Health-related quality of life for children with rare diagnoses, their parents' satisfaction with life and the association between the two

Heidi Johansen
Brede Dammann
Inger-Lise Andresen
Morten Wang Fagerland
Health-related quality of life for children with rare diagnoses, their parents' satisfaction with life and the association between the two
R E S E A R C H Open AccessSchool childrenDisabilitiesRare disordersChildren's health related quality of lifePedsQLParent's satisfaction of lifeSWLS
Purpose: To examine children's health-related quality of life and parents' satisfaction with life and explore the association between the two in families where a child has a rare disorder. Methods: We used a cross-sectional study design. A questionnaire was sent to parents of 439 school children (6-18 years) with congenital rare disorders. Children's health-related quality of life (HRQOL) was examined by Pediatric Quality of Life Inventory TM 4.0 (PedsQL) Norwegian version. Satisfaction with life was examined by Satisfaction with Life Scale (SWLS).Results: The response rate was 48% (n = 209). The average age of the children was 12 years and 50% were girls. The parents scored their children with reduced physical, emotional, social and school functioning. The reductions were greatest in the physical area. Parents scored average to high on SWLS but significantly lower than the general Norwegian population. There was a positive association between parental SWLS and the children's social functioning and school functioning. Conclusion: Children with congenital, rare disorders often require assistance from many parts of the public service system. Caring for their physical needs should not conflict with their educational and social needs. It is important that the children's school-life is organized so that the diagnosis does not interfere with the children's education and social life more than necessary.

Background

Living with illness and disability can affect everyday life in several ways. Some people with disabilities are continually or periodically in need of specialized medical care. Many need individual facilitation and adaptation in education, work and everyday life. For children, physical disability may lead to reduced interaction with other children because of decreased ability to play and keep up with children without disability, and because of accessibility problems. Cognitive and emotional problems may present challenges in learning and social participation. It has been shown that children with disability have lower health-related quality of life (HRQOL) than most children [1,2] and that many experience challenges in relation to independence and transition into adulthood [3].

Parenting brings both joys and sorrows; however, parents of children with disabilities may face additional strains that affect their health and well-being. A child's disability can lead to additional work and worries and have an impact on parents' employment and social life. Parents of chronically ill children may have reduced HRQOL [4,5] and well-being [6]. There is considerable variation in how parents cope with their parental role, and this also applies to parents of children with disabilities [7]. The factors that seem to be related to parents' HRQOL include degree of emotional support, knowledge about the condition, available leisure time and other family members' health problems [5].

Research often focused on strains and problems for people living with disabilities, both for the people who are disabled and their family members. This perspective is important to promote understanding for the strenuous aspects of life with a disability and to ensure necessary interventions and services. However, in clinical practice we meet children and adults with disabilities and their family members that live good lives despite the worries and extra strain.

Parental wellbeing can influence their ability to take good care of their children. To our knowledge, no studies have focused on which areas of the disabled children's lives are most important to their parents' well-being.

The aims of this study are to examine: (1) HRQOL in school children with seven rare disorders compared with average Norwegian school children; (2) satisfaction with life for parents of children with rare congenital disorders compared with the general population; and (3) the association between parental satisfaction with life and their children's HRQOL.

Participants and methods

The study was designed as a cross-sectional postal survey.

Participants

TRS National Resource Centre for Rare Disorders (TRS) provides services to all people in Norway with some specific rare diagnoses primarily related to the musculoskeletal system. The severity of these disabilities varies, both between the different diagnoses and within the individual diagnoses. Some of the diagnoses are hereditary, none can be cured, but some problems can be prevented and symptoms can be treated. There are seven diagnostic groups: congenital limb deficiency (CLD), arthrogryposis multiplex congenita (AMC), Marfans syndrome (MRF), Ehlers-Danlos syndrome (EDS), short stature due to skeletal dysplasia (StSh), osteogenesis imperfect (OI) and spina bifida/myelomeningocele (MMC).

Persons seeking services at TRS agree to be included in a data-based register. In October 2010 a questionnaire was sent to parents of all children 6-18 years in that register (439 children). After three weeks, a reminder was sent to those who had not responded.

The study was approved by the Regional Committees for Medical and Health Research Ethics in April 2010.

Methods

The questionnaires were divided into five sections:

1. Parents' health, education and employment. 2. Children's diagnosis, medical follow-up, local welfare services and school conditions. 3. Parents' satisfaction and experience of participation in designing the services. 4. Children's HRQOL (PedsQL) reported by both the parents and the children. 5. Parents' satisfaction with life (SWLS).

The Norwegian version of the Pediatric Quality of Life Inventory™ 4.0 (PedsQL) was used [8]. PedsQL is a generic instrument widely used to measure health-related quality of life for children, both reported by the children and by proxy, usually parents [9]. Because the purpose of this study was to explore the association between parents' satisfaction with life and their perception of their children's HRQOL, we used the parents' report. The instrument spans ages 2-18 with age adjusted versions. The 23-item PedsQL can be expressed as a total score or grouped into four domains: physical functioning (eight items), emotional functioning (five items), social functioning (five items), and school functioning (five items). All domains have a scale ranging from 0-100 where higher scores indicate better HRQOL. The PedsQL Norwegian version has shown adequate psychometric properties [8].

We used the Norwegian translation of the Satisfaction with Life Scale (SWLS) to measure the parents' satisfaction with life [10]. SWLS is an instrument widely used to measure subjective well-being and life satisfaction [11], and it does not focus on problems or strains. SWLS is a self-report questionnaire with five global indicators of quality of life, each scored on a seven-point scale. Results are expressed either as five individual scores (1-7), or a total sum score (5-35) where higher scores indicate better satisfaction with life. We used the sum score in this study. Scores between 20 and 24 are considered an average level of satisfaction with life [12]. The instrument has been tested for reliability and validity and has shown adequate psychometric properties [11].

To compare the PedsQL and SWLS scores from this study with the general Norwegian population, we used PedsQL scores from a study of Norwegian school children [8] and SWLS scores from a Norwegian population-based study [13,14].

Statistics

We used Glass's delta effect size (ES) scores to estimate the differences between the scores observed in this study and those of the general Norwegian population. The ES is obtained by dividing the difference in scores by the standard deviation in the general population [15]. Values of ES less than 0.5, from 0.5 to 0.8, and greater than 0.8 are commonly interpreted as indicating small, moderate, and large differences, respectively [16]. One-sample t-tests were used to test the null hypothesis that the ES scores equaled zero. We used paired-samples t-tests to compare PedsQL scores reported by children and parents. Linear regression models were used to examine the influence of different factors on the parents' SWLS. We considered the following factors: mother's and father's education (less than 12 years/12 years or more); mother's employment (working more than 50% or not); others with health problems in the family (yes/no); child living with both parents (yes/no); the child's age and gender; and parent-reported PedsQL scores using the four domains of physical, emotional, social and school functioning. P < 0.05 was considered statistically significant.

Results

The total response rate was 48% and it ranged between 41% and 54% for the different diagnostic groups. There were only small differences in the children's gender and age among responders and non-responders, both for the total sample and for the individual diagnoses (Additional file 1: Table S1).

Most children (82%) lived with both their mother and father. In 37% of the families another family member had health problems. The mean age of the children was 11.5 years (range 6-18 years). About one third of the children used a wheelchair, and the proportion was highest (83%) among those with MMC ( Table 1).

The total PedsQL score for Norwegian schoolchildren was 86.1, for the total study sample 67.6, varying between 55.9 (MMC) and 78.8 (DSM) for the different diagnostic groups (Additional file 1: Table S2).

On the PedsQL physical, social and school functioning scales, scores were significantly lower than for Norwegian school children, both for the total study sample and for all the diagnostic groups. On the emotional functioning scale the total study sample, EDS, ShSt and MMC groups scored significantly lower than healthy Norwegian children. However, the CLD, AMC, MFS and OI groups had scores comparable with healthy Norwegian children (Table 2).

For the total study sample, we observed moderate to large ES scores in all PedsQL domains. Children with CLD had the smallest HRQOL reductions (ES 0.11 to 1.03), while children with MMC had the greatest HRQOL reductions (ES 0.91 to 3.85) compared to Norwegian school children ( Table 2).

Both for the total study sample and for the individual diagnostic groups, the children reported better health on nearly all PedsQL scales than did their parents. Most differences were small (moderate on one scale for two groups) (ES 0.00 to 0.67), some were statistically significant (Additional file 1: Table S3).

