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THE PROGRESSION OF EROSION AND JOINT SPACE NARROWING SCORES IN RHEUMATOID ARTHRITIS DURING THE FIRST TWENTY-FIVE YEARS OF DISEASE JOHN T. SHARP, FREDERICK WOLFE, DONALD M. MITCHELL, and DANIEL A. BLOCH
Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study, we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis, Rheumatism, and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists, obtained from 210 patients, were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score, which sums erosion and joint space abnormalities and has a maximum possible score of 314, was approximately 4 units per year over the first From the University of Colorado School of Medicine, Denver; The Joe and Betty Alpert Arthritis Center at Rose Medical Center, Denver, Colorado; the University of Kansas School of Medicine, Wichita; The Arthritis Center, Wichita, Kansas; and the Divisions of ImmunologylRheumatologyand Biostatistics, Stanford University School of Medicine, Stanford, California. Supported in part by NIH grant AR-21393, and by clinical research funds from Rose Medical Center. John T. Sharp, MD: Professor of Medicine, University of Colorado School of Medicine, and Director, The Joe and Betty Alpert Arthritis Center at Rose Medical Center (current address: Clinical Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia); Frederick Wolfe, MD: Clinical Professor of Medicine, University of Kansas School of Medicine, Wichita, and Director, The Arthritis Center; Daniel A. Bloch, PhD: Senior Research Associate, Stanford University School of Medicine. Dr. Mitchell is deceased. Address reprint requests to John T. Sharp, MD, 712 East 18th Street, Tifton, GA 31794. Submitted for publication April 5 , 1990; accepted in revised form December 31, 1990. Arthritis and Rheumatism, Vol. 34, No. 6 (June 1991)
25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that frequently follows a course which is continually progressive for many years. A number of features have been proposed to measure its progression and outcome. One of these, radiologic assessment, measures the extent of bony erosions and loss of articular cartilage. Several methods have been proposed to assess these features (1-12), and studies comparing various methods have concluded that there is strong agreement among different observers using either the same or different techniques, and among the scores assigned to the same set of radiographs by the same observer using different methods (4,6,7,10-13). These studies have established the reproducibility of scoring radiologic abnormalities. The present study utilized one of these scoring methods (1 1) to determine the progression of radiologic abnormalities in approximately 100 consecutive patients from each of 3 different centers. Radiologic abnormalities were observed to develop at a nearly steady rate between 3 and 25 years after onset of disease. Although limitations were imposed on the study by the discontinuous nature of the data, it is unlikely that more complete data can be obtained.
METHODS This multicenter study utilized data maintained in the databanks of the Arthritis, Rheumatism, and Aging Medical
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS Table 1. Number of patients and films, by patient location No. with 2or
with films
more films
No. of
films
films per patient
100 90 (90) 103 58 (56.3) 89 62 (69.7) 292 210(71.9)
67 57 39 163
199 270 181 650
2.2 4.7 2.9 3.1
80 77 49 206
76 (95) 50 (64.9) 48 (98) 174 (84.5)
63 49 31 143
180 245 153 578
2.4 4.9 3.2 3.3
20 26 40 86
14 (70) 8 (30.8) 14 (35) 36 (41.9)
4 8 8 20
19 25 28 72
1.4 3.1 2.0 2.0
No.
(14). The last 103 patients with a diagnosis of definite or classic RA (15) were selected for this study. The Wichita databank was begun in 1976 by entering data on established and new patients from the practice of one of the authors (FW). Laboratory and radiographic data were obtained on patients as needed for clinical care. The first consecutive 100 patients from this databank with a diagnosis of definite or classic RA were chosen for the present study. The first 100 consecutive patients admitted to the Alpert Arthritis Center on or after January 1, 1975 with an admitting diagnosis of RA were selected from the Denver databank. The diagnosis in 11 patients was changed at the time of hospital discharge or during the course of followup, leaving 89 patients with definite or classic RA who were included in this study. During the study, efforts were made to reexamine every living patient. The evaluation included a detailed joint examination and general physical examination. Laboratory data obtained included a complete blood cell count, erythrocyte sedimentation rate, rheumatoid factor titer by latex fixation, and fluorescent antinuclear antibody titer. A disability index was calculated from items on the Health Assessment Questionnaire (16). Patients who could not come to the centers were sent questionnaires or interviewed by telephone and were asked to have radiography and laboratory tests performed by their family physicians. All patients were successfully traced. Eighty-six of the 292 had died. All the known previous hand and wrist films were collected, and new films were obtained when possible. A total of 650 films were obtained from 210 (72%) of the 292 patients (Table I ) . Of those with films, there was an average of 3.1 films per person, and 163 had 2 or more films. Films were obtained on 48 of 49 living patients in the Denver group (98%), but only 14 of the 40 who had died (35%). The Kansas center obtained films from 90% of their
Average
No. (%)
no. of
All patients
Kansas Saskatoon Denver Total Patient still living at time of study Kansas Saskatoon Denver Total Patients deceased at time of study Kansas Saskatoon Denver Total
66 1
Information System, from the University of Saskatchewan, Saskatoon, Canada, The Arthritis Center of Wichita, Kansas, and The Joe and Betty Alpert Arthritis Center, Rose Medical Center, Denver, Colorado. One thousand two hundred five patients over the age of 16 with a clinical diagnosis of RA, who were enrolled in a followup program at the University of Saskatchewan between 1966 and 1974, constitute the Saskatoon databank
Table 2. Characteristics of the study population, by patient location* ~~
Kansas No. of patients
Age at first visit, years Age at last visit, years Age at disease onset, years % female Disease duration at first visit, years Disability index at first visit, 0-3 scale Nodules, % ever hadt Morning stiffness, hours ESR, mm/hour$
Hemoglobin, gm/dl RF, log titer9
52.4 60.4 44.3 8.0 1.21 2.10 36.5 12.7 743
100 t 1.42 t 1.37 t 1.39 72 t 0.907 t 0.106 45 2 0.252 t 1.98 2 0.127 t 124
Saskatoon
Denver
103
89 55.9 t 1.44 65.1 t 1.40 45.5 t 1.44 66 10.4 2 0.959 1.35 t 0.150 34 1.97 ? 0.347 49.0 t 2.40 12.9 t 0.159 818 t 163
53.4 62.3 43.7
* 1.57 ? ?
1.41 1.53
63 9.7 t 1.12 1.09 t 0.102 55 I .47 ? 0.133 47.0 t 2.64 12.9 ? 0.157 2,181 t 266
292 53.8 62.5 44.4 67 9.4 1.20 45 1.82 44.1 12.9 1,317
* Unless otherwise indicated, values are the mean t SEM. Values for morning stiffness, erythrocyte sedimentation rate (ESR), and hemoglobin were averaged over all observations. I A patient was considered to have nodules if a nodule was recorded as present at any time during the course of observation. For comparison of nodule frequency across groups, 2 = 9.022, degrees of freedom [dfl = 2, P = 0.01 1. $ The average ESR values were significantly different across groups (one-way F statistic = 8.002, df = 2,285, P < 0.001). 0 The average titers of rheumatoid factor (RF; by latex fixation) were significantly different across groups (one-way F statistic = 16.350, df = 2,257, P < 0,001).
