The Risk of Cancer in Patients with Psoriasis a Population-Based Cohort Study in the Health Improvement Network

Research

Original Investigation The Risk of Cancer in Patients With Psoriasis A Population-Based Cohort Study in the Health Improvement Network

Zelma C. Chiesa Fuxench, MD; Daniel B. Shin, MS; Alexis Ogdie Beatty, MD, MSCE; Joel M. Gelfand, MD, MSCE

IMPORTANCE The risk of cancer in patients with psoriasis remains a cause of special concern due to the chronic inflammatory nature of the disease, the use of immune-suppressive treatments and UV therapies, and the increased prevalence of comorbid, well-established risk factors for cancer, such as smoking and obesity, all of which may increase the risk of carcinogenesis.

OBJECTIVE To compare the overall risk of cancer, and specific cancers of interest, in patients with psoriasis compared with patients without psoriasis.

DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of patients ages 18 to 89 years with no medical history of human immunodeficiency virus, cancer, organ transplants, or hereditary disease (albinism and xeroderma pigmentosum), prior to the start date, conducted using The Health Improvement Network, a primary care medical records database in the United Kingdom. The data analyzed had been collected prospectively from 2002 through January 2014. The analysis was completed in August 2015.

EXPOSURES OF INTEREST Patients with at least 1 diagnostic code for psoriasis were classified as having moderate-to-severe disease if they had been prescribed psoralen, methotrexate, cyclosporine, acitretin, adalimumab, etanercept, infliximab, or ustekinumab or phototherapy for psoriasis. Patients were classified as having mild disease if they never received treatment with any of these agents.

MAIN OUTCOMES AND MEASURES Incident cancer diagnosis.

RESULTS A total of 937 716 control group patients without psoriasis, matched on date and practice visit, and 198 366 patients with psoriasis (186 076 with mild psoriasis and 12 290 with moderate-to-severe disease) were included in the analysis. The adjusted hazard ratios (aHRs) with 95% CIs for any incident cancer excluding nonmelanoma skin cancer (NMSC) were 1.06 (95% CI, 1.02-1.09), 1.06 (95% CI, 1.02-1.09), and 1.08 (95% CI, 0.96-1.22) in the overall, mild, and severe psoriasis group. The aHRs for incident lymphoma were 1.34 (95% CI, Author Affiliations: Departments of Dermatology, University of 1.18-1.51), 1.31 (95% CI, 1.15-1.49), and 1.89 (95% CI, 1.25-2.86); for NMSC, 1.12 (95% CI, Pennsylvania Perelman School of 1.07-1.16), 1.09 (95% CI, 1.05-1.13), and 1.61 (95% CI, 1.42-1.84); and for lung cancer, 1.15 (95% Medicine, Philadelphia (Chiesa CI, 1.03-1.27), 1.12 (95% CI, 1.01-1.25), and 1.62 (95% CI, 1.16-2.28) in the overall, mild, and Fuxench, Shin, Gelfand); severe psoriasis groups, respectively. No significant association was seen with cancer of the Epidemiology and Biostatistics, Center for Clinical Epidemiology and breast, colon, prostate, or leukemia. Biostatistics, University of Pennsylvania Perelman School of CONCLUSIONS AND RELEVANCE The association between psoriasis and cancer, albeit small, Medicine, Philadelphia (Chiesa Fuxench, Ogdie Beatty, Gelfand); was present in our cohort of patients with psoriasis. This association was primarily driven by Department of Rheumatology, NMSC, lymphoma, and lung cancer. University of Pennsylvania Perelman School of Medicine, Philadelphia (Ogdie Beatty). Corresponding Author: Zelma C. Chiesa Fuxench, MD, Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, 3400 Spruce St, 1107 Dulles, Philadelphia, PA 19104 JAMA Dermatol. 2016;152(3):282-290. doi:10.1001/jamadermatol.2015.4847 (zelma.chiesafuxench Published online December 16, 2015. @uphs.upenn.edu).

