Comorbidities associated with psoriatic arthritis: Review and update

Clinical Immunology 214 (2020) 108397

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Clinical Immunology journal homepage: www.elsevier.com/locate/yclim

Review Article

Comorbidities associated with psoriatic arthritis: Review and update a

Lourdes M. Perez-Chada , Joseph F. Merola a b

a,b,⁎

T

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Medicine, Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Psoriatic arthritis Comorbidity Screening Management

Psoriatic arthritis is an inflammatory arthropathy frequently associated with psoriasis and several other comorbidities. The goal of this review is to summarize the available evidence on the epidemiology, clinical implications, pathological mechanisms proposed, and screening and management recommendations for the comorbidities related with PsA. Reported comorbidities include cardiovascular disease, metabolic syndrome, obesity, diabetes mellitus, dyslipidemia, inflammatory bowel disease, fatty liver disease, uveitis, kidney disease, infections, osteoporosis, depression, central sensitization syndrome, and gout. Given that these comorbidities may affect both clinical outcomes and the management for these patients, their recognition and monitoring by all health-care providers caring for patients with psoriatic arthritis is of utmost importance.

1. Introduction

2. Cardiovascular disease

Psoriatic arthritis (PsA) is a chronic, inflammatory arthritis associated with psoriasis. Beyond the joint and skin manifestations, most patients with PsA have more than one comorbid condition such as cardiometabolic disease, inflammatory bowel disease, uveitis, infections, malignancy and fibromyalgia [1]. The recognition and appropriate management of comorbidities in patients with PsA is critical as these may affect patient outcomes. For example, patients with PsA and concomitant fibromyalgia present higher mean tender points and enthesitis scores [2] as well as higher burden of disease in patient-reported outcome measures than patients without fibromyalgia [3]. Comorbidities may also influence treatment choices for PsA. For example, tumor necrosis factor (TNF) inhibitors are not recommended in patients with history of frequent infections [4]. Herein, we present and discuss the evidence related to the most common comorbidities associated with PsA.

2.1. Epidemiology and clinical implications Cardiovascular disease is the leading cause of death among psoriatic patients [5]. While clinic-based studies suggest that patients with PsA have a higher risk of mortality than the general population [6–8], one large population-based study and others suggest no increased risk of mortality among patients with PsA [9,10]. Compared to the general population, patients with PsA have a 43% increased risk of developing a prevalent cardiovascular event, and a 55% increased risk of developing an incident cardiovascular event. In particular, the risk of myocardial infarction (MI), cerebrovascular diseases, and heart failure, is 68%, 22% and 31% higher, respectively [11]. In psoriasis, the risk of MI, coronary artery disease, stroke and cardiovascular mortality is highest among patients with severe disease, psoriasis of early onset and younger patients (aged < 40 years) [12]. 2.2. Predictors of cardiovascular disease Psoriatic disease is strongly associated with traditional risk factors of cardiovascular disease in the general population such as obesity,

Abbreviations: Psoriatic arthritis, (PsA); Tumor necrosis factor, (TNF); Myocardial infarction, (MI); Erythrocyte sedimentation rate, (ESR); Nonsteroidal antiinflammatory drugs, (NSAID); Interleukin, (IL); American College of Cardiology/American Heart Association, (ACC/AHA); Body Mass Index, (BMI); Framingham risk score, (FRS); European League Against Rheumatism, (EULAR); Disease modifying anti-rheumatic drugs, (DMARD); Vascular Inflammation in Psoriasis, (VIP); Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, (GRAPPA); Minimal disease activity, (MDA); American College of Rheumatology/National Psoriasis Foundation, (ACR/NPF); Oral small molecules, (OSM); Ankylosing spondylitis, (AS); Inflammatory bowel disease, (IBD); Human leukocyte antigen, (HLA); Nonmelanoma skin cancer, (NMSC); Nonalcoholic fatty liver disease, (NALFD) ⁎ Corresponding author at: Department of Dermatology, Brigham and Women's Hospital, 221 Longwood Avenue Boston, MA 02115, USA. E-mail address: [email protected] (J.F. Merola). https://doi.org/10.1016/j.clim.2020.108397 Received 13 March 2020; Accepted 25 March 2020 Available online 27 March 2020 1521-6616/ © 2020 Published by Elsevier Inc.

