Comorbidities in Patients with Psoriasis

REVIEW

Comorbidities in Patients with Psoriasis Alice B. Gottlieb, MD, PhD,a Frank Dann, MDb a

Tufts Medical Center, Boston, Mass; bVA Medical Center, Long Beach, Calif.

ABSTRACT Psoriasis is a common chronic inflammatory disease that is associated with serious comorbidities, including psoriatic arthritis, reduced quality of life, depression, malignancy, and cardiovascular comorbidities. Patients with psoriasis have been shown to have an increased incidence of metabolic syndrome and cardiovascular disease compared with the general population. The chronic inflammatory nature of psoriasis has been suggested to be a contributing and potentially independent risk factor for the development of cardiovascular comorbidities. Understanding the interrelationship between these conditions is important for the management of psoriasis and the associated comorbidities. This review will focus on the range of comorbidities associated with psoriasis, with emphasis on cardiometabolic conditions and the aim of encouraging primary care physicians to screen psoriatic patients for cardiometabolic disorders and risk factors. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 1150.e1-1150.e9 KEYWORDS: Cardiovascular disease; Metabolic syndrome; Psoriasis; Psoriatic arthritis comorbidities

The management of psoriasis traditionally has focused on skin symptoms. However, there are serious auxiliary concerns that often are not readily apparent to primary care physicians focusing on alleviating psoriatic skin eruptions. Recent findings have shown that patients with psoriasis also have an increased risk for cardiovascular disease and mortality, as well as metabolic syndrome and its components.1 The immune-mediated chronic inflammatory processes underlying psoriasis may contribute to, or even amplify, certain comorbidities associated with psoriasis. The relationship beFunding: Funding for writing assistance was provided by Amgen. Conflict of Interest: Almost all of Dr Gottlieb’s consulting and speaking fees are paid to Tufts Medical Center. Dr Gottlieb is a member of the speakers bureau of Amgen Inc, and Wyeth Pharmaceuticals; has current consulting/advisory board agreements with Amgen Inc, Centocor, Inc, Wyeth Pharmaceuticals, Celgene Corp, Bristol-Myers Squibb Co, Beiersdorf, Inc, Abbott, Roche, TEVA, Actelion, UCB, Novo Nordisk, Almirall, Immune Control, Dermipsor Ltd., Incyte, Magen Biosciences, Stieffel, and Puretech; Tufts Medical Center has received research/educational grants from Centocor, Inc, Amgen Inc, Wyeth Pharmaceuticals, Immune Control, Celgene Corp, Pharmacare, Incyte, Novo Nordisk, Pfizer, and Abbott. Dr Dann is a former Amgen employee. He has participated on speakers bureaus for Amgen Inc and Wyeth Pharmaceuticals and has a consulting agreement with Amgen. Authorship: All authors had access to the data and played a role in writing this manuscript. Reprint requests should be addressed to Alice B. Gottlieb, MD, PhD, Tufts Medical Center, 800 Washington St, Box 114, Boston, MA 021111533. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.06.021

tween psoriasis and cardiometabolic conditions, such as obesity, cardiovascular disease, diabetes, and metabolic syndrome, holds relevance for the management of psoriasis and its associated comorbidities. The objective of this review is to raise awareness of the constellation of comorbid conditions experienced by patients with psoriasis, with an emphasis on cardiovascular comorbidities in this patient population. Although the pathophysiologic link among psoriasis, inflammation, and coronary artery atherosclerotic disease has not been completely elucidated, an awareness of associated comorbidities will help primary care physicians address the entire scope of psoriatic diseases.

PSORIASIS AND PSORIATIC ARTHRITIS Psoriasis is a common chronic, systemic, inflammatory disease most commonly manifested by painful and pruritic skin lesions on the elbows, knees, scalp, genitals, and trunk2 that has been estimated to affect 1% to 3% of the population worldwide.3,4 Psoriasis is classified according to morphologic appearance5 and includes plaque, inverse, erythrodermic, pustular, and guttate forms, as well as nail manifestations (Figure 1). Although psoriasis is a chronic lifelong condition, appropriate treatment regimens can reduce the severity of the disease. A common comorbidity associated with psoriasis is psoriatic arthritis, an inflammatory arthritic condition characterized by the development of pain, swelling, and tenderness of the joints surrounding ligaments and tendons, which occurs con-

