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Arthritis & Rheumatism Official Journal of the American College of Rheumatology
DEFINITION, INCIDENCE, AND CLINICAL DESCRIPTION OF FLARE IN SYSTEMIC LUPUS ERYTHEMATOSUS A Prospective Cohort Study MICHELLE PETRI, MARK GENOVESE, ERIC ENGLE, and MARC HOCHBERG The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study, 3 disease activity indices, the physician’s global assessment, the Lupus Activity Index, and the University of Toronto SLE Disease Activity Index, have been recorded, at least quarterly since 1987, on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of 21.0 in the physician’s global assessment of disease activity (measured on a 6 3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients, 98 (53%) had 1 1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms, musculoskeletal involvement, cutaneous involvement, and decreasing levels of C3 and C4. At the time of flare, the mean
University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician’s global assessment) increased by 0.26. Overall, 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study, compared with those who did not have flares. By survival analysis, no specific clinical or laboratory variables present at entry were found to predict the time to first flare. These data show that quantification of flare is possible, flare is frequent in patients with SLE of long duration, and the majority of flares involve the so-called “minor” organ systems.
Systemic lupus erythematosus (SLE) is a disease whose course is characterized by exacerbations (flares) and by remissions, which are usually associated with drug treatment. There is a general consensus that the concept of exacerbation or flare of SLE includes 1) the presence of new symptoms or signs of organ system involvement, and/or 2) the worsening of already present organ system involvement (i.e., increasing disease activity) (1). Crucial to this concept is the ability of the physician to differentiate organ involvement caused by new and/or increasing disease activity from the progression of organ damage resulting from a previously existing degree of disease activity. Previous attempts to classify exacerbations in SLE have been based on qualitative definitions, including 1) the physician’s decision to introduce or augment antiinflammatory and/or immunosuppressive
From the Division of Molecular and Clinical Rheumatology, the Division of Internal Medicine, Department of Medicine, and the Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Dr. Petri is the recipient of a Clinical Associate Physician award from the NIH OCRC (RR-00722). Dr. Hochberg’s work was supported in part by NIH grant AR-21393. Michelle Petri, MD, MPH; Mark Genovese; Eric Engle; Marc Hochberg, MD, MPH. Address reprint requests to Michelle Petri, MD, MPH, Suite 7500, 1830 East Monument Street, Baltimore, MD 21205. Submitted for publication September 20, 1990; accepted in revised form February 28, 1991. Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
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938 therapy, or 2) the occurrence of major or minor exacerbations, depending on the type of organ system involvement (2-6). Recently, Liang and colleagues identified the need for a quantitative measure of disease activity to be used in clinical research in SLE (7,8). Several such scales have been developed and have been shown to be valid and reliable as measures of disease activity in these patients (9). As part of an ongoing prospective cohort study, the ph.ysician’s global assessment of disease activity, the University of California, San Francisco/Johns Hopkins University Lupus Activity Index (LAI) (1013), and the University of Toronto Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (1416) have been completed at least quarterly since 1987, on 185 patients with SLE. Using the physician’s global assessment of disease activity as a measure of disease activity, a quantitative definition of flare was developed and the incidence of flare was estimated. In addition, the change in both the LA1 score and the SLEDAI score at the time of flare was measured, and the clinical and laboratory features of flare were characterized. The results suggest that disease flare is a common event in patients with SLE and further validate the use of disease activity indices in routine patient care.
PATIENTS AND METHODS Patients. All patients with a clinical diagnosis of SLE who are being followed up by physicians in the Division of Molecular and Clinical Rheumatology, Johns Hopkins Hospital Rheumatology Faculty Practice have been entered into a prospective cohort study of outcomes in SLE. The protocol includes routine visits at 3-month intervals and additional visits as necessitated by disease activity or complications. Physicians. Three faculty rheumatologists (MP, MH, and Dr. David Hellmann) and 5 rheumatology fellows participated in this study. We have previously shown that faculty rheumatologists and rheumatology fellows do not differ in the reliability of their assessments on either the SLEDAI or the LA1 measures (13). Data collection. At each visit, the rheumatologist or rheumatology fellow completes a data sheet (available from MP on request) that includes a physician’s global assessment of disease activity on a scale of 0-3 (only activity, not damage, is included in this assessment) and 2 quantitative measures of disease activity: the LA1 and the SLEDAI. All data sheets are examined for completeness and accuracy, and the information is entered into a database file programmed in Double Helix I1 (Odesta Corp., Northbrook, IL) on a Macintosh SE microcomputer (Apple Computer, Cupertino, CA). Routine laboratory testing (complete blood cell count, measurement of the erythrocyte sedimentation rate, urinalysis, and determination of creatinine, C3, C4, and
anti-DNA levels) is performed in the hospital laboratories, and the data are added to the database. As of June 1, 1989, 198 patients were included in the database. Of these 198 patients, 185 had been assessed on 2 or more occasions and were included in the present analysis. These 185 patients were compared, in terms of more than 25 demographic or cIinicaVlaboratory features, with the 13 who had only 1 visit, and no significant differences were found (a = 0.05). The LA1 has been used in studies of fatal infection (10) and renal function (1 1,12) in SLE. It is a 5-part scale, reflecting disease activity over the previous 2 weeks, which can be completed by the physician in approximately 1 minute. Part 1 is the physician’s global assessment of disease activity on a 0-3-point visual analog scale (VAS). Part 2 is an assessment of 4 symptoms (fatigue, rash, joint involvement, serositis), each on a 0-3-point VAS. Part 3 quantifies involvement of 4 organ systems (neurologic, renal, pulmonary, and hematologic), each on a 0-3-point VAS. Part 4 assigns scores for medication use, i.e., prednisone (1 point for 0-15 mg/day, 2 points for 16-39 mg/day, 3 points for 240 mg/day) and immunosuppressive agents (cyclophosphamide, chlorambucil, azathioprine, or methotrexate: 3 points for any). Part 5 assesses 3 laboratory variables: proteinuria (0 points for negative or trace, 1 point for 1+ , 2 points for 2-3+, and 3 points for 4+ on urine dipstick), anti-DNA (0-3 points assigned according to the range used in the local laboratory), and C3, C4, or CH50 (0-3 points assigned according to the range used in the local laboratory). The LA1 summary score is the arithmetic mean of the following values: (a) part 1 score, (b) mean of the 4 values in part 2, (c) maximum of the 4 values in part 3, (d) mean of the 2 values in part 4, and (e) mean of the 3 laboratory values. The range of possible LA1 scores is 0-3. We also obtained a modified LA1 score, in which the physician’s global assessment was omitted. SLEDAI consists of 24 items, grouped according to 9 organ systems. Definitions of the 24 items are shown on the 1-page form. The index is calculated by assigning a predetermined weight to an item that is “present,” and summing across all items. Weights are higher for organ system involvement that is more life threatening. The range of possible SLEDAI scores is 0-105. We have compared, and found no difference between, results using the original SLEDAI form with definitions and those using a short form, without definitions, that could be reproduced on our encounter form; therefore, we used the latter. Definition of flare. Flare was defined as an increase of 2 1.O on the physician’s global assessment, compared with the previous visit or a visit within the last 93 days. Each patient’s physician’s global assessment scores were plotted against time, and the plot was visually inspected by the authors to insure that this definition of flare did not exclude patients with apparent exacerbations. Change-in-treatment analysis. An alternative means of identifying important change in lupus activity is the physician’s decision to initiate or increase treatment. This is the basis for the British Isles Lupus Assessment Group activity measure (BILAG) index (5,17) and several other activity indices ( 2 4 ) . In the present study, “change in treatment” was defined as an increase in prednisone dosage,
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FLARE IN SLE or the addition of an immunosuppressive agent, hydroxychloroquine, or a nonsteroidal antiinflammatory drug (NSAID). Statistical analysis. Data were transferred in the form of ASCII text t o an IBM-PC (AT) microcomputer, and the files were then transferred to an IBM-4381 mainframe computer at the Academic Data Processing Center, Johns Hopkins University School of Hygiene and Public Health. Data were then analyzed using the Statistical Analysis System (SAS Institute, Cary, NC).
