Relationship between health-related quality of life, disease activity and disease damage in a prospective international multicenter cohort of childhood onset systemic lupus erythematosus patients.

Previously, we described associations between health-related quality of life (HRQOL) and disease-related factors among childhood onset systemic lupus erythematosus (cSLE) patients. Here we determined the relationship between HRQOL, disease activity and damage in a large prospective international cohort of cSLE. We compared HRQOL, disease activity and disease damage across different continents and examined the relationship between children's and parents' assessments of HRQOL. Patients with cSLE and their parents completed HRQOL measures at enrollment and ≥4 follow-up visits. Physicians assessed disease activity and damage. The multinational cohort ( n = 467) had relatively low disease activity and damage. Patient and parent HRQOL scores were significantly correlated. Asian and European patients had the highest HRQOL, while South and North American patients had lower HRQOL scores. Renal, CNS, skin and musculoskeletal systems exhibited the highest levels of damage. North and South American and Asian patients were more likely to have disease damage and activity scores above median values, compared with Europeans. Asians were more likely to use cyclophosphamide/rituximab. Female gender, high disease activity and damage, non-White ethnicity, and use of cyclophosphamide and/rituximab were related to lower HRQOL. HRQOL domain scores continue to emphasize that SLE has widespread impact on all aspects of children's and parents' lives.

Validation of the Portuguese Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY) in Brazil.

BACKGROUND AND OBJECTIVE: Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY) is a health-related quality of life (HRQOL) assessment tool for pediatric systemic lupus erythematosus (SLE), which has been translated into Portuguese for Brazil. We are reporting preliminary data on cross-cultural validation and reliability of SMILEY in Portuguese (Brazil). METHODS: In this multi-center cross-sectional study, Brazilian children and adolescents 5-18 years of age with SLE and parents participated. Children and parents completed child and parent reports of Portuguese SMILEY and Portuguese Pediatric Quality of Life Inventory (PedsQL™) Generic and Rheumatology modules. Parents also completed the Childhood Health Assessment Questionnaire (CHAQ). Physicians completed the SLE disease activity index (SLEDAI), Physician's Global Assessment of disease activity (PGA) and Systemic Lupus Erythematosus International Collaborating Clinics ACR Damage Index (SDI). RESULTS: 99 subjects (84 girls) were enrolled; 93 children and 97 parents filled out the SMILEY scale. Subjects found SMILEY relevant and easy to understand and completed SMILEY in 5-15 minutes. Brazilian SMILEY was found to have good psychometric properties (validity and reliability), and the child-parent agreement was moderate. CONCLUSION: SMILEY may eventually be used routinely as a research/clinical tool in Brazil. It may be also adapted for other Portuguese-speaking nations offering critical information regarding the effect of SLE on HRQOL for children with SLE.

An update on cross-cultural adaptation of US English SMILEY.

We previously developed a health-related quality of life (HRQOL) tool for children with systemic lupus erythematosus (SLE) that is valid in English for the United States, called Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY). In order to determine the effect of SLE on the well-being of children, adolescents and their parents and examine the response to treatment modalities, it is critical to have an HRQOL tool that is applicable for different cultures. After validation in US English, we reported the translation and cultural adaptation process undertaken by our team to make SMILEY available in the following 13 accepted modern language variants: Danish, Dutch, French (France), German (Germany), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico) and Turkish. In this report we will describe the translation and adaptation of SMILEY into Afrikaans, Xhosa, Arabic (Saudi Arabia), Arabic (Egypt), Chinese, Czech, English (UK), German (Austria), German (Switzerland), Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Spanish for Venezuela. We followed the earlier reported procedure in this study consisting of: establishing collaborative relationships with different physicians caring for children with rheumatic diseases; forward and back translation of SMILEY and revisions; and cultural adaptation of SMILEY content.

Preliminary cross-cultural adaptation of a new pediatric health-related quality of life scale in children with systemic lupus erythematosus: an international effort.