Parents' SWLS were significantly lower than the general Norwegian population, both for the total sample (ES = 0.21, p = 0.018) and for the EDS sample (ES = 0.90, p = 0.003), but not for the other diagnostic groups (Table 3).

For the total study population, univariate analyses showed positive associations between parents' SWLS and all domains of the children's PedsQL, but no association between parental SWLS and the gender and age of the children. In a multiple linear regression model, we observed significant associations between parental SWLS and others with health Table 1 Socio-demographic and clinical characteristics of the total study sample and the individual diagnostic groups  problems in the family (p <0.001), children's social functioning (p = 0.002) and school functioning (p < 0.001) ( Table 4). For both the CLD and MMC groups separately, we observed significant associations between parental SWLS and all domains of the PedsQL. In multiple regression models, only school functioning remained significant in the CLD group. In the MMC group, none of the domains remained significant, although school functioning had a similar regression coefficient as in the univariate analysis but with a wider confidence interval that barely included zero (Table 4).

Discussion

This study shows that parent-reported HRQOL is significantly lower for children with rare disorders than for Norwegian school children. The greatest reduction in HRQOL was found in physical functioning, and the smallest reduction was found in emotional functioning. There were considerable differences between the diagnoses.

This study also shows that parents report somewhat reduced SWLS compared to the general Norwegian population. For the total study sample, multiple regression analyses showed significant associations between parental SWLS and the following factors: others with health problems in the family and the child's social and school functioning. Children's gender and age did not influence parental SWLS.

Several studies have shown a reduced HRQOL for children with different diagnoses [1,2,17,18]. We expected a similar result for the children in this study. Since they have diagnoses with mainly physical disabilities, we expected the most reduction on the physical scale. This was confirmed for the whole group and for all diagnoses. A physical disability may influence life for a child in many ways: it may lead to some discomfort or pain, give some extra strain and make play with other children difficult. Therefore we expected a reduction also on the emotional scale. This reduction, however, was small, and did not apply to all diagnoses.

Because of the different nature of the diagnoses in this study we expected differences in reported HRQOL, and this was confirmed. The children with MMC, a complex condition with several medical and cognitive challenges [2,19], had lowest scores on all PedsQL scales. On the other hand, the children with CLD, a less complicated diagnosis that influences daily life to a lesser degree than the other diagnoses [20], scored similar to Norwegian school children on most scales.

The fact that a diagnosis is rare can be a burden in itself [21]. However, it is unclear whether this applies to children with rare disorders, or mainly to their parents and adults who themselves have a rare diagnosis. We have not found studies that report PedsQL subscale scores for Norwegian children with common diagnoses, but a study of Norwegian children with CP report total PedsQL scores, parent report [22]. CP is a congenital disorder that gives challenges comparable to those of the diagnoses in this study, especially MMC. The scores for the CP group are similar to those for the diagnoses with lowest scores in this study, MMC and EDS. This may indicate that children with rare disorders do not have lower quality of life than  children with well-known common diagnoses. Another interpretation is that PedsQL total score does not capture the specific burdens of having a rare diagnosis. We expected that having a child with a rare disease would influence parents' satisfaction with life in a negative way. This was largely confirmed by the fact that the parents in this study had somewhat lower SWLS than the general Norwegian population. However, according to the interpretation of scores [12], the scores observed in this study were between average and high. The mean score for the general Norwegian population is high compared with other countries [13]. That parents of children Note: Child gender: girls = 1 and boys =2, lives with both parents: 0 = no and 1 = yes, other with health problems in family: no = 0 and yes = 1, mothers employment level: work 50% or more = 1 and work less than 50% = 2, education level: ≤ 12 years = 1and > 12 years = 2.

with disabilities score themselves relatively high on an international scale may reflect that their lives are satisfactory in most ways. However, the reduced score compared with other Norwegians suggests that there are some strains associated with having a disabled child. There was, however, a difference between the diagnostic groups. For most diagnoses, the parents reported SWLS at nearly the same level as the general Norwegian population. Only parents of children with EDS reported significantly reduced SWLS. This may be explained by the fact that many of the families with EDS had other family members with health problems , which has been shown to give reduced HRQOL [5]. In addition, it can take a long time to establish a diagnosis of EDS, and many feel that they have to struggle to get necessary help from the health-and welfare support system [23].

Many different factors influence satisfaction with life [11,12]. We expected that the better the children function, the more satisfied their parents would be. This was supported by the univariate analyses, where the children's PedsQL scores on all scales were significantly and positively correlated with parental SWLS.

We also expected that the children's functioning in different areas of life would influence their parent's life satisfaction in different degree. In the multiple regression analyses, the most pronounced positive associations were between parental SWLS and the children's social and school functioning. Our clinical experience is that parents fear that their children may be excluded or bullied because of their diagnoses. Therefore it is logical that the parents' SWLS is strongly influenced by their children's social functioning. Parents also worry about how the diagnoses may restrict the child in school [24], because success in school forms the basis for further education and later employment. Education level is strongly associated with participation in the labor force, especially for people with disabilities [25,26]. This may explain why the child's functioning at school show significant association with parental SWLS.

With increasing age comes an increasing gap in mobility, pace and independence between children with disabilities and their peers [3,27]. This may be of great concern for parents. We expected a negative correlation between the children's age and parents' SWLS, but this assumption was not confirmed in this study. Other studies found that parents' quality of life is reduced in families where more than one family member has health problems [5]. In accordance with this, we found reduced satisfaction with life for parents when other family members had health problems.

Methodological considerations

There are several methodological and ethical challenges concerning research in rare disorders; it is difficult to find samples of sufficient magnitude [28], and small sample sizes give challenges in relation to anonymity [29].

The study population is recruited through the TRS register. Registration at the center is voluntary with no systematic referral. It is likely that most parents would register their children in order to ensure access to expertise and services at the centre; therefore we assume that most children with these rare disorders are registered at TRS.

The relatively low response rate is usual in self-reported postural cross-sectional studies [30]. There were no significant differences between responders and non-responders in relation to the gender and age of the children. The study samples are small for several diagnoses, and therefore the findings must be interpreted with caution.

Since the aim of this study was to explore associations between parental SWLS and the children's HRQOL, the parents' evaluation of their children's HRQOL was used even though children's self-reported HRQOL is considered the gold standard [31]. This article does not aim to focus on the problematic side of having a child with disability. Therefore we chose to use a global instrument of life satisfaction to give voice to the coping side of life in families where a child has a rare diagnosis. Not asking both parents to fill out the SWLS separately weakened the study, but it can be justified to use the data as a whole because population studies have found little difference between the sexes [13].

Conclusion

This study shows that parents of children with rare diagnoses score their children with lower health-related quality of life than the parents of the general population. The greatest reductions in scores are in the physical domain and the lowest reductions in scores are in the emotional domain. Most parents show a similar satisfaction with life as parents of the general population. There were considerable differences between the individual diagnoses for the children's health-related quality of life and the parents' satisfaction with life. Associations between children's school functioning and parents' satisfaction with life was significant both for the total study sample and for the two diagnostic samples where multivariate analysis was possible.

Implications

In addition to being an important learning arena, school is also the main arena for participation, social learning and preparation for independent adult life, particularly for children with disabilities. Many need assistance from many parts of the public service system, often simultaneously. Sometimes it seems that the physical needs of these children are taken better care of than their educational and social needs. Health providers may expose children and families for requirements (follow-up, treatment, training) that may conflict with ordinary school life. Prioritizing between the children's physical, social and educational needs may be difficult. It is important that the children and their parents are involved in decisions about this and about how the children's school-day is organized.

Consent

Written informed consent regarding participation in the study was obtained from the parents.