SHARP ET AL
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Table 3. Characteristics of patients who were still living at the time of the study and patients who were deceased at the time of the study, according to availability of films*
No. of patients Age at first visit, yearst Age at last visit, yearst Age at disease onset, yearst % female Disease duration at first visit, years$ Disease duration at last visit, years Disease duration at first film, years§ Disease duration at last film, years Radiologic progression rate, units/years§ Disability index at first visit, 0-3 scale Nodules, % ever had Morning stiffness, hours ESR, mm/hourt Hemoglobin. gm/dl$ RF, 10gtiter -
Living patients with films
Living patients without films
Deceased patients with films
Deceased patients without films
174 48.9 2 1.05 58.8 2 1.05 41.2 -t 0.999 71.7 7.5 2 0.688
32 54.0 t 2.72 62.5 rt 2.59 43.8 t 2.74 56.3 10.2 t 1.62
36 62.0 2 1.29 68.6 t 1.39 49.7 2 2.20 58.3 12.2 ? 1.75
50 65.2 2 1.69 70.8 t 1.63 52.1 t 2.08 64.0 13.1 t 1.61
17.5 t 0.707
18.7 2 1.55
18.9
1.82
18.7 t 1.61
?
9.6 2 0.773
13.3 2 1.73
16.2 t 0.729
15.7 t 1.89
4.71 t 0.424
7.90 2 1.80
1.11 t 0.073
0.762 t 0.206
47.7 1.76 t 0.137 37.8 2 1.48 13.1 t 0.101 1,271 f 176
40.6 1.32 t 0.239 44.0 t 4.17 13.1 rt 0.299 1,321 t 280
1.77
0.207
2.00 t 0.277
44.4 2.85 t 0.706 51.7 t 3.88 12.6 ? 0.224 1,811 ? 347
40.0 1.63 t 0.366 60.3 t 4.11 12.2 t 0.225 1,141 t 248
f
* P values for comparisons of living patients who had films with living patients who did not have films and of deceased patients who had films with deceased patients who did not have films varied between 0.057 and 0.943, with only 2 values CO.10. The 2-sample t-test was used to compare means of continuous variables, and the chi-square test was used to compare dichotomous variables. Unless otherwise indicated, values are the mean t SEM. See Table 2 for additional explanations and definitions. t P < 0.001, all living patients versus all deceased patients. j: 0.001 < P < 0.01, all living patients versus all deceased patients. $ 0.01 < P < 0.05, all living patients versus all deceased patients. patients, including 76 of the 80 who were living (95%) and 14 of the 20 who had died (70%). The largest number of available films per patient was from the Saskatoon group. For scoring of radiologic changes, individual paTable 4. Progression of radiologic scores in patients who had 2 or more films, by disease duration
Disease duration, mean (range) years*
No. of patients
2.0 (0.91-3.3) 6.1 (5.05-7.29) 10.0 (8.81-11.15) 14.0 (12.90-14.82) 18.1 (17.33-18.83) 22.8 (21.8624.36)
23 31 22 12 9 6
Radiologic progression rate, mean t SEM unitdyeart 9.076 5.270 6.291 10.109 5.089 2.819
2
3.275
t 1.240 t 2.214 t 2.124 2 2.046
t 0.821
* Patients were selected who had 2 or more films in 4-year intervals between 0 and 20 years of disease, or between 20 and 25 years of disease. Ranges given are the actual disease durations. t The mean radiologic progression rate was determined from the rates of progression in all patients in the duration interval who had 2 or more films, using method I , as described in Methods.
tient’s films were identified in sets. Within sets, the sequence of films was blinded, using random number tables to assign a label A, B , C, . . . etc. For example, a patient with 3 films would be equally likely to have the first film labeled A, B, or C. All radiographs were scored by one of the authors (JTS) for extent of erosions and joint space narrowing, using a modification of the method he originally described, which has been thoroughly tested ( I , 11). Films from Kansas were also scored by FW, and films from Saskatoon by DMM. Correlation coefficients were 0.953 (n = 122) between FW and JTS and 0.948 (n = 229) between DMM and JTS. Since JTS was the only one who read all films, the scores used in the studies reported here are those he assigned. Total radiologic scores were the sum of erosion scores for 34 joints and joint space narrowing scores for 36 joints (1 1). If surgery had been performed during the interval between 2 films, the score of the film obtained before the surgery was assigned to each joint that was affected by the operation, so that progression rates would not artifactually retrogress. Data on 142 variables collected on patients in each center were extracted into special files and merged. Analysis was carried out using Medlog (17) and SAS (18) software programs.
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS
Table 5. Progression of radiologic scores in films taken early in the disease course and films taken late in the disease course, in the same patients*
First film Last film
No. of patients
Disease duration, mean years
Radiologic progression rate, mean t SEM units/year
62 62
4.057 14.206
4.1 10 t 0.898 4.218 k 0.474
* All patients were selected who (a) had their first film within 10 years after disease onset, (b) had their last film more than 10 years after onset and more than 1 1 months after the first film, and (c) had the last film obtained after January I , 1984. The mean interval between films was 10.2 years (range 1.5-14.5 years). Radiologic progression rates shown in this table were calculated by method 2, i.e., progression rate = score + disease duration.
Three different methods of measuring the rate of progression of radiologic abnormalities for each patient were tested. Method 1 used the slope of radiologic scores for each individual patient who had 2 or more films, by employing the regression equation using radiologic scores as the dependent variable and years from disease onset as the independent variable. Method 2 calculated the progression rate by dividing the radiologic score by the duration of disease in years for each film, and determined the mean for all films as that individual’s progression rate. Method 3 took the difference between the first and last radiologic scores and divided by the difference in time in years. Methods 1 and 3 required that the patient have 2 or more films, whereas every patient with 1 or more films was included in the rates determined by method 2. Methods I and 3 were based on observed lime between films, whereas method 2 relied on the patient’s own report of the date of disease onset. Progression rates presented herein were determined by method 1 except where otherwise indicated.
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Table 7. Progression of radiologic scores in patients at each center, by disease duration Disease duration, years 0.01-3 3-10 1C15
15-25
Mean radiologic progression rate, units/year* Kansas
Saskatoon
8.628 (7) 6.829 (23) 2.932 (5) 3.144 (9)
3.827 (8) 5.174 (28) 5.953 (8) 2.560 (15)
Denver 2.164 8.270 2.768 5.348
(5) (14) (14) (7)
* Determined by method I , as described in Methods. Values in parentheses are the number of patients.
RESULTS Patients from the 3 centers were comparable in most important respects (Table 2). To assess the potential bias created by incomplete radiologic data, patients with radiographs available were compared with those without. There were significant differences with regard to age at first and last examination, age at onset of disease, and duration of disease at first examination. These differences are accounted for by the greater proportion of deaths in the group without films. When clinical and laboratory features of disease were compared between living patients with films and living patients without films, the living patients with films were representative of all living patients and the deceased patients with films were representative of all deceased patients (Table 3). This suggests that our assessment of the radiologic progression rate may be Table 8. Ceiling scores at 5-year intervals for the first 25 years of rheumatoid arthritis* % of joints given ceiling scores,
mean 2 SEM Table 6 . Progression of radiologic scores in the 29 patients who had 5 or more films, all more than 1 year apart Disease duration at midpoint between films, mean SEM years
*
Film pair Films Films Films Films
I and 2 and 3 and 4 and
2 3 4 5
4.23 6.87 9.77 12.68
t 0.687 t 0.711 t 0.750
t 0.741
Radiologic progression rate, mean t SEM units/ year* 4.554 5.368 7.231 5.017
2
0.192
t 0.172
t 0.318 5 0.281
* Radiologic progression rates shown in this table were calculated by the following formula for each sequential pair of films (method 3): progression rate = radiologic score (second film) - radiologic score (first film) time between films in years
Disease duration, mean (range) years 2.7 (0-5) 7.6 (5-10) 12.3 (10-15) 17.2 (15-20) 22.3 (2C25) 3 1.7 (2548)
No. of films 132 159 111 59 38 45
Erosion score of 5 0.7 3.5 5.4 14.7 19.4 19.7
JSN score of 4
Erosion score of 5 and JSN score of 4
t 0.243 0.05 2 0.047 t 0.593 0.7 2 0.189
1.05 2.45 t 3.99 t 3.67 4 2
0.3 t 0.135 2.1 2 0.330 1.5 k 0.336 3.4 0.591 2.5 2 0.684 8.5 t 1.36 3.6 t 1.45 11.2 C 2.20 3.8 t 0.976 11.5 2 2.16
* Ceiling scores are the highest scores used in the scoring system (score of 5 for erosion, score of 4 for joint space narrowing [JSN]). Percent ofjoints given ceiling scores were determined as the number ofjoints scored 5 for erosions divided by the number ofjoints scored for erosions, the number of joints scored 4 for JSN divided by the number of joints scored for JSN, and the sum of joints scored 5 for erosions and 4 for JSN divided by the sum of the number of joints scored for erosions and those scored for JSN.
