Nicole W. Kittler, MD1,2 and Kelly M. Cordoro, MD1,3

1Department of Dermatology, University of California, San Francisco, CA, USA
2Benioff Children’s Hospital, Oakland, CA, USA
3UCSF Benioff Children’s Hospital, San Francisco, CA, USA

Conflict of interest: All of the authors have no conflicts to declare for this work.

Abstract:
While the association between psoriasis and various comorbidities is well documented in adults, questions remain as to whether the same relationships exist in the pediatric population. However, psoriasis develops in childhood or adolescence in approximately 40% of patients, suggesting that the risk of comorbidities may also begin early in life. This presents an opportunity for prevention, early detection and intervention for children who may suffer from, or be at risk of, comorbidities. The pediatric psoriasis Comorbidity Screening Initiative, a multidisciplinary panel, devised and published consensus-based screening recommendations for pediatric psoriasis patients in 2017. As these guidelines closely align with the routine age-related screening recommendations for healthy children set forth by the American Academy of Pediatrics, in the absence of signs and symptoms of comorbidities prompting additional evaluation, dermatologists should partner with patients’ primary care physicians to ensure up-to-date, routine, and age-based screening.

Key Words:
arthritis, celiac disease, comorbidities, diabetes, inflammatory bowel disease, metabolic syndrome, obesity, pediatric, psoriasis, quality of life, uveitis

Case Presentation

A 10 year-old male presents with a 5 year history of psoriasis that has been increasing in severity over time. His psoriasis has been treated with topical therapies only until recently, when a course of Goeckerman therapy provided temporary improvement but then flared significantly after 1 month. Upon presentation to pediatric dermatology, he has near erythroderma with large bright red scaly plaques and scattered guttate papules and small plaques covering more than 75% of his body surface area (Figures 1A and 1B). There are scattered superficial erosions within the larger plaques. He has missed the last 4 weeks of school due to malaise, intermittent chills, and severity of his psoriasis, which is painful and has reduced his ability to walk and sit comfortably. During the visit, he does not make eye contact and answers questions with shoulder shrugs and one-word answers. He is otherwise healthy, has no known recent infections and takes no medications. A review of systems is positive for malaise, fatigue, skin tenderness, reduced range of motion of the extremities due to erosions at flexural sites, depressed mood and social withdrawal. He has not had pain, swelling or stiffness of his joints and denies ocular symptoms. His family history is positive for psoriasis and vitiligo. He is accompanied by his parents, who are separated. His mother is in tears, and his father is very frustrated throughout the visit. The patient has been having rage attacks at home and has withdrawn from his friends and social activities. How should we approach this child in terms of psoriasis comorbidities?

10 year-old male with a 5-year history of psoriasis covering more than 75% of body surface area.
Figures 1A & 1B: Initial presentation of a 10 year-old male with a 5-year history of psoriasis covering more than 75% of body surface area.

Discussion

Approximately 40% of patients with psoriasis report onset in childhood or adolescence.1,2 While the association between psoriasis and various extracutaneous comorbidities in adult patients is well established, questions remain about whether the same is true for pediatric patients. If the risk of comorbidities begins early in life, there is an opportunity for prevention, early detection and intervention for children suffering from or at risk of comorbid conditions. In 2017, the Pediatric Psoriasis Comorbidity Screening Initiative (CSI) published consensus-based screening recommendations for pediatric psoriasis patients,3 which do not differ significantly from the routine age-appropriate screening guidelines for healthy children set forth by the American Academy of Pediatrics (AAP). Pediatricians and dermatologists caring for children and adolescents with psoriasis should understand the risk of various potential comorbidities so that they may appropriately screen and counsel patients and their parents.