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comitantly with psoriasis. Between 25% and 34% of patients bone formation, rheumatoid factor negativity, and psoriwith psoriasis have psoriatic arthritis.6 Skin disease typically atic nail dystrophy.10 manifests before arthritis in more than 80% of patients, and There are no serologic tests available to aid in the diagnosis psoriasis symptoms usually precede joint symptoms by an of psoriatic arthritis. Radiographs and other imaging techaverage of 10 years.7,8 Psoriatic arthritis is classified according niques (magnetic resonance and computed tomography) can be to criteria established by Moll and used to detect joint involvement, Wright9 or the Classification Critewhich, when present concurrently ria for Psoriatic Arthritis.10 Accordwith skin lesions, can be used in CLINICAL SIGNIFICANCE ing to Moll and Wright criteria, a the diagnosis of psoriatic arthritis. diagnosis of psoriatic arthritis reHowever, these diagnostic criteria ● Psoriasis is a debilitating chronic inquires the presence of psoriasis and are not exclusive to psoriatic arthriflammatory disease that predisposes painflammatory arthritis accompanied tis and could include seronegative tients to serious comorbidities. by polyarticular symmetric arthritis, patients who have developed psori● Psoriasis comorbidities include psorioligoarticular (⬍5 joints) asymmetasis. Because psoriatic arthritis and atic arthritis, reduced quality of life, ric arthritis, distal interphalangeal rheumatoid arthritis share some joint involvement, predominant characteristics, particularly polyarmalignancy, cardiovascular disease, and spondylitis, or arthritis mutilans.9 ticular joint involvement, clinical metabolic syndrome. Classification Criteria for Psoriatic features are important for differen● Primary care physicians should be aware tiating psoriatic arthritis from rheuArthritis criteria for psoriatic arthriof potential cardiometabolic conditions matoid factor-negative rheumatoid tis require the presence of estaband risk factors when treating patients arthritis with unrelated psoriasis. lished inflammatory articular diswith psoriasis. Distinguishing characteristics of ease and at least 3 points from the psoriatic arthritis that are typically following features: current psoriasis not present in rheumatoid arthritis (assigned a score of 2; all other feainclude psoriatic plaques, negative tures are assigned a score of 1), a rheumatoid factor, asymmetric arthritis, proliferative bone personal history of psoriatic arthritis, a family history of changes, dactylitis, enthesitis, and distal interphalangeal joint psoriasis, past or present dactylitis, juxtaarticular new involvement.11 It also is important to note that the severity of skin disease does not reliably correlate with the severity of psoriatic arthritis (eg, number of involved joints and extent of joint damage).12 Patients with psoriatic arthritis can present with a wide range of symptoms, from mild to severe, and often undergo bouts of flares and remissions. The severity of psoriatic arthritis is highly variable and can range from a mild arthritis to debilitating polyarticular disease with joint damage and loss of functionality (Figure 2).13-15 Approximately one half of patients with early-onset psoriatic arthritis develop erosive joint damage within 2 years of onset.16 A clinically distinct form of uveitis that is bilateral and prolonged can develop in patients with psoriatic arthritis and in patients with psoriasis.17,18 In addition, psoriatic arthritic patients have an increased mortality rate, with cardiovascular complications reported to be the most common cause of death.7,19 Psoriatic arthritis patients can experience sleep apnea20 and a reduced quality of life and increased functional disabilities compared with the general population,21 and the reduction in quality of life is greater in those with increased psoriasis severity.22 Figure 1 Clinical manifestations of psoriasis. Psoriasis affecting the knee and surrounding tissue characterized by well-defined erythematous lesions with scaling. Reproduced with permission from the Johns Hopkins University Dermatlas: 2000-2008.

CARDIOVASCULAR COMORBIDITIES Metabolic Syndrome Patients with psoriasis have an increased risk of developing cardiovascular disease and metabolic syndrome compared with controls without psoriasis.23,24 Although metabolic

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1150.e3 psoriatic controls.31 More recently, a study of 581 patients hospitalized for psoriasis found an increased odds ratio (3.27) for hypertension after controlling for age and sex, compared with hospitalized non-psoriatic controls.24 These data suggest that additional studies are needed to delineate the relationship between hypertension and psoriasis.

Dyslipidemia

Figure 2 Clinical manifestations of psoriatic arthritis. Dactylitis of the phalanges. Reproduced with permission of the American Academy of Dermatology National Library of Dermatologic Teaching Slides.

syndrome has multiple definitions, in general it is defined as the presence of 3 or more of the following components: abdominal obesity, increased insulin resistance/elevated fasting glucose level, decreased high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension (Table 1).25-28 The factors defining metabolic syndrome go hand in hand with an increased risk for diabetes and atherosclerotic cardiovascular disease. Emerging data also indicate that psoriasis might be an independent risk factor for cardiovascular disease even after correcting for components of the metabolic syndrome.29,30 A summary of recent clinical studies (published between 2006 and 2008) describing the factors that define metabolic syndrome and comorbidities among patients with psoriasis is presented in Table 2.

Hypertension Some investigators have reported that hypertension occurs more often in patients with psoriasis than in controls without psoriasis;24,31-34 however, this association has not been completely supported by all of the current literature. Two recent studies have failed to demonstrate a relationship between hypertension and psoriasis or its severity. A recent large population-based study of 127,706 psoriatic patients failed to demonstrate a clinically meaningful relationship between psoriasis and hypertension in patients with mild or severe psoriasis after controlling for risk factors such as obesity.32 Another study of 200 patients with mild psoriasis did not find significant blood pressure differences between psoriatic patients and matched controls.35 These data suggest that hypertension might not be independently associated with severe psoriasis. Conversely, multiple cross-sectional trials have reported a higher occurrence of hypertension in patients with psoriasis compared with controls.24,31,33 A German database of 42,461 dermatologic patients, 2941 with psoriasis, reported that after controlling for age and sex, the rate of hypertension was twice as high in psoriatic patients compared with non-

A number of published reports support the well-established association between psoriasis and dyslipidemia, including studies that controlled for age, sex, and cardiovascular comorbidities.24,35-38 There also is evidence that a dyslipidemic profile is present at the onset of psoriasis in some patients, suggesting that dyslipidemia may precede the onset of psoriasis.35 Patients with psoriasis tend to have significantly higher concentrations of triglycerides and total cholesterol, as well as higher concentrations of low-density lipoprotein and very low-density lipoprotein cholesterol,36,39 all of which are established risk factors for cardiovascular disease.40,41 Metabolically, a direct relationship between psoriasis and altered lipid metabolism has not been established. However, there is a relationship between obesity, which is common among psoriatic patients, and