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he risk of cancer in patients with psoriasis has been of ferred out of the practice prior to the implementation of EMR. special concern owing to the chronic inflammatory na- Each patient with psoriasis was matched to up to 5 unex- T ture of the disease, use of immune suppressive treat- posed controls that were also 18 to 89 years at the start date ments and UV therapies, and the increased prevalence of and were from the same practice. Unexposed controls were as- comorbid, well-established risk factors for cancer, such as signed a “diagnosis” date based on having a recorded visit with smoking, all of which may increase the risk of carcinogenesis.1 the GP within 6 months (ie, ±180 days) of the corresponding Indeed, studies2-8 have previously demonstrated that pa- patient’s visit date to the GP. This algorithm was designed to tients with more severe psoriasis are at an increased risk of minimize bias by ensuring that exposed patients and unex- cancer-related mortality, and psoriasis has been associated with posed controls were followed by similar clinicians during simi- an increased risk of cancer, including lymphoma. However, lar time periods. Patients were initially excluded from the en- these studies have generally not controlled for important con- tire cohort if they had a personal history of any cancer, organ founders, and have often failed to examine the rates of spe- transplant, or human immunodeficiency virus (HIV) and/or cific cancers or the impact of disease severity on cancer risk. AIDS, or had a diagnosis of hereditary diseases that have an Furthermore, there have often been conflicting data on the increased susceptibility for developing malignant abnormali- risk of specific cancers including lymphoma.1,3,4,6,9 Addi- ties, including albinism and xeroderma pigmentosum. tional studies are necessary to further define the risk of cancer in patients with this disease. Protection of Study Subjects We performed a population-based cohort study using a na- This study was developed in accordance with the STROBE tionwide, electronic medical records database from the United guidelines and was approved by the institutional review board Kingdom to evaluate the association between psoriasis and of the University of Pennsylvania and by the Scientific Re- cancer. In addition, our study also evaluated whether the risk view Committee of CSD Medical Research, United Kingdom. of cancer in patients with psoriasis could be explained by a spe- This study was a population-based study using data already cific group of cancers and if this risk was higher in patients with collected for these purposes. Data were collected by a third more severe disease. party and deidentified before they were made available for research purposes. Because our study analyzed data already collected for these purposes, patient consent was not required. Methods Definition of Exposure This study is a population-based cohort study analyzing data Patients with psoriasis were identified by the presence of at that had been collected prospectively since 2002 through Janu- least one diagnostic Read code for psoriasis in the patient’s ary 2014 by general practitioners (GPs) in the United King- medical file. Read codes are a comprehensive numerical sys- dom who were unaware of the hypothesis being tested. tem developed in the United Kingdom to record diagnosis, symptoms, and tests, and is similar to the International Clas- Data Source sification of Disease (ICD) codes.16 The use of Read codes for Our source of data was The Health Improvement Network modeling disease outcomes in patients with psoriasis has been (THIN), an electronic medical records (EMR) database that con- previously validated in THIN.13 Severity of psoriasis was clas- tains anonymized medical record information from nearly 11.9 sified as mild or moderate-to-severe depending on whether the million patients across the United Kingdom. THIN has been patient was prescribed systemic therapy or phototherapy for extensively used for epidemiological research, and prior psoriasis. Patients were classified as having moderate-to- studies10-13 have validated the diagnostic accuracy of psoria- severe psoriasis if they had ever received any prescription for sis and malignant disease codes used in THIN. Participants psoralen, phototherapy, methotrexate, cyclosporine, acitre- within THIN are considered to be representative of the gen- tin, adalimumab, etanercept, infliximab, and/or ustekinumab. eral population of the United Kingdom in terms of their age, Patients were classified as having mild disease if they had never sex, geography, and medical diagnoses.14 Information re- received treatment with any of these agents. This approach has corded includes patient demographics, medical diagnosis, and been used in previous studies as a proxy for estimating treatments prescribed, as well as referrals to specialists, hos- disease severity.4,17 pitalizations, and laboratory results. THIN has the advantage over administrative claims databases (ie, Medicare) because Person-Time Calculation it contains information on important risk factors for cancer, For exposed patients (ie, those who received at least 1 diag- such as smoking, alcohol intake, and body mass index (BMI).15 nostic code for psoriasis) the start of follow-up time occurred at the latest of the following: date of first diagnostic code for Study Population psoriasis in THIN; 180 days after patient registration with the Our initial cohort within THIN consisted of all patients with a practice; or when the practice began recording information diagnosis of psoriasis and unexposed controls (ie, those with using Vision software. For unexposed patients (ie, those with no recorded diagnosis of psoriasis). All patients with psoria- no diagnosis of psoriasis) the start time occurred at the latest sis who were ages 18 to 89 years at the start date and had ob- of 3 dates: 180 days after patient registration, when the prac- servation time within THIN, after implementation of the EMR, tice began recording information using Vision software, or the were included. Patients were excluded if they died or trans- closest corresponding visit to the exposed patient’s visit date

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Table 1. Baseline Characteristics of Study Participantsa

Mild Moderate-to-Severe Variable Control Psoriasis Psoriasis Participants, No. 937 716 186 076 12 290 Age at start of follow-up, y Mean (SD) 49.73 (17.53) 46.21 (17.36) 49.20 (15.03) Median (IQR) 49 (34-63) 44 (32-59) 49 (38-60) Sex, No. (%) Male 413 044 (44.05) 89 857 (48.29) 5968 (48.56) History of psoriatic arthritis, No. (%) 5312 (2.85) 4669 (37.99) Smoking, No. (%) Never 424 497 (45.27) 72 412 (38.92) 4763 (38.76) Current 202 492 (21.59) 54 382 (29.23) 3282 (26.70) Former 174 050 (18.56) 39 682 (21.33) 3525 (28.68) Drinking, No. (%) Never 99 820 (10.65) 19 412 (10.43) 6287 (10.83) Current 561 087 (59.84) 120 667 (64.84) 33 978 (58.52) Abbreviations: BMI, body mass index Former 34 723 (3.70) 7056 (3.79) 2019 (3.48) (calculated as weight in kilograms BMI divided by height in meters squared); IQR, interquartile range. Mean (SD) 25.64 (5.10) 26.02 (5.28) 27.10 (5.68) a All P values are <.001; error bars Median (IQR) 24.8 (22.2-28.1) 25.2 (22.4-28.6) 26.2 (23.2-30) indicate 95% CIs.

with the GP (±180 days), whichever was latest. Patient fol- Analysis low-up continued for both groups until the earliest of the fol- Descriptive statistics were used to examine age, sex, disease lowing: first diagnosis of cancer, death, transfer out of the prac- severity, person-time, and covariate distribution among the co- tice, or end of the study period. hort with exposed psoriasis and the control group. χ2 Test was used to examine dichotomous variables. The nonparametric Outcome of Interest Wilcoxon-Mann-Whitney rank sum test was used to examine The outcome of interest was incident cancer diagnosis. Can- the continuous variables age and BMI. The rates of incident cer cases were identified using a series of Read codes selected cancer diagnosis were descriptively reported as the cumula- a priori by the primary investigator (Z.C.C.F.).Patients were clas- tive incidence with 95% CIs for all cancers overall and strati- sified as having an incident cancer diagnosis if they received fied by cancer type in controls and patients with mild and se- a code for any cancer (except carcinoma in situ or metastatic vere psoriasis, separately. An unadjusted Cox proportional cancer) after the start date and on or before the end date of the hazards model was then used to determine the HRs with 95% study period. We also selected a priori specific cancer out- CIs for incident cancer diagnosis. The overall models were then comes that were of interest to us, as part of secondary out- adjusted for age and sex and were also adjusted for additional come analyses, either because prior studies have shown a pos- covariates using a purposeful selection modeling approach.18 sible association between psoriasis and risk of developing these Covariates with biological plausible relationship to the expo- malignant diseases or because they are considered important sure and outcome and those that resulted in a change in the owing to public health implications. point estimates of the main effects by more than 10% were kept in the final model. Multivariate models were examined for pro- Covariates portionality using diagnostic log-log plots. Finally, we per- Covariates assessed in multivariable models as potential con- formed multiple sensitivity analyses to test the underlying as- founders included age, sex, BMI, smoking, and alcohol in- sumptions of our primary analysis. Statistical analyses were take. Age and BMI were treated as continuous variables whereas performed using STATA statistical software (version 13; Stata smoking and alcohol intake were treated as categorical vari- Corp). ables.

