Prevalence of Malignancy in Psoriatic Arthritis

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 58, No. 1, January 2008, pp DOI /art , American College of Rheumatology Prevalence of Malignancy in Psoriatic Arthritis Sherry Rohekar, 1 Brian D. M. Tom, 2 Agnes Hassa, 3 Cathy T. Schentag, 3 Vernon T. Farewell, 2 and Dafna D. Gladman 4 Objective. To determine the prevalence and types of malignancy in a large cohort of patients with psoriatic arthritis (PsA), and to compare this rate with that in the general population. Methods. A cohort analysis of patients who were followed up prospectively from 1978 to 2004 at the University of Toronto Psoriatic Arthritis Clinic was performed. Patients were followed up at 6 12-month intervals according to a standard protocol, which included recording of malignancy, and tracked on a computer database. The cohort was linked with a provincial database to find malignancies that may have been missed by the protocol or developed after patients were lost to followup. Data were presented and analyzed using descriptive statistics and the Cox regression model with robust estimate of variance. Rates of first malignancy in the cohort were compared with rates in the population to derive standardized incidence ratios (SIRs). Results. Of the 665 patients included, 68 (10.2%) developed a malignancy at an average age of 62.4 years. The most frequently seen malignancies were breast (20.6%), lung (13.2%), and prostate (8.8%) cancer. The SIR for all cancers was 0.98 (95% confidence interval ). Overall cancer type specific SIRs were 0.69 (95% CI ) for hematologic and 0.88 (95% CI 1 Sherry Rohekar, MD, FRCPC: University of Toronto, and Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada; 2 Brian D. M. Tom, PhD, Vernon T. Farewell, PhD: Institute of Public Health, Cambridge, UK; 3 Agnes Hassa, BSc, Cathy T. Schentag, MSc: Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada; 4 Dafna D. Gladman, MD, FRCPC: Toronto Western Research Institute, and Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada. Address correspondence and reprint requests to Dafna D. Gladman, MD, FRCPC, 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 May 18, 2007; accepted in revised form September 7, ) for lung cancer. In females, the SIR for breast cancer was 1.55 (95% CI ), and in males, the SIR for prostate cancer was 0.65 (95% CI ). Conclusion. Overall, 10.2% of patients in the Toronto PsA cohort developed cancer. The most frequent cancers were breast, lung, and prostate cancer. The incidence of malignancy in the large PsA cohort did not differ from that in the general population. Psoriatic arthritis (PsA) is a chronic inflammatory joint disease that affects 5 42% of those with psoriasis (1). Its rheumatic manifestations range from mild enthesopathy to a mutilating polyarthritis (2 5). Historically, PsA has been thought to be a benign disease compared with other forms of inflammatory arthritis, such as rheumatoid arthritis (RA). However, recent studies have revealed the destructive nature of PsA. Studies of radiographic evaluation, both at the Psoriatic Arthritis Clinic at the University of Toronto and in a clinic in Spain, have shown erosive changes in 67% of patients (2,4). In the Toronto cohort, 20% of PsA patients had complete joint destruction or ankylosis. Clinically, 11% of this cohort had pronounced physical disability (2). The prevalence of severe disease in this study approached that of RA. Studies in Britain and Spain also support the notion that there is progressive joint damage in PsA over time, and that severe disease at presentation is predictive of disease progression (4 7). RA and other inflammatory joint diseases have been linked to an increased prevalence of malignancy (8 11). Psoriasis is also known to predispose patients to malignancy, particularly nonmelanoma cancers of the skin (12 15). Studies have also found increased rates of lung cancer (12,15) and hematologic malignancy such as lymphoma (13,16,17) in the psoriatic population. However, it is difficult to attribute the increased risk of malignancy in either inflammatory arthritis or psoriasis to disease activity alone. Traditionally, both conditions have been treated with highly cytotoxic medications. The 82