RESULTS Patient characteristics. The 198 patients in the database had a total of 1,654 visits recorded; the 185 patients included in the study had a total of 1,641 visits recorded. Of the 14 patients who did not meet 4 or more of the American Rheumatism Association (ARA) criteria for the diagnosis of SLE (I@, 12 met 3 criteria. The remaining 2 patients each met 2 criteria (1 had lupus nephritis [proteinuria, hypocomplementemia, and positive antinuclear antibody] and 1 had hematologic features of lupus). Demographic and clinical characteristics of the 185 patients at entry into the
Table 1. Characteristics of the 185 systemic lupus erythematosus (SLE) patients studied*
Age, mean 2 S D years % female % black/% white Time since disease diagnosis, mean S D years Time since first symptoms, mean SD years Cutaneous involvement, % Musculoskeletal involvement, % Serositis, % Renal disease, % Neurologic disease, % Hematologic disease, % Sjogren’s syndrome, % Cardiac involvement, % Pulmonary involvement, % Gastrointestinal involvement, % Immunologic abnormality, % 2 4 ARA SLE criteria, %
*
*
35.7
* 12.0
91 58/42t 6.7 6.7 8.9 2 7.8 94 92 54 61 42 85 25 53 14 36 100 92
*
* Cutaneous involvement = history of new malar or discoid rash, photosensitivity, alopecia, aphthous ulcers, Raynaud’s phenomenon, subcutaneous lupus erythematosus, vasculitis, leg ulcers, panniculitis, or livedo reticularis; musculoskeletal involvement = arthralgias, erosions, arthritis, or myositis; renal disease = nephrotic syndrome, renal insufficiency, renal failure, casts, hematuria, proteinuria, or pyuria; neurologic disease = seizures, psychosis, organic brain syndrome, meningitis, depression, mononeuritis multiplex, abnormality on computed tomography or magnetic resonance imaging of the brain, visual defect, cranial neuropathy, lupus headache, or stroke; hematologic disease = leukopenia, thrombocytopenia, anemia, positive direct Coombs’ test result. ARA = American Rheumatism Association. t 1 patient was Oriental.
Table 2. Treatment history in the 185 patients*
Prednisone Aspirin or NSAID H ydroxychloroquine Immunosuppressive agentt
91 60 54 24
* Values are the percent of patients who had ever received the treatment. NSAID = nonsterodial antiinflammatory drug. t Azathioprine, cyclophosphamide, chlorambucil, or methotrexate.
cohort study are shown in Table 1; cumulative treatment history at entry into the study is shown in Table 2. Distribution of activity scores. Figure 1 shows the distribution of patients’ scores on the 4 activity indices (the physician’s global assessment, the LAI, the modified LAI, and the SLEDAI) at the first visit after entry into the study. The physician’s global assessment score was 0 in 37 patients, 0-1 in 110 patients, 1-2 in 30 patients, and 2-3 in 8 patients. The mean (+SD) physician’s global assessment score for the first visit was 0.82 (+0.71), with a median of 1.00 (minimum 0, maximum 3.00; maximum possible score 3.00). The mean LA1 score for the first visit was 0.60 (?0.43), with a median of 0.52 (minimum 0, maximum 2.05; maximum possible score 3.00). The mean modified LA1 score (with the physician’s global assessment omitted) was 0.54 (+0.40), with a median of 0.44 (minimum 0, maximum 1.81; maximum possible score 3.00). The mean SLEDAI score was 5.43 (+5.04), with a median of 4 (minimum 0, maximum 31; maximum possible score 105). The LA1 and SLEDAI differ in some of the specific clinical symptoms and signs measured. Table 3 presents data on organ system involvement at the first visit; information from both the LA1 and the SLEDAI is included. As seen, the 2 indices yielded major differences in the frequency of musculoskeletal involvement and cutaneous involvement. The SLEDAI defines musculoskeletal involvement as arthritis or myositis, whereas the LA1 defines it as joint involvement, thereby allowing physicians to include arthralgias, as well as arthritis, in the rating. Thus, the 13% difference in the percentage of patients shown to have involvement of the musculoskeletal system would be attributed to patients who had arthralgias. The SLEDAI, as originally developed and used herein, defined cutaneous involvement as a new malar rash, aphthous ulcers, or alopecia, whereas the LA1 allows the physician to score any cutaneous involvement, and thus would include, for example, worsening of preexisting malar rash, discoid rash, or livedo reticularis. This explains the rather remarkable differ-
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Toronto SLEDAI Figure 1. Distribution of patients’ lupus activity index scores at the first visit after entry into the study. A, Physician’s global assessment. B,Lupus Activity Index. C, Modified Lupus Activity Index (with the physician’s global assessment not included). D, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).