Sample Size Results The sample size was fixed as we included all patients with a diagnosis of psoriasis in THIN who met our inclusion criteria. We identified 937 716 controls and 198 366 patients with pso- Using data on the incidence rates for all cancers, we would ex- riasis; 186 076 were classified as having mild psoriasis, and pect to detect a hazard ratio (HR) of 1.06 to 1.98 for patients 12 290 were classified as having moderate-to-severe disease with mild psoriasis and 2.02 to 7.79 for patients with severe based on having received treatment with either photo- disease for specific cancers assuming a 2-sided .05 signifi- therapy or systemic therapies (Table 1). Overall, patients with cance level with a median follow-up period of 5 years and 80% psoriasis were younger, had higher BMI, and a greater propor- power. tion were male and current smokers compared with controls.

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In patients with moderate-to-severe disease, the most com- Table 2. Characteristics of Systemic Therapies in Patients monly prescribed systemic therapy was methotrexate (69.48%) With Moderate-to-Severe Psoriasis (Table 2). Systemic Therapies No. (%) The mean follow-up time across all outcomes varied from Patients, No. 12 290 6.39 to 6.57 years in the control group and 6.06 to 6.22 in the Methotrexate 8539 (69.48) overall psoriasis group. The mean follow-up time in the mild Any phototherapy 3251 (18.71) and moderate-to-severe psoriasis group varied from 6.11 to 6.28 years, and 5.20 to 5.35 years, respectively. For all cancers, ex- PUVA 903 (7.35) cluding NMSC, the number of new cancer cases identified was Cyclosporine 1273 (10.36) 32 241 in the control group and 6289 in the overall psoriasis Oral retinoids 730 (5.94) group, of which 5490 were in the mild psoriasis group and 2186 Any biologic 122 (0.99) in the moderate-to-severe psoriasis group. Unadjusted HRs Abbreviation: PUVA, psoralen and ultraviolet A. with 95% CI showed that patients with moderate-to-severe psoriasis had a statistically significant higher risk of any lym- previously described in the literature and has been primarily phoma (HR, 1.69; 95% CI, 1.12-2.55); cutaneous T-cell lym- attributed to phototherapy exposure, particularly psoralen and phoma (CTCL) (HR, 8.86; 95% CI, 3.53-22.20); lung cancer (HR, ultraviolet A (PUVA).1,9,19,20 Chen et al6 postulated that al- 1.73; 95% CI, 1.26-2.39); and NMSC (HR, 1.40; 95% CI, 1.23- though systemic medications, including PUVA, increased the 1.60) compared with patients without psoriasis (Table 3). risk of cancer in patients with psoriasis, they are not the sole The adjusted HR with 95% CI for specific cancer types cause of malignant neoplasms seen in this population. In- are summarized in the Figure. Fully adjusted models deed, multiple studies have suggested that in the case of lym- showed a statistically significant increased risk for any can- phoma, including CTCL, prolonged immune stimulation could cer excluding NMSC, lymphoma, CTCL, lung cancer, and potentially lead to the development of a dominant clone which NMSC in patients with any psoriasis compared with con- in turn promotes lymphomagenesis.4,21,22 Our results showed trols, with this risk being higher in patients classified as hav- that patients with psoriasis had an increased risk of any lym- ing moderate-to-severe disease. A similar association was phoma across all study groups (overall: HR, 1.34 [95% CI, 1.18- seen for any lymphoma, excluding CTCL, melanoma, and 1.51]; mild disease: HR, 1.31 [95% CI, 1.15-1.49]; and moderate- pancreatic cancer, where an increased risk was seen across to-severe disease: HR, 1.89 [95% CI, 1.25-2.86]). These results all 3 groups; however, results were not statistically signifi- replicate those of Gelfand et al3 who, using a similar study cant in the moderate-to-severe psoriasis group. In fully population and case definition, found that patients with mild adjusted models, no statistically significant increased risk psoriasis had increased risk for any lymphoma (HR, 1.34; 95% was observed across any of the groups for leukemia, breast, CI, 1.16-1.54) and patients with moderate-to-severe disease had prostate, or colon cancer (Table 3). increased risk (HR, 1.59; 95% CI, 0.88-2.89) compared with Results were robust to a number of sensitivity analyses patients without psoriasis. (Table 4). Because smoking is an especially strong risk factor The risk for common solid organ malignant neoplasms, for lung cancer, we performed additional sensitivity analyses breast, colon, and prostate cancer was not higher than the gen- with the fully adjusted model limited to patients who were clas- eral population. This finding suggests that positive associa- sified as never smokers. In this model, the association be- tions seen for other internal malignant neoplasms, lym- tween psoriasis and lung cancer was lost in the overall (HR, phoma, and lung cancer are not likely owing to screening bias. 0.98; 95% CI, 0.76-1.25) and mild (HR, 0.97; 95% CI, 0.75- In our age-, sex-, and smoking-adjusted model, patients with 1.24) group and was decreased in the severe psoriasis group moderate-to-severe psoriasis had an approximately 60% in- (HR, 1.18; 95% CI, 0.44-3.17). In contrast, an age- and sex- creased risk of developing lung cancer compared with pa- adjusted model for lung cancer including only patients clas- tients without psoriasis (HR, 1.62; 95% CI, 1.16-2.28). Three pro- sified as current smokers showed a positive association be- spective cohort studies23-25 showed a positive association tween psoriasis and risk of lung cancer across all study groups. between psoriasis and lung cancer; however, models were not adjusted for smoking. In 2 prior studies in which adjustment for smoking was performed, one8 found no positive associa- Discussion tion between psoriasis and lung cancer (incidence rate ratio [IRR], 0.79; 95% CI, 0.60-1.06), and the other26 resulted in loss Prior studies evaluating the risk of cancer in patients with pso- of the association when adjusting for this risk factor (HR, 1.3; riasis have often shown conflicting results. Our results are con- 95% CI, 0.8-2.0). In additional sensitivity analyses, we showed sistent with those of a meta-analysis1 that showed a small in- a loss of this association when only including patients who were creased risk of cancer overall excluding NMSC (HR, 1.16; 95% classified as never smokers. However, in models including only CI, 1.07-1.25). As expected, we observed an increased risk for patients classified as former or current smokers, this associa- NMSC and lymphoma. In both instances, this risk was high- tion persisted. This observation would suggest that the rela- est in patients with psoriasis who received systemic treat- tionship between smoking and lung cancer in patients with ment or phototherapy. In patients defined as having moderate- psoriasis is more complex. to-severe disease, the HR for incident NMSC was 1.61 (95% CI, We found no clear association between psoriasis and either 1.42-1.84). The risk for NMSC in patients with psoriasis has been melanoma or pancreatic cancer. In the case of melanoma,