664
SHARP ET AL centers, the possibility that this may have introduced bias by causing overrepresentation of patients with active and progressive disease was considered. To assess this, we selected 62 patients who (a) had 2 or more films, (b) had their first film within the first 10 years after onset of disease, (c) had their last film more than 10 years after onset and at least 11 months after the first film, and (d) had their last radiography performed after January 1, 1984, as part of the routine fbllowup for this study. The progression rates for the early films were not different from the late ones, as determined by method 2 (Table 5). Twenty-nine patients had 5 or more films, with at least a I-year interval between each pair of films. The rates of radiologic progression for each sequential film pair were not significantly different (Table 6). Progression rates were determined for each of the centers separately, using longer intervals to allow
250
200
w 150
8
s:>a
p:
>;:
ii
100
50
0
10
20
30
40
50
160 60
DURATION OF DISEASE (years) Figure 1. Total radiologic scores as a function of disease duration, ih all patients for whom 2 or more films were available.
140 120
slightly underestimated because of the underrepresentation of those patients who died during the followup period. However, deaths were not clustered in the early years of disease, and in fact, the duration of disease at last visit was similar for patients who had died and those who were still living at the end of the study. Therefore, no attempt was made to adjust progression rates, due to the small correction that would be required. Using several methods, a significant change in rates of progression of radiologic scores with increasing duration of disease was not detected. Progression rates at 4-year intervals, determined by method 1, varied substantially but did not show a trend, and mean rates were not significantly different at different durations (Table 4). In this analysis, 4-year intervals were chosen as the shortest intervals that include a meaningful number of patients in each interval who had 2 or more films taken at least 11 months apart within the interval. Since films were obtained during the early years of the study as part of routine patient care in all
w
100
U
0
5: >.
80
a
g:
x
60
40 20 1
(n) = ## patients contributing 0
10
20
30
40 DURATION OF DISEASE (years)
50
Figure 2. Progression of radiologic scores as illustrated using the averages of constrained cubics at increasing durations of disease.
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS
larger numbers of patients in each subset. N o trends or consistent differences were observed (Table 7). The possibility that a ceiling effect might have occurred as a result of the scoring method was examined by tabulating the number of joints in each individual radiologic score that were assigned the highest score for erosion and/or joint space narrowing. The percentage of joints scored at the top of the scales steadily increased with increasing duration of disease (Table 8), indicating that a ceiling effect may have accounted for part of the apparent decline in the rate of progression of radiologic scores with increasing duration of disease. The relationship of radiologic scores to duration of disease was examined further by fitting several models. The complexity of the task is illustrated in Figure 1 , which plots radiologic scores against duration of disease for all patients who had 2 or more films. It is evident that subjects were observed for varying lengths of time at different durations of disease. The first model-based method fitted a constrained cubic through patients’ data (86 patients had 3 or more data points), using the following constraints: 1) the model would pass through the origin, corresponding to a score of 0, at the onset of disease, and 2) the cubic would be nondecreasing. These cubics, which are averaged in Figure 2, suggest a gradually decreasing rate up to approximately 25 years of disease. After this time, there were data on only 4 subjects. The second method, based on fitting a quadratic curve through each patient’s data, was chosen because a preponderance of subjects would be expected to have negative regression coefficients for the quadratic term if the rate of progression of radiologic scores were decreasing with increasing duration of disease. This analysis demonstrated closely similar proportions of subjects having positive and negative quadratic regression coefficients. One nonparametric method fitted a smooth curve through the scatterplot of first-order differences using moving averages. This method suggested a decreasing rate after approximately 25 years of disease, but, using 25 bootstrap replicates, the variability of the results was large. In summary, the results of one modeling technique and a nonparametric analysis suggested a decreasing rate of radiologic progression after longer durations of disease, though the data were not conclusive. Based on the data in Tables 4,5, and 6 and Figure 2, the mean rate of progression of radiologic scores is
665
approximately 4 units per year over the first 25 years of disease, but the rate may be more rapid by as much as twofold in the very early years and slower by twofold in the later years. Data beyond 25 years duration were too scanty to enable estimation of the rate of progression.
