Improved Survival in Psoriatic Arthritis With Calendar Time

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1 ARTHRITIS & RHEUMATISM Vol. 56, No. 8, August 2007, pp DOI /art , American College of Rheumatology Improved Survival in Psoriatic Arthritis With Calendar Time Yaser Ali, 1 Brian D. M. Tom, 2 Catherine T. Schentag, 1 Vernon T. Farewell, 2 and Dafna D. Gladman 1 Objective. To determine whether there has been a change in mortality rates over the last 3 decades in patients with psoriatic arthritis (PsA) whose cases were followed prospectively. Methods. Patients receiving followup care according to a standard protocol at the University of Toronto PsA Clinic between 1978 and 2004 were included. Information on patient deaths was collected prospectively. Mortality data for the general population of Ontario, Canada, stratified by 5-year age bands, sex, and calendar year from 1978 to 2004, were used to calculate the reference rates. Standardized mortality ratios (SMRs) were calculated through use of Poisson regression models for the number of observed deaths. Time trend analyses were performed through the use of 10-year rolling-average SMRs and followup period specific SMRs stratified by the period of entry into clinic. Results. Of 680 patients with PsA, 106 (15.6%) (55 women and 51 men) have died. Major causes of death were disease of the circulatory system, neoplasms, diseases of the respiratory system, diseases of the gastrointestinal system, injuries/poisoning, and unknown. The overall SMR for the period was 1.36 (95% confidence interval 1.12, 1.64). The estimated number of life-years lost by the PsA patient cohort overall was 2.99 years (95% confidence interval 1.14, 4.77). For patients who entered the cohort during the years , the SMRs were 1.89, 1.83, and 1.21 for followup periods , , and , respectively. For The University of Toronto Psoriatic Arthritis Program is supported by the Krembil Foundation. 1 Yaser Ali, MD, Catherine T. Schentag, MSc, Dafna D. Gladman, MD, FRCPC: University of Toronto, and Toronto Western Hospital, Toronto, Ontario, Canada; 2 Brian D. M. Tom, PhD, Vernon T. Farewell, PhD: Institute of Public Health, Cambridge, UK. Address correspondence and reprint requests to Dafna D. Gladman, MD, FRCPC, Director, Psoriatic Arthritis Program, Centre for Prognosis Studies in The Rheumatic Diseases, Toronto Western Hospital, 1E-410B, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. dafna.gladman@utoronto.ca. Submitted for publication August 3, 2006; accepted in revised form April 30, patients who entered the cohort during the years , the SMRs were 0.55 and 0.82, while the SMR for those who entered during was Conclusion. The drop in SMRs in this PsA clinic population suggests that the mortality risk has improved over time. This improved survival may reflect disease severity at presentation in the earlier cohort as well as earlier diagnosis and more aggressive treatment in the more recent followup period. Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. The disease affects men and women almost equally, with a mean age at onset of 36 years (1). PsA is characterized by bony proliferation and osteolysis, particularly at tendon, ligament, and capsular insertions (entheses). In the past, it was thought to be a benign arthropathy (2 4). Recent investigations, however, suggest that PsA is more severe than previously considered. In a study of 220 patients followed up prospectively at the University of Toronto PsA Clinic (5), we found that 67% of patients had at least 1 erosion on radiographs obtained at presentation to the clinic, and 20% had complete joint destruction. Moreover, 11% of the study patients had severe functional limitations or marked restrictions of daily activities that were attributable to the arthritis (American College of Rheumatology [ACR] functional class 3 or 4, according to the Steinbrocker criteria). A Spanish cohort of 180 patients with PsA identified 57% with erosions and 19% with ACR functional class 3 or 4 (6). Kane et al (7) found that of 129 patients with PsA who were entered into a cohort within 5 months of the onset of arthritis, 47% developed at least 1 erosion by the second year of followup. Queiro-Silva et al (8) and McHugh et al (9) have also demonstrated progression of disease in PsA. We previously reported that patients enrolled in our PsA clinic between 1978 and 1993 had an increased mortality risk (10). Of the 428 patients with PsA enrolled by January 1993, 53 had died by September