We developed a brief, new health-related quality of life measure for children with systemic lupus erythematosus that is valid in English for the United States, called Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY). The United States-English language questionnaire may not be applicable to most of the countries in the world and several United States population subgroups, such as Hispanics. In order to measure the impact of morbidity of systemic lupus erythematosus on the lives of children, adolescents, and their parents and assess the outcome of new therapies, it is critical to have a uniform measure of systemic lupus erythematosus-specific health-related quality of life that is valid for different cultures. We report the translation and cultural adaptation process undertaken by our team with the goal of cross-cultural validation of SMILEY in the following thirteen languages: Danish, Dutch, French (France), German (Germany), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico), and Turkish. We employed the following steps: establishing collaborative relationships with institutions across the globe; forward and back translation of SMILEY text; and cultural adaptation of SMILEY content. We are in the process of enrolling patients and conducting validation of the translated and adapted versions of SMILEY.

Does acute synovitis (pseudogout) occur in patients with chronic pyrophosphate arthropathy (pseudo-osteoarthritis)?

OBJECTIVES: Pyrophosphate arthropathy has been linked to diverse clinical subtypes. The two most common are: acute synovitis (pseudogout) and chronic pyrophosphate arthropathy ("pseudo-osteoarthritis"). We have conducted a study to examine whether these are overlapping syndromes. METHODS: We reviewed all synovial fluid (SF) analyses performed in our laboratory from January 1988 to May 1997 to determine if patterns of SF leukocyte counts and Alizarin red stains in patients with repeated samples suggest that some patients were prone to acute attacks and some to chronic pyrophosphate arthropathy and whether acute attacks superimposed on chronic symptoms were common. Joint x-rays were screened for osteoarthritis (OA) and chondrocalcinosis. RESULTS: We identified 67 patients who had Calcium pyrophosphate dehydrate (CPPD) in their SF and had more than one SF examined (185 SF). We divided the patients into 2 groups. Group A (n=25) had at least one SF leukocyte count > than 2000 per mm(3) and group B (n=42) had SF leukocyte counts always < than 2000 per mm(3). Chondrocalcinosis detected on x-ray was more common in group A versus group B, 48% versus 19% (p<0.05, Fisher's exact test). OA was mild (grades 0-1) in 39% of group A versus 12.5% of group B patients, but the difference between groups was not significant. CPPD crystals were not detected in 13.5% SFs previously having CPPD crystals. Alizarin red staining for suspected hydroxyapatite was more often 2+ to 3+ in group B (31.6%) compared to group A (15.5%; p<0.05, Fisher's exact test). CONCLUSION: Acute synovitis and chronic pyrophosphate arthropathy are often two distinctive syndromes with some patients never having inflammatory attacks. Acute synovitis is more common in patients with chondrocalcinosis while chronic pyrophosphate arthropathy is associated with increased alizarin red staining and a trend suggestive of increased severity of OA.

The major histocompatibility complex of the rat.

Immunogenetic studies in the rat began with the investigation of blood group antigens (1-7) and evolved into the investigation of histocompatibility antigens and transplantation phenomena (8-17). In the course of this work, several nomenclature systems evolved that were eventually reconciled in a series of comparison studies (18-24). The biennial Workshops on Alloantigenic Systems in the Rat held under the aegis of the Transplantation Society (24) have provided the forum for the continued evolution of this field. In addition, several reviews (24-31) and books (32-35) have provided periodic summaries of different aspects of rat immunogenetics. This review will focus on the structure of the major histocompatibility complex (MHC) of the rat from the serological, biochemical, and molecular points of view.

Relationship between health-related quality of life and SLE activity and damage in children over time.

