Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]-Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT):  A Pilot Study FREE

Psoriasis is a chronic inflammatory disease affecting 2% to 3% of the adult population.^1- 2 It is associated with an inflammatory arthritis (psoriatic arthritis) in about 10% of patients, with much higher frequencies in patients with more extensive skin disease.³ Psoriasis is also associated with increases in markers of inflammation in the skin and blood and increasingly is thought to be a systemic inflammatory disease and risk factor for incident diabetes mellitus, myocardial infarction, stroke, and premature cardiovascular (CV) death.^4- 18 The mechanism behind these associated comorbidities, however, remains unknown. It has been widely suggested that a possible common pathway linking psoriasis to metabolic and CV disease is chronic inflammation mediated by T_H17 and T_H1 cells.^19- 23 Yet, despite evidence of systemic inflammation in psoriasis, few techniques have been successfully used to identify and quantify locations of inflammation in vivo in these patients. Because traditional markers of systemic inflammation, such as high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate, only modestly correlate with psoriasis severity and do not provide regional information about disease involvement, novel assessments of inflammation in vivo are particularly important in understanding the impact of psoriasis on systemic inflammation and systemic comorbidities.²⁴

The development of [18F]-fluorodeoxyglucose positron emission tomography –computed tomography (FDG-PET/CT), a validated technique used extensively in cancer and neuroimaging, enables highly precise, novel measurements of inflammatory activity, including vascular, visceral, and whole-body inflammation in vivo.²⁵ Previous studies using animal models and immunohistochemical analysis in humans indicate that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity, an important source of cellular inflammation in numerous tissues, including early stages of atherosclerosis in vessel walls.^26- 30 The high sensitivity of FDG-PET/CT to detect early, subclinical inflammation with minimal error from operator dependence, demonstrated in studies of vasculitis,^29- 30 atherosclerosis,^31- 34 and joint disease,^35- 37 has expanded its use as a novel investigative tool to detect regional inflammatory disease. Importantly, observational studies indicate that aortic and carotid inflammation measured by FDG-PET/CT are strong predictors of future major vascular events.^34,38- 39 Furthermore, randomized controlled trials demonstrate that statin and therapeutic lifestyle interventions improve vascular inflammation as measured by FDG-PET/CT within 12 weeks and 16 months, respectively.^40- 41

FDG-PET/CT therefore represents an innovative approach to studying systemic inflammation in a manner that is sensitive, quantifiable, and anatomically localizable. Furthermore, inflammation detected by FDG-PET/CT has been shown to be responsive to modulation by anti-inflammatory medical treatments and predictive of future vascular events. Such a tool could therefore be valuable in further defining systemic inflammation in patients with psoriasis. We therefore conducted a proof-of-principle study to describe FDG tracer uptake consistent with inflammation in the skin, liver, blood vessels, and joints in a series of patients with moderate to severe psoriasis. The second part of the pilot study attempted to determine if FDG-PET/CT can discriminate systemic inflammation in a subset of our patients with psoriasis compared with healthy controls using a nested case-control design.

We conducted a proof-of-principle study (in  6 patients) evaluating the role of FDG-PET/CT in psoriasis to detect sites of inflammation. This study enrolled patients 18 to 70 years old with psoriasis involving a body surface area (BSA) greater than 10%. Because this study was designed to demonstrate the feasibility of applying FDG-PET/CT to this novel population, we allowed inclusion of treated patients with psoriasis to ensure a broad range of patients and improve the generalizability of our experience. Therefore, patients with psoriasis undergoing active light therapy, topical therapy, or being treated with stable doses (not changed within 12 weeks of study enrollment) of oral systemic medications (eg, methotrexate) or biologic agents were eligible. We excluded individuals with diabetes mellitus, tobacco use, history of CV disease, uncontrolled hypertension (defined as systolic blood pressure >180 mm Hg or diastolic blood pressure >95 mm Hg), warfarin sodium use, coagulopathy, pregnancy or lactation, regular use of alcoholic beverages (>2 drinks per day), nonskin malignant disease within 5 years, positive status for human immunodeficiency virus, major surgery within 3 months of imaging, history of intravenous drug use within the past year, research drug study participation in the 6 weeks prior to imaging, or active infection within preceding 72 hours or other serious medical or psychiatric conditions.