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Table 3. Incident Cancers and Unadjusted Hazard Ratios (95% CIs) for Risk of Any Cancer Except Nonmelanoma Skin Cancer (NMSC) and Specific Cancer Types Among Study Groups

Cancer Type Control Any Psoriasis Mild Psoriasis Moderate-to-Severe Psoriasis Any cancer except NMSC New cancer cases, No. 32 241 6289 5940 2186 Incidence per 100 000 PY 547.07 (541.13-553.07) 531.90 (518.92-545.21) 530.54 (517.22-544.21) 554.69 (531.92-578.44) UHR 1 [Reference] 0.98 (0.95-1.00) 0.97 (0.95-1.00) 1.05 (0.94-1.16) Any lymphoma New cancer cases, No. 1305 320 297 23 Incidence per 100 000 PY 21.20 (20.08-22.38) 25.94 (23.25-28.94) 25.43 (22.69-28.49) 35.00 (23.26-52.68) UHR 1 [Reference] 1.23 (1.09-1.39) 1.20 (1.06-1.36) 1.69 (1.12-2.55) Any lymphoma excluding CTCL New cancer cases, No. 1254 283 265 18 Incidence per 100 000 PY 20.37 (19.28-21.53) 22.94 (20.42-25.78) 22.69 (20.12-25.59) 27.40 (17.27-43.49) UHR 1 [Reference] 1.13 (0.99-1.29) 1.12 (0.98-1.27) 1.38 (0.87-2.20) CTCL New cancer cases, No. 51 37 32 5 Incidence per 100 000 PY 0.83 (0.63-1.09) 3.00 (2.17-4.14) 2.74 (1.94-3.87) 7.60 (3.16-18.27) UHR 1 [Reference] 3.59 (2.35-5.49) 3.29 (2.11-5.12) 8.86 (3.53-22.20) Leukemia New cancer cases, No. 2194 414 394 20 Incidence per 100 000 PY 35.65 (34.19-37.18) 33.56 (30.48-36.95) 33.73 (30.56-37.23) 30.43 (19.63-47.16) UHR 1 [Reference] 0.95 (0.85-1.05) 0.95 (0.85-1.05) 0.88 (0.57-1.37) Lung New cancer cases, No. 2128 497 459 38 Incidence per 100 000 PY 34.56 (33.12-36.06) 40.27 (36.88-43.97) 39.28 (35.85-43.04) 57.79 (42.05-79.42) UHR 1 [Reference] 1.17 (1.06-1.29) 1.14 (1.03-1.26) 1.73 (1.26-2.39) Prostatea New cancer cases, No. 5641 1116 1056 60 Incidence per 100 000 PY 213.77 (208.26-219.42) 186.87 (176.22-198.16) 186.85 (175.91-198.46) 187.25 (145.39-241.16) UHR 1 [Reference] 0.88 (0.82-0.93) 0.87 (0.82-0.93) 0.91 (0.71-1.18) Pancreatic New cancer cases, No. 754 187 177 10 Incidence per 100 000 PY 12.24 (11.40-13.15) 15.15 (13.12-17.48) 15.14 (13.07-17.55) 15.20 (8.18-28.25) UHR 1 [Reference] 1.24 (1.06-1.46) 1.24 (1.05-1.46) 1.29 (0.69-2.41) Breastb New cancer cases, No. 6281 1118 1056 62 Incidence per 100 000 PY 180.87 (176.45-185.40) 177.84 (167.71-188.57) 177.37 (166.98-188.39) 186.26 (145.22-238.91) UHR 1 [Reference] 0.99 (0.93-1.05) 0.99 (0.92-1.05) 1.06 (0.82-1.36) Colon New cancer cases, No. 3080 629 596 33 Incidence per 100 000 PY 50.07 (48.34-51.87) 51.01 (47.18-55.16) 51.06 (47.12-55.33) 50.23 (35.71-70.65) UHR 1 [Reference] 1.03 (0.94-1.12) 1.02 (0.94-1.12) 1.05 (0.74-1.47) Melanoma New cancer cases, No. 1587 340 320 20 Incidence per 100 000 PY 25.79 (24.55-27.09) 27.57 (24.79-30.66) 27.41 (24.56-30.58) 30.44 (19.64-47.17) UHR 1 [Reference] 1.08 (0.96-1.21) 1.07 (0.95-1.20) 1.23 (0.79-1.90) Nonmelanoma skin cancer New cancer cases, No. 15 978 3136 2907 229 Incidence per 100 000 PY 262.3 (25.83-26.64) 25.68 (24.80-26.60) 251.4 (24.25-26.08) 353.0 (31.01-40.18) UHR 1 [Reference] 0.98 (0.95-1.02) 0.96 (0.93-1.00) 1.40 (1.23-1.60)

Abbreviations: CTLC, cutaneous T-cell lymphoma; PY, person-years; UHR, unadjusted hazard ratio. a Only includes males. b Only includes females.

