Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
15172042 Leflunomide. 2004 May Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide.
12358851 Allelic frequency of the MCP-1 promoter -2518 polymorphism in the Korean population and in 2002 Oct The frequency of the monocyte chemoattractant protein-1 (MCP-1) -2518 G-type polymorphism in Koreans is significantly higher than the frequencies reported for Caucasians and Afro-Americans. The G- vs. A-allele profile in patients with systemic autoimmune diseases is similar to that in healthy Koreans, and does not appear to contribute to elevated MCP-1 production in patients.
14651524 Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lup 2004 Jan Human toll-like receptors (TLRs) participate in the innate response and signal the activation of adaptive immunity. Therefore, these TLRs may be important in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We investigated, by using a polymerase chain reaction restriction-fragment length polymorphism method, the possible association between the polymorphisms of TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes with the susceptibility or severity of RA and SLE. Our study population consisted of 122 patients with SLE, 224 patients with RA, and a control group of 199 healthy individuals. The TLR2 polymorphisms were very rare in our population; no individual carrying the TLR2-Arg677Trp polymorphism was observed, whereas the TLR2-Arg753Gln polymorphism was present in only 1% of the total population. We found no statistically significant differences in the TLR4-Asp299Gly and the TLR4-Thr399Ile genotype or allele distribution between SLE patients, RA patients, and control individuals. Similarly, no association was found with any of the demographic and clinical parameters tested either in RA or in SLE patients. In conclusion, a case-control study was used to analyze, for the first time, the influence of TLR2 and TLR4 gene polymorphism on the predisposition and clinical characteristics of SLE and RA but provided no evidence for association of TLR2 or TLR4 gene polymorphism with either disease in the population under study.
15034508 Intravascular or intralymphatic histiocytosis associated with rheumatoid arthritis: a repo 2004 Apr BACKGROUND: Various skin lesions occur in association with rheumatoid arthritis (RA). OBSERVATION: We report a distinctive skin lesion observed in 4 patients with RA. All patients had RA for many years and developed asymptomatic, irregularly shaped erythema over the swollen elbow joints and the nearby part of the forearm. Histopathologically, all cases showed massive aggregates mainly composed of histiocytes in markedly dilated vessels in the dermis, accompanied by a dermal infiltrate of lymphocytes, plasma cells, neutrophils, or a combination of these. A total of 9 cases, including ours, showing similar histopathologic findings have been reported in the literature, of which 7 were associated with RA and presented relatively common clinical appearance. CONCLUSION: In spite of some disagreement as to whether the dilated vessels are blood vessels or lymphatics, it is most likely that these 7 cases belong to the same clinical entity closely associated with RA.
15605667 Efficacy, safety and tolerability of lumiracoxib in patients with rheumatoid arthritis. 2004 Nov A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p < 0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.
12695160 Anti-saccharomyces cerevisiae IgA antibodies are raised in ankylosing spondylitis and undi 2003 May OBJECTIVES: To investigate whether anti-Saccharomyces cerevisiae antibodies (ASCA), a marker for Crohn's disease (CD), are present in spondyloarthropathies (SpA) and in the subgroups ankylosing spondylitis (AS), undifferentiated SpA (uSpA), and psoriatic arthritis (PsA), in comparison with healthy and inflammatory controls (patients with rheumatoid arthritis (RA)). METHODS: ASCA IgA and IgG levels were measured with an enzyme linked immunosorbent assay (ELISA) kit (Medipan, Germany) in 26 patients with CD, 108 patients with SpA (43 patients with AS, 20 patients with uSpA, 45 patients with PsA), 56 patients with RA and 45 healthy controls. Gut biopsy samples were available in 18 AS and 10 patients with uSpA, these samples were screened for the presence of inflammation. RESULTS: Both ASCA IgG and IgA levels were raised in CD compared with healthy controls and patients with RA. ASCA IgA, but not IgG levels, were higher in SpA than in both healthy and RA controls. ASCA IgA levels were raised in AS and uSpA, but not in PsA. No significant differences in ASCA IgA levels were noted between patients with SpA with and without histological gut inflammation. CONCLUSION: ASCA IgA levels are significantly higher in SpA, and more specifically in AS, than in healthy controls and patients with RA. This is the first serum marker associated with SpA. No correlation between the presence of subclinical bowel inflammation and ASCA IgA levels was noted. However, it remains to be evaluated whether patients with SpA with ASCA have an increased risk of developing CD.