Table 2
2PedsQL scores reported by parents compared with PedsQL scores of Norwegian school children (Nsc)Physical functioning
Emotional functioning
Social functioning
School functioning

N
Mean (SD) ES (p-value) Mean (SD)
ES (p-value)
Mean (SD) ES (p-value) Mean (SD)
ES (p-value)

Nsc
419 88. 8 (11.8)
80.0 (14.1)
88.1 (13.4)
89.0 (12.3)

Total study sample 209 59.6 (27.2)
2.42 (< 0.001) 71.8 (18,8)
0.58 (< 0.001) 68.8 (22.7)
1.45 (< 0.001) 69.4 (21.1)
1.59 (< 0.001)

CLD
67
77.3 (23.6)
1.00 (< 0.001) 78.5 (17.3)
0.11 (0.477)
80.5 (23.0)
0.57 (0.012)
80.3 (18.6)
0.71 (< 0.001)

AMC
17
47.1 (27.0)
3.53 (< 0.001) 72.7 (20.4)
0.52 (0.186)
61.7 (20.9)
1.97 (< 0.001) 69.7 (23.6)
1.57 (0.007)

MFS
11
73.1 (12.7)
1.33 (0.003)
71.8 (19.1)
0.58 (0.187)
68.6 (13.8)
1.46 (0.001)
66.4 (23.6)
1.84 (0.010)

EDS
21
52.4 (23.3)
3.08 (< 0.001) 59.0 (20.8)
1.49 (< 0.001) 66.0 (23.3)
1.65 (< 0.001) 56.9 (15.3)
2.61 (< 0.001)

ShSt
28
51.2 (21.0)
3.19 (< 0,001) 70.7 (17.1)
0.66 (0,009)
61.9 (18.9)
1.96 (< 0,001) 69.3 (17.7)
1.60 (< 0.001)

OI
23
53.9 (28.6)
2.92 (< 0,001) 73.4 (19.0)
0.47 (0.118)
68.0 (20.7)
1.50 (< 0.001) 71.4 (18.9)
1.43 (< 0.001)

MMC
42
44.5 (24.1)
3.67 (< 0.001) 67.1 (16.7)
0.91 (< 0.001) 59.3 (20.8)
2.20 (< 0.001) 58.4 (21.5)
2.50 (< 0.001)

Note: Some missing values but less than 13% for all variables (Additional file 1: Table S4).

Table 3
3SWLS scores of parents compared with SWLS scores of the Norwegian general population (NGP)N
Mean (SD)
ES (p-value)

NGP
26.2 (6.3)

Parents of the total study sample
199
24.9 (6.6)
0.21 (0.018)

CLD-parents
65
26.1 (6.4)
0.02 (0.878)

AMC-parents
15
22.5 (7.1)
0.59 (0.078)

MFS-parents
10
23.6 (5.9)
0.41 (0.228)

EDS-parents
21
20.5 (7.4)
0.90 (0.003)

ShSt-parents
26
25.5 (6.9)
0.11 (0.716)

OI-parents
22
25.7 (5.8)
0.08 (0.855)

MMC-parents
40
25.5 (5.8)
0.08 (0.589)

Table 4
4Associations between parents SWLS and factors concerning the families and the childrenIndependent variable
Univariat regresion
Multiple regresion

Coeffecient (95% CI)
p-value
Coefficient (95% CI)
p-value

Totale sample (N = 209)
PedsQL Parent report

Physical functioning
0.9 (0.6 to 1.1)
< 0.001
−0.4 (−0.8 to 0.06)
0.093

Emotional functioning
1.6 (1.1 to 2.0)
< 0.001

Social functioning
1.2 (0.9 to 1.6)
< 0.001
0.7 (0.2 to 1.3)
0.002

School functioning
1.6 (1.3 to 2.0)
< 0.001
1.3 (0.8 to 1.8)
< 0.001

Child gender
4.8 (−13.7 to 23.2)
0.612

Child age
−1.5 (−4.2 to 1.3)
0.293

Lives with both parents
28.2 (4.8 to 51.6)
0.019

Other with health problems in family
−45.9 (−64.1 to −27.7)
< 0.001
−36.5 (−53.2 to −20.0)
< 0001

Mother work 50% or more
−29.8 (−49.6 to −9.9)
0.003

Mother education level >12 years
19.5 (0.8 to 38.3)
0.042

Father education level >12 years
29.9 (11.4 to 48.4)
0.002

CLD (N = 67)
PedsQL Parent report

Physical functioning
1.2 (0.6 to 1.9)
< 0.001
−0.4 (−1.5 to 0.7)
0.482

Emotional functioning
1.6 (0.7 to 2.4)
0.001
−0.3 (−1.5 to 0.8)
0.565

Social functioning
1.6 (1.0 to2.2)
< 0.001
1.2 (0.04 to 2.4)
0.057

School functioning
2.0 (1.3 to 2.7)
< 0.001
1.5 (0.3 to 2.7)
0.015

Child gender
19.7 (−12.3 to 51.7
0.223

Child age
2.1 (−2.6 to 6.7)
0.381

Lives with both parents
16.9 (−29.4 to 63.2
0.468

Other with health problems in family
−20.5 (−57.9 to 16.8)
0.276

Mother work 50% or more
−22.0 (−61.0 to 16.9)
0.263

Mother education level >12 years
23.6 (−10.2 to 57.4)
0.168

Father education level >12 years
29.9 (−3.1 to 63.0)
0.075

MMC (N = 42)
PedsQL Parent report

Physical functioning
0.8 (0.02 to 1.6)
0.044
−0.1 (−1,2 to1,0)
0,906

Emotional functioning
1.2 (0.1 to 2,3)
0.034
−0.2 (−2.1 to1.7)
0.821

Social functioning
1.2 (0.3 to 2.1)
0.013
0.3 (−1.5 to 2.0)
0.768

School functioning
1.4 (0.6 to 2.2 )
0.001
1.4 (−0.1 to 2.9)
0.067

Child gender
−29.2 (−66.0 to 7.7)
0.117

Child age
−1.5 (−7.4 to 4.5)
0.620

Lives with both parents
−19.4 (−81.8 to 42.9)
0.532

Other with health problems in family
−15.4 (−54.5 to 23.7)
0.431

Mother work 50% or more
−8.3 (−49.3 to 32.6)
0.683

Mother education level >12 years
−36.4 (−73.2 to 0.3)
0.052

Father education level >12 years
40.6 (−36.8 to 44.9)
0.841

http://www.hqlo.com/content/11/1/152
AcknowledgmentsWe want to thank the TRS Resource Centre for founding the study, the user's organization for valuable help and participation and the families who answered the questionnaire and made this study possible.Additional fileAdditional file 1:Table S1. Differences between responders and non-responders.Table S2: PedsQL total score, parents' report.Table S3: Differences between PedsQL parents' report and children's report (observations where both the children's and parents' reports are available).Table S4: Number of responders in the individual PedsQL scales.Competing interestsThe authors declare that they have no competing interests.Authors' contributions HJ, ILA and BD initiated and designed the study and participated in the data collection, the statistical analysis and drafted the manuscript. MWF supervised the study process and contributed to conceptualization and design, data analysis, interpretation of results, drafting and revising the manuscript. All authors participated in the discussions of results in the writing of the paper and read and approved the final manuscript.
Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL™ 4.0 generic core scales. J W Varni, C A Limbers, T M Burwinkle, Health Qual Life Outcomes. 5143Varni JW, Limbers CA, Burwinkle TM: Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL™ 4.0 generic core scales. Health Qual Life Outcomes 2007, 5(1):43.

Quality of life in individuals with spina bifida: a research update. K J Sawin, M H Bellin, Dev Disabil Res Rev. 161Sawin KJ, Bellin MH: Quality of life in individuals with spina bifida: a research update. Dev Disabil Res Rev 2010, 16(1):47-59.

Growing into disability benefits? Psychosocial course of life of young adults with a chronic somatic disease or disability. E Verhoof, H Maurice-Stam, H Heymans, M Grootenhuis, Acta Paediatr. 1011Verhoof E, Maurice-Stam H, Heymans H, Grootenhuis M: Growing into disability benefits? Psychosocial course of life of young adults with a chronic somatic disease or disability. Acta Paediatr 2012, 101(1):1651-2227.

Hidden consequences of success in pediatrics: parental healthrelated quality of life-results from the care project. J Hatzmann, H S Heymans, A Ferrer-I-Carbonell, B M Van Praag, M A Grootenhuis, Pediatrics. 1225Hatzmann J, Heymans HS, Ferrer-i-Carbonell A, van Praag BM, Grootenhuis MA: Hidden consequences of success in pediatrics: parental health- related quality of life-results from the care project. Pediatrics 2008, 122(5):2008-0582.

