Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment.

OBJECTIVE: To provide context for the malignancy experience in the rheumatoid arthritis (RA) abatacept clinical development programme (CDP) by performing comparisons with similar RA patients and the general population. METHODS: Malignancy outcomes included total malignancy (excluding non-melanoma skin cancer (NMSC)), breast, colorectal, lung cancers and lymphoma. Comparisons were made between the observed incidence in patients within the abatacept CDP and RA patients on disease-modifying antirheumatic drugs (DMARD) identified from five data sources: the population-based British Columbia RA Cohort, the Norfolk Arthritis Register, the National Data Bank for Rheumatic Diseases, the Sweden Early RA Register and the General Practice Research Database. Age and sex-adjusted incidence rates (IR) and standardised incidence ratios (SIR) were used to compare events in the abatacept trials with the RA DMARD cohorts and the general population. RESULTS: A total of 4134 RA patients treated with abatacept in seven trials and 41,529 DMARD-treated RA patients in the five observational cohorts was identified for study inclusion. In the abatacept-treated patients, the 51 malignancies (excluding NMSC), seven cases of breast, two cases of colorectal, 13 cases of lung cancer and five cases of lymphoma observed were not greater than the range of expected cases from the five RA cohorts. The SIR comparing RA patients with the general population were consistent with those reported in the literature. CONCLUSIONS: The IR of total malignancy (excluding NMSC), breast, colorectal, lung cancers and lymphoma in the abatacept CDP were consistent with those in a comparable RA population. These data suggest no new safety signals with respect to malignancies, which will continue to be monitored.

The effect of arthritis on working life expectancy.

OBJECTIVE: To measure the effect of arthritis and musculoskeletal conditions on working life expectancy. METHODS: Cross sectional data from the 1994 Canadian National Population Health Survey (NPHS) were used to calculate and compare the working life expectancy of individuals who reported "arthritis or rheumatism" with that of the general population. Age and sex-specific workforce participation rates were calculated for the population reporting arthritis or rheumatism as a chronic condition, excluding back pain, and for the entire population surveyed. Age and sex-specific population figures and mortality data were obtained from annual estimates produced by Statistics Canada. Working life expectancy was estimated by constructing multiple-decrement life tables for the total and for the arthritis and rheumatism populations. RESULTS: The NPHS surveyed 22,000 households, yielding a sample size of 58,439 individuals. The percentage of the population aged 15 to 65 yrs who reported having arthritis or rheumatism was 8.9%. The percentage of persons employed for each group was reduced compared to the total population, by 3 to 23%. Working life expectancy of individuals with arthritis or rheumatism was reduced by 4.19 +/- 0.02 yrs (mean +/- SE) for men and 3.12 +/- 0.01 yrs for women at age 15 (p < 0.001 for both), with a persistent reduction through all age groups. Working life expectancy of men at age 15 was 37.42 +/- 0.01 yrs for the population with arthritis or rheumatism compared to 41.62 +/- 0.01 yrs for the total population; for women it was 31.06 +/- 0.01 and 34.19 +/- 0.001 yrs for both groups, respectively. CONCLUSION: The working life expectancy of people with arthritis and musculoskeletal conditions is significantly reduced compared to the general Canadian population.

Identification of four novel dinucleotide repeat polymorphisms in the IL-2 and IL-2beta receptor genes.

Two polymorphic regions have been described within the IL-2 and IL-2 receptor beta genes comprising 15 and 8 alleles, respectively. Whether these polymorphisms have biologic importance is unknown, although they have been variably identified in associated with certain chronic disease states. We report here the detection of four new alleles designated IL-2 A* (122 bp), IL-2R-2 (169 bp), IL-2R 0 (165 bp), and IL-2R 9 (147 bp) in patients with rheumatoid arthritis and normal controls from the Pacific Northwest. The number of alleles now recognized at these loci within the IL-2 and IL-2Rbeta genes increases to 16 and 12, respectively.

Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis ranges from a mild, non-deforming arthropathy with little long-term disability to severe, incapacitating, deforming arthritis which may be refractory to conventional disease-modifying agents. Epidemiological studies show an important genetic influence in rheumatoid arthritis, and MHC region genes and cytokine genes within and outside this region have been considered as candidates. We did a case-control study to test whether polymorphisms in the interferon-gamma gene are associated with severity of rheumatoid arthritis. METHODS: Interferon gamma dinucleotide repeat polymorphisms were examined with quantitative genescan technology, and HLA-DR alleles were identified by PCR and restriction-fragment-length polymorphism analysis. We studied 60 patients with severe rheumatoid arthritis, 39 with mild disease, and 65 normal controls. FINDINGS: Susceptibility to, and severity of, rheumatoid arthritis were related to a microsatellite polymorphism within the first intron of the interferon-gamma gene. A 126 bp allele was seen in 44 (73%) of 60 patients with severe rheumatoid arthritis, compared with eight (21%) of 39 with mild disease (odds ratio 10.66 [95% CI 4.1-24.9]), and with eight (12%) of 65 normal controls (19.59 [7.7-49.9]). Conversely, a 122 bp allele at the same locus was found in four (7%) patients with severe disease compared with 25 (64%) of those with mild disease (0.04 [0.01-0.1]) and with 52 (80%) of controls (0.018 [0.005-0.06]). INTERPRETATION: This association may be valuable for understanding the mechanism of disease progression, for predicting the course of the disease, and for guiding therapy.