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3. Cardiovascular risk factors: insulin resistance, diabetes mellitus, dyslipidemia, obesity, hypertension, metabolic syndrome

dyslipidemia, glucose intolerance and hypertension [13,14]. In addition, the extent of inflammatory burden, as measured by erythrocyte sedimentation rate (ESR) among women (RR 1.83, p = .02), and disease activity, as measured by the number of dactylitic digits (RR 1.20, p < .001), have been identified as independent predictors of cardiovascular risk in PsA [15]. Importantly, two European claims-based cohort studies described the severity of psoriasis as a predictor of cardiovascular events in psoriatic disease [12,16]. A small prospective study further suggested that serum uric acid concentration correlates with subclinical atherosclerosis evaluated by carotid intima-media wall thickness in PsA patients without clinically evident cardiovascular disease [17]. Nonsteroidal anti-inflammatory drugs (NSAID) have also been suggested as predictors of cardiovascular disease in these patients [18].

3.1. Epidemiology and clinical implications Patients with PsA present a high prevalence of insulin resistance (16%), and this association is independent of severe psoriasis, metabolic syndrome and other confounders [35]. The increased cardiovascular morbidity associated with psoriatic disease can be partly explained by endothelial cell dysfunction associated with insulin resistance. Indeed, endothelial cell dysfunction may lead to atherosclerosis and the onset of cardiovascular events such as stroke or myocardial infarction [36]. Patients with PsA also present a higher prevalence and incidence of diabetes, probably due to unhealthy lifestyles, insulin resistance associated with PsA inflammation [37–39], and common genetic loci for susceptibility to psoriasis and diabetes [40]. Similarly, PsA patients present a higher prevalence of dyslipidemia and obesity compared to controls [41–44]. Lower serum levels of highdensity lipoprotein (HDL)-cholesterol and higher serum levels of triglycerides constitute the main lipid abnormalities identified [44]. These abnormalities were more prevalent among patients with active psoriatic disease, suggesting a potential relationship between the degree of inflammation and the lipid profile [45]. The prevalence of metabolic syndrome in patients with PsA ranges from 23.5% to 58.1%, and these rates are higher than those reported for the general population and even patients with RA [41,42,44–46]. Compared to patients with psoriatic disease and no metabolic syndrome, patients with PsA and metabolic syndrome present a higher overall maximum carotid artery intima-media thickness and prevalence of carotid plaques, reflecting the increasing burden of inflammation in PsA [19,20]. In addition, PsA severity is associated with metabolic syndrome independent of insulin resistance, severity of skin psoriasis, and other confounders [35]. PsA disease activity may be negatively affected by obesity and metabolic syndrome. Indeed, these are risk factors for not achieving minimal disease activity (MDA) [47,48]. Likewise, higher BMI is associated with reduced treatment response in RA, PsA, and PsO.

2.3. PsA versus psoriasis cardiovascular risk PsA seems to be associated with an increased cardiovascular risk than patients with psoriasis alone. Cross-sectional studies have shown that patients with PsA have a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08–2.95], P = .025) than patients with psoriasis. In addition, the thickness of carotid intima-media as measured by ultrasound was greater among patients with PsA, independent of traditional cardiovascular risk factors. This difference correlated with PsA disease duration, more severe skin disease and increased inflammatory markers [19,20]. These findings along with the results from other prospective cohort studies [12,16,21,22] suggest that the extent of inflammation in psoriatic disease correlates with the severity of vascular abnormalities. 2.4. Pathological mechanisms proposed Psoriatic disease is a chronic inflammatory condition in which both the innate and adaptive immune systems are affected, leading to a proinflammatory state. Inflammation is the key mediator that initiates and accelerates the progression of atherosclerosis, the main cause of cardiovascular diseases (Fig. 1) [23]. High serum levels of pro-inflammatory cytokines released in psoriatic disease such as interleukin (IL)-17, interferon-alpha and TNF promote vasoconstriction and endothelial dysfunction, which may lead to plaque formation [24,25].

