MORTALITY STUDIES IN PSORIATIC ARTHRITIS

Transcription

1 1868 ARTHRITlS & RHEUMATISM Vol 40, No 10, October 1997, pp , American College of Rheumntology MORTALITY STUDIES IN PSORIATIC ARTHRITIS Results from a Single Outpatient Clinic. I. Causes and Risk of Death KATY WONG, DAFNA D. GLADMAN, JANICE HUSTED, JENNIFER A. LONG, and VERNON T. FAREWELL Objective. To identify the causes of death and mortality risk in patients with psoriatic arthritis (PsA) who were being followed up at a single outpatient clinic in Toronto, Ontario, Canada. Methods. Patients enrolled in the PsA Clinic between 1978 and 1993 were compared with the general population of Ontario. Deaths were identified from the clinic database and through linkage with the provincial mortality database, and causes were confirmed by death certificates. A standardized mortality ratio (SMR) was computed, based on the assumption that patients lost to followup were alive at the end of the study. Results. Of the 428 patients with PsA (194 women and 234 men), 53 (26 women and 27 men) died. The 4 leading causes of death were diseases of the circulatory (36.2%) or respiratory (21.3%) system, malignant neoplasms (17.0%), and injuries/poisoning (14.9%). The SMR for the female cohort was 1.59, and for the men, it was 1.65, indicating a 59% and 65% increase in the death rate, respectively. Deaths due to respiratory causes were particularly increased in these patients. Conclusion. The results suggest that this PsA Clinic outpatient population had an increased mortality risk. Supported by a research grant from the Medical Research Council of Canada. Katy Wong, MSc: McMaster University, Hamilton, Ontario, Canada; Dafna D. Gladman, MD, FRCPC: University of Toronto, and The Toronto Hospital, Toronto, Ontario, Canada; Janice Husted, PhD: University of Waterloo, Waterloo, Ontario, Canada; Jennifer A. Long, BSc: The Toronto Hospital, Toronto, Ontario, Canada; Vernon T. Farewell, PhD: University College, London, UK. Address reprint requests to Dafna D. Gladman, MD, FRCPC, Centre for Prognosis Studies in the Rheumatic Diseascs, The Toronto Hospital, Western Division, 399 Bathurst Street, Suite 1-318, Toronto, Ontario M5T 2S8, Canada. Submitted for publication January 21, 1997; accepted in revised from May 28, Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis, and may affect 1 % of the population. In the past, it was thought to be a benign arthropathy (1-4). Consequently, physicians have been reluctant to undertake aggressive therapeutic regimens to suppress the disease, because of the incidence of serious adverse effects associated with such interventions. Recent investigations, however, challenge the concept of PsA as a benign arthropathy. In a study of 220 patients followed up prospectively at the University of Toronto PsA Clinic (5), we found that approximately half of the patients (46%) had at least 1 deformed joint, and that 16% had 25 deformed joints, suggesting that the mutilating form of arthritis was more common than had been reported in the literature. Radiographs substantiated these observations, indicating erosive disease in 67% of patients and Steinbrocker stage IV changes (6) resulting in complete joint destruction or ankylosis in nearly 30% of patients (5). In addition, 11 % of the study patients had severe functional limitations or marked restriction of daily activities attributable to arthritis. Thus, the prevalence of severe disease found among these patients was similar to that reported for a group of patients with rheumatoid arthritis (RA) (7). Similar results were obtained using our enlarged clinic database of 441 patients with PsA (8). Moreover, clear evidence of progression of deformities was demonstrated when the clinical characteristics of the patients were compared at presentation and at followup (9). One hundred twenty-six patients were followed up prospectively for a minimum of 5 years after their first clinic visit. During the followup period, the number of patients with 25 damaged joints doubled, from 19% initially to 41% at last visit. Recent study findings from other centers support our data and suggest that the disease is indeed more severe than initially thought (10,ll). In an attempt to further clarify the course of this illness, we