We then conducted a substudy to evaluate the ability of this modality to discriminate inflammation with high sensitivity by comparing patients with psoriasis from our case series with healthy controls matched based on age, sex, and a restricted body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, lower than 30. Of the 6 patients with psoriasis in our case series, 2 were excluded from this analysis: 1 had an existing diagnosis of psoriatic arthritis (a known cause of systemic inflammation), and the second had a BMI of 35.7 (obesity is associated with systemic inflammation). The substudy focused on quantification of subclinical vascular inflammation and hepatic inflammation in both groups to test the hypothesis that psoriasis is associated with increased inflammation in vivo compared with controls. To compare vascular inflammation assessed by FDG-PET/CT, we matched patients with psoriasis by age and sex to 3 prospectively recruited controls and a single historical control from another FDG-PET/CT study at our institution. The inclusion and exclusion criteria for controls were similar to those for our patients with psoriasis, except that controls were excluded if they had known chronic inflammatory diseases. All 4 patients with psoriasis included in this analysis would have otherwise qualified as healthy controls (if they did not have psoriasis) based on the criteria used.

All patients underwent a whole-body FDG-PET/CT scan using the standard protocol described herein. Patients fasted for 8 hours prior to the FDG-PET/CT scan. Fasting serum glucose levels were checked by fingerstick to assure glucose levels lower than 150 mg/dL prior to FDG administration. (To convert glucose to millimoles per liter, multiply by 0.0555.) Whole-body PET/CT image acquisition (Gemini TF; Philips Medical Systems, Bothell, Washington) commenced  approximately  60 minutes after intravenous administration of 140 μCi/kg FDG. Axial, sagittal, and coronal PET reconstructions were interpreted with and without attenuation correction using noncontrast CT images for attenuation correction and anatomical correlation of FDG uptake. After qualitative review of PET and CT images, 2-dimensional (2D) circular regions of interests (ROIs) were manually placed on PET images around the external aortic contour, around the hepatic margin, and around articular spaces on all transverse slices passing through these structures using low-dose CT images for anatomic guidance. Mean standardized uptake values (SUVs) and areas of each ROI were measured for each slice using dedicated PET/CT image analysis software that autocalculates the SUV per slice within the specified ROI (Extended Brilliance Workstation; Philips Healthcare, Bothell, Washington). The total numbers of slices differ slightly from patient to patient depending on body habitus and anatomical variation, but these differences do not alter interpretation of regional data.³³ Details of this method have been published previously by our group and have been validated for the quantification of atherosclerosis, hepatic, and joint inflammation.^{33,37,42- 45}

