THE MORTALITY OF RHEUMATOID ARTHRITIS

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1 ARTHRITIS & RHEUMATISM Volume 37 Number 4, April 1994, pp , American College of Rheumatology 48 1 THE MORTALITY OF RHEUMATOID ARTHRITIS FREDERICK WOLFE, DONALD M. MITCHELL, JOHN T. SIBLEY, JAMES F. FRIES, DANIEL A. BLOCH, CATHERINE A. WILLIAMS, PATRICIA W. SPITZ, MAY HAGA, SUE M. KLEINHEKSEL, and MARY ANN CATHEY Objective. To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). Methods. RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n =, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. Results. The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use. Supported in part by grants from the Kansas Chapter, Arthritis Foundation, Wichita, Kansas, and the National Institutes of Arthritis, Diabetes, Digestive, and Kidney Diseases (AM-21393) to the Arthritis, Rheumatism, and Aging Medical Information System. Frederick Wolfe, MD: University of Kansas School of Medicine, Wichita; John T. Sibley, MD: University of Saskatchewan, Saskatoon, Saskatchewan, Canada; James F. Fries, MD: Stanford University, Stanford, California; Daniel A. Bloch, PhD: Stanford University; Catherine A. Williams, MS: Stanford University; Patricia W. Spitz, MS: Stanford University; May Haga: University of Saskatchewan; Sue M. Kleinheksel, BA: Arthritis Center, Wichita, Kansas; Mary Ann Cathey, MA: Arthritis Center, Wichita. Dr. Mitchell is deceased. Address reprint requests to Frederick Wolfe, MD, Arthritis Center, 1035 N. Emporia, Suite 230, Wichita, KS Submitted for publication April 21, 1993; accepted in revised form August 19, Conclusion. Mortality rates are increased at least 2-fold in RA, and are linked to clinical severity. In the 1950 s reports began to emerge suggesting that patients with rheumatoid arthritis (RA) were at increased risk of dying early (1). Over the next 30 years numerous studies were performed, with all but one of them (2) suggesting increased mortality rates among RA patients (3-21). But the extent of this increase has not been consistent (Table 1). In population-based epidemiologic studies where diagnostic accuracy is difficult to ensure, the standardized mortality ratio (SMR) has been no higher than 1.32 (6). In 4 of the 10 clinical studies, the SMR has averaged 1.3, while the unweighted average of the remaining studies (not including the current report) was With the issue of the extent and importance of mortality in RA not fully settled, one expert suggested that... RA is on balance an essentially benign, nonfatal disease (22), while another indicated that... there is strong evidence that accelerated mortality is the general finding among RA patients (23). The increased mortality rates in RA shown by most studies has raised questions concerning the nature of that mortality, including factors that predict death. But only a few studies have addressed clinical predictors such as joint examinations, grip strength, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), or radiographic findings, or have assessed function with modern functional status instruments. Studies have been relatively small, which limits evaluation of specific causes of death and associated risk factors. Most studies that have incorporated clinical predictors have utilized univariate methodologies, and have examined only a few predictors. While the link

2 482 WOLFE ET AL Table 1. Standardized mortality ratios (SMR) in rheumatoid arthritis studies* Authors, Duration year (ref.) n SMR Country (years) Setting Prior et al, 1984 (8) UK 11.2 Clinical Allebeck, 1982 (11) 1, Sweden 7.5 Clinical Wolfe et al, present study 3, US, Canada Clinical Duthie et al, 1964 (3) UK 9.0 Clinical Monson and Hall, 1976 (10) 1, us Clinical Mutru et al, 1985 (12) 1,OOO 1.73 Finland 10.0 Clinical Mitchell et al, 1986 (17) Canada 12.0 Clinical Cobb et al, 1953 (1) us 9.6 Clinical Alleback et al, 1981 (6) Sweden 11.0 Community Pincus et al, 1984 (15) us 9.0 Clinical Uddin et al, 1970 (13) Canada 10.0 Clinical Jacobson et al, 1993 (21) 2, us 2-25 Community Lewis et al, 1980 (9) UK 11.0 Clinical Linos et al, 1980 (2) us 24.0 Community ~~~~~~~~~~~~ * Includes those studies providing SMRs or (similar statistics) or studies in which the SMR could be calculated. The study by Mitchell et al is updated in the current report. between disease severity and early death seems likely, far less certain is the relative importance of the individual components of disease severity (e.g., ESR, radiographs, etc.) on mortality, particularly in the multivariate clinical setting where demographic, clinical, laboratory, and radiographic factors are considered simultaneously by the clinician in the assessment of the patient with RA. Further confounding our understanding of RA mortality has been the changing definition and concept of RA itself. Inclusion of patients with non-ra spondylarthropathies may have contaminated the data in some reports. In addition, different criteria for RA (24-27), including idiosyncratic criteria, have been used to identify subjects. Probable RA (24), a concept that has now been shown to mis-identify patients as having RA (28,29) and has been abandoned (27), was the method of case identification in a number of studies. Most studies, moreover, have concerned patients hospitalized for RA; this has led to problems regarding the generalizability of data to the average RA patient. To obtain a more definite picture of mortality in RA, we have brought together 4 longstanding ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data banks. In 3 of these data banks (Saskatoon, Saskatchewan, Canada; Wichita, KS; and Stanford, CA), consecutive RA outpatients meeting either the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1958 criteria for definite or classic RA (24) or the 1987 criteria (27) have been identified and followed prospectively. Stanford is a tertiary referral center, where patients with severe RA may be referred and might be expected to have a worse prognosis. The Santa Clara, CA, data bank, on the other hand, represents a group of community RA patients recruited by notices in pharmacies and newspaper advertisements. Santa Clara subjects differ primarily from the other groups in that their cases were generally not followed up or diagnosed by rheumatologists. In all, 3,501 RA patients were identified. Of these 922 have died. We brought these 4 data sets together to address 3 questions of interest concerning RA mortality: 1) Are mortality rates increased in RA patients? If so, what is the extent of the increase? Is it constant over time? and Is it clinically important? (Is RA an essentially benign, nonfatal disease [22]?) 