Cairo University



SENSITIVITY AND SPECIFICITY OF IMMUNOGLOBULIN A ISOTYPE OF ANTI-?2 GLYCOPROTEIN I IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND SECONDARY ANTIPHOSPHOLIPID SYNDROMEAzza H. El-awar M.D.1, Tamer M. A. Gheita M.D.1, Doaa H. Sayed M.D.1, Magda I. M. Ayoub M.D.2, Asmaa M. Abd-Alaal M.D.31 Department of Rheumatology and Rehabilitation1, Microbiology and Immunology2, and Chemical Pathology3, Faculty of Medicine, Cairo University, Cairo, EgyptAbstract Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease of chronic course characterized by the presence of autoantibodies to the cell nucleus. Antiphospholipid syndrome (APS) is considered the most common cause of acquired thrombophilias. The diagnosis of APS is made on the presence of clinical manifestations of thrombosis/pregnancy morbidity as well as persistently positive antiphospholipid antibodies [aPL] of ant type i.e. anticardiolipin [aCL] IgM/IgG or anti-?2 glycoprotein I [anti-?2GPI] IgM/IgG) or lupus anticoagulant [LA]. Aim of the work: Identifying the sensitivity and specificity of anti-?2-GPI of IgA isotype among Egyptian SLE patients having and lacking APS.Patients and methods: The study was done on 54 SLE patients. Twenty seven (50%) of patients had no APS while others had secondary APS. Patients having other known forms of thrombophilia were excluded. Twenty seven apparently normal control persons of matched age and sex were included. Clinical assessment and routine laboratory tests were done. Patients and controls were assessed for positivity of lupus anticoagulant, anti-?2GPI of IgM, IgG and IgA isotypes in addition to aCL of IgM, IgG and IgA isotypes.Results: IgA isotype of anti-?2GPI antibodies had low specificity but high sensitivity in Egyptian lupus patients.Conclusion: Anti-β2GPI of IgA isotype could be considered in assessing lupus patients for APS when all the standardized aPL are negative owing to its high sensitivity.Keywords:Antiphospholipid syndrome, Systemic lupus erythematosus, Antiphospholipid antibodies, Anti-?2 glycoprotein I antibodies, Anticardiolipin antibodies, Lupus anticoagulantCorrespondence: Tel.: +20 1001547310 (Mobile)E-mail address: doaahaassan@kasralainy.edu.eg (Doaa H. Sayed)Introduction:Systemic lupus erythematosus (SLE) is an autoimmune disease of chronic course of remissions and exacerbations. It is characterized by the presence of autoantibodies to cell nucleus. Almost all organ systems could be affected producing protean clinical manifestations [1].Antiphospholipid syndrome (APS) is considered the most common form of thrombophilias [2]. Stroke is considered the most common manifestation of arterial thrombosis while deep venous thrombosis is considered the most frequent form of venous thrombosis. Pregnancy losses in those patients typically occur after the 10th week of pregnancy. The diagnosis of APS is made on the presence of clinical manifestations as well as persistently positive antiphospholipid antibodies (aPL) of any type (anticardiolipin [aCL] IgM/IgG or anti-?2 glycoprotein I [anti-?2GPI] IgM/IgG) or lupus anticoagulant [LA]. APS may be primary or associate other rheumatic diseases, mostly SLE [3].Anti-?2-glycoprotein I antibodies are formed against a phospholipid-binding plasma protein known as ?2-glycoprotein I or apolipoprotein H [4]. The relation between anti-?2GPI and APS manifestations is of greater strength compared to that of aCL [5] and testing for anti-?2GPI is indicated in patients experiencing APS manifestations but with negative aCL and LA [6].Although classification criteria of APS don’t include IgA isotype of anti-?2GPI antibodies, it was found that many SLE patients are positive for these antibodies [7,8]. Measuring IgA