Fatigue and the Impact of Musculoskeletal Pain on Quality of Life in Pediatric Patients With Psoriasis

Abstract

Background and aims

Musculoskeletal pain associated to psoriasis without the presence of psoriatic arthritis is a poor explored issue in pediatric population. The aim of this study was to compare the health-related quality of life (HRQoL) and fatigue scores of pediatric patients with psoriasis and healthy peers and estimate the impact of musculoskeletal pain.

Methods

The pediatric Gait Arms Legs and Spine (pGALS) questions were used to screen for musculoskeletal pain. General HRQoL was measured using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and fatigue was assessed using the PedsQL-Multidimensional Fatigue Scale (PedsQL-MFS).

Results

Fifty psoriatic patients (12.1years old; IQR 9-15) and 50 controls (12.3 years old; IQR 8.8-15.9) were evaluated. Patients with psoriasis had long disease duration of 6.9 years (IQR 3.7-9.5) and predominantly low disease activity (PASI 3.2, IQR 0.8-6; BSA 3.0, IQR 1-8), mainly treated with topical therapy. The PedsQL 4.0 total score of psoriatic patients with musculoskeletal pain was poorer than controls with pain. Fatigue by PedsQL-MFS was also worse in patients with psoriasis and pain. The risk of impaired HRQoL was 7.7 times higher in the presence of musculoskeletal pain (OR = 7.71, 95%CI 1.66-35.78); other variables such as age, sex and severity of psoriasis did not increase the risk of HRQoL impairment.

Conclusions

Musculoskeletal pain and fatigue may provide clues for systemic impairment in pediatric psoriatic disease and calls for effective systemic treatment to reduce disease burden and accumulated damage.

Background

Psoriasis is a chronic inflammatory disease with rising incidence that affects mainly the skin but may be associated to rheumatic manifestations and increased cardiovascular risk. ¹ Extending beyond the scope of physical symptoms, it affects psychological and social aspects of life what implies in a high burden for affected individuals. Complications of skin involvement such as chronic itching and stigmatization due to exposed areas affected are associated to stress and anxiety and negatively impact health related quality of life (HRQoL). ² Pediatric patients with moderate to severe psoriasis demonstrated better HRQoL assessed by the Pediatric Quality of Life Inventory version 4.0 (PedsQL^tm 4.0) generic core scales than psychiatric patients, comparable to juvenile arthritis and asthma and more impaired than children with diabetes. ³ In adults, it is known that when musculoskeletal disease overlays, the impact on HRQoL is greater: patients with psoriatic arthritis (PsA) have worse HRQoL than psoriasis alone, probably because in addition to the cutaneous impairment, there are musculoskeletal pain, limit on motion, deformities and the need for more aggressive treatment. ⁴ Children with juvenile PsA having simultaneously arthritis and skin disease have more depressive symptoms at diagnosis than patients with juvenile PsA without psoriasis. ⁵

Musculoskeletal pain is a common complaint in patients with psoriasis without PsA ⁶ and causes poorer HRQoL. ⁷ Fatigue is also more frequent in adults with psoriasis (51%) than healthy controls (4%) and is associated to impaired HRQoL. ⁸ Both symptoms predict the future development of PsA, what makes the population of psoriasis patients with pain and fatigue a source to understand risks and biomarkers for development of PsA ⁹ and to act timely in order to guarantee better outcomes. While the impact of fatigue and musculoskeletal pain with or without the presence of arthritis are increasingly recognized issues in the management of adults with psoriasis, these systemic impairments associated with psoriasis are largely unrecognized and neglected in the management of children with the disease. It may happen because PsA in pediatric patients is rare and studies focusing on musculoskeletal complaints in pediatric population with psoriasis are scarce.

We previously showed that musculoskeletal pain and fatigue were frequent among children and adolescents with psoriasis, were related to the severity of skin and nail disease, and negatively affected HRQoL. ¹⁰ In the present study, we aim to assess musculoskeletal complaints in children and adolescents with psoriasis, comparing to healthy controls, and verify its impact in quality of life and fatigue.