2) What factors are associated with (predict) mortality in RA and what are the strengths of the associations when a large number of different clinical and demographic factors are considered simultaneously? 3) What are the causes of death in patients with rheumatoid arthritis? PATIENTS AND METHODS The ARAMIS system represents a consortium of data banks with a common core support group at Stanford University (30). The core group provides design and biostatistical support, and serves as a data repository; but each data bank is a separate entity with a separate principal investigator. Stanford and Saskatoon initiated data collection within the ARAMIS system in Wichita was added

3 MORTALITY IN RA 483 in 1979, and the Santa Clara data bank in The 4 centers were collecting data before the formal association with ARAMIS. At Stanford, this data collection began in 1965, at Saskatoon in 1955, at Wichita in 1973, and at Santa Clara in In ARAMIS introduced standardized methods of outcome assessment at all centers. The development of a common data resource from diverse centers has imposed restrictions on the data that are importaht to this study. Although common methodology is now used at each center, this was not the case when a large proportion of RA patients were seen in the respective clinics and their data were made available for study. Therefore, data elements that are available in some data banks are not available in others. A strength of the ARAMIS project is that each data bank has collected nonstandard elements that were of interest to the individual principal investigator. Thus, in each of the data banks, elements are present that are not found in the others. In this report, we have used these elements to explore relationships between RA and mortality that would not have been available if only the commonly defined variables were used. Individual centers. Saskatoon. The data collection and mortality characteristics of this center through 1982 have been previously described (17). All consecutive new patients with a clinical diagnosis of RA in whom symptoms started after age 16 and who were seen between 1966 and 1974 were enrolled into the Saskatoon data bank. Over 90% were first seen as outpatients. The University of Saskatchewan constituted the only referral center for RA during the enrollment period. Prospective data collection began in For patients seen in the clinic between 1955 and 1965 ( old patients ) as well as during the years , the data were extracted into the data bank. These patients were entered into the study as of the date of their earliest clinic visit. Only those patients with definite or classic RA (24) were eligible for the study of mortality. The additional 100 patients in this report not included in the 1986 mortality study are those who have since met the criteria for definite or classic RA. By the time of study closure (March 1990), 905 eligible RA patients were identified, of whom 459 (50.7%) had died and 41 (4.5%) were lost to followup. The current report adds 7 additional years of followup for this data set. Wichita. Eligible for this study were all consecutive outpatients who were seen between March 1973 and March 1990 at the Wichita Arthritis Center (a private practice rheumatology clinic) and who were diagnosed as having RA and satisfied either the 1958 (definite or classic RA) (24) or the 1987 (27) ACR criteria for RA prior to March Of the RA patients, 228 had died (16.2%), and 35 (2.5%) were lost to followup. Forty-three percent of patients seen at this center are self-referred. The characteristics of patients in the Wichita data bank have been described previously (31). Stanford. Eligible for this study were all consecutive patients seen at Stanford University (a tertiary referral center) from 1965 through March 1990, who were diagnosed as having RA and satisfied either the 1958 (definite or classic RA) (24) or the 1987 (27) ACR criteria for RA prior to March Eight patients (0.9%) were originally seen as inpatients. Of the 886 patients identified as having RA, 175 (19.8%) had died, and 298 (33.6%) were lost to followup. Santa Clara County. In an attempt was made to identify RA patients in the community by newspaper advertisements and recruitment notices in pharmacies. Of a greater number who responded, 305 patients were ultimately diagnosed as having RA; verification methods included review of medical records and contact with medical personnel. A 10% sample of the 305 patients was examined by a rheumatologist, and there was confirmation of the diagnosis of RA in all of them. Record review of these patients during followup at 6-month intervals during further substantiated the diagnosis of RA. Of the 305 patients, 60 (19.7%) had died and 32 (10.5%) were lost to followup. The Santa Clara data bank patients differ from those in the other data banks in that they constitute a closed cohort; they were recruited at a single time, and subsequent addition to the data bank was not made. In addition, clinical, laboratory, and physical examination data concerning these patients are limited. Associations of demographic, work status, and clinical variables with mortality have been reported, in part, previously (32) and will not be reported here. The current study for Santa Clara center presents new (unpublished) data regarding standardized mortality ratios, survival curves, and causes of death. Study variables. Variables (and their definitions) selected for inclusion in the univariate analyses are described in Table 2. Anorexia and rales were associated with mortality in a previous study using the Saskatoon center data and were therefore included in