3.2. Pathological mechanisms proposed The development of metabolic syndrome is mainly driven by the chronic ‘low-grade’ inflammatory state of psoriatic disease (Fig. 1) [49]. Psoriatic disease, obesity, type 2 diabetes and insulin resistance share common pro-inflammatory cytokines and signaling pathways. In particular, TNF is overexpressed in the adipose tissue that links obesity, diabetes and chronic inflammation [49]. In addition, obesity promotes expansion of Th17 cells in adipose tissue and peripheral tissues [50].

2.5. Screening and management recommendations As recommended by the 2019 American College of Cardiology/ American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease screening should focus on the measurement of blood pressure (seated), Body Mass Index (BMI), fasting glucose, and cholesterol [26]. Cardiovascular risk estimation is also recommended. However, physicians should be aware that scores such as the Framingham risk score (FRS) often underestimate the risk for cardiovascular events given that they do not account for the effect of systemic inflammation secondary to psoriatic disease. For this reason, the ACC/AHA guideline includes psoriasis as a “risk enhancer” to revise the 10-year atherosclerotic cardiovascular disease risk and initiate or intensify statin therapy accordingly [26]. The excess cardiovascular risk conferred by psoriatic disease was estimated to be 6.2% in one cohort study [27]. Mehta and colleagues subsequently suggested adding a 6.2% to the baseline FRS of patients with psoriasis [28]. Recommendations for the screening and management of cardiovascular disease in patients with PsA and other inflammatory joint disorders have also been recently provided by the European League Against Rheumatism (EULAR) [29]. Importantly, EULAR recommends maintaining a low psoriatic disease activity to minimize cardiovascular risk and to follow cardiovascular disease treatment guidelines developed for the general population [29]. (Table 1).

3.3. Screening and management recommendations Screening and management recommendations should be in accordance with national guidelines for the general population. The Canadian Dermatology-Rheumatology Comorbidity Initiative recommends healthcare providers to promote a healthy BMI, since higher BMI is associated with reduced treatment response in RA, PsA, and PsO [51]. The 2018 American College of Rheumatology (ACR)/National Psoriasis Foundation (NPF) Guideline for the Treatment of Psoriatic Arthritis provides specific recommendations for the management of patients with concomitant diabetes. For patients with active PsA and concomitant diabetes who are naïve to oral small molecules (OSM; including methotrexate, sulfasalazine, cyclosporine, leflunomide, apremilast) or biologic treatment, an OSM other than methotrexate is recommended over a TNF inhibitor given that this patient population 2

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Fig. 1. Association between psoriatic disease, its comorbidities, inflammation and cardiovascular disease. Footnote: Psoriatic disease and its associated comorbidities (metabolic syndrome, hypertension, insulin resistance, obesity and dyslipidemia) favor the onset of a chronic low-grade inflammatory state. In turn, inflammation is the key mediator that initiates and accelerates the progression of atherosclerosis and subsequent cardiac events. CVD, cardiovascular disease; hsCRP, high sensitivity C-reactive protein; IL, interleukin; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; ICAM, intracellular adhesion molecule.

it is not disease-specific, fecal calprotectin test, a functional quantitative measure of intestinal inflammation, may also be considered [61]. The 2018 ACR/NPF guidelines provides specific recommendations for the management of patients with concomitant IBD. For patients with active PsA and concomitant active IBD who are OSM- and biologic–naïve, monoclonal TNF inhibitors are recommended over OSM. For patients with active PsA and concomitant active IBD that are already receiving an OSM, monoclonal TNF inhibitors are preferred over soluble TNF inhibitors (etanercept is not recommended as it was not approved for IBD due to lack of efficacy) [62]. Monoclonal TNF inhibitors are also preferred over IL17 and IL12/23 inhibitors. In patients who have contraindications to TNF inhibitors, IL12/23 inhibitors are favored over anti-IL17 agents (secukinumab, ixekizumab and brodalumab) given that they have been associated with IBD exacerbation [63]. However, this association remains controversial. A recent pooled analysis of 21 clinical trials concluded that IBD was uncommon among patients with psoriatic disease and ankylosing spondylitis (AS) treated with secukinumab [64]. The use of NSAIDs in IBD may also exacerbate IBD symptoms; thus, their use should be avoided or patients should be monitored carefully [65]. (Table 1).