Psoriatic Arthritis

Juvenile psoriatic arthritis affects 5-40% (most estimate 10%) of children with psoriasis.4 This constitutes a heterogeneous group with varying clinical features (Table 1); some have features similar to juvenile idiopathic arthritis (JIA),5 while others resemble adult psoriatic arthritis. The average age of symptom onset is 8 years,5 but there is a bimodal distribution. The first peak occurs around 2-3 years of life and resembles JIA, with a female predominance, antinuclear antibody (ANA) positivity and oligoarthritis (characterized by <4 affected joints) or polyarthritis, primarily affecting the small joints and wrist bones, and stronger association with chronic uveitis.6 A second peak resembling spondyloarthritis occurs at 10-12 years and is characterized by a male predominance, axial predilection, enthesitis and HLA-B27 positivity.4,6 Patients in both groups are often affected by dactylitis.

  • Pain and/or swelling in 1+ joints
  • Inflammation of a digit (dactylitis)
  • Joint stiffness after sleep or rest that improves with activity
  • Limp
  • Heel pain or back pain (enthesitis)
  • Eye pain or redness (uveitis)
Table 1: Clinical features of psoriatic arthritis in children.
Adapted from Osier et al. JAMA Dermatology, 2017.3

 

Pediatric psoriatic arthritis may present before the skin disease and can be insidious, posing a diagnostic challenge. Whereas adults tend to develop psoriasis 8.5 years prior to joint disease, 80% of children develop arthritis prior to the onset of skin findings.4,7 While nail psoriasis is a predictor of psoriatic arthritis in children as in adults, it is a less frequent finding among pediatric patients with psoriatic arthritis compared to adults (37-57%).5 Correlation between skin disease severity and arthritis is poor.8 Children and adolescents with juvenile psoriatic arthritis are more likely to be obese (1 in 5) and overweight (1 in 3) compared to the general population; obese patients with juvenile psoriatic arthritis are also older at the onset of joint symptoms.9

Psoriatic arthritis may be underdiagnosed in children. The diagnosis is based on clinical and imaging features; unfortunately, there are no specific biomarkers. Two sets of diagnostic criteria exist for juvenile psoriatic arthritis: International League of Associations for Rheumatology (ILAR) and Classification for Psoriatic Arthritis (CASPAR). One study reported that 20% of patients meeting either CASPAR or ILAR criteria for psoriatic arthritis were not diagnosed as having psoriatic arthritis by their rheumatologists.5 There is also on average a 1-year delay from symptom onset until first rheumatology appointment.5

While there are no validated screening tools for psoriatic arthritis in pediatric patients, children should undergo a directed review of systems (with emphasis on limp and morning stiffness) and exam evaluating for arthritis.7 Outcomes for pediatric psoriatic arthritis are favorable, with ~60% of treated patients achieving remission within 2 years.6 Younger age of onset and female sex are both associated with better outcomes.

Uveitis

Uveitis is associated with psoriatic arthritis in pediatric patients, although rare cases of uveitis in patients with psoriasis but without joint disease have been reported.10-12 It can present with acute onset eye pain, redness, miosis, photophobia, or blurred vision. Compared to the uveitis associated with ankylosing spondylitis, uveitis in patients with psoriasis is more likely bilateral and insidious in onset.13 The incidence of uveitis among children with juvenile psoriatic arthritis ranges from 8-19%, with higher rates among children with early-onset psoriatic arthritis.4,5 In patients with onset of psoriasis and arthritis before 6 years of age uveitis appears to be severe, vision threatening and treatment refractory.11

A review of systems for pediatric patients with psoriasis, and particularly those with psoriatic arthritis, should include questions about ocular symptoms; patients with concerning findings should be evaluated by a pediatric ophthalmologist. Providers should maintain a lower threshold for referring patients younger than 6 years with psoriatic arthritis for ophthalmologic evaluation, as uveitis in these patients is more common and more severe.

