Rheumatoid Arthritis: St-Pierre Y

Kilani RT, Maksymowych WP, Aitken A, Boire G, St-Pierre Y, Li Y, Ghahary A. · Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. · J Rheumatol. · Pubmed #17611984 No free full text.

Abstract: OBJECTIVE: To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with inflamed joints, and if so, what isoform(s); and to examine whether there was a correlation between the levels of these proteins and those of MMP-1 and MMP-3 in the same samples. METHODS: In general, 2 sets of synovial and serum samples were analyzed. The first set of 17 SF -samples from patients with inflamed joints were analyzed for 14-3-3 eta isoform by Western blot. The second set of 12 matching serum and SF samples were analyzed for 14-3-3 eta, gamma, MMP-1, and MMP-3 by the same procedure. The MMP-1 stimulatory effect of various concentrations of 14-3-3 eta in cultured fibroblasts was then evaluated. RESULTS: We found that of the seven 14-3-3 isoforms tested (beta, gamma, epsilon, eta, sigma, Theta, and zeta), the levels of only 2 isoforms, eta and gamma, were easily detectable in SF samples from patients with inflammatory joint diseases. The levels of these proteins were significantly higher in inflammatory SF and serum samples relative to controls. The values of these proteins correlated strongly with the levels of MMP-1 and MMP-3, 2 biomarkers for rheumatoid arthritis, detected in sera. Further, the level of 14-3-3 eta was significantly higher in a pool of 12 serum samples from patients with inflammatory joint disease than those from healthy individuals. CONCLUSION: Detection of only 2 (14-3-3 eta and gamma) out of 7 different isoforms in SF suggests they are specific to the site of inflammation, and that distinguishes them from barely detectable levels of these isoforms found in normal serum. The MMP-1 stimulatory effect of the eta isoform explains its correlation with MMP-1 levels seen in these samples.

Fautrel B, Clarke AE, Guillemin F, Adam V, St-Pierre Y, Panaritis T, Fortin PR, Menard HA, Donaldson C, Penrod JR. · Department of Rheumatology, University of Paris VI-Pierre et Marie Curie, Hospital Pitié-Salpêtrière, Paris, France. · Med Decis Making. · Pubmed #17409364 No free full text.

Abstract: BACKGROUND: Individuals' valuation of changes in health states in monetary terms have been measured by examining changes in the direct and indirect costs of disease and by the willingness-to-pay (WTP) methodology. METHODS: In 2002, a 2-part study was conducted in Quebec. In one part of the study, 121 rheumatoid arthritis (RA) patients from the McGill University Health Centre were mailed the Stanford Cost Assessment Questionnaire, which enabled the elicitation of direct costs and indirect costs, according to the friction cost and the human capital methods. The other part was a phone survey conducted in a representative sample of the general population and in the same sample of patients, aiming to elicit the societal WTP for a complete cure of RA in the context of 2 different scenarios: a public coverage or private insurance. These estimates were then compared. RESULTS: Estimates of the cost of illness of RA ranged from 11,717 to 28,498 Canadian Dollars (CAD) depending on the method. These estimates are higher than those previously published in Canada from the 1990s, which is partly due to the recent and costly biological therapies and to a change in the measurement of productivity losses. These estimates are somewhat lower than the societal WTP elicited from the WTP survey, that is, 26,717 and 36,817 CAD per RA case, depending on the public or private health insurance context in which the cure would be available. CONCLUSION: Given that neither method is ideal, data from both methods would provide an important sensitivity analysis when monetary estimates of health state changes are required.

Simard N, Boire G, de Brum-Fernandes AJ, St-Pierre Y. · INRS-Institut Armand-Frappier, University of Québec, Laval, Québec, Canada. · Arthritis Res Ther. · Pubmed #16859524 links to  free full text

Abstract: Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis.

Fautrel B, Clarke AE, Guillemin F, Adam V, St-Pierre Y, Panaritis T, Fortin PR, Menard HA, Donaldson C, Penrod JR. · Department of Rheumatology, Hospital Pitié-Salpêtrière, 83 bd de l'Hôpital, 75013 Paris, France. · J Rheumatol. · Pubmed #15742435 No free full text.