A predictive model of health related quality of life of parents of chronically ill children: the importance of care-dependency of their child and their support system. J Hatzmann, H Maurice-Stam, H S Heymans, M A Grootenhuis, Health Qual Life Outcomes. 772Hatzmann J, Maurice-Stam H, Heymans HS, Grootenhuis MA: A predictive model of health related quality of life of parents of chronically ill children: the importance of care-dependency of their child and their support system. Health Qual Life Outcomes 2009, 7:72.

Stress and wellbeing among parents of children with rare diseases: a prospective intervention study. L Dellve, L Samuelsson, A Tallborn, A Fasth, L R Hallberg, J Adv Nurs. 534Dellve L, Samuelsson L, Tallborn A, Fasth A, Hallberg LR: Stress and well- being among parents of children with rare diseases: a prospective intervention study. J Adv Nurs 2006, 53(4):392-402.

Effects of pediatric chronic physical disorders on child and family adjustment. J L Wallander, J W Varni, J Child Psychol Psychiatry. 391Wallander JL, Varni JW: Effects of pediatric chronic physical disorders on child and family adjustment. J Child Psychol Psychiatry 1998, 39(1):29-46.

Measuring health-related quality of life in young adolescents: reliability and validity in the Norwegian version of the Pediatric Quality of Life Inventory™ 4.0 (PedsQL) generic core scales. T Reinfjell, T H Diseth, M Veenstra, A Vikan, Health Qual Life Outcomes. 4161Reinfjell T, Diseth TH, Veenstra M, Vikan A: Measuring health-related quality of life in young adolescents: reliability and validity in the Norwegian version of the Pediatric Quality of Life Inventory™ 4.0 (PedsQL) generic core scales. Health Qual Life Outcomes 2006, 4(1):61.

PedsQL 4.0: reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. J W Varni, M Seid, P S Kurtin, Med Care. 398Varni JW, Seid M, Kurtin PS: PedsQL 4.0: reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001, 39(8):800-812.

Satisfaction with life scale (SWLS). SWLS translationsSatisfaction with life scale (SWLS). SWLS translations. [http://internal. psychology.illinois.edu/~ediener/SWLS.html]

The satisfaction with life scale. E Diener, R A Emmons, R J Larsen, S Griffin, J Pers Assess. 491Diener E, Emmons RA, Larsen RJ, Griffin S: The satisfaction with life scale. J Pers Assess 1985, 49(1):71-75.

Psykisk helse i Norge : levekårsundersøkelsen 2005 : tilstandsrapport med internasjonale sammenligninger. J Clench-Aas, M Rognerud, O S Dalgard, Understanding Scores on the Satisfaction with Life Scale. Oslo6Nasjonalt folkehelseinstitutt; 2009:78. s. : ill., tabUnderstanding Scores on the Satisfaction with Life Scale. [http://internal. psychology.illinois.edu/~ediener/SWLS.html] 13. Clench-Aas J, Rognerud M, Dalgard OS: Psykisk helse i Norge : levekårsundersøkelsen 2005 : tilstandsrapport med internasjonale sammenligninger. In vol. 2009:6. Oslo: Nasjonalt folkehelseinstitutt; 2009:78. s. : ill., tab.

Dimensionality and measurement invariance in the satisfaction with life scale in Norway. J Clench-Aas, R B Nes, O S Dalgard, L E Aaro, Qual Life Res. 208Clench-Aas J, Nes RB, Dalgard OS, Aaro LE: Dimensionality and measurement invariance in the satisfaction with life scale in Norway. Qual Life Res 2011, 20(8):1307-1317.

P D Ellis, The Essential Guide to Effect Sizes. CambridgeCambridge University PressEllis PD: The Essential Guide to Effect Sizes. Cambridge: Cambridge University Press; 2010.

Statistical power analysis for the behavioral sciences. J Cohen, Hillsdale, N. J.: Laurence ErlbaumCohen J: Statistical power analysis for the behavioral sciences. Hillsdale, N. J.: Laurence Erlbaum; 1988.

Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire. A M Selvaag, B Flato, G Lien, D Sorskaar, O Vinje, O Forre, J Rheumatol. 307Selvaag AM, Flato B, Lien G, Sorskaar D, Vinje O, Forre O: Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire. J Rheumatol 2003, 30(7):1602-1610.

Barn med skjelettdysplasi slik deres foreldre ser dem-en kartleggingsstudie. Pediatrisk Endokrinologi (Pediatric Endocrinology). H Johansen, I L Andresen, 23Johansen H, Andresen IL: Barn med skjelettdysplasi slik deres foreldre ser dem-en kartleggingsstudie. Pediatrisk Endokrinologi (Pediatric Endocrinology) 2009, 23(1):42-47.

Rehabilitation and medical management of the adult with spina bifida. B E Dicianno, B G Kurowski, J M Yang, M B Chancellor, G K Bejjani, A D Fairman, N Lewis, J Sotirake, Am J Phys Med Rehabil. 8712Dicianno BE, Kurowski BG, Yang JM, Chancellor MB, Bejjani GK, Fairman AD, Lewis N, Sotirake J: Rehabilitation and medical management of the adult with spina bifida. Am J Phys Med Rehabil 2008, 87(12):1027-1050.

Impact of prostheses on function and quality of life for children with unilateral congenital below-the-elbow deficiency. M A James, A M Bagley, K Brasington, C Lutz, S Mcconnell, F Molitor, J Bone Joint Surg Br. 8811James MA, Bagley AM, Brasington K, Lutz C, McConnell S, Molitor F: Impact of prostheses on function and quality of life for children with unilateral congenital below-the-elbow deficiency. J Bone Joint Surg Br 2006, 88(11):2356-2365.

Facing ignorance: people with rare disorders and their experiences with public health and welfare services. L Grut, M H Kvam, Grut L, Kvam MH: Facing ignorance: people with rare disorders and their experiences with public health and welfare services; 2012.

Mental health, health related quality of life and recurrent musculoskeletal pain in children with cerebral palsy 8-18 years old. K Ramstad, R Jahnsen, O H Skjeldal, T H Diseth, Disabil Rehabil. 3419Ramstad K, Jahnsen R, Skjeldal OH, Diseth TH: Mental health, health related quality of life and recurrent musculoskeletal pain in children with cerebral palsy 8-18 years old. Disabil Rehabil 2012, 34(19):1589-1595.

Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. M Castori, ISRN Dermatol. 7517681022Castori M: Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol 2012, 751768(10):22.

Parental experiences of children's disabilities and special education in the United States and Japan: implications for school social work. M Kayama, Soc Work. 552Kayama M: Parental experiences of children's disabilities and special education in the United States and Japan: implications for school social work. Soc Work 2010, 55(2):117-125.

Life course determinants for early disability pension: a follow-up of Norwegian men and women born 1967-1976. H M Gravseth, T Bjerkedal, L M Irgens, O O Aalen, R Selmer, P Kristensen, Eur J Epidemiol. 228Gravseth HM, Bjerkedal T, Irgens LM, Aalen OO, Selmer R, Kristensen P: Life course determinants for early disability pension: a follow-up of Norwegian men and women born 1967-1976. Eur J Epidemiol 2007, 22(8):533-543.

A follow up of persons who received basic and/or supplemental benefits in childhood. T Bjerkedal, P Kristensen, G A Skjeret, J I Brevik, Tidsskr Nor Laegeforen. 1264Bjerkedal T, Kristensen P, Skjeret GA, Brevik JI: A follow up of persons who received basic and/or supplemental benefits in childhood. Tidsskr Nor Laegeforen 2006, 126(4):436-439.

How does participation of youth with spina bifida vary by age?. E H Kelly, H Altiok, J A Gorzkowski, J R Abrams, L C Vogel, Clin Orthop Relat Res. 4695Kelly EH, Altiok H, Gorzkowski JA, Abrams JR, Vogel LC: How does participation of youth with spina bifida vary by age? Clin Orthop Relat Res 2011, 469(5):1236-1245.

M Loeb, L Grut, Sjeldne funksjonshemminger i Norge. Behov for kunnskap om insidens og prevalens. Norway: SINTEF-rapport A9263. Loeb M, Grut L: Sjeldne funksjonshemminger i Norge. Behov for kunnskap om insidens og prevalens. Norway: SINTEF-rapport A9263; 2008.

Ethical review of research into rare genetic disorders. M Parker, R Ashcroft, A O Wilkie, A Kent, Bmj. 3297460Parker M, Ashcroft R, Wilkie AO, Kent A: Ethical review of research into rare genetic disorders. Bmj 2004, 329(7460):288-289.