ence in the measurement of cutaneous involvement by the 2 activity indices (12% versus 32%). Recent revisions of the SLEDAI use the term “new onset or recurrence of inflammatory rash” rather than “new malar rash,” which should obviate much of this difference. Incidence of flare. The distribution of flares over a total followup time of 224 patient-years is shown in Table 4. One hundred forty-six flares occurred, in 98 of the 185 patients (53%); thus, the incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to the occurrence of a flare was 12 months. Among the patients in whom flare occurred, the mean number of flares per patient was 1.5. Change in SLEDAI or LA1 score compared with flare defined by physician’s global assessment. The score on the modified LA1 changed by a mean of 0.26
(SEM 0.03; 95% confidence interval 0.20-0.32) and the SLEDAI score changed by a mean of 3.0 (SEM 0.5; 95% confidence interval 2 4 when the physician’s global assessment increased by 2 1.O (a “flare”). Both of these changes were statistically significant (P < 0.05). The percentage change in the modified LA1 was equal to 14.4% of the observed maximum score of 1.81 and 8.7% of the maximum possible score of 3.0. The percentage change in the SLEDAI was 9.7% of the observed maximum score of 31 and 2.9% of the maximum possible score of 105. Thus, the percentage of change required in order to meet our definition of flare was higher for the LA1 than for the SLEDAI. Description of flares. Table 5 shows clinical symptoms and signs that were present or were new or worsening at the time of the first study visit during a flare, as determined using both the SLEDAI and the
FLARE IN SLE
94 1
Table 3. Clinical activity by organ system at the first visit* Cutaneous SLEDAI LA1 Musculoskeletal SLEDAI
12 32 26 39
LA1
Serositis 7
SLEDAI LA1 Renal SLEDAI LA1 Neurologic SLEDAI LA1 Hematologic SLEDAI LA1 Pulmonary (LAI) Vasculitis (SLEDAI) Hypocomplementemia or anti-DNA Constitutional Fever (SLEDAI) Fatigue (LAI)
9
31 27 8 9
23 22 8 1.6 52.4 6 51
* Values are the percent of patients (n = 185). There were differences in the criteria for involvement of the various organ systems as defined in the Systemic Lupus Erythernatosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI), and results from both are shown, when applicable. LAI. (“Worsening” was measured with the LA1 only, and was defined as a change of 0.5 points on the scale.) As indicated in the table, new or worsening cutaneous involvement, musculoskeletal involvement, constitutional systems, and hypocomplementemia were frequently found at these visits. Flare as defined by change in treatment. The occurrence of a change in treatment (increase in prednisone dosage or addition of an immunosuppressive agent, aspirin or NSAID, or hydroxychloroquine) was examined for 131 of the 146 flares. The mean SD prednisone dosage increased from 14.2 -+ 14.1 mg/day to 18.3 -+ 16.5 mg/day for all flares combined. The prednisone dosage was unchanged at 48.1% of the
*
Table 3. Distribution of flares in the 185 patients* No. of flares 0 1
2 3 4 2 15
No. of patients 97 65 22 8 2 1
98
* Among the 98 patients who had any flares (53% of the total group of patients), there were 146 flares.
flares, increased at 39.7%, and, surprisingly, decreased at 12.2%. When the 16 visits in which the prednisone dosage was decreased were reviewed, a number of apparent explanations were found. First, several patients had increased their prednisone dosage at home, prior to the clinic visit at which the physician diagnosed the flare. Second, several patients did not comply with the prescribed prednisone dosage regimens. Third, several flares were treated by an increase in the dosage of other medications, because of side effects of high-dose prednisone. Fourth, several patients were treated with pulse methylprednisolone, enabling a rapid reduction in the daily prednisone dosage. Fifth, in several cases, the prednisone dosages were altered by physicians who were not rheumatologists. A cytotoxic agent was added at 3.1% of the Table 5. Clinical activity at the first visit during a flare, in 98 patients* Present Cutaneous SLEDAI LA1 Musculoskeletal SLEDAI LA1 Serositis SLEDAI LA1 Renal SLEDAI LA1 Neurologic SLEDAI LA1 Hematologic SLEDAI LA1 Pulmonary (LAI) Vasculitis (SLEDAI) H ypocomplementemia SLEDAI LAI, C3 LAI, C4 Anti-DNA SLEDAI LA1 Constitutional Fever (SLEDAI) Fatigue (LAI) Raynaud’s phenomenon
New or worsening
12.2 46.9
9.2 38.0
37.8 58.2
20.4 49.0
10.2 12.2
9.2 10.2
30.6 22.4
16.3 18.0
16.3 21.4
12.2 19.4
27.6 17.3 7.1 9.2
7.1 11.2 6.1 6.1
54.1 NA NA
6.1 (new) 43.9 (worsening) 40.8 (worsening)
26.5 NA
10.2 (new)? 17.4 (worsening)
4.1 66.3 18.0
3.0 48.0 10.0
* Values are the percent of patients. There were differences in the criteria for involvement of the various organ systems as defined in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI), and results from both are shown, when applicable. NA = not applicable. t Anti-DNA was considered new if it was recorded as present at the visit during the flare, and absent at the previous visit, on the SLEDAI form.
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flares. Hydroxychloroquine was added at 5.3%. Aspirin and/or an NSAID was added at 6.1%. Overall, an increase in treatment occurred at 39 of the 87 firstflares for which the data were available (44.8%) and at 23 of the 44 subsequent flares for which the data were available (52.3%). It is possible that some lupus flares may be induced as a result of the physician’s decision to taper prednisone. In our cohort, 28% of the flares were preceded by a reduction in the prednisone dosage. Risk factors for occurrence of the first flare. Patients who experienced flares fulfilled more of the ARA criteria for SLE at entry into the study (mean 6.5 versus 6.0; P = 0.04) and were followed up for a longer period of time after entry (mean 1.4 years versus 1.0 years; P 5 O.OOl), compared with those in whom flare did not occur. Using survival analysis, no specific clinical or laboratory variables present at entry were found to predict the length of time to first flare.