the current study (17). Statistical methods. Followup times. Patients known to be alive at the end of the study had their time to death censored as of that date (March 1990). The National Death Index (NDI; National Center for Health Statistics [NCHS], US Department of Health and Human Services, Hyattsville, MD) was used to trace all US patients lost to followup before and after 1979, the year the NDI began. Twenty-nine of the 175 Stanford deaths were determined by use of the NDI. At Stanford, 162 patients were lost to followup after If the NDI captures a high percentage of US deaths (since 1979), it might be correct to assume the 162 patients not in the NDI were actually alive at the end of the study period. We therefore conducted a study to estimate the percentage of RA deaths reported to the NDI. Two groups of known dead RA patients, 50 from Wichita and 100 from Stanford, were submitted to the NDI. The NDI correctly identified 145 of the 150. For primary analysis, patients lost to followup had their times to death censored at the date they were considered lost to followup. Since the NDI was estimated to include most of the RA patients who died between 1979 and 1990, we also performed a secondary analysis on the Stanford data, assuming patients lost to followup after 1979 and not found by the NDI were alive as of Data pooling. Differences among centers in variables collected, definitions of variables, method of ascertainment, amount of missing data, and era led us to study each center individually rather than pool the data (except for the SMR). Survival curves. At each center, survival curves were constructed for the general population, matched to patient groups for age at entry, year of entry, sex, race, and length of followup. The 3 US centers had expected survival

4 484 WOLFE ET AL Table 2. Rheumatoid arthritis mortality study variables, definitions, and usage* Variable Joints with active RA Alcohol use AM stiffness Anorexia Body mass index DMARD at visit 1 Past DMARD therapy Education Erosions ESR Ethnic origin Family history of RA Functional class Global severity (physician) Grip strength HAQ disability index GI history HCQ at visit 1 HCQ prior to visit 1 IM gold at visit 1 IM gold prior to visit 1 Mean blood pressure Muscle weakness (distal) Muscle weakness (proximal) Nodules Pain Global severity (patient) DP at visit I DP prior to visit 1 Prednisone at visit I Prednisone past Radiographic RA Rales RF Sex Smoking Weakness Definition SK 0-78, WI 0-24, ST 0-28 Occasional, regular, heavy SK positive (>30 minutes) or negative; WI and ST actual minutes Loss of appetite (yeslno) Weight (kg)/height(m)2 Any of the following drugs at first clinic visit: DP, HCQ, gold (oral or injectable), SSZ, MTX, CYC, AZA Any of the following drugs prior to first clinic visit: DP, HCQ, gold (oral or injectable), SSZ, MTX, CYC, AZA Years of formal education Radiographic erosions (0-3 scale), hand erosions (WI only) Westergren, mm/hour White, Black, Oriental, Hispanic, other Presentlabsent Functional class I-IV Physician s estimate of disease activity, VAS Folded blood pressure CUE mean of left and right hands (mm Hg) Functional disability index (0-3) History of gastric or duodenal ulcer or GI bleeding at first visit Yeslno Yeslno Yeslno Yes/no (Systolic- diastolic)/3 diastolic Grade 0-3 Grade 0-3 Rheumatoid nodules Visual analog scale (0-3) (different at each center) Patient s estimate of disease activity, VAS Yeslno Yeslno Yeslno Yeslno Grade 0-4 by 1958 ACR diagnostic criteria (ref. 24) By auscultation (presentlabsent) Titer >1:20 (present/absent); log of dilutions Male/female Packs per day Maximum of proximal and distal muscle weakness Center SK WI ST * SK = Saskatoon; WI = Wichita; ST = Stanford; RA = rheumatoid arthritis; DMARD = disease-modifying antirheumatic drug; DP = D-penicillamine; HCQ = hydroxychloroquine; SSZ = sulfasalazine; MTX = methotrexate; CYC = cyclophosphamide; AZA = azathioprine; ESR = erythrocyte sedimentation rate; VAS = visual analog scale; HAQ = Health Assessment Questionnaire; GI = gastrointestinal; IM = intramuscular; ACR = American College of Rheumatology; RF = rheumatoid factor (log-latex 0-16 in Saskatoon and 0-10 in other centers).

5 MORTALITY IN RA 485 Table 3. Selected demographic and clinical variables for 3,501 RA patients at study entry* Saskatoon Wichita Stanford Santa Clara P or P or CL or CL or Variable No. % SEM No. % SEM No. % SEM No. % SEM Demographics Age (years) Sex (% female) Caucasian (%) Education (years) Family history of RA (%) Disease duration (years) Followup (years) GI ulcerbleeding (%) Smoking (packdday) Symptom and physical measures Anorexia (%) Proximal weakness (0-3) Distal weakness (0-3) Rheumatoid nodules (%)t BP diastolic (mm Hg) BP systolic (mm Hg) BP mean (mm Hg) Body mass index Rales (0-3) Active joints (no.)$ Functional assessment Disability index (0-3) AM stiffness >30 min. (%) AM stiffness (hours) Functional class (1-4) Grip strength (mm Hg) Pain scales (0-3)ti Laboratory and radiography ESR (mdhour) RF latex titer >1:20 (%) RF log-latex Erosions (any site) (0-3) Hand joint narrowing (0-3) Hand joint erosions (0-3) Radiographic grade (0-4) Drug therapy DMARD past (%) DMARD at visit 1 (%) Gold past (%) Gold at visit 1 (%) Penicillamine past (%) Penicillamine at visit 1 Prednisone past (%) Prednisone at visit 1 (%) ,391 1,401 1,220 1,235 1,382 1,358 1,364 1,357 1,290 1,398 1,372 1, ,283 1,347 1,347 I, , * BP = blood pressure; see Table 2 for additional explanations and definitions. t Self assessed at Santa Clara. t. Different scales used at each center probabilities calculated on the basis of probabilities published by the NCHS (33). Saskatoon population survival properties were based on Canadian health statistics (34). At each center, Kaplan-Meier curves were constructed for all patients and for females and males separately to estimate survival. Cause of death. For comparison with general population mortality statistics, the cause of death of RA patients was determined by death certificate review. Death certificates for all patients were obtained. The probabilities of death from the various causes were calculated for the general population, using data from the 1985 Vital Statistics of the United States, matched to patients sex and age at entry (35). To determine if deaths were caused, or contributed to, by RA or if they were related to gastrointestinal (GI) problems such as hemorrhage or perforation or to similar events, additional data were considered, including hospital summaries and physician records. A written protocol for causality was developed in consultation with the centers and