Obesity

There is a strong association between psoriasis and obesity in children, though the evidence for this link is less robust than in adults.14-18 Compared to children presenting to pediatric dermatologists for non-inflammatory skin conditions such as warts, the odds ratio for obesity (defined as waist circumference >90th percentile) for children with psoriasis is 2.52, and 3 for patients with severe psoriasis, with the greatest risk occurring in Hispanic and African American children.17

The nature of the association between psoriasis and obesity is complex and likely bidirectional. Obesity predates psoriasis by at least 2 years in >90% of children, with a mean delay in onset of psoriasis of >4 years.18 Children with higher body mass indices (BMI) are more likely to have greater body surface area of involvement of their psoriasis18 and more severe disease.16 Children with psoriasis have increased central adiposity, even in the absence of obesity.19,20 It has been hypothesized that excess adipose tissue contributes to a proinflammatory state and the development of psoriasis.21 Psoriasis leads to decreased physical activity due to embarrassment over appearance and increased itching from heat and sweat during exercise,22 which can amplify the psoriasis-obesity cycle. However, a recent study demonstrated that children with psoriasis who are not obese at the time of diagnosis are just as likely to develop obesity after diagnosis as those without psoriasis.23

Obesity may be the strongest contributor to the development of other comorbidities in children with psoriasis including hyperlipidemia, hypertension, diabetes, metabolic syndrome, polycystic ovarian syndrome and nonalcoholic liver disease.24 It is therefore critical that providers screen for, and manage, obesity and overweight in children with psoriasis. Because psoriasis is an independent risk factor for subsequent cardiovascular disease, providers providers should aim to minimize any additional risk through lifestyle modifications that control weight gain. Weight loss may also have a positive impact on the severity of psoriasis.25 The AAP recommends annual BMI screening for all children beginning at age 2 years.3 Providers should discuss the importance of maintaining healthy weight with patients and their families and, if available, consider referrals for nutritional counseling or to a weight management center.

Metabolic Syndrome, Dyslipidemia, Hypertension, Nonalcoholic Fatty Liver Disease

There is an increased prevalence of metabolic syndrome among pediatric patients with psoriasis, with rates up to 30%.26,27 This increased risk may reflect the combination of both psoriasis and obesity, rather than psoriasis alone.28 While lipids may be normal in children with psoriasis, other markers of atherogenesis have been shown to be significantly elevated, including serum apolipoprotein B concentrations, decreased HDL and reduced cholesterol efflux capacity, a measure of HDL function.19

The increased risk of early myocardial infarctions (MI) in patients with psoriasis has been well established. A 30 year-old man with severe psoriasis has a relative risk of having an MI of 3.1 compared to non-psoriatic matched controls.29 Risk for early cardiovascular disease likely begins in childhood or young adulthood, though the relationship between psoriasis and the independent risk factors that lead to MI remains to be delineated.

In adults, psoriasis constitutes an independent risk factor for type 2 diabetes,30 and earlier age of onset of psoriasis may increase that risk.31 While studies have shown increased insulin resistance among pediatric psoriasis patients, this correlates most strongly with obesity,19,24 and therefore the true effect of psoriasis on risk of type 2 diabetes remains to be determined. There is limited data on a potential association between psoriasis and hypertension in children and adolescents, although adult studies support a correlation. Hospitalized children with psoriasis have been found to have an increased risk of hypertension (relative risk 2.63),32 although these results may not be generalizable to otherwise healthy children with psoriasis. Psoriasis has been identified as an independent risk factor for the development of nonalcoholic fatty liver disease (NAFLD) in adults.33 Pediatric studies are needed to identify the risk of NAFLD in childhood psoriasis.

The association between psoriasis, metabolic syndrome and, ultimately, cardiovascular disease can be understood as a “psoriatic march”, where psoriasis and obesity lead to systemic inflammation, insulin resistance, endothelial dysfunction, atherosclerosis and eventually cardiovascular and cerebrovascular diseases (Figure 2).34 The goal of caring for pediatric patients is always prevention. The psoriatic march is a useful conceptual framework for understanding the severe downstream effects of psoriasis and obesity, and for explaining the importance of prevention and early intervention. The preventive effects of early and aggressive treatment for psoriasis in pediatric patients on risk of MI and other long-term outcomes remains to be delineated.