DISCUSSION Systemic lupus erythematosus is characterized by episodic changes of activity, or “flare.” It is this episodic nature of its course that makes it very different from other rheumatic diseases, such as rheumatoid arthritis, which usually involve more constant disease activity. Although clinicians recognize intuitively the concept of lupus flare, it has not been defined in a quantitative manner that would enable the conduct of clinical research studies of flare. In fact, lupus disease activity indices currently under development do not incorporate the concept of flare, or change in activity. In our determination of a quantitative definition of flare, we included 2 basic concepts: 1) a flare represents a change in activity, but this change can occur anywhere on the disease spectrum, i.e., from no activity to mild, from mild to moderate, or from moderate to severe activity; and 2) a flare implies a change in the slope, or rate of change, of disease activity over time, i.e., a change in activity from none to mild that occurred gradually over several years would not represent a flare. Thus, our quantitative definition of flare is a change in lupus activity of 21.0 on the physician’s global assessment (which has a range of 0-3 on a visual analog scale), that occurs over a 93-day period or since the last visit. Others have chosen to define flare differently. For example, in a Markov analysis of disease activity and outcome, flare is defined as the most severe level
of activity (6). Another definition of flare is derived from the physician’s decision to change treatment; this is the basis for the BILAG index and other disease activity indices (2-5,17). Indices based on this “change-in-treatment” paradigm may be weighted toward revealing “flares” in those organ systems in which prednisone or immunosuppressive treatment is generally used. Ninety-eight of the 185 patients in our cohort (53%) had a flare, by our quantitated definition, during the study period. Thirty-three patients had more than 1 flare. Previous investigations (3,4) have suggested that lupus activity declines over time. Although our study did not directly address this, our results indicate that the patients, who had a mean 6.7-year duration of disease since the diagnosis of lupus (and an 8.9-year duration since the onset of the first symptoms), have continued to show important changes in disease activity. The incidence of flare was 0.65 per patient-year of followup, with a mean time to flare of 12 months. Information on the incidence and time of flare has potential utility in setting practice guidelines for timing of routine followup visits. We characterized the flares using information from 2 activity indices, the LA1 and the SLEDAI, which were completed at each patient visit. Fatigue (48% by LAI), musculoskeletal involvement (49% by LAI), and cutaneous lupus (38% by LAI), were the symptoms most likely to be newly occurring or worsening at the time of flare (Table 5). Because fatigue is difficult to evaluate, it has been omitted in some indices, such as the SLEDAI, but retained in others, including the LA1 and the Systemic Lupus Activity Measure (9). Our results in this study highlight the association of fatigue with flare. The characteristics at the time of the first flare, shown in Table 5, reflect differences between the SLEDAI and the LAI. The SLEDAI cannot be used to determine worsening of a flare descriptor, since the descriptor is coded only as present or absent. It can be used to identify a descriptor that has newly appeared at the time of flare. Important differences between results with the SLEDAI and those with the LA1 were found for the cutaneous, musculoskeletal, and hematologic systems. In the SLEDAI, cutaneous involvement is determined by only 3 possible descriptors; the LA1 allows the physician to score any cutaneous lupus activity. This is the reason for the large difference between the 2 indices (46.9% versus 12.2%) in terms of “presence” of cutaneous activity at the time of flare. Similarly, in the SLEDAI, musculoskeletal descrip-
FLARE IN SLE
tors are limited to arthritis or myositis, while the LA1 allows grading of arthralgias. The differences in hematologic activity are more difficult to explain, but probably represent the physicians’ opinion that chronic stable thrombocytopenia or leukopenia did not represent lupus activity based on the LA1 scale for hematologic involvement, yet these descriptors did meet the definition of hematologic lupus involvement on the SLEDAI. In contrast to the results of other studies (19,20), we did not find abnormal serologic values during most flares. Only 10.2% of the flares were characterized by the new appearance of anti-doublestranded DNA and only 17.4% by an increasing titer of anti-double-stranded DNA. C3 and C4 levels were more likely to have changed, with 43.9% of flares characterized by a decrease in C3, and 40.8% by a decrease in C4 (Table 5). As a way of validating our quantitative definition of flare, we investigated whether the “flare” led to a change in treatment. Our method for determining this differed from that used in the BILAG index (5,17) in 2 respects: 1) physicians did not record at the visit during the flare whether they intended to change treatment; rather, this information was obtained by determining whether the medication was changed at the subsequent visit; and 2) the definition of change in treatment was not limited to prednisone or immunosuppressive agents, but could include the addition of an NSAID or antimalarial agent. This better enabled identification of flares in “minor” organ systems, e.g., the cutaneous and musculoskeletal systems. The results showed a change in treatment at 44.8% of the first flares and 52.3% of subsequent flares. There were several reasons for the apparent low concordance between “flare” and change in treatment. First, our data form did not enable the recording of an increase in NSAID or hydroxychloroquine dosage, only that their use was “present.” Second, many transitory changes in treatment, initiated by physicians or patients, were no longer in effect at the subsequent visit. Our study revealed that there were changes in the LA1 and the SLEDAI indices at the time of a flare. Both increased significantly (the LA1 by a mean of 0.26 points and the SLEDAI by a mean of 3.0 points). This demonstrates, for the first time, that both of these indices are sensitive to change and suggests that both may be useful in the routine clinic setting, to follow changes in disease activity. We have demonstrated in this study that lupus flare is quantifiable, that flare occurs frequently in
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patients with SLE of long duration, and that the majority of flares involve the so-called “minor” organ systems, i.e., constitutional (fatigue), musculoskeletal, and cutaneous. Characterization of the flare will vary depending on which activity index is used (e.g., SLEDAI or LAI). We recommend that several lupus activity indices be used in similar studies to evaluate their clinical utility. Research of this nature may play an important role in the setting of paradigms for the timing of followup visits and other practice guidelines for clinicians who see patients with SLE.
REFERENCES 1. Lahita RG: Systemic Lupus Erythematosus. New York, John Wiley & Sons, 1987 2. Jonsson H , Nived 0, Sturfelt G: Outcome in systemic lupus erythematosus: a prospective study of patients from a defined population. Medicine (Baltimore) 68: 141150, 1989 3. Swaak AJG, Nossent JC, Bronsveld W, van Rooyen A, Nieuwenhuys EJ, Theuns L, Smeenk RJT: Systemic lupus erythematosus. 11. Observations on the occurrence of exacerbations in the disease course: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis 48:455-460, 1989 4. Swaak AJG, Nossent JC, Bronsveld W, van Rooyen A, Nieuwenhuys EJ, Theuns L, Smeenk RJT: Systemic lupus erythematosus. I. Outcome and survival: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis 48:447-454, 1989 5. Symmons DPM, Coppock JS, Bacon PA, Bresnihan B, Isenberg DA, Maddison P, McHugh N , Snaith ML, Zoma AA: Development and assessment of a computerized index of clinical disease activity in systemic lupus erythematosus. Q J Med 69:927-937, 1988 6. Silverstein MD, Albert DA, Hadler NM, Ropes MW: Prognosis in SLE: comparison of Markov model to life table analysis. J Clin Epidemiol 41 :623-633, 1988 7. Liang MH, Socher SA, Roberts WN, Esdaile JM: Measurement of systemic lupus erythematosus activity in clinical research. Arthritis Rheum 3 1:817-825, 1988 8. Liang MH, Stern S, Esdaile JM: Towards an operational definition of SLE activity for clinical research. Clin Rheum Dis 1457-66, 1988 9. Liang MH, Socher SA, Larson MG, Schur PH: Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 32: 1107-1 118, 1989 10. Hellmann DB, Petri M, Whiting-O’Keefe Q: Fatal infections in systemic lupus erythematosus: role of opportunistic organisms. Medicine (Baltimore) 66:341-348, 1987 11. Ratain JS, Petri M, Hochberg MC, Hellmann DB: Accuracy of creatinine clearance in measuring glomerular
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filtration rate in patients with systemic lupus erythematosus without clinical evidence of renal disease. Arthritis Rheum 33:277-280, 1990 Petri M, Bockenstedt L , Colman J , Whiting-O’Keefe Q, Fitz G, Sebastian A, Hellmann D: Serial assessment of glomerular filtration rate in lupus nephropathy. Kidney Int 34:832-839, 1988 Petri M, Hellmann D, Hochberg M: Validity and reliability of the Lupus Activity Index (LAI): comparison with the Toronto Activity Index (SLEDAI) and Systemic Lupus Activity Measure (SLAM) (abstract). Arthritis Rheum 32 (suppl 4):S30, 1989 Committee on Prognosis Studies in SLE: Prognosis studies in SLE: an activity index (abstract). Arthritis Rheum 29 (suppl 4):S93, 1986 Bombardier C, Gladman DD, Urowitz MB, Karon D, Chang CH, and the Committee on Prognosis Studies in SLE: Development and validation of the SLEDAI: a disease activity index for lupus patients. Submitted Gladman DD, Goldsmith C-H, Urowitz MB, Bacon P, Bombardier C, Chang C, Isenberg D, Kalunian K, Liang M, Maddison P, Nived 0 , Richter M, Snaith M, Sym-
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19.