6 486 WOLFE ET AL was used at each center in the determination of causality. A death was considered to have been caused by RA if a generally accepted and predominant link could be established between RA and the death. Examples of RAcaused deaths include deaths from RA lung disease, vasculitis, and myocarditis, as well as deaths occurring as a direct result of RA treatment, such as drug-induced agranulocytosis or pulmonary embolism or fatal infection following joint surgery. An RA-contributed to death was one in which RA was one important factor in the death. Examples of RA-contributed to deaths include deaths related to falls and fractures, resulting from immobility, or indirectly related to adverse effects of therapy. GI-caused deaths were those directly caused by a GI event, such as fatal GI hemorrhage, ulcer, or perforation. GI-contributed to deaths were those in which the GI event was not the major factor leading to death. In a few instances, we were unable to obtain records other than the death certificate and, therefore, may have missed some RAor GI-related deaths. Determinations of causes of death as listed on the death certificate and whether deaths were from RA- and GI-related causes were made at the individual center and then reviewed for accuracy by the senior author. While some of the GI deaths may have been related to RA, we have presented the two constructs separately for clarity. Standardized mortality ratios. SMRs were calculated for each center. The SMR expresses the overall mortality experience of the study group of interest compared with the general population, by the ratio of the observed-to-expected number of deaths (36). For example, an SMR of 2 indicates that mortality in RA patients was double that expected in the general population over the period of observation. Cox proportional hazards regressions. The predictive value of each variable with regard to time to death was examined with a (univariate) Cox proportional hazards model. A variable significant at the 0.05 level was chosen for study in a multivariate stepwise Cox regression, provided that at least two-thirds of all patients at the center had data for that variable. In addition, variables considered important on the basis of previous investigations (e.g., anorexia, weakness, rales) (17) were also chosen. The multivariate Cox proportional hazards model quantifies the predictive value of each variable in the model when all variables are considered together. The Cox model does not allow for missing values; therefore, several strategies for missing data were employed. First, variables missing at the initial visit but present within 1 year of the initial visit were substituted, provided such data were not expected to change importantly with time (RF test result, functional class, nodules, joints with active RA, anorexia, blood pressure, disability index, radiographic variables, rales, muscle weakness, grip strength, and ESR; grip strength and ESR were further stratified by sex). Second, when data within 1 year were not available for these variables, and for all other variables not listed above, the mean of the variable at the first visit for each center was substituted for the missing variable. For dichotomous variables, normal values were substituted when missing at the first visit. RESULTS Demographics. The demographic characteristics of study patients are displayed in Table 3. The mean age of study participants at the first visit was 53.3 (13.8 SD) years, with patients from Wichita being slightly older (55.3 [14.2 SD] years) and those from Stanford younger (51.2 [13.7 SD] years) at the initial visit. The 3 clinical centers (Saskatoon, Wichita, Stanford) noted disease durations averaging between 7.3 and 8.6 years at the first visit, while the Santa Clara patients disease duration averaged 14.2 years. The shorter duration of disease at Saskatoon, Wichita, and Stanford reflected the continuous enrollment of new (and newly diagnosed) RA patients into the data sets. Differences in sex were noted as well, with the Santa Clara group being 82.6% female while Saskatoon had a 67.7% female proportion. The average education level was highest in California (13.0 and 13.8 years, Stanford and Santa Clara, respectively) and lowest in Saskatoon (10.1 years). Race also differed, with fewer Caucasians in the California groups. Overall, these differences were expected, reflecting the rural nature of the Saskatoon center as opposed to the more wealthy, highly urbanized, and culturally diverse California groups; and reflecting as well samples from clinical settings as opposed to those recruited from the community. In addition, at Santa Clara, fewer patients were RF positive (40.7%), while self-reports of rheumatoid nodules (42.3%) were more common than physician-identified nodules in the other groups. Survival: standardized mortality ratios. For each group studied, the mortality of RA patients, both males and females, far exceeded that of the US and Canadian populations (Table 4). The SMR was highest at Stanford (3.08) and lowest in Wichita (1.98). These Table 4. Standardized mortality ratios for 3,501 rheumatoid arthritis patients at 4 ARAMIS centers* Standardized mortality ratio (SEMI Center No. of deaths ~~ ~ Total Females Males Saskatoon (0.07) 2.44 (0.09) 2.04 (0.09) Wichita (0.11) 1.94 (0.14) 2.05 (0.17) Stanford (0.16) 3.29 (0.23) 2.77 (0.22) Santa Clara (0.24) 1.98 (0.28) 2.83 (0.46) All centers (0.05) 2.36 (0.07) 2.14 (0.07) * The standardized mortality ratio is the ratio of observed deaths in the group under study to expected deaths in the general population. ARAMIS = Arthritis, Rheumatism, and Aging Medical Information System.