has a higher prevalence of fatty liver disease and liver toxicity with MTX use [4]. GRAPPA recommends physicians should be cautious about prescribing glucocorticoids to patients with metabolic syndrome and diabetes, and methotrexate to patients with obesity, metabolic syndrome and diabetes [34]. (Table 1). 4. Inflammatory bowel disease 4.1. Epidemiology and clinical implications The association between psoriatic disease and inflammatory bowel disease (IBD) is relative understudied. Patients with psoriasis and PsA present a higher prevalence of subclinical bowel inflammation [52] and an increased risk for Crohn's disease [53,54]. Compared to individuals with psoriasis alone, patients with PsA have a higher risk (RR, 6.43, 95% CI 2.04 to 20.32 vs. 3.86, 95% CI 2.23 to 6.67). Meanwhile, the risk of ulcerative colitis was not increased in either group [54]. 4.2. Pathological mechanisms proposed Psoriasis, PsA, and IBD share pathogenic pathways including TH1 and Th17 responses [55]. The model proposes that the gut microbiota may be a triggering factor that derives the inflammatory state leading to gut, skin and joint inflammation in genetically susceptible individuals [56,57]. In addition, PsA and IBD share common genetic associations: the gene SLC22A5 (chr.5q31) is a susceptibility gene to both conditions and it is involved in intestinal absorption [58]. IL12B and IL23R are also common genes between psoriasis and Crohn's disease [59,60].

5. Ocular manifestations 5.1. Epidemiology and clinical implications Uveitis, keratoconjunctivitis sicca, keratitis, blepharitis, conjunctivitis, episcleritis and scleritis are estimated to occur in 31% of patients with PsA [66] and 10% of patients with psoriasis [67]. Of these, uveitis is the most common ocular manifestations in PsA with a prevalence of up to 25%, with substantial variability across studies [68–70]. Anterior uveitis represents the most common type of uveitis in spondyloarthropathies. Similar to the uveitis associated with IBD, uveitis in PsA tends to be more insidious in onset, bilateral, chronic and may be anterior, intermediate, posterior or panuveitis [70,71].

4.3. Screening and management recommendations Screening includes asking patients about gastrointestinal symptoms and referral to a specialist if suggestive symptoms are reported. Though 3

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Table 1 Summary of screening and management recommendations from available guidelines. Screening recommendations

Management recommendations

Cardiovascular disease and risk factors

- Measure blood pressure (seated) - Measure BMI - Check fasting glucose - Check total cholesterol and HDL (ideally when disease activity is stable or in remission) - Calculate cardiovascular risk score (e.g. Framingham risk score). Because traditional risk score may underestimate patients' true risk of CVD, consider adding a 6.2% to the baseline to Framingham risk score

Inflammatory bowel disease

- Ask patients about gastrointestinal symptoms and refer to a specialist if suggestive symptoms are reported - Fecal calprotectin test may also be considered, though it is not diseasespecific

Uveitis

- Ask patients about ocular symptoms (e.g. dryness, redness, pain, vision loss) and refer to a specialist if suggestive symptoms are reported

Malignancy

- Follow screening recommendations for general population - Consider yearly or more frequent skin checks for patients at increased risk for skin cancer - Check liver function before initiating therapy - Check HCV Ab, HVB antigen, HVB core antibody, HBV surface antibody - In patients older than 50 years of age with diabetes and/or features of metabolic syndrome, consider adding an abdominal ultrasound