2 IMPROVED SURVIVAL IN PsA WITH CALENDAR TIME 2709 The 4 leading causes of death were diseases of the circulatory (36.2%) or respiratory (21.3%) system, malignant neoplasm (17.0%), and injuries/poisoning (14.9%). The overall standardized mortality ratio (SMR) was 1.62 (1.59 for women and 1.65 for men). However, a more recent study from Olmstead County, Minnesota (11), found that the rate of survival among patients with PsA was not different from that of the general population. Since there have been recent advances in managing PsA, we sought to investigate whether mortality risk has changed over the last decade in our patient cohort. PATIENTS AND METHODS Patients who were enrolled into, and followed up at, the University of Toronto PsA Clinic between January 1, 1978 and December 31, 2004 were included in the study. Patients were entered into the cohort if they had an inflammatory arthritis associated with psoriasis. Patients with other forms of arthritis, such as seropositive nodular rheumatoid arthritis (RA), systemic lupus erythematosus, gout, inflammatory bowel disease, or grade 4 osteoarthritis were excluded from the cohort (5). Patients have been referred to the PsA Clinic from general practitioners, dermatologists, other rheumatologists, and other physicians. Thus, the clinic serves as a primary, secondary, or tertiary referral center. Patients were evaluated at the initial clinic visit and at 6 12-month intervals thereafter according to a standard protocol. Information on patient deaths and causes of death was collected prospectively and through linkage with the provincial cancer registry, through telephone interviews and correspondence with family physicians and patients relatives, and through daily checks of death notices in the newspaper. Death certificates were used, where possible, to verify patient deaths and to identify the primary cause of death. To determine whether this cohort of PsA patients had an excessive number of deaths as compared with the general population of Ontario, Canada, standardized mortality ratios (SMRs) were computed. Mortality data for the general population of Ontario, stratified by 5-year age bands, sex, and calendar year (from 1978 to 2004), were used to calculate the reference rates. Overall SMRs were calculated, and SMRs by male and female sex were calculated separately, through the use of Poisson regression models for the number of observed deaths, with the logarithm of the expected number of deaths as an offset in the models. Time trend analyses were performed through the use of 10-year rolling-average SMRs (through 10-year periods , , to , and ), as well as followup period specific SMRs (followup periods , , and ) stratified by the period of entry into clinic (entry periods , , and ). Unadjusted and adjusted 10-year rolling-average SMRs were computed. The variables adjusted for were radiologic damage, the interaction between sex and radiologic damage, the logarithm of the sex-standardized erythrocyte Table 1. Primary causes of death in the study patients No. (%) Primary cause of death of patients Cancers 25 (23.6) Diseases of the circulatory system 26 (24.5) Diseases of the respiratory system 11 (10.4) Diseases of the digestive system 7 (6.6) Accidents/poisonings 5 (4.7) Other 5 (4.7) Unknown 27 (25.5) Total 106 (100) sedimentation rate (ESR), highest level of medication taken, presence or absence of hypertension, and disease activity (as measured by the number of joints with active disease), all of which were recorded at entry into the clinic; in addition, we adjusted for smoking status at the time of PsA diagnosis. These variables were chosen based on previous studies, clinical judgment, and through use of stratified Cox regression models to investigate the prognostic indicators of death. The adjustment was made assuming that the effects of these covariates were calendar time independent. Also, all analyses performed were based on the assumption that any patient lost to followup was still alive at the end of Life expectancies and numbers of life-years lost for this PsA patient population overall and separately by male and female sex were calculated based on the unadjusted SMRs (overall and by sex). Statistical analyses were performed using the statistical packages Stata version 9.0 (StataCorp, College Station, TX) and S-Plus version 6.2 (Insightful, Seattle, WA). RESULTS During the period January 1, 1978 through December 31, 2004, 680 patients were enrolled into the University of Toronto PsA Clinic. Of