7 MORTALITY IN RA o 0.9 SASKATOON S U RVlVAL CURVES WICHITA SURVIVAL CURVES - 0._ > L 3 cn Canadian Males _-- Saskatoon RA Males 0.1 t -- 0.oL ' I ' I ' I ' I " " ' ' I Years After Entry A STANFORD SURVIVAL CURVES x Q O n 2 Q U.S. Females.- U.S. Males Wichita RA Females - -- Wichita RA Males ' I ' ' ' ' I ' ' I I I ' ' SMR=3.08 X SMR=2.18 a Q _ >.- > U.S. Females (A 0.2 U.S. Males 0.1 Stanford RA Females Stanford RA Males I I I 1, I U.S. Females US. Males Santa Clara RA Females -- Santa Clara RA Males I, I I I I I, two groups effectively define the limits of mortality for the 3,501 US and Canadian RA patients in this study. The other centers, Saskatoon and Santa Clara, each had SMRs of about 2.2. As can be seen from Table 4, the weighted SMR for all groups was In general, then, the data indicate that mortality rates for RA patients are at least twice as high as for those without RA, and possibly higher. The death rate was particularly high in Saskatoon (50.7%), reflecting the long duration of followup at that center (mean of 15.8 years) compared with the other centers (Table 3). No consistent difference in sex distribution was identified in the SMR data. The SMR was greater in males than females in the Santa Clara data bank, but

8 WOLFE ET AL Table 5. Results of univariate Cox regression analyses of selected variables for RA patients at study entry* Saskatoon Wichita Stanford Variable No. RR P No. RR P No. RR P Demographics Age (years) Sex (% female) Caucasian (%) Education (years) Family history of RA (%) Disease duration (years) GI ulcer/bleeding (%) Smoking (packslday) Symptom and physical measures Anorexia (%) Weakness (0-3) Rheumatoid nodules (%) BP diastolic (mm Hg) BP systolic (mm Hg) BP mean (mm Hg) Body mass index Rales (0-3) Active joints (no.) Functional assessment Disability index (0-3) AM stiffness >15 min (%) AM stiffness (hours) Functional class (1-4) Grip strength (mmhg) Pain scales (0-3) Laboratory and radiography ESR (mm/hour) RF latex titer >1:20 (%) RF log-latex Erosions (any site) (0-3) Hand joint narrowing (&3) Hand joint erosions (0-3) Radiographic grade (04) Drug therapy DMARD past (%) DMARD at visit 1 (%) Gold past (%) Gold at visit 1 (%) Penicillamine past (%) Penicillamine at visit 1 Prednisone at visit 1 (%) Prednisone past (%) oo oo S O t t O.0000t t t I oo so t t mt t t t t oo oo 1.00 I t t t t t t t t t f * Relative risk (RR) = relative multiplicative effect of the variable on the hazard function corresponding to a 1-unit change in that variable only. See Tables 2 and 3 for explanations and other definitions. t Used in multivariate analysis. greater in females in both Saskatoon and Stanford. No difference between the sexes was noted in Wichita, though a slightly higher SMR was noted for hales. Survival: Kaplan-Meier survival curves. Figures 1A-D describe Kaplan-Meier survival curves for each center. The survival curves for the general population matched to the RA study subjects for date of entry into the study, duration of followup, age, and sex are also displayed. As examples, in Saskatoon (Figure IA), the median (50%) survivorship among RA subjects was 21 years for both sexes combined, 17 years shorter than expected for the general Canadian population (38 years). After 12 years of followup in Wichita, expected mortality was 18%, while observed RA mortality was 32% (both sexes combined). Important in each of the curves is the gradually increasing mortality rates for RA patients compared with persons without RA in the population. The increases can be detected at about the third year of followup, and continue for the entire duration of observation. These data suggest that the

9 MORTALITY IN RA 489 effect of RA on mortality increases with increasing duration of RA. The figures also suggest that the Kaplan-Meier curves for females and males are relatively parallel throughout the entire period of observation in 3 of the centers. In Stanford, however, male and female survival is similarly relatively parallel until about year 9, when survival decreases more rapidly in males. Kaplan-Meier curves were recalculated for Stanford patients under the assumption that patients lost to followup after 1979 were alive as of March There was little difference between the new curves and those displayed in Figure 1. (Survival curves and data are available from the authors.) This recalculation could not be performed for the 136 patients who were lost to followup at Stanford prior to the inception of the NDI (1979). If a large proportion of these patients were actually dead, then the Stanford curves and SMRs would underestimate RA mortality. Factors associated with mortality. Univariate analyses. Table 3 presents the means and percentages positive for the clinical and treatment variables at baseline in RA patients in all centers. Table 5 presents the results of univariate Cox proportional hazard regressions for the variables. These analyses test whether a variable present at the first clinic visit is associated with subsequent mortality. In general, almost all clinical, laboratory, and radiographic variables in all centers were associated with subsequent mortality. Only 2 of these variables (joint swelling and hematocrit) were not associated with mortality in at least 1 center. Among demographic variables (and non-ra clinical variables), family history of RA, body mass index, and alcohol use were not associated with subsequent mortality. Hydroxychloroquine, auranofin, and azathioprine therapy were not related to mortality in any center, while prednisone, in particular, as well as therapy with disease-modifying antirheumatic drugs (as defined in Table 2) were related. Multivariate Cox proportional hazards model analyses. Table 6 presents the results of the multivariate Cox proportional hazards regressions. These analyses consider the simultaneous effect of multiple factors on the hazard of death, and quantify the effect of individual covariates on the hazard of death, adjusting for the effect of all other covariates in the model. Because models and the variables in them differ at each center, and because variable definition and collection also differ, no pooling across centers was performed. As displayed in Table 6, the first variable stepped into the model was age (3 of 3 