20.
mons D, Zoma A: International validation of three disease activity measures in systemic lupus erythematosus. Arthritis Rheum 32 (suppl 4):S48, 1989 Bacon PA, Coppock JS, Isenberg DA, Maddison PH, Snaith ML, Symmons DPM, Zoma AA: A comparison of disease activity scores in SLE (abstract). Br J Rheumatol 15:16A, 1986 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Tala1 N , Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271-1277, 1982 Swaak AJG, Groenwold J, Aarden LA, Statius van Eps LW, Feltkamp TEW: Prognostic value of anti-dsDNA in SLE. Ann Rheum Dis 41:388-395, 1982 Ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CGM: Measurement of increases in antidouble-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus: a long-term, prospective study. Arthritis Rheum 33:634643, 1990
~
Arthritis & Rheumatism Official Journal of the American College of Rheumatology
DEFINITION, INCIDENCE, AND CLINICAL DESCRIPTION OF FLARE IN SYSTEMIC LUPUS ERYTHEMATOSUS A Prospective Cohort Study MICHELLE PETRI, MARK GENOVESE, ERIC ENGLE, and MARC HOCHBERG The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study, 3 disease activity indices, the physician’s global assessment, the Lupus Activity Index, and the University of Toronto SLE Disease Activity Index, have been recorded, at least quarterly since 1987, on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of 21.0 in the physician’s global assessment of disease activity (measured on a 6 3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients, 98 (53%) had 1 1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms, musculoskeletal involvement, cutaneous involvement, and decreasing levels of C3 and C4. At the time of flare, the mean
University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician’s global assessment) increased by 0.26. Overall, 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study, compared with those who did not have flares. By survival analysis, no specific clinical or laboratory variables present at entry were found to predict the time to first flare. These data show that quantification of flare is possible, flare is frequent in patients with SLE of long duration, and the majority of flares involve the so-called “minor” organ systems.
Systemic lupus erythematosus (SLE) is a disease whose course is characterized by exacerbations (flares) and by remissions, which are usually associated with drug treatment. There is a general consensus that the concept of exacerbation or flare of SLE includes 1) the presence of new symptoms or signs of organ system involvement, and/or 2) the worsening of already present organ system involvement (i.e., increasing disease activity) (1). Crucial to this concept is the ability of the physician to differentiate organ involvement caused by new and/or increasing disease activity from the progression of organ damage resulting from a previously existing degree of disease activity. Previous attempts to classify exacerbations in SLE have been based on qualitative definitions, including 1) the physician’s decision to introduce or augment antiinflammatory and/or immunosuppressive
From the Division of Molecular and Clinical Rheumatology, the Division of Internal Medicine, Department of Medicine, and the Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Dr. Petri is the recipient of a Clinical Associate Physician award from the NIH OCRC (RR-00722). Dr. Hochberg’s work was supported in part by NIH grant AR-21393. Michelle Petri, MD, MPH; Mark Genovese; Eric Engle; Marc Hochberg, MD, MPH. Address reprint requests to Michelle Petri, MD, MPH, Suite 7500, 1830 East Monument Street, Baltimore, MD 21205. Submitted for publication September 20, 1990; accepted in revised form February 28, 1991. Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
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938 therapy, or 2) the occurrence of major or minor exacerbations, depending on the type of organ system involvement (2-6). Recently, Liang and colleagues identified the need for a quantitative measure of disease activity to be used in clinical research in SLE (7,8). Several such scales have been developed and have been shown to be valid and reliable as measures of disease activity in these patients (9). As part of an ongoing prospective cohort study, the ph.ysician’s global assessment of disease activity, the University of California, San Francisco/Johns Hopkins University Lupus Activity Index (LAI) (1013), and the University of Toronto Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (1416) have been completed at least quarterly since 1987, on 185 patients with SLE. Using the physician’s global assessment of disease activity as a measure of disease activity, a quantitative definition of flare was developed and the incidence of flare was estimated. In addition, the change in both the LA1 score and the SLEDAI score at the time of flare was measured, and the clinical and laboratory features of flare were characterized. The results suggest that disease flare is a common event in patients with SLE and further validate the use of disease activity indices in routine patient care.
PATIENTS AND METHODS Patients. All patients with a clinical diagnosis of SLE who are being followed up by physicians in the Division of Molecular and Clinical Rheumatology, Johns Hopkins Hospital Rheumatology Faculty Practice have been entered into a prospective cohort study of outcomes in SLE. The protocol includes routine visits at 3-month intervals and additional visits as necessitated by disease activity or complications. Physicians. Three faculty rheumatologists (MP, MH, and Dr. David Hellmann) and 5 rheumatology fellows participated in this study. We have previously shown that faculty rheumatologists and rheumatology fellows do not differ in the reliability of their assessments on either the SLEDAI or the LA1 measures (13). Data collection. At each visit, the rheumatologist or rheumatology fellow completes a data sheet (available from MP on request) that includes a physician’s global assessment of disease activity on a scale of 0-3 (only activity, not damage, is included in this assessment) and 2 quantitative measures of disease activity: the LA1 and the SLEDAI. All data sheets are examined for completeness and accuracy, and the information is entered into a database file programmed in Double Helix I1 (Odesta Corp., Northbrook, IL) on a Macintosh SE microcomputer (Apple Computer, Cupertino, CA). Routine laboratory testing (complete blood cell count, measurement of the erythrocyte sedimentation rate, urinalysis, and determination of creatinine, C3, C4, and