anti-?2GPI could be considered for assessing the risk of thrombosis, particularly the venous thrombosis, in SLE patients [6,9]. Moreover, Lakos and his colleagues detected a strong relation between elevated IgA anti-?2-GPI antibody level and each of venous thrombosis, heart valve disease, thrombocytopenia, epilepsy and livedo reticularis [10]. Mehrani and Petri documented that, in the contrary to the IgG and IgM isotypes of anti-?2GPI, IgA isotype positivity had significant association with pulmonary hypertension. Hence, they suggested that a revision of the classification criteria of APS should be made to include IgA isotype [11].??A large number of lupus and APS patients as well as patients experiencing pregnancy morbidity or thrombosis without fulfilling the classification criteria of APS have positive IgA aPL with or without other aPL isotypes [10,11,12,13]. This motivated many researchers to keep evaluating the significance of aPL IgA isotype. They suggested that aPL IgA could help classifying patients having manifestations highly suggestive of the syndrome but lacking the standardized aPL. However, their work revealed controversial results [7,8,10,14,15,16,17,18,19,20]. Our study aimed at identifying the sensitivity and specificity of anti-?2GPI of IgA isotype among Egyptian lupus patients with and without APS.Patients and Methods:Patients:The study included 54 Egyptian lupus patients. Age of the patients ranged from 13-46 years. The age of the control persons ranged from 14-45 years. Four of the patients, all with APS, were males. Ten of the enrolled patients, five with APS, had juvenile-onset SLE while the others developed lupus during adulthood. Age of onset ranged from 12-42 years. The range of disease duration was 0.6-23.3 years. SLE was diagnosed based on satisfying the 1997 update of the 1982 American College of Rheumatology revised criteria of SLE. [21,22]. Half of the patients had secondary antiphospholipid syndrome (SAPS) based on satisfying the Revised preliminary Sapporo classification criteria for APS [23]. Group 1 patients refers to lupus patients without APS while group 2 patients refers to those with APS. The patients were recruited from the Rheumatology and Rehabilitation Department, Kasr Alainy Hospital, Cairo University. Risk factors of thrombosis as history of smoking, dyslipidemia, uncontrolled systemic hypertension, diabetes mellitus, nephrotic syndrome, use of estrogen containing contraceptive medications or hormone replacement treatment and other known thrombophilic disorders were excluded.Controls:Twenty seven healthy control persons of matched age and sex were included. Local ethical committee approval was obtained.Methods:Full history taking, clinical examination as well as routine laboratory investigations were done. Other investigations were performed when indicated.Patients and controls were evaluated for aPL positivity:Measurement of lupus anticoagulant level: Screening was performed using the dilute Russell viper venom time (dRVVT). A confirmatory step followed screening. The screen ratio which is the ratio of screen clotting time of the tested plasma to that of the reference pool was calculated. The confirm ratio that is the ratio of confirm clotting time of the tested plasma to that of the reference pool was calculated as well. Lupus anticoagulant prolongation was confirmed if the normalized ratio, the ratio of the screen ratio to confirm ratio, was equal to or greater than 1.2. Kits were purchased from DIAGNOSTICA STAGO, 9, rue des Frères Chausson 92600 ASNIERES, France and analyzer of the STA? line.Measurement of anticardiolipin antibodies IgA, G and M levels: ELISA kits were purchased from Demeditec Diagnostics GmbH, Lise-Meitner- Stra?e 