these 680 patients, 385 (56.6%) were men and 295 (43.4%) were women. There were 106 deaths during this time period, of which 51 occurred in men and 55 in women. The primary causes of death are shown in Table 1. The most common known causes of death were from cancers (n 25) and cardiovascular diseases (n 26). Significantly, there were 27 deaths for which the primary cause of death was unknown. The total number of years of followup, assuming those who were lost to followup were still alive at the end of 2004, was 9,302 (5,044 men and 4,258 women). Patient characteristics are shown in Table 2. The mean SD age of the patients at entry into the clinic was years (range years). The mean SD duration of arthritis at entry was years (median 4.5 years; range years). Before 1994, the mean arthritis duration at entry was 7.4 years, whereas since 1994, the mean arthritis

3 2710 ALI ET AL Table 2. Characteristics of the study patients at first presentation* Men (n 385) Women (n 295) Overall (n 680) Age, mean SD years At entry into the clinic At onset of PsA At onset of psoriasis Arthritis duration, median (range) years At first visit, all patients 4.4 (0 41.9) 4.9 (0 47.7) 4.5 (0 47.7) At first visit, by entry period Years (0 39.1) 4.3 (0 33.2) 4.7 (0 39.1) Years ( ) 5.0 ( ) 4.5 ( ) Joint counts, median (range) No. with radiologic damage 1 (0 42) 1 (0 41) 1 (0 42) No. with clinical damage 0 (0 53) 0 (0 48) 0 (0 53) No. with active disease 6 (0 48) 9 (0 55) 8 (0 55) No. with effusions 0 (0 33) 0 (0 30) 0 (0 33) ESR, median (range) mm/hour 18 (0 99) 30 (0 105) 23 (0 105) Smoking history at diagnosis, no. (%) of patients Nonsmokers 190 (49) 133 (45) 323 (48) Smokers 51 (13) 24 (8) 75 (11) Unknown 144 (37) 138 (47) 282 (41) Hypertension, no. (%) of patients No 346 (90) 253 (86) 599 (88) Yes 38 (10) 41 (14) 79 (12) Total no. of patients with available data Highest level of medication taken, no. (%) of patients None 242 (66) 171 (60) 413 (63) NSAIDs 77 (21) 67 (23) 144 (22) DMARDs 20 (5) 32 (11) 52 (8) Steroids 29 (8) 17 (6) 46 (7) Total no. of patients with available data * PsA psoriatic arthritis; ESR erythrocyte sedimentation rate; NSAIDs nonsteroidal antiinflammatory drugs; DMARDs disease-modifying antirheumatic drugs. duration was 7.7 years. There was no evidence of any difference in arthritis duration before or since 1994 (P 0.64 by t-test and P 0.4 by Mann-Whitney U test). The overall SMR in the PsA patient cohort as compared with the general population of Ontario for the study period was estimated to be 1.36 (95% confidence interval [95% CI] 1.12, 1.64). The sexspecific SMRs for this cohort of patients during the same study period and using the same reference population were 1.25 (95% CI 0.95, 1.65) in men and 1.47 (95% CI 1.13, 1.91) in women. The SMRs calculated by Wong et al (10) for the Toronto cohort of PsA patients during the period 1978 to September 1994 were 1.62 (95% CI 1.21, 2.12) overall, 1.65 (95% CI 1.09, 2.40) in men, and 1.59 (95% CI 1.04, 2.33) in women. The estimated life expectancies of the PsA cohort were 78.5 years in the overall group, 77.4 years in men, and 80.3 years in women. The corresponding life expectancies for the Ontario general population were 81.5 years, 79.7 years, and 83.9 years, respectively. Therefore, the estimated number of life-years lost by the PsA patient cohort was 2.99 years (95% CI 1.14, 4.77) in the overall group, 2.30 years (95% CI 0.51, 4.96) in men, and 3.60 years (95% CI 1.15, 5.96) in women. Figure 1 presents the 10-year rolling-average unadjusted SMRs. A clear decline with calendar period is present in the overall cohort, as well as for men and women separately. Although initially, the SMRs for women remained relatively constant at 1.5, the values then increased and gradually declined. Figure 2 presents the comparable SMR curves adjusted for patient characteristics at entry into the clinic (see Patients and Methods for details). The overall adjusted SMR curve corresponds to that for a randomly selected PsA patient from the Toronto Clinic population who had no radiologic damage at first presentation to the clinic, a median sex-specific ESR value, 8 joints with active disease, no hypertension, and was receiving no medication at the first clinic visit, and whose smoking status at the time of diagnosis was unknown. The male-specific SMR curve corresponds to that for a male PsA patient with no radiologic damage, an ESR of 18 mm/hour, 8 joints with active disease, no hypertension,