In our case series of 6 patients with psoriasis, our primary outcomes were defined as any finding on FDG-PET/CT consistent with inflammation, measured by SUV, the unit for FDG uptake, in the vasculature, viscera, and musculoskeletal system. Vascular SUVs were compared descriptively with expected norms based on age and sex from published literature.³¹ In the nested case-control substudy, our primary outcome was aortic mean SUV, defined as the average of all mean SUVs recorded from sequential 2D ROIs in the aorta. The mean aortic SUV was calculated for 5 segments of the aorta: ascending aorta, aortic arch, descending thoracic aorta, suprarenal abdominal aorta, and infrarenal abdominal aorta. These segments were defined to consider separately various regions of aortic disease that are associated with different clinical phenotypes (eg, aortic arch disease with stroke, abdominal aortic disease with abdominal aortic aneurysm). As a secondary analysis, we also examined hepatic SUV in psoriasis and controls. Unadjusted analyses were performed using 2-sided t tests and Mann-Whitney tests for continuous data and Fisher exact tests for dichotomous data. Linear regression was performed to adjust for known CV risk factors (age, sex, hypertension, low-density lipoprotein cholesterol [LDL-C] level, and BMI), with mean SUV as the outcome. Hypertension in our models was adjusted as a dichotomous variable; all other variables were continuous. To study the effect of psoriasis on hepatic inflammation, we adjusted for CV risk factors, including BMI, and further adjusted analysis for alcohol use in the multivariate regression model. Finally, to accommodate within-patient correlation of SUV, we performed random effects regression models. Given that we did not observe any difference in estimates for psoriasis, we present the β-coefficient from the linear regression models. All analyses were performed with Stata 11 statistical software (StataCorp, College Station, Texas). The study was approved by the institutional review board at the University of Pennsylvania, Philadelphia, and complies with the Declaration of Helsinki. Written informed consent was obtained from all study participants.

The characteristics and measurements of FDG uptake in the vasculature, liver, and musculoskeletal structures of all 6 patients with psoriasis in the case series are shown in Table 1. Patients with psoriasis had the disease for a median of 14 years (interquartile range [IQR], 3-24) and had a median BSA of 14% (IQR, 11%-19%), median physician's global assessment of 2.5 (IQR, 2.0-2.7) and median Psoriasis Area Severity Index of 9.9 (IQR, 7.2-12.1) (Table 1). Current psoriasis therapies (within 3 months) included topical steroids (in 4 patients), combination treatment with methotrexate and abatacept (in 1 patient), and narrowband phototherapy (in 1 patient). Thus, 5 patients were not receiving systemic treatment or phototherapy at the time of the study. One patient (ie, the individual treated with methotrexate-abatacept) had a diagnosis of psoriatic arthritis established by rheumatologic testing that was clinically symptomatic, and another patient had a history of anterior cruciate ligament repair 12 months prior to the study and was asymptomatic. The remaining patients had no history of joint disease or joint symptoms. The CV risk factors are noted in Table 1, with 3 patients having diagnosed hyperlipidemia while prescribed statins and 1 having hypertension while prescribed a single agent.

Whole-body FDG-PET/CT imaging revealed areas of systemic inflammation, including vascular, articular, periarticular, visceral, and skin territories, in patients with psoriasis. Focal areas of inflammation in the skin observed clinically as areas of plaque psoriasis corresponded to areas of skin inflammation observed on FDG-PET/CT (Figure 1). In addition, among the 5 patients without diagnosis or symptoms of psoriatic arthritis, vascular inflammation in all 5 aortic segments was increased compared with age-adjusted normal values (1.0-1.2 SUVs corrected for the scanner used).^32- 33 FDG-PET/CT imaging of the liver also demonstrated increased metabolic activity, likely indicative of increased hepatic inflammation. In addition, both clinical and subclinical joint inflammation were detected in the sample (Table 1). Of note, 1 patient without psoriatic arthritis, joint symptoms, or previous joint surgery demonstrated focal areas of FDG uptake on FDG-PET/CT in various tendons, entheses, and joint spaces, particularly in the knees (with maximum SUVs of 3.0 on the right and 2.2 on the left), consistent with inflammatory arthritis.³⁷ Similar findings of tendon, entheses, and joint inflammation were demonstrated on FDG-PET/CT for the patient with clinical psoriatic arthritis (Table 1).

We next matched controls to 4 patients from our psoriasis sample by age and sex. Patients in the substudy were restricted to those with a BMI lower than 30. The characteristics of this nested case-control study are shown in Table 2. The 4 patients with psoriasis (3 were male [75%]; mean age, 50 years [range, 43-57 years]) had similar, low-risk CV profiles compared with the 4 controls (3 were male [75%], mean age, 49 years [range, 43-52 years]) (Table 2). Both patients with psoriasis and controls also had a median BMI in the overweight category (26.9 [range, 21.5-29.5] vs 29.7 [28.5-29.9], respectively). We show an image from the PET component of a FDG-PET/CT study in a patient with psoriasis and an image from a control patient as an example of how the difference in inflammation detected between these 2 patients is visualized using FDG-PET/CT (Figure 2).

