Cross-sectional quantitative validation of the paediatric Localized Scleroderma Quality of Life Instrument (LoSQI): A disease-specific patient-reported outcome measure.

BACKGROUND: The Localized Scleroderma Quality of Life Instrument (LoSQI) is a disease-specific patient-reported outcome (PRO) measure designed for children and adolescents with localized scleroderma (LS; morphea). This tool was developed using rigorous PRO methods and previously cognitively tested in a sample of paediatric patients with LS. OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the LoSQI in a clinical setting. METHODS: Cross-sectional data from four specialized clinics in the US and Canada were included in the analysis. Evaluation included reliability of scores, internal structure of the survey, evidence of convergent and divergent validity, and test-retest reliability. RESULTS: One hundred and ten patients with LS (age: 8-20 years) completed the LoSQI. Both exploratory and confirmatory factor analysis supported the use of two sub-scores: Pain and Physical Functioning, and Body Image and Social Support. Correlations with other PRO measures were consistent with pre-specified hypotheses. LIMITATIONS: This study did not evaluate longitudinal validity or responsiveness of scores. CONCLUSION: Results from a representative sample of children and adolescents with LS continue to support the validity of the LoSQI when used in a clinical setting. Future work to evaluate the responsiveness is ongoing.

Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

Exploring the impact of paediatric localized scleroderma on health-related quality of life: focus groups with youth and caregivers.

BACKGROUND: Paediatric localized scleroderma (LS) can negatively impact health-related quality of life (HRQoL) by causing skin fibrosis, abnormal limb development, disfigurement, and side-effects from immunosuppressive treatment. Studies to date have rarely included qualitative data gathered directly from paediatric patients with LS. OBJECTIVES: To assess the impact of LS on HRQoL among affected youth and their caregivers using qualitative description. METHODS: Youth with all subtypes of LS and their caregivers were purposively sampled to participate in age-appropriate focus groups (younger children, early adolescents, adolescents). Each group started with a drawing exercise followed by in-depth discussion of topics including skin symptoms (e.g. itch, pain, tightness), functional impairment, physical appearance, family and peer relationships, and treatment burden. Focus groups were transcribed verbatim and co-coded, with adjudication of differentially applied codes. The study findings were triangulated via comparison with adult reports and published literature. RESULTS: Eleven youth aged 9-16 years and 16 caregivers participated in three focus groups each. Major identified areas of impact included uncomfortable skin symptoms, physical functioning limitations, extracutaneous manifestations, body image, bullying and teasing, unwanted questioning from others, and treatment side-effects and burden. CONCLUSIONS: This is the first qualitative study of HRQoL in LS to include all major LS subtypes. We identified domains of HRQoL impacted by LS, some of which replicate earlier findings and some of which were novel. As impact also changed with developmental stage, our findings support the need for ongoing, formal evaluation of HRQoL in children and adolescents with LS. What is already known about this topic? Paediatric localized scleroderma (LS) negatively impacts health-related quality of life (HRQoL) via skin fibrosis, musculoskeletal and other extracutaneous manifestations from the disease process, and side-effects of systemic immunosuppression. The full impact of LS and its treatment on HRQoL is incompletely understood, with only one published qualitative study of youth with LS, which was limited to facial involvement. There are no qualitative studies of HRQoL in other LS subtypes to date. What does this study add? This is the first qualitative evaluation of HRQoL in youth with LS inclusive of all disease subtypes. Our study confirms that LS affects HRQoL across multiple distinct domains, including uncomfortable skin sensations, impacts on body image, bullying and teasing from peers, unwanted intrusive questioning, physical limitations, extracutaneous manifestations and high treatment burden. These results indicate the need for ongoing clinical assessment of paediatric patients in these domains. What are the clinical implications of the work? These results support the need to care for patients with LS holistically by synthesizing cutaneous, musculoskeletal and extracutaneous disease assessments with multidimensional evaluation of psychosocial impact and adverse effects of treatments. The development of an LS-specific HRQoL measure would advance such efforts.

A novel patient-reported outcome for paediatric localized scleroderma: a qualitative assessment of content validity.

BACKGROUND: According to current standards, no existing patient-reported outcome (PRO) measures have high-quality validity evidence for use with individuals diagnosed with paediatric localized scleroderma (LS). This severely hinders patient-centred LS-focused research, including much needed clinical trials. OBJECTIVES: To develop a valid health-related quality of life measure for individuals with paediatric LS and to qualitatively evaluate its content validity using a patient-centred approach. METHODS: Previously collected qualitative data from youth with LS and their caregivers was used to develop items. The resulting item set was administered in a clinical setting to participants aged 8-18 years old. Cognitive interviews were used to evaluate time to survey completion, readability/understanding of the items, appropriateness of the recall period and construct representation. RESULTS: Seventeen children and adolescents with LS participated in the study. Interviews supported readability, understanding of the items and appropriateness of the recall period in individuals > 10 years old. Revisions were made to simplify the instructions and to be more inclusive of different subtypes of LS. Three items were added to improve content representation. CONCLUSIONS: Content validity was supported by the patient-centred development process of the outcome measure and via direct feedback from individuals with LS and their families. Although an important first step, the resulting PRO, termed the Localized Scleroderma Quality of Life Instrument, should be further evaluated in a larger sample before being implemented. What's already known about this topic? No current health-related quality of life (HRQoL) measures have been created using direct input from children and adolescents with localized scleroderma (LS). When compared with qualitative reports of HRQoL impact in youth with all LS subtypes, no existing patient-reported outcome (PRO) measures have appropriate content validity for individuals with paediatric LS. What does this study add? This study proposes a novel LS-specific PRO and is the first qualitative assessment of content validity for any PRO measure in this population. Results from cognitive interviews with children and adolescents support the content validity of the newly developed item set and its ability to capture HRQoL impact in a clinical context. What are the clinical implications of this work? Incorporating a content-valid PRO of HRQoL impact into clinical practice would allow for the valid, ongoing capture of patient experience in LS. Although content validity is an important and necessary step in the process of evaluating validity, items within this novel measure will undergo additional psychometric evaluation before implementation in research and clinical settings.