4 IMPROVED SURVIVAL IN PsA WITH CALENDAR TIME 2711 Figure 1. Unadjusted rolling standardized mortality ratios in patients with psoriatic arthritis. Shown are overall rates in the 680 study patients, as well as sex-specific rates (385 men and 295 women). Figure 2. Adjusted standardized mortality ratios. Data were adjusted for patient characteristics at entry into the University of Toronto Psoriatic Arthritis Clinic (see Patients and Methods for details). Shown are overall rates in the 680 study patients, as well as sex-specific rates (385 men and 295 women).

5 2712 ALI ET AL Table 3. SMRs in the study patients, by followup period, sex, and clinic entry period* Patient group, SMR (95% CI), by followup period clinic entry period Years Years Years Men (1.45, 3.98) 1.45 (0.86, 2.44) 0.97 (0.58, 1.64) (0.07, 3.32) 0.85 (0.35, 2.04) (0.22, 3.50) Women (0.62, 2.73) 2.18 (1.45, 3.28) 1.45 (0.94, 2.25) (0.09, 4.76) 0.79 (0.30, 2.11) Overall (1.25, 2.87) 1.83 (1.33, 2.52) 1.21 (0.86, 1.69) (0.14, 2.20) 0.82 (0.43, 1.58) (0.14, 2.25) * See Patients and Methods for a description of the followup and clinic entry periods used. SMR standardized mortality ratio; 95% CI 95% confidence interval. No deaths occurred in women during the period for the group who also entered the study during that period. and receiving no medication at first presentation, and whose smoking status at diagnosis was unknown. The female-specific SMR curve corresponds to that for a female PsA patient who had no radiologic damage, 8 joints with active disease, no hypertension, and was receiving no medication at first presentation to the clinic, but whose ESR at the first visit was 30 mm/hour and whose smoking status at diagnosis was unknown. While the dramatic decline for men remained evident, the decline for the overall population was less marked, and no decline was apparent for women. Table 3 presents followup period specific SMRs stratified by period of entry into the clinic. While the confidence intervals were wide, there was a strong indication that the rates had declined from the early existence of the clinic to the present, when the SMRs are compared along the diagonals (corresponding to the same period of time within the clinic for different periods of clinic entry). From a sensitivity analysis of the assumption that any patient lost to followup was still alive at the end of 2004, there was some indication that most of the SMRs in Table 3 are quite robust, except for the patient entries corresponding to entry period and followup band Here, there exists the possibility that these entries may have been underestimated because of the long followup attributed to, but not observed for, some patients who entered during the earliest entry period. The overall SMRs for the followup bands collapsed over entry period were 1.89 (95% CI 1.25, 2.87), 1.63 (95% CI 1.19, 2.24), and 1.05 (95% CI 0.79, 1.41) for the calendar periods , , and , respectively. DISCUSSION Wright and Moll s description of PsA (12) suggested that the disease was less severe than RA. Coulton et al (4) also suggested that PsA was less severe than RA, since PsA patients were less disabled and no deaths occurred during their study. However, Sokoll et al (13) showed that patients with PsA had greater disability and lower quality of life than did patients with RA, despite their lower Larsen scores. Rahman et al (14) showed that radiologic changes in patients with PsA and in age-, sex-, and disease duration matched RA patients were similar. Husted et al (15) showed that patients with PsA had less vitality than did patients with RA. Our previous studies revealed that disease progression was common among patients with PsA and that by 10 years after diagnosis, 55% of the patients had 5 or more deformed joints (16). We further demonstrated that the presence of 5 swollen joints at presentation and actively inflamed joints at each visit predicted the progression of clinical damage (17,18). Queiro-Silva et al (8) and McHugh et al (9) also identified polyarticular presentation as a predictor of disease progression, in terms of both clinical and radiologic damage, in their patients. In contrast, the study from Olmstead County, Minnesota, suggested that the disease was mild among the 66 patients with PsA identified in the administrative database (11). We have previously reported that 17.6% of our patients achieved a period of remission that lasted more than 2.5 years. Patients with remission tended to be males and had fewer inflamed joints at presentation to the clinic (19).