- Control PsA disease activity to reduce CVD risk - Promote a healthy diet, regular exercise and smoking cessation - Anti-hypertensives and statins may be used as in the general population - Psoriasis is a “risk enhancer” for CVD risk: for patients with ‘borderline’ or ‘intermediate’ risk, consider initiating or intensifying statin therapy CVD: Caution with NSAIDs. Data on glucocorticoids is limited but concerns have been raised Congestive heart failure: Caution with NSAIDs, TNFi and glucocorticoids. Data on the association between glucocorticoids and CVD is limited but concerns have been raised Obesity: Caution with methotrexate Metabolic syndrome: Caution with glucocorticoids and methotrexate Diabetes: Caution with glucocorticoids and methotrexate - OSM (other than methotrexate) is recommended over a TNFi - In severe PsA/psoriasis or when diabetes is well controlled (i.e., with a potentially lower risk of infections): TNFi may be used over OSM - First-line treatment: sulfasalazine, adalimumab, infliximab, golimumab (ulcerative colitis), and certolizumab (Crohn's disease) - mAb TNFi are recommended over etanercept, OSM, IL-12/23 inhibitor and IL-17 inhibitors - In patients without severe PsA who prefer oral therapy or have contraindications to TNFi, an OSM may be used - In patients with contraindications to TNFi or who prefer less frequent drug administration, an IL-12/ 23 inhibitor may be used - Caution with IL17 inhibitors in IBD - Off-label for Crohn's disease: methotrexate and cyclosporine - Data on the association between NSAIDs and IBD is limited but concerns have been raised - Management will vary depending on the severity of the disease and the impact it has on activities of daily living - Adalimumab, infliximab and glucocorticoids are the preferred therapy for uveitis - Data on the association between uveitis and etanercept and IL17 inhibitors is limited but concerns have been raised - Caution with TNFi - Data on the association between ustekinumab and malignancy is limited but concerns have been raised - Promote a healthy diet, regular exercise for weight loss - Control hyperlipidemia and diabetes - Remove any offending drugs and toxins Fatty liver disease: - Caution with NSAIDs, sulfasalazine, methotrexate and leflunomide Chronic hepatitis B or C: - Caution with NSAIDs, methotrexate and leflunomide - Special monitoring of patients with chronic hepatitis B treated with TNFi

Liver disease

Chronic kidney disease

- Check creatinine before initiating therapy

Infections

- Ask patients about symptoms of infection (e.g. fever, chills, sweats, cough, nasal congestion) and refer to a specialist if suggestive symptoms are reported - Test for tuberculosis before initiating therapy

Osteoporosis

- Follow general screening recommendations for general population

Depression and anxiety

- Ask patients about symptoms of depression and anxiety and refer to a specialist if suggestive symptoms are reported

- Data on the association between TNFi and chronic hepatitis C is limited but concerns have been raised - Data on the association between ustekinumab and chronic hepatitis B, chronic hepatitis C is limited but concerns have been raised - Caution with NSAIDs and methotrexate - Data on the association between leflunomide and chronic kidney disease is limited but concerns have been raised - Cyclosporine may require special monitoring Frequent serious infections: - OSM is recommended over a TNFi (black box warning against TNFi) - An IL-12/23 inhibitor or IL-17 inhibitor is recommended over a TNFi - In severe PsA with IBD: TNFi may be considered - Data on the association between ustekinumab and HIV is limited but concerns have been raised - Patients with HIV treated with TNFi require special monitoring - Caution with glucocorticoids: refer to the ACR recommendations for management and consider concomitant use of a bisphosphonate based on risk level - Caution with brodalumab in patients with history of depression - Data on the association between apremilast and depression is limited but concerns have been raised.

BMI, Body Mass Index; HDLc, high-density lipoprotein cholesterol; CVD, cardiovascular disease; NSAID, non-steroidal anti-inflammatory drug; TNFi, tumor necrosis factor inhibitor; PsA, psoriatic arthritis; mAb, monoclonal antibody; OSM, oral small molecules including methotrexate, sulfasalazine, cyclosporine, leflunomide, apremilast; IBD, inflammatory bowel disease; IL, interleukin; HCV, Hepatitis C Virus; AB, antibody; HBV, Hepatitis B Virus; ACR, American College of Rheumatology.