We previously described the development and validation of the 'Simple Measure of the Impact of Lupus Erythematosus in Youngsters' (SMILEY) for the reliable assessment of health-related quality of life (HRQOL) in children with systemic lupus erythematosus (SLE). The objectives of this new study were to determine the relationship of SMILEY scores to patient's/parent's assessment of HRQOL and SLE status, and physician's assessment of disease activity and damage over time. In this multicentre study, 68 children with SLE and parents completed SMILEY including the global HRQOL and SLE status assessments, physicians completed disease activity and damage tools at two time-points. Spearman rho was calculated between SMILEY scores and other scales, and between interval changes in SMILEY scores and other scales. SMILEY scores correlated with patient/parent assessments of global HRQOL and SLE status, disease activity and damage, confirming previous findings. The change in disease activity and damage measures correlated most strongly with the changes in SMILEY domains, Limitation and Burden of SLE. Results provide preliminary evidence that Limitation and Burden of SLE domains of SMILEY reflect the impact of disease activity and damage on HRQOL.

Molecular analysis of the rat MHC. I. Delineation of the major regions in the MHC and in the grc.

Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R21, and R22), congenic (Y0.1U.grc+, Y0.1U.grc+/Y0.1L.grc, and Y0.1L.grc) and inbred rats has been performed to examine the restriction fragment length polymorphisms of class I genes. After digestion with Xba I or Eco RI, the genomic DNA was resolved on agarose gels, was transferred to nitrocellulose membranes, and was hybridized with murine H-2 cDNA probes. Eighteen to 25 bands of varying intensities could be clearly resolved in any given strain. Analysis of these hybridization patterns detected restriction fragment length polymorphisms that permitted the assignment of 17 specific fragments to regions within the major histocompatibility complex: RT1.A, RT1.B/D, and the RT1.E-grc-T1 alpha region. Fragments have been identified that are specific for grc, grc+, and RT1.E, and mark the junction sites between these loci. In addition, several markers identify the region around the sites of recombination in some strains. The hybridization pattern of the R18 recombinant had a unique band that specified a point of recombination within the grc. The recombinant R11 presented a unique restriction pattern unrelated to either of the parental strains or other related strains. This result suggests that R11 arose from a recombination event(s) undetected by conventional serologic methods.

Polymorphism of the Pa gene.

PROBLEM: This study was undertaken to identify the number of alleles of the Pa gene at the DNA level and to correlate the presence of the different alleles with the ability of a strain to elicit an anti-Pa antibody response when mated with a WF female. The Pa gene is present in both Pa+ and Pa- strains of rats, but it has unique restriction fragment length polymorphisms (RFLP) in the two types of strains: 1.7 kb in Pa- and 1.8 kb in Pa+XbaI digests using a probe derived from the Pa gene. RESULTS: Examination of DNA from a variety of strains using different enzymes showed that there were characteristic RFLP patterns for Pa+ and Pa- strains. Strains of the b haplotype, however, had an intermediate RFLP pattern, and all of these strains had a relatively low level of reactivity with anti-Pa antibody. CONCLUSIONS: Thus, there are three alleles of the Pa gene based on their level of expression: Paa, high; Pab, low; and Pa-, none.

Genomic DNA sequence and organization of a TL-like gene in the grc-G/C region of the rat.

Genes in the grc-G/C region, which is linked to the rat major histocompatibility complex, influence the control of growth, development, and susceptibility to chemical carcinogens. As an initial approach to analyzing the structure and organization of these genes, a class I hybridizing fragment designated RT(5.8) was isolated from an R21 genomic DNA library and sequenced from overlapping restriction enzyme fragments. The RT(5.8) clone has 5788 base pairs and contains the eight exons characteristic of a class I gene. There are CAAT and TATA boxes upstream of the signal peptide, and the recognition sequence that precedes the site of polyadenylation is located downstream from the third cytoplasmic domain. Comparison of the RT(5.8) gene with representative class I genes from the rat and other species shows that the nucleotide sequences of RT(5.8) have a high level of similarity to those of TL region genes of several strains of mice. The peptide sequence deduced from the RT(5.8) clone is distinct from all previously published class I gene sequences, and at many positions there are amino acid residues that are unique to the RT(5.8) sequence. Probes have been isolated from the third exon and from the 5' and 3' flanking regions of the RT(5.8) clone, and Southern blot analysis with genomic DNA of various rat strains shows that these probes are specific for the RT(5.8) fragment. Northern blot analysis shows that the gene is transcribed in the thymus but not in the liver or spleen. The RT(5.8) sequence is more similar to some mouse TL genes (especially in the alpha 2 and cytoplasmic domains and in the 5' and 3' untranslated regions) than it is to other rat class I genes. Hence, TL-like genes are not restricted to the mouse.