Methods

It was an observational, analytical, and cross-sectional study with prospective data collection from December 2020 to March 2023. Children and adolescents aged 3 to 19 years in follow-up for psoriasis at a pediatric dermatology referral center were included. Control peers were selected between patients waiting for surgical procedures like tonsillectomy, circumcision, and plastic surgeries, otherwise healthy, without psoriasis, and without previous medical history of remarkable painful experiences. The exclusion criteria were the presence of overlapping skin diseases, traumatic or congenital musculoskeletal abnormalities, and cognitive impairment. The protocol of the study was approved by the research ethics committee (IRB – 4.908.455). Parents and participants signed informed consent and assent documents.

Participants were screened for musculoskeletal complaints using the three questions from pGALS (pediatric Gait Arms Legs and Spine) ¹¹ : Do you (or does your child) have any pain or stiffness in your (their) joints, muscles or back? Do you (or does your child) have any difficulty getting yourself (him/ herself) dressed without any help? Or lifting an object above shoulder level? Do you (or does your child) have any problem going up and down steps? Or being able to squat? Children and their parents were instructed to answer “yes” only if the complaint were “recurrent”, happening frequently; and to focus on limitations not related to skin lesions. The musculoskeletal pain was then classified as “inflammatory” (if happens after resting and improve with movement), “mechanical” (if triggered by movement) or “widespread” (diffuse, continuous, with signs of pain hypersensitivity). Patients with psoriasis were submitted to examination of the musculoskeletal system by a pediatric rheumatologist, looking for joint swelling, tenderness, and limit on motion and evaluating 10 entheseal sites located in legs and feet looking for tenderness.

Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) were used to measure skin disease activity, ¹² and was estimated by a pediatric dermatologist. A PASI above 5 were considered moderate and above 10 and/or a BSA above 10% were considered severe skin disease activity. ¹³ The Nail Psoriasis Severity Index (NAPSI) was used to determine nail involvement (12). ¹⁴ Pain was measured using a visual analogue scale (VAS) in electronic device (tablet) where the participant was allowed to both tapping or sliding to select/adjust the marker location on the line ranging from 0 (no pain) to 100 (severe pain) (the numbers were not priorly displayed). ¹⁵ Skin disease HRQoL was assessed using Children’s Dermatology Life Quality Index (CDLQI), ranging from 0 (no compromise) to 30 (worst HRQoL). ¹⁶ General HRQoL was measured using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and a cut-off point of one standard deviation below the mean of the control population was considered as an alert for impaired HRQoL. ¹⁷ Fatigue was assessed using the Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale (PedsQL-MFS). ¹⁸ For both, a higher score (close to 100) indicates no impairment. All questionnaires were translated, culturally adapted, and validated in Brazil, applied by the researcher, and completed by the participant, except for the five children under five years of age (all of them from psoriasis group), when it was completed by the parents, following authors instructions.

Subgroup findings were compared using Fisher’s exact test and non-parametric Wilcoxon test. Non-parametric Kruskal-Wallis and Dunn’s test were used to compare HRQoL and fatigue scores in patients and controls with and without musculoskeletal pain. A multiple logistic regression analysis identified the factors associated with impaired HRQoL, using sex, age, duration of disease, severity of psoriasis by PASI, skin lesions exposed or in areas of negative impact, and musculoskeletal pain as covariates. For all tests, a significance level of 5% was applied (Software R® 4.0.2).

Results

Fifty children and adolescents with psoriasis were recruited (median age 12.1 years-old; IQR = 9 -15) and 50 controls (median age 12.3 years-old; IQR = 8.8 – 15.9). Table 1 shows general characteristics of participants, musculoskeletal symptoms and signs and the scores of HRQoL and fatigue. According to the PedsQL 4.0 cut-off value, 22 psoriatic patients (44%) showed risk status of impaired HRQoL.