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Conversely, the uveitis observed in AS and reactive arthritis is generally sudden, unilateral, confined to the anterior chamber and completely resolve between episodes [72]. While peripheral arthritis can be equally anterior or posterior, the axial pattern of PsA is associated with unilateral, anterior uveitis. Patients with positive human leukocyte antigen (HLA)-27 tend to be males and have an axial pattern compared to HLAB27- patients [70,71]. Because uveitis tends to appear after psoriasis onset, and before PsA, uveitis has been suggested as a risk factor for PsA [71].

adalimumab and patients receiving phototherapy also showed no differences between groups [33]. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommends caution with the use of TNF inhibitors and glucocorticoids in patients with congestive heart failure. Furthermore, caution is also recommended for the use of NSAIDs in patients with cardiovascular disease and congestive heart failure [34].

5.2. Pathological mechanisms proposed A bidirectional relationship supported by shared pathogenic pathway between psoriasis and PsA, and uveitis has been suggested. Mirroring that of psoriasis and PsA, the pathogenesis of uveitis includes TH17- and TH1-dependent immune responses [73]. IL-2, IL-6, IL-17 and TNF have been found in increased concentrations in the aqueous humor of patients with uveitis [73]. The beneficial effect of TNF inhibitors on the frequency and severity of ocular attacks in patients with uveitis further support this theory [74–76]. The HLA-DR13 haplotype is a genetic risk factor for the development of uveitis in patients with PsA [77]. Likewise, HLA-B27 is also associated with the development of spondyloarthropathies and uveitis, though the relationship among psoriasis, uveitis, and HLA-B27 is not fully understood [78]. Approximately, 50% of patients with PsA who develop uveitis are HLAeB27+ [70]. The gut microbiome also seems to contribute to the pathogenesis of acute anterior uveitis [79].

Malignancy rates in patients with PsA remain understudied. In general, patients with PsA present similar prevalence and incidence rates of cancer compared with the general population [83] or compared with patients with RA [84,85]. However, the rate of hematologic cancer was slightly higher in the PsA cohort compared with controls in a population-based UK cohort study. Interestingly, PsA patients who received prescriptions for PsA therapy presented higher incidence rates compared with those who did not [86]. Non-melanoma skin cancer (NMSC) was reported as the most common malignancy in both PsA and RA [85]. One study reported similar malignancy risk between patients with PsA and matched-controls. However, the risk of malignancy was significantly higher in the PsA cohort, when NMSC was excluded from the analysis [87]. In a longitudinal cohort study conducted in the UK, malignancy was identified as the second most common cause of death in patients with PsA and RA. However, both patients with PsA and controls had a similar risk of death from cancer (HR 1.03, 95% CI 0.86–1.25) [88].

5.3. Screening and management recommendations

6.3. Screening and management recommendations

Screening entails asking patients about ocular symptoms (e.g. dryness, redness, pain, vision loss) and referral to a specialist if suggestive symptoms are reported. Management will vary depending on the severity of the disease and the impact it has on activities of daily living [69]. While infliximab/adalimumab have shown profound success and certolizumab/golimumab have shown moderate success, etanercept has demonstrated less encouraging results [80]. The efficacy of IL-17, IL12/23 and JAK/STAT inhibitors is currently under evaluation [81,82]. Of these, secukinumab is the only agent with evidence from completed clinical trials for uveitis to date. While a phase 2 clinical trials showed promise, secukinumab did not meet the primary efficacy endpoint in phase 3 studies [81,82]. (Table 1).

As suggested by the Canadian recommendations for the management of comorbidities in RA PsA and PsO, cancer screening beyond the nationally recommended guidelines for age and sex is not required prior to initiating systemic therapy. In subjects at increased risk for skin cancer closer monitoring may be required [51]. In patients with history of cancer, the use of TNF inhibitors should be carefully discussed given the potential risk of de novo or recurrent malignancy [51]. (Table 1).