centers; i.e., 3 centers with improvement P values <0.05; 3 centers collecting data for this variable). Male sex was also associated with early mortality (3 of 3). Disability, measured either as the score on the Stanford Health Assessment Questionnaire (HAQ) or as the functional class, was a predictor (2 of 3), as was joint count (2 of 3), RF (2 of 3), prednisone therapy (2 of 3), hypertension (2 of 3), rales (2 of 2), nodules (1 of 3), ESR (2 of 2), and education (1 of 2). Two variables collected only in Wichita were also predictors of mortality: smoking history and history of GI ulcer or bleeding. Anorexia, a variable collected only at Saskatoon, was associated with mortality as well. The results shown in Table 6 may be understood with the following examples. The positive coefficient for age implies that older patients have poorer survival prospects. The relative risk (RR) of at Stanford, for example, indicates that a patient 1 year older in age has a 6.6% increased hazard of death, controlling for the other covariates in the model. Similarly, the hazard of death is 43.4% higher for males than for females, after controlling for the other covariates. Perhaps of more direct interest to rheumatoid arthritis are the following data. At Wichita (controlling for the effect of other variables in the model), a 10-mm increase in ESR at the first visit is associated with an increased death hazard of 7% (RR = 1.007); a single doubling of the RF is associated with a 4.9% increase in death hazard; a 33% increase in the HAQ disability index is associated with a 1-unit increase; receiving prednisone at the first visit is associated with a 60.6% increase (compared with not taking prednisone at the first visit). At Saskatoon, when other variables are controlled for, a 1-grade increase in functional class increased the hazard of death by 24.1%, prednisone use at first visit by 42.2%, a 10-mm increase in ESR by 4.0%, a 1-titer increase in RF by 3.2%, and the presence of nodules by 33.6%. Similar results were obtained at Stanford, where the RR for each additional joint involved was 3.7%, controlling for other variables in the model. Further exploration of RA-related variables in the individual data sets yielded additional information. In the Saskatoon data set, presence of nodules enters at step 2. Its chi-square to enter is while that of RF is After entry of nodules, the chi-square for RF falls to and only enters at the eighth step.

10 490 WOLFE ET AL Table 6. Stepwise Cox proportional hazards models for RA patients* Center, 95% CI Improvement step, variable Coefficient SEM RR for RR P Sas katoon 1 Age 2 Nodules 3 Functional class 4 Sex 5 Prednisone use 6 Rales 7 Joint count 8 RF log-latex 9 Anorexia 10 MeanBP 11 ESR 12 Joint swelling Wichita 1 Age 2 Sex 3 Disability index 4 Smoking 5 GI history 6 Prednisone use 7 RF log-latex 8 Education 9 Mean BP 10 ESR 11 Nodules Stanford 1 Age 2 Rales 3 Sex 4 Joint count 5 Prednisone use lyear 1.336/ 1.241/unit 1.547/M:F 1.422/ 1.447/ 2/joint 1.032Aog 1.354/ 1.009lmm Hg 1.004/mm hour year 1.675lM:F 1.330/unit 1.472lpack 1.579/ 1.606/ 1.049Ilog 0.931lyear 7lmm Hg 1.007/mm hour l.o66/year 1.339/ 1.434lM:F oint OO O <o.oo * Relative risk (RR) = relative multiplicative effect of the variable on the hazard function corresponding to a l-unit change in that variable only. 95% CI = 95% confidence interval. See Tables 2 and 3 for explanations and other definitions. This finding is explained by the correlation between RF and the presence of nodules (r = 0.23, P < ). A similar co-linearity between RF and nodules can be seen in the Wichita data set, where the correlation between RF and nodules is 0.19 (P < ). If RF is entered as a dichotomous variable (yesho), then RF is replaced by nodules, which enters first, and both variables will enter the model. These findings suggest that to some degree, RF and nodules may be measuring a common disease-related feature of RA. Among the RA-related factors, radiographic variables, powerful in the univariate analyses, did not step out in any of the multivariate models studied because they were highly correlated with variables that had already been entered into the model. In Wichita, the correlation of hand erosion scores with other variables was as follows: disease duration 0.48, nodules 0.15, RF 0.12, and ESR 0.12 (all P < ). In Saskatoon, the radiographic variable is the ACR 1958 diagnostic criteria (24) radiographic criterion. The correlations of this criterion with other variables were: disease duration 0.41, age 0.24, nodules 0.23, functional class 0.19; RF 0.15, and ESR 0.13 (all P < ). We performed 2 further analyses on the Wichita data set. First, we studied deaths that were caused by GI bleeding, ulcer, or similar problems to determine if a history of a previous GI ulcer or hemorrhage (which was associated with a 57.9% increase in the hazard of mortality when controlling for the other variables in the multivariate Cox regression) was actually associated with death from GI causes. In a Cox regression using age, sex, and disease duration as covariates, the relative risk of a history of GI problems for the hazard of death from GI causes was (95% confidence interval [95% CI] , P = 0.492). The number

11 MORTALITY IN RA 49 1 Table 7. Causes of death and 0bserved:expected (0:E) death ratios, matching US vital statistics (stats.) (1985) with individual and combined ARAMIS centers, adjusted for sex and age by 10-year intervals* All centers combined Proportion Santa us Saskatoon Wichita Stanford Clara Category stats. Observed O:E ratio O:E ratio O:E ratio O:E ratio O:E ratio Infection Cancer Leukernidlymphoma Circulatory Cerebrovascular Respiratory Pneumonia Digestive (GI) Renal RA Injury/accident Other O.OO * Values are for 898 rheumatoid arthritis (RA) patients whose cause of death was known. The cancer category is exclusive of leukernidlymphomas. The circulatory category includes International Classification of Diseases (Ninth Edition) codes , while cardiovascular includes Circulatory is exclusive of cerebrovascular disorders ( ). Respiratory is exclusive of pneumonia. ARAMIS = Arthritis, Rheumatism, and Aging Medical Information System; GI = gastrointestinal. of deaths from GI causes in the Wichita set was small, so the 78.2% clinically important