2 MALIGNANCY IN PsA 83 same cytotoxic and immunosuppressive medications taken for RA, such as azathioprine, methotrexate (MTX), and tumor necrosis factor inhibitors, are used in the treatment of PsA. Evidence suggests that these treatments are themselves associated with the development of malignancy (13,18 24). The associations between rheumatic disease, psoriasis, immunosuppressive medication, and malignancy remain enigmatic. There are few current data on the baseline prevalence of malignancy in patients with PsA and their risk of developing cancer. These data would be most useful, and would allow important prognostic information to be determined. Furthermore, they would allow for investigation into potential links between the immunosuppressive therapy used for PsA and malignancy risk. The aim of this study was to determine the prevalence of malignancy in patients with PsA, using a cohort of 680 Toronto PsA patients followed up prospectively since There are extremely detailed data on this cohort of patients. Thus, the objectives of this study were to determine the prevalence of malignancy and the type of cancers that developed in that cohort of patients, to determine if there was an increased risk of malignancy in the Toronto PsA cohort when compared with the general Ontario population, to determine which types and sites of malignancy occurred at different rates in the Toronto PsA cohort compared with the general Ontario population, and to determine whether there was any evidence of prognostic factors that have an impact on the time to development of malignancy in PsA. PATIENTS AND METHODS Patient population and protocol. A cohort of 680 patients with PsA was followed up prospectively from 1978 to 2004, using standard research protocols, at the University of Toronto Psoriatic Arthritis Clinic. The cohort consisted of patients referred to a specialty clinic for the management of PsA. The clinic serves as primary, secondary, and tertiary referral centers. The spectrum of disease activity and duration in these patients was very broad. Patients entered the cohort at their initial visit to the clinic, at which time other forms of arthritis were ruled out, and were then reevaluated at month intervals (2). At each visit, a standardized protocol was completed and used to record historical, physical, and laboratory findings. Information on the presence of malignancy was collected. Radiologic evaluation was performed every 2 years. The data were then entered and stored in a computerized database. Data abstraction. The database and paper charts were searched for any reports of malignancy in any of the patients in the cohort. Pathology, laboratory, or radiography reports were obtained to confirm the diagnosis. Cancer type and site were coded according to the International Classification of Diseases, Ninth Revision. The date of diagnosis and the location of the malignancy were also recorded. In instances of death, coroner s and autopsy reports were searched, if available. The cohort data were confirmed by a simultaneous search of the Ontario Cancer Registry for all reported malignancies in any of the patients who had been included in the cohort. The Ontario Cancer Registry is a computerized database of all Ontario residents, and tracks the incidence of and mortality from cancer. All new cases are registered, but nonmelanoma skin cancers are excluded. Statistical analysis. The standardized incidence ratios (SIRs) of observed to expected first malignancies are reported with 95% confidence intervals (95% CIs). The Ontario general population provided the reference population for calculating the SIRs. Cancer incidence data were obtained from Cancer Care Ontario, and were analyzed in 5-year age groups for each calendar year of occurrence from 1978 to 2004 and by sex. Cancer incidence rates for 2003 and 2004 were not available. Thus, the 2002 incidence rates were used for these 2 years. Persons were considered at risk only when they came under active followup in the clinic. Time-dependent Cox regression models were fitted to investigate the