2, D-24145 kiel (Germany). Test was considered positive when Ig A/G level was greater than 10 U/ml and IgM level was greater than 7 U/ml.Measurement of anti-β2glycoprotein I IgA, G and M levels: ELISA kits were purchased from Demeditec Diagnostics GmbH, Lise-Meitner- Stra?e 2, D-24145 kiel (Germany). Result was considered positive when the level of antibodies was greater than 8 U/ml. Assessment of SLE activity and damage:Disease activity and damage were measured using Systemic Lupus Erythematosus Disease activity Index (SLEDAI) [24] and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/SDI) respectively [25]. Both scores were measured at the time of aPL testing.Statistical methods:Accuracy of testing of IgA isotype of anti-?2GPI was expressed as sensitivity and specificity. Sensitivity was calculated using the following equation:Sensitivity=Number of true positivesNumber of true positives+number of false negativesSpecificity was calculated using the following equation:Specifictiy=Number of true negativesNumber of true negatives+number of false positivesP values less than 0.05 was considered statistically significant. value less than 0.001 was considered highly significant.Results:Table 1 shows the demographic features and obstetric history of the two patient groups and parison between the two patient groups concerning the clinical manifestations as well as disease indices revealed the existence of statistically significant differences regarding APS nephropathy, venous thromboses, DVT, superficial thrombophlebitis, arterial thrombosis, digital gangrene/threatened digital ischemia and Lymphopenia where these features were more frequent in group 2 patients (p value: 0.038, 0.002, 0.002, 0.038, 0.002, 0.038 and 0.043 respectively) . Dry mouth, discoid rash and cutaneous vasculitis were more frequent in group 1 patients than group 2 patients (p value: 0.038, 0.017 and 0.026 respectively). SLICC-SDI was of higher value in group 2 patients than group 1 patients (p value: 0.028).Comparison between disease indices of the studied patient groups is shown in table 2.Table 1: Demographic features and obstetric history of the two patient groups and controlsFeatureGroup 1 patients (SLE)Group 2 patients (SLE with APS)ControlP-ValueFeatureGroup 1 patients (SLE)Group 2 patients (SLE with APS)Demographic features N(%)Obstetric History N(%)N=27N=27N=27N=18N=18Sex Males0 (0)4 (14.8)3 (11.1)0.1History of pregnancy ever18 (85.7)16 (94.1)Female27 (100)23 (85.2)24 (88.9)Pregnancy morbidity4 (21.1)13 (81.25)Abortion3 (16.7)11 (68.75)Disease onset: Juvenile onset5 (18.5)5 (18.5)-1Stillbirth3 (16.7)6 (37.5)Adult onset22 (81.5)22 (81.5)IUGR2 (11.1)0 (0)Demographic features Mean(SD)Preterm labor1 (5.6)1 (6.25)Age in years27.06±5.8329.09±7.527.6±7.30.4Disease duration(years)6.7 ± 4.057.04 ± 5.7-0.89Pre-eclampsia 1(5.6)4 (25)Table 2: Comparison between disease indices of the two patient groups Index SLICC-SDI(Mean± SD)p valueSLEDAI(Mean± SD)p valueSLEDAI N (%)Inactive disease (≤3)Mild-moderate flare (4-12)Severe flare (>12)Group 1 (SLE) (N=27)0.78± 1.120.0288.22± 8.90.05511 (40.7)11 (40.7)5 (18.5)Group 2 (SLE with APS) (N=27)1.5± 1.333.7± 3.0215 (55.6)12 (44.4)0 (0)Routine laboratory features of the patients groups are shown in table 3 with the comparison between the two groups.Immunological laboratory features of the two patient groups and control with the comparison between the two patient groups and the comparison between the patients and the controls are shown in Table 4. Table 3: Routine laboratory features of the two patients groups Feature (Mean±SD)Group 1 (SLE) (N=27)Group 2 (SLE with APS)(N=27) P valueFeature (Mean±SD)Group 1 (SLE) (N=27)Group 2 (SLE with APS)(N=27) P valueESR (mm/1st hour)50.33±35.9733.52 ±24.60.084Serum albumin (3.5-5.5 gm/dL)3.53±0.643.98 ±0.470.006Hb (mg/dL)11.31±1.7712.08 ±1.950.21Serum creatinine (0.4-1.2 mg/dL)0.69±0.210.83 ±0.450.993TLC (cell/mm3)6.97±3.316.63 ±1.690.959Blood urea (10-50 mg/dL)27.3±10.7128.11±13.320.515PLT (cell/mm3)252.22±77.53285.15 ±72.950.186Proteinuria during activity of nephritis (0.15 gm/24 hours)1.88±1.212.06±1.060.422AST (0-41 U/L)24.21±11.5322.63 ±10.210.678Current level of proteinuria (0.15 gm/24 hours)0.86±0.850.98±1.110.631ALT (0-41 U/L)21.39±9.7227.11 ±16.590.216C3 (80-160 mg/dL)99.67±69.81110.26±78.030.728C4 (20-40 mg/dL)18.73±13.0821.58±19.340.931Table 4: Immunological laboratory features of the two patient groups and controlsFeature+ANA+anti-ds DNALow complementLevelProlongedLA+ aCL+aCL IgM+aCL IgG+aCL IgA+ anti-B2GPI+anti-?2GPI IgM+anti-?2GPI IgG+anti-?2GPI IgAGroup 1(N/%)27/10026/96.323/85.25/18.59/33.35/18.56/22.20/014/51.94/14.84/14.812/44.4Group 2(N/%)27/10027/10023/85.211/40.76/22.23/11.14/14.80/016/59.34/14.84/14.813/48.1P value of the comparison between the two patient groups-0.310.070.360.440.48-0.584110.79Control(N/%)---1/3.73/11.12/7.40/01/3.77/25.90/01/3.76/22.2P value of the comparison between the patients and the controls---0.0060.160.480.0260.330.020.0470.260.052Levels of antiphospholipid antibodies in patient groups and controls with the comparison between the two patient groups and the comparison between the patients and the controls are shown in table 5.The specificity and sensitivity of each of aPL were calculated. Regarding sensitivity of aPL among SLE patients with APS, anti-?2GPI antibodies were the most sensitive (59.3%), followed by LA (40.7%) and aCL (22.2%). Among anti-?2-GPI isotypes, the most sensitive isotype was IgA (48.1%), followed by IgG and IgM (14.8% for each). Among aCL isotypes, the most sensitive isotype was IgG (14.8%) followed by IgM (11.1%) and lastly IgA (0%). Table 5: Levels of antiphospholipid antibodies in patient groups and controls Feature Diluted RVVT (Prolonged if ≥ 1.2)aCL IgM(normal:<7U/mL)aCL IgG(normal:<10U/mL)aCL IgA(normal:<10U/mL)Anti-?2GPI IgM(normal:<8U/mL)Anti-?2GPI IgG(normal:<8U/mL)Anti-?2GPI IgA(normal:<8U/mL)Group 1(Mean±SD)0.78±1.126.11 ±13.39.37±19.281.87±2.166.79±15.693.09±2.0411.3±13.13Group 2(Mean±SD)1.06±0.213.41 ±5.385.33 ±6.771.22 ±1.124.02 ± 3.949.52±12.718.54±7.23P value of the comparison between the two patient groups0.1360.8530.7150.4270.8410.3010.597Control (Mean±SD)0.8895 ± 0.107852.7 ±4.1592.52 ± 1.3191.48 ± 4.752.15 ± 2.033.093 ± 12.7148.04 ± 12.714P value of the comparison between the patents and the controls0.0010.1630.0210.0090.0560.0730.048The most specific antibodies for APS that can discriminate between SLE patients without APS and those with APS were in the following order: LA (81.5%), aCL (62.96%) and lastly anti-?2GPI (48.1%). Among anti-?2GPI isotypes, the most specific isotype was IgM (85.2%), followed by IgG (85.2%) and lastly IgA (55.6%). Among aCL isotypes, the most specific isotype was IgA (100%) followed by IgM (81.5%) and lastly IgG (77.8%). When specificity is calculated using test results of the controls, the most specific antibodies were in the following order: LA (96.3%), aCL (88.9%) and lastly anti-?2GPI (74.1%). Among anti-?2GPI isotypes, the most specific isotype was IgM (100%) and IgG (96.3%) and lastly IgA (77.8%). Among aCL isotypes, the most specific isotype was IgG (100%) followed by IgA (96.3%) and lastly IgM (92.3%).Discussion:Antiphospholipid antibodies of IgA isotype were not incuded in APS classification criteria due to lacking specificity and providing no additional benefit to that given by IgM or IgG isotypes [8]. Being not fully standardized makes it difficult to compare