anti-DNA levels) is performed in the hospital laboratories, and the data are added to the database. As of June 1, 1989, 198 patients were included in the database. Of these 198 patients, 185 had been assessed on 2 or more occasions and were included in the present analysis. These 185 patients were compared, in terms of more than 25 demographic or cIinicaVlaboratory features, with the 13 who had only 1 visit, and no significant differences were found (a = 0.05). The LA1 has been used in studies of fatal infection (10) and renal function (1 1,12) in SLE. It is a 5-part scale, reflecting disease activity over the previous 2 weeks, which can be completed by the physician in approximately 1 minute. Part 1 is the physician’s global assessment of disease activity on a 0-3-point visual analog scale (VAS). Part 2 is an assessment of 4 symptoms (fatigue, rash, joint involvement, serositis), each on a 0-3-point VAS. Part 3 quantifies involvement of 4 organ systems (neurologic, renal, pulmonary, and hematologic), each on a 0-3-point VAS. Part 4 assigns scores for medication use, i.e., prednisone (1 point for 0-15 mg/day, 2 points for 16-39 mg/day, 3 points for 240 mg/day) and immunosuppressive agents (cyclophosphamide, chlorambucil, azathioprine, or methotrexate: 3 points for any). Part 5 assesses 3 laboratory variables: proteinuria (0 points for negative or trace, 1 point for 1+ , 2 points for 2-3+, and 3 points for 4+ on urine dipstick), anti-DNA (0-3 points assigned according to the range used in the local laboratory), and C3, C4, or CH50 (0-3 points assigned according to the range used in the local laboratory). The LA1 summary score is the arithmetic mean of the following values: (a) part 1 score, (b) mean of the 4 values in part 2, (c) maximum of the 4 values in part 3, (d) mean of the 2 values in part 4, and (e) mean of the 3 laboratory values. The range of possible LA1 scores is 0-3. We also obtained a modified LA1 score, in which the physician’s global assessment was omitted. SLEDAI consists of 24 items, grouped according to 9 organ systems. Definitions of the 24 items are shown on the 1-page form. The index is calculated by assigning a predetermined weight to an item that is “present,” and summing across all items. Weights are higher for organ system involvement that is more life threatening. The range of possible SLEDAI scores is 0-105. We have compared, and found no difference between, results using the original SLEDAI form with definitions and those using a short form, without definitions, that could be reproduced on our encounter form; therefore, we used the latter. Definition of flare. Flare was defined as an increase of 2 1.O on the physician’s global assessment, compared with the previous visit or a visit within the last 93 days. Each patient’s physician’s global assessment scores were plotted against time, and the plot was visually inspected by the authors to insure that this definition of flare did not exclude patients with apparent exacerbations. Change-in-treatment analysis. An alternative means of identifying important change in lupus activity is the physician’s decision to initiate or increase treatment. This is the basis for the British Isles Lupus Assessment Group activity measure (BILAG) index (5,17) and several other activity indices ( 2 4 ) . In the present study, “change in treatment” was defined as an increase in prednisone dosage,
939
FLARE IN SLE or the addition of an immunosuppressive agent, hydroxychloroquine, or a nonsteroidal antiinflammatory drug (NSAID). Statistical analysis. Data were transferred in the form of ASCII text t o an IBM-PC (AT) microcomputer, and the files were then transferred to an IBM-4381 mainframe computer at the Academic Data Processing Center, Johns Hopkins University School of Hygiene and Public Health. Data were then analyzed using the Statistical Analysis System (SAS Institute, Cary, NC).
RESULTS Patient characteristics. The 198 patients in the database had a total of 1,654 visits recorded; the 185 patients included in the study had a total of 1,641 visits recorded. Of the 14 patients who did not meet 4 or more of the American Rheumatism Association (ARA) criteria for the diagnosis of SLE (I@, 12 met 3 criteria. The remaining 2 patients each met 2 criteria (1 had lupus nephritis [proteinuria, hypocomplementemia, and positive antinuclear antibody] and 1 had hematologic features of lupus). Demographic and clinical characteristics of the 185 patients at entry into the
Table 1. Characteristics of the 185 systemic lupus erythematosus (SLE) patients studied*
Age, mean 2 S D years % female % black/% white Time since disease diagnosis, mean S D years Time since first symptoms, mean SD years Cutaneous involvement, % Musculoskeletal involvement, % Serositis, % Renal disease, % Neurologic disease, % Hematologic disease, % Sjogren’s syndrome, % Cardiac involvement, % Pulmonary involvement, % Gastrointestinal involvement, % Immunologic abnormality, % 2 4 ARA SLE criteria, %
*
*
35.7
* 12.0
91 58/42t 6.7 6.7 8.9 2 7.8 94 92 54 61 42 85 25 53 14 36 100 92
*
* Cutaneous involvement = history of new malar or discoid rash, photosensitivity, alopecia, aphthous ulcers, Raynaud’s phenomenon, subcutaneous lupus erythematosus, vasculitis, leg ulcers, panniculitis, or livedo reticularis; musculoskeletal involvement = arthralgias, erosions, arthritis, or myositis; renal disease = nephrotic syndrome, renal insufficiency, renal failure, casts, hematuria, proteinuria, or pyuria; neurologic disease = seizures, psychosis, organic brain syndrome, meningitis, depression, mononeuritis multiplex, abnormality on computed tomography or magnetic resonance imaging of the brain, visual defect, cranial neuropathy, lupus headache, or stroke; hematologic disease = leukopenia, thrombocytopenia, anemia, positive direct Coombs’ test result. ARA = American Rheumatism Association. t 1 patient was Oriental.
Table 2. Treatment history in the 185 patients*
Prednisone Aspirin or NSAID H ydroxychloroquine Immunosuppressive agentt
91 60 54 24
* Values are the percent of patients who had ever received the treatment. NSAID = nonsterodial antiinflammatory drug. t Azathioprine, cyclophosphamide, chlorambucil, or methotrexate.
cohort study are shown in Table 1; cumulative treatment history at entry into the study is shown in Table 2. Distribution of activity scores. Figure 1 shows the distribution of patients’ scores on the 4 activity indices (the physician’s global assessment, the LAI, the modified LAI, and the SLEDAI) at the first visit after entry into the study. The physician’s global assessment score was 0 in 37 patients, 0-1 in 110 patients, 1-2 in 30 patients, and 2-3 in 8 patients. The mean (+SD) physician’s global assessment score for the first visit was 0.82 (+0.71), with a median of 1.00 (minimum 0, maximum 3.00; maximum possible score 3.00). The mean LA1 score for the first visit was 0.60 (?0.43), with a median of 0.52 (minimum 0, maximum 2.05; maximum possible score 3.00). The mean modified LA1 score (with the physician’s global assessment omitted) was 0.54 (+0.40), with a median of 0.44 (minimum 0, maximum 1.81; maximum possible score 3.00). The mean SLEDAI score was 5.43 (+5.04), with a median of 4 (minimum 0, maximum 31; maximum possible score 105). The LA1 and SLEDAI differ in some of the specific clinical symptoms and signs measured. Table 3 presents data on organ system involvement at the first visit; information from both the LA1 and the SLEDAI is included. As seen, the 2 indices yielded major differences in the frequency of musculoskeletal involvement and cutaneous involvement. The SLEDAI defines musculoskeletal involvement as arthritis or myositis, whereas the LA1 defines it as joint involvement, thereby allowing physicians to include arthralgias, as well as arthritis, in the rating. Thus, the 13% difference in the percentage of patients shown to have involvement of the musculoskeletal system would be attributed to patients who had arthralgias. The SLEDAI, as originally developed and used herein, defined cutaneous involvement as a new malar rash, aphthous ulcers, or alopecia, whereas the LA1 allows the physician to score any cutaneous involvement, and thus would include, for example, worsening of preexisting malar rash, discoid rash, or livedo reticularis. This explains the rather remarkable differ-
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Toronto SLEDAI Figure 1. Distribution of patients’ lupus activity index scores at the first visit after entry into the study. A, Physician’s global assessment. B,Lupus Activity Index. C, Modified Lupus Activity Index (with the physician’s global assessment not included). D, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).