DISCUSSION Radiologic abnormalities in rheumatoid arthritis accurately represent disease severity and progression. Erosions and loss of cartilage are direct effects of the disease process of RA. Scoring of radiologic abnormalities is reproducible (4,6,7,10-13), and these scores correlate with the extent of deformities, limitation of motion, and disability (1,19-21). The progression of radiologic abnormalities correlates with the extent of joint swelling during the interval between films (22), the presence of nodules ( l ) , and laboratory abnormalities which reflect the severity of disease (1,9,19,2325). X-ray films represent a permanent record, and objectivity in scoring is assured by assigning a random and blinded sequence. The rate of progression of radiologic abnormalities is very important in defining the “natural history” of the disease and in determining the effectiveness of therapeutic measures. Previous long-term, longitudinal studies on radiologic changes in the hands and wrists were limited. Initially, Scott et al, in following the cases of 88 patients with RA for 10 years, observed no relation between the rate of radiologic progression and the duration of disease (24). In another study of patients at the same institution, however, total Larsen scores (2,3) for 13 groups of joints (10 groups in addition to fingers and wrists) demonstrated a weak relationship between radiologic abnormality and duration of disease when analyzed by linear regression (21): The rate ofjoint damage was negatively related to the square root of disease duration (r = -0.44). However, the number of cases was small, and 2 outliers may have accounted for an undue proportion of the association. Subsequently, Scott and colleagues demonstrated that radiologic progression decreased in the later years when plotted as an absolute score, but was linear when calculated as a percentage of maximum possible change (26), a result that would be expected with a ceiling effect. De Carvalho et a1 (27), who studied the sum of Larsen scores on “all limb joints, the cervical spine and the sacroiliac joints” and Larsen (28), who studied hands and wrists, reported that radiologic scores in-
SHARP ET AL creased at a steady rate when plotted against the square root of duration of disease. However, de Carvalho and colleagues (29) demonstrated a high proportion of maximal scores in study patients with longer disease duration, and Larsen and Thoen (28) recognized the possibility that a ceiling effect was responsible for the leveling off of the progression in the later years. Ideally, we would like to know the radiologic scores at regular intervals from the onset of disease through the remaining lifetime, for a sufficient number of typical patients to define the mean progression rate and the variability across patients. Unfortunately, these data are not likely to ever be obtained. Some patients do not receive care in the early years of their arthritis. Many shift care between providers, and others discontinue their visits to providers because their disease has gone into remission or they have become discouraged by poor response to treatment. Other patients are lost to followup when they enter nursing homes. There are no practices and very few clinics that have been established long enough to have followed patients for the 50 years or longer that would be required to collect clinical data on a large group of patients from disease onset to death. Films are not obtained at regular intervals and may not be kept more than a few years. Some drugs have been demonstrated to slow the course of radiologic progression over the short term, and these drugs are used regularly in modern clinics for patients who appear to have progressive disease (30-34). For these reasons, we have accepted the premise that it is unlikely that complete data will be obtained and have studied consecutive patients from 3 geographically disparate centers which represent different forms of practice. The rate of progression of radiologic abnormalities was found to be minimally influenced by the duration of disease, up to 25 years from the time of onset. How firm is this conclusion? Can we believe that RA (measured by radiologic abnormality scores) progresses at a nearly steady rate for the first 25 years across the “universe” of RA patients, or must we have some reservations that the sample in this study was not representative of RA in the general population? A number of factors that might influence the analysis must be considered. Films were obtained on 84% of living patients from all centers and on more than 94% from 2 of the centers (Table 1). Since there were no apparent differences among the 3 centers in the rates of radiologic progression (Table 7) and no
clinical or laboratory features were overrepresented in patients without films (Table 3), we conclude that factors influencing which living patients had films obtained did not produce a large bias. The problem is more serious with regard to deceased patients, of whom only 41% had films available. Among deceased patients, those without films were older at onset of disease and when first examined, but other differences were not significant. The duration of illness at the time of the last followup and the duration at the time the last film was obtained were not appreciably different between those with and without films, whether living or- deceased. Therefore, it seems reasonable to conclude that the deceased patients with films are representative of all deceased patients and that the data are representative of rheumatoid arthritis in these 3 centers during the observation period. Other investigators have emphasized that radiologic abnormalities are common in the first few years of disease but have not undertaken longitudinal studies comparing the rate of progression in the early period with that in the subsequent years. The data presented here are somewhat scanty with regard to the first 2 years of RA and do not enable firm conclusions to be drawn regarding the progression rate in this early phase of the disease. This caution is reinforced by the observation that the graph of radiologic progression drawn from the regression equation shows a positive radiologic score at zero duration of disease. This effect might result from a different slope during the first 2 or 3 years of illness or from a systematic error in determining the date of onset of disease. The number of films obtained after 25 years of disease is limited, and we have not attempted to draw any conclusions about the progression of radiologic abnormalities in this late period of illness. One would expect that a ceiling effect might occur in the late stage of disease. When scores for individual joints were analyzed, the percentage that had reached the maximum score increased with greater duration of disease, suggesting that a ceiling effect in the individual joint scores could account for some of the gradual decrease in the progression rate of radiologic scores shown in Figure 2. It should also be pointed out that individual readers use the scoring system differently. JTS, who read all the films in this study, is one of the more conservative scorers among multiple readers who scored a test set of films in a recent study (11). Films read by a reader who regularly scores involved joints
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS higher in the scale would s h o w a greater ceiling effect in a group encompassing t h e wide time span a n d extremes of severity represented in this study. Although data from t h e first 3 years of disease a n d after 25 years are scanty, t h e results shown in Figure 2 suggest that progression of radiologic scores over the first 25 years of RA is fairly constant, with an average rate of increase of approximately 4 units per year, perhaps somewhat more rapid in the very early years a n d slowing to a b o u t 3 units in t h e later years.
ACKNOWLEDGMENTS The authors thank Byron William Brown, Jr., for advice on statistical aspects of the study and for helpful comments on the manuscript. Jerry Halpern made the calculations depicted in Figure 2. J. T. Sibley assisted in providing missing details about the Saskatoon databank and made thoughtful suggestions on the manuscript. John Oehlert assisted by creating the merged data file using extracted data from the 3 study centers. May Haga, Mary Ann Cathey, and Melinda Tharan assisted in data collection in Saskatoon, Wichita, and Denver, respectively.
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of scoring the progression of radiologic changes in rheumatoid arthritis: correlation of radiologic, clinical and laboratory abnormalities. Arthritis Rheum 14:’70& 720, 1971 Larsen A: A radiologic method for grading the severity of rheumatoid arthritis (thesis). University of Helsinki, Helsinki, Finland, 1974 Larsen A, Dale K, Eck M: Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol [Diagn] (Stockh) 18:481491, 1977 Sharp JT, Bluhm GB, Brook A, Brower AC, Corbett M, Decker JL, Genant HK, Gofton JP, Goodman N, Larsen A, Lidsky MD, Pussila P, Weinstein AS, Weissman BN, Young DY: Reproducibility of multi-observer scoring of radiologic abnormalities in the hands and wrists of patients with rheumatoid arthritis. Arthritis Rheum 28: 16-24, 1985 Bluhm GB, Smith DW, Mikulaschek WM: A radiologic method of assessment of bone and joint destruction in rheumatoid arthritis. Henry Ford Hosp Med J 3 1: 152161, 1983 Nance E P Jr, Kaye JJ, Callahan LF, Carroll FE, Winfield AC, Earthman WJ, Phillips KA, Fuchs HA, Pincus T: Observer variation in quantitative assessment of rheumatoid arthritis. I. Scoring erosions and joint space narrowing. Invest Radiol 21 :922-927, 1986
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7. Genant HK: Methods of assessing radiographic change in rheumatoid arthritis. Am J Med 75:35-47, 1983 8. Gofton JP, O’Brien WM: Effects of auranofin on the radiological progression of joint erosion in rheumatoid arthritis. J Rheumatol [Suppl] 8: 169-172, 1982 9. Amos RS, Constable TJ, Crockson RA, Crockson AP, McConkey B: Rheumatoid arthritis: relation of serum C-reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J 1:195-197, 1977 10. Grindulis KA, Scott DL, Struthers GR: The assessment of radiological changes in the hands and wrists in rheumatoid arthritis. Rheumatol Int 3:39-42, 1983 11. Sharp JT, Young DY, Bluhm GB, Brook A, Brower AC, Corbett M, Decker JL, Genant HK, Gofton JP, Goodman N, Larsen A, Lidsky MD, Pussila P, Weinstein AS, Weissman BN: How many joints in the hand and wrist should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis? Arthritis Rheum 28:132&1335, 1985 12. Fries JF, Bloch DA, Sharp JT, McShane DJ, Spitz P, Bluhm GB, Forrester D, Genant H , Gofton P, Richman S, Weissman B, Wolfe F: Assessment of radiologic progression in rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 29: 1-9, 1986 13. Larsen A, Edgren J , Harju E, Laasonen L , Reitamo T: Interobserver variation in the evaluation of radiologic changes of rheumatoid arthritis. Scand J Rheumatol 8: 109-1 12, 1979 14. Mitchell DM, Spitz PW, Young DY, Bloch DA, McShane DJ, Fries JF: Survival, prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum 29:70& 714, 1986 15. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA: 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9: 175-176, 1958 16. Fries JF, Spitz P, Kraines RG, Holman HR: Measurement of patient outcome in arthritis. Arthritis Rheum 23: 137-145, 1980 17. Medlog, Clinical Data Management System. Mountain View, CA, Information Analysis Corporation, 1989 18. SAS for Personal Computers, Version 6. Cary, NC, SAS Institute, 1985 19. De Carvalho A, Graudal H: Relationship between radiologic and clinical findings in rheumatoid arthritis. Acta Radiol [Diagn] (Stockh) 21:797-802, 1980 20. Fuchs HA, Callahan LF, Kaye JJ, Brooks RH, Nance EP, Pincus T: Radiographic and joint count findings of the hand in rheumatoid arthritis: related and unrelated findings. Arthritis Rheum 31:44-51, 1988 21. Scott DL, Coulton BL, Bacon PA, Popert AJ: Methods of x-ray assessment in rheumatoid arthritis: a reevaluation. Br J Rheumatol 24:31-39, 1985 22. Sharp JT, Lidsky MD, Duffy J: Clinical responses during gold therapy for rheumatoid arthritis: changes in synovitis, radiologically detectable erosive lesions, se-
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23.