Psoriatic march chart
Figure 2: Psoriatic march.
Adapted from Boehncke et al. Experimental Dermatology, 2011.34

The psoriasis CSI has advocated following the AAP and National Heart, Lung, Blood Institute recommendations35 for screening of metabolic syndrome:

  • Fasting lipid panel at ages 9-11 years and again at 17-21 years. Additional screening based on risk profile.
  • Annual hypertension screening beginning at age 3 years.
  • Fasting glucose every 3 years starting at age 10 years or puberty if patient is overweight and has 2+ risk factors. Additional screening based on risk profile.
  • Alanine transferase (ALT) measurement starting at age 9-11 years if obese or overweight with additional risk factors, prediabetes or diabetes, dyslipidemia, obstructive sleep apnea or family history of NAFLD/nonalcoholic steatohepatitis (NASH, an advanced form of NAFLD). Additional and repeat screening based on risk profile.

Complete recommendations are delineated in Table 2.

 

ComorbiditiesScreening Recommendations
Overweight or obesity
  • Yearly BMI starting at 2 years of age.
Type 2 diabetes mellitus
  • Screen with fasting glucose every 3 years starting at age 10 years or puberty if patient is overweight and has 2+ risk factors.
  • Screen with fasting glucose patients with obesity every 3 years starting at age 10 years regardless of risk factors.
Dyslipidemia
  • Universal screening with fasting lipid panel between ages 9-11 years and 17-21 years.
  • Additional screening determined by presence of additional cardiovascular risk factors.
Hypertension
  • Yearly screening starting at age 3 years using age, sex and height reference charts.
Nonalcoholic fatty liver disease
  • Screening ALT starting at age 9-11 years if obese or overweight with additional risk factors, prediabetes or diabetes,
  • dyslipidemia, obstructive sleep apnea or family history of NFALD/NASH.
  • Earlier screening can be considered in younger patients with more risk factors.
  • Repeat screen every 2-3 years if risk factors remain unchanged.
Polycystic ovary syndrome
  • Screening determined by presence of symptoms or signs.
Gastrointestinal diseases
  • Formal gastrointestinal evaluation in patients with signs or symptoms of IBD or celiac disease.
Psoriatic arthritis
  • Directed review of systems and physical examination as part of routine management.
Uveitis
  • Ophthalmology evaluations for patients with psoriatic arthritis or those with signs/symptoms.
Mood disorders and
substance abuse
  • Yearly screen for depression and anxiety.
  • Yearly screen for substance abuse beginning at 11 years of age.
Quality of lifeQuery effects of psoriasis on home, school and social lives routinely. Consider use of a formal QOL instrument.
Table 2: Screening recommendations for pediatric patients with psoriasis.
Adapted from Osier et al. JAMA Dermatology, 2017.3

Psychiatric Disturbances & Impaired Quality of Life

Understanding and managing the association between psoriasis and mental health is critical to caring for pediatric patients with psoriasis. Children with psoriasis have a significantly increased risk of developing depression (6.65-fold higher) and/or anxiety (9.21-fold higher) compared to their peers;36,37 this association is stronger in younger children (8-12 years) compared to adolescents.38 This trend is particularly concerning because depressive episodes earlier in life increase the risk of chronic psychiatric disability.39 Adults with psoriasis have a significantly higher rate of suicidal ideation, attempts and completed suicides.40 This increased risk correlates with disease severity40,41 and is stronger among younger adult patients (20-30 years) compared to older adults (>60 years).40,42

There may also be an association between psoriasis and other psychiatric conditions such as bipolar disorder and schizophrenia in pediatric patients with psoriasis,43 but the nature of that association remains unclear. An increased tendency towards substance use and abuse has been demonstrated among adult patients with psoriasis, and early data suggests a similarly increased risk among pediatric psoriasis patients.43 Environmental tobacco exposure at home is a risk factor for the development of pediatric psoriasis,44 although the relationship between pediatric psoriasis and personal history of cigarette smoking has not been explored. The psychosocial stress caused by having psoriasis likely engenders depressive symptoms that lead to increased risk-taking behavior such as substance abuse, which may then worsen psoriasis. Since mental illness, tobacco smoke and substance abuse are independent risk factors for cardiovascular disease, these sequential associations may be another mechanism by which psoriasis can lead to cardiovascular disease.