12830454 Serum cystatin C in the aged: relationships with health status. 2003 Jul BACKGROUND: Serum cystatin C (Cys C) is claimed to be superior to serum creatinine (Cr) in estimating glomerular filtration rate, but its utility in assessing renal function in the polymorbid elderly needs to be evaluated. METHODS: In a cross-sectional, community-based survey performed in Lieto in southwestern Finland, Cys C, Cr, and urinary albumin-creatinine ratio (ACR) were measured in 1,260 subjects aged 64 to 100 years. Associations of demographic characteristics and health status factors with levels of Cys C, Cr, and ACR were assessed by means of linear models. RESULTS: In men, hypertension, coronary heart disease, urinary infection, rheumatoid arthritis, glucocorticoid treatment, older age, and lower functional status were found to be significant predictors of higher Cys C values, whereas hypertension, coronary heart disease, urinary infection, older age, and increasing body mass index (BMI) significantly predicted higher Cr values. Among women, corresponding factors were hypertension, glucocorticoid treatment, age, functional status, and BMI for Cys C and hypertension, BMI, and age for Cr. Diabetes was significantly associated only with ACR. These factors explained 35% of variation in Cys C values in men and 34.5% in women versus only 14.8% and 11.3% for Cr, respectively. CONCLUSION: Glucocorticoid treatment was recognized as an independent Cys C-increasing factor, presumably nonglomerular. In comparison with Cys C, a considerably greater proportion of total variation in Cr values seems to be explained by extrarenal factors.
15207508 Minimal clinically important changes in chronic musculoskeletal pain intensity measured on 2004 Aug OBJECTIVES: To determine the minimal clinically important difference (MCID) of changes in chronic musculoskeletal pain intensity that is most closely associated with improvement on the commonly used and validated measure of the patient's global impression of change (PGIC), and to estimate the dependency of the MCID on the baseline pain scores. METHODS: This was a prospective cohort study assessing patient's pain intensity by the numerical rating scale (NRS) at baseline and at the 3 month follow-up, and by a PGIC questionnaire. A one unit difference at the lowest end of the PGIC ("slightly better") was used to define MCID as it reflects the minimum and lowest degree of improvement that could be detected. In addition we also calculated the NRS changes best associated with "much better" (two units). In order to characterize the association between specific NRS change scores (raw or percent) and clinically important improvement, the sensitivity and specificity were calculated by the receiver operating characteristic (ROC) method. PGIC was used as an external criterion to distinguish between improved or non-improved patients. RESULTS: 825 patients with chronic musculoskeletal pain (233 with osteoarthritis of the knee, 86 with osteoarthritis of the hip, 133 with osteoarthritis of the hand, 290 with rheumatoid arthritis and 83 with ankylosing spondylitis) were followed up. A consistent relationship between the change in NRS and the PGIC was observed. On average, a reduction of one point or a reduction of 15.0% in the NRS represented a MCID for the patient. A NRS change score of -2.0 and a percent change score of -33.0% were best associated with the concept of "much better" improvement. For this reason these values can be considered as appropriate cut-off points for this measure. The clinically significant changes in pain are non-uniform along the entire NRS. Patients with a high baseline level of pain on the NRS (score of >7 cm), who experienced either a slight improvement or a higher level of response, had absolute raw and percent changes greater that did patients in the lower cohort (score of less than 4 cm). CONCLUSIONS: These results are consistent with the recently published findings generated by different methods and support the use of a "much better" improvement on the pain relief as a clinically important outcome. A further confirmation in other patient populations and different chronic pain syndromes will be needed.