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Figure. Adjusted Hazard Ratio (aHR) for Cancer by Study Group

aHR Overall psoriasis group aHR Mild psoriasis group aHR Moderate-to-severe psoriasis group Cancer Type by Study Group, HR (95% CI)

Overall Mild Moderate-to-Severe Adjusted hazard ratio (95% CI) for cancer Source Psoriasis Psoriasis Psoriasis by study group Any cancer except NMSCa 1.06 (1.02-1.09) 1.06 (1.02-1.09) 1.08 (0.96-1.22)

Any lymphomab 1.34 (1.18-1.51) 1.33 (1.17-1.51) 1.86 (1.23-2.80)

Any lymphoma excluding CTCLb 1.25 (1.10-1.43) 1.24 (1.08-1.41) 1.62 (1.16-2.28)

CTCLb 3.82 (2.50-5.85) 3.51 (2.20-5.47) 9.25 (3.69-23.22)

Leukemiab 1.09 (0.98-1.23) 1.10 (0.98-1.23) 1.05 (0.67-1.65)

Lungc 1.15 (1.03-1.27) 1.13 (1.01-1.25) 1.60 (1.14-2.24)

Prostated,e 1.06 (0.99-1.13) 1.05 (0.99-1.12) 1.16 (0.90-1.50)

Pancreatica 1.25 (1.04-1.51) 1.25 (1.03-1.51) 1.29 (0.64-2.61)

Breasta,f 1.04 (0.97-1.12) 1.04 (0.97-1.13) 0.96 (0.71-1.28)

Colona 1.08 (0.98-1.20) 1.07 (0.97-1.19) 1.20 (0.82-1.74)

Melanomab 1.15 (1.02-1.30) 1.14 (1.01-1.29) 1.28 (0.82-1.99)

NMSCb 1.12 (1.07-1.16) 1.09 (1.05-1.13) 1.61 (1.42-1.84)

0 1 10 aHR (95% CI)

This Figure provides information on the adjusted hazard ratio (aHR) (95% CI) for any cancer except nonmelanoma skin cancer (NMSC) as well as individual cancers of interest in the overall, mild, and moderate-to-severe psoriasis groups. a Adjusted for age, BMI, drinking and smoking status, b adjusted for age and sex, c adjusted for age, sex, and smoking status, d adjusted for age only, e includes only men, f includes only women. CTCL indicates cutaneous T-cell lymphoma.

results from prior studies have been mixed. Chen et al6 found Our study has certain strengths. We used a large, an increased risk for melanoma in Taiwanese patients with pso- population-based database that has been used in similar epi- riasis compared with patients without psoriasis (HR, 3.10; 95% demiological studies and contains information on well- CI, 1.24-7.71). A more recent study27 found that patients with established risk factors for cancer. We provide further evi- psoriasis had a lower probability of developing melanoma when dence that the risk of cancer in patients with psoriasis, albeit compared with a group of nondermatological patients. With small, applies to a specific group of cancers, including respect to pancreatic cancer, a standardized incidence ratio NMSC, lymphoma, and lung cancer. Nonetheless, our study (SIR) of 1.46 (95% CI, 1.10-1.95) has been previously reported, has certain limitations. First, because THIN does not capture which is somewhat similar to our results (HR, 1.25; 95% CI, information on disease severity using physician-assessed 1.04-1.51).1 Interestingly, Brauchli et al8 also found an in- measures, we used treatment exposure as a proxy for dis- creased incidence rate of pancreatic cancer in patients with pso- ease severity. This limited our ability to separate the effect of riasis overall (HR, 2.20; 95% CI, 1.18-4.09). Our results showed disease severity from the effect of treatment exposure on a positive association across all study groups, yet we found no cancer risk. Second, the effect of biologic therapies on can- evidence of a dose-response effect with psoriasis severity. cer risk cannot be properly assessed because the use of these Chronic systemic inflammation, such as that seen in patients medications is more restricted in the UK and therefore may with severe psoriasis, has been postulated as a potential risk not be readily captured within THIN. While data on the factor for pancreatic cancer.28 Chronic alcohol consumption, effect of treatment on cancer risk in patients with psoriasis which is reportedly higher in this population and often re- are limited, studies31-33 in patients with other systemic sults in chronic pancreatitis, could be a contributing factor.29,30 inflammatory diseases, such as rheumatoid arthritis, who

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Table 4. Adjusted Hazard Ratio (95% CI) for Risk of Any Cancer Except Nonmelanoma Skin Cancer (NMSC) and Specific Cancer Types by Study Group: Sensitivity Analyses