Table 1

Diagnostic Criteria for Metabolic Syndrome

Measurea

Categoric Cut Points

Elevated waist circumference Elevated triglycerides

ⱖ102 cm (ⱖ40 in) in men ⱖ88 cm (ⱖ35 in) in women ⱖ150 mg/dL (1.7 mmol/L) or Drug treatment for elevated triglycerides (eg, fibrates or nicotinic acid) ⬍40 mg/dL (1.03 mmol/L) in men ⬍50 mg/dL (1.3 mmol/L) in women or Drug treatment for reduced HDL cholesterol (eg, fibrates or nicotinic acid) ⱖ130 mm Hg systolic blood pressure or ⱖ85 mm Hg diastolic blood pressure or Drug treatment for hypertension ⱖ100 mg/dL or Drug treatment for elevated glucose

Reduced HDL cholesterol

Elevated blood pressure

Elevated fasting glucose

HDL ⫽ high-density lipoprotein. a Any 3 of 5 criteria constitute diagnosis of metabolic syndrome. Reproduced with permission from Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752.

1150.e4 Table 2

The American Journal of Medicine, Vol 122, No 12, December 2009 Summary of Studies Linking Psoriasis to Metabolic Syndrome and Cardiovascular Disease

Study 36

Akhyani et al

Boehncke et al101

No. of Patients

Conclusion

50 patients with psoriasis 50 controls 39 patients with psoriasis

Patients with psoriasis had increased total cholesterol, triglycerides, LDL, and very LDL Weak association between Psoriasis Area and Severity Index score and insulin secretion Increased prevalence/risk of diabetes, cardiovascular disease, hypertension, dyslipidemia, and obesity in patients with psoriasis Increased risk of diabetes in patients with psoriasis

Cohen et al102

340 patients with psoriasis 6643 controls

Cohen et al48

16,851 patients with psoriasis 74,987 controls 16,851 patients with psoriasis 48,681 controls 30 patients with psoriasis 30 controls 127,139 patients with mild psoriasis 3837 patients with severe psoriasis 556,995 controls 338 patients with psoriasis 334 controls 3066 patients with psoriatic arthritis 12,264 controls

Cohen et al103 Farshchian et al44 Gelfand et al29

Gisondi et al104 Han et al37

Huerta et al54 Ludwig et al67 Mallbris et al35 Neimann et al32

Shapiro et al45 Sommer et al24

Tekin et al38

3994 patients with psoriasis 10,000 controls 32 patients with psoriasis 32 controls 200 patients with psoriasis 285 controls 127,706 patients with mild psoriasis 3854 patients with severe psoriasis 65,252 controls

Increased risk of diabetes, metabolic syndrome, hypertension, cardiovascular disease, and obesity in patients with psoriasis No difference in triglycerides, total cholesterol, HDL, very LDL, or LDL between patients with psoriasis and controls Patients with psoriasis had an increased risk of myocardial infarction that varied by age Metabolic syndrome, triglyceride elevation, and obesity more common in patients with psoriasis Patients with psoriatic arthritis had increased incidence of cardiovascular disease and diagnostic indicators of metabolic syndrome Obesity is a risk factor for the onset of psoriasis

Patients with psoriasis had increased prevalence and severity of coronary artery calcification Patients with psoriasis had increased total cholesterol, HDL, and apolipoprotein A1 levels Patients with mild psoriasis had a higher risk of diabetes, hypertension, hyperlipidemia, obesity, and smoking than controls. Patients with severe psoriasis had a higher risk of diabetes and obesity 46,095 patients with psoriasis Psoriasis was associated with the development of atherosclerosis 1,579,037 controls and diabetes 625 patients with psoriasis Psoriasis was significantly associated with diabetes, 1044 controls (patients with stage 1 melanoma) hypertension, hyperlipidemia, cardiovascular disease, and obesity 84 patients with psoriasis Patients with psoriasis had higher total cholesterol, triglycerides, 40 controls and LDL, and lower HDL

HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. Adapted with permission from Azfar RS and Gelfand JM. Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheum. 2008;20:416-422.

altered lipid metabolism. Mechanistically, adipocytes have been shown to affect lipid profiles by increasing the levels of proinflammatory cytokine, particularly tumor necrosis factor-␣ and interleukin 6, which can affect free fatty acid, cholesterol, and lipid levels.42,43 The contribution of obesity to the dyslipidemia observed in psoriatic patients is indirectly supported by a small cross-sectional study of nonobese psoriatic patients in Iran.44 In this study, lipid profiles of patients with psoriasis and a body mass index (BMI) less than 30 kg/m2 were comparable with non-psoriatic patients matched for age, sex, and BMI, demonstrating that in the absence of obesity, an independent association between psoriasis and dyslipidemia could not be established.44

Insulin Resistance/Diabetes An association between psoriasis and type 2 diabetes is supported by recent epidemiologic studies, including large European and Middle Eastern databases of patients with psoriasis.24,30,32,45-48 Results from 2 large European databases of patients with psoriasis showed an increased prevalence of diabetes compared with controls and suggested that female patients may be more likely to have diabetes than male patients.31,33 Type 2 diabetes is usually preceded by impaired glucose tolerance,49 and accordingly, psoriatic patients are more likely than healthy individuals to demonstrate insulin resistance when challenged with oral glucose.50 Significant positive correlations between the dura-