effects of disease-related variables on the age at diagnosis of first malignancy. Delayed entry was incorporated into the Cox regression models. RESULTS Through computer and manual review of the clinic s accumulated protocols and linkage with the provincial cancer database, we identified 90 separate malignancies in 83 patients (Figure 1). Fifteen patients were subsequently excluded from analysis because they had a malignancy prior to or upon enrollment into the cohort. Of these, 10 had a malignancy that occurred at or after arthritis diagnosis. Thus, 665 patients were included in the analysis, of whom 68 patients (10.2%) developed a malignancy after entering the cohort. Of these 68 patients, 2 were found to have 2 histologically distinct malignancies, and 66 patients had a single malignancy. Thus, a total of 70 cancers occurred in these 68 patients. However, we considered only first malignancies in the following analyses. In the cohort, the mean SD age at diagnosis of first malignancy was years. Of the 68 patients in whom malignancies were detected, 38 were female (55.9%) and 30 were male (44.1%). The highest proportions of first cancers found in the cohort were breast cancer (20.6% of overall cases, 36.8% of female cases), lung cancer (13.2% of overall cases), and prostate cancer (8.8% of overall cases, 20% of male cases). Figure 2 outlines the breakdown of the incidence of malignancy by site. There were a number of other types of first malignancies that occurred only once in the cohort, thus comprising only 1.5% of the first malignancies. These

3 84 ROHEKAR ET AL Table 1. Standardized incidence ratios (SIRs) for malignancies in the Toronto psoriatic arthritis cohort compared with the general Ontario population Malignancy* SIR (95% CI) All cancers Both sexes 0.98 ( ) Males 0.81 ( ) Females 1.18 ( ) Hematologic 0.69 ( ) Lung 0.88 ( ) Female breast 1.55 ( ) Prostate 0.65 ( ) * Cancer incidence data were obtained from Cancer Care Ontario and analyzed in 5-year age groups for each calendar year of occurrence from 1978 to Data on cancer incidence rates for 2003 and 2004 were not available; thus, 2002 data were used. 95% CI 95% confidence interval. Figure 1. Identification of cancers in the Toronto psoriatic arthritis (PsA) cohort. infrequent tumors included uterine, multiple myeloma, ovarian, vaginal, brain, pancreatic, cervical, esophageal, spinal cord, gastric, connective tissue, vulvar, and endocrine malignancies. SIRs were calculated to compare the rates of cancer in the Toronto PsA cohort with those of the general Ontario population (Table 1). There was no evidence of any difference in the cancer incidence rates when compared with the general Ontario population Figure 2. Prevalence of cancers detected among patients in the Toronto psoriatic arthritis cohort. both overall and by sex. There were also no discernible differences in incidence rates for site-specific cancers between the 2 groups. To assess the impact on the SIRs of excluding the 10 patients who had a malignancy that occurred before entry into the cohort but at or after PsA diagnosis, we performed a sensitivity analysis by including these patients, first assuming that for these 10 patients their date of entry into the clinic was the date of PsA diagnosis, and then assuming that for the 675 patients (including the 10 patients above) the period at risk began from the date of PsA diagnosis. The first assumption generally Table 2. Characteristics of the patients at presentation and medication use in patients with and those without malignancy* No malignancy group Malignancy group Age at presentation, mean SD years Age at onset of PsA, mean SD years Age at onset of psoriasis, mean SD years ESR, mean SD mm/hour No. of actively inflamed joints, mean SD No. of clinically deformed joints, mean SD No. of effused (swollen) joints, mean SD Ever used NSAIDs, % Ever used DMARDs, % Ever used immunosuppressive drugs, % Ever used methotrexate, % Ever used biologic agents, % Ever used intraarticular steroids, % * PsA psoriatic arthritis; ESR erythrocyte sedimentation rate; NSAIDs nonsteroidal antiinflammatory drugs; DMARDs disease-modifying antirheumatic drugs.