Overall Mild Moderate-to-Severe Cancer Type Psoriasis Psoriasis Psoriasis Any cancer except NMSC Primary model 1.06 (1.02-1.09) 1.06 (1.02-1.09) 1.08 (0.96-1.22) Exclude patients with PsA 1.05 (1.02-1.09) 1.05 (1.02-1.09) 1.05 (0.90-1.22) Exclude patients with RA 1.06 (1.02-1.09) 1.06 (1.02-1.09) 1.05 (0.92-1.21) Limit to patients seen at least yearly by GP 1.03 (1.00-1.07) 1.00 (1.00-1.07) 1.04 (0.92-1.17) Any lymphoma Primary model 1.34 (1.18-1.51) 1.33 (1.17-1.51) 1.86 (1.23-2.80) Exclude patients with PsA 1.34 (1.18-1.52) 1.33 (1.17-1.51) 1.69 (0.98-2.91) Exclude patients with RA 1.36 (1.20-1.54) 1.33 (1.17-1.51) 2.06 (1.34-3.17) Limit to patients seen at least yearly by GP 1.31 (1.16-1.49) 1.29 (1.13-1.47) 1.76 (1.17-2.66) Any lymphoma excluding CTCL Primary model 1.25 (1.10-1.43) 1.24 (1.08-1.41) 1.62 (1.16-2.28) Exclude patients with PsA 1.24 (1.08-1.41) 1.23 (1.08-1.41) 1.22 (0.64-2.36) Exclude patients with RA 1.26 (1.10-1.43) 1.24 (1.08-1.42) 1.65 (1.06-2.70) Limit to patients seen at least yearly by GP 1.21 (1.06-1.38) 1.20 (1.05-1.37) 1.44 (0.91-2.30) CTCL Primary model 3.82 (2.50-5.85) 3.51 (2.2-5.47) 9.25 (3.69-23.22) Exclude patients with PsA 3.92 (2.56-6.02) 3.62 (2.32-5.64) 12.01 (4.34-33.27) Exclude patients with RA 3.79 (2.47-5.82) 3.43 (2.19-5.37) 10.97 (4.37-27.57) Limit to patients seen at least yearly by GP 3.82 (2.45-5.95) 3.50 (2.21-5.55) 9.05 (3.57-22.92) Lung Primary model 1.15 (1.03-1.27) 1.13 (1.01-1.25) 1.60 (1.14-2.24) Exclude patients with PsA 1.13 (1.01-1.25) 1.11 (0.99-1.23) 1.67 (1.12-2.51) Exclude patients with RA 1.14 (1.03-1.26) 1.12 (1.01-1.25) 1.47 (0.99-2.19) Limit to patients seen at least yearly by GP 1.07 (0.97-1.19) 1.05 (0.94-1.17) 1.51 (1.07-2.12) Limit to patients classified as never smokers 0.98 (0.76-1.25) 0.97 (0.75-1.24) 1.18 (0.44-3.17) Pancreatic Primary model 1.25 (1.04-1.51) 1.25 (1.03-1.51) 1.29 (0.64-2.61) Exclude patients with PsA 1.24 (1.03-1.51) 1.25 (1.03-1.52) 0.99 (0.37-2.65) Exclude patients with RA 1.26 (1.04-1.52) 1.25 (1.03-1.51) 1.41 (0.67-2.98) Limit to patients seen at least yearly by GP 1.20 (0.99-1.45) 1.20 (0.99-1.45) 1.23 (0.61-2.48) NMSC Primary model 1.12 (1.07-1.16) 1.09 (1.05-1.13) 1.61 (1.42-1.84) Exclude patients with PsA 1.11 (1.07-1.15) 1.09 (1.05-1.14) 1.63 (1.39-1.92) Exclude patients with RA 1.11 (1.07-1.15) 1.09 (1.05-1.13) 1.56 (1.35-1.81) Limit to patients seen at least yearly by GP 1.09 (1.05-1.13) 1.06 (1.02-1.11) 1.55 (1.36-1.77) Melanoma Primary model 1.15 (1.02-1.30) 1.14 (1.01-1.29) 1.28 (0.82-1.99) Exclude patients with PsA 1.15 (1.01-1.29) 1.14 (1.01-1.29) 1.26 (0.71-2.22) Exclude patients with RA 1.15 (1.02-1.30) 1.14 (1.01-1.29) 1.30 (0.81-2.10) Limit to patients seen at least yearly by GP 1.10 (0.98-1.24) 1.10 (0.97-1.24) 1.20 (0.77-1.86)

Abbreviations: GP, indicates general practioner; NMSC, nonmelanoma skin cancer; PsA, prostate-specific antigen; RA, rheumatoid arthritis.

are exposed to similar immune suppressive medications, Finally, although the risk of NMSC associated with PUVA have shown that the risk of malignant neoplasms cannot be treatment has been previously demonstrated, there are lim- entirely explained by exposure to these types of systemic ited data to support that exposure to UV-B therapy, including medications. Third, while data on well-established risk fac- narrowband UV-B, also increases this risk.20,34 In addition, tors for cancer (ie, smoking), are available within THIN, we could not adjust for exposure to environmental UV radia- greater efforts need to be made to improve the capture of tion, a strong risk factor for NMSC,35 because these data are these risk factors in large population-based databases if we not collected in EMR databases such as THIN. Misclassifica- are to further clarify the impact of psoriasis on cancer risk. tion could also have resulted in an increased estimate for

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cancer risk. For example, it is well known that patients with when interpreting our findings; in some cases our effects CTCL are sometimes incorrectly classified as having psoria- were small and could be related to chance because multiple sis, resulting in a biased positive association. Yet, it is outcomes were evaluated. unlikely that the misdiagnosis of psoriasis would completely explain this association. In the United Kingdom, patients who require initiation of systemic treatment would have Conclusions been seen by a dermatologist prior to the start of therapy; therefore, we would expect most of these patients to be cor- In conclusion, our data suggest that there is a small increased rectly classified as having psoriasis and not CTCL.4 risk of cancer overall in patients with psoriasis. Patients with Finally, surveillance bias could have affected our results psoriasis who received treatment with systemic medications because patients with severe psoriasis might be followed more or phototherapy were shown to be at a higher risk for malig- closely than their counterparts who do not have psoriasis or nant neoplasms compared with controls. Future work should only have mild disease. We performed additional analyses lim- be aimed at developing a better understanding of the effect of iting our entire cohort to patients seen at least once a year by disease severity and treatment exposure separately on can- their GP and observed similar results. In addition, if there was cer risk in this population. Dermatologists who care for pa- surveillance bias, we would have expected to see an in- tients with psoriasis should consider incorporating current can- creased risk of common cancers, such as breast, prostate, and cer screening guidelines and counseling, such as smoking colon cancer, and this was not observed. Care must be taken cessation, into their daily practice.