From these patients, we analyzed a total of 386 slices of the aorta in patients with psoriasis and compared them with 317 slices of the aorta in controls. We also performed quantitative analysis of the liver using 161 slices for patients with psoriasis and compared them with 154 slices for controls. FDG-PET/CT imaging detected greater inflammation in the aorta in patients with psoriasis compared with controls (P   <  .001). After stratifying analysis to specific segments of the aorta, we report that the SUVs within each aortic segment were notably higher in patients with psoriasis compared with controls (Table 3). In multivariable regression, psoriasis remained highly associated with SUV in each aortic segment after adjusting for traditional CV factors and BMI compared with controls, and we show the β coefficient for psoriasis in the multivariate model (Table 4). Finally, compared with controls, patients with psoriasis demonstrated increased hepatic inflammation in multivariate analysis adjusting for known confounders and risk factors for liver disease, including age, sex, plasma triglycerides level, and BMI ( β  =  0.18; P   <  .001). However, when the model was further adjusted for alcohol use ( β  =  0.76; P   <  .001), the relationship between hepatic inflammation and psoriasis was no longer significant ( β  =   −0.25; P  =  .07).

To our knowledge, this is the first description of in vivo whole-body inflammation in psoriasis detected by FDG-PET/CT simultaneously in 3 tissues: viscera, vasculature, and musculoskeletal structures. We demonstrate that FDG-PET/CT, a technique validated to assess vascular inflammation, can be used in patients with psoriasis to visualize and quantify anatomic regions of inflammation.^{33,42- 44,46- 47} In our case series, FDG-PET/CT detected numerous areas of inflammation in patients with psoriasis, including increased inflammation in the blood vessels, in the liver, in articular and periarticular structures, and in the skin. Interestingly, all of these findings occurred in patients with psoriasis who otherwise felt well (only 1 patient who had an established diagnosis of psoriatic arthritis had joint symptoms) and had no clinically significant abnormalities in their laboratory data, except for 1 patient (patient 6) who had an elevated hsCRP level of 8.4 mg/L. (To convert hsCRP to nanomoles per liter, multiply by 9.524.) These foci of inflammatory activity were observed with levels of inflammation far exceeding the reference range for joint, liver, and vascular inflammation despite a lack of evidence of clinical disease.⁴⁵

In our nested case-control study, FDG-PET/CT imaging revealed vascular inflammation more severe than in age- and sex-matched controls. The corresponding magnitude of SUV difference observed between patients with psoriasis and controls (0.20) in multiple segments of the aorta is equivalent to the magnitude of vascular inflammation observed over 2 additional decades of aging.³³ Furthermore, FDG-PET/CT imaging of patients with psoriasis demonstrated high-risk findings,^48- 49 including diffusely increased vascular inflammation in each segment of the aorta that remained significant after adjusting for traditional CV risk factors and BMI. We also observed that psoriasis was associated with increased hepatic inflammation in multivariate analysis adjusting for confounders and risk factors for liver disease, including plasma triglycerides level and BMI. This relationship, however, was no longer significant when adjusted for alcohol intake, suggesting that either patients underreported their alcohol use, because inclusion in the study permitted only light drinking ( <2 drinks per day), or that patients with psoriasis may be more susceptible to liver dysfunction in the face of alcohol use. Despite this observation, this degree of hepatic inflammation is similar to that seen in patients with hepatic steatosis or chronic active hepatitis.⁴³ This finding warrants careful follow-up and further study and may present a compelling opportunity to explore the concept of the “psoriatic liver. ” Finally, our observations of musculoskeletal inflammation are consistent with those of previous studies using conventional imaging techniques to demonstrate findings consistent with psoriatic arthritis, such as articular inflammation and enthesitis in patients with psoriasis.^50- 52 In particular, the diffuse distribution of subclinical articular and periarticular involvement observed on imaging suggests that FDG-PET/CT may be a more feasible approach for detecting subclinical psoriatic arthritis than traditional imaging modalities such as ultrasonography or magnetic resonance imaging.