2 CAUSES AND RISK OF DEATH IN PsA 1869 Table 1. Demographic characteristics of the 375 living patients with psoriatic arthritis (PsA) and the 53 patients who died No. of patients No. of femalesimales Age at onset of PsA, years Age at onset of psoriasis, years Arthritis duration at first visit, years No. of active joints at presentation No. of damaged joints at presentation Duration of followup, years Regularly Lost to followed up followup Dcad t i t f t i t i t t i t * Except where otherwise indicated, values arc the mean -t SD. Patients lost to followup were considered alive. examined whether PsA is associated with an increased risk of mortality compared with the general population of Ontario. PATIENTS AND METHODS Patient population. Patients who registered at the University of Toronto PsA Clinic between January 1, 1978 and August 30, 1993 were included in the study. The PsA Clinic is a primary, secondary, and tertiary care referral center, to which patients are referred by family physicians, dermatologists, general internists, rheumatologists, and other physicians from both community and university practices and from the Psoriasis Education and Research Centre (5). The Clinic therefore includes a population of patients with both mild and severe PsA, thus providing a full spectrum of the disease, including its early forms (5). This patient population is similar to other reported series of patients with PsA in terms of clinical characteristics (8). All patients had an inflammatory arthritis associated with psoriasis, and other rheumatologic conditions were excluded (5). Patients were reviewed at the initial Clinic visit and at 6-12-month intervals, using a standard protocol. With the exception of the radiographs, which were taken at the initial assessment and at 2-year intervals, each assessment included a complete history, physical examination, and laboratory evaluation. All data collected on these patients have been entered into a computerized database. Assessment of patients vital status. The vital status of patients who had not been assessed in the Clinic since September 1, 1992 was ascertained by telephone interviews with patients, family physicians, and patients relatives, and by searching the provincial mortality database. Ascertainment of death and cause of death. Information on patient deaths was collected prospectively and ascertained through periodic linkage with the provincial mortality database, through interviews and correspondence with relatives and family physicians, and since 1980, through daily checks of death notices in the newspaper. A thorough check of the provincial mortality database was carried out in the summer of Death certificates were used, where possible, to verify patient deaths and to identify the primary and antecedent cause(s) of death. Causes of death were assigned International Classification of Diseascs, Ninth Revision codes, which were grouped according to the system used in the Registrar General s publications of mortality rates for the general population of Ontario. All death information was recorded in the Clinic s computerized dat, <L b ase. Statistical analysis. To detcrrnine if the number of deaths observed among the PsA patients between January 1, 1978 and September 1, 1994 was greater than would be expected in the general Ontario population, standardized mortality ratios (SMRs) were computed separately for men and for women, using Epilog software (12). The expected numbers of deaths among the PsA patients were calculated by multiplying the number of person-years per category of age and calendar period by the corresponding mortality rate of the Ontario population. In addition, the 95% confidence interval (95% CI) of the SMR was calculated to determine the range of plausible risks. For the calculation of the SMR, any patients lost to followup were assumed to be alive at the end of the study period. This assumption seemed reasonable, given that we checked the provincial mortality database during and at the end of the study, and none of the lost-to-followup patients were registered in the database. Furthermore, the impact of this assumption is known and leads to a conservative SMR estimate. RESULTS The study population comprised 428 patients, 234 of whom were men (54.7%) and 194 of whom were women (45.3%). By the end of the study, 290 of these patients (68%) were being followed up in the Clinic and were therefore known to be alive, 85 (20%) were lost to followup, and 53 (12%) had died. The mean age and mean disease duration at study entry were 43.7 years (range ) and 7.8 years (range 0-48), respectively. The total number of person-years of followup, assuming those lost to followup were alive at the end of the study, was 4,542 (men 2,469, women 2,073). The mean age at death was 67.7 years (range ). The characteristics of the patient population are shown in Table 1.