ARTICLE INFORMATION REFERENCES 11. Haynes K, Forde KA, Schinnar R, Wong P, Strom Accepted for Publication: October 13, 2015. 1. Pouplard C, Brenaut E, Horreau C, et al. Risk of BL, Lewis JD. Cancer incidence in The Health cancer in psoriasis: a systematic review and Improvement Network. Pharmacoepidemiol Drug Saf. Published Online: December 16, 2015. 2009;18(8):730-736. doi:10.1001/jamadermatol.2015.4847. meta-analysis of epidemiological studies. J Eur Acad Dermatol Venereol. 2013;27(suppl 3):36-46. 12. Meal A, Leonardi-Bee J, Smith C, Hubbard R, Author Contributions: Dr Chiesa Fuxench had full Bath-Hextall F. Validation of THIN data for access to all of the data in the study and takes 2. Abuabara K, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Cause-specific mortality in non-melanoma skin cancer. Qual Prim Care. 2008; responsibility for the integrity of the data and the 16(1):49-52. accuracy of the data analysis. patients with severe psoriasis: a population-based Study concept and design: Chiesa Fuxench, Gelfand. cohort study in the U.K. Br J Dermatol. 2010;163(3): 13. Seminara NM, Abuabara K, Shin DB, et al. Acquisition, analysis, or interpretation of data: All 586-592. Validity of The Health Improvement Network authors. 3. Gelfand JM, Berlin J, Van Voorhees A, Margolis (THIN) for the study of psoriasis. Br J Dermatol. Drafting of the manuscript: Chiesa Fuxench. DJ. Lymphoma rates are low but increased in 2011;164(3):602-609. Critical revision of the manuscript for important patients with psoriasis: results from a 14. Blak BT, Thompson M, Dattani H, Bourke A. intellectual content: All authors. population-based cohort study in the United Generalisability of The Health Improvement Statistical analysis: All authors. Kingdom. Arch Dermatol. 2003;139(11):1425-1429. Network (THIN) database: demographics, chronic Obtained funding: Gelfand. 4. Gelfand JM, Shin DB, Neimann AL, Wang X, disease prevalence and mortality rates. Inform Prim Administrative, technical, or material support: Ogdie Margolis DJ, Troxel AB. The risk of lymphoma in Care. 2011;19(4):251-255. Beatty. patients with psoriasis. J Invest Dermatol. 2006;126 15. Taggar JS, Coleman T, Lewis S, Szatkowski L. Study supervision: Chiesa Fuxench, Gelfand. (10):2194-2201. The impact of the Quality and Outcomes Conflict of Interest/Financial Disclosure: Dr 5. Boffetta P, Gridley G, Lindelöf B. Cancer risk in a Framework (QOF) on the recording of smoking Gelfand served as a consultant for AbbVie, Amgen population-based cohort of patients hospitalized targets in primary care medical records: Inc, Coherus, Celgene Corp, Eli Lilly, Merck, Janssen for psoriasis in Sweden. J Invest Dermatol. 2001;117 cross-sectional analyses from The Health Biologics (formerly Centocor), Regeneron Novartis (6):1531-1537. Improvement Network (THIN) database. BMC Corp, Leo Pharmaceuticals, Endo, and Pfizer Inc, Public Health. 2012;12:329. receiving honoraria; had grants or has pending 6. Chen YJ, Wu CY, Chen TJ, et al. The risk of cancer in patients with psoriasis: a population-based 16. Chisholm J. The Read clinical classification. BMJ. grants from AbbVie, Janssen, Regeneron, Novartis 1990;300(6732):1092. Corp, and Pfizer Corp; and received payment for cohort study in Taiwan. J Am Acad Dermatol. 2011; continuing medical education work related to 65(1):84-91. 17. Mehta NN, Azfar RS, Shin DB, Neimann AL, psoriasis. No other disclosures were reported. 7. Margolis D, Bilker W, Hennessy S, Vittorio C, Troxel AB, Gelfand JM. Patients with severe Santanna J, Strom BL. The risk of malignancy psoriasis are at increased risk of cardiovascular Funding/Support: This study was supported by an mortality: cohort study using the General Practice unrestricted grant from Pfizer Pharmaceuticals to associated with psoriasis. Arch Dermatol. 2001;137 (6):778-783. Research Database. Eur Heart J. 2010;31(8):1000- the trustees of the University of Pennsylvania, and 1006. grants from the National Psoriasis Foundation 8. Brauchli YB, Jick SS, Miret M, Meier CR. Psoriasis Fellowship Program (Dr Chiesa Fuxench), Training and risk of incident cancer: an inception cohort 18. Bursac Z, Gauss CH, Williams DK, Hosmer DW. Grant 5T32GM075766-09 from the National study with a nested case-control analysis. JInvest Purposeful selection of variables in logistic Institutes of Health (Dr Chiesa Fuxench), and grant Dermatol. 2009;129(11):2604-2612. regression. Source Code Biol Med. 2008;3:17. K24-AR064310 36 from the National Institute of 9. Stern RS, Väkevä LH; PUVA Follow-up Study. 19. Stern RS; PUVA Follow-up Study. The risk of Arthritis and Musculoskeletal and Skin Diseases (Dr Noncutaneous malignant tumors in the PUVA melanoma in association with long-term exposure Gelfand). follow-up study: 1975-1996. J Invest Dermatol.1997; to PUVA. J Am Acad Dermatol. 2001;44(5):755-761. Role of the Funder/Sponsor: The sponsors had no 108(6):897-900. 20. Archier E, Devaux S, Castela E, et al. role in the design and conduct of the study; in the 10. Dregan A, Moller H, Murray-Thomas T, Gulliford Carcinogenic risks of psoralen UV-A therapy and collection, management, analysis, and MC. Validity of cancer diagnosis in a primary care narrowband UV-B therapy in chronic plaque interpretation of the data; in the preparation, database compared with linked cancer registrations psoriasis: a systematic literature review. J Eur Acad review, or approval of the manuscript; or in the in England: population-based cohort study. Cancer Dermatol Venereol. 2012;26(suppl 3):22-31. decision to submit the manuscript for publication. Epidemiol. 2012;36(5):425-429. 21. Ekström K, Hjalgrim H, Brandt L, et al. Risk of malignant lymphomas in patients with rheumatoid