4 MALIGNANCY IN PsA 85 Table 3. Results of Cox regression analysis of variables assessed as potential predictors of age at diagnosis of first malignancy, controlled for sex* Variable HR (95% CI) Age at onset of PsA 1.01 ( ) Age at onset of psoriasis 1.00 ( ) ESR, cm/hour 1.13 ( ) No. of active joints at 1.00 ( ) No. of effused joints at 1.04 ( ) No. of clinically deformed joints at 0.99 ( ) NSAIDs, past or current use at 0.99 ( ) DMARDs, past or current use at 1.18 ( ) Immunosuppressive drugs, past or current 1.07 ( ) use at Methotrexate, past or current use at 1.25 ( ) Biologic agents, past or current use at 2.39 ( ) Intraarticular steroids, past or current use 0.91 ( ) at * 95% CI 95% confidence interval (see Table 2 for other definitions). Hazard ratio (HR) reported per 10-cm/hour increase, rather than as 1 mm/hour. P resulted in a biased inflation of the SIR estimates obtained in Table 1, while the second assumption generally led to a biased reduction in the SIR estimates obtained in Table 1. Overall, the results of the sensitivity analysis produced SIR estimates and 95% CIs that did not change the conclusions obtained earlier. However, for female breast cancer under the first assumption, there was an inflation of the SIR estimate from 1.55 to 1.77 (95% CI ). Consistently for all cancers (female) under this assumption, the SIR estimate was inflated somewhat to 1.33 (95% CI ). Table 2 shows the disease characteristics at presentation (and before) and medication ever use in the 665 patients in the Toronto PsA cohort, by malignancy group. Information regarding medication ever use in patients with malignancies was obtained from the medication history prior to the diagnosis of the first malignancy, whereas for the patients without malignancies, the medication history was up to the last visit. Medication history was recorded upon entry into the clinic. For most types of medication, ever use was recorded for 50% of the patients in each group. In particular, MTX was taken by 58% of the patients without malignancies and by 44% of the patients who developed malignancies. However, biologic agents had been ever used by only 9.7% of patients in the nonmalignancy group and by 2.9% of patients in the malignancy group, prior to malignancy occurrence. Table 2 is descriptive, and a more formal survival analysis with time-dependent covariates was undertaken to investigate the possible prognostic effects of these variables on the age at first malignancy. Table 3 shows the Cox regression models for each of the potential prognostic variables, controlled for sex. None of the variables was found to be statistically significant at the 5% level, except the erythrocyte sedimentation rate (ESR) (P 0.02), a measure of inflammation. Besides ESR, the only variable that came close to approaching statistical significance was the number of effused joints (P 0.07), another measure of disease activity. A multivariate Cox regression analysis, adjusted for sex and disease-related variables (age at onset of psoriasis and PsA, ESR, effused joints, and clinically deformed joints), generated similar findings. DISCUSSION We found no evidence that patients in this large, closely studied PsA cohort were at a greater risk of developing malignancy than those in the general local Ontario population. Joint activity, as measured by the number of joints with active disease and the number of joints with effusions, was not found to be associated with an increased hazard of malignancy. In addition, both age at onset of psoriasis and age at onset of PsA were not found to be associated with increased cancer rates in the Toronto PsA cohort. This finding is important, both for clinicians and for patients with PsA, in terms of prognosis and treatment. Moreover, there was no evidence that the treatment used in this patient cohort increased the risk of malignancy. Our findings are in contrast to those of similar studies of RA. Several retrospective and prospective studies of RA patients have found an increased risk of lymphoproliferative malignancy in those with RA. A recent study of associations between RA and malignancy reviewed 10 publications and found that patients with RA had an increased SIR of both colorectal tumors and lymphoproliferative disorders (25). This review included data from a Canadian RA cohort of 862 patients similar to the Toronto PsA cohort (26). In this Canadian RA study, the overall incidence of malignancy was reduced, but there was an increased incidence of hematologic malignancy, particularly leukemia (26). Of the excessive malignant lymphomas that occur in RA patients (11), there is an increased association with diffuse large B cell