While it has been suggested that the increased risk of psychiatric disturbance among pediatric psoriasis patients reflects the associated stigmatization of the skin disease, there may also be a shared immunopathogenesis affecting the brain and skin of patients with psoriasis and psychiatric disease.45 Further research is needed to clarify whether psoriasis and psychiatric disturbance are causally and/or intrinsically related. Nonetheless, these statistics highlight the importance of early screening and intervention to mitigate the effects of psoriasis on mental health. The AAP recommends yearly screening for anxiety and depression in all pediatric patients. Dermatologists caring for children with psoriasis should routinely ask patients and their caretakers about the psychosocial impact of psoriasis, inquire about mood symptoms, and maintain a low threshold for referral to mental health providers. The psoriasis CSI echoes the AAP’s recommendation for annual screening for substance abuse beginning at age 11.3,46 In addition, counseling on the deleterious effects of alcohol, recreational drugs and tobacco smoke should be offered to pediatric psoriasis patients. Currently, few patients receive counseling on smoking as a risk factor for psoriasis.47

While stress is a known trigger for psoriasis in adults, it may be even more relevant in pediatric psoriasis. Stressful life events during the year prior to diagnosis correlate with the onset of pediatric psoriasis, and relationship problems are associated with the most significantly increased risk. Half of adults with pediatric-onset psoriasis report developing new psoriatic lesions during times of distress, compared to fewer patients with adult-onset psoriasis.2 Dermatologists caring for pediatric psoriasis patients should routinely inquire about life stressors and counsel patients and their caregivers on the relationship between stress and psoriasis. Currently, this is not standard practice.47

Quality of Life

Psoriasis negatively impacts the quality of life (QOL) of affected children and their caregivers. The effect of psoriasis is estimated to exceed that of diabetes or epilepsy in childhood.48,49 Younger children (ages 8-12 years vs. 13-18 years) and those with associated arthritis are most severely impacted, although it is possible that our QOL measurement tools are not as sensitive in demonstrating the impact on adolescents.38,48,50 Pain, pruritus and fatigue associated with psoriasis all contribute to poor QOL even in children with mild disease;51 in focus groups, however, affected children reported that the “worst part” of their psoriasis is the appearance.50 Psoriasis affects social, emotional and school functioning, and children with psoriasis may be the victims of stigma and/or bullying.48,51,52 Parents and caregivers of children with psoriasis also report decreased QOL.52 Adults with a history of earlier age of onset of psoriasis (as young as 2 years of age) are more likely to report chronic effects on QOL and to attribute their depression to psoriasis than adults with similar severity of disease but later age of onset.53 Providers should routinely inquire about the psychosocial impacts of psoriasis on the patient and their family so that support and resources can be provided as necessary.

Other Comorbidities

Several other comorbidities have been reported in association with psoriasis in adults, but whether the same exists in pediatric patients remains unknown.

Gastrointestinal Disease

Inflammatory Bowel Disease

Psoriasis has been associated with both inflammatory bowel disease (IBD) and celiac disease. Adults with psoriasis have an increased risk of developing IBD, in particular Crohn’s disease;54 that risk is greatest among patients with psoriatic arthritis.55 The association between IBD and psoriasis may stem from a shared genetic susceptibility.56-58 The use of anti-tumor necrosis factor (TNF) agents to treat pediatric IBD adds another layer to the association between IBD and psoriasis. These biologic therapies may result in new onset or exacerbation of psoriasis or psoriasiform eruptions, an effect that has been well documented among adult and pediatric patients.