D G Altman, Practical statistics for medical research. London, New YorkChapman and HallAltman DG: Practical statistics for medical research. London, New York: Chapman and Hall; 1991.

Measuring health-related quality of life in children and adolescents : implications for research and practice. D Drotar, 10.1186/1477-7525-11-152Lawrence Erlbaum Associates PublishersMahwah, N.J.Drotar D: Measuring health-related quality of life in children and adolescents : implications for research and practice. Mahwah, N.J.: Lawrence Erlbaum Associates Publishers; 1998. doi:10.1186/1477-7525-11-152

Health-related quality of life for children with rare diagnoses, their parents' satisfaction with life and the association between the two. Johansen, Health and Quality of Life Outcomes. 11152Cite this article asCite this article as: Johansen et al.: Health-related quality of life for children with rare diagnoses, their parents' satisfaction with life and the association between the two. Health and Quality of Life Outcomes 2013 11:152.


Open Access Role of resistin as a marker of inflammation in systemic lupus erythematosus
Published: 30 Jan 2008

Katarina Almehed email@example.com
Department of Rheumatology and Inflammation Research
Sahlgrenska Academy at Göteborg University
Guldhedsgatan 10S-413 46GöteborgSweden

Helena Forsblad D'elia
Department of Rheumatology and Inflammation Research
Sahlgrenska Academy at Göteborg University
Guldhedsgatan 10S-413 46GöteborgSweden

Maria Bokarewa
Department of Rheumatology and Inflammation Research
Sahlgrenska Academy at Göteborg University
Guldhedsgatan 10S-413 46GöteborgSweden

Hans Carlsten
Department of Rheumatology and Inflammation Research
Sahlgrenska Academy at Göteborg University
Guldhedsgatan 10S-413 46GöteborgSweden

Open Access Role of resistin as a marker of inflammation in systemic lupus erythematosus
Published: 30 Jan 200810.1186/ar2366)Received: 26 Sep 2007 Revisions requested: 22 Nov 2007 Revisions received: 23 Dec 2007 Accepted: 30 Jan 2008Available online http://arthritis-research.com/content/10/1/R15 Page 1 of 9 (page number not for citation purposes) Research article
IntroductionResistin is a cystein-rich secretory adipokine. It is proposed to have proinflammatory properties in humans. The aim of this study was to determine associations between serum levels of resistin and markers of inflammation and bone mineral density (BMD) in female patients with systemic lupus erythematosus (SLE).Methods One hundred sixty-three female patients with SLE (20 to 82 years old) were examined in a cross-sectional study. Venous blood samples were analyzed for resistin, erythrocyte sedimentation rate (ESR), C-reactive protein, creatinine, fasting lipids, complements, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, sIL-6R (soluble IL-6 receptor), ICTP (C-terminal telopeptide of type I collagen), and PINP (N-terminal propeptide of type I procollagen). Simple and multiple regression analyses as well as logistic regression analyses were performed. Resistin in serum was compared with 42 healthy female controls with respect to age.ResultsSerum resistin levels in controls were similar to those of patients with SLE. Markers of inflammation and current dose of glucocorticosteroids correlated positively to resistin in serum. Markers of renal function, number of prevalent vertebral fractures, and BMD were also significantly associated with resistin. In a multiple regression model, ESR, creatinine, C3, current glucocorticosteroid dose, high-density lipoprotein, and BMD radius remained significantly associated with resistin. In logistic regression analyses with resistin as the independent variable, a significant association was found with ESR (normal or elevated) but not with S-creatinine or z score for hip and radius total. Conclusion Although resistin measurements did not differ between patients and controls, resistin was clearly associated with general inflammation, renal disease, treatment with glucocorticosteroids, and bone loss. We hypothesize that resistin has proinflammatory and disease-promoting properties in SLE. Further studies are needed to elucidate the mechanism behind these associations.

Introduction

Resistin is a recently described, low-molecular-weight, cystein-rich secretory peptide [1][2][3]. It is also known as adipocyte-specific secretory factor. Animal studies show that resistin is produced mainly in white adipose tissue and may be the linkage between obesity and insulin resistance. In humans, the role of resistin is not yet fully established. There is evidence that resistin has proinflammatory properties and is abundant in inflammatory diseases (for instance, rheumatoid arthritis (RA) [4] and Crohn disease [5]) and also is associated with inflam-matory markers in several different populations [6][7][8]. In humans, resistin is expressed in inflammatory cells, leukocytes, and macrophages [9] and has the potency of inducing production of interleukin (IL)-6 and tumor necrosis factor-alpha (TNFα) [9,10]. Resistin is accumulated in inflamed joints of patients with RA and has the capacity to induce arthritis in mice [11]. There are also data indicating that resistin levels are inversely associated with renal function and possibly contribute to a low-grade inflammation in patients with chronic renal dysfunction [12]. Resistin seems to be of importance in bone metabolism, stimulating osteoblast and osteoclast differentiation, ACR = American College of Rheumatology; BMD = bone mineral density; CRP = C-reactive protein; ELISA = enzyme-linked immunosorbent assay; ESR = erythrocyte sedimentation rate; GFR = glomerular filtration rate; HDL = high-density lipoprotein; ICTP = C-terminal telopeptide of type I collagen; IgG = immunoglobulin G; IL = interleukin; NF-κB = nuclear factor kappa B; PINP = N-terminal propeptide of type I procollagen; RA = rheumatoid arthritis; ROC = receiver operating characteristic; SD = standard deviation; sIL-6R = soluble interleukin-6 receptor; SLE = systemic lupus erythematosus; Tg = triglycerides; TNF-α = tumor necrosis factor-alpha.

(page number not for citation purposes) possibly mediated directly or indirectly through the nuclear factor kappa B (NF-κB) pathway [13]. Systemic lupus erythematosus (SLE) is a disease characterized by systemic inflammation with the property of affecting several organs throughout the body, including kidneys. Therefore, we wanted to examine the relationship and possible associations between resistin and different markers of disease activity, inflammation, renal function, lipids, and bone mineral density (BMD) in a female cohort of patients with SLE.

Materials and methods

Patients

All patients with SLE treated in the rheumatology clinics in Göteborg and Borås, in western Sweden, were identified from administrative registers and invited to participate in this crosssectional study. The procedure of enrollment has been described in detail [14]. In short, 339 patients (298 women and 41 men) were identified. There was a 70% reply frequency among the female patients. One hundred sixty-three female patients fulfilling at least four of the 1982 American College of Rheumatology (ACR) classification criteria for SLE [15] were included in and completed the study. Only data regarding female patents have been analyzed. For each patient, data on age, duration of disease, weight, and height were recorded. Medication, smoking habits, physical activity, and clinical fractures were assessed by self-administered questionnaires. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) [16] was used to score disease activity. Disease damage was recorded according to the Systemic Lupus International Collaborative Clinics/ACR Damage Index [17]. Glomerular filtration rate (GFR) was predicted using the Cockcroft and Gault equation [18]. GFR (mL/ minute) = (140 -age) × weight (kg) × 1.04/S-creatinine (μmol/L). Cumulative corticosteroid intake was calculated by reading the medical records of all patients. The same rheumatologist assessed all patients (KA).

Laboratory tests

Venous blood samples were taken after a one-night fast. Serum from the venous blood samples was stored at -70°C until the time of analyses. However, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood cell count, creatinine, C3, C4, and the plasma lipoproteins, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides (Tg) were analyzed consecutively using standard laboratory techniques in the Department of Clinical Chemistry of Sahlgrenska University Hospital.

Bone markers

The bone resorption marker, C-terminal telopeptide of type I collagen (ICTP), and the bone formation marker, N-terminal propeptide of type I procollagen (PINP), were analyzed quantitatively in serum by radioimmunoassay (Orion Diagnostica, Espoo, Finland). Detection limits were ICTP 0.7 μg/L and PINP 2 μg/L.

Resistin

Resistin levels were detected with a sandwich enzyme-linked immunosorbent assay (ELISA) (R&D Systems, Inc., Minneapolis, MN, USA). Briefly, samples diluted 1:10 with 1% bovine serum albumin phosphate-buffered saline were introduced into the parallel strips coated with capture polyclonal antiresistin antibodies. Biotin-labelled anti-resistin antibodies, streptavidin-horseradish peroxidase conjugate, and corresponding substrate were used for color development. The obtained absorbance values were compared with the serial dilution of recombinant human resistin. The lowest detectable level was 31 pg/mL.