Longterm therapy of psoriatic arthritis: intramuscular gold or methotrexate?

OBJECTIVE: To compare the efficacy and toxicity of methotrexate (MTX) and intramuscular (im) gold in the treatment of psoriatic arthritis (PsA). METHODS: Medical records from all patients with PsA attending the gold and MTX clinics at the Vancouver Mary Pack Arthritis Centre between 1971 and 1995 were reviewed. The odds of a clinical response (defined as at least a 50% reduction in active joint count from initial to last visit or for at least 6 months) and the relative risk of discontinuing therapy associated with treatment (MTX or im gold) were calculated after controlling for significant baseline covariates, using logistic regression and Cox regression analyses, respectively. The frequency of side effects and the reasons for treatment cessation were also compared between treatment groups. RESULTS: Eighty-seven patients received 111 treatment courses: 43 of MTX and 68 of im gold. The likelihood of a clinical response was 8.9 times greater (95% CI 1.8; 44.0) with MTX than im gold. Patients were 5 times more likely (95% CI 2.4; 10.4) to discontinue therapy with im gold than with MTX. No major toxicity occurred and frequency of side effects was similar for both treatments. Patients with a longer duration of PsA prior to initiation of study treatment were less likely to achieve a clinical response. CONCLUSION: MTX and im gold are safe and well tolerated in the treatment of PsA. In our experience. MTX was superior to im gold in the likelihood of achieving a clinical response and in permitting an individual to continue longterm treatment. Our data suggest that earlier treatment may be associated with a better response.

The impact of disease activity, treatment and disease severity on short-term costs of systemic lupus erythematosus.

OBJECTIVE: To assess the impact of disease activity, current treatment, and global disease severity (or damage) on short-term direct and indirect costs of systemic lupus erythematosus (SLE). METHODS: 150 patients were evaluated twice, one year apart. Disease activity was assessed by the SLE disease activity index, and ordinal scales were used to evaluate treatment (prednisone = 0, 1 to 20 mg/day, > 20 mg/day, and use of immunosuppressive agents) and global disease severity [renal severity = 0 to 3, central nervous system (CNS) severity = 0 to 2, hematologic severity = 0 to 1]. Costs were assessed with the economic portion of the Health Assessment Questionnaire adapted for Canada. RESULTS: Global disease severity was significantly correlated with both direct (p = 0.0001) and indirect (p = 0.02) costs, and current treatment with indirect costs (p = 0.002). The renal and CNS subscales of the global severity measure predicted direct costs (p < 0.01) and the CNS subscale predicted indirect costs (p = 0.002). Stepwise multivariable models selected the global severity index (p = 0.004) as a predictor of direct costs, and either the treatment index (p = 0.02) or the global severity index (p = 0.02) as a predictor of indirect costs. CONCLUSION: The global disease severity index, particularly the subscales involving the renal and CNS organ systems, and the treatment index are predictors of the short-term costs of SLE.

A Canadian study of the total medical costs for patients with systemic lupus erythematosus and the predictors of costs.

OBJECTIVE: We conducted a cost identification analysis on 164 consecutive patients with systemic lupus erythematosus (SLE) who entered the Montreal General Hospital Lupus Registry between January 1977 and January 1990, compared their costs to the population of Quebec, and determined the predictors of cost. METHODS: In January 1990 and 1991, participants completed questionnaires on health services utilization and on employment history over the preceding 6 months, as well as on functional, psychological, and social well-being. The societal burden of SLE was determined in terms of direct costs (all resources consumed in patient care) and indirect costs (wages lost due to lack of work force participation because of morbidity). RESULTS: The mean total annual cost for 1989, as assessed in January 1990 and expressed in 1990 Canadian dollars, was $13,094. Although only 44% of the patients were fully employed, indirect costs were responsible for 54% of this total ($7,071). Ambulatory costs, primarily diagnostic procedures, medications, and visits to health care professionals, comprised 55% of direct costs ($3,331). The results of the 1990 cost determination were similar. On average, hospitalizations among SLE patients were 4 times more frequent than among the general population of Quebec (matched for age and sex), and the number of ambulatory visits to physicians was double that for the average resident of Quebec. Higher 1989 values of creatinine and a poorer level of physical functioning were the best predictors of higher 1990 direct costs (R2 = 0.29). A poorer SLE well-being score, a combination of education and employment status, and a weaker level of social support were the best predictors of higher indirect costs (R2 = 0.29). CONCLUSION: The direct and indirect costs for patients with SLE are substantial, and their respective predictors are distinct. Direct costs arise from organic complications which induce functional disability. Predictors of indirect costs are potentially amenable to psychological or social interventions and may be more easily modified than the determinants of direct costs, thereby improving patient outcome while simultaneously reducing disease costs.

The relationship of socioeconomic status to subsequent health status in systemic lupus erythematosus.

We examined the relationship of socioeconomic status to health status, as determined by the Arthritis Impact Measurement Scales, in 78 systemic lupus erythematosus patients who had been entered into a prospective study. After controlling for age, disease duration, and disease severity, a significant relationship between socioeconomic status and outcome was not demonstrated. All study subjects had health insurance for medical services. The results have potential implications for health care policy.