24.
25.
26.
27.
28.
29.
rum proteins, and serologic abnormalities. Arthritis Rheum 2.5:540-549, 1982 De Carvalho A, Graudal H: Radiographic progression of rheumatoid arthritis related to some clinical and laboratory parameters. Acta Radiol [Diagn] (Stockh) 21 : S S 15.55, 1980 Scott DL, Grindulis KA, Struthers GR, Coulton BL. Popert AJ, Bacon PA: Progression of radiologic changes in rheumatoid arthritis. Ann Rheum Dis 4323-17, 1984 Scott DL, Coulton BL, Popert AJ: Long term progression ofjoint damage in rheumatoid arthritis. Ann Rheum Dis 45:373-378, 1986 Scott DL, Dawes PT, Fowler PD, Shadforth MF: Calculation of radiological progression in rheumatoid arthritis. Clin Rheumatol S:445-449, 1986 De Carvalho A, Graudal H, Jorgensen B: Radiologic evaluation of the progression of rheumatoid arthritis: significance of age at onset and sex. Acta Radiol [Diagn] (Stockh) 21:545-550, 1980 Larsen A, Thoen J: Hand radiography of 200 patients with rheumatoid arthritis repeated after an interval of one year. Scand J Rheumatol 16:395-401, 1987 De Carvalho A, Graudal H, Jorgensen B: Radiologic
30.
3I .
32.
33.
34.
evaluation of the progression of rheumatoid arthritis. Acta Radiol [Diagn] (Stockh) 21:115-121, 1980 Sigler JW, Bluhm GB, Duncan H , Sharp JT, Ensign DC, McCrum WR: Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 80:2126, 1974 The Research Sub-Committee of the Empire Rheumatism Council: Gold therapy in rheumatoid arthritis: final report of a multicentre controlled trial. Ann Rheum Dis 20:31S-333, 1961 The Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of gold salt therapy in rheumatoid arthritis. Arthritis Rheum 16:353358, 1973 Joint Committee of the Medical Research Council and Nuffield Foundation on Clinical Trials of Cortisone, ACTH and Other Therapeutic Measures in Chronic Rheumatic Disease: A comparison of prednisolone with aspirin or other analgesics in the treatment of rheumatoid arthritis. Ann Rheum Dis 18:173-186, 1959 Gofton JP, O’Brien WM, Hurley JN, Scheffler BJ: Radiographic evaluation of erosion in rheumatoid arthritis: double blind study of auranofin vs placebo. J Rheumatol I1:768-771, 1984
THE PROGRESSION OF EROSION AND JOINT SPACE NARROWING SCORES IN RHEUMATOID ARTHRITIS DURING THE FIRST TWENTY-FIVE YEARS OF DISEASE JOHN T. SHARP, FREDERICK WOLFE, DONALD M. MITCHELL, and DANIEL A. BLOCH
Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study, we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis, Rheumatism, and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists, obtained from 210 patients, were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score, which sums erosion and joint space abnormalities and has a maximum possible score of 314, was approximately 4 units per year over the first From the University of Colorado School of Medicine, Denver; The Joe and Betty Alpert Arthritis Center at Rose Medical Center, Denver, Colorado; the University of Kansas School of Medicine, Wichita; The Arthritis Center, Wichita, Kansas; and the Divisions of ImmunologylRheumatologyand Biostatistics, Stanford University School of Medicine, Stanford, California. Supported in part by NIH grant AR-21393, and by clinical research funds from Rose Medical Center. John T. Sharp, MD: Professor of Medicine, University of Colorado School of Medicine, and Director, The Joe and Betty Alpert Arthritis Center at Rose Medical Center (current address: Clinical Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia); Frederick Wolfe, MD: Clinical Professor of Medicine, University of Kansas School of Medicine, Wichita, and Director, The Arthritis Center; Daniel A. Bloch, PhD: Senior Research Associate, Stanford University School of Medicine. Dr. Mitchell is deceased. Address reprint requests to John T. Sharp, MD, 712 East 18th Street, Tifton, GA 31794. Submitted for publication April 5 , 1990; accepted in revised form December 31, 1990. Arthritis and Rheumatism, Vol. 34, No. 6 (June 1991)
25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that frequently follows a course which is continually progressive for many years. A number of features have been proposed to measure its progression and outcome. One of these, radiologic assessment, measures the extent of bony erosions and loss of articular cartilage. Several methods have been proposed to assess these features (1-12), and studies comparing various methods have concluded that there is strong agreement among different observers using either the same or different techniques, and among the scores assigned to the same set of radiographs by the same observer using different methods (4,6,7,10-13). These studies have established the reproducibility of scoring radiologic abnormalities. The present study utilized one of these scoring methods (1 1) to determine the progression of radiologic abnormalities in approximately 100 consecutive patients from each of 3 different centers. Radiologic abnormalities were observed to develop at a nearly steady rate between 3 and 25 years after onset of disease. Although limitations were imposed on the study by the discontinuous nature of the data, it is unlikely that more complete data can be obtained.
METHODS This multicenter study utilized data maintained in the databanks of the Arthritis, Rheumatism, and Aging Medical
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS Table 1. Number of patients and films, by patient location No. with 2or
with films
more films
No. of
films
films per patient
100 90 (90) 103 58 (56.3) 89 62 (69.7) 292 210(71.9)
67 57 39 163
199 270 181 650
2.2 4.7 2.9 3.1
80 77 49 206
76 (95) 50 (64.9) 48 (98) 174 (84.5)
63 49 31 143
180 245 153 578
2.4 4.9 3.2 3.3
20 26 40 86
14 (70) 8 (30.8) 14 (35) 36 (41.9)
4 8 8 20
19 25 28 72
1.4 3.1 2.0 2.0
No.