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tion of psoriasis and insulin sensitivity also have been shown.51 Given that a proportion of patients with psoriasis are obese and abdominal obesity is strongly associated with the development of metabolic syndrome and type 2 diabetes, the relationship between psoriasis and diabetes is not unexpected. A recent large retrospective database of psoriatic patients in Israel found a higher incidence of diabetes in male children (up to 5 years of age) with psoriasis, among whom the odds ratio for diabetes was 24 in comparison with age- and sex-matched non-psoriatic controls.45 The finding was not statistically significant, presumably because of the small number of patients involved, but it may reflect a trend that should be more closely monitored in future studies. A significantly increased odds ratio for developing diabetes also was noted among male and female psoriatic patients between 35 and 55 years of age.45

Obesity Obesity is a common comorbidity of psoriasis, and multiple studies have demonstrated that patients with psoriasis are more frequently overweight (BMI ⱖ 25 kg/m2 and ⬍30 kg/m2) or obese (BMI ⱖ 30 kg/m2) compared with patients without psoriasis.32,52-54 Whether obesity is a contributing factor to or a manifestation of psoriasis is still under debate. Recent data emerging from large cohort studies suggest that obesity is a risk factor for the development of psoriasis.53-55 Conversely, data from 3 large population databases of psoriatic patients found that BMI increased in patients after psoriasis diagnosis, suggesting that obesity is secondary to psoriasis.52 Irrespective of cause and effect, the relationship between obesity and advancing psoriatic disease has been noted in a number of cross-sectional studies in which increased BMI coincides with a greater degree of psoriasis disease severity.32,52 Obesity also is related to the other components of metabolic syndrome and to an increased risk for cardiovascular disease. In addition, obesity is associated with nonalcoholic steatohepatitis.56

CARDIOVASCULAR DISEASE Cardiovascular disease and related mortality in patients with psoriasis have been reported in both cohort and populationbased studies.29,31,34,57,58 Severe psoriasis, as defined by the use of systemic medications or repeated hospitalizations, that occurs at a relatively younger age is associated with an increased risk for cardiovascular mortality or myocardial infarction.23,29 The increase in cardiovascular disease among psoriatic patients is not completely understood and might be the result of multiple mechanisms. One link between cardiovascular disease and psoriasis is the constellation of risk factors for cardiovascular disease, such as increased BMI, hypertension, dyslipidemia, and type 2 diabetes, which also are associated with psoriasis. Underlying chronic inflammatory processes are additional and likely important shared characteristics of psoriasis and cardiovascular disease.

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Chronic Inflammation and Atherosclerosis Detection of subclinical atherosclerosis and identification of patients at risk for developing atherosclerosis are important for the prevention of cardiovascular disease. Systemic inflammation has been associated with the development of atherosclerosis,59 which suggests that psoriatic patients may have a higher risk for cardiovascular disease. Studies report that plasma acute-phase protein levels (C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1) were significantly elevated in patients with psoriasis compared with healthy controls.60-63 Furthermore, elevation in the levels of C-reactive protein is emerging as a risk factor for cardiovascular disease and has been shown to be predictive of cardiovascular disease in healthy patients.64 In a recent trial, C-reactive protein levels in patients with psoriasis (with or without psoriatic arthritis) indicated intermediate to high risk of developing cardiovascular disease.65 A large prospective cohort study in women has shown that C-reactive protein levels may have predictive value for the development of cardiovascular disease,64 with levels over time remaining consistent with cardiovascular risk.66 Patients with psoriasis and psoriatic arthritis, and obese psoriatic patients with or without psoriatic arthritis, were at greater risk for cardiovascular disease.65 Psoriasis also has been shown to be an independent risk factor for myocardial infarction.29 Chronic inflammatory processes and abnormalities in vascular morphology, which are characteristic of psoriasis and atherosclerosis, might be the common link between these conditions.45 An increased prevalence of coronary artery calcification, which is present in the majority of patients on first myocardial infarction, has been detected among psoriatic patients, and psoriasis has been shown to be an independent risk factor for coronary artery calcification.67 Intima–media thickness of the carotid artery is another indicator of atherosclerosis and has been observed in patients with psoriatic arthritis, in whom intima–media thickness was correlated with cardiovascular disease risk factors such as BMI, elevated blood pressure, and elevated serum glucose levels.68 Psoriatic arthritis was determined to be an independent risk factor for atherosclerosis, further supporting the link between chronic inflammation and the development of atherosclerosis.68 Chronic obstructive pulmonary disease, characterized by abnormal inflammation in the lungs, also has been shown to be associated with psoriasis.69

Myocardial Infarction A large prospective study that analyzed the rates of myocardial infarction in patients 20 to 90 years of age with mild and severe psoriasis reported an age-dependent increase in myocardial infarction among psoriatic patients compared with a control population, with the greatest risks found in young patients with severe disease. Psoriasis was an independent risk factor for myocardial infarction, after adjustment for other confounding conditions for cardiovascular disease, such as hypertension, diabetes, history of myocardial infarction, hyperlipidemia, age, sex, smoking, and BMI.29