ence in the measurement of cutaneous involvement by the 2 activity indices (12% versus 32%). Recent revisions of the SLEDAI use the term “new onset or recurrence of inflammatory rash” rather than “new malar rash,” which should obviate much of this difference. Incidence of flare. The distribution of flares over a total followup time of 224 patient-years is shown in Table 4. One hundred forty-six flares occurred, in 98 of the 185 patients (53%); thus, the incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to the occurrence of a flare was 12 months. Among the patients in whom flare occurred, the mean number of flares per patient was 1.5. Change in SLEDAI or LA1 score compared with flare defined by physician’s global assessment. The score on the modified LA1 changed by a mean of 0.26
(SEM 0.03; 95% confidence interval 0.20-0.32) and the SLEDAI score changed by a mean of 3.0 (SEM 0.5; 95% confidence interval 2 4 when the physician’s global assessment increased by 2 1.O (a “flare”). Both of these changes were statistically significant (P < 0.05). The percentage change in the modified LA1 was equal to 14.4% of the observed maximum score of 1.81 and 8.7% of the maximum possible score of 3.0. The percentage change in the SLEDAI was 9.7% of the observed maximum score of 31 and 2.9% of the maximum possible score of 105. Thus, the percentage of change required in order to meet our definition of flare was higher for the LA1 than for the SLEDAI. Description of flares. Table 5 shows clinical symptoms and signs that were present or were new or worsening at the time of the first study visit during a flare, as determined using both the SLEDAI and the
FLARE IN SLE
94 1
Table 3. Clinical activity by organ system at the first visit* Cutaneous SLEDAI LA1 Musculoskeletal SLEDAI
12 32 26 39
LA1
Serositis 7
SLEDAI LA1 Renal SLEDAI LA1 Neurologic SLEDAI LA1 Hematologic SLEDAI LA1 Pulmonary (LAI) Vasculitis (SLEDAI) Hypocomplementemia or anti-DNA Constitutional Fever (SLEDAI) Fatigue (LAI)
9
31 27 8 9
23 22 8 1.6 52.4 6 51
* Values are the percent of patients (n = 185). There were differences in the criteria for involvement of the various organ systems as defined in the Systemic Lupus Erythernatosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI), and results from both are shown, when applicable. LAI. (“Worsening” was measured with the LA1 only, and was defined as a change of 0.5 points on the scale.) As indicated in the table, new or worsening cutaneous involvement, musculoskeletal involvement, constitutional systems, and hypocomplementemia were frequently found at these visits. Flare as defined by change in treatment. The occurrence of a change in treatment (increase in prednisone dosage or addition of an immunosuppressive agent, aspirin or NSAID, or hydroxychloroquine) was examined for 131 of the 146 flares. The mean SD prednisone dosage increased from 14.2 -+ 14.1 mg/day to 18.3 -+ 16.5 mg/day for all flares combined. The prednisone dosage was unchanged at 48.1% of the
*
Table 3. Distribution of flares in the 185 patients* No. of flares 0 1
2 3 4 2 15
No. of patients 97 65 22 8 2 1
98
* Among the 98 patients who had any flares (53% of the total group of patients), there were 146 flares.
flares, increased at 39.7%, and, surprisingly, decreased at 12.2%. When the 16 visits in which the prednisone dosage was decreased were reviewed, a number of apparent explanations were found. First, several patients had increased their prednisone dosage at home, prior to the clinic visit at which the physician diagnosed the flare. Second, several patients did not comply with the prescribed prednisone dosage regimens. Third, several flares were treated by an increase in the dosage of other medications, because of side effects of high-dose prednisone. Fourth, several patients were treated with pulse methylprednisolone, enabling a rapid reduction in the daily prednisone dosage. Fifth, in several cases, the prednisone dosages were altered by physicians who were not rheumatologists. A cytotoxic agent was added at 3.1% of the Table 5. Clinical activity at the first visit during a flare, in 98 patients* Present Cutaneous SLEDAI LA1 Musculoskeletal SLEDAI LA1 Serositis SLEDAI LA1 Renal SLEDAI LA1 Neurologic SLEDAI LA1 Hematologic SLEDAI LA1 Pulmonary (LAI) Vasculitis (SLEDAI) H ypocomplementemia SLEDAI LAI, C3 LAI, C4 Anti-DNA SLEDAI LA1 Constitutional Fever (SLEDAI) Fatigue (LAI) Raynaud’s phenomenon
New or worsening
12.2 46.9
9.2 38.0
37.8 58.2
20.4 49.0
10.2 12.2
9.2 10.2
30.6 22.4
16.3 18.0
16.3 21.4
12.2 19.4
27.6 17.3 7.1 9.2
7.1 11.2 6.1 6.1
54.1 NA NA
6.1 (new) 43.9 (worsening) 40.8 (worsening)
26.5 NA
10.2 (new)? 17.4 (worsening)
4.1 66.3 18.0
3.0 48.0 10.0
* Values are the percent of patients. There were differences in the criteria for involvement of the various organ systems as defined in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI), and results from both are shown, when applicable. NA = not applicable. t Anti-DNA was considered new if it was recorded as present at the visit during the flare, and absent at the previous visit, on the SLEDAI form.
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PETRI ET AL
flares. Hydroxychloroquine was added at 5.3%. Aspirin and/or an NSAID was added at 6.1%. Overall, an increase in treatment occurred at 39 of the 87 firstflares for which the data were available (44.8%) and at 23 of the 44 subsequent flares for which the data were available (52.3%). It is possible that some lupus flares may be induced as a result of the physician’s decision to taper prednisone. In our cohort, 28% of the flares were preceded by a reduction in the prednisone dosage. Risk factors for occurrence of the first flare. Patients who experienced flares fulfilled more of the ARA criteria for SLE at entry into the study (mean 6.5 versus 6.0; P = 0.04) and were followed up for a longer period of time after entry (mean 1.4 years versus 1.0 years; P 5 O.OOl), compared with those in whom flare did not occur. Using survival analysis, no specific clinical or laboratory variables present at entry were found to predict the length of time to first flare.