Practice-based differences in paediatric discoid lupus erythematosus.

BACKGROUND: Children with discoid lupus erythematosus (DLE) are at risk for disfigurement and progression to systemic lupus erythematosus (SLE). Consensus is lacking regarding optimal care for children with DLE. OBJECTIVES: The aim of this study was to compare practice patterns among paediatric dermatologists/rheumatologists treating paediatric DLE. METHODS: An online survey was sent to 292 paediatric rheumatologists in the Childhood Arthritis and Rheumatology Research Alliance and 200 paediatric dermatologists in the Pediatric Dermatology Research Alliance. Consensus was defined as ≥ 70% agreement. RESULTS: Survey response rates were 38% (76 of 200) for dermatology and 21% (60 of 292) for rheumatology. Both specialties agreed that screening labs should include complete blood counts with differential, urinalysis, complement levels, erythrocyte sedimentation rate, antinuclear antibody and other autoantibodies, hepatic function and renal function/electrolytes. Both specialties agreed that arthritis or nephritis should prompt intensified evaluation for SLE. No other patient features achieved consensus as disease-modifying risk factors. Hydroxychloroquine was agreed upon as first-line systemic therapy, but consensus was lacking for second- or third-line treatment. CONCLUSIONS: We found few areas of consensus and significant practice differences between paediatric dermatologists and rheumatologists treating DLE. Knowledge gaps include risk factors for SLE, optimal screening and treatment of refractory skin disease.

Evaluation of the reliability and validity of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in paediatric cutaneous lupus among paediatric dermatologists and rheumatologists.

BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a reliable outcome measure for cutaneous lupus erythematosus (CLE) in adults used in clinical trials. However, it has not been validated in children, limiting clinical trials for paediatric CLE. OBJECTIVES: This study aimed to validate the CLASI in paediatrics. METHODS: Eleven paediatric patients with CLE, six dermatologists and six rheumatologists participated. The physicians were trained to use the CLASI and Physician's Global Assessment (PGA), and individually rated all patients using both tools. Each physician reassessed two randomly selected patients. Within each physician group, the intraclass correlation coefficient (ICC) was calculated to assess the reliability of each measure. RESULTS: CLASI activity scores demonstrated excellent inter- and intrarater reliability (ICC > 0·90), while the PGA activity scores had good inter-rater reliability (ICC 0·73-0·77) among both specialties. PGA activity scores showed excellent (ICC 0·89) and good intrarater reliability (ICC 0·76) for dermatologists and rheumatologists, respectively. Limitations of this study include the small sample size of patients and potential recall bias during the physician rerating session. CONCLUSIONS: CLASI activity measurement showed excellent inter- and intrarater reliability in paediatric CLE and superiority over the PGA. These results demonstrate that the CLASI is a reliable and valid outcome instrument for paediatric CLE.

Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Site of action of two novel pyrimidine biosynthesis inhibitors accurately predicted by the compare program.

The computer algorithm COMPARE provides information regarding the biological mechanism of action of a compound. In this study, excellent correlations were obtained for 2,2'-[3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)diimino]bis- benzoic acid (redoxal) and 1-(p-bromophenyl)-2-methyl-1H- naphth[2,3-d]imidazole-4,9-dione (BNID) and two well-studied dihydroorotate dehydrogenase (DHOD) inhibitors, dichloroallyl lawsone and brequinar, in terms of antiproliferative activity against tumor cell lines in vitro. When redoxal and BNID were incubated with MOLT-4 cells for 72 hr, 50% growth inhibition was achieved at 0.7 and 3.5 microM, respectively. After 24 hr of incubation, pyrimidine triphosphate pools were shown to be decreased by 50% by redoxal (1 microM) and BNID (0.25 microM). Addition of either uridine (50 microM) or cytidine (100 microM) antagonized the cellular cytotoxicity caused by either drug; uridine corrected the UTP and CTP deficit, whereas cytidine corrected only the CTP deficit. Exposure of MOLT-4 cells to a 1 microM concentration of either drug for 18 hr followed by a 1-hr exposure to [14C]bicarbonate showed a 97% decrease of incorporation of [14C] into pyrimidine triphosphates accompanied by a 91- and 82-fold increase in radioactive incorporation into L-dihydroorotate and N-carbamyl-L-aspartate, respectively. By direct exposure of DHOD prepared from MOLT-4 cell mitochondria to a range of concentrations of the two drugs, apparent Ki values of 0.33 microM (redoxal) and 0.53 microM (BNID) were determined. These data provide direct evidence for inhibition of DHOD by redoxal and BNID in MOLT-4 lymphoblasts.