Cytokines

Quantitative sandwich ELISA kits were used for measurement of proinflammatory cytokines TNF-α, IL-1β, IL-6, and soluble IL-6 receptor (sIL-6R) (Quantikine; R&D Systems, Inc.) with detection limits of 0.12, 0.1, 0.7, and 6.5 pg/mL, respectively.

Bone mineral density measurements

Lumbar spine (L2-L4), non-dominant hip (femoral neck and total hip), and non-dominant distal forearm were measured by DXA (dual-energy x-ray absorptiometry) with a Lunar Prodigy densitometer 12165 (GE Healthcare, Little Chalfont, Buckinghamshire, UK). The precisions for duplicate measurements were 0.9% for lumbar spine, 0.5% for left total hip and femoral neck, and 2.8% for radius. All BMD results were expressed in absolute values (g/cm 2 ) and as the number of standard deviations (SDs) above or below the mean results of age-matched women (z score).

Fractures

Lateral x-rays of thoracic and lumbar spine (Th4-L4) were evaluated for prevalent vertebral compression fractures by a visual semiquantitative method (the method of Genant and colleagues [19]). All vertebral deformities of at least 20% to 25% reduction of height, anterior, middle and/or dorsal were regarded as compression fractures. One radiologist performed all analyses.

Healthy controls

A control group of 12 female healthy blood donors and 30 healthy female staff members and PhD students in the Department of Rheumatology were analyzed for serum levels of resistin.

Ethical considerations

All patients gave informed written consent prior to participation, and the study was approved by the ethics committee at Sahlgrenska Academy at Göteborg University.

Statistical analysis

Analyses were performed using SPSS version 12.0.1 (SPSS Inc., Chicago, IL, USA). Descriptive statistics are presented as median and range or as mean and SD. All variables were tested with the Kolmogorov-Smirnov normality test. Pearson correlation was used when the variables were normally distributed; otherwise, Spearman correlation was used. Significant variables were then entered in the multiple linear regression analyses as independent variables and resistin as a dependent variable. A forward stepwise method was used.

ESR and S-creatinine were defined as normal or pathological according to standard laboratory normal values. These variables were dependent in a logistic forward regression analyses with resistin as the independent variable. The same method was used for z score hip total and radius total with the cutoff value of -1 SD. A receiver operating characteristic (ROC) curve was then calculated with ESR (elevated or not), S-creatinine (elevated or not), z score hip total, and z score radius total (cutoff value of -1 SD) as the state variable and resistin as the test variable. The constant and the regression coefficients of patients with SLE were compared with controls with respect to resistin and age by means of a special t test. All tests were two-tailed, and a p value of less than 0.05 was considered statistically significant.

Results

Demographic and disease-related variables

The SLE patients participating in this study did not differ significantly in age from those who were invited but did not participate. The general characteristics of the study population are presented in Table 1. The participants' ages ranged from 20 to 82 years. Seventy-two (44%) women were premenopausal. Ninety-one (56%) were on disease-modifying antirheumatic drugs, and 85 (52%) were treated with glucocorticosteroids. Only one person had end-stage renal disease, but 4 (2.5%) had impaired renal function with a GFR of less than 30 mL/minute, and 23 (14%) had a GFR of less than 50 mL/minute by use of the predicted GFR value.

Resistin and associated factors

The median serum resistin level was 6.53 (2.23 to 19.14) ng/ mL. Several clinical and laboratory disease-related variables were significantly associated with resistin levels in serum using a simple regression model ( Table 2). Markers of inflammation in SLE such as raised ESR, CRP, immunoglobulin G (IgG), proinflammatory cytokines, and low S-albumin levels correlated to resistin in serum. There was also an association between resistin and impaired renal function and current dose of corticosteroids. Bone variables such as number of vertebral fractures, low BMD in three of four measured sites, and the bone resorption marker ICTP also correlated to high resistin. Tg values were positively associated with resistin, whereas HDL was inversely associated with resistin. A multiple regression model, with resistin as the dependent variable and with the variables significantly correlated to resistin ( Table 2) as independent variables, was performed. High inflammation, impaired renal function, medication with glucocorticosteroids, high HDL, and low BMD in radius remained significant markers of high resistin levels (Table 3).

Logistic forward regression analyses were performed with resistin as the independent variable and normal or pathological ESR or S-creatinine as dependent variables. Analyses were also performed with z score total hip and radius as dependent variables using a cutoff value as -1 SD for normal or reduced bone mass. Resistin was significantly associated with ESR but not with S-creatinine, z score hip total, or z score radius total ( Table 4).

Resistin in patients with systemic lupus erythematosus compared with controls

Forty-two healthy controls with a median age of 52 (18 to 67) years had a median serum resistin value of 6.24 (0.47 to 17.12) ng/mL. The constant and the regression coefficients of the patients with SLE, with respect to resistin values and age, were compared versus the corresponding parameters of the controls by use of a special t test. No significant difference was found between the patients with SLE and the controls (Figure 1).

Discussion

Resistin is an adipokine and a novel cytokine with proinflammatory properties in humans. To our knowledge, this is the first time resistin has been analyzed in the serum of a large cohort of patients with SLE. Our results indicate a clear association between resistin and inflammation, complement levels, BMD, and renal function in SLE. It is too early to assess resistin as a pathogenic factor in SLE disease, although the associations of resistin with low complement levels and the apparent central position in the proinflammatory cytokine cascade make it an interesting subject for further investigation.

In this cross-sectional study of female patients with SLE, resistin was positively associated with inflammation even though resistin levels were not significantly increased compared with controls. Resistin exerts its main action locally in different tissue departments, and the measured serum levels may reflect only a small spillover into the blood compartment [11].

Inflammation in SLE is in contrast to inflammation in other rheumatic diseases characterized by elevated ESR while CRP often remains low. In spite of this, there were associations between resistin and CRP (r = 0.193) as well as between resistin and ESR (r = 0.316). Severe SLE flares (for example, in kidneys and skin) are known to be immune-complex-mediated and accompanied by complement activation and consumption. In our material, resistin correlated to low C3 and high IgG as well as to elevated proinflammatory cytokines such as IL-1β, IL-6, sIL-6R, and TNF-α. The low serum albumin reflects inflammation, but in the case of nephrotic syndrome in 9 (6%) patients, large renal loss of proteins could affect the simple regression outcome. In multiple regression analyses,

Demographic and disease-related variables in 163 female patients with systemic lupus erythematosus

An association between resistin and inflammation has been reported in several different diseases, including RA [21] and inflammatory bowel disease [5], but is very weak or nonexistent in studies of apparently healthy individuals [22]. We found that current glucocorticosteroid dose correlated positively to resistin levels and remained a significant variable of resistin in multiple regression analyses. Resistin production in mouse adipocytes has been shown to increase after exposure to dexamethasone [23]. In a patient population, however, it is difficult, if not impossible, to separate the effect of steroid medication by itself from the disease activity it is meant to influence.

The relationship between obesity and expression of resistin is not clear in humans, although the transcription of resistin mRNA is high in preadipocytes during differentiation. Resistin has been shown to correlate to low HDL in a cross-sectional Japanese population [24] and to low HDL and high Tg in a European general population [25]. In rheumatic diseases, dyslipoproteinemia is seen and is also known to be linked to inflammation in SLE [26][27][28] and possibly also to the use of glucocorticosteroids [29]. We found that resistin was associated with high Tg and low HDL but not with total cholesterol, weight, or body mass index. HDL was significantly associated with resistin in the multiple regression model. If resistin acts as a proinflammatory molecule, it could be one important link in the intricate interactions between inflammation and dyslipoproteinemia and subsequently atherosclerosis seen in SLE and other inflammatory conditions [30,31].