6.2. Epidemiology and clinical implications

7. Liver disease 7.1. Epidemiology and clinical implications One study showed that patients with psoriasis, PsA and RA have an increased risk of liver disease compared to controls, with nonalcoholic fatty liver disease (NALFD) being the leading cause. In this populationbased study, psoriasis patients treated with systemic therapy had the highest risk whereas patients with RA receiving systemic therapy had the lowest risk. Compared to patients with mild disease, the patients with moderate and severe disease had a higher prevalence of liver disease and cirrhosis [89]. Another study revealed that the risk of NAFLD is greater in patients with PsA and patients with severe psoriasis compared to patients with mild psoriasis and non-psoriatic controls [90]. This association appears to be independent of coexisting metabolic syndrome components and the use of hepatotoxic medications such as methotrexate [91,92]. Interestingly, hepatic steatosis was reported as an independent predictor of not achieving MDA [93].

6. Malignancy 6.1. Psoriatic-directed interventions and cardiovascular risk The impact of psoriatic-directed interventions on cardiovascular risk remains controversial as prospective randomized studies to quantify their risk/benefit are missing. A systematic literature review including retrospective claims and registry studies suggests a favorable effect of disease modifying anti-rheumatic drugs (DMARD) on cardiovascular surrogate markers [30]. For example, one study showed that patients receiving biologic therapy had reduced coronary inflammation, as assessed by the perivascular fat attenuation index, compared with patients receiving topical or light therapy after 1 year of treatment [31]. Similarly, patients receiving secukinumab in the CARIMA trial presented improved endothelial function as measured by flow-mediated dilation at week 52 compared to baseline [32]. In the Vascular Inflammation in Psoriasis (VIP) trial, patients treated with ustekinumab showed reduced inflammatory markers and aortic vascular inflammation, as measured by aortic 18F-FDG PET/CT uptake, with an increase in apolipoprotein B lipoproteins compared with placebo. However, after 52 weeks, there was no statistically significant difference in the aortic vascular inflammation between groups [33]. Another study comparing vascular inflammation between patients treated with

7.2. Pathological mechanisms proposed The low-grade systemic inflammation and insulin resistance in psoriatic disease may explain the link between the two conditions [94–96]. TNF, IL-1, IL- 2, IL-6 and IL-17 expressed in psoriatic disease may influence glucose metabolism and insulin sensitivity particularly in hepatocytes and adipocytes [97]. In addition, psoriatic patients have elevated levels of leptin and reduced levels of adiponectin, which 5

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more infections, 27.7% of the patients with PsA had 3 or more infections [113]. In the PSOLAR registry, time-dependent physician global assessment 4 and 5, history of infection, older age, and diabetes were identified as predictors of serious infections in patients with psoriatic disease, independent of exposure to biologic agents [114].

promote insulin resistance and are etiologically linked to NAFLD development and progression [98,99]. 7.3. Liver disease and psoriatic-directed therapies The use of NSAIDs may lead to hepatotoxicity and liver enzymes abnormalities [100]. Likewise, methotrexate and leflunomide may cause liver enzymes abnormalities, and, even permanent liver damage and/or cirrhosis [101,102]. Risk factors for liver toxicity in patients with psoriasis or RA treated with methotrexate include pre-existing liver disease, cumulative methotrexate dose, obesity and diabetes [103]. Liver enzymes abnormalities have also been reported with the use of TNF inhibitors. However, patients treated with combination TNF inhibitor and methotrexate exhibited a lower risk of liver fibrosis compared with patients treated with methotrexate alone [104,105].

9.2. Infections and PsA medications While formal guidelines for the management of infections associated with TNF inhibitors are lacking, identification of at-risk patients, appropriate vaccination, and screening for latent or active tuberculosis and hepatitis B before initiation of TNF inhibitors is recommended. Both the ACR/NPF and GRAPPA guidelines caution against the use of TNF inhibitors in patients with active serious infections or in those with chronic or recurrent infections [4,34]. (Table 1).

