Preliminary criteria for the classification of systemic lupus erythematosus SLE evaluation in early diagnosed SLE and rheumatoid arthritis.
код для вставкиСкачатьBRIEF COMMUNICATION Preliminary Criteria for the Classification of Systemic Lupus Erythematosus (SLE) Evaluation in Early Diagnosed SLE and Rheumatoid Arthritis R. Bruce Trimble, Alexander S. Townes, Harry Robinson, Stanley B. Kaplan, Robert W. Chandler, Aram S. Hanissian and Alfonse T. Masi Preliminary criteria for the classificationof systemic lupus erythematosus (SLE)were applied to patients with early diagnosed SLE and rheumatoid arthritis (RA) who are participants in a prospective community study of arthritis of recent onset. Sensitivity of the criteria was 88 % , and specificity against RA was 97.5 ye. Sensitivity increased to 92 % without loss of specificity when high titer antinuclear antibody (ANA) was used as an alternative criteria manifestation to LE cells. These results show the efficacy of the proposed criteria for early diagnosed patients, and support the inclusion of high titer ANA in the SLE criteria. Recently published preliminary criteria of rheumatoid arthritis (RA)who met the for the classification of systemic lupus ery- American Rheumatism Association (ARA) thematosus (SLE) (1) were applied to 25 criteria for definite or classical disease (2). patients with a clinical diagnosis of SLE, These groups comprised all patients of ages and to 40 patients with a clinical diagnosis 16 to 45 years admitted consecutively from 1968 to 1973 to the Memphis and Shelby From the Departments of Medicine and Community Medicine, University of Tennessee School County Arthritis Research Program, who of Medicine, Memphis, Tennessee. were so diagnosed on initial or subsequent Supported in part by US Public Health Service annual evaluations. This continuing, comGrants AM 12049 and AM 05055. prehensive, prospective study (3) recruits R BRUCE TRIMBLE, MD': Fellow in Rheumatology, supported by the Baptist Memorial Hospital, Mem- patients under age 45 years who are resiphis Tennessee; ALEXANDER s TOWNES, MD: Professor dents of Memphis or Shelby County, and of Medicine and Chief, Section of Rheumatology; who are referred to the program within 6 HARRY ROBINSON, ScD: Associate Professor and Chief, Section of Biostatistics, Dept of Community Medi- months of first diagnosis of arthritis. Thus, cine; STANLEY B WPWN, MD: Professor of Medicine; unlike the preliminary criteria report, this ROWT w CHANDLER, PhD: Assistant Professor of Immunology in Medicine; ARAM s HANISSIAN, MD: study provides data on the applicability of Associate Professor of Pediatrics and Chief, Section the proposed SLE criteria in a community of Pediatric Rheumatology; ALFONSE T MASI, MD, sample of early diagnosed SLE and RA paD P H Director, Division of Connective Tissue Distients. The value of high titer antinuclear eases. Address reprint requests to Dr A T Masi, MD, antibody (A-NA) as an alternate criteria DPH. university of Tennessee, 858 Madison Avemanifestation to a positive LE cell test was nue, Memphis, Tennessee 1 1 6 3 . 'Present address: Park Clinic, Mason City, Iowa also analyzed. 50401. All ANA tests were performed in our Submitted for publication July 24, 1973; accepted laboratory using a standard indirect imOctober 29. 1973. 184 Arthritia and Rheumatism, Vol. 17, No. 2 (March-April 1974) CLASSIFICATION OF SLE munofluorescent technique with fresh frozen rat kidney sections and fluorescein conjugated polyvalent rabbit antihuman immunoglobulin prepared from lyophilized aliquots of the same large pool of antiserum. High-titer ANA was arbitrarily defined prior to this analysis as a titer of 1:64 or greater on the basis of extensive previous experience in the clinical application of this particular test system. The proposed SLE criteria were tested against the clinical diagnoses of SLE or RA made by experienced rheumatologists on patients entered into our study, and corroborated by follow-up diagnosis. Under this assumption, a true positive diagnosis in terms of the proposed SLE criteria (1) corresponds to satisfying the criteria in a patient with the clinical diagnosis of SLE. A true negative in terms of the SLE criteria indicates failure to satisfy the criteria in a patient clinically diagnosed RA (non-SLE). The term sensitivity may be considered equivalent to the proportion of true positives among all clinically diagnosed SLE patients, and the term specificity equivalent to the proportion of true negatives among the patients diagnosed RA. Table 1 shows that 18 (72%) of our SLE patients (23 women, 2 men, mean age at entry 28 years) satisfied the proposed criteria for the classification of SLE (four or more of the 14 specified manifestations) on initial evaluation, and 22 (88%) did so over the course of followup, which averaged 17.5 months. None of the 40 R A patients (31 women, 9 men, mean age at entry 30.7 years) met four or more criteria initially, and only one (2.5y0) did so over a mean follow-up of 37.5 months. If high titer ANA is used as an alternate criteria manifestation to a positive LE cell test, then 88y0 of SLE patients satisfied four or more criteria on initial evaluation, and 92y0 did Table 1. Number of Patients with SLE and RA who Satisfied Varying Numbers of Proposed ARA Criteria for SLE Number of SLE