(14). The last 103 patients with a diagnosis of definite or classic RA (15) were selected for this study. The Wichita databank was begun in 1976 by entering data on established and new patients from the practice of one of the authors (FW). Laboratory and radiographic data were obtained on patients as needed for clinical care. The first consecutive 100 patients from this databank with a diagnosis of definite or classic RA were chosen for the present study. The first 100 consecutive patients admitted to the Alpert Arthritis Center on or after January 1, 1975 with an admitting diagnosis of RA were selected from the Denver databank. The diagnosis in 11 patients was changed at the time of hospital discharge or during the course of followup, leaving 89 patients with definite or classic RA who were included in this study. During the study, efforts were made to reexamine every living patient. The evaluation included a detailed joint examination and general physical examination. Laboratory data obtained included a complete blood cell count, erythrocyte sedimentation rate, rheumatoid factor titer by latex fixation, and fluorescent antinuclear antibody titer. A disability index was calculated from items on the Health Assessment Questionnaire (16). Patients who could not come to the centers were sent questionnaires or interviewed by telephone and were asked to have radiography and laboratory tests performed by their family physicians. All patients were successfully traced. Eighty-six of the 292 had died. All the known previous hand and wrist films were collected, and new films were obtained when possible. A total of 650 films were obtained from 210 (72%) of the 292 patients (Table I ) . Of those with films, there was an average of 3.1 films per person, and 163 had 2 or more films. Films were obtained on 48 of 49 living patients in the Denver group (98%), but only 14 of the 40 who had died (35%). The Kansas center obtained films from 90% of their
Average
No. (%)
no. of
All patients
Kansas Saskatoon Denver Total Patient still living at time of study Kansas Saskatoon Denver Total Patients deceased at time of study Kansas Saskatoon Denver Total
66 1
Information System, from the University of Saskatchewan, Saskatoon, Canada, The Arthritis Center of Wichita, Kansas, and The Joe and Betty Alpert Arthritis Center, Rose Medical Center, Denver, Colorado. One thousand two hundred five patients over the age of 16 with a clinical diagnosis of RA, who were enrolled in a followup program at the University of Saskatchewan between 1966 and 1974, constitute the Saskatoon databank
Table 2. Characteristics of the study population, by patient location* ~~
Kansas No. of patients
Age at first visit, years Age at last visit, years Age at disease onset, years % female Disease duration at first visit, years Disability index at first visit, 0-3 scale Nodules, % ever hadt Morning stiffness, hours ESR, mm/hour$
Hemoglobin, gm/dl RF, log titer9
52.4 60.4 44.3 8.0 1.21 2.10 36.5 12.7 743
100 t 1.42 t 1.37 t 1.39 72 t 0.907 t 0.106 45 2 0.252 t 1.98 2 0.127 t 124
Saskatoon
Denver
103
89 55.9 t 1.44 65.1 t 1.40 45.5 t 1.44 66 10.4 2 0.959 1.35 t 0.150 34 1.97 ? 0.347 49.0 t 2.40 12.9 t 0.159 818 t 163
53.4 62.3 43.7
* 1.57 ? ?
1.41 1.53
63 9.7 t 1.12 1.09 t 0.102 55 I .47 ? 0.133 47.0 t 2.64 12.9 ? 0.157 2,181 t 266
292 53.8 62.5 44.4 67 9.4 1.20 45 1.82 44.1 12.9 1,317
* Unless otherwise indicated, values are the mean t SEM. Values for morning stiffness, erythrocyte sedimentation rate (ESR), and hemoglobin were averaged over all observations. I A patient was considered to have nodules if a nodule was recorded as present at any time during the course of observation. For comparison of nodule frequency across groups, 2 = 9.022, degrees of freedom [dfl = 2, P = 0.01 1. $ The average ESR values were significantly different across groups (one-way F statistic = 8.002, df = 2,285, P < 0.001). 0 The average titers of rheumatoid factor (RF; by latex fixation) were significantly different across groups (one-way F statistic = 16.350, df = 2,257, P < 0,001).
SHARP ET AL
662
Table 3. Characteristics of patients who were still living at the time of the study and patients who were deceased at the time of the study, according to availability of films*
No. of patients Age at first visit, yearst Age at last visit, yearst Age at disease onset, yearst % female Disease duration at first visit, years$ Disease duration at last visit, years Disease duration at first film, years§ Disease duration at last film, years Radiologic progression rate, units/years§ Disability index at first visit, 0-3 scale Nodules, % ever had Morning stiffness, hours ESR, mm/hourt Hemoglobin. gm/dl$ RF, 10gtiter -
Living patients with films
Living patients without films
Deceased patients with films
Deceased patients without films
174 48.9 2 1.05 58.8 2 1.05 41.2 -t 0.999 71.7 7.5 2 0.688
32 54.0 t 2.72 62.5 rt 2.59 43.8 t 2.74 56.3 10.2 t 1.62
36 62.0 2 1.29 68.6 t 1.39 49.7 2 2.20 58.3 12.2 ? 1.75
50 65.2 2 1.69 70.8 t 1.63 52.1 t 2.08 64.0 13.1 t 1.61
17.5 t 0.707
18.7 2 1.55
18.9
1.82
18.7 t 1.61
?
9.6 2 0.773
13.3 2 1.73
16.2 t 0.729
15.7 t 1.89
4.71 t 0.424
7.90 2 1.80
1.11 t 0.073
0.762 t 0.206
47.7 1.76 t 0.137 37.8 2 1.48 13.1 t 0.101 1,271 f 176
40.6 1.32 t 0.239 44.0 t 4.17 13.1 rt 0.299 1,321 t 280
1.77
0.207
2.00 t 0.277
44.4 2.85 t 0.706 51.7 t 3.88 12.6 ? 0.224 1,811 ? 347
40.0 1.63 t 0.366 60.3 t 4.11 12.2 t 0.225 1,141 t 248
f
* P values for comparisons of living patients who had films with living patients who did not have films and of deceased patients who had films with deceased patients who did not have films varied between 0.057 and 0.943, with only 2 values CO.10. The 2-sample t-test was used to compare means of continuous variables, and the chi-square test was used to compare dichotomous variables. Unless otherwise indicated, values are the mean t SEM. See Table 2 for additional explanations and definitions. t P < 0.001, all living patients versus all deceased patients. j: 0.001 < P < 0.01, all living patients versus all deceased patients. $ 0.01 < P < 0.05, all living patients versus all deceased patients. patients, including 76 of the 80 who were living (95%) and 14 of the 20 who had died (70%). The largest number of available films per patient was from the Saskatoon group. For scoring of radiologic changes, individual paTable 4. Progression of radiologic scores in patients who had 2 or more films, by disease duration
Disease duration, mean (range) years*
No. of patients
2.0 (0.91-3.3) 6.1 (5.05-7.29) 10.0 (8.81-11.15) 14.0 (12.90-14.82) 18.1 (17.33-18.83) 22.8 (21.8624.36)
23 31 22 12 9 6
Radiologic progression rate, mean t SEM unitdyeart 9.076 5.270 6.291 10.109 5.089 2.819
2
3.275
t 1.240 t 2.214 t 2.124 2 2.046
t 0.821
* Patients were selected who had 2 or more films in 4-year intervals between 0 and 20 years of disease, or between 20 and 25 years of disease. Ranges given are the actual disease durations. t The mean radiologic progression rate was determined from the rates of progression in all patients in the duration interval who had 2 or more films, using method I , as described in Methods.
tient’s films were identified in sets. Within sets, the sequence of films was blinded, using random number tables to assign a label A, B , C, . . . etc. For example, a patient with 3 films would be equally likely to have the first film labeled A, B, or C. All radiographs were scored by one of the authors (JTS) for extent of erosions and joint space narrowing, using a modification of the method he originally described, which has been thoroughly tested ( I , 11). Films from Kansas were also scored by FW, and films from Saskatoon by DMM. Correlation coefficients were 0.953 (n = 122) between FW and JTS and 0.948 (n = 229) between DMM and JTS. Since JTS was the only one who read all films, the scores used in the studies reported here are those he assigned. Total radiologic scores were the sum of erosion scores for 34 joints and joint space narrowing scores for 36 joints (1 1). If surgery had been performed during the interval between 2 films, the score of the film obtained before the surgery was assigned to each joint that was affected by the operation, so that progression rates would not artifactually retrogress. Data on 142 variables collected on patients in each center were extracted into special files and merged. Analysis was carried out using Medlog (17) and SAS (18) software programs.
