Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis.

OBJECTIVES: Recently published research suggests that statins may have beneficial structural effects in persons with knee osteoarthritis (OA). The potential effects of statins on patient-reported knee pain and function have not been examined. We studied a large prospective community-based cohort of persons with knee OA to determine if statin usage was associated with changes in knee structure, pain and function trajectories. METHODS: Data were obtained from the Osteoarthritis Initiative using a subset of 2207 persons with radiographically suspected or confirmed knee OA. The changes in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain and Physical Function scores, pain intensity and Kellgren-Lawrence radiographic grade over 4 years were examined. Data from persons were coded based on whether they were incident users of statins over the 4-year period. Outcome trajectories and probability of statin use were examined over the 4-year study period using parallel processing growth curve modelling. The analysis adjusted for potential confounders and determined if statin use predicted outcome trajectories. RESULTS: Statin users accounted for 6.7% of the sample in year 1 and 16.4% in year 4. Statin use was not associated with improvements in knee pain, function or structural progression trajectories. The only significant finding indicated that increased duration of statin use was associated with worsening in WOMAC Physical Function scores over the study period (ß=0.161, p=0.005). CONCLUSIONS: Statin use was not associated with improvements in knee pain, function or structural progression over the 4-year study period.

Genetic studies, clinical heterogeneity, and disease outcome studies in rheumatoid arthritis.

HLA haplotypes influence various clinical RA features considered to reflect severity in case-control and cohort studies. Of particular note is the fact that HLA generally influences the development of erosive and sometimes seropositive and nodular disease; in prospective studies, it noticeably affects joint surgical intervention. These are valuable clues indicating that HLA influences RA severity and chronicity. Nevertheless, HLA influences are generally weak enough so as to require large study subject numbers for detection. As a result, HLA genotyping has restricted usefulness for prediction of clinical severity in individual patients.

Rheumatic disorders and functional disability with aromatase inhibitor therapy.

BACKGROUND: Aromatase inhibitor therapy is often effective for breast cancer, yet it can be accompanied by musculoskeletal pain and stiffness. This prevalence assessment aimed to characterize a rheumatologist's view of frequency and clinical features, including associated disability, within a breast cancer clinic panel of 77 patients. PATIENTS AND METHODS: The "aromatase inhibitor arthralgia" frequency was estimated at 50%, including both those with new and worsened discomfort. Substantial functional disability was associated, whether measured by individual functional disability (frequencies ranging from 39% to 61%) or composite score of 7 functional disability areas (median score 5 compared with median 0 in the comparison group; P = .00003). RESULTS: The frequency of clinical hand osteoarthritis appeared somewhat increased in the aromatase inhibitor arthralgia group (28% vs. 14%; not statistically significant). Yet the distribution of aromatase inhibitor-related symptoms and functional disabilities appeared to parallel those joint regions commonly affected by osteoarthritis. Using clinical criteria to assess 5 common rheumatic disorders (hand osteoarthritis, trigger finger, carpal tunnel syndrome, Raynaud's phenomenon, and sicca syndrome), the aromatase inhibitor arthralgia group tended to have more common rheumatic disorders (P < .05), consistent with nociceptive mechanisms making latent disorders symptomatic. CONCLUSION: Aromatase inhibitor therapy for postmenopausal breast cancer might be associated with common musculoskeletal symptoms and with substantial functional disability and should prompt patient education. In view of the potential relevance of estrogen deprivation to osteoarthritis onset and severity, future studies of natural history should include systematic assessment of osteoarthritis frequency and severity.

Premenopausal sexual dimorphism in lipopolysaccharide-stimulated production and secretion of tumor necrosis factor.

OBJECTIVE: To establish whether sexual dimorphism in tumor necrosis factor (TNF) concentration in lipopolysaccharide (LPS)-stimulated whole blood culture is related to menopausal status or hormone concentrations. METHODS: Healthy volunteers (72 premenopausal female, 159 male, and 62 postmenopausal female) completed questionnaires and gave peripheral blood specimens for whole blood LPS-stimulated TNF assay and for selected hormone levels. TNFab microsatellite markers were genotyped. RESULTS: Mean LPS-stimulated TNF level in the premenopausal female group was 18% lower than the postmenopausal female mean (1579 +/- 913 pg/ml compared with 2257 +/- 881 in the men and 1965 +/- 950 in the postmenopausal women; p < 0.0003 and p 0.058, respectively). Analyzing a subset for which blood counts were obtained, mean stimulated TNF per monocyte was lower in the premenopausal female group than in the postmenopausal female group and appeared lower than in the male group (2.67 +/- 1.96 pg/ml per 10(3) monocytes vs 4.44 +/- 2.16 and 3.60 +/- 1.40; p = 0.018 and p = 0.12, respectively). Total plasma cortisol was higher in premenopausal women than men, and, in turn, higher in men than postmenopausal women (mean +/- SD 16.1 +/- 5.7, 12.2 +/- 3.6, and 10.4 +/- 4.3 microg/dl, respectively; p < 0.05 for each comparison). Using multiple linear regression to correct for covariates and TNF allelic effects, premenopausal status predicted TNF level independently from potential confounders or TNF genetic markers (covariate-adjusted decrement of 408 pg/ml; p = 0.0241). In the male group, total cortisol predicted lower TNF level (coefficient -67.5 pg/ml for each microg/dl cortisol; p = 0.0006 after stepwise selection), but total testosterone had no effect. In premenopausal women, LPS-stimulated TNF was not related to total estradiol, testosterone, or cortisol level. CONCLUSION: Premenopausal women had a lower mean whole blood LPS-stimulated TNF level than postmenopausal women, but there was no significant relation to total estradiol, testosterone, or cortisol levels in premenopausal women.