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Stroke

treatments targeting chronic underlying inflammation could theoretically target both psoriasis and cardiovascular disease. For example, in a cohort study of more than 7600 veterans with psoriasis, methotrexate reduced the risk of cardiovascular disease, cerebrovascular disease, and atherosclerosis, particularly at lower doses.84 These findings suggest that the anti-inflammatory properties of methotrexate override its ability to increase homocysteine levels and promote cardiovascular disease in psoriatic patients. In overweight and obese psoriatic patients, etanercept treatment has been shown to reduce the level of C-reactive protein.65 Although there are currently few studies showing that treatments for psoriasis can reduce cardiovascular disease, there are a number of studies in patients with rheumatoid arthritis demonstrating that treating the inflammatory processes in rheumatoid arthritis results in positive outcomes on cardiovascular comorbidities. For example, patients with rheumatoid arthritis treated with methotrexate had a 70% decrease in cardiovascular mortality compared with patients treated with disease-modifying antirheumatic drugs only.85 In addition, the risk of developing cardiovascular disease was reduced in patients with rheumatoid arthritis treated with etanercept or infliximab compared with untreated patients.86 In a large, multinational cohort study of predominantly white female patients with rheumatoid arthritis treated with traditional disease-modifying antirheumatic drugs or tumor necrosis factor antagonists, the prevalence of cardiovascular morbidity was reduced as a result of long-term treatment exposure.87 Treatment with methotrexate also might reduce the risk of cardiovascular risk factors, such as atherosclerosis and dyslipidemia in patients with rheumatoid arthritis with a disease duration less than 1 year.88 Although some therapies might have a benefit in reducing the risk for comorbid conditions, some might have adverse effects on comorbidities, such as increasing the risk of malignancy (including lymphoma).81,89-91 Because psoriatic patients appear to have an intrinsically increased risk of lymphoma, it is difficult to determine any degree of additional risk associated with treatment. For example, there are reports of lymphoma associated with use of tumor necrosis factor inhibitors in psoriatic patients,92,93 but interpreting this information remains difficult given the anecdotal nature of these reports and the absence of long-term safety studies. Other risks of therapy include new-onset arthritis or exacerbation of existing arthritis94 and elevated lipid levels.95 Patients with psoriatic arthritis might be more susceptible to methotrexate toxicity than patients with rheumatoid arthritis.96 This observation, along with the knowledge that risk factors (eg, diabetes and obesity) associated with an increased risk of methotrexate-related hepatotoxicity are more prevalent in patients with psoriasis and psoriatic arthritis, underscores the need for diligent monitoring of methotrexate in such patients.97 Patients’ comorbid conditions should be considered when selecting therapy.

Information is emerging that suggests an association between psoriasis and stroke. A case-control study from the General Practice Research database in the United Kingdom reported that patients with severe psoriasis had a 43% increased risk of stroke compared with patients with mild psoriasis. Increased systemic inflammation is thought to be the underlying pathology linking these conditions.70 In addition, a cohort study of 44,164 psoriatic patients reported a significant increase in the risk of incident stroke compared with non-psoriatic matched controls.71

MALIGNANCIES Lymphomas are a significant comorbidity associated with inflammatory diseases, including rheumatoid arthritis and psoriasis.72-74 Defining the contribution of psoriasis to the cause of lymphomas has been complicated by the overall rarity of this malignancy and the large clinical study patient base needed to establish statistically meaningful conclusions. The risk of psoriatic patients developing lymphoid malignancies may be attributable to the pathophysiology or treatment of psoriasis. Abnormal immune activation has been demonstrated in psoriatic patients75-77 and might contribute to subsequent malignancy. A large, controlled cohort study (1988-2002) found a modest increase in lymphomas, particularly Hodgkin’s lymphoma and cutaneous T-cell lymphoma, among psoriatic patients compared with the general population, and a greater overall risk for these lymphomas was evident among patients with more severe psoriasis (ie, those who received psoralen/phototherapy or systemic treatments, eg, methotrexate, azathioprine, or cyclosporine).73 In addition to lymphoma, psoriatic patients have an increased risk for other malignancies, including those of the head and neck, solid organs (liver, pancreas, lung, breast, kidney), and genitals, as well as nonmelanoma skin cancer.78-80 The use of psoralen ultraviolet A/psoralen ultraviolet A regimens has been implicated in the development of squamous cell carcinoma.81,82 The use of cyclosporine in dermatologic regimens has been associated with an increase in non-melanoma skin cancers, particularly squamous cell carcinoma.83 Other antipsoriatic treatments, such as ionizing radiation and oral arsenic therapies, and the increased use of alcohol and tobacco, might be contributing factors for the increased incidence of solid tumors among psoriatic patients.78,79

TREATMENT OF PSORIASIS Treatment options for psoriasis have traditionally been based on disease severity and can be grouped according to modality: topical and phototherapy, systemic, and biologic therapies. Topical treatments and phototherapy can be safe and effective in reducing psoriasis skin manifestations, but they do not affect the underlying inflammatory processes that drive psoriasis and its associated comorbidities. Although the pathophysiology linking psoriasis with cardiometabolic conditions is still unclear, systemic and biologic

Gottlieb and Dann Table 3

Psoriasis Comorbidities

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Comorbidity Screening for Psoriatic Patients

Comorbidity

Screening Parameter

Recommendation

Psoriatic arthritis

There is no consensus on screening tools for psoriatic arthritis. Radiography is used most often to detect joint damage.