studies performed by different laboratories [11,26,27,28,29]. Moreover, there is a significant difference among the studies performed on different ethnicities providing further difficulty to the comparison of the different studies [30,31,32,33]. Furthermore, most of the studies supporting the value of IgA aPL are of different designs. In addition, these antibodies are frequently associated with other aPL isotypes [34].Our study aimed at identifying the sensitivity and specificity of anti-?2GPI of IgA isotype among Egyptian lupus patients with and without APS. The different isotypes of anti-?2GPI were tested in an equal number of apparently normal age and sex-matched control subjects.When specificity is calculated using test results of the controls, the most specific anti-?2GPI isotype was IgM (100%), followed by IgG (96.3%) and lastly IgA (77.8%).On the contrary to our results where 22.2% of normal persons had anti-β2GPI IgA, none of the control subjects had anti-β2GPI IgA in a study done by Lakos and his colleagues [10]. The most specific anti-?2-GPI isotype that can discriminate between SLE patients without APS and those with APS was IgM (85.2%), followed by IgG (85.2%) and lastly IgA (55.6%). We detected no difference in the prevalence and level of anti-β2GPI IgA between lupus patients without and with APS. In disagreement with our results, Fanopoulos and his colleagues reported that IgA anti-β2GPI were more prevalent and had a higher level in SLE patients with APS than those without APS [15]. In a study of 70 patients with SLE, 3 women with primary APS and 30 with secondary APS, both the frequency and the level of aPL were significantly higher in patients with SLE with APS than those without; this significant difference was stronger for IgA than IgG and IgM [10]. On the contrary, it was reported that aPL of IgG isotype are associated with a higher risk of thrombosis than other isotypes, IgM and IgA [35,36,37]. Moreover, Samarkos and his colleagues found that the addition of IgA aPL to the diagnostic tests of APS, even, decreased the accuracy of the test [35].Racial differences were considered to have a role in the frequency, isotype distribution and clinical value of aCL and anti-?2-GPI [31].Prospective studies are mandatory to confirm the clinical usefulness of IgA isotype of anti-?2GPI in different races [5].From our findings, we can conclude that testing for IgA isotype of anti-β2GPI in SLE patients with manifestations suggestive for APS, but having none of the standardized aPL could be helpful owing to its high sensitivity. However, more studies performed on a larger number of patients excluding those with inherited thrombophilias, although this may not be feasible in anticoagulated patients, are needed. References:[1] Tassiulas IO, Boumpas DT. Clinical Features and Treatment of Systemic Lupus Erythematosus in Kelley’s Textbook of Rheumatology; 8th edition; ed. by Firestein GS, Budd RC, Harris ED, Mclnnes IB, Ruddy S and Sergent JS; Elsevier Saunders; Philadelphia, 1263-1300, 2009.[2] Thomas RH. Hypercoagulability syndromes. Arch Intern Med, 161:2433-2439, 2001.[3] Erkan D, Salmon JE, Lockshin MD. Antiphospholipid syndrome in Kelley’s Textbook of Rheumatology; 9th edition; ed. by Firestein GS, Budd RC, Gabriel SE, Mclnnes IB, O’Dell JR. Elsevier Saunders; Philadelphia, volume 3, chapter 82, 1331-1341, 2013. [4] Roubey RAS. Review Article: Autoantibodies to phospholipid-binding plasma proteins: a new view of Lupus Anticoagulants and other "antiphospholipid" autoantibodies. Blood, 84 (9): 2854-2867, 1994. [5] Tsutsumi A, Matsuura E, Ichikawa K, Fujisaku A, Mukai M, Kobayashi S, Koike T. Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus. Arthritis Rheum, 39: 1466-1474, 1996. [6] Lee SS, Cho ML, Joo YS, Hong YS, Min JK, Lee SH,?Park SH,?Cho CS,?Kim HY. Isotypes of Anti-?2-Glycoprotein I Antibodies: Association with Thrombosis in Patients with Systemic Lupus Erythematosus. J Rheumatol, 28: 520-524, 2001.[7] Danowski A, Kickler T, Petri M. Anti- ? 2-glycoprotein I: prevalence, clinical correlations, and importance of persistent positivity in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Rheumatol, 33:1775-1779, 2006. [8] Sweiss NJ, Ronghai Bo, Kapadia R, KapadiaR, Manst D, Mahmood F, Adhikari T, Volkov S, Badaracco M, Smaron M, Chang A, Baron J, Levine JS. IgA Anti-b2-Glycoprotein I Autoantibodies Are Associated with an Increased Risk of Thromboembolic Events in Patients with Systemic Lupus Erythematosus. PLoS ONE, 5 (8): e12280, 2010. [9] Mehrani T, Petri M. Association of IgA Anti- ? 2 Glycoprotein I with Clinical and Laboratory Manifestations of Systemic Lupus Erythematosus. J Rheumatol, 38(1):64-68, 2011.[10] Lakos G, Kiss E, Regeczy P, Tarján P,?HYPERLINK ""Soltész P,?HYPERLINK ""Zeher M,?HYPERLINK ""Bodolay E,Szakony Sz, Sipka S, Szegedi GY. Isotype distribution and clinical relevance of anti- ? 2-glycoprotein I antibodies: importance of IgA isotype. Clin Exp Immunol, 117: 574-579, 1999.[11] Selva-O’Callaghan A, Ordi-Ros J, Monegal-Ferran F,?Martinez N,?Cortes-Hernandez F,?HYPERLINK ""Vilardell-Tarres M. IgA anticardiolipin antibodies–relation with other antiphospholipid antibodies and clinical significance. Thromb Haemost,79: 282-285, 1998. [12] Shen YM, Lee R, Frenkel E, Sarode R. IgA antiphospholipid antibodies are an independent risk factor for thromboses. Lupus, 17: 996-1003, 2008. [13] Boin F, Franchini S, Colantuoni E, Rosen A,?HYPERLINK ""Wigley FM,?HYPERLINK ""Casciola-Rosen L. Independent association of anti-beta[2]-glycoprotein I antibodies with macrovascular disease and mortality in scleroderma patients. Arthritis Rheum, 60: 2480-2489, 2009. [14] Ferro GV D, Basili S. Transient antiphospholipid antibodies positivity in patients with primary antiphospholipid syndrome. Lupus, 5:551-551, 1996. [15] Fanopoulos D, Teodorescu MR, Varga J, Teodorescu M. High frequency of abnormal levels of IgA anti- ? 2-glycoprotein I antibodies in patients with systemic lupus erythematosus: relationship with antiphospholipid syndrome. J Rheumatol, 25:675-680, 1998.??? [16] Pierangel SS, Rand JH. Laboratory Heterogeneity of Antiphospholipid Antibodies in Handbook of Systemic Autoimmune Diseases; 1st edition; ed. By series editor Asherson RA; volume 10: Antiphospholipid Syndrome in Systemic Autoimmune Diseases; ed. by: Cervera R, Reverter JK and Khamashta M; Elsevier, Amsterdam – Boston – Heidelberg – London – New York – Oxford-Paris – San Diego – San Francisco – Singapore – Sydney – Tokyo, chapter 3: 35, 2009. [17] Mahler M, Norman GL, Meroni PL, Khamashta M. Autoantibodies to domain 1 of beta 2 glycoprotein 1: A promising candidate biomarker for risk management in antiphospholipid syndrome. Autoimmunity Reviews, 12: 313-317, 2012. [18] Bertolaccini ML, Atsumi T, Contreras AE, Khamashta MA, Hughes GRV. The value of IgA antiphospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus. J Rheumatol, 28:2637-2643, 2001. [19] Carmo-Pereira S, Bertolaccini ML, Escudero-Contreras A, Khamashta M A,, Hughes G R V. Value of IgA anticardiolipin and anti-?2-glycoprotein I antibody testing in patients with pregnancy morbidity. Ann Rheum Dis, 62:540-543, 2003. [20] Samarkos M, Davies KA, Gordon C, Loizou S. Clinical significance of IgA anticardiolipin and anti-? 2-GPI antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Clin Rheumatol, 25:199-204, 2006. [21] Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF,?Schaller JG,?HYPERLINK ""Talal N,?Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum; 25:1271-1277, 1982. [22] Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum, 40:1725, 1997. [23] Wilson WA, Charavi AE, Koike T, Lockshin MD,?Branch DW,?HYPERLINK ""Piette JC,?HYPERLINK ""Brey R,?HYPERLINK ""Derksen R,?Harris EN, Hughes GR,?Triplett DA,?HYPERLINK ""Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum, 42: 1309-1311, 1999. [24] Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum, 35:630-640, 1992. [25] Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, Bacon P, Bombardieri S, Hanly J, Hay E, Isenberg D, Jones J, Nived O, Petri M, Richter M, Sanchez-Guerrero J, Snaith M, Sturfelt G, Symmons D. The development and initial validation of The Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis and Rheumatism, 39 (3):363-369, 1992.[26] Lewis S, Keil LB, Binder WL, DeBari VA. Standardized measurement of major immunoglobulin class (IgG, IgA, and IgM) antibodies to beta2glycoprotein I in patients with antiphospholipid syndrome. J Clin Lab Anal, 12: 293-297, 1998.[27] Galeazzi, M, Sebastiani, GD, Tincani, A, ?HYPERLINK ""Piette JC,?HYPERLINK ""Allegri F,?HYPERLINK ""Morozzi G,?Bellisai F,?HYPERLINK ""Scorza R,?Ferrara GB,Carcassi C,?Font J,?HYPERLINK ""Passiu G,?HYPERLINK ""Smolen J,?HYPERLINK ""Papasteriades C,?HYPERLINK ""Houssiau F,?HYPERLINK ""Nebro AF,?Ramon Garrido ED,Jedryka-Goral A,?HYPERLINK ""Marcolongo R. HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Lupus, 9: 47-55, 2000. [28] Reber G, Boehlen F, de Moerloose P. Technical aspects in laboratory testing for antiphospholipid antibodies: is standardization an impossible dream? Semin Thromb Hemost, 34: 340-346, 2008. [29] Tincani A, Filippini M, Scarsi M, Galli M,?HYPERLINK ""Meroni PL. European attempts for the standardisation of the antiphospholipid antibodies. Lupus, 18: 913-919, 2009. [30] Wong KL, Liu HW, Ho K, Chan K,?Wong R. Anticardiolipin antibodies and lupus anticoagulant in Chinese patients with systemic lupus erythematosus. J Rheumatol, 18: 1187-1192, 1991. [31] Molina JF, Gutierrez-Urena S, Molina J, Uribe O, Richards S, De Ceulaer C, Garcia C, Wilson W.A., Gharavi A.E., Espinoza L.R. Variability of anticardiolipin antibody isotype distribution in 3 geographic populations of patients with systemic lupus erythematosus. J Rheumatol, 24:291-296, 1997. [32] Cucurull E, Gharavi AE, Diri E, E, Mendez E, Kapoor D, Espinoza LR. IgA anticardiolipin and anti-β2-glycoprotein I are the most prevalent isotypes in African American patients with systemic lupus erythematosus. Am J Med Sci, 318:55-60, 1999. [33] Greco TP, Amos MD, Conti-Kelly AM, Naranjo JD, Ijdo JW. Testing for the antiphospholipid syndrome: importance of IgA anti-beta 2-glycoprotein I. Lupus, 9:33-41, 2000. [34] Meijide H, Sciascia S, Sanna G, Khamashta MA, Bertolaccini ML. The clinical relevance of IgA anticardiolipin and IgA anti-β2 glycoprotein I antiphospholipid antibodies, A systematic review. Autoimmunity Reviews, 12: 421-425, 2013. [35] Sammaritano LR, Ng S, Sobel R, Simantov R,?HYPERLINK ""Furie R,?HYPERLINK ""Kaell A,?Silverstein R,?Salmon JE. Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis. Arthritis Rheum, 40:1998-2006, 1997.[36] Giannakopoulos B, Passam F, Rahgozar S, Krilis SA. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood, 109:422-430, 2007.[37] Ruffatti A, Del Ross T, Ciprian M, ?Nuzzo M,?Rampudda M,?Bertero MT,?Bergia R,?Caramaschi P,?Biasi D,Capsoni F,?Montaguti L,?Ruffini R,?Brucato A,?Picillo U,?Fanelli V,?Riccieri V,?Piccoli A,?Valesini G,?Doria A,Meroni PL,?Tincani A. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis; 68:397-399,2009. ................
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