Abstract: OBJECTIVE: A willingness-to-pay (WTP) survey measures the value of a given intervention in money terms. We examined the WTP of Canadian patients with rheumatoid arthritis (RA) for a hypothetical cure for RA under private and public scenarios. The validity of the survey was explored by studying the association between WTP and variables thought to be associated with WTP and randomly-varied variables of the survey materials. METHODS: A telephone survey was carried out in a sample of 121 patients with RA from 5 rheumatologists affiliated with the McGill University Health Centre. In advance, patients had been sent a 4-page brochure providing a comprehensive description of the disease (including photos or no photos). The hypothetical cure for RA was presented through 2 scenarios: a private insurance implying an annual premium and a public coverage requiring additional income taxes. The survey included questions related to their WTP, socioeconomic status (ability to pay), general health, opinion about the performance of the healthcare system, and their opinion about the difficulty of the survey. For elicitation of WTP, patients were randomized to one of 3 payment cards. Mailed questionnaires concerning RA health status were also completed. A series of univariate comparisons and multivariate ordered logit regressions were carried out to examine the association of WTP and patient and study variables. RESULTS: Patients were willing to pay annually significantly more for the private program (mean 1190 Canadian dollars) than for the public program (mean 502 Canadian dollars). Annual WTP was associated with age, household income, site of care (private program), private health insurance, opinion about the performance of the public healthcare system (public program), and presence of brochure photos. The payment card did not affect WTP for either program. CONCLUSION: The WTP survey was well understood and accepted by the patients with RA. Although measures of RA-specific health status (e.g., Health Assessment Questionnaire) were not found to be associated with WTP, many variables thought to be associated with WTP were found to be related in the expected directions. Since WTP for the private program was higher than that for the public program, our study design did not fully capture altruistic valuations of RA patients. Thus, our estimates represent a lower bound on patients' WTP for an RA cure.

Adam V, St-Pierre Y, Fautrel B, Clarke AE, Duffy CM, Penrod JR. · Division of Clinical Epidemiology, McGill University Health Centre, The Montreal General Hospital, Montreal, Canada. · J Rheumatol. · Pubmed #15693099 No free full text.

Abstract: OBJECTIVE: Adolescent arthritis or rheumatism (AAR) has been shown to influence the activities, mental health, and healthcare utilization of affected individuals. However, these effects have never been estimated in a population-based sample. We examined the association of AAR with health status, health services use, health behaviors, and activity limitations. We also investigated the effect of socioeconomic status and family background on respondents with AAR. METHODS: The 1996 National Population Health Survey is a nationally representative survey exploring the health status and behaviors of Canadians. Among the 26,012 individuals aged 12 to 19 with complete responses on the presence of chronic illnesses, the 213 self-reporting arthritis or rheumatism (AAR) were compared to: (1) all other adolescents as a single group; or (2) the group of 9161 adolescents reporting other chronic diseases (OCD) but not AAR, and the group of 16,638 adolescents without chronic disease (WCD). Between-group differences were examined for the following variables: health status; use of health services; presence of activity limitations in school, work, or at home; and school enrollment and work status. RESULTS: Compared to those without, respondents with AAR reported more diagnoses of non-AAR chronic illnesses. Depression among AAR individuals was more prevalent than among non-AAR individuals, as was suffering from moderate or severe pain. Those with AAR were more likely than WCD individuals to use physician services, hospital services, and pain relief medications. AAR patients were more likely to be limited in their activities, and less likely to be enrolled in school than OCD or WCD individuals. CONCLUSION: This study indicates a broad range of effects of AAR in a nationally representative sample. Arthritis or rheumatism affected measures of mental health, health service use, and the school, work, and home activities of affected individuals, compared to individuals without chronic disease or with other chronic disease.

Clarke AE, St-Pierre Y, Joseph L, Penrod J, Sibley JT, Haga M, Genant HK. · Department of Medicine, Montreal General Hospital, Quebec, Canada. · J Rheumatol. · Pubmed #11708412 No free full text.

Abstract: OBJECTIVE: Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships. METHODS: One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data. RESULTS: At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs. CONCLUSION: A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.