Cardiometabolic conditions98

BMI Blood pressure Fasting lipids

“Upon diagnosis of psoriatic arthritis, patients should be treated and/or referred to a rheumatologist to alleviate signs and symptoms, inhibit structural damage, and improve quality of life parameters.” ⬍25 kg/m2 Target ⬍ 120/80 mm Hg LDL (optimal) ⬍ 100 mg/dL LDL (near optimal) 100-129 mg/dL HDL ⱖ 50 mg/dL Target ⬍ 200 mg/dL ⬍100 mg/dL Visual examinations should be performed to detect skin malignancies. Lymph nodes should be assessed for enlargement.

100

Malignancy99

Total cholesterol Fasting blood glucose Specific clinical assessment criteria for skin cancers and lymphoma are not currently recommended by the American Cancer Society.

BMI ⫽ body mass index; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein.

CONCLUSIONS Psoriasis is a common, serious systemic disease that can affect more than the skin. Physicians should be aware of the predominant comorbidities associated with psoriasis so they can effectively manage treatment. Recognizing the potential for, and early signs of, psoriatic arthritis can minimize joint destruction and lasting deformities. Although there is no consensus regarding screening for metabolic conditions in psoriatic patients, physicians should be aware of the association between components of the metabolic syndrome, cardiovascular disease, and psoriasis, and consult the American Medical Association guidelines for general cardiovascular risk factor screening (Table 3).98-100 Physicians should also be aware of the increased risk of malignancy, particularly lymphomas, among psoriatic patients, and suggest their patients undergo routine screening for cancer according to the American Cancer Society guidelines.98 When treating psoriatic patients, physicians must look past the skin symptoms and address associated comorbid conditions. Recognition of the potential for serious arthritic and cardiovascular comorbidities associated with psoriasis and intervention with appropriate and timely therapy may reduce the risk of progressive joint damage, cardiovascular disease, and metabolic syndrome. Further understanding of the disease’s underlying inflammatory processes may improve the management of patients with psoriasis.

ACKNOWLEDGMENT The authors thank Susan DeRocco, PhD, and Rick Davis, RPh, MS, of Complete Healthcare Communications, Inc., Chadds Ford, Penn, whose work was funded by Amgen Inc, for assistance with writing the article.

References 1. Gottlieb AB, Chao C, Dann F. Psoriasis comorbidities. J Dermatolog Treat. 2008;19:5-21. 2. Nickoloff BJ, Nestle FO. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 2004;113:1664-1675. 3. Myers WA, Gottlieb AB, Mease P. Psoriasis and psoriatic arthritis: clinical features and disease mechanisms. Clin Dermatol. 2006;24: 438-447. 4. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005; 64(suppl 2):ii18-25. 5. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850. 6. Gladman DD. Psoriatic arthritis. Dermatol Ther. 2004;17:350-363. 7. Gladman DD, Antoni C, Mease P, et al. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005; 64(suppl 2):ii14-17. 8. Gottlieb AB, Mease PJ, Mark Jackson J, et al. Clinical characteristics of psoriatic arthritis and psoriasis in dermatologists’ offices. J Dermatolog Treat. 2006;17:279-287. 9. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973; 3:55-78. 10. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665-2673. 11. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851-864. 12. Cohen MR, Reda DJ, Clegg DO. Baseline relationships between psoriasis and psoriatic arthritis: analysis of 221 patients with active psoriatic arthritis. Department of Veterans Affairs Cooperative Study Group on Seronegative Spondyloarthropathies. J Rheumatol. 1999; 26:1752-1756. 13. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis (PSA)—an analysis of 220 patients. Q J Med. 1987;62:127-141. 14. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, et al. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol. 1991;30:245-250.

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15. Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, et al. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis. 2003;62:68-70. 16. Kane D, Stafford L, Bresnihan B, et al. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford). 2003;42:1460-1468. 17. Durrani K, Foster CS. Psoriatic uveitis: a distinct clinical entity? Am J Ophthalmol. 2005;139:106-111. 18. Paiva ES, Macaluso DC, Edwards A, et al. Characterisation of uveitis in patients with psoriatic arthritis. Ann Rheum Dis. 2000;59:67-70. 19. Gladman DD, Farewell VT, Wong K, et al. Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum. 1998;41:1103-1110. 20. Callis KD, Wong B, Krueger G. Sleep disturbance and medical co-morbidities in patients with psoriasis, psoriatic arthritis, and controls 67th Annual Meeting, March 6-10, 2009, San Francisco, California. 21. Husted JA, Gladman DD, Farewell VT, et al. Validating the SF-36 health survey questionnaire in patients with psoriatic arthritis. J Rheumatol. 1997;24:511-517. 22. Zachariae H, Zachariae R, Blomqvist K, et al. Quality of life and prevalence of arthritis reported by 5,795 members of the Nordic Psoriasis Associations. Data from the Nordic Quality of Life Study. Acta Derm Venereol. 2002;82:108-113. 23. Mallbris L, Akre O, Granath F, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol. 2004;19:225-230. 24. Sommer DM, Jenisch S, Suchan M, et al. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res. 2006;298:321-328. 25. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 26. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. 27. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006;47:10931100. 28. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov. 2006;5: 295-309. 29. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735-1741. 30. Brauchli YB, Jick SS, Miret M, et al. Psoriasis and risk of incident myocardial infarction, stroke or transient ischaemic attack: an inception cohort study with a nested case-control analysis. Br J Dermatol. 2009;160:1048-1056. Epub 2009 Feb 4. 31. Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol. 1995;32:982-986. 32. Neimann AL, Shin DB, Wang X, et al. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006; 55:829-835. 33. Lindegard B. Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes. Dermatologica. 1986;172:298-304. 34. Ena P, Madeddu P, Glorioso N, et al. High prevalence of cardiovascular diseases and enhanced activity of the renin-angiotensin system in psoriatic patients. Acta Cardiol. 1985;40:199-205. 35. Mallbris L, Granath F, Hamsten A, et al. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol. 2006;54:614-621. 36. Akhyani M, Ehsani AH, Robati RM, et al. The lipid profile in psoriasis: a controlled study. J Eur Acad Dermatol Venereol. 2007; 21:1330-1332.