13130465 Tie2 receptor tyrosine kinase, a major mediator of tumor necrosis factor alpha-induced ang 2003 Sep OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory disease and an angiogenic disease. However, the molecular mechanisms promoting angiogenesis in RA are not clearly identified. Our objective was to study the role of an endothelium-specific receptor tyrosine kinase, Tie2, in angiogenesis of inflammatory arthritis. METHODS: Expression of Tie2 and its ligand, angiopoietin 1 (Ang1), in human synovium was examined by immunohistochemistry and Western blot. A novel synovium vascular window model was established to study the role of Tie2 in angiogenesis in vivo. Primary cultured endothelial cells and synoviocytes were used to study tumor necrosis factor alpha (TNF alpha)-induced Tie2 and Ang1 expression. RESULTS: Tie2 was implicated in pathologic angiogenesis. We observed that Tie2 and Ang1 were elevated in human RA synovium. Using a novel collagen-induced arthritis synovial window model, we demonstrated that Tie2 signaling regulated arthritis angiogenesis in vivo. We also showed that Tie2 mediated TNF alpha-induced angiogenesis in a mouse cornea assay. In addition, we observed that TNF alpha can regulate Tie2 activation in multiple ways that may involve interactions between endothelial cells and synoviocytes. TNF alpha up-regulates Tie2 in endothelial cells through nuclear factor kappa B, and it up-regulates Ang1 in synoviocytes. These findings suggest paracrine regulation of angiogenesis between endothelial cells and synoviocytes. CONCLUSION: This study demonstrates that Tie2 regulates angiogenesis in inflammatory synovium. Tie2 signaling is an important angiogenic mediator that links the proinflammatory cytokine TNF alpha to pathologic angiogenesis.
12110289 Cysteine dioxygenase: modulation of expression in human cell lines by cytokines and contro 2002 Aug Cysteine dioxygenase (CDO) is the initial and rate-limiting enzyme involved in the oxidative degradation of cysteine to inorganic sulphate. It is believed to be the major source of sulphate in vivo. Inflammatory conditions such as rheumatoid arthritis have been linked with high plasma cysteine:sulphate ratios in patients. The cytokines tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) have been shown to inhibit the expression of CDO in neuronal (TE671) and hepatic (Chang) human cell lines at nanomolar concentrations. Cytokine release may therefore modulate sulphate production and hence regulate formation of sulphated biocomponents.
15181489 Different familial association patterns of autoimmune diseases between juvenile-onset syst 2004 Apr The aim of this study was to determine if the prevalence of autoimmune disorders in the relatives of patients with systemic lupus erythematosus (SLE) is greater than that of relatives of patients with juvenile rheumatoid arthritis (JRA). Interviews were used to obtain histories of the following autoimmune disorders among living or deceased first-, second-, and third-degree relatives of 91 SLE and 110 JRA families: ankylosing spondylitis, SLE, rheumatoid arthritis (RA), JRA, multiple sclerosis, juvenile dermatomyositis, Sjögren's syndrome, myasthenia gravis, psoriasis, and thyroid diseases. There were statistically significant differences between the SLE and JRA probands in mean age and gender ratio (19.1 +/- 4.8 vs 14.0 +/- 5.5 years; M (male)/F (female): 17/74 vs 62/48, p<0.005). The prevalence rate of autoimmune diseases in relatives of SLE families (20.9%) was greater than in JRA families (11.8%), but not statistically significantly so. The mean age (18.0 +/- 5.3 vs 14.0 +/- 4.3 years), mean age at diagnosis (13.4 +/- 4.3 vs 7.9 +/- 3.9 years) and gender ratio (F/M, 16/3 vs 5/8) of the patients with affected relatives between these 2 groups all had statistically significant differences. A higher prevalence of SLE in relatives was found in SLE families than in JRA cases. Furthermore, this study revealed a higher incidence of autoimmune disorders among second- and third-degree relatives of SLE or JRA probands versus first-degree ones, especially sisters (including 1 pair of twins) and the maternal aunt in SLE families. These data demonstrate that the prevalence of autoimmune disorders in the relatives of patients with SLE is greater than those of relatives of patients with JRA. This suggests that clinically different autoimmune phenotypes may share common susceptibility genes, which may act as risk factors for autoimmunity.
