ARTHRITIS & RHEUMATISMVol. 43, No. 2, February 2000, pp 440–443© 2000, American College of Rheumatology

VALIDATION OF THE SAPPORO CRITERIA FORANTIPHOSPHOLIPID SYNDROME

MICHAEL D. LOCKSHIN, LISA R. SAMMARITANO, and SERGIO SCHWARTZMAN

Objective. To test the Sapporo criteria for theclassification of the antiphospholipid syndrome (APS).

Methods. We classified 243 consecutive patientswho had clinical diagnoses of primary APS (n 5 49),secondary APS (n 5 26), systemic lupus erythematosus(SLE) without clinical APS (n 5 131), and lupus-likedisease without clinical APS (n 5 37).

Results. Sensitivity, specificity, positive predictivevalue, and negative predictive value were 0.71, 0.98, 0.95,and 0.88, respectively. False-negative findings were theresult of patients being classified on the basis of minorcriteria that were not included in the Sapporo criteria,such as livedo reticularis, thrombocytopenia, low-titerIgG or IgM anticardiolipin antibody, IgA anticardio-lipin antibody, and anti–b2-glycoprotein I antibody.Some patients with false-negative results were trueseronegative cases.

Conclusion. The Sapporo criteria for APS com-pare favorably with the American College of Rheuma-tology criteria for SLE and are usable for clinicalstudies.

In October 1998, participants in a workshop inSapporo, Japan, devised classification criteria for theantiphospholipid syndrome (APS) (1). The Workshopused a consensus process that did not validate thecriteria against actual patient populations. We thereforetested the Sapporo criteria by performing a prospectivecross-sectional classification of our own patients as theyattended our offices between February and August 1999.

PATIENTS AND METHODS

Two hundred forty-three patients had clinical diag-noses of primary APS, secondary APS (APS accompanyinganother rheumatic disease), systemic lupus erythematosus(SLE), or an illness likely to be confused with SLE or APS(lupus-like disease [LLD]). LLD patients had Sjogren’s syn-drome with overlap features, small vessel vasculitis, and mixedand undifferentiated connective tissue disease, but not sclero-derma, dermatomyositis, rheumatoid arthritis, other vasculitis,or atherosclerosis with vascular occlusion.

Serologic tests were those commercially available, themajority of which were performed in the clinical laboratoriesof the Hospital for Special Surgery, which routinely tests forIgG, IgM, and IgA anticardiolipin antibody (aCL). Antibody tob2-glycoprotein I is sought only for patients clinically thoughtto have APS but with negative results on enzyme-linkedimmunosorbent assay for antiphospholipid antibody or lupusanticoagulant tests. For some patients, insurance requirementsprevented the repetition of tests that had shown negativeresults.

The patient visits included both new consultations(33%) and followup visits for established disease. We didnot adjust data for the duration of a patient’s illness, whichranged from 0 to 34 years, nor for the number of times a testhad been performed; however, positive findings on tests forantiphospholipid antibody and lupus anticoagulant wereconfirmed by repeat examination. For comparison, we alsoclassified patients according to the American College ofRheumatology (ACR) revised criteria for systemic lupuserythematosus (SLE) (2).

Fisher’s exact test for 2-tailed 2 3 2 contingency tablesand Student’s 2-tailed t-test were calculated using Excel soft-ware (Microsoft, Redmond, WA).

RESULTS

The results of the validation survey are presentedin Table 1. Clinically diagnosed groups were similar inage, sex, and disease duration, but APS patients werepredominantly white. More women clinically diagnosedas having primary or secondary APS than diagnosed ashaving SLE or LLD had been pregnant, likely reflectingthe known interest of the authors in antiphospholipidantibody and pregnancy.

Michael D. Lockshin, MD, Lisa R. Sammaritano, MD, SergioSchwartzman, MD: Hospital for Special Surgery, Weill/Cornell Med-ical College, New York, New York.

Address reprint requests to Michael D. Lockshin, MD, Bar-bara Volcker Center, Hospital for Special Surgery, 535 East 70thStreet, New York, NY 10021.

Submitted for publication July 19, 1999; accepted in revisedform October 5, 1999.

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Very few SLE or LLD patients had high-titeraCL. Seventeen percent of them had low-titer aCLwithout clinical events suggesting secondary APS. Only 2SLE patients not classified as secondary APS had lupusanticoagulant. Of the patients who were clinically con-sidered to have primary APS, 36% had antinuclearantibody, 20% had arthritis, and 9% had anti-DNAantibody.