Table 1.

General Characteristics of Patients With Psoriasis and Controls, Musculoskeletal Symptoms and Signs, Quality of Life and Fatigue Scores.

Features		Psoriasis (n = 50)	Controls (n = 50)	P value
Age in years - median (IQR)		12.1 (9.0-15.0)	12.3 (8.8-15.9)	0.63 a
Sex – female – (n%)		29 (58)	24 (48)	0.42 b
Psoriasis in first degree relatives n (%)		13 (26)	2 (4)	<0.01 b
Psoriatic arthritis in relatives n (%)		1 (2)	0	0.31 b
pGALS – problem going up and down n (%)		4 (8)	1 (2)	0.36 b
pGALS – problem getting dressed n (%)		2 (4)	0	0.49 b
pGALS – MSK pain n (%)		15 (30)	12 (23)	0.65 b
Type of MSK pain n (%)	Mechanical	11 (22)	12 (23)	1.00 b
	Inflammatory	3 (6)	0	0.24 b
	Widespreadd	2 (4)	1 (2)	1.00 b
Frequency of MSK pain n (%)	Twice a week or more	6 (37.5)	3 (25)
	Once a week	6 (37.5)	1 (8.3)	0.05 b
	Twice a month	3 (18.7)	4 (33.3)
	Monthly	1 (6.2)	4 (33.3)
Joint examination	Swelling	1 (2) e	-
	Pain	1 (2) e	-
	Limit on motion	0	-
Entheseal tenderness	No	42 (84)	-
	One site	3 (6)	-
	Two sites	3 (6)	-
	Three or more	2 (4)
Pain VAS- median (IQR)		40 (17-56)	-
CDLQI - mean (± SD)		5.2 (4.5)	-
PedsQL 4.0 - mean (± SD)	Physical health	84 (14.5)	94 (7.6)	<0.01 c
	Psychosocial health	73.4 (14.6)	80.6 (10.3)	0.03 c
	Total score	78.7 (13.3)	87.1 (7.6)	<0.01 c
PedsQL MFS - mean (± SD)	Total score	73.7 (17.9)	83.1 (11.2)	<0.001 c

^aMann-Whitney test.

^bFisher exact test.

^cStudent t test.

^d2 patients with mechanical + widespread pain and 1 control with both.

^elocal trauma, not chronic arthritis.

SD, standard deviation; gGALS, pediatrics Gait Arms Legs and Spine; MSK, musculoskeletal; VAS, visual analogue scale; CDLQI, Children’s Dermatology Life Quality Index; PedsQL 4.0, Pediatric Quality of Life Inventory 4.0 Generic Core Scales; PedsQL-MFS Pediatric Quality of Life Inventory - Multidimensional Fatigue Scale. Bold values indicates P-values <0.05.

Concerning to psoriasis characteristics, the median age of skin disease onset was 4 years old (IQR 2-6), and the median duration of psoriasis was 6.9 (IQR 3.7-9.5) years. Plaque psoriasis was present in 30 (60%), scalp in 30 (60%) inverted psoriasis in 11 (22%), guttate in 10 (20%), erythrodermic in 1(2%) and pustulous in 1 (2%), with some patients presenting overlapped forms. Ten patients (20%) presented many lesions on exposed areas of the body and 17 (34%) had lesions on areas of negative impact (face, palms, soles, nails, and genital area). The median of skin disease activity measured by PASI and by BSA were 3.7 (IQR 0.8-6) and 3 (IQR 1-8), respectively. The nail involvement mean assessed by NAPSI was 13 (IQR 4-21). In this sample, the presence of musculoskeletal pain was not related to skin disease activity assessed by PASI (OR = 1, 95% CIs = 0.75;1.32) or by BSA (OR = 0.99, 95% CIs = 0.83;1.19), nor nail disease measured by NAPSI (OR = 0.99, 95% CI = 0.95;1.04). HRQoL by CDLQI showed moderate correlation to PASI and BSA (r = 0.52), but general HRQoL assessed by PedsQL 4.0 and fatigue by PedsQL MFS scores did not correlate to skin disease activity (simple linear regression). The frequency of musculoskeletal complaints was similar in patients and controls, but patients with psoriasis tend to complain on more days of the month (Table 1).