15485529 Granulocyte adsorptive apheresis for leg ulcers complicated by rheumatoid arthritis: a rep 2004 Oct BACKGROUND: The treatment of inflammatory leg ulcers complicated by rheumatoid arthritis (RA), which are unresponsive to conventional care, can be frustrating. Furthermore, as granulocytes and monocytes (GM) are major sources of inflammatory cytokines, they have the potential to initiate and perpetuate inflammatory skin lesions. Accordingly, a recent study reported the remission of pyoderma gangrenosum following the reduction of activated peripheral blood GM by adsorptive apheresis (GMA). METHODS: In this clinical study, we applied GMA to three cases, each with one leg ulcer below the knee and RA. The ulcers had not responded to conventional therapy, including disinfection, dressing, and antimicrobials, and therefore were thought to represent inflammatory vasculitic lesions. GMA was performed using a column with a capacity of 335 mL, filled with cellulose acetate beads that selectively adsorb granulocytes and monocytes/macrophages (Adacolumn). Each patient received one GMA session/week for five consecutive weeks. The duration of one session was 60 min, with a flow rate of 30 mL/min. RESULTS: The ulcers began to recede after two GMA sessions and, by the end of the fifth session, the ulcers in all three patients had healed. No recurrence has been observed up to the time of this report. The treatment was well tolerated and no severe side-effects were observed. CONCLUSIONS: GMA, which depletes activated neutrophils and monocytes/macrophages, appears to be effective for inflammatory skin ulcers which do not respond to conventional medications.
12096503 [A case of pulmonary infiltration with eosinophilia (PIE) syndrome induced by bucillamine 2002 Apr Bucillamine is used mainly in treating rheumatoid arthritis (RA). We report a case of bucillamine-induced pulmonary infiltration with eosinophilia (PIE) syndrome in a 51-year-old woman. When RA was diagnosed, she was treated with bucillamine from December 2000. In April 2001, she was admitted to our hospital because of fever and skin eruptions. Chest radiography and CT revealed both diffuse ground-glass opacity and fine nodular shadows. Laboratory data showed a normal white cell count with eosinophilia. Bronchoalveolar lavage (BAL) studies showed that total cell counts and the proportion of eosinophils were increased, and that the CD4/CD8 ratio of the T-cell subsets was decreased to 0.93. The patch test to bucillamine was positive. After bucillamine was withdrawn, the fever and the abnormal chest shadows improved. We concluded from the patient's clinical course, laboratory data and BAL findings that this was a case of bucillamine-induced PIE syndrome. Since most cases of bucillamine-induced interstitial pneumonitis are lymphocytic alveolitis, we consider that PIE syndrome in such a case is a very rare condition. We concluded that bucillamine should be added to the list of drugs capable of producing PIE syndrome.
12079907 Prevalence of hepatitis C virus infection in patients with rheumatoid arthritis. 2002 Jul BACKGROUND: Various viruses have been implicated in the cause and pathogenesis of rheumatoid arthritis (RA). Hepatitis C virus (HCV) infection, which has been recognised as a cause of some autoimmune diseases, and which has been described as sometimes presenting with rheumatic manifestations indistinguishable from RA, might be a candidate. OBJECTIVE: To evaluate the prevalence of HCV infection in patients with RA. METHODS: Consecutive patients with RA admitted to hospital in two departments of rheumatology were prospectively studied. Patients' serum samples were screened for the presence of anti-HCV antibodies. Patients with positive serology were further evaluated for the presence of HCV ribonucleic acid by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: 309 patients (232 women, 77 men, mean age (SD) 54.1 (14.8) years) were studied. Their mean (SD) disease duration was 74.1 (91) months. Tests for rheumatoid factors and antinuclear antibodies were positive in 213 (69%) and 114 (37%) of the patients respectively. Systemic vasculitis was found in 12 (4%) of the patients. Mean erythrocyte sedimentation rate was 36.4 (SD 30.5) mm at the first hour (normal <10 mm) and C reactive protein was 36.8 (SD 45.8) mg/l (normal range <5 mg/l), respectively, with 181(58.6%) of patients considered as having active disease. Aspartate transaminases were increased in 14 (4%) patients, and alkaline phosphatase in 14 (4%). A positive anti-HCV serology was found in two (0.65%) patients, including one with a previously diagnosed HCV infection. HCV RNA was positive by RT-PCR in one of those two patients. CONCLUSION: A 0.65% prevalence of past or active HCV infection was found in patients with RA, which did not differ from the prevalence of HCV in the general French population. This result does not support the participation of HCV infection in the pathogenesis of RA.