5 86 ROHEKAR ET AL lymphoma in particular (27). Interestingly, these lymphomas tend to occur more frequently in patients with medium or high levels of disease activity (27,28). Several other RA studies also showed an association between increased disease activity and the development of cancer (25). This differs from our findings in PsA, which showed no association between the number of actively inflamed or effused joints at presentation to the clinic and the risk of developing malignancy. In contrast to the extensive literature regarding malignancy risk in RA, few published data exist about cancer risk in the seronegative inflammatory arthritides. A large Swedish study examined the incidence of cancer among patients with ankylosing spondylitis (AS) (29). That study found no increased overall cancer risk in AS patients, although the risk of rectal cancer was decreased and that of kidney cancer increased. The authors theorized that these site-specific differences might be due to the use of nonsteroidal antiinflammatory drugs and therapeutic pelvic irradiation, respectively (29). Contrary to studies in RA populations, this large cohort study found no increased incidence of hematologic malignancy (29). A second study of the same Swedish AS cohort specifically examined the issue of lymphoma incidence in hospitalized patients (30). This investigation also found no elevation in the average lymphoma risk in hospitalized AS patients (30). Furthermore, there were no increased risks of the major lymphoma types (30). On the other hand, a retrospective cohort study (published in abstract only) based on the General Practice Research Database in the UK between 1994 and 2001 identified increased incidence risk ratios for lymphoma among patients with AS that were similar to those calculated for RA (2.8 and 3.0, respectively) (31). From the above data, as well as the data from our study, there appears to be a notable difference in malignancy risk in seropositive inflammatory RA when compared with seronegative inflammatory arthritis (AS and PsA). This may be related to differences in systemic inflammation, since generally only half of the patients with PsA and AS demonstrated elevated levels of acutephase reactants. However, the current study shows that an elevated ESR is predictive of the development of malignancy among patients with PsA. In patients with psoriasis, the reported risk of malignancy has been a subject of controversy. Stern et al (33) reported a nonsignificant increase in nonskin cancers (SIR 1.2) among 1,380 patients with psoriasis treated with psoralen ultraviolet A (PUVA), but a higher prevalence of colon cancer and primary neoplasms of the central nervous system. A Danish study found a 2.5-fold increased risk in nonmelanoma skin cancer, excesses of lung cancer, cancer of the larynx and pharynx in men, and of colon and kidney cancer in women (15). The same authors confirmed their findings in a later study (12). Margolis et al (34) reported that patients with psoriasis are at an increased risk of developing a malignancy compared with patients with hypertension. The increased risk is greatest for those with severe disease (i.e., patients with psoriasis treated with systemic agents) and minimal (if an increased risk at all) for those with less severe disease compared with those in the hypertension group. The increased risk was mainly for lymphoproliferative cancers and nonmelanoma skin cancers. A population-based study in the UK (17) also demonstrated a low prevalence but increased risk of lymphomas among patients with psoriasis. The risk for lymphoma was found to be associated with the use of MTX or cyclosporine in patients with psoriasis treated with PUVA (35). In contrast, a population study in Sweden found no difference in the prevalence of malignancy among patients with psoriasis as compared with that of the general population (36). The incidence of nonskin cancer was not increased compared with the general population in a cohort of 1,252 patients with psoriasis treated with cyclosporine (37). The immunosuppressive/cytotoxic medications used in PsA may themselves impact malignancy rates (13,18 24,34,35). However, we found that the ever use of these medications was not associated with age at onset of first malignancy. Thus, in our study we cannot implicate medications in the development of malignancy. Note, however, that very few patients had ever taken biologic agents. Our study is the first to examine malignancy rates in a large, prospectively followed cohort of patients with clearly established PsA. We have found no evidence to suggest that there is a higher risk of malignancy in our study population than in the general Ontario population. Importantly, neither joint activity nor medication use was associated with an increased cancer risk in our PsA patients. These findings differ from those in RA, but are consistent with the known data regarding other seronegative disorders (AS). These data may serve as background information for the calculation of risk associated with biologic agents. 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.