Criteria 4 or More Initial Visit 25SLE 40RA Any Visit 25SLE 40RA 18(21) O(0) 22 (23) l(1) Percent with 4 or More 72 (84) 0 (0) 88 (92) 2.5 (2.5) ‘Numbers in parentheses refer to number of pacritients fulfilling “alternate” SLE criteria-ie, teria which allow a high titer ANA to be substituted for a positive LE cell test. so overall. No additional RA patient met criteria as a result of this modification. Two RA patients had high titer ANA’s, but had only one additional manifestation (non-deforming arthritis); and the one RA patient who developed four manifestations did not have a high titer ANA at any time. No RA patient had a positive LE cell test. As Table 2 indicates, the prevalence or‘ various manifestations was similar in our SLE patients and in those presented in the analysis of the preliminary criteria (l), with statistically significant differences by the Chi-square test only in the frequencies of nondeforming arthritis, Raynaud’s phenomenon, facial erythema, positive LE cell tests, and cellular casts. Although some of these differences might occur by chance because of our relatively small sample, other Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974) 185 TRIMBLE ET AL Table 2. Percent Frequency of Manifestations in Patients with SLE from Memphis and 245 Patients with SLE Included in the Prellminaty Criteria Group Manifestations Criteria Memphis Group Facial erythema 40 Discoid lupus 32 Raynaud’s phenomenon 44 Alopecia 40 Photosensitivity 28 Oral or nasopharyngeal ulceration 16 Arthritis without deformity 100’ LE cells 48 Chronic false positive STS 12 Profuse proteinuria 16 Cellular casts 16 Pleurisy/pericarditis 60 Psychosis/convulsions 20 Hemoiytic anemia/ leukopenia/ thrombocytopenia 52 ANA titer 1:64 or greater &4 64 17 15 43 37 15 84 92 12 20 48 60t 19t 40t - ‘Minimal decrease of ability to fully extend the elbows and limitation of motion secondary to effusion or pain were not considered deformity. ?The proposed criteria group had 60.4% pleuritis and 18.8% pericarditis; 19.2% psychosis and 12.7% convulsions; and 39.6% leukopenia, 16.3% hemolytic anemia, and 11.4% thrombocytopenia. The most frequent single manifestation in each combination is cited since no data are provided on the presence of one or the other individual manifestations. factors relating to patient evaluation and duration of disease seem to be a more likely explanation. Since arthritis was a prerequisite for inclusion of patients in our study, the difference in the frequency of this manifestation in our patients as compared with the ARA series is anticipated. The higher prevalence of Raynaud’s phenomenon in our patients may reflect the interest in this manifestation at our center, and the careful historical search for it incorporated in the detailed protocols of this prospective study. The prevalence of facial erythema and positive LE cell tests was 186 higher in the ARA criteria group than in our patients, but the ARA criteria frequency was also higher than reported in two large series (4,5) and in two other patient groups to which the criteria have recently been applied (6,7). This may be the result, as suggested by Fries and Siege1 (7), of having selected patients with “classical” manifestations of SLE and RA for the study groups from which the criteria were derived. The lower prevalence of cellular casts in our patients probably reflects their early, generally milder disease, compared with the patients used in formulating the ARA criteria. Arthritis without deformity did not discriminate between these early diagnosed RA and SLE patients, since only one RA patient had deforming arthritis. No significant difference was found in the prevalence of mouth ulcers between the SLE (4 of 25) and RA (3 of 40) patients, and omission of this manifestation did not change the sensitivity or specificity of the criteria in our patients. Also, the Chi-square test (with Yate’s correction when appropriate) confirmed the highly discriminating value of high titer ANA which was positive in 21 of 25 SLE and only 2 of 40 RA patients (P < 0.001). I n order to rank the independent contributions of the 14 individual SLE criteria variables, plus high titer ANA, to the variability of the clinical diagnosis of SLE or RA, the data were further analyzed using the technique of stepwise multiple regression (8). In brief, the technique quantitates the independent contributions of variables - e g , each of the SLE criteria manifestations, to the total variance of a dependent variable--eg. the clinical diagnosis of SLE or RA, after allowing for any intercorrelations which may exist in the independent variables. I n Table 3, the multiple correla- Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974) CLASSIFICATION OF SLE Table 3. Multiple Regression Analysis of SLE Criteria Manifestations Plus Positive ANA In Relation to the Clinical Diagnosis of SLE Versus RA SLE Criteria Manifestations. > ANA (titer 1:64) Hemolytic anemia, leukopenia thrombocytopenia Pleuritis, pericarditis Photosensitivity LE cells Raynaud’s phenomenon *Manifestations contributing significantly (P sus RA. Cumulative Percent Variability Accounted for (RP) Increase in R’ due to Variable Specified (% 1 0.8038 64.61 64.61 0.8631 0.8809 0.8955 0.9046 0.9118 74.50 77.61 80.19 81.83 83.13 9.87 3.11 2.58 1.64 1.30 Multiple Correlation