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS
Table 5. Progression of radiologic scores in films taken early in the disease course and films taken late in the disease course, in the same patients*
First film Last film
No. of patients
Disease duration, mean years
Radiologic progression rate, mean t SEM units/year
62 62
4.057 14.206
4.1 10 t 0.898 4.218 k 0.474
* All patients were selected who (a) had their first film within 10 years after disease onset, (b) had their last film more than 10 years after onset and more than 1 1 months after the first film, and (c) had the last film obtained after January I , 1984. The mean interval between films was 10.2 years (range 1.5-14.5 years). Radiologic progression rates shown in this table were calculated by method 2, i.e., progression rate = score + disease duration.
Three different methods of measuring the rate of progression of radiologic abnormalities for each patient were tested. Method 1 used the slope of radiologic scores for each individual patient who had 2 or more films, by employing the regression equation using radiologic scores as the dependent variable and years from disease onset as the independent variable. Method 2 calculated the progression rate by dividing the radiologic score by the duration of disease in years for each film, and determined the mean for all films as that individual’s progression rate. Method 3 took the difference between the first and last radiologic scores and divided by the difference in time in years. Methods 1 and 3 required that the patient have 2 or more films, whereas every patient with 1 or more films was included in the rates determined by method 2. Methods I and 3 were based on observed lime between films, whereas method 2 relied on the patient’s own report of the date of disease onset. Progression rates presented herein were determined by method 1 except where otherwise indicated.
663
Table 7. Progression of radiologic scores in patients at each center, by disease duration Disease duration, years 0.01-3 3-10 1C15
15-25
Mean radiologic progression rate, units/year* Kansas
Saskatoon
8.628 (7) 6.829 (23) 2.932 (5) 3.144 (9)
3.827 (8) 5.174 (28) 5.953 (8) 2.560 (15)
Denver 2.164 8.270 2.768 5.348
(5) (14) (14) (7)
* Determined by method I , as described in Methods. Values in parentheses are the number of patients.
RESULTS Patients from the 3 centers were comparable in most important respects (Table 2). To assess the potential bias created by incomplete radiologic data, patients with radiographs available were compared with those without. There were significant differences with regard to age at first and last examination, age at onset of disease, and duration of disease at first examination. These differences are accounted for by the greater proportion of deaths in the group without films. When clinical and laboratory features of disease were compared between living patients with films and living patients without films, the living patients with films were representative of all living patients and the deceased patients with films were representative of all deceased patients (Table 3). This suggests that our assessment of the radiologic progression rate may be Table 8. Ceiling scores at 5-year intervals for the first 25 years of rheumatoid arthritis* % of joints given ceiling scores,
mean 2 SEM Table 6 . Progression of radiologic scores in the 29 patients who had 5 or more films, all more than 1 year apart Disease duration at midpoint between films, mean SEM years
*
Film pair Films Films Films Films
I and 2 and 3 and 4 and
2 3 4 5
4.23 6.87 9.77 12.68
t 0.687 t 0.711 t 0.750
t 0.741
Radiologic progression rate, mean t SEM units/ year* 4.554 5.368 7.231 5.017
2
0.192
t 0.172
t 0.318 5 0.281
* Radiologic progression rates shown in this table were calculated by the following formula for each sequential pair of films (method 3): progression rate = radiologic score (second film) - radiologic score (first film) time between films in years
Disease duration, mean (range) years 2.7 (0-5) 7.6 (5-10) 12.3 (10-15) 17.2 (15-20) 22.3 (2C25) 3 1.7 (2548)
No. of films 132 159 111 59 38 45
Erosion score of 5 0.7 3.5 5.4 14.7 19.4 19.7
JSN score of 4
Erosion score of 5 and JSN score of 4
t 0.243 0.05 2 0.047 t 0.593 0.7 2 0.189
1.05 2.45 t 3.99 t 3.67 4 2
0.3 t 0.135 2.1 2 0.330 1.5 k 0.336 3.4 0.591 2.5 2 0.684 8.5 t 1.36 3.6 t 1.45 11.2 C 2.20 3.8 t 0.976 11.5 2 2.16
* Ceiling scores are the highest scores used in the scoring system (score of 5 for erosion, score of 4 for joint space narrowing [JSN]). Percent ofjoints given ceiling scores were determined as the number ofjoints scored 5 for erosions divided by the number ofjoints scored for erosions, the number of joints scored 4 for JSN divided by the number of joints scored for JSN, and the sum of joints scored 5 for erosions and 4 for JSN divided by the sum of the number of joints scored for erosions and those scored for JSN.
664
SHARP ET AL centers, the possibility that this may have introduced bias by causing overrepresentation of patients with active and progressive disease was considered. To assess this, we selected 62 patients who (a) had 2 or more films, (b) had their first film within the first 10 years after onset of disease, (c) had their last film more than 10 years after onset and at least 11 months after the first film, and (d) had their last radiography performed after January 1, 1984, as part of the routine fbllowup for this study. The progression rates for the early films were not different from the late ones, as determined by method 2 (Table 5). Twenty-nine patients had 5 or more films, with at least a I-year interval between each pair of films. The rates of radiologic progression for each sequential film pair were not significantly different (Table 6). Progression rates were determined for each of the centers separately, using longer intervals to allow
250
200
w 150
8
s:>a
p:
>;:
ii
100
50
0
10
20
30
40
50
160 60
DURATION OF DISEASE (years) Figure 1. Total radiologic scores as a function of disease duration, ih all patients for whom 2 or more films were available.
140 120
slightly underestimated because of the underrepresentation of those patients who died during the followup period. However, deaths were not clustered in the early years of disease, and in fact, the duration of disease at last visit was similar for patients who had died and those who were still living at the end of the study. Therefore, no attempt was made to adjust progression rates, due to the small correction that would be required. Using several methods, a significant change in rates of progression of radiologic scores with increasing duration of disease was not detected. Progression rates at 4-year intervals, determined by method 1, varied substantially but did not show a trend, and mean rates were not significantly different at different durations (Table 4). In this analysis, 4-year intervals were chosen as the shortest intervals that include a meaningful number of patients in each interval who had 2 or more films taken at least 11 months apart within the interval. Since films were obtained during the early years of the study as part of routine patient care in all
w
100
U
0
5: >.
80
a
g:
x
60
40 20 1
(n) = ## patients contributing 0
10
20
30
40 DURATION OF DISEASE (years)
50
Figure 2. Progression of radiologic scores as illustrated using the averages of constrained cubics at increasing durations of disease.