6 MALIGNANCY IN PsA 87 Study design. Hassa, Schentag, Gladman. Acquisition of data. Hassa, Rohekar, Schentag, Gladman. Analysis and interpretation of data. Rohekar, Tom, Schentag, Farewell, Gladman. Manuscript preparation. Rohekar, Tom, Schentag, Farewell, Gladman. Statistical analysis. Tom, Schentag, Farewell. REFERENCES 1. Gladman DD. Psoriatic arthritis. In Harris ED, Budd RC, Firestein GS, Genovese MC, Sergent JS, Ruddy S, Sledge CB, editors. Kellye s textbook of rheumatology, 7th ed. Philadelphia: Saunders Elsevier; p Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis (PsA): an analysis of 220 patients. Q J Med 1987;62: Gladman DD, Stafford-Brady F, Chang CH, Lewandowski K, Russell ML. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheumatol 1990;17: Torre Alonso JC, Rodriquez Perez A, Arribas Castrillo JM, Ballina Garcia J, Riestra Noriega JL, Lopez Larrea C. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;30: McHugh NJ, Balachrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis: a 5-yr prospective study. Rheumatology (Oxford) 2003;42: Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, Lopez- Lagunas I. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis 2003;62: Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ. Psoriatic arthritis: outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33: Hakulinen T, Isomaki H, Knekt P. Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 1985;78: Mellemkjaer L, Linet MS, Gridley G, Frisch M, Moller H, Olsen JH. Rheumatoid arthritis and cancer risk. Eur J Cancer 1996;32A: Thomas E, Brewster DH, Black RJ, Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000;88: Baecklund E, Askling J, Rosenquist R, Ekbom A, Klareskog, L. Rheumatoid arthritis and malignant lymphomas [review]. Curr Opin Rheumatol 2004;16: Frentz G, Olsen JH. Malignant tumours and psoriasis: a follow-up study. Br J Dermatol 1999;140: Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K, Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol 2000;114: Boffetta P, Gridley G, Lindelof B. Cancer risk in a populationbased cohort of patients hospitalized for psoriasis in Sweden. J Invest Dermatol 2001;117: Olsen JH, Moller H, Frentz G. Malignant tumors in patients with psoriasis. J Am Acad Dermatol 1992;27: Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of malignancy associated with psoriasis. Arch Dermatol 2001;137: Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 2003;139: Asten P, Barrett J, Symmons D. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 1999; 26: Franklin JP, Symmons DP, Silman AJ. Risk of lymphoma in patients with RA treated with anti-tnf agents [review]. Ann Rheum Dis 2005;64: Keystone EC. Safety of biologic therapies: an update [review]. J Rheumatol Suppl 2005;74: Geborek P, Bladstrom A, Turesson C, Gulfe A, Petersson IF, Saxne T, et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64: Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50: Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310: Shephard SE, Panizzon RG. Carcinogenic risk of bath PUVA in comparison to oral PUVA therapy. Dermatology 1999;199: Chakravarty EF, Genovese MC. Associations between rheumatoid arthritis and malignancy [review]. Rheum Dis Clin North Am 2004;30: Cibere J, Sibley J, Haga, M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997;40: Baecklund E, Sundstrom C, Ekbom A, Catrina AI, Biberfeld P, Feltelius N, et al. Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003;48: Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 1998;317: Feltelius N, Ekbom A, Blomqvist P. Cancer incidence among patients with ankylosing spondylitis in Sweden : a population based cohort study. Ann Rheum Dis 2003;62: Askling J, Klareskog L, Blomqvist P, Fored M, Feltelius N. Risk for malignant lymphoma in ankylosing spondylitis: a nationwide Swedish case-control study. Ann Rheum Dis 2006;65: Chibata A, Zhao S, Makuch RW, Wentworth C, Veith J, Wallis W. Lymphoma risk in ankylosing spondylitis patients is greater that that observed in the general population. Ann Rheum Dis 2004; 63(Suppl 1): Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course and outcome. Ann Rheum Dis 2005;64(Suppl II): Stern RS, Lange R. Cardiovascular disease, cancer, and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1,380 patients [published erratum appears in J Invest Dermatol 1989;92:300]. J Invest Dermatol 1988;91: Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of malignancy associated with psoriasis. Arch Dermatol 2001;137: Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol 2006;142: Lindelof B, Eklund G, Liden S, Stern RS. The prevalence of malignant tumors in patients with psoriasis. J Am Acad Dermatol 1990;22: Paul CF, Ho VC, McGeown C, Christophers E, Schmidtmann B, Guillaume JC, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 yr cohort study. J Invest Dermatol 2003;120:211 6.