increased hazard of death was not statistically significant. A possible explanation is that a positive GI history could be a marker for comorbidity or could co-associate with severe disease. In contrast to the GI finding, cigarette smoking was statistically associated with deaths from cardiopulmonary causes. Measured as packs per day, the RR for smoking (controlling for age, sex, and RA duration) was (95% CI , P = 0.042). With the Cox analyses, then, the 3 data sets indicate the following: that, as expected, the non-ra factors of age, sex, education, hypertension, and smoking are predictive of early mortality; that RA features (joint counts, functional disability, RF titer, ESR, and rheumatoid nodules) are similarly associated; that general disease factors (either RA or non- RA: anorexia and rales) are related; and that a treatment-related or comorbid factor (GI history) is associated as well. Causes of death. Table 7 describes causes of death for the 898 that were known in this study, as well as the proportion of deaths expected from the US population, matched to the RA study populations for age and sex at death. Beyond RA as a cause of death, there are striking increases related to pneumonia (ob- served proportion of deaths over expected proportion [O:E] ratio 5.3) and nonpulmonary infection (0:E ratio 6.2). Increases were also noted for GI-related deaths and for leukemidlymphoma, but not for other cancers or for renal disease. 0bserved:expected ratios, however, do not take into account the effect of the overall mortality increase in RA demonstrated by the SMR. An estimate of this effect can be obtained by considering that if the observed SMR of 2.26 were constant across all of the causes of death described in Table 6, then mortality rates would be increased more than 2-fold for each cause for RA patients. For example, the O:E ratio adjusted for RA mortality would be 2.24 for circulatory disorders, 3.31 for digestive disorders, and for infection. For purposes of comparison with national statistics, we used death certificate diagnoses for the RA patients. Because death certificates are often filled out inaccurately, we also examined hospital final summaries, clinical records, and made telephone calls to physicians in an effort to obtain additional deathrelated information which might allow us to categorize mortality relating to RA and GI disease for the analyses that follow. Of the 898 deaths, 88 (9.8%) were directly caused by RA, and an additional 108 (12.0%) were contributed to by RA. In all, 196 (21.8%) of the

12 492 WOLFE ET AL deaths were either caused by or contributed to by rheumatoid arthritis. Although RA was clearly a direct and indirect cause of mortality in these patients, as well as an important comorbid condition, RA was mentioned on the death certificate of only 40.7%. We also examined the role of GI bleeding and other GI events in the deaths of RA patients. Of the 898 deaths, 50 (5.6%) were from a direct GI cause, and an additional 51 (5.7%) were contributed to by GI events. In all, 101 (1 1.2%) of deaths were either caused by or contributed to by GI events. DISCUSSION The data from the 3,501 patients in this ARAMIS study demonstrate not only the extent of the increase in mortality imposed by RA (Table 4), but also the potential causal links between RA and early mortality from RA. It is important that the major findings of this report are confirmed across the 4 study centers, even though centers differed geographically and in the content of patients (tertiary centers, rheumatology practice, and community sample), among other factors. This important diversity and the concordance of results were among the reasons that led us to report the data from the centers individually. In the 3 centers that reflected community and practice data, the SMRs ranged from 1.98 to 2.24, while only at the Stanford tertiary referral center was the SMR increased further (3.08). As can be seen in Table 1, the increased mortality noted in the current study is substantially greater than that found in all previous US and Canadian reports, underscoring the importance of mortality in RA. We also noted that mortality in RA increases at an accelerated rate over time. This important finding, which had not been noted in a number of previous shorter studies, suggests that it is not merely having RA that is bad, but it is the progressive burden of disability, decrepitude, pain, treatment, and treatment side effects, operating over time, that increasingly leads to death in RA patients. The increase in the SMR in Saskatoon, from 1.51 noted in the 1985 report (17) to 2.24 seen in the current report, is additional evidence of the effect of time on RA mortality rates. We found no consistent difference in SMRs between the sexes, consistent with previous studies, and we found no evidence to suggest that the SMR was lower in women early in the course of RA, an observation suggested by Symmons et a1 (37), who felt that an estrogen effect might forestall death. The increased mortality that we observed can be explained in part by the analysis of cause of death data presented in Table 7. In this analysis we have compared the expected proportion of cause-specific deaths to the observed proportion. Major increases are noted in deaths caused by infection, particularly pulmonary infection, by lymphoproliferative malignancies (though not in other cancers where the rates were substantially decreased), by RA itself, and to a lesser extent, by GI disease. Of interest, renal diseases had a decreased observed-to-expected ratio, a finding noted by all other investigators but in contradiction to the results of Finnish studies, where renal amyloidosis is a common finding (1 1,38). Because death certificates are frequently inaccurate, we also examined clinical records and hospital death summaries for additional evidence of causation relating to RA and to GI causes. In this separate analysis, 9.8% of deaths were directly related to RA, while in another 12.0%, RA was a contributing cause. In performing this analysis, we noted death directly caused by GI events (perforations and hemorrhage) in 5.6%, and GI events as a contributory cause in 5.7%. While 261 of the 898 deaths (29.1%) were related to causes that are specifically increased