The Sapporo criteria correctly classified 76% of

primary APS and 61% of secondary APS patients, whilemisclassifying 1% and 3% of SLE and LLD patients,respectively. Compared with the ACR criteria for SLE, theSapporo criteria for APS are somewhat less sensitive butmuch more specific (Table 2). The sensitivity and specific-ity of the Sapporo criteria were not skewed by diagnosesrefined by the authors over long periods of followupbecause the criteria performed similarly for the 49 patientswho were seen for the first time during the study period.

Table 1. Percentages of patients meeting selected criteria, by diagnostic group*

PAPSpatients(n 5 49)

SAPSpatients(n 5 26)

SLEpatients

(n 5 131)

LLDpatients(n 5 37)

Group totals

All APSpatients(n 5 75)

All non-APS

patients(n 5 168)

Demographic characteristicsAge, mean 6 SD years 42.3 6 11.4 43.0 6 11.9 40.1 6 12.5 39.3 6 11.5 43.3 6 13.2 39.9 6 12.3Disease duration, mean 6 SD years 6.2 6 7.2 10.8 6 9.3 9.0 6 8.2 6.9 6 10.8 7.8 6 8.2 8.2 6 8.2Women, % 88 96 99 89 91 97White, % 90 73 69 81 84 71†

Sapporo APS criteria, % (no. tested)Fulfill Sapporo APS criteria

All 76 62 1 3 67 2‡First visit 75 86 8 4 78 6

Women ever pregnant 86 (43) 83 (25) 55 (130) 55 (33) 85 55‡Fetal loss at $10 weeks, as % ever pregnant 43 30 13 11 39 12§Pregnant $3 times, as % ever pregnant 68 40 35 33 58 35¶3 fetal losses at ,10 weeks, as % pregnant $3 times 8 25 0 0 14 0†

Arterial thrombosis 37 31 3 5 35 4‡Venous thrombosis 27 27 5 5 27 5‡High-titer IgG or IgM aCL 63 (47) 61 (26) 6 (116) 10 (30) 64 7‡Lupus anticoagulant# 63 (43) 71 (24) 2 (101) 0 (25) 54 2‡

Noncriteria APS findings, % (no. tested)**Low-titer IgG or IgM aCL 15 19 16 20 16 17IgA aCL 18 (40) 24 (21) 3 (99) 0 (26) 20 3‡IgA aCL, with negative IgG and IgM aCL 10 5 1 0 8 1¶False-positive findings on syphilis test 49 (39) 32 (19) 3 (103) 18 (11) 37 4‡Platelet count ,100 3 109/liter 22 27 9 11 24 10¶Pregnant, 1–2 fetal losses at ,10 weeks 37 20 13 11 31 12Preeclampsia 19 15 14 6 18 12Autoimmune hemolytic anemia 2 19 5 0 8 6

ACR SLE criteria, % (no. tested)Fulfill ACR SLE criteria

All 10 81 79 16 35 65‡First visit 0 86 65 15 12 78‡

Anti-DNA antibody 9 (44) 54 (26) 71 (129) 3 (31) 26 58Antinuclear antibody 36 (45) 92 (26) 90 (129) 39 (36) 56 79§Arthritis 20 81 84 38 41 74‡

* PAPS 5 primary antiphospholipid syndrome; SAPS 5 secondary antiphospholipid syndrome; SLE 5 systemic lupus erythematosus; LLD 5lupus-like disease (Sjogren’s syndrome with overlap features, small vessel vasculitis, and mixed and undifferentiated connective tissue disease, butnot scleroderma, dermatomyositis, rheumatoid arthritis, other vasculitis, or atherosclerosis with vascular occlusion); aCL 5 anticardiolipin antibody;ACR 5 American College of Rheumatology.† P # 0.05 versus all APS patients.‡ P # 0.0001 versus all APS patients.§ P # 0.001 versus all APS patients.¶ P # 0.01 versus all APS patients.# At least 1 of the following tests was performed: activated partial thromboplastin time, dilute Russell’s viper venom time, or phospholipid-basedtest. Abnormal results were confirmed by an inhibition test.** Livedo reticularis was not routinely recorded and is therefore not listed.

VALIDATION OF SAPPORO CRITERIA FOR APS 441

Patients who failed to meet the Sapporo criteriafor APS but who were clinically diagnosed by the authorsas having primary APS (false-negative cases) had livedoreticularis or thrombocytopenia without thrombosis orpregnancy loss, or had negative or low-titer aCL withlivedo reticularis and thrombosis (for example, seroneg-ative patients with Sneddon’s syndrome). Some, but notall, patients who did not meet the Sapporo APS criteriahad antibody to b2-glycoprotein I or IgA aCL, which arenot included in the Sapporo criteria.