Comparison of rat MHC class I antigens by peptide mapping.

Monoclonal antibodies specific for the rat major histocompatibility complex (MHC) class I antigens RT1.An, RT1.Au, and RT1.Eu were used for immunoprecipitation of antigens biosynthetically radiolabeled with 14C- or 3H-labeled arginine, lysine, and tyrosine; with arginine or tyrosine alone; and with or without tunicamycin in the culture medium. Heavy chains of the glycosylated and unglycosylated antigens were purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and their tryptic and chymotryptic peptides were compared by high performance liquid chromatography. The antigens coded by the same locus in two different haplotypes (An and Au) differed by 30%, whereas the products of two different loci in the same haplotype (Au and Eu) differed only by 1-3%. Comparative analysis of the data for samples labeled with single amino acids indicated that two amino acids in Au have been substituted by an arginine and probably by a tyrosine residue, respectively, in Eu. The high degree of homology between the products of the A and E loci in the same haplotype accounts for the difficulty in detecting recombinational events within the MHC of the rat by classical serological approaches.

The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome.

OBJECTIVE: Although 2 recent studies have found associations between catastrophizing and poor medical outcomes in patients with fibromyalgia syndrome (FMS), neither assessed these findings in comparison with a similar group of patients with chronic pain. Our study examined the complex relationships between depression, catastrophizing, and the multidimensional aspects of pain in women with FMS and compared these relationships with those in women with rheumatoid arthritis (RA). METHODS: Sixty-four FMS patients and 30 RA patients completed the Coping Strategies Questionnaire (CSQ), the Beck Depression Inventory II (BDI-II), and the McGill Pain Questionnaire. RESULTS: Compared with subjects with RA, FMS subjects scored significantly higher on the catastrophizing subscale of the CSQ. FMS patients also earned higher scores on overall depression and on the cognitive subscale of the BDI-II. Furthermore, the relationship between catastrophizing and depression was significant in the FMS group only. Regression analyses revealed that in FMS, catastrophizing as a measure of coping predicted patients' perception of pain better than demographic variables such as age, duration of illness, and education. CONCLUSION: Cognitive factors, such as catastrophizing and depressive self-statements, have a more pronounced role in the self-reported pain of patients with FMS than in patients with RA. Clinically, this indicates that treating pain and depression in FMS by adding cognitive therapy and coping skills components to a comprehensive treatment program may improve the outcomes obtained with pharmacologic interventions.

Molecular analysis of the rat MHC. II. Isolation of genes that map to the RT1.E-grc region.

An initial mapping analysis of growth and reproduction complex (grc) and grc+ genomic DNA identified several restriction fragment length polymorphisms specific for the grc region of the MHC. To analyze further the genomic organization and structure of the grc, a cosmid library was constructed from a grc+-bearing strain (R21). One cosmid cluster, encompassing 41.4 kb of DNA, contained four, or possibly five, class I genes that mapped to the RT1.E-grc region Two unique non-class I fragments were isolated from certain cosmids within this cluster. These fragments were hybridized to genomic DNA derived from five rat strains (BIL/2, R18, R21, R22, and BIL/1), and the results showed that grc-bearing rats have a deletion of at least 3.1 kb of DNA in the region immediately adjacent to the MHC. The loss of the genes in this region is probably the cause of the growth and reproductive defects in these animals and probably also of their increased susceptibility to chemical carcinogens.

The RT1.G locus in the rat encodes a Qa/TL-like antigen.