37. Han C, Robinson DW Jr, Hackett MV, et al. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33:2167-2172. 38. Tekin NS, Tekin IO, Barut F, et al. Accumulation of oxidized lowdensity lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm. 2007;2007:78454. Epub 2006 Dec 27. 39. Mallbris L, Ritchlin CT, Stahle M. Metabolic disorders in patients with psoriasis and psoriatic arthritis. Curr Rheumatol Rep. 2006;8: 355-363. 40. Adult Treatment Panel III. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary. National Institutes of Health. Bethesda, MD: National Heart, Lung, and Blood Institute; 2001:140. 41. Arnett DK, McGovern PG, Jacobs DR Jr, et al. Fifteen-year trends in cardiovascular risk factors (1980-1982 through 1995-1997): the Minnesota Heart Survey. Am J Epidemiol. 2002;156:929-935. 42. Ruan H, Miles PD, Ladd CM, et al. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes. 2002;51: 3176-3188. 43. Zuliani G, Volpato S, Ble A, et al. High interleukin-6 plasma levels are associated with low HDL-C levels in community-dwelling older adults: The InChianti study. Atherosclerosis. 2007;192:384-390. 44. Farshchian M, Zamanian A, Farshchian M, et al. Serum lipid level in Iranian patients with psoriasis. J Eur Acad Dermatol Venereol. 2007; 21:802-805. 45. Shapiro J, Cohen AD, David M, et al. The association between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a casecontrol study. J Am Acad Dermatol. 2007;56:629-634. 46. Cohen AD, Gilutz H, Henkin Y, et al. Psoriasis and the metabolic syndrome. Acta Derm Venereol. 2007;87:506-509. 47. Cohen AD, Dreiher J, Shapiro Y, et al. Psoriasis and diabetes: a population-based cross-sectional study. J Eur Acad Dermatol Venereol. 2008;22:585-589. 48. Cohen AD, Sherf M, Vidavsky L, et al. Association between psoriasis and the metabolic syndrome. A cross-sectional study. Dermatology. 2008;216:152-155. 49. Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988;318:1217-1225. 50. Ucak S, Ekmekci TR, Basat O, et al. Comparison of various insulin sensitivity indices in psoriatic patients and their relationship with type of psoriasis. J Eur Acad Dermatol Venereol. 2006;20:517-522. 51. Reynoso-von Drateln C, Martinez-Abundis E, Balcazar-Munoz BR, et al. Lipid profile, insulin secretion, and insulin sensitivity in psoriasis. J Am Acad Dermatol. 2003;48:882-885. 52. Herron MD, Hinckley M, Hoffman MS, et al. Impact of obesity and smoking on psoriasis presentation and management. Arch Dermatol. 2005;141:1527-1534. 53. Naldi L, Chatenoud L, Linder D, et al. Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol. 2005;125:61-67. 54. Huerta C, Rivero E, Rodriguez LA. Incidence and risk factors for psoriasis in the general population. Arch Dermatol. 2007;143:15591565. 55. Setty AR, Curhan G, Choi HK. Obesity, waist circumference, weight change, and the risk of psoriasis in women: Nurses’ Health Study II. Arch Intern Med. 2007;167:1670-1675. 56. Jiang J, Torok N. Nonalcoholic steatohepatitis and the metabolic syndrome. Metab Syndr Relat Disord. 2008;6:1-7. 57. McDonald CJ, Calabresi P. Psoriasis and occlusive vascular disease. Br J Dermatol. 1978;99:469-475. 58. Pearce DJ, Morrison AE, Higgins KB, et al. The comorbid state of psoriasis patients in a university dermatology practice. J Dermatolog Treat. 2005;16:319-323.