Two patients fulfilled the Sapporo criteria butwere clinically thought not to have APS. One was ayoung lupus patient who developed an undocumenteddeep vein thrombosis while taking oral contraceptives;she subsequently experienced seizures, but had normal

findings on magnetic resonance imaging of the brain.The other false-positive patient had digital infarcts dueto small vessel vasculitis. Both patients had high-titerantiphospholipid antibody. The high frequencies of ar-thritis, antinuclear antibody, and anti-DNA antibody inprimary APS patients have been noted by others (3).

Among clinical abnormalities not included in theSapporo criteria, thrombocytopenia, IgA aCL, and bio-logic false-positive serologic test for syphilis, althoughinfrequent, identified patients as having APS, but low-titer aCL, autoimmune hemolysis, preeclampsia, and1–2 early pregnancy losses did not (Table 2). Totalpregnancy history distinguishes APS from non-APS but,because very few women had 3 or more pregnancies, thecriterion of 3 early losses does not.

Analysis of the 23 false-negative cases is shown inTable 3. Low-titer positive findings on serologic testsoccurred in only 3 patients who were clinically diagnosedas having APS, and 8 patients met clinical criteria thatwere not included in the Sapporo criteria set.

DISCUSSION

Among these selected patients, the Sapporocriteria are specific and sensitive for the classificationof the primary and secondary antiphospholipid syn-dromes. A strength of this survey is that classificationwas performed by experienced clinicians who have aspecial interest in APS. Because the authors partici-pated in the creation of the Sapporo criteria, theywere conscious of how patients under their careshould be classified; thus this test of the criteria mayreflect our attentive biases in classifying patients.Because we compared APS patients with lupus and

Table 2. Sensitivity, specificity, PPV, and NPV for the Sapporo APScriteria and the ACR SLE criteria in the populations studied*

Criteria, comparison Sensitivity Specificity PPV NPV

Sapporo APS criteriaPAPS 1 SAPS 0.71 0.98 0.95 0.88

versus SLE 1 LLDPAPS 0.76 0.98 0.93 0.93

versus SLE 1 LLDPAPS 0.76 0.98 0.95 0.91

versus SLEACR SLE criteria

SLE 0.79 0.59 0.97 0.58versus PAPS 1 LLD

* PPV 5 positive predictive value; NPV 5 negative predictive value;ACR 5 American College of Rheumatology; SLE 5 systemic lupuserythematosus; PAPS 5 primary antiphospholipid syndrome; SAPS 5secondary antiphospholipid syndrome; LLD 5 lupus-like disease(Sjogren’s syndrome with overlap features, small vessel vasculitis, andmixed and undifferentiated connective tissue disease, but not sclero-derma, dermatomyositis, rheumatoid arthritis, other vasculitis, oratherosclerosis with vascular occlusion).

Table 3. Analysis of the 23 patients who were clinically diagnosed as having antiphospholipid syndrome(APS) but who did not fulfill the Sapporo criteria (false-negative cases)

Clinical criteriaSerologicfindings*

No. ofpatients Comment (no. of patients)

Present Low titer 3Present Negative 5 Anti–b2-glycoprotein I positive (1)Present Unavailable 1Noncriteria APS symptoms Positive 3 Thrombocytopenia (2), autoimmune

hemolysis (1)Noncriteria APS symptoms Low titer 5 Myelopathy, abnormal findings on magnetic

resonance imaging of the brain, multiplesclerosis–like symptoms (5; of which 1was anti–b2-glycoprotein I positive)

Absent Positive 6 Identified because of other rheumaticdisease (3) or in vitro fertilization orpregnancy (3)

* Anticardiolipin antibody and/or lupus anticoagulant.

442 LOCKSHIN ET AL

lupus-like patients—with whom they are likely to beconfused—but not to general medical patients, we donot know that the Sapporo criteria will distinguishAPS patients from those with atherosclerotic vascularocclusion or nonrheumatic pregnancy loss.

The intent of Sapporo criteria for APS is toassemble uniform patient groups for clinical studies.Since such studies will most often include SLE and LLDpatients, our choice of comparison patient groups isappropriate. Use of the Sapporo criteria for otherpurposes will require testing the criteria against otherpatient populations.

Addendum. Two of the 23 patients with false-negative

findings (Table 3), both identified because of other rheumaticdisease, recently developed major thromboses.

REFERENCES

1. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW,Piette J-C, et al. International consensus statement on preliminaryclassification criteria for definite antiphospholipid syndrome: re-port of an international workshop. Arthritis Rheum 1999;42:1309–11.

2. Hochberg MC. Updating the American College of Rheumatologyrevised criteria for the classification of systemic lupus erythema-tosus [letter]. Arthritis Rheum 1997;40:1725.

3. Vianna JL, Khamashta MA, Ordi-Ros J, Font J, Cervera R,Lopez-Soto A, et al. Comparison of the primary and secondaryantiphospholipid syndrome: a European Multicenter Study of 114patients. Am J Med 1994;96:3–9.

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