DISCUSSION Systemic lupus erythematosus is characterized by episodic changes of activity, or “flare.” It is this episodic nature of its course that makes it very different from other rheumatic diseases, such as rheumatoid arthritis, which usually involve more constant disease activity. Although clinicians recognize intuitively the concept of lupus flare, it has not been defined in a quantitative manner that would enable the conduct of clinical research studies of flare. In fact, lupus disease activity indices currently under development do not incorporate the concept of flare, or change in activity. In our determination of a quantitative definition of flare, we included 2 basic concepts: 1) a flare represents a change in activity, but this change can occur anywhere on the disease spectrum, i.e., from no activity to mild, from mild to moderate, or from moderate to severe activity; and 2) a flare implies a change in the slope, or rate of change, of disease activity over time, i.e., a change in activity from none to mild that occurred gradually over several years would not represent a flare. Thus, our quantitative definition of flare is a change in lupus activity of 21.0 on the physician’s global assessment (which has a range of 0-3 on a visual analog scale), that occurs over a 93-day period or since the last visit. Others have chosen to define flare differently. For example, in a Markov analysis of disease activity and outcome, flare is defined as the most severe level
of activity (6). Another definition of flare is derived from the physician’s decision to change treatment; this is the basis for the BILAG index and other disease activity indices (2-5,17). Indices based on this “change-in-treatment” paradigm may be weighted toward revealing “flares” in those organ systems in which prednisone or immunosuppressive treatment is generally used. Ninety-eight of the 185 patients in our cohort (53%) had a flare, by our quantitated definition, during the study period. Thirty-three patients had more than 1 flare. Previous investigations (3,4) have suggested that lupus activity declines over time. Although our study did not directly address this, our results indicate that the patients, who had a mean 6.7-year duration of disease since the diagnosis of lupus (and an 8.9-year duration since the onset of the first symptoms), have continued to show important changes in disease activity. The incidence of flare was 0.65 per patient-year of followup, with a mean time to flare of 12 months. Information on the incidence and time of flare has potential utility in setting practice guidelines for timing of routine followup visits. We characterized the flares using information from 2 activity indices, the LA1 and the SLEDAI, which were completed at each patient visit. Fatigue (48% by LAI), musculoskeletal involvement (49% by LAI), and cutaneous lupus (38% by LAI), were the symptoms most likely to be newly occurring or worsening at the time of flare (Table 5). Because fatigue is difficult to evaluate, it has been omitted in some indices, such as the SLEDAI, but retained in others, including the LA1 and the Systemic Lupus Activity Measure (9). Our results in this study highlight the association of fatigue with flare. The characteristics at the time of the first flare, shown in Table 5, reflect differences between the SLEDAI and the LAI. The SLEDAI cannot be used to determine worsening of a flare descriptor, since the descriptor is coded only as present or absent. It can be used to identify a descriptor that has newly appeared at the time of flare. Important differences between results with the SLEDAI and those with the LA1 were found for the cutaneous, musculoskeletal, and hematologic systems. In the SLEDAI, cutaneous involvement is determined by only 3 possible descriptors; the LA1 allows the physician to score any cutaneous lupus activity. This is the reason for the large difference between the 2 indices (46.9% versus 12.2%) in terms of “presence” of cutaneous activity at the time of flare. Similarly, in the SLEDAI, musculoskeletal descrip-
FLARE IN SLE
tors are limited to arthritis or myositis, while the LA1 allows grading of arthralgias. The differences in hematologic activity are more difficult to explain, but probably represent the physicians’ opinion that chronic stable thrombocytopenia or leukopenia did not represent lupus activity based on the LA1 scale for hematologic involvement, yet these descriptors did meet the definition of hematologic lupus involvement on the SLEDAI. In contrast to the results of other studies (19,20), we did not find abnormal serologic values during most flares. Only 10.2% of the flares were characterized by the new appearance of anti-doublestranded DNA and only 17.4% by an increasing titer of anti-double-stranded DNA. C3 and C4 levels were more likely to have changed, with 43.9% of flares characterized by a decrease in C3, and 40.8% by a decrease in C4 (Table 5). As a way of validating our quantitative definition of flare, we investigated whether the “flare” led to a change in treatment. Our method for determining this differed from that used in the BILAG index (5,17) in 2 respects: 1) physicians did not record at the visit during the flare whether they intended to change treatment; rather, this information was obtained by determining whether the medication was changed at the subsequent visit; and 2) the definition of change in treatment was not limited to prednisone or immunosuppressive agents, but could include the addition of an NSAID or antimalarial agent. This better enabled identification of flares in “minor” organ systems, e.g., the cutaneous and musculoskeletal systems. The results showed a change in treatment at 44.8% of the first flares and 52.3% of subsequent flares. There were several reasons for the apparent low concordance between “flare” and change in treatment. First, our data form did not enable the recording of an increase in NSAID or hydroxychloroquine dosage, only that their use was “present.” Second, many transitory changes in treatment, initiated by physicians or patients, were no longer in effect at the subsequent visit. Our study revealed that there were changes in the LA1 and the SLEDAI indices at the time of a flare. Both increased significantly (the LA1 by a mean of 0.26 points and the SLEDAI by a mean of 3.0 points). This demonstrates, for the first time, that both of these indices are sensitive to change and suggests that both may be useful in the routine clinic setting, to follow changes in disease activity. We have demonstrated in this study that lupus flare is quantifiable, that flare occurs frequently in
943
patients with SLE of long duration, and that the majority of flares involve the so-called “minor” organ systems, i.e., constitutional (fatigue), musculoskeletal, and cutaneous. Characterization of the flare will vary depending on which activity index is used (e.g., SLEDAI or LAI). We recommend that several lupus activity indices be used in similar studies to evaluate their clinical utility. Research of this nature may play an important role in the setting of paradigms for the timing of followup visits and other practice guidelines for clinicians who see patients with SLE.
REFERENCES 1. Lahita RG: Systemic Lupus Erythematosus. New York, John Wiley & Sons, 1987 2. Jonsson H , Nived 0, Sturfelt G: Outcome in systemic lupus erythematosus: a prospective study of patients from a defined population. Medicine (Baltimore) 68: 141150, 1989 3. Swaak AJG, Nossent JC, Bronsveld W, van Rooyen A, Nieuwenhuys EJ, Theuns L, Smeenk RJT: Systemic lupus erythematosus. 11. Observations on the occurrence of exacerbations in the disease course: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis 48:455-460, 1989 4. Swaak AJG, Nossent JC, Bronsveld W, van Rooyen A, Nieuwenhuys EJ, Theuns L, Smeenk RJT: Systemic lupus erythematosus. I. Outcome and survival: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis 48:447-454, 1989 5. Symmons DPM, Coppock JS, Bacon PA, Bresnihan B, Isenberg DA, Maddison P, McHugh N , Snaith ML, Zoma AA: Development and assessment of a computerized index of clinical disease activity in systemic lupus erythematosus. Q J Med 69:927-937, 1988 6. Silverstein MD, Albert DA, Hadler NM, Ropes MW: Prognosis in SLE: comparison of Markov model to life table analysis. J Clin Epidemiol 41 :623-633, 1988 7. Liang MH, Socher SA, Roberts WN, Esdaile JM: Measurement of systemic lupus erythematosus activity in clinical research. Arthritis Rheum 3 1:817-825, 1988 8. Liang MH, Stern S, Esdaile JM: Towards an operational definition of SLE activity for clinical research. Clin Rheum Dis 1457-66, 1988 9. Liang MH, Socher SA, Larson MG, Schur PH: Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 32: 1107-1 118, 1989 10. Hellmann DB, Petri M, Whiting-O’Keefe Q: Fatal infections in systemic lupus erythematosus: role of opportunistic organisms. Medicine (Baltimore) 66:341-348, 1987 11. Ratain JS, Petri M, Hochberg MC, Hellmann DB: Accuracy of creatinine clearance in measuring glomerular
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12.
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