Effect of sex and haplotype on plasma tryptase levels in healthy adults.

BACKGROUND: The total level of alpha-tryptase and ss-tryptase in serum or plasma is used as a clinical indicator of the mast cell burden. OBJECTIVE: The effect of the tryptase haplotype and of sex on the total tryptase level of healthy individuals was determined. METHODS: A novel hot-stop PCR technique was used to determine the tryptase genotype, and a standard fluoroenzyme immunoassay was used to measure total plasma tryptase levels in 106 healthy subjects. Mx modeling and the QTL association routine of Mendel 5.0 were used to analyze the data. RESULTS: Tryptase haplotypes exhibit a 1 (betaalpha/betaalpha):2 (betabeta/betaalpha):1 (betabeta/betabeta) distribution, monomorphic for ss at 1 position and allelic for ss and alpha at the other position. The betaalpha haplotype has a frequency of 0.49. The betaalpha haplotype increases total tryptase levels by 0.5 ng/mL from the overall mean, whereas female sex increases the level by 0.2 ng/mL from the mean. CONCLUSION: The tryptase haplotype and sex each have a statistically significant effect on the total plasma tryptase level of healthy subjects.

Sexual dimorphism in innate immunity.

OBJECTIVE: To establish whether variation in innate immunity, as measured by the level of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-stimulated whole-blood culture, is related to sex or HLA. METHODS: Normal volunteers (72 women, 159 men) completed questionnaires and donated peripheral blood specimens. Blood samples were exposed to LPS in a 4-hour in vitro culture, and supernatants were then tested by sandwich-type immunoassay measuring TNF levels. Statistical techniques included multivariate analysis and maximal-likelihood modeling of allelic effects. RESULTS: Both male and female groups showed substantial within-group variation (coefficient of variation 59.1% for women, 40.3% for men). However, the mean +/- SD LPS-stimulated TNF level in the female group was nearly 30% lower than in the male group (1,556+/-919 pg/ml versus 2,203+/-889 pg/ml; P < 0.0001, unadjusted for covariates). Sex was independent of any microsatellite marker allele of TNF (covariate-adjusted increment of 785 pg/ml from female to male sex; P < 0.0001). In multivariate modeling of the female group, the LPS-stimulated TNF level was not independently influenced by menstrual cycle phase, oral contraceptive use, or plasma estradiol level. Allelic modeling showed that significant TNFab microsatellite allelic effects existed (P = 0.002 versus model omitting allelic effects). The female group showed a significantly downward deviation from mean TNF level with TNFa4b5 (-903 pg/ml deviation from the overall mean) and an upward deviation with TNFa10b4 (598 pg/ml). The male group showed significantly higher-than-mean levels with TNFa1b5 (909 pg/ml), TNFa5b7 (1,191 pg/ml), and TNFa6b5 (332 pg/ml). Thus, the two sex groups differed in which of their TNFab marker alleles showed significant deviations from the overall mean. CONCLUSION: Female subjects have a nearly 30% lower innate immune response, stemming largely from influence independent of the HLA-region TNF locus and without further independent variation stemming from plasma estrogen level.

Tryptase precursors are preferentially and spontaneously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells, and human skin-derived mast cells.

Tryptase (alpha and beta) levels in serum are used to assess mast cell involvement in human disease. Using cultured cells, the current study examines the hypothesis that protryptase(s) are spontaneously secreted by mast cells at rest, whereas mature tryptase(s) are stored in secretory granules until their release by activated cells. HMC-1 cells have only beta-tryptase genes and the corresponding mRNA. Mono-Mac-6 cells have both alpha- and beta-tryptase genes but preferentially express alpha-tryptase. Mono-Mac-6 cells spontaneously secrete most of their tryptase, which consists of alpha-protryptase, whereas mature tryptase is retained inside these cells. HMC-1 cells also spontaneously secrete most of their tryptase, identified as beta-protryptase, and retain mature tryptase. Skin-derived mast cells retain most of their tryptase, which is mature, and spontaneously secrete protryptase(s). Total tryptase levels in plasma are detectable but no different in healthy subjects with and without the gene for alpha-tryptase, consistent with pro forms of both alpha- and beta-tryptase being spontaneously secreted. Thus, protryptase(s) are spontaneously secreted by resting mast cells, whereas mature tryptase is retained by mast cells until they are activated to degranulate.