As expected, psoriasis negatively impacted on HRQoL and fatigue scores, comparing to controls (Table 1). Figure 1 shows that the presence of musculoskeletal pain was associated to lower scores of HRQoL in controls and patients. Nevertheless, patients with psoriasis and musculoskeletal pain showed the most impaired scores of HRQoL (Figure 1). Fatigue was also worse among psoriasis patients with musculoskeletal pain in all three PedsQL MFS domains (general fatigue, sleep/rest fatigue and cognitive fatigue) (p<0.01, factorial ANOVA with Duncan's post hoc test).

Figure 1.

PEDSQL total Escore and domains box plot according to the presence of musculoskeletal pain in patients with psoriasis and controls. *Factorial Anova, Duncan’s post-hoc test; ^&Kruskal-Wallis Anova, Mann-Whitney’s post-hoc test.

According to the multiple logistic regression analysis, musculoskeletal pain was an independent predictor of poorer HRQoL by PedsQL in patients with psoriasis. The risk of impaired HRQoL was 7.7 times higher in the presence musculoskeletal pain (OR = 7.71,95% CI = 1.66;35.78); other variables such as age, sex, duration of disease and severity of psoriasis did not increase the risk of HRQoL impairment (Figure 2).

Figure 2.

Forest plot of factors associated to poorer health-related quality of life in patients with psoriasis. Multiple logistic regression analysis P < 0.001. BSA – Body surface area. PASI - Psoriasis Area and Severity Index. MSK - Musculoskeletal.

Discussion

Musculoskeletal pain is the third cause of ache in pediatric population (after abdominal and headache) ¹⁹ and that may be the reason why we could not detect significant differences in musculoskeletal pain answers when comparing patients and controls. However, this study reveals that the impact of musculoskeletal pain in lives of pediatric patients with psoriasis is different from their peers. We showed that children and adolescents with psoriasis and pain have worse HRQoL and poorer fatigue scores than healthy controls. Musculoskeletal impairment is a relevant contributor to disease burden in pediatric population with psoriasis, even with predominantly mild disease.

A large Danish population-based survey exploring the influence of musculoskeletal pain on patient-report outcomes of adults with psoriasis without arthritis showed that patients with pain have decreased quality of life, similar to patients with PsA, ⁷ being female and younger patients the most affected. They did not find association between disease severity by BSA and musculoskeletal pain, as our study, because systemic inflammation and rheumatic disease activity even in patients with PsA not always correlate to skin disease severity.

Later, Felbo et al. (2022) investigated clinical features and ultrasound (US) signs of inflammation in joints and entheses in patients with psoriasis with and without musculoskeletal pain and observed a high frequency of pain, which was related to US findings; but still they reported patients with clinical complaints of pain without corresponding findings in US and color doppler. ⁶ These cases are usually attributed to altered perception and pain sensitization ⁶ ; nevertheless it is necessary to reflect that musculoskeletal pain may represent a systemic impairment in psoriatic disease that may not be accessible by current investigation methods, although it already impacts the lives of patients with psoriasis since childhood, because it is associated with fatigue and reduces HRQoL, as we have shown in the present study. It is necessary to investigate and expand scientific knowledge about the origin of this pain, identifying new biomarkers of inflammation or connective tissue remodeling that can help to detect this type of systemic involvement in psoriasis. Concerning to the quality of musculoskeletal impairment, both studies from Felbo et al. have shown that adults with psoriasis and pain have more anamnestic and clinical parameters related to PsA than general population and patients with psoriasis without pain. In our limited sample, it was not possible to observe differences in the type of pain (inflammatory, mechanical, or widespread) between patients and controls; widespread pain was seen associated to mechanical pain and not severe or frequent enough to characterize fibromyalgia.