3 1870 WONG ET AL Table 2. Primary causes of death in patients with psoriatic arthritis Primary cause No. (%)* Diseases of the circulatory systcm Myocardial infarcts Ccrebrovascular accident Congestive heart failureiarleriosclerosis Diseases of the respiratory system Pneumonia Respiratory arrest due to chronic obstructive pulmonary disease Diseases of the digestive system Cirrhosis or liver failurc Malignant neoplasms lnjuriesipoisoning Other known causes Total, known causes Total, unknown causes Total deaths -$ Percentage of total no. of deaths from known causes. 17 (36.2) 13 (27.6) 2 (4.3) 2 (4.3) 10 (21.3) I (1 4.9) 3 (6.4) 4 (8.5) 8 (17.0) I (14.9) 1 (2.1) With regard to their clinical characteristics at first visit, patients who were lost to followup did not differ from the patients who were followed up regularly. The only difference was in the duration of followup, which, as cxpected, was significantly shorter in those lost to followup. However, patients who died were older at the diagnosis of both psoriasis and PsA, and their disease duration was longer at their first visit to the Clinic. Both results are cxpected, since death rates vary with age and, in this population, would be expected to increase with age. While the disease activity of the patients who died was similar to that in the rest of the Clinic population, they had a higher number of damaged joints at presentation. Causes of death in patients with PsA. Deaths and causes of death were verified by death certificate for 47 of the 53 deaths (88.7%). Cause of death was unknown in 6 patients (1 1.3%). The primary cause of death was defined as the main clinical and/or pathologic process directly responsible for the death (Table 2). Diseases of the circulatory system were the most common cause of death in the PsA group (36.2% of all deaths with known causes). Of the 17 patients who died of diseases of the circulatory system, acute myocardial infarction contributed to death in 13, stroke in 2, and congestive heart failure in 2. Diseases of the respiratory system were the second leading cause of death, accounting for 21.3% of all deaths with known causes. Seven of these patients died from pneumonia, while 3 died from respiratory arrest due to chronic obstructive pulmonary disease. Cancers, with no particular type dominating, accounted for 17.0% of the deaths, while injuries/poisonings accounted for 14.9% of all deaths with known causes. PsA was considered a contributory factor in only 1 death. Death rate compared with the general population. Table 3 shows the sex-specific SMRs in the PsA cohort compared with the general population of Ontario for the study period The ratio of the observed to the expected number of deaths indicated a 65% and 59% increased risk for male and female PsA patients, respectively, compared with the general population of Ontario. The 95% CI surrounding both estimates of risk indicated a statistically significant increase in the death rate. A combined SMR for both the men and the women would be estimated to be 1.62, with an associated 95% CI of These SMR estimates are conservative, since the 85 individuals lost to followup were assumed to be alive at the end of the study period. Results of further analysis of the cause-specific death rates by sex, comparing the 428 PsA patients with those of the Ontario population, are shown in Table 4. The rates for deaths due to circulatory system disease and deaths due to cancer in the PsA cohort did not differ significantly from the rates in the general population. However, among the PsA patients, the observed 10 deaths due to respiratory diseases was higher than that expected on the basis of mortality rates for the general population of Ontario. There was no difference in the frequency of use of methotrexate among patients with PsA who died versus those who were alive, nor was there a higher use of methotrexate among those who died of respiratory causes. Deaths due to external causes (injuriesipoisonings) exceeded the rate for the general population in men only, while deaths due to other causes were higher in women with PsA than in the general population. The small expected numbers involved in the various cause-specific calculations suggest that these SMRs must be interpreted with caution. DISCUSSION In the past, PsA was viewed as a benign arthropathy that presented most commonly as an asymmetric oligoarthritis (13,14). Although arthritis mutilans was recognized as a distinct pattern of the disease, it was Table 3. Estimated risk of death in the psoriatic arthritis cohort compared with the general population of Ontario* Observed Expcctcd Scx no. of death\ no of deaths SMR (95% CI) P Male ( ) 0.02 Female ( ) 0.03 * The standardized mortality ratio (SMR) estimates are based on the assumption that patients lost to followup were alive at the end of thc study period. 9.5% CI = 95% confidence interval.

4 ~ CAUSES AND RISK OF DEATH IN PsA 1871 Table 4. Cause-specific standardized mortalily ratios (SMR) in the psoriatic arthritis cohort compared with the general population of Ontario Mcn Women Combined No. of Expected No. of Expected Cause deaths no. of deaths SMR 95% CI P deaths no. of deaths SMK 95% CI P SMR 95% CI Diseases of the circulatory system Diseases of the respiratory system Malignant neoplasms Tnjuriesipoisoning All other Y * These analyses included only thc 47 paticnts with known causc of death. 