We demonstrated a positive correlation between resistin, creatinine, and ever having had nephritis and a negative correla- Table 2 Correlation coefficients (r) of resistin (dependent variable) and disease-related variables (independent variables). tion between resistin and GFR. Similar associations have been shown in different patient groups (for example, in patients with coronary heart disease [32], in kidney allograft recipients [7], and in a small number of children with end-stage renal disease [33]). Yaturu and colleagues [12] found significantly higher resistin levels in patients with chronic kidney disease compared with controls but no correlation to GFR. Several of the mentioned reports also revealed a correlation between resistin and inflammation. In our study, serum levels of creatinine remained a significant variable to resistin in the multiple regression analyses. Whether this is due to high systemic inflammation in the patients having ongoing lupus nephritis or to resistin merely being accumulated in the serum of patients with low GFR cannot be decided. Resistin has been shown to be a regulator and to increase the release of IL-1β, IL-6, and TNF-α in human peripheral blood mononuclear cells via the NF-κB pathway. Several endogenous substances like proinflammatory cytokines have also been shown to upregulate resistin gene expression [11,34]. The NF-κB pathway is involved in osteoclastogenesis, and resistin has been found to stimulate osteoclast differentiation from human peripheral monocytes and, to a lesser extent, osteoblast proliferation in humans [13].

Resistin (ng/mL

Several studies indicate a more pronounced development of osteopenia and osteoporosis in patients with SLE than in controls, and not only due to the use of glucocorticosteroids [14]. Therefore, it was interesting that BMD in three of four measured locations and the number of radiological vertebral compression fractures correlated inversely to resistin. The bone resorption marker ICTP correlated positively to resistin. In multiple regression analyses, only BMD in radius remained associated with resistin. Oh and colleagues [35] have shown an inverse correlation of resistin to BMD in lumbar spine in an adult male Korean patient cohort also indicating the connection between resistin and bone metabolism.  a Erythrocyte sedimentation rate (ESR) and S-creatinine were defined as normal or pathological according to standard laboratory normal values. These variables were dependent in logistic conditional forward regression analyses with resistin as independent variable. The same method was used for z score hip total and radius total with the cutoff value of -1 standard deviation (SD). b Area under the receiver operating characteristic (ROC) curve was calculated with ESR (normal or not), S-creatinine (normal or not), z score hip total, and z score radius total (above or below -1 SD) as the state variable and resistin as test variable. Null hypothesis: true area under ROC curve = 0.5. CI, confidence interval.

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Conclusion

In patients with SLE, we now show a clear association between resistin and inflammation, impaired kidney function, low complement levels, use of glucocorticosteroids, BMD, and low HDL. Whether resistin has pathophysiological significance in SLE or whether it should be regarded solely as a marker of inflammation is, for the moment, impossible to say. We encourage and look forward to both clinical and mechanistical studies in this field.

Figure 1

Correlation between serum resistin levels and age in systemic lupus erythematosus (SLE) patients and controls Correlation between serum resistin levels and age in systemic lupus erythematosus (SLE) patients and controls. The constant and the regression coefficients, with respect to resistin values and age, were compared with the corresponding parameters of the controls by use of a special t test. The regression coefficient is the slope. No significant difference was found between these parameters.

were tested with the Kolmogorov-Smirnov normality test. Pearson correlation was used when the variables were normally distributed; otherwise, Spearman correlation was used. Only significant variables are shown. a p < 0.001; b p < 0.01; c p < 0.05. BMD, bone mineral density; ICTP, C-terminal telopeptide of type I collagen; IgG, immunoglobulin G; r, Pearson correlation coefficient; r s , Spearman correlation coefficient; sIL-6R, soluble interleukin-6 receptor; SLE, systemic lupus erythematosus.

Table 1
1Demographic and disease-related variables in 163 female patients with systemic lupus erythematosusDemographic variables

Table 1 (
1Continued)

Table 3
3Multiple stepwise regression analysis of resistin (dependent variable) and demographic and disease-related variables (independent variables)The regression equation of resistin (ng/mL) = 11.155 + 0.044 × erythrocyte sedimentation rate (mm/hour) + 0.035 × S-creatinine (μmol/L) -2.915 × C3 (g/L) + 0.127 × current steroid dose (mg/day) -1.438 × high-density lipoprotein (mmol/L) -7.133 × bone mineral density radius (g/ cm 2 ). Beta values are unstandardized regression coefficients. R 2 is equal to the variance explained in the model. SE, standard error.Resistin (ng/mL)

11.155

β
SE
P value

Table 4
4Resistin as independent variable in logistic regressions and test variable in area under ROC curvesLogistic regression with resistin as independent variable a ROC curve with resistin as test variable bP value
Area under ROC curve (95% CI)

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AcknowledgementsThis study was supported by grants from the regional research sources from Västra Götaland, the Medical Society of Göteborg, Rune and Ulla Amlövs Foundation for Rheumatology Research, and the Swedish and Göteborg Association Against Rheumatism. We are grateful to all of the patients in the study. We thank Andrej Shestakov for technical assistance and Anders Odén for statistical advice and support. We thank Anna Jacobsson, Gunilla Håwi, and Ingela Carlberg for their assistance with the patients and Gunnar Sturfelt for critical evaluation of the manuscript.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsKA conceived the study, participated in its design and coordination, performed most of the statistical analyses, and drafted the manuscript. HFd'E participated in study design and coordination, interpretation of statistical analyses, and revision of the manuscript. MB contributed with samples from controls, contributed important knowledge about resistin, and participated in revision of the manuscript. HC participated in study design, interpretation of data, and revision of the manuscript. All authors read and approved the final manuscript.
The hormone resistin links obesity to diabetes. C M Steppan, S T Bailey, S Bhat, E J Brown, R R Banerjee, C M Wright, H R Patel, R S Ahima, M A Lazar, Nature. 409Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 2001, 409:307-312.

A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. K H Kim, K Lee, Y S Moon, H S Sul, J Biol Chem. 276Kim KH, Lee K, Moon YS, Sul HS: A cysteine-rich adipose tis- sue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001, 276:11252-11256.

Hébert CC: FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. I N Holcomb, R C Kabakoff, B Chan, T W Baker, A Gurney, W Henzel, C Nelson, H B Lowman, B D Wright, N J Skelton, G D Frantz, D B Tumas, F V PealeJr, D L Shelton, EMBO J. 19Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL, Hébert CC: FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000, 19:4046-4055.

The serum levels ofresistin in rheumatoid arthritis patients. K Migita, Y Maeda, T Miyashita, H Kimura, M Nakamura, H Ishibashi, K Eguchi, Clin Exp Rheumatol. 24Migita K, Maeda Y, Miyashita T, Kimura H, Nakamura M, Ishibashi H, Eguchi K: The serum levels ofresistin in rheumatoid arthritis patients. Clin Exp Rheumatol 2006, 24:698-701.

Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. K Karmiris, I E Koutroubakis, C Xidakis, M Polychronaki, T Voudouri, E A Kouroumalis, Inflamm Bowel Dis. 12Karmiris K, Koutroubakis IE, Xidakis C, Polychronaki M, Voudouri T, Kouroumalis EA: Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm Bowel Dis 2006, 12:100-105.

. P G Mcternan, C M Kusminski, S: Kumar, Resistin, Curr Opin Lipidol. 17McTernan PG, Kusminski CM, Kumar S: Resistin. Curr Opin Lipidol 2006, 17:170-175.

Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients. J Malyszko, J S Malyszko, K Pawlak, M Mysliwiec, Transplant Proc. 38Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M: Resistin, a new adipokine, is related to inflammation and renal function in kid- ney allograft recipients. Transplant Proc 2006, 38:3434-3436.

Relationship between serum resistin concentrations and inflammatory markers in patients with type 2 diabetes mellitus. H Hui-Bing, K Migita, T Miyashita, Y Maeda, M Nakamura, H Yatsuhashi, H Ishibashi, K Eguchi, H Kimura, Metabolism. 55Hui-Bing H, Migita K, Miyashita T, Maeda Y, Nakamura M, Yatsu- hashi H, Ishibashi H, Eguchi K, Kimura H: Relationship between serum resistin concentrations and inflammatory markers in patients with type 2 diabetes mellitus. Metabolism 2006, 55:1670-1673.

Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. L Patel, A C Buckels, I J Kinghorn, P R Murdock, J D Holbrook, C Plumpton, C H Macphee, S A Smith, Biochem Biophys Res Commun. 300Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA: Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 2003, 300:472-476.

Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes. I Nagaev, M Bokarewa, A Tarkowski, U Smith, PLoS ONE. 131Nagaev I, Bokarewa M, Tarkowski A, Smith U: Human resistin is a systemic immune-derived proinflammatory cytokine target- ing both leukocytes and adipocytes. PLoS ONE 2006, 1:e31.