12734889 National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthr 2003 May OBJECTIVE: To quantify risks for cause-specific mortality among hospitalized patients with rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), and 4 other rheumatic conditions in a nationwide, population based cohort over a 20 year period. METHODS: All subjects were identified from Scottish hospital inpatient records from 1981 to 2000 and were followed up by computer linkage to the national registry of deaths. Expected mortality was calculated from national mortality rates and was related to the observed incidence by the standardized mortality ratio (SMR) and the corresponding 95% confidence interval (95% CI). RESULTS: Overall mortality was elevated in each of the 6 rheumatic conditions examined, most notably in JCA (males: SMR 3.4, 95% CI 2.0,5.5; females: SMR 5.1, 95% CI 3.2,7.8). Among patients with RA, there was an increased risk for death in all International Classification of Disease chapters other than those relating to mental disorders. Specific causes of death with an increased risk for subjects with RA included lung cancer [males: 1.4 (1.2,1.5); females: 1.6 (1.5,1.8)], hematopoietic malignancies [M: 1.8 (1.4,2.3); F: 2.0 (1.7,2.3)], coronary artery disease (CAD) [M: 1.6 (1.5,1.7); F: 1.95 (1.9,2.0)], respiratory infections [M: 1.9 (1.7,2.2); F: 2.4 (2.3,2.6)], chronic obstructive pulmonary disease [M: 1.8 (1.6,2.0); F: 2.1 (1.9,2.3)], and renal failure [M: 3.1 (2.5,3.9); F: 3.5 (3.0,4.0)]. Conversely, RA subjects were less likely to die from gastrointestinal tract malignancies [M: 0.82 (0.7,1.0); F: 0.8 (0.7,0.9)]. CONCLUSION: Population studies for primary data collection are required to extend our knowledge about the underlying mechanisms of early mortality in patients with rheumatic conditions.
11953987 Evaluation of quantitative trait loci regulating severity of mycobacterial adjuvant-induce 2002 Apr OBJECTIVE: To evaluate the regulatory potential of genetic loci controlling Mycobacterium butyricum adjuvant-induced arthritis (Mbt-AIA) using mono- and polycongenic rats. METHODS: Of 4 quantitative trait loci (QTLs) that regulate Mbt-AIA, F344 alleles at 3 of these loci, Aia1, Aia2, and Aia3, are associated with lower arthritis severity, whereas F344 alleles at Aia4 are associated with greater arthritis severity. In this study, we constructed congenic lines by transferring 1 or more of the F344 genomic segments containing Aia1, Aia2, and Aia3 onto the DA genome. We comparatively evaluated their responses to Mbt-AIA with the responses of parental DA and F344 rats. RESULTS: Aia1, encompassing the rat major histocompatibility complex, reduced arthritis severity in monocongenic rats of both sexes. The arthritis-lowering effects of Aia2 and Aia3 were sex-influenced and were therefore observed in only males and only females, respectively. Polycongenic rats containing F344 genomic regions at Aia1, Aia2, and Aia3 developed Mbt-AIA of relatively greater severity than did F344 rats, implying that in DA and F344 rats, there could be other Mbt-AIA loci in addition to Aia1, Aia2, Aia3, and Aia4. To test the possibility that some of these Mbt-AIA-regulatory loci may colocalize with other arthritis QTLs, we evaluated Mbt-AIA in DA.F344 monocongenic rats containing collagen-induced arthritis QTLs. Cia5 (the QTL region on chromosome 10), but not Cia5a, Cia4, or Cia6, also regulated Mbt-AIA, and was named Aia5. CONCLUSION: F344 genomic regions at Aia1, Aia2, and Aia3 and the newly identified Aia5 contain genes that reduce Mbt-AIA severity in DA rats. These Mbt-AIA-regulatory loci overlap rheumatoid arthritis-susceptibility loci in humans.