A new antigenic system in the rat homologous to the Qa/TL antigen system in the mouse has been characterized. It was detected by antibodies raised in donor-recipient combinations that were matched for the RT1.A, B, D, E loci in the major histocompatibility complex (MHC): (R11 X BN)F1 anti-BN.1L(LEW), (R18 X BN)F1 anti-BN.1L, and BN.1LV1(F344) anti-BN.1L. Absorption analyses using these antisera and a variety of inbred, congenic, and recombinant strains identified three alleles, RT1.Ga, Gb, Gc, of which Gc is a null allele. The strain distribution of these alleles was determined using 37 strains of rats representative of all of the prototypic haplotypes and a number of congenic and recombinant strains. The use of the congenic and recombinant strains showed that the RT1.G locus was linked to the MHC and that the most probable gene order was A-E-G. Testcross analysis showed that the map distance between A and G was 1.4 cM (4/285 recombinants). The RT1.G antigen has a heavy chain of Mr 46,000 and is present on both T and B cells.

Physical mapping of the E/C and grc regions of the rat major histocompatibility complex.

Alignment of class I-hybridizing cosmids from an R21 (AlBlDlEugrc+) genomic DNA library gave two contigs: one [150 kilobases (kb)] encompassed the E/C region, or a large part thereof, and the other (110 kb) contained the grc region which has genes influencing resistance to chemical carcinogens (rcc), fertility (ft), and growth (dw-3). Amplification of gene sequences in the four cosmids in the E/C region using Eu-specific and LW2 (RT1.C)-specific primers showed that each cosmid contained both Eu-like and C-like genes. They are clearly different but closely associated, and they show some variation from the prototypic E (Eu) and C (LW2) genes, respectively. Comparison of DNA from grc+ and grc- strains of rats showed that the deletion in the grc- strains was approximately 50 kb, and that it was located on two of the three cosmids in the grc-region contig. The use of specific class I probes showed that the grc region contained tandemly duplicated RT1.O-RT1.N genes and that the RT.BM1 loci lay outside of the grc region. Neither contig reacted with probes specific for class II, TNFA, Hsp70, or RT1.M genes. The data presented here and the previous data in the literature (summarized in Gill et al. 1995) suggest that the gene order in the major histocompatibility complex (MHC) and MHC-linked region of the rat is: A-E/C-grc-M.

Genomic structure and organization of a Q-like gene in the GRC-G/C region of the rat.

In the rat homologue of the mouse Q/TL region, grc-G/C, a TL-like gene (RT1.N) has been identified recently. This paper reports on a Q-like gene, designated RT1.0, that maps in the same region. It contains a 5' untranslated region (UT), signal peptide, alpha 3 domain, transmembrane region, cytoplasmic domain (three exons) and 3'UT region. Comparison with mouse class-I genes shows that the greatest similarity is to the H-2Q, K, D and L genes; it is very different from the TL genes of the mouse and rat. A sequence that includes many CT repeats occurs in the 3'UT region of RT1.0 and in three to five other class I-hybridizing fragments. Thus, the MHC-linked region of the rat contains both Q-like and TL-like class-I genes.

Immunogenetics of development and its relationship to carcinogenesis.

We have been exploring the classical idea that there is a close relationship between embryogenesis and carcinogenesis. The clinical literature provides evidence for a relationship among the presence of developmental anomalies, an increased incidence of cancer, and genes linked to the major histocompatibility complex (MHC). This relationship was explored experimentally by testing the possibility that rats having the growth and reproduction complex (grc), which causes developmental abnormalities, might be more susceptible to the development of cancer following exposure to a chemical carcinogen. Two groups of animals which were genetically similar except for the presence or absence of the grc were fed the carcinogen 2-aminoacetylfluorene. The animals carrying the grc developed the morphological changes associated with early cancer of the liver, whereas their normal counterparts did not. These susceptible animals also had a number of biochemical alterations, especially in cholesterol biosynthesis, which may be associated with the development of cancer. Molecular analysis of genomic DNA by blot hybridization revealed restriction fragment length polymorphism differences between the DNA from grc and grc+ rats, and these differences may be related to the differential susceptibility of the strains to cancer.