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS
larger numbers of patients in each subset. N o trends or consistent differences were observed (Table 7). The possibility that a ceiling effect might have occurred as a result of the scoring method was examined by tabulating the number of joints in each individual radiologic score that were assigned the highest score for erosion and/or joint space narrowing. The percentage of joints scored at the top of the scales steadily increased with increasing duration of disease (Table 8), indicating that a ceiling effect may have accounted for part of the apparent decline in the rate of progression of radiologic scores with increasing duration of disease. The relationship of radiologic scores to duration of disease was examined further by fitting several models. The complexity of the task is illustrated in Figure 1 , which plots radiologic scores against duration of disease for all patients who had 2 or more films. It is evident that subjects were observed for varying lengths of time at different durations of disease. The first model-based method fitted a constrained cubic through patients’ data (86 patients had 3 or more data points), using the following constraints: 1) the model would pass through the origin, corresponding to a score of 0, at the onset of disease, and 2) the cubic would be nondecreasing. These cubics, which are averaged in Figure 2, suggest a gradually decreasing rate up to approximately 25 years of disease. After this time, there were data on only 4 subjects. The second method, based on fitting a quadratic curve through each patient’s data, was chosen because a preponderance of subjects would be expected to have negative regression coefficients for the quadratic term if the rate of progression of radiologic scores were decreasing with increasing duration of disease. This analysis demonstrated closely similar proportions of subjects having positive and negative quadratic regression coefficients. One nonparametric method fitted a smooth curve through the scatterplot of first-order differences using moving averages. This method suggested a decreasing rate after approximately 25 years of disease, but, using 25 bootstrap replicates, the variability of the results was large. In summary, the results of one modeling technique and a nonparametric analysis suggested a decreasing rate of radiologic progression after longer durations of disease, though the data were not conclusive. Based on the data in Tables 4,5, and 6 and Figure 2, the mean rate of progression of radiologic scores is
665
approximately 4 units per year over the first 25 years of disease, but the rate may be more rapid by as much as twofold in the very early years and slower by twofold in the later years. Data beyond 25 years duration were too scanty to enable estimation of the rate of progression.
DISCUSSION Radiologic abnormalities in rheumatoid arthritis accurately represent disease severity and progression. Erosions and loss of cartilage are direct effects of the disease process of RA. Scoring of radiologic abnormalities is reproducible (4,6,7,10-13), and these scores correlate with the extent of deformities, limitation of motion, and disability (1,19-21). The progression of radiologic abnormalities correlates with the extent of joint swelling during the interval between films (22), the presence of nodules ( l ) , and laboratory abnormalities which reflect the severity of disease (1,9,19,2325). X-ray films represent a permanent record, and objectivity in scoring is assured by assigning a random and blinded sequence. The rate of progression of radiologic abnormalities is very important in defining the “natural history” of the disease and in determining the effectiveness of therapeutic measures. Previous long-term, longitudinal studies on radiologic changes in the hands and wrists were limited. Initially, Scott et al, in following the cases of 88 patients with RA for 10 years, observed no relation between the rate of radiologic progression and the duration of disease (24). In another study of patients at the same institution, however, total Larsen scores (2,3) for 13 groups of joints (10 groups in addition to fingers and wrists) demonstrated a weak relationship between radiologic abnormality and duration of disease when analyzed by linear regression (21): The rate ofjoint damage was negatively related to the square root of disease duration (r = -0.44). However, the number of cases was small, and 2 outliers may have accounted for an undue proportion of the association. Subsequently, Scott and colleagues demonstrated that radiologic progression decreased in the later years when plotted as an absolute score, but was linear when calculated as a percentage of maximum possible change (26), a result that would be expected with a ceiling effect. De Carvalho et a1 (27), who studied the sum of Larsen scores on “all limb joints, the cervical spine and the sacroiliac joints” and Larsen (28), who studied hands and wrists, reported that radiologic scores in-
SHARP ET AL creased at a steady rate when plotted against the square root of duration of disease. However, de Carvalho and colleagues (29) demonstrated a high proportion of maximal scores in study patients with longer disease duration, and Larsen and Thoen (28) recognized the possibility that a ceiling effect was responsible for the leveling off of the progression in the later years. Ideally, we would like to know the radiologic scores at regular intervals from the onset of disease through the remaining lifetime, for a sufficient number of typical patients to define the mean progression rate and the variability across patients. Unfortunately, these data are not likely to ever be obtained. Some patients do not receive care in the early years of their arthritis. Many shift care between providers, and others discontinue their visits to providers because their disease has gone into remission or they have become discouraged by poor response to treatment. Other patients are lost to followup when they enter nursing homes. There are no practices and very few clinics that have been established long enough to have followed patients for the 50 years or longer that would be required to collect clinical data on a large group of patients from disease onset to death. Films are not obtained at regular intervals and may not be kept more than a few years. Some drugs have been demonstrated to slow the course of radiologic progression over the short term, and these drugs are used regularly in modern clinics for patients who appear to have progressive disease (30-34). For these reasons, we have accepted the premise that it is unlikely that complete data will be obtained and have studied consecutive patients from 3 geographically disparate centers which represent different forms of practice. The rate of progression of radiologic abnormalities was found to be minimally influenced by the duration of disease, up to 25 years from the time of onset. How firm is this conclusion? Can we believe that RA (measured by radiologic abnormality scores) progresses at a nearly steady rate for the first 25 years across the “universe” of RA patients, or must we have some reservations that the sample in this study was not representative of RA in the general population? A number of factors that might influence the analysis must be considered. Films were obtained on 84% of living patients from all centers and on more than 94% from 2 of the centers (Table 1). Since there were no apparent differences among the 3 centers in the rates of radiologic progression (Table 7) and no
clinical or laboratory features were overrepresented in patients without films (Table 3), we conclude that factors influencing which living patients had films obtained did not produce a large bias. The problem is more serious with regard to deceased patients, of whom only 41% had films available. Among deceased patients, those without films were older at onset of disease and when first examined, but other differences were not significant. The duration of illness at the time of the last followup and the duration at the time the last film was obtained were not appreciably different between those with and without films, whether living or- deceased. Therefore, it seems reasonable to conclude that the deceased patients with films are representative of all deceased patients and that the data are representative of rheumatoid arthritis in these 3 centers during the observation period. Other investigators have emphasized that radiologic abnormalities are common in the first few years of disease but have not undertaken longitudinal studies comparing the rate of progression in the early period with that in the subsequent years. The data presented here are somewhat scanty with regard to the first 2 years of RA and do not enable firm conclusions to be drawn regarding the progression rate in this early phase of the disease. This caution is reinforced by the observation that the graph of radiologic progression drawn from the regression equation shows a positive radiologic score at zero duration of disease. This effect might result from a different slope during the first 2 or 3 years of illness or from a systematic error in determining the date of onset of disease. The number of films obtained after 25 years of disease is limited, and we have not attempted to draw any conclusions about the progression of radiologic abnormalities in this late period of illness. One would expect that a ceiling effect might occur in the late stage of disease. When scores for individual joints were analyzed, the percentage that had reached the maximum score increased with greater duration of disease, suggesting that a ceiling effect in the individual joint scores could account for some of the gradual decrease in the progression rate of radiologic scores shown in Figure 2. It should also be pointed out that individual readers use the scoring system differently. JTS, who read all the films in this study, is one of the more conservative scorers among multiple readers who scored a test set of films in a recent study (11). Films read by a reader who regularly scores involved joints
RADIOLOGIC PROGRESSION IN RA OVER 25 YEARS higher in the scale would s h o w a greater ceiling effect in a group encompassing t h e wide time span a n d extremes of severity represented in this study. Although data from t h e first 3 years of disease a n d after 25 years are scanty, t h e results shown in Figure 2 suggest that progression of radiologic scores over the first 25 years of RA is fairly constant, with an average rate of increase of approximately 4 units per year, perhaps somewhat more rapid in the very early years a n d slowing to a b o u t 3 units in t h e later years.
ACKNOWLEDGMENTS The authors thank Byron William Brown, Jr., for advice on statistical aspects of the study and for helpful comments on the manuscript. Jerry Halpern made the calculations depicted in Figure 2. J. T. Sibley assisted in providing missing details about the Saskatoon databank and made thoughtful suggestions on the manuscript. John Oehlert assisted by creating the merged data file using extracted data from the 3 study centers. May Haga, Mary Ann Cathey, and Melinda Tharan assisted in data collection in Saskatoon, Wichita, and Denver, respectively.
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