Heldin CH, Ronnstrand L. Characterization ofthe receptor for platelet-derived growthfactoronhumanfibroblasts. J Bioi Chem 1983;258:10054-61. 23. Lynch DM, HowSE. Antigenic determinants inidiopathic thrombocytopenic purpura. Br J HematoI1986;63:301-8. 24. Kalunian KC, Peter 18, Middlekauff HR, et aJ. Clinical significance ofa single test foranti-cardiolipin antibodies in patients with systemic lupus erythematosus. Am 1 Med 1988;85:602-8.
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