7.4. Screening and management recommendations

10. Osteoporosis

Despite the significant morbidity associated with the disease, there is no consensus regarding screening for NAFLD in high risk populations. However, abdominal ultrasound and liver enzymes evaluation are usually recommended in patients older than 50 years of age with diabetes and/or features of metabolic syndrome [106]. Despite being the gold standard for hepatic fibrosis, liver biopsy is currently discouraged due to its high morbidity and mortality [107]. Lifestyle changes and dietary modification for weight loss, removal of offending drugs and toxins, and control of associated metabolic disorders as hyperlipidemia and diabetes represent the most common management recommendations [108]. Physicians should be cautious about prescribing methotrexate, leflunomide, sulfasalazine and NSAIDs in patients with established liver disease. (Table 1).

Psoriatic disease presents similar prevalence of osteoporosis to the general population [115]. According to the Canadian DermatologyRheumatology Comorbidity Initiative, screening and management of osteoporosis in psoriatic disease should be the same as for the general population [51]. However, specific guidelines should be followed for patients treated with chronic systemic glucocorticoids [116]. (Table 1). 11. Central sensitization syndrome Fibromyalgia occurs in 16–22% of patients with PsA [117]. Because fibromyalgia may influence disease activity measurements and patientreported outcomes in PsA, its recognition is important to avoid unnecessary treatment escalation. In a prospective, cross-sectional study, patients with concomitant PsA and fibromyalgia had higher disease activity scores compared with patients with PsA only. Furthermore, none of the patients with coexisting PsA and fibromyalgia met the criteria for MDA [118].

8. Kidney disease 8.1. Epidemiology and clinical implications

12. Depression and anxiety

PsA was identified as an independent risk factor for renal damage in patients with psoriasis. In a cross-sectional study of 30 patients [109], serum levels of creatinine, urea, and phosphate were higher in PsA compared to patients with psoriasis and healthy controls. Additionally, PsA patients had the lowest glomerular filtration rate as compared to the other groups. Furthermore, while only 10% of the patients with psoriasis had proteinuria, 96.7% of the patients with PsA presented with proteinuria. Haroon et al. further found a significant association between chronic kidney disease and cardiovascular diseases even after adjusting for age, gender, duration of arthritis, high C-reactive protein, use of anti-rheumatic drugs [110]. (Table 1).

Psoriatic disease is closely related with depression and anxiety, and prevalence of these mood disorders in PsA appears to be higher than in psoriasis [119]. In PsA, the prevalence of depression ranges between 9 and 36%, and anxiety between 15 and 30% [119,120]. Appropriate screening and management of these disorders is critical as both depression and anxiety may affect pain perception, quality of life and treatment outcomes [121–123]. The use of apremilast in individuals with depression is discouraged as it may worsen depression [124]. The use of brodalumab has also raised concerns since 6 patients completed suicides across all clinical trials [125]. This led the Food and Drug Administration to issue a black box warning against the use of brodalumab in patients with history of depression and/or suicidal ideation or behavior. (Table 1).

8.2. Kidney disease and PsA medications Methotrexate should be avoided in patients with significant renal insufficiency or end-stage renal disease on hemodialysis given that renal impairment is a major risk factor for developing methotrexate toxicity [111]. NSAIDs should also be avoided given that they may increase the risk for acute kidney injury [112]. (Table 1).

13. Gout Because gout is an important differential diagnosis of PsA, awareness about its increased incidence in this population is critical [126]. One study showed that the incidence of gout in patients with psoriasis and PsA is higher compared to the general population. Of note, the risk of incident gout is higher among patients with PsA compared with patients with psoriasis only (HR, 4.95, 95% CI 2.72 to 9.01 vs. 1.71, 95% CI 1.36 to 2.15). Furthermore, the incidence of gout was higher in men than in women [126].

9. Infections 9.1. Epidemiology and clinical implications While both psoriasis and PsA are associated with a higher risk of infection, patients with PsA seem to have a higher risk compared with patients with psoriasis alone. Among 695 patients with PsA enrolled in a prospective cohort study, 264 (40.0%) patients developed an infection, compared to 62 (12.2%) of those who only had cutaneous disease. In addition, while 3.2% of patients with psoriasis alone who had two or

Funding source None. 6

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Disclosures

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