in RA (0:E > 1.1, see Table 6), the largest contribution to the SMR of 2.26 came from other causes. The major contributing cause was cardiovascular disease, where the number of deaths expected was 161 (accounting for the increased RA mortality indicated by the SMR of 2.26), while the observed deaths were 361. Cerebrovascular diseases were the second greatest cause of excess mortality, with an observed-to-expected difference of 37. Thus, RA contributes to a general increase in mortality, with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases, while quantitatively, fewer deaths are the result of specifically increased causes noted in Table 6: infection, pulmonary disease, lymphoproliferative malignancy, and GI bleeding or perforation. The results of previous studies led Symmons (39) to comment that little is known about the causes of mortality and where interventions should be directed to reduce mortality. Epidemiologic studies have generally lacked clinical data, and clinical and sociodemographic data have not been collected or have not been collected uniformly in what have been mainly retrospective studies of mortality (39). Our results indicate that there are clearly recognizable factors that predict mortality. First, there are the well-known factors of age,

13 MORTALITY IN RA 493 sex, education level, and smoking, as well as the non-ra-related disease factor, hypertension. Next, we found a number of RA-related factors that predicted mortality. Among these were markers of disease severity, activity, and disability. The RF titer and the presence of rheumatoid nodules at the first visit were both predictive of mortality. We found evidence of a significant correlation between these variables, suggesting that they were, in part, measuring the same process. These factors might be considered to be measures of innate disease severity or virulence. Finally, disease activity (and outcome) measures, including ESR, joint counts, and HAQ functional disability index and functional class, also predicted mortality. Data presented elsewhere show similar results among the 305 Santa Clara community subjects, even though they differed in method of recruitment and disease duration at first assessment (32). Of interest, a history of GI hemorrhage or perforation was associated with mortality, as was prednisone therapy. The meaning of these findings is not entirely clear, since although GI history was associated with mortality, this group did not have increased mortality directly from GI hemorrhage or perforation. In a Cox analysis in which time-to-a-gicaused-death was the dependent variable and the independent variables at entry were a positive history of ulcer or GI bleeding, age, and sex, GI history was not predictive of specifically GI-caused death (P = 0.47). Both prednisone therapy and GI history might simply be other, independent markers of RA severity and activity. The observations regarding predictors of mortality suggest the following. Mortality is not only linked to RA, it is strongly linked to RA severity. In the clinic it is clearly useful to collect variables that are significant predictors, including sociodemographic data, serologic data, and clinical and laboratory data. Functional assessment using the HAQ is a powerful predictor of mortality, and its use (or the use of a similar instrument) appears to be strongly indicated in the care of the RA patient. Variables found to be predictors in this study have also been found useful as predictors Of RA outcome (40)* This is still another reason to suggest their use in clinical practice. The demonstration of associations and potential causal relationships between clinical activity and mortality makes a strong case for vigorous, active treatment Of RA~ particularly in those with high joint counts, elevated ESR, and decreased functional abil- ity. Many patients in this series did receive aggressive therapy, and additional questions remain that cannot be answered here. Would mortality have been (further) increased without such therapy? Would more effective therapies reduce mortality? Does the net effect of some therapies (e.g., prednisone) increase mortality? Even so, the data suggest the possibility that control of disease activity might reduce the 2-fold or greater increase in mortality that follows the development of rheumatoid arthritis, an illness that affects 1% of the population. A limitation of the present study is that the groups studied at each center were, as in almost all previous mortality studies, not inception cohorts. One hazard of studying prevalent RA cases found in clinics is that patients might have more severe disease than those with RA in the community, and study outcomes might be more adverse than in cases seen in the community. The low SMR (1.31) in the one community epidemiologic survey that attempted to use modern diagnostic criteria (6) suggests this may be the case. Our study, however, offers a firm description of the outcome of RA in the equally important world of the clinic. Of the 3,501 patients included in the SMR analyses, 305 (8.7%) were from Santa Clara. As indicated above, these patients differed from the rheumatology clinic patients of the other 3 centers in their method of recruitment and duration of disease. The current report supplies tantalizing information regarding prednisone usage and mortality. But it does not answer the question as to whether prednisone is merely a marker of RA severity or is, in and of itself, deleterious. In addition, the prednisone data presented here refer only to the initial study visit. Clearly, an important question is the effect of dose and duration of prednisone therapy on the course of RA. Followup studies to assess long-term (cumulative) prednisone effects are in progress. ACKNOWLEDGMENTS The authors thank Dena Ramey, Gurkirpal Singh, MD, and Das for their assistance in the compilation of Stanford data and deaths; Hong Shi, MS, for preparation of us and Canadian population mortality life-tables and survival curves; and Donna Hawley, MN, EdD, for assistance With the Cause-sPeCific mortality tables. REFERENCES 1. Cobb s, Anderson F, Bauer W: Length of life and cause of death in rheumatoid arthritis. N Engl J Med , 1953

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