The findings of excess vascular, hepatic, musculoskeletal, and cutaneous inflammation on FDG-PET/CT are novel and suggest the potential of FDG-PET/CT technology to investigate systemic inflammation. The underlying inflammation linking chronic inflammatory disease states, such as atherosclerosis, metabolic syndrome, diabetes mellitus, and psoriatic arthritis, with psoriasis is captured in vivo by FDG-PET/CT, thereby providing a measureable phenotype (ie, biomarker) in a dynamic disease such as psoriasis. In this study, we demonstrate this novel application of FDG-PET/CT, which has exquisite sensitivity for detecting picomolar to nanomolar concentrations of glucose uptake with inflammatory cells. We further report a systematic approach to image analysis that can be used in future studies to regionally and globally quantify inflammation in the aorta, liver, and joints.

We note, however, that the findings we report are based on a pilot study that has important limitations, and thus additional studies are necessary to confirm and extend our findings. First, the small sample size and referral-based source of our patients may affect the generalizability of our results. However, our study is comparable in size and design with other landmark studies using FDG-PET/CT in inflammatory disease states.^27,53- 54 We also note that use of FDG-PET/CT is limited by the need for sophisticated hardware and software that may not be widely available, the need for patients to be willing to fast for 8 hours, and radiation exposure similar to that of a standard contrast-enhanced CT scan. As a result, patients may need to be highly motivated to enter studies using FDG-PET/CT, which may lead to particular challenges in recruiting healthy controls. In addition, in this pilot study patients were not required to undergo washout of topical or UV light treatments, and systemic treatments were permissible as long as the dose had been stable for 3 months. Thus, additional studies in patients with psoriasis who are treatment na ïve or have washouts of psoriasis therapies will be necessary to further interpret our findings. Furthermore, the nested case-control study is subject to error introduced by selection bias and confounding. For example, it is possible that one group could have been more health conscious than the other (ie, through selection bias), although the laboratory and anthropometric data do not support this possibility as a potential source of error. We carefully adjusted for confounding variables for which we had detailed data; however, incomplete measurement of confounders, such as diet and exercise, could affect our measurement of association. In addition, while our study attempted to adjust for LDL-C and hypertension, it is possible that incomplete adjustment for these confounders still exist, and we did not have LDL-C data for 1 of the controls. Finally, 3 patients with psoriasis in the case series and 1 patient with psoriasis in the nested case-control study were receiving active statin therapy. While statins may interfere with vascular inflammation, we would expect that they attenuate vascular inflammation, as demonstrated in a previously published clinical trial using FDG-PET/CT,⁴⁰ and therefore would bias our results toward the null. In addition, we note that none of the study participants had existing CV disease, and most CV risk prediction tools, such as the Framingham Risk Score, use current blood pressure and LDL-C measurements to assess CV risk without regard to medication usage because biometric data are more significantly correlated with CV outcomes.⁴⁹

In this study, we demonstrate that FDG-PET/CT represents a powerful molecular imaging modality to assess whole-body inflammation in association with psoriasis. Further studies are needed to (1) confirm and extend our results of increased vascular and hepatic inflammation in a larger series of patients, carefully selecting cases and controls and measuring confounding variables to determine if increased inflammation measured by FGD-PET/CT is due to psoriasis, its treatments, or other associated factors; (2) understand how to relate these findings to clinical prognosis; and (3) assess the effect of psoriasis treatment on the inflammation observed in various tissues.