We did not observe correlation between the severity of psoriasis and general HRQoL assessed by PedsQL 4.0; that may have happened because most of the patients had low disease activity and PedsQL 4.0 is a generic measure, interesting to compare patients and controls, or the impact of different diseases in HRQoL,^3,17 but may have lost the sensitivity to capture all the impact of psoriasis. Nevertheless, PedsQL 4.0 distinguished well patients with psoriasis and controls, even in a group of patients with predominantly mild skin disease. The physical health domain, which include a question about the presence of pain, was responsive to capture the impact of musculoskeletal pain in this population. Indeed, the Brazilian version of PedsQL 4.0 applied to pediatric population with rheumatic diseases (mainly juvenile idiopathic arthritis) correlated to the measures of pain using VAS and faces scale, demonstrating good construct validity. ²⁰

Fatigue is common in systemic inflammatory conditions. Pain and fatigue intercorrelate in pediatric patients with rheumatic diseases ²¹ and both were ranked as the outcomes most important to patients receiving treatment for PsA; although fatigue is commonly underrepresented within existing composite measures. ²² Interventions addressing this problem are an unmet need. ²³ Skoie et al. assessed fatigue in 84 adults with psoriasis and 84 age and sex-matched healthy subjects; they observed that half of the patients suffer with clinically significant fatigue, its correlation to skin disease activity is not consistent, but fatigue correlates to musculoskeletal pain, ⁸ as we observed in the pediatric population of the present study. Fatigue was rarely investigated in pediatric psoriasis. Recently, Thomas SE et al described the longitudinal behavior of subjective symptoms pediatric patients with psoriasis experience. They documented that itch and severity of disease are a bigger burden for those patients, but both decrease with treatment as PASI decreases. However, fatigue is not responsive and may even worsen over the course of treatment with methotrexate or biologics. ²⁴ The origin of this problem still needs to be understood so that appropriate approaches to alleviate it can emerge.

Patients from this sample showed low disease activity by PASI and BSA, mostly treated with topical therapies, although the disease had a high negative impact on HRQoL. Considering that the decision to start systemic therapies in psoriasis is frequently based on skin disease severity, our data should draw attention to a broader view of children with psoriasis, with attention to all forms of systemic involvement and the harm to HRQoL. Lowering the threshold for systemic treatment may be necessary to achieve better long-term outcomes, reduce damage and treat the patient comprehensively.

Strengths of this study include the possibility to investigate the burden of psoriasis and pain in the pediatric age and compare its effect to healthy peers. One limitation was the impossibility to perform ultrasound images, due to reorganization of the clinic after the pandemic period. The image would help to clarify if there are subclinical inflammation or nociplastic pain induced by psoriasis cytokines acting in central nervous system. Nevertheless, there is no consensual definition of ultrasonographic enthesitis in children and the image is challenging because of the different stages of growth and vascularization in immature entheses. The method still lacks validation in pediatric age and the concordance between ultrasound and clinical examination is generally low. ²⁵ In our previous study, from nine pediatric patients with psoriasis and pain on palpation of entheses, one had positive ultrasound sign (9). ²⁶

In conclusion, this study documents the presence of fatigue and the negative impact of musculoskeletal pain in HRQoL of children and adolescents with psoriasis. Psoriatic disease is currently seen as a continuum in which targeted therapies have the potential to halt disease progression and change the prognosis. It is time to broaden our view of pediatric psoriasis even in its mild forms. Studies focusing on the etiology, biomarkers and approach of systemic impairment of psoriatic disease in pediatric age are warranted.

Ethical Statement

Ethical Approval

The protocol of the present study was developed based on the ethical standards in force and approved by the research ethics committee (IRB – 4.908.455).

Informed Consent

Parents signed informed consent and participants over seven years old signed assent documents.

ORCID iD

Thaís Cugler Meneghetti https://orcid.org/0000-0001-6843-2035