95% CI = 95% confidcncc interval. thought to be rare (1,8). Gladman et a1 (5) were the first to suggest that PsA was more severe than previously accepted. They demonstrated that most patients had a polyarthritis, and that -20% of the patients had a significant degree of joint damage, with osteolysis and ankylosis seen both clinically and radiologically. Moreover, the same group noted that over a 5-year followup, an increase in the number of deformed joints occurred (8). Jones et a1 (11) have recently reported that the disease course in patients with PsA progresses over time. Torre Alonso et a1 (10) also concluded, from their study of 180 patients with PsA, that PsA is not a harmless disease. They found that 57% of the patients had erosive arthritis and 19% were in Steinbrocker functional class I11 or 1V. Information regarding mortality in PsA is scarce. Roberts et a1 (14), who followed up 168 patients for 1-10 years, observed 18 deaths. Nine patients died of cardiovascular causes, 3 died of infections, 2 had malignancies, 2 had hemorrhages, and the causes of the remaining 2 deaths could not be ascertained. None of the 40 patients described by Coulton et a1 died (4). Jones et a1 (15) recently reported that 9 of their cohort of 100 patients died, but they did not report the causes of death. Furthermore, there have been only 2 studies of mortality in psoriasis (16,17). The first study reported on causes of death in a cohort of 1,390 patients with psoriasis who had been enrolled in a photochemotherapy followup study (16). There were 179 deaths among the cohort, an overall rate similar to that observed in the geographically matched population. However, when analyzing cause-specific deaths, the authors found an excess of deaths from cirrhosis of the liver among their female patients. We are not told whether any of these patients had PsA. In the second study (17), a sample of 354 men and 300 women with psoriasis was identified among the general population of 125,035 men and 135,725 women in Gothenburg, Sweden. As compared with the general population, the men and women with psoriasis showed an overall excess mortality, which was particularly noted in the women. Moreover, the authors reported that there was an excess of deaths due to lung cancer among psoriasis patients. Again, this report did not specify whether any of these patients had PsA. The current investigation represents the first systematic study of mortality in a group of outpatients with PsA. The University of Toronto Psoriatic Arthritis Clinic, which includes patients with mild as well as severe disease (5), has provided a unique opportunity to study long-term outcome and prognosis in this patient population. At the time the study was performed, the clinic population included 428 patients with PsA who were followed up prospectively according to a standard protocol over a period of 16 years. In earlier studies, we have shown that patients enrolled in the Clinic in the first 5 years were not different from patients who were enrolled in the second 5-year period (9), and the disease characteristics of patients who were lost to followup did not differ, at either the first or last visit, from those of patients who were followed up regularly (18), suggesting that patients who continue to be seen at the Clinic are not different from those who choose to be seen in a community setting or by family physicians. The study demonstrates that these PsA Clinic patients are at an increased risk of death compared with the general population of Ontario. Our study also shows that the leading causes of death in patients with PsA are similar to those in both the general population and patients with RA (19-21); however, respiratory causes appear to be more significant in this PsA patient population.

5 1872 WONG ET AL Patients with chronic illness such as arthritis need to be followed up for a long time so that their prognosis will be clarified. RA was not thought to be associated with increased mortality until the findings of several long-term studies showed that RA limits life expectancy (19-22). A Canadian study (20) of the mortality rate in a cohort of patients with RA who were followed up at The University of Saskatchewan and whose average disease duration was 12 years, revealed an SMR of 1.51, while more recent studies of mortality in RA have provided SMRs that are somewhat higher, with a mean SMR of 2.26 (range ) for 4 North American centers (22). Thus, only when prospective followup studies were conducted was the increased mortality risk or patients with RA identified. In the same way that the death certificates for patients with RA typically do not mention RA, the death certificates for our patients with PsA rarely included the diagnosis of psoriasis or PsA (22,23). Thus, it would be difficult to obtain information on the risk of death in patients with PsA without conducting a prospective followup study such as that presented in this report. One potential limitation of our study pertains to the generalizability of the finding?. It could be argued that the population used in this study reflects a disproportionate number of severe cases of PsA, and this may have led to an overestimate of mortality risk among individuals with PsA. However, the Psoriatic Arthritis Clinic is a primary, secondary, and tertiary care referral center, with the patient population representing a full spectrum of disease. Another limitation is that our study population was not an inception cohort, and it is difficult to assess whether the study of a prevalent cohort has led to a biased estimate of mortality risk. In summary, we have now extended our earlier work by demonstrating that, as well as experiencing significant joint deformity and damage, patients with PsA who were being followed up at a single outpatient clinic also had a higher mortality rate than did the general population. Our findings indicate that patients with PsA need to be evaluated properly and treated appropriately in order to prevent these outcomes. Additional studies of the mortality experience of individuals with PsA are warranted. ACKNOWLEDGMENT The authors acknowledge the contribution of Gary Young, RSc, to this work. REFERENCES 1. Wright V: Psoriasis and arthritis. Ann Rheum Dis 15: , Gladman DD: Psoriatic arthritis. In, Prognosis in the Rheumatic Diseases. Edited by N Bellamy. Dordrecht, Kluwer Academic Publishers Scarpa R, Della Valle G, del Pucnte A, di Girolamo C, Lubrano E, Pucino A, Oriente P: Psoriatic arthritis (PA): a harmless diseasc? 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