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arthritis and in their first-degree relatives. Arthritis 27. Paradisi A, Tabolli S, Didona B, Sobrino L, Russo immunosuppressive therapy: a single-center Rheum. 2003;48(4):963-970. N, Abeni D. Reduced frequency of melanoma in experience [published online June 23, 2015]. Intern 22. Ekström Smedby K, Vajdic CM, Falster M, et al. 72,739 patients with psoriasis: a retrospective Emerg Med. doi:10.1007/s11739-015-1270-0. Autoimmune disorders and risk of non-Hodgkin study. Eur J Dermatol. 2015;25(2):133-137. 32. England BR, Sayles H, Michaud K, et al. lymphoma subtypes: a pooled analysis within the 28. Komura T, Sakai Y, Harada K, et al. Cause-specific mortality in US veteran men with InterLymph Consortium. Blood. 2008;111(8):4029- Inflammatory features of pancreatic cancer rheumatoid arthritis [published online June 19, 4038. highlighted by monocytes/macrophages and CD4+ 2015. Arthritis Care Res (Hoboken). 23. Frentz G, Olsen JH. Malignant tumours and T cells with clinical impact. Cancer Sci. 2015;106 doi:10.1002/acr.22642. psoriasis: a follow-up study. Br J Dermatol. 1999; (6):672-686. 33. Ogdie A, Haynes K, Troxel AB, et al. Risk of 140(2):237-242. 29. McAleer MA, Mason DL, Cunningham S, et al. mortality in patients with psoriatic arthritis, 24. Hannuksela-Svahn A, Pukkala E, Läärä E, Alcohol misuse in patients with psoriasis: rheumatoid arthritis and psoriasis: a longitudinal Poikolainen K, Karvonen J. Psoriasis, its treatment, identification and relationship to disease severity cohort study. Ann Rheum Dis. 2014;73(1):149-153. and cancer in a cohort of Finnish patients. JInvest and psychological distress. Br J Dermatol. 2011;164 34. Hearn RM, Kerr AC, Rahim KF, Ferguson J, Dermatol. 2000;114(3):587-590. (6):1256-1261. Dawe RS. Incidence of skin cancers in 3867 patients 25. Ji J, Shu X, Sundquist K, Sundquist J, Hemminki 30. Kirby B, Richards HL, Mason DL, Fortune DG, treated with narrow-band ultraviolet B K. Cancer risk in hospitalised psoriasis patients: Main CJ, Griffiths CE. Alcohol consumption and phototherapy. Br J Dermatol. 2008;159(4):931-935. a follow-up study in Sweden. Br J Cancer. 2009;100 psychological distress in patients with psoriasis. Br J 35. Armstrong BK, Kricker A. The epidemiology of (9):1499-1502. Dermatol. 2008;158(1):138-140. UV induced skin cancer. J Photochem Photobiol B. 26. Prizment AE, Alonso A, Folsom AR, et al. 31. Fantò M, Peragallo MS, Pietrosanti M, et al. Risk 2001;63(1-3):8-18. Association between psoriasis and incident cancer: of malignancy in patients with rheumatoid arthritis, the Iowa’s Women’s Health Study. Cancer Causes psoriatic arthritis and ankylosing spondylitis under Control. 2011;22(7):1003-1010.

NOTABLE NOTES

Henna—A Temporary Body of Art

Mindy X. Wang, BS; Eric L. Maranda, BS; Jacqueline Cortizo, BS; Victoria Lim, BS; Joaquin Jimenez, MD

Amidst joyous chatter, choreographed dances, and the aromas of South The red paste traditionally used, known as “red henna,” rarely pro- Asian food, a bride is joined by close friends in her childhood home as duces adverse effects. However, recent reports of allergic reactions she delights in a once-in-a-lifetime celebration. As part of the festivi- have been attributed to the use of new additives such as coffee, black ties, a red-brown paste is expertly applied to her arms, hands, legs, and tea, and even animal urine, which help achieve a darker pigment feet in intricate designs of leaves, flowers, and geometric shapes. This known as “black henna.”1 The primary culprit in the recent rise of skin paste, otherwise known as henna, is an integral part of this timeless reactions is the ingredient paraphenylenediamine (PPD), a coal-tar Mehndi ceremony. hair dye.1 In addition to achieving a darker and longer-lasting color, Derived from the plant Lawsonia inermis, temporary henna tattoo PPD helps shorten the duration of the tattooing process.1 While tradi- paste (or mehndi) is a mixture of the plant’s extracts with water or oil.1 tional henna sessions can last up to 12 hours, black henna reduces the Decorative patterns are skillfully drawn onto the skin with a brush or thin time to less than 2 hours.3 Use of black henna may be tempting, but stick and allowed to dry. A dressing can be applied to improve its potential for allergic contact dermatitis, severe delayed-type reac- penetration1 of the paste into the stratum corneum. Over the course of tions, and more permanent effects, such as persistent leukoderma or a few weeks, as corneocytes gradually shed, the tattoos will fade.1 hyperpigmentation, is cause for concern.1 Perhapsitisbesttorespect The practice of henna has a celebrated history dating back over the traditional practice of red henna, lest a temporary tattoo result in 5000 years to South Asia, the Middle East, and Africa.2 Largely asso- a permanent scar. ciated with the feminine form, use of henna by brides dates back to 2100 BC in Syria, and ancient spiritual rituals dedicated to goddesses Author Affiliations: Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. often included henna tattoos.2 Owing to its unique pigment, henna can also provide relief from the heat when applied to the hands, feet, Corresponding Author: Eric L. Maranda, BS, Department of Dermatology and and scalp. In the past, henna even played a role in the treatments of Cutaneous Surgery, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136 ([email protected]). leprosy and smallpox.1 Contemporary decorative henna maintains a 1. Cartwright-Jones C. Developing guidelines on henna: a geographical strong association with traditional celebrations, and its designs often approach [dissertation]. Kent, OH: Kent State University; 2006. vary with geographic region or culture. In India, fine lines of lacy, flo- 2. De Cuyper C, D’hollander D. Dermatologic Complications with Body Art: ral, paisley patterns are used, while African henna displays bold lines Tattoos, Piercings, and Permanent Make-up. Heidelberg, Germany: Springer; 2 and geometric designs. Recent popularization of henna in Western 2010:13-28. 1 culture has been sparked by tourists and even popular musicians like 3. Wolf R, Wolf D, Matz H, Orion E. Cutaneous reactions to temporary tattoos. the Spice Girls.3 Dermatol Online J. 2003;9(1):3.

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