Coefficient (R) 4 .a15) to the variance of clinical diagnosis of SLE ver- tion coefficient squared (RZ) has the same pendently to the variability in diagnosis at interpretation as the squared coefficient (r2) a 5 percent significance level. in univariate analysis. In both cases, the This study shows the effectiveness of the squared coefficient corresponds to the pro- preliminary SLE criteria when applied to portion of variability in the dependent early diagnosed SLE and RA patients, esvariable accounted for by the “independ- pecially if high titer ANA is used as an ent” variables. All variables were analyzed alternative manifestation for a positive LE as dichotomies although the technique was cell test. Such substitution improved the devised basically for multinormal distribu- sensitivity of the criteria, especially at initions. The modification was utilized as an tial evaluation, without sacrificing specificavailable method to approximately rank ity against RA. Thus, an ANA titer of 1:64 the various criteria in terms of their rela- or greater had a sensitivity of 84y0 for SLE tive independent contributions to diagnos- patients, and a specificity of 95y0 against tic variability, and is not intended as a RA patients. definitive statement which would require a It should be realized, however, that while technique specifically designed for discrete high titer ANA was the most discriminatvariables, and a much larger population of ing factor in this reported series, standardpatients. ization of technique such as obtained here As shown in Table 3, high titer ANA is not always possible, and that there is no accounted for by far the largest amount of standard for comparison of results between the variance, supporting the widespread different laboratories. Although the LE cell clinical impression of its diagnostic value. test has advantages regarding availability It is probable, of course, that a positive LE and standardization, the ANA as in our cell test would have contributed much series is a more sensitive test for antinuclear more had ANA been omitted from the antibodies. Another recent study (9) has analysis, since the ANA and LE cell tests confirmed a high degree of correlation were highly significantly correlated in the (92%) of proposed SLE criteria in clinictotal group of patients (P < 0.001). Only ally diagnosed SLE patients with raised the six variables shown contributed inde- levels of antibodies to a specific nuclear Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974) 187 TRIMBLE ET AL antigen, DNA. These considerations urge that standardization of ANA tests be developed, and that further testing of the value of ANA as a criteria manifestation for SLE classification be pursued in comparison of SLE patients with other groups, including patients with RA more advanced than in this series, and patients with other connective tissue diseases. Both SLE and RA patients in our Arthritis Research Program met additional SLE criteria with time. Thus, the cumulative proportion of true positives (sensitivity) of 92 percent for the proposed but modified criteria (including ANA) may increase even further with follow-up of our early diagnosed SLE patients. However, it is also possible that the proportion of true negatives (specificity) may decrease in our RA patients as they continue to be followed, and only later analysis will reveal whether the present proportion of 97.5 percent will be maintained. Although arthritis of recent onset was a necessary prerequisite for referral of patients to this study, these patients presented a typically broad range of clinical problems due to SLE (Table 2) during the course of subsequent follow-up, from mild disease requiring no specific treatment to fatal termination due to renal disease (3 cases) or central nervous system involvement (1 case). Thus, the high degree of sensitivity and specificity of the preliminary ARA criteria for SLE in these patients with early diag- 188 nosed disease even at the time of initial evaluation strongly supports the efficacy of these criteria in the classification of patients with SLE. REFERENCES 1. Cohen AS, Reynolds WE, Franklin EC, et al: Preliminary criteria for the classification of systemic lupus erythematosus. Bull Rheum Dis 21:643-648, 1971 2. Ropes MW, Bennett GA, Cobb S, et al: 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958 3. Masi AT, Robinson H, Hughen M: The Arthritis Research Program survey of newly diagnosed arthritis among residents of Memphis and Shelby County. Memphis Mid-South Med J 43:359-364, 1968 4. Tuffanelli DL, Dubois EL: Cutaneous manifestations of systemic lupus erythematosus. Arch Dermatol 90:377-386, 1964 5. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 50:85-95, 1971 6. Lie T H , Rothfield NF: An evaluation of the preliminary criteria for the diagnosis of systemic lupus erythematosus. Arth Rheum 15: 532-534, 1972 7. Fries JF, Siege1 RC: Testing the ‘Preliminary Criteria for Classification of SLE.’ Ann Rheum Dis 32171-177, 1973 8. Draper NR, Smith H: Applied regression analysis. New York, John Wiley & Sons, Inc, 1966, pp 163-216 9. Davis P, Atkins B, Josse RG, et al: Criteria for classification of SLE. Br Med J 2:88-89, 1973 Arthritis and Rheumatism, Vol. 17, No. 2 (March-April 1974)
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