Resistin, an adipokine with potent proinflammatory properties. M Bokarewa, I Nagaev, L Dahlberg, U Smith, A Tarkowski, J Immunol. 174Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A: Resis- tin, an adipokine with potent proinflammatory properties. J Immunol 2005, 174:5789-5795.

Plasma and urine levels of resistin and adiponectin in chronic kidney disease. S Yaturu, R D Reddy, J Rains, S K Jain, Cytokine. 37Yaturu S, Reddy RD, Rains J, Jain SK: Plasma and urine levels of resistin and adiponectin in chronic kidney disease. Cytokine 2007, 37:1-5.

Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. L Thommesen, A K Stunes, M Monjo, K Grøsvik, M V Tamburstuen, E Kjøbli, S P Lyngstadaas, J E Reseland, U Syversen, J Cell Biochem. 99Thommesen L, Stunes AK, Monjo M, Grøsvik K, Tamburstuen MV, Kjøbli E, Lyngstadaas SP, Reseland JE, Syversen U: Expression and regulation of resistin in osteoblasts and osteoclasts indi- cate a role in bone metabolism. J Cell Biochem 2006, 99:824-834.

K Almehed, H Forsblad D'elia, G Kvist, C Ohlsson, H Carlsten, Prevalence and risk factors of osteoporosis in female SLE patients-extended report. Almehed K, Forsblad d'Elia H, Kvist G, Ohlsson C, Carlsten H: Prevalence and risk factors of osteoporosis in female SLE patients-extended report.

. Rheumatology (Oxford). 46Rheumatology (Oxford) 2007, 46:1185-1190.

The 1982 revised criteria for the classification of systemic lupus erythematosus. E M Tan, A S Cohen, J F Fries, A T Masi, D J Mcshane, N F Rothfield, J G Schaller, N Talal, R J Winchester, Arthritis Rheum. 25Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982, 25:1271-1277.

Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. C Bombardier, D D Gladman, M B Urowitz, D Caron, C H Chang, Arthritis Rheum. 35Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992, 35:630-640.

The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. D D Gladman, M B Urowitz, C H Goldsmith, P Fortin, E Ginzler, C Gordon, J G Hanly, D A Isenberg, K Kalunian, O Nived, M Petri, J Sanchez-Guerrero, M Snaith, G Sturfelt, Arthritis Rheum. 40Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gor- don C, Hanly JG, Isenberg DA, Kalunian K, Nived O, Petri M, Sanchez-Guerrero J, Snaith M, Sturfelt G: The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with sys- temic lupus erythematosus. Arthritis Rheum 1997, 40:809-813.

Prediction of creatinine clearance from serum creatinine. D W Cockcroft, M H Gault, Nephron. 16Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976, 16:31-41.

Vertebral fracture assessment using a semiquantitative technique. H K Genant, C Y Wu, C Van Kuijk, M C Nevitt, J Bone Miner Res. 8Genant HK, Wu CY, van Kuijk C, Nevitt MC: Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993, 8:1137-1148.

UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. A I Adler, R J Stevens, A Neil, I M Stratton, A J Boulton, R R Holman, Diabetes Care. 25Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR: UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002, 25:894-899.

Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. L Senolt, D Housa, Z Vernerová, T Jirásek, R Svobodová, D Veigl, K Anderlová, U Müller-Ladner, K Pavelka, M Haluzík, Ann Rheum Dis. 66Senolt L, Housa D, Vernerová Z, Jirásek T, Svobodová R, Veigl D, Anderlová K, Müller-Ladner U, Pavelka K, Haluzík M: Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum. Ann Rheum Dis 2007, 66:458-463.

Genetic and environmental determinants of circulating resistin level in a community-based sample. I Pantsulaia, G Livshits, S Trofimov, E Kobyliansky, Pantsulaia I, Livshits G, Trofimov S, Kobyliansky E: Genetic and environmental determinants of circulating resistin level in a community-based sample.

. Eur J Endocrinol. 156Eur J Endocrinol 2007, 156:129-135.

Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. F Haugen, A Jorgensen, C A Drevon, P Trayhurn, FEBS Lett. 507Haugen F, Jorgensen A, Drevon CA, Trayhurn P: Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. FEBS Lett 2001, 507:105-108.

Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population. H Osawa, Y Tabara, R Kawamoto, J Ohashi, M Ochi, H Onuma, W Nishida, K Yamada, J Nakura, K Kohara, T Miki, H Makino, Diabetes Care. 30Osawa H, Tabara Y, Kawamoto R, Ohashi J, Ochi M, Onuma H, Nishida W, Yamada K, Nakura J, Kohara K, Miki T, Makino H: Plasma resistin, associated with single nucleotide polymor- phism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Jap- anese general population. Diabetes Care 2007, 30:1501-1506.

Plasma resistin levels correlate with determinants of the metabolic syndrome. G D Norata, M Ongari, K Garlaschelli, S Raselli, L Grigore, A L Catapano, Eur J Endocrinol. 156Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Cata- pano AL: Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol 2007, 156:279-284.

Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. E Svenungsson, I Gunnarsson, G Z Fei, I E Lundberg, L Klareskog, J Frostegard, Arthritis Rheum. 48Svenungsson E, Gunnarsson I, Fei GZ, Lundberg IE, Klareskog L, Frostegard J: Elevated triglycerides and low levels of high-den- sity lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum 2003, 48:2533-2540.

Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. E F Borba, E Bonfa, Lupus. 6Borba EF, Bonfa E: Dyslipoproteinemias in systemic lupus ery- thematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus 1997, 6:533-539.

Dyslipoproteinemia during the active course of systemic lupus erythematosus in association with anti-double-stranded DNA (anti-dsDNA) antibodies. S Kashef, M M Ghaedian, A Rajaee, A Ghaderi, Rheumatol Int. 27Kashef S, Ghaedian MM, Rajaee A, Ghaderi A: Dyslipoproteine- mia during the active course of systemic lupus erythematosus in association with anti-double-stranded DNA (anti-dsDNA) antibodies. Rheumatol Int 2007, 27:235-241.

Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids. W H Ettinger, A P Goldberg, D Applebaum-Bowden, W R Hazzard, Am J Med. 83Ettinger WH, Goldberg AP, Applebaum-Bowden D, Hazzard WR: Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids. Am J Med 1987, 83:503-508.

Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. W Khovidhunkit, M S Kim, R A Memon, J K Shigenaga, A H Moser, K R Feingold, C Grunfeld, J Lipid Res. 45Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C: Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and conse- quences to the host. J Lipid Res 2004, 45:1169-1196.

The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: Roles of inflammation and dyslipidemia. B H Hahn, J Grossman, W Chen, M Mcmahon, J Autoimmun. 28Hahn BH, Grossman J, Chen W, McMahon M: The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: Roles of inflammation and dyslipidemia. J Autoimmun 2007, 28:69-75.

Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function. L Risch, C Saely, G Hoefle, P Rein, P Langer, G Gouya, T Marte, S Aczel, H Drexel, Clin Chim Acta. 376Risch L, Saely C, Hoefle G, Rein P, Langer P, Gouya G, Marte T, Aczel S, Drexel H: Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in cor- onary patients with predominantly normal or mildly impaired renal function. Clin Chim Acta 2007, 376:108-113.

Circulating resistin concentrations in children depend on renal function. K D Nusken, J Kratzsch, V Wienholz, W Stohr, W Rascher, J Dotsch, Nephrol Dial Transplant. 21Nusken KD, Kratzsch J, Wienholz V, Stohr W, Rascher W, Dotsch J: Circulating resistin concentrations in children depend on renal function. Nephrol Dial Transplant 2006, 21:107-112.

Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. S Kaser, A Kaser, A Sandhofer, C F Ebenbichler, H Tilg, J R Patsch, Biochem Biophys Res Commun. 309Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR: Resistin messenger-RNA expression is increased by proin- flammatory cytokines in vitro. Biochem Biophys Res Commun 2003, 309:286-290.

The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. K W Oh, W Y Lee, E J Rhee, K H Baek, K H Yoon, M I Kang, E J Yun, C Y Park, S H Ihm, M G Choi, H J Yoo, S W Park, Clin Endocrinol (Oxf). 63Oh KW, Lee WY, Rhee EJ, Baek KH, Yoon KH, Kang MI, Yun EJ, Park CY, Ihm SH, Choi MG, Yoo HJ, Park SW: The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. Clin Endocrinol (Oxf) 2005, 63:131-138.