Celiac Disease

Patients with psoriasis may be at increased risk of developing celiac disease, a chronic immune-mediated gluten-dependent enteropathy. And psoriasis may be more prevalent among children and adolescents with celiac disease.59 The nature of this association remains unclear. A gluten-free diet may benefit a subset of psoriatic patients with elevated anti-gliaden antibodies.60

Providers should inquire about gastrointestinal symptoms and growth during clinical visits with pediatric psoriasis patients and pursue further evaluation as indicated. Currently, there is insufficient data to suggest universal screening for IBD or celiac disease among pediatric patients with psoriasis.

Type 1 Diabetes

There may be an increased risk of psoriasis among children with type 1 diabetes.61 Whether children with psoriasis carry an increased risk of type I diabetes is not known, and additional studies are needed to delineate this relationship.

Polycystic Ovarian Syndrome (PCOS)

Adult women with PCOS have an increased risk of severe psoriasis,62,63 which may compound the risk of metabolic syndrome. There is to date no evidence linking PCOS with psoriasis in pediatric patients.

Risk of Malignancy

Adults with psoriasis have an increased risk of malignancy, in particular lymphoma, with a relative risk of 2.95.29 One retrospective review suggested that pediatric psoriasis patients may also have an increased risk of developing malignancy, although this difference was not statistically significant.64 As there may be an additional risk of malignancy conferred by the use of conventional and biologic systemic therapies, the independent risk of psoriasis on development of cancer is difficult to determine.

Case Resolution (Denouement)

A reasonable approach to this patient is to confirm his diagnosis given the severity and disease escalation despite treatment with an aggressive form of phototherapy (Goeckerman), assess for triggers such as infection, and investigate for comorbidities. A skin biopsy revealed psoriasis, and bacterial cultures from the skin erosions, pharynx and anus were negative. A comprehensive review of systems and discussion with the patient and his family revealed depression, social isolation, and social stigma. As his disease improved (he was initially treated with methotrexate while awaiting insurance approval for an anti-TNF agent; once approved, he started adalimumab), his mood remained low and the rage attacks continued. Despite near total skin clearance on biologic therapy, he remained anxious and depressed, spoke very little during office visits, and was referred for psychological evaluation and therapy. Over time, both his skin and his psychological health improved. Now, 4 years after his initial presentation, he remains on adalimumab, has a few localized plaques on the legs, his mood has normalized, and he enjoys and is doing well in school. During check-ups, he engages, smiles, answers questions, makes eye contact, and has hopes and dreams for his future which he shares openly.

This case highlights the importance of a thorough evaluation for comorbid conditions and triggers in patients with psoriasis, as well as the disease impact on social and psychological health and well-being. Consider both extrinsic (i.e., the patient is sad, depressed and withdrawn because he does not like the way he looks and feels) and intrinsic factors (e.g., the inflammation in the skin leading to psoriasis may also be at play in the brain, resulting in altered mood or potentially organic mental health disease; i.e., not just a “cause and effect” phenomenon). Many children with psoriasis are undertreated often due to age, a paucity of short- and long-term safety data for newer targeted therapies, and lack of experience and comfort with systemic therapies for children on the part of dermatologists. As we enter a new era of pediatric patient population involvement in clinical trials and the US FDA approval of biologic therapies for children, hopefully the treatment gap between children and adults with psoriasis will narrow. In addition, as we learn more about the long-term consequences of chronic, undertreated inflammation on the cardiovascular and other organ systems (i.e., the “psoriatic march”), the psychosocial impact of having a disfiguring, severe chronic disease in childhood, and other comorbidities associated with pediatric psoriasis, we will be better positioned to face the demands, challenges and opportunities of comprehensively and optimally managing children with psoriasis.

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