6 IMPROVED SURVIVAL IN PsA WITH CALENDAR TIME 2713 RA, the prototypical inflammatory arthritis, has been associated with a greater mortality risk as compared with the general population (20 22). This risk has been related to disease activity and severity as well as to other disease characteristics. We have previously reported that the risk of mortality in our PsA cohort was increased and was related to disease severity (10,23). Our previous study of 428 patients registered with the clinic between 1978 and 1993, reported 53 deaths. Assuming that the 85 patients who were lost to followup at that time were alive, the SMR was This should be considered an underestimate, given the possibility of further deaths among those lost to followup. Causes of death that were seen more frequently than expected were diseases of the respiratory system (SMR 5.05), and injuries/poisoning (SMR 3.54). The study from Olmstead County (11) paints a different picture for community-based psoriatic arthritis. Followup of the 66 cases of PsA for a mean of 7.2 years, using information from medical records only, showed that only 8% in the incident cohort developed erosive changes on radiographs of the hand, and mortality was not significantly different from that in the general population. Similar observations were noted in this community for RA, where there was no increased mortality risk overall, but in patients with extraarticular features analyzed separately, the mortality risk was similar to that observed in other series (24). The current study of 680 patients with PsA from a longitudinal observational cohort followed prospectively since 1978 demonstrates that there has been an increased mortality risk in these patients. The overall SMR for the whole period of observation was 1.36 (95% CI 1.12, 1.64). The estimated loss of life expectancy for patients with PsA was 3 years. The SMR for this extended cohort appears to be better than that identified for the first 428 patients in However, after performing 10-year rolling SMR calculations, we found that the SMR was generally higher in this population earlier on, and the estimated SMR of 1.05 over approximately the last decade was much smaller than those for the previous 2 decades, with SMRs of 1.89 and 1.63, respectively. The study thus demonstrates a trend for improvement in survival in these patients. The mortality risk in patients with PsA was higher in the 1970s and 1980s. The reasons for this trend are not yet known. However, one explanation, which is consistent with our estimated adjusted rolling average SMRs, could be a higher severity of disease in patients who entered the clinic during the first 20 years. Another contribution could be better control of the disease in the most recent 10-year period. This hypothesis is supported by our recent observation that in the past 10 years, methotrexate has been given to our patients earlier in their disease course and at a higher dosage than in the previous 20 years (25). Other possible explanations include earlier referral of patients, more aggressive patient care (in addition to methotrexate use), and more effective management of other components of the patients conditions, such as hyperlipidemia, diabetes, and heart disease. It should be noted, however, that we have shown that death reporting is not a function of disease severity or proximity to the clinic (26). AUTHOR CONTRIBUTIONS Dr. Gladman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Schentag, Farewell, Gladman. Acquisition of data. Ali, Schentag, Gladman. Analysis and interpretation of data. Ali, Tom, Farewell, Gladman. Manuscript preparation. 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