15227670 Biodegradable radiation delivery system utilizing glass microspheres and ethylenediaminete 2004 Aug 1 Dysprosium lithium-borate (DyLB) glass microspheres have been developed as a biodegradable radiation delivery vehicle for the treatment of rheumatoid arthritis and other diseases. Radioactive microspheres of these glasses are intended to be injected into a joint infected with rheumatoid arthritis to safely deliver a localized dose (100 Gy) of beta radiation. Once injected, the microspheres react nonuniformly with body fluids. The nonradioactive, lithium-borate component is dissolved from the glass, whereas the radioactive (165)Dy reacts with phosphate anions in the body fluids, and becomes "chemically" trapped in a solid, dysprosium phosphate reaction product that has the same size as the unreacted microsphere. The glass microspheres lose approximately 80% of their weight after nonuniform reaction (<1 day), but the dysprosium phosphate reaction product is slowly metabolized by the body over several months. Ethylenediaminetetraacetate (EDTA) chelation therapy can be used to dissolve the dysprosium phosphate reaction product in vitro in <2 h. The dysprosium phosphate reaction product which formed in vivo in the joint of a Sprague-Dawley rat was also dissolved by EDTA chelation therapy in <1 week, without causing any detectable joint damage. The combination of DyLB glass microspheres and EDTA chelation therapy provides a unique "tool" for the medical community because it can deliver a large dose (>100 Gy) of localized beta radiation to a treatment site within the body, followed by complete biodegradability.
12064828 A cost effectiveness analysis of treatment options for methotrexate-naive rheumatoid arthr 2002 Jun OBJECTIVE: New treatment options for patients with methotrexate (MTX)-naive rheumatoid arthritis (RA) have become available. Given wide variability in efficacy and cost among different treatment options, we sought to determine their relative cost effectiveness to help guide policy in different cost constrained settings. METHODS: We performed a cost effectiveness analysis comparing 5 monotherapy options for patients with MTX-naive RA: (1) etanercept, (2) leflunomide, (3) MTX (up to 15 mg weekly), (4) sulfasalazine (SSZ), and (5) no second line agent. A decision analysis model was used with a time horizon of 6 months. We employed 2 measures of effectiveness based on published clinical trial data: American College of Rheumatology (ACR) 20% response proportion (ACR 20) and a weighted average of proportions achieving ACR 70, ACR 50, and ACR 20 (ACR 70 weighted response, ACR 70WR). Incremental cost effectiveness ratios were calculated as additional cost per patient achieving either outcome, compared with the next most expensive option. RESULTS: In both base case analyses employing ACR 20 and ACR 70WR as effectiveness measures, MTX and SSZ both cost less and were more effective (i.e., cost saving) than no second line agent. Leflunomide cost more and was less efficacious than SSZ (dominated) in analyses using either outcome. The most efficacious option, etanercept, cost US $41,900 per ACR 20 and $40,800 per ACR 70 WR compared with SSZ and MTX, respectively. When we included only direct costs in analyses, the least expensive non-dominated option was SSZ with incremental cost effectiveness ratios of US $900 per ACR 20 and $1500 per ACR 70WR compared with no second line agent. Overall, relative cost effectiveness between MTX and SSZ was sensitive to variation in relevant variables in sensitivity analyses. Otherwise, our extensive sensitivity analyses did not substantially affect the base case results. CONCLUSION: MTX is cost effective (cost saving vs the no second line agent option) for MTX-naive RA in achieving ACR 20 or ACR 70WR over a 6 month period. Based on available data, the relative cost effectiveness between SSZ and MTX cannot be determined with reasonable certainty and SSZ therapy appears to be as cost effective as MTX (cost saving) in achieving ACR outcomes over a 6 month period. The most efficacious option, etanercept, incurs much higher incremental costs per ACR 20 or ACR 70WR than other options analyzed. Whether etanercept compared with MTX is cost effective depends on whether > $40,000 per ACR 20 or ACR 70WR over a 6 month period is considered acceptable.
