Humeira Badsha

Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage (P = 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers (P = 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups (P < 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups.

Women, men, and rheumatoid arthritis: Analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study

IntroductionGender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA).MethodsThe cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents.ResultsWomen had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies.ConclusionsIn this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: Data from 32 countries in the QUEST-RA Study

IntroductionWork disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.MethodsThe Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.ResultsAt the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.ConclusionsWork disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST–RA database

Objective: To analyse associations between the clinical status of patients with rheumatoid arthritis (RA) and the gross domestic product (GDP) of their resident country. Methods: The Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST–RA) cohort includes clinical and questionnaire data from 6004 patients who were seen in usual care at 70 rheumatology clinics in 25 countries as of April 2008, including 18 European countries. Demographic variables, clinical characteristics, RA disease activity measures, including the disease activity score in 28 joints (DAS28), and treatment-related variables were analysed according to GDP per capita, including 14 “high GDP” countries with GDP per capita greater than US

Remission and rheumatoid arthritis: Data on patients receiving usual care in twenty-four countries

24 000 and 11 “low GDP” countries with GDP per capita less than US

Hospitalization of individuals with systemic lupus erythematosus: characteristics and predictors of outcome

11 000. Results: Disease activity DAS28 ranged between 3.1 and 6.0 among the 25 countries and was significantly associated with GDP (r  =  −0.78, 95% CI −0.56 to −0.90, r2  =  61%). Disease activity levels differed substantially between “high GDP” and “low GDP” countries at much greater levels than according to whether patients were currently taking or not taking methotrexate, prednisone and/or biological agents. Conclusions: The clinical status of patients with RA was correlated significantly with GDP among 25 mostly European countries according to all disease measures, associated only modestly with the current use of antirheumatic medications. The burden of arthritis appears substantially greater in “low GDP” than in “high GDP” countries. These findings may alert healthcare professionals and designers of health policy towards improving the clinical status of patients with RA in all countries.

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

OBJECTIVE To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

Low-dose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications

We performed a retrospective study of patients with systemic lupus erythematosus (SLE) admitted to hospital during a one-year period to describe characteristics associated with a poor outcome. There were 348 episodes of hospitalization of 223 individuals. The cause of admission was clinical flare of SLE (58%), infection (37%) and thromboembolic disease (8%). Readmission occurred in 35.8% and was associatedwith: active nephritis (HR 2.53, P < 0.01), flare of lupus (HR 2.0, P < 0.01) and more ACR criteria (HR 1.34 per extra criteria, P < 0.01). Individuals with multiple reasons for admission had a longer duration of stay [one four days (2,6), two five days (3,7) and three 9.5 days (6.5,14.5),P < 0.01]. There were 11 deaths (3.2% of admissions). The deaths were due to infection in nine cases (four with concurrent active SLE). In multivariate modelling, the main predictors of death were: previous multiple admissions (OR 12.4, P < 0.01), the presence of infection (OR 7.3, P < 0.01) and youngerage (OR 0.93 per increaseof one year, P 0.03). The presenceof active lupus nephritis and multisystem disease makes readmission more likely and individuals with multiple problems at the time of admission have longer hospital stays. Young patients with frequent readmissions and coexistent infections are most likely to die.

The benefits of yoga for rheumatoid arthritis: results of a preliminary, structured 8-week program

A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23–42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21–43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P = 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P = 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5′ untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.

Discordant assessment of lupus activity between patients and their physicians: the Singapore experience

We sought to test our clinical impression that using a low dose methylprednisolone pulse (MEP; µ1500 mg over 3 days) in treating flares of systemic lupus erythematosus (SLE) was effective and associated with fewer serious infections. We retrospectively studied SLE patients who received MEP between 1989 and 2000. A ‘low dose’ group of 26 patients who had received 1–1.5 g and a ‘high dose’ group of 29 patients who received 3–5 g of MEP were identified. SLEDAI scores and prednisolone doses were recorded at the time of MEP pulses and 6 months later. All serious infections (requiring admission and i.v. antibiotics) occurring during this 6 month period and their outcomes were recorded. Both groups had similar demographic data, initial SLEDAI scores, i.v. cyclophosphamide use, and SLE organ involvement. Despite high-and low-dose MEP being efficacious in controlling disease activity (lowering of SLEDAI scores and subsequent prednisolone dose) there were only nine episodes of serious infection in seven patients in the low-dose group compared with 20 episodes in 17 patients from the high-dose group (P ^ 0.04). In both groups a majority of infections (75 and 77% in the high-and low-dose groups) occurred in the first month after MEP. Those with a low serum albumin (< 20 g/l) had an increased risk of mortality (OR 44, 90% CI 6.19–312.98) and a trend towards greater numbers of infections. Low-dose MEP was effective in controlling SLE flares and associated with fewer serious infections than traditional high-dose MEP.