Gottlieb and Dann

Psoriasis Comorbidities

59. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685-1695. 60. Chodorowska G, Wojnowska D, Juszkiewicz-Borowiec M. C-reactive protein and alpha2-macroglobulin plasma activity in mediumsevere and severe psoriasis. J Eur Acad Dermatol Venereol. 2004; 18:180-183. 61. Nielsen HJ, Christensen IJ, Svendsen MN, et al. Elevated plasma levels of vascular endothelial growth factor and plasminogen activator inhibitor-1 decrease during improvement of psoriasis. Inflamm Res. 2002;51:563-567. 62. Vanizor Kural B, Orem A, Cimsit G, et al. Evaluation of the atherogenic tendency of lipids and lipoprotein content and their relationships with oxidant-antioxidant system in patients with psoriasis. Clin Chim Acta. 2003;328:71-82. 63. Vanizor Kural B, Orem A, Cimsit G, et al. Plasma homocysteine and its relationships with atherothrombotic markers in psoriatic patients. Clin Chim Acta. 2003;332:23-30. 64. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326-333. 65. Strober B, Teller C, Yamauchi P, et al. Effects of etanercept on C-reactive protein levels in psoriasis and psoriatic arthritis. Br J Dermatol. 2008;159:322-330. 66. Glynn RJ, MacFadyen JG, Ridker PM. Tracking of high-sensitivity C-reactive protein after an initially elevated concentration: the JUPITER Study. Clin Chem. 2009;55:305-312. 67. Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol. 2007;156:271-276. 68. Kimhi O, Caspi D, Bornstein NM, et al. Prevalence and risk factors of atherosclerosis in patients with psoriatic arthritis. Semin Arthritis Rheum. 2007;36:203-209. 69. Dreiher J, Weitzman D, Shapiro J, et al. Psoriasis and chronic obstructive pulmonary disease: a case-control study. Br J Dermatol. 2008;159:956-960. 70. Gelfand JM, Azfar R, Shin D, et al. Incidence of stroke in patients with psoriasis: a population-based study. J Invest Dermatol. 2008; 128:81. 71. Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis. Br J Dermatol. 2008;159:895-902. 72. Margolis D, Bilker W, Hennessy S, et al. The risk of malignancy associated with psoriasis. Arch Dermatol. 2001;137:778-783. 73. Gelfand JM, Shin DB, Neimann AL, et al. The risk of lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126:2194-2201. 74. Baecklund E, Askling J, Rosenquist R, et al. Rheumatoid arthritis and malignant lymphomas. Curr Opin Rheumatol. 2004;16:254-261. 75. Jeffes EW 3rd, Lee GC, Said S, et al. Elevated numbers of proliferating mononuclear cells in the peripheral blood of psoriatic patients correlate with disease severity. J Invest Dermatol. 1995;105:733-738. 76. Mahmoud F, Abul H, al Saleh Q, et al. Elevated B-lymphocyte levels in lesional tissue of non-arthritic psoriasis. J Dermatol. 1999;26:428433. 77. Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis. 2005;64:ii30-ii36. 78. Boffetta P, Gridley G, Lindelof B. Cancer risk in a population-based cohort of patients hospitalized for psoriasis in Sweden. J Invest Dermatol. 2001;117:1531-1537. 79. Olsen JH, Moller H, Frentz G. Malignant tumors in patients with psoriasis. J Am Acad Dermatol. 1992;27:716-722. 80. Frentz G, Olsen JH. Malignant tumours and psoriasis: a follow-up study. Br J Dermatol. 1999;140:237-242. 81. Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen⫹ultraviolet A: a cohort study. J Invest Dermatol. 2003;121:252-258.

1150.e9 82. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol. 1999;141:108-112. 83. Behnam SM, Behnam SE, Koo JY. Review of cyclosporine immunosuppressive safety data in dermatology patients after two decades of use. J Drugs Dermatol. 2005;4:189-194. 84. Prodanovich S, Ma F, Taylor JR, et al. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262-267. 85. Choi HK, Hernan MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173-1177. 86. Jacobsson LT, Turesson C, Gulfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32:1213-1218. 87. Naranjo A, Sokka T, Descalzo MA, et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis Res Ther. 2008;10:R30. 88. Georgiadis AN, Voulgari PV, Argyropoulou MI, et al. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum. 2008;38:13-19. 89. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA follow-up study. N Engl J Med. 1997;336:1041-1045. 90. Paul CF, Ho VC, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol. 2003;120:211-216. 91. Franklin J, Lunt M, Bunn D, et al. Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis. Ann Rheum Dis. 2006;65:617-622. 92. Ganguly S. Leukemic phase of follicular lymphoma after treatment with etanercept in a patient with psoriasis. Am J Clin Dermatol. 2009;10:125-126. 93. Hurley MY, George MN, Leonardi CL, et al. A transient benign lymph node-based proliferation of T-cells simulating non-Hodgkin lymphoma in a patient with psoriasis treated with tumor necrosis factor alpha and CD11a antagonists. Diagn Pathol. 2008;3:13. 94. Scheinfeld N. Efalizumab: a review of events reported during clinical trials and side effects. Expert Opin Drug Saf. 2006;5:197-209. 95. Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol. 1999;41:S7-S12. 96. Tilling L, Townsend S, David J. Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. Clin Drug Investig. 2006; 26:55-62. 97. Lindsay K, Gough A. Psoriatic arthritis, methotrexate and the liver— are rheumatologists putting their patients at risk? Rheumatology (Oxford). 2008;47:939-941. 98. Kimball AB, Gladman D, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol. 2008;58:1031-1042. 99. Screening for skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:188-193. 100. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851-864. 101. Boehncke S, Thaci D, Beschmann H, et al. Psoriasis patients show signs of insulin resistance. Br J Dermatol. 2007;157:1249-1251. 102. Cohen AD, Gilutz H, Henkin Y, et al. Psoriasis and the metabolic syndrome. Acta Derm Venereol. 2007;87:506-509. 103. Cohen AD, Dreiher J, Shapiro Y, et al. Psoriasis and diabetes: a population-based cross-sectional study. J Eur Acad Dermatol Venereol. 2008;22:585-589. 104. Gisondi P, Tessari G, Conti A, et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol. 2007;157:68-73.