14872483 A TNFR1 genotype with a protective role in familial rheumatoid arthritis. 2004 Feb OBJECTIVE: Results of genome scans in rheumatoid arthritis (RA) have suggested that the tumor necrosis factor receptor I (TNFRI) and TNFRII loci (TNFR1 and TNFR2) are susceptibility loci. A TNFR2 polymorphism was found to be associated with familial RA. TNFR1 is mutated in TNFR-associated periodic syndrome (TRAPS). We undertook this study to test the TNFR1 exonic polymorphism closest to the TRAPS mutations site (+36 A/G) for association with RA. METHODS: DNA samples were available from two groups of the French Caucasian population: 1) 100 families with 1 RA patient and both parents and 2) 86 RA index patients from families with at least 2 siblings with RA (affected sibpairs [ASPs]). The +36 A/G polymorphism of TNFR1 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The analysis was performed using the transmission disequilibrium test, the genotype relative risk, and a linkage-based test previously described. RESULTS: A negative association between RA and the +36 A/A genotype, suggested in the first sample (P = 0.084), was demonstrated in the second (ASP RA) sample (odds ratio [OR] 0.465; P = 0.012) and confirmed by the linkage-based test (OR 0.17; P = 0.008). The protective genotype, present in 41% of controls, was less frequent in RA patients: 33% in the first sample, 24% in the ASP RA sample, and 11% in the linkage-derived subgroup. Distribution of both TNFR2 196 R/R and TNFR1 +36 A/A genotypes in the ASP RA sample showed that both suspected genotypes were exclusive. CONCLUSION: We found evidence for an association between RA and a TNFR1 protective genotype, restricted to familial RA. Distribution of the TNFR2 196 R/R and TNFR1 +36 A/A genotypes in familial RA could suggest an interaction between TNFR1 and TNFR2 in the genetic susceptibility for RA.
12905468 Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after init 2003 Aug OBJECTIVE: To determine whether treatment with the chimeric anti-tumor necrosis factor alpha antibody infliximab could reduce cellularity by the induction of apoptosis in synovial tissue. METHODS: Twenty-four rheumatoid arthritis patients with active disease were randomized to receive either infliximab (3 mg/kg) (n = 12) or placebo (n = 12) intravenously. All patients were subjected to arthroscopic synovial biopsy directly before initiation of treatment. A second arthroscopic synovial biopsy of the same index joint was performed 48 hours after the first arthroscopy. After the second arthroscopy, the patients who had initially received placebo were also treated with infliximab in an extension study. A third arthroscopy was performed in all patients on day 28. Immunohistologic analysis was performed to characterize the cell infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and electron microscopy. RESULTS: At 48 hours after initiation of infliximab treatment, there was a significant reduction in the number of intimal macrophages; this was not observed in the placebo group. The number of sublining macrophages, T cells, and plasma cells also tended to be decreased in infliximab-treated patients, but not in the placebo group. Of interest, we did not detect any increase in the number of apoptotic cells after infliximab treatment. CONCLUSION: Infliximab therapy may reduce the number of inflammatory cells in rheumatoid synovial tissue as soon as 48 hours after initiation of treatment, but apparently not by induction of apoptosis. Conceivably, decreased cell infiltration primarily results from early inhibition of cell migration.